papers

J Pharm Sci. 2019 Feb 19. pii: S0022-3549(19)30090-5. doi:
10.1016/j.xphs.2019.02.005. [Epub ahead of print]

Validation of Human MDR1-MDCK and BCRP-MDCK Cell Lines to Improve the Prediction
of Brain Penetration.

Feng B, West M, Patel NC, Wager T, Hou X, Johnson J, Tremaine L, Liras J.

It is of great challenge to predict human brain penetration for substrates of
multidrug resistance protein 1 (MDR1) and/or breast cancer resistance protein
(BCRP), two major efflux transporters at blood-brain barrier. Thus, a PBPK model
with the incorporation of in vitro MDR1 and BCRP transporter function data and
transporter protein expression levels has been developed. As such, it is crucial
to generate MDR1 and BCRP substrate data with a high fidelity. In this study, two
widely use human MDR1 cell lines from Borst and NIH labs were evaluated using
rodent brain penetration data, and the study suggested that the MDR1-MDCK cell
line from NIH lab predicted brain penetration better, particularly for compounds
with a high passive permeability. Additionally, human BCRP-MDCK cell line with 1
μM PSC833, a specific MDR1 inhibitor, demonstrated the ability to identify BCRP
substrates without the confounding of endogenous canine Mdr1. Comparison of human
BCRP and mouse Bcrp transporter functions revealed that the functional
differences of BCRP between the two species is minimal. The incorporation of both
the validated MDR1 and BCRP assays into our brain PBPK model has significantly
improved the prediction for the brain penetration of MDR1 and BCRP substrates
across species.

DOI: 10.1016/j.xphs.2019.02.005
PMID: 30794795

PLoS Comput Biol. 2019 Feb 22;15(2):e1006799. doi: 10.1371/journal.pcbi.1006799.
[Epub ahead of print]

Integrated structural variation and point mutation signatures in cancer genomes
using correlated topic models.

Funnell T(1), Zhang AW(2), Grewal D(1), McKinney S(2), Bashashati A(2), Wang
YK(2), Shah SP(1)(2)(3).

Author information:
(1)Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer
Center, New York, New York, United States of America.
(2)Department of Molecular Oncology, BC Cancer Agency, Vancouver, British
Columbia, Canada.
(3)Department of Pathology and Laboratory Medicine, University of British
Columbia, Vancouver, British Columbia, Canada.

Mutation signatures in cancer genomes reflect endogenous and exogenous mutational
processes, offering insights into tumour etiology, features for prognostic and
biologic stratification and vulnerabilities to be exploited therapeutically. We
present a novel machine learning formalism for improved signature inference,
based on multi-modal correlated topic models (MMCTM) which can at once infer
signatures from both single nucleotide and structural variation counts derived
from cancer genome sequencing data. We exemplify the utility of our approach on
two hormone driven, DNA repair deficient cancers: breast and ovary (n = 755
samples total). We show how introducing correlated structure both within and
between modes of mutation can increase accuracy of signature discovery,
particularly in the context of sparse data. Our study emphasizes the importance
of integrating multiple mutation modes for signature discovery and patient
stratification, and provides a statistical modeling framework to incorporate
additional features of interest for future studies.

DOI: 10.1371/journal.pcbi.1006799
PMID: 30794536

Conflict of interest statement: SPS and SA are shareholders and consultants of
Contextual Genomics Inc.

J Natl Cancer Inst. 2019 Feb 22. pii: djz020. doi: 10.1093/jnci/djz020. [Epub
ahead of print]

Methylation-based biological age and breast cancer risk.

Kresovich JK(1), Xu Z(1), O’Brien KM(1), Weinberg CR(2), Sandler DP(1), Taylor
JA(1)(3).

Author information:
(1)Epidemiology Branch, National Institute of Environmental Health Sciences, NIH,
Research Triangle Park, NC.
(2)Biostatistics and Computational Biology Branch, National Institute of
Environmental Health Sciences, NIH, Research Triangle Park, NC.
(3)Epigenetic and Stem Cell Biology Laboratory, National Institute of
Environmental Health Sciences, NIH, Research Triangle Park, NC.

BACKGROUND: Age is one of the strongest predictors of cancer, chronic disease and
mortality, but biological responses to aging differ among people. Epigenetic DNA
modifications have been used to estimate «biological age,» which may be a useful
predictor of disease risk. We test this hypothesis for breast cancer.
METHODS: Using a case-cohort approach, we measured baseline blood DNA methylation
of 2,764 women enrolled in the Sister Study, 1,566 of whom subsequently developed
breast cancer after an average of six years. Using three previously established
methylation-based «clocks» (Hannum, Horvath, and Levine) we defined biological
age acceleration for each woman by comparing her estimated biological age with
her chronological age. Hazard ratios (HRs) and 95% confidence intervals (CIs) for
breast cancer risk were estimated using Cox regression models. All statistical
tests were two-sided.
RESULTS: Each of the three clocks showed that biological age acceleration was
statistically significantly associated with increased risk of developing breast
cancer (5 year age acceleration, Hannum’s clock: HR = 1.10, 95% CI: 1.00, 1.21,
P= 0.04; Horvath’s clock: HR = 1.08, 95% CI: 1.00, 1.17, P= 0.04; Levine’s clock:
HR: 1.15, 95% CI: 1.07, 1.23, P < 0.001 ). For Levine’s clock, each five-year
acceleration in biological age corresponded with a 15% increase in breast cancer
risk. Although biological age may accelerate with menopausal transition, age
acceleration in premenopausal women independently predicted breast cancer.
Case-only analysis suggested that, among women who develop breast cancer,
increased age acceleration is associated with invasive cancer (OR for
invasive=1.09, 95% CI: 0.98, 1.22, P = 0.10).
CONCLUSIONS: DNA methylation-based measures of biological age may be important
predictors of breast cancer risk.

Published by Oxford University Press 2019.

DOI: 10.1093/jnci/djz020
PMID: 30794318

JAMA Netw Open. 2019 Feb 1;2(2):e190083. doi: 10.1001/jamanetworkopen.2019.0083.

Association of Prepubertal and Adolescent Androgen Concentrations With Timing of
Breast Development and Family History of Breast Cancer.

Houghton LC(1), Knight JA(2)(3), Wei Y(4), Romeo RD(5), Goldberg M(1), Andrulis
IL(3)(6), Bradbury AR(7)(8), Buys SS(9), Daly MB(10), John EM(11)(12), Chung
WK(13)(14)(15), Santella RM(16), Stanczyk FZ(17)(18), Terry MB(1)(13).

Author information:
(1)Department of Epidemiology, Columbia University Mailman School of Public
Health, New York, New York.
(2)Division of Epidemiology, Dalla Lana School of Public Health, University of
Toronto, Toronto, Ontario, Canada.
(3)Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario,
Canada.
(4)Department of Biostatistics, Columbia University Mailman School of Public
Health, New York, New York.
(5)Psychology and the Neuroscience and Behavior Program, Barnard College of
Columbia University, New York, New York.
(6)Department of Molecular Genetics, University of Toronto, Toronto, Ontario,
Canada.
(7)Department of Medical Ethics and Health Policy, Perelman School of Medicine,
University of Pennsylvania, Philadelphia.
(8)Division of Hematology/Oncology, Department of Medicine, The Perelman School
of Medicine of the University of Pennsylvania, Philadelphia.
(9)Department of Medicine, University of Utah Health Sciences Center, Huntsman
Cancer Institute, Salt Lake City.
(10)Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia,
Pennsylvania.
(11)Division of Oncology, Department of Medicine, Stanford University School of
Medicine, Stanford, California.
(12)Stanford Cancer Institute, Stanford University School of Medicine, Stanford,
California.
(13)Herbert Irving Comprehensive Cancer Center, Columbia University Medical
Center, New York, New York.
(14)Department of Pediatrics, Columbia University Medical Center, New York, New
York.
(15)Department of Medicine, Columbia University Medical Center, New York, New
York.
(16)Environmental Health Sciences, Columbia University Mailman School of Public
Health, New York, New York.
(17)Department of Obstetrics and Gynecology, Keck School of Medicine, University
of Southern California, Los Angeles.
(18)Department of Preventive Medicine, Keck School of Medicine, University of
Southern California, Los Angeles.

Importance: Early breast development is a risk factor for breast cancer, and
girls with a breast cancer family history (BCFH) experience breast development
earlier than girls without a BCFH.
Objectives: To assess whether prepubertal androgen concentrations are associated
with timing of breast development (analysis 1) and to compare serum androgen
concentrations in girls with and without a BCFH (analysis 2).
Design, Setting, and Participants: Prospective cohort study of 104 girls aged 6
to 13 years at baseline using data collected between August 16, 2011, and March
24, 2016, from the Lessons in Epidemiology and Genetics of Adult Cancer From
Youth (LEGACY) Girls Study, New York site.
Exposures: Analysis 1 included serum concentrations of dehydroepiandrosterone
sulfate, androstenedione, and testosterone (free and total) measured before
breast development and divided at the median into high and low categories.
Analysis 2 included the degree of BCFH: first-degree was defined as having a
mother with breast cancer and second-degree was defined as having a grandmother
or aunt with breast cancer.
Main Outcomes and Measures: Analysis 1 included age at onset of breast
development measured using the Pubertal Development Scale (scores range from 1-4;
scores ≥2 indicate breast development), and analysis 2 included serum androgen
concentrations. We also assessed breast cancer-specific distress using the 8-item
Child Impact of Events Scale.
Results: Our analyses included 36 girls for the prospective model, 92 girls for
the cross-sectional model, and 104 girls for the longitudinal model. Of the 104
girls, the mean (SD) age at baseline was 10.3 (2.5) years, and 41 (39.4%) were
non-Hispanic white, 41 (39.4%) were Hispanic, 13 (12.5%) were non-Hispanic black,
and 9 (8.7%) were other race/ethnicity. Forty-two girls (40.4%) had a positive
BCFH. Girls with prepubertal androstenedione concentrations above the median
began breast development 1.5 years earlier than girls with concentrations below
the median (Weibull survival model-estimated median age, 9.4 [95% CI, 9.0-9.8]
years vs 10.9 [95% CI, 10.4-11.5] years; P = .001). Similar patterns were
observed for dehydroepiandrosterone sulfate (1.1 years earlier: age, 9.6 [95% CI,
9.1-10.1] years vs 10.7 [95% CI, 10.2-11.3] years; P = .009), total testosterone
(1.4 years earlier: age, 9.5 [95% CI, 9.1-9.9] years vs 10.9 [95% CI, 10.4-11.5]
years; P = .001), and free testosterone (1.1 years earlier: age, 9.7 [95% CI,
9.2-10.1] years vs 10.8 [95% CI, 10.2-11.4] years; P = .01). Compared with girls
without BCFH, girls with a first-degree BCFH, but not a second-degree BCFH, had
240% higher androstenedione concentrations (geometric means: no BCFH, 0.49 ng/mL
vs first-degree BCFH, 1.8 ng/mL vs second-degree, 1.6 ng/mL; P = .01), 10% higher
total testosterone concentrations (12.7 ng/dL vs 14.0 ng/dL vs 13.7 ng/dL;
P = .01), and 92% higher free testosterone concentrations (1.3 pg/mL vs 2.5 pg/mL
vs 0.3 pg/mL; P = .14). The dehydroepiandrosterone sulfate concentration did not
differ between BCFH-positive and BCFH-negative girls but was elevated in girls
with breast cancer-specific distress.
Conclusions and Relevance: Our findings suggest that androgen concentrations may
differ between girls with and without a BCFH and that elevated hormone
concentrations during adolescence may be another factor to help explain the
familial clustering of breast cancer.

DOI: 10.1001/jamanetworkopen.2019.0083
PMID: 30794303

Health Care Women Int. 2019 Feb 22:1-27. doi: 10.1080/07399332.2019.1578360.
[Epub ahead of print]

Posttraumatic growth experiences and its contextual factors in women with breast
cancer: An integrative review.

Zhai J(1), Newton J(1)(2), Copnell B(3).

Author information:
(1)a Nursing and Midwifery , Monash University Melbourne , Melbourne , VIC ,
Australia.
(2)b School of Nursing , McMaster University , Hamilton , ON , Canada.
(3)c School of Nursing and Midwifery , Latrobe University , Melbourne , VIC ,
Australia.

In this article, we synthesize current research that examines determinants and
manifestations of posttraumatic growth (the phenomenon of posttraumatic growth
can be embodied in several domains) in women with breast cancer. The findings of
the integrative literature review may contribute to facilitating person-centered
oncology care by raising health care professionals’ awareness and understanding
of posttraumatic growth phenomenon among breast cancer survivors. The
identification of factors contributing to posttraumatic growth and manifestations
of posttraumatic growth are important in increasing the effectiveness of
interventions in supporting women during their breast cancer journey. The methods
proposed by Whittemore and Knafl ( 2005 ) were adopted to guide this integrative
review. Quality assessment was conducted using recognized critical appraisal
tools relating to quantitative and qualitative studies. Four main manifestations
were synthesized from the literature: new perception of self; relatedness to
others; new life philosophy; and spiritual and religious growth. Personal
characteristics, illness factors, cognitive processing, coping strategies, social
support, religion and spirituality, the body’s role and physical activities were
identified as influencing posttraumatic growth in women with breast cancer.

DOI: 10.1080/07399332.2019.1578360
PMID: 30794107

Stat Med. 2019 Feb 22. doi: 10.1002/sim.8116. [Epub ahead of print]

Correlation-adjusted regression survival scores for high-dimensional variable
selection.

Welchowski T(1), Zuber V(2)(3), Schmid M(1).

Author information:
(1)Department of Medical Biometry, Informatics and Epidemiology, University
Hospital Bonn, Bonn, Germany.
(2)MRC Biostatistics Unit, Cambridge University, Cambridgeshire, UK.
(3)Department of Epidemiology and Biostatistics, Imperial College London, London,
UK.

BACKGROUND: The development of classification methods for personalized medicine
is highly dependent on the identification of predictive genetic markers. In
survival analysis, it is often necessary to discriminate between influential and
noninfluential markers. It is common to perform univariate screening using Cox
scores, which quantify the associations between survival and each of the markers
to provide a ranking. Since Cox scores do not account for dependencies between
the markers, their use is suboptimal in the presence of highly correlated
markers.
METHODS: As an alternative to the Cox score, we propose the correlation-adjusted
regression survival (CARS) score for right-censored survival outcomes. By
removing the correlations between the markers, the CARS score quantifies the
associations between the outcome and the set of «decorrelated» marker values.
Estimation of the scores is based on inverse probability weighting, which is
applied to log-transformed event times. For high-dimensional data, estimation is
based on shrinkage techniques.
RESULTS: The consistency of the CARS score is proven under mild regularity
conditions. In simulations with high correlations, survival models based on CARS
score rankings achieved higher areas under the precision-recall curve than
competing methods. Two example applications on prostate and breast cancer
confirmed these results. CARS scores are implemented in the R package carSurv.
CONCLUSIONS: In research applications involving high-dimensional genetic data,
the use of CARS scores for marker selection is a favorable alternative to Cox
scores even when correlations between covariates are low. Having a
straightforward interpretation and low computational requirements, CARS scores
are an easy-to-use screening tool in personalized medicine research.

DOI: 10.1002/sim.8116
PMID: 30793795

J Org Chem. 2019 Feb 22. doi: 10.1021/acs.joc.8b02832. [Epub ahead of print]

Synthesis of 4- epi-Parviflorons A, C and E: Structure-Activity Relationship
Study of Antiproliferative Abietane Derivatives.

Miyajima Y, Saito Y, Takeya M, Goto M, Nakagawa-Goto K.

The first syntheses of 4- epi-parviflorons A, C, and E (4- epi-1-3) were achieved
in 12-13 steps from commercially available (-)-abietic acid (5). All synthesized
compounds, including intermediates and derivatives, were evaluated for
antiproliferative activity against five human tumor cell lines. A
structure-activity relationship study revealed the importance of two oxygen
functional groups at C-11 and C-12 for cytotoxic activity, as well as a
combination of carbomethoxy at C4 and a benzoyl ester with electron-drawing group
at C-12 or hydroxymethyl at C4 and an appropriate oxidation stage of ring-B/C for
triple-negative breast cancer cell selectivity.

DOI: 10.1021/acs.joc.8b02832
PMID: 30793595

Thorac Cancer. 2019 Feb 21. doi: 10.1111/1759-7714.13002. [Epub ahead of print]

Non-invasive analysis of tumor mutation profiles and druggable mutations by
sequencing of cell free DNA of Chinese metastatic breast cancer patients.

Li S(1)(2), Wang X(3), Li Y(4), Lai H(1)(2), Liu Y(1)(2), Jin L(1)(2).

Author information:
(1)Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene
Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou,
510120, China.
(2)Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University,
Guangzhou, 510120, China.
(3)Department of Otorhinolaryngology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen
University, Guangzhou, 510120, China.
(4)Division of Cardiac Surgery, The First Affiliated Hospital of Sun Yat-Sen
University, Guangzhou, 510080, China.

BACKGROUND: Metastatic breast cancer (MBC) remains an incurable disease
worldwide. Tumor gene mutations have evolved and led to drug resistance in the
treatment course of MBC. However, data on the mutation profiles and druggable
genomic alterations of MBC remain limited, particularly among Chinese patients.
Our study aimed to depict the mutation profiles and identify druggable mutations
in circulating tumor DNA (ctDNA) in Chinese MBC patients.
METHODS: Targeted deep sequencing of a 1021-gene panel was performed on 17 blood
samples and 5 available tissue samples from 17 Chinese MBC patients.
RESULTS: We identified 60 somatic mutations in 17 blood samples (sensitivity
100%). Somatic mutations were identified in the blood samples of all patients,
and 41.18% (7/17) of patients harbored at least one druggable mutation. A high
ctDNA level in plasma is associated with shorter progression-free survival.
CONCLUSION: Targeted deep sequencing of cell free DNA is a highly sensitive,
noninvasive method to depict tumor mutation profiles, identify druggable
mutations in MBC, and predict patient outcome. Our study shed light on the
utility of ctDNA as noninvasive «liquid biopsy» in the management of MBC.

DOI: 10.1111/1759-7714.13002
PMID: 30793491

J Cell Physiol. 2019 Feb 21. doi: 10.1002/jcp.28376. [Epub ahead of print]

Resistance to bortezomib in breast cancer cells that downregulate Bim through
FOXA1 O-GlcNAcylation.

Liu Y(1), Wang X(1), Zhu T(1), Zhang N(1), Wang L(1), Huang T(1), Cao Y(1), Li
W(1)(2), Zhang J(1).

Author information:
(1)Department of Biochemistry, School of Life Science & Medicine, Dalian
University of Technology, Panjin, China.
(2)Department of Biochemistry, School of Life Science & Biotechnology, Dalian
University of Technology, Dalian, China.

Bortezomib (BTZ), a well-established proteasome inhibitor used in the clinical
therapy, leads the modulation of several biological alterations and in turn
induces apoptosis. Although clinical trials with BTZ have shown promising results
for some types of cancers, but not for some others, including those of the
breast. The molecular basis of BTZ resistance in breast cancer remains elusive.
In the present study, we found that cellular O-GlcNAc modification was
dramatically elevated by BTZ treatment in intrinsic resistant MCF-7 and T47D
cells, but not in sensitive MDA-MB-231 cells. A progressive increase in
O-GlcNAcylation characterized the increased acquired resistance of
MDA-MB-231-derived cells. We showed that elevated O-GlcNAc subsequently modified
breast cancer related pioneer factor FOXA1 and reduced its protein stability.
Further, we demonstrated that FOXA1 attenuation was involved in transcriptional
downregulation of proapoptotic Bim and thus suppressed breast cancer cell
apoptosis. Finally, the combination of O-GlcNAc inhibitor L01 to BTZ sensitized
resistant cells. Our results have revealed a new regulatory mechanism that
involves O-GlcNAc elevation mediated Bim deficiency, which plays a key role in
the apoptotic dysregulation and BTZ resistance in breast cancer cells.

DOI: 10.1002/jcp.28376
PMID: 30793308

J Cell Physiol. 2019 Feb 21. doi: 10.1002/jcp.28364. [Epub ahead of print]

Upregulation of DLEU1 expression by epigenetic modification promotes
tumorigenesis in human cancer.

Pang B(1), Sui S(2), Wang Q(2), Wu J(2), Yin Y(2), Xu S(2).

Author information:
(1)Department of Surgery, Rui Jin Hospital, Shanghai Key Laboratory of Gastric
Neoplasm, Shanghai Institute of Digestive Surgery, Shanghai Jiao Tong University
School of Medicine, Shanghai, China.
(2)Department of Breast Surgery, Harbin Medical University Cancer Hospital,
Harbin, China.

The function of DLEU1 in human cancer is largely unknown. The Cancer Genome Atlas
data were applied to identify the landscape of differential genes between tumor
tissues and normal tissues, which was further validated by our cohort data and
pan-cancer data including 33 cancer types with 11,060 patients. Next, DLEU1 was
selected to validate the novel finding and result showed that it promoted
tumorigenesis in vitro and in vivo. Mechanistically, DLEU1 promotes SRP4
expression via increasing H3K27ac enrichment to SRP4 locus epigenetically.
Moreover, epigenetic modification leads to upregulation of DLEU1 expression via
decreased DNA methylation and increased H3K27ac and H3K4me3 histone modification
in its locus. Finally, high expression of DLEU1 correlates with worse prognosis
not only in specific cancer type patients but also in patients in the pan-cancer
cohort. In summary, the work broadens the function landscape of known long
noncoding RNAs in human cancer and provides novel insights into their roles in
tumorigenesis.

DOI: 10.1002/jcp.28364
PMID: 30793303

Pathol Oncol Res. 2019 Feb 21. doi: 10.1007/s12253-019-00614-3. [Epub ahead of
print]

MEG3: an Oncogenic Long Non-coding RNA in Different Cancers.

Al-Rugeebah A(1), Alanazi M(1), Parine NR(2).

Author information:
(1)Genome Research Chair, College of Science, King Saud University, Riyadh, Saudi
Arabia.
(2)Genome Research Chair, College of Science, King Saud University, Riyadh, Saudi
Arabia. reddyparine@gmail.com.

Long noncoding RNAs (lncRNAs) have recently considered as central regulators in
diverse biological processes and emerged as vital players controlling
tumorigenesis. Several lncRNAs can be classified into oncogenes and tumor
suppressor genes depending on their function in cancer. A maternally expressed
gene 3 (MEG3) gene transcripts a 1.6 kb lncRNA whose act as an
antitumor component in different cancer cells, such as breast, liver, glioma,
colorectal, cervical, gastric, lung, ovarian and osteosarcoma cancer cells. The
present review highlights biological function of MEG3 to repress tumor through
regulating the major tumor suppressor genes p53 and Rb, inhibiting
angiogenesis-related factor, or controlling miRNAs. On the other hand, previous
studies have also suggested that MEG3 mediates epithelial-mesenchymal transition
(EMT). However, deregulation of MEG3 is associated with the development and
progression of cancer, suggesting that MEG3 may function as a potential biomarker
and therapeutic target for human cancers.

DOI: 10.1007/s12253-019-00614-3
PMID: 30793226

Jpn J Clin Oncol. 2019 Feb 22. pii: hyz018. doi: 10.1093/jjco/hyz018. [Epub ahead
of print]

Biomarker discordance between primary breast cancer and bone or bone marrow
metastases.

Yuda S(1), Shimizu C(1)(2), Yoshida M(3), Shiino S(4), Kinoshita T(4), Maeshima
AM(3), Tamura K(1).

Author information:
(1)Department of Breast and Medical Oncology, National Cancer Center Hospital.
(2)Department of Breast Medical Oncology, National Center for Global Health and
Medicine.
(3)Department of Pathology and Clinical Laboratory, National Cancer Center
Hospital.
(4)Department of Breast Surgery, National Cancer Center Hospital.

BACKGROUND: Discordance in biomarker expression between primary and metastatic
tumor sites has been reported in several studies; yet, few have examined this
feature in bone lesions.
METHODS: We retrospectively enrolled patients with breast cancer metastasis to
the bone or bone marrow, excluding cases where samples from both the primary and
metastatic lesions were not available. Expression patterns of the estrogen
receptor (ER), progesterone receptor (PgR), human epidermal growth factor
receptor 2 (HER2) and Ki67 were compared in primary tumors and bone or bone
marrow lesions.
RESULTS: Forty-six patients with a median age of 52 years (range, 34-72 years)
were included in the study. Discordant rates of ER, PgR and HER2 were 20%, 46%
and 0%, respectively. Physicians usually determined treatment options considering
the results of biomarker re-evaluation. It is unlikely that biomarker discordance
was related to prior treatment.
CONCLUSIONS: Biomarker discordance in bone or bone marrow lesions is common in
patients with breast cancer. An accurate and thorough analysis of biomarkers and
metastatic tumor properties is important for clinical decision-making.

DOI: 10.1093/jjco/hyz018
PMID: 30793198

Jpn J Clin Oncol. 2019 Feb 22. pii: hyz005. doi: 10.1093/jjco/hyz005. [Epub ahead
of print]

Smartphone problem-solving therapy to reduce fear of cancer recurrence among
breast cancer survivors: an open single-arm pilot study.

Imai F(1)(2), Momino K(3), Katsuki F(3), Horikoshi M(4), Furukawa TA(5), Kondo
N(6), Toyama T(6), Yamaguchi T(7), Akechi T(1)(2).

Author information:
(1)Division of Psycho-Oncology and Palliative Care, Nagoya City University
Hospital, Mizuho-cho, Mizuho-ku, Nagoya, Japan.
(2)Department of Psychiatry and Cognitive-Behavioral Medicine, Nagoya City
University Graduate School of Medical Sciences, Mizuho-cho, Mizuho-ku, Nagoya,
Japan.
(3)Nagoya City University Graduate School of Nursing, Mizuho-cho, Mizuho-ku,
Nagoya, Japan.
(4)National Center for Cognitive Behavior Therapy and Research, National Center
of Neurology and Psychiatry, 4-1-1 Ogawahigashi-cho, Kodaira-shi, Tokyo, Japan.
(5)Department of Health Promotion and Human Behavior, Kyoto University Graduate
School of Medicine/School of Public Health, Yoshidakonoe-cho, Sakyo-ku, Kyoto,
Japan.
(6)Department of Breast Surgery, Nagoya City University Graduate School of
Medical Sciences, Mizuho-cho, Mizuho-ku, Nagoya, Japan.
(7)Division of Biostatistics, Tohoku University Graduate School of Medicine, 2-1
Seiryo-machi, Aoba-ku, Sendai, Miyagi, Japan.

OBJECTIVES: The purpose of this study was to investigate a newly developed
smartphone problem-solving therapy (PST) application’s feasibility and
preliminary effectiveness for reducing fear of cancer recurrence (FCR) among
breast cancer survivors.
METHODS: Female disease-free breast cancer survivors aged 20-49 years who were
more than 6 months post-breast surgery participated in the study. The patients
received the smartphone PST using an iPhone or iPad for 8 weeks. The feasibility
of the intervention program was evaluated using the overall participation rate,
the percentage of survivors who expressed interest in the intervention, and the
percentage of completion of the study. Patients were also asked to complete the
Concern About Recurrence Scale (CARS) as a primary outcome at baseline, 4 weeks
and 8 weeks.
RESULTS: A total of 38 patients participated in this study. The overall
participation and completion rates in the study were 47.1% and 97.4%,
respectively. The overall fear assessed by CARS was significantly reduced at 8
weeks compared with baseline. A pairwise comparison showed a significant decrease
from 4 weeks to 8 weeks and from baseline to 8 weeks.
CONCLUSIONS: Smartphone PST, a novel brief intervention to reduce FCR, was well
accepted by breast cancer survivors and yielded a favorable effect on FCR. The
efficacy of this newly developed smartphone PST needs to be confirmed in a future
well-designed randomized controlled trial.

DOI: 10.1093/jjco/hyz005
PMID: 30793156

Dalton Trans. 2019 Feb 22. doi: 10.1039/c9dt00335e. [Epub ahead of print]

A platinum(iv) prodrug to defeat breast cancer through disrupting vasculature and
inhibiting metastasis.

Guo Y(1), Zhang S(1), Yuan H(1), Song D(1), Jin S(2), Guo Z(1), Wang X(2).

Author information:
(1)State Key Laboratory of Coordination Chemistry, School of Chemistry and
Chemical Engineering, Nanjing University, Nanjing 210023, P. R. China.
zguo@nju.edu.cn.
(2)State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences,
Nanjing University, Nanjing 210023, P. R. China. boxwxy@nju.edu.cn.

A PtIV prodrug (PDMA) exhibits great potential for the therapy of metastatic
triple-negative breast cancer (TNBC) through a synergistic action of
antiangiogensis and antimetastasis.

DOI: 10.1039/c9dt00335e
PMID: 30793153

NPJ Breast Cancer. 2019 Feb 13;5:8. doi: 10.1038/s41523-019-0103-0. eCollection
2019

Supporting data sharing.

Kirk R(1), Norton L(2).

Author information:
(1)Nature Partner Journals, Nature Research, 4 Crinan Street, London, N1 9XW UK.
(2)2Memorial Sloan-Kettering Cancer Center, New York, NY USA.

DOI: 10.1038/s41523-019-0103-0
PMCID: PMC6374458
PMID: 30793024

Conflict of interest statement: The authors declare no competing interests.

Biomed Res Int. 2019 Jan 17;2019:1407167. doi: 10.1155/2019/1407167. eCollection
2019

Methylation Changes of Primary Tumors, Monolayer, and Spheroid Tissue Culture
Environments in Malignant Melanoma and Breast Carcinoma.

Şükrüoğlu Erdoğan Ö(1), Kılıç Erciyas S(1), Bilir A(2), Buğra Tunçer Ş(1),
Akdeniz Ödemiş D(1), Kurul S(3), Karanlık H(3), Cabıoğlu N(4), Yazıcı H(1).

Author information:
(1)Istanbul University, Institute of Oncology, Department of Basic Oncology,
Cancer Genetics Division, Istanbul, Turkey.
(2)Istanbul Aydin University, Faculty of Medicine, Department of Histology and
Embryology, Istanbul, Turkey.
(3)Istanbul University, Institute of Oncology, Department of Clinical Oncology,
Surgical Unit, Istanbul, Turkey.
(4)Istanbul University, Istanbul Faculty of Medicine, Department of Surgery,
Istanbul, Turkey.

Epigenetic changes have major role in the normal development and programming of
gene expression. Aberrant methylation results in carcinogenesis. The primary
objective of our study is to determine whether primary tumor tissue and cultured
tumor cells in 2D and 3D tissue culture systems have the same methylation
signature for PAX5, TMPRSS2, and SBDS. These findings will play an important role
in developing in vitro model system to understand the effect of methylation
inhibitors on primary tumor tissue. In a previous study PAX5, TMPRSS2, and SBDS
genes that we are investigating were reported to be methylated more than 60% in
breast cancer and malignant melanoma cell lines. However, these genes have never
been studied in primary tumor tissues. Thus, primary tumor tissues of breast
cancer and malignant melanoma were first grown in 2D and 3D cultures. Then these
two types of tumor tissues and their 2D and 3D cultures were investigated for
changes considering methylation levels in PAX5, TMPRSS2, and SBDS genes using
real-time polymerase chain reaction. No differences were observed in the primary
tissues and culture systems for both PAX5 and TMPRSS2 in malignant melanoma
tissues. We found that PAX5 gene was an efficient marker to measure the effects
of methylation inhibitors for in vitro systems for malignant melanoma tissue.

DOI: 10.1155/2019/1407167
PMCID: PMC6354143
PMID: 30792990

Ecancermedicalscience. 2019 Jan 22;13:898. doi: 10.3332/ecancer.2019.898.
eCollection 2019.

Access to high-cost drugs for advanced breast cancer in Latin America,
particularly trastuzumab.

Barrios CH(1), Reinert T(1), Werutsky G(1).

Author information:
(1)Latin American Cooperative Oncology Group, 99 A, Av Ipiranga 6681, Porto
Alegre, RS 90619-900, Brazil.

Provision of high-level healthcare is a challenge for all low- to middle-income
countries (LMICs) since healthcare systems are heterogeneous, face many
challenges such as inadequate funding, inequitable distribution of resources and
services and usually are not adequately equipped to deal with a huge problem such
as breast cancer. The development of anti-HER2 therapies can be considered one of
the most important examples of the translation of molecular biology knowledge
into clinical benefits for cancer patients. While a variety of novel therapeutic
strategies are emerging, current treatment regimens remain focussed on targeted
therapy with monoclonal antibodies, mainly trastuzumab, the first agent developed
in this field. While these results have revolutionised the outcome of HER2+
patients in clinical trials and in high-income countries where they are widely
available, results have not impacted the natural history of this aggressive
disease in most of the world. Unfortunately, the availability of these drugs is
far from universal in many LMICs, and in Latin America, in particular, patients
with HER2+ breast cancer are treated exclusively with standard chemotherapy, a
more toxic and less efficient therapy. While the complexity of the situation and
the multiple factors that have an impact in this scenario are recognised, we need
to map the future and develop feasible strategies to address possible solutions
to the problem of drug access. A clear and unbiased diagnosis of the situation is
a good starting point. Defining healthcare priorities and a clear strategy for
the allocation of resources is difficult but mandatory. In this article, we will
discuss current and future challenges regarding access (and lack of access) to
high-cost cancer drugs in Latin America, with a focus on anti-HER2 therapies.

DOI: 10.3332/ecancer.2019.898
PMCID: PMC6372298
PMID: 30792815

Ecancermedicalscience. 2019 Jan 22;13:897. doi: 10.3332/ecancer.2019.897.
eCollection 2019.

Barriers in Latin America for the management of locally advanced breast cancer.

Pinto JA(1), Pinillos L(2), Villarreal-Garza C(3), Morante Z(4)(5), Villarán
MV(1), Mejía G(6), Caglevic C(7)(8), Aguilar A(4), Fajardo W(9), Usuga F(10),
Carrasco M(11)(12), Rebaza P(12), Posada AM(12), Tirado-Hurtado I(1), Flores
C(1), Vallejos CS(4).

Author information:
(1)Unidad de Investigación Básica y Traslacional, Oncosalud-AUNA, Lima 15036,
Peru.
(2)Departamento de Radioterapia, Oncosalud-AUNA, Lima 15036, Peru.
(3)Departamento de Investigación y de Tumores Mamarios, Instituto Nacional de
Cancerología, Mexico City 14080, Mexico.
(4)Departamento de Medicina Oncológica, Oncosalud-AUNA, Lima 15036, Peru.
(5)Departamento de Oncología Médica, Instituto Nacional de Enfermedades
Neoplásicas, Lima 15038, Peru.
(6)Departamento de Oncología Médica, Hospital Clínico Viedma, Cochabamba 00725,
Bolivia.
(7)Medical Oncology Department, Clinica Alemana, Santiago 5951, Chile.
(8)Facultad de Medicina Clínica Alemana, Universidad del Desarrollo, Santiago
700, Chile.
(9)Departamento de Medicina Especializada, Hospital Nacional Dos de Mayo, Lima
15003, Peru.
(10)Grupo de Radioterapia Oncológica, Instituto Nacional de Cancerología, Bogotá
9-85, Colombia.
(11)Departamento de Oncología, Hospital Santa Rosa, Lima 95405, Peru.
(12)Unidad de la Mama, Oncosalud-AUNA, Lima 15036, Peru.

Breast cancer (BC) is a highly prevalent malignancy in Latin American women, most
cases being diagnosed at locally advanced or metastatic stages when options for
cancer care are limited. Despite its label as a public health problem in the
region, Latin American BC patients face several barriers in accessing standard of
care treatment when compared with patients from developed countries. In this
review, we analyse the landscape of the four main identified barriers in the
region: i) high burden of locally advanced/advanced BC; ii) inadequate access to
medical resources; iii) deficient access to specialised cancer care and iv)
insufficient BC research in Latin America. Unfortunately, these barriers
represent the main factors associated with the BC poor outcomes seen in the
region. Targeted actions should be conducted independently by each country and as
a region to overcome these limitations and create an enhanced model of BC care.

DOI: 10.3332/ecancer.2019.897
PMCID: PMC6372299
PMID: 30792814

Ecancermedicalscience. 2019 Jan 22;13:896. doi: 10.3332/ecancer.2019.896.
eCollection 2019.

Precision medicine for locally advanced breast cancer: frontiers and challenges
in Latin America.

Pinto JA(1), Saravia CH(1), Flores C(1), Araujo JM(1), Martínez D(2), Schwarz
LJ(3), Casas A(4), Bravo L(4), Zavaleta J(4), Chuima B(5), Alvarado H(6), Fujita
R(7), Gómez HL(3)(8).

Author information:
(1)Unidad de Investigación Básica y Traslacional, Oncosalud-AUNA, Lima 15036,
Perú.
(2)Departamento de Radioterapia, Oncosalud-AUNA, Lima 15036, Perú.
(3)Departamento de Medicina Oncológica, Oncosalud-AUNA, Lima 15036, Perú.
(4)Escuela Profesional de Medicina Humana, Universidad Privada San Juan Bautista,
Lima 15067, Perú.
(5)Laboratorio Clínico, Clínica Delgado, Lima 15074, Perú.
(6)Facultad de Ciencias Biológicas, Universidad Nacional San Luis Gonzaga de Ica,
Ica 11004, Perú.
(7)Centro de Genética y Biología Molecular, Universidad de San Martín de Porres,
Lima 15024, Perú.
(8)Departamento de Medicina Oncológica, Instituto Nacional de Enfermedades
Neoplásicas, 15038, Perú.

Advances in high-throughput technologies and their involvement in the ‘omics’ of
cancer have made possible the identification of hundreds of biomarkers and the
development of predictive and prognostic platforms that model the management of
cancer from evidence-based medicine to precision medicine. Latin America (LATAM)
is a region characterised by fragmented healthcare, high rates of poverty and
disparities to access to a basic standard of care not only for cancer but also
for other complex diseases. Patients from the public setting cannot afford
targeted therapy, the facilities offering genomic platforms are scarce and the
use of high-precision radiotherapy is limited to few facilities. Despite the fact
that LATAM oncologists are well-trained in the use of genomic platforms and
constantly participate in genomic projects, a medical practice based in precision
oncology is a great challenge and frequently limited to private practice. In
breast cancer, we are waiting for the results of large basket trials to
incorporate the detection of actionable mutations to select targeted treatments,
in a similar way to the management of lung cancer. On the other hand and
paradoxically, in the ‘one fit is not for all’ era, clinical and genomic studies
continue grouping our patients under the single label ‘Latin American’ or
‘Hispanic’ despite the different ancestries and genomic backgrounds seen in the
region. More regional cancer genomic initiatives and public availability of this
data are needed in order to develop more precise oncology in locally advanced
breast cancer.

DOI: 10.3332/ecancer.2019.896
PMCID: PMC6372295
PMID: 30792813

Ecancermedicalscience. 2019 Jan 22;13:895. doi: 10.3332/ecancer.2019.895.
eCollection 2019.

Locally advanced breast cancer in Brazil: current status and future perspectives.

Werutsky G(1)(2), Nunes P(1)(2), Barrios C(1)(2).

Author information:
(1)Latin American Cooperative Oncology Group, Porto Alegre 90619-900, Brazil.
(2)Department of Medical Oncology, Hospital São Lucas PUCRS, Porto Alegre
90619-900, Brazil.

Breast cancer (BC) is the most frequent cancer and the main cause of cancer
deaths among women worldwide and in Brazil. A high proportion of patients are
diagnosed with locally advanced breast cancer (LABC) in Brazil, mainly due to
limited coverage of screening programmes. A disparity in the access to optimal
treatment is evident between the public and private health systems which impact
patient outcomes. Clinical research is an opportunity for patients, institutions
and investigators and therefore should be facilitated through a better regulatory
environment. In a country facing a trend of increasing BC incidence for the next
years, it is critical to improve BC screening and incorporate new medicines and
devices into the public health system to control the burden of LABC.

DOI: 10.3332/ecancer.2019.895
PMCID: PMC6372296
PMID: 30792812

Ecancermedicalscience. 2019 Jan 22;13:894. doi: 10.3332/ecancer.2019.894.
eCollection 2019.

Locally advanced breast cancer in young women in Latin America.

Villarreal-Garza C(1)(2)(3), Lopez-Martinez EA(1)(3), Muñoz-Lozano JF(1)(3),
Unger-Saldaña K(4).

Author information:
(1)Breast Cancer Center, TecSalud, Tecnologico de Monterrey, Monterrey 66278,
Mexico.
(2)Research and Breast Cancer Department, Mexican National Cancer Institute,
Mexico City 14080, Mexico.
(3)Joven and Fuerte Program for Young Women with Breast Cancer, Mexico City
03720, Mexico.
(4)CONACYT fellow-Epidemiology Unit, Mexican National Cancer Institute, Mexico
City 14080, Mexico.

The purpose of this review is to organise, summarise and critically assess
existing knowledge on locally advanced breast cancer (LABC) among young women in
Latin America. We discuss the most relevant findings in six sections: 1)
epidemiology of breast cancer in young women in Latin America; 2) being young as
a factor for worse prognosis; 3) LABC in young women in the region; 4) aggressive
tumour behaviour among young women; 5) delays in diagnosis and treatment and 6)
burden of advanced disease. We point out the need to dedicate resources to
enhance earlier diagnosis and prompt referrals of young women with breast cancer;
promote research regarding prevalence, biologic characteristics, outcomes and
reasons for diagnosis and treatment delays for this age group; and finally,
implement supportive care programmes as a means of improving patients and their
families’ well-being. The recognition of the current standpoint of breast cancer
in young patients across the continent should shed some light on the importance
of this pressing matter.

DOI: 10.3332/ecancer.2019.894
PMCID: PMC6372300
PMID: 30792811

Ecancermedicalscience. 2019 Jan 22;13:893. doi: 10.3332/ecancer.2019.893.
eCollection 2019.

Triple-negative breast cancer: the reality in Chile and in Latin America.

Caglevic C(1), Anabalón J(2), Soza C(3)(4), Milla E(2), Gaete F(5), Carrasco
AM(2), Panay S(2), Gallardo C(2), Mahave M(2).

Author information:
(1)Medical Oncology Department, Clinica Alemana Santiago; Faculty of Medicine,
Universidad del Desarrollo, Santiago 456, Chile.
(2)Oncology Institute Arturo López Pérez Foundation, Santiago 878, Chile.
(3)School of Biochemistry, Faculty of Science, San Sebastián University, Santiago
1457, Chile.
(4)Oncoloop Foundation, Faculty of Medicine, Andrés Bello University, Santiago
890, Chile.
(5)Hospital Santiago Oriente Dr Luis Tisné, Santiago 5150, Chile.

Breast cancer is the leading cause of cancer death among women worldwide. While
triple-negative breast cancer is less common among various sub-types of breast
cancer, it tends to affect younger women and is more aggressive, having a higher
rate of early recurrence and mortality compared to other sub-types. We know about
the association between triple-negative breast cancer and BRCA mutations, which
are highly prevalent in founding populations of European origin, but the true
prevalence of these mutations in Latin American populations is unknown. There is
also very little information about the demographic and epidemiological aspects of
triple-negative breast cancer in Latin America, which we will try to summarise in
this article. In addition, we will try to provide a brief introduction to the
most common recommendations for treating this histological class in Latin
America.

DOI: 10.3332/ecancer.2019.893
PMCID: PMC6372297
PMID: 30792810

Ecancermedicalscience. 2019 Jan 15;13:891. doi: 10.3332/ecancer.2019.891.
eCollection 2019.

Proteomics characterisation of central nervous system metastasis biomarkers in
triple negative breast cancer.

Rojas L K(1)(2), Trilla-Fuertes L(3)(2), Gámez-Pozo A(3)(4), Chiva C(5)(6),
Sepúlveda J(1), Manso L(1), Prado-Vázquez G(3)(4), Zapater-Moros A(3)(4),
López-Vacas R(4), Ferrer-Gómez M(4), Mendiola C(1), Espinosa E(7)(8), Sabidó
E(5)(6), Ciruelos E(1), Vara JÁF(3)(4)(8).

Author information:
(1)Department of Medical Oncology, Hospital Universitario 12 de Octubre, 28041
Madrid, Spain.
(2)Katerin L Rojas and Lucía Trilla-Fuertes contributed equally to this work.
(3)Biomedica Molecular Medicine SL, 28049 Madrid, Spain.
(4)Molecular Oncology and Pathology Lab, Instituto de Genética Médica y
Molecular-INGEMM, Hospital Universitario La Paz-IdiPAZ, 28029 Madrid, Spain.
(5)Proteomics Unit, Center of Genomics Regulation, Barcelona Institute of Science
and Technology, 08036 Barcelona, Spain.
(6)Proteomics Unit, Universitat Pompeu Fabra, 08002 Barcelona, Spain.
(7)Medical Oncology Service, Hospital Universitario La Paz-IdiPAZ, 28029 Madrid,
Spain.
(8)CIBERONC, Instituto de Salud Carlos III, 28029 Madrid, Spain.

Background: Breast cancer (BC) is the most frequent tumour in women. Triple
negative tumours (TNBC)-which are associated with minor survival rates-lack
markers predictive of response to anticancer drugs. Triple negative tumours
frequently metastasise to the central nervous system (CNS).
Objective: The main objective of this study was to study differences in tumour
protein expression between patients with CNS metastases and those without this
kind of spread, and propose new biomarkers.
Methods: A retrospective study was performed. Targeted proteomics and statistical
analyses were used to identify possible biomarkers.
Results: Proteins were quantified by a targeted proteomics approach and protein
expression data were successfully obtained from 51 triple negative formalin-fixed
paraffin-embedded samples. ISG15, THBS1 and AP1M1 were identified as possible
biomarkers related with CNS metastasis development.
Conclusions: Three possible biomarkers associated with CNS metastases in TNBC
tumours were identified: ISG15, THBS1 and AP1M1. They may become markers
predicting the appearance of CNS infiltration in triple negative BC.

DOI: 10.3332/ecancer.2019.891
PMCID: PMC6369972
PMID: 30792808

Int J Biomed Imaging. 2019 Jan 17;2019:5987425. doi: 10.1155/2019/5987425.
eCollection 2019.

Magnetic Resonance Angiography Shows Increased Arterial Blood Supply Associated
with Murine Mammary Cancer.

Mustafi D(1), Leinroth A(1), Fan X(1), Markiewicz E(1), Zamora M(1), Mueller
J(2), Conzen SD(3), Karczmar GS(1).

Author information:
(1)Department of Radiology, The University of Chicago, Chicago, Illinois 60637,
USA.
(2)Department of Pathology, The University of Chicago, Chicago, Illinois 60637,
USA.
(3)Department of Medicine, Section of Hematology and Oncology, The University of
Chicago, Chicago, Illinois 60637, USA.

Breast cancer is a major cause of morbidity and mortality in Western women. Tumor
neoangiogenesis, the formation of new blood vessels from pre-existing ones, may
be used as a prognostic marker for cancer progression. Clinical practice uses
dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) to detect cancers
based on increased blood flow and capillary permeability. However, DCE-MRI
requires repeated injections of contrast media. Therefore we explored the use of
noninvasive time-of-flight (TOF) MR angiography for serial studies of mouse
mammary glands to measure the number and size of arteries feeding mammary glands
with and without cancer. Virgin female C3(1) SV40 TAg mice (n=9), aged 18-20
weeks, were imaged on a 9.4 Tesla small animal scanner. Multislice T2-weighted
(T2W) images and TOF-MRI angiograms were acquired over inguinal mouse mammary
glands. The data were analyzed to determine tumor burden in each mammary gland
and the volume of arteries feeding each mammary gland. After in vivo MRI,
inguinal mammary glands were excised and fixed in formalin for histology. TOF
angiography detected arteries with a diameter as small as 0.1 mm feeding the
mammary glands. A significant correlation (r=0.79; p< 0.0001) was found between
tumor volume and the arterial blood volume measured in mammary glands. Mammary
arterial blood volumes ranging from 0.08 mm3 to 3.81 mm3 were measured. Tumors
and blood vessels found on in vivo T2W and TOF images, respectively, were
confirmed with ex vivo histological images. These results demonstrate increased
recruitment of arteries to mammary glands with cancer, likely associated with
neoangiogenesis. Neoangiogenesis may be detected by TOF angiography without
injection of contrast agents. This would be very useful in mouse models where
repeat placement of I.V. lines is challenging. In addition, analogous methods
could be tested in humans to evaluate the vasculature of suspicious lesions
without using contrast agents.

DOI: 10.1155/2019/5987425
PMCID: PMC6354161
PMID: 30792738

Front Microbiol. 2019 Feb 7;10:181. doi: 10.3389/fmicb.2019.00181. eCollection
2019

Transcriptome Sequencing Investigated the Tumor-Related Factors Changes After T.
gondii Infection.

Lu G(1), Zhou J(2)(3), Zhao YH(1), Li QL(1), Gao YY(1), Wang L(4).

Author information:
(1)Institute of Pathogen Biology, Taishan Medical College, Tai’an, China.
(2)Department of Orthopedics, The Second Xiangya Hospital, Central South
University, Changsha, China.
(3)Department of Sports Medicine Research Center, Central South University,
Changsha, China.
(4)Department of Ji Nan Children’s Hospital, Jinan, China.

Toxoplasma gondii is an intracellular parasite and causes a global epidemic
parasitic disease. T. gondii-infection could inhibit the growth of tumor. In this
study, the transcriptomes of samples were detected by deep sequencing analysis.
The transcriptome data was compared with reference genome to perform sequence
alignment and the further analysis. The analyses of differential expression and
the differentially expressed genes were performed in the present study. Genes
involved in P53 signaling pathway, COLORECTAL cancer pathway, NON-SMALL CELL LUNG
cancer signaling pathway, and BREAST cancer signaling pathway were up-regulated
or down-regulated among the samples. The KEGG analysis indicated that the cancer
pathways changed after infection of T. gondii. Furthermore, tumor-related mRNAs
from different samples had a large difference, which suggested that the
difference might provide important information in resisting cancer. The protein
results indicated that tumor-related protein changes occurred after infection of
T. gondii. In conclusion, the infection changed the cancer pathways, which could
possibly inhibit the growth of tumor.

DOI: 10.3389/fmicb.2019.00181
PMCID: PMC6374557
PMID: 30792708

Case Rep Oncol. 2019 Jan 3;12(1):1-6. doi: 10.1159/000495031. eCollection 2019
Jan-Apr.

Treatment of Chemotherapy-Induced Thrombotic Microangiopathy with Eculizumab in a
Patient with Metastatic Breast Cancer.

Hausberg M(1), Felten H(1), Pfeffer S(2).

Author information:
(1)Department of General Internal Medicine, Nephrology, Rheumatology and
Pneumology, Karlsruhe General Hospital, Karlsruhe, Germany.
(2)Dialysis Center Ludwigsburg, Ludwigsburg, Germany.

The unexpected occurrence of thrombotic microangiopathy (TMA), characterised by
microangiopathic haemolytic anaemia and thrombocytopenia, in a patient with
cancer requires urgent diagnosis and appropriate management. TMA in patients with
metastatic cancer can be a manifestation of the malignancy itself or a
therapeutic complication. Distinguishing the cause of TMA is complicated but
clinically important to initiate appropriate treatment of metastatic cancer and
avoid potential drug toxicity. Eculizumab, which inhibits alternative complement
pathway activation, has been shown to be effective in chemotherapy-induced TMA.
We report the case of a 69-year-old woman with breast cancer who experienced a
mitomycin-C-induced TMA manifestation. TMA did not respond to conservative
therapy, plasmapheresis or rituximab and rapidly lead to dialysis dependency.
Despite disease progression and metastases, eculizumab treatment was associated
with recovered renal function and enabled the patient to avoid dialysis,
improving her quality of life.

DOI: 10.1159/000495031
PMCID: PMC6381888
PMID: 30792638

Cancer Cell Int. 2019 Feb 11;19:29. doi: 10.1186/s12935-019-0749-6. eCollection
2019

Correction to: Membrane expression of thymidine kinase 1 and potential clinical
relevance in lung, breast, and colorectal malignancies.

Weagel EG(1), Burrup W(1), Kovtun R(1), Velazquez EJ(1), Felsted AM(1), Townsend
MH(1), Ence ZE(2), Suh E(2), Piccolo SR(2)(3), Weber KS(1), Robison RA(1),
O’Neill KL(1).

Author information:
(1)1Department of Microbiology and Molecular Biology, Brigham Young University,
3142 Life Sciences Building, Provo, UT 84602 USA.
(2)2Department of Biology, Brigham Young University, Provo, UT USA.
(3)3Department of Biomedical Informatics, University of Utah, Salt Lake City, UT
USA.

Erratum for
Cancer Cell Int. 2018 Sep 10;18:135.

[This corrects the article DOI: 10.1186/s12935-018-0633-9.].

DOI: 10.1186/s12935-019-0749-6
PMCID: PMC6369547
PMID: 30792612

Cancer Inform. 2019 Feb 13;18:1176935119828746. doi: 10.1177/1176935119828746.
eCollection 2019.

MicroRNAs in Female Malignancies.

Liolios T(1), Kastora SL(2), Colombo G(2).

Author information:
(1)Hellenic Republic National and Kapodistrian, University of Athens, Faculty of
Biology, Athens, Greece.
(2)University of Aberdeen, School of Medicine and Dentistry, Aberdeen, UK.

MicroRNAs (miRNAs) are endogenous 22-nucleotide RNAs that can play a fundamental
regulatory role in the gene expression of various organisms. Current research
suggests that miRNAs can assume pivotal roles in carcinogenesis. In this article,
through bioinformatics mining and computational analysis, we determine a single
miRNA commonly involved in the development of breast, cervical, endometrial,
ovarian, and vulvar cancer, whereas we underline the existence of 7 more miRNAs
common in all examined malignancies with the exception of vulvar cancer.
Furthermore, we identify their target genes and encoded biological functions. We
also analyze common biological processes on which all of the identified miRNAs
act and we suggest a potential mechanism of action. In addition, we analyze
exclusive miRNAs among the examined malignancies and bioinformatically explore
their functionality. Collectively, our data can be employed in in vitro assays as
a stepping stone in the identification of a universal machinery that is derailed
in female malignancies, whereas exclusive miRNAs may be employed as putative
targets for future chemotherapeutic agents or cancer-specific biomarkers.

DOI: 10.1177/1176935119828746
PMCID: PMC6376555
PMID: 30792572

Conflict of interest statement: Declaration of conflicting interests:The
author(s) declared no potential conflicts of interest with respect to the
research, authorship, and/or publication of this article.

Geburtshilfe Frauenheilkd. 2019 Feb;79(2):184-188. doi: 10.1055/a-0805-9113. Epub
2019 Feb 18.

Mechanisms of Metastasis and Cell Mobility – The Role of Metabolism.

Gründker C(1), Läsche M(1), Hellinger JW(1), Emons G(1).

Author information:
(1)Universitätsmedizin Göttingen, Klinik für Gynäkologie und Geburtshilfe,
Göttingen, Germany.

Tumour metastasis is responsible for more than 90% of tumour-associated
mortality. About one third of breast cancer patients in the early stage develop
metastases. The transformation in tumour development referred to as the
metastatic cascade or «metastatic cycle» is a complex and multi-stage event.
While it is generally recognised that epithelial-mesenchymal transformation (EMT)
plays a crucial role in cancer progression and metastasis, the metabolic events
in this process have received little attention to date. We would therefore like
to provide a brief overview here of the influence of the metabolism on the
progression and metastasis of tumours.

Publisher: Die Tumormetastasierung ist verantwortlich für über 90% der
tumorassoziierten Mortalität. Etwa ein Drittel der Brustkrebspatientinnen im
Frühstadium entwickeln Metastasen. Die als „metastatische Kaskade“ oder
„metastatischer Zyklus“ bezeichnete Transformation in der Tumorentwicklung ist
ein komplexes und mehrstufiges Geschehen. Während allgemein anerkannt ist, dass
die epithelial-mesenchymale Transformation (EMT) eine entscheidende Rolle bei der
Krebsprogression und -metastasierung spielt, werden die metabolischen Vorgänge in
diesem Prozess bisher wenig beachtet. Daher wollen wir hier einen kurzen
Überblick über den Einfluss des Metabolismus auf die Progression und
Metastasierung der Tumoren geben.
DOI: 10.1055/a-0805-9113
PMCID: PMC6379160
PMID: 30792548

Sci Rep. 2019 Feb 21;9(1):2466. doi: 10.1038/s41598-019-39328-6.

BRAF V600E and SRC mutations as molecular markers for predicting prognosis and
conversion surgery in Stage IV colorectal cancer.

Shimada Y(1), Muneoka Y(2), Nagahashi M(2), Ichikawa H(2), Tajima Y(2), Hirose
Y(2), Ando T(2), Nakano M(2), Sakata J(2), Kameyama H(2), Takii Y(3), Ling Y(4),
Okuda S(4), Takabe K(2)(5)(6)(7)(8), Wakai T(9).

Author information:
(1)Division of Digestive and General Surgery, Niigata University Graduate School
of Medical and Dental Sciences, Niigata, Japan. shimaday@med.niigata-u.ac.jp.
(2)Division of Digestive and General Surgery, Niigata University Graduate School
of Medical and Dental Sciences, Niigata, Japan.
(3)Department of Surgery, Niigata Cancer Center Hospital, Niigata, Japan.
(4)Division of Bioinformatics, Niigata University Graduate School of Medical and
Dental Sciences, Niigata, Japan.
(5)Division of Breast Surgery, Roswell Park Comprehensive Cancer Center, Elm &
Carlton Streets, Buffalo, NY, 14263, USA.
(6)Department of Surgery, University at Buffalo Jacobs School of Medicine and
Biomedical Sciences, The State University of New York, Buffalo, NY, USA.
(7)Department of Breast Surgery and Oncology, Tokyo Medical University, Tokyo,
Japan.
(8)Department of Surgery, Yokohama City University, Yokohama, Japan.
(9)Division of Digestive and General Surgery, Niigata University Graduate School
of Medical and Dental Sciences, Niigata, Japan. wakait@med.niigata-u.ac.jp.

Comprehensive genomic sequencing (CGS) enables us to detect numerous genetic
alterations in a single assay. We aimed to identify molecular markers for
predicting prognosis and conversion surgery in Stage IV colorectal cancer (CRC)
using CGS. One-hundred eleven patients with Stage IV CRC who underwent primary
tumor resection were analyzed. We retrospectively investigated genetic
alterations using CGS of a 415-gene panel. Clinicopathological variables and
genetic alterations were analyzed to identify independent prognostic factors of
overall survival (OS). Forty-five of 111 patients had R0 resection; of these, 11
patients underwent conversion surgery. Univariate and multivariate analyses
identified histopathological grade 3, R0 resection, BRAF V600E mutation, and SRC
mutation as independent prognostic factors for OS (P = 0.041, P = 0.013,
P = 0.005, and P = 0.023, respectively). BRAF V600E and SRC mutations were
mutually exclusive, and SRC mutation was significantly associated with left-sided
tumor and liver metastasis compared to BRAF V600E mutation (P = 0.016 and
P = 0.025, respectively). Eleven of the 74 initially unresectable patients
underwent conversion surgery for R0 resection, yet none harbored BRAF V600E or
SRC mutations. BRAF V600E and SRC mutations are important molecular markers which
can predict prognosis and conversion surgery in Stage IV CRC.

DOI: 10.1038/s41598-019-39328-6
PMID: 30792536

Sci Rep. 2019 Feb 21;9(1):2521. doi: 10.1038/s41598-018-38340-6.

Dynamic Effects of CYP2D6 Genetic Variants in a Set of Poor Metaboliser Patients
with Infiltrating Ductal Cancer Under Treatment with Tamoxifen.

Ariza Márquez YV(1), Briceño I(2)(3), Aristizábal F(1), Niño LF(4), Yosa Reyes
J(5).

Author information:
(1)Universidad Nacional de Colombia, Instituto de Biotecnología IBUN,
Departamento de Farmacia, Bogota, 111321, Colombia.
(2)Universidad de la Sabana, Facultad de Medicina, Bogota, 140013, Colombia.
(3)Pontificia Universidad Javeriana, Facultad de Medicina, Instituto de Genética
Humana IGH, Bogota, 110231, Colombia.
(4)Universidad Nacional de Colombia, Facultad de Ingeniería, Departamento de
Ingeniería de Sistemas e Industrial, Bogota, 111321, Colombia.
(5)Universidad Simón Bolivar, Facultad de Ciencias Básicas y Biomédicas,
Laboratorio de Simulación Molecular y Bioinformática, Barranquilla, 080002,
Colombia. juvenal.yosa@unisimonbolivar.edu.co.

Breast cancer is a group of multigenic diseases. It is the most common cancer
diagnosed among women worldwide and is often treated with tamoxifen. Tamoxifen is
catalysed by cytochrome P450 2D6 (CYP2D6), and inter-individual variations in the
enzyme due to single nucleotide polymorphisms (SNPs) could alter enzyme activity.
We evaluated SNPs in patients from Colombia in South America who were receiving
tamoxifen treatment for breast cancer. Allelic diversity in the CYP2D6 gene was
found in the studied population, with two patients displaying the
poor-metaboliser phenotype. Molecular dynamics and trajectory analyses were
performed for CYP2D6 from these two patients, comparing it with the common
allelic form (CYP2D61). Although we found no significant structural change in the protein, its dynamics differ significantly from those of CYP2D61, the effect
of such differential dynamics resulting in an inefficient enzyme with serious
implications for tamoxifen-treated patients, increasing the risk of disease
relapse and ineffective treatment.

DOI: 10.1038/s41598-018-38340-6
PMID: 30792473

Sci Rep. 2019 Feb 21;9(1):2526. doi: 10.1038/s41598-019-38920-0.

Detection of Volatile Organic Compounds (VOCs) in Urine via Gas
Chromatography-Mass Spectrometry QTOF to Differentiate Between Localized and
Metastatic Models of Breast Cancer.

Woollam M(1)(2), Teli M(3)(2), Angarita-Rivera P(3)(2), Liu S(3), Siegel
AP(1)(2), Yokota H(3)(4), Agarwal M(5)(6)(7).

Author information:
(1)IUPUI, Department of Chemistry and Chemical Biology, Indianapolis, 46202, USA.
(2)Integrated Nanosystems Development Institute, Indianapolis, 46202, USA.
(3)IUPUI, Department of Biomedical Engineering, Indianapolis, 46202, USA.
(4)Biomechanics and Biomaterials Research Center, Indianapolis, 46202, USA.
(5)IUPUI, Department of Chemistry and Chemical Biology, Indianapolis, 46202, USA.
agarwal@iupui.edu.
(6)IUPUI, Department of Mechanical Engineering and Energy, Indianapolis, 46202,
USA. agarwal@iupui.edu.
(7)Integrated Nanosystems Development Institute, Indianapolis, 46202, USA.
agarwal@iupui.edu.

Breast cancer is the most common cancer detected in women and current screening
methods for the disease are not sensitive. Volatile organic compounds (VOCs)
include endogenous metabolites that provide information about health and disease
which might be useful to develop a better screening method for breast cancer. The
goal of this study was to classify mice with and without tumors and compare
tumors localized to the mammary pad and tumor cells injected into the iliac
artery by differences in VOCs in urine. After 4T1.2 tumor cells were injected
into BALB/c mice either in the mammary pad or into the iliac artery, urine was
collected, VOCs from urine headspace were concentrated by solid phase
microextraction and results were analyzed by gas chromatography-mass spectrometry
quadrupole time-of-flight. Multivariate and univariate statistical analyses were
employed to find potential biomarkers for breast cancer and metastatic breast
cancer in mice models. A set of six VOCs classified mice with and without tumors
with an area under the receiver operator characteristic (ROC AUC) of 0.98 (95%
confidence interval [0.85, 1.00]) via five-fold cross validation. Classification
of mice with tumors in the mammary pad and iliac artery was executed utilizing a
different set of six VOCs, with a ROC AUC of 0.96 (95% confidence interval [0.75,
1.00]).

DOI: 10.1038/s41598-019-38920-0
PMID: 30792417

Cell Death Dis. 2019 Feb 21;10(3):180. doi: 10.1038/s41419-019-1429-0.

Potassium channel activity controls breast cancer metastasis by affecting
β-catenin signaling.

Breuer EK(1), Fukushiro-Lopes D(2), Dalheim A(3), Burnette M(4), Zartman J(4),
Kaja S(2)(5)(6), Wells C(7), Campo L(1), Curtis KJ(8), Romero-Moreno R(8),
Littlepage LE(8), Niebur GL(8)(9), Hoskins K(10), Nishimura MI(3), Gentile
S(11)(12).

Author information:
(1)Department of Radiation Oncology, Loyola University Chicago, Stritch School of
Medicine, Maywood, IL, 60153, USA.
(2)Department of Molecular Pharmacology & Therapeutics, Loyola University
Chicago, Stritch School of Medicine, Maywood, IL, 60153, USA.
(3)Department of Surgery, Loyola University Chicago, Stritch School of Medicine,
Maywood, IL, 60153, USA.
(4)Department of Chemical and Biomolecular Engineering, University of Notre Dame,
Notre Dame, IN, 46556, USA.
(5)Department of Ophthalmology, Loyola University Chicago, Stritch School of
Medicine, Maywood, IL, USA.
(6)Research Service, Edward Hines Jr. VA Hospital, Hines, IL, USA.
(7)Division of Cancer Studies, King’s College London, Rm. 2.34 A New Hunts House,
Guy’s Campus, London, SE1 1 UL, UK.
(8)Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN,
46556, USA.
(9)Bioengineering Graduate Program, University of Notre Dame, Notre Dame, IN,
46556, USA.
(10)Division of Hematology Oncology, Department of Medicine, University of
Illinois Chicago, Chicago, IL, 60612, USA.
(11)Department of Molecular Pharmacology & Therapeutics, Loyola University
Chicago, Stritch School of Medicine, Maywood, IL, 60153, USA. sgentile@uic.edu.
(12)Division of Hematology Oncology, Department of Medicine, University of
Illinois Chicago, Chicago, IL, 60612, USA. sgentile@uic.edu.

Potassium ion channels are critical in the regulation of cell motility. The
acquisition of cell motility is an essential parameter of cancer metastasis.
However, the role of K+ channels in cancer metastasis has been poorly studied.
High expression of the hG1 gene, which encodes for Kv11.1 channel associates with
good prognosis in estrogen receptor-negative breast cancer (BC). We evaluated the
efficacy of the Kv11.1 activator NS1643 in arresting metastasis in a triple
negative breast cancer (TNBC) mouse model. NS1643 significantly reduces the
metastatic spread of breast tumors in vivo by inhibiting cell motility,
reprogramming epithelial-mesenchymal transition via attenuation of Wnt/β-catenin
signaling and suppressing cancer cell stemness. Our findings provide important
information regarding the clinical relevance of potassium ion channel expression
in breast tumors and the mechanisms by which potassium channel activity can
modulate tumor biology. Findings suggest that Kv11.1 activators may represent a
novel therapeutic approach for the treatment of metastatic estrogen
receptor-negative BC. Ion channels are critical factor for cell motility but
little is known about their role in metastasis. Stimulation of the Kv11.1 channel
suppress the metastatic phenotype in TNBC. This work could represent a
paradigm-shifting approach to reducing mortality by targeting a pathway that is
central to the development of metastases.

DOI: 10.1038/s41419-019-1429-0
PMID: 30792401

Cell Death Dis. 2019 Feb 21;10(3):176. doi: 10.1038/s41419-019-1437-0.

miR-29a contributes to breast cancer cells epithelial-mesenchymal transition,
migration, and invasion via down-regulating histone H4K20 trimethylation through
directly targeting SUV420H2.

Wu Y(1), Shi W(1), Tang T(1), Wang Y(1), Yin X(1), Chen Y(1), Zhang Y(1), Xing
Y(1), Shen Y(1), Xia T(2), Guo C(1), Pan Y(3), Jin L(4).

Author information:
(1)State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of
Druggability of Biopharmaceuticals, School of life Science and Technology, China
Pharmaceutical University, 24 Tongjiaxiang, Nanjing, Jiangsu province, China.
(2)Department of Breast Surgery, Breast Disease Center of Jiangsu Province, First
Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing,
Jiangsu province, China.
(3)State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of
Druggability of Biopharmaceuticals, School of life Science and Technology, China
Pharmaceutical University, 24 Tongjiaxiang, Nanjing, Jiangsu province, China.
panyi@cpu.edu.cn.
(4)State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of
Druggability of Biopharmaceuticals, School of life Science and Technology, China
Pharmaceutical University, 24 Tongjiaxiang, Nanjing, Jiangsu province, China.
ljstemcell@cpu.edu.cn.

Breast cancer is the most prevalent cancer in women worldwide, which remains
incurable once metastatic. Breast cancer stem cells (BCSCs) are a small subset of
breast cancer cells which are essential in tumor formation, metastasis, and drug
resistance. microRNAs (miRNAs) play important roles in the breast cancer cells
and BCSCs by regulating specific genes. In this study, we found that miR-29a was
up-regulated in BCSCs, in aggressive breast cancer cell line and in breast cancer
tissues. We also confirmed suppressor of variegation 4-20 homolog 2 (SUV420H2),
which is a histone methyltransferase that specifically trimethylates Lys-20 of
histone H4 (H4K20), as the target of miR-29a. Both miR-29a overexpression and
SUV420H2 knockdown in breast cancer cells promoted their migration and invasion
in vitro and in vivo. Furthermore, we discovered that SUV420H2-targeting miR-29a
attenuated the repression of connective tissue growth factor (CTGF) and growth
response protein-1 (EGR1) by H4K20 trimethylation and promoted the EMT progress
of breast cancer cells. Taken together, our findings reveal that miR-29a plays
critical roles in the EMT and metastasis of breast cancer cells through targeting
SUV420H2. These findings may provide new insights into novel molecular
therapeutic targets for breast cancer.

DOI: 10.1038/s41419-019-1437-0
PMID: 30792382

Cell Death Dis. 2019 Feb 21;10(3):179. doi: 10.1038/s41419-019-1427-2.

Angiomotin-p130 inhibits β-catenin stability by competing with Axin for binding
to tankyrase in breast cancer.

Yang J(1), Zhang X(1), Chen Z(1), Shen Y(1), Wang F(1), Wang Y(2), Liu Y(3), Liu
P(4), Yang J(5).

Author information:
(1)Department of Medical Oncology, The First Affiliated Hospital of Xi’an
Jiaotong University, Xi’an, China.
(2)Center for Translational Medicine, The First Affiliated Hospital of Xi’an
Jiaotong University College of Medicine, Xi’an, China.
(3)Department of Biology and Biochemistry, University of Houston, Houston, TX,
USA.
(4)Center for Translational Medicine, The First Affiliated Hospital of Xi’an
Jiaotong University College of Medicine, Xi’an, China.
liupeijun@mail.xjtu.edu.cn.
(5)Department of Medical Oncology, The First Affiliated Hospital of Xi’an
Jiaotong University, Xi’an, China. yangjin@mail.xjtu.edu.cn.

Growing evidence indicates that Angiomotin (Amot)-p130 and Amot-p80 have
different physiological functions. We hypothesized that Amot-p130 is a tumor
suppressor gene in breast cancer, in contrast with the canonical oncogenicity of
Amot-p80 or total Amot. To clarify the role of Amot-p130 in breast cancer, we
performed real-time quantitative PCR, western blotting, flow cytometry,
microarray, immunofluorescence, immunoprecipitation, and tumor sphere-formation
assays in vitro, as well as tumorigenesis and limited-dilution analysis in vivo.
In this study, we showed that Amot-p130 inhibited the proliferation, migration,
and invasion of breast cancer cells. Interestingly, transcriptional profiles
indicated that genes differentially expressed in response to Amot-p130 knockdown
were mostly related to β-catenin signaling in MCF7 cells. More importantly, most
of the downstream partners of β-catenin were associated with stemness. In a
further validation, Amot-p130 inhibited the cancer stem cell potential of breast
cancer cells both in vitro and in vivo. Mechanistically, Amot-p130 decreased
β-catenin stability by competing with Axin for binding to tankyrase, leading to a
further inhibition of the WNT pathway. In conclusions, Amot-p130 functions as a
tumor suppressor gene in breast cancer, disrupting β-catenin stability by
competing with Axin for binding to tankyrase. Amot-p130 was identified as a
potential target for WNT pathway-targeted therapies in breast cancer.

DOI: 10.1038/s41419-019-1427-2
PMID: 30792381

Q J Nucl Med Mol Imaging. 2019 Feb 21. doi: 10.23736/S1824-4785.19.03114-5. [Epub
ahead of print]

Comparison of different motion correction techniques for dynamic FDG-PET/CT
studies in breast cancer patients.

Tőkés T(1), Dank M(2), Lengyel Z(3), Kajáry K(3).

Author information:
(1)Oncology Center, Semmelweis University, Budapest, Hungary –
timi.tokes@gmail.com.
(2)Oncology Center, Semmelweis University, Budapest, Hungary.
(3)Pozitron PET/CT Center, Budapest, Hungary.

BACKGROUND: Our aim was evaluate interchangeability of different motion
correction methods in the assessment of dynamic FDG-PET/CT studies in breast
cancer patients as well as to assess the interrater reliability of these methods.
METHODS: In our prospective study we included patients with malignant breast
tumours. Dynamic PET acquisition lasted for 60 minutes after tracer (FDG)
injection. Every study was assessed by the same two experienced observers. We
assessed plasma activity noninvasively. In case of the primary tumour VOIs we
applied two different approaches to correct motion artefacts: Method I)
frame-by-frame manual motion correction; Method II) frame-by-frame semi-automatic
software-based motion correction. FDG two-compartment kinetic modelling was
applied to assess K1, k2, k3 rate coefficients and to calculate Ki (tracer flux
constant) and MRFDG (FDG metabolic rate).
RESULTS: 35 lesions detected during 34 dynamic studies were included in this
current analysis. Interrater reliability of both applied motion correction
methods proved to be excellent (ICC= 0.89-0.99), except Ki measured by Method I
(ICC=0.66). Bland-Altman analysis revealed that Method II resulted in
significantly lower values than Method I regarding k3 and Ki in case of both
observers, and regarding MRFDG in one of the observers. In case of K1 and k2 the
two methods were in good agreement.
CONCLUSIONS: Both applied methods proved to be reproducible and reliable,
especially Method II, where every measured kinetic parameter showed excellent
interrater reliability. Different approaches of motion correction could have a
significant effect on the results of the kinetic modelling; therefore careful
selection of the most reliable method is advised.

DOI: 10.23736/S1824-4785.19.03114-5
PMID: 30792380

Cancer Prev Res (Phila). 2019 Feb 21. doi: 10.1158/1940-6207.CAPR-18-0492. [Epub
ahead of print]

HER2 Expression in NF1 Breast Cancer-Response.

Wang X(1), Chitale D(2).

Author information:
(1)H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
xia.wang@moffitt.org.
(2)Henry Ford Hospital, Detroit, Michigan.

DOI: 10.1158/1940-6207.CAPR-18-0492
PMID: 30792347

Cancer Prev Res (Phila). 2019 Feb 21. doi: 10.1158/1940-6207.CAPR-18-0392. [Epub
ahead of print]

NF1 Alterations are Linked to Increased HER2 Expression in Breast Cancer-Letter.

Gambini D(1), Natacci F(2), Cesaretti C(2), Fusco N(3)(4).

Author information:
(1)Division of Medical Oncology, Fondazione IRCCS Ca’ Granda-Ospedale Maggiore
Policlinico, Milan, Italy.
(2)Medical Genetics Unit, Woman-Child-Newborn Department, Fondazione IRCCS Ca’
Granda-Ospedale Maggiore Policlinico, Milan, Italy.
(3)Division of Pathology, Fondazione IRCCS Ca’ Granda-Ospedale Maggiore
Policlinico, Milan, Italy. nicola.fusco@unimi.it.
(4)Department of Biomedical, Surgical, and Dental Sciences, University of Milan,
Milan Italy.

DOI: 10.1158/1940-6207.CAPR-18-0392
PMID: 30792346

Arch Med Res. 2019 Feb 18. pii: S0188-4409(19)30135-3. doi:
10.1016/j.arcmed.2019.02.001. [Epub ahead of print]

MT4-MMP Modulates the Expression of miRNAs in Breast Cancer Cells.

Cervantes-Garduño A(1), Zampedri C(2), Espinosa M(2), Maldonado V(3),
Melendez-Zajgla J(2), Ceballos-Cancino G(4).

Author information:
(1)Laboratorio de Genómica Funcional, Instituto Nacional de Medicina Genómica,
Ciudad de México, México; Posgrado en Ciencias Biológicas, Universidad Nacional
Autónoma de México, Ciudad Universitaria, Ciudad de México, México.
(2)Laboratorio de Genómica Funcional, Instituto Nacional de Medicina Genómica,
Ciudad de México, México.
(3)Laboratorio de Epigenética, Instituto Nacional de Medicina Genómica, Ciudad de
México, México.
(4)Laboratorio de Genómica Funcional, Instituto Nacional de Medicina Genómica,
Ciudad de México, México. Electronic address: gceballos@inmegen.gob.mx.

BACKGROUND: MT4-MMP is a member of the metalloproteinases family, although with a
controversial role in the extracellular matrix remodelation. Overexpression of
this metalloproteinase has been observed in breast cancer and it has been
suggested that it can regulate tumor growth and cancer progression. The
mechanisms by which MT4-MMP participates in breast cancer includes tumor blood
vessels desestabilization, the activation of an angiogenic switch, and increase
of EGFR signaling. However, all the mechanisms by which MT4-MMP participates in
breast cancer are still unknowns.
AIM OF THE STUDY: To study if MT4-MMP could modulate the expression of microRNAs
(miRNAs) related to biological processes associated with tumor formation and
progression.
METHODS: MT4-MMP was ectopically overexpressed in MDA-MB-231 cells and the miRNAs
expression profile modulated by the metalloproteinase was studied by using miRNAs
microarrays. Microarray data were analyzed with different tools to find the
molecular and cellular functions related to the differentially expressed miRNAs.
The clinical relevance of some miRNAs was analyzed using a public database.
RESULTS: MT4-MMP overexpression in breast cancer cells induced the modulation of
65 miRNAs, which were related to the alteration of pathways dependent of p53,
TGF-β, MAPK, ErbB, and Wnt, as well as processes such as cell cycle, adherens
junctions, apoptosis, and focal adhesion. Several of the upregulated miRNAs were
associated to a worse prognosis in breast cancer patients.
CONCLUSIONS: In breast cancer cells, the overexpression of MT4-MMP modulates the
expression of miRNAs involved in several biological processes associated with
tumor formation and progression and with clinical relevance.

DOI: 10.1016/j.arcmed.2019.02.001
PMID: 30792164

Bioorg Med Chem. 2019 Feb 15. pii: S0968-0896(18)31877-7. doi:
10.1016/j.bmc.2019.02.027. [Epub ahead of print]

Design and molecular modeling of novel P38α MAPK inhibitors targeting breast
cancer, synthesized from oxygen heterocyclic natural compounds.

Abdelhafez OM(1), Ahmed EY(2), Abdel Latif NA(2), Arafa RK(3), Abd Elmageed
ZY(4), Ali HI(5).

Author information:
(1)Chemistry of Natural Compounds Department, Pharmaceutical and Drug Industries
Research Division, National Research Centre, Dokki, Cairo, Egypt. Electronic
address: dromaima45@gmail.com.
(2)Chemistry of Natural Compounds Department, Pharmaceutical and Drug Industries
Research Division, National Research Centre, Dokki, Cairo, Egypt.
(3)Biomedical Sciences, University of Science and Technology, Zewail City of
Science and Technology, Cairo, Egypt.
(4)Rangel College of Pharmacy, Health Science Center, Texas A&M University,
Kingsville, TX 78363, United States.
(5)Rangel College of Pharmacy, Health Science Center, Texas A&M University,
Kingsville, TX 78363, United States. Electronic address:
alyismail@pharmacy.tamhsc.edu.

Two new series of furochromone and benzofuran derivatives were designed,
synthesized and evaluated for their in vitro anticancer activity against MCF-7
and MDA231 breast cancer cell lines. Compounds 5, 6, 7, 9, 15a, 16, 17a and 18
exhibited the best antiproliferative activities with IC50 values ranging from
1.19 to 2.78 µM against MCF-7 superior to lapatinib as reference standard (IC50;
4.69 µM). Compounds 15a and 18 revealed significant cytotoxic activity against
MCF-7 and MDA231, therefore their inhibitory potencies against p38α MAP kinase
were evaluated. Remarkably they exhibited significant IC50 of 0.04 µM comparable
to SB203580 (IC50; 0.50 µM) as a reference standard. These promising results of
cytotoxic activity and significant inhibition of p38α MAP kinase, were confirmed
by exploring the effect of benzofuran derivative (18) on the apoptotic induction
and cell cycle progression of MCF-7 cell line. Compound 18 induced preG1
apoptosis and cell growth arrest at G2/M phase preventing the mitotic cycle.
Moreover it activated the caspase-7 which executes apoptosis. Molecular docking
study was carried out using GOLD program to predict the mode of binding
interaction of the synthesized compounds into the target p38α MAPK. Additionally,
the physicochemical properties and ADME parameters of compound 18 were examined
in silico to investigate its drug-likeness.

DOI: 10.1016/j.bmc.2019.02.027
PMID: 30792101

Clin Ther. 2019 Feb 18. pii: S0149-2918(19)30048-7. doi:
10.1016/j.clinthera.2019.01.012. [Epub ahead of print]

Risk Factors of QTc Prolongation in Women With Hormone Receptor‒Positive/Human
Epidermal Growth Factor Receptor 2‒Negative Metastatic Breast Cancer: A
Retrospective Analysis of Health Care Claims Data.

Ward M(1), Harnett J(1), Bell TJ(2), Mardekian J(1).

Author information:
(1)Pfizer Inc, New York, NY, USA.
(2)Pfizer Inc, New York, NY, USA. Electronic address: timothy.j.bell@pfizer.com.

PURPOSE: In addition to biomarker status, treatment selection for metastatic
breast cancer (mBC) includes individual patient and clinical characteristics such
as tumor burden, timing of disease recurrence, and comorbidities. Women with mBC
may take medications that can increase the risk of drug-induced toxicities,
including prolongation of cardiac repolarization (prolongation of QT interval).
Corrected QT (QTc) prolongation, a toxicity associated with many cancer
treatments, can lead to potentially life-threatening ventricular arrhythmias. As
such, it is important to identify patients at risk for QTc prolongation due to
comorbid conditions, concomitant medications, or electrolyte abnormalities. This
real-world study estimated the proportion of women with hormone receptor‒positive
(HR+)/human epidermal growth factor receptor 2‒negative (HER2‒) mBC who may be at
risk of developing QTc prolongation. Results in the elderly are also included.
METHODS: This retrospective, cross-sectional cohort study used the Truven Health
MarketScan and Optum Clinformatics administrative claims databases. Patients’
medical and pharmacy data were evaluated to assess the risk of QTc prolongation.
Prescription and medication administration claims were evaluated during the 7-day
period before the index date (ie, first secondary neoplasm diagnosis). In
addition, International Classification of Diseases, Ninth/Tenth Revision,
Clinical Modification, codes were evaluated 12 months before the index date to
describe congenital long QT syndrome, cardiac disease, and electrolyte
abnormalities.
FINDINGS: A cohort of 24,340 women with HR+/HER2‒ mBC were identified, including
5059 women aged 65-74 years and 4851 aged ≥75 years. Based on an overall analysis
of risk factors (congenital long QT syndrome, cardiovascular disease, electrolyte
abnormalities, or concomitant medications), 29.5% of all patients, 33.2% of
patients aged 65-74 years, and 40.5% of patients aged ≥75 years had risk factors
for QTc prolongation.
IMPLICATIONS: This analysis of real-world data indicates that almost 1 in 3 women
with HR+/HER2‒ mBC had congenital long QT syndrome, cardiovascular disease,
and/or electrolyte abnormalities or received a concomitant medication that could
increase the risk of developing QTc prolongation. The risk factors for congenital
long QT syndrome, cardiovascular disease, or electrolyte abnormalities were more
common in older patients. This analysis emphasizes the importance of
individualized benefit/risk assessment during treatment decisions, especially
when considering drugs with known or possible QTc prolongation risk. (Clin Ther.
2019;41:XXX-XXX) © 2019 Elsevier HS Journals, Inc.

DOI: 10.1016/j.clinthera.2019.01.012
PMID: 30792074

Brachytherapy. 2019 Feb 18. pii: S1538-4721(18)30674-3. doi:
10.1016/j.brachy.2019.01.008. [Epub ahead of print]

Monte Carlo study of the relationship between skin dose and optically stimulated
luminescence dosimeter dose in Pd-103 permanent breast seed implant
brachytherapy.

Nich S(1), Kirkby C(2), Villarreal-Barajas JE(3).

Author information:
(1)Department of Physics and Astronomy, University of Calgary, Calgary Alberta,
Canada. Electronic address: snich@ucalgary.ca.
(2)Department of Physics and Astronomy, University of Calgary, Calgary Alberta,
Canada; Department of Oncology, University of Calgary, Calgary Alberta, Canada;
Department of Medical Physics, Jack Ady Cancer Centre, Lethbridge, Alberta,
Canada.
(3)Department of Physics and Astronomy, University of Calgary, Calgary Alberta,
Canada; Department of Medical Physics, Royal Devon and Exeter Hospital NHS,
Exeter, Devon, UK.

PURPOSE: To establish a method for estimating skin dose for patients with
permanent breast seed implant based on in vivo optically stimulated luminescence
dosimeters (OSLDs) measurements.
METHODS AND MATERIALS: Monte Carlo simulations were performed in a simple breast
phantom using the EGSnrc user code egs_brachy. Realistic models of the IsoAid
Advantage Pd-103 brachytherapy source and Landauer nanoDot OSLD were created to
model in vivo skin dose measurements where an OSLD would be placed on the skin of
a patient with permanent breast seed implant following implantation. Doses to a
0.2 cm3 volume of skin beneath the OSLD and to the sensitive volume within the
OSLD were calculated, and the ratio of these values was found for various seed
positions inside the breast phantom. The maximum value of this ratio may be used
as a conversion factor that would allow skin dose to be estimated from in vivo
OSLD measurements.
RESULTS: Conversion factors of 0.5 and 1.44 are recommended for OSLDs calibrated
to dose to Al2O3 and water, respectively, at the point of measurement in the
OSLD. These factors were not significantly affected by the addition of extra
seeds in the dose calculations.
CONCLUSIONS: A method for estimating skin dose from OSLD measurements was
proposed. Individual institutions should calibrate OSLDs to Pd-103 seeds to apply
the results of this work clinically.

DOI: 10.1016/j.brachy.2019.01.008
PMID: 30792005

J Exp Clin Cancer Res. 2019 Feb 21;38(1):94. doi: 10.1186/s13046-019-1100-8.

Long non-coding RNA LINC00968 attenuates drug resistance of breast cancer cells
through inhibiting the Wnt2/β-catenin signaling pathway by regulating WNT2.

Xiu DH(1), Liu GF(1), Yu SN(1), Li LY(2), Zhao GQ(2), Liu L(1), Li XF(3).

Author information:
(1)Department of Radiology, China-Japan Union Hospital of Jilin University,
Changchun, 130033, People’s Republic of China.
(2)Department of Anesthesiology, China-Japan Union Hospital of Jilin University,
No. 126, Xiantai Street, Changchun, 130033, Jilin Province, People’s Republic of
China.
(3)Department of Anesthesiology, China-Japan Union Hospital of Jilin University,
No. 126, Xiantai Street, Changchun, 130033, Jilin Province, People’s Republic of
China. Lixfbility@163.com.

BACKGROUND: Breast cancer is one the most common cancers, making it the second
leading cause of cancer-related death among women. Long non-coding RNAs
(lncRNAs), with tightly regulated expression patterns, also serve as tumor
suppressor during tumorigenesis. The present study aimed to elucidate the role of
LINC00968 in breast cancer via WNT2-mediated Wnt2/β-catenin signaling pathway.
METHODS: Breast cancer chip GSE26910 was utilized to identify differential
expression in LINC00968 and WNT2. The possible relationship among LINC00968,
transcriptional repressor HEY and WNT2 was analyzed and then verified. Effects of
LINC00968 on activation of the Wnt2/β-catenin signaling pathway was also tested.
Drug resistance, colony formation, cell migration, invasion ability and cell
apoptosis after transfection were also determined. Furthermore, tumor xenograft
in nude mice was performed to test tumor growth and weight in vivo.
RESULTS: WNT2 expression exhibited at a high level, whereas LINC00968 at a low
expression in breast cancer which was also associated with poor prognosis in
patients. LINC00968 targeted and negatively regulated WNT2 potentially via HEY1.
Either overexpressed LINC00968 or silenced inhibited activation of the
Wnt2/β-catenin signaling pathway, thereby reducing drug resistance, decreasing
colony formation ability, as well as suppressing migration and invasion abilities
of breast cancer cells in addition to inducing apoptosis. Lastly, in vivo
experiment suggested that LINC00968 overexpression also suppressed transplanted
tumor growth in nude mice.
CONCLUSION: Collectively, overexpressed LINC00968 contributes to reduced drug
resistance in breast cancer cells by inhibiting the activation of the
Wnt2/β-catenin signaling pathway through silencing WNT2. This study offers a new
target for the development of breast cancer treatment.

DOI: 10.1186/s13046-019-1100-8
PMID: 30791958

Breast Cancer Res. 2019 Feb 21;21(1):29. doi: 10.1186/s13058-019-1107-2.

AMP-activated protein kinase: a potential therapeutic target for triple-negative
breast cancer.

Cao W(1)(2), Li J(2)(3), Hao Q(2), Vadgama JV(4), Wu Y(5).

Author information:
(1)Department of Nuclear Medicine, Union Hospital, Tongji Medical College,
Huazhong University of Science and Technology, Wuhan, 430022, China.
(2)Division of Cancer Research and Training, Department of Internal Medicine,
Charles R. Drew University of Medicine and Science, David Geffen UCLA School of
Medicine, and UCLA Jonsson Comprehensive Cancer Center, 1748 E. 118th Street, Los
Angeles, CA, 90059, USA.
(3)Department of Breast Surgery, Tianjin Central Hospital of Gynecology and
Obstetrics, Tianjin, China.
(4)Division of Cancer Research and Training, Department of Internal Medicine,
Charles R. Drew University of Medicine and Science, David Geffen UCLA School of
Medicine, and UCLA Jonsson Comprehensive Cancer Center, 1748 E. 118th Street, Los
Angeles, CA, 90059, USA. jayvadgama@cdrewu.edu.
(5)Division of Cancer Research and Training, Department of Internal Medicine,
Charles R. Drew University of Medicine and Science, David Geffen UCLA School of
Medicine, and UCLA Jonsson Comprehensive Cancer Center, 1748 E. 118th Street, Los
Angeles, CA, 90059, USA. yongwu@cdrewu.edu.

Triple-negative breast cancer (TNBC) is an aggressive subset of breast carcinomas
that lack expression of estrogen receptor (ER), progesterone receptor (PR), and
human epidermal growth factor receptor-2 (HER2). Unlike other breast cancer
subtypes, targeted therapy is presently unavailable for patients with TNBC. In
spite of initial responses to chemotherapy, drug resistance tends to develop
rapidly and the prognosis of metastatic TNBC is poor. Hence, there is an urgent
need for novel-targeted treatment methods or development of safe and effective
alternatives with recognized mechanism(s) of action. AMP-activated protein kinase
(AMPK), an energy sensor, can regulate protein and lipid metabolism responding to
alterations in energy supply. In the past 10 years, interest in AMPK has
increased widely since it appeared as an attractive targeting molecule for cancer
therapy. There has been a deep understanding of the possible role of abnormal
AMPK signaling pathways in the regulation of growth and survival and the
development of drug resistance in TNBC. The increasing popularity of using AMPK
regulators for TNBC-targeted therapy is supported by a considerable development
in ascertaining the molecular pathways implicated. This review highlights the
available evidence for AMPK-targeted anti-TNBC activity of various agents or
treatment strategies, with special attention placed on recent preclinical and
clinical advances in the manipulation of AMPK in TNBC. The elaborative analysis
of these AMPK-related signaling pathways will have a noteworthy impact on the
development of AMPK regulators, resulting in efficacious treatments for this
lethal disease.

DOI: 10.1186/s13058-019-1107-2
PMID: 30791936

BMC Genomics. 2019 Feb 21;20(1):152. doi: 10.1186/s12864-019-5523-6.

Proteome profiling of triple negative breast cancer cells overexpressing NOD1 and
NOD2 receptors unveils molecular signatures of malignant cell proliferation.

Velloso FJ(1), Campos AR(2), Sogayar MC(1), Correa RG(3).

Author information:
(1)Cell and Molecular Therapy Center (NUCEL), Internal Medicine Department,
School of Medicine, University of São Paulo (USP), São Paulo, SP, 05360-130,
Brazil.
(2)SBP Medical Discovery Institute, 10901 North Torrey Pines Rd, La Jolla, CA,
92037, USA.
(3)SBP Medical Discovery Institute, 10901 North Torrey Pines Rd, La Jolla, CA,
92037, USA. rcorrea@sbpdiscovery.org.

BACKGROUND: Triple negative breast cancer (TNBC) is a malignancy with very poor
prognosis, due to its aggressive clinical characteristics and lack of response to
receptor-targeted drug therapy. In TNBC, immune-related pathways are typically
upregulated and may be associated with a better prognosis of the disease,
encouraging the pursuit for immunotherapeutic options. A number of immune-related
molecules have already been associated to the onset and progression of breast
cancer, including NOD1 and NOD2, innate immune receptors of bacterial-derived
components which activate pro-inflammatory and survival pathways. In the context
of TNBC, overexpression of either NOD1or NOD2 is shown to reduce cell
proliferation and increase clonogenic potential in vitro. To further investigate
the pathways linking NOD1 and NOD2 signaling to tumorigenesis in TNBC, we
undertook a global proteome profiling of TNBC-derived cells ectopically
expressing each one of these NOD receptors.
RESULTS: We have identified a total of 95 and 58 differentially regulated
proteins in NOD1- and NOD2-overexpressing cells, respectively. We used
bioinformatics analyses to identify enriched molecular signatures aiming to
integrate the differentially regulated proteins into functional networks. These
analyses suggest that overexpression of both NOD1 and NOD2 may disrupt
immune-related pathways, particularly NF-κB and MAPK signaling cascades.
Moreover, overexpression of either of these receptors may affect several stress
response and protein degradation systems, such as autophagy and the
ubiquitin-proteasome complex. Interestingly, the levels of several proteins
associated to cellular adhesion and migration were also affected in these
NOD-overexpressing cells.
CONCLUSIONS: Our proteomic analyses shed new light on the molecular pathways that
may be modulating tumorigenesis via NOD1 and NOD2 signaling in TNBC. Up- and
downregulation of several proteins associated to inflammation and stress response
pathways may promote activation of protein degradation systems, as well as
modulate cell-cycle and cellular adhesion proteins. Altogether, these signals
seem to be modulating cellular proliferation and migration via NF-κB,
PI3K/Akt/mTOR and MAPK signaling pathways. Further investigation of altered
proteins in these pathways may provide more insights on relevant targets,
possibly enabling the immunomodulation of tumorigenesis in the aggressive TNBC
phenotype.

DOI: 10.1186/s12864-019-5523-6
PMID: 30791886

Integr Cancer Ther. 2019 Jan-Dec;18:1534735419829573. doi:
10.1177/1534735419829573.

The Efficacy of Cognitive Behavioral Therapy to Treat Depression and Anxiety and
Improve Quality of Life Among Early-Stage Breast Cancer Patients.

Sun H(1), Huang H(2), Ji S(1), Chen X(1), Xu Y(2), Zhu F(3), Wu J(1).

Author information:
(1)1 The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou,
Jiangsu, People’s Republic of China.
(2)2 Community Health Service Center, Economic-Technical Development Zone,
Taicang, Jiangsu, People’s Republic of China.
(3)3 Taicang First People’s Hospital Affiliated to Soochow University, Taicang,
Jiangsu, People’s Republic of China.

PURPOSE: Positive results have appeared among nonmetastatic breast cancer
patients with the use of cognitive behavioral therapy (CBT). However, earlier
stage patient results have been mixed. This novelty of this study was the focus
on stage I and II breast cancer patients. The objective of the current study was
to conduct a meta-analysis of psychosocial functions in early-stage breast cancer
survivors to determine its efficacy.
METHODS: A search of Cochrane Library, EMBASE, MEDLINE, PsycInfo, and PubMed
yielded 3237 abstracts, which were independently evaluated by research pairs.
Meta-analysis was conducted on 8 studies that included a total of 1053 patients.
Psychosocial functions were categorized according to 3 domains: (1) anxiety, (2)
depression, and (3) quality of life.
RESULTS: Improvement in anxiety was observed in patients treated with CBT
relative to controls without CBT ( P = .04). Depression and quality of life
improvement was not observed in the CBT group within or after 4 months of
treatment ( P > .05).
CONCLUSIONS: The results indicated that observed improvements in anxiety in
patients with early-stage breast cancer were moderate. The effectiveness of CBT
for the improvement of patient outcomes could not be determined, given the
methodological and clinical shortcomings of the included trials.

DOI: 10.1177/1534735419829573
PMID: 30791739

J Evid Based Integr Med. 2019 Jan-Dec;24:2515690X19828325. doi:
10.1177/2515690X19828325.

Yoga-Specific Enhancement of Quality of Life Among Women With Breast Cancer:
Systematic Review and Exploratory Meta-Analysis of Randomized Controlled Trials.

El-Hashimi D(1), Gorey KM(1).

Author information:
(1)1 School of Social Work, University of Windsor, Windsor, Ontario, Canada.

Physical activities during and after cancer treatment have favorable psychosocial
effects. Increasingly, yoga has become a popular approach to improving the
quality of life (QoL) of women with breast cancer. However, the extant synthetic
evidence on yoga has not used other exercise comparison conditions. This
meta-analysis aimed to systematically assess yoga-specific effects relative to
any other physical exercise intervention (eg, aerobics) for women with breast
cancer. QoL was the primary outcome of interest. Eight randomized controlled
trials with 545 participants were included. The sample-weighted synthesis at
immediate postintervention revealed marginally statistically and modest
practically significant differences suggesting yoga’s potentially greater
effectiveness: d = 0.14, P = .10. However, at longer term follow-up, no
statistically or practically significant between-group difference was observed.
This meta-analysis preliminarily demonstrated that yoga is probably as effective
as other exercise modalities in improving the QoL of women with breast cancer.
Both interventions were associated with clinically significant improvements in
QoL. Nearly all of the yoga intervention programs, however, were very poorly
resourced. Larger and better controlled trials of well-endowed yoga programs are
needed.

DOI: 10.1177/2515690X19828325
PMID: 30791697

Pharmaceutics. 2019 Feb 20;11(2). pii: E89. doi: 10.3390/pharmaceutics11020089.

Strontium Sulfite: A New pH-Responsive Inorganic Nanocarrier to Deliver
Therapeutic siRNAs to Cancer Cells.

Karim ME(1), Shetty J(2), Islam RA(3), Kaiser A(4), Bakhtiar A(5), Chowdhury
EH(6).

Author information:
(1)Jeffrey Cheah School of Medicine and Health Sciences, Monash University
Malaysia, Jalan Lagoon Selatan, Bandar Sunway, 47500 Petaling Jaya, Malaysia.
karim604306@gmail.com.
(2)Jeffrey Cheah School of Medicine and Health Sciences, Monash University
Malaysia, Jalan Lagoon Selatan, Bandar Sunway, 47500 Petaling Jaya, Malaysia.
jayashetty21@gmail.com.
(3)Jeffrey Cheah School of Medicine and Health Sciences, Monash University
Malaysia, Jalan Lagoon Selatan, Bandar Sunway, 47500 Petaling Jaya, Malaysia.
Rowshan.Islam@monash.edu.
(4)Jeffrey Cheah School of Medicine and Health Sciences, Monash University
Malaysia, Jalan Lagoon Selatan, Bandar Sunway, 47500 Petaling Jaya, Malaysia.
ahsanul.kaiser@monash.edu.
(5)Faculty of Pharmacy, Mahsa University, 2, Jalan SP 4/4, Bandar Saujana Putra,
42610 Jenjarom, Malaysia. athirahbakhtiar@gmail.com.
(6)Jeffrey Cheah School of Medicine and Health Sciences, Monash University
Malaysia, Jalan Lagoon Selatan, Bandar Sunway, 47500 Petaling Jaya, Malaysia.
md.ezharul.hoque@monash.edu.

Inorganic nanoparticles hold great potential in the area of precision medicine,
particularly for treating cancer owing to their unique physicochemical
properties, biocompatibility and improved pharmacokinetics properties compared to
their organic counterparts. Here we introduce strontium sulfite nanoparticles as
new pH-responsive inorganic nanocarriers for efficient transport of siRNAs into
breast cancer cells. We employed the simplest nanoprecipitation method to
generate the strontium sulfite nanoparticles (SSNs) and demonstrated the dramatic
roles of NaCl and d-glucose in particle growth stabilization in order to produce
even smaller nanosize particles (Na-Glc-SSN) with high affinity towards
negatively charged siRNA, enabling it to efficiently enter the cancer cells.
Moreover, the nanoparticles were found to be degraded with a small drop in pH,
suggesting their potential capability to undergo rapid dissolution at endosomal
pH so as to release the payload. While these particles were found to be nontoxic
to the cells, they showed higher potency in facilitating cancer cell death
through intracellular delivery and release of oncogene-specific siRNAs targeting
ros1 and egfr1 mRNA transcripts, than the strontium sulfite particles prepared in
absence of NaCl and d-glucose, as confirmed by growth inhibition assay. The mouse
plasma binding analysis by Q-TOF LC-MS/MS demonstrated less protein binding to
smaller particles of Na-Glc-SSNs. The biodistribution studies of the particles
after 4 h of treatment showed Na-Glc-SSNs had less off-target distribution than
SSNs, and after 24 h, all siRNAs were cleared from all major organs except the
tumors. ROS1 siRNA with its potential therapeutic role in treating 4T1-induced
breast tumor was selected for subsequent in vivo tumor regression study,
revealing that ROS1 siRNA-loaded SSNs exerted more significant anti-tumor effects
than Na-Glc-SSNs carrying the same siRNA following intravenous administration,
without any systemic toxicity. Thus, strontium sulfite emerged as a powerful
siRNA delivery tool with potential applications in cancer gene therapy.

DOI: 10.3390/pharmaceutics11020089
PMID: 30791612

Int J Mol Sci. 2019 Feb 20;20(4). pii: E919. doi: 10.3390/ijms20040919.

Systematical Identification of Breast Cancer-Related Circular RNA Modules for
Deciphering circRNA Functions Based on the Non-Negative Matrix Factorization
Algorithm.

Wang S(1), Xia P(2), Zhang L(2), Yu L(3), Liu H(4), Meng Q(5), Liu S(6), Li J(7),
Song Q(8), Wu J(9), Wang W(10), Yang L(11), Xiao Y(12)(13), Xu C(14).

Author information:
(1)College of Bioinformatics Science and Technology, Harbin Medical University,
Harbin 150081, China. bioccwsy@gmail.com.
(2)College of Bioinformatics Science and Technology, Harbin Medical University,
Harbin 150081, China. xiapeng231515@outlook.com.
(3)College of Bioinformatics Science and Technology, Harbin Medical University,
Harbin 150081, China. biomathnmghebyulei@outlook.com.
(4)College of Bioinformatics Science and Technology, Harbin Medical University,
Harbin 150081, China. liuhui870320@gmail.com.
(5)College of Bioinformatics Science and Technology, Harbin Medical University,
Harbin 150081, China. mqq1992hmu@outlook.com.
(6)College of Bioinformatics Science and Technology, Harbin Medical University,
Harbin 150081, China. liusiyao29@outlook.com.
(7)College of Bioinformatics Science and Technology, Harbin Medical University,
Harbin 150081, China. jacklee2THU@outlook.com.
(8)College of Bioinformatics Science and Technology, Harbin Medical University,
Harbin 150081, China. songqian@hrbmu.edu.cn.
(9)College of Bioinformatics Science and Technology, Harbin Medical University,
Harbin 150081, China. wujie_bio@outlook.com.
(10)College of Bioinformatics Science and Technology, Harbin Medical University,
Harbin 150081, China. zjhzwang@outlook.com.
(11)College of Bioinformatics Science and Technology, Harbin Medical University,
Harbin 150081, China. leiyang@hrbmu.edu.cn.
(12)College of Bioinformatics Science and Technology, Harbin Medical University,
Harbin 150081, China. xiaoyun@ems.hrbmu.edu.cn.
(13)Key Laboratory of Cardiovascular Medicine Research, Ministry of Education,
College of Pharmacy, Harbin Medical University, Harbin 150081, China.
xiaoyun@ems.hrbmu.edu.cn.
(14)College of Bioinformatics Science and Technology, Harbin Medical University,
Harbin 150081, China. chaohanxu@hrbmu.edu.cn.

Circular RNA (circRNA), a kind of special endogenous RNA, has been shown to be
implicated in crucial biological processes of multiple cancers as a gene
regulator. However, the functional roles of circRNAs in breast cancer (BC) remain
to be poorly explored, and relatively incomplete knowledge of circRNAs handles
the identification and prediction of BC-related circRNAs. Towards this end, we
developed a systematic approach to identify circRNA modules in the BC context
through integrating circRNA, mRNA, miRNA, and pathway data based on a
non-negative matrix factorization (NMF) algorithm. Thirteen circRNA modules were
uncovered by our approach, containing 4164 nodes (80 circRNAs, 2703 genes, 63
miRNAs and 1318 pathways) and 67,959 edges in total. GO (Gene Ontology) function
screening identified nine circRNA functional modules with 44 circRNAs. Within
them, 31 circRNAs in eight modules having direct relationships with known
BC-related genes, miRNAs or disease-related pathways were selected as BC
candidate circRNAs. Functional enrichment results showed that they were closely
related with BC-associated pathways, such as ‘KEGG (Kyoto Encyclopedia of Genes
and Genomes) PATHWAYS IN CANCER’, ‘REACTOME IMMUNE SYSTEM’ and ‘KEGG MAPK
SIGNALING PATHWAY’, ‘KEGG P53 SIGNALING PATHWAY’ or ‘KEGG WNT SIGNALING PATHWAY’,
and could sever as potential circRNA biomarkers in BC. Comparison results showed
that our approach could identify more BC-related functional circRNA modules in
performance. In summary, we proposed a novel systematic approach dependent on the
known disease information of mRNA, miRNA and pathway to identify BC-related
circRNA modules, which could help identify BC-related circRNAs and benefits
treatment and prognosis for BC patients.

DOI: 10.3390/ijms20040919
PMID: 30791568

Cells. 2019 Feb 19;8(2). pii: E181. doi: 10.3390/cells8020181.

Wound Healing Fluid Reflects the Inflammatory Nature and Aggressiveness of Breast
Tumors.

Agresti R(1), Triulzi T(2), Sasso M(3), Ghirelli C(4), Aiello P(5), Rybinska
I(6), Campiglio M(7), Sfondrini L(8), Tagliabue E(9), Bianchi F(10).

Author information:
(1)Division of Surgical Oncology, Breast Unit, Fondazione IRCCS Istituto
Nazionale dei Tumori di Milano, 20133 Milan, Italy.
Roberto.agresti@istitutotumori.mi.it.
(2)Molecular Targeting Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di
Milano, 20133 Milan, Italy. Tiziana.triulzi@istitutotumori.mi.it.
(3)Molecular Targeting Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di
Milano, 20133 Milan, Italy. Marianna.sasso@gmail.com.
(4)Molecular Targeting Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di
Milano, 20133 Milan, Italy. ghirelli.cristina@istitutotumori.mi.it.
(5)Molecular Targeting Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di
Milano, 20133 Milan, Italy. piera.chef@gmail.com.
(6)Molecular Targeting Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di
Milano, 20133 Milan, Italy. ilona.rybinska@istitutotumori.mi.it.
(7)Molecular Targeting Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di
Milano, 20133 Milan, Italy. manuela.campiglio@me.com.
(8)Dipartimento di Scienze Biomediche per la Salute, Università degli Studi di
Milano, 20133 Milan, Italy. Lucia.sfondrini@unimi.it.
(9)Molecular Targeting Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di
Milano, 20133 Milan, Italy. elda.tagliabue@istitutotumori.mi.it.
(10)Molecular Targeting Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di
Milano, 20133 Milan, Italy. francesca.bianchi@istitutotumori.mi.it.

Wound healing fluid that originates from breast surgery increases the
aggressiveness of cancer cells that remain after the surgery. We determined the
effects of the extent of surgery and tumor-driven remodeling of the surrounding
microenvironment on the ability of wound-healing to promote breast cancer
progression. In our analysis of a panel of 34 cytokines, chemokines, and growth
factors in wound healing fluid, obtained from 27 breast carcinoma patients after
surgery, the levels of several small molecules were associated with the extent of
cellular damage that was induced by surgery. In addition, the composition of the
resulting wound healing fluid was associated with molecular features of the
removed tumor. Specifically, IP-10, IL-6, G-CSF, osteopontin, MIP-1a, MIP-1b, and
MCP1-MCAF were higher in more aggressive tumors. Altogether, our findings
indicate that the release of factors that are induced by removal of the primary
tumor and subsequent wound healing is influenced by the extent of damage due to
surgery and the reactive stroma that is derived from the continuously evolving
network of interactions between neoplastic cells and the microenvironment, based
on the molecular characteristics of breast carcinoma cells.

DOI: 10.3390/cells8020181
PMID: 30791501

Int J Environ Res Public Health. 2019 Feb 19;16(4). pii: E598. doi:
10.3390/ijerph16040598.

Biogenic Nanoparticle‒Chitosan Conjugates with Antimicrobial, Antibiofilm, and
Anticancer Potentialities: Development and Characterization.

Bilal M(1), Zhao Y(2), Rasheed T(3), Ahmed I(4), Hassan STS(5), Nawaz MZ(6),
Iqbal HMN(7).

Author information:
(1)School of Life Science and Food Engineering, Huaiyin Institute of Technology,
Huaian 223003, China. bilaluaf@hotmail.com.
(2)School of Life Science and Food Engineering, Huaiyin Institute of Technology,
Huaian 223003, China. zhaoyuping@hyit.edu.cn.
(3)School of Chemistry and Chemical Engineering, State Key Laboratory of Metal
Matrix Composites, Shanghai Jiao Tong University, Shanghai 200240, China.
masil@sjtu.edu.cn.
(4)School of Medical Science, Menzies Health Institute Queensland, Griffith
University (Gold Coast campus), Parklands Drive, Southport, QLD 4222, Australia.
i.ahmed@griffith.edu.au.
(5)Department of Natural Drugs, Faculty of Pharmacy, University of Veterinary and
Pharmaceutical Sciences Brno, Palackého tř. 1946/1, 612 42 Brno, Czech Republic.
sherif.hassan@seznam.cz.
(6)Department of Computer Science, Center for Advanced Studies in Agriculture and
Food Security, University of Agriculture, Faisalabad 38040, Pakistan.
zohaib_binm@yahoo.com.
(7)Tecnologico de Monterrey, School of Engineering and Sciences, Campus
Monterrey, Ave. Eugenio Garza Sada 2501, Monterrey, N.L. CP 64849, Mexico.
hafiz.iqbal@itesm.mx.

In the 21st century, with ever-increasing consciousness and social awareness,
researchers must tackle the microbial infections that pose a major threat to
human safety. For many reasons, the emergence/re-emergence of threatening
pathogens has increased and poses a serious challenge to health care services.
Considering the changing dynamics of 21st-century materials with medical
potentialities, the integration of bioactive agents into materials to engineer
antibacterial matrices has received limited attention so far. Thus, antimicrobial
active conjugates are considered potential candidates to eradicate infections and
reduce microbial contaminations in healthcare facilities. In this context,
eco-friendly and novel conjugates with antimicrobial, antibiofilm, and anticancer
potentialities were developed using biogenic silver nanoparticles (AgNPs) from
Convolvulus arvensis (C. arvensis) extract and chitosan (CHI). A range of
instrumental and imaging tools, i.e., UV-Vis and FTIR spectroscopy, scanning
electron microscopy (SEM), transmission electron microscopy (TEM),
energy-dispersive spectroscopy (EDX), and X-ray diffraction (XRD), were employed
to characterize the freshly extracted C. arvensis AgNPs. Biogenic AgNPs obtained
after a 24-h reaction period were used to engineer CHI-based conjugates and
designated as CHI‒AgNPs1 to CHI‒AgNPs5, subject to the C. arvensis AgNPs
concentration. After the stipulated loading period, 92% loading efficiency (LE)
was recorded for a CHI‒AgNPs3 conjugate. Gram+ and Gram- bacterial isolates,
i.e., Staphylococcus aureus, and Escherichia coli, were used to test the
antibacterial activities of newly developed CHI‒AgNPs conjugates. In comparison
to the control sample with bacterial cell count 1.5 × 10⁸ CFU/mL, a notable
reduction in the log values was recorded for the CHI‒AgNPs3 conjugate. The
antibiofilm potential of CHI‒AgNPs conjugates was tested against Pseudomonas
aeruginosa. Moreover, the CHI‒AgNPs3 conjugate also showed substantial
cytotoxicity against the MCF-7 (breast cancer) cell line. In summary, the newly
engineered CHI‒AgNPs conjugates with antibacterial, antibiofilm, and anticancer
potentialities are potential candidate materials for biomedical applications.

DOI: 10.3390/ijerph16040598
PMID: 30791374

Br J Surg. 2019 Feb 21. doi: 10.1002/bjs.11079. [Epub ahead of print]

Sentinel lymph node biopsy in microinvasive ductal carcinoma in situ.

Magnoni F(1), Massari G(1), Santomauro G(1), Bagnardi V(2), Pagan E(2),
Peruzzotti G(1), Galimberti V(1), Veronesi P(1), Sacchini VS(3).

Author information:
(1)European Institute of Oncology, University of Milan-Bicocca, Milan, Italy.
(2)Department of Statistics and Quantitative Methods, University of
Milan-Bicocca, Milan, Italy.
(3)Breast Service, Department of Surgery, Memorial Sloan Kettering Cancer Center,
New York, USA.

BACKGROUND: Microinvasive breast cancer is an uncommon pathological entity. Owing
to the rarity of this condition, its surgical axillary management and overall
prognosis remain controversial.
METHODS: A database was analysed to identify patients with microinvasive ductal
carcinoma in situ (DCIS) who had surgery for invasive breast cancer at the
European Institute of Oncology, Milan, between 1998 and 2010. Women who had
undergone axillary staging by sentinel lymph node biopsy were included in the
study.
RESULTS: Of 257 women with microinvasive breast cancer who underwent sentinel
lymph node biopsy (SLNB), 226 (87·9 per cent) had negative sentinel lymph nodes
(SLNs) and 31 had metastatic SLNs. Twelve patients had isolated tumour cells
(ITCs), 14 had micrometastases and five had macrometastases in sentinel nodes.
Axillary lymph node dissection was performed in 16 of the 31 patients with
positive SLNs. After a median follow-up of 11 years, only one regional first
event was observed in the 15 patients with positive SLNs who did not undergo
axillary lymph node dissection. There were no regional first events in the 16
patients with positive SLNs who had axillary dissection.
CONCLUSION: Good disease-free and overall survival were found in women with
positive SLNs and microinvasive DCIS. This study is in line with studies showing
that SLNB in microinvasive DCIS may not be useful, and supports the evidence that
less surgery can provide the same level of overall survival with better quality
of life.

DOI: 10.1002/bjs.11079
PMID: 30791092

Planta Med. 2019 Feb 21. doi: 10.1055/a-0826-0483. [Epub ahead of print]

Cytotoxic Alkaloids from Leaves of Pilea aff. martinii.

Doan Thi Thuy A(1)(2), Trinh Thi Thanh V(1), Doan Thi Mai H(1), Le HT(3),
Litaudon M(4), Nguyen VH(1), Chau VM(1), Pham VC(1).

Author information:
(1)Advanced Center for Bioorganic Chemistry, Institute of Marine Biochemistry of
the Vietnam Academy of Science and Technology (VAST), Hanoi, Vietnam.
(2)National University of Agriculture, Trau Quy, Hanoi, Vietnam.
(3)Hanoi University of Science and Technology (HUST), Hanoi, Vietnam.
(4)Institut de Chimie des Substances Naturelles, CNRS-ICSN, UPR 2301, Université
Paris-Sud, Paris, France.

Two new phenanthroquinolizidine alkaloids (1: and 2: ) and a new piperidine
derivative (3: ) were isolated from the leaves of Pilea aff. martinii together
with 3 known alkaloids: julandine (4: ), cryptopleurine (5: ), and
1,3,6,6-tetramethyl-5,6,7,8-tetrahydro-isoquinolin-8-one (6: ). Their structures
were determined by spectral data analyses including mass spectrometry and
2-dimensional nuclear magnetic resonance data. The absolute configurations of 1:
-3: were established by comparison of their experimental circular dichroism data
with the calculated electronic circular dichroism spectra. The isolated compounds
were evaluated for their cytotoxicity against 4 cancer cell lines: KB (mouth
epidermal carcinoma cells), HepG-2 (human liver hepatocellular carcinoma cells),
LU-1 (human lung adenocarcinoma cells), and MCF-7 (human breast cancer cells).
The new phenanthroquinolizidine pileamartine D (2: ) showed strong and selective
proliferation inhibition toward KB and HepG-2 cells with IC50 values of 25 and
27 nM, respectively. Pileamartine C (1: ), julandine (4: ), and cryptopleurine
(5: ) exhibited cytotoxicity against 4 tested cancer cell lines with IC50 values
less than 1 µM.

Georg Thieme Verlag KG Stuttgart · New York.

DOI: 10.1055/a-0826-0483
PMID: 30791057

Conflict of interest statement: The authors declare no competing financial
interests.

Cancer Lett. 2019 Feb 18. pii: S0304-3835(19)30110-7. doi:
10.1016/j.canlet.2019.02.032. [Epub ahead of print]

Pharmacological inhibition of the IKKε/TBK-1 axis potentiates the anti-tumour and
anti-metastatic effects of Docetaxel in mouse models of breast cancer.

Bishop RT(1), Marino S(2), de Ridder D(1), Allen RJ(1), Lefley DV(1), Sims AH(3),
Wang N(1), Ottewell PD(1), Idris AI(4).

Author information:
(1)Department of Oncology and Metabolism, Medical School, Beech Hill Road,
Sheffield, S10 2RX, UK.
(2)Department of Oncology and Metabolism, Medical School, Beech Hill Road,
Sheffield, S10 2RX, UK; Bone and Cancer Group, Edinburgh Cancer Research Centre,
University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, EH4
2XR, UK.
(3)Applied Bioinformatics of Cancer, MRC Institute of Genetics and Molecular
Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UK.
(4)Department of Oncology and Metabolism, Medical School, Beech Hill Road,
Sheffield, S10 2RX, UK; Bone and Cancer Group, Edinburgh Cancer Research Centre,
University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, EH4
2XR, UK. Electronic address: aymen.idris@sheffield.ac.uk.

IκB kinase subunit epsilon (IKKε), a key component of NFκB and interferon
signalling, has been identified as a breast cancer oncogene. Here we report that
the IKKε/TBK1 axis plays a role in the initiation and progression of breast
cancer osteolytic metastasis. Cancer-specific knockdown of IKKε in the human
MDA-MB-231-BT cells and treatment with the verified IKKε/TBK1 inhibitor Amlexanox
reduced skeletal tumour growth and osteolysis in mice. In addition, combined
administration of Amlexanox with Docetaxel reduced mammary tumour growth of
syngeneic 4T1 cells, inhibited metastases and improved survival in mice after
removal of the primary tumour. Functional and mechanistic studies in breast
cancer cells, osteoclasts and osteoblasts revealed that IKKε inhibition reduces
the ability of breast cancer cells to grow, move and enhance osteoclastogenesis
by engaging both IRF and NFκB signalling pathways. Thus, therapeutic targeting of
the IKKε/TBK1 axis may be of value in the treatment of advanced triple negative
breast cancer.

DOI: 10.1016/j.canlet.2019.02.032
PMID: 30790681

J Control Release. 2019 Feb 18. pii: S0168-3659(19)30092-6. doi:
10.1016/j.jconrel.2019.02.017. [Epub ahead of print]

Poly(ethylene glycol)-block-poly(d,l-lactic acid) micelles containing
oligo(lactic acid)8-paclitaxel prodrug: In Vivo conversion and antitumor
efficacy.

Tam YT(1), Shin DH(1), Chen KE(1), Kwon GS(2).

Author information:
(1)Pharmaceutical Sciences Division, School of Pharmacy, University of
Wisconsin-Madison, 777 Highland Avenue, Madison, WI 53705-2222, USA.
(2)Pharmaceutical Sciences Division, School of Pharmacy, University of
Wisconsin-Madison, 777 Highland Avenue, Madison, WI 53705-2222, USA. Electronic
address: glen.kwon@wisc.edu.

Poly(ethylene glycol)-block-poly(d,l-lactic acid) (PEG-b-PLA) micelles affect
drug solubilization, and a paclitaxel (PTX) loaded-PEG-b-PLA micelle (PTX-PM) is
approved for cancer treatment due to injection safety and dose escalation
(Genexol-PM®) compares to Taxol®. However, PTX-PM is unstable in blood, has rapid
clearance, and causes dose-limiting toxicity. We have synthesized a prodrug for
PTX (7-OH), using oligo(lactic acid) as a novel pro-moiety (o(LA)8-PTX)
specifically for PEG-b-PLA micelles, gaining higher loading and slower release of
o(LA)8-PTX over PTX. Notably, o(LA)8-PTX prodrug converts into PTX by a
backbiting reaction in vitro, without requiring esterases. We hypothesize that
o(LA)8-PTX-loaded PEG-b-PLA micelles (o(LA)8-PTX-PM) has a lower Cmax and higher
plasma AUC than PTX-PM for improved therapeutic effectiveness. In Sprague-Dawley
rats at 10 mg/kg, compared to o(LA)8-PTX-PM (10% w/w loading) and PTX-PM (10%),
o(LA)8-PTX-PM (50% w/w loading) produced a 2- and 3-fold higher plasma AUC0-24 of
PTX, lactic acid-PTX, and o(LA)2-PTX (o(LA)0-2-PTX), respectively. For
o(LA)8-PTX-PM at 10 and 50% w/w loading, PTX and lactic acid-PTX are major
bioactive metabolites, respectively. Fast prodrug conversion of o(LA)8-PTX in
vivo versus in vitro (by backbiting) suggests that o(LA)8 is a good substrate for
esterases. At 60 mg/kg (qwx3), o(LA)8-PTX-PM (50%) has higher antitumor activity
than o(LA)8-PTX-PM (10%) and PTX-PM (10%) in a syngeneic 4T1-luc breast tumor
model based on measurements of tumor volume, 4T1-luc breast tumor
bioluminescence, and survival. Importantly, intravenous administration of
o(LA)8-PTX-PM was well tolerated by BALB/c mice. In summary, oligo(lactic
acid)8-PTX is more compatible than PTX with PEG-b-PLA micelles, more stable, and
may expand the role of PEG-b-PLA micelles from «solubilizer» into «nanocarrier»
for PTX as a next-generation taxane for cancer.

DOI: 10.1016/j.jconrel.2019.02.017
PMID: 30790593

Breast J. 2019 Feb 21. doi: 10.1111/tbj.13208. [Epub ahead of print]

Post-mastectomy radiation in node-positive breast cancer in Ontario.

Latosinsky S(1)(2), Jenkyn KMB(2), Li L(2), Shariff SZ(2)(3).

Author information:
(1)Department of Surgery, Schulich School of Medicine and Dentistry, Western
University, London, Ontario, Canada.
(2)Institute of Clinical Evaluative Sciences, Western Site (ICES Western),
London, Ontario, Canada.
(3)Arthur Labatt School of Nursing, University of Western Ontario, London,
Ontario, Canada.

More recent guidelines are more supportive for post-mastectomy radiation in all
node-positive breast cancer patients. We examined the rate and predictors of
post-mastectomy radiation receipt in Ontario Canada from 2010 to 2014. Of 6535
node-positive post-mastectomy patients, 73.9% received radiation. The rate was
68.7% (2903/4227) among women with 1-3 positive nodes. Radiation was less likely
to be administered to women who were older, had high levels of comorbidity, or
presented with early stages of breast cancer. Regional practice variation was
reassuringly modest.

DOI: 10.1111/tbj.13208
PMID: 30790386

Breast J. 2019 Feb 21. doi: 10.1111/tbj.13203. [Epub ahead of print]

Internet use and preferences among women living with advanced breast cancer.

Kemp E(1), Koczwara B(1)(2), Turner J(3), Girgis A(4)(5), Schofield P(6),
Hulbert-Williams N(7), Levesque J(4), Spence D(8), Vatandoust S(1)(2),
Kichenadasse G(1)(2), Roy A(1)(2), Sukumaran S(1)(2), Karapetis CS(1)(2),
Richards C(2), Fitzgerald M(2), Beatty L(1)(2).

Author information:
(1)College of Medicine and Public Health, Flinders University, Adelaide,
Australia.
(2)Flinders Centre for Innovation in Cancer, Flinders Medical Centre, Bedford
Park, Australia.
(3)School of Medicine, University of Queensland, Herston, Australia.
(4)South Western Sydney Clinical School, University of New South Wales, Sydney,
Australia.
(5)Ingham Institute for Applied Medical Research, Liverpool, Australia.
(6)Department of Psychology, Swinburne University, Melbourne, Australia.
(7)Department of Psychology, University of Chester, Chester, UK.
(8)Breast Cancer Network Australia, Camberwell, Australia.

Despite high distress and unmet informational and psychosocial needs, and
recommendations for development of advanced breast cancer (ABC)-specific
resources, there remains a paucity of appropriate, accessible psychological
interventions. This survey study examined internet use and preferences of women
with ABC, to gauge feasibility of providing an ABC-specific internet
intervention. Most participants (83%) used the internet daily. Results indicated
most women with ABC would find an ABC-specific internet intervention helpful, and
that it would address gaps in current internet resources, including provision of
strategies to manage treatment side-effects and fear of cancer progression.

DOI: 10.1111/tbj.13203
PMID: 30790383

Eur J Cancer Care (Engl). 2019 Feb 20:e13011. doi: 10.1111/ecc.13011. [Epub ahead
of print]

Lived experiences and support needs of women who developed chemotherapy-induced
peripheral neuropathy following treatment for breast and ovarian cancer.

Tanay MA(1), Armes J(2).

Author information:
(1)Florence Nightingale Faculty of Nursing, Midwifery and Palliative Care, King’s
College London, London, UK.
(2)School of Health Sciences, University of Surrey, Guildford, UK.

OBJECTIVES: This study explored lived experiences of women who developed
chemotherapy-induced peripheral neuropathy (CIPN) following treatment for breast
and ovarian cancer. It also explored cancer survivors’ perceptions of information
and advice offered by clinicians about CIPN and for managing CIPN.
METHODS: The study was advertised through cancer charity websites and social
media accounts. Purposeful, convenience sampling was carried out using set
eligibility criteria. Individuals with diagnosis of breast or ovarian cancer who
experienced or are still experiencing CIPN were recruited. Fifteen
semi-structured interviews were conducted. Data were analysed using
interpretative phenomenological analysis (IPA).
RESULTS: Similar to previous studies, participants used comparisons to describe
their symptoms. Four main themes emerged from the analysis: (a) struggle to
process CIPN information, (b) information and trust are key in the treatment
decision-making process, (c) experience of symptom reporting and (d) challenges
of managing symptoms. Findings suggest interventions to improve understanding of
CIPN risk are needed in practice.
CONCLUSION: A better and broader understanding of the patient experience of CIPN
could pave the way for improved communication, assessment and management of
symptoms. Results suggest the need for interventions to guide cancer survivors to
recognise and report CIPN symptoms early and address the impact of CIPN symptoms
in their lives.

DOI: 10.1111/ecc.13011
PMID: 30790382

J Cell Biochem. 2019 Feb 20. doi: 10.1002/jcb.28430. [Epub ahead of print]

Silencing of HAS2-AS1 mediates PI3K/AKT signaling pathway to inhibit cell
proliferation, migration, and invasion in glioma.

Zhao Z(1), Liang T(2), Feng S(3).

Author information:
(1)Department of Neurosurgery, Tianjin Baodi Hospital, Baodi Clinical College of
Tianjin Medical University, Tianjin, China.
(2)Department of Radiotherpy, The First Affiliated Hospital of Zhengzhou
University, Zhengzhou, Henan, China.
(3)Department of Neurosurgery, The First Hospital Attached to Baotou Medical
College of Inner Mongolia University of Science & Technology, Baotou, Inner
Mongolia, China.

Hyaluronan synthase 2 (HAS2)-AS1 (natural antisense transcript of HAS2) functions
as oncogenic long noncoding RNA (lncRNA) in oral squamous cell carcinoma, breast
cancer, and osteosarcoma. The role of HAS2-AS1 in glioma remains unknown. In our
research, HAS2-AS1 expression was elevated in glioma tissues compared with normal
brain tissues. Moreover, high levels of HAS2-AS1 expression was observed in
patients with glioma with high WHO grade (III-IV) or large tumor size ( > 4 cm).
The survival analysis from The Cancer Genome Atlas showed glioma cases with high
HAS2-AS1 expression that had shorter disease-free survival time and overall
survival time than those with low HAS2-AS1 expression. In vitro studies suggested
that knocking down HAS2-AS1 expression inhibited glioma cell viability,
migration, and invasion through phosphoinositide 3-kinase/protein kinase B
signaling pathway. In conclusion, HAS2-AS1 may be considered as a predictor for
clinical outcome and a potential therapeutic target in glioma.

DOI: 10.1002/jcb.28430
PMID: 30790335

Hastings Cent Rep. 2019 Jan;49(1):4-5. doi: 10.1002/hast.969.

Requests for PAD and the Assessment of Capacity.

Strouse TB.

I was asked to evaluate M by her medical oncologist, Dr. T. As a psychiatrist, I
was to perform the duties of a mental health specialist in the care of this
fifty-eight-year-old woman with metastatic breast cancer who had requested
physician aid in dying. Dr. T had no specific concerns, but she was adhering to
the letter of the law by referring the patient to me-a «mental health
specialist»-because, according to the patient’s medical history, there was
evidence of a mental disorder. That evidence was comprised of depression
treated in the remote past. Some years before California passed its End of Life
Options Act in 2015, M had begun talking with Dr. T about the circumstances under
which she might no longer want to be alive and might even choose to take active
steps to end her life. She had fairly specific and durable criteria for knowing
when the time had come. In our interview, she asserted very clearly that the
time had not come but that, with the law now active, she hoped to have access to
a lethal prescription in case it did.

DOI: 10.1002/hast.969
PMID: 30790304

Qual Life Res. 2019 Feb 21. doi: 10.1007/s11136-019-02124-w. [Epub ahead of
print]

Correction to: The impact of caregiver’s role preference on decisional conflicts
and psychiatric distresses in decision making to help caregiver’s disclosure of
terminal disease status.

Yoo SH(1), Yun YH(2), Kim KN(3), Lee JL(4), Park J(5), Choi YS(6), Lim YK(7), Kim
S(8), Jeong HS(9), Kang JH(10), Oh HS(11), Park JC(12), Kim SY(13), Song HS(14),
Lee KS(15), Heo DS(1), Hong YS(16).

Author information:
(1)Department of Internal Medicine, Seoul National University College of
Medicine, Seoul, Republic of Korea.
(2)Department of Biomedical Science, Seoul National University College of
Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 110-799, Republic of Korea.
lawyun@snu.ac.kr.
(3)Institute of Public Health and Medical Service, Seoul National University
Hospital, Seoul, Republic of Korea.
(4)Department of Hemato-Oncology, Daegu Fatima Hospital, Daegu, Republic of
Korea.
(5)Palliative Care and Hospice Center, Bobath Memorial Hospital, Bundang,
Seongnam, Republic of Korea.
(6)Department of Family Medicine, Korea University Guro Hospital, Seoul, Republic
of Korea.
(7)Department of Internal Medicine, Kwangju Christian Hospital, Kwangju, Republic
of Korea.
(8)Division of Hemato-Oncology, Department of Internal Medicine, College of
Medicine, Chungnam National University, Daejeon, Republic of Korea.
(9)Department of Hematology and Oncology, GSAM Hospital, Gunpo, Republic of
Korea.
(10)Department of Internal Medicine, Postgraduate Medical School, Gyeongsang
National University, Jinju, Republic of Korea.
(11)Department of Internal Medicine, Gangneung Asan Hospital, University of Ulsan
College of Medicine, Gangneung, Republic of Korea.
(12)Division of Hemato-Oncology, Department of Internal Medicine, Daejeon St
Mary’s Hospital, The Catholic University of Korea, Daejeon, Republic of Korea.
(13)Departments of Medical Oncology and Hematology, Kyung Hee University
Hospital, Seoul, Republic of Korea.
(14)Department of Internal Medicine, Keimyung University Dongsan Medical Center,
Daegu, Republic of Korea.
(15)Center for Breast Cancer, Research Institute and Hospital, National Cancer
Center, Goyang, Republic of Korea.
(16)Department of Internal Medicine, Seoul St Mary’s Hospital, The Catholic
University of Korea, Seoul, Republic of Korea.

Erratum for
Qual Life Res. 2018 Jun;27(6):1571-1581.

In the original publication of the article, the incorrect grant number HC13C1391
was published in the acknowledgement section. The correct grant number is
HC15C1391.

DOI: 10.1007/s11136-019-02124-w
PMID: 30790153

J Nat Med. 2019 Feb 21. doi: 10.1007/s11418-018-01279-z. [Epub ahead of print]

Two new quassinoids and other constituents from Picrasma javanica wood, and their
biological activities.

Prema(1)(2), Wong CP(1), Nugroho AE(3), Awouafack MD(1)(4), Win YY(2), Win NN(1),
Ngwe H(2), Morita H(5), Morita H(6).

Author information:
(1)Institute of Natural Medicine, University of Toyama, 2630-Sugitani, Toyama,
930-0194, Japan.
(2)Department of Chemistry, University of Yangon, Yangon, 11041, Myanmar.
(3)Faculty of Pharmaceutical Sciences, Hoshi University, Ebara 2-4-41
Shinagawa-ku, Tokyo, 142-8501, Japan.
(4)Natural Products Chemistry Research Unit, Department of Chemistry, Faculty of
Science, University of Dschang, P. O. Box 67, Dschang, Cameroon.
(5)Faculty of Pharmaceutical Sciences, Hoshi University, Ebara 2-4-41
Shinagawa-ku, Tokyo, 142-8501, Japan. moritah@hoshi.ac.jp.
(6)Institute of Natural Medicine, University of Toyama, 2630-Sugitani, Toyama,
930-0194, Japan. hmorita@inm.u-toyama.ac.jp.

Picrasma javanica Blume (Simaroubaceae) is a medium-sized tree that is
distributed widely in tropical Asia. In our previous study, we isolated
quassinoids from P. javanica bark collected in Myanmar, and reported their
antiproliferative activities. In our ongoing research for the discovery of
bioactive compounds from Myanmar medicinal plants, two new quassinoids,
(16R)-methoxyjavanicin B (1) and (16S)-methoxyjavanicin B (2), along with seven
known compounds (3-9), were isolated during the phytochemical investigation of
the CHCl3 soluble portion of the MeOH extract of P. javanica wood. The structures
of the new compounds were elucidated by analyses of their spectroscopic data (1D-
and 2D-NMR, HRESIMS, and CD). A cytotoxicity assay revealed that compound 8
showed moderate activities against all tested cancer cell lines, the human lung
(A549), breast (MCF7), and cervical (HeLa), and the normal fibroblast cell line,
with IC50 values ranging from 48.6 to 65.9 μM. Furthermore, the antibacterial
assay demonstrated that 1 and 2 had the highest activities (MIC value of 1.6 μM
each), followed by 5 and 3 (MIC values of 3.1 and 6.3 μM, respectively) against
the Gram-positive bacterium B. subtilis.

DOI: 10.1007/s11418-018-01279-z
PMID: 30790130

Ann Surg Oncol. 2019 Feb 21. doi: 10.1245/s10434-019-07247-5. [Epub ahead of
print]

Impact of the SSO-ASTRO Margin Guideline on Rates of Re-excision After Lumpectomy
for Breast Cancer: A Meta-analysis.

Havel L(1), Naik H(1), Ramirez L(1), Morrow M(2), Landercasper J(3).

Author information:
(1)Gundersen Medical Foundation, La Crosse, WI, USA.
(2)Breast Service, Department of Surgery, Memorial Sloan Kettering Cancer Center,
New York, NY, USA.
(3)Gundersen Medical Foundation, La Crosse, WI, USA.
jlanderc@gundersenhealth.org.

BACKGROUND: One in five patients undergoing initial lumpectomy for invasive
breast cancer subsequently undergoes re-excision or mastectomy. A lack of clarity
of when to re-excise based on lumpectomy margin width contributes to this high
rate of reoperation. We sought to determine the impact of the Society of Surgical
Oncology (SSO) and American Society of Radiation Oncologist (ASTRO) margin
guideline on reoperation rates after lumpectomy. The guideline recommended
omission of routine re-excision in specimens with «no ink on tumor».
METHODS: A systematic literature review was performed. For eligible studies, a
random-effects model was used for a meta-analysis of lumpectomy re-excision
prevalence before and after publication of the SSO-ASTRO margin guideline. Study
heterogeneity was measured by the Cochran’s Q test.
RESULTS: Five institutional, one population-based, and one national registry
study met inclusion requirements. Sample size per study ranged from 237 to
26,102. There was significant interstudy heterogeneity (Q = 19.779; p = 0.003).
Pooled re-excision prevalence was 22% (confidence interval [CI] 20-23) before and
14% (CI 12-15) after guideline publication. With the pre-guideline re-excision
prevalence used as the reference value, the associated odds ratio for re-excision
after the guideline was 0.65 (CI 0.54-0.78; p < 0.0001).
CONCLUSIONS: The findings of a 35% reduction in the odds of re-excision after the
guideline publication and a reduction in re-excision prevalence from 22 to 14%
supports the notion that the SSO-ASTRO margin guideline was impactful. These
findings are congruent with the projected reductions in re-excision at the time
of guideline publication.

DOI: 10.1245/s10434-019-07247-5
PMID: 30790112

Eur J Health Econ. 2019 Feb 21. doi: 10.1007/s10198-019-01038-1. [Epub ahead of
print]

Economic modeling of risk-adapted screen-and-treat strategies in women at high
risk for breast or ovarian cancer.

Müller D(1), Danner M(2), Schmutzler R(3), Engel C(4), Wassermann K(3),
Stollenwerk B(5), Stock S(2), Rhiem K(3).

Author information:
(1)Institute for Health Economics and Clinical Epidemiology, The University
Hospital of Cologne (AöR), Gleueler Straße 176-178, 50935, Cologne, Germany.
dirk.mueller@uk-koeln.de.
(2)Institute for Health Economics and Clinical Epidemiology, The University
Hospital of Cologne (AöR), Gleueler Straße 176-178, 50935, Cologne, Germany.
(3)Center for Hereditary Breast and Ovarian Cancer, University Hospital Cologne,
Kerpener Straße 34, 50931, Cologne, Germany.
(4)Institute for Medical Informatics, Statistics and Epidemiology, University of
Leipzig, Härtelstraße 16-18, 04107, Leipzig, Germany.
(5)Institute of Health Economics and Health Care Management, Helmholtz Zentrum
München, German Research Center for Environmental Health, Ingolstädter Landstraße
1, 85764, Neuherberg, Germany.

BACKGROUND: The ‘German Consortium for Hereditary Breast and Ovarian Cancer’
(GC-HBOC) offers women with a family history of breast and ovarian cancer genetic
counseling. The aim of this modeling study was to evaluate the cost-effectiveness
of genetic testing for BRCA 1/2 in women with a high familial risk followed by
different preventive interventions (intensified surveillance, risk-reducing
bilateral mastectomy, risk-reducing bilateral salpingo-oophorectomy, or both
mastectomy and salpingo-oophorectomy) compared to no genetic test.
METHODS: A Markov model with a lifelong time horizon was developed for a cohort
of 35-year-old women with a BRCA 1/2 mutation probability of ≥ 10%. The
perspective of the German statutory health insurance (SHI) was adopted. The model
included the health states ‘well’ (women with increased risk), ‘breast cancer
without metastases’, ‘breast cancer with metastases’, ‘ovarian cancer’, ‘death’,
and two post (non-metastatic) breast or ovarian cancer states. Outcomes were
costs, quality of life years gained (QALYs) and life years gained (LYG).
Important data used for the model were obtained from 4380 women enrolled in the
GC-HBOC.
RESULTS: Compared with the no test strategy, genetic testing with subsequent
surgical and non-surgical treatment options provided to women with deleterious
BRCA 1 or 2 mutations resulted in additional costs of €7256 and additional QALYs
of 0,43 (incremental cost-effectiveness ratio of €17,027 per QALY; cost per LYG:
€22,318). The results were robust in deterministic and probabilistic sensitivity
analyses.
CONCLUSION: The provision of genetic testing to high-risk women with a BRCA1 and
two mutation probability of ≥ 10% based on the individual family cancer history
appears to be a cost-effective option for the SHI.

DOI: 10.1007/s10198-019-01038-1
PMID: 30790097

Hum Genet. 2019 Feb 21. doi: 10.1007/s00439-019-01981-2. [Epub ahead of print]

Author response to «a response to ‘personalised medicine and population health:
breast and ovarian cancer'».

Narod SA(1)(2).

Author information:
(1)Women’s College Research Institute, Women’s College Hospital, 76 Grenville
Street, M5S 1B2, Toronto, Ontario, Canada. steven.narod@wchospital.ca.
(2)Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario,
Canada. steven.narod@wchospital.ca.

The author engages in further debate between numerous signatories of a letter who
disputes that the author has put forward that the anticipated benefits of a
personalised program for cancer prevention and screening are unwarranted. In the
event that a cancer screening program is an effective means of mortality
reduction, then the best strategy is universality. The benefit of a novel
intervention should be evaluated prior to its introduction.

DOI: 10.1007/s00439-019-01981-2
PMID: 30790050

Support Care Cancer. 2019 Feb 21. doi: 10.1007/s00520-019-04698-0. [Epub ahead of
print]

PROMs following breast-conserving therapy for breast cancer: results from a
prospective longitudinal monocentric study.

Kindts I(1)(2), Laenen A(3), van den Akker M(4)(5), Weltens C(6)(7).

Author information:
(1)Department of Oncology, Experimental Radiation Oncology, KU Leuven-University
of Leuven, B-3000, Leuven, Belgium. Isabelle.kindts@uzleuven.be.
(2)Department of Radiation Oncology, University Hospitals Leuven, Herestraat 49,
B-3000, Leuven, Belgium. Isabelle.kindts@uzleuven.be.
(3)Leuven Biostatistics and Statistical Bioinformatics Centre (L-Biostat), KU
Leuven University, Kapucijnenvoer 35, B-3000, Leuven, Belgium.
(4)Department of Family Medicine, School CAPRI, Maastricht University,
Maastricht, The Netherlands.
(5)Academic Center for General Practice, Department of Public Health and Primary
Care, KU Leuven, Leuven, Belgium.
(6)Department of Oncology, Experimental Radiation Oncology, KU Leuven-University
of Leuven, B-3000, Leuven, Belgium.
(7)Department of Radiation Oncology, University Hospitals Leuven, Herestraat 49,
B-3000, Leuven, Belgium.

BACKGROUND: Treatment of breast cancer includes many options and shared decision
making is becoming standard practice. Within the context of treatment
individualization, the omission of radiotherapy (RT) can be considered. It is
thereby of great importance to correctly foresee the side effects attributed to
RT. Data from longitudinal studies with contemporary techniques however are
sparse. The purpose of the present study was to evaluate patient-reported outcome
measures (PROMs) and long-term aesthetic outcome (AO) related to RT in the
breast-conserving therapy (BCT) setting for breast cancer over time.
METHODS: Patients treated with BCT between April 2015 and April 2016 were
prospectively included in the cohort. Evaluations were made at six time points:
at baseline (before RT), during and at the end of RT, between 3 and 6 months,
1 year and 2 years after RT. AO was scored by the patient and by the BCCT.core
software. Further PROMs were measured with the European Organisation for Research
and Treatment of Cancer (EORTC) Quality of Life Questionnaire QLQ-C30/-BR23 and
the Body Image after Breast Cancer Questionnaire BIBCQ. Patients were evaluated
over 2 years. First, we assessed the evolution in time. Second, we tested the
differences in mean scale scores of the PROMs between patients with a favourable
and an unfavourable AO.
RESULTS: One hundred seventy-five patients were included in the analysis. At
baseline, unsatisfactory levels were already present for several scales. Most
unsatisfactory PROMs improved up to 1 year after RT. Complaints of fatigue
increased at the start but decreased up to a lower level than that at baseline up
to 1 year after RT (mean difference (MD) 7.6, - 12.3, respectively). Cognitive
functioning showed a small decrease at the start with no further significant
decrease (MD - 4.73, - 0.21, respectively). Breast symptoms significantly
increased during RT but decreased afterwards up to 2 years after RT to lower
values than those at baseline and were then considered satisfactory (MD 15.6,
- 19.7, - 4.1, respectively). AO scored as PROM associated with BCCT.core and
with the body image measures.
CONCLUSIONS: The study suggests that quality of life and body image are
temporarily impaired due to RT. Around one third of patients score their
long-term AO as unfavourable. These results should be discussed with the patient
and could help in the decision making of the treatment plan and in the
clarification of the patient’s expectations.

DOI: 10.1007/s00520-019-04698-0
PMID: 30790047

N Z Med J. 2019 Feb 22;132(1490):26-35.

Patterns of referral and uptake of BReast CAncer (BRCA) gene testing of eligible
women with ovarian cancer in New Zealand.

Fraser K(1), Tan AL(2), Innes C(3), Stephens R(4), Tristram A(5), Petrich S(6),
Lintott C(7), Sykes PH(8), Gamet K(9), Christian A(10), Simcock B(8).

Author information:
(1)Medical Student, University of Otago, Christchurch.
(2)Gynaecological Oncologist, National Women’s Health, Auckland District Health
Board, Auckland.
(3)Research Fellow, University of Otago, Christchurch.
(4)Medical Oncologist, Auckland District Health Board, Auckland.
(5)Gynaecological Oncologist, Obstetrics and Gynaecology, Wellington Hospital,
Wellington.
(6)Gynaecological Oncologist, Dunedin Hospital, Dunedin.
(7)Senior Genetic Associate/Team Leader, Genetic Health Service NZ, Southern Hub,
Christchurch.
(8)Senior Lecturer, Department of Obstetrics & Gynaecology, University of Otago,
Christchurch & Gynaecological Oncologist, Christchurch Women’s Hospital,
Christchurch.
(9)Team Leader/Senior Genetic Counsellor, Genetic Health Service NZ, Northern
Hub, Auckland.
(10)Senior Genetic Counsellor/Team Leader, Genetic Health Service NZ, Central
Hub, Wellington.

AIMS: To determine the proportion of eligible patients with high-grade serous
carcinoma of the ovary, fallopian tube or peritoneum discussed at gynaecological
oncology multidisciplinary meetings (MDMs) in New Zealand and subsequently
referred for genetic counselling and BRCA pathogenic variant testing.
METHODS: Eligible cases were identified from Auckland, Wellington, Christchurch
and Dunedin gynaecologic oncology MDM databases between 1 January 2015 to 31
December 2016. Patients who met the eligibility criteria for genetics referral
were identified, and cross-referenced against genetic services databases to
ascertain the rates of referrals received, the numbers attending appointments,
genetic testing offered and range of results.
RESULTS: During the two-year period, 205 patients were eligible for referral. Of
these, 143 (70%) patients were referred for genetic counselling with 128 (90%) of
this group recommended for BRCA pathogenic variant testing. Of the 126 who
undertook the test, results were available for 120 (95%). Nineteen patients (16%)
tested positive for a germline BRCA pathogenic variant.
CONCLUSIONS: The New Zealand rate of referral to genetic counselling for women
with high-grade serous cancer, (HGSC), of the ovary, fallopian tube or peritoneum
diagnosed between 2015-2016 is encouraging when compared with others
internationally. The rate of BRCA positive pathogenic variants is comparable to
international data.

PMID: 30789886

Conflict of interest statement: Nil.

Curr Opin Oncol. 2019 Feb 14. doi: 10.1097/CCO.0000000000000516. [Epub ahead of
print]

Integrating poly(ADP-ribose) polymerase (PARP) inhibitors in the treatment of
early breast cancer.

Garber HR(1), Litton JK(2).

Author information:
(1)Division of Cancer Medicine – Hematology/Oncology Fellowship Program.
(2)Division of Cancer Medicine, Department of Breast Medical Oncology, Clinical
Cancer Genetics, The University of Texas MD Anderson Cancer Center, Houston, USA.

PURPOSE OF REVIEW: Poly(ADP-ribose) polymerase (PARP) inhibitors were recently
approved for the treatment of patients with BRCA1 or BRCA2 germline pathogenic
variants and metastatic breast cancer. PARP inhibitors have also demonstrated
activity in early stage breast cancer, and this review discusses completed and
ongoing trials of PARP inhibitors in the neoadjuvant and adjuvant setting.
RECENT FINDINGS: A recent phase II trial of neoadjuvant talazoparib monotherapy
in patients with BRCA1 or BRCA2 germline pathogenic variants and early stage
breast cancer demonstrated a pathological complete response in 10/19 (53%)
patients. Previous trials of PARP inhibition in early stage breast cancer
included the I-SPY-2 and BrighTNess trials, which ultimately failed to show a
benefit for adding the PARP inhibitor veliparib to standard neoadjuvant
chemotherapy in patients with triple-negative breast cancer. Investigators are
building on these results by designing novel clinical trials for patients with
BRCA1/2-deficient tumors and/or triple-negative breast cancer.
SUMMARY: The OlympiAD and EMBRACA trials that led to the recent approval of PARP
inhibitors for metastatic breast cancer patients with BRCA1/2 germline pathogenic
variants are practice changing. Investigators are now working to translate this
success into the early breast cancer setting where ongoing trials incorporate new
dosing schedules, PARP inhibitor monotherapy, and novel PARP combinations.

DOI: 10.1097/CCO.0000000000000516
PMID: 30789866

Bioconjug Chem. 2019 Feb 21. doi: 10.1021/acs.bioconjchem.9b00027. [Epub ahead of
print]

Dendron-polymer Conjugate based Crosslinked Micelles: A Robust and Versatile
Nanosystem for Targeted Delivery.

Calik F, Degirmenci A, Eceoglu M, Sanyal A, Sanyal R.

Among various nanomedicine platforms, biodegradable polymeric micelles offer a
viable approach to targeted cancer therapy. Herein, we report fabrication of
core-crosslinked micelles using dendron-polymer conjugates as building blocks.
Hydrophobic polyester dendrons containing peripheral alkene groups are conjugated
to a hydrophilic poly(ethylene glycol) based copolymer bearing activated ester
groups for appending an amine-containing peptide based targeting group, namely,
cRGDfK. Micellar constructs assembled in aqueous media were crosslinked using a
tetra-thiol molecule via the photochemical thiol-ene reaction. Crosslinked and
non-crosslinked micelles were compared in terms of their critical micellar
concentration, stability, drug loading and drug release characteristics. It was
observed that the crosslinked micelles were stable upon excessive dilution
compared to their non-crosslinked counterparts. Importantly, the amount of
passive drug release in neutral pH was considerably lower for the crosslinked
micellar systems. Furthermore, treatment of MDA-MB-231 breast cancer cells with
non-targeted and targeted crosslinked micelles demonstrated higher
internalization of the targeted construct. In corroboration, in vitro assay
revealed that drug loaded targeted micelles possessed higher cytotoxicity than
the non-targeted ones. Facile fabrication of this modular platform which can
carry desired therapeutic agent and be conjugated with appropriate targeting
units, along with the attributes necessary to serve as a viable drug delivery
system, offers a platform with potential for addressing various challenges in the
field of micellar drug delivery.

DOI: 10.1021/acs.bioconjchem.9b00027
PMID: 30789707

N Engl J Med. 2019 Feb 21;380(8):796. doi: 10.1056/NEJMc1816595.

Palbociclib and Fulvestrant in Breast Cancer.

McCaw ZR, Vassy JL, Wei LJ.

Comment in
N Engl J Med. 2019 Feb 21;380(8):797.

Comment on
N Engl J Med. 2018 Nov 15;379(20):1926-1936.

PMID: 30789681 [Indexed for MEDLINE]

J Natl Cancer Inst. 2019 Feb 21. pii: djz023. doi: 10.1093/jnci/djz023. [Epub
ahead of print]

Genomic, transcriptomic, epigenetic, and immune profiling of mucinous breast
cancer.

Nguyen B(1)(2), Veys I(3), Leduc S(1)(4), Bareche Y(1), Majjaj S(1), Brown DN(5),
Boeckx B(6)(7), Sotiriou C(1), Larsimont D(8), Desmedt C(1)(4).

Author information:
(1)Breast Cancer Translational Research Laboratory, Université Libre de
Bruxelles, Institut Jules Bordet, U-CRC, Brussels, Belgium.
(2)Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan
Kettering Cancer Center, New York, NY, USA.
(3)Department of Surgery, Institut Jules Bordet, Brussels, Belgium.
(4)Laboratory for Translational Breast Cancer Research, Katholieke Universiteit
Leuven, Leuven, Belgium.
(5)Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY
10065 USA.
(6)Laboratory of Translational Genetics, VIB Center for Cancer Biology, Campus
Gasthuisberg, Leuven, Belgium.
(7)Laboratory of Translational Genetics, Department of Human Genetics, Katholieke
Universiteit Leuven, Leuven, Belgium.
(8)Department of Pathology, Institut Jules Bordet, Brussels, Belgium.

While invasive ductal breast cancer (IDC) represents the most common histological
type of breast cancer, minor subtypes exist such as mucinous breast cancer
(MuBC). MuBC patients are generally older and have an excellent prognosis while
at the pathological level, these tumors present with cells floating in
extracellular mucin. To unravel the molecular architecture of MuBC, we applied
low pass whole genome sequencing and microscopic evaluation of stromal tumor
infiltrating lymphocytes (TIL) to 30 MuBC from a retrospective institutional
cohort. We further analyzed two independent datasets from the International
Cancer Genomics Consortium (ICGC) and The Cancer Genome Atlas (TCGA). Genomic
data (n = 26 MuBC, n = 535 estrogen-receptor (ER) positive/HER2-negative IDC),
methylation data (n = 28 MuBC, n = 529 ER-positive/HER2-negative IDC) and
transcriptomic data (n = 27 MuBC, n = 467 ER-positive/HER2-negative IDC) were
analyzed. MuBC was characterized by low TIL levels (median = 0.0%, average =
3.4%, 95% CI = 1.9-4.9%). Compared to IDC, MuBC had a lower genomic instability
(P = .01, two-sided Mann-Whitney U test), and a decreased prevalence of PIK3CA
mutations (39.7% in IDC vs. 6.7% in MuBC, P = .01 in ICGC; and 34.8% vs 0.0%, P =
.02 in TCGA, two-sided Fisher’s exact test). Finally, our report identifies
aberrant DNA methylation of MUC2 as a possible cause of extracellular production
of mucin in MuBC.

DOI: 10.1093/jnci/djz023
PMID: 30789657

JAMA Oncol. 2019 Feb 21. doi: 10.1001/jamaoncol.2018.7217. [Epub ahead of print]

Techniques and Thresholds for Quantifying Circulating Tumor Cells in Breast
Cancer.

Liu B(1), Dong K(1), Dong R(1).

Author information:
(1)Department of Pediatric Surgery, Children’s Hospital of Fudan University,
Shanghai Key Laboratory of Birth Defects and Key Laboratory of Neonatal Diseases,
Ministry of Health, Shanghai, China.

DOI: 10.1001/jamaoncol.2018.7217
PMID: 30789652

Aesthet Surg J. 2019 Feb 21. pii: sjy327. doi: 10.1093/asj/sjy327. [Epub ahead of
print]

Validation of a CD30 Enzyme-Linked Immunosorbant Assay for the Rapid Detection of
Breast Implant-Associated Anaplastic Large Cell Lymphoma.

Hanson SE(1), Hassid VJ(1), Branch-Brooks C(1), Liu J(1), Kadin ME(2), Miranda
R(3), Butler CE(1), Clemens MW.

Author information:
(1)Department of Plastic Surgery, The University of Texas MD Anderson Cancer
Center, Houston, TX.
(2)Department of Dermatology, Roger Williams Medical Center, Providence, RI.
(3)Department of Hematopathology, The University of Texas MD Anderson Cancer
Center, Houston, TX.

BACKGROUND: Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL)
is an uncommon type of non-Hodgkin lymphoma occurring in the fluid or capsule
adjacent to textured breast implants. Diagnosis of BIA-ALCL of symptomatic
patients requires demonstration of large anaplastic cells with uniform expression
of CD30 protein on immunohistochemistry.
OBJECTIVE: The authors investigated a novel, rapid, office-based, and economic
in-situ enzyme-linked immunosorbent assay (ELISA) for screening BIA-ALCL
patients.
METHODS: A commercially available in-situ ELISA was standardized and validated
for patients with confirmed BIA-ALCL diagnosis with clinical isolates. A panel of
9 pathologically confirmed BIA-ALCL patients was screened by serum, plasma, and
periprosthetic effusion specimens and compared against serum, plasma, and
nonneoplastic delayed seromas in 7 control patients. Statistical analysis
demonstrated assay consistency and reliability.
RESULTS: All BIA-ALCL effusions demonstrated CD30 ELISA detection at full and all
serial concentrations. BIA-ALCL serum specimens and all control specimens were
negative at full concentration and serial dilutions (1:100, 1:250, 1:500, and
1:1000). BIA-ALCL plasma specimens were weakly positive at full concentration and
revealed no activity with serial dilution.
CONCLUSIONS: This is the first study to demonstrate a viable alternative to CD30
immunohistochemistry for the screening of BIA-ALCL. Our study demonstrates 100%
sensitivity in seroma fluid with no detectable CD30 in benign seroma samples. A
CD30 ELISA represents a novel, low-cost screening test, which may be used to
screen suspicious aspirations of delayed periprosthetic fluid collections in an
office-based setting.
LEVEL OF EVIDENCE: 3:

DOI: 10.1093/asj/sjy327
PMID: 30789639

JAMA Oncol. 2019 Feb 21. doi: 10.1001/jamaoncol.2018.7236. [Epub ahead of print]

Techniques and Thresholds for Quantifying Circulating Tumor Cells in Breast
Cancer-In Reply.

Sparano JA(1).

Author information:
(1)Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New
York.

DOI: 10.1001/jamaoncol.2018.7236
PMID: 30789630

Khirurgiia (Mosk). 2019;(1):50-52. doi: 10.17116/hirurgia201901150.

[The method of endoprosthesis deployment in breast cancer surgery].

[Article in Russian; Abstract available in Russian from the publisher]

Saveliyev VN(1), Tkachev MV(1), Borisov AP(1).

Author information:
(1)Samara Regional Clinical Oncology Center, Samara, Russia.

AIM: To improve immediate results of treatment in patients with breast cancer
using a new method of reconstruction.
MATERIAL AND METHODS: Prospective study included 215 patients with breast cancer.
Patients were treated at the Samara Regional Clinical Oncology Center in
2013-2016. Patients of the control group (n=111) underwent subcutaneous
mastectomy followed by conventional endoprosthesis deployment with its complete
muscular covering. Patients of the main group (n=104) underwent subcutaneous
mastectomy with a new method of single-stage reconstruction.
RESULTS: Mean time of operation was 115±15 min in the control group and 90±10 min
in the main group (p=0.000). Intraoperative blood loss reached 115±15 ml in the
control group, 70±10 ml – in the main group (p=0.000). Duration of postoperative
lymphorrhea was 14.6±3.5 days in the control group, 10±3.4 days – in the main
group (p=0.000). Postoperative hospital-stay was 17.1±3.7 day in the control
group and 14.2±2.4 days in the main group (p=0.001).
CONCLUSION: New surgical approach significantly improves early outcomes in
patients with breast cancer in comparison with those who undergo conventional
surgical repair.

Publisher: Цель исследования – улучшить ближайшие результаты лечения больных с
диагнозом рака молочной железы при использовании нового способа реконструкции.
Материал и методы. Проведено плановое проспективное исследование среди 215
больных раком молочной железы, леченных в Самарском областном клиническом
онкологическом диспансере с 2013 по 2016 г. Пациенткам контрольной группы (n=111)
выполнили подкожную мастэктомию с пластикой эндопротезом стандартным способом,
больным основной группы (n=104) – подкожную мастэктомию новым способом
одноэтапной реконструкции. Результаты. Среднее время операции в контрольной
группе составило 115±15 мин, в основной – 90±10 мин, разница статистически
значима (р=0,000). Интраоперационная кровопотеря у больных контрольной группы
достигала 115±15 мл, основной – 70±10 мл (р=0,000). Послеоперационная лимфорея в
контрольной группе длилась 14,6±3,5 дня, в основной – 10±3,4 дня (р=0,000). Время
нахождения в стационаре после операции в контрольной группе составило 17,1±3,7
койко-дня, в основной – 14,2±2,4 койко-дня (р=0,001). Выводы. Применение нового
способа реконструкции статистически значимо улучшает ближайшие результаты лечения
больных раком молочной железы по сравнению с пациентками, которым выполняли
мастэктомию с пластикой эндопротезом стандартным способом.
DOI: 10.17116/hirurgia201901150
PMID: 30789608

Plast Reconstr Surg. 2019 Feb 13. doi: 10.1097/PRS.0000000000005500. [Epub ahead
of print]

SPECIAL UPDATE: The epidemiology of Breast Implant Associated Large Cell Lymphoma
in Australia and New Zealand confirms the highest risk for grade 4 surface breast
implants.

Magnusson M(1)(2), Beath K(3), Cooter R(4)(2), Locke M(5), Prince HM(6), Elder
E(7)(2), Deva AK(3)(2)(8).

Author information:
(1)Griffith University.
(2)Australian joint BIA-ALCL task force.
(3)Macquarie University.
(4)Monash University, Australian Breast Device Registry.
(5)NZ Association of Plastic Surgeons.
(6)Epworth Healthcare, Sir Peter MacCallum Cancer Center and Department of
Oncology, University of Melbourne.
(7)Westmead Breast Cancer Institute, Breast Surgeons in Australia & New Zealand.
(8)Integrated Specialist Healthcare Education and Research Foundation.

BACKGROUND: The epidemiology and implant specific risk for BIA-ALCL has been
previously reported for Australia and New Zealand. We now present updated data
and risk assessment since our last report.
METHODS: New cases in Australia and New Zealand were identified and analyzed.
Updated sales data from three leading breast implant manufacturers (i.e., Mentor,
Allergan, and Silimed) were secured to estimate implant-specific risk.
RESULTS: A total of 26 new cases of ALCL were diagnosed between January 2017 to
April 2018 increasing the total number of confirmed cases in Australia and New
Zealand to 81. This represents a 47% increase in number of reported cases over
this time period. The mean age and time to development remains unchanged. The
implant specific risk has increased for Silimed Polyurethane (23.4 times higher)
as compared with Biocell, which has remained relatively static (16.5 times
higher) compared with Siltex implants.
CONCLUSIONS: The number of confirmed cases of BIA-ALCL in Australia and New
Zealand continues to rise. The implant specific risk has now changed to reflect a
strong link to implant surface area/roughness as a major association with this
cancer.

DOI: 10.1097/PRS.0000000000005500
PMID: 30789476

Plast Reconstr Surg. 2019 Feb 13. doi: 10.1097/PRS.0000000000005522. [Epub ahead
of print]

Locoregional cancer recurrence after breast reconstruction: detection,
management, and secondary reconstructive strategies.

Mirzabeigi MN(1), Rhemtulla IA(1), Mcdonald ES(2), Sataloff DM(3), Kovach SJ(1),
Wu LC(1), Serletti JM(1), Kanchwala S(1).

Author information:
(1)Division of Plastic Surgery, Department of Surgery, University of Pennsylvania
Health System, Philadelphia, Pennsylvania.
(2)Department of Radiology, University of Pennsylvania Health System,
Philadelphia, Pennsylvania.
(3)Department of Surgery, University of Pennsylvania Health System, Philadelphia,
Pennsylvania.

PURPOSE: Locoregional recurrence (LRR) of the previously reconstructed breast
poses a diagnostic and operative challenge. This study examines detection,
management, and reconstructive strategies of LRR following post-mastectomy breast
reconstruction.
METHODS: A retrospective review of records was performed on patients treated
within the health system for breast cancer from January 2000 – July 2014. Of
these patients, descriptive factors and operative details were collected for
those that developed LRR. Subsequent reconstructive surgeries were also examined.
Utilizing a multidisciplinary team, a surveillance/management algorithm was
generated.
RESULTS: A total of 41 patients with LRR were identified (mean time to recurrence
4.6 years). 2-year and 5-year survival following LRR was 88 percent and 39
percent respectively. LRR was found to occur in the following tissue planes:
subcutaneous (27 percent), subcutaneous/pectoralis (24 percent), chest wall (37
percent), and axillary (12 percent). The most frequent method of detection was
patient concern leading to examination. Older age at the time of LRR (p=0.028),
increased time to recurrence /detection (p=0.024), and chemotherapy before LRR
(p=0.014) were associated with the need for a secondary salvage flap. Patients
who experienced a subcutaneous recurrence were far less likely to undergo a
secondary flap (p=0.011). Factors associated with loss of the index
reconstruction included lower BMI (p=0.009), pectoralis invasion (p=0.05), and
implant reconstruction (p=0.03).
CONCLUSIONS: Detection and management of LRR requires appropriate physical exam
and imaging. Significant factors associated with failure to salvage the initial
reconstruction included BMI, plane of recurrence and type of initial
reconstruction.

DOI: 10.1097/PRS.0000000000005522
PMID: 30789475

Epidemiology. 2019 Feb 15. doi: 10.1097/EDE.0000000000000981. [Epub ahead of
print]

A pooled analysis of breast-feeding and breast cancer risk by hormone receptor
status in parous Hispanic women.

Sangaramoorthy M(1), Hines LM(2), Torres-Mejía G(3), Phipps AI(4)(5), Baumgartner
KB(6), Wu AH(7), Koo J(1)(8), Ingles SA(7), Slattery ML(9), John EM(1)(8)(10).

Author information:
(1)Cancer Prevention Institute of California, Fremont, CA 94538.
(2)Department of Biology, University of Colorado at Colorado Springs, Colorado
Springs, CO 80918.
(3)Instituto Nacional de Salud Puública, Population Health Research Center,
Cuernavaca Morelos, Mexico.
(4)Department of Epidemiology, University of Washington, Seattle, WA 98195.
(5)Epidemiology Program, Public Health Sciences Division, Fred Hutchinson Cancer
Research Center, Seattle, WA 98109.
(6)Department of Epidemiology and Population Health, School of Public Health &
Information Sciences, James Graham Brown Cancer Center, University of Louisville,
Louisville, KY 40202.
(7)Department of Preventive Medicine, Keck School of Medicine of USC, Norris
Comprehensive Cancer Center, University of Southern California, Los Angeles, CA
90089
(8)Stanford Cancer Institute, Stanford University School of Medicine, Stanford,
CA 94304.
(9)Department of Medicine, University of Utah, Salt Lake City, UT 84108.
(10)Department of Medicine, Division of Oncology, Stanford University School of
Medicine, Stanford, CA 94304.

BACKGROUND: Data on breast-feeding and breast cancer risk are sparse and
inconsistent for Hispanic women.
METHODS: Pooling data for nearly 6,000 parous Hispanic women from four
population-based studies conducted between 1995 and 2007 in the U.S. and Mexico,
we examined the association of breast-feeding with risk of breast cancer overall
and subtypes defined by estrogen receptor (ER) and progesterone receptor (PR)
status, as well as the joint effects of breast-feeding, parity, and age at first
birth. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) using
logistic regression.
RESULTS: Among parous Hispanic women, older age at first birth was associated
with increased breast cancer risk, whereas parity was associated with reduced
risk. These associations were found for hormone receptor positive (HR+) breast
cancer only and limited to premenopausal women. Age at first birth and parity
were not associated with risk of ER-PR- breast cancer. Increasing duration of
breast-feeding was associated with decreasing breast cancer risk (≥25 vs. 0
months: OR=0.73, 95% CI=0.60-0.89, Ptrend =0.03), with no heterogeneity by
menopausal status or subtype. At each parity level, breast-feeding further
reduced HR+ breast cancer risk. Additionally, breast-feeding attenuated the
increase in risk of HR+ breast cancer associated with older age at first birth.
CONCLUSIONS: Our findings suggest that breast-feeding is associated with reduced
risk of both HR+ and ER-PR- breast cancer among Hispanic women, as reported for
other populations, and may attenuate the increased risk in women with a first
pregnancy at older ages.

DOI: 10.1097/EDE.0000000000000981
PMID: 30789436

JMIR Mhealth Uhealth. 2019 Feb 21;7(2):e10820. doi: 10.2196/10820.

Breast Cancer Survivors’ Experiences With an Activity Tracker Integrated Into a
Supervised Exercise Program: Qualitative Study.

Wu HS(1), Gal R(2), van Sleeuwen NC(3), Brombacher AC(3), IJsselsteijn WA(1), May
AM(2), Monninkhof EM(2).

Author information:
(1)Human-Technology Interaction Group, Department of Industrial Engineering &
Innovation Sciences, Eindhoven University of Technology, Eindhoven, Netherlands.
(2)Julius Center of Health Sciences and Primary Care, University Medical Center
Utrecht, University of Utrecht, Utrecht, Netherlands.
(3)Systematic Change Group, Department of Industrial Design, Eindhoven University
of Technology, Eindhoven, Netherlands.

BACKGROUND: There is growing evidence that physical activity is related to a
better prognosis after a breast cancer diagnosis, whereas sedentary behavior is
associated with worse outcomes. It is therefore important to stimulate physical
activity and reduce sedentary time among patients with breast cancer. Activity
trackers offer a new opportunity for interventions directed at stimulating
physical activity behavior change.
OBJECTIVE: This study aimed to explore the experience of patients with breast
cancer who used an activity tracker in addition to a supervised exercise
intervention in the randomized UMBRELLA Fit trial.
METHODS: A total of 10 patients with breast cancer who completed cancer treatment
participated in semistructured in-depth interviews about their experience with
and suggestions for improvements for the Jawbone UP2 activity tracker.
RESULTS: The activity tracker motivated women to be physically active and created
more awareness of their (sedentary) lifestyles. The women indicated that the
automatically generated advice (received via the Jawbone UP app) lacked
individualization and was not applicable to their personal situations (ie, having
been treated for cancer). Furthermore, women felt that the daily step goal was
one-dimensional, and they preferred to incorporate other physical activity goals.
The activity tracker’s inability to measure strength exercises was a noted
shortcoming. Finally, women valued personal feedback about the activity tracker
from the physiotherapist.
CONCLUSIONS: Wearing an activity tracker raised lifestyle awareness in patients
with breast cancer. The women also reported additional needs not addressed by the
system. Potential improvements include a more realistic total daily physical
activity representation, personalized advice, and personalized goals.

©Hoi San Wu, Roxanne Gal, Niek C van Sleeuwen, Aarnout C Brombacher, Wijnand A
IJsselsteijn, Anne M May, Evelyn M Monninkhof. Originally published in JMIR
Mhealth and Uhealth (http://mhealth.jmir.org), 21.02.2019.

DOI: 10.2196/10820
PMID: 30789349

LGBT Health. 2019 Feb 21. doi: 10.1089/lgbt.2018.0217. [Epub ahead of print]

Differences in Family Health History Knowledge Among Bisexual and Lesbian Women.

Roberts MC(1), Krakow M(1), Wheldon CW(1), Silver MI(1).

Author information:
(1)Division of Cancer Control and Population Sciences, National Cancer Institute,
Rockville, Maryland.

PURPOSE: We aimed to determine whether there are differences between sexual
minority women and heterosexual women in family health history knowledge.
METHODS: We used data from Dr. Susan Love Research Foundation’s The Health of
Women Study®. We included women who completed two of six online surveys between
2012 and 2015 (n = 22,410).
RESULTS: Compared with heterosexual women, bisexual and lesbian women had
consistently greater odds of not knowing their family health history (e.g., odds
ratios of 2.59 and 1.56 for breast cancer, respectively).
CONCLUSION: To avoid exacerbating existing health disparities, in the era of
precision medicine, we must address gaps in knowledge of family health history.

DOI: 10.1089/lgbt.2018.0217
PMID: 30789301

J Adolesc Young Adult Oncol. 2019 Feb 21. doi: 10.1089/jayao.2018.0091. [Epub
ahead of print]

Cancer-Related Fatigue and Associated Factors in Young Adult Cancer Patients.

Nowe E(1), Friedrich M(1), Leuteritz K(1), Sender A(1), Stöbel-Richter Y(2),
Schulte T(3), Hinz A(1), Geue K(1).

Author information:
(1)1 Medical Psychology and Medical Sociology, University of Leipzig, Leipzig,
Germany.
(2)2 Faculty of Managerial and Cultural Studies, University of Applied Sciences
Zittau/Görlitz, Görlitz, Germany.
(3)3 Rehabilitation Clinic Bad Oexen, Bad Oexen, Germany.

PURPOSE: Cancer-related fatigue (CRF) is a highly burdensome and long-lasting
symptom of cancer and its therapy. This study aims to examine the severity of CRF
in its different dimensions and to assess medical and sociodemographic factors
associated with CRF in young adults with cancer (adolescents and young adults
[AYAs]).
METHODS: Patients with malignant cancer (diagnosed within the last 4 years) aged
18-39 years at diagnosis were assessed. CRF was measured using the European
Organisation for Research and Treatment of Cancer Quality of Life Fatigue Module
(EORTC QLQ-FA12) Questionnaire. Sociodemographic and medical data were collected
with self-report questionnaires. Descriptive analyses, cluster analysis, and
multiple regression analysis were used to examine CRF in AYAs.
RESULTS: In total, n = 577 patients were included. Respondents’ fatigue scores
were highest for the physical subscale (mean = 45.6; standard deviation
[SD] = 28.2), followed by the emotional (mean = 26.7; SD = 28.8) and cognitive
dimensions (mean = 19.7; SD = 22.7). Female participants, patients with an
additional disease, and patients with financial problems resulting from having
cancer reported significantly higher fatigue scores for all three of the
subscales (R2 range: 0.10-0.22). Testicular cancer patients had the lowest CRF
scores for every dimension. Breast and gynecological cancer patients had the
highest emotional and cognitive fatigue scores.
CONCLUSION: Medical variables such as cancer site and therapy scheme seem to have
little influence. Caregivers should assess CRF in AYAs independent of their
medical characteristics. Reducing additional burdens may represent a way of
reducing CRF in AYA cancer patients.

DOI: 10.1089/jayao.2018.0091
PMID: 30789284

J Agric Food Chem. 2019 Feb 21. doi: 10.1021/acs.jafc.8b06444. [Epub ahead of
print]

Ampelopsin A and ampelopsin C induce apoptosis and metastasis through
down-regulating AxL, TYRO3, and FYN expressions in MDA-MB-231 breast cancer
cells.

Huang C, Huang YL, Wang CC, Pan YL, Lai YH, Huang HC.

Ampelopsin A and ampelopsin C are resveratrol oligostilbenes whose role in cancer
development remains unknown. This study evaluated the anti-metastatic and
apoptosis-inducing properties of ampelopsin A and ampelopsin C in MDA-MB-231
cells. The IC50 value of ampelopsin A and ampelopsin C against MDA-MB-231 cells
at 72 hours were 38.75±4.61 μM and 2.71±0.21 μM, respectively. However, at 24
hours, ampelopsin A and ampelopsin C decreased significantly cell metastasis.
Among the 71 proteins present on the human phospho-receptor tyrosin kinase array,
ampelopsin C decreased the phosphorylated protein level of AXL, Dtk (TYRO3),
EphA2, EphA6, Fyn, Hck and SRMS. Additionally, anti-proliferation effects of
ampelopsin C were enhanced when combined with luteolin and chrysin compared with
either two or a single agent in MDA-MB-231 cells. Overall, ampelopsin A and
ampelopsin C extracted from Vitis thunbergii are both novel anti-metastatic
agents and potential therapeutic targets in patients with breast cancer.

DOI: 10.1021/acs.jafc.8b06444
PMID: 30789269

J Am Chem Soc. 2019 Feb 21. doi: 10.1021/jacs.9b00007. [Epub ahead of print]

λ-DNA and Aptamer Mediated Sorting and Analysis of Extracellular Vesicles.

Liu C, Zhao J, Tian F, Chang J, Zhang W, Sun J.

Extracellular vesicles (EVs) are heavily implicated in diverse pathological
processes. Due to their small size, distinct biogenesis, and heterogeneous marker
expression, isolation and detection of single EV subpopulations are difficult.
Here we develop a λ-DNA and aptamer mediated approach allowing for simultaneous
size-selective separation and surface protein analysis of individual EVs. Using a
machine learning algorithm to EV signature based on their size and marker
expression, we demonstrate that the isolated microvesicles are more efficient
than exosomes and apoptotic bodies in discriminating breast cell lines, and Stage
II breast cancer patients with varied immunohistochemical expression of HER2. Our
method provides an important tool to assess the EV heterogeneity at the single EV
level with potential value in clinical diagnostics.

DOI: 10.1021/jacs.9b00007
PMID: 30789261

ACS Appl Mater Interfaces. 2019 Feb 21. doi: 10.1021/acsami.8b21906. [Epub ahead
of print]

Facile Synthesis of Monodisperse Hollow Mesoporous Organosilica/Silica
Nanospheres by an In-Situ Dissolution and Reassembly Approach.

Su X, Tang Y, Li Y, Wang ZF, Tao J, Chen K, Liu Y, Wu J, Wang D, Teng Z.

Hollow structured mesoporous organosilicas are a research hotspot because of
their molecularly organic-inorganic hybrid frameworks, large void space,
permeable shells, high surface areas, uniform pores, and various applications.
However, the previous reported hard-core templating method and liquid-interface
assembly approach suffered from complex preparation procedures and poor
uniformity for the products. In the work, we demonstrate an in-situ dissolution
and reassembly method to synthesize monodisperse benzene-bridged hollow
mesoporous organosilica/silica nanoparticles (HMOSNs) by sequential addition of
tetraethoxysilane and 1,4-bis(triethoxysilyl)benzene in a solution containing
cetyltri-methylammonium bromide (CTAB) surfactant. The formation of the HMOSNs is
completed in one-pot, which is very effective and convenient. The formation
mechanism of HMOSNs is ascribed to the fact the TEOS first assemble with CTAB to
form mesostructured silica cores, which further dissolve and migrate to the outer
layers during the deposition of mesostructued organosilica shells. The prepared
benzene-bridged HMOSNs possess uniform diameter (140 nm), large pore volume (2.79
m3/g), high specific surface area (2926 m2/g), and a high doxorubicin loading
content of 16.7%. The HMOSNs can deliver Dox into human breast cancer cells and
reduce their excretion. Thus, the Dox loaded HMOSNs show a high killing effect
against the cancer cells.

DOI: 10.1021/acsami.8b21906
PMID: 30789253

Clin Ter. 2019 Jan-Feb;170(1):e1-e3. doi: 10.7417/CT.2019.2100.

Therapeutic effect of RA223 in the management of breast cancer bone metastases.

Costa RP(1), Tripoli V(1), Princiotta A, Murabito A(1), Licari M(1), Piazza D(2),
Verderame F(3), Pinto A(4).

Author information:
(1)Nuclear Medicine, Biomedical Department of Internal and Specialist Medicine,
University of Palermo.
(2)Clinical Risk Management and Quality Unit, A.O.U.P. «P. Giaccone», Palermo.
(3)Department of Oncology, Villa Sofia Cervello Hospital, Palermo.
(4)Internal Medicine, Biomedical Department of Internal and Specialist Medicine,
University of Palermo, Italy.

Radium 223 dichloride (Ra223) is the only targeted alpha therapy able to extend
survival in patients with bone metastases from prostate cancer. Mechanism of
action and data currently available focused mainly on osteoblastic metastases
from prostate cancer. Phase 1 and 2 trials documented a clinical efficacy also in
breast cancer patients with predominately bone disease, highlighting a reduction
in alkaline phosphatase and other bone biomarkers. In our institution, a patient
with breast cancer affected by osteolytic metastases was treated with off-label
use of Ra223. Our patient had a good treatment compliance and up to now she has
not been revealed the presence of SSE or hematological complications. Our
preliminary experience shows that Ra223 may play a critical role to bone
metastates in patients with breast cancer.

DOI: 10.7417/CT.2019.2100
PMID: 30789190

Zhongguo Ying Yong Sheng Li Xue Za Zhi. 2018 Apr 8;34(4):375-378. doi:
10.12047/j.cjap.5657.2018.086.

[Effect of matrine on tumor growth and inflammatory factors and immune function
in Wistar rat with breast cancer].

[Article in Chinese]

Zhang RK(1), Wang C(1).

Author information:
(1)Department of Surgical Oncology, Affiliated Hospital of Logistics College of
Chinese People’s Armed Police Force, Tianjin 300162, China.

OBJECTIVE: To study the effect of matrine on tumor growth, inflammatory factors
and immune function in Wistar rat with breast cancer.
METHODS: Sixty female Wistar rats were randomly divided into control group (n=10)
and the modeling group of breast cancer cell tumor-bearing rat (n=50), then the
rats in modeling group were randomly divided into five groups (n=10):vehicle
group, matrine low dose group (50 mg/kg), medium dose group (100 mg/kg), high
dose group (200 mg/kg), and lentinan group (200 mg/kg). Except the control group,
each rat in the other groups was subcutaneously inoculated 0.4 ml Walker 256
breast cancer cell suspension (5×107 cells/ml) in the right axillary. Each group
was treated with corresponding drug by ig administration (10 ml/kg body weight)
twice a day for 14 days. After 14 days, the blood sample was collected from
ventral aorta, the tumor was removed and weighed to calculate tumor inhibitory
rate. The levels of interleukin-2 (IL-2), interferon-γ (IFN-γ), interleukin-6
(IL-6), interleukin-10 (IL-10), transforming growth factor-β (TGF-β), CD3+, CD4+,
CD8+, IgG, IgM, IgA in peripheral blood were determined.
RESULTS: The mean tumor weight of matrine low-dose, medium-dose, high-dose groups
and lentinan group were (4.99±0.93) g, (4.52±0.92) g, (4.22±1.18) g and
(4.52±0.92) g respectively, which were significantly lower than that in model
group. There was no statistical difference on the mean tumor weight among matrine
groups and lentinan group (P>0.05). After the drug intervention, the tumor
inhibitory rates of matrine low-dose, medium dose, high-dose groups and lentinan
group were 24.6%, 31.7%, 36.3%, and 27.9% respectively, there was no statistical
difference among the four groups. The levels of IL-2, IFN-γ, CD8+ in vehicle
group were lower than those of control group obviously (P<0.01), however, the
levels of IL-6, IL-10, TGF-β, CD3+, CD4+, IgG, IgM, IgA were higher significantly
than those of control group (P<0.01). The levels of IL-2, IFN-γ, CD8+ in matrine
low-dose, medium dose, high-dose groups and lentinan group were higher than those
of vehicle group obviously (P<0.01, P<0.05); while the levels of IL-6, IL-10,
TGF-β, CD3+, CD4+, IgG, IgM, IgA were lower than those of model group markedly
(P<0.01, P<0.05). The levels of IgM and IgA in matrine low-dose and medium-dose
groups were higher than those of lentinan group obviously (P<0.01, P<0.05); the
levels of IL-2, IFN-γ and IgA in matrine high-dose group were higher than those
of lentinan group obviously (P<0.01, P<0.05); while the levels of IFN-γ in
matrine low-dose group were lower than those of lentinan group markedly (P<0.05);
the levels of IL-10 and CD4+ in matrine high-dose group were lower than those of
lentinan group markedly (P<0.01, P<0.05).
CONCLUSIONS: Matrine has an obvious antitumor action which is related to its
ability to enhance cellular and humoral immunity, reduce inflammatory reaction.

DOI: 10.12047/j.cjap.5657.2018.086
PMID: 30788949

Clin Transl Oncol. 2019 Feb 20. doi: 10.1007/s12094-019-02051-9. [Epub ahead of
print]

Over-expression of both VEGF-C and Twist predicts poor prognosis in human breast
cancer.

Zhang YQ(1)(2), Chen WL(3), Zhang F(4), Wei XL(5), Zeng D(2), Liang YK(2)(6), Wu
JD(1), Zhang LY(5), Guo CP(1), Zeng HC(1), Hao SS(2), Li RH(2), Huang WH(7)(8),
Zhang GJ(9)(10).

Author information:
(1)The Breast Center, Cancer Hospital of Shantou University Medical College, 7
Rao ping Road, Shantou, China.
(2)Chang Jiang Scholar’s Laboratory of Shantou University Medical College, 22 Xin
ling Road, Shantou, China.
(3)Department of Head Neck and Breast Surgery, Yue Bei People’s Hospital, 133
Huimin South Road, Shao Guan, China.
(4)Guangdong Provincial Key Laboratory for Breast Cancer Diagnosis and Treatment,
Cancer Hospital of Shantou University Medical College, 7 Rao ping Road, Shantou,
China.
(5)Department of Pathology, Cancer Hospital of Shantou University Medical
College, 7 Rao ping Road, Shantou, China.
(6)Department of Medical Oncology, University of Groningen, University Medical
Center Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.
(7)The Breast Center, Cancer Hospital of Shantou University Medical College, 7
Rao ping Road, Shantou, China. huangwenhe2009@163.com.
(8)The Cancer Center and Breast-Thyroid-Surgery, Xiang’ an Hospital of Xiamen
University, Xiamen, China. huangwenhe2009@163.com.
(9)Chang Jiang Scholar’s Laboratory of Shantou University Medical College, 22 Xin
ling Road, Shantou, China. gjzhang@xah.xmu.edu.cn.
(10)The Cancer Center and Breast-Thyroid-Surgery, Xiang’ an Hospital of Xiamen
University, Xiamen, China. gjzhang@xah.xmu.edu.cn.

BACKGROUND: Angiogenesis is an indispensable step in the growth and invasiveness
of breast cancers involving a series of exquisite molecular steps. Pro-angiogenic
factors, including vascular endothelial growth factor (VEGF), have been
recognized as pivotal therapeutic targets in the treatment of breast cancer. More
recently, a highly conserved transcription factor Twist has been reported to be
involved in tumor angiogenesis and metastasis.
METHODS: The expression of VEGF-C and Twist was immunohistochemically determined
in tissue samples of primary tumors from 408 patients undergoing curative
surgical resection for breast cancer. The correlations of VEGF-C and Twist
expressions with clinicopathologic parameters as well as survival outcomes were
evaluated.
RESULTS: Of the 408 patients evaluated, approximately 70% had high expression of
VEGF-C which was significantly associated with advanced tumor stages (P = 0.019).
Similarly, VEGF-C expression was associated with the proliferation index Ki67, N3
lymph node metastasis, and D2-40-positive lymphatic vessel invasion (LVI) in a
univariate analysis. Furthermore, patients with high expressions of VEGF-C and
Twist (V + T+) had significantly increased lymph node metastasis, higher clinical
stage, and worse disease-free survival, DFS (P = 0.001) and overall survival, OS
(P = 0.011).
CONCLUSIONS: Our results suggested that co-expression of VEGF-C and Twist was
associated with larger tumor size, higher numbers of lymph node involvement,
D2-40-positive LVI, higher risk of distant metastasis, and worse DFS or OS in
breast cancer patients.

DOI: 10.1007/s12094-019-02051-9
PMID: 30788837

Qual Life Res. 2019 Feb 20. doi: 10.1007/s11136-019-02133-9. [Epub ahead of
print]

A pilot study on aesthetic treatments performed by qualified aesthetic
practitioners: efficacy on health-related quality of life in breast cancer
patients.

Oliveri S(1)(2), Faccio F(3)(4), Pizzoli S(3)(4), Monzani D(3), Redaelli C(5),
Indino M(5), Pravettoni G(3)(4).

Author information:
(1)Department of Oncology and Hematoncology (DIPO), University of Milan, Via
Festa del Perdono 7, 20122, Milan, Italy. serena.oliveri@unimi.it.
(2)Applied Research Division for Cognitive and Psychological Science, IEO,
Istituto Europeo di Oncologia IRCCS, via Ripamonti 435, 20141, Milan, Italy.
serena.oliveri@unimi.it.
(3)Department of Oncology and Hematoncology (DIPO), University of Milan, Via
Festa del Perdono 7, 20122, Milan, Italy.
(4)Applied Research Division for Cognitive and Psychological Science, IEO,
Istituto Europeo di Oncologia IRCCS, via Ripamonti 435, 20141, Milan, Italy.
(5)Dermophisiologique Oncology Aesthetics Center, IEO, Istituto Europeo di
Oncologia IRCCS, via Ripamonti 435, 20141, Milan, Italy.

PURPOSE: Cancer treatments often produce undesirable side-effects, such as skin
toxicity, impacting on everyday functioning and health-related quality of life
(HRQoL). This experimental study sought to determine whether aesthetic products
and treatments could significantly decrease perceived skin symptoms,
psychological distress and improve skin-related QoL (SRQoL).
METHODS: An experimental group composed of 100 breast patients was enrolled for
specialized aesthetic treatments at the European Institute of Oncology (IEO) and
compared to a control group of 70 breast patients who did not receive any
aesthetic treatment. A measure of SRQoL (i.e., Skindex-16) and a distress
thermometer were administered longitudinally at three time points: at baseline
(T0), at 7 days from beginning of aesthetic treatment (T1) and at 28 days from
beginning of aesthetic treatment (T2).
RESULTS: Results demonstrated the efficacy of aesthetic treatment in reducing
distress and improving SRQoL: while the experimental group showed significant
improvements in all HRQoL areas, the control group worsened. Specifically, at T1
and T2 there were significant improvements on distress and Skindex subscales in
the experimental group, with an almost complete remission of perceived symptoms
at T2. Moreover, all reported cutaneous reactions significantly improved after
the specialized treatments, with no differences in SRQoL in skin reaction type.
CONCLUSIONS: These findings demonstrate that aesthetic treatments for
side-effects of cancer therapies can alleviate perceived distress and improve
skin symptoms and HRQoL.

DOI: 10.1007/s11136-019-02133-9
PMID: 30788654

Support Care Cancer. 2019 Feb 20. doi: 10.1007/s00520-019-04694-4. [Epub ahead of
print]

Psychosocial distress in oncology: using the distress thermometer for assessing
risk classes.

Cormio C(1), Caporale F(2), Spatuzzi R(3), Lagattolla F(2), Lisi A(2), Graziano
G(2).

Author information:
(1)Psycho-Oncology Unit, IRCCS Istituto Tumori «Giovanni Paolo II», Viale Orazio
Flacco 65, 70124, Bari, BA, Italy. clacormio@gmail.com.
(2)Psycho-Oncology Unit, IRCCS Istituto Tumori «Giovanni Paolo II», Viale Orazio
Flacco 65, 70124, Bari, BA, Italy.
(3)Palliative Care Unit, San Carlo Hospital, Via Potito Petrone, 85100, Potenza,
PZ, Italy.

PURPOSE: Cancer patients often suffer for psychological distress, which can
compromise their quality of life. Our study aimed to recognize risk classes for
the development of psychosocial distress.
METHODS: Three hundred seventy-two adult cancer patients were assessed by the
Distress Thermometer (DT) and Problem List at the National Cancer Research Centre
Giovanni Paolo II of Bari. We also compiled a socio-medical and
clinical-medical record survey ad hoc for collecting socio-demographic
information and clinical variables. To examine the interplay among the different
variables and distinguish internally homogeneous subgroups of patients with
diverse risks of distress, the RECursive Partitioning and Amalgamation (RECPAM)
technique was used.
RESULTS: Most of patients were female and the most frequent diagnosis was breast
cancer, followed by gastro-intestinal cancer and hematological cancer. Distress
was present in 43% of the sample, with a total of 156 patients with a DT > 5. The
RECPAM analysis identified three distinct and homogeneous patient subgroups
(RECPAM classes) with different risks of distress: diagnosis, marital status, and
Eastern Cooperative Oncology Group Performance Status.
CONCLUSION: The use of the distress thermometer allows clinicians to identify
patients with certain characteristics that may increase the risk of developing
psychosocial distress. This evaluation can allow timely psychological
intervention and improve the patient’s therapeutic program.

DOI: 10.1007/s00520-019-04694-4
PMID: 30788626

Support Care Cancer. 2019 Feb 20. doi: 10.1007/s00520-019-04677-5. [Epub ahead of
print]

Examining the «usual» in usual care: a critical review and recommendations for
usual care conditions in psycho-oncology.

Arch JJ(1)(2), Stanton AL(3)(4)(5)(6).

Author information:
(1)Department of Psychology and Neuroscience, University of Colorado Boulder, 345
UCB Muenzinger, Boulder, CO, 80309-0345, USA. Joanna.Arch@Colorado.edu.
(2)Division of Cancer Prevention and Control, University of Colorado Cancer
Center, Aurora, CO, 80045, USA. Joanna.Arch@Colorado.edu.
(3)Department of Psychology, University of California Los Angeles, Los Angeles,
CA, 90095, USA.
(4)Department of Psychiatry and Biobehavioral Sciences, University of California
Los Angeles, Los Angeles, CA, 90095, USA.
(5)Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los
Angeles, CA, 90095, USA.
(6)Cousins Center for Psychoneuroimmunology, UCLA Semel Institute for
Neuroscience, Los Angeles, CA, 90095, USA.

PURPOSE: Within psycho-oncology clinical trials, usual care (UC) represents a
common and important control condition. Yet recent shifts in oncology, coupled
with insufficient description of such conditions, threaten to render UC
increasingly difficult to define and interpret. This paper offers evidence of
these shifts and recommendations for addressing them.
METHODS: The broader literature on usual care as a control condition in
psychosocial/behavioral intervention trials was assessed, and usual
care-controlled trials in psycho-oncology were selectively reviewed, toward to
goal of conceptual synthesis.
RESULTS: We offer evidence that (1) UC control conditions are often
insufficiently defined and assessed; and (2) the context of supportive care in
oncology has shifted in a manner that contributes to this problem, with
implications for interpreting and comparing findings across clinical trials.
Three converging findings support these conclusions. First, the scientific
literature increasingly documents the diversity in how «usual care» conditions
are defined across psychosocial and behavioral trials, with important
considerations for trial interpretation. Second, evidence suggests that the
availability of psychosocial oncology care has increased over the past few
decades. The increasing availability and variety of psychosocial care introduces
potential confounds for UC conditions. Third, mental health care trends in the
general population affect the supportive interventions available to oncology
patients in UC conditions today versus in the past.
CONCLUSIONS: Shifts in psychosocial oncology and broader mental health care
underscore the importance of carefully defining and assessing UC in
psycho-oncology trials. Recommendations are offered for improving the design,
evaluation, and interpretation of UC conditions, toward the ultimate goal of
improving the quality of the evidence in psycho-oncology.

DOI: 10.1007/s00520-019-04677-5
PMID: 30788625

Med J Islam Repub Iran. 2018 Sep 17;32:87. doi: 10.14196/mjiri.32.87. eCollection
2018

Investigating of variations in BRCA1 gene in Iranian families with breast cancer.

Mehrgou A(1), Akouchekian M(1), Hemati S(2).

Author information:
(1)Department of Medical Genetics and Molecular Biology, School of Medicine, Iran
University of Medical Sciences, Tehran, Iran.
(2)Department of Oncology, Faculty of Medicine, Isfahan University of Medical
Sciences, Isfahan, Iran.

Background: Breast cancer is one of the most common cancers among Iranian women
whose relationship with mutation status in BRCA1 is previously approved.
Therefore, screening of the most mutated exons in BRCA1 in hereditary breast
cancer patients provides beneficial information about the main disease-causing
reason. Methods: A total of 14 Iranian hereditary breast cancer patients
participated in this case series study. DNA was extracted from patients’ blood
samples for PCR assay. The quality of PCR products was determined using
horizontal electrophoresis. Then, sequencing and analysis of the sequencing
results were performed to investigate variation status in the sequences. Results:
Five variants in 4 patients were found, including 1 pathogenic variant in exon 16
(H1686Q, NM_007294.3:c.5058T>A) and 4 novel intronic variants of uncertain
significance (NC_000017.11:41228314G>T, NC_000017.11:41228309C>T,
NC_000017.11:41228317G>T, and NC_000017.11:41203042G>A) in BRCA1. This study was
the first to report 1 rare pathogenic variant in BRCA1 (H1686Q, NM_007294.3:
c.5058T>A) in an Iranian family as the main disease-causing reason. Another
interesting finding was non-existence of variations in almost all
globally-reported and mutated exons in BRCA1. Conclusion: Investigation of these
exons in BRCA1 showed the uniqueness of mutation pattern in Iranian breast cancer
patients compared to other world regions. Due to the existence of other BRCA1
exons and also other predisposing genes in breast cancer, the main cause of
cancer development in other participants might have been put in those exons and
genes. We concluded that the most mutated exons in BRCA1 in Iranian population
may not be the same as those found in other parts of the world.

DOI: 10.14196/mjiri.32.87
PMCID: PMC6376998
PMID: 30788324

Front Oncol. 2019 Feb 6;9:43. doi: 10.3389/fonc.2019.00043. eCollection 2019.

Differential Oxygenation in Tumor Microenvironment Modulates Macrophage and
Cancer Cell Crosstalk: Novel Experimental Setting and Proof of Concept.

Campillo N(1)(2), Falcones B(1)(2), Otero J(1)(2), Colina R(1), Gozal D(3),
Navajas D(1)(2)(4), Farré R(1)(2)(5), Almendros I(1)(2)(5).

Author information:
(1)Unitat de Biofísica i Bioenginyeria, Facultat de Medicina i Ciències de la
Salut, Universitat de Barcelona, Barcelona, Spain.
(2)CIBER de Enfermedades Respiratorias, Madrid, Spain.
(3)Department of Child Health, University of Missouri-School of Medicine,
Columbia, MO, United States.
(4)Institute for Bioengineering of Catalonia, The Barcelona Institute of Science
and Technology, Barcelona, Spain.
(5)Institut d’Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain.

Hypoxia is a common characteristic of many solid tumors that has been associated
with tumor aggressiveness. Limited diffusion of oxygen generates a gradient of
oxygen availability from the blood vessel to the interstitial space and may
underlie the recruitment of macrophages fostering cancer progression. However,
the available data based on the recruitment of circulating cells to the tumor
microenvironment has been so far carried out by conventional co-culture systems
which ignore the hypoxic gradient between the vessel to the tumor interstitium.
Here, we have designed a novel easy-to-build cell culture device that enables
evaluation of cellular cross-talk and cell migration while they are being
simultaneously exposed to different oxygenation environments. As a
proof-of-concept of the potential role of differential oxygenation among
interacting cells we have evaluated the activation and recruitment of macrophages
in response to hypoxic melanoma, breast, and kidney cancer cells. We found that
hypoxic melanoma and breast cancer cells co-cultured with normoxic macrophages
enhanced their directional migration. By contrast, hypoxic kidney cells were not
able to increase their recruitment. We also identified well-described
hypoxia-induced pathways which could contribute in the immune cell recruitment
(VEGFA and PTGS2 genes). Moreover, melanoma and breast cancer increased their
proliferation. However, oxygenation levels affected neither kidney cancer cell
proliferation nor gene expression, which in turn resulted in no significant
changes in macrophage migration and polarization. Therefore, the cell culture
device presented here provides an excellent opportunity for researchers to
reproduce the in vivo hypoxic gradients in solid tumors and to study their role
in recruiting circulating cells to the tumor in specific types of cancer.

DOI: 10.3389/fonc.2019.00043
PMCID: PMC6373430
PMID: 30788287

Front Oncol. 2019 Feb 6;9:40. doi: 10.3389/fonc.2019.00040. eCollection 2019.

The CXCL8-CXCR1/2 Axis as a Therapeutic Target in Breast Cancer Stem-Like Cells.

Ruffini PA(1).

Author information:
(1)Research and Development Department, Dompé farmaceutici S.p.A., Milan, Italy.

Cancer stem-like cells (CSC) have been targeted by different strategies over the
last decade. This mini review focuses on preclinical and clinical results
obtained by interfering with chemokine receptors CXCR1 and CXCR2 in breast
cancer. This strategy is currently being tested in a randomized, double blind
phase 2 clinical trial.

DOI: 10.3389/fonc.2019.00040
PMCID: PMC6373429
PMID: 30788286

Bioimpacts. 2019;9(1):45-56. doi: 10.15171/bi.2019.06. Epub 2018 Jul 2.

In silico design of a triple-negative breast cancer vaccine by targeting cancer
testis antigens.

Parvizpour S(1), Razmara J(2), Pourseif MM(1), Omidi Y(1)(3).

Author information:
(1)Research Center for Pharmaceutical Nanotechnology, Biomedicine Institute,
Tabriz University of Medical Sciences, Tabriz, Iran.
(2)Department of Computer Science, Faculty of Mathematical Sciences, University
of Tabriz, Tabriz, Iran.
(3)Department of Pharmaceutics, Faculty of Pharmacy, Tabriz University of Medical
Sciences, Tabriz, Iran.

Introduction: Triple-negative breast cancer (TNBC) is an important subtype of
breast cancer, which occurs in the absence of estrogen, progesterone and HER-2
receptors. According to the recent studies, TNBC may be a cancer testis antigen
(CTA)-positive tumor, indicating that the CTA-based cancer vaccine can be a
treatment option for the patients bearing such tumors. Of these antigens (Ags),
the MAGE-A family and NY-ESO-1 as the most immunogenic CTAs are the potentially
relevant targets for the development of an immunotherapeutic way of the breast
cancer treatment. Methods: In the present study, immunoinformatics approach was
used to design a multi-epitope peptide vaccine to combat the TNBC. The vaccine
peptide was constructed by the fusion of three crucial components, including the
CD8+ cytotoxic T lymphocytes (CTLs) epitopes, helper epitopes and adjuvant. The
epitopes were predicted from the MAGE-A and NY-ESO-1 Ags. In addition, the
granulocyte-macrophage-colony-stimulating factor (GM-CSF) was used as an adjuvant
to promote the CD4+ T cells towards the T-helper for more strong induction of CTL
responses. The components were conjugated by proper linkers. Results: The vaccine
peptide was examined for different physiochemical characteristics to confirm the
safety and immunogenic behavior. Furthermore, the 3D-structure of the vaccine
peptide was predicted based on the homology modeling approach using the MODELLER
v9.17 program. The vaccine structure was also subjected to the molecular dynamics
simulation study for structure refinement. The results verified the
immunogenicity and safety profile of the constructed vaccine as well as its
capability for stimulating both the cellular and humoral immune responses.
Conclusion: Based on our in-silico analyses, the proposed vaccine may be
considered for the immunotherapy of TNBC.

DOI: 10.15171/bi.2019.06
PMCID: PMC6378095
PMID: 30788259

Bioimpacts. 2019;9(1):1-3. doi: 10.15171/bi.2019.01. Epub 2018 Oct 21.

Indoleamine 2, 3-dioxygenase inhibitors in immunochemotherapy of breast cancer:
challenges and opportunities.

Hashemzadeh N(1)(2), Adibkia K(1)(3), Barar J(1)(3).

Author information:
(1)Research Center for Pharmaceutical Nanotechnology, Biomedicine Institute,
Tabriz University of Medical Sciences, Tabriz, Iran.
(2)Students’ Research Committee, Faculty of Pharmacy, Tabriz University of
Medical Sciences, Tabriz, Iran.
(3)Department of Pharmaceutics, Faculty of Pharmacy, Tabriz University of Medical
Sciences, Tabriz, Iran.

Trafficking of macromolecular immunotherapy agent into the tumor microenvironment
(TME) is a challenging issue. In the TME, cancer cells exploit indoleamine 2,
3-dioxygenase (IDO), as a cytosolic enzyme that catalyzes the L-tryptophan (Trp)
through the kynurenine (Kyn) pathway, which could negatively regulate the
activity of T cells. Thus, Trp/Kyn pathway, can be targeted with novel treatment
modalities such as IDO1 inhibitor to benefit patients with aggressive solid
tumors.

DOI: 10.15171/bi.2019.01
PMCID: PMC6378097
PMID: 30788254

Quant Imaging Med Surg. 2019 Jan;9(1):63-74. doi: 10.21037/qims.2019.01.05.

3D-printed breast phantom for multi-purpose and multi-modality imaging.

He Y(1), Liu Y(2), Dyer BA(3), Boone JM(4), Liu S(5), Chen T(1)(2), Zheng F(1),
Zhu Y(1), Sun Y(1), Rong Y(3), Qiu J(1).

Author information:
(1)Medical Engineering and Technology Center, Taishan Medical University, Taian
271016, China.
(2)Department of Radiology, Hubei Cancer Hospital, Wuhan 430079, China.
(3)Department of Radiation Oncology, University of California Davis Medical
Center, Sacramento, CA 95630, USA.
(4)Department of Radiology, University of California Davis Medical Center,
Sacramento, California 95817, USA.
(5)Department of Radiology, Affiliated Hospital of Taishan Medical University,
Taian 271016, China.

Background: Breast imaging technology plays an important role in breast cancer
planning and treatment. Recently, three-dimensional (3D) printing technology has
become a trending issue in phantom constructions for medical applications, with
its advantages of being customizable and cost-efficient. However, there is no
current practice in the field of multi-purpose breast phantom for quality control
(QC) in multi-modalities imaging. The purpose of this study was to fabricate a
multi-purpose breast phantom with tissue-equivalent materials via a 3D printing
technique for QC in multi-modalities imaging.
Methods: We used polyvinyl chloride (PVC) based materials and a 3D printing
technique to construct a breast phantom. The phantom incorporates structures
imaged in the female breast such as microcalcifications, fiber lesions, and
tumors with different sizes. Moreover, the phantom was used to assess the
sensitivity of lesion detection, depth resolution, and detectability thresholds
with different imaging modalities. Phantom tissue equivalent properties were
determined using computed tomography (CT) attenuation [Hounsfield unit (HU)] and
magnetic resonance imaging (MRI) relaxation times.
Results: The 3D-printed breast phantom had an average background value of 36.2
HU, which is close to that of glandular breast tissue (40 HU). T1 and T2
relaxation times had an average relaxation time of 206.81±17.50 and 20.22±5.74
ms, respectively. Mammographic imaging had improved detection of
microcalcification compared with ultrasound and MRI with multiple sequences
[T1WI, T2WI and short inversion time inversion recovery (STIR)]. Soft-tissue
lesion detection and cylindrical tumor contrast were superior with mammography
and MRI compared to ultrasound. Hemispherical tumor detection was similar
regardless of the imaging modality used.
Conclusions: We developed a multi-purpose breast phantom using a 3D printing
technique and determined its value for multi-modal breast imaging studies.

DOI: 10.21037/qims.2019.01.05
PMCID: PMC6351809
PMID: 30788247

Conflict of interest statement: Conflicts of Interest: The authors have no
conflicts of interest to declare.

J Surg Case Rep. 2019 Feb 8;2019(2):rjz015. doi: 10.1093/jscr/rjz015. eCollection
2019 Feb.

When breast cancer gets complicated. A case report of synchronous bilateral
breast cancers with discordant tumor markers from the primary to nodes with
findings of a sentinel internal mammary subpectoral lymph node.

Brock CM(1), Clippard L(1).

Author information:
(1)FACOS, Board Certified General Surgery and Surgical Critical Care, C/O
Advanced Surgical Associates, 3460 NE Ralph Powell Rd., Lee’s Summit, MO 64064,
USA.

This case reviews synchronous bilateral breast cancer with left infiltrating
ductal carcinoma ER+/PR-, Her2- and right invasive lobular carcinoma ER+/PR-,
Her2-. Independent primary bilateral breast tumors are present in 0.2-3.2% of
breast cancer. Biopsy also showed differing ER status on the left breast versus
the node which was triple negative. The final sentinel node was a left internal
mammary node. Recent studies have found that the ER, PR and HER2 status of the
primary tumor do not always correlate to the ER, PR and HER2 status of the
metastatic sites. This can have deleterious effects on survival. There are no
clear guidelines on course of treatment for these complex cases. A review of the
current literature is supportive of treating the highest-risk breast malignancy.
Despite the unusual pathology and severity of disease, our patient is doing well
with treatment.

DOI: 10.1093/jscr/rjz015
PMCID: PMC6368207
PMID: 30788096

J Surg Case Rep. 2019 Feb 8;2019(2):rjy365. doi: 10.1093/jscr/rjy365. eCollection
2019 Feb.

Paraneoplastic opsoclonus-myoclonus syndrome as a rare presentation of breast
cancer.

Martins L(1), Galvão D(1), Silva A(1), Vieira B(1), Reis Ó(1), Vitorino R(2),
Pires P(3).

Author information:
(1)Department of Surgery, Hospital de Santo Espírito da Ilha Terceira, Angra do
Heroísmo 9700, Portugal.
(2)Department of Medical Oncology, Hospital de Santo Espírito da Ilha Terceira,
Angra do Heroísmo 9700, Portugal.
(3)Department of Neurology, Hospital de Santo Espírito da Ilha Terceira, Angra do
Heroísmo 9700, Portugal.

Opsoclonus-myoclonus paraneoplastic syndrome is a medical condition that includes
opsoclonus along with diffuse or focal body myoclonus and truncal titubation with
or without ataxia and other cerebellar signs. This rare neurological syndrome is
poorly understood and can result in long-term cognitive, behavioral and motor
sequelae. We report a case of a 49-year-old woman with anti-Ri antibody
opsoclonus-myoclonus syndrome and an invasive ductal carcinoma with axillary
nodes involvement. Following the diagnosis of opsoclonus-myoclonus syndrome, a
multimodal immunotherapy treatment, with partial remission of the neurological
symptoms. The patient underwent lumpectomy and axillary node dissection and the
surgical pathology confirmed the diagnosis of breast cancer stage IIA. This was
followed by chemotherapy, radiotherapy and hormone therapy with tamoxifen. At the
6 months follow-up there was a partial improvement, anti-Ri antibody was
subsequently reported as negative and there was no evidence of disease
recurrence.

DOI: 10.1093/jscr/rjy365
PMCID: PMC6368204
PMID: 30788093

Am J Transl Res. 2019 Jan 15;11(1):245-256. eCollection 2019.

MT1JP inhibits tumorigenesis and enhances cisplatin sensitivity of breast cancer
cells through competitively binding to miR-24-3p.

Zhu D(1), Zhang X(1), Lin Y(1), Liang S(1), Song Z(1), Dong C(1).

Author information:
(1)Department of Oncology, Shanghai East Hospital, Tongji University School of
Medicine Shanghai, People’s Republic of China.

Accumulating evidence indicates that long non-coding RNAs (lncRNAs) play a key
role in the development of many human cancers. MT1JP is a lncRNA that is
reportedly involved in gastric cancer development, but a biological role and
mechanism for MT1JP in breast cancer is unknown. Here, we found that MT1JP
expression was significantly down-regulated in breast cancer tissues and cell
lines, and that decreased MT1JP expression was associated with breast cancer
progression and poor survival of breast cancer patients. Additionally, we found
that overexpression of MT1JP in breast cancer cells significantly inhibited cell
proliferation and invasion, and also enhanced the cisplatin sensitivity of breast
cancer cells. We then investigated a possible mechanism for these results,
finding that MT1JP binds to and negatively regulates miR-24-3p, which is known to
be an oncogene in some human cancers. Our rescue experiments showed that the
tumor suppressive and cisplatin-sensitizing functions of MT1JP were mediated by
negative regulation of miR-24-3p. Finally, western blot results showed that MT1JP
inhibited the Wnt/β-catenin signaling pathway. Collectively, our data indicate
that MT1JP functions as an anti-tumor lncRNA, enhances cisplatin sensitivity in
breast cancer, and may serve as a novel diagnostic and therapeutic marker of
breast cancer.

PMID: 30787983

Conflict of interest statement: None.

Am J Transl Res. 2019 Jan 15;11(1):31-44. eCollection 2019.

lncRNA GHET1 knockdown suppresses breast cancer activity in vitro and in vivo.

Han M(1)(2), Wang Y(3), Gu Y(1), Ge X(1), Seng J(1), Guo G(1), Zhang X(1), Zhao
Y(1), Dou D(1)(2).

Author information:
(1)Department of Breast Surgery, The First Affiliated Hospital of Zhengzhou
University Zhengzhou 450052, China.
(2)The Key Laboratory, The First Affiliated Hospital of Zhengzhou University
Zhengzhou 450052, China.
(3)Department of Geriatric Endocrinology, The First Affiliated Hospital of
Zhengzhou University Zhengzhou 450052, China.

Long non-coding RNA gastric carcinoma high-expressed transcript 1 (lncRNA GHET1)
is highly expressed in many tumors. The aim of the present study was to determine
whether GHET1 inhibition decreases growth and metastasis of MCF-7 breast cancer
cells by modulating epidermal growth factor receptor (EGFR) expression. In vitro,
lncRNA GHET1 knockdown suppressed cell proliferation, migration, and invasion and
enhanced cell apoptosis by maintaining MCF-7 cells in the G1 phase of the cell
cycle. Furthermore, lncRNA GHET1 knockdown reduced the expression of EGFR and
related proteins. Treatment of mice with a GHET1 inhibitor prevented tumor growth
in vivo. The results indicate that lncRNA GHET1 inhibition directly suppresses
EGFR expression, significantly inhibiting the downstream PI3K/AKT/Cyclin
D1/MMP2/9 pathway. This mechanism may underlie the suppression of breast cancer
cell activities including proliferation, migration, and invasion. In conclusion,
lncRNA GHET1 knockdown suppresses tumor growth and metastasis by suppressing the
activity of EGFR and downstream pathways.

PMID: 30787968

Conflict of interest statement: None.

Front Pharmacol. 2019 Feb 6;10:79. doi: 10.3389/fphar.2019.00079. eCollection
2019

Evaluation of Riboflavin Transporters as Targets for Drug Delivery and
Theranostics.

Bartmann L(1)(2), Schumacher D(2), von Stillfried S(3), Sternkopf M(2),
Alampour-Rajabi S(2), van Zandvoort MAMJ(2)(4), Kiessling F(1), Wu Z(1)(2).

Author information:
(1)Institute for Experimental Molecular Imaging, University Clinic, RWTH Aachen
University, Aachen, Germany.
(2)Institute for Molecular Cardiovascular Research, University Clinic, RWTH
Aachen University, Aachen, Germany.
(3)Institute of Pathology, University Clinic, RWTH Aachen University, Aachen,
Germany.
(4)Department of Genetics and Molecular Cell Biology, School for Cardiovascular
Diseases (CARIM), School for Oncology and Developmental Biology (GROW),
Maastricht University, Maastricht, Netherlands.

The retention and cellular internalization of drug delivery systems and
theranostics for cancer therapy can be improved by targeting molecules. Since an
increased uptake of riboflavin was reported for various cancers, riboflavin and
its derivatives may be promising binding moieties to trigger internalization via
the riboflavin transporters (RFVT) 1, 2, and 3. Riboflavin is a vitamin with
pivotal role in energy metabolism and indispensable for cellular growth. In
previous preclinical studies on mice, we showed the target-specific accumulation
of riboflavin-functionalized nanocarriers in cancer cells. Although the uptake
mechanism of riboflavin has been studied for over a decade, little is known about
the riboflavin transporters and their expression on cancer cells, tumor stroma,
and healthy tissues. Furthermore, evidence is lacking concerning the
representativeness of the preclinical findings to the situation in humans. In
this study, we investigated the expression pattern of riboflavin transporters in
human squamous cell carcinoma (SCC), melanoma and luminal A breast cancer
samples, as well as in healthy skin, breast, aorta, and kidney tissues. Low
constitutive expression levels of RFVT1-3 were found on all healthy tissues,
while RFVT2 and 3 were significantly overexpressed in melanoma, RFVT1 and 3 in
luminal A breast cancer and RFVT1-3 in SCC. Correspondingly, the SCC cell line
A431 was highly positive for all RFVTs, thus qualifying as suitable in vitro
model. In contrast, activated endothelial cells (HUVEC) only presented with a
strong expression of RFVT2, and HK2 kidney cells only with a low constitutive
expression of RFVT1-3. Functional in vitro studies on A431 and HK2 cells using
confocal microscopy showed that riboflavin uptake is mostly ATP dependent and
primarily driven by endocytosis. Furthermore, riboflavin is partially trafficked
to the mitochondria. Riboflavin uptake and trafficking was significantly higher
in A431 than in healthy kidney cells. Thus, this manuscript supports the
hypothesis that addressing the riboflavin internalization pathway may be highly
valuable for tumor targeted drug delivery.

DOI: 10.3389/fphar.2019.00079
PMCID: PMC6372557
PMID: 30787877

Front Pharmacol. 2019 Feb 6;10:75. doi: 10.3389/fphar.2019.00075. eCollection
2019

Iron-Chelated Polydopamine Decorated Doxorubicin-Loaded Nanodevices for Reactive
Oxygen Species Enhanced Cancer Combination Therapy.

Li XJ(1), Li WT(1)(2), Li ZH(1), Zhang LP(3), Gai CC(1), Zhang WF(2)(3), Ding
DJ(2)(3).

Author information:
(1)Department of Pathology, Weifang Medical University, Weifang, China.
(2)Collaborative Innovation Center for Target Drug Delivery System, Weifang
Medical University, Weifang, China.
(3)College of Pharmacy, Weifang Medical University, Weifang, China.

Combination therapy which enhances efficacy and reduces toxicity, has been
increasingly applied as a promising strategy for cancer therapy. Here, a reactive
oxygen species (ROS) that enhanced combination chemotherapy nanodevices was
fabricated based on the Fe-chelated polydopamine (PDA) nanoparticles (NPs). The
structure was characterized by dynamic light scattering-autosizer, transmission
electron microscopy, energy dispersive spectroscopy, and Fourier-transform
infrared (FT-IR) spectrophotometer. The in vitro drug release profile triggered
by low intracellular pH indicated that the system demonstrated controlled
therapeutic activity. In vitro cell uptake studies showed that doxorubicin
(DOX)-loaded Fe-PDA/ folic acid (FA)- polyethylene glycol (DOX@Fe-PDA/FA-PEG) had
a strong uptake capacity and can be rapidly internalized by MCF-7 cells. The in
vitro experiments demonstrated that DOX@Fe-PDA/FA-PEG triggered the intracellular
ROS overproduction, thereby enhancing its therapeutic effect on breast cancer. In
summary, this experiment demonstrated the novel DOX-loaded composite NPs used as
a potential targeted nanocarrier for breast cancer treatment, which could be a
promising therapeutic strategy against breast cancer.

DOI: 10.3389/fphar.2019.00075
PMCID: PMC6372743
PMID: 30787876

Cancer Manag Res. 2019 Feb 5;11:1199-1210. doi: 10.2147/CMAR.S184340. eCollection
2019

Attenuated ZHX3 expression serves as a potential biomarker that predicts poor
clinical outcomes in breast cancer patients.

You Y(1), Ma Y(1), Wang Q(2), Ye Z(3), Deng Y(1), Bai F(1).

Author information:
(1)Department of Gastroenterology, Ningxia Hui Autonomous Region People’s
Hospital, Yinchuan 750021, China, youyanjie@163.com; baifeihu@sohu.com.
(2)Department of Science and Education, Ningxia Hui Autonomous Region People’s
Hospital, Yinchuan 750021, China.
(3)Endoscopy Center, Ningxia Hui Autonomous Region People’s Hospital, Yinchuan
750021, China.

Background: The ZHX family has recently been in the spotlight as an integrator
and an indispensable node in carcinogenesis, whose expression is frequently
dysregulated in multiple cancers. The current study provides a novel
investigation of the expression profiles of ZHX factors in breast cancer.
Materials and methods: The mRNA levels of ZHXs and follow-up periods in breast
cancer patients were mined through the Oncomine, Cancer Cell Line Encyclopedia,
bc-GenExMiner, cBioPortal and Kaplan-Meier plotter databases. In addition, ZHX3
protein expression was examined in 98 primary tumor samples by
immunohistochemistry to investigate its association with clinicopathological
parameters and patient outcomes.
Results: We found that the transcriptional levels of ZHX1, ZHX2 and ZHX3 were not
significantly altered in tumor tissues compared with those in nontumor tissues.
ZHX2 and ZHX3 mRNA levels were observed to be positively correlated with estrogen
receptor and progesterone receptor expression, while ZHX2 mRNA levels were
negatively associated with HER2 expression. Survival analyses revealed that high
mRNA levels of ZHX2 and ZHX3 correlated with better overall survival in patients
with breast cancer. Immunohistochemical analysis revealed that patients with
decreased ZHX3 protein levels had poorer outcomes. Multivariate analysis
exhibited that ZHX3 expression may serve as an independent high-risk prognostic
predictor.
Conclusion: Dysregulated expression of ZHXs may be involved in the progression of
breast cancer and could serve as a novel biomarker and potential target for
breast cancer.

DOI: 10.2147/CMAR.S184340
PMCID: PMC6368119
PMID: 30787639

Conflict of interest statement: Disclosure The authors report no conflicts of
interest in this work.

Cancer Manag Res. 2019 Feb 4;11:1125-1132. doi: 10.2147/CMAR.S189883. eCollection
2019

Modeling risk assessment for breast cancer in symptomatic women: a Saudi Arabian
study.

Ahmed AE(1)(2), McClish DK(3), Alghamdi T(4), Alshehri A(4), Aljahdali Y(4),
Aburayah K(4), Almaymoni A(4), Albaijan M(1), Al-Jahdali H(1)(4)(5)(6), Jazieh
AR(4)(5)(6).

Author information:
(1)King Abdullah International Medical Research Center (KAIMRC), Riyadh, Saudi
Arabia, ahmeda5@vcu.edu.
(2)College of Public Health and Health Informatics, King Saud Bin Abdulaziz
University for Health Sciences, Riyadh, Saudi Arabia, ahmeda5@vcu.edu.
(3)Department of Biostatistics, School of Medicine, Virginia Commonwealth
University, Richmond, VA, USA.
(4)College of Medicine, King Saud Bin Abdulaziz University for Health Sciences,
Riyadh, Saudi Arabia.
(5)King Abdulaziz Medical City, Riyadh, Saudi Arabia.
(6)Ministry of the National Guard – Health Affairs, Riyadh, Saudi Arabia.

Background: Despite the continuing increase in the breast cancer incidence rate
among Saudi Arabian women, no breast cancer risk-prediction model is available in
this population. The aim of this research was to develop a risk-assessment tool
to distinguish between high risk and low risk of breast cancer in a sample of
Saudi women who were screened for breast cancer.
Methods: A retrospective chart review was conducted on symptomatic women who
underwent breast mass biopsies between September 8, 2015 and November 8, 2017 at
King Abdulaziz Medical City, Riyadh, Saudi Arabia.
Results: A total of 404 (63.8%) malignant breast biopsies and 229 (36.2%) benign
breast biopsies were analyzed. Women ≥40 years old (aOR: 6.202, CI 3.497-11.001,
P=0.001), hormone-replacement therapy (aOR 24.365, 95% CI 8.606-68.987, P=0.001),
postmenopausal (aOR 3.058, 95% CI 1.861-5.024, P=0.001), and with a family
history of breast cancer (aOR 2.307, 95% CI 1.142-4.658, P=0.020) were
independently associated with an increased risk of breast cancer. This model
showed an acceptable fit and had area under the receiver-operating characteristic
curve of 0.877 (95% CI 0.851-0.903), with optimism-corrected area under the curve
of 0.865.
Conclusion: The prediction model developed in this study has a high ability in
predicting increased breast cancer risk in our facility. Combining information on
age, use of hormone therapy, postmenopausal status, and family history of breast
cancer improved the degree of discriminatory accuracy of breast cancer
prediction. Our risk model may assist in initiating population-screening programs
and prompt clinical decision making to manage cases and prevent unfavorable
outcomes.

DOI: 10.2147/CMAR.S189883
PMCID: PMC6366356
PMID: 30787637

Conflict of interest statement: Disclosure The authors report no conflicts of
interest in this work.

J Pain Res. 2019 Feb 5;12:597-603. doi: 10.2147/JPR.S190201. eCollection 2019.

Preoperative ultrasound-guided multilevel paravertebral blocks reduce the
incidence of postmastectomy chronic pain: a double-blind, placebo-controlled
randomized trial.

Qian B(1), Fu S(2), Yao Y(3)(4), Lin D(3), Huang L(3).

Author information:
(1)Department of Anesthesiology, People’s Hospital Affiliated to Fujian
University of Traditional Chinese Medicine, Fuzhou, Fujian, China.
(2)Department of Pathology, Union Hospital of Fujian Medical University, Fuzhou,
Fujian, China.
(3)Department of Anesthesiology, Shengli Clinical Medical College of Fujian
Medical University, Fuzhou, Fujian, China, fjslyys@126.com.
(4)Department of Anesthesiology, Fujian Provincial Hospital, Fuzhou, Fujian,
China, fjslyys@126.com.

Purpose: Chronic postsurgical pain is a challenging problem after breast cancer
surgery. This prospective, randomized, double-blinded, parallel-group,
placebo-controlled trial was conducted to evaluate the influence of preoperative
ultrasound-guided multilevel paravertebral blocks (PVBs) on chronic pain
following mastectomy.
Patients and methods: One hundred eighty-four women were randomized to receive
ultrasound-guided multilevel (T1-T5) PVBs with 5 mL of ropivacaine 0.5% or normal
saline per level. The primary end point was the incidence of chronic pain at 3
months following mastectomy assessed by the brief pain inventory (BPI), while the
secondary end points were the acute postoperative pain, the number of patients
requiring rescue analgesia, postoperative nausea and vomiting (PONV), side
effects, and chronic pain at 6 months after surgery assessed by the BPI.
Results: A total of 172 patients completed the study. Ultrasound-guided
multilevel PVBs significantly decreased immediate postoperative pain for the
first 12 hours (P<0.001). Additionally, fewer patients in the PVB group required
rescue analgesia in the first 48 hours post-operatively compared to the control
group (5/86 vs 28/86, OR =0.128, 95% CI: 0.047-0.351, P<0.001). No statistically
significant difference was tested between the two groups (9.3% vs 17.4%, OR
=0.419, 95% CI: 0.162-1.087, P=0.068) in the incidence of PONV. At 3 months, the
incidence of chronic pain (BPI average pain score ≥3) was 34.5% and 51.2% (OR
=0.511, 95% CI: 0.277-0.944, P=0.031) in the PVB and control groups,
respectively, and at 6 months, the incidence was 22.1% and 37.2% (OR =0.479, 95%
CI: 0.245-0.936, P=0.03), respectively. No complications occurred during the
study.
Conclusion: This study indicated that perioperative ultrasound-guided multilevel
PVBs with ropivacaine improved acute postoperative pain and decreased
postmastectomy chronic pain at 3 and 6 months postoperatively.

DOI: 10.2147/JPR.S190201
PMCID: PMC6368114
PMID: 30787636

Conflict of interest statement: Disclosure The authors report no conflicts of
interest in this work.

Onco Targets Ther. 2019 Feb 5;12:993-1005. doi: 10.2147/OTT.S193024. eCollection
2019

Longdaysin inhibits Wnt/β-catenin signaling and exhibits antitumor activity
against breast cancer.

Xiong Y(1), Zhou L(1), Su Z(1), Song J(1), Sun Q(1), Liu SS(1), Xia Y(1), Wang
Z(1), Lu D(1).

Author information:
(1)Guangdong Key Laboratory for Genome Stability and Disease Prevention, Shenzhen
University International Cancer Center, Department of Pharmacology, Shenzhen
University Health Science Center, Shenzhen 518060, Guangdong, China,
wangzhongyuan@szu.edu.cn; delu@szu.edu.cn.

Background: CK1 is involved in regulating Wnt/β-catenin signaling and represents
a promising target for the treatment of breast cancer. A purine derivative
longdaysin has recently been identified as a novel modulator of cellular
circadian rhythms through targeting the protein kinases CK1δ, CK1α, and ERK2.
However, the antitumor activity of longdaysin and its underlying mechanisms
remain unclear.
Methods: The inhibitory effect of longdaysin on Wnt/β-catenin signaling was
investigated using the SuperTOPFlash reporter system. The levels of
phosphorylated LRP6, total LRP6, DVL2, active β-catenin, and total β-catenin were
examined by Western blot. The expression of Wnt target genes was determined using
real-time PCR. The ability of colony formation of breast cancer cells was
measured by colony formation assay. The effects of longdaysin on cancer cell
migration and invasion were assessed using transwell assays. The effect of
longdaysin on cancer stem cells was tested by sphere formation assay. The in vivo
antitumor effect of longdaysin was evaluated using MDA-MB-231 breast cancer
xenografts.
Results: Longdaysin suppressed Wnt/β-catenin signaling through inhibition of CK1δ
and CK1ε in HEK293T cells. In breast cancer Hs578T and MDA-MB-231 cells,
micromolar concentrations of longdaysin attenuated the phosphorylation of LRP6
and DVL2 and reduced the expression of active β-catenin and total β-catenin,
leading to the downregulation of Wnt target genes Axin2, DKK1, LEF1, and
Survivin. Furthermore, longdaysin inhibited the colony formation, migration,
invasion, and sphere formation of breast cancer cells. In MDA-MB-231 breast
cancer xenografts, treatment with longdaysin suppressed tumor growth in
association with inhibition of Wnt/β-catenin signaling.
Conclusion: Longdaysin is a novel inhibitor of the Wnt/β-catenin signaling
pathway. It exerts antitumor effect through blocking CK1δ/ε-dependent Wnt
signaling.

DOI: 10.2147/OTT.S193024
PMCID: PMC6368421
PMID: 30787621

Conflict of interest statement: Disclosure The authors report no conflicts of
interest in this work.

Genet Med. 2019 Feb 21. doi: 10.1038/s41436-019-0459-4. [Epub ahead of print]

Correction: BOADICEA: a comprehensive breast cancer risk prediction model
incorporating genetic and nongenetic risk factors.

Lee A(1), Mavaddat N(1), Wilcox AN(2), Cunningham AP(1), Carver T(1), Hartley
S(1), de Villiers CB(3), Izquierdo A(4), Simard J(5), Schmidt MK(6), Walter
FM(3), Chatterjee N(7)(8), Garcia-Closas M(2), Tischkowitz M(9), Pharoah
P(1)(10), Easton DF(1)(10), Antoniou AC(11).

Author information:
(1)Centre for Cancer Genetic Epidemiology, Department of Public Health and
Primary Care, The Strangeways Research Laboratory, University of Cambridge,
Cambridge, UK.
(2)Division of Cancer Epidemiology and Genetics, National Cancer Institute,
National Institutes of Health, Rockville, MD, USA.
(3)The Primary Care Unit, Department of Public Health & Primary Care, University
of Cambridge, Cambridge, UK.
(4)Hereditary Cancer Program, Epidemiology Unit and Girona Cancer Registry,
Catalan Institute of Oncology, Girona Biomedical Research Institute (IdiBGi),
Girona, Spain.
(5)Centre Hospitalier Universitaire de Québec-Université Laval Research Center,
Québec City, QC, Canada.
(6)Division of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, The
Netherlands.
(7)Department of Biostatistics, Bloomberg School of Public Health, Johns Hopkins
University, Baltimore, MD, USA.
(8)Department of Oncology, School of Medicine, Johns Hopkins University,
Baltimore, MD, USA.
(9)Department of Medical Genetics and National Institute for Health Research,
Cambridge Biomedical Research Centre, University of Cambridge, Cambridge, UK.
(10)Centre for Cancer Genetic Epidemiology, Department of Oncology, University of
Cambridge, Cambridge, UK.
(11)Centre for Cancer Genetic Epidemiology, Department of Public Health and
Primary Care, The Strangeways Research Laboratory, University of Cambridge,
Cambridge, UK. a.antoniou@srl.cam.ac.uk.

Erratum for
Genet Med. 2019 Jan 15;:.

This has now been corrected in both the PDF and HTML versions of the Article. The
authors regret this error.

DOI: 10.1038/s41436-019-0459-4
PMID: 30787466

Genet Med. 2019 Feb 21. doi: 10.1038/s41436-019-0463-8. [Epub ahead of print]

Toward automation of germline variant curation in clinical cancer genetics.

Ravichandran V(1)(2), Shameer Z(1), Kemel Y(1)(2), Walsh M(2), Cadoo K(2), Lipkin
S(3), Mandelker D(4), Zhang L(4), Stadler Z(2), Robson M(1)(2)(3)(5), Offit
K(1)(2)(3)(6), Vijai J(7)(8)(9).

Author information:
(1)Niehaus Center For Inherited Cancer Genomics, Memorial Sloan Kettering Cancer
Center, New York, NY, USA.
(2)Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering
Cancer Center, New York, NY, USA.
(3)Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
(4)Diagnostic Molecular Pathology, Memorial Sloan Kettering Cancer Center, New
York, NY, USA.
(5)Breast Medicine Service, Department of Medicine, Memorial Sloan Kettering
Cancer Center, New York, NY, USA.
(6)Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center,
New York, NY, USA.
(7)Niehaus Center For Inherited Cancer Genomics, Memorial Sloan Kettering Cancer
Center, New York, NY, USA. josephv@mskcc.org.
(8)Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering
Cancer Center, New York, NY, USA. josephv@mskcc.org.
(9)Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
josephv@mskcc.org.

PURPOSE: Cancer care professionals are confronted with interpreting results from
multiplexed gene sequencing of patients at hereditary risk for cancer.
Assessments for variant classification now require orthogonal data searches and
aggregation of multiple lines of evidence from diverse resources. The clinical
genetics community needs a fast algorithm that automates American College of
Medical Genetics and Genomics (ACMG) based variant classification and provides
uniform results.
METHODS: Pathogenicity of Mutation Analyzer (PathoMAN) automates germline genomic
variant curation from clinical sequencing based on ACMG guidelines. PathoMAN
aggregates multiple tracks of genomic, protein, and disease specific information
from public sources. We compared expertly curated variant data from clinical
laboratories to assess performance.
RESULTS: PathoMAN achieved a high overall concordance of 94.4% for pathogenic and
81.1% for benign variants. We observed negligible discordance (0.3% pathogenic,
0% benign) when contrasted against expert curated variants. Some loss of
resolution (5.3% pathogenic, 18.9% benign) and gain of resolution (1.6%
pathogenic, 3.8% benign) were also observed.
CONCLUSION: Automation of variant curation enables unbiased, fast, efficient
delivery of results in both clinical and laboratory research. We highlight the
advantages and weaknesses related to the programmable automation of variant
classification. PathoMAN will aid in rapid variant classification by generating
robust models using a knowledgebase of diverse genetic data (
https://pathoman.mskcc.org).

DOI: 10.1038/s41436-019-0463-8
PMID: 30787465

Br J Cancer. 2019 Feb 21. doi: 10.1038/s41416-019-0393-x. [Epub ahead of print]

Genome-wide association study of germline variants and breast cancer-specific
mortality.

Escala-Garcia M(1), Guo Q(2), Dörk T(3), Canisius S(1)(4), Keeman R(1), Dennis
J(5), Beesley J(6), Lecarpentier J(5), Bolla MK(5), Wang Q(5), Abraham
J(7)(8)(9), Andrulis IL(10)(11), Anton-Culver H(12), Arndt V(13), Auer
PL(14)(15), Beckmann MW(16), Behrens S(17), Benitez J(18)(19), Bermisheva M(20),
Bernstein L(21), Blomqvist C(22)(23), Boeckx B(24)(25), Bojesen SE(26)(27)(28),
Bonanni B(29), Børresen-Dale AL(30)(31)(32)(33)(34)(35)(36)(37)(38)(39), Brauch
H(40)(41)(42), Brenner H(13)(42)(43), Brentnall A(44), Brinton L(45), Broberg
P(46), Brock IW(47), Brucker SY(48), Burwinkel B(49)(50), Caldas C(8)(9)(51),
Caldés T(52), Campa D(17)(53), Canzian F(50), Carracedo A(54)(55)(56), Carter
BD(57), Castelao JE(58), Chang-Claude J(17)(59), Chanock SJ(45), Chenevix-Trench
G(6), Cheng TD(60), Chin SF(61), Clarke CL(62); NBCS Collaborators,
Cordina-Duverger E(63), Couch FJ(64), Cox DG(65)(66), Cox A(47), Cross SS(67),
Czene K(68), Daly MB(69), Devilee P(70)(71), Dunn JA(72), Dunning AM(7), Durcan
L(73)(74), Dwek M(75), Earl HM(9)(76), Ekici AB(77), Eliassen AH(78)(79), Ellberg
C(46), Engel C(80)(81), Eriksson M(68), Evans DG(82)(83), Figueroa J(45)(84)(85),
Flesch-Janys D(86)(87), Flyger H(88), Gabrielson M(68), Gago-Dominguez M(54)(89),
Galle E(24)(25), Gapstur SM(57), García-Closas M(45)(90), García-Sáenz JA(52),
Gaudet MM(57), George A(91)(92), Georgoulias V(93), Giles GG(94)(95)(96), Glendon
G(10), Goldgar DE(97), González-Neira A(18), Alnæs GIG(30), Grip M(98), Guénel
P(63), Haeberle L(99), Hahnen E(100)(101), Haiman CA(102), Håkansson N(103), Hall
P(68)(104), Hamann U(105), Hankinson S(106), Harkness EF(107)(108)(109),
Harrington PA(7), Hart SN(110), Hartikainen JM(111)(112)(113), Hein A(16),
Hillemanns P(3), Hiller L(72), Holleczek B(114), Hollestelle A(115), Hooning
MJ(115), Hoover RN(45), Hopper JL(95), Howell A(116), Huang G(105), Humphreys
K(68), Hunter DJ(79)(117)(118), Janni W(85), John EM(119)(120)(121), Jones
ME(90), Jukkola-Vuorinen A(122), Jung A(17), Kaaks R(17), Kabisch M(105),
Kaczmarek K(123), Kerin MJ(124), Khan S(125), Khusnutdinova E(20)(126), Kiiski
JI(125), Kitahara CM(127), Knight JA(128)(129), Ko YD(130), Koppert LB(131),
Kosma VM(111)(112)(113), Kraft P(79)(117), Kristensen
VN(30)(31)(32)(33)(34)(35)(36)(37)(38)(39), Krüger U(46), Kühl T(59), Lambrechts
D(24)(25), Le Marchand L(132), Lee E(102), Lejbkowicz F(133), Li L(134), Lindblom
A(135), Lindström S(136)(137), Linet M(127), Lissowska J(138), Lo WY(40)(41),
Loibl S(139), Lubiński J(123), Lux MP(99), MacInnis RJ(94)(95), Maierthaler
M(50), Maishman T(73)(74), Makalic E(95), Mannermaa A(111)(112)(113), Manoochehri
M(105), Manoukian S(140), Margolin S(141), Martinez ME(89)(142), Mavroudis D(93),
McLean C(143), Meindl A(144), Middha P(17)(145), Miller N(124), Milne RL(94)(95),
Moreno F(52), Mulligan AM(146)(147), Mulot C(148), Nassir R(149), Neuhausen
SL(21), Newman WT(82)(83), Nielsen SF(26)(27), Nordestgaard BG(26)(27)(28),
Norman A(110), Olsson H(46), Orr N(150), Pankratz VS(151), Park-Simon TW(3),
Perez JIA(152), Pérez-Barrios C(153), Peterlongo P(154), Petridis C(155), Pinchev
M(133), Prajzendanc K(123), Prentice R(14), Presneau N(75), Prokofieva D(126),
Pylkäs K(156)(157), Rack B(144), Radice P(158), Ramachandran D(3), Rennert
G(133), Rennert HS(133), Rhenius V(7), Romero A(153), Roylance R(159), Saloustros
E(160), Sawyer EJ(155), Schmidt DF(95), Schmutzler RK(100)(101), Schneeweiss
A(49)(161), Schoemaker MJ(91), Schumacher F(162), Schwentner L(85), Scott
RJ(163)(164)(165)(166), Scott C(110), Seynaeve C(115), Shah M(7), Simard J(167),
Smeets A(168), Sohn C(161), Southey MC(169)(170), Swerdlow AJ(91)(171), Talhouk
A(172)(173)(174), Tamimi RM(78)(79)(117), Tapper WJ(175), Teixeira MR(176)(177),
Tengström M(111)(178)(179), Terry MB(180), Thöne K(59), Tollenaar RAEM(181),
Tomlinson I(182)(183), Torres D(105)(184), Truong T(63), Turman C(79), Turnbull
C(91), Ulmer HU(185), Untch M(186), Vachon C(110), van Asperen CJ(187), van den
Ouweland AMW(188), van Veen EM(82)(83), Wendt C(189), Whittemore AS(120)(121),
Willett W(79)(190)(191), Winqvist R(156)(157), Wolk A(192), Yang XR(45), Zhang
Y(13)(42), Easton DF(5)(7), Fasching PA(16)(193), Nevanlinna H(125), Eccles
DM(74), Pharoah PDP(5)(7), Schmidt MK(1)(194).

Author information:
(1)The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Division of
Molecular Pathology, Amsterdam, The Netherlands.
(2)University of Cambridge, Cardiovascular Epidemiology Unit, Department of
Public Health and Primary Care, Cambridge, UK. qg209@medschl.cam.ac.uk.
(3)Hannover Medical School, Gynaecology Research Unit, Hannover, Germany.
(4)The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Division of
Molecular Carcinogenesis, Amsterdam, The Netherlands.
(5)University of Cambridge, Centre for Cancer Genetic Epidemiology, Department of
Public Health and Primary Care, Cambridge, UK.
(6)QIMR Berghofer Medical Research Institute, Department of Genetics and
Computational Biology, Brisbane, Queensland, Australia.
(7)University of Cambridge, Centre for Cancer Genetic Epidemiology, Department of
Oncology, Cambridge, UK.
(8)Cambridge Experimental Cancer Medicine Centre, Cambridge, UK.
(9)University of Cambridge NHS Foundation Hospitals, Cambridge Breast Unit and
NIHR Cambridge Biomedical Research Centre, Cambridge, UK.
(10)Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Fred A.
Litwin Center for Cancer Genetics, Toronto, ON, Canada.
(11)University of Toronto, Department of Molecular Genetics, Toronto, ON, Canada.
(12)University of California Irvine, Department of Epidemiology, Genetic
Epidemiology Research Institute, Irvine, CA, USA.
(13)German Cancer Research Center (DKFZ), Division of Clinical Epidemiology and
Aging Research, Heidelberg, Germany.
(14)Fred Hutchinson Cancer Research Center, Cancer Prevention Program, Seattle,
WA, USA.
(15)University of Wisconsin-Milwaukee, Zilber School of Public Health, Milwaukee,
WI, USA.
(16)University Hospital Erlangen, Friedrich-Alexander-University
Erlangen-Nuremberg, Department of Gynecology and Obstetrics, Comprehensive Cancer
Center ER-EMN, Erlangen, Germany.
(17)German Cancer Research Center (DKFZ), Division of Cancer Epidemiology,
Heidelberg, Germany.
(18)Spanish National Cancer Research Centre (CNIO), Human Cancer Genetics
Programme, Madrid, Spain.
(19)Biomedical Network on Rare Diseases (CIBERER), Madrid, Spain.
(20)Ufa Scientific Center of Russian Academy of Sciences, Institute of
Biochemistry and Genetics, Ufa, Russia.
(21)Beckman Research Institute of City of Hope, Department of Population
Sciences, Duarte, CA, USA.
(22)University of Helsinki, Department of Oncology, Helsinki University Hospital,
Helsinki, Finland.
(23)Örebro University Hospital, Department of Oncology, Örebro, Sweden.
(24)VIB, VIB Center for Cancer Biology, Leuven, Belgium.
(25)University of Leuven, Laboratory for Translational Genetics, Department of
Human Genetics, Leuven, Belgium.
(26)Copenhagen University Hospital, Copenhagen General Population Study,
Herlevand Gentofte Hospital, Herlev, Denmark.
(27)Copenhagen University Hospital, Department of Clinical Biochemistry, Herlev
and Gentofte Hospital, Herlev, Denmark.
(28)University of Copenhagen, Faculty of Health and Medical Sciences, Copenhagen,
Denmark.
(29)Division of Cancer Prevention and Genetics, IEO, European Institute of
Oncology IRCCS Milan, Milan, 20141, Italy.
(30)Oslo University Hospital-Radiumhospitalet, Department of Cancer Genetics,
Institute for Cancer Research, Oslo, Norway.
(31)University of Oslo, Institute of Clinical Medicine, Faculty of Medicine,
Oslo, Norway.
(32)Department of Research, Vestre Viken Hospital, Drammen, Norway; Section for
Breast- and Endocrine Surgery, Department of Cancer, Division of Surgery, Cancer
and Transplantation Medicine, Oslo University Hospital-Ullevål, Oslo, Norway.
(33)Department of Radiology and Nuclear Medicine, Oslo University Hospital, Oslo,
Norway.
(34)Department of Pathology at Akershus University hospital, Lørenskog, Norway.
(35)Department of Tumor Biology, Institute for Cancer Research, Oslo University
Hospital, Oslo, Norway.
(36)Department of Oncology, Division of Surgery and Cancer and Transplantation
Medicine, Oslo University Hospital-Radiumhospitalet, Oslo, Norway.
(37)National Advisory Unit on Late Effects after Cancer Treatment, Department of
Oncology, Oslo University Hospital, Oslo, Norway.
(38)Department of Oncology, Akershus University Hospital, Lørenskog, Norway.
(39)Breast Cancer Research Consortium, Oslo University Hospital, Oslo, Norway.
(40)Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart,
Germany.
(41)University of Tübingen, Tübingen, Germany.
(42)German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK),
Heidelberg, Germany.
(43)German Cancer Research Center (DKFZ) and National Center for Tumor Diseases
(NCT), Division of Preventive Oncology, Heidelberg, Germany.
(44)Queen Mary University of London, Centre for Cancer Prevention, Wolfson
Institute of Preventive Medicine, London, UK.
(45)National Cancer Institute, Division of Cancer Epidemiology and Genetics,
Bethesda, MD, USA.
(46)Lund University, Department of Cancer Epidemiology, Clinical Sciences, Lund,
Sweden.
(47)University of Sheffield, Sheffield Institute for Nucleic Acids (SInFoNiA),
Department of Oncology and Metabolism, Sheffield, UK.
(48)University of Tübingen, Department of Gynecology and Obstetrics, Tübingen,
Germany.
(49)University of Heidelberg, Department of Obstetrics and Gynecology,
Heidelberg, Germany.
(50)German Cancer Research Center (DKFZ), Molecular Epidemiology Group, C080,
Heidelberg, Germany.
(51)The Institute of Cancer Research, Section of Cancer Genetics, London, UK.
(52)Instituto de Investigación Sanitaria San Carlos (IdISSC), Centro
Investigación Biomédica en Red de Cáncer (CIBERONC), Medical Oncology Department,
Hospital Cl’nico San Carlos, Madrid, Spain.
(53)University of Pisa, Department of Biology, Pisa, Italy.
(54)Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS),
Genomic Medicine Group, Galician Foundation of Genomic Medicine, SERGAS, Santiago
de Compostela, Spain.
(55)Universidad de Santiago de Compostela, Centro de Investigación en Red de
Enfermedades Raras (CIBERER), Santiago De Compostela, Spain.
(56)King Abdulaziz University, Center of Excellence in Genomic Medicine, Jeddah,
Kingdom of Saudi Arabia.
(57)American Cancer Society, Epidemiology Research Program, Atlanta, GA, USA.
(58)Instituto de Investigación Sanitaria Galicia Sur (IISGS), Xerencia de Xestion
Integrada de Vigo-SERGAS, Oncology and Genetics Unit, Vigo, Spain.
(59)University Medical Center Hamburg-Eppendorf, Cancer Epidemiology Group,
University Cancer Center Hamburg (UCCH), Hamburg, Germany.
(60)Roswell Park Cancer Institute, Division of Cancer Prevention and Control,
Buffalo, NY, USA.
(61)University of Cambridge, Cancer Research UK Cambridge Institute, Cambridge,
UK.
(62)University of Sydney, Westmead Institute for Medical Research, Sydney, NSW,
Australia.
(63)INSERM, University Paris-Sud, University Paris-Saclay, Cancer & Environment
Group, Center for Research in Epidemiology and Population Health (CESP),
Villejuif, France.
(64)Mayo Clinic, Department of Laboratory Medicine and Pathology, Rochester, MN,
USA.
(65)Imperial College London, Department of Epidemiology and Biostatistics, School
of Public Health, London, UK.
(66)Cancer Research Center of Lyon, INSERM U1052, Lyon, France.
(67)University of Sheffield, Academic Unit of Pathology, Department of
Neuroscience, Sheffield, UK.
(68)Karolinska Institutet, Department of Medical Epidemiology and Biostatistics,
Stockholm, Sweden.
(69)Fox Chase Cancer Center, Department of Clinical Genetics, Philadelphia, PA,
USA.
(70)Leiden University Medical Center, Department of Pathology, Leiden, The
Netherlands.
(71)Leiden University Medical Center, Department of Human Genetics, Leiden, The
Netherlands.
(72)University of Warwick, Warwick Clinical Trials Unit, Coventry, UK.
(73)University of Southampton, Southampton Clinical Trials Unit, Faculty of
Medicine, Southampton, UK.
(74)University of Southampton, Cancer Sciences Academic Unit, Faculty of
Medicine, Southampton, UK.
(75)University of Westminster, Department of Biomedical Sciences, Faculty of
Science and Technology, London, UK.
(76)University of Cambridge, Department of Oncology, Cambridge, UK.
(77)Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer
Center Erlangen-EMN, Institute of Human Genetics, University Hospital Erlangen,
Erlangen, Germany.
(78)Harvard Medical School, Channing Division of Network Medicine, Department of
Medicine, Brigham and Women’s Hospital, Boston, MA, USA.
(79)Harvard T.H. Chan School of Public Health, Department of Epidemiology,
Boston, MA, USA.
(80)University of Leipzig, Institute for Medical Informatics, Statistics and
Epidemiology, Leipzig, Germany.
(81)University of Leipzig, LIFE – Leipzig Research Centre for Civilization
Diseases, Leipzig, Germany.
(82)University of Manchester, Manchester Academic Health Science Centre, Division
of Evolution and Genomic Medicine, School of Biological Sciences, Faculty of
Biology, Medicine and Health, Manchester, UK.
(83)St Marys Hospital, Central Manchester University Hospitals NHS Foundation
Trust, Manchester Academic Health Science Centre, Manchester Centre for Genomic
Medicine, Manchester, UK.
(84)The University of Edinburgh Medical School, Usher Institute of Population
Health Sciences and Informatics, Edinburgh, UK.
(85)Cancer Research UK Edinburgh Centre, Edinburgh, UK.
(86)University Medical Centre Hamburg-Eppendorf, Institute for Medical Biometrics
and Epidemiology, Hamburg, Germany.
(87)University Medical Centre Hamburg-Eppendorf, Department of Cancer
Epidemiology, Clinical Cancer Registry, Hamburg, Germany.
(88)Copenhagen University Hospital, Department of Breast Surgery, Herlev and
Gentofte Hospital, Herlev, Denmark.
(89)University of California San Diego, Moores Cancer Center, La Jolla, CA, USA.
(90)Institute of Cancer Research, Division of Genetics and Epidemiology, London,
UK.
(91)The Institute of Cancer Research, Division of Genetics and Epidemiology,
London, UK.
(92)The Royal Marsden NHS Foundation Trust, Cancer Genetics Unit, London, UK.
(93)University Hospital of Heraklion, Department of Medical Oncology, Heraklion,
Greece.
(94)Cancer Council Victoria, Cancer Epidemiology & Intelligence Division,
Melbourne, VIC, Australia.
(95)The University of Melbourne, Melbourne School of Population and Global
Health, Centre for Epidemiology and Biostatistics, Melbourne, VIC, Australia.
(96)Monash University, Department of Epidemiology and Preventive Medicine,
Melbourne, VIC, Australia.
(97)Huntsman Cancer Institute, University of Utah School of Medicine, Department
of Dermatology, Salt Lake City, UT, USA.
(98)University of Oulu, Department of Surgery, Oulu University Hospital, Oulu,
Finland.
(99)Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer
Centre Erlangen-EMN, Department of Gynaecology and Obstetrics, University
Hospital Erlangen, Erlangen, Germany.
(100)University Hospital of Cologne, Centre for Hereditary Breast and Ovarian
Cancer, Cologne, Germany.
(101)University of Cologne, Centre for Molecular Medicine Cologne (CMMC),
Cologne, Germany.
(102)University of Southern California, Department of Preventive Medicine, Keck
School of Medicine, Los Angeles, CA, USA.
(103)Karolinska Institutet, Institute of Environmental Medicine, Stockholm,
Sweden.
(104)South General Hospital, Department of Oncology, Stockholm, Sweden.
(105)German Cancer Research Centre (DKFZ), Molecular Genetics of Breast Cancer,
Heidelberg, Germany.
(106)University of Massachusetts, Amherst, Department of Biostatistics &
Epidemiology, Amherst, MA, USA.
(107)University of Manchester, Manchester Academic Health Science Centre,
Division of Informatics, Imaging and Data Sciences, Faculty of Biology, Medicine
and Health, Manchester, UK.
(108)Wythenshawe Hospital, Manchester University NHS Foundation Trust,
Nightingale Breast Screening Centre, Manchester, UK.
(109)Manchester University NHS Foundation Trust, Manchester Academic Health
Science Centre, NIHR Manchester Biomedical Research Unit, Manchester, UK.
(110)Mayo Clinic, Department of Health Sciences Research, Rochester, MN, USA.
(111)University of Eastern Finland, Translational Cancer Research Area, Kuopio,
Finland.
(112)University of Eastern Finland, Institute of Clinical Medicine, Pathology and
Forensic Medicine, Kuopio, Finland.
(113)Kuopio University Hospital, Imaging Centre, Department of Clinical
Pathology, Kuopio, Finland.
(114)Saarland Cancer Registry, Saarbruecken, Germany.
(115)Erasmus MC Cancer Institute, Department of Medical Oncology, Family Cancer
Clinic, Rotterdam, The Netherlands.
(116)University of Manchester, Institute of Cancer studies, Manchester, UK.
(117)Harvard T.H. Chan School of Public Health, Program in Genetic Epidemiology
and Statistical Genetics, Boston, MA, USA.
(118)University of Oxford, Nuffield Department of Population Health, Oxford, UK.
(119)Cancer Prevention Institute of California, Department of Epidemiology,
Fremont, CA, USA.
(120)Stanford University School of Medicine, Department of Health Research and
Policy – Epidemiology, Stanford, CA, USA.
(121)Stanford University School of Medicine, Department of Biomedical Data
Science, Stanford, CA, USA.
(122)Tampere University Hospital, Department of Oncology, Tampere, Finland.
(123)Pomeranian Medical University, Department of Genetics and Pathology,
Szczecin, Poland.
(124)National University of Ireland, Surgery, School of Medicine, Galway,
Ireland.
(125)University of Helsinki, Department of Obstetrics and Gynaecology, Helsinki
University Hospital, Helsinki, Finland.
(126)Bashkir State University, Department of Genetics and Fundamental Medicine,
Ufa, Russia.
(127)National Cancer Institute, Radiation Epidemiology Branch, Division of Cancer
Epidemiology and Genetics, Bethesda, MD, USA.
(128)Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Prosserman
Centre for Population Health Research, Toronto, ON, Canada.
(129)University of Toronto, Division of Epidemiology, Dalla Lana School of Public
Health, Toronto, ON, Canada.
(130)Johanniter Krankenhaus, Department of Internal Medicine, Evangelische
Kliniken Bonn gGmbH, Bonn, Germany.
(131)Erasmus MC Cancer Institute, Department of Surgical Oncology, Family Cancer
Clinic, Rotterdam, The Netherlands.
(132)University of Hawaii Cancer Center, Epidemiology Program, Honolulu, HI, USA.
(133)Carmel Medical Center and Technion Faculty of Medicine, Clalit National
Cancer Control Center, Haifa, Israel.
(134)Tianjin Medical University Cancer Institute and Hospital, Department of
Epidemiology, Tianjin, China.
(135)Karolinska Institutet, Department of Molecular Medicine and Surgery,
Stockholm, Sweden.
(136)University of Washington School of Public Health, Department of
Epidemiology, Seattle, WA, USA.
(137)Fred Hutchinson Cancer Research Center, Public Health Sciences Division,
Seattle, WA, USA.
(138)M. Sklodowska-Curie Cancer Centre, Oncology Institute, Department of Cancer
Epidemiology and Prevention, Warsaw, Poland.
(139)GmbH, German Breast Group, Neu Isenburg, Germany.
(140)Fondazione IRCCS (Istituto Di Ricovero e Cura a Carattere Scientifico)
Istituto Nazionale dei Tumori (INT), Unit of Medical Genetics, Department of
Medical Oncology and Haematology, Milan, Italy.
(141)Karolinska Institutet, Department of Clinical Science and Education,
Sšdersjukhuset, Stockholm, Sweden.
(142)University of California San Diego, Department of Family Medicine and Public
Health, La Jolla, CA, USA.
(143)The Alfred Hospital, Anatomical Pathology, Melbourne, VIC, Australia.
(144)Ludwig Maximilian University of Munich, Department of Gynaecology and
Obstetrics, Munich, Germany.
(145)University of Heidelberg, Faculty of Medicine, Heidelberg, Germany.
(146)University of Toronto, Department of Laboratory Medicine and Pathobiology,
Toronto, ON, Canada.
(147)University Health Network, Laboratory Medicine Program, Toronto, ON, Canada.
(148)INSERM UMR-S1147, Université Paris Sorbonne Cité, Paris, France.
(149)University of California Davis, Department of Biochemistry and Molecular
Medicine, Davis, CA, USA.
(150)Queen’s University Belfast, Centre for Cancer Research and Cell Biology,
Belfast, Ireland, UK.
(151)University of New Mexico, University of New Mexico Health Sciences Center,
Albuquerque, NM, USA.
(152)Hospital Monte Naranco, Servicio de Cirug’a General y Especialidades,
Oviedo, Spain.
(153)Hospital Universitario Puerta de Hierro, Medical Oncology Department,
Madrid, Spain.
(154)The FIRC (Italian Foundation for Cancer Research) Institute of Molecular
Oncology, IFOM, Milan, Italy.
(155)King’s College London, Research Oncology, Guy’s Hospital, London, UK.
(156)University of Oulu, Laboratory of Cancer Genetics and Tumour Biology, Cancer
and Translational Medicine Research Unit, Biocentre Oulu, Oulu, Finland.
(157)Northern Finland Laboratory Centre Oulu, Laboratory of Cancer Genetics and
Tumour Biology, Oulu, Finland.
(158)Fondazione IRCCS (Istituto Di Ricovero e Cura a Carattere Scientifico)
Istituto Nazionale dei Tumori (INT), Unit of Molecular Bases of Genetic Risk and
Genetic Testing, Department of Research, Milan, Italy.
(159)UCLH Foundation Trust, Department of Oncology, London, UK.
(160)University Hospital of Larissa, Department of Oncology, Larissa, Greece.
(161)University of Heidelberg, National Centre for Tumour Diseases, Heidelberg,
Germany.
(162)Case Western Reserve University, Department of Population and Quantitative
Health Sciences, Cleveland, OH, USA.
(163)John Hunter Hospital, Division of Molecular Medicine, Pathology North,
Newcastle, NSW, Australia.
(164)University of Newcastle, Discipline of Medical Genetics, School of
Biomedical Sciences and Pharmacy, Faculty of Health, Callaghan, NSW, Australia.
(165)John Hunter Hospital, Hunter Medical Research Institute, Newcastle, NSW,
Australia.
(166)University of Newcastle, Centre for Information Based Medicine, Callaghan,
Newcastle, NSW, Australia.
(167)Centre Hospitalier Universitaire de Québec – Université Laval Research
Centre, Genomics Centre, Québec City, QC, Canada.
(168)University Hospitals Leuven, Department of Surgical Oncology, Leuven,
Belgium.
(169)Monash University, Precision Medicine, School of Clinical Sciences at Monash
Health, Clayton, Victoria, Australia.
(170)The University of Melbourne, Department of Clinical Pathology, Melbourne,
VIC, Australia.
(171)The Institute of Cancer Research, Division of Breast Cancer Research,
London, UK.
(172)BC Cancer Agency and University of British Columbia, British Columbia’s
Ovarian Cancer Research (OVCARE) Program, Vancouver General Hospital, Vancouver,
BC, Canada.
(173)University of British Columbia, Department of Pathology and Laboratory
Medicine, Vancouver, BC, Canada.
(174)University of British Columbia, Department of Obstetrics and Gynaecology,
Vancouver, BC, Canada.
(175)University of Southampton, Faculty of Medicine, Southampton, UK.
(176)Portuguese Oncology Institute, Department of Genetics, Porto, Portugal.
(177)University of Porto, Biomedical Sciences Institute (ICBAS), Porto, Portugal.
(178)Kuopio University Hospital, Cancer Centre, Kuopio, Finland.
(179)University of Eastern Finland, Institute of Clinical Medicine, Oncology,
Kuopio, Finland.
(180)Columbia University, Department of Epidemiology, Mailman School of Public
Health, New York, NY, USA.
(181)Leiden University Medical Centre, Department of Surgery, Leiden, The
Netherlands.
(182)University of Birmingham, Institute of Cancer and Genomic Sciences,
Birmingham, UK.
(183)University of Oxford, Wellcome Trust Centre for Human Genetics and Oxford
NIHR Biomedical Research Centre, Oxford, UK.
(184)Pontificia Universidad Javeriana, Institute of Human Genetics, Bogota,
Colombia.
(185)Frauenklinik der Stadtklinik Baden-Baden, Baden-Baden, Germany.
(186)Helios Clinics Berlin-Buch, Department of Gynaecology and Obstetrics,
Berlin, Germany.
(187)Leiden University Medical Centre, Department of Clinical Genetics, Leiden,
The Netherlands.
(188)Erasmus University Medical Centre, Department of Clinical Genetics,
Rotterdam, The Netherlands.
(189)Karolinska Institutet, Department of Clinical Science and Education,
Södersjukhuset, Stockholm, Sweden.
(190)Harvard T.H. Chan School of Public Health, Department of Nutrition, Boston,
MA, USA.
(191)Brigham and Women’s Hospital and Harvard Medical School, Channing Division
of Network Medicine, Boston, MA, USA.
(192)Karolinska Institutet, Department of Environmental Medicine, Division of
Nutritional Epidemiology, Stockholm, Sweden.
(193)University of California at Los Angeles, David Geffen School of Medicine,
Department of Medicine Division of Hematology and Oncology, Los Angeles, CA, USA.
(194)The Netherlands Cancer Institute – Antoni van Leeuwenhoek hospital, Division
of Psychosocial Research and Epidemiology, Amsterdam, The Netherlands.

BACKGROUND: We examined the associations between germline variants and breast
cancer mortality using a large meta-analysis of women of European ancestry.
METHODS: Meta-analyses included summary estimates based on Cox models of twelve
datasets using ~10.4 million variants for 96,661 women with breast cancer and
7697 events (breast cancer-specific deaths). Oestrogen receptor (ER)-specific
analyses were based on 64,171 ER-positive (4116) and 16,172 ER-negative (2125)
patients. We evaluated the probability of a signal to be a true positive using
the Bayesian false discovery probability (BFDP).
RESULTS: We did not find any variant associated with breast cancer-specific
mortality at P < 5 × 10-8. For ER-positive disease, the most significantly
associated variant was chr7:rs4717568 (BFDP = 7%, P = 1.28 × 10-7, hazard ratio
[HR] = 0.88, 95% confidence interval [CI] = 0.84-0.92); the closest gene is
AUTS2. For ER-negative disease, the most significant variant was chr7:rs67918676
(BFDP = 11%, P = 1.38 × 10-7, HR = 1.27, 95% CI = 1.16-1.39); located within a
long intergenic non-coding RNA gene (AC004009.3), close to the HOXA gene cluster.
CONCLUSIONS: We uncovered germline variants on chromosome 7 at BFDP < 15% close
to genes for which there is biological evidence related to breast cancer outcome.
However, the paucity of variants associated with mortality at genome-wide
significance underpins the challenge in providing genetic-based individualised
prognostic information for breast cancer patients.

DOI: 10.1038/s41416-019-0393-x
PMID: 30787463

Cancer Gene Ther. 2019 Feb 21. doi: 10.1038/s41417-019-0087-9. [Epub ahead of
print]

Expression profile and bioinformatics analysis of COMMD10 in BALB/C mice and
human.

Fan Y(1), Zhang L(1), Sun Y(1), Yang M(1), Wang X(1), Wu X(1), Huang W(1), Chen
L(2), Pan S(3), Guan J(4).

Author information:
(1)Department of Radiation Oncology, Nanfang Hospital, Southern Medical
University, Guangzhou, Guangdong, China.
(2)Department of Radiation Oncology, Nanfang Hospital, Southern Medical
University, Guangzhou, Guangdong, China. chenlh5461@163.com.
(3)Department of Radiotherapy, Yue Bei People’s Hospital, Shaoguan, Guangdong
Province, China. 13826331948@139.com.
(4)Department of Radiation Oncology, Nanfang Hospital, Southern Medical
University, Guangzhou, Guangdong, China. guanjian5461@163.com.

COMMD10, a member of COMMD protein, has been proved to target p65 NF-kappaB
(nuclear factor-kappaB) subunit and reduce its nuclear translocation, thereby
leading to the inactivation of NF-kappaB pathway and suppression of colorectal
cancer invasion and metastasis. The aim of this study is to explore its
expression pattern and tissue distribution in human normal tissues and other
tumor tissues and to investigate the relevant mechanism. We firstly provided the
expression profile and histological distribution of COMMD10 in various BALB/c
mice tissues and identified the biological distribution of COMMD10 in different
kinds of human normal and tumor tissues. We verified the expression profile of
COMMD10 using TCGA database. The interacting genes of COMMD10 were predicted by
using STRING using. Finally, we performed database, and the microRNAs targeting
COMMD10 were predicted using miRDB, miRWalk, TargetScan and microRNA. GO and KEGG
pathway analyses were performed to predict the biological function of COMMD10 and
its interacting genes. mRNA expression of COMMD10 showed the highest level in the
lung and spleen, and the lowest level in the heart and brain.
Immunohistochemistry detection revealed that COMMD10 was expressed in different
tissues with different degrees and was was located mainly in the cytoplasm.
Subsequently, we showed that COMMD10 displayed various degrees of expression in
different human normal tissues that mainly located in cytoplasm, while COMMD10 of
liver cells resided in both nucleus and cytoplasm. All the tumor tissues except
breast small cell carcinoma, breast phyllodes tumor, lung adenocarcinoma,
thymoma, cervical cancer and bladder urothelial carcinoma showed that COMMD10 was
positive staining in cytoplasm. Kaplan-Meier plotter indicated that renal clear
cell carcinoma patients with increased expression level of COMMD10 exhibited
longer survival. STRING database revealed that COMMD10 had 41 interacting genes,
and data from 4 different databases indicated that hsa-miR-590-3p may be the
potential regulator of COMMD10. GO analysis demonstrated that COMMD10 and its
interacting genes were mainly enriched in Cullin-RING ubiquitin ligase complexes,
binding and transport of copper ions, the transport and steady-state maintenance
of copper ions, transcription, translation and transport of proteins, and
negatively regulate the activity of NF-kappaB transcription factors. KEGG pathway
showed that COMMD10 and its interacting genes were mainly involved in renal cell
carcinoma, HIF-1 signaling pathways, ubiquitination-mediated proteolysis,
endocytosis and mineral absorption. COMMD10 may play a tumor suppressive role in
renal clear cell carcinoma through the
miR-590-3p-COMMD10-Cul2-RBX1-NF-κB/HIF/NRF2 pathway and regulate the chemotherapy
resistance of various tumor cells to cisplatin.

DOI: 10.1038/s41417-019-0087-9
PMID: 30787448

Nat Commun. 2019 Feb 20;10(1):932. doi: 10.1038/s41467-019-08956-x.

Publisher Correction: Pharmacological reactivation of MYC-dependent apoptosis
induces susceptibility to anti-PD-1 immunotherapy.

Haikala HM(1)(2), Anttila JM(1), Marques E(1), Raatikainen T(1), Ilander M(3),
Hakanen H(3), Ala-Hongisto H(1), Savelius M(1), Balboa D(4), Von Eyss B(5),
Eskelinen V(1), Munne P(1), Nieminen AI(6), Otonkoski T(4), Schüler J(7), Laajala
TD(8)(9), Aittokallio T(8)(9), Sihto H(10)(11), Mattson J(11), Heikkilä P(12),
Leidenius M(13), Joensuu H(10)(11), Mustjoki S(3), Kovanen P(14), Eilers M(15),
Leverson JD(16), Klefström J(17).

Author information:
(1)Cancer Cell Circuitry Laboratory, Research Programs Unit/Translational Cancer
Biology and Medicum, University of Helsinki, Street address: Haartmaninkatu 8,
P.O. Box 63, 00014, Helsinki, Finland.
(2)Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard
Medical School, 360 Longwood Ave, 02215, Boston, MA, USA.
(3)Hematology Research Unit Helsinki, Department of Clinical Chemistry and
Hematology, University of Helsinki and Helsinki University Hospital Comprehensive
Cancer Center, Haartmaninkatu 8, 00290, Helsinki, Finland.
(4)Research Programs Unit/Molecular Neurology, Biomedicum Stem Cell Center,
University of Helsinki, Haartmaninkatu 8, 00290, Helsinki, Finland.
(5)Leibniz Institute of Age Research, Fritz Lipmann Institute e.V,
Beutenbergstraße 11, 07745, Jena, Germany.
(6)Department of Biosciences and Institute of Biotechnology, University of
Helsinki, Viikinkaari 5, 00790, Helsinki, Finland.
(7)Oncotest GmbH, (Now part of Charles River Laboratories Inc, 251 Ballardvale
St, Wilmington, MA 01887, USA), Freiburg, Germany.
(8)Institute for Molecular Medicine Finland (FIMM), University of Helsinki,
Tukholmankatu 3, 00290, Helsinki, Finland.
(9)Department of Mathematics and Statistics, University of Turku, Vesilinnantie
5, 20500, Turku, Finland.
(10)Research Programs Unit / Translational Cancer Biology & Medicum, University
of Helsinki, P.O. Box 63, (Street address: Haartmaninkatu 8), 00290, Helsinki,
Finland.
(11)Department of Oncology, University of Helsinki and Helsinki University
Hospital, Haartmaninkatu 4, 00290, Helsinki, Finland.
(12)Department of Pathology, University of Helsinki and Helsinki University
Hospital, Haartmaninkatu 3, 00290, Helsinki, Finland.
(13)Breast Surgery Unit, Helsinki University Hospital, Kasarmikatu 11-13, 00290,
Helsinki, Finland.
(14)Department of Pathology, HUSLAB and Haartman Institute, University of
Helsinki and Helsinki University Hospital, Haartmaninkatu 3, 00290, Helsinki,
Finland.
(15)Theodor Boveri Institute and Comprehensive Cancer Center Mainfranken,
Biocenter, University of Würzburg, Am Hubland, D-970074, Germany.
(16)Oncology Development, AbbVie, Inc., 1 N Waukegan Road, North Chicago, 60064,
IL, USA.
(17)Cancer Cell Circuitry Laboratory, Research Programs Unit/Translational Cancer
Biology and Medicum, University of Helsinki, Street address: Haartmaninkatu 8,
P.O. Box 63, 00014, Helsinki, Finland. Juha.Klefstrom@helsinki.fi.

Erratum for
Nat Commun. 2019 Feb 6;10(1):620.

The original version of this Article contained an error in Fig. 7. In panel b,
the survival curves were shifted relative to the y axis. This error has been
corrected in both the PDF and HTML versions of the Article.

DOI: 10.1038/s41467-019-08956-x
PMID: 30787321

Cell Death Dis. 2019 Feb 20;10(3):175. doi: 10.1038/s41419-019-1382-y.

circTADA2As suppress breast cancer progression and metastasis via targeting
miR-203a-3p/SOCS3 axis.

Xu JZ(1), Shao CC(2), Wang XJ(3), Zhao X(4), Chen JQ(3), Ouyang YX(2), Feng J(2),
Zhang F(5), Huang WH(6), Ying Q(3), Chen CF(7), Wei XL(8), Dong HY(9), Zhang
GJ(10)(11)(12), Chen M(13)(14).

Author information:
(1)Department of Bioinformatics, Shantou University Medical College (SUMC),
515041, Shantou, China. jzxu01@stu.edu.cn.
(2)ChangJiang Scholar’s Laboratory, Shantou University Medical College, 515041,
Shantou, China.
(3)Key Lab of Diagnosis & Treatment Technology on Thoracic Oncology, Zhejiang
Cancer Hospital, 310000, Hangzhou, China.
(4)Department of Bioinformatics, Shantou University Medical College (SUMC),
515041, Shantou, China.
(5)Guangdong Provincial Key Laboratory on Breast Cancer Diagnosis and Treatment,
Cancer Hospital of Shantou University Medical College, 515041, Shantou, China.
(6)The Breast Center, Cancer Hospital of Shantou University Medical College,
515041, Shantou, China.
(7)Department of Thyroid and Breast Surgery, First Affiliated Hospital of Shantou
University Medical College, 515041, Shantou, China.
(8)Department of Pathology, Cancer Hospital of Shantou University Medical
College, 515041, Shantou, China.
(9)Department of Pathology, Linyi People’s Hospital, 276000, Linyi, China.
(10)ChangJiang Scholar’s Laboratory, Shantou University Medical College, 515041,
Shantou, China. guoj_zhang@yahoo.com.
(11)The Breast Center, Cancer Hospital of Shantou University Medical College,
515041, Shantou, China. guoj_zhang@yahoo.com.
(12)The Cancer Center, Xiang’an Hospital of Xiamen University, 2000 Xiang’an East
Rd., 361111, Xiamen, Fujian, China. guoj_zhang@yahoo.com.
(13)ChangJiang Scholar’s Laboratory, Shantou University Medical College, 515041,
Shantou, China. mchen@xah.xmu.edu.cn.
(14)The Cancer Center, Xiang’an Hospital of Xiamen University, 2000 Xiang’an East
Rd., 361111, Xiamen, Fujian, China. mchen@xah.xmu.edu.cn.

More and more evidence indicates that circular RNAs (circRNAs) have important
roles in several diseases, especially in cancers. However, their involvement
remains to be investigated in breast cancer. Through screening circRNA profile,
we identified 235 differentially expressed circRNAs in breast cancer.
Subsequently, we explored the clinical significance of two circTADA2As in a large
cohort of triple-negative breast cancer (TNBC), and performed functional analysis
of circTADA2A-E6 in vitro and in vivo to support clinical findings. Finally, we
evaluated the effect of circTADA2A-E6 on miR-203a-3p and its target gene SOCS3.
We detected two circRNAs, circTADA2A-E6 and circTADA2A-E5/E6, which were among
the top five differentially expressed circRNAs in breast cancer. They were
consistently and significantly decreased in a large cohort of breast cancer
patients, and their downregulation was associated with poor patient survival for
TNBC. Especially, circTADA2A-E6 suppressed in vitro cell proliferation,
migration, invasion, and clonogenicity and possessed tumor-suppressor capability.
circTADA2A-E6 preferentially acted as a miR-203a-3p sponge to restore the
expression of miRNA target gene SOCS3, resulting in a less aggressive oncogenic
phenotype. circTADA2As as promising prognostic biomarkers in TNBC patients, and
therapeutic targeting of circTADA2As/miRNA/mRNA network may be a potential
strategy for the treatment of breast cancer.

DOI: 10.1038/s41419-019-1382-y
PMID: 30787278

Cell Death Dis. 2019 Feb 20;10(3):169. doi: 10.1038/s41419-019-1335-5.

ZFP57 suppress proliferation of breast cancer cells through down-regulation of
MEST-mediated Wnt/β-catenin signalling pathway.

Chen L(1), Wu X(1), Xie H(1), Yao N(1), Xia Y(1), Ma G(1), Qian M(1), Ge H(1),
Cui Y(1), Huang Y(1), Wang S(2), Zheng M(3).

Author information:
(1)Department of Breast Surgery, The First Affiliated Hospital of Nanjing Medical
University, 300 Guangzhou Road, Nanjing, Jiangsu, 210029, China.
(2)Department of Breast Surgery, The First Affiliated Hospital of Nanjing Medical
University, 300 Guangzhou Road, Nanjing, Jiangsu, 210029, China.
ws0801@hotmail.com.
(3)Department of Breast Surgery, The First Affiliated Hospital of Nanjing Medical
University, 300 Guangzhou Road, Nanjing, Jiangsu, 210029, China.
zhengmingjie1014@163.com.

Activation of oncogenes by promoter hypomethylation plays an important role in
tumorigenesis. Zinc finger protein 57 (ZFP57), a member of KRAB-ZFPs, could
maintain DNA methylation in embryonic stem cells (ESCs), although its role and
underlying mechanisms in breast cancer are not well understood. In this study, we
found that ZFP57 had low expression in breast cancer, and overexpression of ZFP57
could inhibit the proliferation of breast cancer cells by inhibiting the
Wnt/β-catenin pathway. MEST was validated as the direct target gene of ZFP57 and
MEST may be down-regulated by ZFP57 through conserving DNA methylation.
Furthermore, overexpression of MEST could restore the tumour-suppressed and the
Wnt/β-catenin pathway inactivated effects of ZFP57. ZFP57-MEST and the
Wnt/β-catenin pathway axis are involved in breast tumorigenesis, which may
represent a potential diagnostic biomarker, and provide a new insight into a
novel therapeutic strategy for breast cancer patients.

DOI: 10.1038/s41419-019-1335-5
PMID: 30787268

Tohoku J Exp Med. 2019;247(2):99-110. doi: 10.1620/tjem.247.99.

Association between Family History of Cancer and Lung Cancer Risk among Japanese
Men and Women.

Yoshida K(1)(2)(3)(4), Takizawa Y(1), Nishino Y(4)(5), Takahashi S(6), Kanemura
S(4), Omori J(2), Kurosawa H(3), Maemondo M(7)(8), Minami Y(1)(4)(9).

Author information:
(1)Division of Community Health, Tohoku University Graduate School of Medicine.
(2)Division of Public Health Nursing, Tohoku University Graduate School of
Medicine.
(3)Department of Occupational Health, Tohoku University Graduate School of
Medicine.
(4)Division of Cancer Epidemiology and Prevention, Miyagi Cancer Center Research
Institute.
(5)Department of Epidemiology and Public Health, Kanazawa Medical University.
(6)Department of Thoracic Surgery, Miyagi Cancer Center Hospital.
(7)Department of Respiratory Medicine, Miyagi Cancer Center Hospital.
(8)Division of Pulmonary Medicine, Allergy, and Rheumatology, Department of
Internal Medicine, Iwate Medical University School of Medicine.
(9)Center for Preventive Medicine, Osaki Citizen Hospital.

Although cigarette smoking is a major risk factor for lung cancer, genetic
susceptibility may also affect lung cancer risk. To explore the role of genetic
risk, this case-control study investigated the association between family history
of cancer at several sites and lung cancer risk. A total of 1,733 lung cancer
cases and 6,643 controls were selected from patients aged 30 years and over
admitted to a single hospital in Japan between 1997 and 2009. Information on
family history of cancer was collected using a self-administered questionnaire
and odds ratios (ORs) were estimated by unconditional logistic regression. Family
history of lung cancer in first-degree relatives was associated with an increased
risk of lung cancer among both sexes. According to histology and type of
relatives, a parental history of lung cancer was significantly associated with an
increased risk of female adenocarcinoma (OR = 1.72). Stratification by smoking
status revealed that this significant positive association in women was limited
to ever-smokers (OR = 4.13). In men, a history of lung cancer in siblings was
significantly associated with an increased risk of small cell carcinoma (OR =
2.28) and adenocarcinoma (OR = 2.25). Otherwise, positive associations between
history of breast (OR = 1.99) and total (OR = 1.71) cancers in siblings and the
risk of male adenocarcinoma were observed. These results suggest that inherited
genetic susceptibility may contribute to the development of lung cancer. In men,
shared exposure to environmental factors among siblings may also be responsible
for the increase in lung cancer risk.

DOI: 10.1620/tjem.247.99
PMID: 30787235

Biol Pharm Bull. 2019 Feb 21. doi: 10.1248/bpb.b18-01026. [Epub ahead of print]

Discovery of inhibitors of membrane traffic from a panel of clinically effective
anticancer drugs.

Kamata H(1)(2), Sadahiro S(2), Yamori T(1).

Author information:
(1)Division of Molecular Pharmacology, Cancer Chemotherapy Center, Japanese
Foundation for Cancer Research.
(2)Tokai University, Graduate School of Medicine.

In addition to their major targets, clinically effective drugs may have unknown
off-targets. By identifying such off-targets it may be possible to repurpose
approved drugs for new indications. We are interested in the Golgi apparatus as a
novel target for cancer therapy, but there is a paucity of candidate
Golgi-disrupting drugs. Here, we aimed to identify Golgi-disrupting compounds
from a panel of 34 approved anticancer drugs by using HBC-4 human breast cancer
cells and immunofluorescence microscopy to visualize the Golgi apparatus. The
screen identified five drugs having Golgi-disrupting activity. Four of them were
vinca alkaloids (vinorelbine, vindesine, vincristine and vinblastine), and the
fifth drug was eribulin. This is the first study to demonstrate that vinorelbine,
vindesine and eribulin possess Golgi-disrupting activity. The 5 drugs are known
to inhibit tubulin polymerization and to induce microtubule depolymerization.
Interestingly, a microtubule-stabilizer paclitaxel did not induce
Golgi-disruption, suggesting that the three-dimensionally preserved microtubules
are partly responsible for maintaining the Golgi complex. Concerning eribulin, a
noteworthy drug because of its high clinical efficacy against advanced breast
cancer, we further confirmed its Golgi-disrupting activity in three different
human breast cancer cell lines, BSY-1, MDA-MB-231 and MCF-7. Golgi-disruption may
contribute to anticancer efficacy of eribulin. In conclusion, the present study
revealed that four vinca alkaloids and eribulin possessed potential
Golgi-disrupting activity among a panel of 34 approved anticancer drugs. Other
drugs covering various molecular-targeted drugs and classical DNA-damaging drugs
showed no Golgi-disrupting effect. These results suggest that tubulin
polymerization-inhibitors might be promising candidate drugs with
Golgi-disrupting activity.

DOI: 10.1248/bpb.b18-01026
PMID: 30787205

Aging (Albany NY). 2019 Feb 20. doi: 10.18632/aging.101803. [Epub ahead of print]

Towards a more precise and individualized assessment of breast cancer risk.

Wood ME(1)(2), Farina NH(1)(3), Ahern TP(1)(3)(4), Cuke ME(1)(2), Stein JL(1)(3),
Stein GS(1)(3)(4), Lian JB(1)(3).

Author information:
(1)University of Vermont Cancer Center, The Robert Larner MD College of Medicine,
University of Vermont, Burlington, VT 05405, USA.
(2)Division of Hematology and Oncology, The Robert Larner MD College of Medicine,
University of Vermont Medical Center, Burlington, VT 05405, USA.
(3)Department of Biochemistry, and The Robert Larner MD College of Medicine,
University of Vermont, Burlington, VT 05405, USA.
(4)Department of Surgery, The Robert Larner MD College of Medicine, University of
Vermont, Burlington, VT 05405, USA.

Many clinically based models are available for breast cancer risk assessment;
however, these models are not particularly useful at the individual level,
despite being designed with that intent. There is, therefore, a significant need
for improved, precise individualized risk assessment. In this Research
Perspective, we highlight commonly used clinical risk assessment models and
recent scientific advances to individualize risk assessment using precision
biomarkers. Genome-wide association studies have identified >100 single
nucleotide polymorphisms (SNPs) associated with breast cancer risk, and polygenic
risk scores (PRS) have been developed by several groups using this information.
The ability of a PRS to improve risk assessment is promising; however, validation
in both genetically and ethnically diverse populations is needed. Additionally,
novel classes of biomarkers, such as microRNAs, may capture clinically relevant
information based on epigenetic regulation of gene expression. Our group has
recently identified a circulating-microRNA signature predictive of long-term
breast cancer in a prospective cohort of high-risk women. While progress has been
made, the importance of accurate risk assessment cannot be understated. Precision
risk assessment will identify those women at greatest risk of developing breast
cancer, thus avoiding overtreatment of women at average risk and identifying the
most appropriate candidates for chemoprevention or surgical prevention.

DOI: 10.18632/aging.101803
PMID: 30787204

Mol Cancer Ther. 2019 Feb 20. pii: molcanther.1085.2018. doi:
10.1158/1535-7163.MCT-18-1085. [Epub ahead of print]

TAS0728, a covalent-binding, HER2-selective kinase inhibitor shows potent
antitumor activity in preclinical models.

Irie H(1), Ito K(2), Fujioka Y(2), Oguchi K(3), Fujioka A(3), Hashimoto A(4),
Ohsawa H(3), Tanaka K(2), Funabashi K(2), Araki H(2), Kawai Y(2), Shimamura T(2),
Wadhwa R(5), Ohkubo S(3), Matsuo K(3).

Author information:
(1)Discovery and Preclinical Research Division, Taiho Pharmaceutical Co.,Ltd
hiroki-irie@taiho.co.jp.
(2)Discovery and Preclinical Research Division, Taiho Pharmaceutical Co.,Ltd.
(3)Discovery and Preclinical Research Division, Taiho Pharmaceutical Co., Ltd.
(4)Discovery and Preclinical Research Divisionr, Taiho Pharmaceutical Co.,Ltd.
(5)DBT-AIST International Laboratory for Advanced Biomedicine (DAILAB), National
Institute of Advanced Industrial Science & Technology (AIST).

Activated human epidermal growth receptor (HER) 2 is a promising therapeutic
target for various cancers. Although several reports have described HER2
inhibitors in development, no covalent-binding inhibitor selective for HER2 has
been reported. Here, we report a novel compound, TAS0728 that covalently binds to
HER2 at C805 and selectively inhibits its kinase activity. Once TAS0728 bound to
HER2 kinase, the inhibitory activity was not affected by a high-ATP
concentration. A kinome-wide biochemical panel and cellular assays established
that TAS0728 possesses high specificity for HER2 over wild-type epidermal growth
factor receptor (EGFR). Cellular pharmacodynamics assays using MCF10A cells
engineered to express various mutated HER2 genes revealed that TAS0728 potently
inhibited the phosphorylation of mutated HER2 and wild-type HER2. Furthermore,
TAS0728 exhibited robust and sustained inhibition of the phosphorylation of HER2,
HER3, and downstream effectors, thereby inducing apoptosis of HER2-amplified
breast cancer cells and in tumor tissues of a xenograft model. TAS0728 induced
tumor regression in mouse xenograft models bearing HER2 signal-dependent tumors
and exhibited a survival benefit without any evident toxicity in a peritoneal
dissemination mouse model bearing HER2-driven cancer cells. Taken together, our
results demonstrated that TAS0728 may offer a promising therapeutic option with
improved efficacy as compared to current HER2 inhibitors for HER2-activated
cancers. Assessment of TAS0728 in ongoing clinical trials is awaited
(NCT03410927).

DOI: 10.1158/1535-7163.MCT-18-1085
PMID: 30787176

J Natl Compr Canc Netw. 2019 Feb;17(2):190-192. doi: 10.6004/jnccn.2018.7271.

CDK4/6 Inhibitors for Advanced Hormone Receptor-Positive Breast Cancer, 2019 and
Beyond.

Layman RM.

DOI: 10.6004/jnccn.2018.7271
PMID: 30787131

J Natl Compr Canc Netw. 2019 Feb;17(2):149-158. doi: 10.6004/jnccn.2018.7078.

Impact of Incident Cancer on Short-Term Coronary Artery Disease-Related
Healthcare Expenditures Among Medicare Beneficiaries.

Chopra I(1), Mattes MD(1), Findley P(1), Tan X(1), Dwibedi N(1), Sambamoorthi
U(1).

Author information:
(1)Department of Pharmaceutical Systems and Policy, West Virginia University, and
Department of Medical Education, WVU School of Medicine, Morgantown, West
Virginia; and School of Social Work, Rutgers University, New Brunswick, New
Jersey.

Background: Healthcare spending for coronary artery disease (CAD)-related
services is higher than for other chronic conditions. Diagnosis of incident
cancer may impede management of CAD, thereby increasing the risk of CAD-related
complications and associated healthcare expenditures. This study examined the
relationship between incident cancer and CAD-related expenditures among elderly
Medicare beneficiaries. Patients and Methods: A retrospective longitudinal study
was conducted using the SEER-Medicare linked registries and a 5% noncancer random
sample of Medicare beneficiaries. Elderly fee-for-service Medicare beneficiaries
with preexisting CAD and with incident breast, colorectal, or prostate cancer
(N=12,095) or no cancer (N=34,237) were included. CAD-related healthcare
expenditures comprised Medicare payments for inpatient, home healthcare, and
outpatient services. Expenditures were measured every 120 days during the 1-year
preindex and 1-year postindex periods. Adjusted relationship between incident
cancer and expenditures was analyzed using the generalized linear mixed models.
Results: Overall, CAD-related mean healthcare expenditures in the preindex period
accounted for approximately 32.6% to 39.5% of total expenditures among women and
41.5% to 46.8% among men. All incident cancer groups had significantly higher
CAD-related expenditures compared with noncancer groups (P<.0001). Men and women
with colorectal cancer (CRC) had 166% and 153% higher expenditures, respectively,
compared with their noncancer counterparts. Furthermore, men and women with CRC
had 57% and 55% higher expenditures compared with those with prostate or breast
cancer, respectively. Conclusions: CAD-related expenditures were higher for
elderly Medicare beneficiaries with incident cancer, specifically for those with
CRC. This warrants the need for effective programs and policies to reduce
CAD-related expenditures. Close monitoring of patients with a cancer diagnosis
and preexisting CAD may prevent CAD-related events and expenditures.

DOI: 10.6004/jnccn.2018.7078
PMID: 30787128

J Natl Compr Canc Netw. 2019 Feb;17(2):141-147. doi: 10.6004/jnccn.2018.7094.

Retrospective Analysis of Treatment Patterns and Effectiveness of Palbociclib and
Subsequent Regimens in Metastatic Breast Cancer.

Xi J(1)(1), Oza A(1), Thomas S(1), Ademuyiwa F(1), Weilbaecher K(1), Suresh R(1),
Bose R(1), Cherian M(1), Hernandez-Aya L(1), Frith A(1), Peterson L(1), Luo J(1),
Krishnamurthy J(1), Ma CX(1).

Author information:
(1)Washington University School of Medicine, and St. Luke’s Hospital, St. Louis,
Missouri.

Background: Cyclin-dependent kinase (CDK) 4/6 inhibitors are now the standard of
care for hormone receptor-positive (HR+), HER2-negative (HER-) metastatic breast
cancer (MBC). However, guidelines are lacking regarding their optimal sequencing
with other available agents. This study examines physician practice patterns and
treatment outcomes of palbociclib and subsequent therapies in a real-world
setting. Methods: A retrospective chart review was conducted for consecutive
patients with MBC who received palbociclib between February 2015 and August 2017
at the Alvin J. Siteman Cancer Center. Kaplan-Meier method was used to generate
time-to-event curves and estimate median progression-free survival (mPFS).
Log-rank test was used to compare differences. Results: A total of 200 patients,
with a median age of 59.4 years and a follow-up of 19.5 months, were included.
Palbociclib was most frequently combined with letrozole (73.5%), followed by
fulvestrant (25%), anastrozole (1%), and tamoxifen (0.5%). Most patients received
palbociclib in the endocrine-resistant setting (n=42, n=50, and n=108 in the
first-, second-, and subsequent-line settings, respectively), and the fraction of
patients receiving palbociclib as first- or second-line therapy increased in
recent months (P=.0428). mPFS was 20.7, 12.8, and 4.0 months with palbociclib
administered in the first-, second-, and subsequent-line settings, respectively
(P<.0001). Incidences of grade 3/4 neutropenia (41.5%) and dose reductions (29%)
were comparable to reports in the literature. Among patients whose disease
progressed on palbociclib (n=104), the most frequent next-line treatment was
capecitabine (n=21), followed by eribulin (n=16), nab-paclitaxel (n=15), and
exemestane + everolimus (n=12). mPFS with hormone therapy alone or in combination
with targeted agents (n=32) after first-, second-, and subsequent-line
palbociclib was 17.0, 9.3, and 4.2 months, respectively (P=.04). mPFS with
chemotherapy (n=70) was not reached, 4.7, and 4.1 months after first-, second-,
and subsequent-line palbociclib, respectively (P=.56). Conclusions: Palbociclib
is effective for HR+/HER2- MBC in real-world practice. Hormone therapy alone or
in combination with targeted agents remains an effective option after palbociclib
progression.

DOI: 10.6004/jnccn.2018.7094
PMID: 30787127

J Natl Compr Canc Netw. 2019 Feb;17(2):118-126. doi: 10.6004/jnccn.2019.0009.

NCCN Guidelines Insights: Breast Cancer, Version 3.2018.

Goetz MP(1), Gradishar WJ(1), Anderson BO(1), Abraham J(1), Aft R(1), Allison
KH(1), Blair SL(1), Burstein HJ(1), Dang C(1), Elias AD(1), Farrar WB(1),
Giordano SH(1), Goldstein LJ(1), Isakoff SJ(1), Lyons J(1), Marcom PK(1), Mayer
IA(1), Moran MS(1), Mortimer J(1), O’Regan RM(1), Patel SA(1), Pierce LJ(1), Reed
EC(1), Rugo HS(1), Sitapati A(1), Smith KL(1), Smith ML(1), Soliman H(1), Telli
ML(1), Ward JH(1), Young JS(1), Shead DA(1), Kumar R(1).

Author information:
(1)Mayo Clinic Cancer Center; Robert H. Lurie Comprehensive Cancer Center of
Northwestern University; University of Washington/Seattle Cancer Care Alliance;
Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Center and
Cleveland Clinic Taussig Cancer Institute; Siteman Cancer Center at Barnes-Jewish
Hospital and Washington University School of Medicine; Stanford Cancer Institute;
UC San Diego Moores Cancer Center; Dana-Farber/Brigham and Women’s Cancer Center;
Memorial Sloan Kettering Cancer Center; University of Colorado Cancer Center; The
Ohio State University Comprehensive Cancer Center – James Cancer Hospital and
Solove Research Institute; The University of Texas MD Anderson Cancer Center; Fox
Chase Cancer Center; Massachusetts General Hospital Cancer Center; Duke Cancer
Institute; Vanderbilt-Ingram Cancer Center; Yale Cancer Center/Smilow Cancer
Hospital; City of Hope National Medical Center; University of Wisconsin Carbone
Cancer Center; University of Michigan Rogel Cancer Center; Fred & Pamela Buffett
Cancer Center; UCSF Helen Diller Family Comprehensive Cancer Center; The Sidney
Kimmel Comprehensive Cancer Center at Johns Hopkins; Research Advocacy Network;
Moffitt Cancer Center; Huntsman Cancer Institute at the University of Utah;
Roswell Park Comprehensive Cancer Center; and National Comprehensive Cancer
Network.

These NCCN Guidelines Insights highlight the updated recommendations for use of
multigene assays to guide decisions on adjuvant systemic chemotherapy therapy for
women with hormone receptor-positive, HER2-negative early-stage invasive breast
cancer. This report summarizes these updates and discusses the rationale behind
them.

DOI: 10.6004/jnccn.2019.0009
PMID: 30787125

Cancer Epidemiol Biomarkers Prev. 2019 Feb 20. pii: cebp.1132.2018. doi:
10.1158/1055-9965.EPI-18-1132. [Epub ahead of print]

Genetic ancestry analysis reveals misclassification of commonly used cancer cell
lines.

Hooker SE(1), Woods-Burnham L(1), Bathina M(1), Lloyd SM(2), Gorjala P(3), Mitra
R(4), Nonn L(5), Kimbro KS(6), Kittles R(7).

Author information:
(1)Population Sciences, City Of Hope National Medical Center.
(2)Molecular and Cellular Biology, Baylor College of Medicine.
(3)Dept of Biomedical Sciences, Roseman University of Health Sciences.
(4)Roseman University of Health Sciences.
(5)Pathology, University of Illinois at Chicago.
(6)Biomedical Biotechnology Research Institute, North Carolina Central
University.
(7)Population Sciences, City Of Hope National Medical Center rkittles@coh.org.

BACKGROUND: Given the scarcity of cell lines from underrepresented populations,
it is imperative that genetic ancestry for these cell lines is characterized.
Consequences of cell line mischaracterization include squandered resources and
publication retractions.
METHODS: We calculated genetic ancestry proportions for 15 cell lines to assess
the accuracy of previous race/ethnicity classification and determine previously
unknown estimates. DNA was extracted from cell lines and genotyped for ancestry
informative markers (AIMs) representing West African (WA), Native American (NA),
and European (EUR) ancestry.
RESULTS: Of the cell lines tested, all previously classified as White/Caucasian
were accurately described with mean EUR ancestry proportions of 97%. Cell lines
previously classified as Black/African American were not always accurately
described. For instance, the 22Rv1 prostate cancer cell line was recently found
to carry mixed genetic ancestry using a much smaller panel of markers. However,
our more comprehensive analysis determined the 22Rv1 cell line carries 99% EUR
ancestry. Most notably, the E006AA-hT prostate cancer cell line, classified as
African American, was found to carry 92% EUR ancestry. We also determined the
MDA-MB-468 breast cancer cell line carries 23% NA ancestry suggesting possible
Afro-Hispanic/Latina ancestry.
CONCLUSIONS: Our results suggest predominantly EUR ancestry for the
White/Caucasian-designated cell lines, yet high variance in ancestry for the
Black/African American-designated cell lines. Additionally, we revealed an
extreme misclassification of the E006AA-hT cell line.
IMPACT: Genetic ancestry estimates offer more sophisticated characterization
leading to better contextualization of findings. Ancestry estimates should be
provided for all cell lines to avoid erroneous conclusions in disparities
literature.

DOI: 10.1158/1055-9965.EPI-18-1132
PMID: 30787054

Clin Epigenetics. 2019 Feb 20;11(1):33. doi: 10.1186/s13148-019-0626-0.

A two-gene epigenetic signature for the prediction of response to neoadjuvant
chemotherapy in triple-negative breast cancer patients.

Pineda B(1)(2)(3), Diaz-Lagares A(3)(4)(5), Pérez-Fidalgo JA(1)(3)(6), Burgués
O(1)(3)(7), González-Barrallo I(6), Crujeiras AB(4)(8), Sandoval J(4)(9),
Esteller M(3)(4)(10)(11)(12), Lluch A(1)(3)(6), Eroles P(13)(14)(15).

Author information:
(1)Biomedical Research Institute (INCLIVA), Valencia, Spain.
(2)Department of Physiology, Faculty of Medicine, University of Valencia,
Valencia, Spain.
(3)Centro de Investigacion Biomedica en Red Cancer (CIBERONC), Madrid, Spain.
(4)Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research
Institute (IDIBELL), Barcelona, Spain.
(5)Present Address: Cancer Epigenomics, Translational Medical Oncology (Oncomet),
Health Research Institute of Santiago (IDIS), University Clinical Hospital of
Santiago (CHUS/SERGAS), CIBERONC, Santiago de Compostela, Spain.
(6)Oncology Department, Hospital Clínico Universitario de Valencia, Valencia,
Spain.
(7)Pathology Department, Hospital Clínico Universitario de Valencia, Valencia,
Spain.
(8)Present Address: Laboratory of Epigenomics in Endocrinology and Nutrition,
Instituto de Investigacion Sanitaria (IDIS), Complejo Hospitalario Universitario
de Santiago (CHUS), Santiago de Compostela University (USC) and CIBER
Fisiopatologia de la Obesidad y Nutricion (CIBERobn), Madrid, Spain.
(9)Biomarkers and Precision Medicne Unit (UByMP), Instituto de Investigación
Sanitaria La Fe (IISLaFeValencia), Valencia, Spain.
(10)Physiological Sciences Department, School of Medicine and Health Sciences,
University of Barcelona (UB), Barcelona, Spain.
(11)Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona,
Catalonia, Spain.
(12)Institució Catalana de Recerca i Estudis Avançats (ICREA), Badalona,
Barcelona, Catalonia, Spain.
(13)Biomedical Research Institute (INCLIVA), Valencia, Spain. pilar.eroles@uv.es.
(14)Centro de Investigacion Biomedica en Red Cancer (CIBERONC), Madrid, Spain.
pilar.eroles@uv.es.
(15)COST action, CA15204, Brussels, Belgium. pilar.eroles@uv.es.

BACKGROUND: Pathological complete response (pCR) after neoadjuvant chemotherapy
(NAC) in triple-negative breast cancer (TNBC) varies between 30 and 40%
approximately. To provide further insight into the prediction of pCR, we
evaluated the role of an epigenetic methylation-based signature.
METHODS: Epigenetic assessment of DNA extracted from biopsy archived samples
previous to NAC from TNBC patients was performed. Patients included were
categorized according to previous response to NAC in responder (pCR or residual
cancer burden, RCB = 0) or non-responder (non-pCR or RCB > 0) patients. A
methyloma study was performed in a discovery cohort by the Infinium
HumanMethylation450 BeadChip (450K array) from Illumina. The epigenetic silencing
of those methylated genes in the discovery cohort were validated by bisulfite
pyrosequencing (PyroMark Q96 System version 2.0.6, Qiagen) and qRT-PCR in an
independent cohort of TN patients and in TN cell lines.
RESULTS: Twenty-four and 30 patients were included in the discovery and
validation cohorts, respectively. In the discovery cohort, nine genes were
differentially methylated: six presented higher methylation in non-responder
patients (LOC641519, LEF1, HOXA5, EVC2, TLX3, CDKL2) and three greater
methylation in responder patients (FERD3L, CHL1, and TRIP10). After validation, a
two-gene (FER3L and TRIP10) epigenetic score predicted RCB = 0 with an area under
the ROC curve (AUC) = 0.905 (95% CI = 0.805-1.000). Patients with a positive
epigenetic two-gene score showed 78.6% RCB = 0 versus only 10.7% RCB = 0 if
signature were negative.
CONCLUSIONS: These results suggest that pCR in TNBC could be accurately predicted
with an epigenetic signature of FERD3L and TRIP10 genes. Further prospective
validation of these findings is warranted.

DOI: 10.1186/s13148-019-0626-0
PMID: 30786922

World J Surg Oncol. 2019 Feb 20;17(1):37. doi: 10.1186/s12957-019-1582-z.

Higher axillary lymph node metastasis burden in breast cancer patients with
positive preoperative node biopsy: may not be appropriate to receive sentinel
lymph node biopsy in the post-ACOSOG Z0011 trial era.

Liang Y(1), Chen X(2), Tong Y(1), Zhan W(3), Zhu Y(3), Wu J(1), Huang O(1), He
J(1), Zhu L(1), Li Y(1), Chen W(1), Shen K(4).

Author information:
(1)Comprehensive Breast Health Center, Ruijin Hospital, Shanghai Jiaotong
University School of Medicine, 197 Ruijin Er Road, Shanghai, 200025, China.
(2)Comprehensive Breast Health Center, Ruijin Hospital, Shanghai Jiaotong
University School of Medicine, 197 Ruijin Er Road, Shanghai, 200025, China.
chenxiaosong0156@hotmail.com.
(3)Department of Ultrasound Imaging, Ruijin Hospital, Shanghai Jiaotong
University School of Medicine, Shanghai, China.
(4)Comprehensive Breast Health Center, Ruijin Hospital, Shanghai Jiaotong
University School of Medicine, 197 Ruijin Er Road, Shanghai, 200025, China.
kwshen@medmail.com.cn.

BACKGROUND: Breast cancer patients with suspicious axillary lymph node (ALN) at
ultrasound and positive fine-needle aspiration (FNA) results were required to
receive ALN dissection (ALND), which was not certain in the post-ACOSOG Z0011
era. We aim to evaluate the ALN metastasis burden in these patients, thus to
illustrate whether they can follow the ACOSOG Z0011 trial procedure.
METHODS: Clinically, T1-2 N0 breast cancer patients with positive preoperative
ALN biopsy (FNA group) or 1-2 positive sentinel nodes (SLNB group) were
retrospectively analyzed. ALN metastasis burden was compared between the two
groups, which were further analyzed in certain subtypes. An association between
clinicopathological factors and ≥ 3 ALN metastasis was also analyzed.
RESULTS: A total of 388 patients were included: 202 in the FNA group and 186 in
the SLNB group. The FNA group had a significantly higher number of positive ALN
(5.18 vs. 1.77, P < 0.001) and a larger proportion of patients with ≥ 3 ALN
metastasis (58.42% vs. 11.83%, P < 0.001) than the SLNB group, which was not
influenced by different tumor size stage and molecular subtypes. ALN metastasis
identified by FNA was independently associated with a high rate of ≥ 3 ALN
metastasis (OR = 6.98, 95% CI 1.95-25.02, P = 0.003).
CONCLUSIONS: Patients with positive preoperative ALN biopsy had a higher ALN
metastasis burden than patients with 1-2 positive SLNs, which was also the
strongest factor associated with ≥ 3 ALN metastasis, indicating that these
patients are not appropriate to receive SLNB in the post-ACOSOG Z0011 trial era.

DOI: 10.1186/s12957-019-1582-z
PMID: 30786903

Cell Commun Signal. 2019 Feb 20;17(1):15. doi: 10.1186/s12964-019-0328-4.

Cholesterol content in cell membrane maintains surface levels of ErbB2 and
confers a therapeutic vulnerability in ErbB2-positive breast cancer.

Zhang J(1), Li Q(1)(2), Wu Y(1), Wang D(1), Xu L(2), Zhang Y(1), Wang S(1), Wang
T(1), Liu F(1), Zaky MY(1)(3), Hou S(1), Liu S(1), Zou K(4), Lei H(1), Zou L(2),
Zhang Y(5), Liu H(6)(7).

Author information:
(1)Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.
(2)The Second Affiliated Hospital, Dalian Medical University, Dalian, China.
(3)Molecular Physiology Division, Department of Zoology, Faculty of Science,
Beni-Suef University, Beni Suef, Egypt.
(4)Department of Radiotherapy Oncology, the First Affiliated Hospital of Dalian
Medical University, Dalian, China.
(5)Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.
zhangyingqiu.no.1@163.com.
(6)Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.
liuhan@dlmedu.edu.cn.
(7)Cancer Biotherapy & Translational Medicine Center of Liaoning Province, Dalian
Medical University, Dalian, China. liuhan@dlmedu.edu.cn.

BACKGROUND: ErbB2 overexpression identifies a subset of breast cancer as
ErbB2-positive and is frequently associated with poor clinical outcomes. As a
membrane-embedded receptor tyrosine kinase, cell surface levels of ErbB2 are
regulated dynamically by membrane physical properties. The present study aims to
investigate the influence of membrane cholesterol contents on ErbB2 status and
cellular responses to its tyrosine kinase inhibitors.
METHODS: The cholesterol abundance was examined in ErbB2-positive breast cancer
cells using filipin staining. Cellular ErbB2 localizations were investigated by
immunofluorescence with altered membrane cholesterol contents. The inhibitory
effects of the cholesterol-lowering drug lovastatin were assessed using cell
proliferation, apoptosis, immunoblotting and immunofluorescence assays. The
synergistic effects of lovastatin with the ErbB2 inhibitor lapatinib were
evaluated using an ErbB2-positive breast cancer xenograft mouse model.
RESULTS: Membrane cholesterol contents positively correlated with cell surface
distribution of ErbB2 through increasing the rigidity and decreasing the fluidity
of cell membranes. Reduction in cholesterol abundance assisted the
internalization and degradation of ErbB2. The cholesterol-lowering drug
lovastatin significantly potentiated the inhibitory effects of ErbB2 kinase
inhibitors, accompanied with enhanced ErbB2 endocytosis. Lovastatin also
synergized with lapatinib to strongly suppress the in vivo growth of
ErbB2-positive breast cancer xenografts.
CONCLUSION: The cell surface distribution of ErbB2 was closely regulated by
membrane physical properties governed by cholesterol contents. The
cholesterol-lowering medications can hence be exploited for potential
combinatorial therapies with ErbB2 kinase inhibitors in the clinical treatment of
ErbB2-positive breast cancer.

DOI: 10.1186/s12964-019-0328-4
PMID: 30786890

Immunotherapy. 2019 Apr;11(5):365-368. doi: 10.2217/imt-2018-0204.

Optimal primary end point in Phase II trials of immune checkpoint inhibitors for
advanced solid cancers: an evolving issue.

Roviello G(1), Generali D(2)(3), Ianza A(4).

Author information:
(1)Translational Oncology Unit, Department of Health Sciences, University of
Florence, viale Pieraccini, 6, 50139 Florence, Italy.
(2)Department of Medical, Surgery & Health Sciences, University of Trieste,
Trieste, Italy.
(3)Breast Cancer Unit & Translational Research Unit, ASST Cremona, Cremona,
Italy.
(4)Department of Medical, Surgery & Health Sciences, University of Trieste,
Piazza Ospitale 1, 34129 Trieste, Italy.

DOI: 10.2217/imt-2018-0204
PMID: 30786842

Technol Cancer Res Treat. 2019 Jan 1;18:1533033819828709. doi:
10.1177/1533033819828709.

Plasma microRNAs Predict Chemoresistance in Patients With Metastatic Breast
Cancer.

Shao B(1), Wang X(2), Zhang L(2), Li D(3), Liu X(1), Song G(1), Cao H(2), Zhu
J(1), Li H(1).

Author information:
(1)1 Department of Medical Oncology, Key laboratory of Carcinogenesis and
Translational Research (Ministry of Education), Peking University Cancer Hospital
& Institute, Beijing, People’s Republic of China.
(2)2 Laboratory of Nucleic Acid Technology, Institute of Molecular Medicine,
Peking University, Beijing, People’s Republic of China.
(3)3 Kunshan RNAi institute, Kunshan, Jiangsu province, People’s Republic of
China.

BACKGROUND: MicroRNAs contribute to chemotherapy response in different types of
cancer. We hypothesized that plasma miRNAs are potentially associated with
chemotherapy response in patients with metastatic breast cancer.
PATIENTS AND METHODS: Fourteen candidate microRNAs were chosen from the
literature, and their plasma levels were measured by quantitative polymerase
chain reaction (PCR). Forty metastatic breast cancer patients were chosen as the
training groups. The potential significant microRNAs were validated in another
103 plasma samples.
RESULTS: In the training set, we identified 3 microRNAs (miR-200a, miR-210, and
miR-451) as significantly dysregulated miRNAs between sensitive group (partial
response (and stable disease) and resistant group (progressive disease). Then, in
the validation set, miR-200a (area under the curve = 0.881, sensitivity = 94.1%,
specificity = 76.7%) and miR-210 (area under the curve = 0.851, sensitivity =
88.2%, specificity = 72.1%) showed high diagnostic accuracy for distinguishing
sensitive group from resistant group. Furthermore, the plasma level of miR-200a
was significantly associated with the stage in surgery ( P = .035), and the high
level of miR-210 expression was associated with internal organ metastasis (liver,
lung, and brain; P = .024).
CONCLUSIONS: Plasma miR-200a and miR-210 could be effective biomarkers for the
prediction of chemotherapy resistance in metastatic breast cancer patients.

DOI: 10.1177/1533033819828709
PMID: 30786836

Pol J Pathol. 2018;69(4):347-355. doi: 10.5114/pjp.2018.81694.

BRCA1 and PARP1 mRNA expression during progression from normal breast to ductal
carcinoma in situ and invasive breast cancer: a laser microdissection study.

Hybiak J, Domagala P, Domagala W.

The contribution of DNA damage repair mechanisms to the progression of normal
breast to ductal carcinoma in situ (DCIS) and invasive ductal carcinoma is
largely unknown. The purpose of this report was to assess the mRNA expression
levels of two important genes associated with DNA repair, BRCA1 and PARP1, in
normal breast tissue, DCIS G1, G2 and G3, and co-existing adjacent invasive
ductal carcinoma. BRCA1 and PARP1 mRNA expression was assessed in 32 ductal
carcinomas in situ of the breast using a laser microdissection and pressure
catapulting system and quantitative real-time PCR. The relative expression of
BRCA1 mRNA was significantly increased in DCIS G2 and DCIS G3 relative to normal
breast tissue (p = 0.02, p = 0.001, respectively). Significant differences in
BRCA1 expression were observed between DCIS G1 and G2 (p = 0.02) and between DCIS
G1 and G3 (p = 0.0007). No significant differences in BRCA1 expression were
observed between normal breast tissue and DCIS G1 and between DCIS component and
adjacent invasive ductal carcinoma. No significant differences in the relative
expression of PARP1 mRNA were observed between groups. Increased BRCA1 mRNA
expression (but not PARP1 mRNA) occurs early in the development of breast cancer,
i.e. at the noninvasive (DCIS) stage, suggesting a demand for increased activity
of a DNA double-strand break repair by homologous recombination. DCIS G1 and
normal breast tissue share highly similar BRCA1 and PARP1 expression level. This
finding supports the idea that DCIS G1 belongs to a separate family of precursor
lesions with low malignant potential.

DOI: 10.5114/pjp.2018.81694
PMID: 30786684

Pol J Pathol. 2018;69(4):342-346. doi: 10.5114/pjp.2018.81693.

Searching for new breast cancer-associated genes. ABRAXAS1 gene mutations in the
group of BRCA1-negative patients.

Bąk A, Junkiert-Czarnecka A, Heise M, Januchowska D, Krzywińska O, Haus O.

In the present study, we analysed the association of mutations of a
BRCA1-associated gene, ABRAXAS1, with the risk of development of breast cancer
(BC) in BRCA1-negative women from North-Central Poland. A hundred women with
consecutively diagnosed BC and 100 women belonging to the control group were
screened for new mutations predisposing to breast cancer. The first step was a
test carried out in order to find one of the three Polish founder mutations in
the BRCA1 gene. In 96 BRCA1-negative patients two missense variants: c.422C>T and
c.1042G>A as well as two intronic variants: IVS3-34G>A, IVS3-44T>C were detected
in the ABRAXAS1 gene. The c.422C>T mutation was detected in one of 96 women
diagnosed with breast cancer (1.04%); it was not associated with increased risk
of disease in this group, compared to the controls (p = 0.49), but the odds ratio
was 3.314; 95% CI: 0.122-75.352. IVS3-44T>C was found more frequently in the
control group (15/93) than in the tested group (1/85), OR 0.062; 95% CI:
0.008-0.480, p = 0.007, which may suggest protective properties of this variant
against tumorigenicity. The data obtained from the present study suggest the
necessity for further research to be conducted on the ABRAXAS1 gene in relation
to hereditary predisposition to breast cancer.

DOI: 10.5114/pjp.2018.81693
PMID: 30786683

Pol J Pathol. 2018;69(4):335-341. doi: 10.5114/pjp.2018.81692.

Distribution of CXCR4 and tumour-infiltrating lymphocytes in breast cancer
subtypes; their relationship with each other, axillary lymph node involvement,
and other prognostic indicators.

Pehlivan FS, Sivrikoz ON, Dag F, Kececi SD, Sanal SM.

We have investigated the distribution of chemokine receptor 4 (CXCR4) and
CD8-positive, tumour-infiltrating T lymphocytes (CD8+ TILs) in breast cancer
subtypes and explored the relationship between them and the well-established
conventional prognostic markers, including axillary lymph node involvement. A
total of 250 breast cancer patients were included in the study. The patients were
separated into luminal A+B, HER2 enriched/overexpressed (HER2+), and triple-
negative, on the basis of their staining characteristics, via conventional
staining methods. Immunohistochemical (IHC) staining for CXCR4 and CD8+ TILs were
performed on the archival tissues from each patient. With increasing intensity of
CXCR4 staining, there was a higher incidence of lymph node metastasis (p < 0.01).
Similarly, there was a positive correlation between the primary tumour size,
HER2+ subtype, lymphovascular invasion, and axillary lymph node involvement.
Dense lymphocytic infiltration was observed in HER2+ and triple-negative
patients. No correlation between CD8+ TILs in all sites and breast cancer
subtypes was discovered. A reverse correlation was discovered with CD8+ TILs
stained only intratumorally and CXCR4 expression. In conclusion, lymph node
involvement correlates with higher CXCR4 expression in all breast cancer
subtypes. Conversely, no such correlation is found with CD8+ TILs.

DOI: 10.5114/pjp.2018.81692
PMID: 30786682

N Engl J Med. 2019 Feb 21;380(8):797. doi: 10.1056/NEJMc1816595.

Palbociclib and Fulvestrant in Breast Cancer. Reply.

Turner NC(1), Huang X(2), Cristofanilli M(3).

Author information:
(1)Royal Marsden Hospital, London, United Kingdom nicholas.turner@icr.ac.uk.
(2)Pfizer Oncology, San Diego, CA.
(3)Robert H. Lurie Comprehensive Cancer Center of Northwestern University,
Chicago, IL.

Comment on
N Engl J Med. ;380(8):796.
N Engl J Med. 2019 Feb 21;380(8):796.

DOI: 10.1056/NEJMc1816595
PMID: 30786200 [Indexed for MEDLINE]

N Engl J Med. 2019 Feb 21;380(8):796. doi: 10.1056/NEJMc1816595.

Palbociclib and Fulvestrant in Breast Cancer.

Naik RD(1), Batra A(1), Gupta VG(2).

Author information:
(1)All India Institute of Medical Sciences, New Delhi, India
batraatul85@gmail.com.
(2)Max Institute of Cancer Care, New Delhi, India.

Comment in
N Engl J Med. 2019 Feb 21;380(8):797.

Comment on
N Engl J Med. 2018 Nov 15;379(20):1926-1936.

DOI: 10.1056/NEJMc1816595
PMID: 30786199 [Indexed for MEDLINE]

N Engl J Med. 2019 Feb 21;380(8):741-751. doi: 10.1056/NEJMoa1814213.

Sacituzumab Govitecan-hziy in Refractory Metastatic Triple-Negative Breast
Cancer.

Bardia A(1), Mayer IA(1), Vahdat LT(1), Tolaney SM(1), Isakoff SJ(1), Diamond
JR(1), O’Shaughnessy J(1), Moroose RL(1), Santin AD(1), Abramson VG(1), Shah
NC(1), Rugo HS(1), Goldenberg DM(1), Sweidan AM(1), Iannone R(1), Washkowitz
S(1), Sharkey RM(1), Wegener WA(1), Kalinsky K(1).

Author information:
(1)From the Massachusetts General Hospital Cancer Center (A.B., S.J.I.) and
Dana-Farber Cancer Institute (S.M.T.), Harvard Medical School, Boston;
Vanderbilt-Ingram Cancer Center, Nashville (I.A.M., V.G.A.); Weill Cornell
Medical College (L.T.V.) and New York-Presbyterian-Columbia University Irving
Medical Center (K.K.), New York; University of Colorado Cancer Center, Aurora
(J.R.D.); Texas Oncology, Baylor University Medical Center, US Oncology, Dallas
(J.O.); Orlando Health University of Florida Health Cancer Center, Orlando
(R.L.M., N.C.S.); Yale University School of Medicine, New Haven, CT (A.D.S.);
University of California, San Francisco, Helen Diller Family Comprehensive Cancer
Center, San Francisco (H.S.R.); Immunomedics, Morris Plains, NJ (D.M.G., R.I.,
S.W., R.M.S., W.A.W.); and AIS Consulting, Ann Arbor, MI (A.M.S.).

BACKGROUND: Standard chemotherapy is associated with low response rates and short
progression-free survival among patients with pretreated metastatic
triple-negative breast cancer. Sacituzumab govitecan-hziy is an antibody-drug
conjugate that combines a humanized monoclonal antibody, which targets the human
trophoblast cell-surface antigen 2 (Trop-2), with SN-38, which is conjugated to
the antibody by a cleavable linker. Sacituzumab govitecan-hziy enables delivery
of high concentrations of SN-38 to tumors.
METHODS: We conducted a phase 1/2 single-group, multicenter trial involving
patients with advanced epithelial cancers who received sacituzumab govitecan-hziy
intravenously on days 1 and 8 of each 21-day cycle until disease progression or
unacceptable toxic effects. A total of 108 patients received sacituzumab
govitecan-hziy at a dose of 10 mg per kilogram of body weight after receiving at
least two previous anticancer therapies for metastatic triple-negative breast
cancer. The end points included safety; the objective response rate (according to
Response Evaluation Criteria in Solid Tumors, version 1.1), which was assessed
locally; the duration of response; the clinical benefit rate (defined as a
complete or partial response or stable disease for at least 6 months);
progression-free survival; and overall survival. Post hoc analyses determined the
response rate and duration, which were assessed by blinded independent central
review.
RESULTS: The 108 patients with triple-negative breast cancer had received a
median of 3 previous therapies (range, 2 to 10). Four deaths occurred during
treatment; 3 patients (2.8%) discontinued treatment because of adverse events.
Grade 3 or 4 adverse events (in ≥10% of the patients) included anemia and
neutropenia; 10 patients (9.3%) had febrile neutropenia. The response rate (3
complete and 33 partial responses) was 33.3% (95% confidence interval [CI], 24.6
to 43.1), and the median duration of response was 7.7 months (95% CI, 4.9 to
10.8); as assessed by independent central review, these values were 34.3% and 9.1
months, respectively. The clinical benefit rate was 45.4%. Median
progression-free survival was 5.5 months (95% CI, 4.1 to 6.3), and overall
survival was 13.0 months (95% CI, 11.2 to 13.7).
CONCLUSIONS: Sacituzumab govitecan-hziy was associated with durable objective
responses in patients with heavily pretreated metastatic triple-negative breast
cancer. Myelotoxic effects were the main adverse reactions. (Funded by
Immunomedics; IMMU-132-01 ClinicalTrials.gov number, NCT01631552.).

DOI: 10.1056/NEJMoa1814213
PMID: 30786188

Pediatr Blood Cancer. 2019 Feb 20:e27666. doi: 10.1002/pbc.27666. [Epub ahead of
print]

Abbreviated breast magnetic resonance imaging (FAST-MRI): A novel approach to
breast cancer screening in patients with previous Hodgkin lymphoma.

Indolfi C(1), Cappabianca S(2), Rossi F(1), Perrotta S(1), Procaccini E(3), Pota
E(1), Martino MD(1), Pinto DD(1), Casale F(1), Indolfi P(1).

Author information:
(1)Pediatric Hematology-Oncology Unit, University of Campania «Luigi
Vanvitelli,», Naples, Italy.
(2)Radiology Unit, University of Campania «Luigi Vanvitelli,», Naples, Italy.
(3)Breast Unit, University of Campania «Luigi Vanvitelli,», Naples, Italy.

DOI: 10.1002/pbc.27666
PMID: 30786169

Clin Pharmacol Ther. 2019 Feb 20. doi: 10.1002/cpt.1404. [Epub ahead of print]

Factors affecting tamoxifen metabolism in breast cancer patients; preliminary
results of the French PHACS study (NCT01127295).

Puszkiel A(1), Arellano C(1), Vachoux C(1), Evrard A(2)(3), Le Morvan V(4), Boyer
JC(2), Robert J(4), Delmas C(1)(5), Dalenc F(1)(5), Debled M(4), Venat-Bouvet
L(6), Jacot W(3)(7), Suc E(8), Sillet Bach I(9), Filleron T(5), Roché H(5),
Chatelut E(1)(5), White-Koning M(1), Thomas F(1)(5).

Author information:
(1)Cancer Research Center of Toulouse (CRCT), Inserm U1037, Université Paul
Sabatier, Toulouse, France.
(2)Laboratoire de Biochimie et Biologie Moléculaire, CHU Nîmes-Carémeau, Nîmes,
France.
(3)IRCM, Inserm, Université de Montpellier, ICM, Montpellier, France.
(4)Institut Bergonié, Bordeaux, France.
(5)Institut Claudius Regaud, Institut Universitaire du Cancer de Toulouse-
Oncopole, Toulouse, France.
(6)CHU Dupuytren, Limoges, France.
(7)Institut du Cancer de Montpellier, Montpellier, France.
(8)Clinique Saint Jean du Languedoc, Toulouse, France.
(9)CH, Brive, France.

In addition to the effect of CYP2D6 genetic polymorphisms, the metabolism of
tamoxifen may be impacted by other factors with possible consequences on
therapeutic outcome (efficacy, toxicity). This analysis focused on the
pharmacokinetic-pharmacogenetic evaluation of tamoxifen in 730 adjuvant breast
cancer patients included in a prospective multicenter study. Plasma
concentrations of tamoxifen and six major metabolites, the genotype for 63 single
nucleotide polymorphisms and co-medications were obtained 6 months after
treatment initiation. Plasma concentrations of endoxifen were significantly
associated with CYP2D6 diplotype (p < 0.0001), CYP3A422 genotype (p = 0.0003) and concomitant intake of potent CYP2D6 inhibitors (p < 0.001). Comparison of endoxifen levels showed that the CYP2D6 phenotype classification could be improved by grouping IM/IM and IM/PM diplotype into intermediate metaboliser (IM) phenotype for future use in tamoxifen therapy optimisation. Finally, the multivariable regression analysis showed that formation of tamoxifen metabolites was independently impacted by CYP2D6 diplotype and CYP3A422, CYP2C192 and CYP2B66 genetic polymorphisms. This article is protected by copyright. All
rights reserved.

DOI: 10.1002/cpt.1404
PMID: 30786012

J Radiat Res. 2019 Feb 20. pii: rry098. doi: 10.1093/jrr/rry098. [Epub ahead of
print]

Density of bone metastatic lesions increases after radiotherapy in patients with
breast cancer.

Wang Q(1), Sun B(1), Meng X(1), Liu C(1), Cong Y(1), Wu S(1).

Author information:
(1)Department of Radiation Oncology, 307 Hospital of People’s Liberation Army,
Beijing, China.

The aim of this study was to assess local response to radiotherapy (RT) in a
quantitative manner by evaluating the bone density of metastases. Spinal and
pelvic bone metastases in 44 patients with breast cancer who were treated between
May 2010 and December 2016 were retrospectively assessed. Bone density values of
irradiated and unirradiated bone metastases before, 1-3 months after, 4-6 months
after, and 7-9 months after RT were compared. At each time point, mean bone
density ± standard deviation values were measured in Hounsfield units (HU) from
computed tomography (CT) scans. Student’s t-test was used for statistical
analyses of the differences in bone density and for univariate analysis of the
prognostic factors for differences in bone density at various time points after
RT. Mean bone densities in irradiated and unirradiated bone metastases before RT
were 297.31 ± 211.93 HU and 326.29 ± 228.61 HU, respectively. At the subsequent
three time points examined, the mean bone density values in the irradiated and
unirradiated bone metastases were: 61.97 ± 78.58 HU (P = 0.000) and 36.93 ± 52.49
HU (P = 0.001); 149.07 ± 133.27 HU (P = 0.000) and 68.40 ± 101.10 HU (P = 0.000);
and 183.94 ± 168.30 HU (P = 0.000) and 88.21 ± 159.49 HU (P = 0.004),
respectively, in each case. Patients receiving bisphosphonates exhibited greater
increases in bone density in their metastases 1-3 months after RT (83.04 ± 82.18
HU vs 26.86 ± 60.55 HU, respectively; P = 0.044), whereas chemotherapy before RT
was associated with significantly lower increases in bone density at the
subsequent three time points [(37.53 ± 67.66 HU vs 93.63 ± 80.36 HU, P = 0.027),
(99.30 ± 107.92 HU vs 180.24 ± 127.85 HU, P = 0.030), and (126.07 ± 141.77 HU vs
236.28 ± 158.22 HU, P = 0.024), respectively, in each case]. Comparing bone
density values determined from CT scans appears to be a practicable and
reproducible method for assessing local response to RT for bone metastasis of
breast cancer. Increased bone density was also observed in the irradiated bone
metastases.

© The Author(s) 2019. Published by Oxford University Press on behalf of The Japan
Radiation Research Society and Japanese Society for Radiation Oncology.

DOI: 10.1093/jrr/rry098
PMID: 30785994

PLoS One. 2019 Feb 20;14(2):e0211821. doi: 10.1371/journal.pone.0211821.
eCollection 2019.

Preliminary results of identification and quantification of paclitaxel and its
metabolites in human meconium from newborns with gestational chemotherapeutic
exposure.

Cardonick E(1), Broadrup R(2), Xu P(2), Doan MT(2), Jiang H(2), Snyder NW(2).

Author information:
(1)Cooper Medical School, Rowan University, Camden, New Jersey, United States of
America.
(2)AJ Drexel Autism Institute, Drexel University, Philadelphia, Pennsylvania,
United States of America.

OBJECTIVE: Cancer diagnosis during pregnancy occurs in 1 out of 1000 pregnancies
with common malignancies including breast and hematological cancers. Fetal
exposure to currently utilized agents is poorly described. We directly assessed
fetal exposure by screening meconium from 23 newborns whose mothers had undergone
treatment for cancer during pregnancy.
STUDY DESIGN: Meconium was collected from newborns whose mothers were diagnosed
with cancer during pregnancy and underwent chemotherapy in the second or third
trimester as part of the Cancer and Pregnancy Registry. We conducted screening of
23 meconium samples for chemotherapeutics and known metabolites of
chemotherapeutics by liquid chromatography-high resolution mass spectrometry
(LC-HRMS). Putative identification of paclitaxel and/or its metabolites was made
in 8 screened samples. In positively screened samples, we quantified paclitaxel,
3′-p-hydroxypaclitaxel, and 6α-hydroxypaclitaxel by stable isotope
dilution-LC-HRMS.
RESULTS: Mean (standard deviation) levels of paclitaxel in positively screened
samples were 399.9 (248.6) pg/mg in meconium samples from newborn born to mothers
that underwent chemotherapy during pregnancy. 3′-p-hydroxypaclitaxel and
6α-hydroxypaclitaxel mean levels were 105.2 (54.6) and 113.4 (48.9) pg/mg
meconium, respectively.
CONCLUSION: Intact paclitaxel, 3′-p-hydroxypaclitaxel, and 6α-hydroxypaclitaxel
were detected in meconium, providing unambiguous confirmation of human fetal
exposure. Variability in meconium levels between individuals may indicate a
potential for reducing fetal exposure based on timing, dosing, and individual
characteristics. This preliminary study may provide an approach for examining the
effects of cancer diagnosis during pregnancy on other outcomes by providing a
measure of direct fetal exposure.

DOI: 10.1371/journal.pone.0211821
PMID: 30785914

Conflict of interest statement: The authors have declared that no competing
interests exist.

J Clin Oncol. 2019 Feb 20:JCO1800028. doi: 10.1200/JCO.18.00028. [Epub ahead of
print]

West German Study PlanB Trial: Adjuvant Four Cycles of Epirubicin and
Cyclophosphamide Plus Docetaxel Versus Six Cycles of Docetaxel and
Cyclophosphamide in HER2-Negative Early Breast Cancer.

Nitz U(1)(2), Gluz O(1)(2)(3), Clemens M(4), Malter W(3), Reimer T(5), Nuding
B(6), Aktas B(7)(8), Stefek A(9), Pollmanns A(10), Lorenz-Salehi F(11), Uleer
C(12), Krabisch P(13), Kuemmel S(14), Liedtke C(1)(15), Shak S(16), Wuerstlein
R(1)(17), Christgen M(18), Kates RE(1), Kreipe HH(18), Harbeck N(1)(17); West
German Study Group PlanB Investigators.

Author information:
(1)1 West German Study Group, Mönchengladbach, Germany.
(2)2 Evangelical Hospital Bethesda, Mönchengladbach, Germany.
(3)3 University of Cologne, Cologne, Germany.
(4)4 Mutterhaus der Borromäerinnen, Trier, Germany.
(5)5 Clinics Suedstadt, Rostock, Germany.
(6)6 Evangelical Hospital Bergisch Gladbach, Bergisch Gladbach, Germany.
(7)7 University Clinics Essen, Essen, Germany.
(8)8 University of Leipzig, Leipzig, Germany.
(9)9 Johanniter-Krankenhaus Genthin-Stendal Hospitals, Stendal, Germany.
(10)10 Protestant Hospital Oberhausen, Oberhausen, Germany.
(11)11 Horst-Schmidt-Kliniken, Wiesbaden, Germany.
(12)12 Gynecological-Oncological Practice, Hildesheim, Germany.
(13)13 City Hospital, Chemnitz, Germany.
(14)14 Clinics Essen-Mitte, Essen, Germany.
(15)15 Unversity Hospital Charite, Berlin, Germany.
(16)16 Genomic Health, Redwood City, CA.
(17)17 University of Munich, Munich, Germany.
(18)18 Hannover Medical School, Hanover, Germany.

PURPOSE: The West German Study Group PlanB trial evaluated an anthracycline-free
chemotherapy standard (six cycles of docetaxel and cyclophosphamide [TC]) in the
routine treatment of human epidermal growth factor receptor 2-negative early
breast cancer (EBC).
PATIENTS AND METHODS: Patients with pT1 to pT4c, all pN+, and pN0/high-risk EBC
were eligible. High-risk pN0 was defined by one or more of the following: pT
greater than 2, grade 2 to 3, high urokinase-type plasminogen
activator/plasminogen activator inhibitor-1, hormone receptor (HR) negativity,
and less than 35 years of age. After an early amendment, all HR-positive tumors
underwent recurrence score (RS) testing, with chemotherapy omission recommended
in RS less than or equal to 11 pN0 to pN1 disease. Patients were randomly
assigned to four cycles of epirubicin (E)90/cyclophoshamide (C)600 followed by
four cycles of docetaxel (T)100 or six cycles of T75C600 (administered once every
3 weeks). The primary end point was disease-free survival (DFS); secondary end
points were overall survival (OS) and safety. The protocol specified P = .05 for
a noninferiority margin of 4.4% for all patients combined.
RESULTS: Of the 3,198 registered patients, 348 (RS ≤ 11) omitted chemotherapy,
and 401 were not randomly assigned. The intention-to-treat population included
2,449 patients (1,227 EC-T v 1,222 TC: postmenopausal, 62.2% v 60.8%; pN0, 58.2%
v 59.5%; pT1, 57.6% v 52.3%; HR positive, 81.4% v 82.2%; RS greater than 25 [in
HR-positive patients], 26.2% v 27.5%). Within the safety population (1,167 v
1,178 patients), 87.5% v 93.0% completed therapy. After a 60-month median
follow-up, 5-year outcomes were similar in the EC-T and TC arms (DFS, 89.6% [95%
CI, 87.9% to 91.5%] v 89.9% [95% CI, 88.1% to 91.8%]; OS, 94.5% [95% CI, 93.1% to
95.9%] v 94.7% [95% CI, 93.3% to 96.1%]). The DFS difference was within the
noninferiority margin of the original trial design. Five treatment-related deaths
were reported for TC (one for EC-T), despite a trend toward more-severe adverse
events in the latter. Interaction analysis revealed no predictive trends with
respect to key factors, including triple-negative, luminal A/B-like, pN, age, and
RS status.
CONCLUSION: In the West German Study Group PlanB trial, 5-year outcomes for TC
and EC-T were equally excellent. Six cycles of TC is an effective/safe option in
human epidermal growth factor receptor 2-negative EBC with pN0 high genomic risk
or pN1 EBC with genomically intermediate- to high-risk disease.

DOI: 10.1200/JCO.18.00028
PMID: 30785826

N Engl J Med. 2019 Feb 14;380(7):694. doi: 10.1056/NEJMc1817537.

Lymphedema after Breast Cancer Treatment.

Jindeel A.

Comment in
N Engl J Med. 2019 Feb 14;380(7):694.

Comment on
N Engl J Med. 2018 Nov 15;379(20):1937-1944.

PMID: 30785712 [Indexed for MEDLINE]

Congenit Anom (Kyoto). 2019 Feb 20. doi: 10.1111/cga.12329. [Epub ahead of print]

Association between hereditary predisposition to common cancers and congenital
multimalformations.

Kwiatkowski F(1)(2), Perthus I(3), Uhrhammer N(1), Francannet C(3), Arbre M(1),
Bidet Y(1), Bignon YJ(1).

Author information:
(1)Centre Jean Perrin (Comprehensive Cancer Center), Clermont-Ferrand, France.
(2)Clermont-Auvergne University, Laboratory of Mathematics: probabilities and
applied statistics, CS, Clermont-Ferrand, France.
(3)Study Center of congenital malformations in Auvergne (Centre d’Etude des
Malformations Congénitales en Auvergne), Medical genetics department,
Clermont-Ferrand Cédex 1, France.

INTRODUCTION: in a previous article we reported that mutations favoring cancer at
adulthood seemed to improve fertility and limit miscarriages. Because spontaneous
abortion may result from anomalies in embryo, we questioned if an increased
frequency of congenital malformation could be evidenced among cancer prone
families.
METHODS: oncogenetics database (≈193,000 members) of the comprehensive cancer
center Jean Perrin was crossed with regional registry of congenital malformations
(≈10,000). Among children born between 1986 and 2011, 176 children with
malformation matched in both databases.
RESULTS: in breast/ovaries cancer prone families, the risk for malformations was
multiplied by 2.4 [1.2-4.5] in case of a BRCA1 mutation. Frequencies of
malformation in BRCA2 and MMR mutated families were similar to families without a
cancer syndrome. In comparison to malformations concerning a unique anatomical
system, multimalformations were significantly more frequent in case of BRCA or
MMR mutations: compared to families without cancer syndrome, the risk of
multimalformations was multiplied by 4.1 [0.8-21.7] for cancer prone families but
with no known deleterious mutation, by 6.9 [1.2-38.6] in families with a known
mutation but an unknown parental mutational status and by 10.4 [2.3-46.0] when
one parent carried the familial mutation. No association with the type of
anatomical system was found, nor with multiple births.
DISCUSSION: these results suggest that BRCA and MMR genes play an important role
in human embryogenesis and that if their function is lowered because of
heterozygote mutations, congenital malformations are either more likely (BRCA1
mutations) and/or more susceptible to concern several anatomical systems. This
article is protected by copyright. All rights reserved.

DOI: 10.1111/cga.12329
PMID: 30785647

Epigenomics. 2019 Feb 20. doi: 10.2217/epi-2018-0111. [Epub ahead of print]

Circular RNA expression in exosomes derived from breast cancer cells and
patients.

Wang J(1), Zhang Q(2), Zhou S(3), Xu H(4), Wang D(2), Feng J(5), Zhao J(6), Zhong
S(6).

Author information:
(1)Department of General Surgery, Jiangsu Cancer Hospital & Jiangsu Institute of
Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University,
Nanjing 210009, PR China.
(2)Department of General Surgery, The First Affiliated Hospital of Nanjing
Medical University, Nanjing 210029, PR China.
(3)The First Clinical Medical College, Nanjing University of Chinese Medicine,
Nanjing 210023, PR China.
(4)Department of Radiation Oncology, Jiangsu Cancer Hospital & Jiangsu Institute
of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical
University, Nanjing 210009, PR China.
(5)Department of Medical Oncology, Jiangsu Cancer Hospital & Jiangsu Institute of
Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University,
Nanjing 210009, PR China.
(6)Center of Clinical Laboratory Science, Jiangsu Cancer Hospital & Jiangsu
Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical
University, Nanjing 210009, PR China.

AIM: We aimed to explore the roles of circular RNAs (circRNAs) in breast cancer
(BCa).
MATERIALS & METHODS: RNA was extracted from exosomes and BCa cells and analyzed
using the RNA sequencing technique or microarray.
RESULTS: Compared with controls, 1147 and 1195 circRNAs were dysregulated in
exosomes from metastatic and localized BCa patients, respectively. A total of 480
dysregulated circRNAs were found in metastatic patients compared with localized
patients, and these dysregulated circRNAs were enriched in eight pathways.
Compared with MCF-7 cells and their exosomes, there were 5842 and 1137
dysregulated circRNAs in MDA-MB-231 cells and exosomes, respectively, and 5
circRNAs were confirmed using real-time quantitative PCR.
CONCLUSION: We identified a number of dysregulated circRNAs in exosomes from BCa
cells and patients.

DOI: 10.2217/epi-2018-0111
PMID: 30785332

Psychooncology. 2019 Feb 20. doi: 10.1002/pon.5035. [Epub ahead of print]

Comparing provider and patient views of issues for low resourced breast cancer
patients.

Enzler CJ(1), Torres S(2), Jabson J(3), Ahlum Hanson A(4), Bowen DJ(5).

Author information:
(1)UT Health Science Center at Houston.
(2)Boston University, MA.
(3)Department of Public Health, University of Tennessee, Knoxville, TN.
(4)Living Beyond Breast Cancer, Bala Cynwyd, PA.
(5)University of Washington.

OBJECTIVE: The purpose of this study was to compare provider and patient views
from the same clinical settings on issues raised by low socioeconomic status
(SES) breast cancer survivors.
METHODS: We conducted qualitative interviews among two groups: low SES breast
cancer survivors (n=37) and medical personnel (ie, physicians, nurses,
navigators; n=8) that interact and serve with these patients from two
geographically distinct low resourced clinical settings. These semi-structured
qualitative interviews used grounded theory to identify several potential themes,
such as finances, resources, and medical care. Transcripts were coded and
summarized into themes.
RESULTS: We analyzed each type of interview data separately, then compared
patient and provider perspectives. From these qualitative interviews, we
discovered that low SES breast cancer survivors reported many unmet needs,
including transportation, housing, health literacy, and language, among others.
Providers reported that many of these needs are served by the extensive network
of supports surrounding these patients.
CONCLUSIONS: These results illustrate that low-SES breast cancer survivors have
unique needs that differ from other breast cancer survivors. Many providers feel
that these needs are being met, but patients have more diverse experiences. By
better addressing the links between resource needs and low-SES breast cancer
survivors, quality of life can be improved.

DOI: 10.1002/pon.5035
PMID: 30785226

Cancer Treat Res Commun. 2019 Feb 6;19:100121. doi: 10.1016/j.ctarc.2019.100121.
[Epub ahead of print]

Treatment patterns, clinical outcomes, health resource utilization, and cost in
patients with BRCA-mutated metastatic breast cancer treated in community oncology
settings.

Houts AC(1), Olufade T(2), Shenolikar R(2), Walker MS(3), Schwartzberg LS(4).

Author information:
(1)Vector Oncology, 6555 Quince, Suite 400, Memphis, TN 38119, United States.
(2)AstraZeneca, 101 Orchard Ridge Dr. (3233D), Gaithersburg, MD 20878, United
States.
(3)Vector Oncology, 6555 Quince, Suite 400, Memphis, TN 38119, United States.
Electronic address: mwalker@concertohealthai.com.
(4)West Cancer Center, 7945 Wolf River Boulevard, Germantown, TN 38138, United
States.

PURPOSE: This retrospective study of community oncology patients with breast
cancer gene (BRCA)-mutated metastatic breast cancer (MBC) examined treatment
outcomes and health resource utilization (HRU) and costs for a sample of patients
with human epidermal growth factor receptor 2 (HER2)-negative disease who were
either hormone receptor positive (HR+) or triple negative breast cancer (TNBC).
METHODS: Evidence from the Vector Oncology Data Warehouse, a repository of
electronic medical records/billing data and provider notes, was analyzed.
Treatment outcomes were progression-free survival (PFS) and overall survival (OS)
from start of first-line therapy in the metastatic setting. HRU and cost measures
were collected from the time of MBC diagnosis to end of the record. HRU included
hospitalizations, emergency room visits, infused/parenteral supportive care
drugs, and outpatient visits. Costs were computed both as total and monthly
costs.
RESULTS: 57 HR+ and 57 TNBC patients (2013-2015) met inclusion criteria. Eight
TNBC patients did not get treatment. HR+ patients had median first line PFS of
12.1 months and TNBC patients had 6.1 months. HR+ patients had median OS from
start of first line of 38.4 months, and TNBC patients had 23.4 months. Rate of
use of infused/parenteral supportive care drugs was 25.5% overall and 36.7% among
TNBC patients with 15.8% among HR+ patients.
CONCLUSION: There is an unmet need in BRCA-mutated patients with MBC, including
those with HR+ and TNBC disease. The unmet need among TNBC patients was most
evident in that 12% were not treated and TNBC patients appeared to have poor
treatment outcomes.
MICRO ABSTRACT: Reviewed medical records for outcomes, resource utilization, and
costs in 114 community patients with BRCA mutated metastatic breast cancer. 57
hormone positive (HP); 57 triple negative (TN).
RESULTS: median PFS: 12.1 months HP; 6.1 TN. HP OS was 38.4; TN 23.4. Rate of
infused supportive care drugs: 25.5% HP; 36.7% TN. Patients with TN disease need
better therapeutic options.

DOI: 10.1016/j.ctarc.2019.100121
PMID: 30785027

Cancer Treat Res Commun. 2019 Feb 6;19:100122. doi: 10.1016/j.ctarc.2019.100122.
[Epub ahead of print]

Is human papillomavirus associated with breast cancer or papilloma presenting
with pathologic nipple discharge?

Balci FL(1), Uras C(2), Feldman SM(3).

Author information:
(1)Department of General Surgery, Bahcesehir University Faculty of Medicine,
Medical Park Hospitals, Istanbul, Turkey. Electronic address:
levent.balci@acibadem.com.
(2)Department of General Surgery, Acibadem Research Institute of Senology,
Istanbul, Turkey.
(3)Breast Surgery, Montefiore Medical Center, The University Hospital for the
Albert Einstein College of Medicine, New York, NY, USA.

PURPOSE: There are little data on the presence or interaction of human
papillomavirus (HPV) in intraductal papilloma or Breast cancer (BC) presenting
with pathologic nipple discharge (PND). The study aimed to determine whether the
HPV-genotypes are identifiable in papilloma or carcinoma of the breast by
real-time PCR with broad-spectrum genotyping.
METHODS: Formalin-fixed-paraffin-blocks obtained from the patients who were
suffering from PND and underwent ductoscopic papilloma extraction (n = 27) or
segmental/total mastectomy for cancer diagnosis (n = 18). HPV-DNAs were
identified by PCR with broad-spectrum genotyping. Mc Nemar test was used to
compare cancer-involved cases to normal-adjacent tissue concerning HPV
positivity. Chi-Square test was used to analyze the association for receptor
status in HPV positive cancer-involved cases.
RESULTS: The mean age (±SD) was 49 ± 16 in papilloma and 52 ± 14 in BC patients,
respectively. We found high prevalence of HPV in papilloma and carcinoma: 29.6%
(n = 8) and 44.4% (n = 8), respectively. The most common type identified in
breast lesions was HPV-11, and the others were HPV- 6, -11, -39, and -82.
Cancer-involved samples were more contaminated by HPV in comparison to
normal-adjacent tissues (p = 0.016). In HPV positive cancer-involved cases,
hormone receptors were found to be more positive than HER2-Neu (p = 0.035).
CONCLUSIONS: Our data suggest that HPV might be a causative agent for the
development of papilloma and carcinoma of the breast in some cases presenting
with PND. HPV positive breast cancers are more likely to be hormone positive.
Further studies needed for validation regarding the integration of HPV-DNAs into
the human genome that causes BC.

DOI: 10.1016/j.ctarc.2019.100122
PMID: 30785026

Breast. 2019 Feb 11;44:153-159. doi: 10.1016/j.breast.2019.02.004. [Epub ahead of
print]

Recurrence in early breast cancer: Analysis of data from 3,765 Australian women
treated between 1997 and 2015.

Stuart-Harris R(1), Dahlstrom JE(2), Gupta R(3), Zhang Y(4), Craft P(5), Shadbolt
B(6).

Author information:
(1)Medical Oncology Unit, The Canberra Hospital, Woden, ACT 2606, Australia; ANU
Medical School, Australian National University, Barry Drive, Acton, ACT 0200,
Australia. Electronic address: robin.stuart-harris@act.gov.au.
(2)ANU Medical School, Australian National University, Barry Drive, Acton, ACT
0200, Australia; ACT Pathology, The Canberra Hospital, Woden, ACT 2606,
Australia.
(3)ACT Pathology, The Canberra Hospital, Woden, ACT 2606, Australia.
(4)ACT and SE NSW Breast Cancer Treatment Group, ACT Health, GPO Box 825, ACT
2601, Australia.
(5)Medical Oncology Unit, The Canberra Hospital, Woden, ACT 2606, Australia; ANU
Medical School, Australian National University, Barry Drive, Acton, ACT 0200,
Australia.
(6)ANU Medical School, Australian National University, Barry Drive, Acton, ACT
0200, Australia; Health Analytics Research Centre, ACT Health, GPO Box 825, ACT
2601, Australia.

BACKGROUND: Evidence suggests recent improvements in outcome in early breast
cancer (EBC).
AIM: To analyse recurrence in women with EBC from our region from 1997 to 2015.
METHODS: We analysed recurrence in 3,765 women with EBC. Median follow up was
83·0 months. 62·5% had a symptomatic presentation. 81·8% were hormone receptor
positive and 38·5% were node positive. Lymphovascular invasion (LVI) was present
in 24·3%. Of the 2,686 women entered from 2002 onwards tested for HER2 status,
72·7% had a luminal tumour, 15·2% had a HER2+ tumour and 12·1% had a triple
negative (TN) tumour.
RESULTS: Recurrence occurred in 459 (12·2%), predominantly in distant sites
(71·7%). In women entered from 2002 onwards, the five and 10 year recurrence
rates were significantly lower in the luminal group than the HER2+ and the TN
groups. Few recurrences occurred in HER2+ and TN cancers after 36 months. On
multivariate analysis the following were associated with a significantly
increased risk of recurrence: nodal involvement (p < 0·0001), tumour grade (p < 0·0001), symptomatic presentation (p < 0·0001), presence of LVI (p = 0·001), non-luminal tumour type (p < 0·0001) and tumour size >50 mm (p = 0·02).
CONCLUSION: The recurrence rate in this series was much lower than in previous
older series. Lymph node involvement, tumour grade, symptomatic presentation,
presence of LVI, non-luminal tumour type and tumour size (>50 mm) were associated
with an increased risk of recurrence. We strongly recommend that clinicians
include the presence of LVI and symptomatic presentation as well as the other
established tumour factors, when assessing the risk of recurrence in women with
EBC.

DOI: 10.1016/j.breast.2019.02.004
PMID: 30785024

Comput Biol Chem. 2019 Jan 21;79:110-118. doi:
10.1016/j.compbiolchem.2019.01.008. [Epub ahead of print]

Novel 2,4-disubstituted quinazolines as cytotoxic agents and JAK2 inhibitors:
Synthesis, in vitro evaluation and molecular dynamics studies.

Jyothi Buggana S(1), Paturi MC(1), Perka H(2), Gade DR(3), Vvs RP(4).

Author information:
(1)Department of Pharmaceutical Chemistry, Bojjam Narasimhulu Pharmacy College
for Women, Hyderabad, India.
(2)Department of Pharmaceutical Chemistry, Teegala Krishna Reddy College of
Pharmacy, Hyderabad, India.
(3)Centre for Molecular Cancer Research (CMCR), Vishnu Institute of
Pharmaceutical and Educational Research, Narsapur, India.
(4)Centre for Molecular Cancer Research (CMCR), Vishnu Institute of
Pharmaceutical and Educational Research, Narsapur, India. Electronic address:
rajendraprasad.vvs@viper.ac.in.

Recent studies reported the involvement of JAK2/STAT3 pathway in various solid
tumours including breast, ovarian, prostate and lung cancers. Clinical literature
also reported the lowered burden in breast and ovarian cancers by targeting JAK2
pathway. In this study, a series of novel 2,4-disubstituted quinazolines (2a-2 j
and 3a-3 j) were synthesized and were evaluated for their cytotoxicity against
human breast cancer (MDA-MB-231) and ovarian cancer (SK-O-V3) cell lines using
MTT assay. Moderate to good in vitro cytotoxic potentials of the newly
synthesized molecules were reported against selected human cancer cell lines.
Among the tested molecules, compound 3b has shown better cytotoxic activity
against MD-MB-231 (10.1 ± 0.51 μM). in vitro JAK2 inhibition assay elucidated the
mechanistic profile of the derivatives with moderate percentage of inhibition.
Compounds 3b and 3d were reported with 35.4% and 34.2% inhibition of JAK2
protein. SAR studies suggest that the larger hydrophobic aromatic nucleus with
hydrophilic linkage could probably increase the cytotoxic and JAK2 potentials and
hydroxyl or nitro substitution could be more beneficial. Molecular dynamics
simulation studies with JAK2-3b, and JAK2-3d complexes elucidated the
conformational changes. With the reported bioactivities of these derivatives,
further studies on the derivatization could elucidate the broader cytotoxic
potentials.

DOI: 10.1016/j.compbiolchem.2019.01.008
PMID: 30785020

Biomed Pharmacother. 2019 Feb 20;112:108607. doi: 10.1016/j.biopha.2019.108607.
[Epub ahead of print]

Network-pharmacology-based identiﬁcation of caveolin-1 as a key target of
Oldenlandia diffusa to suppress breast cancer metastasis.

Yang B(1), Wang N(2), Wang S(3), Li X(1), Zheng Y(3), Li M(4), Song J(4), Zhang
F(2), Mei W(5), Lin Y(6), Wang Z(7).

Author information:
(1)Integrative Research Laboratory of Breast Cancer, Discipline of Integrated
Chinese and Western Medicine, the Research Center of Integrative Medicine, School
of Basic Medical Sciences & the Second Clinical College of Guangzhou University
of Chinese Medicine, Guangzhou, Guangdong, China; Guangdong Provincial Key
Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome,
Guangdong Provincial Academy of Chinese Medical Sciences, Guangdong Provincial
Hospital of Chinese Medicine, Guangzhou, Guangdong, China.
(2)Integrative Research Laboratory of Breast Cancer, Discipline of Integrated
Chinese and Western Medicine, the Research Center of Integrative Medicine, School
of Basic Medical Sciences & the Second Clinical College of Guangzhou University
of Chinese Medicine, Guangzhou, Guangdong, China.
(3)Integrative Research Laboratory of Breast Cancer, Discipline of Integrated
Chinese and Western Medicine, the Research Center of Integrative Medicine, School
of Basic Medical Sciences & the Second Clinical College of Guangzhou University
of Chinese Medicine, Guangzhou, Guangdong, China; Guangdong Provincial Key
Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome,
Guangdong Provincial Academy of Chinese Medical Sciences, Guangdong Provincial
Hospital of Chinese Medicine, Guangzhou, Guangdong, China; Post-doctoral Research
Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China.
(4)School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China.
(5)School of Pharmacy, Guangdong Pharmaceutical University, China.
(6)Integrative Research Laboratory of Breast Cancer, Discipline of Integrated
Chinese and Western Medicine, the Research Center of Integrative Medicine, School
of Basic Medical Sciences & the Second Clinical College of Guangzhou University
of Chinese Medicine, Guangzhou, Guangdong, China; Guangdong Provincial Key
Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome,
Guangdong Provincial Academy of Chinese Medical Sciences, Guangdong Provincial
Hospital of Chinese Medicine, Guangzhou, Guangdong, China. Electronic address:
linyi1942@126.com.
(7)Integrative Research Laboratory of Breast Cancer, Discipline of Integrated
Chinese and Western Medicine, the Research Center of Integrative Medicine, School
of Basic Medical Sciences & the Second Clinical College of Guangzhou University
of Chinese Medicine, Guangzhou, Guangdong, China; Guangdong Provincial Key
Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome,
Guangdong Provincial Academy of Chinese Medical Sciences, Guangdong Provincial
Hospital of Chinese Medicine, Guangzhou, Guangdong, China; Post-doctoral Research
Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China.
Electronic address: wangzhiyu@gzucm.edu.cn.

BACKGROUND: Breast cancer remains the most common female malignancy and
metastasis is the leading cause of death in breast cancer patients. Oldenlandia
diffusa has been empirically and extensively used as an adjuvant therapy for
metastatic breast cancer patients in Traditional Chinese Medicine (TCM) with
proven efficacy. However, its anti-metastasis mechanism has been poorly revealed.
METHODS: Multiple molecular biology experiments as well as network pharmacology,
bioinformatics analysis were conducted to investigate the anti-metastasis
mechanism of Oldenlandia diffusa in breast cancer.
RESULTS: We demonstrated that ethanol extract of Oldenlandia diffusa (EEOD)
significantly inhibited proliferation and induced apoptosis of high-metastatic
breast cancer cell lines MDA-MB-231 and MDA-MB-453, while having no obvious
cytotoxic effect on multiple nonmalignant cells. Furthermore, EEOD remarkably
suppressed the migration and invasion capacities of the above breast cancer cells
by modulating the matrix metalloproteinases (MMPs) and the epithelial-mesenchymal
transition (EMT) pathway. More importantly, EEOD also significantly inhibited
breast cancer metastasis in zebrafish xenotransplantation model in vivo. Network
pharmacology and bioinformatics analysis further demonstrated that EEOD yielded
12 candidate compounds and 225 potential targets, and shared 85 putative targets
associated with breast cancer metastasis. Mechanistically, RNA sequencing and
experimental validation results suggested that EEOD might inhibit breast cancer
metastasis by attenuating the expression of caveolin-1 (Cav-1) as overexpression
of Cav-1 could weaken the anti-metastasis efficacy of EEOD.
CONCLUSIONS: Overall, our findings proved that EEOD could inhibit breast cancer
metastasis by attenuating the expression of Cav-1, highlighting the use of EEOD
as an adjunctive therapy for metastatic breast cancer patients. This study also
provides novel insights into network pharmacology and bioinformatics analysis as
effective tools to illuminate the scientific basis of TCM.

DOI: 10.1016/j.biopha.2019.108607
PMID: 30784915

Eur J Med Chem. 2019 Jan 26;166:514-530. doi: 10.1016/j.ejmech.2019.01.049. [Epub
ahead of print]

Synthesis, in vitro and in vivo biological evaluation of substituted
3-(5-imidazo[2,1-b]thiazolylmethylene)-2-indolinones as new potent anticancer
agents.

Morigi R(1), Locatelli A(2), Leoni A(2), Rambaldi M(2), Bortolozzi R(3),
Mattiuzzo E(3), Ronca R(4), Maccarinelli F(4), Hamel E(5), Bai R(5), Brancale
A(6), Viola G(7).

Author information:
(1)Dipartimento di Farmacia e Biotecnologie Fa.Bi.T, Università di Bologna,
40100, Bologna, Italy. Electronic address: rita.morigi@unibo.it.
(2)Dipartimento di Farmacia e Biotecnologie Fa.Bi.T, Università di Bologna,
40100, Bologna, Italy.
(3)Dipartimento di Salute della Donna e del Bambino, Laboratorio di
Oncoematologia, Università di Padova, 35128, Padova, Italy.
(4)Dipartimento di Medicina Molecolare e Traslazionale Unità di Oncologia
Sperimentale ed Immunologia, Università di Brescia, 25123, Brescia, Italy.
(5)Screening Technologies Branch, Developmental Therapeutics Program, Division of
Cancer Treatment and Diagnosis, Frederick National Laboratory for Cancer
Research, National Cancer Institute, National Institutes of Health, Frederick,
MD, 21702, USA.
(6)The Welsh School of Pharmacy, Cardiff University, Cardiff, CF10 3NB, UK.
(7)Dipartimento di Salute della Donna e del Bambino, Laboratorio di
Oncoematologia, Università di Padova, 35128, Padova, Italy. Electronic address:
giampietro.viola.1@unipd.it.

A small library of 3-(5-imidazo[2,1-b]thiazolylmethylene)-2-indolinones has been
synthesized and screened according to protocols available at the National Cancer
Institute (NCI). Some derivatives were potent antiproliferative agents, showing
GI50 values in the nanomolar range. Remarkably, when most active compounds
against leukemia cells were tested in human peripheral blood lymphocytes from
healthy donors, were 100-200 times less cytotoxic. Some compounds, selected by
the Biological Evaluation Committee of NCI, were examined to determine tubulin
assembly inhibition. Furthermore, flow cytometric studies performed on HeLa,
HT-29, and A549 cells, showed that compounds 14 and 25 caused a block in the G2/M
phase. Interestingly, these derivatives induced apoptosis through the
mitochondrial death pathway, causing in parallel significant activation of both
caspase-3 and -9, PARP cleavage and down-regulation of the anti-apoptotic
proteins Bcl-2 and Mcl-1. Finally, compound 25 was also tested in vivo in the
murine BL6-B16 melanoma and E0771 breast cancer cells, causing in both cases a
significant reduction in tumor volume.

DOI: 10.1016/j.ejmech.2019.01.049
PMID: 30784885

Eur J Med Chem. 2019 Feb 12;167:485-498. doi: 10.1016/j.ejmech.2019.02.014. [Epub
ahead of print]

Design, synthesis, and biological evaluation of truncated deguelin derivatives as
Hsp90 inhibitors.

Yao H(1), Xu F(1), Wang G(1), Xie S(1), Li W(1), Yao H(1), Ma C(2), Zhu Z(3), Xu
J(4), Xu S(5).

Author information:
(1)State Key Laboratory of Natural Medicines and Department of Medicinal
Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR
China.
(2)State Key Laboratory of Chemical Biology and Drug Discovery, and Department of
Applied Biology and Chemical Technology, The Hong Kong Polytechnic University,
Kowloon, Hong Kong.
(3)Division of Molecular Therapeutics & Formulation, School of Pharmacy, The
University of Nottingham, University Park Campus, Nottingham NG7 2RD, UK.
(4)State Key Laboratory of Natural Medicines and Department of Medicinal
Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR
China. Electronic address: jinyixu@china.com.
(5)State Key Laboratory of Natural Medicines and Department of Medicinal
Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR
China. Electronic address: cpuxst@cpu.edu.cn.

A series of novel B and C-rings truncated deguelin derivatives have been designed
and synthesized in the present study as heat shock protein 90 (Hsp90) inhibitors.
The synthesized compounds exhibited micromolar antiproliferative potency toward a
panel of human cancer cell lines. Their structure-activity relationships (SARs)
were investigated in a systematic manner. Compound 21c was identified to have
high Hsp90 binding potency (60 nM) and caused degradation of client proteins
through ubiquitin proteasome system. Further biological studies showed that
compound 21c induced a dose-dependent S and G2-phase cell cycle arrest on human
breast cancer MCF-7 cells. Flow cytometry and Western blot analyses confirmed
that compound 21c caused apoptosis of MCF-7 cells. In addition, compound 21c
showed much potent inhibition on the migration and invasion of MCF-7 cells. Taken
together, these results suggest that 21c might be a promising lead compound for
further development of Hsp90 inhibitors.

DOI: 10.1016/j.ejmech.2019.02.014
PMID: 30784881

Soc Sci Med. 2019 Feb 13;225:26-33. doi: 10.1016/j.socscimed.2019.02.020. [Epub
ahead of print]

Negotiating jurisdictional boundaries in response to new genetic possibilities in
breast cancer care: The creation of an ‘oncogenetic taskscape’.

Wright S(1), Porteous M(2), Stirling D(2), Young O(3), Gourley C(4), Hallowell
N(5).

Author information:
(1)Usher Institute of Population Health Sciences and Informatics, University of
Edinburgh, Edinburgh, UK. Electronic address: S.J.Wright@ed.ac.uk.
(2)MRC Institute of Genetics and Molecular Medicine, University of Edinburgh,
Edinburgh, UK.
(3)Edinburgh Breast Unit, Western General Hospital, Edinburgh, UK.
(4)MRC Institute of Genetics and Molecular Medicine, University of Edinburgh,
Edinburgh, UK; Cancer Research UK Edinburgh Centre; MRC Institute of Genetics and
Molecular Medicine, University of Edinburgh, Edinburgh, UK.
(5)Ethox Centre and Wellcome Centre for Ethics and Humanities, Nuffield
Department of Population Health, Big Data Institute University of Oxford, UK.

Changes in the nature and structure of healthcare pathways have implications for
healthcare professionals’ jurisdictional boundaries. The introduction of
treatment focused BRCA1 and 2 genetic testing (TFGT) for newly diagnosed patients
with breast cancer offers a contemporary example of pathway change brought about
by technological advancements in gene testing and clinical evidence, and reflects
the cultural shift towards genomics. Forming part of an ethnographically informed
study of patient and practitioner experiences of TFGT at a UK teaching hospital,
this paper focuses on the impact of a proposal to pilot a mainstreamed TFGT
pathway on healthcare professionals’ negotiations of professional jurisdiction.
Based upon semi-structured interviews (n = 19) with breast surgeons, medical
oncologists and members of the genetics team, alongside observations of breast
multidisciplinary team meetings, during the time leading up to the implementation
of the pilot, we describe how clinicians responded to the anticipated changes
associated with mainstreaming. Interviews suggest that mainstreaming the breast
cancer pathway, and the associated jurisdictional reconfigurations, had advocates
as well as detractors. Medical oncologists championed the plans, viewing this
adaptation in care provision and their professional role as a logical next step.
Breast surgeons, however, regarded mainstreaming as an unfeasible expansion of
their workload and questioned the relevance of TFGT to their clinical practice.
The genetics team, who introduced the pilot, appeared cautiously optimistic about
the potential changes. Drawing on sociological understandings of the negotiation
of professional jurisdictions our work contributes a timely, micro-level
examination of the responses among clinicians as they worked to renegotiate
professional boundaries in response to the innovative application of
treatment-focused BRCA testing in cancer care – a local and dynamic process which
we refer to as an ‘oncogenetic taskscape in the making’.

DOI: 10.1016/j.socscimed.2019.02.020
PMID: 30784848

Neoplasma. 2019 Feb 14. pii: 180819N624. doi: 10.4149/neo_2018_180819N624. [Epub
ahead of print]

High expression of carbonic anhydrase 12 (CA12) is associated with good prognosis
in breast cancer.

Li Y(1), Lei B(2), Zou J(2), Wang W(2), Chen A(2), Zhang J(2), Fu Y(2), Li Z(2).

Author information:
(1)Department of Oncology, The Second Affiliated Hospital of Harbin Medical
University, Harbin Medical University, Harbin, China.
(2)Department of Breast Surgery, The Affiliated Tumor Hospital of Harbin Medical
University, Harbin Medical University, Harbin, China.

The purpose of this research was to explore whether the expression of carbonic
anhydrase 12 (CA12) and the prognosis had a significant relationship in breast
cancer patients. A total of 262 breast cancer specimens and 75 normal breast
tissue specimens were recruited in this study. The expression of CA12 was
detected by immunohistochemistry (IHC), and its correlation with the
clinicopathological characteristics of breast cancer patients and their prognosis
were further analyzed through standard statistical algorithms. The result of
immunohistochemical staining showed that CA12 was detected in both normal breast
tissue and breast cancer tissue. Compared to normal breast tissue, CA12 was
significant higher expressing in cancer tissues (P=0.009). Statistical analysis
showed that the high expression of CA12 in breast cancer tissue was related to
estrogen receptor expression level (P<0.001). The follow-up of 262 cases of
breast cancer patients within 5 years showed that patients with high expression
of CA12 had significant better outcome in DFS (P=0.020) and OS (P=0.019) than
patients with low expression of CA12. Univariate analysis of DFS showed that
lymph node metastasis (P=0.034) and CA12 (P=0.024) are prognostic indicators.
Multivariate analysis manifested that the expression of CA12 (P=0.025) and lymph
node metastasis (P=0.024) are two independent factors affecting the prognosis of
breast cancer. Conclusion: In breast cancer patients, CA12 can be seen as a new
prognostic indicator and even a new target for treatment.

DOI: 10.4149/neo_2018_180819N624
PMID: 30784287

Neoplasma. 2019 Feb 14. pii: 180710N467. doi: 10.4149/neo_2018_180710N467. [Epub
ahead of print]

Ambra1 inhibits paclitaxel-induced apoptosis in breast cancer cells by modulating
the Bim/mitochondrial pathway.

Sun WL(1), Wang L(1), Luo J(1), Zhu HW(1), Cai ZW(1).

Author information:
(1)Department of Medical Oncology, The Second Affiliated Hospital, Guangxi
Medical University, Nanning, China.

Cancer cells often evade apoptosis induced by anti-cancer drugs, which reduces
the efficacy of the drugs. Autophagy/Beclin 1 regulator 1 (Ambra1) is a crucial
proautophagic protein. It also plays an important role in the execution of
apoptosis. However, the mechanism by which Ambra1 regulates apoptosis has not
been fully clarified. Moreover, whether Ambra1 participates in the regulation of
paclitaxel-induced apoptosis in breast cancer cells is not clear. Here, we show
that Ambra1 inhibits paclitaxel-induced apoptosis in breast cancer cells.
Moreover, Bim and mitochondria are key effectors of Ambra1 in this process. Thus,
Ambra1 is a protein that makes breast cancer cells resistant to apoptosis by
modulating the Bim/mitochondrial pathway. Therefore, Ambra1 may be a potential
target for the treatment of breast cancer.

DOI: 10.4149/neo_2018_180710N467
PMID: 30784282

Nat Prod Bioprospect. 2019 Feb 19. doi: 10.1007/s13659-019-0198-x. [Epub ahead of
print]

Bioactivity-Guided Isolation of Totarane-Derived Diterpenes from Podocarpus
neriifolius and Structure Revision of 3-Deoxy-2α-hydroxynagilactone E.

Benatrehina PA(1), Chen WL(2), Czarnecki AA(2), Kurina S(2), Chai HB(1), Lantvit
DD(2), Ninh TN(3), Zhang X(4), Soejarto DD(2)(5), Burdette JE(2), Kinghorn AD(1),
Rakotondraibe LH(6).

Author information:
(1)Division of Medicinal Chemistry and Pharmacognosy, The Ohio State University,
College of Pharmacy, Columbus, OH, USA.
(2)College of Pharmacy, University of Illinois at Chicago, Chicago, IL, USA.
(3)Institute of Ecology and Biological Resources, Vietnam Academy of Science and
Technology Hanoi, Hanoi, Vietnam.
(4)Center for Biostatistics, The Ohio State University, Columbus, OH, USA.
(5)John G. Searle Herbarium of the Field Museum of Natural History, Chicago, IL,
USA.
(6)Division of Medicinal Chemistry and Pharmacognosy, The Ohio State University,
College of Pharmacy, Columbus, OH, USA. rakotondraibe.1@osu.edu.

Bioactivity-guided phytochemical investigation of Podocarpus neriifolius D. Don.
(Podocarpaceae) has led to the isolation of one new (2) and three known (1, 3,
and 4) B-type podolactones, along with three totarane-type diterpenes (5-7).
Their structures were determined by interpretation of High Resolution
ElectroSpray Ionization Mass Spectrometry (HRESIMS) and 1D and 2D NMR data, and
comparison with the values reported in the literature. The structure of compound
1, previously identified as 3-deoxy-2α-hydroxynagilactone E (8), was revised as
its 2β-epimer, which has been reported recently as a new compound. All of the
isolates were evaluated for their antiproliferative activity against a panel of
four human cancer cell lines, namely, ovarian (OVCAR3), breast (MDA-MB-231),
colon (HT-29), and melanoma (MDA-MB-435), and compounds 1 and 3 were found to be
cytotoxic with IC50 values in the low micromolar range for most of the cell lines
used. The major compound, inumakilactone A (3), was further tested in vivo using
the HT-29, MDA-MB-435, and OVCAR3 cells in a murine hollow fiber model, for the
first time.

DOI: 10.1007/s13659-019-0198-x
PMID: 30783922

Surg Case Rep. 2019 Feb 19;5(1):31. doi: 10.1186/s40792-019-0591-z.

Amyloid tumor of the breast.

Mori M(1), Kotani H(2), Sawaki M(2), Hattori M(2), Yoshimura A(2), Gondo N(2),
Adachi Y(2), Kataoka A(2), Sugino K(2), Horisawa N(2), Terada M(2), Ozaki Y(2),
Iwata H(2).

Author information:
(1)Department of Breast Oncology, Aichi Cancer Center, 1-1 Kanokoden, Chikusa-ku,
Nagoya, 464-8681, Japan. m.mori@aichi-cc.jp.
(2)Department of Breast Oncology, Aichi Cancer Center, 1-1 Kanokoden, Chikusa-ku,
Nagoya, 464-8681, Japan.

BACKGROUND: Amyloid tumor of the breast is a rare disease, which was first
reported in 1973. To date, only six cases have been reported in Japan.
CASE PRESENTATION: A 45-year-old woman who had a medical history of Sjogren’s
syndrome presented with a lump of 3 cm in diameter on the outer side of the right
breast. Mammography showed no abnormality. Ultrasonography showed a well-defined
and rough hypoechoic mass of 32 mm in diameter at the site of the lump. With
suspicion of breast cancer, an ultrasound-guided vacuum-assisted breast biopsy
was performed. For pathological diagnosis, hematoxylin and eosin staining showed
deposits of nonstructural substances in the interstitium. The specimen stained
red with Congo red staining and showed green birefringence under a polarizing
microscope. Thus, the mass was diagnosed as an amyloid tumor. Since the patient
had Sjogren’s syndrome, it was considered a breast finding of autoimmune disease.
We considered further therapy to be unnecessary, and annual follow-up was
recommended.
CONCLUSIONS: We diagnosed the mass as an amyloid tumor by an ultrasound-guided
vacuum-assisted breast biopsy without resection. The patient had no systemic
symptoms suspected systemic amyloidosis, and we diagnosed localized amyloidosis.
An amyloid tumor of the breast may show findings suggestive of breast cancer.
Pathological diagnosis before surgery is important to avoid excessive invasion.
If deposits of nonstructural substances are observed by hematoxylin and eosin
staining, Congo red staining should be added.

DOI: 10.1186/s40792-019-0591-z
PMID: 30783867

Cancer Causes Control. 2019 Feb 19. doi: 10.1007/s10552-019-01141-x. [Epub ahead
of print]

Rural-urban differences in health behaviors and outcomes among older, overweight,
long-term cancer survivors in the RENEW randomized control trial.

Gray MS(1), Judd SE(2), Sloane R(3), Snyder DC(4), Miller PE(5),
Demark-Wahnefried W(6).

Author information:
(1)Department of Epidemiology, University of Alabama at Birmingham (UAB),
Birmingham, AL, USA.
(2)Department of Biostatistics, UAB, Birmingham, AL, USA.
(3)Center for Aging and Human Development, Duke University Medical Center,
Durham, NC, USA.
(4)Duke University School of Medicine, Durham, NC, USA.
(5)Cancer Epidemiology and Surveillance Branch, Texas Department of State Health
Services, Austin, TX, USA.
(6)Department of Nutrition Sciences, UAB, Birmingham, AL, USA. demark@uab.edu.

PURPOSE: Rural cancer survivors (RCS) have poorer health outcomes and face
multiple challenges-older age, and limited transportation, education, income, and
healthcare access. Yet, RCS are understudied. The Reach-out to ENhancE
Wellness(RENEW) trial, a home-based, diet and exercise intervention among 641
breast, prostate, and colorectal cancer survivors addressed many of these
challenges.
METHODS: We examined whether rural and urban participants differed in their
response to the RENEW intervention (e.g., physical functioning, quality-of-life,
intakes of fruits and vegetables (F&V) and saturated fat, body mass index(BMI),
physical activity, and adverse events).
RESULTS: Rural versus urban survivors report significantly more favorable mean
(SE) changes in physical functioning [- 0.66 (1.47) v - 1.71 (1.00)], physical
health [+ 0.14 (0.71) v - 0.74 (0.50)], and fewer adverse events [1.58 (0.08) v
1.64 (0.06)]. Rural versus urban survivors reported smaller increases in F&Vs
[+ 1.47 (0.23) v + 1.56(0.16); p = 0.018], and lower percentages achieved goal
behavior for endurance exercise and intakes of F&Vs and saturated fat.
CONCLUSIONS: The RENEW intervention reduced declines in physical health and
functioning among RCS to a significantly greater extent than for urban cancer
survivors. All survivors significantly improved intakes of F&V and saturated fat,
and endurance exercise; however, lower percentages of rural versus urban
survivors met goal suggesting that more intensive interventions may be needed for
RCS.

DOI: 10.1007/s10552-019-01141-x
PMID: 30783858

Ann Surg Oncol. 2019 Feb 19. doi: 10.1245/s10434-019-07210-4. [Epub ahead of
print]

Long-Term Outcomes After Surgical Treatment of Malignant/Borderline Phyllodes
Tumors of the Breast.

Spanheimer PM(1), Murray MP(2), Zabor EC(3), Stempel M(1), Morrow M(1), Van Zee
KJ(1), Barrio AV(4).

Author information:
(1)Breast Service, Department of Surgery, Memorial Sloan Kettering Cancer Center,
New York, NY, USA.
(2)Breast Pathology Service, Department of Pathology, Memorial Sloan Kettering
Cancer Center, New York, NY, USA.
(3)Biostatistics Service, Department of Epidemiology and Biostatistics, Memorial
Sloan Kettering Cancer Center, New York, NY, USA.
(4)Breast Service, Department of Surgery, Memorial Sloan Kettering Cancer Center,
New York, NY, USA. barrioa@mskcc.org.

BACKGROUND: Malignant/borderline phyllodes tumors (PTs) are rare, and little is
known about their long-term prognosis. This study sought to evaluate recurrence
rates and identify factors associated with local and distant failure.
METHODS: From 1957 to 2017, we identified 124 patients with 125 PTs (86 malignant
and 39 borderline). Recurrence rates and survival were assessed using the
Kaplan-Meier method, and correlated with clinicopathologic factors using the
log-rank test.
RESULTS: The median age of the patients was 44 years, and the median tumor size
was 5 cm. Breast-conserving surgery was performed for 57% of the patients. At a
median follow-up of 7.1 years, 14 patients experienced a locoregional recurrence
(LRR), with a 10-year cumulative LRR incidence of 12%. On univariable analysis,
age younger than 40 years (p = 0.02) and close/positive margins (p = 0.001) were
associated with increased risk of LRR. Seven patients developed distant disease,
all occurring in malignant PTs. The 10-year distant recurrence-free survival was
94%. Uniformly poor pathologic features consisting of marked stromal cellularity,
stromal overgrowth, infiltrative borders, and 10 or more mitoses per 10
high-power fields (hpf) were identified in 25 PTs (20%), and all distant
recurrences occurred in this group. For the patients who did not have uniformly
poor features, the 10-year disease-specific survival was 100%, and the overall
survival was 94% compared with 66% and 57%, respectively, among those with poor
features.
CONCLUSION: Malignant/borderline PTs without uniformly poor histologic features
have an excellent prognosis after surgical resection, with a 10-year
disease-specific survival of 100%. The presence of uniformly poor pathologic
features predicts a poor prognosis. Efforts should be directed toward new
treatment approaches for these tumors.

DOI: 10.1245/s10434-019-07210-4
PMID: 30783853

Ann Surg Oncol. 2019 Feb 19. doi: 10.1245/s10434-019-07244-8. [Epub ahead of
print]

ASO Author Reflections: Role of Genomic Assay to Predict Neoadjuvant Chemotherapy
Response in Breast Cancer.

Pease AM(1), James TA(2).

Author information:
(1)Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
(2)Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
tajames@bidmc.harvard.edu.

DOI: 10.1245/s10434-019-07244-8
PMID: 30783852

Arch Gynecol Obstet. 2019 Feb 19. doi: 10.1007/s00404-019-05097-w. [Epub ahead of
print]

The impact of EndoPredict ® on decision making with increasing oncological work
experience: can overtreatment be avoided?

Thangarajah F(1)(2), Eichler C(3)(4)(5), Fromme J(3), Malter W(3)(4), Caroline
Radosa J(6), Ludwig S(3), Puppe J(3), Paepke S(7), Warm M(5).

Author information:
(1)Department of Gynecology and Obstetrics, University of Cologne, Medical
Faculty, Cologne, Germany. Fabinshy.Thangarajah@uk-koeln.de.
(2)Breast Center, University of Cologne, Medical Faculty, Kerpener Str. 34,
50931, Cologne, Germany. Fabinshy.Thangarajah@uk-koeln.de.
(3)Department of Gynecology and Obstetrics, University of Cologne, Medical
Faculty, Cologne, Germany.
(4)Breast Center, University of Cologne, Medical Faculty, Kerpener Str. 34,
50931, Cologne, Germany.
(5)Breast Cancer Center, Municipal Hospital Holweide, Cologne, Germany.
(6)Clinic for Gynecology, Obstetrics and Reproductive Medicine, Saarland
University Medical Center, 66421, Homburg, Germany.
(7)Breast Cancer Center, Technical University Munich, Munich, Germany.

BACKGROUND: Estimating distant recurrence risk in women with estrogen
receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative early
breast cancer is still challenging. EndoPredict® is a gene expression-based test
predicting the likelihood of recurrent disease. We analyzed the difference in
oncological decision making with and without the knowledge of gene expression
tests.
PATIENTS AND METHODS: This is a retrospective analysis including patients
diagnosed with hormone-receptor positive, Her2 negative breast cancer between
2011 and 2015 at the Municipal Breast Cancer Centre Cologne, Germany. All
patients received an evaluation by EndoPredict®. An oncological tumor board (TB)
with knowledge of these results served as a baseline (control group). This
baseline was compared to the treatment decision (adjuvant chemotherapy yes vs.
no) made by oncologists with different experience levels (less than 5 years,
between 5 and 15 years, and more than 15 years) who were not provided the
EndoPredict® scores. All clinicians had access to clinical as well to
histopathological data.
RESULTS: There was no significant difference between control group and the
oncologists with different experience levels concerning a chemotherapy
indication. A trend could be shown in the subgroup of nodal negative patients
between the treatment recommendation and physicians with more than 15 years of
experience (p = 0.088). A further trend could be demonstrated in the subgroup of
patients with a low Ki67 index (≤ 14%) (p = 0.063) between physician with
5-10 years of clinical experience and official treatment recommendation.
CONCLUSION: It seems that inexperienced physicians may profit from the use of
EndoPredict® to avoid an overtreatment. In nodal negative patients and patients
with a low Ki67 index, undertreatment can be avoided with the use of EndoPredict®
(borderline significance). Further prospective studies with larger study cohorts
are needed to further validate this tool.

DOI: 10.1007/s00404-019-05097-w
PMID: 30783737

Aesthetic Plast Surg. 2019 Feb 19. doi: 10.1007/s00266-019-01331-7. [Epub ahead
of print]

Trauma on a Recently Augmented Breast as a Trigger for Mondor’s Disease.

Yordanov YP(1).

Author information:
(1)Adella Aesthetic, 15G, Tintyava Str., 1172, Sofia, Bulgaria.
yordanov_vma@abv.bg.

Mondor’s disease is the eponym used to describe a self-limited phlebitis or
thrombophlebitis of the superficial veins localized mainly on the
thoracoabdominal area of the human body. Its clinical manifestation includes
painful superficial cords causing skin retraction. This medical condition could
be idiopathic, iatrogenic or a manifestation of underlying pathology such as
breast cancer and seems to be more common than has been previously thought. The
vast majority of the clinical studies and case reports to date focus on Mondor’s
disease as a disorder which is more or less directly related to a previous
surgical intervention. In this case report, the author discusses the possible
role of breast surgery as a predisposing factor only and the trauma on the
operated breast as a trigger for onset and earlier manifestation of Mondor’s
disease. A special emphasis is put on the importance of trauma prevention in
breast augmentation surgery, especially when maneuvers like postoperative
massages are considered.Level of Evidence V This journal requires that authors
assign a level of evidence to each article. For a full description of these
Evidence-Based Medicine ratings, please refer to the Table of Contents or the
online Instructions to Authors http://www.springer.com/00266 .

DOI: 10.1007/s00266-019-01331-7
PMID: 30783723

Aesthet Surg J. 2019 Feb 3. pii: sjz023. doi: 10.1093/asj/sjz023. [Epub ahead of
print]

Patient-Reported Outcome Measures for Breast Implant Surgery: A Pilot Study.

Ng S(1), Pusic A(2), Parker E(1), Vishwanath S(1), Cooter RD(3), Elder E(4),
Moore C(5), McNeil J(5), Hopper I(1).

Author information:
(1)Department of Epidemiology and Preventive Medicine, School of Public Health
and Preventive Medicine, Monash University, Melbourne, Victoria, Australia.
(2)Memorial Sloan-Kettering Cancer Center, New York, NY.
(3)Australian Society of Plastic Surgeons, Sydney, New South Wales, Australia.
(4)Breast Surgeons of Australia and New Zealand, Randwick, New South Wales,
Australia.
(5)Australasian College of Cosmetic Surgery, Parramatta, New South Wales,
Australia.

BACKGROUND: The Breast-Q Implant Surveillance (BREAST-Q IS) is a patient-reported
outcome measure (PROM) asking five questions on satisfaction (shape, feel, and
rippling) and symptoms (pain and tightness) derived from the BREAST-Q.
OBJECTIVES: We aimed to pilot BREAST-Q IS on patients within the Australian
Breast Device Registry (ABDR), an opt-out clinical quality device registry, and
explored Short Message Service (SMS) for follow up.
METHODS: Patients with a breast device surgery in the previous 10-15 months, age
≥18, with a mobile phone number, were invited to complete the 5-question PROM via
SMS initially, followed by three phone call attempts if no response, an email,
and then a letter by post as a final engagement strategy.
RESULTS: 197 participants were included (breast augmentation, BA=118 and breast
reconstruction, BR=79). Mean age was 40±12SD years (BA) and 44±11SD years (BR).
Mean time since surgery was 414±36SD days (BA), and 413±51SD days (BR). The total
response rate, including opt outs, was 76%. 90% of BA and over 80% of BR were
very or somewhat satisfied with shape, feel, and wrinkling. Over 70% of BA and
over 46% of BR reported no pain or tightness. Completion of survey via SMS was
51% (BA) and 55% (BR). Further responses were received by phone (25%, 26%), post
(21%, 16%), and email (3%, 3%).
CONCLUSIONS: This pilot demonstrated effectiveness of our engagement strategy,
with a 76% response rate. Over 50% of respondents used SMS to reply to a
5-question PROM assessing long-term surgical outcomes. This engagement strategy
will be used as BREAST-Q IS is rolled out nationally.

DOI: 10.1093/asj/sjz023
PMID: 30783646

Lab Chip. 2019 Feb 20. doi: 10.1039/c8lc01153b. [Epub ahead of print]

Formation of precisely composed cancer cell clusters using a cell assembly
generator (CAGE) for studying paracrine signaling at single-cell resolution.

Fatsis-Kavalopoulos N(1), O’Callaghan P(2), Xie B(2), Hernández Vera R(2),
Idevall-Hagren O(2), Kreuger J(2).

Author information:
(1)Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden.
johan.kreuger@mcb.uu.se and Gradientech AB, Uppsala, Sweden.
(2)Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden.
johan.kreuger@mcb.uu.se.

The function and behaviour of any given cell in a healthy tissue, or in a tumor,
is affected by interactions with its neighboring cells. It is therefore important
to create methods that allow for reconstruction of tissue niches in vitro for
studies of cell-cell signaling and associated cell behaviour. To this end we
created the cell assembly generator (CAGE), a microfluidic device which enables
the organization of different cell types into precise cell clusters in a flow
chamber compatible with high-resolution microscopy. In proof-of-concept paracrine
signalling experiments, 4-cell clusters consisting of one pancreatic β-cell and
three breast cancer cells were formed. It has previously been established that
extracellular ATP induces calcium (Ca2+) release from the endoplasmic reticulum
(ER) to the cytosol before it is cleared back into the ER via sarcoplasmic/ER
Ca2+ ATPase (SERCA) pumps. Here, ATP release from the β-cell was stimulated by
depolarization, and dynamic changes in Ca2+ levels in the adjacent cancer cells
measured using imaging of the calcium indicator Fluo-4. We established that
changes in the concentration of cytosolic Ca2+ in the cancer cells were
proportional to the distance from the ATP-releasing β-cell. Additionally, we
established that the relationship between distance and cytosolic calcium changes
were dependent on Ca2+-release from the ER using 5-cell clusters composed of one
β-cell, two untreated cancer cells and two cancer cells pretreated with
Thapsigargin (to deplete the ER of Ca2+). These experiments show that the CAGE
can be used to create exact cell clusters, which affords precise control for
reductionist studies of cell-cell signalling and permits the formation of
heterogenous cell models of specific tissue niches.

DOI: 10.1039/c8lc01153b
PMID: 30783638

Oncotarget. 2019 Jan 25;10(8):917. doi: 10.18632/oncotarget.26650. eCollection
2019 Jan 25.

Correction: The prognostic significance of combined androgen receptor,
E-Cadherin, Ki67 and CK5/6 expression in patients with triple negative breast
cancer.

Adamo B(#)(1), Ricciardi GRR(#)(2), Ieni A(3), Franchina T(2), Fazzari C(4), Sanò
MV(5), Angelico G(6), Caruso M(5), Tuccari G(3), Adamo V(2).

Author information:
(1)Department of Medical Oncology, Hospital Clínic of Barcelona, Barcelona,
Spain.
(2)Medical Oncology Unit A.O. Papardo & Department of Human Pathology University
of Messina, Messina, Italy.
(3)Department of Human Pathology of Adult and Evolutive Age «Gaetano Barresi»,
Section of Pathology, University of Messina, AOU Policlinico «G. Martino»
Messina, Italy.
(4)Pathology Unit, Humanitas Center of Oncology, Catania, Italy.
(5)Medical Oncology, Humanitas Catania Oncology Center, Catania, Italy.
(6)G. F. Ingrassia Department, Section of Anatomic Pathology, University Hospital
Policlinico-Vittorio Emanuele, Catania, Italy.
(#)Contributed equally

Erratum for
Oncotarget. 2017 Aug 16;8(44):76974-76986.

[This corrects the article DOI: 10.18632/oncotarget.20293.].

DOI: 10.18632/oncotarget.26650
PMCID: PMC6368234
PMID: 30783520

Oncotarget. 2019 Jan 25;10(8):916. doi: 10.18632/oncotarget.26649. eCollection
2019 Jan 25.

Correction: γKlotho is a novel marker and cell survival factor in a subset of
triple negative breast cancers.

Trošt N(1)(2), Peña-Llopis S(2), Koirala S(3), Stojan J(1), Potts PR(3), Fon
Tacer K(3), Martinez ED(2)(4).

Author information:
(1)Institute of Biochemistry, Faculty of Medicine, University of Ljubljana,
Ljubljana, Slovenia.
(2)Department of Pharmacology, University of Texas Southwestern Medical Center,
Dallas, Texas, USA.
(3)Department of Physiology, University of Texas Southwestern Medical Center,
Dallas, Texas, USA.
(4)Hamon Center for Therapeutic Oncology Research, University of Texas
Southwestern Medical Center, Dallas, Texas, USA.

Erratum for
Oncotarget. 2016 Jan 19;7(3):2611-28.

[This corrects the article DOI: 10.18632/oncotarget.6006.].

DOI: 10.18632/oncotarget.26649
PMCID: PMC6368237
PMID: 30783519

Oncotarget. 2019 Jan 25;10(8):803-804. doi: 10.18632/oncotarget.26611.
eCollection 2019 Jan 25.

Pregnancies in young women with diagnosis and treatment of HER2-positive breast
cancer.

Lambertini M(1), Viglietti G(1).

Author information:
(1)Department of Medical Oncology, U.O.C. Clinica di Oncologia Medica, Ospedale
Policlinico San Martino, Genova, Italy; Department of Internal Medicine and
Medical Specialties, School of Medicine, University of Genova, Genova, Italy.

DOI: 10.18632/oncotarget.26611
PMCID: PMC6368228
PMID: 30783509

Exp Ther Med. 2019 Mar;17(3):1896-1902. doi: 10.3892/etm.2018.7145. Epub 2018 Dec
28

HOXA1 upregulation is associated with poor prognosis and tumor progression in
breast cancer.

Liu J(1), Liu J(2), Lu X(1).

Author information:
(1)Department of Breast Surgery, Dalian Central Hospital Affiliated to Dalian
Medical University, Dalian, Liaoning 116033, P.R. China.
(2)Department of Clinical Medicine, Datong University School of Medicine, Datong,
Shanxi 037009, P.R. China.

Breast cancer (BC) is the most commonly diagnosed cancer and the second leading
cause of cancer-associated mortality among females worldwide. As a member of the
homeobox (HOX) gene family, HOXA1 is involved in tumor progression and prognosis
in several types of human cancer. However, the clinical significance and
biological functions of HOXA1 in BC remains unknown. The current study assessed
the expression of HOXA1 in BC tissues and cells via western blotting and reverse
transcription-quantitative polymerase chain reaction. The association between
HOXA1 expression and the clinicopathological features of patients with BC was
analyzed using the Chi-square test. The overall survival of patients was
calculated using the Kaplan-Meier method and examined using the log-rank test.
Cell proliferation was examined via an MTT assay. Cell cycle distribution and
cell apoptosis were analyzed using flow cytometry. The current study demonstrated
that HOXA1 mRNA and protein expression was upregulated in BC. In addition, HOXA1
overexpression was associated with poor prognosis and advanced
clinicopathological features in patients with BC. Furthermore, knockdown of HOXA1
significantly inhibited cell proliferation by enhancing cell apoptosis and cell
cycle arrest in BC cells, which was accompanied with aberrant expression of cell
cycle and apoptosis-associated proteins, cyclin D1, B-cell lymphoma 2 (Bcl-2) and
Bcl-2-like protein 4. Taken together, the results suggested that HOXA1 may serve
as a novel prognostic marker and therapeutic target in BC.

DOI: 10.3892/etm.2018.7145
PMCID: PMC6364196
PMID: 30783466

Contemp Oncol (Pozn). 2018;22(4):247-251. doi: 10.5114/wo.2018.82644. Epub 2018
Dec 31.

Analysis of the causes of false negative and false positive results of
preoperative axillary ultrasound in patients with early breast cancer – a
single-centre study.

Nowikiewicz T(1)(2), Nowak A(3), Wiśniewska M(4)(5), Wiśniewski M(6), Nowikiewicz
M(7), Zegarski W(1)(2).

Author information:
(1)Chair and Department of Surgical Oncology, Ludwik Rydygier’s Collegium Medicum
in Bydgoszcz, Nicolaus Copernicus University in Torun, Bydgoszcz, Poland.
(2)Department of Breast Cancer and Reconstructive Surgery, Prof. Franciszek
Łukaszczyk Oncology Centre, Bydgoszcz, Poland.
(3)Diagnostic Imaging and Interventional Radiology Unit, Prof. Franciszek
Łukaszczyk Oncology Centre, Bydgoszcz, Poland.
(4)Department of Oncology and Brachytherapy, Ludwik Rydygier’s Collegium Medicum
in Bydgoszcz, Nicolaus Copernicus University in Torun, Bydgoszcz, Poland.
(5)Chemotherapy Department, Prof. Franciszek Łukaszczyk Oncology Centre,
Bydgoszcz, Poland.
(6)Outpatient Chemotherapy Department, Prof. Franciszek Łukaszczyk Oncology
Centre, Bydgoszcz, Poland.
(7)Student Scientific Society, Chair and Department of Surgical Oncology, Ludwik
Rydygier’s Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in
Torun, Bydgoszcz, Poland.

Introduction: Properly planned and performed diagnostic tests allow the optimal
treatment option to be chosen for the patient. They also allow qualification for
the correct surgical procedure.
Aim of the study: In this study we evaluated the clinical value of preoperative
ultrasound scan (USS) testing performed during primary disease staging in
patients with early breast cancer qualified to sentinel lymph node biopsy (SLNB).
Material and methods: The group of breast cancer patients who underwent SLNB from
March 2012 to May 2013. As well as the standard procedure of the preoperative
diagnostics model, in each patient the USS of axillary lymph nodes was performed
additionally. The results were compared with the data from postoperative
pathological reports. We attempted to define the factors influencing the
possibility of obtaining false positive and false negative USS results.
Results: The analysis comprised 172 patients. In 14.4% of cases with normal USS
result the pathological result was different from the expected one (pN1). In
42.3% of patients with suspicious axillary lymph nodes the result of the
pathological report was positive. The sensitivity of the USS testing was 89.3%,
and the specificity was 34.4%, PPV – 85.6%, NPV – 42.3%.
Conclusions: Ultrasonographic assessment of axillary lymph nodes in breast cancer
patients qualified for SLNB is a test with high sensitivity and high predictive
value of the positive test result. The possibility of a result contrary to the
actual nodal status may result primarily from the technical limitations of USS
testing.

DOI: 10.5114/wo.2018.82644
PMCID: PMC6377422
PMID: 30783389

Conflict of interest statement: The authors declare no conflict of interest.

Contemp Oncol (Pozn). 2018;22(4):240-246. doi: 10.5114/wo.2018.82643. Epub 2018
Dec 31.

Evaluation of distant sequelae of breast cancer treatment among patients after
breast-conserving surgery depending on the type of intervention in the axillary
fossa.

Głowacka-Mrotek I(1), Tarkowska M(2), Nowikiewicz T(3), Siedlecki Z(4), Zegarski
W(3), Hagner W(1).

Author information:
(1)Department of Rehabilitation, Ludwik Rydygier’s Collegium Medicum in
Bydgoszcz, Nicolaus Copernicus University in Torun, Bydgoszcz, Poland.
(2)Department of Laser Therapy and Physiotherapy, Ludwik Rydygier’s Collegium
Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Bydgoszcz, Poland.
(3)Department of Surgical Oncology, Ludwik Rydygier’s Collegium Medicum in
Bydgoszcz Nicolaus Copernicus University in Torun, Oncology Centre in Bydgoszcz,
Bydgoszcz, Poland.
(4)Department of Neurosurgery, Ludwik Rydygier’s Collegium Medicum in Bydgoszcz,
Nicolaus Copernicus University in Torun, Bydgoszcz, Poland.

Aim of the study: The goal of this work was to assess upper-limb sequelae among
patients undergoing breast-conserving therapy (BCT) for breast cancer 5-6 years
after the surgical procedure.
Material and methods: A controlled clinical study was conducted on 128 patients
who had undergone surgery 5-6 years prior. BCT + ALND (axillary lymph node
dissection) was performed in 58 patients and 69 underwent BCT + SLND (sentinel
lymph node dissection). Patients declared active participation in physiotherapy.
The following parameters were assessed in studied subjects: range of motion in
the shoulder joint, superficial sensation, upper limb circumference, skin
sensation, and presence of winged scapula sign.
Results: Five to six years after BCT, patients who had undergone BCT + ALND
presented with significantly poorer outcomes concerning upper limb range of
motion on the operated side compared to the BCT + SLND group with regard to the
following features: flexion (p = 0.00004), external rotation (p = 0.0292), and
internal rotation (p = 0.0448). However, no statistically significant differences
were noted between compared groups with regard to upper limb circumference and
sensation disturbances. Statistically significant differences between limb on the
operated side (operated limb – OL) vs. contralateral limb (healthy limb – HL)
were noted in the BCT + SLND group with regard to the range of motion in
extension (p = 0.0004), external rotation (p = 0.0055), and internal rotation (p
< 0.0001), as well as the occurrence of winged scapula sign (p < 0.0001) and
sensation disturbances (p < 0.0001).
Conclusions: Our study demonstrated that both procedures are not free of distant
sequelae, although the BCT + ALND group is more frequently affected.

DOI: 10.5114/wo.2018.82643
PMCID: PMC6377421
PMID: 30783388

Conflict of interest statement: The authors declare no conflict of interest.

Contemp Oncol (Pozn). 2018;22(4):236-239. doi: 10.5114/wo.2018.80038. Epub 2018
Dec 31.

Analysis of Treg cell population in patients with breast cancer with respect to
progesterone receptor status.

Dziobek K(1), Biedka M(2)(3), Nowikiewicz T(4), Szymankiewicz M(5), Łukaszewska
E(6), Dutsch-Wicherek M(5).

Author information:
(1)Department of Oncological Gynecology, Maria Sklodowska-Curie Memorial Cancer
Centre and Institute of Oncology, Krakow Branch, Krakow.
(2)Department of Radiotherapy, Professor Franciszek Lukaszczyk Oncology Center in
Bydgoszcz, Poland.
(3)Department of Oncology and Brachytherapy, Ludwik Rydygier Collegium Medicum in
Bydgoszcz, Nicolaus Copernicus University in Torun, Bydgoszcz, Poland.
(4)Clinical Department of Breast Cancer and Reconstructive Surgery, Professor
Franciszek Lukaszczyk Oncology Center in Bydgoszcz, Poland.
(5)Department of Oncology, Radiotherapy, and Gynecologic Oncology, Ludwik
Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun,
Bydgoszcz, Poland.
(6)Department of Pathology, Professor Franciszek Lukaszczyk Oncology Center in
Bydgoszcz, Poland.

Breast cancer is the most frequently diagnosed type of cancer in women worldwide.
Both the development and progression of breast cancer are related to tumour
evasion of the immune system through a process called cancer immune-editing, in
which regulatory lymphocytes play an important role. The infiltration of Treg
cells in patients with breast cancer has been proposed as an independent
unfavourable prognostic factor. In the present study, we aimed to evaluate the
percentages of the Treg cell populations in the peripheral blood of patients with
breast cancer with respect to progesterone receptor expression. Peripheral blood
samples were collected from 27 patients with breast cancer treated in the
Clinical Department of Breast Cancer and Reconstructive Surgery of the Professor
Franciszek Lukaszczyk Oncological Centre, Bydgoszcz. Flow cytometry was used to
evaluate the percentage of CD25+/FOXP3+/CD127 (-/low) T cells within CD3+/CD4+ T
cells. The presence of CD25+/FOXP3+/CD127 (-/low) T cells within CD3+/CD4+ T
cells was identified in all the examined blood samples. A statistically
significantly higher percentage of CD25+/FOXP3+/CD127 (-/low) T cells within
CD3+/CD4+ T cells was observed in progesterone receptor (PR)-negative breast
cancer patients when compared to PR-positive breast cancer patients. The observed
high percentage of CD25+/FOXP3+/CD127 (-/low) T cells within CD3+/CD4+ T cells in
PR (-) breast cancer patients when compared to PR (+) breast cancer patients
seems to confirm the unfavourable prognostic significance of these cells in
breast cancer patients. This may indicate a rationale for combining standard
oncological treatment in breast cancer patients with Treg-depleting therapy.

DOI: 10.5114/wo.2018.80038
PMCID: PMC6377420
PMID: 30783387

Conflict of interest statement: The authors declare no conflict of interest.

J Craniovertebr Junction Spine. 2018 Oct-Dec;9(4):267-270. doi:
10.4103/jcvjs.JCVJS_32_18.

The repair using a fibular graft of cervical vertebral collapse due to renal cell
carcinoma: Late results with a case report.

Köksal V(1), Eren H(2), Güçer H(3).

Author information:
(1)Department of Neurosurgery, Research and Training Hospital, Recep Tayyip
Erdogan University, Rize, Turkey.
(2)Department of Urology, Research and Training Hospital, Recep Tayyip Erdogan
University, Rize, Turkey.
(3)Department of Pathology, Research and Training Hospital, Recep Tayyip Erdogan
University, Rize, Turkey.

The most common cause of spinal tumors is metastases, but the cervical vertebra
is the least common region of spinal metastasis, and relatively, little is
published about surgery in metastasis to the cervical vertebra. While spinal
metastasis is most often caused by neoplasms originating from the lung, breast,
and prostate, renal cell carcinoma (RCC) metastasis is very rare. A 47-year-old
patient introduced here presented with severe pain spontaneously on his neck and
in his arm. In the radiology of the patient without neurological deficit, a
pathologic vertebral collapse was detected in the C6 vertebral corpus. The
patient underwent anterior cervical corpectomy. The fibula graft taken from his
right leg was implanted in the emptied area and supported by an anterior plaque,
and restoration of physiological cervical lordosis was established. From the
pathological tissue that was taken, it was determined that the cause of the lysis
was an RCC metastasis. After surgical repair of the cervical spine, a primary
pathology with a diameter of 10 cm was detected in the patient’s kidney, and a
radical nephrectomy was performed. After 6 years of follow-up, there was no
recurrence, and the patient continued his normal daily life. Radiologically
between the autologous fibula graft and its own vertebral body was observed to
achieve very good fusion. In this study, we emphasized the importance of
resection of metastasis together with a primary tumor in a metastatic RCC case to
cure the patient and provide the desired quality of life.

DOI: 10.4103/jcvjs.JCVJS_32_18
PMCID: PMC6364372
PMID: 30783351

Conflict of interest statement: There are no conflicts of interest.

Br J Cancer. 2019 Feb 20. doi: 10.1038/s41416-018-0366-5. [Epub ahead of print]

A phase 1b/2, open-label, dose-escalation, and dose-confirmation study of
eribulin mesilate in combination with capecitabine.

Twelves C(1), Anthoney A(2), Savulsky CI(3), Guo M(4), Reyderman L(5), Cresti
N(6), Semiglazov V(7), Timcheva C(8), Zubairi I(9), Morrison R(10), Plummer R(6),
Evans TRJ(10)(11).

Author information:
(1)Leeds Institute of Cancer and Pathology, University of Leeds and Leeds
Teaching Hospitals Trust, Leeds, UK. C.J.Twelves@leeds.ac.uk.
(2)Leeds Institute of Cancer and Pathology, University of Leeds and Leeds
Teaching Hospitals Trust, Leeds, UK.
(3)Clinical Development Oncology, Oncology Production Creation Unit, Eisai Ltd,
Hatfield, UK.
(4)Biostatistics, Oncology PCU, Eisai Inc, Woodcliff Lake, NJ, USA.
(5)Clinical Pharmacology and Translational Medicine, Oncology, Eisai Inc,
Woodcliff Lake, NJ, USA.
(6)Northern Centre for Cancer Care, The Newcastle upon Tyne Hospitals NHS
Foundation Trust, Newcastle upon Tyne, UK.
(7)Department of Tumors of Reproductive System and Breast Cancer, NN Petrov
Research Institute of Oncology, St Petersburg, Russia.
(8)Medical Oncology Clinic, Multiprofile Hospital for Active Treatment «Nadezhda»
Sofia, Sofia, Bulgaria.
(9)Department of Medical Oncology, Beatson West of Scotland Cancer Centre,
Glasgow, UK.
(10)Clinical Research Unit, Beatson West of Scotland Cancer Centre, Glasgow, UK.
(11)Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.

BACKGROUND: Capecitabine and eribulin are widely used as single agents in
metastatic breast cancer (MBC) and have nonoverlapping toxicities.
METHODS: In phase 1b (dose escalation), patients with advanced,
treatment-refractory, solid tumours received eribulin mesilate intravenously in
21-day cycles according to schedule 1 (day 1) or schedule 2 (days 1, 8) with
twice-daily oral capecitabine (1000 mg/m2 days 1-14). In phase 2 (dose
confirmation), women with advanced/MBC and ≤3 prior chemotherapies received
eribulin mesilate at the maximum tolerated dose (MTD) per the preferred schedule
plus capecitabine. Primary objectives were MTD and dose-limiting toxicities
(DLTs; phase 1b) and objective response rate (ORR; phase 2). Secondary objectives
included progression-free survival (PFS), safety, and pharmacokinetics.
RESULTS: DLTs occurred in 4/19 patients (schedule 1) and 2/15 patients (schedule
2). Eribulin pharmacokinetics were dose proportional, irrespective of schedule or
capecitabine coadministration. The MTD of eribulin was 1.6 mg/m2 day 1 for
schedule 1 and 1.4 mg/m2 days 1 and 8 for schedule 2. ORR in phase 2 (eribulin
1.4 mg/m2 days 1, 8 plus capecitabine) was 43% and median PFS 7.2 months. The
most common treatment-related adverse events were neutropenia, leukopenia,
alopecia, nausea, and lethargy.
CONCLUSIONS: The combination of capecitabine and eribulin showed promising
efficacy with manageable tolerability in patients with MBC.

DOI: 10.1038/s41416-018-0366-5
PMID: 30783204

Br J Cancer. 2019 Feb 20. doi: 10.1038/s41416-019-0395-8. [Epub ahead of print]

MicroRNA-196a is regulated by ER and is a prognostic biomarker in ER+ breast
cancer.

Milevskiy MJG(1)(2), Gujral U(3), Del Lama Marques C(3), Stone A(4), Northwood
K(3)(5), Burke LJ(3), Gee JMW(6), Nephew K(7), Clark S(4), Brown MA(3).

Author information:
(1)School of Chemistry and Molecular Biosciences, University of Queensland, St
Lucia, QLD, Australia. milevskiy.m@wehi.edu.au.
(2)ACRF Stem Cells and Cancer, The Walter and Eliza Hall Institute of Medical
Research, Parkville, VIC, Australia. milevskiy.m@wehi.edu.au.
(3)School of Chemistry and Molecular Biosciences, University of Queensland, St
Lucia, QLD, Australia.
(4)Division of Genomics and Epigenetics, Epigenetics Research Laboratory, Garvan
Institute of Medical Research, Sydney, NSW, Australia.
(5)UQ Centre for Clinical Research, The University of Queensland, Herston, QLD,
Australia.
(6)School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff,
UK.
(7)School of Medicine, Indiana University, Bloomington, IN, USA.

BACKGROUND: MicroRNAs are potent post-transcriptional regulators involved in all
hallmarks of cancer. Mir-196a is transcribed from two loci and has been
implicated in a wide range of developmental and pathogenic processes, with
targets including Hox, Fox, Cdk inhibitors and annexins. Genetic variants and
altered expression of MIR196A are associated with risk and progression of
multiple cancers including breast cancer, however little is known about the
regulation of the genes encoding this miRNA, nor the impact of variants therein.
METHODS: Genomic data and chromatin interaction analysis were used to discover
functional promoter and enhancer elements for MIR196A. Expression data were used
to associate MIR196A with mechanisms of resistance, breast cancer subtypes and
prognosis.
RESULTS: Here we demonstrate that MIR196A displays complex and dynamic expression
patterns, in part controlled by long-range transcriptional regulation between
promoter and enhancer elements bound by ERα. Expression of this miRNA is
significantly increased in drug-resistant models of hormone-receptor positive
disease. The expression of MIR196A also proves to be a robust prognostic factor
for patients with advanced and post-menopausal ER+ disease.
CONCLUSION: This work sheds light on the normal and abnormal regulation of
MIR196A and provides a novel stratification method for therapeutically resistant
breast cancer.

DOI: 10.1038/s41416-019-0395-8
PMID: 30783203

Sci Rep. 2019 Feb 19;9(1):2250. doi: 10.1038/s41598-019-38759-5.

Impact of gynecologic cancer on pelvic floor disorder symptoms and quality of
life: an observational study.

Neron M(1), Bastide S(2), Tayrac R(3), Masia F(3), Ferrer C(3), Labaki M(3),
Boileau L(3), Letouzey V(3), Huberlant S(3).

Author information:
(1)Department of Obstetrics and Gynecology, Nîmes University Hospital, Univ.,
Montpellier, Nîmes, France. mathias.neron@orange.fr.
(2)Department of BESPIM (Biostatistics, Epidemiology, Public Health and
Innovation in Methodology), Nîmes University Hospital, Univ., Montpellier, Nîmes,
France.
(3)Department of Obstetrics and Gynecology, Nîmes University Hospital, Univ.,
Montpellier, Nîmes, France.

The objective of our observational prospective study was to investigate the
severity and prevalence of urinary and pelvic floor disorders in gynecologic
cancer survivors. All patients surviving gynecological cancer in the region as
well as women receiving invitations to attend breast-screening checkups as the
control population were asked to fill-in questionnaires assessing pelvic prolapse
symptoms (PFDI-20, Wexner) and associated quality of life (PFIQ-7). Eighty-nine
women were included in the cancer survivor group and 1088 in the control group.
Pelvic floor symptoms (PFDI-20 questionnaire) were significantly worse in cancer
survivors than in control women (score: 33.3 [14.6-74.1] vs. 20 [4.2-50.0],
p = 0.0003). Urge incontinence was significantly worse in cancer survivors in
both univariable (ORb = 2.061 [95% CI = 1.284-3.309], p = 0.0027) and
multivariable analyses (ORa = 1.672 [95% CI = 1.014-2.758], p = 0.0442), as was
fecal incontinence in univariable (ORb = 3.836 [95% CI = 1.710-8.602],
p = 0.0011) and in multivariable (ORa = 3.862 [95% CI = 1.657-9.001], p = 0.0018)
analyses. Women with benign hysterectomies had poorer quality of life and
increased pelvic floor disorders compared to women with no history of surgery.
Survivors of gynecological cancer experience significantly more pelvic floor
symptoms and an associated reduction in quality of life.

DOI: 10.1038/s41598-019-38759-5
PMCID: PMC6381087
PMID: 30783163

Sci Rep. 2019 Feb 19;9(1):2240. doi: 10.1038/s41598-019-38502-0.

Preoperative Prediction of Axillary Lymph Node Metastasis in Breast Cancer using
Radiomics Features of DCE-MRI.

Cui X(1), Wang N(1), Zhao Y(1), Chen S(1), Li S(2), Xu M(1), Chai R(3).

Author information:
(1)Northeastern University, Sino-Dutch Biomedical and Information Engineering
School, Wisdom Street, Shenyang, 110819, China.
(2)Radiology Department, The first hospital of China Medical University, 155#
North Nanjing street, Heping district, Shenyang, 110001, China.
(3)Radiology Department, The first hospital of China Medical University, 155#
North Nanjing street, Heping district, Shenyang, 110001, China.
wn1535522188@163.com.

The accurate and noninvasive preoperative prediction of the state of the axillary
lymph nodes is significant for breast cancer staging, therapy and the prognosis
of patients. In this study, we analyzed the possibility of axillary lymph node
metastasis directly based on Magnetic Resonance Imaging (MRI) of the breast in
cancer patients. After mass segmentation and feature analysis, the SVM, KNN, and
LDA three classifiers were used to distinguish the axillary lymph node state in
5-fold cross-validation. The results showed that the effect of the SVM classifier
in predicting breast axillary lymph node metastasis was significantly higher than
that of the KNN classifier and LDA classifier. The SVM classifier performed best,
with the highest accuracy of 89.54%, and obtained an AUC of 0.8615 for
identifying the lymph node status. Each feature was analyzed separately and the
results showed that the effect of feature combination was obviously better than
that of any individual feature on its own.

DOI: 10.1038/s41598-019-38502-0
PMID: 30783148

Sci Rep. 2019 Feb 19;9(1):2318. doi: 10.1038/s41598-018-37259-2.

The prognostic relevance of urokinase-type plasminogen activator (uPA) in the
blood of patients with metastatic breast cancer.

Banys-Paluchowski M(1), Witzel I(2), Aktas B(3), Fasching PA(4), Hartkopf A(5),
Janni W(6), Kasimir-Bauer S(7), Pantel K(8), Schön G(9), Rack B(6), Riethdorf
S(8), Solomayer EF(10), Fehm T(11), Müller V(12).

Author information:
(1)Department of Gynecology and Obstetrics, Asklepios-Klinik Barmbek, Hamburg,
Germany.
(2)Department of Gynecology, University Medical Center Hamburg-Eppendorf,
Hamburg, Germany.
(3)Department of Obstetrics and Gynecology, University Hospital Leipzig, Leipzig,
Germany.
(4)Department of Gynecology and Obstetrics, University Hospital Erlangen,
Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University
Erlangen-Nuremberg, Erlangen, Germany.
(5)Department of Obstetrics and Gynecology, University Hospital Tübingen,
University of Tübingen, Tübingen, Germany.
(6)Department of Gynecology and Obstetrics, University Hospital Ulm, Ulm,
Germany.
(7)Department of Obstetrics and Gynecology, University Hospital Essen, University
of Duisburg-Essen, Essen, Germany.
(8)Department of Tumour Biology, University Medical Center Hamburg-Eppendorf,
Hamburg, Germany.
(9)Department of Medical Biometry and Epidemiology, University Medical Center
Hamburg-Eppendorf, Hamburg, Germany.
(10)Department of Gynecology and Obstetrics, Saarland University Hospital,
Homburg/Saar, Germany.
(11)Department of Obstetrics and Gynecology, Heinrich-Heine-University
Düsseldorf, Düsseldorf, Germany.
(12)Department of Gynecology, University Medical Center Hamburg-Eppendorf,
Hamburg, Germany. vmueller@uke.de.

In breast cancer (BC), elevated levels of urokinase-type plasminogen activator
(uPA) in tumor tissue have been confirmed as a strong prognostic factor in
level-of-evidence-1 studies. The aim of the present study was to evaluate the
clinical relevance of uPA levels in serum of metastatic BC patients and to
compare uPA with other blood-based biomarkers. 252 patients were enrolled in this
prospective, multicentre study. Blood samples were collected before begin of
first-line or later-line systemic treatment. Serum uPA was quantified by a
commercially available ELISA. Circulating tumor cells (CTCs) were detected using
CellSearch; other biomarkers (EGFR, VEGF, HER2, RAS p21, TIMP1, CAIX) by ELISA.
Using the ROC analysis, the optimal cut-off value (determined by the Youden
index) of serum uPA was 2.52 ng/ml. Using this value, 26% of patients had
elevated uPA levels. Patients with visceral metastasis and more than one
metastatic site were significantly more likely to present with elevated uPA
levels. CTC status, serum HER2, RAS p21, CAIX, TIMP1 and VEGF correlated
significantly with uPA levels. Elevated uPA levels predicted shorter overall and
progression-free survival in univariate analysis (median OS: 7.5 months [95%-CI
4.5-10.5 months] vs. not reached, p < 0.001; PFS: 4.8 [95%-CI: 3.1-6.5] vs. 9.1
[7.4-10.8] months, p < 0.001). In multivariate analysis, elevated uPA, presence
of ≥5 CTCs, elevated RAS p21, higher grading and higher line of therapy were
independent predictors of shorter OS, while elevated CTC counts, higher line of
therapy and negative estrogen receptor status were independent predictors of
shorter PFS. In conclusion, elevated uPA levels independently predict reduced
overall survival and improved prognostication in patients with known CTC status.
Whether high serum uPA might identify patients most likely to benefit from
therapies targeting uPA, remains to be evaluated in future trials.

DOI: 10.1038/s41598-018-37259-2
PMID: 30783124

Nat Commun. 2019 Feb 19;10(1):836. doi: 10.1038/s41467-019-08769-y.

Single gold-bridged nanoprobes for identification of single point DNA mutations.

Ma X(1), Song S(1), Kim S(1), Kwon MS(2), Lee H(2), Park W(3), Sim SJ(4).

Author information:
(1)Department of Chemical & Biological Engineering, Korea University, Seoul,
136713, Republic of Korea.
(2)Department of Biological Sciences & Institute of Molecular Biology and
Genetics (IMBG), Seoul National University, Seoul, 151742, Republic of Korea.
(3)Department of Electrical, Computer & Energy Engineering, Materials Science &
Engineering Program, University of Colorado, Boulder, CO, 80309, USA.
(4)Department of Chemical & Biological Engineering, Korea University, Seoul,
136713, Republic of Korea. simsj@korea.ac.kr.

Consensus ranking of protein affinity to identify point mutations has not been
established. Therefore, analytical techniques that can detect subtle variations
without interfering with native biomolecular interactions are required. Here we
report a rapid method to identify point mutations by a single nanoparticle
sensing system. DNA-directed gold crystallization forms rod-like nanoparticles
with bridges based on structural design. The nanoparticles enhance Rayleigh light
scattering, achieving high refractive-index sensitivity, and enable the system to
monitor even a small number of protein-DNA binding events without interference.
Analysis of the binding affinity can compile an atlas to distinguish the
potential of various point mutations recognized by MutS protein. We use the atlas
to analyze the presence and type of single point mutations in BRCA1 from samples
of human breast and ovarian cancer cell lines. The strategy of
synthesis-by-design of plasmonic nanoparticles for sensors enables direct
identification of subtle biomolecular binding distortions and genetic
alterations.

DOI: 10.1038/s41467-019-08769-y
PMCID: PMC6381086
PMID: 30783107

BMJ Open. 2019 Feb 19;9(2):e025783. doi: 10.1136/bmjopen-2018-025783.

Making headlines: an analysis of US government-funded cancer research mentioned
in online media.

Maggio LA(1), Ratcliff CL(2), Krakow M(3), Moorhead LL(4), Enkhbayar A(5),
Alperin JP(5).

Author information:
(1)Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA.
(2)University of Utah, Salt Lake City, Utah, USA.
(3)National Cancer Institute, Rockville, Maryland, USA.
(4)San Francisco State University, San Francisco, California, USA.
(5)Simon Fraser University at Harbour Centre, Vancouver, British Columbia,
Canada.

OBJECTIVE: To characterise how online media coverage of journal articles on
cancer funded by the US government varies by cancer type and stage of the cancer
control continuum and to compare the disease prevalence rates with the amount of
funded research published for each cancer type and with the amount of media
attention each receives.
DESIGN: A cross-sectional study.
SETTING: The United States.
PARTICIPANTS: The subject of analysis was 11 436 journal articles on cancer
funded by the US government published in 2016. These articles were identified via
PubMed and characterised as receiving online media attention based on data
provided by Altmetric.
RESULTS: 16.8% (n=1925) of articles published on US government-funded research
were covered in the media. Published journal articles addressed all common
cancers. Frequency of journal articles differed substantially across the common
cancers, with breast cancer (n=1284), lung cancer (n=630) and prostate cancer
(n=586) being the subject of the most journal articles. Roughly one-fifth to
one-fourth of journal articles within each cancer category received online media
attention. Media mentions were disproportionate to actual burden of each cancer
type (ie, incidence and mortality), with breast cancer articles receiving the
most media mentions. Scientific articles also covered the stages of the cancer
continuum to varying degrees. Across the 13 most common cancer types, 4.4%
(n=206) of articles focused on prevention and control, 11.7% (n=550) on diagnosis
and 10.7% (n=502) on therapy.
CONCLUSIONS: Findings revealed a mismatch between prevalent cancers and cancers
highlighted in online media. Further, journal articles on cancer control and
prevention received less media attention than other cancer continuum stages.
Media mentions were not proportional to actual public cancer burden nor volume of
scientific publications in each cancer category. Results highlight a need for
continued research on the role of media, especially online media, in research
dissemination.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No
commercial re-use. See rights and permissions. Published by BMJ.

DOI: 10.1136/bmjopen-2018-025783
PMID: 30782941

Conflict of interest statement: Competing interests: None declared.

Mol Pharmacol. 2019 Feb 19. pii: mol.118.114314. doi: 10.1124/mol.118.114314.
[Epub ahead of print]

Organic Anion Transporting Polypeptides: Emerging Roles in Cancer Pharmacology.

Schulte RR(1), Ho RH(2).

Author information:
(1)Vanderbilt University Medical Center.
(2)Vanderbilt University Medical Center richard.ho@vanderbilt.edu.

The organic anion transporting polypeptides (OATPs) are a superfamily of drug
transporters involved in the uptake and disposition of a wide array of
structurally divergent endogenous and exogenous substrates, including steroid
hormones, bile acids, and commonly used drugs, such as anti-infectives,
anti-hypertensives, and cholesterol lowering agents. In the past decade, OATPs,
primarily OATP1A2, OATP1B1, and OATP1B3, have emerged as potential mediators of
chemotherapy disposition, including drugs such as methotrexate, doxorubicin,
paclitaxel, docetaxel, irinotecan and its important metabolite SN-38, and certain
tyrosine kinase inhibitors. Furthermore, OATP family members are polymorphic and
numerous studies have shown OATP variants to have differential uptake,
disposition, and/or pharmacokinetics of numerous drug substrates with important
implications for interindividual differences in efficacy and toxicity.
Additionally, certain OATPs have been found to be overexpressed in a variety of
human solid tumors, including breast, liver, colon, pancreatic and ovarian
cancers suggesting potential roles for OATPs in tumor development, progression
and as novel targets for cancer therapy. This review focuses on the emerging
roles for selected OATPs in cancer pharmacology, including preclinical and
clinical studies suggesting roles in chemotherapy disposition, the
pharmacogenetics of OATPs in cancer therapy, and OATP overexpression in various
tumor tissues with implications for OATPs as therapeutic targets.

The American Society for Pharmacology and Experimental Therapeutics.

DOI: 10.1124/mol.118.114314
PMID: 30782852

Biosci Rep. 2019 Feb 19. pii: BSR20181809. doi: 10.1042/BSR20181809. [Epub ahead
of print]

The association of FOXP3 gene polymorphisms with cancer susceptibility: a
comprehensive systemic review and meta-analysis.

Chen Y(1), Qi X(2), Bian C(1), Ling C(1), Yi T(1), Mu X(3), Zhao X(1).

Author information:
(1)West China Second Hospital, Chengdu, China.
(2)Chengdu First People’ Hospital, Chengdu, China.
(3)West China Second Hospital, Chengdu, China xiyanmu1991@163.com.

The role of forkhead box P3 (FOXP3) protein in tumorigenesis has long been
controversial and existing data on the association between FOXP3 gene
polymorphisms and cancer susceptibility were inconsistent. Here, we conducted a
meta-analysis to better clarify the relationship. A comprehensive search of
studies published from July 2008 to June 2018 was conducted. The statistical
analyses of the pooled odds ratios (ORs) and the corresponding 95% confidence
intervals (95%CIs) were performed using the Revman 5.2 software. Twelve articles
with 19 case-control studies and 10,389 participants were included. Three FOXP3
polymorphisms and 6 cancer types were evaluated. While no significant results
were observed in overall and breast cancer groups for rs3761548 (A/C)
polymorphisms, the pooled data showed an elevated risk of cancer in variant AA
genotypes and A allele for Chinese population (AA vs. AC+CC: OR=1.61, 95%CI=1.09,
2.39; AA vs. CC: OR=1.74, 95%CI=1.05, 2.89; A vs. C: OR=1.34, 95%CI=1.00, 1.78).
Neither the overall group analyses nor the subgroup analyses stratified by cancer
type and ethnicity proposed any significant association of rs2280883 (C/T) and
rs3761549 (T/C) polymorphisms with cancer susceptibility. This meta-analysis
suggested that FOXP3 rs3761548 (A/C) polymorphisms were associated with increased
cancer risk in Chinese population while rs2280883 (C/T) and rs3761549 (T/C)
polymorphisms were not. More large-sample researches with diverse ethnicities and
cancer types are needed to draw a concrete conclusion.

DOI: 10.1042/BSR20181809
PMID: 30782783

BMJ Open. 2019 Feb 1;9(1):e025185. doi: 10.1136/bmjopen-2018-025185.

Online tool for monitoring adverse events in patients with cancer during
treatment (eRAPID): field testing in a clinical setting.

Warrington L(#)(1), Absolom K(#)(1), Holch P(1)(2), Gibson A(1)(3), Clayton B(1),
Velikova G(1)(3).

Author information:
(1)Section of Patient Centred Outcomes Research, Leeds Institute of Medical
Research at St James’s, University of Leeds, Leeds, UK.
(2)Psychology Group, School of Social Sciences, Faculty of Health and Social
Sciences, Leeds Beckett University, Leeds, UK.
(3)Leeds Teaching Hospitals NHS Trust, Leeds, UK.
(#)Contributed equally

OBJECTIVES: Electronic patient self-Reporting of Adverse-events: Patient
Information and aDvice (eRAPID) is an online system developed to support patient
care during cancer treatment by improving the detection and management of
treatment-related symptoms. Patients can complete symptom reports from home and
receive severity-based self-management advice, including notifications to contact
the hospital for severe symptoms. Patient data are available in electronic
records for staff to review. Prior to the commencement of a randomised controlled
trial (RCT), field testing of the intervention was undertaken to troubleshoot
practical issues with intervention integration in clinical practice.
DESIGN: Observational clinical field testing.
SETTING: Medical oncology breast service in a UK cancer centre.
PARTICIPANTS: 12 patients receiving chemotherapy for early breast cancer and 10
health professionals (oncologists and specialist nurses).
INTERVENTION: Patients were asked to use the eRAPID intervention and complete
weekly online symptom reports during four cycles of chemotherapy. Clinical staff
were invited to access and use patient data in clinical assessments.
ANALYSIS: Descriptive data on the frequency of online symptom report completion
and severe symptom notifications were collated. Verbal and written feedback was
collected from patients and staff and semistructured interviews were conducted to
explore patient experiences. Interviews were transcribed and analysed
thematically.
RESULTS: The testing ran from January 2014 to March 2014. Feedback from patients
and staff was largely positive. Patients described eRAPID as ‘reassuring’ and
‘comforting’ and valued the tailored management advice. Several changes were made
to refine eRAPID. In particular, improvement of the clinical notification,
patient reminder systems and changes to patient and staff training.
CONCLUSIONS: The field testing generated valuable results used to guide
refinement of eRAPID prior to formal intervention evaluation. Feedback indicated
that eRAPID has the potential to improve patients’ self-efficacy, knowledge and
confidence with managing symptoms during treatment. A large-scale RCT is underway
with data collection due to finish in October 2018.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No
commercial re-use. See rights and permissions. Published by BMJ.

DOI: 10.1136/bmjopen-2018-025185
PMID: 30782751

Conflict of interest statement: Competing interests: None declared.

BMJ Open. 2019 Jan 28;9(1):e023723. doi: 10.1136/bmjopen-2018-023723.

Development of a binational thyroid cancer clinical quality registry: a protocol
paper.

Ioannou LJ(1), Serpell J(2)(3), Dean J(1), Bendinelli C(4), Gough J(5), Lisewski
D(6), Miller JA(7), Meyer-Rochow W(8), Sidhu S(9), Topliss D(10), Walters D(11),
Zalcberg J(1), Ahern S(1).

Author information:
(1)Department of Epidemiology and Preventive Medicine, Monash University,
Melbourne, Victoria, Australia.
(2)Endocrine Surgery Unit, Alfred Hospital, Melbourne, Victoria, Australia.
(3)Endocrine Surgery Unit, Monash University, Melbourne, Victoria, Australia.
(4)Department of Surgery, John Hunter Hospital, New Lambton Heights, New South
Wales, Australia.
(5)Breast and Endocrine Surgery, The Wesley Hospital, Queensland, Australia.
(6)Department of General Surgery, Fiona Stanley Hospital, Perth, Western
Australia, Australia.
(7)Endocrine Surgery Unit, The Royal Melbourne Hospital, Melbourne, Victoria,
Australia.
(8)Department of Surgery, Waikato Hospital, Hamilton, New Zealand.
(9)Endocrine Surgery Unit, University of Sydney, Royal North Shore Hospital,
Sydney, New South Wales, Australia.
(10)Department of Endocrinology and Diabetes, Alfred Health, Melbourne, Victoria,
Australia.
(11)Breast and Endocrine Surgical Unit, University of Adelaide, The Queen
Elizabeth Hospital, Sydney, New South Wales, Australia.

INTRODUCTION: The occurrence of thyroid cancer is increasing throughout the
developed world and since the 1990s has become the fastest increasing malignancy.
In 2014, a total of 2693 Australians and 302 New Zealanders were diagnosed with
thyroid cancer, with this number projected to rise to 3650 in 2018. The purpose
of this protocol is to establish a binational population-based clinical quality
registry with the aim of monitoring and improving the quality of care provided to
patients diagnosed with thyroid cancer in Australia and New Zealand.
METHODS AND ANALYSIS: The Australian and New Zealand Thyroid Cancer Registry
(ANZTCR) aims to capture clinical data for all patients over the age of 16 years
with thyroid cancer, confirmed by histopathology report, who have been diagnosed,
assessed or treated at a contributing hospital. A multidisciplinary steering
committee was formed which, with operational support from Monash University,
established the ANZTCR in early 2017. The pilot phase of the registry is
currently operating in Victoria, New South Wales, Queensland, Western Australia
and South Australia, with over 20 sites expected to come on board across
Australia in 2018. A modified Delphi process was undertaken to determine the
clinical quality indicators to be reported by the registry, and a minimum data
set was developed comprising information regarding thyroid cancer diagnosis,
pathology, surgery and 90-day follow-up.
FUTURE PLANS: The establishment of the ANZTCR provides the opportunity for
Australia and New Zealand to further understand current practice in the treatment
of thyroid cancer and identify variation in outcomes. The engagement of endocrine
surgeons in supporting this initiative is crucial. While the pilot registry has a
focus on early clinical outcomes, it is anticipated that future collection of
longer term outcome data particularly for patients with poor prognostic disease
will add significant further value to the registry.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No
commercial re-use. See rights and permissions. Published by BMJ.

DOI: 10.1136/bmjopen-2018-023723
PMID: 30782713

Conflict of interest statement: Competing interests: None declared.

BMJ Open. 2019 Jan 28;9(1):e023171. doi: 10.1136/bmjopen-2018-023171.

Social determinants and individual health-seeking behaviour among women in Kenya:
protocol for a breast cancer cohort feasibility study.

Gakunga R(1), Ali Z(2), Korir A(3), Kinyanjui AW(2), Ochieng’ E(3), Gikaara N(2),
Maluni F(3), Subramanian S(4).

Author information:
(1)Independent Research Scientist, Nairobi, Kenya.
(2)Kenya Hospices and Palliative Care Association, Nairobi, Kenya.
(3)Kenya Cancer Association, Nairobi, Kenya.
(4)RTI International, Research Triangle Park, North Carolina, USA.

INTRODUCTION: A catastrophic 35% increase in the burden of breast cancer in Kenya
has been predicted by 2025. Mitigating this burden is critical, and local
research is necessary to generate the evidence to inform policy, public health
and medical practice. Most of the knowledge available has been derived from
studies in high-income countries that are not directly applicable due to
economic, social, cultural and ethnic differences. At the time of writing this
paper, we had no knowledge of any longitudinal cohort studies in sub-Saharan
Africa of both breast cancer survivors and a matching cohort of women who have
never had a diagnosis of cancer. We aim to assess feasibility of cohort studies
in Kenya that consider clinical characteristics social determinants and
individual health seeking behaviour.
METHODS AND ANALYSIS: This study aims to inform best practices for initiating a
longitudinal cohort study in Kenya. It is a two-pronged, prospective mixed
methods study of women with and without a diagnosis of breast cancer with
baseline data collection and one follow-up data collection approximately 3 months
later by telephone. Quantitative and qualitative data will be collected
concurrently, analysed separately and together to enrich understanding of
concepts by triangulation. We aim to include 800 women aged 30-60 years: 400 in
the survivorship cohort and 400 in the non-cancer cohort. Two focus group
discussions from each cohort will be carried out to enhance understanding of
concepts and to guide recommendations.
ETHICS AND DISSEMINATION: Independent ethical approval was obtained from Kenyatta
National Hospital-University of Nairobi Ethics and Research Committee and the
Research Triangle Institute International. Only consenting participants will be
enrolled. Counselling support, debriefing discussions and referrals for formal
support services will be available for both participants and research assistants.
Findings will be disseminated through publications, websites and presentations.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No
commercial re-use. See rights and permissions. Published by BMJ.

DOI: 10.1136/bmjopen-2018-023171
PMID: 30782697

Conflict of interest statement: Competing interests: None declared.

Cancer Immunol Res. 2019 Feb 19. pii: canimm.0654.2018. doi:
10.1158/2326-6066.CIR-18-0654. [Epub ahead of print]

Radiotherapy and cisplatin increase immunotherapy efficacy by enabling local and
systemic intratumoral T-cell activity.

Kroon P(1), Frijlink E(2), Iglesias-Guimarais V(3), Volkov A(2), Van Buuren
MM(4), Schumacher TN(5), Verheij M(6), Borst J(3), Verbrugge I(7).

Author information:
(1)Tumor Biology & Immunology, The Netherlands Cancer Institute.
(2)Tumor Biology and Immunology, The Netherlands Cancer Institute.
(3)Tumor Biology and Immunology, Netherlands Cancer Institute.
(4)Netherlands Cancer Institute.
(5)Immunology, Netherlands Cancer Institute.
(6)Radiation Oncology, Netherlands Cancer Institute.
(7)Tumor Biology and Immunology, The Netherlands Cancer Institute
i.verbrugge@nki.nl.

To increase cancer immunotherapy success, PD-1 blockade must be combined with
rationally selected treatments. Here, we examined, in a poorly immunogenic mouse
breast cancer model, the potential of antibody-based immunomodulation and
conventional anticancer treatments to collaborate with anti-PD-1 treatment. One
requirement to improve anti-PD-1-mediated tumor control was to promote
tumor-specific cytotoxic T-cell (CTL) priming, which was achieved by stimulating
the CD137 costimulatory receptor. A second requirement was to overrule
PD-1-unrelated mechanisms of CTL suppression in the tumor micro-environment
(TME). This was achieved by radiotherapy (RT) and cisplatin treatment. In the
context of CD137/PD-1-targeting immunotherapy, RT allowed for tumor elimination
by altering the TME, rather than intrinsic CTL functionality. Combining this
radioimmunotherapy (RIT) regimen with low-dose cisplatin improved CTL-dependent
regression of a contralateral tumor outside the radiation field. Thus, systemic
tumor control may be achieved by combining immunotherapy protocols that promote
T-cell priming with (chemo)radiation protocols that permit CTL activity in both
the irradiated tumor and (occult) metastases.

DOI: 10.1158/2326-6066.CIR-18-0654
PMID: 30782666

Bioorg Chem. 2019 Feb 10;86:538-549. doi: 10.1016/j.bioorg.2019.02.017. [Epub
ahead of print]

Identification of a new tamoxifen-xanthene hybrid as pro-apoptotic anticancer
agent.

Catanzaro E(1), Seghetti F(2), Calcabrini C(1), Rampa A(2), Gobbi S(2), Sestili
P(3), Turrini E(1), Maffei F(1), Hrelia P(4), Bisi A(2), Belluti F(5), Fimognari
C(6).

Author information:
(1)Department for Life Quality Studies, Alma Mater Studiorum-University of
Bologna, Corso d’Augusto 237, 47921 Rimini, Italy.
(2)Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of
Bologna, Via Belmeloro 6, 40126 Bologna, Italy.
(3)Department of Biomolecular Sciences, University of Urbino Carlo Bo, Via I
Maggetti 26, 61029 Urbino (PU), Italy.
(4)Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of
Bologna, Via Irnerio 48, 40126 Bologna, Italy.
(5)Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of
Bologna, Via Belmeloro 6, 40126 Bologna, Italy. Electronic address:
federica.belluti@unibo.it.
(6)Department for Life Quality Studies, Alma Mater Studiorum-University of
Bologna, Corso d’Augusto 237, 47921 Rimini, Italy. Electronic address:
carmela.fimognari@unibo.it.

Breast cancer is the most diagnosed type of cancer among women for which an
exhaustive cure has not been discovered yet. Nowadays, tamoxifen still represents
the gold standard for breast cancer therapy; it acts on both estrogen
receptor-positive and estrogen receptor-negative breast cancers. Unfortunately,
its toxicity and the related chemoresistance undermine its antitumor potential.
In this paper, new tamoxifen-based derivatives with a rigid structural motif in
their structure were designed, synthesized, and evaluated to assess their
antitumor behavior. All the tested compounds affected estrogen receptor-positive
tumor (MCF-7) cell growth, even with different extents, among which, the most
active ones proved also to induce mitochondria-mediated apoptosis through
activation of PARP cleavage, decrease in Bax/Bcl-2 ratio and increase in Bim gene
expression levels. Here we found that the compound 1, carrying a rigid xanthene
core, turned out to be the most promising of the set showing an activity profile
comparable to that of tamoxifen. Furthermore, a more favorable genotoxic profile
than tamoxifen made compound 1 a promising candidate for further studies.

DOI: 10.1016/j.bioorg.2019.02.017
PMID: 30782572

J Electrocardiol. 2019 Feb 12;54:5-9. doi: 10.1016/j.jelectrocard.2019.02.003.
[Epub ahead of print]

Fragmented QRS formation and its predictors in patients with breast cancer
receiving anthracycline-based chemotherapy.

Dural M(1), Demir L(2), Babayiğit E(3), Junushova B(2), Mert KU(3), Ulus T(3),
Çavuşoğlu Y(3), Yıldız B(2), Dinçer M(2), Görenek B(3).

Author information:
(1)Department of Cardiology, Eskişehir Osmangazi University, Faculty of Medicine,
Eskişehir, Turkey. Electronic address: muhammet_dural@hotmail.com.
(2)Department of Medical Oncology, Eskişehir Osmangazi University, Faculty of
Medicine, Eskişehir, Turkey.
(3)Department of Cardiology, Eskişehir Osmangazi University, Faculty of Medicine,
Eskişehir, Turkey.

DOI: 10.1016/j.jelectrocard.2019.02.003
PMID: 30782548

Clin Oncol (R Coll Radiol). 2019 Feb 16. pii: S0936-6555(19)30054-8. doi:
10.1016/j.clon.2019.02.001. [Epub ahead of print]

Incidental Dose to Ipsilateral and Contralateral Internal Mammary Chain by
Partial Tangential Arc Technique: A Single Institutional Analysis in Breast
Cancer Patients.

Munshi A(1), Agrawal S(2), Sarkar B(2), Ganesh T(2), Mohanti BK(2).

Author information:
(1)Department of Radiation Oncology, Fortis Memorial Research Institute, Gurgaon,
Haryana, India. Electronic address: anusheel8@gmail.com.
(2)Department of Radiation Oncology, Fortis Memorial Research Institute, Gurgaon,
Haryana, India.

DOI: 10.1016/j.clon.2019.02.001
PMID: 30782445

Pharmazie. 2019 Feb 1;74(2):83-90. doi: 10.1691/ph.2019.8152.

Hyaluronic acid-coated single-walled carbon nanotubes loaded with doxorubicin for
the treatment of breast cancer.

Liu D, Zhang Q, Wang J, Fan L, Zhu W, Cai D.

Hyaluronic acid (HA)-modified amino single-walled carbon nanotubes (NH₂-SWCNTs)
were developed for targeted delivery of doxorubicin (DOX) to improve breast
cancer treatment. HA, which specifically binds to the CD44 receptor, was
non-covalently coated on NH₂-SWCNTs through simply electrostatic adsorption. The
formed SWCNTs-DOX-HA complexes were characterized in terms of morphology,
particle size and zeta potential by different techniques. The DOX loading
percentage on the SWCNTs-DOX-HA complexes was 81.5±1.0 %. In vitro release study
showed that the release of DOX was pH-triggered and was faster at a lower pH 5.5
(tumor cell microenvironment) than that under physiological conditions (pH 7.4),
which was beneficial for intracellular drug release. The SWCNTs-DOX-HA showed a
significantly improved intracellular delivery of DOX in CD44 overexpressing
MDA-MB-231 cells by flow cytometry and confocal microscopy. Of particular
importance, the SWCNTs-DOX-HA complexes were better than the unmodified
SWCNTs-DOX on inhibiting proliferation and inducing apoptosis of cells. In
addition, the migration of MDA-MB-231 cells was significantly blocked by
SWCNTs-DOX-HA. In the cancer cell spheroids assay, SWCNTs-DOX-HA exhibited
notable effect to inhibit the growth of cancer cell spheroids. All these results
indicated that this developed SWCNTs-DOX-HA complexes hold a great promise to be
used as an efficient nano-sized anticancer drug formulation for tumor-targeted
treatment.

DOI: 10.1691/ph.2019.8152
PMID: 30782256

Pharmazie. 2019 Jan 1;74(1):54-61. doi: 10.1691/ph.2019.8746.

Cyanidin-3-O-glucoside chloride acts synergistically with luteolin to inhibit the
growth of colon and breast carcinoma cells.

Yin H, Wang L, Wu M, Liu Y, Li N, Chen T.

In this study, we investigated whether the combination of cyanidin-3-O-glucoside
chloride and luteolin could inhibit the growth of HCT-8 colon and MCF-7 breast
carcinoma cells, and whether the effect of the combination was greater than the
effect of either drug on its own. Growth inhibition was assessed using the CCK-8
assay, level of apoptosis and cell cycle distribution were determined using flow
cytometry, and the mechanism of apoptosis induction was explored using a
colorimetric assay of caspases-3 and -9. Experiments indicated that combination
treatment inhibited proliferation and increased apoptosis in both cell lines to a
greater extent than either drug on its own. These results suggest that luteolin
and cyanidin-3-O-glucoside chloride synergistically inhibitthe growth of colon
cancer and breast cancer cells. This work justifies further effort to develop
this potential combination therapy.

DOI: 10.1691/ph.2019.8746
PMID: 30782251

Cell Commun Signal. 2019 Feb 19;17(1):13. doi: 10.1186/s12964-019-0325-7.

Metastasis-associated protein 1 (MTA1) is transferred by exosomes and contributes
to the regulation of hypoxia and estrogen signaling in breast cancer cells.

Hannafon BN(1)(2), Gin AL(1), Xu YF(1), Bruns M(1), Calloway CL(1), Ding
WQ(3)(4).

Author information:
(1)Department of Pathology, University of Oklahoma Health Sciences Center, 975 NE
10th Street, BRC 411A, Oklahoma City, OK, 73104, USA.
(2)Peggy and Charles Stephenson Cancer Center, Oklahoma City, OK, USA.
(3)Department of Pathology, University of Oklahoma Health Sciences Center, 975 NE
10th Street, BRC 411A, Oklahoma City, OK, 73104, USA. weiqun-ding@ouhsc.edu.
(4)Peggy and Charles Stephenson Cancer Center, Oklahoma City, OK, USA.
weiqun-ding@ouhsc.edu.

BACKGROUND: Exosomes are small membrane-bound vesicles that contribute to tumor
progression and metastasis by mediating cell-to-cell communication and modifying
the tumor microenvironment at both local and distant sites. However, little is
known about the predominant factors in exosomes that contribute to breast cancer
(BC) progression. MTA1 is a transcriptional co-regulator that can act as both a
co-activator and co-repressor to regulate pathways that contribute to cancer
development. MTA1 is also one of the most up-regulated proteins in cancer, whose
expression correlates with cancer progression, poor prognosis and increased
metastatic potential.
METHODS: We identified MTA1 in BC exosomes by antibody array and confirmed
expression of exosome-MTA1 across five breast cancer cells lines. Ectopic
expression of tdTomato-tagged MTA1 and exosome transfer were examined by
fluorescent microscopy. CRISPR/Cas9 genetic engineering was implemented to
knockout MTA1 in MCF7 and MDA-MB-231 breast cancer cells. Reporter assays were
used to monitor hypoxia and estrogen receptor signaling regulation by
exosome-MTA1 transfer.
RESULTS: Ectopic overexpression of tdTomato-MTA1 in BC cell lines demonstrated
exosome transfer of MTA1 to BC and vascular endothelial cells. MTA1 knockout in
BC cells reduced cell proliferation and attenuated the hypoxic response in these
cells, presumably through its co-repressor function, which could be rescued by
the addition of exosomes containing MTA1. On the other hand, consistent with its
co-activator function, estrogen receptor signaling was enhanced in MTA1 knockout
cells and could be reversed by addition of MTA1-exosomes. Importantly, MTA1
knockout sensitized hormone receptor negative cells to 4-hydroxy tamoxifen
treatment, which could be reversed by the addition of MTA1-exosomes.
CONCLUSIONS: This is the first report showing that BC exosomes contain MTA1 and
can transfer it to other cells resulting in changes to hypoxia and estrogen
receptor signaling in the tumor microenvironment. These results, collectively,
provide evidence suggesting that exosome-mediated transfer of MTA1 contributes to
BC progression by modifying cellular responses to important signaling pathways
and that exosome-MTA1 may be developed as a biomarker and therapeutic target for
BC.

DOI: 10.1186/s12964-019-0325-7
PMID: 30782165

BMC Bioinformatics. 2019 Feb 19;20(1):87. doi: 10.1186/s12859-019-2675-y.

Prediction of lncRNA-disease associations by integrating diverse heterogeneous
information sources with RWR algorithm and positive pointwise mutual information.

Fan XN(1)(2), Zhang SW(3), Zhang SY(1), Zhu K(2)(4), Lu S(5).

Author information:
(1)Key Laboratory of Information Fusion Technology of Ministry of Education,
School of Automation, Northwestern Polytechnical University, 127 West Youyi Road,
Xi’an, 710072, Shaanxi, China.
(2)Department of Biomedical Informatics, University of Pittsburgh, 5607 Baum
Blvd, Pittsburgh, PA, 15206, USA.
(3)Key Laboratory of Information Fusion Technology of Ministry of Education,
School of Automation, Northwestern Polytechnical University, 127 West Youyi Road,
Xi’an, 710072, Shaanxi, China. zhangsw@nwpu.edu.cn.
(4)The First Affiliated Hospital and Clinical Medicine Research Institute, Jinan
University, Guangzhou, China.
(5)Department of Biomedical Informatics, University of Pittsburgh, 5607 Baum
Blvd, Pittsburgh, PA, 15206, USA. songjian@pitt.edu.

BACKGROUND: Long non-coding RNAs play an important role in human complex
diseases. Identification of lncRNA-disease associations will gain insight into
disease-related lncRNAs and benefit disease diagnoses and treatment. However,
using experiments to explore the lncRNA-disease associations is expensive and
time consuming.
RESULTS: In this study, we developed a novel method to identify potential
lncRNA-disease associations by Integrating Diverse Heterogeneous Information
sources with positive pointwise Mutual Information and Random Walk with restart
algorithm (namely IDHI-MIRW). IDHI-MIRW first constructs multiple lncRNA
similarity networks and disease similarity networks from diverse lncRNA-related
and disease-related datasets, then implements the random walk with restart
algorithm on these similarity networks for extracting the topological
similarities which are fused with positive pointwise mutual information to build
a large-scale lncRNA-disease heterogeneous network. Finally, IDHI-MIRW
implemented random walk with restart algorithm on the lncRNA-disease
heterogeneous network to infer potential lncRNA-disease associations.
CONCLUSIONS: Compared with other state-of-the-art methods, IDHI-MIRW achieves the
best prediction performance. In case studies of breast cancer, stomach cancer,
and colorectal cancer, 36/45 (80%) novel lncRNA-disease associations predicted by
IDHI-MIRW are supported by recent literatures. Furthermore, we found lncRNA
LINC01816 is associated with the survival of colorectal cancer patients.
IDHI-MIRW is freely available at https://github.com/NWPU-903PR/IDHI-MIRW .

DOI: 10.1186/s12859-019-2675-y
PMID: 30782113

Expert Rev Endocrinol Metab. 2011 Sep;6(5):661-663. doi: 10.1586/eem.11.53.

Predicting response: identifying molecular determinants of endocrine response and
resistance in breast cancer.

Butt AJ(1).

Author information:
(1)a Cancer Research Program, Garvan Institute of Medical Research, 384 Victoria
Street, Darlinghurst, New South Wales 2010, Australia and St Vincent’s Clinical
School, Faculty of Medicine, University of New South Wales, New South Wales 2052,
Australia. abutt@garvan.org.au.

Evaluation of: Fernandez-Cuesta L, Anaganti S, Hainaut P, Olivier M. p53 status
influences response to tamoxifen but not to fulvestrant in breast cancer cell
lines. Int. J. Cancer 128, 1813-1821 (2011). Blocking estrogen activity or
production through the use of anti-estrogens such as tamoxifen and aromatase
inhibitors, respectively, has had a significant impact on improving the survival
of breast cancer patients. However, innate or acquired resistance to these
endocrine therapies remains a major clinical problem and a challenge to the
successful treatment of this disease. A recent article explored the role of the
tumor-suppressor gene TP53 in the response of breast cancer cell lines to
tamoxifen and the pure anti-estrogen, fulvestrant. Mutations in TP53, which occur
frequently in breast cancer like many other types of neoplasia, are already known
to negatively influence prognosis, but here their role in the response to
anti-estrogen treatment was evaluated. This study found that cells harboring p53
mutations were more resistant to the cytotoxic effects of 4-hydroxytamoxifen than
their p53 wild-type counterparts. Furthermore, mutant p53 cells were actually
stimulated by low concentrations of 4-hydroxytamoxifen, with evidence that this
may be mediated through enhanced growth factor signaling. By contrast, p53 status
did not affect the response to fulvestrant. This article further delineates the
role of p53 as a determinant of the endocrine response.

DOI: 10.1586/eem.11.53
PMID: 30780881

Expert Rev Endocrinol Metab. 2011 Sep;6(5):723-730. doi: 10.1586/eem.11.57.

Gynecomastia: incidence, causes and treatment.

Deepinder F(1), Braunstein GD(1)(2).

Author information:
(1)a Division of Endocrinology, Diabetes and Metabolism, Department of Medicine,
Cedars Sinai Medical Center, Los Angeles, CA 90048, USA.
(2)b braunstein@cshs.org.

Gynecomastia is a benign proliferation of glandular tissue of the breast in
males. It is common during three phases in the age distribution curve: the
neonatal period, puberty and senescence. An imbalance between estrogen and
androgen action at the level of breast tissue is believed to be the underlying
pathophysiology. Initial steps in the clinical evaluation involve differentiating
it from pseudogynecomastia and ruling out male breast carcinoma. A selective
laboratory and radiological work-up should follow to identify the underlying
cause. Pubertal gynecomastia resolves spontaneously in the majority of
adolescents, and hence reassurance and observation is regarded as the best
approach. In adults with persistent painful gynecomastia, a short-term trial of
medical therapy is an option that has shown good results. For chronic, bothersome
gynecomastia, removal by plastic surgery is the treatment of choice.

DOI: 10.1586/eem.11.57
PMID: 30780874

Breast Cancer Treatment (PDQ®): Health Professional Version.

PDQ Adult Treatment Editorial Board.
In: PDQ Cancer Information Summaries [Internet]. Bethesda (MD): National Cancer
Institute (US); 2002-.
2019 Feb 15.

This PDQ cancer information summary for health professionals provides
comprehensive, peer-reviewed, evidence-based information about the treatment of
breast cancer. It is intended as a resource to inform and assist clinicians who
care for cancer patients. It does not provide formal guidelines or
recommendations for making health care decisions. This summary is reviewed
regularly and updated as necessary by the PDQ Adult Treatment Editorial Board,
which is editorially independent of the National Cancer Institute (NCI). The
summary reflects an independent review of the literature and does not represent a
policy statement of NCI or the National Institutes of Health (NIH).

PMID: 26389187

J Fungi (Basel). 2019 Feb 13;5(1). pii: E16. doi: 10.3390/jof5010016.

Effect of Marine Basidiomycetes Fulvifomes sp.-Derived Ergosterol Peroxide on
Cytotoxicity and Apoptosis Induction in MCF-7 Cell Line.

Govindharaj M(1), Arumugam S(2), Nirmala G(3), Bharadwaj M(4), Murugiyan K(5).

Author information:
(1)Centre of Advanced Study in Marine Biology, Annamalai University,
Parangipettai 608 502, India. mano.govindraj@gmail.com.
(2)Molecular Biology Group, National Institute of Cancer Prevention and Research,
Noida 201 301, India. sathiishkumarbiotech@gmail.com.
(3)Experimental Cancer Therapeutics and Chemical Biology Laboratory, UM-DAE
Centre for Excellence in Basic Sciences, Kalina, Mumbai 400098, India.
gracenirmalaj@gmail.com.
(4)Molecular Biology Group, National Institute of Cancer Prevention and Research,
Noida 201 301, India. mausumi.bharadwaj@gmail.com.
(5)Centre of Advanced Study in Marine Biology, Annamalai University,
Parangipettai 608 502, India. kalaifms@gmail.com.

The aim of the present study is to extract the bioactive compounds which can
induce the apoptosis in breast cancer cell line MCF-7 by marine basidiomycetes.
Internal Transcribed Spacer (ITS) sequences based molecular taxonomic study
confirmed that collected the marine basidiomycetes belongs to Fulvifomes sp.
Further, the isolated compounds from the Fulvifomes sp. confirmed as ergosterol
peroxide (EP) by spectroscopic studies. The compound inhibited 50% of the cell
growth (IC50) at the concentration of 40 µg/mL and induced 90% cell death (IC 90)
at the concentration of 80 µg/mL. The ergosterol peroxide generated Reactive
Oxygen Species (ROS) and induced apoptotic cell death in MCF-7. Ethidium
bromide/Acridine Orange (Et/Br) staining showed the increased number of early and
late apoptosis in treated MCF-7 cells. The compounds treated cells indicated the
significant loss of mitochondrial membrane potential (Δψm) with p < 0.05. The
induction of apoptosis by marine basidiomycetes derived ergosterol peroxide was
confirmed by chromatin condensation in MCF7 cells using Hoechst staining 33342.

DOI: 10.3390/jof5010016
PMID: 30781890

Nutrients. 2019 Feb 13;11(2). pii: E394. doi: 10.3390/nu11020394.

Time Trends in Age at Menarche and Related Non-Communicable Disease Risk during
the 20th Century in Mexico.

Petersohn I(1), Zarate-Ortiz AG(2), Cepeda-Lopez AC(3), Melse-Boonstra A(4).

Author information:
(1)Division of Human Nutrition and Health, Wageningen University and Research,
6708WE Wageningen, The Netherlands. inga.petersohn@outlook.de.
(2)Division of Human Nutrition and Health, Wageningen University and Research,
6708WE Wageningen, The Netherlands. arli.zarateortiz@wur.nl.
(3)Health Sciences Division, Universidad de Monterrey, San Pedro Garza García,
N.L. 66238, Mexico. ana.cepeda@udem.edu.
(4)Division of Human Nutrition and Health, Wageningen University and Research,
6708WE Wageningen, The Netherlands. alida.melse@wur.nl.

Developed countries have shown a time trend towards a younger age at menarche
(AAM), which is associated with increased risk of later obesity and
non-communicable diseases. This study aimed to assess whether a time trend in AAM
is associated with disease risk in Mexican women (n = 30,826), using data from
the Mexican National Health Survey (2000). Linear and log binomial regression was
used for nutritional and disease outcomes, while Welch⁻ANOVA was used to test for
a time trend. AAM (in years) decreased over time (p < 0.001), with a maximal
difference of 0.99 years between the 1920s (13.6 years) and 1980s (12.6 years ).
AAM was negatively associated with weight (β = -1.01 kg; 95% CI -1.006, -1.004)
and body mass index (BMI) (β = -1.01 kg/m²; -1.007, -1.006), and positively with
height (β = 0.18 cm; 0.112, 0.231). AAM was associated with diabetes (RR = 0.95;
0.93, 0.98) and hypercholesterolemia (RR = 0.93; 0.90, 0.95), but not with
hypertension, breast cancer or arthritis. In Mexico, AAM decreased significantly
during the 20th century. AAM was inversely associated with adult weight and BMI,
and positively with height. Women with a later AAM had a lower risk of diabetes
and hypercholesterolemia.

DOI: 10.3390/nu11020394
PMID: 30781889

Cancers (Basel). 2019 Feb 13;11(2). pii: E216. doi: 10.3390/cancers11020216.

New Insights into Long Non-Coding RNA MALAT1 in Cancer and Metastasis.

Sun Y(1), Ma L(2).

Author information:
(1)Department of Molecular and Cellular Oncology, the University of Texas MD
Anderson Cancer Center, Houston, TX 77030, USA. ysun2@mdanderson.org.
(2)Department of Experimental Radiation Oncology, the University of Texas MD
Anderson Cancer Center, Houston, TX 77030, USA. lma4@mdanderson.org.

Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is one of the
most abundant, long non-coding RNAs (lncRNAs) in normal tissues. This lncRNA is
highly conserved among mammalian species, and based on in vitro results, has been
reported to regulate alternative pre-mRNA splicing and gene expression. However,
Malat1 knockout mice develop and grow normally, and do not show alterations in
alternative splicing. While MALAT1 was originally described as a prognostic
marker of lung cancer metastasis, emerging evidence has linked this lncRNA to
other cancers, such as breast cancer, prostate cancer, pancreatic cancer, glioma,
and leukemia. The role described for MALAT1 is dependent on the cancer types and
the experimental model systems. Notably, different or opposite phenotypes
resulting from different strategies for inactivating MALAT1 have been observed,
which led to distinct models for MALAT1’s functions and mechanisms of action in
cancer and metastasis. In this review, we reflect on different experimental
strategies used to study MALAT1’s functions, and discuss the current mechanistic
models of this highly abundant and conserved lncRNA.

DOI: 10.3390/cancers11020216
PMID: 30781877

Conflict of interest statement: The authors declare no conflict of interest.

Cancers (Basel). 2019 Feb 13;11(2). pii: E214. doi: 10.3390/cancers11020214.

The Enigmatic Protein Kinase C-eta.

Basu A(1).

Author information:
(1)Department of Microbiology, Immunology & Genetics, University of North Texas
Health Science Center, Fort Worth, TX 76107, USA. Alakananda.basu@unthsc.edu.

Protein kinase C (PKC), a multi-gene family, plays critical roles in signal
transduction and cell regulation. Protein kinase C-eta (PKCη) is a unique member
of the PKC family since its regulation is distinct from other PKC isozymes. PKCη
was shown to regulate cell proliferation, differentiation and cell death. It was
also shown to contribute to chemoresistance in several cancers. PKCη has been
associated with several cancers, including renal cell carcinoma, glioblastoma,
breast cancer, non-small cell lung cancer, and acute myeloid leukemia. However,
mice lacking PKCη were more susceptible to tumor formation in a two-stage
carcinogenesis model, and it is downregulated in hepatocellular carcinoma. Thus,
the role of PKCη in cancer remains controversial. The purpose of this review
article is to discuss how PKCη regulates various cellular processes that may
contribute to its contrasting roles in cancer.

DOI: 10.3390/cancers11020214
PMID: 30781807

Int J Mol Sci. 2019 Feb 13;20(4). pii: E804. doi: 10.3390/ijms20040804.

Cytotoxic Activity of the Histone Deacetylase 3-Selective Inhibitor Pojamide on
MDA-MB-231 Triple-Negative Breast Cancer Cells.

Luparello C(1), Asaro DML(2), Cruciata I(3), Hassell-Hart S(4), Sansook S(5),
Spencer J(6), Caradonna F(7).

Author information:
(1)Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche
(STEBICEF), Università di Palermo, Viale delle Scienze, 90128 Palermo, Italy.
claudio.luparello@unipa.it.
(2)Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche
(STEBICEF), Università di Palermo, Viale delle Scienze, 90128 Palermo, Italy.
daliaasaro@libero.it.
(3)Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche
(STEBICEF), Università di Palermo, Viale delle Scienze, 90128 Palermo, Italy.
ilenia.cruciata@unipa.it.
(4)Department of Chemistry, School of Life Sciences, University of Sussex,
Falmer, Brighton BN1 9QJ, UK. S.Hassell-Hart@sussex.ac.uk.
(5)Department of Chemistry, School of Life Sciences, University of Sussex,
Falmer, Brighton BN1 9QJ, UK. sansook_s@yahoo.com.
(6)Department of Chemistry, School of Life Sciences, University of Sussex,
Falmer, Brighton BN1 9QJ, UK. j.spencer@sussex.ac.uk.
(7)Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche
(STEBICEF), Università di Palermo, Viale delle Scienze, 90128 Palermo, Italy.
fabio.caradonna@unipa.it.

We examined the effects of the ferrocene-based histone deacetylase-3 inhibitor
Pojamide (N¹-(2-aminophenyl)-N⁸-ferrocenyloctanediamide) and its two derivatives
N¹-(2-aminophenyl)-N⁶-ferrocenyladipamide and
N¹-(2-aminophenyl)-N⁸-ferroceniumoctanediamide tetrafluoroborate on
triple-negative MDA-MB-231 breast cancer cells. Viability/growth assays indicated
that only the first two compounds at 70 μM concentration caused an approximate
halving of cell number after 24 h of exposure, whereas the tetrafluoroborate
derivative exerted no effect on cell survival nor proliferation. Flow cytometric
and protein blot analyses were performed on cells exposed to both Pojamide and
the ferrocenyladipamide derivative to evaluate cell cycle distribution,
apoptosis/autophagy modulation, and mitochondrial metabolic state in order to
assess the cellular basis of the cytotoxic effect. The data obtained show that
the cytotoxic effect of the two deacetylase inhibitors may be ascribed to the
onset of non-apoptotic cell death conceivably linked to a down-regulation of
autophagic processes and an impairment of mitochondrial function with an increase
in intracellular reactive oxygen species. Our work expands the list of
autophagy-regulating drugs and also provides a further example of the role played
by the inhibition of autophagy in breast cancer cell death. Moreover, the
compounds studied may represent attractive and promising targets for subsequent
molecular modeling for anti-neoplastic agents in malignant breast cancer.

DOI: 10.3390/ijms20040804
PMID: 30781804

Int J Environ Res Public Health. 2019 Feb 13;16(4). pii: E534. doi:
10.3390/ijerph16040534.

Double Discourse: Qualitative Perspectives on Breast Screening Participation
among Obese Women and Their Health Care Providers.

McBride KA(1)(2), Fleming CAK(3)(4), George ES(5)(6), Steiner GZ(7)(8), MacMillan
F(9)(10).

Author information:
(1)Translational Health Research Institute (THRI), Western Sydney University,
Penrith, NSW 2750, Australia. k.mcbride@westernsydney.edu.au.
(2)School of Medicine, Western Sydney University, Penrith, NSW 2750, Australia.
k.mcbride@westernsydney.edu.au.
(3)Translational Health Research Institute (THRI), Western Sydney University,
Penrith, NSW 2750, Australia. catharine.fleming@westernsydney.edu.au.
(4)School of Science and Health, Western Sydney University, Penrith, NSW 2750,
Australia. catharine.fleming@westernsydney.edu.au.
(5)Translational Health Research Institute (THRI), Western Sydney University,
Penrith, NSW 2750, Australia. e.george@westernsydney.edu.au.
(6)School of Science and Health, Western Sydney University, Penrith, NSW 2750,
Australia. e.george@westernsydney.edu.au.
(7)Translational Health Research Institute (THRI), Western Sydney University,
Penrith, NSW 2750, Australia. g.steiner@westernsydney.edu.au.
(8)NICM Health Research Institute, Western Sydney University, Penrith, NSW 2750,
Australia. g.steiner@westernsydney.edu.au.
(9)Translational Health Research Institute (THRI), Western Sydney University,
Penrith, NSW 2750, Australia. f.macmillan@westernsydney.edu.au.
(10)School of Science and Health, Western Sydney University, Penrith, NSW 2750,
Australia. f.macmillan@westernsydney.edu.au.

Obesity in Australia is rising rapidly, and is a major public health concern.
Obesity increases the risk of breast cancer and worsens associated outcomes, yet
breast screening participation rates in Australia are suboptimal and can be lower
in higher risk, obese women. This study qualitatively explored barriers to breast
screening participation in obese women in Australia. In-depth interviews (n =
29), were conducted with obese women (body mass index ≥ 30) and key health
providers. A disconnect between providers’ and women’s perceptions was found. For
women, low knowledge around a heightened need to screen existed, they also
reported limited desire to prioritize personal health needs, reluctance to screen
due to poor body image and prior negative mammographic experiences due to issues
with weight. Providers perceived few issues in screening obese women beyond
equipment limitations, and health and safety issues. Overall, weight was a taboo
topic among our interviewees, indicating that a lack of discourse around this
issue may be putting obese women at increased risk of breast cancer morbidity and
mortality. Consideration of breast screening policy in obese women is warranted.
Targeted health promotion on increased breast cancer risk in obese women is
required as is a need to address body image issues and encourage screening
participation.

DOI: 10.3390/ijerph16040534
PMID: 30781792

Cancers (Basel). 2019 Feb 18;11(2). pii: E238. doi: 10.3390/cancers11020238.

Cell-Free DNA Variant Sequencing Using CTC-Depleted Blood for Comprehensive
Liquid Biopsy Testing in Metastatic Breast Cancer.

Keup C(1), Storbeck M(2), Hauch S(3), Hahn P(4), Sprenger-Haussels M(5), Tewes
M(6), Mach P(7), Hoffmann O(8), Kimmig R(9), Kasimir-Bauer S(10).

Author information:
(1)Department of Gynecology and Obstetrics, University Hospital of Essen, 45122
Essen, Germany. Corinna.Keup@uk-essen.de.
(2)QIAGEN GmbH, 40724 Hilden, Germany. Markus.Storbeck@qiagen.com.
(3)QIAGEN GmbH, 40724 Hilden, Germany. Siegfried.Hauch@qiagen.com.
(4)QIAGEN GmbH, 40724 Hilden, Germany. Peter.Hahn@qiagen.com.
(5)QIAGEN GmbH, 40724 Hilden, Germany. Markus.Sprenger-Haussels@qiagen.com.
(6)Department of Medical Oncology, University Hospital of Essen, 45122 Essen,
Germany. Mitra.Tewes@uk-essen.de.
(7)Department of Gynecology and Obstetrics, University Hospital of Essen, 45122
Essen, Germany. pawel.mach@uk-essen.de.
(8)Department of Gynecology and Obstetrics, University Hospital of Essen, 45122
Essen, Germany. Oliver.Hoffmann@uk-essen.de.
(9)Department of Gynecology and Obstetrics, University Hospital of Essen, 45122
Essen, Germany. rainer.kimmig@uk-essen.de.
(10)Department of Gynecology and Obstetrics, University Hospital of Essen, 45122
Essen, Germany. Sabine.Kasimir-bauer@uk-essen.de.

Liquid biopsy analytes such as cell-free DNA (cfDNA) and circulating tumor cells
(CTCs) exhibit great potential for personalized treatment. Since cfDNA and CTCs
are considered to give additive information and blood specimens are limited,
isolation of cfDNA and CTC in an «all from one tube» format is desired. We
investigated whether cfDNA variant sequencing from CTC-depleted blood (CTC-depl.
B; obtained after positive immunomagnetic isolation of CTCs (AdnaTest EMT-2/Stem
Cell Select, QIAGEN)) impacts the results compared to cfDNA variant sequencing
from matched whole blood (WB). Cell-free DNA was isolated using matched WB and
CTC-depl. B from 17 hormone receptor positive/human epidermal growth factor
receptor 2 negative (HR+/HER2-) metastatic breast cancer patients (QIAamp
MinElute ccfDNA Kit, QIAGEN). Cell-free DNA libraries were constructed
(customized QIAseq Targeted DNA Panel for Illumina, QIAGEN) with integrated
unique molecular indices. Sequencing (on the NextSeq 550 platform, Illumina) and
data analysis (Ingenuity Variant Analysis) were performed. RNA expression in CTCs
was analyzed by multimarker quantitative PCR. Cell-free DNA concentration and
size distribution in the matched plasma samples were not significantly different.
Seventy percent of all variants were identical in matched WB and CTC-depl. B, but
115/125 variants were exclusively found in WB/CTC-depl. B. The number of detected
variants per patient and the number of exclusively detected variants per patient
in only one cfDNA source did not differ between the two matched cfDNA sources.
Even the characteristics of the exclusively detected cfDNA variants in either WB
or CTC-depl. B were comparable. Thus, cfDNA variants from matched WB and
CTC-depl. B exhibited no relevant differences, and parallel isolation of cfDNA
and CTCs from only 10 mL of blood in an «all from one tube» format was feasible.
Matched cfDNA mutational and CTC transcriptional analyses might empower a
comprehensive liquid biopsy analysis to enhance the identification of actionable
targets for individual therapy strategies.

DOI: 10.3390/cancers11020238
PMID: 30781720

Genes (Basel). 2019 Feb 18;10(2). pii: E154. doi: 10.3390/genes10020154.

PheWAS-Based Systems Genetics Methods for Anti-Breast Cancer Drug Discovery.

Gao M(1), Quan Y(2)(3), Zhou XH(4), Zhang HY(5).

Author information:
(1)Hubei Key Laboratory of Agricultural Bioinformatics, College of Informatics,
Huazhong Agricultural University, Wuhan 430070, China. gm@webmail.hzau.edu.cn.
(2)School of Computer Science and Technology, Harbin Institute of Technology
Shenzhen Graduate School, Shenzhen 518055, China. quanyuan725@163.com.
(3)Lab of Epigenetics and Advanced Health Technology, Space Institute of Southern
China, Shenzhen 518117, China. quanyuan725@163.com.
(4)Hubei Key Laboratory of Agricultural Bioinformatics, College of Informatics,
Huazhong Agricultural University, Wuhan 430070, China.
zhouxionghui@mail.hzau.edu.cn.
(5)Hubei Key Laboratory of Agricultural Bioinformatics, College of Informatics,
Huazhong Agricultural University, Wuhan 430070, China. zhy630@mail.hzau.edu.cn.

Breast cancer is a high-risk disease worldwide. For such complex diseases that
are induced by multiple pathogenic genes, determining how to establish an
effective drug discovery strategy is a challenge. In recent years, a large amount
of genetic data has accumulated, particularly in the genome-wide identification
of disorder genes. However, understanding how to use these data efficiently for
pathogenesis elucidation and drug discovery is still a problem because the
gene⁻disease links that are identified by high-throughput techniques such as
phenome-wide association studies (PheWASs) are usually too weak to have
biological significance. Systems genetics is a thriving area of study that aims
to understand genetic interactions on a genome-wide scale. In this study, we
aimed to establish two effective strategies for identifying breast cancer genes
based on the systems genetics algorithm. As a result, we found that the
GeneRank-based strategy, which combines the prognostic phenotype-based
gene-dependent network with the phenotypic-related PheWAS data, can promote the
identification of breast cancer genes and the discovery of anti-breast cancer
drugs.

DOI: 10.3390/genes10020154
PMID: 30781719

Genes (Basel). 2019 Feb 18;10(2). pii: E153. doi: 10.3390/genes10020153.

Genetic Epidemiology of Breast Cancer in Latin America.

Zavala VA(1), Serrano-Gomez SJ(2), Dutil J(3), Fejerman L(4).

Author information:
(1)Department of Medicine, Division of General Internal Medicine, University of
California San Francisco, San Francisco, CA 94143-1793, USA.
valentina.zavala@ucsf.edu.
(2)Grupo de investigación en biología del cáncer, Instituto Nacional de
Cancerología, Bogotá 11001000, Colombia. silviajserrano@gmail.com.
(3)Cancer Biology Division, Ponce Research Institute, Ponce Health Sciences
University, Ponce, PR 00732, USA. jdutil@psm.edu.
(4)Department of Medicine, Division of General Internal Medicine, University of
California San Francisco, San Francisco, CA 94143-1793, USA.
laura.fejerman@ucsf.edu.

The last 10 years witnessed an acceleration of our understanding of what genetic
factors underpin the risk of breast cancer. Rare high- and moderate-penetrance
variants such as those in the BRCA genes account for a small proportion of the
familial risk of breast cancer. Low-penetrance alleles are expected to underlie
the remaining heritability. By now, there are about 180 genetic polymorphisms
that are associated with risk, most of them of modest effect. In combination,
they can be used to identify women at the lowest or highest ends of the risk
spectrum, which might lead to more efficient cancer prevention strategies. Most
of these variants were discovered in populations of European descent. As a
result, we might be failing to discover additional polymorphisms that could
explain risk in other groups. This review highlights breast cancer genetic
epidemiology studies conducted in Latin America, and summarizes the information
that they provide, with special attention to similarities and differences with
studies in other populations. It includes studies of common variants, as well as
moderate- and high-penetrance variants. In addition, it addresses the gaps that
need to be bridged in order to better understand breast cancer genetic risk in
Latin America.

DOI: 10.3390/genes10020153
PMID: 30781715

Conflict of interest statement: The authors declare no conflicts of interest.

J Clin Med. 2019 Feb 18;8(2). pii: E254. doi: 10.3390/jcm8020254.

Long-Term Safety and Real-World Effectiveness of Trastuzumab in Breast Cancer.

Mazzotta M(1), Krasniqi E(2), Barchiesi G(3), Pizzuti L(4), Tomao F(5), Barba
M(6), Vici P(7).

Author information:
(1)Department of Clinical and Molecular Medicine, «Sapienza» University of Rome,
Azienda Ospedaliera Sant’Andrea, 00189 Rome, Italy.
mmazzotta@ospedalesantandrea.it.
(2)Division of Medical Oncology 2, IRCCS Regina Elena National Cancer Institute,
Via Elio Chianesi, 53, 00144 Rome, Italy. krasniqier@gmail.com.
(3)Division of Medical Oncology 2, IRCCS Regina Elena National Cancer Institute,
Via Elio Chianesi, 53, 00144 Rome, Italy. giacomo.barchiesi88@gmail.com.
(4)Division of Medical Oncology 2, IRCCS Regina Elena National Cancer Institute,
Via Elio Chianesi, 53, 00144 Rome, Italy. laura.pizzuti@ifo.gov.it.
(5)Department of Gynecology-Obstetrics and Urology, «Sapienza» University of
Rome, 00161 Rome, Italy. federica.tomao@uniroma1.it.
(6)Division of Medical Oncology 2, IRCCS Regina Elena National Cancer Institute,
Via Elio Chianesi, 53, 00144 Rome, Italy. maddalena.barba@gmail.com.
(7)Division of Medical Oncology 2, IRCCS Regina Elena National Cancer Institute,
Via Elio Chianesi, 53, 00144 Rome, Italy. patrizia.vici@ifo.gov.it.

Trastuzumab is a milestone in the treatment of human epidermal growth factor
receptor 2 positive (HER2+) breast cancer (BC), in both the early and metastatic
settings. Over the last two decades, clinical trials have established the good
safety profile of trastuzumab. Cardiotoxicity remains the most frequent adverse
event, more commonly exemplified by an asymptomatic decline in the left
ventricular ejection fraction rather than congestive heart failure. Results from
several long-term (>5 years) safety analyses have been recently published, with
the inherent evidence substantially confirming the findings from previous trials.
The clinical experience gained over the years in the use of trastuzumab has also
fueled a number of observational studies focused on the effectiveness of this
drug in the real-world settings. We herein reviewed the evidence available from
tree major databases, namely, PubMed, EMBASE and the Cochrane Central Register of
Controlled Trials (CENTRAL), to explore and critically discuss key issues related
to the long-term safety and effectiveness of trastuzumab in clinical practice.

DOI: 10.3390/jcm8020254
PMID: 30781624

Int J Mol Sci. 2019 Feb 18;20(4). pii: E876. doi: 10.3390/ijms20040876.

Involvement of Actin Cytoskeletal Components in Breast Cancer Cell Fusion with
Human Mesenchymal Stroma/Stem-Like Cells.

Melzer C(1), von der Ohe J(2), Hass R(3).

Author information:
(1)Biochemistry and Tumor Biology Lab, Department of Obstetrics and Gynecology,
Hannover Medical School, D-30625 Hannover, Germany.
Melzer.Catharina@mh-hannover.de.
(2)Biochemistry and Tumor Biology Lab, Department of Obstetrics and Gynecology,
Hannover Medical School, D-30625 Hannover, Germany.
Ohe.Juliane.von.der@mh-hannover.de.
(3)Biochemistry and Tumor Biology Lab, Department of Obstetrics and Gynecology,
Hannover Medical School, D-30625 Hannover, Germany. hass.ralf@mh-hannover.de.

Cell fusion as a rare event was observed following the co-culture of human
MDA-MB-231cherry breast cancer cells or benign neoplastic MCF10Acherry breast
epithelial cells together with different mesenchymal stroma/stem-like cells
(MSCGFP) cultures, respectively, resulting in the generation of
double-fluorescing hybrid cells. Analysis of potential molecular mechanisms for
the formation of cancer hybrid cells revealed cytoskeletal components, including
F-actin. Thus, a sub-lethal concentration of cytochalasin D, which blocks
elongation of actin filaments, was able to significantly reduce cancer hybrid
cell formation. Simultaneously, cell cycle progression of the different
co-cultures remained unaffected following treatment with cytochalasin D,
indicating continued proliferation. Moreover, exposure to 50 nM cytochalasin D
revealed little if any effect on the expression of various integrins and cell
adhesion molecules in the different co-cultures. However, LC-MS proteome analysis
of the different control co-cultures compared to corresponding
cytochalasin-treated co-cultures demonstrated predominant differences in the
expression of actin-associated cytoskeletal proteins. In addition, the
requirement of structured actin to provide an appropriate cytoskeletal network
for enabling subsequent fusion processes was also substantiated by the actin
filament disrupting latrunculin B, which inhibits the fusion process between the
breast cancer populations and mesenchymal stroma/stem-like cells (MSC). Together,
these findings suggest an important role of distinct actin structures and
associated cytoskeletal components during cell fusion and the formation of breast
cancer hybrid cells.

DOI: 10.3390/ijms20040876
PMID: 30781614

Cells. 2019 Feb 17;8(2). pii: E167. doi: 10.3390/cells8020167.

Proteins of the Nucleolus of Dictyostelium discoideum: Nucleolar
Compartmentalization, Targeting Sequences, Protein Translocations and Binding
Partners.

O’Day DH(1)(2).

Author information:
(1)Department of Biology, University of Toronto Mississauga, Mississauga, ON L5L
1C6, Canada. danton.oday@utoronto.ca.
(2)Department of Cell and Systems Biology, University of Toronto, Toronto, ON M5S
3G5, Canada. danton.oday@utoronto.ca.

The nucleoli of Dictyostelium discoideum have a comparatively unique,
non-canonical, localization adjacent to the inner nuclear membrane. The verified
nucleolar proteins of this eukaryotic microbe are detailed while other potential
proteins are introduced. Heat shock protein 32 (Hsp32), eukaryotic translation
initiation factor 6 (eIF6), and tumour necrosis factor receptor-associated
protein 1 (TRAP1) are essential for cell survival. NumA1, a breast cancer type 1
susceptibility protein-C Terminus domain-containing protein linked to cell cycle,
functions in the regulation of nuclear number. The cell cycle checkpoint kinase 2
homologue forkhead-associated kinase A (FhkA) and BRG1-associated factor 60a
homologue Snf12 are also discussed. While nucleoli appear homogeneous
ultrastructurally, evidence for nucleolar subcompartments exists. Nucleolar
localization sequences (NoLS) have been defined that target proteins to either
the general nucleolar area or to a specific intranucleolar domain. Protein
translocations during mitosis are protein-specific and support the multiple
functions of the Dictyostelium nucleolus. To enrich the picture, binding partners
of NumA1, the most well-characterized nucleolar protein, are examined: nucleolar
Ca2+-binding protein 4a (CBP4a), nuclear puromycin-sensitive aminopeptidase A
(PsaA) and Snf12. The role of Dictyostelium as a model for understanding the
contribution of nucleolar proteins to various diseases and cellular stress is
discussed throughout the review.

DOI: 10.3390/cells8020167
PMID: 30781559

Micromachines (Basel). 2019 Feb 17;10(2). pii: E132. doi: 10.3390/mi10020132.

A Silicon-based Coral-like Nanostructured Microfluidics to Isolate Rare Cells in
Human Circulation: Validation by SK-BR-3 Cancer Cell Line and Its Utility in
Circulating Fetal Nucleated Red Blood Cells.

Ma GC(1)(2), Lin WH(3), Huang CE(4)(5), Chang TY(6), Liu JY(7), Yang YJ(8), Lee
MH(9), Wu WJ(10), Chang YS(11), Chen M(12)(13)(14)(15)(16)(17).

Author information:
(1)Department of Genomic Medicine and Center for Medical Genetics, Changhua
Christian Hospital; and Department of Genomic Science and Technology, Changhua
Christian Hospital Healthcare System, Changhua 50046, Taiwan. 128729@cch.org.tw.
(2)Department of Medical Laboratory Science and Biotechnology, Central Taiwan
University of Science and Technology, Taichung 40601, Taiwan. 128729@cch.org.tw.
(3)Department of Genomic Medicine and Center for Medical Genetics, Changhua
Christian Hospital; and Department of Genomic Science and Technology, Changhua
Christian Hospital Healthcare System, Changhua 50046, Taiwan.
397620cch@gmail.com.
(4)International College of Semiconductor Technology, National Chiao Tung
University, Hsinchu 30010, Taiwan. cehuang5858@gmail.com.
(5)Cytoaurora Biotechnologies, Inc. Hsinchu Science Park, Hsinchu 30016, Taiwan.
cehuang5858@gmail.com.
(6)Department of Genomic Medicine and Center for Medical Genetics, Changhua
Christian Hospital; and Department of Genomic Science and Technology, Changhua
Christian Hospital Healthcare System, Changhua 50046, Taiwan.
taiwanbird@gmail.com.
(7)Department of Genomic Medicine and Center for Medical Genetics, Changhua
Christian Hospital; and Department of Genomic Science and Technology, Changhua
Christian Hospital Healthcare System, Changhua 50046, Taiwan. 182011@cch.org.tw.
(8)Department of Genomic Medicine and Center for Medical Genetics, Changhua
Christian Hospital; and Department of Genomic Science and Technology, Changhua
Christian Hospital Healthcare System, Changhua 50046, Taiwan. 157097@cch.org.tw.
(9)Department of Genomic Medicine and Center for Medical Genetics, Changhua
Christian Hospital; and Department of Genomic Science and Technology, Changhua
Christian Hospital Healthcare System, Changhua 50046, Taiwan. 29561@cch.org.tw.
(10)Department of Obstetrics and Gynecology, Changhua Christian Hospital,
Changhua 50006, Taiwan. crystalwu835@gmail.com.
(11)Department of Molecular Biotechnology, Da-Yeh University, Changhua 51591,
Taiwan. yschang@mail.dyu.edu.tw.
(12)Department of Genomic Medicine and Center for Medical Genetics, Changhua
Christian Hospital; and Department of Genomic Science and Technology, Changhua
Christian Hospital Healthcare System, Changhua 50046, Taiwan.
mingchenmd@gmail.com.
(13)Department of Obstetrics and Gynecology, Changhua Christian Hospital,
Changhua 50006, Taiwan. mingchenmd@gmail.com.
(14)Department of Molecular Biotechnology, Da-Yeh University, Changhua 51591,
Taiwan. mingchenmd@gmail.com.
(15)Department of Obstetrics and Gynecology, College of Medicine, National Taiwan
University, Taipei 10041, Taiwan. mingchenmd@gmail.com.
(16)Department of Medical Genetics, National Taiwan University Hospital, Taipei
10041, Taiwan. mingchenmd@gmail.com.
(17)Department of Life Science, Tunghai University, Taichung 40704, Taiwan.
mingchenmd@gmail.com.

Circulating fetal cells (CFCs) in maternal blood are rare but have a strong
potential to be the target for noninvasive prenatal diagnosis (NIPD). «Cell
RevealTM system» is a silicon-based microfluidic platform capable to capture rare
cell populations in human circulation. The platform is recently optimized to
enhance the capture efficiency and system automation. In this study, spiking
tests of SK-BR-3 breast cancer cells were used for the evaluation of capture
efficiency. Then, peripheral bloods from 14 pregnant women whose fetuses have
evidenced non-maternal genomic markers (e.g., de novo pathogenic copy number
changes) were tested for the capture of circulating fetal nucleated red blood
cells (fnRBCs). Captured cells were subjected to fluorescent in situ
hybridization (FISH) on chip or recovered by an automated cell picker for
molecular genetic analyses. The capture rate for the spiking tests is estimated
as 88.1%. For the prenatal study, 2⁻71 fnRBCs were successfully captured from 2
mL of maternal blood in all pregnant women. The captured fnRBCs were verified to
be from fetal origin. Our results demonstrated that the Cell RevealTM system has
a high capture efficiency and can be used for fnRBC capture that is feasible for
the genetic diagnosis of fetuses without invasive procedures.

DOI: 10.3390/mi10020132
PMID: 30781548

Cancers (Basel). 2019 Feb 16;11(2). pii: E232. doi: 10.3390/cancers11020232.

PDL-1 Antibody Drug Conjugate for Selective Chemo-Guided Immune Modulation of
Cancer.

Sau S(1), Petrovici A(2), Alsaab HO(3)(4), Bhise K(5), Iyer AK(6)(7).

Author information:
(1)Department of Pharmaceutical Sciences, Wayne State University Eugene Applebaum
College of Pharmacy and Health Sciences, 259 Mack Ave, Detroit, MI 48201, USA.
samaresh.sau@wayne.edu.
(2)Department of Pharmaceutical Sciences, Wayne State University Eugene Applebaum
College of Pharmacy and Health Sciences, 259 Mack Ave, Detroit, MI 48201, USA.
alex.o.petrovici@gmail.com.
(3)Department of Pharmaceutical Sciences, Wayne State University Eugene Applebaum
College of Pharmacy and Health Sciences, 259 Mack Ave, Detroit, MI 48201, USA.
hashem.alsaab@wayne.edu.
(4)Department of Pharmaceutics and Pharmaceutical Technology, College of
Pharmacy, Taif University, Taif 26571, Saudi Arabia. hashem.alsaab@wayne.edu.
(5)Department of Pharmaceutical Sciences, Wayne State University Eugene Applebaum
College of Pharmacy and Health Sciences, 259 Mack Ave, Detroit, MI 48201, USA.
ketki.bhise@wayne.edu.
(6)Department of Pharmaceutical Sciences, Wayne State University Eugene Applebaum
College of Pharmacy and Health Sciences, 259 Mack Ave, Detroit, MI 48201, USA.
arun.iyer@wayne.edu.
(7)Molecular Imaging Program, Barbara Ann Karmanos Cancer Institute. Wayne State
University School of Medicine, 4100 John R St, Detroit, MI 48201, USA.
arun.iyer@wayne.edu.

Targeting immune checkpoint molecules such as programmed death ligand-1 (PDL1) is
an emerging strategy for anti-cancer therapy. However, transient expression of
PDL1 and difficulty in tumor stroma penetration has limited the utility of
anti-PDL1 therapy. To overcome these limitations, we report a new conjugate
between the clinically approved PDL1 antibody (PDL1 AB) and drug Doxorubicin
(Dox), named PDL1-Dox. We conjugated PDL1-Dox through a hydrazone linker
containing a polyethylene glycol (PEG) spacer, which allows it to dissociate in a
tumor environment and improves solubility. The purpose of using Dox is to disrupt
the tumor extracellular environment so that PDL-1 antibody can penetrate the
tumor core. PDL1-Dox demonstrates significant cell killing, disruption of tumor
spheroid and induction of apoptosis in a breast cancer cell line. Significant
release of IFN-γ suggests PDL1-Dox can upmodulate T cell activation. Optical
imaging of dye conjugate supports the selective tumor targeting ability and core
penetration of the construct.

DOI: 10.3390/cancers11020232
PMID: 30781490

Int J Mol Sci. 2019 Feb 16;20(4). pii: E857. doi: 10.3390/ijms20040857.

Endoplasmic Reticulum Stress and Unfolded Protein Response in Breast Cancer: The
Balance between Apoptosis and Autophagy and Its Role in Drug Resistance.

Sisinni L(1), Pietrafesa M(2), Lepore S(3), Maddalena F(4), Condelli V(5),
Esposito F(6), Landriscina M(7)(8).

Author information:
(1)Laboratory of Pre-Clinical and Translational Research, IRCCS, Referral Cancer
Center of Basilicata, 85028 Rionero in Vulture, Italy. lorisi@hotmail.com.
(2)Laboratory of Pre-Clinical and Translational Research, IRCCS, Referral Cancer
Center of Basilicata, 85028 Rionero in Vulture, Italy.
michele.pietrafesa@crob.it.
(3)Laboratory of Pre-Clinical and Translational Research, IRCCS, Referral Cancer
Center of Basilicata, 85028 Rionero in Vulture, Italy. silvia.lepore@crob.it.
(4)Laboratory of Pre-Clinical and Translational Research, IRCCS, Referral Cancer
Center of Basilicata, 85028 Rionero in Vulture, Italy.
francesca.maddalena@crob.it.
(5)Laboratory of Pre-Clinical and Translational Research, IRCCS, Referral Cancer
Center of Basilicata, 85028 Rionero in Vulture, Italy.
valentina.condelli@crob.it.
(6)Department of Molecular Medicine and Medical Biotechnology, University of
Napoli Federico II, 80131 Naples, Italy. franca.esposito@unina.it.
(7)Laboratory of Pre-Clinical and Translational Research, IRCCS, Referral Cancer
Center of Basilicata, 85028 Rionero in Vulture, Italy.
matteo.landriscina@unifg.it.
(8)Medical Oncology Unit, Department of Medical and Surgical Sciences, University
of Foggia, 71100 Foggia, Italy. matteo.landriscina@unifg.it.

The unfolded protein response (UPR) is a stress response activated by the
accumulation of unfolded or misfolded proteins in the lumen of the endoplasmic
reticulum (ER) and its uncontrolled activation is mechanistically responsible for
several human pathologies, including metabolic, neurodegenerative, and
inflammatory diseases, and cancer. Indeed, ER stress and the downstream UPR
activation lead to changes in the levels and activities of key regulators of cell
survival and autophagy and this is physiologically finalized to restore metabolic
homeostasis with the integration of pro-death or/and pro-survival signals. By
contrast, the chronic activation of UPR in cancer cells is widely considered a
mechanism of tumor progression. In this review, we focus on the relationship
between ER stress, apoptosis, and autophagy in human breast cancer and the
interplay between the activation of UPR and resistance to anticancer therapies
with the aim to disclose novel therapeutic scenarios. The hypothesis that
autophagy and UPR may provide novel molecular targets in human malignancies is
discussed.

DOI: 10.3390/ijms20040857
PMID: 30781465

Int J Mol Sci. 2019 Feb 15;20(4). pii: E854. doi: 10.3390/ijms20040854.

o-Vanillin Derived Schiff Bases and Their Organotin(IV) Compounds: Synthesis,
Structural Characterisation, In-Silico Studies and Cytotoxicity.

Yusof ENM(1)(2), Latif MAM(3), Tahir MIM(4), Sakoff JA(5), Simone MI(6)(7), Page
AJ(6), Veerakumarasivam A(8)(9), Tiekink ERT(10), Ravoof TBSA(11)(12).

Author information:
(1)Department of Chemistry, Faculty of Science, Universiti Putra Malaysia, 43400
UPM Serdang, Selangor Darul Ehsan, Malaysia. enisnadia89@gmail.com.
(2)Discipline of Chemistry, School of Environmental and Life Sciences, University
of Newcastle, University Drive, Callaghan, NSW 2308, Australia.
enisnadia89@gmail.com.
(3)Department of Chemistry, Faculty of Science, Universiti Putra Malaysia, 43400
UPM Serdang, Selangor Darul Ehsan, Malaysia. aliflatif@upm.edu.my.
(4)Department of Chemistry, Faculty of Science, Universiti Putra Malaysia, 43400
UPM Serdang, Selangor Darul Ehsan, Malaysia. ibra@upm.edu.my.
(5)Experimental Therapeutics Group, Department of Medical Oncology, Calvary Mater
Newcastle Hospital, Edith Street, Waratah NSW 2298, Australia.
michela.simone@newcastle.edu.au.
(6)Discipline of Chemistry, School of Environmental and Life Sciences, University
of Newcastle, University Drive, Callaghan, NSW 2308, Australia.
alister.page@newcastle.edu.au.
(7)Priority Research Centre for Chemical Biology & Clinical Pharmacology,
University of Newcastle, University Drive, Callaghan, NSW 2308, Australia.
alister.page@newcastle.edu.au.
(8)Department of Biological Sciences, School of Science and Technology, Sunway
University, No. 5 Jalan Universiti, 47500 Bandar Sunway, Selangor Darul Ehsan,
Malaysia. jennette.sakoff@newcastle.edu.au.
(9)Medical Genetics Laboratory, Faculty of Medicine and Health Sciences,
Universiti Putra Malaysia, 43400 UPM Serdang, Selangor Darul Ehsan, Malaysia.
jennette.sakoff@newcastle.edu.au.
(10)Research Centre for Crystalline Materials, School of Science and Technology,
Sunway University, No. 5 Jalan Universiti, 47500 Bandar Sunway, Selangor Darul
Ehsan, Malaysia. abhiv@sunway.edu.my.
(11)Department of Chemistry, Faculty of Science, Universiti Putra Malaysia, 43400
UPM Serdang, Selangor Darul Ehsan, Malaysia. thahira@upm.edu.my.
(12)Materials Synthesis and Characterization Laboratory, Institute of Advanced
Technology, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor Darul Ehsan,
Malaysia. thahira@upm.edu.my.

Six new organotin(IV) compounds of Schiff bases derived from S-R-dithiocarbazate
[R = benzyl (B), 2- or 4-methylbenzyl (2M and 4M, respectively)] condensed with
2-hydroxy-3-methoxybenzaldehyde (oVa) were synthesised and characterised by
elemental analysis, various spectroscopic techniques including infrared, UV-vis,
multinuclear (¹H, 13C, 119Sn) NMR and mass spectrometry, and single crystal X-ray
diffraction. The organotin(IV) compounds were synthesised from the reaction of
Ph₂SnCl₂ or Me₂SnCl₂ with the Schiff bases (S2MoVaH/S4MoVaH/SBoVaH) to form a
total of six new organotin(IV) compounds that had a general formula of [R₂Sn(L)]
(where L = Schiff base; R = Ph or Me). The molecular geometries of Me₂Sn(S2MoVa),
Me₂Sn(S4MoVa) and Me₂Sn(SBoVa) were established by X-ray crystallography and
verified using density functional theory calculations. Interestingly, each
experimental structure contained two independent but chemically similar molecules
in the crystallographic asymmetric unit. The coordination geometry for each
molecule was defined by thiolate-sulphur, phenoxide-oxygen and imine-nitrogen
atoms derived from a dinegative, tridentate dithiocarbazate ligand with the
remaining positions occupied by the methyl-carbon atoms of the organo groups. In
each case, the resulting five-coordinate C₂NOS geometry was almost exactly
intermediate between ideal trigonal-bipyramidal and square-pyramidal geometries.
The cytotoxic activities of the Schiff bases and organotin(IV) compounds were
investigated against EJ-28 and RT-112 (bladder), HT29 (colon), U87 and SJ-G2
(glioblastoma), MCF-7 (breast) A2780 (ovarian), H460 (lung), A431 (skin), DU145
(prostate), BE2-C (neuroblastoma) and MIA (pancreatic) cancer cell lines and one
normal breast cell line (MCF-10A). Diphenyltin(IV) compounds exhibited greater
potency than either the Schiff bases or the respective dimethyltin(IV) compounds.
Mechanistic studies on the action of these compounds against bladder cancer cells
revealed that they induced the production of reactive oxygen species (ROS). The
bladder cancer cells were apoptotic after 24 h post-treatment with the
diphenyltin(IV) compounds. The interactions of the organotin(IV) compounds with
calf thymus DNA (CT-DNA) were experimentally explored using UV-vis absorption
spectroscopy. This study revealed that the organotin(IV) compounds have strong
DNA binding affinity, verified via molecular docking simulations, which suggests
that these organotin(IV) compounds interact with DNA via groove-binding
interactions.

DOI: 10.3390/ijms20040854
PMID: 30781445

Conflict of interest statement: The authors declare no conflict of interest.

Nutrients. 2019 Feb 15;11(2). pii: E412. doi: 10.3390/nu11020412.

(-)-Oleocanthal Combined with Lapatinib Treatment Synergized against HER-2
Positive Breast Cancer In Vitro and In Vivo.

Siddique AB(1), Ebrahim HY(2), Akl MR(3), Ayoub NM(4), Goda AA(5), Mohyeldin
MM(6), Nagumalli SK(7), Hananeh WM(8), Liu YY(9), Meyer SA(10), El Sayed KA(11).

Author information:
(1)School of Basic Pharmaceutical and Toxicological Sciences, College of
Pharmacy, University of Louisiana at Monroe, 1800 Bienville Drive, Monroe, LA
71201, USA. siddiqab@warhawks.ulm.edu.
(2)School of Basic Pharmaceutical and Toxicological Sciences, College of
Pharmacy, University of Louisiana at Monroe, 1800 Bienville Drive, Monroe, LA
71201, USA. hassanchem.phd@outlook.com.
(3)School of Basic Pharmaceutical and Toxicological Sciences, College of
Pharmacy, University of Louisiana at Monroe, 1800 Bienville Drive, Monroe, LA
71201, USA. mohamedreda_pharmacy@yahoo.com.
(4)Department of Clinical Pharmacy, Faculty of Pharmacy, Jordan University of
Science and Technology, Irbid 22110, Jordan. nmayoub@just.edu.jo.
(5)School of Basic Pharmaceutical and Toxicological Sciences, College of
Pharmacy, University of Louisiana at Monroe, 1800 Bienville Drive, Monroe, LA
71201, USA. amirakareem16@gmail.com.
(6)School of Basic Pharmaceutical and Toxicological Sciences, College of
Pharmacy, University of Louisiana at Monroe, 1800 Bienville Drive, Monroe, LA
71201, USA. mohyelmm@warhawks.ulm.edu.
(7)School of Basic Pharmaceutical and Toxicological Sciences, College of
Pharmacy, University of Louisiana at Monroe, 1800 Bienville Drive, Monroe, LA
71201, USA. nagumask@warhawks.ulm.edu.
(8)Department of Pathology and Public Health, Faculty of Veterinary Medicine,
Jordan University of Science and Technology (JUST), Irbid 22110, Jordan.
whananeh@just.edu.jo.
(9)School of Basic Pharmaceutical and Toxicological Sciences, College of
Pharmacy, University of Louisiana at Monroe, 1800 Bienville Drive, Monroe, LA
71201, USA. yliu@ulm.edu.
(10)School of Basic Pharmaceutical and Toxicological Sciences, College of
Pharmacy, University of Louisiana at Monroe, 1800 Bienville Drive, Monroe, LA
71201, USA. meyer@ulm.edu.
(11)School of Basic Pharmaceutical and Toxicological Sciences, College of
Pharmacy, University of Louisiana at Monroe, 1800 Bienville Drive, Monroe, LA
71201, USA. elsayed@ulm.edu.

Dysregulation of epidermal growth factor receptor (EGFR)/human epidermal growth
factor-2 (HER2) family is a hallmark of aggressive breast cancer. Small-molecule
tyrosine kinase inhibitors are among the most effective cancer targeted
treatments. (-)-Oleocanthal (OC) is a naturally occurring phenolic secoiridoid
lead from extra-virgin olive oil with documented anti-cancer activities via
targeting mesenchymal epithelial transition factor (c-Met). Dysregulation of
c-Met promotes aggressiveness to breast cancer-targeted therapies. Lapatinib (LP)
is an FDA-approved dual EGFR/HER2 inhibitor for HER2-amplified breast cancer.
HER2-Positive tumor cells can escape targeted therapies like LP effects by
overexpressing c-Met. Combined OC-LP treatment is hypothesized to be
mechanistically synergistic against HER2-overexpressing breast cancer. Combined
sub-effective treatments of OC-LP resulted in synergistic anti-proliferative
effects against the HER2-positive BT-474 and SK-BR-3 breast cancer cell lines,
compared to OC or LP monotherapy. Antibody array and Western blot analysis showed
that combined OC-LP treatment significantly inhibited EGFR, HER2, and c-Met
receptor activation, as well as multiple downstream signaling proteins, compared
to individual OC or LP treatment. OC-LP Combination significantly inhibited
invasion and migration of breast cancer cells through reduced activation of focal
adhesion kinase (FAK) and paxillin. Combined treatment of OC-10 mg/kg with
LP-12.5 mg/kg suppressed more than 90% of BT-474 tumor cells growth in a nude
mouse xenograft model, compared to individual OC or LP treatment. Activated
c-Met, EGFR, HER2, and protein kinase B (AKT) were significantly suppressed in
combination-treated mice tumors, compared to OC or LP monotherapy. This study
reveals the OC future potential as combination therapy to sensitize
HER2-overexpressing breast cancers and significantly reduce required doses of
targeted HER family therapeutics.

DOI: 10.3390/nu11020412
PMID: 30781364

Nutrients. 2019 Feb 15;11(2). pii: E410. doi: 10.3390/nu11020410.

Curcumae Radix Extract Decreases Mammary Tumor-Derived Lung Metastasis via
Suppression of C-C Chemokine Receptor Type 7 Expression.

Kaya P(1), Lee SR(2), Lee YH(3), Kwon SW(4), Yang H(5), Lee HW(6), Hong EJ(7).

Author information:
(1)College of Veterinary Medicine, Chungnam National University, Daejeon 34134,
Korea. pelinkaya.217@gmail.com.
(2)College of Veterinary Medicine, Chungnam National University, Daejeon 34134,
Korea. srlee5@naver.com.
(3)College of Veterinary Medicine, Chungnam National University, Daejeon 34134,
Korea. lee05@cnu.ac.kr.
(4)College of Veterinary Medicine, Chungnam National University, Daejeon 34134,
Korea. ksunwoo12@gmail.com.
(5)Herbal Medicine Research Division, Korea Institute of Oriental Medicine,
Daejeon 34054, Korea. hyunyang@kiom.re.kr.
(6)Herbal Medicine Research Division, Korea Institute of Oriental Medicine,
Daejeon 34054, Korea. anywon1975@gmail.com.
(7)College of Veterinary Medicine, Chungnam National University, Daejeon 34134,
Korea. ejhong@cnu.ac.kr.

Curcumae radix is the dry root of Curcuma longa L. (turmeric) that can be used
either as a spice or traditional medicine. The aim of this study was to
investigate the survival benefits and the anti-metastatic activity of curcumae
radix extract (CRE) in MCF7 cells and in MMTV-PyMT transgenic mice-a mouse model
of breast cancer metastasis. In vitro wound scratch assay revealed that CRE
treatment inhibited cell motility and cell migration in a dose-dependent manner.
To investigate the effect of CRE in breast cancer metastasis, MMTV-PyMT
transgenic female virgin mice were used and randomly divided into two groups. For
survival curve analysis, CRE was administered in a dose of 50 mg/kg to
8⁻20-week-old mice. Interestingly, CRE treatment significantly increased the
median and prolonged survival of MMTV-PyMT mice. Furthermore, CRE treatment
decreased tumor burden and inhibited cell proliferation in primary breast tumor,
and also suppressed mammary tumor-derived lung metastasis. The size of the lung
metastases substantially decreased in the CRE-treated group compared with the
ones in the control group. Curcumae radix extract showed anti-metastatic activity
through regulating the expression of metastasis markers including C-C Chemokine
Receptor Type 7, Matrix Metalloproteinase 9 and the proto-oncogenes c-fos and
c-jun. We demonstrated that these metastatic regulators were decreased when CCR7
expression was suppressed in MCF7 cells transfected with CCR7 siRNA. The results
of this study show that curcumae radix exerts antitumor and anti-metastatic
activities, and we suggest that curcumae radix might be a potential supplement
for the treatment and prevention of breast cancer metastasis.

DOI: 10.3390/nu11020410
PMID: 30781353

Breast. 2019 Feb 12;44:144-152. doi: 10.1016/j.breast.2019.02.001. [Epub ahead of
print]

Physical activity in breast cancer survivors: A systematic review and
meta-analysis on overall and breast cancer survival.

Spei ME(1), Samoli E(2), Bravi F(3), La Vecchia C(4), Bamia C(5), Benetou V(6).

Author information:
(1)Department of Hygiene, Epidemiology, and Medical Statistics, School of
Medicine, National and Kapodistrian University of Athens, 75 M. Asias Street,
Goudi, 115 27, Athens, Greece. Electronic address: marilena_0108@hotmail.com.
(2)Department of Hygiene, Epidemiology, and Medical Statistics, School of
Medicine, National and Kapodistrian University of Athens, 75 M. Asias Street,
Goudi, 115 27, Athens, Greece. Electronic address: esamoli@med.uoa.gr.
(3)Department of Clinical Sciences and Community Health, University of Milan,
20133, Milan, Italy. Electronic address: francesca.bravi@unimi.it.
(4)Department of Clinical Sciences and Community Health, University of Milan,
20133, Milan, Italy. Electronic address: carlo.lavecchia@unimi.it.
(5)Department of Hygiene, Epidemiology, and Medical Statistics, School of
Medicine, National and Kapodistrian University of Athens, 75 M. Asias Street,
Goudi, 115 27, Athens, Greece. Electronic address: cbamia@med.uoa.gr.
(6)Department of Hygiene, Epidemiology, and Medical Statistics, School of
Medicine, National and Kapodistrian University of Athens, 75 M. Asias Street,
Goudi, 115 27, Athens, Greece. Electronic address: vbenetou@med.uoa.gr.

AIM: To further quantify the association between physical activity (PA) after
breast cancer diagnosis and all-cause mortality, breast cancer mortality and/or
breast cancer recurrence.
METHODS AND RESULTS: PubMed was searched until November 2017 for observational
studies investigating any type of PA in association with total mortality, breast
cancer mortality and/or breast cancer recurrence among women with breast cancer
diagnosis. Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were
estimated using random-effects models for highest versus lowest categories of PA.
Ten studies were included in the meta-analysis. During an average follow-up
ranging from 3.5 to 12.7 years there were 23,041 breast cancer survivors, 2,522
deaths from all causes, 841 deaths from breast cancer and 1,398
recurrences/remissions. Compared to women in the lowest recreational PA level
(lowest quintile/quartile), women in the highest level had a lower risk of
all-cause mortality (HR = 0.58, 95% CIs: 0.45-0.75; 8 studies), of death from
breast cancer (HR = 0.60, 95% CIs 0.36-0.99; 5 studies) and a lower, albeit
non-significant, risk of recurrence (HR = 0.79, 95% CIs 0.60-1.05; 5 studies).
There was evidence of heterogeneity between the studies evaluating recreational
PA and total mortality (Ι2 = 52.4%) and even higher for breast cancer mortality
(Ι2 = 77.7%) or recurrence (Ι2 = 66.4%).
CONCLUSION: Highest recreational PA after breast cancer diagnosis was associated
with lower all-cause and breast cancer mortality. This finding probably reflects
the favorable impact of PA on cardiovascular mortality, and a possible favorable
role on breast cancer survival, though reverse causation cannot be excluded.

DOI: 10.1016/j.breast.2019.02.001
PMID: 30780085

Gene. 2019 Feb 16. pii: S0378-1119(19)30129-5. doi: 10.1016/j.gene.2019.01.046.
[Epub ahead of print]

A four-miRNA signature as a novel biomarker for predicting survival in
endometrial cancer.

Wu YS(1), Lin H(2), Chen D(3), Yi Z(1), Zeng B(1), Jiang Y(4), Ren G(5).

Author information:
(1)Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First
Affiliated Hospital of Chongqing Medical University, Chongqing, PR China.
(2)Department of Intensive Care Unit, Affiliated Hangzhou First People’s
Hospital, Zhejiang University School of Medicine, PR China.
(3)Department of Oncology, The First Affiliated Hospital of Chongqing Medical
University, Chongqing, PR China.
(4)Department of Oncology, The People’s Hospital of Chongqing Hechuan, Chongqing,
China.
(5)Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First
Affiliated Hospital of Chongqing Medical University, Chongqing, PR China;
Department of Endocrine and Breast Surgery, The First Affiliated Hospital of
Chongqing Medical University, Chongqing, PR China. Electronic address:
rengs726@126.com.

BACKGROUND: The microRNAs (miRNAs) have been validated as prognostic markers in
many cancers. The aim of this study was to identify new miRNA prognostic
biomarkers in endometrial cancer (EC) and to develop an expression-based miRNA
signature to provide survival risk prediction for EC patients.
METHODS: From TCGA database, the miRNA datasets of EC and clinical information
were downloaded in April 2018. Using univariate and multivariate Cox regression
analyses identify prognostic factors. Using area under the curve (AUC) of
receiver operating characteristic (ROC) curve assess the sensitivity and
specificity of prognostic model.
RESULTS: 530 patients were randomly divided into training set and testing set.
Among 561 differentially expressed miRNAs, 4 miRNAs (miR-4758, miR-876, miR-142,
miR-190b) were demonstrated to be predictive biomarkers of overall survival (OS)
for EC patients in training set. Based on the risk score of 4-miRNA model,
patients in the training set were divided into high-risk and low-risk groups with
significantly different OS. This 4-miRNA model was validated in testing and
entire set. The AUC for the ROC curves in the entire set was 0.704. Meanwhile,
multivariate Cox regression combined with other traditional clinical parameters
indicated that the 4-miRNA model can be used as an independent OS prognostic
factor. Functional enrichment analysis revealed that these miRNAs are involved in
biological processes and pathways that are closely related to cancer.
CONCLUSION: A robust 4-miRNA signature as an independent prognostic factor for OS
in EC patients was established.

DOI: 10.1016/j.gene.2019.01.046
PMID: 30779946

J Steroid Biochem Mol Biol. 2019 Feb 16. pii: S0960-0760(18)30754-4. doi:
10.1016/j.jsbmb.2019.02.004. [Epub ahead of print]

Fast liquid chromatography-mass spectrometry reveals side chain oxysterol
heterogeneity in breast cancer tumour samples.

Solheim S(1), Hutchinson SA(2), Lundanes E(1), Wilson SR(1), Thorne JL(3),
Roberg-Larsen H(4).

Author information:
(1)Department of Chemistry, University of Oslo, Norway.
(2)School of Food Science and Nutrition, University of Leeds, United Kingdom.
(3)School of Food Science and Nutrition, University of Leeds, United Kingdom.
Electronic address: j.l.thorne@leeds.ac.uk.
(4)Department of Chemistry, University of Oslo, Norway. Electronic address:
hanne.roberg-larsen@kjemi.uio.no.

Oxysterols can contribute to proliferation of breast cancer through activation of
the Estrogen Receptors, and to metastasis through activation of the Liver X
Receptors. Endogenous levels of both esterified and free sidechain-hydroxylated
oxysterols were examined in breast cancer tumours from Estrogen Receptor positive
and negative breast tumours, using a novel fast liquid chromatography tandem mass
spectrometry method. Multiple aliquots of five milligram samples of 22 tumours
were analysed for oxysterol content to assess intra- and inter-tumour variation.
Derivatization was performed with Girard T reagent (with and without alkaline
hydrolysis) and sample clean-up was performed using a robust automatic on-line
column switching system («AFFL»). Oxysterols were separated isocratically on a
2.1 mm inner diameter column packed with ACE SuperPhenylHexyl core shell
particles using a mobile phase consisting of 0.1 % formic acid in
H2O/methanol/acetonitrile (57/10/33, v/v/v) followed by a wash out step (0.1 %
formic acid in methanol/acetonitrile, 50/50, v/v). The total analysis time,
including sample clean-up and column reconditioning, was 8 minutes (80 % time
reduction compared to other on-line systems). Analysis revealed large
intra-tumour variations of sidechain oxysterols, resulting in no significant
differences in endogenous oxysterols levels between Estrogen Receptor positive
and Estrogen Receptor negative breast cancers. However, a correlation between
esterified and free 27-hydroxycholesterol was observed. The same correlation was
not observed for 24S-hydroxycholesterol or 25-hydroxycholesterol. The oxysterol
heterogeneity of tumour tissue is a critical factor when assessing the role of
these lipids in cancer.

DOI: 10.1016/j.jsbmb.2019.02.004
PMID: 30779932

Exp Cell Res. 2019 Feb 16. pii: S0014-4827(19)30058-8. doi:
10.1016/j.yexcr.2019.02.014. [Epub ahead of print]

Molecular Functions of Brain Expressed X-Linked 2 (BEX2) in Malignancies.

Naderi A(1).

Author information:
(1)University of Portsmouth, School of Pharmacy and Biomedical Sciences, White
Swan Road, St. Michael’s Building PO1 2DT, Portsmouth, United Kingdom; University
of Hawaii Cancer Center, Cancer Biology Program, 701 Ilalo street, Honolulu,
Hawaii 96813, USA. Electronic address: Ali.Naderi@myport.ac.uk.

Over the last decade there has been growing evidence that Brain Expressed
X-Linked 2 (BEX2) has a significant role in the process of carcinogenesis.
Collectively, available studies suggest a pro-oncogenic function for this gene in
multiple malignancies, including breast, colorectal and hepatocellular cancers in
addition to brain tumors. The identification of BEX2 in breast cancer resulted
from gene expression microarray studies. Subsequent studies showed that BEX2
promotes breast cancer cell growth and survival by modulating the mitochondrial
apoptotic pathway and G1 cell cycle. In this process, BEX2 has cross-talk with
the NF-κB, c-Jun/JNK and ErbB2 pathways. Of note, several studies have found a
pro-oncogenic function for BEX2 in other malignancies associated with a similar
signalling function to that observed in breast cancer. In brain tumors, BEX2
promotes cell migration and invasion in oligodendroglioma and glioblastoma cells.
In addition, BEX2 expression protects glioma cells against apoptosis mediated
through the JNK pathway and is required for glioma cell proliferation through the
NF-κB p65. Furthermore, it has been shown that BEX2 promotes cell proliferation
through the JNK/c-Jun pathway and regulates JNK/c-Jun phosphorylation in
colorectal cancer. Most recently, it has been demonstrated that BEX2 expression
is required for cell proliferation and Hepatitis B Virus-mediated development of
hepatocellular carcinoma. Therefore, a pro-oncogenic function for BEX2 is
supported by reproducible data in multiple malignancies and the NF-κB and
JNK/c-Jun pathways are commonly regulated by BEX2 in this process. In view of
these findings, targeting BEX2 may provide an attractive therapeutic strategy in
multiple malignancies.

DOI: 10.1016/j.yexcr.2019.02.014
PMID: 30779920

J Natl Cancer Inst. 2018 Nov 20. pii: djy149. doi: 10.1093/jnci/djy149. [Epub
ahead of print]

Auranofin/Vitamin C: A Novel Drug Combination Targeting Triple-Negative Breast
Cancer.

Hatem E(1), Azzi S(2), El Banna N(1), He T(1), Heneman-Masurel A(1), Vernis L(1),
Baïlle D(1), Masson V(3), Dingli F(3), Loew D(3), Azzarone B(4), Eid P(2),
Baldacci G(5), Huang ME(1).

Author information:
(1)Institut Curie, PSL Research University, CNRS UMR3348, Université Paris-Sud,
Université Paris-Saclay, Orsay, France.
(2)INSERM U1197, Hôpital Paul Brousse, Villejuif, France.
(3)Institut Curie, Centre de Recherche, PSL Research University, Laboratoire de
Spectrométrie de Masse Protéomique, Paris, France.
(4)Immunology Research Area, IRCCS, Ospedale Bambino Gesù, Rome, Italy.
(5)Institut Jacques Monod, CNRS-Université Paris Diderot, Paris, France.

BACKGROUND: Cancer cells from different origins exhibit various basal redox
statuses and thus respond differently to intrinsic or extrinsic oxidative stress.
These intricate characteristics condition the success of redox-based anticancer
therapies that capitalize on the ability of reactive oxygen species to achieve
selective and efficient cancer cell killing.
METHODS: Redox biology methods, stable isotope labeling by amino acids in cell
culture (SILAC)-based proteomics, and bioinformatics pattern comparisons were
used to decipher the underlying mechanisms for differential response of lung and
breast cancer cell models to redox-modulating molecule auranofin (AUF) and to
combinations of AUF and vitamin C (VC). The in vivo effect of AUF, VC, and two
AUF/VC combinations on mice bearing MDA-MB-231 xenografts (n = 5 mice per group)
was also evaluated. All statistical tests were two-sided.
RESULTS: AUF targeted simultaneously the thioredoxin and glutathione antioxidant
systems. AUF/VC combinations exerted a synergistic and hydrogen peroxide
(H2O2)-mediated cytotoxicity toward MDA-MB-231 cells and other breast cancer cell
lines. The anticancer potential of AUF/VC combinations was validated in vivo on
MDA-MB-231 xenografts in mice without notable side effects. On day 14 of
treatments, mean (SD) tumor volumes for the vehicle-treated control group and the
two AUF/VC combination-treated groups (A/V1 and A/V2) were 197.67 (24.28) mm3,
15.66 (10.90) mm3, and 10.23 (7.30)mm3, respectively; adjusted P values of the
differences between mean tumor volumes of vehicle vs A/V1 groups and vehicle vs
A/V2 groups were both less than .001. SILAC proteomics, bioinformatics analysis,
and functional experiments linked prostaglandin reductase 1 (PTGR1) expression
levels with breast cancer cell sensitivity to AUF/VC combinations.
CONCLUSION: The combination of AUF and VC, two commonly available drugs, could be
efficient against triple-negative breast cancer and potentially other cancers
with similar redox properties and PTGR1 expression levels. The redox-based
anticancer activity of this combination and the discriminatory potential of PTGR1
expression are worth further assessment in preclinical and clinical studies.

DOI: 10.1093/jnci/djy149
PMID: 30779852

Radiat Res. 2019 Feb 19. doi: 10.1667/RR15267.1. [Epub ahead of print]

Dosimetric Impact of a New Computational Voxel Phantom Series for the Japanese
Atomic Bomb Survivors: Children and Adults.

Griffin K(1), Paulbeck C(2), Bolch W(2), Cullings H(3), Egbert S(4), Funamoto
S(3), Sato T(5), Endo A(5), Hertel N(6), Lee C(1).

Author information:
(1)a Division of Cancer Epidemiology and Genetics, National Cancer Institute,
National Institutes of Health, Rockville, Maryland.
(2)b J. Crayton Pruitt Family Department of Biomedical Engineering, University
of Florida, Gainesville, Florida.
(3)c Department of Statistics, Radiation Effects Research Foundation,
Hiroshima, Japan.
(4)d Leidos, Inc., Reston, Virginia.
(5)e Nuclear Science and Engineering Center, Japan Atomic Energy Agency,
Tokai-mura, Japan.
(6)f George W. Woodruff School of Mechanical Engineering, Georgia Institute of
Technology, Atlanta, Georgia.

One of the largest sources of data on radiation exposure in humans is the study
of the atomic bomb survivors at Hiroshima and Nagasaki, Japan performed by the
Radiation Effects Research Foundation (RERF). As part of their retrospective
dosimetry efforts for the atomic bomb survivors, RERF published two core systems:
Dosimetry System 1986 (DS86) and Dosimetry System 2002 (DS02). Due to computing
limitations at the time, only three stylized phantoms (an infant, child and
adult) were used in DS86 and DS02 to represent the entire Japanese population. In
this study, we sought to evaluate the dosimetric differences that should be
expected from using an updated and age-expanded RERF phantom series with the
survivor cohort. To this end, we developed a new series of hybrid phantoms, based
on the Japanese population of 1945, which has greater anatomical realism and
improved age resolution over those used by RERF. These phantoms were converted to
voxel format and compared to their older counterparts through the calculation of
organ dose coefficients using DS02 free-in-air particle fluences at three
distances from the bomb hypocenter. From the photon portion of the spectra, organ
dose differences of up to nearly 25% are expected between the old and new series,
while organ dose differences of up to nearly 70% are expected from the neutron
portion. We also compared organ dose coefficients among themselves to determine
the accuracy in the use of one organ dose as the epidemiological surrogate to
another. Certain organ-surrogate pairs were shown to be inappropriate, such as
the use of colon dose for breast risk analyses. Overall, our new series of
phantoms provides significant improvements to survivor organ dosimetry,
especially to those survivors who were previously misrepresented in body size by
their stylized phantom and to those who experienced a highly-directional
irradiation field.

DOI: 10.1667/RR15267.1
PMID: 30779693

AJR Am J Roentgenol. 2019 Feb 19:1-6. doi: 10.2214/AJR.18.20526. [Epub ahead of
print]

Imaging Characteristics of Liver Metastases Overlooked at Contrast-Enhanced CT.

Nakai H(1), Arizono S(1), Isoda H(1)(2), Togashi K(1).

Author information:
(1)1 Department of Diagnostic Imaging and Nuclear Medicine, Kyoto University
Graduate School of Medicine, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507,
Japan.
(2)2 Preemptive Medicine and Lifestyle Disease Research Center, Kyoto University
Hospital, Kyoto, Japan.

OBJECTIVE: The purpose of this study was to evaluate the imaging characteristics
of liver metastases overlooked at contrast-enhanced CT.
MATERIALS AND METHODS: The records of 746 patients with a diagnosis of liver
metastases from colorectal, breast, gastric, or lung cancer between November 2010
and September 2017 were reviewed. Images were reviewed when liver metastases were
first diagnosed, and images from prior contrast-enhanced CT examinations were
checked if available. These lesions were classified into two groups: missed
lesions (those missed on the prior images) and detected lesions (those correctly
identified and invisible on the prior images or there were no prior images).
Tumor size, contrast-to-noise ratio, location, presence of coexisting liver cysts
and hepatic steatosis, and indications for examination were compared between the
groups. The t test and Fisher exact test were used to analyze the imaging
characteristics of previously overlooked lesions.
RESULTS: The final analysis included 137 lesions, of which 68 were classified as
missed. In univariate analysis, contrast-to-noise ratio was significantly lower
in missed lesions (95% CI, 2.65 ± 0.24 vs 3.90 ± 0.23; p < 0.001). The proportion
of subcapsular lesions (odds ratio, 3.44; p < 0.001), hepatic steatosis (odds
ratio, 6.35; p = 0.007), and examination indication other than survey of
malignant tumors (odds ratio, 9.07; p = 0.02) were significantly higher for
missed lesions.
CONCLUSION: Liver metastases without sufficient contrast enhancement, those in
patients with hepatic steatosis, those in subcapsular locations, and those found
at examinations for indications other than to assess for tumors were
significantly more likely to be overlooked.

DOI: 10.2214/AJR.18.20526
PMID: 30779660

AJR Am J Roentgenol. 2019 Feb 19:1-2. doi: 10.2214/AJR.18.20419. [Epub ahead of
print]

Impact of Artificial Intelligence on Women’s Imaging: Cost-Benefit Analysis.

Mayo RC(1), Leung JWT(1).

Author information:
(1)1 Department of Diagnostic Radiology, The University of Texas MD Anderson
Cancer Center, 1515 Holcombe Blvd, Unit 1350, Houston, TX 77030-4009.

OBJECTIVE: The purpose of this article is to identify and discuss four areas in
which artificial intelligence (AI) must excel to become clinically viable:
performance, time, work flow, and cost.
CONCLUSION: AI holds tremendous potential for transforming the practice of
radiology, but certain metrics are needed to objectively quantify its impact. As
patients, physicians, hospitals, and insurance companies look for value, AI must
earn a role in medical imaging.

DOI: 10.2214/AJR.18.20419
PMID: 30779657

Circulation. 2019 Feb 19;139(8):1110-1120. doi:
10.1161/CIRCULATIONAHA.118.039371.

Management of Cardiovascular Disease in Women With Breast Cancer.

Barish R(1), Lynce F(2), Unger K(2), Barac A(3).

Author information:
(1)Division of Cardiology, MedStar Georgetown University Hospital Physicians
Group, Washington, DC (R.B.).
(2)Division of Oncology, Georgetown Lombardi Comprehensive Cancer Center,
Georgetown University Medical Center, Washington, DC (F.L., K.U.).
(3)Division of Cardiology, MedStar Heart and Vascular Institute, MedStar
Washington Hospital Center, Georgetown University, Washington, DC (A.B.).

Cardio-oncology is a rapidly developing field which seeks to improve patient
outcomes through enhanced clinical and research collaboration across the
disciplines of oncology and cardiology. Breast cancer (BC) is the most common
cancer diagnosis among women in the United States and, as decades of research
have resulted in decreased mortality rates, there has been an increasing focus on
reducing short- and long-term treatment toxicity and improving morbidity among
survivors. Preexisting or emergent cardiovascular disease in a patient with BC
requires a multidisciplinary, team-based approach to balance the need for
curative cancer treatment while preventing increased cardiovascular disease
morbidity and mortality. Given the overlap in risk factors for BC and
cardiovascular disease, such as smoking, sedentary lifestyle, and obesity, there
are opportunities for cardiovascular disease prevention and detection before,
during, and after BC treatment. Cardiology providers also play an important role
in preventing, diagnosing, and treating cardiac dysfunction and other
cardiovascular complications that may develop as a result of BC treatment. A
number of recent clinical practice guidelines address approaches to
cardiotoxicity, however, they focus on specific agents or treatment modality,
rather than on collaborative disease management. In this review we present
cardiovascular concerns associated with contemporary, multimodality BC treatment
and illustrate how current guideline recommendations apply to clinical cardiology
and oncology questions. We provide a cardio-oncology team-based approach to
cardiovascular assessment and management of patients with BC from diagnosis
through treatment and in survivorship.

DOI: 10.1161/CIRCULATIONAHA.118.039371
PMID: 30779651

Circulation. 2019 Feb 19;139(8):1094-1101. doi:
10.1161/CIRCULATIONAHA.118.038092.

A Review of the Role of Breast Arterial Calcification for Cardiovascular Risk
Stratification in Women.

Bui QM(1), Daniels LB(1).

Author information:
(1)Division of Cardiovascular Medicine, Department of Medicine, University of
California, San Diego.

Cardiovascular disease continues to be the leading cause of death among women in
the United States. One of the barriers to improving cardiovascular disease
outcomes in women is the lack of reliable, effective screening modalities. Breast
arterial calcification has emerged as a potential risk stratification tool.
Localized deposition in the media of the artery, known as Mönckeberg medial
calcific sclerosis, is notably different from the intimal atherosclerotic process
commonly associated with coronary artery disease. Nonetheless, studies favor a
correlation between breast arterial calcification and cardiovascular risk factors
or coronary artery disease, defined as coronary artery calcification on computed
tomography scan or both nonobstructive and obstructive lesions on angiography.
Since a majority of women over the age of 40 undergo yearly breast cancer
screening with mammography, measurement of breast arterial calcification may
offer a personalized, noninvasive approach to risk-stratify women for
cardiovascular disease at no additional cost or radiation. Mammography has the
potential to alter the course of the leading cause of death in women, heart
disease, through the evaluation of breast arterial calcification and
identification of opportunities for prevention. Current evidence supports the
universal reporting of breast arterial calcifications and personalized
patient-provider discussions to more aggressively treat cardiac risk factors
through targeted medical therapies or healthy lifestyle changes.

DOI: 10.1161/CIRCULATIONAHA.118.038092
PMID: 30779650

J Biochem Mol Toxicol. 2019 Feb 19:e22304. doi: 10.1002/jbt.22304. [Epub ahead of
print]

Aryl hydrocarbon-estrogen alpha receptor-dependent expression of miR-206,
miR-27b, and miR-133a suppress cell proliferation and migration in MCF-7 cells.

Mobini K(1), Tamaddon G(2)(3), Fardid R(4)(5), Keshavarzi M(1)(2),
Mohammadi-Bardbori A(1).

Author information:
(1)Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz
University of Medical Sciences, Shiraz, Iran.
(2)Department of Laboratory Sciences, Faculty of Paramedical Sciences, Shiraz
University of Medical Sciences and Health Services, Shiraz, Iran.
(3)Diagnostic Laboratory Sciences and Technology Research Center, School of
Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran.
(4)Department of Radiology, School of Paramedical Sciences, Shiraz University of
Medical Sciences, Shiraz, Iran.
(5)Ionizing and Non-Ionizing Radiation Protection Research Center (INIRPRC),
Shiraz University of Medical Sciences, Shiraz, Iran.

The underlying functions of miR-206, miR-133a, miR-27b, and miR-21, and their
link to the estrogen receptor alpha (ERα) and aryl hydrocarbon receptor (AhR)
signaling pathways remain largely unexplored. In this study, we detect the
expression of miR-206, miR-133a, miR-27b, and miR-21 in MCF-7 through
quantificational real-time polymerase chain reaction assay along with the
activation/inhibition of ERα and AhR receptors. Aside from this, cell
proliferation and migration as well as AhR-dependent CYP1A1 enzyme activity were
measured. Here, we found that the forced increased expression of miR-206,
miR-133a, and miR-27b were closely associated with the suppression of MCF-7 cell
proliferation and migration. The anti-proliferative-metastatic effect of miR-206,
miR-133a, and miR-27b was probably mediated by targeting the ERα and AhR
signaling pathways. Considered together, our study indicated that the
overexpression of miR-206, miR-133a, and miR-27b might be potential biomarkers
for prognosis and therapeutic strategies in breast cancer.

DOI: 10.1002/jbt.22304
PMID: 30779469

Eur J Cancer Care (Engl). 2019 Feb 18:e13021. doi: 10.1111/ecc.13021. [Epub ahead
of print]

Radiation oncology outpatients’ patterns of life expectancy discussions.

Waller A(1)(2)(3), Mackenzie L(1)(2)(3), Carey M(1)(2)(3), Sanson-Fisher
R(1)(2)(3).

Author information:
(1)Health Behaviour Research Collaborative, School of Medicine and Public Health,
Faculty of Health and Medicine, University of Newcastle, Callaghan, New South
Wales, Australia.
(2)Priority Research Centre for Health Behaviour, Faculty of Health and Medicine,
The University of Newcastle, Callaghan, New South Wales, Australia.
(3)Hunter Medical Research Institute, New Lambton, New South Wales, Australia.

OBJECTIVES: To describe the (a) number and type of cancer care providers that
radiation oncology outpatients report discussing life expectancy with, and (b)
perceptions of the acceptability and utility of life expectancy information.
METHODS: A cross-sectional survey of patients receiving radiotherapy was
undertaken in four treatment centres. Patients indicated whether they had
discussed life expectancy with a cancer doctor (i.e., medical oncologists,
radiation oncologists, surgeon, haematologists) and/or other cancer care provider
(i.e., general practitioner, radiation therapist, nurse); and acceptability and
utility of information.
RESULTS: Of 207 respondents, 133 (64%) had discussed life expectancy with at
least one provider. General practitioners (GPs) were the most frequent source of
information. Of those who had discussed life expectancy, half (n = 110/207)
perceived cancer would not impact life expectancy. Information was easy to
understand (91%), discussed sensitively (90%), helped plan for future (83%) and
gave them certainty (86%). The information made 11% feel overloaded and 34% feel
anxious.
CONCLUSION: Two-thirds of respondents had discussed life expectancy with at least
one cancer care provider. Providers from the range of disciplines involved in
cancer care need to be skilled at communicating life expectancy information and
recognising the adverse impact this may have on some patients.

DOI: 10.1111/ecc.13021
PMID: 30779258

Cochrane Database Syst Rev. 2019 Feb 19;2:CD011433. doi:
10.1002/14651858.CD011433.pub2. [Epub ahead of print]

Surgical interventions for the prevention or treatment of lymphoedema after
breast cancer treatment.

Markkula SP(1), Leung N, Allen VB, Furniss D.

Author information:
(1)Department of Plastic Surgery, Helsinki University Hospital, PL 266, Helsinki,
Finland, FIN-00029 HUS.

BACKGROUND: Breast cancer is the most common type of cancer amongst women
worldwide, and one distressing complication of breast cancer treatment is breast
and upper-limb lymphoedema. There is uncertainty regarding the effectiveness of
surgical interventions in both the prevention and management of lymphoedema
affecting the arm after breast cancer treatment.
OBJECTIVES: 1. To assess and compare the efficacy of surgical interventions for
the prevention of the development of lymphoedema (LE) in the arm after breast
cancer treatment.2. To assess and compare the efficacy of surgical interventions
for the treatment of established LE in the arm after breast cancer treatment.
SEARCH METHODS: We searched the Cochrane Breast Cancer Group’s Specialised
Register, the Cochrane Central Register of Controlled Trials, MEDLINE, Embase,
the Cumulative Index to Nursing and Allied Health Literature (CINAHL), the WHO
International Clinical Trials Registry Platform (ICTRP) and ClinicalTrials.gov
for all prospectively registered and ongoing trials on 2 November 2017. Reference
lists of included studies were also handsearched by three review authors for
additional eligible trials.
SELECTION CRITERIA: All randomised controlled trials (RCTs) comparing a surgical
intervention for the prevention or treatment of lymphoedema of the arm after
breast cancer treatment to either standard intervention, placebo intervention, or
another surgical intervention were included. Patients of both sexes and all ages
who have had treatment for their breast cancer were considered. No limits were
applied to language or study location. Three authors independently determined the
eligibility of each study.
DATA COLLECTION AND ANALYSIS: Three authors independently extracted data for each
included study using a pre-designed data extraction pro forma and used Cochrane’s
‘risk of bias’ tool for assessing risk of bias. Dichotomous variables were
analysed using the Mantel-Haenszel method to estimate risk ratios (RRs).
Differences in continuous variables were expressed as mean differences (MDs).
GRADE was used to assess the certainty of the evidence provided by the included
studies.
MAIN RESULTS: Two studies involving 95 participants examined surgical
interventions for preventing breast cancer-related lymphoedema. Both studies
evaluated the efficacy of the lymphaticovenular anastomosis technique as part of
a preventative management protocol. Both studies were deemed to be at unclear
risk of bias overall. Statistical variation between the studies was low, which
increases the reliability of the evidence. However, the two studies were
conducted in the same centre. Lymphaticovenular anastomosis appears to result in
a reduction in the incidence of lymphoedema compared to nonoperative management
with a risk ratio of 0.20 (95% CI 0.06 to 0.63, P = 0.006; 95 participants;
low-certainty evidence). The RCTs did not evaluate any of the secondary
outcomes.One study involving 36 participants evaluated the effectiveness of
vascularised lymph node transfer for treating breast cancer-related lymphoedema.
The trial was deemed to be at unclear risk of bias. For participants suffering
from stage 2 lymphoedema, the evidence suggested reductions in limb volume (MD
-39.00%, 95% CI -47.37% to -30.63%, very low-certainty evidence), pain scores (MD
-4.16, 95% CI -5.17 to -3.15, very low-certainty evidence), heaviness sensation
(MD -4.27, 95% CI -5.74 to -2.80, very low-certainty evidence), mean number of
infections/year (MD -1.22, 95% CI -2.00 to -0.44, very low-certainty evidence),
and an improvement in overall function scores (MD -3.77, 95% CI -4.89 to -2.65,
very low-certainty evidence) for those who had undergone vascularised lymph node
transfer compared to those who had undergone no treatment.
AUTHORS’ CONCLUSIONS: There is low-certainty evidence that lymphaticovenular
anastomosis is effective in preventing the development of lymphoedema after
breast cancer treatment based on the findings from two studies. One study
providing very low-certainty evidence found that vascularised lymph node transfer
is an efficacious option in the treatment of established stage 2 lymphoedema
related to breast cancer. Important secondary outcomes in this review were rarely
reported in the included studies. More high-quality RCTs are required to further
elucidate the effectiveness of surgical interventions in the prevention and
treatment of lymphoedema after breast cancer treatment. At the time of this
review, no ongoing trials on this topic were identified.

DOI: 10.1002/14651858.CD011433.pub2
PMID: 30779124

Eur Rev Med Pharmacol Sci. 2019 Feb;23(3):1158-1164. doi:
10.26355/eurrev_201902_17007.

Breast cancer in women living with HIV.

D’Andrea F(1), Ceccarelli M, Facciolà A, Nunnari G, Pellicanò GF, Venanzi Rullo
E.

Author information:
(1)Department of Clinical and Experimental Medicine, University of Messina,
Messina, Italy. gnunnari@unime.it.

With the introduction of HAART, the life expectancy of the patients infected with
HIV almost approached that of the general population. The incidence of certain
HIV-Associated cancers as Kaposi Sarcoma (KS) and Non-Hodgkin Lymphoma (NHL)
decreased, while an increase in Non-AIDS-Defining cancers (NADCs) has been
documented. HIV infection is a risk factor for numerous cancers in PLWH. Breast
cancer is the most common cancer worldwide among all women. The association
between HIV infection and breast cancer has not been thoroughly investigated:
when compared to the general population, people living with HIV/AIDS (PLWHA) have
a similar or slightly lower risk of breast cancer. Screening tests are essential
weapons to fight cancer burden and more effective therapeutic and preventive
strategies are needed, especially among PLWHA. Further and more comprehensive
studies are needed to better characterize breast cancer among PLWH.

DOI: 10.26355/eurrev_201902_17007
PMID: 30779085

Eur Rev Med Pharmacol Sci. 2019 Feb;23(3):1151-1157. doi:
10.26355/eurrev_201902_17006.

Effect of miR-34a on resistance to sunitinib in breast cancer by regulating the
Wnt/β-catenin signaling pathway.

Gong LG(1), Shi JC, Shang J, Hao JG, Du X.

Author information:
(1)Department of Breast Surgery, Yantaishan Hospital, Yantai, China.
dxsj22@126.com.

OBJECTIVE: The aim of this study was to investigate the influence of micro
ribonucleic acid (miR)-34a on resistance to sunitinib in breast cancer, and to
explore its possible underlying mechanism.
MATERIALS AND METHODS: Breast cancer MCF-7 cells were transfected with miR-34a
inhibitor or mimics to downregulate or upregulate the expression of miR-34a.
Then, the transfected cells were treated with sunitinib. Next, transwell assay
was applied to detect the changes in cell invasion ability. Cell viability was
measured via cell counting kit-8 (CCK8) assay. Dual-Luciferase reporter gene
assay was employed to determine the interaction between miR-34a and the
Wnt/β-catenin signaling pathway. The immunoblotting assay was used to measure the
expression changes of proteins in the pathway.
RESULTS: The overexpression of miR-34a significantly reduced the invasive ability
of MCF-7 cells after treatment with sunitinib. After miR-34a expression was
downregulated, the sensitivity of MCF-7 cells to sunitinib was significantly
lowered. MiR-34a interacted with the 3′-untranslated region (3′-UTR) on Wnt1.
Meanwhile, the overexpression of miR-34a remarkably downregulated the messenger
RNA (mRNA) and the protein levels of Wnt1, whereas upregulated the expressions of
Wnt1 and β-catenin.
CONCLUSIONS: MiR-34a affects the sensitivity to sunitinib in breast cancer by
regulating the Wnt/β-catenin signaling pathway.

DOI: 10.26355/eurrev_201902_17006
PMID: 30779084

Breast Cancer Res Treat. 2019 Feb 19. doi: 10.1007/s10549-019-05135-w. [Epub
ahead of print]

A high-risk luminal A dominant breast cancer subtype with increased mobility.

Guo L(1), Chen G(2), Zhang W(3), Zhou L(1), Xiao T(1), Di X(1), Wang Y(4), Feng
L(5), Zhang K(6).

Author information:
(1)State Key Laboratory of Molecular Oncology, Department of Etiology and
Carcinogenesis, National Cancer Center/National Clinical Research Center for
Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union
Medical College, Beijing, 100021, China.
(2)Department of Breast Surgery, National Cancer Center/National Clinical
Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences
and Peking Union Medical College, Beijing, 100021, China.
(3)Department of Immunology, National Cancer Center/National Clinical Research
Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking
Union Medical College, Beijing, 100021, China.
(4)Department of Breast Surgery, National Cancer Center/National Clinical
Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences
and Peking Union Medical College, Beijing, 100021, China. wangyi-82@126.com.
(5)State Key Laboratory of Molecular Oncology, Department of Etiology and
Carcinogenesis, National Cancer Center/National Clinical Research Center for
Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union
Medical College, Beijing, 100021, China. fenglin@cicams.ac.cn.
(6)State Key Laboratory of Molecular Oncology, Department of Etiology and
Carcinogenesis, National Cancer Center/National Clinical Research Center for
Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union
Medical College, Beijing, 100021, China. zhangkt@cicams.ac.cn.

PURPOSE: Breast cancer is a heterogeneous disease, and although advances in
molecular subtyping have been achieved in recent years, most subtyping strategies
target individual genes independent of one another and primarily concentrate on
proliferative markers. The contributions of biological processes and immune
patterns have been neglected in breast cancer subtype stratification.
METHODS: We performed a gene set variation analysis to simplify the information
on biological processes using hallmark terms and to decompose immune cell data
using the immune cell gene terms on 985 breast invasive ductal/lobular carcinoma
RNAseq samples in the TCGA database.
RESULTS: The samples were gathered into three clusters following implementation
of the t-SNE and DBSCAN algorithms and were categorized as ‘hallmark-tsne’
subtypes. Here, we identified a high-risk luminal A dominant breast cancer
subtype (C3) that displayed increased motility, cancer stem cell-like features, a
higher expression of hormone/luminal-related genes, a lower expression of
proliferation-related genes and immune dysfunction. With regard to immune
dysfunction, we observed that the motility-increased C3 subtype exhibited high
granulocyte colony stimulating factor (G-CSF) expression accompanied by
neutrophil aggregation. Cancer cells that produce high levels of G-CSF can
stimulate neutrophils to form neutrophil extracellular traps, which promote
cancer cell migration. This finding sheds light on one potential explanation for
why the C3 subtype correlates with poor prognosis.
CONCLUSIONS: The hallmark-tsne subtypes confirmed again that even the luminal A
subtype is heterogeneous and can be further subdivided. The biological processes
and immune heterogeneity of breast cancer must be understood to facilitate the
improvement of clinical treatments.

DOI: 10.1007/s10549-019-05135-w
PMID: 30778902

Clin Transl Oncol. 2019 Feb 16. doi: 10.1007/s12094-019-02033-x. [Epub ahead of
print]

Relationship between tumor-associated immune infiltrate and p16 staining over
clinicopathological features in acral lentiginous melanoma.

Castaneda CA(1)(2), Castillo M(3), Torres-Cabala C(4), Bernabe LA(3), Casavilca
S(5), Villegas V(3), Sanchez J(3), de la Cruz M(6), Dunstan J(6), Cotrina JM(6),
Gomez HL(7), Chavez C(3), Landa-Baella MP(3), Tello K(3), Felix BF(3), Abugattas
J(6).

Author information:
(1)Medical Oncology Department and Research Department, Instituto Nacional de
Enfermedades Neoplasicas, Av. Angamos Este 2520 Surquillo, 15038, Lima, Peru.
carloscastanedaaltamirano@yahoo.com.
(2)Faculty of Medicine, Universidad Privada San Juan Bautista, 15067, Lima, Peru.
carloscastanedaaltamirano@yahoo.com.
(3)Medical Oncology Department and Research Department, Instituto Nacional de
Enfermedades Neoplasicas, Av. Angamos Este 2520 Surquillo, 15038, Lima, Peru.
(4)Departments of Pathology and Dermatology, The University of Texas MD Anderson
Cancer Center, Houston, TX, 77030, USA.
(5)Pathology Department, Instituto Nacional de Enfermedades Neoplasicas., Av.
Angamos Este 2520 Surquillo, 15038, Lima, Peru.
(6)Breast Cancer Surgery Department, Instituto Nacional de Enfermedades
Neoplasicas, Av. Angamos Este 2520 Surquillo, 15038, Lima, Peru.
(7)Medical Oncology Department, Instituto Nacional de Enfermedades Neoplasicas,
Av. Angamos Este 2520 Surquillo, 15038, Lima, Peru.

PURPOSE: This study aims to evaluate the association between composition of
tumor-infiltrating lymphocytes (TIL) and expression of p16 in acral lentiginous
melanoma (ALM), and their impact on prognosis.
MATERIALS AND METHODS: A cohort of 148 surgical pathology specimens of ALM was
studied. TIL were evaluated by immunohistochemical detection of CD3 and CD8,
along with CD20, CD4, CD68, and CD163 in a subset of 43 cases. p16 protein
expression was also investigated in all the cases.
RESULTS: The median age was 66 years, median Breslow thickness was 6.0 mm, grade
III TIL was found in 28.4% and lymph nodes were involved in 54.2%. Breslow
thickness (p < 0.001), stage I-II (p < 0.001), negative lymph nodes (p < 0.001) and < 10% p16 (p = 0.01) were associated with longer survival. Grade III of TIL was associated with thinner Breslow thickness (p = 0.008) and lower mitosis (p = 0.047). A higher density of CD3 TIL was associated with male gender (p = 0.008), thinner Breslow thickness (p = 0.047), negative lymph node (p = 0.031), early stage (p = 0.046), and p16 nuclear expression of > 10%
(p = 0.045). Higher CD8 TIL was associated with > p16 (p = 0.03). Survival
analysis found that longer survival had a trend to be associated with high TIL
(p = 0.090). Levels of CD3+ and CD8+ cells were correlated with those of CD4+,
CD20+, CD68+ and CD163+ immune cells.
CONCLUSIONS: Higher levels of TIL tend to be associated with better overall
survival in ALM. Loss of expression of p16 is associated with lower levels of
CD3+ and CD8+ TIL, indicating a probable relationship between p16 and TIL immune
response in ALM .

DOI: 10.1007/s12094-019-02033-x
PMID: 30778854

Jpn J Radiol. 2019 Feb 18. doi: 10.1007/s11604-019-00819-1. [Epub ahead of print]

A heart atlas for breast radiation therapy and the influence of delination
education on both intra and interobserver variability.

Kırlı M(1)(2), Akçay D(3), Barış MM(4), Görken İB(3).

Author information:
(1)Departmant of Radiation Oncology, Dokuz Eylül University Faculty of Medicine,
Mithatpaşa Street, Balçova, 35340, İzmir, Turkey. meltemkrl@gmail.com.
(2)Department of Radiation Oncology, Health Sciences University Erzurum Regional
Training and Research Hospital, Çaykara Street Yakutiye, 25100, Erzurum, Turkey.
meltemkrl@gmail.com.
(3)Departmant of Radiation Oncology, Dokuz Eylül University Faculty of Medicine,
Mithatpaşa Street, Balçova, 35340, İzmir, Turkey.
(4)Departmant of Radiology, Dokuz Eylül University Faculty of Medicine,
Mithatpaşa Street, Balçova, 35340, İzmir, Turkey.

PURPOSE: We developed a heart atlas for breast radiation therapy and evaluated
the influence of education on intra and inter-observer similarity, and cardiac
dose reporting.
MATERIALS AND METHODS: The data of 16 left breast cancer patients were analyzed.
Eight observers delineated heart and cardiac subunits [left (LCA) and right (RCA)
coronary arteries, left anterior descending artery (LAD), bilateral atrium and
ventricles] before the education. A radiologist and radiation oncologist
developed the atlas and delineated the gold standard (GS) volumes. Observers
repeated the delineation after education. RT plans were made for pre/post-atlas
contours. The similarity was assessed by Dice (DSC) and Jaccard (JSC) similarity
coefficient indices. The absolute difference rate was calculated for the dose
analysis.
RESULTS: The inter-observer similarity increased in heart and all subunits. The
intra-observer similarity showed a heterogeneous distribution. The absolute
difference rate in dose reporting was statistically significant for the bilateral
atrium, right ventricle, LAD, LCA + LAD, RCA’s maximum doses (p < 0.05). The
maximum dose reporting differences from the GS decreased from 16.9 to 8.9% for
LAD (p = 0.011); from 14.8 to 9.3% for LCA + LAD (p = 0.010).
CONCLUSION: The cardiac atlas reduces the intra-interobserver differences and
improves dose reporting consistency. The first intra-observer similarity analysis
was made in our study and revealed the need for repeated education to increase
the consistency.

DOI: 10.1007/s11604-019-00819-1
PMID: 30778823

J Occup Rehabil. 2019 Feb 16. doi: 10.1007/s10926-019-09831-8. [Epub ahead of
print]

Two-Year Follow-Up of a Multi-centre Randomized Controlled Trial to Study
Effectiveness of a Hospital-Based Work Support Intervention for Cancer Patients.

Tamminga SJ(1), Verbeek JHAM(1)(2), Bos MMEM(3), Fons G(4), Kitzen JJEM(5),
Plaisier PW(6), Frings-Dresen MHW(1), de Boer AGEM(7).

Author information:
(1)Coronel Institute of Occupational Health, Amsterdam Public Health Research
Institute, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, Amsterdam, The
Netherlands.
(2)Finnish Institute of Occupational Health, Kuopio, Finland.
(3)Department of Internal Medicine, Reinier de Graaf Groep, Delft, The
Netherlands.
(4)Department of Gynaecology, Academic Medical Center, University of Amsterdam,
Amsterdam, The Netherlands.
(5)Department of Internal Medicine, Albert Schweitzer Hospital, Dordrecht, The
Netherlands.
(6)Department of Surgery, Albert Schweitzer Hospital, Dordrecht, The Netherlands.
(7)Coronel Institute of Occupational Health, Amsterdam Public Health Research
Institute, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, Amsterdam, The
Netherlands. a.g.deboer@amc.nl.

Purpose Purpose is to: (1) study effectiveness of the hospital-based work support
intervention for cancer patients at two years of follow-up compared to usual care
and (2) identify which early factors predict time to return-to-work (RTW).
Methods In this multi-center randomised controlled trial (RCT), 106
(self-)employed cancer patients were randomized to an intervention group or
control group and provided 2 years of follow-up data. The intervention group
received patient education and work-related support at the hospital. Primary
outcome was RTW (rate and time) and quality of life (SF-36), and secondary
outcomes were, work ability (WAI), and work functioning (WLQ). Univariate Cox
regression analyses were performed to study which early factors predict time to
full RTW. Results Participants were diagnosed with breast (61%), gynaecological
cancer (35%), or other type of cancer (4%). RTW rates were 84% and 90% for
intervention versus control group. They were high compared to national
register-based studies. No differences between groups were found on any of the
outcomes. Receiving chemotherapy (HR = 2.43, 95% CI 1.59-3.73 p < 0.001), low
level of education (HR = 1.65, 95% CI 1.076-2.52 p = 0.02) and low work ability
(HR = 1.09 [95% CI 1.04-1.17] p = 0.02) were associated with longer time to full
RTW. Conclusions We found high RTW rates compared to national register-based
studies and we found no differences between groups. Future studies should
therefore focus on reaching the group at risk, which consist of patients who
receive chemotherapy, have a low level of education and have a low work ability
at diagnosis. TRIAL REGISTRATION: Netherlands Trial Registry (NTR) (
http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=1658 ): NTR1658.

DOI: 10.1007/s10926-019-09831-8
PMID: 30778742

Surg Case Rep. 2019 Feb 18;5(1):25. doi: 10.1186/s40792-019-0583-z.

Surgical treatment of rectal cancer with a Retzius shunt: a case report.

Sueda T(1), Tei M(2), Furukawa H(2), Matsumura T(2), Koga C(2), Wakasugi M(2),
Miyagaki H(2), Kawabata R(2), Shimizu J(2), Okada A(3), Hasegawa J(2).

Author information:
(1)Department of Surgery, Osaka Rosai Hospital, 1179-3 Nagasonecho, Kita-ku,
Sakai, 591-8025, Japan. sueda811@yahoo.co.jp.
(2)Department of Surgery, Osaka Rosai Hospital, 1179-3 Nagasonecho, Kita-ku,
Sakai, 591-8025, Japan.
(3)Department of Diagnostic and Interventional Radiology, Osaka Rosai Hospital,
1179-3 Nagasonecho, Kita-ku, Sakai, 591-8025, Japan.

BACKGROUND: A case of a short circuit (Retzius shunt) from the inferior
mesenteric vein (IMV) to the inferior vena cava (IVC) without accompanying portal
hypertension due to liver cirrhosis is rare.
CASE PRESENTATION: An 83-year-old woman who was followed after surgery for
thyroid and breast cancer was incidentally found to have rectal cancer on
computed tomography (CT). Preoperative three-dimensional CT showed a venous
malformation forming a short circuit (Retzius shunt) from the IMV to the IVC.
Laparoscopic anterior rectal resection was performed. Operative findings included
the Retzius vein crossing the abdominal aorta and the inferior mesenteric artery
(IMA) to the IVC and a number of engorged vessels in the mesentery. The Retzius
vein and IMA were clipped without major bleeding, and tumor-specific mesorectal
excision was then performed. The patient’s postoperative clinical course was
good, and she was discharged without complications.
CONCLUSIONS: Preoperative imaging enabled identification of an unexpected rare
disease, thus reinforcing the importance of preoperative imaging.

DOI: 10.1186/s40792-019-0583-z
PMID: 30778696

Histochem Cell Biol. 2019 Feb 16. doi: 10.1007/s00418-019-01775-7. [Epub ahead of
print]

High-throughput quantification of the effect of DMSO on the viability of lung and
breast cancer cells using an easy-to-use spectrophotometric trypan blue-based
assay.

Hammoudeh SM(1), Hammoudeh AM(1), Hamoudi R(2)(3).

Author information:
(1)Sharjah Institute for Medical Research, College of Medicine, University of
Sharjah, 27272, Sharjah, UAE.
(2)Sharjah Institute for Medical Research, College of Medicine, University of
Sharjah, 27272, Sharjah, UAE. rhamoudi@sharjah.ac.ae.
(3)Department of Clinical Sciences, College of Medicine, University of Sharjah,
Sharjah, UAE. rhamoudi@sharjah.ac.ae.

One of the main aspects investigated in potential therapeutic compounds is their
effect on cells viability and proliferative ability. Although various methods
have been developed to investigate these aspects, these methods present with
shortcomings in terms of either cost, availability, accuracy, precision, or
throughput. This study describes a simple, economic, reproducible, and
high-throughput assay to quantify cell death and proliferation. In this assay,
adherent cells are fixed, stained with trypan blue, and measured for trypan blue
internalization using a spectrophotometric absorbance plate reader. Corresponding
cell counts to the absorbance measurements are extrapolated from a standard
curve. This assay was used to measure the effect of dimethyl sulfoxide (DMSO) on
the viability of breast and lung cancer cells. Decrease in cell count associated
with the increase in DMSO percentage and exposure time. The assay’s results
closely correlated with the conventional trypan blue exclusion assay (Pearson
correlation coefficient (r) > 0.99; p < 0.0001), but with higher precision. The
assay developed in this study can be used for various applications such as
optimization, cell treatment investigations, proliferation, and cytotoxicity
studies.

DOI: 10.1007/s00418-019-01775-7
PMID: 30778673

Ann Oncol. 2019 Feb 18. pii: mdz055. doi: 10.1093/annonc/mdz055. [Epub ahead of
print]

De-escalated therapy for HR+/HER2+ breast cancer patients with Ki67 response
after 2 weeks letrozole: results of the PerELISA neoadjuvant study.

Guarneri V(1)(2), Dieci MV(1)(2), Bisagni G(3), Frassoldati A(4), Bianchi GV(5),
De Salvo GL(6), Orvieto E(7), Urso L(1), Pascual T(8)(9), Paré L(8)(9), Galván
P(8)(9), Ambroggi M(10), Giorgi CA(2), Moretti G(3), Griguolo G(1)(2)(9), Vicini
R(11), Prat A(8)(9), Conte PF(1)(2).

Author information:
(1)Department of Surgery, Oncology and Gastroenterology, University of Padova,
Padova, Italy.
(2)Medical Oncology 2, Istituto Oncologico Veneto IOV – IRCCS, Padova, Italy.
(3)Department of Oncology and Advanced Technologies, Oncology Unit, IRCCS
Arcispedale Santa Maria Nuova, Reggio Emilia, Italy.
(4)Clinical Oncology, Department of Morphology, Surgery and Experimental
Medicine, S Anna University Hospital, Ferrara, Italy.
(5)Medical Oncology 1, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan,
Italy.
(6)Clinical Trials and Biostatistics Unit, Istituto Oncologico Veneto IOV –
IRCCS, Padova, Italy.
(7)Pathology Unit, Azienda ULSS 5 Polesana, Rovigo, Italy.
(8)Department of Medical Oncology, Hospital Clinic, Barcelona, Spain.
(9)Translational Genomics and Targeted Therapeutics in Solid Tumours Lab,
Institut d’Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona,
Spain.
(10)Departments of Oncology-Hematology, Ospedale «G. da Saliceto», Piacenza,
Italy.
(11)Department of Diagnostic and Clinical Medicine and Public Health, Statistics
Unit, University Hospital of Modena and Reggio Emilia, Modena, Italy.

BACKGROUND: In HER2+ breast cancers, neoadjuvant trials of chemotherapy plus
anti-HER2 treatment consistently showed lower pathologic complete response (pCR)
rates in hormone receptor (HR) positive vs negative tumors. The PerELISA study
was aimed to evaluate the efficacy of a de-escalated, chemotherapy-free
neoadjuvant regimen in HR+/HER2+ breast cancer patients selected on the basis of
Ki67 inhibition after 2-weeks letrozole.
PATIENTS AND METHODS: PerELISA is a phase II, multicentric study for
postmenopausal patients with HR+/HER2+ operable breast cancer. Patients received
2-weeks letrozole, then underwent re-biopsy for Ki67 evaluation. Patients
classified as molecular responders (Ki67 relative reduction >20% from baseline)
continued letrozole and started trastuzumab-pertuzumab for 5 cycles. Patients
classified as molecular non-responders started weekly paclitaxel for 13 weeks
combined with trastuzumab-pertuzumab. Primary aim was breast and axillary pCR.
According to a 2-stage Simon’s design, to reject the null hypothesis, at least
8/43 pCR had to be documented.
RESULTS: Sixty-four patients were enrolled, 44 were classified as molecular
responders. All these patients completed the assigned treatment with
letrozole-trastuzumab-pertuzumab and underwent surgery. A pCR was observed in
9/44 cases (20.5%, 95%CI 11.1%-34.5%). Among molecular non-responders, 16/17
completed treatment and underwent surgery, with pCR observed in 81.3% of the
cases. PAM50 intrinsic subtype was significantly associated with Ki67 response
and pCR. Among molecular responders, the pCR rate was significantly higher in
HER2-enriched vs other subtypes (45.5% vs 13.8%, p=0.042).
CONCLUSIONS: The primary endpoint of the study was met, by reaching the
pre-specified pCRs. In patients selected using Ki67 reduction after short-term
letrozole exposure, a meaningful pCR rate can be achieved without chemotherapy.
PAM50 intrinsic subtyping further refines our ability to identify a subset of
patients for whom chemotherapy might be spared.

DOI: 10.1093/annonc/mdz055
PMID: 30778520

Front Oncol. 2019 Feb 4;9:24. doi: 10.3389/fonc.2019.00024. eCollection 2019.

The Effect of Hexavalent Chromium on the Incidence and Mortality of Human
Cancers: A Meta-Analysis Based on Published Epidemiological Cohort Studies.

Deng Y(1)(2), Wang M(1)(2), Tian T(1)(2), Lin S(1), Xu P(1), Zhou L(1), Dai C(1),
Hao Q(1), Wu Y(1), Zhai Z(1), Zhu Y(1), Zhuang G(3), Dai Z(1)(2).

Author information:
(1)Department of Breast Surgery, Guangzhou Women and Children’s Medical Center,
Guangzhou Medical University, Guangzhou, China.
(2)Department of Oncology, The Second Affiliated Hospital of Xi’an Jiaotong
University, Xi’an, China.
(3)Department of Epidemiology and Biostatistics, Xi’an Jiaotong University Health
Science Center, School of Public Health, Xi’an, China.

Background: Hexavalent chromium [Cr(VI)] is an occupational carcinogen that can
cause lung and nasal cancers, but its association with mortality and incidence in
many other cancers is unclear. Objectives: In this meta-analysis, we aimed to
evaluate the relationship between exposure to Cr(VI) and the mortality and
incidence of human cancers. Methods: We performed a search of the literature and
extracted the standardized mortality ratios (SMRs), standardized incidence ratios
(SIRs), and their corresponding 95% confidence intervals (CIs), to estimate risk
values. Subgroup analyses were conducted by sex, occupation, and types of cancer
to identify groups that were at high-risk or predisposed to certain cancers.
Results: A total of 47 cohort studies covering the period 1985-2016 were included
(37 studies reporting SMRs and 16 studies reporting SIRs). The summary SMR for
all studies combined was 1.07 (95% CI: 1.01-1.15). Summary SMRs were higher among
chromate production workers, chrome platers, and masons, and especially male
workers. In the subgroup analysis, Cr(VI) exposure was related to a higher risk
of death owing to lung, larynx, bladder, kidney, testicular, bone, and thyroid
cancer. The meta-SIR of all studies combined was 1.06 (95% CI: 1.04-1.09).
Summary SIRs were elevated among cement industry workers and tanners. Cr(VI)
exposure was related to an elevated risk of respiratory system, buccal cavity,
pharynx, prostate, and stomach cancers. Conclusions: Cr(VI) might cause cancers
of the respiratory system, buccal cavity and pharynx, prostate, and stomach in
humans, and it is related to increased risk of overall mortality owing to lung,
larynx, bladder, kidney, testicular, bone, and thyroid cancer. In addition, there
was a strong association between incidence and mortality risk of cancers and
concentration of Cr(VI) in the air and the exposure time.

DOI: 10.3389/fonc.2019.00024
PMCID: PMC6369173
PMID: 30778374

Nat Immunol. 2019 Mar;20(3):257-264. doi: 10.1038/s41590-019-0321-5. Epub 2019
Feb 18.

Inhibition of the dipeptidyl peptidase DPP4 (CD26) reveals IL-33-dependent
eosinophil-mediated control of tumor growth.

Hollande C(1)(2)(3), Boussier J(1)(2), Ziai J(4), Nozawa T(5), Bondet V(1)(2),
Phung W(6), Lu B(7), Duffy D(1)(2)(8), Paradis V(9), Mallet V(10), Eberl G(11),
Sandoval W(6), Schartner JM(5), Pol S(1)(2)(8)(10), Barreira da Silva R(12),
Albert ML(13).

Author information:
(1)Immunobiology of Dendritic Cells, Institut Pasteur, Paris, France.
(2)Inserm U1223, Institut Pasteur, Paris, France.
(3)École Doctorale Physiologie, Physiopathologie et Thérapeutique, Université
Pierre et Marie Curie, Paris, France.
(4)Department of Research Pathology, Genentech, South San Francisco, CA, USA.
(5)Department of Translational Oncology, Genentech, South San Francisco, CA, USA.
(6)Department of Microchemistry, Proteomics and Lipidomics, Genentech, South San
Francisco, CA, USA.
(7)University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.
(8)Center for Translational Research, Inserm UMS20, Institut Pasteur, Paris,
France.
(9)Department of Pathology, Physiology and Imaging, Hôpital Beaujon, Clichy,
France.
(10)Département d’Hépatologie, Assistance Publique-Hôpitaux de Paris, Hôpital
Cochin, Université Paris Descartes, Paris, France.
(11)Microenvironment & Immunity Unit, Inserm U1224, Institut Pasteur, Paris,
France.
(12)Department of Cancer Immunology, Genentech, South San Francisco, CA, USA.
(13)Department of Cancer Immunology, Genentech, South San Francisco, CA, USA.
albertm7@gene.com.

Post-translational modification of chemokines mediated by the dipeptidyl
peptidase DPP4 (CD26) has been shown to negatively regulate lymphocyte
trafficking, and its inhibition enhances T cell migration and tumor immunity by
preserving functional chemokine CXCL10. By extending those initial findings to
pre-clinical models of hepatocellular carcinoma and breast cancer, we discovered
a distinct mechanism by which inhibition of DPP4 improves anti-tumor responses.
Administration of the DPP4 inhibitor sitagliptin resulted in higher
concentrations of the chemokine CCL11 and increased migration of eosinophils into
solid tumors. Enhanced tumor control was preserved in mice lacking lymphocytes
and was ablated after depletion of eosinophils or treatment with degranulation
inhibitors. We further demonstrated that tumor-cell expression of the alarmin
IL-33 was necessary and sufficient for eosinophil-mediated anti-tumor responses
and that this mechanism contributed to the efficacy of checkpoint-inhibitor
therapy. These findings provide insight into IL-33- and eosinophil-mediated tumor
control, revealed when endogenous mechanisms of DPP4 immunoregulation are
inhibited.

DOI: 10.1038/s41590-019-0321-5
PMID: 30778250

Mod Pathol. 2019 Feb 18. doi: 10.1038/s41379-019-0205-0. [Epub ahead of print]

Whole slide imaging equivalency and efficiency study: experience at a large
academic center.

Hanna MG(1), Reuter VE(1)(2), Hameed MR(1)(2), Tan LK(1), Chiang S(1), Sigel
C(1), Hollmann T(1), Giri D(1), Samboy J(1)(2), Moradel C(1), Rosado A(1),
Otilano JR 3rd(1), England C(1), Corsale L(1), Stamelos E(1), Yagi Y(1)(2),
Schüffler PJ(1)(2), Fuchs T(1)(2), Klimstra DS(1)(2), Sirintrapun SJ(3)(4).

Author information:
(1)Department of Pathology, Memorial Sloan Kettering, New York, NY, USA.
(2)Warren Alpert Center for Digital and Computational Pathology, New York, NY,
USA.
(3)Department of Pathology, Memorial Sloan Kettering, New York, NY, USA.
sirintrs@mskcc.org.
(4)Warren Alpert Center for Digital and Computational Pathology, New York, NY,
USA. sirintrs@mskcc.org.

Whole slide imaging is Food and Drug Administration-approved for primary
diagnosis in the United States of America; however, relatively few pathology
departments in the country have fully implemented an enterprise wide digital
pathology system enabled for primary diagnosis. Digital pathology has significant
potential to transform pathology practice with several published studies
documenting some level of diagnostic equivalence between digital and conventional
systems. However, whole slide imaging also has significant potential to disrupt
pathology practice, due to the differences in efficiency of manipulating digital
images vis-à-vis glass slides, and studies on the efficiency of actual digital
pathology workload are lacking. Our randomized, equivalency and efficiency study
aimed to replicate clinical workflow, comparing conventional microscopy to a
complete digital pathology signout using whole slide images, evaluating the
equivalency and efficiency of glass slide to whole slide image reporting,
reflective of true pathology practice workloads in the clinical setting. All
glass slides representing an entire day’s routine clinical signout workload for
six different anatomic pathology subspecialties at Memorial Sloan Kettering
Cancer Center were scanned on Leica Aperio AT2 at ×40 (0.25 µm/pixel).
Integration of whole slide images for each accessioned case is through an
interface between the Leica eSlide manager database and the laboratory
information system, Cerner CoPathPlus. Pathologists utilized a standard
institution computer workstation and viewed whole slide images through an
internally developed, vendor agnostic whole slide image viewer, named the «MSK
Slide Viewer». Subspecialized pathologists first reported on glass slides from
surgical pathology cases using routine clinical workflow. Glass slides were
de-identified, scanned, and re-accessioned in the laboratory information system
test environment. After a washout period of 13 weeks, pathologists reported the
same clinical workload using whole slide image integrated within the laboratory
information system. Intraobserver equivalency metrics included top-line
diagnosis, margin status, lymphovascular and/or perineural invasion, pathology
stage, and the need to order ancillary testing (i.e., recuts,
immunohistochemistry). Turnaround time (efficiency) evaluation was defined by the
start of each case when opened in the laboratory information system and when the
case was completed for that day (i.e., case sent to signout queue or pending
ancillary studies). Eight pathologists participated from the following
subspecialties: bone and soft tissue, genitourinary, gastrointestinal, breast,
gynecologic, and dermatopathology. Glass slides signouts comprised of 204 cases,
encompassing 2091 glass slides; and digital signouts comprised of 199 cases,
encompassing 2073 whole slide images. The median whole slide image file size was
1.54 GB; scan time/slide, 6 min 24 s; and scan area 32.1 × 18.52 mm. Overall
diagnostic equivalency (e.g., top-line diagnosis) was 99.3% between digital and
glass slide signout; however, signout using whole slide images showed a median
overall 19% decrease in efficiency per case. No significant difference by reader,
subspecialty, or specimen type was identified. Our experience is the most
comprehensive study to date and shows high intraobserver whole slide image to
glass slide equivalence in reporting of true clinical workflows and workloads.
Efficiency needs to improve for digital pathology to gain more traction among
pathologists.

DOI: 10.1038/s41379-019-0205-0
PMID: 30778169

Br J Cancer. 2019 Feb 19. doi: 10.1038/s41416-018-0371-8. [Epub ahead of print]

Adult height in relation to risk of cancer in a cohort of 22,809,722 Korean
adults.

Choi YJ(1)(2), Lee DH(3)(4), Han KD(5), Yoon H(1), Shin CM(1), Park YS(1), Kim
N(1)(6).

Author information:
(1)Department of Internal Medicine, Seoul National University Bundang Hospital,
Seongnam, South Korea.
(2)Department of Internal Medicine, Korea University Guro Hospital, Seoul, South
Korea.
(3)Department of Internal Medicine, Seoul National University Bundang Hospital,
Seongnam, South Korea. dhljohn@yahoo.com.
(4)Department of Internal Medicine and Liver Research Institute, Seoul National
University College of Medicine, Seoul, South Korea. dhljohn@yahoo.com.
(5)Department of Biostatistics, College of Medicine, The Catholic University of
Korea, Seoul, South Korea.
(6)Department of Internal Medicine and Liver Research Institute, Seoul National
University College of Medicine, Seoul, South Korea.

BACKGROUND: The present study examined whether adult height was associated with
all site-combined or site-specific cancers.
METHODS: We used a nationwide claim data of 22,809,722 Korean participants
including both men and women (2009-2012). The deciles of height from different
age and sex groups were merged into a new quintile. We used Cox proportional
hazards model to estimate hazard ratios (HRs) and 95% confidence intervals.
RESULTS: During a 5-year follow-up period, 765,651 patients were diagnosed with
cancer. Height was positively associated with risk of all site-combined cancers
and with malignancy in the oral cavity, larynx, lung, stomach, colorectum, liver,
pancreas, biliary tract and gallbladder, breast, ovary, cervix and corpus uteri,
prostate, testes, kidney, bladder, central nervous system, thyroid, skin, and
lymphatic and haematopoietic systems. The HRs for all-site cancers per 5 cm
increment in height was 1.09 and that of each site was the highest in thyroid,
breast, lymphoma, testicular, and renal cancers. This association was more
prominent in women and male non-smokers than in other counterparts.
CONCLUSIONS: Taller adult height was significantly related to an increased risk
of most cancers including neoplasm in the gallbladder or biliary tract and
testes, but except for oesophagus.

DOI: 10.1038/s41416-018-0371-8
PMID: 30778143

Pol Arch Intern Med. 2019 Feb 19. doi: 10.20452/pamw.4450. [Epub ahead of print]

BREAST cancer: tele- cardio- onco AID- a new concept for a coordinated care
program (BREAST-AID) – rationale and study protocol.

Styczkiewicz K, Styczkiewicz M, Mędrek S, Jankowski P, Szmit S, Stec S.

DOI: 10.20452/pamw.4450
PMID: 30778018

Cancer Prev Res (Phila). 2019 Feb 18. pii: canprevres.0356.2017. doi:
10.1158/1940-6207.CAPR-17-0356. [Epub ahead of print]

JAK3 variant, immune signatures, DNA methylation, and social determinants linked
to survival racial disparities in head and neck cancer patients.

Guerrero-Preston R(1), Lawson F(2), Rodriguez-Torres S(3), Noordhuis MG(4),
Pirini F(5), Manuel L(6), Valle B(2), Hadar T(7), Rivera BL(8), Folawiyo O(2),
Báez A(9), Marchionni L(10), Koch WM(2), Westra WH(11), Kim YJ(12), Eshleman
JR(13), Sidransky D(14).

Author information:
(1)University of Puerto Rico School of Medicine rafael.guerrero@upr.edu.
(2)Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University
School of Medicine.
(3)Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard
University.
(4)Dept. of Otorhinolaryngology / Head and Neck Surgery, University Medical
Center Groningen.
(5)Biosciences Laboratory,, Istituto Scientifico Romagnolo per lo Studio e la
Cura dei Tumori (IRST) IRCCS.
(6)Department of Epidemiology and Biostatistics, The University of Texas Health
Science Center.
(7)Breast Health Unit, Department of General Surgery, Shaare Zedek Medical
Center.
(8)Department of Otolaryngology-Head and Neck Surgery, University of Puerto Rico,
Medical Sciences Campus.
(9)Department of Otolaryngology-Head and Neck Surgery, University of Puerto Rico
School of Medicine.
(10)The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University
School of Medicine.
(11)Dept of Pathology, Johns Hopkins University.
(12)Otolaryngology – Head & Neck Surgery, Vanderbilt University Medical Center
Center.
(13)Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns
Hopkins Medical Institutions.
(14)Otolaryngology-Head and Neck Surgery and Oncology, Johns Hopkins University.

To inform novel personalized medicine approaches for race and socioeconomic
disparities in head and neck cancer. We examined germ-line and somatic mutations,
immune signatures, and epigenetic alterations linked to neighborhood determinants
of health in Black and Non-Latino White (NLW) head and neck cancer patients. Cox
proportional hazards revealed that Black HNSCC patients with PAX5 (p=0.06) and
PAX1 (p=0.017) promoter methylation had worse survival than NLW patients, after
controlling for education, zipcode and TNM stage (n=118). We also found that
promoter methylation of PAX1 and PAX5 (n=78), was correlated with neighborhood
characteristics at the zip code level (p<0.05). Analyses also showed differences in the frequency of TP53 mutations (n=32) and Tumor Infiltrating Lymphocyte (TIL) counts (n=24), and the presence of a specific C -> A germ-line mutation in JAK3,
chr19:17954215 (protein P132T), in Black HNSCC (n=73) patients (p<0.05), when compared to NLW (n=37) patients. TIL counts are associated (p=0.035) with long-term (>5 years), when compared with short-term survival (< 2 years). We show
bio-social determinants of health associated with survival in Black HNSCC
patients which, together with racial differences shown in germ-line mutations,
somatic mutations and TIL counts, suggests that contextual factors may
significantly inform precision oncology services for diverse populations.

DOI: 10.1158/1940-6207.CAPR-17-0356
PMID: 30777857

Radiology. 2019 Feb 19:182394. doi: 10.1148/radiol.2019182394. [Epub ahead of
print]

Digital Mammography versus Digital Mammography Plus Tomosynthesis in Breast
Cancer Screening: The Oslo Tomosynthesis Screening Trial.

Skaane P(1), Bandos AI(1), Niklason LT(1), Sebuødegård S(1), Østerås BH(1),
Gullien R(1), Gur D(1), Hofvind S(1).

Author information:
(1)From the Division of Radiology and Nuclear Medicine, Oslo University Hospital,
University of Oslo, Breast Imaging Center, PO Box 4950, Nydalen, 0424 Oslo,
Norway (P.S., R.G.); Departments of Biostatistics (A.I.B.) and Radiology (D.G.),
University of Pittsburgh, Pittsburgh, Pa; Retired, former employee of Hologic
(L.T.N.); Department of Screening, Cancer Registry of Norway, Oslo, Norway (S.S.,
S.H.); Department of Diagnostic Physics, Institute of Clinical Medicine, Oslo
University Hospital, University of Oslo, Oslo, Norway (B.H.Ø.); and Department of
Health Sciences, Oslo Metropolitan University, Oslo, Norway (S.H.).

Background Digital breast tomosynthesis (DBT) is replacing digital mammography
(DM) in the clinical workflow. Currently, there are limited prospective studies
comparing the diagnostic accuracy of both examinations and the role of synthetic
mammography (SM) and computer-aided detection (CAD). Purpose To compare the
accuracy of DM versus DM + DBT in population-based breast cancer screening.
Materials and Methods This prospective study, performed from November 2010 to
December 2012, included 24 301 women (mean age, 59.1 years ± 5.7 [standard
deviation]) with 281 cancers, of which 51 were interval cancers. Each examination
was independently interpreted with four reading modes: DM, DM + CAD, DM + DBT,
and SM + DBT. Sensitivity and specificity were compared for DM versus DM + DBT,
DM versus DM + CAD, DM + DBT versus SM + DBT, and DM versus DM + DBT at double
reading. Reader-adjusted performance characteristics of reading modes were
evaluated on the basis of pre-arbitration (initial interpretation) scores.
Statistical analysis was based on cluster bootstrap analysis using 10 000 random
resamples. Results Sensitivity was 54.1% (152 of 281) for DM and 70.5% (198 of
281) for DM + DBT. Reader-adjusted difference was 12.6% (95% confidence interval
[CI]: 5.2%, 19.7%; P = .001). Specificity was 94.2% (false-positive fraction
[FPF], 5.8%; 1388 of 24 020) for DM and 95.0% (FPF, 5.0%; 1209/24 020) for DM +
DBT, with a reader-adjusted difference in FPF of -1.2% (95% CI: -1.7%, -0.7%; P < .001). Sensitivity was 69.0% (194 of 281) for SM + DBT and 70.5% (198 of 281) for DM + DBT, with a reader-adjusted difference of 1.0% (95% CI: -6.2%, 8.5%; P = .77). Specificity was 95.4% (FPF, 4.6%; 1111 of 24 020) for SM + DBT and 95.0% (FPF, 5.0%;1209 of 24 020) for DM + DBT, with reader-adjusted 95% CIs for FPF of 4.7%, 5.4% and 5.0%, 5.7%, respectively, and a difference of -0.3% (95% CI: -0.8%, 0.2%; P = .23). Differences in sensitivity and specificity with the addition of CAD were small and not significant (P > .2). Conclusion Addition of
digital breast tomosynthesis to digital mammography resulted in significant gains
in sensitivity and specificity. Synthetic mammography in combination with digital
breast tomosynthesis had similar sensitivity and specificity to digital
mammography in combination with digital breast tomosynthesis. © RSNA, 2019 See
also the editorial by Lång in this issue.

DOI: 10.1148/radiol.2019182394
PMID: 30777808

J Plast Reconstr Aesthet Surg. 2019 Jan 14. pii: S1748-6815(19)30033-6. doi:
10.1016/j.bjps.2019.01.012. [Epub ahead of print]

First look: A mixed-methods study exploring women’s initial experiences of their
appearance after mastectomy and/or breast reconstruction✰.

Paraskeva N(1), Herring B(2), Tollow P(2), Harcourt D(2).

Author information:
(1)Centre for Appearance Research, Faculty of Health & Applied Sciences,
University of the West of England, Coldharbour Lane, Bristol BS16 1QY, United
Kingdom. Electronic address: Nicole.Paraskeva@uwe.ac.uk.
(2)Centre for Appearance Research, Faculty of Health & Applied Sciences,
University of the West of England, Coldharbour Lane, Bristol BS16 1QY, United
Kingdom.

OBJECTIVES: Increasing numbers of women are undergoing appearance-altering
surgery for the treatment and/or prevention of breast cancer. However, women’s
experiences of seeing the results of their breast surgery for the first time, and
the support available to them, are currently omitted from the research
literature. This study aimed to explore women’s initial experiences of seeing
their appearance after mastectomy and/or breast reconstruction.
DESIGN: An online mixed-methods survey explored participants’ feelings and
expectations before seeing their breast surgery for the first time, their
experiences of looking at the results of their surgery, and the support they
received.
METHODS: Women (n = 128) who had undergone mastectomy and/or breast
reconstruction following a diagnosis of invasive breast cancer, DCIS or increased
risk of breast cancer participated. Data were analysed using descriptive
statistics and qualitative content analysis.
RESULTS: Most respondents had worried about looking at their breast/breast area
for the first time, with 75% concerned about what they would see. Women found the
experience moderately distressing, and younger women were particularly concerned
about other people’s reactions to their altered appearance. Approximately half of
the women (51%) felt they received enough support, while 29% thought this aspect
of care could be improved. Areas for improvement were suggested, including
increased preparation, privacy and support.
CONCLUSION: Women’s experiences of looking at their breast/breast area and any
donor site after surgery vary considerably. The results indicate important
implications for provision of care and further research.

DOI: 10.1016/j.bjps.2019.01.012
PMID: 30777606

Acta Oncol. 2019 Feb 19:1-8. doi: 10.1080/0284186X.2018.1557341. [Epub ahead of
print]

Return to work after cancer. A multi-regional population-based study from
Germany.

Arndt V(1), Koch-Gallenkamp L(2), Bertram H(3), Eberle A(4), Holleczek B(5),
Pritzkuleit R(6), Waldeyer-Sauerland M(7), Waldmann A(7)(8), Zeissig SR(9), Doege
D(1), Thong MSY(1), Brenner H(2)(10)(11).

Author information:
(1)a Unit of Cancer Survivorship, Division of Clinical Epidemiology and Aging
Research , German Cancer Research Center (DKFZ) , Heidelberg , Germany.
(2)b Division of Clinical Epidemiology and Aging Research , German Cancer
Research Center (DKFZ) , Heidelberg , Germany.
(3)c Cancer Registry of North Rhine-Westphalia , Münster , Germany.
(4)d Bremen Cancer Registry, Leibniz Institute for Prevention Research and
Epidemiology – BIPS , Bremen , Germany.
(5)e Saarland Cancer Registry , Saarbrücken , Germany.
(6)f Cancer Registry of Schleswig-Holstein , Lübeck , Germany.
(7)g Ministry of Health and Consumer Protection , Hamburg Cancer Registry ,
Hamburg , Germany.
(8)h Institute of Social Medicine and Epidemiology, University Lübeck , Lübeck ,
Germany.
(9)i Cancer Registry of Rhineland-Palatinate , Mainz , Germany.
(10)j Division of Preventive Oncology , German Cancer Research Center (DKFZ) ,
Heidelberg , Germany.
(11)k German Cancer Consortium (DKTK) , German Cancer Research Center (DKFZ) ,
Heidelberg , Germany.

BACKGROUND: With improving prognosis, the ability to return to work after cancer
has become a realistic goal but only little is known regarding details such as
sustainability, financial consequences, and potential determinants of return to
work in long-term survivors in Germany.
METHODS: We studied return to work in a population-based sample of 1558 long-term
cancer survivors, diagnosed in 1994-2004 with breast, colorectal or prostate
cancer before age 60 (mean 50.1). Information regarding employment status and
financial difficulties was obtained via mailed questionnaires from patients who
were identified by six population-based cancer registries in Germany. Cumulative
incidence of return to work was determined by time-to-event analysis with
consideration of competing events. Chi2 tests and multiple logistic regression
modeling were employed to identify potential sociodemographic and clinical
determinants of return to work.
RESULTS: Within a mean period since diagnosis of 8.3 years, 63% of all
working-age cancer survivors initially returned to their old job and another 7%
took up a new job. Seventeen percent were granted a disability pension, 6% were
early retired (not cancer-related), 4% became unemployed, and 1% left the job
market for other reasons. Resumption of work occurred within the first 2 years
after diagnosis in 90% of all returnees. Cancer-related reduction of working
hours was reported by 17% among all returnees and 6% quit their job due to cancer
within 5 years past return to work. The probability of return to work was
strongly related with age at diagnosis, tumor stage, education, and occupational
class but did not differ with respect to the tumor site, gender nor marital
status.
CONCLUSIONS: Most long-term survivors after breast, colorectal, or prostate
cancer of working-age are able to return to work. However, financial problems
might arise due to a reduction in working hours. An additional provision of
targeted interventions for high-risk groups should be discussed.

DOI: 10.1080/0284186X.2018.1557341
PMID: 30777496

Surgery. 2019 Feb 15. pii: S0039-6060(19)30002-9. doi:
10.1016/j.surg.2019.01.001. [Epub ahead of print]

Surgical resection of breast cancers: Molecular analysis of cancer stem cells in
residual disease.

Pommier SJ(1), Morgan RE(2), Limbach KE(2), Jackson CM(3), Naik AM(3), Peckham
JL(3), Muller PJ(3), Condron ME(2), Jameson NE(3), Pommier RF(3).

Author information:
(1)Division of Surgical Oncology, Department of Surgery, Oregon Health & Science
University, Portland. Electronic address: pommiers@ohsu.edu.
(2)Division of General Surgery, Department of Surgery, Oregon Health & Science
University, Portland.
(3)Division of Surgical Oncology, Department of Surgery, Oregon Health & Science
University, Portland.

BACKGROUND: Approximately 70% of breast cancer patients have residual disease
after neoadjuvant chemotherapy. This study was designed to determine whether
breast cancer cells with stemlike properties are present in residual disease
after neoadjuvant chemotherapy and whether they exhibit oncogenic mutations. The
presence of breast cancer cells with stemlike properties with specific mutations
may help explain the poor prognosis associated with residual disease.
METHODS: A total of 68 breast cancer specimens were collected at the time of
mastectomy or lumpectomy. A total of 44 were chemotherapy naïve and 24 were
collected as residual disease after neoadjuvant chemotherapy. Tumor cells were
collected by fluorescence-activated cell sorting, with breast cancer cells with
stemlike properties specifically identified using breast stem cell associated
antibodies. Whole tumor specimens and fluorescence-activated cell sorting breast
cancer cells with stemlike properties were analyzed for genetic mutations,
including PIK3CA.
RESULTS: Breast cancer cells with stemlike properties, demonstrating
EpCAM-positive, CD44-positive, CD49f±, CD24± expression were present in
chemotherapy-naïve tumors and residual disease. In both chemotherapy-naïve and
residual disease specimens the highest frequency of PIK3CA mutations were
detected in CD49f-CD24+ BCSCs (39% and 33%, respectively). PIK3CA mutations were
detected in all stages of breast cancer (35%), in both chemotherapy naïve (39%)
and residual disease (29%) and in both estrogen receptor positive (41%) and
negative tumors (14%) (P = ns). Various PIK3CA mutations were identified in
chemotherapy-naïve specimens versus residual disease specimens in both
patient-paired and unpaired breast cancers.
CONCLUSION: Breast cancer cells with stemlike properties with mutations in PIK3CA
were present in chemotherapy-naïve breast cancers and residual disease after
neoadjuvant chemotherapy. These results demonstrate that neoadjuvant chemotherapy
does not completely eradicate PIK3CA-defective breast cancer cells with stemlike
properties. Although these findings may help explain the poor clinical outcomes
in patients with residual disease, they also identify breast cancer cells with
stemlike-property targets for therapies.

DOI: 10.1016/j.surg.2019.01.001
PMID: 30777364

Biochem Biophys Res Commun. 2019 Feb 15. pii: S0006-291X(19)30222-0. doi:
10.1016/j.bbrc.2019.02.035. [Epub ahead of print]

Prognostic significance of high metabolic activity in breast cancer: PET
signature in breast cancer.

Kang S(1), Kim EH(2), Hwang JE(3), Shin JH(4), Jeong YS(4), Yim SY(5), Joo EW(6),
Eun YG(7), Lee DJ(8), Sohn BH(4), Lee SH(4), Lim B(9), Lee JS(10).

Author information:
(1)Department of Systems Biology, The University of Texas MD Anderson Cancer
Center, Houston, TX, USA; Department of Surgery, Korea University College of
Medicine, Seoul, Republic of Korea.
(2)Department of Systems Biology, The University of Texas MD Anderson Cancer
Center, Houston, TX, USA; Department of Neurosurgery, Severance Hospital, Brain
Tumor Center, Yonsei University College of Medicine, Seoul, Republic of Korea.
(3)Department of Hematology-Oncolgy, Chonnam National University Medical School,
Gwangju, Republic of Korea.
(4)Department of Systems Biology, The University of Texas MD Anderson Cancer
Center, Houston, TX, USA.
(5)Department of Systems Biology, The University of Texas MD Anderson Cancer
Center, Houston, TX, USA; Division of Gastroenterology and Hepatology, Department
of Internal Medicine, Korea University College of Medicine, Seoul, Republic of
Korea.
(6)Department of Gynecology, School of Medicine, Kyung Hee University, Seoul,
Republic of Korea.
(7)Department of Otolaryngology-Head and Neck Surgery, School of Medicine, Kyung
Hee University, Seoul, Republic of Korea.
(8)Department of Otolaryngology-Head and Neck Surgery, School of Medicine, Hallym
University, Seoul, Republic of Korea.
(9)Department of Breast Medical Oncology, The University of Texas MD Anderson
Cancer Center, Houston, TX, USA.
(10)Department of Systems Biology, The University of Texas MD Anderson Cancer
Center, Houston, TX, USA. Electronic address: jlee@mdanderson.org.

High metabolic activity, reflected in increased glucose uptake, is one of the
hallmarks of many cancers including breast cancer. However, not all cancers
avidly take up glucose, suggesting heterogeneity in their metabolic demand. Thus,
we aim to generate a genomic signature of glucose hypermetabolism in breast
cancer and examine its clinical relevance. To identify genes significantly
associated with glucose uptake, gene expression data were analyzed together with
the standardized uptake values (SUVmax) of 18F-fluorodeoxy-glucose on positron
emission tomography (PET) for 11 breast cancers. The resulting PET signature was
evaluated for prognostic significance in four large independent patient cohorts
(n = 5417). Potential upstream regulators accountable for the high glucose uptake
were identified by gene network analysis. A PET signature of 242 genes was
significantly correlated with SUVmax in breast cancer. In all four cohorts, high
PET signature was significantly associated with poorer prognosis. The prognostic
value of this PET signature was further supported by Cox regression analyses
(hazard ratio 1.7, confidential interval 1.48-2.02; P < 0.001). The PET signature
was also strongly correlated with previously established prognostic genomic
signatures such as PAM50, Oncotype DX, and NKI. Gene network analyses suggested
that MYC and TBX2 were the most significant upstream transcription factors in the
breast cancers with high glucose uptake. A PET signature reflecting high glucose
uptake is a novel independent prognostic factor in breast cancer. MYC and TBX2
are potential regulators of glucose uptake.

DOI: 10.1016/j.bbrc.2019.02.035
PMID: 30777332

Am J Surg. 2019 Jan 31. pii: S0002-9610(18)31403-X. doi:
10.1016/j.amjsurg.2019.01.029. [Epub ahead of print]

Pathology results of architectural distortion on detected with digital breast
tomosynthesis without definite sonographic correlate.

Walcott-Sapp S(1), Garreau J(2), Johnson N(2), Thomas KA(3).

Author information:
(1)Department of Surgery, Oregon Health and Science University, 3181 S.W. Sam
Jackson Park Rd. Mail Code: L223, Portland, OR, 97239, USA. Electronic address:
sarah.walcott-sapp@cshs.org.
(2)Surgical Oncology, Legacy Medical Group, 1040 N.W. 22nd Ave., Suite 560,
Building 2, Legacy Good Samaritan Medical Center Campus, Portland, OR, 97227,
USA.
(3)Diagnostic Imaging Northwest PC, Legacy Good Samaritan Hospital, 1015 N.W.
22nd Ave, Portland, OR, 97210, USA.

BACKGROUND: Digital breast tomosynthesis (DBT) is a mammographic technique which
improves the detection of breast cancer. Architectural distortion of malignancy
may be occult on 2D mammography and ultrasound but detected by DBT.
METHODS: 110 patients who underwent 116 DBT-guided needle biopsies for
architectural distortion were identified between June 2014 and August 2017 and
underwent review of medical records.
RESULTS: 59 of 116 biopsies (51%) revealed lesions warranting further
consideration or excision. These included 21 specimens with invasive carcinoma, 2
ductal carcinoma in situ (DCIS), 5 atypical ductal hyperplasia, 4 atypical
lobular hyperplasia, and 2 other lesions. 46 lesions were excised. Surgical
pathology demonstrated 22 malignant lesions (20 invasive carcinomas and 2 DCIS).
11 patients continued surveillance and two patients were lost to follow up. 94
lesions (87%) were not visible on ultrasonography.
CONCLUSIONS: DBT-guided biopsy for architectural distortion detected a malignancy
in 19% of lesions, demonstrating the importance of pathologic diagnosis for
lesions without correlating ultrasound findings.

DOI: 10.1016/j.amjsurg.2019.01.029
PMID: 30777292

Am J Surg. 2019 Mar;217(3):519. doi: 10.1016/j.amjsurg.2018.12.053.

Effect of wound complications following mastectomy with reconstruction on breast
cancer recurrence.

[No authors listed]

DOI: 10.1016/j.amjsurg.2018.12.053
PMID: 30777274

Am J Surg. 2019 Mar;217(3):478. doi: 10.1016/j.amjsurg.2018.12.042.

The impact of obesity on treatment choices and outcomes in operable breast
cancer.

[No authors listed]

DOI: 10.1016/j.amjsurg.2018.12.042
PMID: 30777268

Eur J Radiol. 2019 Mar;112:14-21. doi: 10.1016/j.ejrad.2019.01.006. Epub 2019 Jan
7

Meta-analysis of ultrasound for cervical lymph nodes in papillary thyroid cancer:
Diagnosis of central and lateral compartment nodal metastases.

Zhao H(1), Li H(2).

Author information:
(1)Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University,
Wuhan, 430060, China. Electronic address: zhaochewh@whu.edu.cn.
(2)Department of Pancreatic Surgery, Union Hospital, Tongji Medical College,
Huazhong University of Science and Technology, Wuhan, 430022, China.

PURPOSE: To evaluate the performance of preoperative ultrasound in the diagnosis
of cervical lymph nodes metastases (CLNM) of papillary thyroid cancer (PTC) and
its value in assisting cervical lymph node dissection (CLND).
METHODS: PubMed, EMBASE and Cochrane Library databases were searched to identify
relevant studies up to Sep. 2017. Overall sensitivity, specificity, and
diagnostic odds ratio (DOR) were used to assess the diagnostic efficacy of
ultrasound in detecting central and lateral CLNM of PTC.
RESULTS: Nineteen studies comprising 4014 patients were included in the
meta-analysis. The pooled sensitivity, specificity, DOR and area under curve
(AUC) of ultrasound in detecting central CLNM were 0.33 (95% confidence interval
(95% CI): 0.31-0.35), 0.93 (95% CI: 0.92-0.94), 5.63 (95% CI: 3.50-9.04), and
0.69, respectively; and lateral CLNM were 0.70 (95% CI: 0.68-0.72), 0.84 (95% CI:
0.82-0.85), 18.7 (95% CI: 10.3-33.9) and 0.88, respectively. We found that the
rate of central CLNM of PTC was 48.0%, and 36.2% of the dissected lymph nodes
were metastatic, meanwhile, the rate of lateral CLNM of PTC was 59.2%, and 46.6%
of the dissected lymph nodes were metastatic in the meta-analysis.
CONCLUSIONS: Preoperative ultrasound demonstrates poor sensitivity in the
diagnosis of central CLNM, and good diagnostic efficacy for lateral CLNM of PTC.
Prophylactic central CLND is recommended to PTC patients due to the high
incidence of central CLNM and low diagnostic efficacy of ultrasound.

DOI: 10.1016/j.ejrad.2019.01.006
PMID: 30777203

J Hematol Oncol. 2019 Feb 18;12(1):18. doi: 10.1186/s13045-019-0704-y.

Mesothelin is a target of chimeric antigen receptor T cells for treating gastric
cancer.

Lv J(1)(2)(3), Zhao R(1)(2)(3), Wu D(1)(2)(4), Zheng D(1)(2)(3), Wu Z(1)(2)(3),
Shi J(1)(2)(3), Wei X(1)(2), Wu Q(1)(2), Long Y(1)(2), Lin S(1)(2), Wang S(1)(2),
Wang Z(5), Li Y(6), Chen Y(7), He Q(8), Chen S(9), Yao H(10), Liu Z(11), Tang
Z(12), Yao Y(1)(2), Pei D(1)(2), Liu P(13), Zhang X(14), Zhang Z(15), Cui S(16),
Chen R(17), Li P(18)(19)(20)(21).

Author information:
(1)Key Laboratory of Regenerative Biology, South China Institute for Stem Cell
Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and
Health, Chinese Academy of Sciences, Guangzhou, China.
(2)Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine,
South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou
Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou,
China.
(3)University of Chinese Academy of Sciences, Shijingshan District, Beijing,
China.
(4)School of Life Sciences, University of Science and Technology of China, Hefei,
China.
(5)The Center of Research Animal, Guangzhou Institutes of Biomedicine and Health,
Chinese Academy of Sciences, Guangzhou, 510530, China.
(6)Department of Pediatric Hematology/Oncology, Sun Yat-Sen Memorial Hospital,
Sun Yat-Sen University, Guangzhou, China.
(7)Orthopaedics Department, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen
University, Guangzhou, 510120, China.
(8)SICU Department, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University,
Guangzhou, 510120, China.
(9)Huangpu Hospital of Guangdong Second Traditional Chinese Medicine Hospital,
Guangzhou, 510120, China.
(10)Department of Outpatient, The 91th Military Hospital, Jiaozuo, China.
(11)Division of Reproductive Endocrinology, The 91th Military Hospital, Jiaozuo,
China.
(12)Guangdong Zhaotai InVivo Biomedicine Co. Ltd., Guangzhou, China.
(13)School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, Stem Cell and
Regenerative Medicine Centre, University of Hong Kong, Hong Kong, China.
(14)Guangdong Lung Cancer Institute, Medical Research Center, Guangdong General
Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
(15)Department of Radiology, The Second Affiliated Hospital of Guangzhou Medical
University, Guangzhou, China.
(16)Affiliated Cancer Hospital & Institute of Guangzhou Medical University,
Guangzhou, China.
(17)Department of Infectious Disease, Guangdong General Hospital, Guangdong
Academy of Medical Sciences, Guangzhou, China.
(18)Key Laboratory of Regenerative Biology, South China Institute for Stem Cell
Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and
Health, Chinese Academy of Sciences, Guangzhou, China. li_peng@gibh.ac.cn.
(19)Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine,
South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou
Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou,
China. li_peng@gibh.ac.cn.
(20)Division of Reproductive Endocrinology, The 91th Military Hospital, Jiaozuo,
China. li_peng@gibh.ac.cn.
(21)Hefei Institute of Stem Cell and Regenerative Medicine, Guangzhou Institutes
of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China.
li_peng@gibh.ac.cn.

BACKGROUND: Gastric cancer (GC) is a common cancer in Asia and currently lacks a
targeted therapy approach. Mesothelin (MSLN) has been reported to be expressed in
GC tissue and could be targeted by chimeric antigen receptor (CAR) T cells.
Mesothelin targeting CAR-T has been reported in mesothelioma, lung cancer, breast
cancer, and pancreas cancer. However, the feasibility of using anti-MSLN CAR T
cells to treat GC remains to be studied.
METHODS: We verified MSLN expression in primary human GC tissues and GC cell
lines and then redirected T cells with a CAR containing the MSLN scFv
(single-chain variable fragment), CD3ζ, CD28, and DAP10 intracellular signaling
domain (M28z10) to target MSLN. We evaluated the function of these CAR T cells in
vitro in terms of cytotoxicity, cytokine secretion, and surface phenotype changes
when they encountered MSLN+ GC cells. We also established four different
xenograft GC mouse models to assess in vivo antitumor activity.
RESULTS: M28z10 T cells exhibited strong cytotoxicity and cytokine-secreting
ability against GC cells in vitro. In addition, cell surface phenotyping
suggested significant activation of M28z10 T cells upon target cell stimulation.
M28z10 T cells induced GC regression in different xenograft mouse models and
prolonged the survival of these mice compared with GFP-transduced T cells in the
intraperitoneal and pulmonary metastatic GC models. Importantly, peritumoral
delivery strategy can lead to improved CAR-T cells infiltration into tumor tissue
and significantly suppress the growth of GC in a subcutaneous GC model.
CONCLUSION: These results demonstrate that M28z10 T cells possess strong
antitumor activity and represent a promising therapeutic approach to GC.

DOI: 10.1186/s13045-019-0704-y
PMID: 30777106

Breast Cancer Res. 2019 Feb 18;21(1):28. doi: 10.1186/s13058-019-1108-1.

Infiltrating stromal immune cells in inflammatory breast cancer are associated
with an improved outcome and increased PD-L1 expression.

Van Berckelaer C(1)(2), Rypens C(3), van Dam P(4), Pouillon L(5), Parizel M(6),
Schats KA(7), Kockx M(7), Tjalma WAA(4), Vermeulen P(3)(5), van Laere S(3),
Bertucci F(8), Colpaert C(6)(9), Dirix L(3)(5).

Author information:
(1)Translational Cancer Research Unit, GZA Hospitals & CORE, MIPRO, University of
Antwerp, Antwerp, Belgium. christophe.vanberckelaer@uantwerpen.be.
(2)Multidisciplinary Breast Clinic, Unit Gynaecologic Oncology, Antwerp
University Hospital (UZA), Edegem, Belgium.
christophe.vanberckelaer@uantwerpen.be.
(3)Translational Cancer Research Unit, GZA Hospitals & CORE, MIPRO, University of
Antwerp, Antwerp, Belgium.
(4)Multidisciplinary Breast Clinic, Unit Gynaecologic Oncology, Antwerp
University Hospital (UZA), Edegem, Belgium.
(5)Department of Medical Oncology, GZA Hospitals Sint-Augustinus, Antwerp,
Belgium.
(6)Department of Pathology, Antwerp University Hospital (UZA), Edegem, Belgium.
(7)HistoGeneX, Antwerp, Belgium.
(8)Predictive Oncology team, Centre de Recherche en Cancérologie de Marseille
(CRCM), Inserm, CNRS, Aix-Marseille Université, Institut Paoli-Calmettes,
Marseille, France.
(9)Department of Pathology, GZA Hospitals Sint-Augustinus, Antwerp, Belgium.

BACKGROUND: Inflammatory breast cancer (IBC) is a rare and rapidly progressive
form of invasive breast cancer. The aim of this study was to explore the clinical
evolution, stromal tumour-infiltrating lymphocytes (sTIL) infiltration and
programmed death-ligand 1 (PD-L1) expression in a large IBC cohort.
PATIENTS AND METHODS: Data were collected prospectively from patients with IBC as
part of an international collaborative effort since 1996. In total, 143 patients
with IBC starting treatment between June 1996 and December 2016 were included.
Clinicopathological variables were collected, and sTIL were scored by two
pathologists on standard H&E stained sections. PD-L1 expression was assessed
using a validated PD-L1 (SP142) assay. A validation cohort of 64 patients with
IBC was used to test our findings.
RESULTS: Survival outcomes of IBC remained poor with a 5-year overall survival
(OS) of 45.6%. OS was significantly better in patients with primary
non-metastatic disease who received taxane-containing (neo)adjuvant therapy
(P = 0.01), had a hormone receptor-positive tumour (P = 0.001) and had lower cN
stage at diagnosis (P = 0.001). PD-L1 positivity on immune cells (42.9%) was
higher in IBC than in non-IBC in both our patient samples and the validation
cohort. Furthermore, PD-L1 expression predicted pCR (P = 0.002) and correlated
with sTIL infiltration (P < 0.001). sTIL infiltration of more than 10% of the
stroma was a significant predictor of improved OS (HR 0.47, 95% CI 0.27-0.81,
P = 0.006) in a multivariate model.
CONCLUSIONS: IBC is characterised by poor survival and high PD-L1
immunoreactivity on sTIL. This suggests a role for PD1/PD-L1 inhibitors in the
treatment of IBC. Furthermore, we showed that PD-L1 expression predicts response
to neo-adjuvant therapy and that sTIL have prognostic significance in IBC.

DOI: 10.1186/s13058-019-1108-1
PMID: 30777104

J Exp Clin Cancer Res. 2019 Feb 18;38(1):85. doi: 10.1186/s13046-019-1075-5.

Blockade of PDGFRβ circumvents resistance to MEK-JAK inhibition via intratumoral
CD8+ T-cells infiltration in triple-negative breast cancer.

Kalimutho M(1), Sinha D(2), Mittal D(3), Srihari S(4), Nanayakkara D(2), Shafique
S(2), Raninga P(2), Nag P(2)(5), Parsons K(2), Khanna KK(6).

Author information:
(1)Signal Transduction laboratory, QIMR Berghofer Medical Research Institute, 300
Herston Road, Herston, Brisbane, QLD, 4006, Australia.
Murugan.Kalimutho@qimrberghofer.edu.au.
(2)Signal Transduction laboratory, QIMR Berghofer Medical Research Institute, 300
Herston Road, Herston, Brisbane, QLD, 4006, Australia.
(3)Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research
Institute, 300 Herston Road, Herston, Brisbane, QLD, 4006, Australia.
(4)Institute for Molecular Bioscience, The University of Queensland, St Lucia,
QLD, 4072, Australia.
(5)School of Environment and Science, Griffith University, Nathan, QLD, 4111,
Australia.
(6)Signal Transduction laboratory, QIMR Berghofer Medical Research Institute, 300
Herston Road, Herston, Brisbane, QLD, 4006, Australia.
Kumkum.Khanna@qimrberghofer.edu.au.

BACKGROUND: Despite the increasing progress in targeted and immune based-directed
therapies for other solid organ malignancies, currently there is no targeted
therapy available for TNBCs. A number of mechanisms have been reported both in
pre-clinical and clinical settings that involve inherent, acquired and adaptive
resistance to small molecule inhibitors. Here, we demonstrated a novel resistance
mechanism in TNBC cells mediated by PDGFRβ in response to JAK2 inhibition.
METHODS: Multiple in vitro (subG1, western blotting, immunofluorescence, RT-PCR,
Immunoprecipitation), in vivo and publically available datasets were used.
RESULTS: We showed that TNBC cells exposed to MEK1/2-JAK2 inhibitors exhibit
resistant colonies in anchorage-independent growth assays. Moreover, cells
treated with various small molecule inhibitors including JAK2 promote PDGFRβ
upregulation. Using publically available databases, we showed that patients
expressing high PDGFRβ or its ligand PDGFB exhibit poor relapse-free survival
upon chemotherapeutic treatment. Mechanistically we found that JAK2 expression
controls steady state levels of PDGFRβ. Thus, co-blockade of PDGFRβ with JAK2 and
MEK1/2 inhibitors completely eradicated resistant colonies in vitro. We found
that triple-combined treatment had a significant impact on CD44+/CD24-
stem-cell-like cells. Likewise, we found a significant tumor growth inhibition in
vivo through intratumoral CD8+ T cells infiltration in a manner that is reversed
by anti-CD8 antibody treatment.
CONCLUSION: These findings reveal a novel regulatory role of JAK2-mediated PDGFRβ
proteolysis and provide an example of a PDGFRβ-mediated resistance mechanism upon
specific target inhibition in TNBC.

DOI: 10.1186/s13046-019-1075-5
PMID: 30777101

Breast Cancer Res. 2019 Feb 18;21(1):27. doi: 10.1186/s13058-019-1116-1.

MEDI3039, a novel highly potent tumor necrosis factor (TNF)-related
apoptosis-inducing ligand (TRAIL) receptor 2 agonist, causes regression of
orthotopic tumors and inhibits outgrowth of metastatic triple-negative breast
cancer.

Greer YE(1), Gilbert SF(1), Gril B(1), Narwal R(2), Peacock Brooks DL(1), Tice
DA(2), Steeg PS(1), Lipkowitz S(3).

Author information:
(1)Women’s Malignancies Branch, Center for Cancer Research, National Cancer
Institute, Building 10, Room 4B54, Bethesda, MD, 20892-1361, USA.
(2)MedImmune, LLC, Gaithersburg, MD, USA.
(3)Women’s Malignancies Branch, Center for Cancer Research, National Cancer
Institute, Building 10, Room 4B54, Bethesda, MD, 20892-1361, USA.
lipkowis@mail.nih.gov.

BACKGROUND: TNF-related apoptosis-inducing ligand (TRAIL) receptor agonists are
attractive anti-tumor agents because of their capability to induce apoptosis in
cancer cells by activating death receptors (DR) 4 and 5 with little toxicity
against normal cells. Despite an attractive mechanism of action, previous
clinical efforts to use TRAIL receptor agonists have been unsuccessful. In this
study, we examined MEDI3039, a highly potent multivalent DR5 agonist, in breast
cancer cell lines and in vivo models.
METHODS: As in vitro model systems, we used 19 breast cancer cell lines that are
categorized into four subtypes: ER+, HER2 amplified, basal A (triple-negative
breast cancer) TNBC, and basal B TNBC. Cell viability was analyzed by MTS and
RealTime live/dead assays. As in vivo model systems, MDA-MB231T orthotopic
primary tumor growth in the mammary fat pad (MFP) and two experimental lung
metastasis models were used. The effect of MEDI3039 on MFP tumors was assessed
with immunohistochemical analysis. Lung metastases were analyzed with Bouin’s and
H&E staining.
RESULTS: MEDI3039 killed multiple breast cancer cell lines, but the sensitivity
varied among different subtypes. Sensitivity was basal B TNBC >> basal A TNBC >
HER2 amplified > ER+ (average IC50 = 1.4, 203, 314, 403 pM, respectively). While
the pattern of relative sensitivity was similar to GST-TRAIL in most cell lines,
MEDI3039 was at least two orders of magnitude more potent compared with
GST-TRAIL. In the MFP model, weekly treatment with 0.1 or 0.3 mg/kg MEDI3039 for
5 weeks inhibited tumor growth by 99.05% or 100% (median), respectively, compared
with the control group, and extended animal survival (p = 0.08 or p = 0.0032 at
0.1 or 0.3 mg/kg, respectively). MEDI3039-induced caspase activation was
confirmed in tumors grown in MFP (p < 0.05). In an experimental pulmonary metastasis model, MEDI3039 significantly suppressed outgrowth of surface (p < 0.0001) and microscopic metastases (p < 0.05). In an established lung metastasis model, MEDI3039 significantly inhibited growth of metastases (p < 0.01 in surface [> 4 mm], p < 0.01 in tumor percentage) and extended animal survival
(p < 0.0001).
CONCLUSION: MEDI3039 is a potent DR5 agonist in breast cancer cells in vitro and
in vivo and has potential as a cancer drug in breast cancer patients, especially
those with basal B TNBC.

DOI: 10.1186/s13058-019-1116-1
PMID: 30777098

Int J Equity Health. 2019 Feb 18;18(1):35. doi: 10.1186/s12939-019-0936-z.

Factors influencing oncologists’ prescribing hormonal therapy in women with
breast cancer: a qualitative study in Córdoba, Argentina.

Eraso Y(1).

Author information:
(1)School of Social Professions, London Metropolitan University, 166-220 Holloway
Road, London, N7 8DB, UK. y.eraso@londonmet.ac.uk.

BACKGROUND: Hormonal therapy is an integral component for breast cancer treatment
in women with oestrogen receptor positive tumours in early-stage and advanced
cases of the disease. Little is known about what factors influence oncologists’
prescribing practices, especially non-biological factors, although this
information may have important implications for understanding inequalities in
health care quality and outcomes. This paper presents findings from research on
factors influencing oncologists’ prescribing hormonal therapy for women with
early and advanced cases of breast cancer in the city of Córdoba, Argentina.
METHODS: A qualitative study using in-depth, semi-structured interviews with 16
oncologists was conducted. A stratified purposive sampling was used to recruit
female and male participants and working at 3 health subsystems (private, social
security, public). Data was analysed using the Framework approach.
RESULTS: According to the respondents, factors influencing prescribing practices
of hormonal therapy are varied. Women’s socio-economic status (poverty and
wealth) and their level of health literacy can affect oncologists’ prescribing
practices. Overall, in comparison to male, female oncologists reported more
awareness of patients’ needs, more involvement in communicating drug
side-effects, and in offering treatment options in private health settings. The 3
health subsystems provided a differential access to drugs and lines of hormonal
treatment, which ranged from a limited availability in the public sector, to
administrative restrictions imposed by the social security system, and to a
lesser extent, the private sector. This happened in the backdrop of national
legislation covering oncological treatments and drugs free of charge.
CONCLUSIONS: Addressing prescribing practices for hormonal therapy as a distinct
type of breast cancer treatment (chronic care) is fundamental in the
understanding of breast cancer care and can shed light on inequalities in
treatments. Identifying the underlying care gaps in the prescription of hormonal
therapy can help in the design of tailored interventions.

DOI: 10.1186/s12939-019-0936-z
PMID: 30777072

BMC Public Health. 2019 Feb 18;19(1):204. doi: 10.1186/s12889-019-6532-8.

Health system organisation and patient pathways: breast care patients’
trajectories and medical doctors’ practice in Mali.

Grosse Frie K(1), Kamaté B(2), Traoré CB(2), Coulibaly B(2), Mallé B(2),
Kantelhardt EJ(3)(4).

Author information:
(1)Institute for Medical Epidemiology, Biostatistics and Informatics,
Martin-Luther-University Halle-Wittenberg, Magdeburgerstraße 8, 06112, Halle
(Saale), Germany. grossefrie@web.de.
(2)Institute of Pathology, University Hospital Point G, Bamako, Mali.
(3)Institute for Medical Epidemiology, Biostatistics and Informatics,
Martin-Luther-University Halle-Wittenberg, Magdeburgerstraße 8, 06112, Halle
(Saale), Germany.
(4)Department of Gynecology, University Hospital Halle (Saale), Halle, Germany.

BACKGROUND: Information on pathways of women seeking diagnostic services due to
breast- related symptoms can help highlight challenges related to the healthcare
system in improving early diagnosis of breast cancer.
METHODS: We retrospectively analysed the entire patient pathway, from first
symptom recognition via initial healthcare visit up to final diagnosis at the
pathology service in Mali. Data from questionnaire-based structured patient
interviews (n = 124) were used to calculate time to first healthcare visit
(median 91 days) and consecutive time to diagnosis (median 21 days) and to
extract information on type of initially visited healthcare facility (community
healthcare centre, referral hospital, tertiary hospital, private clinic). Median
time to first healthcare visit and time to diagnosis and type of
initially-visited healthcare facility were cross-tabulated with patient
characteristics. An additional survey among (n = 30) medical doctors in the
community healthcare centres and referral hospitals in Bamako was conducted to
understand current knowledge and referral practice with respect to female
patients with breast-related symptoms.
RESULTS: Patients who initially visited private clinics had the shortest time to
first healthcare visit (median 44 days), but the longest time to diagnosis
(median 170 days). Patients visiting community healthcare centres and referral
hospitals took longest for a first healthcare visit (median 153 and 206 days,
respectively), but the time to diagnosis was shorter (median 95 and 7 days,
respectively). The majority of patients (45%) initially visited a tertiary
hospital; these patients had shortest total time to diagnosis (median 56 days
health seeking and 8 days diagnostic time), but did not follow the recommended
pathway for patients in the pyramidal healthcare system in Mali. The doctors’
survey showed lower breast cancer knowledge in the community healthcare centres
than in the referral hospitals. However, most doctors felt able to recognise
suspected cases of cancer and referred patients directly to a hospital.
CONCLUSIONS: The role of different healthcare facilities in ensuring triage of
patients with breast-related symptoms needs to be defined before any early
detection initiatives are implemented. Especially at the entry level of the
healthcare system, the access and quality of health services need to be
strengthened.

DOI: 10.1186/s12889-019-6532-8
PMID: 30777038

Post Reprod Health. 2019 Feb 18:2053369118824920. doi: 10.1177/2053369118824920.
[Epub ahead of print]

The British Menopause Society consensus statement on the management of estrogen
deficiency symptoms, arthralgia and menopause diagnosis in women treated for
early breast cancer.

Marsden J(1), Marsh M(1), Rigg A(2); British Menopause Society.

Author information:
(1)1 King’s College Hospital, London, UK.
(2)2 Guy’s and St Thomas’ Hospital, London, UK.

This guidance document by the British Menopause Society provides an overview of
the management of women experiencing estrogen deficiency symptoms and arthralgia
following a breast cancer diagnosis. It is now recommended that breast cancer
patients are referred to health care professionals with an expertise in menopause
for the management of such symptoms, which in turn often involves liaison with
patients’ breast cancer teams. However, as many women initially present to
primary health care professionals for advice, this statement is aimed to support
the latter in such consultations by providing information about symptom
aetiology, current management strategies and controversies and identifying useful
practice points.

DOI: 10.1177/2053369118824920
PMID: 30776968

Cancer Res Treat. 2019 Feb 18. doi: 10.4143/crt.2018.423. [Epub ahead of print]

Korean First Prospective Phase II Study, Feasibility of Prone Position in
Postoperative Whole Breast Radiotherapy: A Dosimetric Comparison.

Chung Y(1), Yu JI(2), Park W(2), Choi DH(2).

Author information:
(1)Department of Nuclear Engineering, Hanyang University, Seoul, Korea.
(2)Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan
University School of Medicine, Seoul, Korea.

Purpose: This first Korean prospective study is to evaluate the feasibility of
prone breast radiotherapy after breast conserving surgery for left breast cancer
patients who have relatively small breast size and we present dosimetric
comparison between prone and supine positions.
Materials and Methods: Fifty patients underwent two computed tomography (CT)
simulations in supine and prone positions. Whole breast, ipsilateral lung, heart,
and left-anterior-descending coronary artery were contoured on each simulation CT
images. Tangential-fields treatment plan in each position was designed with total
50 Gy in 2-Gy fractions, and then one of the positions was designated for the
treatment by comparing target coverage and dose to normal organs. Also,
interfractional and intrafractional motion was evaluated using portal images.
Results: In total 50 patients, 32 cases were decided as prone-position-beneficial
group and 18 cases as supine-position-beneficial group based on dosimetric
advantage. Target dose homogeneity was comparable, but target conformity in prone
position was closer to optimal than in supine position. For both group, prone
position significantly increased lung volume. However, heart volume was decreased
by prone position for prone-position-beneficial group but was comparable between
two positions for supine-position-beneficial group. Lung and heart doses were
significantly decreased by prone position for prone-position-beneficial group.
However, prone position for supine-position-beneficial group increased heart dose
while decreasing lung dose. Prone position showed larger interfractional motion
but smaller intrafractional motion than supine position.
Conclusion: Prone breast radiotherapy could be beneficial to a subset of small
breast patients since it substantially spared normal organs while achieving
adequate target coverage.

DOI: 10.4143/crt.2018.423
PMID: 30776884

J Clin Anesth. 2019 Feb 15;56:131. doi: 10.1016/j.jclinane.2019.02.012. [Epub
ahead of print]

Bilateral erector spinae nerve block using one injection for bilateral breast
cancer surgery.

Ueshima H(1).

Author information:
(1)Department of Anesthesiology, Showa University Hospital, Hatanodai
Shinagawa-ku, Tokyo, Japan. Electronic address: ueshimhi@med.showa-u.ac.jp.

DOI: 10.1016/j.jclinane.2019.02.012
PMID: 30776776

Breast. 2019 Jan 31;44:135-143. doi: 10.1016/j.breast.2019.01.006. [Epub ahead of
print]

Non-pharmacological therapies for depressive symptoms in breast cancer patients:
Systematic review and meta-analysis of randomized clinical trials.

Coutiño-Escamilla L(1), Piña-Pozas M(1), Tobías Garces A(1), Gamboa-Loira B(1),
López-Carrillo L(2).

Author information:
(1)DPH, Instituto Nacional de Salud Pública, Av. Universidad 655, Sta. Ma.
Ahuacatitlán, C.P. 62100, Cuernavaca, Morelos, Mexico.
(2)DPH, Instituto Nacional de Salud Pública, Av. Universidad 655, Sta. Ma.
Ahuacatitlán, C.P. 62100, Cuernavaca, Morelos, Mexico. Electronic address:
lizbeth@insp.mx.

OBJECTIVE: Depressive symptoms are common comorbidities among breast cancer (BC)
patients. Non-pharmacological therapies (NPTs) such as exercise and psychotherapy
may reduce depressive symptoms; however, the evidence is inconclusive. The
objective of this study is to evaluate if NPTs reduce depressive symptoms among
BC patients.
METHODS: A systematic review and meta-analysis of randomized clinical trials
(RCTs) of NPTs for BC patients were performed. A literature search was conducted
from eight databases in English, Portuguese and Spanish from 2006 to 2017.
Inclusion criteria were: RCTs that evaluated depressive symptoms as a primary or
secondary outcome that did not include pharmacological interventions and did
include a non-intervened control group, with at least 30 participants in
non-terminal BC stage with no current psychiatric illness. A meta-analysis for
each NPT was performed with DerSimonian and Laird’s method for the random effects
model. Sensitivity analyses were conducted. Heterogeneity and publication bias
were assessed.
RESULTS: A total of 41 eligible RCTs were identified. Overall, NPTs significantly
reduced depressive symptoms (Summary standardized mean difference (SMD) = -0.516;
95%CI: -0.814, -0.218; I2 = 96.2). Of the types of NPTs, psychotherapy
significantly reduced depressive symptoms (Summary SMD = -0.819; 95% CI:
-1.608, -0.030; I2 = 91.53). A significant difference emerged for Mindfulness
(Summary SMD = -0.241; 95% CI: -0.412, -0.070; I2 = 28.6%) and yoga (Summary
SMD = -0.305; 95% CI: -0.602, -0.007; I2 = 41.0%) when the heterogeneity was
reduced. No evidence of publication bias was observed.
CONCLUSIONS: Psychotherapy and mind-body therapies may reduce depressive symptoms
in women with BC. Laughter and couples therapy warrant attention in future
studies.

DOI: 10.1016/j.breast.2019.01.006
PMID: 30776733

Phytomedicine. 2018 Nov 15;57:183-190. doi: 10.1016/j.phymed.2018.11.017. [Epub
ahead of print]

Development of curcumin-loaded gemini surfactant nanoparticles: Synthesis,
characterization and evaluation of anticancer activity against human breast
cancer cell lines.

Karimpour M(1), Feizi MAH(1), Mahdavi M(1), Krammer B(2), Verwanger T(2), Najafi
F(3), Babaei E(4).

Author information:
(1)Department of Biological Sciences, School of Natural Sciences, University of
Tabriz, 51555 Tabriz, Iran.
(2)Department of Biosciences, University of Salzburg, Hellbrunnerstrasse 34, 5020
Salzburg, Austria.
(3)Department of Resin and Additives, Institute for Color Science and Technology,
Tehran, Iran.
(4)Department of Biological Sciences, School of Natural Sciences, University of
Tabriz, 51555 Tabriz, Iran; Institute of Environment, University of Tabriz,
Tabriz, Iran. Electronic address: babaei@tabrizu.ac.ir.

BACKGROUND: Curcumin, the polyphenolic constituent of turmeric, has been
recognized as an effective anticancer agent in the treatment of breast cancer.
However, the poor bioavailability of curcumin triggers finding of new approaches
for elevating its therapeutic efficiency.
PURPOSE: We aimed to use gemini surfactant nanocarriers for curcumin in order to
overcome its limitations.
STUDY DESIGN: We investigated the in vitro characterization of gemini
surfactant-curcumin (Gemini-Cur) and examined its antiproliferative & apoptotic
activities on breast cancer cell lines.
METHODS: Gemini-Cur polymersomes were synthesized through nanoprecipitation
method and characterized by dynamic light scattering (DLS), transmission and
scanning electron microscopies, HPLC and X-ray diffraction (XRD). The anticancer
effect of Gemini-Cur nanoparticles was studied on three different breast cancer
cell lines including MCF-7, SkBr-3 and MDA-MB-231 through uptake kinetics,
viability & cytotoxicity recordings and apoptotic assays. Furthermore, qRT-PCR
was performed to evaluate the expression of apoptotic genes including p16INK4a,
p14ARF, Bax and Bcl-2.
RESULTS: According to physicochemical analysis, the average particle size, zeta
potential value and drug entrapment efficiency for Gemini-Cur compound were
recorded as 161 ± 6.2 nm, +5.32 mV and 89.13% ± 0.93, respectively. XRD analysis
also confirmed the incorporation of curcumin in gemini surfactant micelles.
Regarding the enhanced cellular uptake of sphere shaped Gemini-Cur, our data
showed that this nano compound suppresses cancer cell proliferation via induction
of apoptosis. Moreover, qRT-PCR analysis revealed that Gemini-Cur could
effectively upregulate the expression of p16INK4a, p14ARF and Bax, while
significantly decreasing the Bcl-2 expression in these breast cancer cells.
CONCLUSION: Our data demonstrates the great potential of gemini surfactants for
efficient delivery of curcumin and subsequently, the improvement of its
anticancer effect. Therefore, it is sagacious to support the idea that Gemini-Cur
nano compound might have the potential to be considered as an anticancer agent.

DOI: 10.1016/j.phymed.2018.11.017
PMID: 30776589

Bioorg Chem. 2019 Feb 8;85:475-486. doi: 10.1016/j.bioorg.2019.01.070. [Epub
ahead of print]

Click chemistry based multicomponent approach in the synthesis of
spirochromenocarbazole tethered 1,2,3-triazoles as potential anticancer agents.

Chavan PV(1), Desai UV(2), Wadgaonkar PP(3), Tapase SR(4), Kodam KM(4), Choudhari
A(5), Sarkar D(6).

Author information:
(1)Department of Chemistry, Shivaji University, Kolhapur 416 004, India.
(2)Department of Chemistry, Shivaji University, Kolhapur 416 004, India.
Electronic address: uvdchem2011@gmail.com.
(3)Polymer Science and Engineering Division, CSIR, National Chemical Laboratory,
Pune 411 008, India.
(4)Biochemistry Division, Department of Chemistry, Savitribai Phule Pune
University, Pune 411007, India.
(5)Combi – Chem. Bio-Resource Centre, CSIR National Chemical Laboratory, Pune 411
008, India.
(6)Combi – Chem. Bio-Resource Centre, CSIR National Chemical Laboratory, Pune 411
008, India. Electronic address: d.sarkar@ncl.res.in.

A series of spirochromenocarbazole tethered 1,2,3-triazoles were synthesized via
click chemistry based one-pot, five component reaction between N-propargyl
isatins, malononitrile, 4-hydroxycarbazole, aralkyl halides and sodium azide
using cellulose supported CuI nanoparticles (Cell-CuI NPs) as the heterogeneous
catalyst. Antiproliferative activity of all the synthesized compounds was
investigated against panel of cancer cell lines such as MCF-7, MDA-MB-231, HeLa,
PANC-1, A-549, and THP-1. Many of the synthesized compounds exhibited good
anti-proliferative activity against breast (MCF-7 and MDA-MB-231) and cervical
(HeLa) cancer cells with IC50 values less than 10 μM. In case of MCF-7 cells,
among the nine compounds that showed good anti-proliferative activity, compounds
6f and 6j were found to be highly potent (IC50 = 2.13 μM and 4.80 μM,
respectively). In case of MDA-MB-231, three compounds (6k, 6j and 6s) showed
antiproliferative activity amongst which 6k was the most potent one
(IC50 = 3.78 μM). On the other hand, in cervical cancer HeLa cells, compounds 6b,
6g, 6s and 6u showed excellent antiproliferative activity (IC50 = 4.05, 3.54,
3.83, 3.35 μM, respectively). All the compounds were found to be nontoxic to the
human umbilical vein endothelial cells (HUVECs). AO and EtBr staining and
fluorescence microscopy studies of the active compounds (IC50 < 5 μM) suggested
that these compounds induce cell death by apoptosis.

DOI: 10.1016/j.bioorg.2019.01.070
PMID: 30776558

Acta Biomater. 2019 Feb 15. pii: S1742-7061(19)30118-7. doi:
10.1016/j.actbio.2019.02.014. [Epub ahead of print]

Laser-Based 3D Bioprinting for Spatial and Size Control of Tumor Spheroids and
Embryoid Bodies.

Kingsley DM(1), Roberge CL(2), Rudkouskaya A(3), Faulkner DE(4), Barroso M(5),
Intes X(6), Corr DT(7).

Author information:
(1)Department of Biomedical Engineering, Rensselaer Polytechnic Institute, 110
Eighth St., Troy, NY 12180, USA. Electronic address: Kingsd@rpi.edu.
(2)Department of Biomedical Engineering, Rensselaer Polytechnic Institute, 110
Eighth St., Troy, NY 12180, USA. Electronic address: Roberc5@rpi.edu.
(3)Department of Molecular and Cellular Physiology, Albany Medical College,
Albany, NY, 12208, USA. Electronic address: Rudkoua@amc.edu.
(4)Department of Biomedical Engineering, Rensselaer Polytechnic Institute, 110
Eighth St., Troy, NY 12180, USA. Electronic address: Faulkd@rpi.edu.
(5)Department of Molecular and Cellular Physiology, Albany Medical College,
Albany, NY, 12208, USA. Electronic address: BarrosM@amc.edu.
(6)Department of Biomedical Engineering, Rensselaer Polytechnic Institute, 110
Eighth St., Troy, NY 12180, USA. Electronic address: Intesx@rpi.edu.
(7)Department of Biomedical Engineering, Rensselaer Polytechnic Institute, 110
Eighth St., Troy, NY 12180, USA. Electronic address: Corrd@rpi.edu.

3D multicellular aggregates, and more advanced organotypic systems, have become
central tools in recent years to study a wide variety of complex biological
processes. Most notably, these model systems have become mainstream within
oncology (multicellular tumor spheroids) and regenerative medicine (embryoid
bodies) research. However, the biological behavior of these in vitro tissue
surrogates is extremely sensitive to their aggregate size and geometry. Indeed,
both of these geometrical parameters are key in producing pathophysiological
gradients responsible for cellular and structural heterogeneity, replicating in
vivo observations. Moreover, the fabrication techniques most widely used for
producing these models lack the ability to accurately control cellular spatial
location, an essential component for regulating homotypic and heterotypic cell
signaling. Herein, we report on a 3D bioprinting technique, laser direct-write
(LDW), that enables precise control of both spatial patterning and size of
cell-encapsulating microbeads. The generated cell-laden beads are further
processed into core-shelled structures, allowing for the growth and formation of
self-contained, self-aggregating cells (e.g., breast cancer cells, embryonic stem
cells). Within these structures we demonstrate our ability to produce
multicellular tumor spheroids (MCTSs) and embryoid bodies (EBs) with
well-controlled overall size and shape, that can be designed on demand.
Furthermore, we investigated the impact of aggregate size on the uptake of a
commonly employed ligand for receptor-mediated drug delivery, Transferrin,
indicating that larger tumor spheroids exhibit greater spatial heterogeneity in
ligand uptake. Taken together, these findings establish LDW as a versatile
biomanufacturing platform for bioprinting and patterning core-shelled structures
to generate size-controlled 3D multicellular aggregates. STATEMENT OF
SIGNIFICANCE: Multicellular 3D aggregates are powerful in vitro models used to
study a wide variety of complex biological processes, particularly within
oncology and regenerative medicine. These tissue surrogates are fabricated using
environments that encourage cellular self-assembly. However, specific
applications require control of aggregate size and position to recapitulate key
in vivo parameters (e.g., pathophysiological gradients and homotypic/heterotypic
cell signaling). Herein, we demonstrate the ability to create and spatially
pattern size-controlled embryoid bodies and tumor spheroids, using laser-based 3D
bioprinting. Furthermore, we investigated the effect of tumor spheroid size on
internalization of transferrin, a common ligand for targeted therapy, finding
greater spatial heterogeneity in large aggregates. Overall, this technique offers
incredible promise and flexibility for fabricating idealized 3D in vitro models.

DOI: 10.1016/j.actbio.2019.02.014
PMID: 30776506

Drug Discov Today. 2019 Feb 15. pii: S1359-6446(18)30253-8. doi:
10.1016/j.drudis.2019.02.003. [Epub ahead of print]

Emerging role of histone deacetylase inhibitors as anti-breast-cancer agents.

Ediriweera MK(1), Tennekoon KH(2), Samarakoon SR(2).

Author information:
(1)Institute of Biochemistry, Molecular Biology and Biotechnology, University of
Colombo, 90, Cumaratunga Munidasa Mawatha, Colombo 03, Sri Lanka. Electronic
address: mk.ediriweera@gmail.com.
(2)Institute of Biochemistry, Molecular Biology and Biotechnology, University of
Colombo, 90, Cumaratunga Munidasa Mawatha, Colombo 03, Sri Lanka.

Breast cancer (BC) remains the most frequently diagnosed cancer in women. A
balance in the opposing actions of histone acetyltransferases (HATs) and histone
deacetylases (HDACs) is necessary for epigenetic regulation of gene expression.
Impairment in the balance between the actions of HATs and HDACs has been reported
in the development of BC. By targeting histone and several non-histone proteins,
histone deacetylase inhibitors (HDACi) can maintain the cellular acetylation
profile and reverse the function of several proteins responsible for BC
development. Preclinical and clinical data show that HDACi can evoke different
anticancer mechanisms in distinct BC types.

DOI: 10.1016/j.drudis.2019.02.003
PMID: 30776482

J Appl Microbiol. 2019 Feb 18. doi: 10.1111/jam.14227. [Epub ahead of print]

High level extracellular production of recombinant human interferon alpha 2b in
glycoengineered Pichia pastoris: culture medium optimization, high cell density
cultivation and biological characterization.

Katla S(1), Karmakar B(1), Tadi SRR(1), Mohan N(1), Anand B(2), Pal U(3),
Sivaprakasam S(1).

Author information:
(1)BioPAT Laboratory, Department of Biosciences and Bioengineering, Indian
Institute of Technology Guwahati, Guwahati, India.
(2)MAB Lab, Department of Biosciences and Bioengineering, Indian Institute of
Technology Guwahati, Guwahati, India.
(3)Molecular Endocrinology Lab, Department of Biosciences and Bioengineering,
Indian Institute of Technology Guwahati, Guwahati, India.

AIMS: The present study was aimed at design of experiments (DoE) and artificial
intelligence based culture medium optimization for high level extracellular
production of a novel recombinant human interferon alpha 2b (huIFNα2b) in
glycoengineered Pichia pastoris and its characterization.
METHODS AND RESULTS: Artificial neural network- Genetic algorithm (ANN-GA) model
exhibited improved huIFNα2b production and better predictability compared to RSM.
The optimized medium exhibited 5-fold increase in huIFNα2b titer compared to the
complex medium. A maximum titer of huIFNα2b (436 mg l-1 ) was achieved using the
optimized medium in the bioreactor. Real time capacitance data from dielectric
spectroscopy was utilized to model the growth kinetics with unstructured models.
Biological characterization by anti-proliferative assay proved that the purified
recombinant huIFNα2b was biologically active, exhibiting growth inhibition on
breast cancer cell line.
CONCLUSIONS: Culture medium optimization resulted in enhanced production of
huIFNα2b in glycoengineered P. pastoris at both shake flask and bioreactor level.
The purified huIFNα2b was found to be N-glycosylated and biologically active.
SIGNIFICANCE AND IMPACT OF THE STUDY: DoE based medium optimization strategy
significantly improved huIFNα2b production. The anti-proliferative activity of
huIFNα2b substantiates its potential scope for application in cancer therapy.
This article is protected by copyright. All rights reserved.

DOI: 10.1111/jam.14227
PMID: 30776176

Cancer Sci. 2019 Feb 18. doi: 10.1111/cas.13976. [Epub ahead of print]

Somatic alterations of TP53, ERBB2, PIK3CA and CCND1 were associated with
chemosensitivity for breast cancers.

Yang L(1)(2), Ye F(2), Bao L(3)(4)(5), Zhou X(3)(4)(5), Wang Z(6), Hu P(6),
Ouyang N(7), Li X(7), Shi Y(8), Chen G(8), Xia P(9)(10), Chui M(9)(10), Li
W(9)(10), Jia Y(11), Yueping L(11), Liu J(12), Ye J(12), Zhang Z(12), Bu H(1)(2).

Author information:
(1)Department of Pathology, West China Hospital of Sichuan University, Chengdu,
Sichuan Province, 610041, China.
(2)Laboratory of Pathology, West China Hospital of Sichuan University, Chengdu,
Sichuan Province, 610041, China.
(3)Department of Pathology, Shanghai Cancer Center, Fudan University, Shanghai,
200032, China.
(4)Department of Oncology, Shanghai Medical College, Shanghai, 200032, China.
(5)Institute of Pathology, Fudan University, Shanghai, 200032, China.
(6)Department of Pathology, Xijing Hospital and School of Basic Medicine, Air
Force Medical University, Xi’an, Shanxi Province, 710032, China.
(7)Cellular & Molecular Diagnostics Center, Sun Yat-sen Memorial Hospital, Sun
Yat-sen University, Guangzhou, Guangdong Province, 510228, China.
(8)Department of Molecular Pathology, Fujian Cancer Hospital & Fujian Medical
University Cancer Hospital, Fuzhou, Fujian Province, 350014, China.
(9)Department of Pathology, The First Affiliated Hospital of Zhengzhou
University, Zhengzhou, Henan Province, 450052, China.
(10)Department of Pathology, School of Basic Medicine, Zhengzhou University,
Zhengzhou, Henan Province, 450002, China.
(11)Department of Pathology, The Fourth Hospital of Hebei Medical University,
Shijiazhuang, Hebei Province, 050011, China.
(12)Burning Rock Biotech, Guangzhou, Guangdong Province, 510000, China.

The correlation of genetic alterations with responding to neoadjuvant
chemotherapy (NAC) is not fully revealed. In this study, we enrolled 247 breast
cancers receiving anthracycline-taxane-based NAC treatment. Next generation
sequencing (NGS) panel containing 36 hot spot breast cancer related genes was
used in this study. Two different extent of pathologic complete response (pCR)
standards, which were ypT0/isypN0 and ypT0/is, were used as indicators for NAC
treatment. TP53 mutation (n = 149, 60.3%), PIK3CA mutation (n = 109, 44.1%) and
MYC amplification (n = 95, 38.5%) were frequently detected in enrolled cases.
TP53 mutation (P = 0.019 for ypT0/isypN0 and P = 0.003 for ypT0/is) and ERBB2
amplification (P <0.001 for both ypT0/isypN0 and ypT0/is) were related with
higher pCR rates. PIK3CA mutation (P = 0.040 for ypT0/isypN0) and CCND2
amplification (P = 0.042 for ypT0/is) showed reduced sensitivity to NAC. Patients
with MAPK pathway alteration shows pretty low pCR rates (P = 0.043 for ypT0/is).
Patients with TP53 mutation (-) PIK3CA mutation (-) ERBB2 amplification (+) CCND1
amplification (-), TP53 mutation (+) PIK3CA mutation (-) ERBB2 amplification (+)
CCND1 amplification (-) or TP53 mutation (+) PIK3CA mutation (+) ERBB2
amplification (+) CCND1 amplification (-) had significantly higher pCR rates (P
<0.05 for ypT0/isypN0 and ypT0/is) than wild type genotype tumors. Some cancer
genetic alterations as well as pathway alterations were associated with
chemosensitivity to NAC treatment. Our data may shed light on molecular diagnosis
of breast cancer for prediction of NAC expectations when first time diagnosed by
biopsy. This article is protected by copyright. All rights reserved.

DOI: 10.1111/cas.13976
PMID: 30776175

Cochrane Database Syst Rev. 2019 Feb 18;2:CD012873. doi:
10.1002/14651858.CD012873.pub2. [Epub ahead of print]

Sequencing of anthracyclines and taxanes in neoadjuvant and adjuvant therapy for
early breast cancer.

Zaheed M(1), Wilcken N, Willson ML, O’Connell DL, Goodwin A.

Author information:
(1)Medical Oncology Department, Concord Repatriation General Hospital, Concord,
New South Wales, Australia, 2139.

BACKGROUND: Anthracyclines and taxanes are chemotherapeutic agents widely used in
a sequential regimen in the adjuvant and neoadjuvant treatment of early breast
cancer to reduce the risk of cancer recurrence. Standard practice is to
administer anthracycline-based chemotherapy followed by a taxane. Anthracyclines
tend to be administered first as they were established before taxanes for
treatment of early breast cancer.
OBJECTIVES: To assess whether the sequence in which anthracyclines and taxanes
are administered affects outcomes for people with early breast cancer receiving
adjuvant or neoadjuvant therapy.
SEARCH METHODS: We searched Cochrane Breast Cancer’s Specialised Register,
CENTRAL, MEDLINE, Embase, the World Health Organization’s International Clinical
Trials Registry Platform (WHO ICTRP) and ClinicalTrials.gov on 1 February 2018.
SELECTION CRITERIA: Randomised controlled trials comparing administering a taxane
prior to an anthracycline with taxane following anthracycline to people with
early breast cancer receiving chemotherapy. The studies needed to have reported
on at least one of our outcomes of interest, which included overall survival,
disease-free survival, pathological response, treatment adherence, toxicity and
quality of life.
DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data,
assessed risk of bias and quality of the evidence. The primary outcome measure
was overall survival. Secondary outcomes included disease-free survival,
pathological response (in the neoadjuvant setting only), adverse events,
treatment adherence and quality of life. For time-to-event outcomes of overall
survival and disease-free survival, we derived hazard ratios (HRs) with 95%
confidence intervals (CI) where possible. For dichotomous outcomes of
pathological complete response, treatment adherence and adverse events, we
reported the treatment effect as a risk ratio (RR) with 95% CI where possible. We
used GRADE to assess the certainty of the evidence separately for the neoadjuvant
and adjuvant settings.
MAIN RESULTS: There were 1415 participants in five neoadjuvant studies and 280
participants in four adjuvant studies involving five treatment comparisons. Four
of the five neoadjuvant studies collected data for the primary outcome (overall
survival) and two studies had data available; one of the four adjuvant studies
collected overall survival data.The neoadjuvant studies suggested that the
administration of taxanes first probably resulted in little to no difference in
overall survival (HR 0.80, 95% CI 0.60 to 1.08; 947 participants; 2 studies;
moderate-certainty evidence) and disease-free survival (HR 0.84, 95% CI 0.65 to
1.09; 828 participants; 1 study; moderate-certainty evidence). Administration of
taxanes first also resulted in little to no difference in pathological complete
response (absence of cancer in the breast and axilla: RR 1.15, 95% CI 0.96 to
1.38; 1280 participants; 4 studies; high-certainty evidence). However, there
appeared to be a trend in favour of taxanes first. Studies reported treatment
adherence using a range of measures. Administration of taxanes first probably did
not increase the likelihood of requiring dose reductions compared to
administration of anthracyclines first (RR 0.81, 95% CI 0.59 to 1.11; 280
participants; 1 study; moderate-certainty evidence). There was probably little to
no difference in the risk of grade 3/4 neutropenia (RR 1.25, 95% CI 0.86 to 1.82;
280 participants, 1 study; moderate-certainty evidence) or grade 3/4
neurotoxicity (RR 0.95, 95% CI 0.55 to 1.65; 1108 participants; 2 studies;
low-certainty evidence) when taxanes were given first. There were no data on
quality of life.Only one adjuvant study collected data on overall survival and
disease-free survival but did not report data. Administration of taxanes first
reduced the risk of grade 3/4 neutropenia (RR 0.62, 95% CI 0.40 to 0.97; 279
participants; 4 studies, 5 treatment comparisons; high-certainty evidence) and
appeared to result in little to no difference in grade 3/4 neurotoxicity (RR
0.78, 95% CI 0.25 to 2.46; 162 participants; 3 studies; low-certainty evidence).
There was probably little to no difference in the proportions experiencing dose
delays when taxanes are given first compared to anthracyclines given first (RR
0.76, 95% CI 0.52 to 1.12; 238 participants; 3 studies, 4 treatment comparisons;
moderate-certainty evidence). One study reported on quality of life and indicated
that scores (using the Functional Assessment of Cancer Therapy – Breast Cancer
(FACT-B) validated questionnaire) were similar in both groups though did not
provide numerical data.
AUTHORS’ CONCLUSIONS: In the neoadjuvant setting, there is high- to low-certainty
evidence of equivalent outcomes for the sequence in which taxanes are delivered.
In the adjuvant setting, none of the studies reported on overall survival or
disease-free survival. In most institutions, standard practice would be to
deliver anthracycline followed by taxane, and currently available data do not
support a change in this practice. We wait for the full-text publication of a
relevant neoadjuvant study for women with HER2-negative breast cancer for
inclusion in an update of this review.

DOI: 10.1002/14651858.CD012873.pub2
PMID: 30776132

Nutr Cancer. 2019 Feb 18:1-16. doi: 10.1080/01635581.2018.1557217. [Epub ahead of
print]

A Step toward Understanding Diet Quality in Urban African-American Breast Cancer
Survivors: A Cross-sectional Analysis of Baseline Data from the Moving Forward
Study.

Springfield S(1), Odoms-Young A(2)(3)(4), Tussing-Humphreys LM(3)(4), Freels
S(4), Stolley MR(5).

Author information:
(1)a Stanford Prevention Research Center, School of Medicine , Stanford
University , Palo Alto , California , USA.
(2)b Department of Kinesiology and Nutrition , University of Illinois at Chicago
, Chicago , Illinois , USA.
(3)c Division of Academic and Internal Medicine, College of Medicine , University
of Illinois at Chicago, University of Illinois Cancer Center , Chicago , Illinois
, USA.
(4)d Division of Epidemiology and Biostatistics , School of Public Health
University of Illinois at Chicago , Chicago , Illinois , USA.
(5)e Department of Medicine , Medical College of Wisconsin , Milwaukee ,
Wisconsin , USA.

PURPOSE: Little is known about the dietary behaviors of African-American breast
cancer survivors (AABCS). We sought to describe dietary intake and quality in
AABCS and examine associations with demographic, social, lifestyle, and body
composition factors to potentially inform the development of effective dietary
interventions.
METHODS: Baseline data from a prospective weight loss trial of 210 AABCS were
assessed. A food frequency questionnaire was used to evaluate dietary intake and
diet quality via the Healthy Eating Index 2010 (HEI-2010) and Alternative Healthy
Eating Index 2010 (AHEI-2010). Linear regression analysis was conducted to
determine the most influential variables on diet quality.
RESULTS: Mean HEI- and AHEI-2010 total scores were 65.11 and 56.83 indicating
that diet quality needs improvement. Women were the least adherent to
recommendations for intake of whole grains, dairy, sodium, empty calories, sugary
beverages, red/processed meats, and trans-fat. Increased self-efficacy for
healthy eating behaviors, more years of education (AHEI only), negative smoking
status, smaller waist circumference, and increased physical activity (HEI only)
were significantly associated with higher diet quality scores.
CONCLUSION: Our findings suggest the diet quality of AABCS needs improvement.
Intervention programs may achieve higher diet quality in AABCS by focusing on
increasing self-efficacy for healthy eating behaviors.

DOI: 10.1080/01635581.2018.1557217
PMID: 30775929

Clin Lab. 2019 Jan 1;65(1). doi: 10.7754/Clin.Lab.2018.180340.

MicroRNA and LncRNA Expression Profiles in Human Estrogen Receptor Positive
Breast Cancer.

Shao X, Huang P, Shi L, Lei L, Cao W, Chen Z, Wang X, Zheng Y.

BACKGROUND: Recent studies have established non-coding RNAs, which include
microRNAs and lncRNAs, are aberrantly expressed in breast cancer. In this study,
we explore the expression profile of microRNAs and lncRNAs in ER positive (ER+)
breast and paracancerous tissues and define their possible correlations.
METHODS: We collected ER+ breast cancer patients’ and paracancerous tissues from
the specimen bank of Zhejiang Cancer Hospital to extract total RNA for obtaining
the expression level of microRNAs and lncRNAs by qRT-PCR.
RESULTS: The relative expression results indicated that microRNAs such as
MIR-191, MIR-213, MIR-122A had significantly higher expression and MIR-125B-1,
MIR-125B-2, MIR-145 had lower expression in ER positive breast cancer compared to
normal breast. The interaction of microRNA and lncRNA results exhibited
upregulated MIR382-5P and lncRNA 362 in ER+ breast cancer compared to
non-cancerous breast. By contrast, MIR222 and NFIA-AS1 are down-regulated.
Furthermore, MIR222 and NFIA-AS1 showed different expressions in different TNM
stages.
CONCLUSIONS: MicroRNAs and lncRNAs are aberrantly expressed in ER+ breast cancer.
It is inferred that these microRNAs and lncRNAs may be promising biomarkers for
ER positive breast cancer.

DOI: 10.7754/Clin.Lab.2018.180340
PMID: 30775882

Osteoporos Sarcopenia. 2018 Sep;4(3):102-108. doi: 10.1016/j.afos.2018.08.002.
Epub 2018 Sep 7.

Effectiveness of bisphosphonate combined with activated vitamin D in patients
with aromatase inhibitor-induced osteoporosis after breast cancer operation.

Tanaka M(1)(2), Itoh S(1), Takeuchi Y(2).

Author information:
(1)Department of Orthopaedic Surgery, Kawakita General Hospital, Tokyo, Japan.
(2)Department of Endocrinology, Toranomon Hospital, Tokyo, Japan.

Objectives: We compared the effectiveness of bisphosphonates combined with
activated vitamin D administered for therapy of aromatase inhibitor-induced
osteoporosis after a breast cancer operation and primary postmenopausal
osteoporosis through propensity score matching.
Methods: Forty-eight postmenopausal patients with estrogen receptor-positive
early breast cancer, who had postoperative adjuvant treatment with aromatase
inhibitors and whose T-score of bone mineral density (BMD) decreased below -2.5
(AI group), and 48 patients of primary postmenopausal osteoporosis (PO group)
enrolled in this retrospective observational study. They were administered
monthly risedronate or minodronate, and daily alfacalcitol or eldecalcitol were
combined. Their BMD (L2-4, L-BMD), serum-corrected calcium, serum phosphate,
tartrate-resistant acid phosphatase 5b (TRACP-5b), bone alkaline phosphatase
(BAP), estimated glomerular filtration rate, urine calcium/creatinine ratio,
intact-parathyroid hormone, and 25-hydroxy vitamin D were measured before
treatment and until 24 months.
Results: L-BMD values increased with time compared with the baseline values in
each group, and there was no significant difference in the groups. Percentage
value of TRACP-5b decreased rapidly after 6 months and maintained low level until
24 months in both groups. Percentage value of BAP in the AI group decreased
continuously until 24 months. In contrast, the percentage change in the PO group
plateaued after 6 months.
Conclusions: It is suggested that monthly oral bisphosphonate combined with
activated Vitamin D is an effective therapy to increase BMD in the aromatase
inhibitor-induced osteoporosis after breast cancer operation. Monitoring of
kidney function and concentration of Ca in blood and urine may be necessary.

DOI: 10.1016/j.afos.2018.08.002
PMCID: PMC6362968
PMID: 30775551

Sci Adv. 2019 Feb 6;5(2):eaav5590. doi: 10.1126/sciadv.aav5590. eCollection 2019
Feb.

Inhibition of histone methyltransferase DOT1L silences ERα gene and blocks
proliferation of antiestrogen-resistant breast cancer cells.

Nassa G(1), Salvati A(1), Tarallo R(1), Gigantino V(1), Alexandrova E(1)(2),
Memoli D(1), Sellitto A(1), Rizzo F(1), Malanga D(3), Mirante T(3), Morelli E(3),
Nees M(4), Åkerfelt M(4), Kangaspeska S(5), Nyman TA(6), Milanesi L(7), Giurato
G(1)(2), Weisz A(1).

Author information:
(1)Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery
and Dentistry, «Scuola Medica Salernitana», University of Salerno, Baronissi, SA,
Italy.
(2)Genomix4Life Srl, University of Salerno, Baronissi, SA, Italy.
(3)Department of Experimental and Clinical Medicine, University «Magna Graecia»,
Catanzaro (CZ), Italy.
(4)Institute of Biomedicine, University of Turku, Turku, Finland.
(5)Institute for Molecular Medicine, Biomedicum 2U, Helsinki, Finland.
(6)Department of Immunology, Institute of Clinical Medicine, University of Oslo
and Rikshospitalet Oslo, Oslo, Norway.
(7)Institute of Biomedical Technologies, National Research Council, Segrate, MI,
Italy.

Breast cancer (BC) resistance to endocrine therapy results from constitutively
active or aberrant estrogen receptor α (ERα) signaling, and ways to block ERα
pathway in these tumors are sought after. We identified the H3K79
methyltransferase DOT1L as a novel cofactor of ERα in BC cell chromatin, where
the two proteins colocalize to regulate estrogen target gene transcription. DOT1L
blockade reduces proliferation of hormone-responsive BC cells in vivo and in
vitro, consequent to cell cycle arrest and apoptotic cell death, with widespread
effects on ER-dependent gene transcription, including ERα and FOXA1 gene
silencing. Antiestrogen-resistant BC cells respond to DOT1L inhibition also in
mouse xenografts, with reduction in ERα levels, H3K79 methylation, and tumor
growth. These results indicate that DOT1L is an exploitable epigenetic target for
treatment of endocrine therapy-resistant ERα-positive BCs.

DOI: 10.1126/sciadv.aav5590
PMCID: PMC6365116
PMID: 30775443

Gynecol Oncol Rep. 2019 Feb 1;28:18-22. doi: 10.1016/j.gore.2019.01.010.
eCollection 2019 May.

Evaluation of screening and risk-reducing surgery for women followed in a
high-risk breast/ovarian cancer clinic: it is all about the tubes in BRCA
mutation carriers.

Stewart ME(1), Knisely AT(1)(2), Sullivan MW(1), Ring KL(1), Modesitt SC(1).

Author information:
(1)Division of Gynecologic Oncology, Department of Obstetrics & Gynecology,
University of Virginia Health System, Charlottesville, VA, USA.
(2)Department of Obstetrics & Gynecology, Columbia University Medical Center, New
York, NY, USA.

The objectives of this study were to determine both surgical and subsequent
cancer outcomes for high-risk women from the University of Virginia’s High-Risk
Breast/Ovarian Cancer clinic undergoing ovarian cancer risk-reducing surgery.
Retrospective review identified high risk women who had ovarian risk reducing
surgery over the past decade and surgical outcomes, pathology, pre-operative
screening results, and pre-/post-operative cancer diagnoses were evaluated. One
hundred and eighty-three high-risk women had risk reducing surgery at a mean age
of 50.1 years and with a mean BMI of 28.9 kg/m2 at the time of surgery. Most
women (103; 56.3%) had a strong family history of cancer concerning for a
hereditary syndrome without an identified mutation, 35.5% of women carried a
known deleterious mutation and 7.7% of women had a personal history of breast or
ovarian cancer. The most common procedure was a risk-reducing bilateral
salpingo-oophorectomy with or without hysterectomy (RRBSO, 89.1%). All women
underwent the Sectioning and Extensively Examining the Fimbriated End (SEE-FIM)
pathology protocol which found two (1.1%) invasive ovarian cancers (one
ovarian/tubal carcinosarcoma, one granulosa cell ovarian cancer), three (1.6%)
serous tubal intraepithelial carcinomas (STIC), and one (1.1%) invasive fallopian
tube cancer. Subsequent cancer diagnoses included one (0.5%) primary peritoneal
cancer, four (2.2%) DCIS, and seven (3.8%) invasive breast cancers. Ultimately,
among all high-risk women undergoing RR surgery, about 3.3% were diagnosed with a
STIC or an ovarian cancer none of which were identified on screening. All STIC
and tubal cancers were diagnosed in women with BRCA mutations (6.6% rate for this
group).

DOI: 10.1016/j.gore.2019.01.010
PMCID: PMC6365389
PMID: 30775416

Anal Cell Pathol (Amst). 2019 Jan 14;2019:9365654. doi: 10.1155/2019/9365654.
eCollection 2019.

HPV E6/E7, hTERT, and Ki67 mRNA RT-qPCR Assay for Detecting High-Grade Cervical
Lesion with Microscope Slides.

Kim G(#)(1), Taye J(#)(2), Yu K(1), Park S(1), Kim J(1), Kim S(3), Lee D(4), Wang
HY(5), Park KH(2), Lee H(1).

Author information:
(1)Department of Biomedical Laboratory Science, College of Health Sciences,
Yonsei University, Wonju, Gangwon Province, Republic of Korea.
(2)Department of Pathology, Yonsei University Wonju College of Medicine, Wonju,
Gangwon Province, Republic of Korea.
(3)Department of Clinical Laboratory Science, College of Health Sciences,
Catholic University of Pusan, Busan, Republic of Korea.
(4)Department of Clinical Laboratory Science, Hyejeon College, Hongseong,
Chungnam Province, Republic of Korea.
(5)M&D, Inc., Wonju Eco Environmental Technology Center, Wonju, Gangwon Province,
Republic of Korea.
(#)Contributed equally

After breast and colon cancer, cervical cancer is the third most common cancer of
women worldwide. Since human papillomavirus (HPV) infection is known to be the
predominant cause of cervical cancer, molecular HPV screening is currently used
along with cytological and histological examination methods for precancer
diagnosis. Nevertheless, the sensitivity of the current HPV test is less than
80%; thus, many cervical cancer cases are not able to be diagnosed by HPV
screening alone, and likewise, patients with cervical cancer are often determined
to be HPV-negative by the current screening methods. Therefore, human telomerase
reverse transcriptase (hTERT) and Ki67 previously identified as cancer markers
were attempted. And cervical exfoliated cells of high-grade squamous
intraepithelial lesion (HSIL), the most severe precancerous lesion of cancer,
were used in the study. However, it takes a long time to collect enough specimens
to conduct statistical analysis. Therefore, in the present study, microscope
slides, cervical exfoliated cells on glass slides, were attempted. The results of
the analysis demonstrated that hTERT and Ki67 expression levels were useful in
distinguishing between cancerous and normal specimens, exhibiting a higher
sensitivity and specificity than conventional HPV E6/E7 testing. And the study
suggests clinical slide cell samples could be effectively used in the context of
retrospective studies to identify novel biomarkers.

DOI: 10.1155/2019/9365654
PMCID: PMC6350568
PMID: 30775237

Cell Biosci. 2019 Feb 7;9:16. doi: 10.1186/s13578-019-0278-y. eCollection 2019.

Regional methylome profiling reveals dynamic epigenetic heterogeneity and
convergent hypomethylation of stem cell quiescence-associated genes in breast
cancer following neoadjuvant chemotherapy.

Luo Y(1), Huang J(2), Tang Y(2), Luo X(2), Ge L(1), Sheng X(1), Sun X(1), Chen
Y(1), Zhu D(3).

Author information:
(1)1Key Laboratory for Major Obstetric Diseases of Guangdong Province and Key
Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes,
The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150
China.
(2)2Department of General Surgery, The Third Affiliated Hospital of Guangzhou
Medical University, Guangzhou, 510150 China.
(3)3Department of Genetic Medicine, Weill Cornell Medical College, New York, NY
10065 USA.

Background: Neoadjuvant chemotherapy (NAC) induces a pathological complete
response (pCR) in ~ 30% of patients with breast cancer. However, aberrant DNA
methylation alterations are frequent events during breast cancer progression and
acquisition of chemoresistance. We aimed to characterize the inter- and
intra-tumor methylation heterogeneity (MH) in breast cancer following NAC.
Methods: DNA methylation profiles of spatially separated regions of breast tumors
before and after NAC treatment were investigated using high-density methylation
microarray. Methylation levels of genes of interest were further examined using
multiplexed MethyLight droplet digital PCR (ddPCR).
Results: We have discovered different levels of intra-tumor MH in breast cancer
patients. Moreover, NAC dramatically altered the methylation profiles and such
changes were highly heterogeneous between the patients. Despite the high
inter-patient heterogeneity, we identified that stem cell quiescence-associated
genes ALDH1L1, HOPX, WNT5A and SOX9 were convergently hypomethylated across all
the samples after NAC treatment. Furthermore, by using MethyLight ddPCR, we
verified that the methylation levels of these 4 genes were significantly lower in
breast tumor samples after NAC than those before NAC.
Conclusions: Our study has revealed that NAC dramatically alters epigenetic
heterogeneity in breast cancer and induces convergent hypomethylation of stem
cell quiescence-associated genes, ALDH1L1, HOPX, WNT5A and SOX9, which can
potentially be developed as therapeutic targets or biomarkers for
chemoresistance.

DOI: 10.1186/s13578-019-0278-y
PMCID: PMC6367786
PMID: 30774927

Chem Sci. 2018 Nov 20;10(3):665-673. doi: 10.1039/c8sc03390k. eCollection 2019
Jan 21.

The anti-apoptotic proteins NAF-1 and iASPP interact to drive apoptosis in cancer
cells.

Iosub-Amir A(1), Bai F(2), Sohn YS(3), Song L(4), Tamir S(3), Marjault HB(3),
Mayer G(1), Karmi O(3), Jennings PA(5), Mittler R(6), Onuchic JN(2), Friedler
A(1), Nechushtai R(3).

Author information:
(1)Institute of Chemistry , The Hebrew University of Jerusalem , Edmond J. Safra
Campus at Givat Ram , Jerusalem 91904 , Israel . Email:
assaf.friedler@mail.huji.ac.il.
(2)Center for Theoretical Biological Physics , Department of Physics , Rice
University , Houston , TX 77005 , USA . Email: jonuchic@rice.edu.
(3)The Alexander Silberman Institute of Life Science , The Hebrew University of
Jerusalem , Edmond J. Safra Campus at Givat Ram , Jerusalem 91904 , Israel .
Email: rachel@mail.huji.ac.il.
(4)Department of Biological Sciences , University of North Texas , Denton , TX
76203 , USA.
(5)Department of Chemistry & Biochemistry , University of California at San Diego
, La Jolla , CA 92093 , USA.
(6)Department of Surgery , University of Missouri School of Medicine ,
Christopher S. Bond Life Sciences Center , University of Missouri , 1201 Rollins
St , Columbia , MO 65201 , USA.

Suppression of apoptosis is a key Hallmark of cancer cells, and reactivation of
apoptosis is a major avenue for cancer therapy. We reveal an interaction between
the two anti-apoptotic proteins iASPP and NAF-1, which are overexpressed in many
types of cancer cells and tumors. iASPP is an inhibitory member of the ASPP
protein family, whereas NAF-1 belongs to the NEET 2Fe-2S protein family. We show
that the two proteins are stimulated to interact in cells during apoptosis. Using
peptide array screening and computational methods we mapped the interaction
interfaces of both proteins to residues 764-778 of iASPP that bind to a surface
groove of NAF-1. A peptide corresponding to the iASPP 764-780 sequence stabilized
the NAF-1 cluster, inhibited NAF-1 interaction with iASPP, and inhibited
staurosporine-induced apoptosis activation in human breast cancer, as well as in
PC-3 prostate cancer cells in which p53 is inactive. The iASPP 764-780 IC50 value
for inhibition of cell death in breast cancer cells was 13 ± 1 μM. The level of
cell death inhibition by iASPP 764-780 was altered in breast cancer cells
expressing different levels and/or variants of NAF-1, indicating that the peptide
activity is associated with NAF-1 function. We propose that the interaction
between iASPP and NAF-1 is required for apoptosis activation in cancer cells.
This interaction uncovers a new layer in the highly complex regulation of cell
death in cancer cells and opens new avenues of exploration into the development
of novel anticancer drugs that reactivate apoptosis in malignant tumors.

DOI: 10.1039/c8sc03390k
PMCID: PMC6349067
PMID: 30774867

Iran J Pathol. 2018 Fall;13(4):447-453. Epub 2018 Sep 25.

Relationship Between PIK3CA Amplification and P110α and CD34 Tissue Expression as
Angiogenesis Markers in Iranian Women with Sporadic Breast Cancer.

Hosseini S(1), Behjati F(1), Rahimi M(1), Taheri N(1), Khoram Khorshid H(1),
Aghakhani Moghaddam F(1), Ghasemi S(1), Karimlou M(2), Sirati F(3), Keyhani E(1).

Author information:
(1)Genetics Research Center, University of Social Welfare and Rehabilitation
Sciences, Tehran, Iran.
(2)Dept. of Epidemiology and Biostatistics, Tehran Medical Sciences Branch,
Islamic Azad University, Tehran, Iran.
(3)Cancer Institute, Tehran University of Medical Sciences, Tehran, Iran.

Background and Objective: The PI3K/AKT/mTOR pathway is known to play an important
role in regulating angiogenesis both in normal and breast cancer (BC) tissues.
PIK3CA amplification was reported in various malignancies, including
approximately 10% of BC cases. The aim of this study was to identify the
frequency of PIK3CA amplification in Iranian female patients suffering from BC.
Additionally, possible association between PIK3CA amplification and P110α
expression with microvascular density (MVD) was examined.
Methods: DNA samples were extracted from paraffin embedded tumor tissue blocks
and copy number changes were evaluated by MLPA Technique. The results were
analyzed by coffalyzer software. The tissue expression of P110α and CD34 was
assessed using immunohistochemistry.
Results: Ten out of 40 samples (17.5%) showed amplification in PIK3CA gene and 22
out of 40 samples (55%) showed overexpression in P110α. For CD34, from 40
samples, 20 (50%), 15 (37.5%) and 5 (12.5%) had scores 1+, 2+ and 3+,
respectively.
Conclusion: No significant association was detected between gain of PIK3CA copy
number and P110α or CD34 tissue expression.

PMCID: PMC6358562
PMID: 30774684

Conflict of interest statement: The authors declare that there is no conflict of
interest regarding the publication of this article.

World J Nucl Med. 2019 Jan-Mar;18(1):18-24. doi: 10.4103/wjnm.WJNM_9_18.

A preliminary study on treatment of human breast cancer xenografts with a
cocktail of paclitaxel, doxorubicin, and 131I-anti-epithelial cell adhesion
molecule (9C4).

Ali NS(1)(2), Akudugu JM(1)(3), Howell RW(1).

Author information:
(1)Division of Radiation Research, New Jersey Medical School, Rutgers, The State
University of New Jersey, Newark, NJ 07103, USA.
(2)Department of Radiology, University of Vermont Medical Center, Burlington, VT
05401, USA.
(3)Department of Medical Imaging and Clinical Oncology, Division of Radiobiology,
Faculty of Medicine and Health Sciences, University of Stellenbosch, Tygerberg
7505, South Africa.

Triple-negative breast cancer often has devastating outcomes and treatment
options remain limited. Therefore, different treatment combinations are worthy of
testing. The efficacy of a cocktail of paclitaxel, doxorubicin, and
131I-anti-epithelial cell adhesion molecule (EpCAM) (9C4) to treat breast cancer
was tested. Efficacy was tested with an MDA-MB-231 human breast cancer xenograft
model. Anti-EpCAM (9C4) was demonstrated to bind to MDA-MB-231 human
adenocarcinoma cells in vitro. Subsequently, mice-bearing MDA-MB-231× enografts
were treated with either 131I-anti-EpCAM (9C4), unlabeled anti-EpCAM (9C4),
paclitaxel, doxorubicin, or a cocktail of all of the agents. Tumor volume was
measured for up to 70-day postinjection. Exponential regression was performed on
tumor growth curves for each of the therapy groups. Statistical comparison of the
growth constants λ of the regression models for each of the treatment groups with
that of the cold antibody and control groups was done using extra sum-of-square
F-tests. Biexponential clearance of 131I-anti-EpCAM (9C4) was observed with
biological clearance half-times of 1.14 and 17.6 days for the first and second
components, respectively. The mean growth rate of the tumors in animals treated
with a cocktail of all of the agents was slower than in those treated with
unlabeled anti-EpCAM (9C4) (P = 0.022). These preliminary data suggest that a
cocktail of 131I-anti-EpCAM (9C4), paclitaxel, and doxorubicin may be suitable
for treating breast cancers with high expression of EpCAM.

DOI: 10.4103/wjnm.WJNM_9_18
PMCID: PMC6357706
PMID: 30774541

Conflict of interest statement: John M. Akudugu and Roger W. Howell hold United
States patents on related technology (US Patent No. 8,874,380, US Patent No.
9,623,262, and US Patent No. 9,804,167 B2.

Cancer Manag Res. 2019 Jan 29;11:1087-1096. doi: 10.2147/CMAR.S180388.
eCollection 2019.

Identifying the reasons for delayed presentation of Pakistani breast cancer
patients at a tertiary care hospital.

Gulzar F(1)(2), Akhtar MS(1), Sadiq R(3), Bashir S(1), Jamil S(2), Baig SM(4)(5).

Author information:
(1)Department of Pharmacology, College of Pharmacy, University of Sargodha,
Sargodha, Punjab, Pakistan, mfaisalgul33@gmail.com.
(2)Department of Pharmacology, Faculty of Pharmacy, The University of Lahore,
Lahore, Punjab, Pakistan, mfaisalgul33@gmail.com.
(3)Punjab Institute for Nuclear Medicines (PINUM) Cancer Hospital, Faisalabad,
Punjab, Pakistan.
(4)Human Molecular Genetics Laboratory, Health Biotechnology Division, National
Institute for Biotechnology and Genetic Engineering (NIBGE), Faisalabad, Punjab,
Pakistan, shahid_baig2002@yahoo.com.
(5)Pakistan Institute of Engineering and Applied Sciences (PIEAS), Islamabad,
Punjab, Pakistan, shahid_baig2002@yahoo.com.

Background: Delay in seeking health care by breast cancer patients is associated
with advanced stage of disease at presentation and poor survival rates. This
study aimed to identify the reasons for delayed presentation and their
association with various sociodemographic variables.
Methods: A total of 200 female patients with abnormal clinical findings, ie, lump
or palpable mass, were consecutively invited for this study. Diagnostic delay was
defined as a consultation with a health care provider more than 3 months from the
appearance of the first symptoms. Sociodemographic variables, presenting
symptoms, knowledge about diseases and its symptoms, time between seeking medical
attention after appearance of symptoms and causes of delayed presentation were
investigated. Chi-squared and logistic regression tests for significance and
associations were used.
Results: Among 125 women with breast cancer fulfilling the inclusion criteria,
aged 24-75 years, 88.8% (n=111) presented late (≥3 months) and 59% presented with
advanced stage of disease (stage III/IV). The majority (65.6%) were older than 40
years of age, 99.2% were married, 60.8% had <8 years of education, 67.2% had poor
social status, and 64.8% had a negative family history of any cancer type. Almost
all patients (96%) complained about the presence of a painless lump in their
breast. Ignorance of disease or the presence of painless lumps in the breast and
low financial resources for therapy (81.1%) were the main variables associated
with delayed presentation. Educational factors (P<0.001, OR 4.682) and social
status (P<0.001, OR 1.8) were also associated with delayed presentation.
Conclusion: Our study highlighted the variables associated with delayed
presentation in Pakistani breast cancer patients. A significant number of
patients presented late owing to misconceptions and poor knowledge about the
disease and its symptoms, while illiteracy and poor social status were the major
contributing factors for delayed presentation, resulting in an advanced
presentation of disease and ultimately a decreased survival rate.

DOI: 10.2147/CMAR.S180388
PMCID: PMC6357878
PMID: 30774437

Conflict of interest statement: Disclosure The authors report no conflicts of
interest in this work.

Cancer Manag Res. 2019 Jan 22;11:1033-1041. doi: 10.2147/CMAR.S186857.
eCollection 2019.

Circular RNA hsa_circ_0072309 inhibits proliferation and invasion of breast
cancer cells via targeting miR-492.

Yan L(1), Zheng M(1), Wang H(2).

Author information:
(1)Department of Breast Surgery, The Second Affiliated Hospital and Yuying
Children’s Hospital of Wenzhou Medical University, Wenzhou 325000, China.
(2)Department of Neurosurgery, The First Affiliated Hospital of Wenzhou Medical
University, Wenzhou 325000, China, huawangh@163.com.

Background: Although the number of circular RNAs (circRNAs) that has been
identified in multiple cancer tissues continues to increase, the relationship
between circRNA expression and carcinogenesis remains unknown. The role of
hsa_circ_0072309 in breast cancer has remained undefined until now. In this
study, we aimed to investigate the role of hsa_circ_0072309 in breast cancer
progression.
Methods: hsa_circ_0072309 expression in breast cancer tissues was analyzed using
qRT-PCR. A series of functional experiments were carried out to investigate
hsa_circ_0072309 function in breast cancer development and its underlying
molecular mechanisms.
Results: hsa_circ_0072309 expression in breast cancer tissues was upregulated
relative to that in adjacent normal tissues. hsa_circ_0072309 could serve as a
prognostic biomarker of breast cancer. hsa_circ_0072309 overexpression
dramatically inhibited the proliferation, migration, and invasion of breast
cancer cells in vitro. In vivo assays revealed that the ectopic expression of
hsa_circ_0072309 repressed breast cancer growth. The results of our mechanistic
studies indicated that hsa_circ_0072309 could act as the sponge of miR-492, which
exhibited increased expression in breast cancer tissues. Hsa_circ_0072309
suppressed breast cancer cell proliferation, migration, and invasion by
inhibiting miR-492.
Conclusion: Our findings revealed for the first time that the
hsa_circ_0072309-miR-492 axis plays an essential role in breast cancer
progression.

DOI: 10.2147/CMAR.S186857
PMCID: PMC6349082
PMID: 30774431

Conflict of interest statement: Disclosure The authors report no conflicts of
interest in this work.

Cancer Manag Res. 2019 Jan 22;11:931-941. doi: 10.2147/CMAR.S183355. eCollection
2019

Lipase member H is a downstream molecular target of hypoxia inducible factor-1α
and promotes papillary thyroid carcinoma cell migration in BCPAP and KTC-1 cell
lines.

Li Y(1)(2), Zhou X(2), Zhang Q(3), Chen E(2), Sun Y(2), Ye D(2), Wang O(2), Zhang
X(2), Lyu J(1).

Author information:
(1)Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang
Provincial Key Laboratory of Medical Genetics, College of Laboratory Medicine and
Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China,
jxlu313@163.com.
(2)Department of Thyroid and Breast Surgery, The First Affiliated Hospital of
Wenzhou Medical University, Wenzhou, Zhejiang, China, zxhoncology0577@126.com.
(3)Pathology Department, The First Affiliated Hospital of Wenzhou Medical
University, Wenzhou, China.

Background: Papillary thyroid carcinoma (PTC) is the most common type of thyroid
carcinoma, which is associated with a high incidence of lymph-node metastasis.
Multiple biomarkers have been identified for the precise diagnosis of PTC at an
early stage. However, their role in PTC remains poorly elucidated. Previously, we
reported that lipase H (LIPH), a membrane-bound protein, was highly expressed in
PTC. This study aimed to fully elucidate the causal role of LIPH in the
development of PTC and investigated its relationship with lymph-node metastasis
in PTC.
Materials and methods: Quantitative reverse transcription PCR and
immunohistochemistry were used to measure the mRNA and protein expression levels
of LIPH in 45 and 6 pairs of PTC tissues and adjacent normal tissues,
respectively. Clinical tissue data of 504 PTC tissues and 60 normal thyroid
tissues from The Cancer Genome Atlas database were used to analyze the
correlation between LIPH expression level and clinical features in PTC. siRNAs
were used to knock down genes, while plasmids were used to overexpress genes. Two
PTC cell lines (KTC-1 and BCPAP) were used in subsequent cytological function
studies. In addition, a hypoxia stress model was constructed using cobaltous
chloride hexahydrate reagent, and the protein expression level of the
corresponding biomarkers was measured by Western blotting.
Results: This study revealed that high expression of LIPH in PTC was closely
associated with lymph-node metastasis. Our cellular function experiments
indicated that LIPH positively correlated with the malignant behavior of PTC cell
lines. We further confirmed the role of LIPH in hypoxia and its relationship with
the epithelial-mesenchymal transition pathway in PTC.
Conclusion: LIPH plays an important role in PTC oncogenesis and development,
especially in lymph-node metastasis. It can be regarded as a biomarker for the
diagnosis and treatment of PTC in the near future.

DOI: 10.2147/CMAR.S183355
PMCID: PMC6349079
PMID: 30774423

Conflict of interest statement: Disclosure The authors report no conflicts of
interest in this work.

Cancer Manag Res. 2019 Jan 23;11:921-930. doi: 10.2147/CMAR.S190966. eCollection
2019

Feasibility of computer-assisted diagnosis for breast ultrasound: the results of
the diagnostic performance of S-detect from a single center in China.

Zhao C(1), Xiao M(1), Jiang Y(1), Liu H(1), Wang M(1), Wang H(1), Sun Q(2), Zhu
Q(1).

Author information:
(1)Department of Ultrasound, Chinese Academy of Medical Sciences and Peking Union
Medical College Hospital, Beijing 100730, China, zhuqingli@pumch.cn.
(2)Department of Breast Surgery, Chinese Academy of Medical Sciences and Peking
Union Medical College Hospital, Beijing 100730, China.

Objective: To investigate the feasibility of a CAD system S-detect on a database
from a single Chinese medical center.
Materials and methods: An experienced radiologist performed breast US
examinations and made assessments of 266 consecutive breast lesions in 227
patients. S-detect classified the lesions automatically in a dichotomous form. An
in-training resident who was blind to both the US diagnostic results and
histological results reviewed the images afterward. The final histological
results were considered as the diagnostic gold standard. The diagnostic
performances and interrater agreements were analyzed.
Results: A total of 266 focal breast lesions (161 benign lesions and 105
malignant lesions) were assessed in this study. S-detect had a lower sensitivity
(87.07%) and a higher specificity (72.27%) compared with the experienced
radiologist (sensitivity 98.1% and specificity 65.43%). The sensitivity and
specificity of S-detect were better than that of the resident (sensitivity 82.86%
and specificity 68.94%). The AUC value of S-detect (0.807) showed no significant
difference with the experienced radiologist (0.817) and was higher than that of
the resident (0.758). S-detect had moderate agreement with the experienced
radiologist.
Conclusion: In this single-center study, a high level of diagnostic performance
of S-detect on 266 breast lesions of Chinese women was observed. S-detect had
almost equal diagnostic capacity with an experienced radiologist and performed
better than a novice reader. S-detect was also distinguished for its high
specificity. These results supported the feasibility of S-detect in aiding the
diagnosis of breast lesions on an independent database.

DOI: 10.2147/CMAR.S190966
PMCID: PMC6350640
PMID: 30774422

Conflict of interest statement: Disclosure QZ had the role of funding source for
this study. The authors report no other conflicts of interest in this work.

Onco Targets Ther. 2019 Jan 31;12:959-974. doi: 10.2147/OTT.S187739. eCollection
2019

Efficacy and safety of targeted therapy for metastatic HER2-positive breast
cancer in the first-line treatment: a Bayesian network meta-analysis.

Feng F(1), Zhang T(2), Yin F(3), Liu C(2), Zhuang J(1), Qi L(2), Wang X(4), Li
J(5), Wang L(1), Tian J(6), Sun C(1)(7).

Author information:
(1)Department of Oncology, Weifang Traditional Chinese Hospital, Weifang,
Shandong Province, China, scgdoctor@126.com.
(2)College of Traditional Chinese Medicine, Shandong University of Traditional
Chinese Medicine, Jinan, Shandong Province, China.
(3)Department of Pediatrics, Weifang People’s Hospital, Weifang, Shandong
Province, China.
(4)Department of Medicine, Qingdao University, Qingdao, Shandong Province, China.
(5)Department of Oncology, Weifang Medical University, Weifang, Shandong
Province, China.
(6)Evidence-Based Medicine Center, School of Basic Medical Sciences, Lanzhou
University, Lanzhou, Gansu Province, China.
(7)Department of Oncology, Affiliated Hospital of Weifang Medical University,
Weifang, Shandong Province, China, scgdoctor@126.com.

Purpose: Numerous HER2-targeted therapy clinical trials have demonstrated
efficacy and safety in the first-line treatment of metastatic breast cancer
(MBC). However, the direct or indirect comparison of these drugs is unclear. This
network meta-analysis can solve this issue to some extent.
Materials and methods: PubMed, Embase, and the Cochrane Library were searched for
Phase II/III randomized controlled trials (RCTs) on metastatic HER2-positive
breast cancer for first-line treatment up to December 16, 2017. Paired
meta-analyses were performed to compare the regimens directly with the TP
(trastuzumab plus taxane) regimen. Bayesian network meta-analysis was used to
synthesize available evidence of direct or indirect comparison.
Results: The database search identified 1,935 articles, among which 13 articles
(10 RCTs) were eligible for the analysis involving 5,177 patients treated with 11
different regimens. The progression-free survival (PFS) in the Bayesian network
meta-analysis suggested that the PTP (pertuzumab and trastuzumab plus taxane)
regimen had the highest probability to be the preferred treatment (surface under
the cumulative ranking [SUCRA]: 0.967) followed by the TPC (carboplatin and
trastuzumab plus taxane) regimen (SUCRA: 0.923). The PTP regimen (SUCRA: 0.926)
was similarly preferred for overall survival (OS). For objective response rate
(ORR), the PTC regimen might be the optimal treatment (SUCRA: 0.935), followed by
the PTP regimen.
Conclusion: Overall, PTP might be the optimal first-line treatment for
HER-2-positive MBC to improve the PFS and OS. Meanwhile, TPC might be most
effective treatment in terms of the ORR. Regarding safety, the two regimens
showed acceptable grade 3 or greater hematologic toxicity and heart failure.

DOI: 10.2147/OTT.S187739
PMCID: PMC6362967
PMID: 30774382

Conflict of interest statement: Disclosure The authors report no conflicts of
interest in this work.

Onco Targets Ther. 2019 Jan 24;12:825-834. doi: 10.2147/OTT.S192377. eCollection
2019

The inhibitive effect of sh-HIF1A-AS2 on the proliferation, invasion, and
pathological damage of breast cancer via targeting miR-548c-3p through regulating
HIF-1α/VEGF pathway in vitro and vivo.

Guo X(1), Lee S(2), Cao P(3).

Author information:
(1)Department of Breast Surgery, Central Clinical College of Gynecology
Obstetrics, Tianjin Medical University, Tianjin 300110, China.
(2)Department of Surgery, Zhaoqing Medical College, Zhaoqing, Guangdong 526020,
China.
(3)Department of Pathology, The First Affiliated Hospital of Xi’an Jiaotong
University, Xi’an, Shanxi 710061, China, ypeilongcaoxq@sina.com.

Background: Breast cancer (BC) has been the commonest malignant tumor with a low
survival rate among woman. Long non-coding RNA hypoxia-inducible factor-1 alpha
antisense RNA-2 (HIF1A-AS2) was correlated with various cancers.
Purpose: The study aimed to investigate the roles and related underlying
molecular mechanisms of HIF1A-AS2 in BC.
Material and methods: Target relationships were speculated by Targetscan 7.0 and
confirmed by dual luciferase reporter assay. Proteins levels were monitored by
RT-qPCR, Western blot and immunohistochemistry assays. CCK-8 assay, SA-β-gal
staining and transwell assay were used to detect proliferation, senescence and
invasion, respectively. Xenograft nude mice were put into use to evaluate the
tumor growth and motility.
Results: The present study exhibited that HIF1A-AS2 and hypoxia-inducible
factor-1 alpha (HIF-1α) were upregulated while miR-548c-3p was downregulated in
MDA-MB-231, MCF-7, ZR-75-1, and BT-549 BC cell lines. Bioinformatics analysis
showed HIF1A-AS2 and HIF-1α were two targets of miR-548c-3p, and the target
relationship was further confirmed by dual luciferase reporter assay. Moreover,
knockdown of HIF1A-AS2 by shRNA (sh-HIF1A-AS2) markedly elevated miR-548c-3p
level, and the enhanced miR-548c-3p noticeably suppressed cell proliferation,
invasion, and epithelial-mesenchymal transition, and promoted senescence in
vitro. In addition, overexpression of HIF-1α promoted MCF-7 cell invasion.
Intriguingly, low expression of HIF1A-AS2 reduced HIF-1α level by upregulating
the expression of miR-548c-3p. Furthermore, experiment in xenograft nude mice has
indicated that sh-HIF1A-AS2 inhibited tumor growth and motility by targeting
miR-548c-3p through regulating HIF-1α/vascular endothelial growth factor (VEGF)
pathway in vivo.
Conclusion: The inhibitive effect of HIF-1α/VEGF pathway by sh-HIF1A-AS2 through
targeting miR-548c-3p plays crucial regulatory roles in BC. Therefore, designing
targeted drugs against HIF1A-AS2 provides a new direction for the treatment of
BC.

DOI: 10.2147/OTT.S192377
PMCID: PMC6352864
PMID: 30774370

Conflict of interest statement: Disclosure The authors report no conflicts of
interest in this work.

Onco Targets Ther. 2019 Jan 23;12:773-783. doi: 10.2147/OTT.S191239. eCollection
2019

Fenofibrate potentiates chemosensitivity to human breast cancer cells by
modulating apoptosis via AKT/NF-κB pathway.

Sun J(1)(2), Zheng Z(1), Chen Q(2), Pan Y(1), Quan M(1), Dai Y(1).

Author information:
(1)Department of Surgical Oncology, Taizhou Central Hospital (Taizhou University
Hospital), Taizhou, Zhejiang, People’s Republic of China, daiyc@tzzxyy.com.
(2)Precision Medicine Center, Taizhou Central Hospital (Taizhou University
Hospital), Taizhou, Zhejiang, People’s Republic of China.

Background: Cumulatively, evidences revealed that fenofibrate used in the therapy
of hyperlipidemia and hypercholesterolemia has anti-cancer effect in multiple
cancer types. However, its function and underlying mechanism of
chemosensitization in breast cancer remain poorly understood.
Materials and methods: The cytotoxicity of fenofibrate and anti-cancer drugs in
breast cancer cells was determined by MTT. Apoptosis and mitochondrial membrane
potential were measured using flow cytometry. Caspases and PARP cleavage, the
Bcl-2 family members’ protein expression, as well as the activation of AKT and
NF-κB signaling pathways were evaluated using Western blot assay. Real-time PCR
was used to determine the mRNA expression of Bcl-2 family members.
Results: Our data indicated that fenofibrate suppressed SKBR3 and MDA-MB-231 cell
growth in a dose-dependent manner, in the same way as paclitaxel, tumor necrosis
factor-related apoptosis-inducing ligand (TRAIL), ABT-737, and doxorubicin.
Subtoxic levels of fenofibrate significantly augmented paclitaxel, TRAIL,
ABT-737, and doxorubicin-induced apoptosis in both these two cell lines.
Fenofibrate-promoted chemosensitivity is predominantly mediated by caspase-9 and
caspase-3 activation and mitochondrial outer membrane permeabilization.
Meanwhile, chemosensitivity promoted by fenofibrate also increased the expression
of Bax and Bok and decreased the expression of Mcl-1 and Bcl-xl. Mechanistically,
fenofibrate effectively reduced the phosphorylation levels of AKT and NF-κB. In
addition, imiquimod, an NF-κB activator, could reverse fenofibrate-induced
susceptibility to ABT-737-triggered apoptosis.
Conclusion: The present study provided the evidence of the underlying mechanisms
on chemosensitization of fenofibrate by inducing the apoptosis of breast cancer
in an AKT/NF-κB-dependent manner and implicated the potential application of
fenofibrate in potentiating chemosensitivity in breast cancer therapy.

DOI: 10.2147/OTT.S191239
PMCID: PMC6353220
PMID: 30774365

Conflict of interest statement: Disclosure The authors report no conflicts of
interest in this work.

Onco Targets Ther. 2019 Jan 22;12:721-732. doi: 10.2147/OTT.S190432. eCollection
2019

Anticancer activity of 1,25-(OH)2D3 against human breast cancer cell lines by
targeting Ras/MEK/ERK pathway.

Zheng W(1), Cao L(2), Ouyang L(1), Zhang Q(3), Duan B(1), Zhou W(4), Chen S(5),
Peng W(1), Xie Y(1), Fan Q(6), Gong D(7).

Author information:
(1)Department of Thyroid and Breast Surgery, The Third People’s Hospital of
Shenzhen, Shenzhen, Guangdong 518112, China, sztphzhengwei@hotmail.com.
(2)Department of Breast Surgery, Maternal and Child Health Care Hospital of Hunan
Province, Changsha, Hunan 410008, China.
(3)School of Clinical Medicine, Xiangnan University, Chenzhou, Hunan 423000,
China.
(4)Department of Medical Examination, Zhuzhou Central Hospital, Zhuzhou, Hunan
412007, China.
(5)Department of General Surgery, The Third Hospital of Changsha, Changsha, Hunan
410013, China.
(6)Department of Gastrointestinal and Breast and Thyroid Surgery, Changsha
Hospital of Traditional Chinese Medicine (Changsha Eighth Hospital), Changsha,
Hunan 410100, China.
(7)Department of Surgery, The Medical School, University of South China,
Hengyang, Hunan 421000, China.

Purpose: Breast cancer is the most common cancer among women with ~1.67 million
cases diagnosed annually worldwide, and ~1 in 37 women succumbed to breast
cancer. Over the past decades, new therapeutic strategy has substantially
improved the curative effect for women with breast cancer. However, the currently
available ER-targeted and HER-2-based therapies are not effective for
triple-negative breast cancer patients, which account for ~15% of total breast
cancer cases.
Materials and methods: We reported that 1,25-(OH)2D3, a biologically active form
of vitamin D3, exhibited a strong anticancer effects on the proliferation,
migration, invasion, cell cycle arrest, and apoptosis of both ER-positive (MCF-7)
and ER-negative breast cancer cells (MDA-MB-453).
Results: The anticancer effect of 1,25-(OH)2D3 was more potent compared to the
classical chemotherapeutics tamoxifen in MDA-MB-453 cells. Furthermore, we also
found that 1,25-(OH)2D3 decreased the expression of Ras and resulted in decrease
of the phosphorylation of downstream proteins MEK and ERK1/2, indicating that
1,25-(OH)2D3 plays its anticancer roles through targeting the Ras/MEK/ERK
signaling pathway. In addition, Ras overexpression abrogated 1,25-(OH)2D3-induced
G0/G1 cell cycle arrest and apoptosis of breast cancer cells, as well as the
suppression of proliferation, migration, and invasion. Our study suggested that
1,25-(OH)2D3 suppressed breast cancer tumorigenesis by targeting the Ras/MEK/ERK
signaling pathway.
Conclusion: 1,25-(OH)2D3 might serve as a promising supplement for breast cancer
drug therapy, especially for the ER-negative breast cancer and drug-resistant
breast cancer.

DOI: 10.2147/OTT.S190432
PMCID: PMC6348968
PMID: 30774359

Conflict of interest statement: Disclosure The authors report no conflicts of
interest in this work.

Int J Nanomedicine. 2019 Jan 25;14:819-834. doi: 10.2147/IJN.S190946. eCollection
2019

Green synthesis of multifunctional PEG-carboxylate π back-bonded gold
nanoconjugates for breast cancer treatment.

Gajendiran M(1)(2), Jo H(2), Kim K(2), Balasubramanian S(1).

Author information:
(1)Department of Inorganic Chemistry, University of Madras, Guindy Campus,
Chennai 600025, India, bala2010@yahoo.com.
(2)Division of Bioengineering, School of Life Sciences and Bioengineering,
Incheon National University, Incheon 22012, Republic of Korea,
kyobum.kim@inu.ac.kr.

Background: Surface functionalization of gold nanoparticles (AuNPs) has emerged
as a promising field of research with enormous biomedical applications. The
folate (FA)-attached polymer-gold nanoconjugates play vital role in targeting the
cancer cells.
Methods: AuNPs were synthesized by using di- or tri-carboxylate-polyethylene
glycol (PEG) polymers, including citrate-PEG (CPEG), malate-PEG (MAP), and
tartrate-PEG (TAP), as a reducing and stabilizing agent. After synthesis of
polymer-AuNPs, the freely available hydroxyl and carboxylate groups of CPEG, MAP,
and TAP were used to attach a cancer cell-targeting agent, FA, via a
1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide/N-hydroxy succinimide coupling
reaction to obtain FA-CPEG-AuNP, FA-MAP-AuNP, and FA-TAP-AuNP nanocon-jugates,
respectively. The 5-fluorouracil (5FU) was attached to π back-bonded carbonyl
oxygens of the nanoconjugates, and the in vitro drug release profile was studied
by high pressure liquid chromatography. Biocompatibility profiles of the
FA-CPEG-AuNP, FA-MAP-AuNP, and FA-TAP-AuNP nanoconjugates were investigated using
adult human dermal fibroblasts. Anti-breast cancer activity of 5FU-loaded
nanoconjugates was investigated using MCF-7 breast cancer cells.
Results: X-ray photoelectron spectroscopy and Fourier-transform infrared
spectroscopy analyses confirmed that AuNPs attached to CPEG, MAP, or TAP via the
formation of π back bonding between AuNPs and the ester carbonyl group. The π
back-bonded nanoconjugates exhibited sustained release of 5FU up to 27 days.
FA-MAP-AuNPs exhibited an IC50 at 5 µg/mL, while FA-CPEG-AuNPs and FA-TAP-AuNPs
showed the IC50 at 100 µg/mL toward MCF-7 cancer cells.
Conclusion: The developed polymer π back-bonded multifunctional gold
nanoconjugates could be used as a potential drug delivery system for targeting
MCF-7 cancer cells.

DOI: 10.2147/IJN.S190946
PMCID: PMC6354699
PMID: 30774336

Conflict of interest statement: Disclosure The authors report no conflicts of
interest in this work.

Drug Des Devel Ther. 2019 Jan 22;13:423-433. doi: 10.2147/DDDT.S189476.
eCollection 2019.

Design, synthesis, and biologic evaluation of novel chrysin derivatives as
cytotoxic agents and caspase-3/7 activators.

Al-Oudat BA(1), Alqudah MA(2), Audat SA(3), Al-Balas QA(1), El-Elimat T(1),
Hassan MA(1), Frhat IN(1), Azaizeh MM(2).

Author information:
(1)Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy,
Jordan University of Science and Technology, Irbid 22110, Jordan,
baoudat@just.edu.jo.
(2)Department of Clinical Pharmacy, College of Pharmacy, Jordan University of
Science and Technology, Irbid 22110, Jordan.
(3)Department of Chemistry, College of Science and Arts, Jordan University of
Science and Technology, Irbid 22110, Jordan.

Background: Chrysin (5,7-dihydroxyflavone) is a widely distributed natural
flavonoid found in many plant extracts, honey and propolis. Several studies
revealed that chrysin possesses multiple biological activities including
anti-cancer effects. It has been established that activation of apoptosis is the
key molecular mechanism responsible for the cytotoxic potential of chrysin. The
objective of this study was to design and synthesize potent chrysin analogues as
potential cytotoxic agents.
Methods: A series of chrysin derivatives (3a-m) bearing
N’-alkylidene/arylideneacetohydrazide moiety were designed, synthesized, and
evaluated for their antiproliferative activity against two human breast cancer
cell lines, MDA-MB-231 and MCF-7 by applying the MTT colorimetric assay. Selected
compounds were tested for their ability to induce apoptosis through caspase 3/7
activation in MDA-MB-231 cells only since MCF-7 cells lack procaspase 3.
Results: Compounds (3a-m) were obtained as geometrical isomers (E/Z isomers) in
good yields upon treatment of hydrazide 5 with different aliphatic and aromatic
aldehydes. Most of the synthesized compounds demonstrated moderate-to-good
activity against both cell lines. The cytotoxicity results revealed the
importance of lipophilic moieties at C-4 position of ring D in imparting the
cytotoxic activities to the compounds. Compound 3e with 4-benzyloxy substituent
was found to be the most active among the synthesized compounds with IC50 3.3 µM
against MDA-MB-231 and 4.2 µM against MCF-7 cell lines. The cytotoxic potential
of compound 3e is comparable to that of the well-known anti-cancer agent
doxorubicin. In addition, compounds substituted with fluoro (3b), nitro (3h), and
dimethylamino (3j) exhibited good cytotoxicity with IC50 <6.5 µM against
MDA-MB-231 and <12 µM against MCF-7. Selected compounds were able to induce
apoptosis in MDA-MB-231 cells as indicated by caspase-3 and/or -7 activation.
Conclusion: Our results show that the newly designed chrysin derivatives exert
anticancer activity in human breast cancer cell lines, MDA-MB-231 and MCF-7.
Therefore, they can be considered as leads for further development of more potent
and selective cytotoxic agents.

DOI: 10.2147/DDDT.S189476
PMCID: PMC6349410
PMID: 30774307

Conflict of interest statement: Disclosure The authors report no conflicts of
interest in this work.

IET Syst Biol. 2019 Feb;13(1):1-7. doi: 10.1049/iet-syb.2018.5020.

Fuzzy controller design for breast cancer treatment based on fractal dimension
using breast thermograms.

Zade MA(1), Khodadadi H(2).

Author information:
(1)Department of Electrical Engineering, Khomeinishahr Branch, Islamic Azad
University, Isfahan, Iran.
(2)Department of Electrical Engineering, Khomeinishahr Branch, Islamic Azad
University, Isfahan, Iran. khodadadi@iaukhsh.ac.ir.

In this study, three non-linear indices consist of compression, one-dimensional
(1D) and two-dimensional (2D) fractal dimensions are used for the determination
of the malignancy or benignity of cancer tumours in breast thermograms. On the
other hand, by developing the high-precision infrared cameras as well as new
methods of image processing, biomedical thermography images have found a
prominent position among the others. Furthermore, cancerous tissue can be
affected by the laser. In this study, in order to treat the cancerous lesion
identified by breast thermograms, the laser parameters are designed. The basis of
controller designing is the obtained non-linear indices. If the indices are moved
from the chaotic behaviour to normal condition, the treating tissue is going from
cancerous to a healthy condition and the treatment process is completed.
Radiation frequency and the energy density of laser are designed as two key
elements in the cancer treatment. In this study, the type I and type II fuzzy
controllers are employed for the control strategies. Using the proposed
closed-loop control, the non-linear indices of the cancerous lesion will be
reduced during the treatment process. The simulation results on two datasets of
breast thermograms indicate the superiority of type II fuzzy controller.

DOI: 10.1049/iet-syb.2018.5020
PMID: 30774110

Med Sci (Paris). 2019 Feb;35(2):138-151. doi: 10.1051/medsci/2019003. Epub 2019
Feb 18.

[Hereditary predisposition to breast cancer (1): genetics].

[Article in French]

Cohen-Haguenauer O(1).

Author information:
(1)Unité d’Oncogénétique, Service d’oncologie médicale, pôle HI-3RO et faculté de
Médecine, université Paris 7 Denis Diderot, USPC – Hôpital Saint-Louis, 1,
avenue Claude Vellefaux, 75475 Paris Cedex 10, France.

The main objective of oncogenetics is to characterize a subpopulation of patients
at high risk of cancer development at an early age in order to provide specific
recommendations for an optimized follow-up and care path. Oncogenetic counselling
helps to assess individual risk from a family history. By a family approach of
formal genetics, the key issue is to identify families with a strong aggregation
of cancers, and, in particular, suggesting a specific syndrome of inherited
predisposition to cancer. This approach can lead to the proposal of germline
genetic testing in search of causal mutations. As up to know, the search for a
constitutional mutation in the BRCA genes has led to the identification of a
causal deleterious mutation in less than 10% of index-cases analyzed. It is
therefore important to evaluate the impact of new genes in the current panorama
of inherited predisposition to breast and ovarian cancer.

DOI: 10.1051/medsci/2019003
PMID: 30774081

Autophagy. 2019 Feb 17. doi: 10.1080/15548627.2019.1582951. [Epub ahead of print]

A novel orally available seleno-purine molecule suppresses triple-negative breast
cancer cell proliferation and progression to metastasis by inducing cytostatic
autophagy.

Chang CH(1), Bijian K(1), Wernic D(1), Su J(1), da Silva SD(1), Yu H(1), Qiu
D(1), Asslan M(1), Alaoui-Jamali MA(1).

Author information:
(1)a Segal Cancer Centre and Lady Davis Institute for Medical Research, Sir
Mortimer B. Davis-Jewish General Hospital, McGill University , Departments of
Medicine and Oncology , Montreal , Quebec , Canada .

Patients with triple-negative breast cancer (TNBC) often have a poor prognosis
largely due to lack of effective targeted therapy. Using a library of
seleno-purines coupled to a high-throughput biochemical enzymatic assays we
identified a potent pharmacological enhancer of autophagy (referred herein as
SLLN-15) that selectively activated cytostatic macroautophagy/autophagy in TNBC
preclinical models. SLLN-15 induced a dose-dependent anti-proliferative activity
in the TNBC cell lines MDA-MB-231 and BT-20 via induction of autophagy and
autophagic flux. This induction was associated with a selective inhibition of
AKT-MTOR signaling. Conversely, rapamycin, a known autophagy inducer and MTOR
inhibitor, was unable to duplicate SLLN-15’s effect on TNBC cells. Inhibition of
autophagy by siRNA-mediated targeting of the autophagy regulators, BECN1, ATG5
and ATG7 or using 3-methyladenine (3-MA), significantly protected against
SLLN-15-induced inhibition of cell viability, further supporting that
SLLN-15-induced inhibition of cancer cell proliferation was autophagy-dependent.
SLLN-15-induced autophagy in TNBC cells was also associated with decreased AURKA
expression, decreased AKT phosphorylation and subsequent blockage of the AKT-MTOR
pathway. In vivo, oral SLLN-15 revealed a potent anticancer and anti-metastatic
activity in mice bearing TNBC. Altogether, this study describes a novel regulator
of mammalian autophagy, with potential utility as an experimental therapeutic for
TNBCs.

DOI: 10.1080/15548627.2019.1582951
PMID: 30773992

Post Reprod Health. 2019 Feb 16:2053369119825716. doi: 10.1177/2053369119825716.
[Epub ahead of print]

BMS consensus statement: The risks and benefits of HRT before and after a breast
cancer diagnosis.

Marsden J(1); British Menopause Society(1).

Author information:
(1)King’s College Hospital NHS Foundation Trust, London, UK.

In women at population risk of breast cancer (i.e. most), short-term exposure to
hormone replacement therapy (i.e. up to five years’ use) for symptom relief
exceeds its potential harms, including the associated, increased risk of breast
cancer diagnosis. Many women and health care professionals, however, consider
this to be unacceptably high, although the degree of risk conferred appears
equivalent to, or less than that of, other lifestyle risk factors for this
condition. In contrast, it is recommended that symptomatic women at high baseline
risk due to a family history or a biopsy-confirmed high-risk benign breast
condition and those with previous breast cancer should be managed initially with
lifestyle changes and non-hormonal alternatives. In a minority, whose symptoms
are refractory, hormone replacement therapy and or topical estrogen can be
considered but prescription should only take place after a discussion between the
patient, her primary health care and breast specialist teams.

DOI: 10.1177/2053369119825716
PMID: 30773990

J Magn Reson Imaging. 2019 Feb 17. doi: 10.1002/jmri.26688. [Epub ahead of print]

Preoperative prediction of lymphovascular invasion in invasive breast cancer with
dynamic contrast-enhanced-MRI-based radiomics.

Liu Z(1), Feng B(1)(2), Li C(2), Chen Y(2), Chen Q(1), Li X(3), Guan J(4), Chen
X(1), Cui E(1), Li R(5), Li Z(2), Long W(1).

Author information:
(1)Department of Radiology, Affiliated Jiangmen Hospital of Sun Yat-Sen
University, Jiangmen, Guangdong, China.
(2)School of Electronic Information and Automation, Guilin University of
Aerospace Technology, Guilin, Guangxi, China.
(3)Department of Gastrointestinal Surgery, Affiliated Jiangmen Hospital of Sun
Yat-Sen University, Jiangmen, Guangdong, China.
(4)Department of Thyroid and Breast Surgery, Affiliated Jiangmen Hospital of Sun
Yat-Sen University, Jiangmen, Guangdong, China.
(5)Department of Pathology, Affiliated Jiangmen Hospital of Sun Yat-Sen
University, Jiangmen, Guangdong, China.

BACKGROUND: Lymphovascular invasion (LVI) status facilitates the selection of
optimal therapeutic strategy for breast cancer patients, but in clinical practice
LVI status is determined in pathological specimens after resection.
PURPOSE: To explore the use of dynamic contrast-enhanced (DCE)-magnetic resonance
imaging (MRI)-based radiomics for preoperative prediction of LVI in invasive
breast cancer.
STUDY TYPE: Prospective.
POPULATION: Ninety training cohort patients (22 LVI-positive and 68 LVI-negative)
and 59 validation cohort patients (22 LVI-positive and 37 LVI-negative) were
enrolled.
FIELD STRENGTH/SEQUENCE: 1.5 T and 3.0 T, T1 -weighted DCE-MRI.
ASSESSMENT: Axillary lymph node (ALN) status for each patient was evaluated based
on MR images (defined as MRI ALN status), and DCE semiquantitative parameters of
lesions were calculated. Radiomic features were extracted from the first
postcontrast DCE-MRI. A radiomics signature was constructed in the training
cohort with 10-fold cross-validation. The independent risk factors for LVI were
identified and prediction models for LVI were developed. Their prediction
performances and clinical usefulness were evaluated in the validation cohort.
STATISTICAL TESTS: Mann-Whitney U-test, chi-square test, kappa statistics, least
absolute shrinkage and selection operator (LASSO) regression, logistic
regression, receiver operating characteristic (ROC) analysis, DeLong test, and
decision curve analysis (DCA).
RESULTS: Two radiomic features were selected to construct the radiomics
signature. MRI ALN status (odds ratio, 10.452; P < 0.001) and the radiomics
signature (odds ratio, 2.895; P = 0.031) were identified as independent risk
factors for LVI. The value of the area under the curve (AUC) for a model
combining both (0.763) was higher than that for MRI ALN status alone (0.665;
P = 0.029) and similar to that for the radiomics signature (0.752; P = 0.857).
DCA showed that the combined model added more net benefit than either feature
alone.
DATA CONCLUSION: The DCE-MRI-based radiomics signature in combination with MRI
ALN status was effective in predicting the LVI status of patients with invasive
breast cancer before surgery.
LEVEL OF EVIDENCE: 1 Technical Efficacy Stage: 2 J. Magn. Reson. Imaging 2019.

DOI: 10.1002/jmri.26688
PMID: 30773770

J Eval Clin Pract. 2019 Feb 17. doi: 10.1111/jep.13113. [Epub ahead of print]

The Needs Self-Rating Questionnaire for Breast Cancer (NSQ-BC): Development of a
tool for the needs assessment of women with breast cancer in mainland China.

Zhou K(1), Huo L(1), He X(1), Li M(1), An J(1), Wang W(1), Li J(1), Li X(1).

Author information:
(1)School of Nursing, Xi’an Jiaotong University Health Science Center, Xi’an,
Shaanxi, China.

RATIONALE, AIMS, AND OBJECTIVES: A needs assessment tool considering the cultural
background of mainland China has not been reported. This study developed a Needs
Self-rating Questionnaire for Breast Cancer (NSQ-BC) based on Maslow’s hierarchy
of needs for mainland Chinese patients.
METHODS: The Delphi technique and pilot cross-sectional surveys (two rounds) were
performed for item selection. In the Delphi technique, items were selected
according to the experts’ perspective on the item’s significance (ie, 1-5
Likert-scale ratings of importance; mean > 4.0 and coefficients of variation
<0.25). In the pilot cross-sectional surveys, items were selected according to
internal consistency reliability (Cronbach’s α ≥ 0.70), discriminant validity
(stronger correlations of the item with the hypothesized subscale than for other
subscales), and convergent validity (hypothesized item-subscale correlations
≥0.40). All decisions were made based on the results of statistical analyses,
recommendations of the experts, and in-depth discussion among research team
members.
RESULTS: Following the two evaluation rounds, the revised NSQ-BC comprised 26
items across five subscales of needs: physical, psychological,
respect/self-esteem, information, and rehabilitation. Item ratings from the
expert panellists met the aforementioned criteria (ie, Kendall’s W = 0.329,
P < 0.001). Except for the «respect/self-esteem needs» subscale, Cronbach’s α for
all subscales exceeded 0.70. All items had acceptable discriminant and convergent
validity. Additionally, two new items-good environment/facilities and economic
support-were added to the NSQ-BC, as recommended by the experts.
CONCLUSIONS: The NSQ-BC was developed fully via the comprehensive use of Delphi
technique and pilot cross-sectional surveys. It provides evidence of a proper
instrument for needs assessment and evaluation among women with breast cancer in
mainland China.

DOI: 10.1111/jep.13113
PMID: 30773748

Breast J. 2019 Feb 17. doi: 10.1111/tbj.13196. [Epub ahead of print]

Efficacy of gabapentin for the prevention of paclitaxel induced peripheral
neuropathy: A randomized placebo controlled clinical trial.

Aghili M(1), Zare M(2), Mousavi N(1), Ghalehtaki R(1), Sotoudeh S(1), Kalaghchi
B(3), Akrami S(4), Esmati E(3).

Author information:
(1)Radiation Oncology Research Center (RORC), Cancer Institute, Tehran University
of Medical Sciences, Tehran, Iran.
(2)Department of Radiation Oncology, Hafte-e-Tir Hospital, Iran University of
Medical Sciences, Tehran, Iran.
(3)Radiation Oncology Research Center (RORC), Department of Radiation Oncology,
Cancer Institute, Tehran University of Medical Sciences, Tehran, Iran.
(4)Department of Physical Medicine and Rehabilitation, Tehran University of
Medical Sciences, Tehran, Iran.

Neuropathy is a dose limiting side effect of taxanes which may impact the quality
of life and treatment outcomes. This randomized placebo-controlled double-blinded
clinical trial was carried out to assess the efficacy of gabapentin in preventing
chemotherapy induced neuropathy. Women with breast cancer were randomized into
two groups of paclitaxel chemotherapy with gabapentin 300 mg/three times a day
orally or placebo for 2 weeks started at day 1 of each paclitaxel cycle. Two
groups were compared based on the relative frequency of neuropathy and change in
nerve conducting velocity (NCV). Twenty women were assigned to each study arm.
The majority of the neuropathy in gabapentin group was grade 1 in all of the four
cycles with no event of ≥grade 3 neuropathy in this group. Compared to the
placebo, the rate of 2nd and 3rd grade neuropathy was significantly lower in the
gabapentin group (P = 0.000). The change in NCV after four cycles of paclitaxel
was significantly lower in the gabapentin group compared to the placebo group
(17.7% vs 61.0% decline in NCV for sural and 21.9% vs 62.5% declines in NCV for
peroneal nerve). Gabapentin given with paclitaxel is effective in the prevention
of intermediate and high grade neuropathies both objectively and subjectively.

DOI: 10.1111/tbj.13196
PMID: 30773731

Cell Biochem Funct. 2019 Feb 18. doi: 10.1002/cbf.3377. [Epub ahead of print]

Proteomic analysis of the effects of cell culture density on the metastasis of
breast cancer cells.

Guo ML(1)(2), Sun MX(1), Lan JZ(1), Yan LS(1), Zhang JJ(3), Hu XX(1), Xu S(4),
Mao DH(5), Yang HS(5), Liu YW(2), Chen TX(1).

Author information:
(1)Key Laboratory of Tissue Engineering and Stem Cell of Guizhou Province,
Department of Physiology, School of Basic Medicine, Guizhou Medical University,
Guiyang, China.
(2)The Laboratory for Precision Neurosurgery, Nanfang Hospital, Southern Medical
University, Guangzhou, China.
(3)Human Functional Laboratory, School of Basic Medicine, Guizhou Medical
University, Guiyang, China.
(4)Department of Pathology, School of Clinical Medicine, Guizhou Medical
University, Guiyang, China.
(5)Department of Breast Surgery, Wudang Affiliated Hospital, School of Clinical
Medicine, Guizhou Medical University, Guiyang, China.

Cancer cell progression and proliferation increase cell density, resulting in
changes to the tumour site, including the microenvironment. What is not known is
if increased cell density influences the aggressiveness of cancer cells,
especially their proliferation, migration, and invasion capabilities. In this
study, we found that dense cell culture enhances the aggressiveness of the
metastatic cancer cell lines, 4T1 and ZR-75-30, by increasing their
proliferation, migration, and invasion capabilities. However, a less metastatic
cell line, MCF-7, did not show an increase in aggressiveness, following dense
cell culture conditions. We conducted a differential proteomic analysis on 4T1
cells cultured under dense or sparse conditions and identified an increase in
expression for proteins involved in migration, including focal adhesion,
cytoskeletal reorganization, and transendothelial migration. In contrast, 4T1
cells grown under sparse conditions had higher expression levels for proteins
involved in metabolism, including lipid and phospholipid binding, lipid and
cholesterol transporter activity, and protein binding. These results suggest that
the high-density tumour microenvironment can cause a change in cellular
behaviour, leading towards more aggressive cancers. SIGNIFICANCE OF THE STUDY:
Metastasis of cancer cells is an obstacle to the clinical treatment of cancer. We
found that dense cultures made metastatic cancer cells more potent in terms of
proliferation, migration, and invasion. The proteomic and bioinformatic analyses
provided some valuable clues for further intensive studies about the effects of
cell density on cancer cell aggressiveness, which were associated with events
such as pre-mRNA splicing and RNA transport, focal adhesion and cytoskeleton
reorganization, ribosome biogenesis, and transendothelial migration, or
associated with proteins, such as JAM-1 and S100A11. This investigation gives us
new perspectives to investigate the metastasis mechanisms related to the
microenvironment of tumour sites.

DOI: 10.1002/cbf.3377
PMID: 30773657

Bioorg Med Chem. 2019 Feb 4. pii: S0968-0896(18)31799-1. doi:
10.1016/j.bmc.2019.02.002. [Epub ahead of print]

Synthesis, antiproliferative and apoptosis induction potential activities of
novel bis(indolyl)hydrazide-hydrazone derivatives.

Sreenivasulu R(1), Reddy KT(1), Sujitha P(2), Kumar CG(2), Raju RR(3).

Author information:
(1)Department of Chemistry, Acharya Nagarjuna University, Nagarjuna Nagar, 522
510 Andhra Pradesh, India.
(2)Medicinal Chemistry and Pharmacology Division, CSIR-Indian Institute of
Chemical Technology, Uppal Road, Tarnaka, Hyderabad 500007, Telangana, India.
(3)Department of Chemistry, Acharya Nagarjuna University, Nagarjuna Nagar, 522
510 Andhra Pradesh, India. Electronic address: rrraju1@gmail.com.

In recent years, indole-indazolyl hydrazide-hydrazone derivatives with strong
cell growth inhibition and apoptosis induction characteristics are being strongly
screened for their cancer chemo-preventive potential. In the present study,
N-methyl and N,N-dimethyl bis(indolyl)hydrazide-hydrazone analog derivatives were
designed, synthesized and allowed to evaluate for their anti-proliferative and
apoptosis induction potential against cervical (HeLa), breast (MCF-7 and
MDA-MB-231) and lung (A549) cancer cell lines relative to normal HEK293 cells.
The MTT assay in conjunction with mitochondrial potential assays and the trypan
blue dye exclusion were employed to ascertain the effects of the derivatives on
the cancer cells. Further, mechanistic studies were conducted on compound 14a to
understand the biochemical mechanisms and functional interactions with various
signaling pathways triggered in HeLa and MCF-7 cells. Compound 14a induced
apoptosis via caspase independent pathway through the participation of
mitogen-activated protein kinases (MAPK) such as extracellular signal related
kinase (ERK) and p38 as well as p53 pathways. It originates the activation of
pro-apoptotic proteins such as Bak and Mcl-1s and also strongly induced the
generation of reactive oxygen species. In downstream signaling pathway, activated
p53 protein interacted with MAPK pathways, including SAPK/c-Jun N-terminal
protein kinase (JNK), p38 and ERK kinases resulting in apoptotic cell death. The
involvement of MAPK cascades such as p38, ERK and p38 on compound 14a induced
apoptotic cell death was evidenced by the fact that the inclusion of specific
inhibitors of p38, ERK1/2 and JNK MAPK (SB2035809, PD98059 and SP600125)
prevented the compound 14a towards induced apoptosis. The results clearly showed
that MAP kinase cascades were crucial for apoptotic response in compound 14a
induced cellular killing and were dependent on p53 activity. Based on the
results, compound 14a was identified as a promising candidate for cancer
therapeutics and these findings furnish a basis for further in vivo experiments
on anti-proliferative activity.

DOI: 10.1016/j.bmc.2019.02.002
PMID: 30773423

Bioorg Med Chem. 2019 Feb 10. pii: S0968-0896(18)32161-8. doi:
10.1016/j.bmc.2019.02.018. [Epub ahead of print]

Anti-cancer activity of m-carborane-containing trimethoxyphenyl derivatives
through tubulin polymerization inhibition.

Kaise A(1), Endo Y(2), Ohta K(3).

Author information:
(1)Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical
University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan.
(2)Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical
University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan. Electronic
address: yendo@tohoku-mpu.ac.jp.
(3)School of Pharmacy, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo
142-8555, Japan. Electronic address: k-ohta@pharm.showa-u.ac.jp.

m-Carborane-containing compound 1a was identified as a cell growth inhibitor from
a random screening of a boron compound library. As 1a is a mixture of
diastereomers due to the presence of two chiral carbons, we designed achiral
derivatives 2-4 and studied the structure-activity relationships of the methoxy
groups on the benzene ring. 3,4,5-Trimethoxybenzyl derivative 2a and
3,4,5-trimethoxybenzoyl derivative 3a showed more potent anti-cancer activity
against the human breast cancer cell line MDA-MB-453 than lead compound 1a.
Compound 3a inhibited tubulin polymerization in a dose-dependent manner.

DOI: 10.1016/j.bmc.2019.02.018
PMID: 30773422

Radiother Oncol. 2019 Feb;131:60-65. doi: 10.1016/j.radonc.2018.11.020. Epub 2018
Dec 29.

Reducing the dose of gadolinium-based contrast agents for DCE-MRI guided SBRT:
The effects on inter and intra observer variability for preoperative target
volume delineation in early stage breast cancer patients.

Mouawad M(1), Biernaski H(2), Brackstone M(3), Lock M(4), Yaremko B(5), Sexton
T(6), Yu E(7), Dinniwell RE(8), Lynn K(9), Hajdok G(10), Prato FS(11), Thompson
RT(12), Gelman N(13), Gaede S(14).

Author information:
(1)Medical Biophysics, Western University, London, Canada. Electronic address:
mmouawad@uwo.ca.
(2)Lawson Health Research Institute, London, Canada. Electronic address:
Heather.Biernaski@LawsonResearch.Com.
(3)Medical Biophysics, Western University, London, Canada; Lawson Health Research
Institute, London, Canada; London Health Sciences Centre, London, Canada;
Department of Oncology, Western University, London, Canada. Electronic address:
Muriel.Brackstone@lhsc.on.ca.
(4)London Health Sciences Centre, London, Canada; Department of Oncology, Western
University, London, Canada. Electronic address: Michael.Lock@lhsc.on.ca.
(5)London Health Sciences Centre, London, Canada; Department of Oncology, Western
University, London, Canada. Electronic address: Brian.Yaremko@lhsc.on.ca.
(6)London Health Sciences Centre, London, Canada; Department of Oncology, Western
University, London, Canada. Electronic address: Tracy.Sexton@lhsc.on.ca.
(7)London Health Sciences Centre, London, Canada; Department of Oncology, Western
University, London, Canada. Electronic address: Edward.Yu@lhsc.on.ca.
(8)London Health Sciences Centre, London, Canada; Department of Oncology, Western
University, London, Canada. Electronic address: Robert.Dinniwell@lhsc.on.ca.
(9)London Health Sciences Centre, London, Canada. Electronic address:
Kalan.Lynn@lhsc.on.ca.
(10)London Health Sciences Centre, London, Canada. Electronic address:
George.Hajdok@lhsc.on.ca.
(11)Medical Biophysics, Western University, London, Canada; Lawson Health
Research Institute, London, Canada. Electronic address: prato@lawsonimaging.ca.
(12)Medical Biophysics, Western University, London, Canada; Lawson Health
Research Institute, London, Canada. Electronic address:
thompson@lawsonimaging.ca.
(13)Medical Biophysics, Western University, London, Canada; Lawson Health
Research Institute, London, Canada. Electronic address: ngelman@lawsonimaging.ca.
(14)Medical Biophysics, Western University, London, Canada; Lawson Health
Research Institute, London, Canada; London Health Sciences Centre, London,
Canada. Electronic address: Stewart.Gaede@lhsc.on.ca.

BACKGROUND AND PURPOSE: This study aimed to determine the effects of reducing the
dose of contrast agent (CA) in a DCE-MRI scan on inter- and intra-observer
variability in the context of MRI-guided target volume delineation for
stereotactic body radiation therapy of early stage breast cancer patients. This
is in hopes of reducing risks to patients due to findings of residual CA in brain
and bone.
MATERIALS AND METHODS: Twenty-three patients receiving neoadjuvant radiation
therapy were enrolled. Five observers delineated the gross target volume (GTV)
using DCE-MRI for guidance. 14/23 patients received the full clinical dose of CA
and 9/23 received half. Clinical target volumes (CTV) were created through a
0.5 cm uniform expansion. Several metrics were used to quantify the inter and
intra-observer reliability including differences in delineation volume and the
reliability coefficient.
RESULTS: There were no significant differences in the volume, though half
contrast patients had a lower median for both the GTV and CTV (difference of
0.26 cm3 and 1.27 cm3, respectively). All indicated a high degree of agreement
between and within observers for both dose groups. However, the full dose group
had a greater inter-observer variability, most likely due to the full CA causing
more pronounced enhancement in the periphery.
CONCLUSIONS: Reducing the dose of contrast agent did not significantly alter
inter- or intra-observer variability. These results have prompted our centre to
reduce the dose of gadolinium in all patients enrolled in the SIGNAL trial.

DOI: 10.1016/j.radonc.2018.11.020
PMID: 30773188

Radiother Oncol. 2019 Feb;131:45-51. doi: 10.1016/j.radonc.2018.11.022. Epub 2018
Dec 28.

Oligometastatic breast cancer treated with hypofractionated stereotactic
radiotherapy: Some patients survive longer than a decade.

Milano MT(1), Katz AW(2), Zhang H(2), Huggins CF(2), Aujla KS(2), Okunieff P(3).

Author information:
(1)Department of Radiation Oncology, University of Rochester, United States.
Electronic address: michael_milano@urmc.rochester.edu.
(2)Department of Radiation Oncology, University of Rochester, United States.
(3)Department of Radiation Oncology, University of Florida, Gainesville, United
States.

BACKGROUND: The clinical state of oligometastases describes metastases limited in
number and extent, amenable to metastasis-directed therapy. We sought to analyze
long-term outcomes and characterize potential prognostic factors, in women with
breast cancer (BC) oligometastases treated with hypofractionated stereotactic
radiation (HSRT) therapy on a prospective phase II protocol.
METHODS: Forty-eight women with 1-5 extracranial BC oligometastases received HSRT
to all radiographically apparent sites of disease. Various dose-fractionation
schedules were used. Most (n = 27) received 10 daily fractions, typically ≥50 Gy
(n = 17).
RESULTS: BC patients with bone-only oligometastases (BO, n = 12) vs. all other
patients (non-BO; n = 36) were significantly younger, more likely to present with
oligometastases at the time of primary BC diagnosis (i.e., synchronous), and
significantly more likely to have had hormone receptor-positive disease. The
5-year and 10-year overall survival (OS) rates after HSRT were 83% and 75%,
respectively, for BO patients vs. 31% and 17%, respectively, for non-BO patients
(p = 0.002). BO patients experienced a significantly (p = 0.018) greater freedom
from widespread metastases (FFWM). Among non-BO patients, net oligometastatic GTV

25 cc (reflecting disease burden) was a significant factor for freedom from
local recurrence (p = 0.047) and FFWM (p = 0.028). The number of oligometastatic
lesions (p = 0.007) and organs (p = 0.001) involved were also significant factors
for FFWM in non-BO patients.
CONCLUSIONS: Some patients with BC oligometastases treated with HSRT can survive
10 years. Tumor burden (volume and number of lesions) appears to impact risk of
recurrence. Further research is needed to help better identify BC patients most
likely to benefit from metastasis-directed radiotherapy.

DOI: 10.1016/j.radonc.2018.11.022
PMID: 30773186

Breast Cancer Res. 2019 Feb 17;21(1):26. doi: 10.1186/s13058-019-1105-4.

Correction to: Targeted therapy against Bcl-2-related proteins in breast cancer
cells.

Emi M(1), Kim R(2), Tanabe K(1), Uchida Y(1), Toge T(1).

Author information:
(1)Department of Surgical Oncology, Research Institute for Radiation Biology and
Medicine, Hiroshima University, Hiroshima, Japan.
(2)International Radiation Information Center, Research Institute for Radiation
Biology and Medicine, Hiroshima University, Hiroshima, Japan.
rkim@hiroshima-u.ac.jp.

Erratum for
Breast Cancer Res. 2005;7(6):R940-52.

After the publication of this work [1] errors were noticed in Figs. 1a, 6a, and
8a-in which the β-actin bands were mistakenly presented.

DOI: 10.1186/s13058-019-1105-4
PMID: 30773141

Nat Prod Res. 2019 Feb 17:1-5. doi: 10.1080/14786419.2019.1569012. [Epub ahead of
print]

Sesquiterpenes rich essential oil from Garcinia celebica L. and its cytotoxic and
antimicrobial activities.

Tan WN(1), Tan ZH(2), Zulkifli NI(3), Nik Mohamed Kamal NNS(3), Rozman NAS(4),
Tong WY(4), Leong CR(4), Lim JW(5).

Author information:
(1)a School of Distance Education , Universiti Sains Malaysia , Penang ,
Malaysia.
(2)b School of Chemical Sciences , Universiti Sains Malaysia , Penang , Malaysia.
(3)c Cluster of Integrative Medicine , Advanced Medical and Dental Institute,
Universiti Sains Malaysia , Penang , Malaysia.
(4)d Universiti Kuala Lumpur, Malaysian Institute of Chemical and Bioengineering
Technology , Melaka , Malaysia.
(5)e Department of Fundamental and Applied Sciences , Universiti Teknologi
PETRONAS , Perak , Malaysia.

Garcinia celebica L., locally known as «manggis hutan» in Malaysia is widely used
in folkloric medicine to treat various diseases. The present study was aimed to
examine the chemical composition of the essential oil from the leaves of G.
celebica L. (EO-GC) and its cytotoxic and antimicrobial potential. EO-GC obtained
by hydrodistillation was analysed using capillary GC and GC-MS. Twenty-two
compounds were identified, dominated by α-copaene (61.25%), germacrene D (6.72%)
and β-caryophyllene (5.85%). In the in vitro MTT assay, EO-GC exhibited
significant anti-proliferative effects towards MCF-7 human breast cancer cells
with IC50 value of 45.2 μg/mL. Regarding the antimicrobial activity, it showed
better inhibitory effects on Gram-positive bacteria than Gram-negative bacteria
and none on the fungi and yeasts tested.

DOI: 10.1080/14786419.2019.1569012
PMID: 30773054

Langmuir. 2019 Feb 18. doi: 10.1021/acs.langmuir.8b03988. [Epub ahead of print]

Tracing size and surface chemistry dependent endosomal uptake of gold
nanoparticles using surface-enhanced Raman scattering.

Öztaş DY, Altunbek M, Uzunoğlu D, Yılmaz H, Çetin D, Suludere Z, Culha M.

Surface-enhanced Raman scattering (SERS) based-single cell analysis is an
emerging approach to obtain molecular level information from molecular dynamics
in a living cell. In this study, endosomal biochemical dynamics was investigated
based on size and surface chemistry dependent uptake of gold nanoparticles
(AuNPs) on single cells over time using SERS. MDA-MB-231 breast cancer cells were
exposed to 13 nm and 50 nm AuNPs and their poly-Adenine oligonucleotide modified
forms by controlling the order and combination of AuNPs. The average spectra
obtained from 20-single cells were analyzed to study the nature of the
biochemical species or processes taking place on the AuNPs surfaces. The spectral
changes, especially from proteins and lipids of endosomal vesicles, were observed
depending on the size, surface chemistry, and combination as well as the duration
of the AuNP-treatment. The results demonstrate that SERS spectra are sensitive to
trace biochemical changes not only the size, surface chemistry and aggregation
status of AuNPs but also their endosomal maturation steps over time, which can be
simple and fast way for understanding the AuNPs behavior in single cell and
useful for the assisting and controlling of AuNPs-based gene or drug delivery
applications.

DOI: 10.1021/acs.langmuir.8b03988
PMID: 30773019

Med J Aust. 2019 Feb;210(3):115-116.e1. doi: 10.5694/mja2.13003.

My patients prepared me well.

Brennan ME(1)(2).

Author information:
(1)University of Sydney, Sydney, NSW.
(2)University of Notre Dame, Sydney, NSW.

DOI: 10.5694/mja2.13003
PMID: 30772936

J Cancer Educ. 2019 Feb 16. doi: 10.1007/s13187-019-1481-6. [Epub ahead of print]

Characterizing Perceptions Around the Patient-Oncologist Relationship: a
Qualitative Focus Group Analysis.

Palmer Kelly E(1), Meara A(2), Hyer M(3), Payne N(4), Pawlik TM(5).

Author information:
(1)Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
(2)Department of Internal Medicine, The Ohio State University Wexner Medical
Center, Columbus, OH, USA.
(3)Department of Surgery, The Ohio State University Wexner Medical Center,
Columbus, OH, USA.
(4)The Ohio State University College of Medicine, Columbus, OH, USA.
(5)Department of Surgery, The Ohio State University Wexner Medical Center,
Columbus, OH, USA. Tim.Pawlik@osumc.edu.

The purpose of the current study was to characterize the experiences of cancer
patients and their caregiver/family members around their relationship with their
oncologist, health care team, and the hospital environment. Participants were
recruited from The Ohio State University Comprehensive Cancer Center. Participant
sociodemographic factors were assessed. Focus groups were moderated and
recorded by two members of the research team using a semi-structured interview
format. The audio recordings were transcribed and uploaded to NViVO 11 for
analyses. Four focus groups were conducted with 25 participants. The mean age of
participants was 58.4 years (SD = 15.1, range 26.0-76.0). Participants who were
identified as patients (84%) reported different malignancy types including breast
(56%), gynecologic (16%), skin (6%) oral (6%), and non-Hodgkin’s lymphoma (6%).
Three major themes that emerged around the patient-oncologist relationship,
include (1) choosing a physician and health care location, (2) relationship with
the physician, health care team, and hospital environment; and (3) patient
engagement and decision-making. Subthemes highlighted the importance of the
flexible communication behaviors and trustworthiness of the oncologist, and the
impact of other health care team members. Patients also reported the desire to be
engaged in making treatment-related decisions and to include the caregiver/spouse
in all stages of cancer care. Understanding the experience of cancer patients in
a relationship with their oncologist in the context of the health care team and
health care environment will be an important area of future research to provide
optimal, tailored patient-centered cancer care.

DOI: 10.1007/s13187-019-1481-6
PMID: 30772927

J Surg Res. 2019 Feb 14;238:207-217. doi: 10.1016/j.jss.2019.01.010. [Epub ahead
of print]

Factors Leading to Decreased Rates of Immediate Postmastectomy Reconstruction.

Tung L(1), Jeong YJ(2), Lane C(3), Carey JN(4), Sposto R(5), Schechter NR(6),
Sener SF(1), Lang JE(7).

Author information:
(1)Department of Surgery and Norris Comprehensive Cancer Center, Division of
Breast, Soft Tissue and Endocrine Surgery, University of Southern California
(USC), Los Angeles, California.
(2)Department of Surgery, School of Medicine, Catholic University of Daegu,
Daegu, South Korea.
(3)Department of Preventive Medicine, USC, Los Angeles, California.
(4)Department of Surgery, Division of Plastic and Reconstructive Surgery, USC,
Los Angeles, California.
(5)Department of Preventive Medicine and Pediatrics (CHLA) and Norris
Comprehensive Cancer Center, USC, Los Angeles, California.
(6)Department of Radiation Oncology, Norris Comprehensive Cancer Center,
University of Southern California, Los Angeles, California.
(7)Department of Surgery and Norris Comprehensive Cancer Center, Division of
Breast, Soft Tissue and Endocrine Surgery, University of Southern California
(USC), Los Angeles, California. Electronic address: Julie.Lang@med.usc.edu.

BACKGROUND: This study was performed to determine if there was a difference in
immediate breast reconstruction (IBR) rates between our public hospital and
private cancer center, which share a common faculty with a consistent management
philosophy in multidisciplinary care. We investigated the factors affecting
postmastectomy reconstruction and IBR rates.
MATERIALS AND METHODS: We retrospectively identified women with clinical stage
I-II breast cancer who underwent mastectomy at our public hospital, Los Angeles
County Medical Center, and our private cancer center, Keck Hospital of USC/Norris
Comprehensive Cancer Center. Univariate and multivariate analyses were performed
to study predictors of IBR and any breast reconstruction.
RESULTS: Of 293 mastectomy patients, the rate of any breast reconstruction at the
private cancer (56.6%) center was higher than that at the public hospital
(36.2%). IBR rates for the private cancer center (93.6%) and for patients with
private insurance were higher than for the public hospital (40.8%) and likewise
for those without insurance (86.7% versus 45.5%). In a multivariate analysis, the
odds of IBR at our private cancer center were 22.96 times higher than that at our
public hospital. Age >50 y and radiotherapy were independent predictive factors
associated with less likelihood of any breast reconstruction.
CONCLUSIONS: Patients at the public hospital had a much lower rate of breast
reconstruction than the private cancer center patients, even after controlling
for stage and the team of treating physicians. Our results showed that older age
and radiotherapy affect rates of breast reconstruction, as do hospital system and
insurance status.

DOI: 10.1016/j.jss.2019.01.010
PMID: 30772679

Eur J Med Chem. 2019 Feb 7;167:226-244. doi: 10.1016/j.ejmech.2019.02.003. [Epub
ahead of print]

Pyranocarbazole derivatives as potent anti-cancer agents triggering tubulin
polymerization stabilization induced activation of caspase-dependent apoptosis
and downregulation of Akt/mTOR in breast cancer cells.

Patel OPS(1), Arun A(2), Singh PK(3), Saini D(4), Karade SS(5), Chourasia MK(3),
Konwar R(6), Yadav PP(7).

Author information:
(1)Division of Medicinal and Process Chemistry, CSIR-Central Drug Research
Institute, BS-10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow
226031, Uttar Pradesh, India.
(2)Division of Endocrinology, CSIR-Central Drug Research Institute, BS-10/1,
Sector 10, Jankipuram Extension, Sitapur Road, Lucknow 226031, Uttar Pradesh,
India.
(3)Division of Pharmaceutics, CSIR-Central Drug Research Institute, BS-10/1,
Sector 10, Jankipuram Extension, Sitapur Road, Lucknow 226031, Uttar Pradesh,
India.
(4)Division of Medicinal and Process Chemistry, CSIR-Central Drug Research
Institute, BS-10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow
226031, Uttar Pradesh, India; Academy of Scientific and Innovative Research,
CSIR-Central Drug Research Institute, BS-10/1, Sector 10, Jankipuram Extension,
Sitapur Road, Lucknow 226031, Uttar Pradesh, India.
(5)Division of Molecular Structural Biology, CSIR-Central Drug Research
Institute, BS-10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow
226031, Uttar Pradesh, India.
(6)Division of Endocrinology, CSIR-Central Drug Research Institute, BS-10/1,
Sector 10, Jankipuram Extension, Sitapur Road, Lucknow 226031, Uttar Pradesh,
India. Electronic address: r_konwar@cdri.res.in.
(7)Division of Medicinal and Process Chemistry, CSIR-Central Drug Research
Institute, BS-10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow
226031, Uttar Pradesh, India; Academy of Scientific and Innovative Research,
CSIR-Central Drug Research Institute, BS-10/1, Sector 10, Jankipuram Extension,
Sitapur Road, Lucknow 226031, Uttar Pradesh, India. Electronic address:
pp_yadav@cdri.res.in.

A series of new pyranocarbazole derivatives were synthesized via semi-synthetic
modification of koenimbine (1a) and koenidine (1b) isolated from the leaves of
Murraya koenigii. Among all, compound 3bg displayed significant anti-cancer
activity against MDA-MB-231, DU145 and PC3 cell lines with the IC50 values of
3.8, 7.6 and 5.8 μM, respectively. It was also observed that the
halogenated-benzyl substitution at N-9 position, C-3 Methyl and C-7 methoxy group
on carbazole motif are favoured for anti-cancer activity. The detailed
investigation was carried out with compound 3bg and its SEDDS (self-emulsifying
drug delivery systems) formulation 3bgF. The in vivo drug release behavior study
showed that the formulation enhanced slow release and better bioavailability at a
tumor site. Compound 3bg and its formulation (3bgF) significantly inhibited cell
proliferation and colony formation, induced G2/M arrest, reduced cellular ROS
generation and induced caspase-dependent apoptosis in MDA-MB-231 cells. 3bg also
induced significant alteration of Bax/Bcl expression ratio suggesting involvement
of mitochondrial apoptosis. Additionally, 3bg caused down-regulation of mTOR/Akt
survival pathway. 3bg do not bind to DNA, but interacts with tubulin as observed
with in silico molecular docking studies. This interaction results in
stabilization of tubulin polymerization similar to paclitaxel as detected in
cell-free assay. Oral administration of 3bgF for 30 days at dose rate of 10 and
20 mg/kg body weight significantly reduced tumor growth in syngenic rat LA-7
mammary tumor model. These results indicated that the pyranocarbazole natural
product based N-substituted analogues can act as potential anti-cancer lead.

DOI: 10.1016/j.ejmech.2019.02.003
PMID: 30772606

J Proteomics. 2019 Feb 14. pii: S1874-3919(19)30050-8. doi:
10.1016/j.jprot.2019.02.007. [Epub ahead of print]

Quantitative label-free mass spectrometry using contralateral and adjacent breast
tissues reveal differentially expressed proteins and their predicted impacts on
pathways and cellular functions in breast cancer.

Gomig THB(1), Cavalli IJ(1), de Souza RLR(1), Vieira E(1), Lucena ACR(2), Batista
M(3), Machado KC(4), Marchini FK(3), Marchi FA(5), Lima RS(6), de Andrade Urban
C(6), Cavalli LR(7), de Souza Fonseca Ribeiro EM(8).

Author information:
(1)Genetics Department, Federal University of Parana, Curitiba, Brazil.
(2)Functional Genomics Laboratory, Carlos Chagas Institute, Fiocruz, Curitiba,
Parana, Brazil.
(3)Functional Genomics Laboratory, Carlos Chagas Institute, Fiocruz, Curitiba,
Parana, Brazil; Mass Spectrometry Facility – RPT02H, Carlos Chagas Institute,
Fiocruz, Curitiba, Parana, Brazil.
(4)Mass Spectrometry Facility – RPT02H, Carlos Chagas Institute, Fiocruz,
Curitiba, Parana, Brazil.
(5)International Research Center (CIPE) – A.C. Camargo Cancer Center, São Paulo,
SP, Brazil.
(6)Breast Disease Center, Hospital Nossa Senhora das Graças, Curitiba, Brazil.
(7)Research Institute Pele Pequeno Principe, Curitiba, Brazil; Lombardi
Comprehensive Cancer Center, Georgetown University, USA.
(8)Genetics Department, Federal University of Parana, Curitiba, Brazil.
Electronic address: enilzeribeiro@gmail.com.

Proteins play an essential role in the biological processes associated with
cancer. Their altered expression levels can deregulate critical cellular pathways
and interactive networks. In this study, the mass spectrometry-based label-free
quantification followed by functional annotation was performed to investigate the
most significant deregulated proteins among tissues of primary breast tumor (PT)
and axillary metastatic lymph node (LN) and corresponding non-tumor tissues
contralateral (NCT) and adjacent (ANT) from patients diagnosed with invasive
ductal carcinoma. A total of 462 proteins was observed as differentially
expressed (DEPs) among the groups analyzed. A high level of similarity was
observed in the proteome profile of both non-tumor breast tissues and DEPs
(n = 12) were mainly predicted in the RNA metabolism. The DEPs among the
malignant and non-tumor breast tissues [n = 396 (PTxNCT) and n = 410 (LNxNCT)]
were related to pathways of the LXR/RXR, NO, eNOS, eIF2 and sirtuins,
tumor-related functions, fatty acid metabolism and oxidative stress. Remarkable
similarity was observed between both malignant tissues, which the DEPs were
related to metastatic capabilities. Altogether, our findings revealed
differential proteomic profiles that affected cancer associated and
interconnected signaling processes. Validation studies are recommended to
demonstrate the potential of individual proteins and/or pathways as biological
markers in breast cancer. SIGNIFICANCE: The proteomic analysis of this study
revealed high similarity in the proteomic profile of the contralateral and
adjacent non-tumor breast tissues. Significant differences were identified among
the proteome of the malignant and non-tumor tissue groups of the same patients,
providing relevant insights into the hallmarks, signaling pathways, biological
functions, and interactive protein networks that act during tumorigenesis and
breast cancer progression. These proteins are suggested as targets of relevant
interest to be explored as potential biological markers related to tumor
development and metastatic progression in the breast cancer disease.

DOI: 10.1016/j.jprot.2019.02.007
PMID: 30772490

Int J Biochem Cell Biol. 2019 Feb 14. pii: S1357-2725(19)30022-6. doi:
10.1016/j.biocel.2019.01.015. [Epub ahead of print]

Therapeutics strategies against cancer stem cell in breast cancer.

Ghasemi F(1), Sarabi PZ(2), Athari SS(3), Esmaielzadeha A(4).

Author information:
(1)Blood Transfusion Research Center, High Institute for Research and Education
in Transfusion Medicine, Tehran, Iran.
(2)Molecular and Medicine Research Center, Department of Biotechnology, Faculty
of Medicine, Arak University of Medical Sciences, Arak, Iran.
(3)Department of Immunology, Faculty of Medicine, Zanjan University of Medical
Sciences, Zanjan, Iran.
(4)Cancer Gene Therapy Research Center (CGRC), Zanjan University of Medical
Sciences, Zanjan, Iran. Electronic address: a46reza@zums.ac.ir.

Breast cancer is known as a most prevalent cancer and second deadly cancer, among
women worldwide. Due to the high incidence rate of breast cancer and limitations
of conventional therapy it seemed essential to look for new targets in cancer
cells and directly target them such as target therapy on breast cancer stem
cells. In this review we indicate some of therapeutic uses of cancer stem cells
in breast cancer. Some strategies are targeting surface specific markers and
activated signaling pathways in their microenvironment such as Notch, Hedgehog,
Wnt/b-catenin, PI3K/Akt, NF-kB, BMP and TGF-β and their maintenance and drug
resistance, using various miRNAs, enhancement of CSCs apoptosis, differentiation
therapy, blocking epithelial to mesenchymal transition and using different
natural compounds. Recent studies have shown that cancer stem cells play major
roles in target therapy on breast cancer. The new manipulation approaches of
cancer stem cells can be used as target therapy of breast cancer that were
highlighted for immunotherapy of cancer.

DOI: 10.1016/j.biocel.2019.01.015
PMID: 30772480

Int J Pharm. 2019 Feb 14. pii: S0378-5173(19)30134-6. doi:
10.1016/j.ijpharm.2019.02.011. [Epub ahead of print]

Combination of microneedles and microemulsions to increase celecoxib topical
delivery for potential application in chemoprevention of breast cancer.

Mojeiko G(1), de Brito M(1), Salata GC(1), Lopes LB(2).

Author information:
(1)Department of Pharmacology, Institute of Biomedical Sciences, University of
Sao Paulo, Brazil.
(2)Department of Pharmacology, Institute of Biomedical Sciences, University of
Sao Paulo, Brazil. Electronic address: lublopes@usp.br.

In spite of the high incidence of breast cancer worldwide, there are few
strategies for its chemoprevention, and they have limited adherence mainly due to
their serious adverse effects. As a new approach for local breast cancer
chemoprevention, we developed and optimized microemulsions for topical delivery
of celecoxib to the breast skin, and evaluated their combination with
microneedles to improve drug penetration for localization in the mammary tissue.
Microemulsions containing water at 15% (ME-15), 29% (ME-29) and 60% (ME-60) were
obtained and characterized. They were isotropic, displayed Newtonian behavior and
particle size smaller than 100 nm. ME-15 and ME-29 increased transepidermal water
loss (TEWL) compared to ME-60, and displayed stronger vascular toxicity,
evidenced by hemorrhage and lysis in HET-CAM assays. ME-60 was more efficacious
at increasing celecoxib cutaneous and percutaneous delivery (1.3-4-fold).
Increasing the number of microneedle roller applications from 1 to 8 increased
the number of skin punctures and TEWL; its association with ME-60 promoted no
further increase in TEWL, but improved (1.6-4-fold) celecoxib cutaneous and
percutaneous delivery. Microemulsion incorporation reduced celecoxib IC50 in
MCF-7 cells (3.3-fold), suggesting that presence of formulation components in the
mammary tissue might improve drug cytotoxicity.

DOI: 10.1016/j.ijpharm.2019.02.011
PMID: 30772460

Biochem Pharmacol. 2019 Feb 14;163:133-141. doi: 10.1016/j.bcp.2019.02.017. [Epub
ahead of print]

Palbociclib triggers apoptosis in bladder cancer cells by Cdk2-induced
Rad9-mediated reorganization of the Bak.Bcl-xl complex.

Zhang G(1), Ma F(2), Li L(2), Li J(3), Li P(2), Zeng S(2), Sun H(2), Li E(4).

Author information:
(1)Medical School and State Key Laboratory of Pharmaceutical Biotechnology,
Nanjing University, Nanjing, China; State Key Laboratory for Chemistry and
Molecular Engineering of Medicinal Resources, Ministry of Science and Technology
of China, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal
University, Guilin, China. Electronic address: zgh1207@gxnu.edu.cn.
(2)State Key Laboratory for Chemistry and Molecular Engineering of Medicinal
Resources, Ministry of Science and Technology of China, School of Chemistry and
Pharmaceutical Sciences, Guangxi Normal University, Guilin, China.
(3)Medical School and State Key Laboratory of Pharmaceutical Biotechnology,
Nanjing University, Nanjing, China.
(4)Medical School and State Key Laboratory of Pharmaceutical Biotechnology,
Nanjing University, Nanjing, China. Electronic address: erguang@nju.edu.cn.

Palbociclib is a Cdk4/6 inhibitor approved for metastatic estrogen
receptor-positive breast cancer. The drug is also under clinical evaluation for
metastatic urothelial cancer and other solid tumors. Preclinical studies from
multiple tumor types suggest that other factors also affect the sensitivity of
individual tumors to Cdk4/6 inhibitor. We show here that Cdk2 has an essential
role in palbociclib antitumor effect against bladder cancers. We found that
palbociclib induced apoptosis instead of cell cycle arrest to exhibit its
anticancer activity in T24 cells, as was evidenced by membrane blebbing,
caspase-3 activation and AIF release from mitochondria. Cdk2 activation was
important to palbociclib-induced apoptotic triggering activity, since depletion
of Cdk2 significantly inhibited caspase-3 activation and cell apoptosis. Cdk2
activation caused p-Rad9 translocation to the mitochondria and subsequently
interaction with Bcl-xl, leading to conformational activation of Bak and cell
apoptosis. The anticancer activity and Cdk2 activation of palbociclib-treated
mice were finally validated in a T24 xenograft model. Collectively, these results
together demonstrate that palbociclib exerts its anticancer effect in T24 cells
mainly through Cdk2 activation. Our findings provide new insights into the
molecular interactions and anticancer mechanisms of Cdk4/6 inhibitors.

DOI: 10.1016/j.bcp.2019.02.017
PMID: 30772267

J Geriatr Oncol. 2019 Feb 13. pii: S1879-4068(19)30008-6. doi:
10.1016/j.jgo.2019.01.012. [Epub ahead of print]

Potentially inappropriate medication use and associated healthcare utilization
and Costs among older adults with colorectal, breast, and prostate cancers.

Feng X(1), Higa GM(2), Safarudin F(1), Sambamoorthi U(1), Tan X(3).

Author information:
(1)Department of Pharmaceutical Systems and Policy, West Virginia University,
School of Pharmacy, PO Box 9510, Morgantown, West, Virginia 26505, USA.
(2)Department of Clinical Pharmacy, West Virginia University, School of Pharmacy,
PO Box 9510, Morgantown, West, Virginia 26505, USA.
(3)Department of Pharmaceutical Systems and Policy, West Virginia University,
School of Pharmacy, PO Box 9510, Morgantown, West, Virginia 26505, USA.
Electronic address: tanxi@umich.edu.

OBJECTIVES: To assess the association between Potentially Inappropriate
Medication (PIM) use and healthcare utilization and costs among Medicare
beneficiaries with breast, prostate, or colorectal cancer.
MATERIALS AND METHODS: A retrospective cohort study was conducted using the
SEER-Medicare linked database in older adults with breast (N = 17,630), prostate
(N = N = 18,721), or colorectal cancer (female: N = 5652; male: N = 3768). PIM
use was defined based on 2015 Beers Criteria and was measured using prescription
claims. Count models were used to examine the association between PIM use and the
number of inpatient and ER visits. Generalized linear models were utilized with
the log-link function and gamma distribution to analyze associations between PIM
use and medical expenditures. The Inverse Treatment Probability Treatment Weights
were applied in the analyses.
RESULTS: 61.7% of patients with breast cancer, 47.3% of patients with prostate
cancer, and 66.3% (females: 68.0%; males: 63.8%) of patients with colorectal
cancer were found to use one or more PIM. PIM use was positively associated with
number of inpatient visits, number of ER visits, non-drug costs, and total
medical costs in all three types of cancer, except for the number of inpatient
visits among patients with colorectal cancer.
CONCLUSION: PIM use was significantly associated with greater healthcare
utilization and higher healthcare costs in this population. Future research
should be undertaken to obtain additional evidence that can aid in the
optimization of integrated interdisciplinary programs to facilitate effective
management of care for older patients with cancer and other co-morbid medical
problems.

DOI: 10.1016/j.jgo.2019.01.012
PMID: 30772191

Acad Radiol. 2019 Feb 13. pii: S1076-6332(19)30050-9. doi:
10.1016/j.acra.2019.01.020. [Epub ahead of print]

Factors Impacting False Positive Recall in Screening Mammography.

Honig EL(1), Mullen LA(1), Amir T(1), Alvin MD(1), Jones MK(1), Ambinder EB(1),
Falomo ET(1), Harvey SC(2).

Author information:
(1)The Russell H. Morgan Department of Radiology and Radiological Science, Johns
Hopkins University School of Medicine, 601 North Caroline Street, Suite 4120E,
Baltimore, MD 21287.
(2)The Russell H. Morgan Department of Radiology and Radiological Science, Johns
Hopkins University School of Medicine, 601 North Caroline Street, Suite 4120E,
Baltimore, MD 21287. Electronic address: sharvey7@jhmi.edu.

RATIONALE AND OBJECTIVES: Our objective was to identify factors impacting false
positive recalls in screening mammography.
MATERIALS AND METHODS: We retrospectively reviewed our screening mammography
database from August 31, 2015 to September 30, 2016, including full field digital
mammograms (FFDM) and digital breast tomosynthesis (DBT) mammograms. False
positive (FP) exams were defined as Breast Imaging-Reporting and Data System
(BI-RADS) 1 or 2 assessments at diagnostic imaging with 1 year cancer-free
follow-up, Breast Imaging-Reporting and Data System 3 assessment at diagnostic
imaging with 2 years cancer free follow-up, or biopsy with benign pathology. True
positives were defined as malignant pathology on biopsy or surgical excision. We
evaluated the association of FP recalls with multiple patient-level factors and
imaging features.
RESULTS: A total of 22,055 screening mammograms were performed, and 1887 patients
were recalled (recall rate 8.6%). Recall rate was lower for DBT than full field
digital mammograms (8.0% vs 10.6%, p < 0.001). FP results were lower if prior
mammograms were available (90.8% vs 95.8%, p = 0.02), and if there was a previous
benign breast biopsy (87.6% vs 92.9%, p = 0.01). Mean age for the FP group was
lower than the true positive group (56.1 vs 62.9 years, p < 0.001). There were no
significant differences in FP recalls based on history of high-risk lesions,
family history of breast or ovarian cancer, hormone use, breast density, race, or
body mass index.
CONCLUSION: FP recalls were significantly less likely with DBT, in older women,
in patients with prior mammograms available for comparison, and in patients with
histories of benign breast biopsy. This study supports the importance of using
DBT in the screening setting and obtaining prior mammograms for comparison.

DOI: 10.1016/j.acra.2019.01.020
PMID: 30772138

Patient Educ Couns. 2019 Feb 11. pii: S0738-3991(19)30039-4. doi:
10.1016/j.pec.2019.02.014. [Epub ahead of print]

Access to health information, health literacy and health-related quality of life
among women living with breast cancer: Depression and anxiety as mediators.

Kugbey N(1), Meyer-Weitz A(2), Oppong Asante K(3).

Author information:
(1)Discipline of Psychology, School of Applied Human Sciences, University of
KwaZulu-Natal, Durban, South Africa; Department of Family and Community Health,
School of Public Health, University of Health and Allied Sciences, Hohoe-Campus,
Volta Region, Ghana. Electronic address: nkugbey@uhas.edu.gh.
(2)Discipline of Psychology, School of Applied Human Sciences, University of
KwaZulu-Natal, Durban, South Africa.
(3)Discipline of Psychology, School of Applied Human Sciences, University of
KwaZulu-Natal, Durban, South Africa; Department of Psychology, School of Social
Sciences, University of Ghana, Legon, Accra, Ghana.

OBJECTIVE: This study examined the direct and indirect influences of health
literacy and access to health information on the quality of life among 205 women
living with breast cancer in Ghana.
METHODS: A cross-sectional survey design was employed. The
interviewer-administered instrument included the health literacy scale, questions
on access and satisfaction with healthcare information, depression and anxiety
scale, and the Functional Assessment of Cancer Therapy-Breast Cancer.
RESULTS: Access to health information and health literacy had significant
indirect effects on quality of life through depression and anxiety. Whereas
health literacy had direct influence on quality of life after controlling for
other factors, access to information had no direct influence on quality of life.
CONCLUSION: Health literacy and access to health information improve quality of
life in women living with breast cancer by reducing the levels of depression and
anxiety. Depression and anxiety serve as possible mechanisms for the positive
impacts of access to health information and health literacy on improved quality
of life among breast cancer patients.
PRACTICE IMPLICATIONS: Health care providers need to ensure that the information
needs of patients are met in oncology practice to reduce their negative emotional
states which would lead to improved health and wellbeing.

DOI: 10.1016/j.pec.2019.02.014
PMID: 30772116

Patient Educ Couns. 2019 Feb 11. pii: S0738-3991(19)30038-2. doi:
10.1016/j.pec.2019.02.013. [Epub ahead of print]

Engaging limited English proficient and ethnically diverse low-income women in
health research: A randomized trial of a patient navigator intervention.

Nickell A(1), Stewart SL(2), Burke NJ(3), Guerra C(4), Cohen E(5), Lawlor C(1),
Colen S(5), Cheng J(4), Joseph G(6).

Author information:
(1)Shanti Project, San Francisco, USA.
(2)Department of Public Health Sciences, Division of Biostatistics, University of
California, Davis, USA.
(3)Public Health University of California, Merced, USA; Department of
Anthropology, History & Social Medicine, University of California, San Francisco
USA.
(4)Department of Anthropology, History & Social Medicine, University of
California, San Francisco USA.
(5)BreastCancerTrials.org, San Francisco, USA.
(6)Department of Anthropology, History & Social Medicine, University of
California, San Francisco USA. Electronic address: galen.joseph@ucsf.edu.

OBJECTIVE: Evaluate a community-based navigator intervention to increase breast
cancer patients’ and survivors’ access to information about health research
participation opportunities.
METHODS: In the context of a Community Based Participatory Research
collaboration, we conducted a prospective randomized controlled trial of the
Health Research Engagement Intervention with pre- and post-intervention surveys
(n = 133). The primary outcome was health research information-seeking behavior.
Secondary outcomes were health research knowledge, willingness to participate in
health research, and health empowerment. Qualitative interviews (n = 11)
elucidated participant perspectives on the intervention.
RESULTS: There was no statistically significant difference between intervention
and control groups’ information-seeking behavior. Knowledge that not all health
research studies are about drugs or treatments increased significantly from pre-
to post-test among intervention group participants (32% to 48%, p = 0.012), but
not in the control group (43% to 30%, p = 0.059); the difference between arms was
statistically significant (p = 0.0012). Although survey responses indicated
willingness to participate, qualitative interviews identified competing
priorities that limited participants’ motivation to seek enrollment information.
CONCLUSIONS AND PRACTICE IMPLICATIONS: Community-based navigators are a trusted,
and therefore promising link between health research and low-income underserved
communities. However, systemic barriers in health research infrastructures need
to be addressed to include low income, LEP and immigrant populations.

DOI: 10.1016/j.pec.2019.02.013
PMID: 30772115

Cir Esp. 2019 Feb 13. pii: S0009-739X(18)30359-2. doi:
10.1016/j.ciresp.2018.12.003. [Epub ahead of print]

Detection of the sentinel node using a magnetic tracer in thyroid cancer. A
technical pilot study.

[Article in English, Spanish]

Ríos A(1), Rodríguez JM(2), Ibañez N(3), Piñero A(2), Parrilla P(2).

Author information:
(1)Departamento de Cirugía, Pediatría y Obstetricia y Ginecología, Universidad de
Murcia, Murcia, España; Servicio de Cirugía General y de Aparato Digestivo,
Hospital Clínico Universitario Virgen de la Arrixaca, El Palmar, Servicio
Murciano de Salud, Murcia, España; Instituto Murciano de Investigación
Bio-Sanitaria Virgen de la Arrixaca (IMIB-Arrixaca), Murcia, España. Electronic
address: arzrios@um.es.
(2)Departamento de Cirugía, Pediatría y Obstetricia y Ginecología, Universidad de
Murcia, Murcia, España; Servicio de Cirugía General y de Aparato Digestivo,
Hospital Clínico Universitario Virgen de la Arrixaca, El Palmar, Servicio
Murciano de Salud, Murcia, España; Instituto Murciano de Investigación
Bio-Sanitaria Virgen de la Arrixaca (IMIB-Arrixaca), Murcia, España.
(3)Servicio de Cirugía General y de Aparato Digestivo, Hospital Clínico
Universitario Virgen de la Arrixaca, El Palmar, Servicio Murciano de Salud,
Murcia, España; Instituto Murciano de Investigación Bio-Sanitaria Virgen de la
Arrixaca (IMIB-Arrixaca), Murcia, España.

INTRODUCTION: There is no standard procedure for the detection of the sentinel
node (SN) in thyroid disease. However, the recent detection of the SN using a
paramagnetic tracer is proving to be useful in breast cancer and melanoma. The
objective was to assess the utility of super paramagnetic iron oxide tracer for
the intraoperative detection of the SN in patients with papillary thyroid cancer
without nodal involvement in the preoperative study.
METHOD: A single center, prospective pilot study of a class IIa medical device (a
paramagnetic tracer). The study included thyroid cancers which were T1-T2 tumors
in the cytohistological analysis with a negative preoperative nodal assessment,
operated on consecutively during scheduled treatment. For the localization of the
SN, an interlesional injection of 2mL of super paramagnetic iron oxide was
administered. After ten minutes, ferromagnetic activity was detected in the
adjacent nodes. Once the node had been detected, we proceeded by extracting it
for intraoperative analysis. The effectiveness of the procedure for detecting the
SN was assessed, with the main variable being whether it was detected or not.
RESULTS: The project was assessed after the first cases had been carried out. The
SN was located in all cases, which was done easily in the first four, but in the
fifth case the SN detection was complicated by the interference of the reusable
neurostimulation electrodes with the ferromagnetic signal. Intraoperative
histology revealed the SN was positive in 80% (n=4) of cases (20% [n=1] were
macrometastases and 60% [n=3] micrometastases). Total thyroidectomies were
carried out, with central lymph node dissection in 4 of the patients and lateral
in one due to the result of the detected SN. The histology showed the carcinoma
was papillary, a classic type, in 80% (n=4) and a follicular variant in 20%
(n=1). Forty percent (n=2) were multifocal, 40% (n=2) had vascular infiltration,
and 60% (n=3) had extrathyroidal extension. Staging determined the application of
radioactive iodine therapy (150mCi) in 80% of cases (n=4).
CONCLUSIONS: A paramagnetic tracer can be useful for detecting the SN and
correctly staging papillary carcinoma.

DOI: 10.1016/j.ciresp.2018.12.003
PMID: 30771997

Talanta. 2019 May 15;197:86-91. doi: 10.1016/j.talanta.2018.12.089. Epub 2018 Dec
26

Fluorescent Ag clusters conjugated with anterior gradient-2 antigen aptamer for
specific detection of cancer cells.

Lan J(1), Wu X(2), Luo L(3), Liu J(4), Yang L(5), Wang F(6).

Author information:
(1)Laboratory of Environmental Sciences and Technology, Xinjiang Technical
Institute of Physics and Chemistry, Chinese Academy of Sciences, Urumqi, Xinjiang
830011, China; University of Chinese Academy of Sciences, No. 19 Yuquan Road,
Beijing 100049, China. Electronic address: lanjinze16@mails.ucas.edu.cn.
(2)Laboratory of Environmental Sciences and Technology, Xinjiang Technical
Institute of Physics and Chemistry, Chinese Academy of Sciences, Urumqi, Xinjiang
830011, China. Electronic address: wuxx@ms.xjb.ac.cn.
(3)Laboratory of Environmental Sciences and Technology, Xinjiang Technical
Institute of Physics and Chemistry, Chinese Academy of Sciences, Urumqi, Xinjiang
830011, China. Electronic address: luoliang@ms.xjb.ac.cn.
(4)Laboratory of Environmental Sciences and Technology, Xinjiang Technical
Institute of Physics and Chemistry, Chinese Academy of Sciences, Urumqi, Xinjiang
830011, China. Electronic address: liujing@ms.xjb.ac.cn.
(5)Laboratory of Environmental Sciences and Technology, Xinjiang Technical
Institute of Physics and Chemistry, Chinese Academy of Sciences, Urumqi, Xinjiang
830011, China. Electronic address: yanglingyan16@mails.ucas.edu.cn.
(6)Laboratory of Environmental Sciences and Technology, Xinjiang Technical
Institute of Physics and Chemistry, Chinese Academy of Sciences, Urumqi, Xinjiang
830011, China. Electronic address: wangfu@sjtu.edu.cn.

Anterior gradient protein 2 homolog (AGR) is a potential tumor biomarker and
plays an important role in tissue development and regeneration. The intracellular
detection of AGR is rarely reported. By conjugating the AGR aptamer with a
cytosine base sequence as Ag cluster template, a highly fluorescent probe
(MA@AgNCs) was synthesized for targeting intracellular AGR. The MA@AgNCs display
a maximum fluorescence peak at 565 nm, and possess an excellent quantum yield (QY
= 87.43%), small size, great biocompatibility, low toxicity, and good stability.
Moreover, the as synthesized MA@AgNCs show high specificity on recognizing breast
cancer cells.

DOI: 10.1016/j.talanta.2018.12.089
PMID: 30771992

Comput Biol Med. 2019 Jan 3. pii: S0010-4825(18)30421-9. doi:
10.1016/j.compbiomed.2018.12.017. [Epub ahead of print]

Clinical intelligence: New machine learning techniques for predicting clinical
drug response.

Turki T(1), Wang JTL(2).

Author information:
(1)King Abdulaziz University, Department of Computer Science, Jeddah, 21589,
Saudi Arabia. Electronic address: tturki@kau.edu.sa.
(2)New Jersey Institute of Technology, Bioinformatics Program and Department of
Computer Science, Newark, NJ, 07102-1982, USA. Electronic address:
wangj@njit.edu.

Predicting the response, or sensitivity, of a clinical drug to a specific cancer
type is an important research problem. By predicting the clinical drug response
correctly, clinicians are able to understand patient-to-patient differences in
drug sensitivity outcomes, which in turn results in lesser time spent and lower
cost associated with identifying effective drug candidates. Although
technological advances in high-throughput drug screening in cells led to the
generation of a substantial amount of relevant data, the analysis of such data
would be a challenging task. There is a critical need for advanced machine
learning (ML) algorithms to generate accurate predictions of clinical drug
response. A major goal of this work is to provide advanced ML tools to data
analysts, who would in turn build prediction calculators to be incorporated into
intelligent clinical decision support systems. Such innovative tools could be
used to enhance patient-care, among other uses. To achieve this goal, we develop
new ML techniques, including a transfer learning approach coupled with or without
a boosting technique. Experimental results on real clinical data pertaining to
breast cancer, multiple myeloma, and triple-negative cancer patients demonstrate
the effectiveness and superiority of the proposed approaches compared to baseline
approaches, including existing transfer learning methods.

DOI: 10.1016/j.compbiomed.2018.12.017
PMID: 30771879

Crit Rev Oncol Hematol. 2019 Feb;134:72-81. doi:
10.1016/j.critrevonc.2018.12.009. Epub 2019 Jan 9.

The risk of extra-ovarian malignancies among women with endometriosis: A
systematic literature review and meta-analysis.

Gandini S(1), Lazzeroni M(2), Peccatori FA(3), Bendinelli B(4), Saieva C(4),
Palli D(4), Masala G(4), Caini S(5).

Author information:
(1)Department of Experimental Oncology, European Institute of Oncology IRCCS,
Milan, Italy.
(2)Division of Cancer Prevention and Genetics, European Institute of Oncology
IRCCS, Milan, Italy.
(3)Division of Gynecology Oncology, European Institute of Oncology IRCCS, Milan,
Italy.
(4)Cancer Risk Factors and Lifestyle Epidemiology Unit, Institute for Cancer
Research, Prevention and Clinical Network (ISPRO), Florence, Italy.
(5)Cancer Risk Factors and Lifestyle Epidemiology Unit, Institute for Cancer
Research, Prevention and Clinical Network (ISPRO), Florence, Italy. Electronic
address: s.caini@ispro.toscana.it.

We conducted a meta-analysis of studies reporting on the risk of extra-ovarian
malignancies among women with endometriosis. Summary relative risk (SRR) and 95%
confidence intervals (CI) were calculated through random effect models. We
explored causes of between-studies heterogeneity and assessed the presence of
publication bias. We included 32 studies published between 1989 and 2018. We
found an increased risk of endometrial (SRR 1.38, 95%CI 1.10-1.74) and thyroid
cancer (SRR 1.38, 95%CI 1.17-1.63), and inverse association with cervical cancer
(SRR 0.78, 95%CI 0.60-0.95). No association emerged for breast cancer (SRR 1.04,
95%CI 0.99-1.09) and melanoma (SRR 1.31, 95%CI 0.86-1.96). Between-study
heterogeneity was large for breast and endometrial cancer and melanoma.
Associations were generally stronger in case-control, cross-sectional, and cohort
studies with internal control group, compared to cohort studies with external
control group. No indication for publication bias was found. Our conclusions need
to be confirmed in properly designed cohort studies with clinical confirmation of
endometriosis.

DOI: 10.1016/j.critrevonc.2018.12.009
PMID: 30771877

Crit Rev Oncol Hematol. 2019 Feb;134:39-45. doi:
10.1016/j.critrevonc.2018.12.004. Epub 2018 Dec 19.

The clinical use of circulating tumor cells (CTCs) enumeration for staging of
metastatic breast cancer (MBC): International expert consensus paper.

Cristofanilli M(1), Pierga JY(2), Reuben J(3), Rademaker A(4), Davis AA(4),
Peeters DJ(5), Fehm T(6), Nolé F(7), Gisbert-Criado R(8), Mavroudis D(9),
Grisanti S(10), Giuliano M(11), Garcia-Saenz JA(12), Stebbing J(13), Caldas
C(14), Gazzaniga P(15), Manso L(16), Zamarchi R(17), de Lascoiti AF(18), De
Mattos-Arruda L(19), Ignatiadis M(20), Cabel L(2), van Laere SJ(5), Meier-Stiegen
F(6), Sandri MT(21), Vidal-Martinez J(8), Politaki E(9), Consoli F(10), Generali
D(22), Cappelletti MR(22), Diaz-Rubio E(12), Krell J(13), Dawson SJ(23), Raimondi
C(15), Rutten A(5), Janni W(24), Munzone E(7), Carañana V(25), Agelaki S(9),
Almici C(10), Dirix L(5), Solomayer EF(26), Zorzino L(21), Darrigues L(2),
Reis-Filho JS(27), Gerratana L(28), Michiels S(29), Bidard FC(2), Pantel K(30).

Author information:
(1)Department of Medicine, Division of Hematology and Oncology, Robert H. Lurie
Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern
University, Chicago, IL, USA. Electronic address: Massimo.Cristofanilli@nm.org.
(2)Department of Medical Oncology, Institut Curie, PSL Research University,
Paris, France.
(3)Department of Hematopathology, The University of Texas MD Anderson Cancer
Center, Houston, TX, USA.
(4)Department of Medicine, Division of Hematology and Oncology, Robert H. Lurie
Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern
University, Chicago, IL, USA.
(5)Translational Cancer Research Unit, GZA Hospitals Sint-Augustinus, Antwerp,
Belgium; University of Antwerp, Antwerp, Belgium.
(6)Department of Gynecology and Obstetrics, Heinrich Heine University Düsseldorf,
Düsseldorf, Germany.
(7)Division of Medical Senology, European Institute of Oncology, Milan, Italy.
(8)Clinical Laboratory, Hospital Arnau de Vilanova, Valencia, Spain.
(9)Laboratory of Translational Oncology, School of Medicine, University of Crete,
Heraklion, Greece; Department of Medical Oncology, University Hospital of
Heraklion, Greece.
(10)Department of Transfusion Medicine, Laboratory for Stem Cells Manipulation
and Cryopreservation, AO Spedali Civili di Brescia, Brescia, Italy.
(11)Department of Clinical Medicine and Surgery, University Federico II, Naples,
Italy.
(12)DCIBERONC, IdISCC Madrid, Spain.
(13)Division of Cancer, Department of Surgery and Cancer, Imperial College
London, London, UK.
(14)Cancer Research UK Cambridge Institute and Department of Oncology Li Ka Shing
Centre, University of Cambridge, Cambridge, UK.
(15)Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.
(16)Hospital 12 de Octubre, Madrid, Spain.
(17)Veneto Institute of Oncology IOV-IRCCS, Padua, Italy.
(18)Hospital de Navarra, Pamplona, Spain.
(19)Val d’Hebron Institute of Oncology, Val d’Hebron University Hospital, and
Universitat Autònoma de Barcelona, Barcelona, Spain.
(20)Department of Medical Oncology and Breast Cancer Translational Research
Laboratory, Institut Jules Bordet, Université Libre de Bruxelles, Brussels,
Belgium.
(21)Division of Laboratory Medicine, Humanitas Reseach Hospital, Rozzano, Milan,
Italy.
(22)Women Cancer Center, Azienda Socio Sanitaria Territoriale di Cremona,
University of Trieste, Italy.
(23)Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; Sir Peter
MacCallum Department of Oncology, The University of Melbourne, Victoria,
Australia.
(24)Frauenklinik, University of Ulm, Ulm, Germany.
(25)Clinical Oncology, Hospital Arnau de Vilanova, Valencia, Spain.
(26)Saarland University, Homburg, Germany.
(27)Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York,
NY, USA.
(28)Department of Medicine, Division of Hematology and Oncology, Robert H. Lurie
Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern
University, Chicago, IL, USA; Department of Medicine, University of Udine, Udine,
UD, Italy.
(29)Service de Biostatistique et d’Epidémiologie, Gustave Roussy, CESP, INSERM
U1018, University Paris-Saclay, University Paris-Sud, Villejuif, France.
(30)Department of Tumor Biology, Center of Experimental Medicine, University
Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg,
Germany.

BACKGROUND: The heterogeneity of metastatic breast cancer (MBC) necessitates
novel biomarkers allowing stratification of patients for treatment selection and
drug development. We propose to use the prognostic utility of circulating tumor
cells (CTCs) for stratification of patients with stage IV disease.
METHODS: In a retrospective, pooled analysis of individual patient data from 18
cohorts, including 2436 MBC patients, a CTC threshold of 5 cells per 7.5 ml was
used for stratification based on molecular subtypes, disease location, and prior
treatments. Patients with ≥ 5 CTCs were classified as Stage IVaggressive, those
with < 5 CTCs as Stage IVindolent. Survival was analyzed using Kaplan-Meier
curves and the log rank test.
RESULTS: For all patients, Stage IVindolent patients had longer median overall
survival than those with Stage IVaggressive (36.3 months vs. 16.0 months,
P < 0.0001) and similarly for de novo MBC patients (41.4 months Stage IVindolent
vs. 18.7 months Stage IVaggressive, p < 0.0001). Moreover, patients with Stage
IVindolent disease had significantly longer overall survival across all disease
subtypes compared to the aggressive cohort: hormone receptor-positive (44 months
vs. 17.3 months, P < 0.0001), HER2-positive (36.7 months vs. 20.4 months,
P < 0.0001), and triple negative (23.8 months vs. 9.0 months, P < 0.0001).
Similar results were obtained regardless of prior treatment or disease location.
CONCLUSIONS: We confirm the identification of two subgroups of MBC, Stage
IVindolent and Stage IVaggressive, independent of clinical and molecular
variables. Thus, CTC count should be considered an important tool for staging of
advanced disease and for disease stratification in prospective clinical trials.

DOI: 10.1016/j.critrevonc.2018.12.004
PMID: 30771872

Crit Rev Oncol Hematol. 2019 Feb;134:10-21. doi:
10.1016/j.critrevonc.2018.11.007. Epub 2018 Nov 30.

Optimise not compromise: The importance of a multidisciplinary breast cancer
patient pathway in the era of oncoplastic and reconstructive surgery.

Strach MC(1), Prasanna T(2), Kirova YM(3), Alran S(4), O’Toole S(5), Beith JM(6),
Poortmans P(3), McNeil CM(6), Carroll S(7).

Author information:
(1)Department of Medical Oncology, Chris O’Brien Lifehouse, Camperdown, New South
Wales, Australia; Royal Prince Alfred Hospital, Camperdown, New South Wales,
Australia. Electronic address: madeleine@strach.net.
(2)Department of Medical Oncology, Chris O’Brien Lifehouse, Camperdown, New South
Wales, Australia; Royal Prince Alfred Hospital, Camperdown, New South Wales,
Australia.
(3)Department of Radiation Oncology, Institut Curie, Paris, France.
(4)Department of Surgical Oncology, Groupe Hospitalier Paris St Joseph, France.
(5)Garvan Institute of Medical Research, Darlinghurst, New South Wales,
Australia; Sydney Medical School, University of Sydney, New South Wales,
Australia; Australian Clinical Labs, Bella Vista, New South Wales, Australia.
(6)Department of Medical Oncology, Chris O’Brien Lifehouse, Camperdown, New South
Wales, Australia; Royal Prince Alfred Hospital, Camperdown, New South Wales,
Australia; Sydney Medical School, University of Sydney, New South Wales,
Australia.
(7)Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia; Sydney
Medical School, University of Sydney, New South Wales, Australia; Department of
Radiation Oncology, Royal North Shore Hospital, St Leonards, New South Wales,
Australia.

Modern breast cancer care is a complex multidisciplinary undertaking in which the
integrated function of multiple constituent parts is critical, and where changes
to one therapeutic component may profoundly influence the delivery and outcomes
of another. Oncoplastic and reconstructive breast surgery has evolved in the era
of longer survival rates for women with breast cancer and aims to enhance
oncological and cosmetic outcomes. However, concurrently there has been an
expansion in the indications for post-mastectomy radiation therapy (Abdulkarim et
al., 2011; Early Breast Cancer Trialists’ Collaborative Group (EBCTCG), 2014;
Poortmans et al., 2015; Wang et al., 2011), the recognition of several
biologically distinct breast cancer subtypes (Perou et al., 2000; Sørlie et al.,
2001, 2003; Cheang et al., 2008, 2009; Sotiriou et al., 2003; Millar et al.,
2011; Blows et al., 2010; Schnitt, 2010; Haque et al., 2012; Dai et al., 2015)
and the development of recommendations for prophylactic surgery for high-risk
women, including BRCA-mutation carriers (James et al., 2006; Domchek et al.,
2010). Primary systemic therapy is increasingly utilised yet has varying efficacy
depending on tumour biology (Cortazar et al., 2014). In this paper we review the
evidence which informs the multidisciplinary team opinion in the era of
oncoplastic and reconstructive breast surgery. We aim to describe an optimal
multidisciplinary approach which balances competing risks of multimodal therapies
to optimise oncological and cosmetic outcomes.

DOI: 10.1016/j.critrevonc.2018.11.007
PMID: 30771869

Am J Surg. 2019 Jan 24. pii: S0002-9610(18)31453-3. doi:
10.1016/j.amjsurg.2019.01.004. [Epub ahead of print]

Extreme oncoplasty: Expanding indications for breast conservation.

Crown A(1), Laskin R(1), Rocha FG(1), Grumley J(2).

Author information:
(1)Virginia Mason Medical Center, Seattle, WA, USA.
(2)John Wayne Cancer Institute, Providence Saint John’s Health Center, Santa
Monica, CA, USA. Electronic address: janie.grumley@providence.org.

INTRODUCTION: Presence of multiple lesions and/or tumor span ≥5 cm are
traditional indications for mastectomy. Patient desire for breast conservation
has increased the interest in extreme oncoplastic breast conserving surgery
(EOBCS) to avoid mastectomy; however, perioperative outcomes in this population
have not been well described.
METHODS: This is an observational cohort of breast cancer patients with multiple
lesions and disease span ≥5 cm who underwent EOBCS. Patient demographics, disease
span, margin width, mastectomy and re-excision rates, and cosmesis were
evaluated.
RESULTS: One hundred-eleven patients underwent EOBCS between 2012 and 2017.
Eighty-two patients presented with multifocal or multicentric disease with an
average of 3.2 lesions per breast spanning 57.1 ± 23.6 mm. Eighteen patients
presented with unifocal tumors measuring an average of 67.6 mm (range 50-160 mm)
on imaging. Eleven patients with an imaging size of <5 cm had a disease span
≥5 cm on final pathology. No tumor on ink occurred in 87 (78.3%) patients.
Fifty-seven (51.4%) patients had additional surgery for inadequate margins.
Fifteen (12.6%) patients elected to have mastectomy while 42 (37.8%) patients
opted for re-excision. Good to excellent cosmetic results were reported in 95% of
patients who ultimately achieved breast conservation. Recurrence rate was 1.1% in
patients who completed EOBCS and adjuvant radiation therapy.
CONCLUSION: EOBCS can allow for breast conservation in patients who are
traditionally counseled to undergo mastectomy. Although the re-excision rate was
significant, most patients ultimately achieved breast conservation with adequate
margins. Further study is warranted to determine the long-term oncologic outcomes
of this approach.

DOI: 10.1016/j.amjsurg.2019.01.004
PMID: 30771865

Colloids Surf B Biointerfaces. 2019 Feb 5;177:294-305. doi:
10.1016/j.colsurfb.2019.02.001. [Epub ahead of print]

Indocyanine green/doxorubicin-encapsulated functionalized nanoparticles for
effective combination therapy against human MDR breast cancer.

Chen HH(1), Lu IL(2), Liu TI(3), Tsai YC(3), Chiang WH(1), Lin SC(4), Chiu HC(5).

Author information:
(1)Department of Chemical Engineering, National Chung Hsing University, Taichung,
402, Taiwan.
(2)Department of Biomedical Engineering and Environmental Sciences, National
Tsing Hua University, Hsinchu, 300, Taiwan; Department of Surgery, Hsinchu Mackay
Memorial Hospital, Hsinchu, 300, Taiwan.
(3)Department of Biomedical Engineering and Environmental Sciences, National
Tsing Hua University, Hsinchu, 300, Taiwan.
(4)Department of Chemical Engineering, National Chung Hsing University, Taichung,
402, Taiwan. Electronic address: sclin@dragon.nchu.edu.tw.
(5)Department of Biomedical Engineering and Environmental Sciences, National
Tsing Hua University, Hsinchu, 300, Taiwan. Electronic address:
hscchiu@mx.nthu.edu.tw.

To overcome low therapeutic efficacy of chemotherapy against multidrug resistance
(MDR) breast cancer, a combination therapy system based upon functionalized
polymer nanoparticles comprising poly(γ-glutamic acid)-g-poly(lactic-co-glycolic
acid) (γ-PGA-g-PLGA) as the major component was developed. The NPs were loaded
with doxorubicin (DOX) and indocyanine green (ICG) for dual modality cancer
treatment and coated with cholesterol-PEG (C-PEG) for MDR abrogation in treatment
of human MDR breast cancer. The in vitro cellular uptake of the DOX/ICG loaded
nanoparticles (DI-NPs) by MDR cancer cells was significantly enhanced owing to
effective inhibition of the P-gp activity by C-PEG and γ-PGA receptor-mediated
endocytosis. DOX localization in cytoplasm and nucleus was observed particularly
with the photo-thermal effect that facilitated intracellular drug release. As a
result, the C-PEG coated DI-NPs after photo-irradiation exhibited a synergistic
effect of combination (chemo/thermal) therapy to depress the proliferation of MDR
cancer calls. The ex vivo biodistribution study revealed an enhanced tumor
accumulation of C-PEG (2000) coated DI-NPs in MCF-7/MDR tumor-bearing nude mice
due to the excellent EPR effects by the NP surface PEGylation. The MDR tumor
growth was almost entirely inhibited in the group receiving combination therapy
from CP2k-DI-NPs and photo-irradiation along with substantial cell apoptosis of
tumor tissues examined by immunohistochemical staining. The results demonstrate a
promising dual modality therapy system, CP2k-DI-NPs, developed in this work for
effective combination therapy of human MDR breast cancer.

DOI: 10.1016/j.colsurfb.2019.02.001
PMID: 30771581

Mult Scler Relat Disord. 2019 Feb 8;30:119-122. doi: 10.1016/j.msard.2019.02.011.
[Epub ahead of print]

Aquaporin-4 antibody positive short transverse myelitis associated with breast
cancer.

Liao W(1), Li C(2), Tang Y(3), Huang F(1), Kuang H(1), Liang S(1), Yang Y(1).

Author information:
(1)Department of Neurology, The First Affiliated Hospital, Guangxi Medical
University, Nanning, Guangxi, China.
(2)Department of Surgery, Affiliated Wuming Hospital, Guangxi Medical University,
Nanning, Guangxi, China.
(3)Department of Neurology, The First Affiliated Hospital, Guangxi Medical
University, Nanning, Guangxi, China. Electronic address: 13978675500@163.com.

Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory demyelinating
disease of the central nervous system (CNS). A typical finding on spinal magnetic
resonance imaging (MRI) of NMOSD is longitudinally extensive transverse myelitis
(LETM). However, patients with NMOSD presenting with short-segment transverse
myelitis (STM) during myelitis attacks associated with breast cancer are
uncommon. We report a case of a 35-year-old woman with STM and left eye optic
neuritis. The patient was positive for serum aquaporin-4 antibodies (AQP4-IgG),
and a biopsy of the left breast showed invasive ductal carcinoma. The patient was
diagnosed with NMOSD and breast malignancy. This is the first report of a patient
with NMOSD whose spinal MRI showed STM and serum test showed that the patient’s
AQP4-IgG was positive and complicated by breast cancer. This case improves our
understanding of the association between NMOSD and cancer and raises the question
of whether it was a coincidental occurrence. It is important to search for
extensive malignancies in patients presenting with atypical MRI or no reaction to
traditional therapies.

DOI: 10.1016/j.msard.2019.02.011
PMID: 30771577

Biomaterials. 2019 Apr;199:76-87. doi: 10.1016/j.biomaterials.2019.01.036. Epub
2019 Jan 25.

Polymers with distinctive anticancer mechanism that kills MDR cancer cells and
inhibits tumor metastasis.

Zhong G(1), Yang C(2), Liu S(2), Zheng Y(2), Lou W(3), Teo JY(2), Bao C(3), Cheng
W(2), Tan JPK(2), Gao S(2), Park N(4), Venkataraman S(2), Huang Y(5), Tan MH(2),
Wang X(5), Hedrick JL(6), Fan W(7), Yang YY(8).

Author information:
(1)Department of Breast Surgery, The First Affiliated Hospital, College of
Medicine, Zhejiang University, Hangzhou, 310003, China; Program of Innovative
Therapeutics, The First Affiliated Hospital, College of Medicine, Zhejiang
University, Hangzhou, 310003, China.
(2)Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, The Nanos,
138669, Singapore.
(3)Program of Innovative Therapeutics, The First Affiliated Hospital, College of
Medicine, Zhejiang University, Hangzhou, 310003, China.
(4)IBM Research-Almaden, 650 Harry Road, San Jose, CA 95120, United States.
(5)Department of Medical Oncology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang,
310022, China.
(6)IBM Research-Almaden, 650 Harry Road, San Jose, CA 95120, United States.
Electronic address: hedrick@us.ibm.com.
(7)Program of Innovative Therapeutics, The First Affiliated Hospital, College of
Medicine, Zhejiang University, Hangzhou, 310003, China. Electronic address:
fanw@zju.edu.cn.
(8)Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, The Nanos,
138669, Singapore. Electronic address: yyyang@ibn.a-star.edu.sg.

Although mortality continues to decline over the past two decades, cancer is
still a pervasive healthcare problem worldwide due to the increase in the number
of cases, multidrug resistance (MDR) and metastasis. As a consequence of
multidrug resistance, cancer treatment must rely on a host of chemotherapeutic
agents and chemosensitizers to achieve remission. To overcome these problems, a
series of biodegradable triblock copolymers of PEG, guanidinium-functionalized
polycarbonate and polylactide (PEG-PGCx-PDLAy) is designed as chemotherapeutic
agents. These copolymers self-assemble into micellar nanoparticles, and are
highly effective against various cancer cell lines including human breast cancer
(BCap37), liver cancer (HepG2), lung cancer (A549) and epidermoid carcinoma
(A431) cell lines as well as MDR Bats-72 and Bads-200 cancer cells that were
developed from BCap37. Multiple treatments with the polymers at sub-lethal doses
do not induce resistance. The polymers kill cancer cells by a non-apoptotic
mechanism with significant vacuolization and subsequent membrane disruption. In
vivo antitumor efficacy is evaluated in a metastatic 4T1 subcutaneous tumor
model. Treatment with stereocomplexes of PEG-PGC43-PLLA19 and PEG-PGC43-PDLA20 at
a dose of 20 mg/kg of mouse body weight suppresses tumor growth and inhibits
tumor metastasis in vivo. These polymers show promise in the treatment of cancer
without the onset of resistance.

DOI: 10.1016/j.biomaterials.2019.01.036
PMID: 30771551

Comput Biol Med. 2019 Feb 5;107:18-29. doi: 10.1016/j.compbiomed.2019.01.024.
[Epub ahead of print]

RAMS: Remote and automatic mammogram screening.

Cogan T(1), Cogan M(2), Tamil L(3).

Author information:
(1)Quality of Life Technology Laboratory, Department of Electrical and Computer
Engineering, The University of Texas at Dallas, 800 W. Campbell Road, Richardson,
TX, 75080, USA. Electronic address: tcc090020@utdallas.edu.
(2)Quality of Life Technology Laboratory, Department of Electrical and Computer
Engineering, The University of Texas at Dallas, 800 W. Campbell Road, Richardson,
TX, 75080, USA. Electronic address: mxr127730@utdallas.edu.
(3)Quality of Life Technology Laboratory, Department of Electrical and Computer
Engineering, The University of Texas at Dallas, 800 W. Campbell Road, Richardson,
TX, 75080, USA. Electronic address: laxman@utdallas.edu.

About one in eight women in the U.S. will develop invasive breast cancer at some
point in life. Breast cancer is the most common cancer found in women and if it
is identified at an early stage by the use of mammograms, x-ray images of the
breast, then the chances of successful treatment can be high. Typically,
mammograms are screened by radiologists who determine whether a biopsy is
necessary to ascertain the presence of cancer. Although historical screening
methods have been effective, recent advances in computer vision and web
technologies may be able to improve the accuracy, speed, cost, and accessibility
of mammogram screenings. We propose a total screening solution comprised of three
main components: a web service for uploading images and reviewing results, a
machine learning algorithm for accepting or rejecting images as valid mammograms,
and an artificial neural network for locating potential malignancies. Once an
image is uploaded to our web service, an image acceptor determines whether or not
the image is a mammogram. The image acceptor is primarily a one-class SVM built
on features derived with a variational autoencoder. If an image is accepted as a
mammogram, the malignancy identifier, a ResNet-101 Faster R-CNN, will locate
tumors within the mammogram. On test data, the image acceptor had only 2
misclassifications out of 410 mammograms and 2 misclassifications out of 1,640
non-mammograms while the malignancy identifier achieved 0.951 AUROC when tested
on BI-RADS 1, 5, and 6 images from the INbreast dataset.

DOI: 10.1016/j.compbiomed.2019.01.024
PMID: 30771549

Acta Biomater. 2019 Feb 13. pii: S1742-7061(19)30119-9. doi:
10.1016/j.actbio.2019.02.015. [Epub ahead of print]

ROCK isoforms differentially modulate cancer cell motility by mechanosensing the
substrate stiffness.

Peng Y(1), Chen Z(1), Chen Y(1), Li S(2), Jiang Y(2), Yang H(2), Wu C(2), You
F(3), Zheng C(3), Zhu J(3), Tan Y(4), Qin X(5), Liu Y(6).

Author information:
(1)Department of Biophysics, School of Life Science and Technology, University of
Electronic Science and Technology of China, Chengdu 610054, Sichuan, PR China.
(2)Department of Biophysics, School of Life Science and Technology, University of
Electronic Science and Technology of China, Chengdu 610054, Sichuan, PR China;
Center for Information in Biology, University of Electronic Science and
Technology of China, Chengdu 610054, Sichuan, PR China.
(3)Hospital of Chengdu University of Traditional Chinese Medicine, No. 39
Shi-er-qiao Road, Chengdu 610072, Sichuan, PR China.
(4)Department of Biomedical Engineering, Hong Kong Polytechnic University, Hong
Kong, PR China.
(5)Department of Biophysics, School of Life Science and Technology, University of
Electronic Science and Technology of China, Chengdu 610054, Sichuan, PR China;
Center for Information in Biology, University of Electronic Science and
Technology of China, Chengdu 610054, Sichuan, PR China. Electronic address:
qinxiang@uestc.edu.cn.
(6)Department of Biophysics, School of Life Science and Technology, University of
Electronic Science and Technology of China, Chengdu 610054, Sichuan, PR China;
Hospital of Chengdu University of Traditional Chinese Medicine, No. 39
Shi-er-qiao Road, Chengdu 610072, Sichuan, PR China; Center for Information in
Biology, University of Electronic Science and Technology of China, Chengdu
610054, Sichuan, PR China. Electronic address: liuyiyao@uestc.edu.cn.

Tumors are characterized by extracellular matrix (ECM) remodeling and stiffening.
The importance of ECM stiffness in cancer is well known. However, the
biomechanical behavior of tumor cells and the underlying mechanotransduction
pathways remain unclear. Here, we used polyacrylamide (PAA) substrates to
simulate tissue stiffness at different progress stages of breast cancer in vitro,
and we observed that moderate substrate stiffness promoted breast cancer cell
motility. The substrate stiffness directly activated integrin β1 and focal
adhesion kinase (FAK), which accelerate focal adhesion (FA) maturation and induce
the downstream cascades of intracellular signals of the RhoA/ROCK pathway.
Interestingly, the differential regulatory mechanism between two ROCK isoforms
(ROCK1 and ROCK2) in cell motility and mechanotransduction was clearly
identified. ROCK1 phosphorylated the myosin regulatory light chain (MRLC) and
facilitated the generation of traction force, while ROCK2 phosphorylated cofilin
and regulated the cytoskeletal remodeling by suppressing F-actin
depolymerization. The ROCK isoforms differentially regulated the pathways of
RhoA/ROCK1/p-MLC and RhoA/ROCK2/p-cofilin in a coordinate fashion to modulate
breast cancer cell motility in a substrate stiffness-dependent manner through
integrin β1-activated FAK signaling. Our findings provide new insights into the
mechanisms of matrix mechanical property-induced cancer cell migration and
malignant behaviors. STATEMENT OF SIGNIFICANCE: Here, we examined the
relationship between substrate stiffness and tumor cellular motility by using
polyacrylamide (PAA) substrates to simulate the stages in vivo of breast cancer.
The results elucidated the different regulatory roles between the two ROCK
isoforms in cell motility and demonstrated that stiff substrate (38kPa) mediated
RhoA/ROCK1/p-MLC and RhoA/ROCK2/p-cofilin pathways through integrin β1-FAK
activation and eventually promoted directional migration. Our discoveries would
have significant implications in the understanding of the interaction between
cancer cells and tumor microenvironments, and hence, it might provide new
insights into the metastasis inhibition, which could be an adjuvant way of cancer
therapy.

DOI: 10.1016/j.actbio.2019.02.015
PMID: 30771534

Gynecol Obstet Fertil Senol. 2019 Feb 13. pii: S2468-7189(19)30034-0. doi:
10.1016/j.gofs.2019.02.005. [Epub ahead of print]

[Indications and achievements of the extension assessment in breast cancer in
France].

[Article in French]

Gaillard T(1), Latouche A(1), Houzard S(2), Rouzier R(3), Héquet D(4).

Author information:
(1)Institut Curie, INSERM U900, 35 Rue Dailly, 92210 Saint-Cloud, France.
(2)Institut Curie, Département des data, 25, rue d’Ulm, 75005 Paris, France.
(3)Institut Curie, INSERM U900, 35 Rue Dailly, 92210 Saint-Cloud, France;
Institut Curie, Département de chirurgie oncologique, 35 Rue Dailly, 92210
Saint-Cloud, France.
(4)Institut Curie, INSERM U900, 35 Rue Dailly, 92210 Saint-Cloud, France;
Institut Curie, Département de chirurgie oncologique, 35 Rue Dailly, 92210
Saint-Cloud, France. Electronic address: delphine.hequet@curie.fr.

DOI: 10.1016/j.gofs.2019.02.005
PMID: 30771516

Neuroscience. 2019 Feb 13. pii: S0306-4522(19)30105-8. doi:
10.1016/j.neuroscience.2019.02.005. [Epub ahead of print]

Dual Effect of Doxazosin: Anticancer Activity on SH-SY5Y Neuroblastoma Cells and
Neuroprotection on an In Vitro Model of Alzheimer’s Disease.

Coelho BP(1), Gaelzer MM(2), Dos Santos Petry F(2), Hoppe JB(2), Trindade VMT(2),
Salbego CG(2), Guma FTCR(2).

Author information:
(1)Programa de Pós-Graduação em Ciências Biológicas-Bioquímica, Instituto de
Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto
Alegre, RS, Brazil. Electronic address: coelhobarbarap@gmail.com.
(2)Programa de Pós-Graduação em Ciências Biológicas-Bioquímica, Instituto de
Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto
Alegre, RS, Brazil.

Several studies have demonstrated the antitumor effect of doxazosin, an
α1-adrenergic blocker, against glioma and breast, bladder and prostate cancers.
Doxazosin is also being evaluated as a treatment for posttraumatic stress
disorder and alcoholism, and α1-adrenergic blockers have been linked to
neuroprotection in neurodegenerative disorders, such as Alzheimer’s Disease (AD).
Cancer and AD have an inverse relationship in many aspects, with several factors
that contribute to apoptosis inhibition and proliferation being increased in
cancers but decreased in AD. Neuroblastoma (NB) is a pediatric tumor derived from
embryonic neural-crest cells, with an overall cure rate of 40%, despite
aggressive treatment. Thus, due to the need of new therapeutic strategies against
NB and neurodegenerative disorders and the inverse relationship between these
diseases, we investigated whether doxazosin may serve as an antitumor and
neuroprotective agent. We analyzed the drug’s effects on undifferentiated and
retinoic acid-differentiated SH-SY5Y human NB cells and on an in vitro model of
organotypic hippocampal cultures exposed to amyloid-β. Doxazosin showed antitumor
effect on undifferentiated neuroblastoma cells by induction of apoptosis,
necrosis, cell cycle arrest and decrease of p-EGFRTyr1048 levels. On
differentiated cells, doxazosin was less cytotoxic and increased p-EGFRTyr1048,
p-AktSer473 and p-GSK-3βSer9 levels. Moreover, the drug was able to protect
hippocampal slices from amyloid-β toxicity through prevention of GSK-3β
activation and of Tau hyperphosphorylation. Therefore, our results show that
doxazosin has antitumor activity against undifferentiated neuroblastoma and is
neuroprotective on an in vitro model of Alzheimer’s Disease.

DOI: 10.1016/j.neuroscience.2019.02.005
PMID: 30771511

Methods. 2019 Feb 13. pii: S1046-2023(18)30360-8. doi:
10.1016/j.ymeth.2019.02.010. [Epub ahead of print]

Computer-aided detection of mass in digital breast tomosynthesis using a faster
region-based convolutional neural network.

Fan M(1), Li Y(2), Zheng S(2), Peng W(3), Tang W(4), Li L(5).

Author information:
(1)Institute of Biomedical Engineering and Instrumentation, Hangzhou Dianzi
University, High Education Zone, Hangzhou 310018, China. Electronic address:
ming.fan@hdu.edu.cn.
(2)Institute of Biomedical Engineering and Instrumentation, Hangzhou Dianzi
University, High Education Zone, Hangzhou 310018, China.
(3)Department of Radiology, Fudan University Shanghai Cancer Center, Shanghai,
China.
(4)Department of Radiology, Fudan University Shanghai Cancer Center, Shanghai,
China. Electronic address: tangwei12@fudan.edu.cn.
(5)Institute of Biomedical Engineering and Instrumentation, Hangzhou Dianzi
University, High Education Zone, Hangzhou 310018, China. Electronic address:
lilh@hdu.edu.cn.

Digital breast tomosynthesis (DBT) is a newly developed three-dimensional
tomographic imaging modality in the field of breast cancer screening designed to
alleviate the limitations of conventional digital mammography-based breast
screening methods. A computer-aided detection (CAD) system was designed for
masses in DBT using a faster region-based convolutional neural network
(faster-RCNN). To this end, a data set was collected, including 89 patients with
105 masses. An efficient detection architecture of convolution neural network
with a region proposal network (RPN) was used for each slice to generate region
proposals (i.e., bounding boxes) with a mass likelihood score. In each DBT
volume, a slice fusion procedure was used to merge the detection results on
consecutive 2D slices into one 3D DBT volume. The performance of the CAD system
was evaluated using free-response receiver operating characteristic (FROC)
curves. Our RCNN-based CAD system was compared with a deep convolutional neural
network (DCNN)-based CAD system. The RCNN-based CAD generated a performance with
an area under the ROC (AUC) of 0.96, whereas the DCNN-based CAD achieved a
performance with AUC of 0.92. For lesion-based mass detection, the sensitivity of
RCNN-based CAD was 90% at 1.54 false positive (FP) per volume, whereas the
sensitivity of DCNN-based CAD was 90% at 2.81 FPs/volume. For breast-based mass
detection, RCNN-based CAD generated a sensitivity of 90% at 0.76 FP/breast, which
is significantly increased compared with the DCNN-based CAD with a sensitivity of
90% at 2.25 FPs/breast. The results suggest that the faster R-CNN has the
potential to augment the prescreening and FP reduction in the CAD system for
masses.

DOI: 10.1016/j.ymeth.2019.02.010
PMID: 30771490

Biochim Biophys Acta Rev Cancer. 2019 Feb 13;1871(2):281-288. doi:
10.1016/j.bbcan.2019.02.001. [Epub ahead of print]

RLIP: An existential requirement for breast carcinogenesis.

Singhal SS(1), Salgia R(2), Singhal S(3), Horne D(4), Awasthi S(5).

Author information:
(1)Department of Medical Oncology, Beckman Research Institute of City of Hope,
Comprehensive Cancer Center and National Medical Center, Duarte, CA 91010, USA.
Electronic address: ssinghal@coh.org.
(2)Department of Medical Oncology, Beckman Research Institute of City of Hope,
Comprehensive Cancer Center and National Medical Center, Duarte, CA 91010, USA.
(3)University of California at San Diego, La Jolla, CA 92092, USA.
(4)Department of Molecular Medicine, Beckman Research Institute of City of Hope,
Comprehensive Cancer Center and National Medical Center, Duarte, CA 91010, USA.
(5)Department of Internal Medicine, Division of Hematology & Oncology, Texas Tech
University Health Sciences Center, Lubbock, TX 79430, USA.

Breast cancer (BC) is the most common cancer among women worldwide. Due to its
complexity in nature, effective BC treatment can encounter many challenges. The
human RALBP1 gene encodes a 76-kDa splice variant protein, RLIP (ral-binding
protein1, RalBP1), a stress-protective mercapturic acid pathway (MAP) transporter
protein, that also plays a key role in regulating clathrin-dependent endocytosis
(CDE) as a Ral effector. Growing evidence shows that targeting RLIP may be an
effective strategy in cancer therapy, as RLIP is over-expressed in multiple
cancers and is known to induce resistance to apoptosis and chemotherapeutic
drugs. Recent studies demonstrated that RLIP is expressed in human BC tissues, as
well as BC cell lines. Knockdown of RLIP resulted in apoptotic death of BC cells
in vitro, and targeted inhibition and depletion of RLIP resulted in regression of
BC in xenograft studies of nude mice. Signaling studies showed that RLIP
depletion inhibited endocytosis and differentially regulated signaling to Akt,
Myc, and ERK1/2. However, the proliferation and multi-specific transport
mechanisms that promote RLIP-mediated cell death in BC are not well understood.
In this review, we will discuss a missing but an essentially determining and
connecting piece of the puzzle on the understanding of proliferation and
transport mechanisms by focused analyses of the apoptotic, drug- and
radiation-sensitivity regulated by RLIP, a stress-responsive non-ATP-binding
cassette (ABC), high capacity MAP transporter, in breast cancer.

DOI: 10.1016/j.bbcan.2019.02.001
PMID: 30771458

Cancer Lett. 2019 Feb 13. pii: S0304-3835(19)30091-6. doi:
10.1016/j.canlet.2019.02.019. [Epub ahead of print]

ProNGF increases breast tumor aggressiveness through functional association of
TrkA with EphA2.

Romain L(1), Cyril C(1), Léo A(1), Matthieu G(1), Chann L(2), Eric A(1), Jérémy
D(1), Pascal F(3), Daniel B(3), Nicolas M(4), Valérie C(5), François B(3), Xuefen
LB(1), Robert-Alain T(6).

Author information:
(1)Inserm, U908, F-59000, Lille, France; Univ. Lille, U908 – CPAC, Cell
Plasticity and Cancer, F-59000, Lille, France.
(2)Inserm, U908, F-59000, Lille, France.
(3)Département D’Oncologie Moléculaire, Institut Paoli-Calmette, CRCM, UMR1068
Inserm, UMR7258 CNRS, Aix-Marseille Université, 13273, Marseille, France.
(4)Département de Radiothérapie, Institut de Cancérologie Lucien Neuwirth, 42270,
Saint Priest en Jarez, France; Radiobiologie Cellulaire et Moléculaire, EMR3738 –
Equipe 4, Faculté de Médecine Lyon-Sud, 69000, Lyon, France.
(5)Univ. Lille, U908 – CPAC, Cell Plasticity and Cancer, F-59000, Lille, France;
Université de Picardie, 80000, Amiens, France.
(6)Inserm, U908, F-59000, Lille, France; Univ. Lille, U908 – CPAC, Cell
Plasticity and Cancer, F-59000, Lille, France. Electronic address:
robert-alain.toillon@univ-lille.fr.

ProNGF expression has been linked to several types of cancers including breast
cancer, and we have previously shown that proNGF stimulates breast cancer
invasion in an autocrine manner through membrane receptors sortilin and TrkA.
However, little is known regarding TrkA-associated protein partners upon proNGF
stimulation. By proteomic analysis and proximity ligation assays, we found that
proNGF binding to sortilin induced sequential formation of the functional
sortilin/TrkA/EphA2 complex, leading to TrkA-phosphorylation dependent Akt
activation and EphA2-dependent Src activation. EphA2 inhibition using siRNA
approach abolished proNGF-stimulated clonogenic growth of breast cancer cell
lines. Combinatorial targeting of TrkA and EphA2 dramatically reduced colony
formation in vitro, primary tumor growth and metastatic dissemination towards the
brain in vivo. Finally, proximity ligation assay in breast tumor samples revealed
that increased TrkA/EphA2 proximity ligation assay signals were correlated with a
decrease of overall survival in patients. All together, these data point out the
importance of TrkA/EphA2 functional association in proNGF-induced tumor promoting
effects, and provide a rationale to target proNGF/TrkA/EphA2 axis by alternative
methods other than the simple use of tyrosine kinase inhibitors in breast cancer.

DOI: 10.1016/j.canlet.2019.02.019
PMID: 30771434

Cancer Lett. 2019 Feb 13. pii: S0304-3835(19)30090-4. doi:
10.1016/j.canlet.2019.02.018. [Epub ahead of print]

Towards the first targeted therapy for triple-negative breast cancer:
repositioning of clofazimine as a chemotherapy-compatible selective Wnt pathway
inhibitor.

Ahmed K(1), Koval A(2), Xu J(2), Bodmer A(3), Katanaev VL(4).

Author information:
(1)Department of Pharmacology and Toxicology, Faculty of Biology and Medicine,
University of Lausanne, Lausanne, Switzerland.
(2)Department of Pharmacology and Toxicology, Faculty of Biology and Medicine,
University of Lausanne, Lausanne, Switzerland; Department of Cell Physiology and
Metabolism, Translational Research Centre in Oncohaematology, Faculty of
Medicine, University of Geneva, Geneva, Switzerland.
(3)Department of Oncology, Geneva University Hospital, Geneva, Switzerland.
(4)Department of Cell Physiology and Metabolism, Translational Research Centre in
Oncohaematology, Faculty of Medicine, University of Geneva, Geneva, Switzerland;
School of Biomedicine, Far Eastern Federal University, Vladivostok, Russia.
Electronic address: vladimir.katanaev@unige.ch.

Wnt signaling is overactivated in triple-negative breast cancer (TNBC) and
several other cancers, and its suppression emerges as an effective anticancer
treatment. However, no drugs targeting the Wnt pathway exist on the market nor in
advanced clinical trials. Here we provide a comprehensive body of preclinical
evidence that an anti-leprotic drug clofazimine is effective against TNBC.
Clofazimine specifically inhibits canonical Wnt signaling in a panel of TNBC
cells in vitro. In several mouse xenograft models of TNBC, clofazimine
efficiently suppresses tumor growth, correlating with in vivo inhibition of the
Wnt pathway in the tumors. Clofazimine is well compatible with doxorubicin,
exerting additive effects on tumor growth suppression, producing no adverse
effects. Its excellent and well-characterized pharmacokinetics profile, lack of
serious adverse effects at moderate (yet therapeutically effective) doses, its
combinability with cytotoxic therapeutics, and the novel mechanistic mode of
action make clofazimine a prime candidate for the repositioning clinical trials.
Our work may bring forward the anti-Wnt targeted therapy, desperately needed for
thousands of patients currently lacking targeted treatments.

DOI: 10.1016/j.canlet.2019.02.018
PMID: 30771433

Cancer Lett. 2019 Feb 13. pii: S0304-3835(19)30081-3. doi:
10.1016/j.canlet.2019.02.009. [Epub ahead of print]

Squalamine blocks tumor-associated angiogenesis and growth of human breast cancer
cells with or without HER-2/neu overexpression.

Márquez-Garbán DC(1), Gorrín-Rivas M(2), Chen HW(3), Sterling C Jr(4), Elashoff
D(5), Hamilton N(6), Pietras RJ(7).

Author information:
(1)Department of Medicine, Division of Hematology-Oncology, UCLA David Geffen
School of Medicine, Los Angeles, CA, 90095; UCLA Jonsson Comprehensive Cancer
Center, Los Angeles, CA, 90095. Electronic address: dmarquez@mednet.ucla.edu.
(2)Department of Medicine, Division of Hematology-Oncology, UCLA David Geffen
School of Medicine, Los Angeles, CA, 90095; UCLA Jonsson Comprehensive Cancer
Center, Los Angeles, CA, 90095. Electronic address: mjgorrin@ecaa.com.
(3)Department of Medicine, Division of Hematology-Oncology, UCLA David Geffen
School of Medicine, Los Angeles, CA, 90095; UCLA Jonsson Comprehensive Cancer
Center, Los Angeles, CA, 90095. Electronic address: hchen@mednet.ucla.edu.
(4)Department of Medicine, Division of Hematology-Oncology, UCLA David Geffen
School of Medicine, Los Angeles, CA, 90095; UCLA Jonsson Comprehensive Cancer
Center, Los Angeles, CA, 90095.
(5)UCLA Jonsson Comprehensive Cancer Center, Los Angeles, CA, 90095; Department
of Medicine, Division of General Internal Medicine, UCLA David Geffen School of
Medicine, Los Angeles, CA 90095. Electronic address: DElashoff@mednet.ucla.edu.
(6)UCLA Jonsson Comprehensive Cancer Center, Los Angeles, CA, 90095; UCLA School
of Nursing, Los Angeles, CA, 90095. Electronic address:
nhamilton@sonnet.ucla.edu.
(7)Department of Medicine, Division of Hematology-Oncology, UCLA David Geffen
School of Medicine, Los Angeles, CA, 90095; UCLA Jonsson Comprehensive Cancer
Center, Los Angeles, CA, 90095. Electronic address: rpietras@mednet.ucla.edu.

Angiogenesis is critical for breast cancer progression. Overexpression of
HER-2/neu receptors occur in 25-30% of breast cancers, and treatment with
trastuzumab inhibits HER-2-overexpressing tumor growth. Notably, HER-2-mediated
signaling enhances vascular endothelial growth factor (VEGF) secretion to
increase tumor-associated angiogenesis. Squalamine (aminosterol compound)
suppresses VEGF-induced activation of kinases in vascular endothelial cells and
inhibits tumor-associated angiogenesis. We assessed antitumor effects of
squalamine either alone or with trastuzumab in nude mice bearing breast tumor
xenografts without (MCF-7) or with HER2-overexpression (MCF-7/HER-2). Squalamine
alone inhibited progression of MCF-7 tumors lacking HER2 overexpression, and
squalamine combined with trastuzumab elicited marked inhibition of MCF-7/HER2
growth exceeding that of trastuzumab alone. MCF-7/HER-2 cells secrete higher
levels of VEGF than MCF-7 cells, but squalamine elicited no growth inhibition of
either MCF-7/HER-2 or MCF-7 cells in vitro. However, squalamine did stop growth
of human umbilical vein endothelial cells (HUVECs) and reduced VEGF-induced
endothelial tube-like formations in vitro. These effects correlated with blockade
of focal adhesion kinase phosphorylation and stress fiber assembly in HUVECs.
Thus, squalamine effectively inhibits growth of breast cancers with or without
HER-2-overexpression, an effect due in part to blockade of tumor-associated
angiogenesis.

DOI: 10.1016/j.canlet.2019.02.009
PMID: 30771431

Cancer Lett. 2019 Feb 13. pii: S0304-3835(19)30080-1. doi:
10.1016/j.canlet.2019.02.008. [Epub ahead of print]

Long non-coding RNA FGF13-AS1 inhibits glycolysis and stemness properties of
breast cancer cells through FGF13-AS1/IGF2BPs/Myc feedback loop.

Ma F(1), Liu X(1), Zhou S(2), Li W(1), Liu C(1), Chadwick M(3), Qian C(4).

Author information:
(1)Department of Breast Surgery, Harbin Medical University Cancer Hospital,
Harbin, China.
(2)Department of Pharmacy, The Fourth Affiliated Hospital of Harbin Medical
University, Harbin, China.
(3)Cancer Institute of New Jersey, Rutgers University, New Brunswick, United
States.
(4)Department of Breast Surgery, Harbin Medical University Cancer Hospital,
Harbin, China; Translational Medicine Research and Cooperation Center of Northern
China, Heilongjiang Academy of Medical Sciences, Harbin, China. Electronic
address: qiancheng@ems.hrbmu.edu.cn.

LncRNAs have been proven to play crucial roles in various processes of breast
cancer. LncRNA FGF13-AS1 has been identified as one of the 25 downregulated
lncRNAs in breast cancer through analyzing data from two cohorts and TCGA by
another group of our lab. In this study, we report that FGF13-AS1 expression is
decreased in breast cancer tissue compared with corresponding normal tissue, and
the downregulation of FGF13-AS1 is associated with poor prognosis. Functional
studies show that FGF13-AS1 inhibits breast cancer cells proliferation,
migration, and invasion by impairing glycolysis and stemness properties.
Mechanistically, FGF13-AS1 reduces the half-life of c-Myc (Myc) mRNA by binding
RNA-binding proteins, insulin-like growth factor 2 mRNA binding proteins
(IGF2BPs) and disrupting the interaction between IGF2BPs and Myc mRNA.
Furthermore, Myc transcriptionally inhibits FGF13-AS1, forming a feedback loop in
this signaling pathway. These results reveal for the first time that FGF13-AS1
functions as a tumor suppressor by inhibiting glycolysis and stemness properties
of breast cancer cells, and the FGF13-AS1/IGF2BPs/Myc feedback loop could be a
novel therapeutic target for breast cancer patients.

DOI: 10.1016/j.canlet.2019.02.008
PMID: 30771425

Eur J Pharmacol. 2019 Feb 13. pii: S0014-2999(19)30111-6. doi:
10.1016/j.ejphar.2019.02.022. [Epub ahead of print]

Anticancer and antimetastatic potential of enterolactone: clinical, preclinical
and mechanistic perspectives.

Mali AV(1), Padhye SB(2), Anant S(3), Hegde MV(4), Kadam SS(5).

Author information:
(1)Center for Innovation in Nutrition Health and Disease (CINHD), Interactive
Research School for Health Affairs (IRSHA), Bharati Vidyapeeth (Deemed to be
University), Dhankawadi, Pune, Maharashtra 411043, India; Pharmaceutical
Sciences, Poona College of Pharmacy, Bharati Vidyapeeth (Deemed to be
University), Pune, Maharashtra 411038, India.
(2)Interdisciplinary Science and Technology Research Academy, Abeda Inamdar
College, University of Pune, Pune 411001, India; Cancer Biology, University of
Kansas School of Medicine, Kansas City, Kansas 66160 USA.
(3)Cancer Biology, University of Kansas School of Medicine, Kansas City, Kansas
66160 USA.
(4)Center for Innovation in Nutrition Health and Disease (CINHD), Interactive
Research School for Health Affairs (IRSHA), Bharati Vidyapeeth (Deemed to be
University), Dhankawadi, Pune, Maharashtra 411043, India. Electronic address:
mahabaleshwarh@yahoo.com.
(5)Pharmaceutical Sciences, Poona College of Pharmacy, Bharati Vidyapeeth (Deemed
to be University), Pune, Maharashtra 411038, India.

Currently cancer is the second leading cause of death globally and worldwide
incidence and mortality rates of all cancers of males and females are rising
tremendously. In spite of advances in chemotherapy and radiation, metastasis and
recurrence are considered as the major causes of cancer related deaths. Hence
there is a mounting need to develop new therapeutic modalities to treat
metastasis and recurrence in cancers. A significant amount of substantiation from
epidemiological, clinical and laboratory research highlights the importance of
diet and nutrition in cancer chemoprevention. Enterolactone (EL) is a bioactive
phenolic metabolite known as a mammalian lignan derived from dietary lignans.
Here in we review the reported anti-cancer properties of EL at preclinical as
well as clinical level. Several in-vivo and in-vitro studies have provided strong
evidence that EL exhibits potent anti-cancer and/or protective properties against
different cancers including breast, prostate, colo-rectal, lung, ovarian,
endometrial, cervical cancers and hepatocellular carcinoma. Reported laboratory
studies indicate a clear role for EL in preventing cancer progression at various
stages including cancer cell proliferation, survival, angiogenesis, inflammation
and metastasis. In clinical settings, EL has been reported to reduce risk,
decrease mortality rate and improve overall survival particularly in breast,
prostate, colon, gastric and lung cancer. Further, the in-vitro human cell
culture studies provide strong evidence of the anticancer and antimetastatic
mechanisms of EL in several cancers. This comprehensive review supports an idea
of projecting EL as a promising candidate for developing anticancer drug or
adjunct dietary supplements and nutraceuticals.

DOI: 10.1016/j.ejphar.2019.02.022
PMID: 30771348

Med Sci Monit. 2019 Feb 16;25:1275-1282. doi: 10.12659/MSM.912632.

Association Between Activation of the Programmed Cell Death-1 (PD-1)/Programmed
Death-Ligand 1 (PD-L1) Pathway and Pain in Patients with Cancer.

Zhang J(1), Zhang H(2), Luo Y(3)(4).

Author information:
(1)Department of Pain Management, The Third Hospital Affiliated to Hebei Medical
University, Shijiazhuang, Hebei, China (mainland).
(2)Department of Laboratory, The First Hospital of Shijiazhuang, Shijiazhuang,
Hebei, China (mainland).
(3)Department of Palliative Care, The Fourth Hospital of Hebei Medical
University, Shijiazhuang, Hebei, China (mainland).
(4)Department of Oncology, The First Affiliated Hospital of Chengdu Medical
College, Chengdu, Sichuan, China (mainland).

BACKGROUND The aim of this study was to investigate the clinical correlation
between sPD-1 (soluble programmed cell death-1) and PD-1 (programmed cell
death-1) expression and cancer pain. MATERIAL AND METHODS sPD-1 content in
peripheral blood was determined by enzyme-linked immunosorbent assay (ELISA). T
cell surface-positive rate was determined by flow cytometry, and the correlation
of clinical characteristics of patients with cancer pain was analyzed. RESULTS
The positive expression rate of PD-1 in sPD-1 and T cells of patients with cancer
pain was higher than that in normal patients. There was a significant correlation
between sPD-1 and PD-1 positivity on T cell surface with tumor type,
differentiation degree, and VAS scores of patients with cancer pain (P<0.05).
Peripheral blood sPD-1 level and PD-1 positivity in patients with liver cancer
and melanoma cancer were higher than those in patients with renal cell carcinoma
and breast cancer. In addition, peripheral blood sPD-1 level and PD-1 positivity
in patients with poorly-differentiated cancer pain were higher than those in
patients with intermediately- to well-differentiated cancer. The sPD-1 content
was lower and PD-1 positivity rate was higher in cancer pain patients with low
VAS scores. CONCLUSIONS The positive expression rate of sPD-1 and PD-1 in
patients with cancer pain is higher than that in normal people. The activation
rate of the PD-1/PD-L1 pathway was mediated by sPD-1 and PD-1 positive
expression, age, tumor type, and differentiation. There are correlations between
clinical characteristics such as degree and pain level as shown by VAS score.

DOI: 10.12659/MSM.912632
PMID: 30771277

Int J Cancer. 2019 Feb 16. doi: 10.1002/ijc.32214. [Epub ahead of print]

Mortality after breast cancer as a function of time since diagnosis by estrogen
receptor status and age at diagnosis.

Jayasekara H(1)(2)(3)(4), MacInnis RJ(1)(2), Chamberlain JA(2), Dite GS(1), Leoce
NM(5), Dowty JG(1), Bickerstaffe A(1), Win AK(1)(6), Milne RL(1)(2), Giles
GG(1)(2), Terry MB(5)(7), Eccles DM(8), Southey MC(9)(10), Hopper JL(1).

Author information:
(1)Centre for Epidemiology and Biostatistics, Melbourne School of Population and
Global Health, The University of Melbourne, 207 Bouverie Street, Melbourne,
Victoria 3010, Australia.
(2)Cancer Epidemiology and Intelligence Division, Cancer Council Victoria, 615 St
Kilda Road, Melbourne, Victoria 3004, Australia.
(3)Colorectal Oncogenomics Group, Department of Clinical Pathology, Melbourne
Medical School, The University of Melbourne, Melbourne, Victoria 3010, Australia.
(4)Centre for Alcohol Policy Research, La Trobe University, 215 Franklin Street,
Melbourne, Victoria 3000, Australia.
(5)Department of Epidemiology, Mailman School of Public Health, Columbia
University, New York, New York, USA.
(6)Genetic Medicine and Family Cancer Clinic, The Royal Melbourne Hospital,
Parkville, Victoria 3050, Australia.
(7)Herbert Irving Comprehensive Cancer Center, Columbia University Medical
Center, New York, New York, USA.
(8)Cancer Sciences Academic Unit and Southampton Clinical Trials Unit, Faculty of
Medicine, University of Southampton and University Hospital Southampton
Foundation Trust, Southampton S016 6YD, UK.
(9)Genetic Epidemiology Laboratory, Department of Clinical Pathology, Melbourne
Medical School, The University of Melbourne, Melbourne, Victoria 3010, Australia.
(10)Precision Medicine, School of Clinical Sciences at Monash Health, Monash
University, Clayton, Victoria 3168, Australia.

Our aim was to estimate how long-term mortality following breast cancer diagnosis
depends on age at diagnosis, tumor estrogen receptor (ER) status, and the time
already survived. We used the population-based Australian Breast Cancer Family
Study which followed-up 1,196 women enrolled during 1992-99 when aged <60 years at diagnosis with a first primary invasive breast cancer, over-sampled for younger ages at diagnosis, for whom tumor pathology features and ER status were measured. There were 375 deaths (median follow-up=15.7; range=0.8-21.4, years). We estimated the mortality hazard as a function of time since diagnosis using a flexible parametric survival analysis with ER status a time-dependent covariate. For women with ER-negative tumors compared with those with ER-positive tumors, 5-year mortality was initially higher (P<.001), similar if they survived to 5 years (P=0.4), and lower if they survived to 10 years (P=0.02). The estimated mortality hazard for ER-negative disease peaked at ~3 years post-diagnosis, thereafter declined with time, and at 7 years post-diagnosis became lower than that for ER-positive disease. This pattern was more pronounced for women diagnosed at younger ages. Mortality was also associated with lymph node count (hazard ratio (HR) per 10 nodes=2.52 [95% CI:2.11-3.01]) and tumor grade (HR per grade=1.62 [95% CI:1.34-1.96]). The risk of death following a breast cancer diagnosis differs substantially and qualitatively with diagnosis age, ER status and time survived. For women who survive >7 years, those with ER-negative disease
will on average live longer, and more so if younger at diagnosis. This article is
protected by copyright. All rights reserved.

DOI: 10.1002/ijc.32214
PMID: 30771221

Surg Case Rep. 2019 Feb 15;5(1):22. doi: 10.1186/s40792-019-0585-x.

Esophageal metastasis of breast cancer during endocrine therapy for pleural
dissemination 21 years after breast surgery: a case report.

Miyake M(1)(2), Yamada A(3)(4), Miyake K(1)(2), Endo I(2).

Author information:
(1)Department of Breast Surgery, Chigasaki Municipal Hospital, Honson 3-5-1,
Chigasaki, Kanagawa, 253-0042, Japan.
(2)Department of Gastroenterological Surgery, Yokohama City University School of
Medicine, Fukuura 3-9, Kanazawa, Yokohama, Kanagawa, 236-0004, Japan.
(3)Department of Breast Surgery, Chigasaki Municipal Hospital, Honson 3-5-1,
Chigasaki, Kanagawa, 253-0042, Japan. ayamada@yokohama-cu.ac.jp.
(4)Department of Gastroenterological Surgery, Yokohama City University School of
Medicine, Fukuura 3-9, Kanazawa, Yokohama, Kanagawa, 236-0004, Japan.
ayamada@yokohama-cu.ac.jp.

BACKGROUND: The esophageal metastasis of breast cancer is rare. Moreover, it is
extremely unusual for patients to experience the symptoms of esophageal
metastasis during their lifetimes. We present a case of dysphagia caused by
esophageal metastasis after a long interval following a primary mastectomy.
CASE PRESENTATION: A 77-year-old woman with a history of heterochronous bilateral
breast cancer and under treatment for pleural dissemination recurrence
originating from right breast cancer complained of dysphagia. At the age of 56,
she had undergone a right radical mastectomy for right breast cancer. The
histopathological findings revealed invasive ductal carcinoma, pT3N1M0, which was
estrogen receptor (ER)- and progesterone receptor (PgR)-positive. At the age of
73, she underwent a second operation, a left modified radical mastectomy. The
histopathological examination revealed invasive ductal carcinoma, pT1N0M0, which
was negative for ER, PgR, and human epidermal growth factor receptor 2 (HER2).
Four years after completion of adjuvant therapy for the left breast cancer,
pleural effusion on her left side was observed and histopathological examination
of a sample revealed pleural dissemination resulting from the right breast
cancer. After initiation of therapy for recurrence, she developed dysphagia and,
therefore, underwent an upper gastrointestinal tract endoscopic examination. The
examination revealed whole circumferential stenosis and a band unstained by
Lugol’s solution located 30 cm from her incisors. Examination of a biopsy
specimen revealed a subepithelial luminal structure and dysplastic cells.
Immunostaining was positive for CK7 and negative for CK20; furthermore, the
sample was ER and PgR-positive. Considering the pathological findings, the
patient was diagnosed with esophageal metastasis of her right breast cancer.
CONCLUSIONS: Metastatic lesions in the esophagus are often located in the
submucosa; therefore, they may not be definitively diagnosed by histopathological
examination of mucosal biopsy specimens. Esophageal metastasis originating from
breast cancer often occurs as a part of multiple organ metastases; however,
esophageal metastasis is usually not considered a prognostic factor for patients.
Therefore, treatment should be determined according to the severity of the other
metastatic sites and the degree of esophageal stenosis.

DOI: 10.1186/s40792-019-0585-x
PMID: 30771195

Mikrochim Acta. 2019 Feb 15;186(3):185. doi: 10.1007/s00604-019-3302-3.

A voltammetric hybridization assay for microRNA-21 using carboxylated graphene
oxide decorated with gold-platinum bimetallic nanoparticles.

Bharti A(1), Agnihotri N(1), Prabhakar N(2).

Author information:
(1)Department of Biochemistry, Panjab University, Chandigarh, 160014, India.
(2)Department of Biochemistry, Panjab University, Chandigarh, 160014, India.
nirmalprabhakar@gmail.com.

An electrochemical hybridization assay is described for the determination of
microRNA-21. Fluorine tin oxide (FTO) sheets were coated with carboxylated
graphene oxide followed by deposition of gold-platinum bimetallic nanoparticles
by using chronoamperometry at a potential of -0.2 V for 350 s. The capture probe
was immobilized on the surface of the modified FTO sheets by biotin-avidin
interaction. On exposure to microRNA-21, hybridization occurs, and that can be
detected at a relatively low working potential of 0.25 V by using
ferri/ferro-cyanide as an electrochemical probe. The various modifications of the
FTO sheets were characterized by means of FE-SEM, FT-IR, contact angle studies
and electrochemical techniques. The effects of pH value, EDC-NHS activation time,
concentration of capture probe and incubation time were optimized. The sensor has
a wide linear response that extends from 1 fM to 1 μM of microRNA-21, and the
detection limit is 1 fM. The sensor is stable for about 15 days (by retaining 90%
of its initial activity) and can be reused for about 3 times (85% of initial
activity) after regeneration with 50 mM NaOH solution. The sensor was applied to
the analysis of spiked human serum and gave recoveries between 90 and 111%.
Graphical abstract Carboxylated graphene oxide (CGO) coated on a fluorine tin
oxide (FTO) electrode was decorated with Au-Pt bimetallic nanoparticles
(Au-PtBNPs). The Au-PtBNPs/CGO/FTO electrode surface was used for immobilizing
streptavidin and biotinylated capture probe which can electrochemically detect
microRNA-21 based on its sequence complementarity.

DOI: 10.1007/s00604-019-3302-3
PMID: 30771192

Breast Cancer Res Treat. 2019 Feb 15. doi: 10.1007/s10549-019-05165-4. [Epub
ahead of print]

Breast cancer risk in relation to plasma metabolites among Hispanic and African
American women.

Zhao H(1), Shen J(2), Moore SC(3), Ye Y(2), Wu X(2), Zanetti KA(4), Esteva FJ(5),
Tripathy D(6), Chow WH(2).

Author information:
(1)Department of Epidemiology, The University of Texas MD Anderson Cancer Center,
Houston, TX, 77030, USA. hzhao2@mdanderson.org.
(2)Department of Epidemiology, The University of Texas MD Anderson Cancer Center,
Houston, TX, 77030, USA.
(3)Divisions of Cancer Epidemiology and Genetics, National Cancer Institute,
Bethesda, MD, 20892, USA.
(4)Division of Cancer Control and Population Sciences, National Cancer Institute,
Bethesda, MD, 20892, USA.
(5)Perlmutter Cancer Center at New York University Langone Health, New York, NY,
10016, USA.
(6)Department of Breast Medical Oncology, The University of Texas MD Anderson
Cancer Center, 1155 Pressler Street, racial Houston, TX, 77030, USA.

PURPOSE: The metabolic etiology of breast cancer has been explored in the past
several years using metabolomics. However, most of these studies only included
non-Hispanic White individuals.
METHODS: To fill this gap, we performed a two-step (discovery and validation)
metabolomics profiling in plasma samples from 358 breast cancer patients and 138
healthy controls. All study subjects were either Hispanics or non-Hispanic
African Americans.
RESULTS: A panel of 14 identified metabolites significantly differed between
breast cancer cases and healthy controls in both the discovery and validation
sets. Most of these identified metabolites were lipids. In the pathway analysis,
citrate cycle (TCA cycle), arginine and proline metabolism, and linoleic acid
metabolism pathways were observed, and they significantly differed between breast
cancer cases and healthy controls in both sets. From those 14 metabolites, we
selected 9 non-correlated metabolites to generate a metabolic risk score.
Increased metabolites risk score was associated with a 1.87- and 1.63-fold
increased risk of breast cancer in the discovery and validation sets,
respectively (Odds ratio (OR) 1.87, 95% Confidence interval (CI) 1.50, 2.32; OR
1.63, 95% CI 1.36, 1.95).
CONCLUSIONS: In summary, our study identified metabolic profiles and pathways
that significantly differed between breast cancer cases and healthy controls in
Hispanic or non-Hispanic African American women. The results from our study might
provide new insights on the metabolic etiology of breast cancer.

DOI: 10.1007/s10549-019-05165-4
PMID: 30771047

Curr Treat Options Oncol. 2019 Feb 15;20(3):19. doi: 10.1007/s11864-019-0618-5.

Current Treatment Options for Breast Cancer Brain Metastases.

Raghunath A(1), Desai K(2), Ahluwalia MS(3).

Author information:
(1)PGY3 Internal Medicine Resident, Department of Internal Medicine, Cleveland
Clinic Akron General, 1, Akron General Ave, Akron, OH, 44307, USA.
(2)PGY1 Internal Medicine Resident, Department of Internal Medicine, Cleveland
Clinic, 9500 Euclid Avenue, NA10, Cleveland, OH, 44195, USA.
(3)Department of Medicine, Burkhardt Brain Tumor and Neuro-Oncology Center,
Neurological Institute, Cleveland Clinic, 9500 Euclid Ave, S73, Cleveland, OH,
44195, USA. ahluwam@ccf.org.

OPINION STATEMENT: In the past, the standard of care for treatment of BM was
whole brain radiation therapy (WBRT), stereotactic radiosurgery (SRS), and
surgery. There has been a greater role for medical therapies in the last two
decades due to the discovery of driver mutations and corresponding targeted
therapies. These innovations have dramatically altered the approach to treating
these patients. Some of the important mutations include epidermal growth factor
receptor (EGFR) and anaplastic lymphoma kinase (ALK) mutations in small cell lung
cancer, human epidermal growth factor receptor (HER2) mutation in breast cancer,
and BRAF mutation in melanoma. Disease-specific graded prognostic assessments
have identified prognostic factors for each of the major tumor types associated
with BM. These reflect the increased treatment sensitivity of these tumors to
specific agents. Furthermore, there is a difference in the genetic makeup of BM
compared to their primary tumor. Genomic studies of BM patients comparing somatic
point mutations and copy number variations with their primary tumor have
demonstrated that while both the primary tumor and BM share a number of common
mutations, BM can often develop distinct mutations. Therefore, there is a need to
individualize systemic therapies in BM. Several organizations including the Food
and Drug Administration and the American Society of Clinical Oncology now
emphasize the inclusion of BM patients in various phases of clinical drug
development.

DOI: 10.1007/s11864-019-0618-5
PMID: 30771009

Eur Radiol. 2019 Feb 15. doi: 10.1007/s00330-019-06016-y. [Epub ahead of print]

A new automated method to evaluate 2D mammographic breast density according to
BI-RADS® Atlas Fifth Edition recommendations.

Balleyguier C(1), Arfi-Rouche J(2), Boyer B(2), Gauthier E(3), Helin V(3),
Loshkajian A(2), Ragusa S(3), Delaloge S(2).

Author information:
(1)Imaging Department, Gustave Roussy, 114 rue Edouard Vaillant, 94800,
Villejuif, France. corinne.balleyguier@gustaveroussy.fr.
(2)Imaging Department, Gustave Roussy, 114 rue Edouard Vaillant, 94800,
Villejuif, France.
(3)Predlife, Espace Maurice Tubiana, 39 rue Camille Desmoulins, 94800, Villejuif,
France.

OBJECTIVES: Radiologists’ visual assessment of breast mammographic density (BMD)
is subject to inter-observer variability. We aimed to develop and validate a new
automated software tool mimicking expert radiologists’ consensus assessments of
2D BMD, as per BI-RADS V recommendations.
METHODS: The software algorithm was developed using a concept of Manhattan
distance to compare a patient’s mammographic image to reference mammograms with
an assigned BMD category. Reference databases were built from a total of 2289
pairs (cranio-caudal and medio-lateral oblique views) of 2D full-field digital
mammography (FFDM). Each image was independently assessed for BMD by a consensus
of radiologists specialized in breast imaging. A validation set of additional 800
image pairs was evaluated for BMD both by the software and seven blinded
radiologists specialized in breast imaging. The median score was used for
consensus. Software reproducibility was assessed using FFDM image pairs from 214
patients in the validation set to compare BMD assessment between left and right
breasts.
RESULTS: The software showed a substantial agreement with the radiologists’
consensus (unweighted κ = 0.68, 95% CI 0.64-0.72) when considering the four
breast density categories, and an almost perfect agreement (unweighted κ = 0.84,
95% CI 0.80-0.88) when considering clinically significant non-dense (A-B) and
dense (C-D) categories. Correlation between left and right breasts was high
(rs = 0.87; 95% CI 0.84-0.90).
CONCLUSIONS: BMD assessment by the software was strongly correlated to
radiologists’ consensus assessments of BMD. Its performance should be compared to
other methods, and its clinical utility evaluated in a risk assessment model.
KEY POINTS: • A new software tool assesses breast density in a standardized way.
• The tool mimics radiologists’ clinical assessment of breast density. • It may
be incorporated in a breast cancer risk assessment model.

DOI: 10.1007/s00330-019-06016-y
PMID: 30770972

Nat Commun. 2019 Feb 15;10(1):766. doi: 10.1038/s41467-019-08595-2.

Barcoding reveals complex clonal behavior in patient-derived xenografts of
metastatic triple negative breast cancer.

Merino D(1)(2)(3)(4), Weber TS(5)(6), Serrano A(7)(5)(8), Vaillant F(7)(5), Liu
K(7)(5), Pal B(7)(5), Di Stefano L(9), Schreuder J(5)(6)(10), Lin D(5)(6)(10),
Chen Y(5)(9), Asselin-Labat ML(7)(5), Schumacher TN(11), Cameron D(9), Smyth
GK(9)(12), Papenfuss AT(5)(9)(12)(13)(14), Lindeman GJ(7)(15)(16)(17), Visvader
JE(18)(19), Naik SH(20)(21)(22).

Author information:
(1)ACRF Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of
Medical Research, Parkville, VIC, 3052, Australia. delphine.merino@onjcri.org.au.
(2)Department of Medical Biology, The University of Melbourne, Melbourne, VIC,
3010, Australia. delphine.merino@onjcri.org.au.
(3)Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, 3084,
Australia. delphine.merino@onjcri.org.au.
(4)School of Cancer Medicine, La Trobe University, Bundoora, VIC, 3086,
Australia. delphine.merino@onjcri.org.au.
(5)Department of Medical Biology, The University of Melbourne, Melbourne, VIC,
3010, Australia.
(6)Molecular Medicine Division, The Walter and Eliza Hall Institute of Medical
Research, Parkville, VIC, 3052, Australia.
(7)ACRF Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of
Medical Research, Parkville, VIC, 3052, Australia.
(8)Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, 3084,
Australia.
(9)Bioinformatics Division, The Walter and Eliza Hall Institute of Medical
Research, Parkville, VIC, 3052, Australia.
(10)Immunology Division, The Walter and Eliza Hall Institute of Medical Research,
Parkville, VIC, 3052, Australia.
(11)Division of Molecular Oncology & Immunology, Netherlands Cancer Institute,
Amsterdam, 1066 CX, The Netherlands.
(12)School of Mathematics and Statistics, The University of Melbourne, Melbourne,
VIC, 3010, Australia.
(13)Peter MacCallum Cancer Centre, Melbourne, VIC, 3000, Australia.
(14)Sir Peter MacCallum Department of Oncology, University of Melbourne,
Melbourne, VIC, 3010, Australia.
(15)Department of Medical Oncology, The Peter MacCallum Cancer Centre, Melbourne,
VIC, 3000, Australia.
(16)Department of Medicine, The University of Melbourne, Melbourne, VIC, 3010,
Australia.
(17)Parkville Familial Cancer Centre, The Royal Melbourne Hospital and Peter
MacCallum Cancer Centre, Parkville, VIC, 3050, Australia.
(18)ACRF Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of
Medical Research, Parkville, VIC, 3052, Australia. visvader@wehi.edu.au.
(19)Department of Medical Biology, The University of Melbourne, Melbourne, VIC,
3010, Australia. visvader@wehi.edu.au.
(20)Department of Medical Biology, The University of Melbourne, Melbourne, VIC,
3010, Australia. naik.s@wehi.edu.au.
(21)Molecular Medicine Division, The Walter and Eliza Hall Institute of Medical
Research, Parkville, VIC, 3052, Australia. naik.s@wehi.edu.au.
(22)Immunology Division, The Walter and Eliza Hall Institute of Medical Research,
Parkville, VIC, 3052, Australia. naik.s@wehi.edu.au.

Primary triple negative breast cancers (TNBC) are prone to dissemination but
sub-clonal relationships between tumors and resulting metastases are poorly
understood. Here we use cellular barcoding of two treatment-naïve TNBC
patient-derived xenografts (PDXs) to track the spatio-temporal fate of thousands
of barcoded clones in primary tumors, and their metastases. Tumor resection had a
major impact on reducing clonal diversity in secondary sites, indicating that
most disseminated tumor cells lacked the capacity to ‘seed’, hence originated
from ‘shedders’ that did not persist. The few clones that continued to grow after
resection i.e. ‘seeders’, did not correlate in frequency with their parental
clones in primary tumors. Cisplatin treatment of one BRCA1-mutated PDX model to
non-palpable levels had a surprisingly minor impact on clonal diversity in the
relapsed tumor yet purged 50% of distal clones. Therefore, clonal features of
shedding, seeding and drug resistance are important factors to consider for the
design of therapeutic strategies.

DOI: 10.1038/s41467-019-08595-2
PMCID: PMC6377663
PMID: 30770823

Cell Death Dis. 2019 Feb 15;10(3):147. doi: 10.1038/s41419-019-1414-7.

Fhit-Fdxr interaction in the mitochondria: modulation of reactive oxygen species
generation and apoptosis in cancer cells.

Druck T(1), Cheung DG(1), Park D(1), Trapasso F(2), Pichiorri F(3), Gaspari M(2),
Palumbo T(4), Aqeilan RI(1)(5), Gaudio E(6), Okumura H(7), Iuliano R(2), Raso
C(8), Green K(9), Huebner K(1), Croce CM(10).

Author information:
(1)Department of Cancer Biology and Genetics, The Ohio State University
Comprehensive Cancer Center, Columbus, OH, 43210, USA.
(2)Dipartimento di Medicina Sperimentale e Clinica, University «Magna Græcia» of
Catanzaro, Catanzaro, 88100, Italy.
(3)Department of Hematologic Malignancies Translational Science, Beckman Research
Institute, City of Hope, Duarte, CA, USA.
(4)Dipartimento di Farmacologia Sperimentale Preclinica e Clinica, University of
Catania, Catania, 95123, Italy.
(5)Lautenberg Center for Immunology and Cancer Research, Faculty of Medicine,
Hebrew University of Jerusalem, Jerusalem, Israel.
(6)Università della Svizzera italiana, Institute of Oncology Research,
Bellinzona, Switzerland.
(7)Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical
Sciences, Kagoshima University, Sakuragaoka, Kagoshima, Japan.
(8)Systems Biology Ireland, University College Dublin, Belfield, Dublin 4,
Dublin, Ireland.
(9)Department of Chemistry, Mass Spectrometry Research and Education Center,
University of Florida, 126 Sisler Hall, Gainesville, FL, 32611-7200, USA.
(10)Department of Cancer Biology and Genetics, The Ohio State University
Comprehensive Cancer Center, Columbus, OH, 43210, USA. Carlo.Croce@osumc.edu.

Fhit protein is lost in cancers of most, perhaps all, cancer types; when
restored, it can induce apoptosis and suppress tumorigenicity, as shown in vitro
and in mouse tumor models in vivo. Following protein cross-linking and proteomics
analyses, we characterized a Fhit protein complex involved in triggering
Fhit-mediated apoptosis. The complex includes the heat-shock chaperonin pair,
HSP60/10, which is likely involved in importing Fhit into the mitochondria, where
it interacts with ferredoxin reductase, responsible for transferring electrons
from NADPH to cytochrome P450 via ferredoxin, in electron transport chain complex
III. Overexpression of Fhit protein in Fhit-deficient cancer cells modulates the
production of intracellular reactive oxygen species, causing increased ROS,
following peroxide treatment, with subsequent increased apoptosis of lung cancer
cells under oxidative stress conditions; conversely, Fhit-negative cells escape
ROS overproduction and ROS-induced apoptosis, likely carrying oxidative damage.
Thus, characterization of Fhit-interacting proteins has identified direct
effectors of a Fhit-mediated apoptotic signal pathway that is lost in many
cancers. This is of translational interest considering the very recent emphasis
in a number of high-profile publications, concerning the role of oxidative
phosphorylation in the treatment of human cancers, and especially cancer stem
cells that rely upon oxidative phosphorylation for survival. Additionally, we
have shown that cells from a Fhit-deficient lung cancer cell line, are sensitive
to killing by exposure to atovaquone, thought to act as a selective oxidative
phosphorylation inhibitor by targeting the CoQ10 dependence of the mitochondrial
complex III, while the Fhit-expressing sister clone is resistant to this
treatment.

DOI: 10.1038/s41419-019-1414-7
PMCID: PMC6377664
PMID: 30770797

Cell Death Dis. 2019 Feb 15;10(3):157. doi: 10.1038/s41419-019-1303-0.

Sphingomyelin synthase 2 promotes an aggressive breast cancer phenotype by
disrupting the homoeostasis of ceramide and sphingomyelin.

Zheng K(1)(2), Chen Z(3)(4), Feng H(1), Chen Y(1), Zhang C(1), Yu J(1), Luo Y(1),
Zhao L(3)(4), Jiang X(5), Shi F(6).

Author information:
(1)Department of General Surgery, Zhujiang Hospital, Southern Medical University,
Guangzhou, China.
(2)Division of Laboratory Medicine, Zhujiang Hospital, Southern Medical
University, Guangzhou, China.
(3)Department of Pathology, Nanfang Hospital, Southern Medical University,
Guangzhou, China.
(4)Department of Pathology, School of Basic Medical Sciences, Southern Medical
University, Guangzhou, China.
(5)Department of Cell biology, Downstate Medical Centre, State University of New
York, New York, NY, USA.
(6)Department of General Surgery, Zhujiang Hospital, Southern Medical University,
Guangzhou, China. drshifujun@163.com.

Breast cancer is the most common type of carcinoma in women worldwide, but the
mechanisms underlying tumour development and progression remain unclear.
Sphingomyelin synthase 2 (SGMS2) is a crucial regulator involved in ceramide
(Cer) and sphingomyelin (SM) homoeostasis that is mostly studied for its role in
lipid metabolism. Our primary study indicated that high SGMS2 expression is
associated with breast cancer metastasis. Gain- and loss-of-function assays in
vitro and in vivo revealed that SGMS2 promotes cancer cell proliferation by
suppressing apoptosis through a Cer-associated pathway and promotes cancer cell
invasiveness by enhancing epithelial-to-mesenchymal transition (EMT) initiation
through the TGF-β/Smad signalling pathway. Further study determined that SGMS2
activated the TGF-β/Smad signalling pathway primarily by increasing TGF-β1
secretion, which was likely associated with aberrant expression of SM. Thus, our
findings indicate that SGMS2-mediated activation of the TGF-β/Smad signalling
pathway is important in breast cancer progression, which provides new insight
into the mechanisms underlying breast cancer metastasis and suggests a possible
anticancer therapy for breast cancer.

DOI: 10.1038/s41419-019-1303-0
PMCID: PMC6377618
PMID: 30770781

Breast Cancer Res. 2019 Feb 15;21(1):25. doi: 10.1186/s13058-019-1111-6.

Imprint of parity and age at first pregnancy on the genomic landscape of
subsequent breast cancer.

Nguyen B(1)(2), Venet D(3), Lambertini M(3)(4), Desmedt C(3), Salgado R(3)(5),
Horlings HM(6), Rothé F(3), Sotiriou C(3).

Author information:
(1)Breast Cancer Translational Research Laboratory J.-C. Heuson, Institut Jules
Bordet, Université Libre de Bruxelles (ULB), Brussels, Belgium.
bastien.nguyen@gmail.com.
(2)Present Address: Marie-Josée and Henry R. Kravis Center for Molecular
Oncology, Memorial Sloan Kettering Cancer Center, New York, USA.
bastien.nguyen@gmail.com.
(3)Breast Cancer Translational Research Laboratory J.-C. Heuson, Institut Jules
Bordet, Université Libre de Bruxelles (ULB), Brussels, Belgium.
(4)Department of Medical Oncology, Clinica di Oncologia Medica, Ospedale
Policlinico San Martino, & Department of Internal Medicine and Medical
Specialties (DiMI), School of Medicine, University of Genova, Genova, Italy.
(5)Department of Pathology, GZA-ZNA, Antwerp, Belgium.
(6)Department of Pathology, The Netherlands Cancer Institute, Amsterdam, The
Netherlands.

BACKGROUND: Although parity and age at first pregnancy are among the most known
extrinsic factors that modulate breast cancer risk, their impact on the biology
of subsequent breast cancer has never been explored in depth. Recent data suggest
that pregnancy-induced tumor protection is different according to breast cancer
subtypes, with parity and young age at first pregnancy being associated with a
marked reduction in the risk of developing luminal subtype but not triple
negative breast cancer. In this study, we investigated the imprint of parity and
age at first pregnancy on the pattern of somatic mutations, somatic copy number
alterations, transcriptomic profiles, and tumor immune microenvironment by
assessing tumor-infiltrating lymphocytes (TILs) levels of subsequent breast
cancer.
METHODS: A total of 313 patients with primary breast cancer with available whole
genome, RNA sequencing, and TILs data were included in this study. We used a
multivariate analysis adjusted for age at diagnosis, pathological stage,
molecular subtypes, and histological subtypes. We compared nulliparous vs.
parous, late parous vs. early parous, and nulliparous vs. pregnancy-associated
breast cancer (PABC) patients. Late and early parous patients were grouped by
using the median age at first pregnancy. PABC was defined as patients diagnosed
up to 10 years postpartum.
RESULTS: Genomic alterations of breast cancer were associated with age at first
pregnancy but not with parity status alone. Independently of clinicopathological
features, early parous patients developed tumors characterized by a higher number
of Indels (Padj = 0.002), a lower frequency of CDH1 mutations (1.2% vs. 12.7%;
Padj = 0.013), a higher frequency of TP53 mutations (50% vs. 22.5%;
Padj = 0.010), and MYC amplification (28% vs. 7%; Padj = 0.008). PABC were
associated with increased TILs infiltration (Padj = 0.0495).
CONCLUSIONS: These findings highlight an unprecedented link between reproductive
history and the genomic landscape of subsequent breast cancer. We further
hypothesize that TP53-mutant premalignant lesions could be less susceptible to
the protective effect of an early parity, which might explain the difference of
parity-induced protection according to breast cancer subtypes. This work also
advocates that reproductive history should be routinely collected in future
large-scale genomic studies addressing the biology of female cancers.

DOI: 10.1186/s13058-019-1111-6
PMID: 30770770

BMC Cancer. 2019 Feb 15;19(1):153. doi: 10.1186/s12885-019-5364-3.

Insluin and epithelial growth factor (EGF) promote programmed death ligand
1(PD-L1) production and transport in colon cancer stem cells.

Chen M(1)(2)(3), Sharma A(1), Lin Y(1), Wu Y(1), He Q(1), Gu Y(1), Xu ZP(1),
Monteiro M(1), Gu W(4).

Author information:
(1)Australian Institute for Bioengineering and Nanotechnology (Building 75), The
University of Queensland, Cooper Rd., St Lucia, Brisbane, QLD, 4072, Australia.
(2)Laboratory of Immuno-Oncology, Department of Medical Oncology, Fujian
Provincial Cancer Hospital &Institute, Fuzhou, 350014, China.
(3)Fujian Provincial Key Laboratory of Translational Cancer Medicine, Fuzhou,
350014, China.
(4)Australian Institute for Bioengineering and Nanotechnology (Building 75), The
University of Queensland, Cooper Rd., St Lucia, Brisbane, QLD, 4072, Australia.
w.gu@uq.edu.au.

BACKGROUND: Programmed cell death ligand 1 (PD-L1) is an important
immune-inhibitory protein expressed on cancer cells to mediate cancer escape
through interaction with PD-1 expressed on activated T lymphocytes (T cells).
Previously, we reported that colon and breast cancer stem cells (CSCs) expressed
much higher levels of PD-L1 than their parental cells, suggesting they will be
more resistant to immune attack.
METHODS: We investigated the underlining mechanism of PD-L1 increase in colon
CSCs, with a special focus on the effect of insulin and epithelial growth factor
(EGF), the two fundamental components to sustain the metabolism and stemness in
the culture of CSCs.
RESULTS: We found that insulin increased the total and surface PD-L1 levels
through PI3K/Akt/mTOR pathway as the increase could be inhibited by the dual
inhibitor of the pathway, BEZ235. EGF didn’t affect the total PD-L1 levels of
CSCs but increased the cell surface protein levels by flow cytometry analysis,
indicating EGF promotes the transport of PD-L1 to the cell surface. Blocking cell
surface PD-L1 with a specific antibody resulted in a significant reduction of
tumour sphere formation but didn’t interfere with the sphere growth, suggesting
that cell surface PD-L1 may act as an adhering molecule for CSCs.
CONCLUSIONS: Apart from the essential roles in metabolism and stemness, insulin
and EGF involve in up-regulation of PD-L1 expression in colon CSCs, therefore the
inhibition of insulin and EGF/EGFR pathways can be considered for cancer
immunotherapy or combined with PD-1/PD-L1 antibody-based cancer immunotherapy to
eliminate CSCs.

DOI: 10.1186/s12885-019-5364-3
PMID: 30770752

BMC Cancer. 2019 Feb 15;19(1):155. doi: 10.1186/s12885-019-5327-8.

Prognostic impact of mRNA levels of LGR5 transcript variants in OSCC patients.

Rot S(1), Kaune T(2)(3), Taubert H(4), Greither T(5), Kotrba J(2)(6), Güttler
A(7), Wichmann H(2), Bilkenroth U(8), Wienke A(9), Al-Nawas B(2)(10), Bache M(7),
Vordermark D(7), Wickenhauser C(11), Bethmann D(11), Eckert AW(2), Kappler M(2).

Author information:
(1)Department of Oral and Maxillofacial Plastic Surgery, Martin Luther University
Halle-Wittenberg, Ernst-Grube-Str, 40 06097, Halle/Saale, Germany.
swetlana.rot@uk-halle.de.
(2)Department of Oral and Maxillofacial Plastic Surgery, Martin Luther University
Halle-Wittenberg, Ernst-Grube-Str, 40 06097, Halle/Saale, Germany.
(3)Present address: Department of Internal Medicine I, Martin Luther University
Halle-Wittenberg, Halle (Saale), Germany.
(4)Clinic of Urology and Pediatric Urology, FA University Hospital Erlangen, FA
University Erlangen-Nürnberg, Erlangen, Germany.
(5)Centre for Reproductive Medicine and Andrology, Martin Luther University
Halle-Wittenberg, Halle (Saale), Germany.
(6)Present address: Institute of Molecular and Clinical Immunology,
Otto-von-Guericke-University, Magdeburg, Germany.
(7)Department of Radiotherapy, Martin Luther University Halle-Wittenberg, Halle
(Saale), Germany.
(8)Institute of Pathology, Eisleben, Germany.
(9)Institute of Medical Epidemiology, Biostatistics, and Informatics, Martin
Luther University Halle-Wittenberg, Halle (Saale), Germany.
(10)Present address: Department of Oral and Maxillofacial Surgery, Plastic
Surgery, University Medical Center of the Johannes Gutenberg-University Mainz,
Mainz, Germany.
(11)Institute of Pathology, Martin Luther University Halle-Wittenberg, Halle
(Saale), Germany.

BACKGROUND: The human leucine-rich, repeat-containing G protein-coupled receptor
5 (LGR5) is a stem cell marker in numerous adult tissues and is overexpressed in
a large number of human carcinoma including colon cancer, breast cancer and oral
squamous cell carcinomas (OSCC). The role of the full length transcript (LGR5FL)
in progression and prognosis of several cancers was reported. However, the
biological function of three splice variants of LGR5 (LGR5Δ5, LGR5Δ8 and
LGR5Δ5-8) has yet to be thoroughly investigated.
METHODS: Seventy-eight frozen tumor samples from adult OSCC patients were studied
using quantitative real-time TaqMan™ PCR analysis. The mRNA levels of full length
LGR5, the splice variant of LGR5 lacking exon 5 (LGR5Δ5), the splice variant of
LGR5 lacking exon 8 (LGR5Δ8) and the mRNA level of all known transcript variants
together (LGR5all) were quantified and correlated to overall and disease-specific
survival of OSCC patients, clinical parameters and the mRNA level of different
tumor-associated markers.
RESULTS: An elevated level of tumoral LGR5Δ5 mRNA, but not LGR5FL, LGR5Δ8 or
LGR5all mRNA was significantly associated with a poor prognosis for the overall
and disease-specific survival of OSCC patients (hazard ratio (HR) = 2.0;
p = 0.02; 95% CI: 1.1-3.7; HR = 3.2; p = 0.01; 95% CI: 1.3-8.0; multivariable Cox
regression), respectively. Additionally, a higher tumoral level of LGR5Δ5 mRNA in
primary tumors was associated with the occurrence of regional lymph node
metastases in OSCC patients (odds ratio (OR) = 3.1; p = 0.022; 95% CI: 1.2-7.9;
binary logistic regression). Furthermore, the mRNA levels of all investigated
LGR5 transcript variants were significantly correlated with the mRNA expression
of Wnt-target genes and markers of epithelial-to-mesenchymal transition (EMT).
CONCLUSION: The mRNA level of the LGR5 splice variant LGR5Δ5 is an independent
negative prognostic marker for overall and disease-specific survival and
metastasis in OSCC patients. Additionally, we suggest, all LGR5 transcript
variants are involved in the EMT process mainly through activating the
Wnt-signalling pathway.

DOI: 10.1186/s12885-019-5327-8
PMID: 30770730

J Biomed Opt. 2019 Feb;24(2):1-7. doi: 10.1117/1.JBO.24.2.025002.

Dynamic light scattering optical coherence tomography to probe motion of
subcellular scatterers.

Arezza NJJ(1)(2), Razani M(1)(2), Kolios MC(1)(2).

Author information:
(1)Ryerson University, Department of Physics, Faculty of Science, Toronto,
Canada.
(2)Institute for Biomedical Engineering, Science and Technology, Li Ka Shing
Knowledge Institute, St. M, Canada.

Optical coherence tomography (OCT) is used to provide anatomical information of
biological systems but can also provide functional information by characterizing
the motion of intracellular structures. Dynamic light scattering OCT was
performed on intact, control MCF-7 breast cancer cells and cells either treated
with paclitaxel to induce apoptosis or deprived of nutrients to induce oncosis.
Autocorrelations (ACs) of the temporal fluctuations of OCT intensity signals
demonstrate a significant decrease in decorrelation time after 24 h in both the
paclitaxel-treated and nutrient-deprived cell groups but no significant
differences between the two groups. The acquired ACs were then used as input for
the CONTIN deconvolution algorithm, and all produced CONTIN outputs with three
distinct peaks for all experimental conditions. After 24 h of either paclitaxel
treatment or nutrient deprivation, the area-under-the-curve (AUC) of the first
peak increased significantly while the AUC of the third peak decreased
significantly. These results lend strong support to the hypothesis that ACs
acquired from cells are composed of multiple components that correspond to light
scattered by different subcellular structures and organelles.

DOI: 10.1117/1.JBO.24.2.025002
PMID: 30770677

J Cell Physiol. 2019 Feb 15. doi: 10.1002/jcp.28261. [Epub ahead of print]

Ras-PI3K-AKT signaling promotes the occurrence and development of uveal melanoma
by downregulating H3K56ac expression.

Li Y(1), Sun D(2), Sun W(3), Yin D(2).

Author information:
(1)Department of Ophthalmology, The Second Hospital of Jilin University,
Changchun, Jilin, China.
(2)Department of Vascular Surgery, China-Japan Union Hospital of Jilin
University, Changchun, Jilin, China.
(3)Department of Gastrointestinal Colorectal and Anal Surgery, China-Japan Union
Hospital of Jilin University, Changchun, Jilin, China.

BACKGROUND: Uveal melanoma (UM) is an intraocular malignant tumor characterized
by rapid progression and recurrence. The current conventional treatments are
unsatisfactory. Histone acetylation at H3 lysine 56 (H3K56ac) has been reported
to be a tumor suppressor in breast cancer. However, whether H3K56ac prevents the
occurrence and development of UM remains uninvestigated. The study aimed to
explore the regulatory effect of H3K56ac on Ras-PI3K-AKT induced UM cells
proliferation and migration.
METHODS: The vectors of pEGFP-RasWT , pEGFP-K-Ras G12V/Y40C , and pEGFP-N1 were
transfected into MP46 cells, and protein levels of phosphorylated AKT Ser473 and
H3K56ac were examined using western blot analysis. The effect of H3K56ac on cell
proliferation and migration were studied using 3-(4,5-dimethylthiazol-2-yl)-2,5
diphenyl tetrazolium bromide, colony formation, and Transwell assays. Reverse
transcription-quantitative polymerase chain reaction (RT-qPCR) and chromatin
immunoprecipitation assays were performed to determine the phosphoinositide
3-kinase/protein kinase B (PI3K/AKT) downstream genes. Further, the regulatory
effects of silent mating type information regulation 2 homolog-1 (SIRT1), general
control nonderepressible 5 (GCN5), and mouse double minute 2 homolog (MDM2) on
Ras-PI3K-AKT affected H3K56ac expression were also investigated.
RESULTS: H3K56ac expression was specifically downregulated by Ras-PI3K-AKT
activation pathway. H3K56ac inhibited the tumorigenic effect of Ras-PI3K-AKT on
MP46 cells viability, colony formation, and migration, as well as participated in
regulating the transcription of PI3K/AKT downstream genes. SIRT1 silence
recovered H3K56ac expression, and reversed the tumorigenic effect of Ras-PI3K-AKT
activation on MP46 cells. Downregulation of H3K56ac induced by Ras-PI3K-AKT
activation was found to be associated with MDM2-mediated the degradation of GCN5.
CONCLUSIONS: The results demonstrated that Ras-PI3K-AKT signaling promoted UM
cells proliferation and migration via downregulation of H3K56ac expression, which
might be related to MDM2-mediated the degradation of GCN5.

DOI: 10.1002/jcp.28261
PMID: 30770562

J Cell Physiol. 2019 Feb 15. doi: 10.1002/jcp.28268. [Epub ahead of print]

Expression pattern of microRNAs related with response to trastuzumab in breast
cancer.

Yang F(1)(2), Fu Z(1)(3), Yang M(1)(2), Sun C(1)(2), Li Y(1)(2), Chu J(1)(2),
Zhang Y(1)(2), Li W(1), Huang X(1), Li J(1), Wu H(1), Ding X(1)(2), Yin Y(1).

Author information:
(1)Department of Oncology, The First Affiliated Hospital of Nanjing Medical
University, Nanjing, China.
(2)The First Clinical College of Nanjing Medical University, Nanjing, China.
(3)Nanjing Maternal and Child Health Institute, The Affiliated Obstetrics and
Gynecology Hospital of Nanjing Medical University (Nanjing Maternity and Child
Health Care Hospital), Nanjing, China.

BACKGROUND: Although an immense effort has been made to develop a novel biomarker
for response to trastuzumab, no reliable biomarkers are available to guide
management, expect for HER2. The aim of this study was to examine the
relationship between microRNA (miRNA) expression and resistance to trastuzumab.
METHODS: Differentially expressed miRNAs between trastuzumab-resistant and
trastuzumab-sensitive cell lines were analyzed using microarrays. We performed
Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment
analyses to determine the functions of differentially expressed miRNA and their
targeted genes. Furthermore, the protein-protein interactions (PPI) network was
analyzed. Serum samples were collected from patients with HER2-positive breast
cancer who were treated with trastuzumab. We validated the miRNAs expression
levels by quantitative reverse-transcription polymerase chain reaction (qRT-PCR)
in these serums. Receiver operating characteristic (ROC) curve analysis was
performed to evaluate the predictive performance of the miRNA.
RESULTS: Using miRNA microarrays, 151 miRNAs that significant differentially
expressed between the trastuzumab-resistant and sensitive cells were identified,
including 46 upregulated and 105 downregulated miRNAs. Results of real-time PCR
confirmed seven miRNAs in cell lines. PI3K-Akt signaling pathway was involved in
regulating biological function according to KEGG analysis. Compared with the
serums of trastuzumab-sensitive patients, three miRNAs, namely miR-200b,
miR-135b, and miR-29a, were identified to be upregulated, and miR-224 was
downregulated in the trastuzumab-resistant serums. ROC analysis showed that four
miRNAs were correlated with trastuzumab resistance. Furthermore, three subnetwork
modules of PPI network were obtained.
CONCLUSION: The results indicated that miRNAs were reliable predictive biomarkers
for response to trastuzumab.

DOI: 10.1002/jcp.28268
PMID: 30770556

Acta Obstet Gynecol Scand. 2019 Feb 15. doi: 10.1111/aogs.13576. [Epub ahead of
print]

Prevalence of deaths in a cohort of girls and women with cryopreserved ovarian
tissue.

Macklon KT(1).

Author information:
(1)The Fertility Clinic, section 4071, University Hospital of Copenhagen
Rigshospitalet, Copenhagen, Denmark.

INTRODUCTION: Ovarian tissue cryopreservation (OTC) is increasingly offered to
women in need of fertility preservation. However, little is known about the risk
of these women dying before they use the preserved material.
MATERIAL AND METHODS: From 1999 to 2016, 927 girls and women underwent OTC in our
center, prior to receiving gonadotoxic treatment. All patients were without
disseminated disease and with an estimated chance of survival after 5 years of >
50%. For each patient the specific indication for OTC was noted, and through a
national registry linked to a personal identification number, we were able to
identify those who had died and the date and cause of death.
RESULTS: By December 2017, 124/927 patients had died from their disease (13%).
The highest relative prevalence of death was seen in patients suffering from
liver cancer (2/2=100%), gall bladder cancer (2/2=100%), stomach cancer
(1/1=100%), hemophagocytic lymphohistiocytosis (2/3=66%), scleroderma (1/2=50%),
and sarcoma (24/78=31%). The lowest risk of dying was seen in the group of
patients suffering from Non-Hodgkin lymphoma (3/30=10%) and breast cancer
(31/313=10%). The shortest time from OTC to death was seen in those suffering
from hemophagocytic lymphohistiocytosis (mean interval 0.25 years), gall bladder
cancer, Non-Hodgkin disease and acute myeloid leukemia (mean interval 0.7 years)
and the longest time from OTC to death in those suffering from breast cancer
(mean interval 3.4 years). Of those who died 34 had received chemotherapy at some
point before OTC indicating a relapse or non-responsiveness to the initial
treatment.
CONCLUSIONS: Patients with upper gastro-intestinal cancers and sarcoma had the
highest risk of dying from their disease. Breast cancer patients had the lowest
risk. This knowledge may guide clinicians in their decisions on whether to offer
OTC to girls and younger women with a life-threatening disease. This article is
protected by copyright. All rights reserved.

DOI: 10.1111/aogs.13576
PMID: 30770545

Clin Cancer Res. 2019 Feb 15;25(4):1437. doi: 10.1158/1078-0432.CCR-18-4264.

Correction: RAS/MAPK Activation Is Associated with Reduced Tumor-Infiltrating
Lymphocytes in Triple-Negative Breast Cancer: Therapeutic Cooperation Between MEK
and PD-1/PD-L1 Immune Checkpoint Inhibitors.

Loi S, Dushyanthen S, Beavis PA, Salgado R, Denkert C, Savas P, Combs S, Rimm DL,
Giltnane JM, Estrada MV, Sánchez V, Sanders ME, Cook RS, Pilkinton MA, Mallal SA,
Wang K, Miller VA, Stephens PJ, Yelensky R, Doimi FD, Gómez H, Ryzhov SV, Darcy
PK, Arteaga CL, Balko JM.

Erratum for
Clin Cancer Res. 2016 Mar 15;22(6):1499-509.

DOI: 10.1158/1078-0432.CCR-18-4264
PMID: 30770496

Clin Cancer Res. 2019 Feb 15;25(4):1434. doi: 10.1158/1078-0432.CCR-18-4267.

Correction: HER2-Overexpressing Breast Cancers Amplify FGFR Signaling upon
Acquisition of Resistance to Dual Therapeutic Blockade of HER2.

Hanker AB, Garrett JT, Estrada MV, Moore PD, Ericsson PG, Koch JP, Langley E,
Singh S, Kim PS, Frampton GM, Sanford E, Owens P, Becker J, Groseclose MR,
Castellino S, Joensuu H, Huober J, Brase JC, Majjaj S, Brohée S, Venet D, Brown
D, Baselga J, Piccart M, Sotiriou C, Arteaga CL.

Erratum for
Clin Cancer Res. 2017 Aug 1;23(15):4323-4334.

DOI: 10.1158/1078-0432.CCR-18-4267
PMID: 30770493

Clin Cancer Res. 2019 Feb 15;25(4):1433. doi: 10.1158/1078-0432.CCR-18-4268.

Correction: Association of FGFR1 with ERα Maintains Ligand-Independent ER
Transcription and Mediates Resistance to Estrogen Deprivation in ER+ Breast
Cancer.

Formisano L, Stauffer KM, Young CD, Bhola NE, Guerrero-Zotano AL, Jansen VM,
Estrada MM, Hutchinson KE, Giltnane JM, Schwarz LJ, Lu Y, Balko JM, Deas O, Cairo
S, Judde JG, Mayer IA, Sanders M, Dugger TC, Bianco R, Stricker T, Arteaga CL.

Erratum for
Clin Cancer Res. 2017 Oct 15;23(20):6138-6150.

DOI: 10.1158/1078-0432.CCR-18-4268
PMID: 30770492

Clin Cancer Res. 2019 Feb 15;25(4):1431. doi: 10.1158/1078-0432.CCR-18-4270.

Correction: ER+ Breast Cancers Resistant to Prolonged Neoadjuvant Letrozole
Exhibit an E2F4 Transcriptional Program Sensitive to CDK4/6 Inhibitors.

Guerrero-Zotano AL, Stricker TP, Formisano L, Hutchinson KE, Stover DG, Lee KM,
Schwarz LJ, Giltnane JM, Estrada MV, Jansen VM, Servetto A, Gavilá J,
Perez-Fidalgo JA, Lluch A, Llombart-Cussac A, Bayar MA, Michiels S, André F,
Arnedos M, Guillem V, Ruiz-Simon A, Arteaga CL.

Erratum for
Clin Cancer Res. 2018 Jun 1;24(11):2517-2529.

DOI: 10.1158/1078-0432.CCR-18-4270
PMID: 30770490

Clin Cancer Res. 2019 Feb 15;25(4):1430. doi: 10.1158/1078-0432.CCR-18-4271.

Correction: Neratinib: Inching Up on the Cure Rate of HER2+ Breast Cancer?

Unni N, Sudhan DR, Arteaga CL.

Erratum for
Clin Cancer Res. 2018 Aug 1;24(15):3483-3485.

DOI: 10.1158/1078-0432.CCR-18-4271
PMID: 30770489

Proc Natl Acad Sci U S A. 2019 Feb 15. pii: 201819473. doi:
10.1073/pnas.1819473116. [Epub ahead of print]

Reactive oxygen species modulate macrophage immunosuppressive phenotype through
the up-regulation of PD-L1.

Roux C(1)(2), Jafari SM(1), Shinde R(1), Duncan G(1), Cescon DW(1), Silvester
J(1), Chu MF(1), Hodgson K(1), Berger T(1), Wakeham A(1), Palomero L(3),
Garcia-Valero M(3), Pujana MA(3), Mak TW(4), McGaha TL(1), Cappello P(5)(6),
Gorrini C(4).

Author information:
(1)The Campbell Family Institute for Breast Cancer Research, Princess Margaret
Cancer Centre, Toronto, ON M5G 2M9, Canada.
(2)Molecular Biotechnology Center, University of Turin, 10126 Turin, Italy.
(3)Breast Cancer and Systems Biology Laboratory, Program Against Cancer
Therapeutic Resistance, Catalan Institute of Oncology (Oncobell), Bellvitge
Institute for Biomedical Research, L’Hospitalet del Llobregat, 08908 Barcelona,
Catalonia, Spain.
(4)The Campbell Family Institute for Breast Cancer Research, Princess Margaret
Cancer Centre, Toronto, ON M5G 2M9, Canada; tak.mak@uhnresearch.ca
paola.cappello@unito.it Chiara.Gorrini@uhnresearch.ca.
(5)Molecular Biotechnology Center, University of Turin, 10126 Turin, Italy;
tak.mak@uhnresearch.ca paola.cappello@unito.it Chiara.Gorrini@uhnresearch.ca.
(6)Department of Molecular Biotechnology and Health Sciences, University of
Turin, 10126 Turin, Italy.

The combination of immune checkpoint blockade with chemotherapy is currently
under investigation as a promising strategy for the treatment of triple negative
breast cancer (TNBC). Tumor-associated macrophages (TAMs) are the most prominent
component of the breast cancer microenvironment because they influence tumor
progression and the response to therapies. Here we show that macrophages acquire
an immunosuppressive phenotype and increase the expression of programmed death
ligand-1 (PD-L1) when treated with reactive oxygen species (ROS) inducers such as
the glutathione synthesis inhibitor, buthionine sulphoximine (BSO), and
paclitaxel. Mechanistically, these agents cause accumulation of ROS that in turn
activate NF-κB signaling to promote PD-L1 transcription and the release of
immunosuppressive chemokines. Systemic in vivo administration of paclitaxel
promotes PD-L1 accumulation on the surface of TAMS in a mouse model of TNBC,
consistent with in vitro results. Combinatorial treatment with paclitaxel and an
anti-mouse PD-L1 blocking antibody significantly improved the therapeutic
efficacy of paclitaxel by reducing tumor burden and increasing the number of
tumor-associated cytotoxic T cells. Our results provide a strong rationale for
the use of anti-PD-L1 blockade in the treatment of TNBC patients. Furthermore,
interrogation of chemotherapy-induced PD-L1 expression in TAMs is warranted to
define appropriate patient selection in the use of PD-L1 blockade.

DOI: 10.1073/pnas.1819473116
PMID: 30770442

Conflict of interest statement: The authors declare no conflict of interest.

Cancer Res. 2019 Feb 15;79(4):876. doi: 10.1158/0008-5472.CAN-18-4088.

Correction: Kinome-wide Functional Screen Identifies Role of PLK1 in
Hormone-Independent, ER-Positive Breast Cancer.

Bhola NE, Jansen VM, Bafna S, Giltnane JM, Balko JM, Estrada MV, Meszoely I,
Mayer I, Abramson V, Ye F, Sanders M, Dugger TC, Allen EV, Arteaga CL.

Erratum for
Cancer Res. 2015 Jan 15;75(2):405-14.

DOI: 10.1158/0008-5472.CAN-18-4088
PMID: 30770371

Cancer Res. 2019 Feb 15;79(4):875. doi: 10.1158/0008-5472.CAN-18-4087.

Correction: Treatment of Triple-Negative Breast Cancer with TORC1/2 Inhibitors
Sustains a Drug-Resistant and Notch-Dependent Cancer Stem Cell Population.

Bhola NE, Jansen VM, Koch JP, Li H, Formisano L, Williams JA, Grandis JR, Arteaga
CL.

Erratum for
Cancer Res. 2016 Jan 15;76(2):440-52.

DOI: 10.1158/0008-5472.CAN-18-4087
PMID: 30770370

Cancer Res. 2019 Feb 15;79(4):874. doi: 10.1158/0008-5472.CAN-18-4086.

Correction: Kinome-Wide RNA Interference Screen Reveals a Role for PDK1 in
Acquired Resistance to CDK4/6 Inhibition in ER-Positive Breast Cancer.

Jansen VM, Bhola NE, Bauer JA, Formisano L, Lee KM, Hutchinson KE, Witkiewicz AK,
Moore PD, Estrada MV, Sánchez V, Ericsson PG, Sanders ME, Pohlmann PR, Pishvaian
MJ, Riddle DA, Dugger TC, Wei W, Knudsen ES, Arteaga CL.

Erratum for
Cancer Res. 2017 May 1;77(9):2488-2499.

DOI: 10.1158/0008-5472.CAN-18-4086
PMID: 30770369

Cancer Res. 2019 Feb 15;79(4):873. doi: 10.1158/0008-5472.CAN-18-4085.

Correction: Extracellular Matrix/Integrin Signaling Promotes Resistance to
Combined Inhibition of HER2 and PI3K in HER2+ Breast Cancer.

Hanker AB, Estrada MV, Bianchini G, Moore PD, Zhao J, Cheng F, Koch JP, Gianni L,
Tyson DR, Sánchez V, Rexer BN, Sanders ME, Zhao Z, Stricker TP, Arteaga CL.

Erratum for
Cancer Res. 2017 Jun 15;77(12):3280-3292.

DOI: 10.1158/0008-5472.CAN-18-4085
PMID: 30770368

Clin Cancer Res. 2019 Feb 15. pii: clincanres.1821.2018. doi:
10.1158/1078-0432.CCR-18-1821. [Epub ahead of print]

ATR inhibition potentiates the radiation induced inflammatory tumour
microenvironment.

Dillon MT(1), Bergerhoff KF(2), Pedersen M(2), Patin EC(2), Whittock H(2),
Crespo-Rodriguez E(2), Pearson A(3), Paget JT(2), Smith HG(4), Patel RR(5), Foo
S(6), Bozhanova G(2), Ragulan C(7), Fontana E(7), Desai K(7), Wilkins AC(8),
Sadanandam A(7), Melcher A(9), McLaughlin M(2), Harrington KJ(10).

Author information:
(1)Targeted Therapy Team,Division of Radiotherapy and Imaging, Institute of
Cancer Research magnus.dillon@icr.ac.uk.
(2)Targeted Therapy Team,Division of Radiotherapy and Imaging, Institute of
Cancer Research.
(3)The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research.
(4)Targeted Therapy Team, Institute of Cancer Research.
(5)Flow Cytometry and Light Microscopy Facility, Division of Cancer Biology,
Institute of Cancer Research.
(6)Radiotherapy and Imaging, Institute of Cancer Research.
(7)Division of Molecular Pathology, Institute of Cancer Research.
(8)Clinical Trials and Statistics Unit, Institute of Cancer Research.
(9)Division of Radiotherapy and Imaging, Institute of Cancer Research.
(10)Oncology, Institute of Cancer Research.

PURPOSE: ATR inhibitors (ATRi) are in early phase clinical trials and have been
shown to sensitise to chemotherapy and radiotherapy preclinically. No data have
been published about the effect of these drugs on the tumor microenvironment.
EXPERIMENTAL DESIGN: We used an immunocompetent mouse model of HPV-driven
malignancies to investigate the ATR inhibitor AZD6738 in combination with
fractionated radiation (RT). Gene expression analysis and flow cytometry were
performed post-therapy.
RESULTS: Significant radiosensitization to RT by ATRi was observed alongside a
marked increase in immune cell infiltration. We identified increased numbers of
CD3+ and NK cells but most of this infiltrate was composed of myeloid cells. ATRi
plus radiation produced a gene expression signature matching a type I/II
interferon response with upregulation of genes playing a role in nucleic acid
sensing. Increased MHCI levels were observed on tumor cells, with transcript
level data indicating increased antigen processing and presentation within the
tumor. Significant modulation of cytokine gene expression (particularly CCL2,
CCL5 and CXCL10) was found in vivo, with in vitro data indicating CCL3, CCL5 and
CXCL10 are produced from tumor cells after ATRi + RT.
CONCLUSIONS: We hypothesise that DNA damage by ATRi and RT leads to an interferon
response through activation of nucleic acid sensing pathways. This triggers
increased antigen presentation and innate immune cell infiltration. Further
understanding of this combination on the immune response may allow modulation of
these effects to maximise tumor control through anti-tumor immunity.

DOI: 10.1158/1078-0432.CCR-18-1821
PMID: 30770349

Clin Breast Cancer. 2019 Jan 23. pii: S1526-8209(19)30021-7. doi:
10.1016/j.clbc.2019.01.004. [Epub ahead of print]

Prognostic Significance of Obesity and Diabetes Mellitus in Women With Brain
Metastases From Breast Cancer Should Be Revisited.

Altundag DK(1).

Author information:
(1)MKA Breast Cancer Clinic, Tepe Prime, Ankara, Turkey.

DOI: 10.1016/j.clbc.2019.01.004
PMID: 30770265

Surgery. 2019 Feb 12. pii: S0039-6060(19)30006-6. doi:
10.1016/j.surg.2018.12.021. [Epub ahead of print]

Patient preferences on the use of technology in cancer surveillance after
curative surgery: A cross-sectional analysis.

Onuma AE(1), Palmer Kelly E(2), Chakedis J(1), Paredes AZ(1), Tsilimigras DI(1),
Wiemann B(1), Johnson M(1), Merath K(1), Akgul O(1), Cloyd J(1), Pawlik TM(3).

Author information:
(1)Department of Surgery, The Ohio State University Wexner Medical Center,
Columbus.
(2)Comprehensive Cancer Center, The Ohio State University, Columbus.
(3)Department of Surgery, The Ohio State University Wexner Medical Center,
Columbus. Electronic address: Tim.pawlik@osumc.edu.

BACKGROUND: Advances in communication technology have enabled new methods of
delivering test results to cancer survivors. We sought to determine patient
preferences regarding the use of newer technology in delivering test results
during cancer surveillance.
METHODS: A single institutional, cross-sectional analysis of the preferences of
adult cancer survivors regarding the means (secure digital communication versus
phone call or office visit) to receive surveillance test results was undertaken.
RESULTS: Among 257 respondents, the average age was 59.1 years (SD 13.5) and
61.8% were female. Common malignancies included melanoma/sarcoma (29.5%), thyroid
(25.7%), breast (22.8%), and gastrointestinal (22.0%) cancer. Although patients
expressed a relative preference to receive normal surveillance results via
MyChart or secure e-mail, the majority preferred abnormal imaging (87.2%) or
blood results (85.9%) to be communicated by in-office appointments or phone calls
irrespective of age or cancer type. Patients with a college degree or higher were
more likely to prefer electronic means of communication of abnormal blood results
compared with a telephone call or in-person visit (odds ratio 2.18, 95%
confidence interval: 1.01-4.73, P < .05). In contrast, patients >65 years were
more likely to express a preference for telephone or in-person communication of
normal imaging results (odds ratio: 2.03, 95% CI: 1.16-3.56, P < .05) versus
patients ≤65 years. Preference also varied according to malignancy type.
CONCLUSION: Although many cancer patients preferred to receive «normal»
surveillance results electronically, the majority preferred receiving abnormal
results via direct conversation with their provider. Shifting routine
communication of normal surveillance results to technology-based applications may
improve patient satisfaction and decrease health care system costs.

DOI: 10.1016/j.surg.2018.12.021
PMID: 30770135

J Med Vasc. 2019 Feb;44(1):3-8. doi: 10.1016/j.jdmv.2018.11.004. Epub 2018 Dec
20

[General practitioner questionnaire concerning upper limb lymphedema after breast
cancer].

[Article in French]

Simon M(1), Vignes S(2).

Author information:
(1)Unité de Lymphologie, site constitutif du Centre national de référence des
maladies vasculaires rares (lymphœdèmes primaires), hôpital Cognacq-Jay, 15, rue
Eugène-Millon, 75015 Paris, France.
(2)Unité de Lymphologie, site constitutif du Centre national de référence des
maladies vasculaires rares (lymphœdèmes primaires), hôpital Cognacq-Jay, 15, rue
Eugène-Millon, 75015 Paris, France. Electronic address:
stephane.vignes@cognacq-jay.fr.

INTRODUCTION: In France, breast cancer is the most frequent cancer in women.
Lymphedema, the main complication, is poorly known. The objective of this study
was to assess the state of knowledge of upper limb lymphedema (risk factors,
complications, treatment) after treatment of breast cancer among general
practitioners from the Haute-Normandie and Île-de-France regions.
MATERIALS AND METHODS: A cross-sectional study with 23 closed questions was sent
by email to 490 practicing doctors.
RESULTS: One hundred and sixty-two questionnaires (33%) could be analyzed. Among
the participating physicians (men: 55%), 46% were aged over 50 and 75% were from
the Haute-Normandie region; 86% of them followed at least 5 women who had breast
cancer. Risk factors for lymphedema were: axillary dissection (89%), risk
reduction with sentinel lymph node (82%), radiotherapy (81%), mastectomy (45%)
and overweight/obesity (42%). For 54% of physicians, lymphedema appeared within 6
months after cancer treatment and was diagnosed upon examination (clinical signs,
perimeter measurements) in 78%, without the need for radiological examinations
(100%). Physicians with more than 10 years of experience searched for more
lymphedema (86% vs. 62%, P<0.0001). Prescriptions included: elastic compression
during the day (77%), manual lymphatic drainage (74%), overnight compression
(36%) and consultation in a specialized lymphology department (8%). Six percent
of physicians had never managed lymphedema and 22% sent patients to an
oncologist. Advice given was: prevention of infectious risk (80%), weight loss
(42%), avoidance of sports involving the affected limb (22%), and regular arm
elevation (14%). Physicians recommended avoiding blood sampling (75%), measuring
blood pressure (66%) on the limb ipsilateral to cancer, while 20% did not
prohibit any action on the limb.
CONCLUSION: Lymphedema knowledge in general practitioners is generally adequate
although the number of women followed by each of them was low. It seems necessary
to optimize the training of generalists on lymphedema in order to improve patient
management.

DOI: 10.1016/j.jdmv.2018.11.004
PMID: 30770083

Int J Mol Sci. 2019 Feb 15;20(4). pii: E833. doi: 10.3390/ijms20040833.

Antrodia cinnamomea, a Treasured Medicinal Mushroom, Induces Growth Arrest in
Breast Cancer Cells, T47D Cells: New Mechanisms Emerge.

Chen YC(1), Liu YC(2)(3), El-Shazly M(4)(5), Wu TY(6), Chang JG(7)(8)(9)(10), Wu
YC(11)(12)(13)(14).

Author information:
(1)The Ph.D. Program for Cancer Biology and Drug Discovery, China Medical
University and Academia, Sinica, Taichung 404, Taiwan. j520c@hotmail.com.
(2)Division of Hematology-Oncology, Department of Internal Medicine, Kaohsiung
Medical University, Hospital, Kaohsiung 807, Taiwan. ycliu@cc.kmu.edu.tw.
(3)Department of Internal Medicine, Faculty of Medicine, College of Medicine,
Kaohsiung Medical University, Kaohsiung 807, Taiwan. ycliu@cc.kmu.edu.tw.
(4)Department of Pharmacognosy, Faculty of Pharmacy, Ain-Shams University,
Organization of African Unity Street, Abassia, Cairo 11566, Egypt.
mohamed.elshazly@pharma.asu.edu.eg.
(5)Department of Pharmaceutical Biology, Faculty of Pharmacy and Biotechnology,
German University in Cairo, Cairo 11432, Egypt.
mohamed.elshazly@pharma.asu.edu.eg.
(6)Chinese Medicine Research and Development Center, China Medical University
Hospital, Taichung 404, Taiwan. kuma0401@gmail.com.
(7)The Ph.D. Program for Cancer Biology and Drug Discovery, China Medical
University and Academia, Sinica, Taichung 404, Taiwan. d6781@mail.cmuh.org.tw.
(8)School of Medicine, China Medical University, Taichung 404, Taiwan.
d6781@mail.cmuh.org.tw.
(9)Department of Laboratory Medicine, China Medical University Hospital, Taichung
404, Taiwan. d6781@mail.cmuh.org.tw.
(10)Center for Precision Medicine, China Medical University Hospital, Taichung
404, Taiwan. d6781@mail.cmuh.org.tw.
(11)The Ph.D. Program for Cancer Biology and Drug Discovery, China Medical
University and Academia, Sinica, Taichung 404, Taiwan. yachwu@kmu.edu.tw.
(12)Chinese Medicine Research and Development Center, China Medical University
Hospital, Taichung 404, Taiwan. yachwu@kmu.edu.tw.
(13)Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung
Medical University, Kaohsiung 807, Taiwan. yachwu@kmu.edu.tw.
(14)Department of Medical Research, Kaohsiung Medical University Hospital,
Kaohsiung 807, Taiwan. yachwu@kmu.edu.tw.

Reported cases of breast cancer have skyrocketed in the last decades with recent
advances in examination techniques. Brest cancer has become the second leading
cause of mortality among women worldwide, urging the scientific community to
develop or find new drugs from natural sources with potent activity and a
reasonable safety profile to tackle this ailment. Antrodia cinnamomea (AC) is a
treasured medicinal fungus which has attracted attention due to its potent
hepatoprotective and cytotoxic activities. We evaluated the antiproliferative
activity of the ethanol extract of artificially cultured AC (EEAC) on breast
cancer cells (T47D cells) in vivo and in vitro. Ethanol extract of artificially
cultured AC inhibited T47D cells’ proliferation mediated by cell cycle arrest at
G1 phase as well induced autophagy. Immunoblotting assay confirmed that EEAC not
only decreased the expression of the cell-cycle-related proteins but also
increased the expression of transcription factor FOXO1, autophagic marker LC3 II,
and p62. Ethanol extract of artificially cultured AC mediated endoplasmic
reticulum stress by promoting the expression of IRE1 (inositol-requiring enzyme
1α), GRP78/Bip (glucose regulating protein 78), and CHOP (C/EBP homologous
protein). Apart from previous studies, HDACs (histone deacetylases) activity was
inhibited as demonstrated by a cell-free system, immunoblotting, and
immunofluorescence assays following EEAC treatment. The in vivo studies
demonstrated that EEAC decreased tumor volume and inhibited tumor growth without
any significant side effects. High performance liquid chromatography profile
demonstrated similar triterpenoids compared to the profile of wild AC ethanol
extract. The multiple targets of EEAC on breast cancer cells suggested that this
extract may be developed as a potential dietary supplement targeting this
debilitating disease.

DOI: 10.3390/ijms20040833
PMID: 30769922

J Clin Med. 2019 Feb 14;8(2). pii: E246. doi: 10.3390/jcm8020246.

Clinical Features, Survival and Prognostic Factors of Glycogen-Rich Clear Cell
Carcinoma (GRCC) of the Breast in the U.S. Population.

Zhou Z(1), Kinslow CJ(2), Hibshoosh H(3), Guo H(4), Cheng SK(5), He C(6)(7),
Gentry MS(8)(9), Sun RC(10)(11).

Author information:
(1)Department of Molecular and Cellular Biochemistry, University of Kentucky
College of Medicine, Lexington, KY 40536, USA. zhengqiu.zhou@uky.edu.
(2)Department of Radiation Oncology, College of Physicians and Surgeons, Columbia
University Medical Center, New York, NY 10032, USA. cjk2151@cumc.columbia.edu.
(3)Department of Pathology and Cell Biology, College of Physicians and Surgeons,
Columbia University Medical Center, New York, NY 10032, USA.
hhh1@cumc.columbia.edu.
(4)Department of Pathology and Cell Biology, College of Physicians and Surgeons,
Columbia University Medical Center, New York, NY 10032, USA.
hg2489@cumc.columbia.edu.
(5)Department of Radiation Oncology, College of Physicians and Surgeons, Columbia
University Medical Center, New York, NY 10032, USA. sc3225@cumc.columbia.edu.
(6)Department of Internal Medicine, Division of Medical Oncology, University of
Kentucky College of Medicine, Lexington, KY 40536, USA. chunyan.he@uky.edu.
(7)Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA.
chunyan.he@uky.edu.
(8)Department of Molecular and Cellular Biochemistry, University of Kentucky
College of Medicine, Lexington, KY 40536, USA. matthew.gentry@uky.edu.
(9)Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA.
matthew.gentry@uky.edu.
(10)Department of Molecular and Cellular Biochemistry, University of Kentucky
College of Medicine, Lexington, KY 40536, USA. ramon.sun@uky.edu.
(11)Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA.
ramon.sun@uky.edu.

The World Health Organization (WHO) defines glycogen-rich clear cell carcinoma
(GRCC) of the breast as a carcinoma with glycogen accumulation in more than 90%
of its tumor cells. Due to the rarity of this disease, its reported survival and
clinical associations have been inconsistent due to reliance on case reports and
limited case series. As a result, the prognostic implication of this cancer
subtype remains unclear. Using the U.S. Surveillance, Epidemiology, and End
Results (SEER) program database, we compared the incidence, demographics and
prognostic factors of 155 cases of GRCC of the breast to 1,251,584 cases of other
(non-GRCC) breast carcinomas. We demonstrate that GRCC is more likely to be
identified as high grade, advanced stage, and more likely to have triple negative
receptor status. GRCC cases display a poorer prognosis than non-GRCC carcinomas
of the breast irrespective of age, AJCC staging, tumor grade, joint hormone
receptor/human epidermal growth factor receptor 2 (HER2) status, and treatment.
Similar to non-GRCC carcinomas, older age and higher American Joint Committee on
Cancer (AJCC)/TNM staging were associated with poorer prognosis for GRCC, while
treatment with surgery and radiation were associated with improved survival.
Radiation, specifically in the setting of breast-conserving surgery, further
improved survival compared to surgery alone. Our study highlights the poorer
prognosis associated with glycogen accumulation in breast cancers and hence
stresses the importance of identifying this more aggressive tumor type.

DOI: 10.3390/jcm8020246
PMID: 30769905

Conflict of interest statement: The authors declare no conflicts of interest.

Cancers (Basel). 2019 Feb 14;11(2). pii: E222. doi: 10.3390/cancers11020222.

Novel Ran-RCC1 Inhibitory Peptide-Loaded Nanoparticles Have Anti-Cancer Efficacy
In Vitro and In Vivo.

Haggag YA(1)(2), Matchett KB(3), Falconer RA(4), Isreb M(5), Jones J(6), Faheem
A(7), McCarron P(8), El-Tanani M(9)(10)(11).

Author information:
(1)Department of Pharmaceutical Technology, Faculty of Pharmacy, University of
Tanta, Tanta 31111, Egypt. youssif.hagag@pharm.tanta.edu.eg.
(2)School of Pharmacy and Pharmaceutical Sciences, Saad Centre for Pharmacy and
Diabetes, Ulster University, Cromore Road, Coleraine, Co. Londonderry BT52 1SA,
UK. youssif.hagag@pharm.tanta.edu.eg.
(3)Northern Ireland Centre for Stratified Medicine, School of Biomedical
Sciences, C-TRIC, Altnagelvin Hospital Campus, Ulster University, Glenshane Road,
Derry/Londonderry BT47 6SB, Northern Ireland, UK. k.matchett@ulster.ac.uk.
(4)Institute of Cancer Therapeutics, Faculty of Life Sciences, University of
Bradford, Bradford BD7 1DP, UK. r.a.falconer1@bradford.ac.uk.
(5)School of Pharmacy and Clinical Sciences, University of Bradford, Bradford BD7
1DP, UK. M.Isreb1@bradford.ac.uk.
(6)Institute of Cancer Therapeutics, Faculty of Life Sciences, University of
Bradford, Bradford BD7 1DP, UK. J.R.Jones@bradford.ac.uk.
(7)Department of Pharmacy, Health and Well-being, University of Sunderland,
Sunderland SR1 3SD, UK. ahmed.faheem@sunderland.ac.uk.
(8)School of Pharmacy and Pharmaceutical Sciences, Saad Centre for Pharmacy and
Diabetes, Ulster University, Cromore Road, Coleraine, Co. Londonderry BT52 1SA,
UK. p.mccarron@ulster.ac.uk.
(9)Institute of Cancer Therapeutics, Faculty of Life Sciences, University of
Bradford, Bradford BD7 1DP, UK. m.el-tanani@bradford.ac.uk.
(10)Imhotep Diagnostics and Therapeutics, Europa Tool House, Springbank,
Industrial Estate, Dunmurry BT17 0QL, Northern Ireland, UK.
m.el-tanani@bradford.ac.uk.
(11)School of Chemistry and Biosciences, University of Bradford, Bradford BD7
1DP, UK. m.el-tanani@bradford.ac.uk.

The delivery of anticancer agents to their subcellular sites of action is a
significant challenge for effective cancer therapy. Peptides, which are integral
to several oncogenic pathways, have significant potential to be utilised as
cancer therapeutics due to their selectivity, high potency and lack of normal
cell toxicity. Novel Ras protein-Regulator of chromosome condensation 1
(Ran-RCC1) inhibitory peptides designed to interact with Ran, a novel therapeutic
target in breast cancer, were delivered by entrapment into polyethylene
glycol-poly (lactic-co-glycolic acid) PEG-PLGA polymeric nanoparticles (NPs). A
modified double emulsion solvent evaporation technique was used to optimise the
physicochemical properties of these peptide-loaded biodegradable NPs. The
anti-cancer activity of peptide-loaded NPs was studied in vitro using
Ran-expressing metastatic breast (MDA-MB-231) and lung cancer (A549) cell lines,
and in vivo using Solid Ehrlich Carcinoma-bearing mice. The anti-metastatic
activity of peptide-loaded NPs was investigated using migration, invasion and
colony formation assays in vitro. A PEG-PLGA-nanoparticle encapsulating
N-terminal peptide showed a pronounced antitumor and anti-metastatic action in
lung and breast cancer cells in vitro and caused a significant reduction of tumor
volume and associated tumor growth inhibition of breast cancer model in vivo.
These findings suggest that the novel inhibitory peptides encapsulated into
PEGylated PLGA NPs are delivered effectively to interact and deactivate Ran. This
novel Ran-targeting peptide construct shows significant potential for therapy of
breast cancer and other cancers mediated by Ran overexpression.

DOI: 10.3390/cancers11020222
PMID: 30769871

Cancers (Basel). 2019 Feb 14;11(2). pii: E221. doi: 10.3390/cancers11020221.

A H2AX⁻CARP-1 Interaction Regulates Apoptosis Signaling Following DNA Damage.

Sekhar SC(1)(2), Venkatesh J(3)(4), Cheriyan VT(5)(6), Muthu M(7)(8), Levi E(9),
Assad H(10), Meister P(11), Undyala VV(12), Gauld JW(13), Rishi AK(14)(15)(16).

Author information:
(1)John D. Dingell Veterans Administration Medical Center, Detroit, MI 48201,
USA. sreejacsekhar@gmail.com.
(2)Department of Oncology, Karmanos Cancer Institute, Detroit, MI 48201, USA.
sreejacsekhar@gmail.com.
(3)John D. Dingell Veterans Administration Medical Center, Detroit, MI 48201,
USA. jaganvibt@gmail.com.
(4)Department of Oncology, Karmanos Cancer Institute, Detroit, MI 48201, USA.
jaganvibt@gmail.com.
(5)John D. Dingell Veterans Administration Medical Center, Detroit, MI 48201,
USA. vinorcc@gmail.com.
(6)Department of Oncology, Karmanos Cancer Institute, Detroit, MI 48201, USA.
vinorcc@gmail.com.
(7)John D. Dingell Veterans Administration Medical Center, Detroit, MI 48201,
USA. magesh.research@gmail.com.
(8)Department of Oncology, Karmanos Cancer Institute, Detroit, MI 48201, USA.
magesh.research@gmail.com.
(9)John D. Dingell Veterans Administration Medical Center, Detroit, MI 48201,
USA. Edi.Levi@va.gov.
(10)Department of Oncology, Karmanos Cancer Institute, Detroit, MI 48201, USA.
Assadh@karmanos.org.
(11)Department of Chemistry and Biochemistry, University of Windsor, Windsor, ON
N9B 3P4, Canada. meisterp@uwindsor.ca.
(12)Cardiovascular Research Institute, School of Medicine, Wayne State
University, Detroit, MI 48201, USA. uvreddi@gmail.com.
(13)Department of Chemistry and Biochemistry, University of Windsor, Windsor, ON
N9B 3P4, Canada. gauld@uwindsor.ca.
(14)John D. Dingell Veterans Administration Medical Center, Detroit, MI 48201,
USA. rishia@Karmanos.org.
(15)Department of Oncology, Karmanos Cancer Institute, Detroit, MI 48201, USA.
rishia@Karmanos.org.
(16)Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute,
Detroit, MI 48201, USA. rishia@Karmanos.org.

Cell Cycle and Apoptosis Regulatory Protein (CARP-1/CCAR1) is a peri-nuclear
phosphoprotein that regulates apoptosis via chemotherapeutic Adriamycin
(doxorubicin) and a novel class of CARP-1 functional mimetic (CFM) compounds.
Although Adriamycin causes DNA damage, data from Comet assays revealed that
CFM-4.16 also induced DNA damage. Phosphorylation of histone 2AX (γH2AX) protein
is involved in regulating DNA damage repair and apoptosis signaling. Adriamycin
or CFM-4.16 treatments inhibited cell growth and caused elevated CARP-1 and γH2AX
in human breast (HBC) and cervical cancer (HeLa) cells. In fact, a robust nuclear
or peri-nuclear co-localization of CARP-1 and γH2AX occurred in cells undergoing
apoptosis. Knock-down of CARP-1 diminished γH2AX, their co-localization, and
apoptosis in CFM-4.16- or Adriamycin-treated cells. We found that CARP-1 directly
binds with H2AX, and H2AX interacted with CARP-1, but not CARP-1 (Δ600⁻652)
mutant. Moreover, cells expressing CARP-1 (Δ600⁻652) mutant were resistant to
apoptosis, and had diminished levels of γH2AX, when compared with cells
expressing wild-type CARP-1. Mutagenesis studies revealed that H2AX residues 1⁻35
harbored a CARP-1-binding epitope, while CARP-1 amino acids 636⁻650 contained an
H2AX-interacting epitope. Surface plasmon resonance studies revealed that CARP-1
(636⁻650) peptide bound with H2AX (1⁻35) peptide with a dissociation constant
(Kd) of 127 nM. Cells expressing enhanced GFP (EGFP)-tagged H2AX (1⁻35) peptide
or EGFP-tagged CARP-1 (636⁻650) peptide were resistant to inhibition by
Adriamycin or CFM-4.16. Treatment of cells with transactivator of transcription
(TAT)-tagged CARP-1 (636⁻650) peptide resulted in a moderate, statistically
significant abrogation of Adriamycin-induced growth inhibition of cancer cells.
Our studies provide evidence for requirement of CARP-1 interaction with H2AX in
apoptosis signaling by Adriamycin and CFM compounds.

DOI: 10.3390/cancers11020221
PMID: 30769864

Bioorg Chem. 2019 Feb 7;86:410-419. doi: 10.1016/j.bioorg.2019.02.003. [Epub
ahead of print]

Discovery, synthesis and molecular corroborations of medicinally important novel
pyrazoles; drug efficacy determinations through in silico, in vitro and
cytotoxicity validations.

Thangarasu P(1), Manikandan A(2), Thamaraiselvi S(3).

Author information:
(1)Research and Development Centre, Bharathiar University, Coimbatore 641046,
India.
(2)Department of Biotechnology, School of Bio-Sciences and Technology, VIT
University, Vellore 632014, India.
(3)PG & Research Department of Chemistry, Government Arts College, Coimbatore
641018, Tamil Nadu, India. Electronic address: thamaraimohan@gmail.com.

As the global need for drugs getting increases, the necessity of novel and
effective drugs are the need of the day. Pyrazoles are one of the active
molecules in novel drug discovery. The present study deals about the synthesis of
precursors 4-(4-fluorophenyl)-6-isopropyl-2-(methylsulfonyl)
pyrimidine-5-carbohydrazides (3a-m) from
methyl-4-(4-fluorophenyl)-6-isopropyl-2-(methyl sulfonyl)
pyrimidine-5-carboxylate (2) by treating with substituted acetophenone. Further,
Vilsmeier-Haack reaction of compounds 3a-m at 70 °C for 8-10 hrs gave novel
pyrazole carbaldehyde derivatives (4a-m) in good yield. Biological properties
like antioxidant, anti-breast cancer and anti-inflammatory of newly synthesized
compounds (4a-m) were determined. The enzymes Cyclooxygenase-2 and
Phosphoinositide-3-Kinase are most responsible for the corresponding diseases
such as inflammation and breast cancer respectively. In order to examine the
interaction between these two enzymes and our synthesized compounds 4a-m,
molecular docking study was carried out. From the results, few compounds of 4a-m
were found to have anti-inflammatory properties by showing excellent COX-2
inhibition and HRBC membrane stabilization properties. ADMET prediction results
were also valuable to screen the most effective pyrazole derivatives to establish
them as future COX-2 inhibitors or anti-inflammatory drugs.

DOI: 10.1016/j.bioorg.2019.02.003
PMID: 30769266

Bioorg Chem. 2019 Jan 30;86:401-409. doi: 10.1016/j.bioorg.2019.01.066. [Epub
ahead of print]

Benzophenones as xanthone-open model CYP11B1 inhibitors potentially useful for
promoting wound healing.

Gobbi S(1), Hu Q(2), Foschi G(3), Catanzaro E(4), Belluti F(3), Rampa A(3),
Fimognari C(4), Hartmann RW(5), Bisi A(6).

Author information:
(1)Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of
Bologna, Via Belmeloro, 6, I-40126 Bologna, Italy. Electronic address:
silvia.gobbi@unibo.it.
(2)Guangzhou University of Chinese Medicine, Guangzhou, China.
(3)Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of
Bologna, Via Belmeloro, 6, I-40126 Bologna, Italy.
(4)Department for Life Quality Studies, Alma Mater Studiorum-University of
Bologna, corso d’Augusto 237, 47921 Rimini, Italy.
(5)Helmholtz Institute for Pharmaceutical Research Saarland (HIPS),
Universitätscampus E8 1, 66123 Saarbrücken, Germany.
(6)Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of
Bologna, Via Belmeloro, 6, I-40126 Bologna, Italy. Electronic address:
alessandra.bisi@unibo.it.

The inhibition of steroidogenic cytochrome P450 enzymes has been shown to play a
central role in the management of life-threatening diseases such as cancer, and
indeed potent inhibitors of CYP19 (aromatase) and CYP17 (17α hydroxylase/17,20
lyase) are currently used for the treatment of breast, ovarian and prostate
cancer. In the last few decades CYP11B1 (11-β-hydroxylase) and CYP11B2
(aldosterone synthase), key enzymes in the biosynthesis of cortisol and
aldosterone, respectively, have been also investigated as targets for the
identification of new potent and selective agents for the treatment of Cushing’s
syndrome, impaired wound healing and cardiovascular diseases. In an effort to
improve activity and synthetic feasibility of our different series of
xanthone-based CYP11B1 and CYP11B2 inhibitors, a small series of
imidazolylmethylbenzophenone-based compounds, previously reported as CYP19
inhibitors, was also tested on these new targets, in order to explore the role of
a more flexible scaffold for the inhibition of CYP11B1 and -B2 isoforms. Compound
3 proved to be very potent and selective towards CYP11B1, and was thus selected
for further optimization via appropriate decoration of the scaffold, leading to
new potent 4′-substituted derivatives. In this second series, 4 and 8, carrying a
methoxy group and a phenyl ring, respectively, proved to be low-nanomolar
inhibitors of CYP11B1, despite a slight decrease in selectivity against CYP11B2.
Moreover, unlike the benzophenones of the first series, the 4′-substituted
derivatives also proved to be selective for CYP11B enzymes, showing very weak
inhibition of CYP19 and CYP17. Notably, the promising result of a preliminary
scratch test performed on compound 8 confirmed the potential of this compound as
a wound-healing promoter.

DOI: 10.1016/j.bioorg.2019.01.066
PMID: 30769265

Breast. 2019 Feb 7;44:128-134. doi: 10.1016/j.breast.2019.02.003. [Epub ahead of
print]

Peptide vaccines in early breast cancer.

Criscitiello C(1), Viale G(1), Curigliano G(2).

Author information:
(1)IEO, European Institute of Oncology IRCCS, Milan Italy.
(2)IEO, European Institute of Oncology IRCCS, Milan Italy; University of Milan,
Italy. Electronic address: Giuseppe.curigliano@ieo.it.

The immune system plays a dual role of host-protecting and tumor-promoting, as
elegantly expressed by the ‘cancer immunoediting’ hypothesis. Although breast
cancer has not been traditionally considered to be immunogenic, recently there is
accumulating and solid evidence on the association between immune system and
breast cancer. To mount an effective anti-tumor response, host immunosurveillance
must recognize tumor-specific epitopes, thus defining the antigenicity of a
tumor. Neoantigens are mutant cancer peptides that arise as terminal products of
the expression of somatic cancer mutations. Neoantigens and major
histocompatibility complex (MHC) proteins present together to effector cells of
the immune system. Neoantigen vaccines have shown promising results in inducing
neoantigen-specific T-cell responses. Currently, cancer vaccines are under
evaluation in breast cancer to avoid recurrences in patients at high risk despite
optimal standard therapy. Given the promise of a very specific long-term
antitumor immune response, the development of cancer vaccines continues is of
great interest. Combinations of neoantigen vaccines and other immunotherapies are
also studied to evade cancer immune escape.

DOI: 10.1016/j.breast.2019.02.003
PMID: 30769238

Eur J Cancer. 2019 Feb 12;110:53-61. doi: 10.1016/j.ejca.2018.12.034. [Epub ahead
of print]

Effects of adjuvant tamoxifen over three decades on breast cancer-free and
distant recurrence-free interval among premenopausal women with oestrogen
receptor-positive breast cancer randomised in the Swedish SBII:2pre trial.

Ekholm M(1), Bendahl PO(2), Fernö M(2), Nordenskjöld B(3), Stål O(3), Rydén L(4);
South Swedish and South-East Swedish Breast Cancer Groups.

Author information:
(1)Department of Oncology, Jönköping, Region Jönköping County, and Department of
Clinical and Experimental Medicine, Linköping University, Linköping, Sweden;
Department of Clinical Sciences Lund, Division of Oncology and Pathology, Lund
University, Lund, Sweden. Electronic address: maria.ekholm@med.lu.se.
(2)Department of Clinical Sciences Lund, Division of Oncology and Pathology, Lund
University, Lund, Sweden.
(3)Department of Clinical and Experimental Medicine and Department of Oncology,
Linköping University, Linköping, Sweden.
(4)Department of Clinical Sciences Lund, Division of Surgery, Lund University,
Lund, Sweden; Department of Surgery and Gastroenterology, Skåne University
Hospital, Lund, Sweden.

AIMS: The primary aim was to compare 2 years of adjuvant tamoxifen versus no
systemic treatment in premenopausal patients with oestrogen receptor
(ER)-positive tumours, regarding breast cancer-free interval (BCFi) and distant
recurrence-free interval (D-RFi), with 30 years of follow-up and for specified
intervals. Moreover, we aimed to investigate the effects of adjuvant tamoxifen on
the incidence of secondary malignancies and survival after distant recurrence.
METHODS: Premenopausal patients with primary breast cancer were randomised to 2
years of tamoxifen (n = 277) or no systemic treatment (n = 287), irrespective of
ER status. Information regarding events was collected by a review of medical
records and from national registers.
RESULTS: The median follow-up for all patients without events was 28 years, and
only four of the patients alive had a follow-up of <20 years. With 30 years of follow-up, tamoxifen prolonged BCFi in the intention-to-treat population (hazard ratio [HR] = 0.76, 95% confidence interval (CI) 0.61-0.94, p = 0.011) compared with no treatment. In patients with ER-positive tumours (n = 362), tamoxifen prolonged BCFi (HR = 0.62, 95% CI 0.47-0.82, p = 0.001) and D-RFi (HR = 0.73, 95% CI 0.54-0.99, p = 0.043). The positive effect on BCFi was significant also for the interval >15-30 years (HR = 0.53, 95% CI 0.28-0.98, p = 0.042). For patients
with ER-positive tumours who were diagnosed with distant recurrence (n = 165),
survival after distant recurrence was shorter among tamoxifen-treated patients
(median, 29 months versus 43 months). The incidence of contralateral breast
cancer was 42% lower in the tamoxifen group (HR = 0.58, 95% CI 0.35-0.96,
p = 0.035), whereas no differences were observed regarding other secondary
malignancies.
CONCLUSIONS: With three decades of follow-up, 2 years of adjuvant tamoxifen
reduced the incidence of breast cancer-related events and distant recurrence, and
the carryover effect seems to extend beyond 15 years. Moreover, adjuvant
tamoxifen seems to be associated with shorter survival after diagnosis of distant
recurrence.

DOI: 10.1016/j.ejca.2018.12.034
PMID: 30769227

Int J Pharm. 2019 Feb 12. pii: S0378-5173(19)30130-9. doi:
10.1016/j.ijpharm.2019.02.007. [Epub ahead of print]

Lipoic Acid-derived Cross-linked Liposomes for Reduction-responsive Delivery of
Anticancer Drug.

Ling L(1), Ismail M(1), Du Y(1), Yao C(1), Li X(2).

Author information:
(1)School of Chemistry and Chemical Engineering, Southeast University, Nanjing
211189, PR China.
(2)School of Chemistry and Chemical Engineering, Southeast University, Nanjing
211189, PR China. Electronic address: lixs@seu.edu.cn.

Liposomes have emerged as a fascinating nanocarriers for the delivery of cancer
therapeutics. However, their efficacy for cancer therapy is reduced because of
the serum-instability and incomplete drug release. In this study, a novel
disulfide cross-linked liposomes (CLs) assembled from dimeric lipoic acid-derived
glycerophosphorylcholine (di-LA-PC) conjugate was developed. The conjugate was
synthesized by a facial esterification of lipoic acid (LA) and
glycerophosphorylcholine (GPC) and characterized by MS, 1H NMR and 13C NMR.
Featuring the enhanced serum-stability and intracellular drug release determined
by in vitro stability and GSH-responsive behavior, CLs prepared with dried thin
film technique following 10 mol.% DTT cross-linking can attain effective delivery
of anticancer candidates. Notably, CLs stably encapsulated doxorubicin (Dox) in
their vesicular structures and showed a remarkable thiol-sensitive release of
payload upon cellular uptake by cancer cells, compared to that of uncross-linked
liposomes (uCLs) or Doxil-like liposome (DLLs). The cell viability and apoptosis
of Dox-loaded CLs worked the pronounced cytotoxic effects to MCF-7 cells with an
IC50 value of 10.8 μg Dox equiv./mL comparable to free Dox and 2.8-fold higher
than DLLs. More importantly, it is demonstrated that the nanoscale
characteristics of Dox-loaded CLs could prevent the proliferation of
adriamycin-resistant MCF-7/ADR cell line, highlighting their potential in
reversal of drug resistance. Furthermore, the preliminary in vivo test (n=3)
showed that disulfide cross-linked liposomal formulation of Dox (Dox-CLs)
improved the therapeutic efficacy compared to free Dox and DLLs in a human breast
carcinoma xenograft mouse model. Therefore, the current thiol-responsive
cross-linked liposome may provide a robust drug delivery platform for cancer
therapy.

DOI: 10.1016/j.ijpharm.2019.02.007
PMID: 30769133

Int J Pharm. 2019 Feb 12;560:191-204. doi: 10.1016/j.ijpharm.2019.02.009. [Epub
ahead of print]

Ratiometric co-encapsulation and co-delivery of doxorubicin and paclitaxel by
tumor-targeted lipodisks for combination therapy of breast cancer.

Feng C(1), Zhang H(1), Chen J(1), Wang S(1), Xin Y(1), Qu Y(1), Zhang Q(1), Ji
W(1), Yamashita F(2), Rui M(3), Xu X(4).

Author information:
(1)Department of Pharmaceutics, School of Pharmacy, Jiangsu University, Zhenjiang
212013, PR China.
(2)Department of Drug Delivery Research, Graduate School of Pharmaceutical
Sciences, Kyoto University, 46-29 Yoshida-shimoadachi cho, Sakyo-ku, Kyoto
606-8501, Japan.
(3)Department of Pharmaceutics, School of Pharmacy, Jiangsu University, Zhenjiang
212013, PR China. Electronic address: mjrui@ujs.edu.cn.
(4)Department of Pharmaceutics, School of Pharmacy, Jiangsu University, Zhenjiang
212013, PR China. Electronic address: xmxu@ujs.edu.cn.

Combination therapy is a promising treatment for certain advanced drug-resistant
cancers. Although effective inhibition of various tumor cells was reported in
vitro, combination treatment requires improvement in vivo due to uncontrolled
ratiometric delivery. In this study, a tumor-targeting lipodisk nanoparticle
formulation was developed for ratiometric loading and the transportation of two
hydrophobic model drugs, doxorubicin (DOX) and paclitaxel (PTX), in one single
platform. Furthermore, a slightly acidic pH-sensitive peptide (SAPSP)
incorporated into lipodisks effectively enhanced the tumor-targeting and cell
internalization. The obtained co-loaded lipodisks were approximately 30 nm with a
pH-sensitive property. The ratiometric co-delivery of two drugs via lipodisks was
confirmed in both the drug-resistant MCF-7/ADR cell line and its parental MCF-7
cell line in vitro, as well as in a tumor-bearing mouse model in vivo compared
with a cocktail solution of free drugs. Co-loaded lipodisks exerted improved
cytotoxicity to tumor cells in culture, particularly to drug-resistant tumor
cells at synergistic drug ratios. In an in vivo xenograft mouse model, the
anti-tumor ability of co-loaded lipodisks was evidenced by the remarkable
inhibitory effect on tumor growth of either MCF-7 or MCF-7/ADR tumors, which may
be attributed to the increased and ratiometric accumulation of both drugs in the
tumor tissues. Therefore, tumor-specific lipodisks were crucial for the
combination treatment of DOX and PTX to completely exert a synergistic
anti-cancer effect. It is concluded that for co-loaded lipodisks, cytotoxicity
data in vitro could be used to predict their inhibitory activity in vivo,
potentially enhancing the clinical outcome of synergistic therapy.

DOI: 10.1016/j.ijpharm.2019.02.009
PMID: 30769131

Cancer. 2019 Feb 15. doi: 10.1002/cncr.32027. [Epub ahead of print]

Association between primary language, a lack of mammographic screening, and later
stage breast cancer presentation.

Balazy KE(1), Benitez CM(1), Gutkin PM(1), Jacobson CE(1), von Eyben R(1), Horst
KC(1).

Author information:
(1)Department of Radiation Oncology, Stanford University School of Medicine,
Stanford, California.

BACKGROUND: Health determinants are known to influence the stage of breast cancer
presentation, but it is unclear to what extent language affects stage. This study
investigates whether non-English-speaking (NES) patients present at a later stage
than their English-speaking (ES) counterparts and whether language is associated
with mammographic screening.
METHODS: This study was a retrospective, single-institution cohort analysis of
women undergoing breast radiotherapy from 2012 to 2017 (n = 1057). Patients were
categorized as ES (n = 904) or NES (n = 153). Ordinal logistic regression
analysis identified variables associated with later stage presentation, including
language, race/ethnicity, and age. A subcohort analysis investigated the
influence of mammographic screening on stage for NES patients.
RESULTS: NES patients had greater odds of later stage disease than ES patients
(odds ratio, 1.47; 95% confidence, 1.001-2.150). This association persisted
across all races/ethnicities. An additional analysis examined age categories
associated with mammographic screening. For women eligible for screening (ie,
those 40-50 years old or older than 50 years), there was a significant
association between language and stage. NES patients older than 50 years were
twice as likely to present at an advanced stage in comparison with ES patients
(16.19% vs 8.11%; P = .0082). An additional subset analysis accounted for
mammograms. NES patients who did not undergo screening had a higher probability
of stage III disease (40.3% of NES patients vs 12.7% of ES patients). There was
no difference in stage between NES and ES patients who did undergo screening.
CONCLUSIONS: Language is independently associated with later stage breast cancer
for NES patients, regardless of race/ethnicity. NES patients may have difficulty
in accessing the health care system. Future interventions should seek to reduce
language barriers for mammographic screening and diagnosis.

DOI: 10.1002/cncr.32027
PMID: 30768784

Cancer. 2019 Feb 15. doi: 10.1002/cncr.32002. [Epub ahead of print]

«You probably can’t feel as safe as normal women»: Hispanic women’s reactions to
breast density notification.

Pacsi-Sepulveda AL(1), Shelton RC(2)(3), Rodriguez CB(4), Coq AT(4), Tehranifar
P(3)(4).

Author information:
(1)Adult Emergency Department, New York Presbyterian Hospital, New York, New
York.
(2)Department of Sociomedical Sciences, Columbia University Mailman School of
Public Health, New York, New York.
(3)Herbert Irving Comprehensive Cancer Center, Columbia University Medical
Center, New York, New York.
(4)Department of Epidemiology, Columbia University Mailman School of Public
Health, New York, New York.

BACKGROUND: Patient advocacy has led to state-level legislative mandates for the
release of personal mammographic breast density information to women undergoing
screening mammography. More research is needed to understand the impact of this
information on women’s perceptions and mammography screening behavior.
METHODS: Semistructured interviews were conducted in English and Spanish with 24
self-identified Hispanic women who had undergone at least 1 mammogram since
breast density notification was enacted in New York State. The women ranged in
age from 43 to 63 years. Women were asked about their understanding and
perceptions of the communication of New York State-mandated breast density
information, and any actions they have taken or would take in response to this
information. A content analysis of the qualitative data from the translated and
transcribed interviews was conducted.
RESULTS: The majority of participants had no prior knowledge of breast density
and expressed confusion and apprehension regarding the meaning of dense breasts
when presented with the notification information. Many participants understood
having dense breasts to be a serious and abnormal condition, and reported
feelings of worry and vulnerability. Participants mostly expressed a strong
interest in learning about breast density and obtaining additional and more
frequent breast cancer screening tests. These behavioral intentions were
consistent with participants’ overall favorable view of breast cancer screening
and a belief that their faith, as well as regular screening, can help to protect
them from breast cancer morbidity and mortality.
CONCLUSIONS: Hispanic women conveyed proactive breast cancer screening intentions
in response to breast density notification, despite inadequate comprehension of
this information and negative emotional responses.

DOI: 10.1002/cncr.32002
PMID: 30768781

Cancer. 2019 Feb 15. doi: 10.1002/cncr.31943. [Epub ahead of print]

The impact of psychosocial stress and stress management on immune responses in
patients with cancer.

Antoni MH(1), Dhabhar FS(2).

Author information:
(1)Department of Psychology, University of Miami and Sylvester Comprehensive
Cancer Center, University of Miami School of Medicine, Miami, Florida.
(2)Department of Psychiatry and Behavioral Sciences and Sylvester Comprehensive
Cancer Center, University of Miami School of Medicine, Miami, Florida.

The range of psychosocial stress factors/processes (eg, chronic stress, distress
states, coping, social adversity) were reviewed as they relate to immune
variables in cancer along with studies of psychosocial interventions on these
stress processes and immune measures in cancer populations. The review includes
molecular, cellular, and clinical research specifically examining the effects of
stress processes and stress-management interventions on immune variables (eg,
cellular immune function, inflammation), which may or may not be changing
directly in response to the cancer or its treatment. Basic psychoneuroimmunologic
research on stress processes (using animal or cellular/tumor models) provides
leads for investigating biobehavioral processes that may underlie the
associations reported to date. The development of theoretically driven and
empirically supported stress-management interventions may provide important
adjuncts to clinical cancer care going forward.

DOI: 10.1002/cncr.31943
PMID: 30768779

Med Sci Monit. 2019 Feb 15;25:1242-1253. doi: 10.12659/MSM.912421.

Long Non-Coding RNA TFAP2A-AS1 Inhibits Cell Proliferation and Invasion in Breast
Cancer via miR-933/SMAD2.

Zhou B(1), Guo H(2), Tang J(3).

Author information:
(1)Department of General Surgery, Jiangsu Cancer Hospital (Afﬁliated Cancer
Hospital of Nanjing Medical University), Nanjing, Jiangsu, China (mainland).
(2)Department of Infectious Diseases, Jiangsu Province Hospital of Traditional
Chinese medicine (TCM), Affiliated Hospital of Nanjing University of TCM,
Nanjing, Jiangsu, China (mainland).
(3)Department of General Surgery, First Afﬁliated Hospital of Nanjing Medical
University, Nanjing, Jiangsu, China (mainland).

BACKGROUND It is well documented that long non-coding RNAs (lncRNAs) are involved
in the progression of multiple human tumors by sponging microRNAs (miRNAs).
However, whether lncRNA TFAP2A-AS1 plays a role in the tumorigenesis of breast
cancer (BC) remains undetermined. MATERIAL AND METHODS Real-time PCR (qRT-PCR)
assay was performed to detect the relative mRNA expression of TFAP2A-AS1 and
miR-933. Flow cytometry analysis, CCK-8 assay, and Transwell assay were applied
to detect the effects of TFAP2A-AS1 overexpression on cell cycle, apoptosis,
viability, and invasion of BC cells. In vivo proliferation assay was performed to
evaluate the effects of TFAP2A-AS1 overexpression on tumor growth. Bioinformatics
methods, dual-luciferase reporter, RNA immunoprecipitation (RIP), and RNA
pull-down assays were used to predict and validate the interaction between
TFAP2A-AS1 and miR-933, as well as SMAD2 and miR-933. Western blot assay was
performed to examine the protein expression of SMAD2 in treated BC cells. RESULTS
TFAP2A-AS1 expression was significantly lower in BC tissues and cell lines, and
patients with high TFAP2A-AS1 expression exhibited a better prognosis than those
with low TFAP2A-AS1 expression. Overexpression of TFAP2A-AS1 in BC cells caused
cell cycle arrest, promoted cell apoptosis, suppressed cell ability, and
attenuated cell invasion in vitro, and inhibited tumor growth in vivo. TFAP2A-AS1
was revealed to act as a miRNA sponge for miR-933 and then regulated the
expression of Smad2. CONCLUSIONS Results from the present study suggest that
TFAP2A-AS1 acts as a tumor suppressor in BC via the miR-933/SMAD2 axis.

DOI: 10.12659/MSM.912421
PMID: 30768589

Oncol Nurs Forum. 2019 Mar 1;46(2):185-197. doi: 10.1188/19.ONF.185-197.

Effect of Group Dynamics-Based Exercise Versus Personal Training in Breast Cancer
Survivors.

Leach HJ(1), Covington KR(1), Voss C(2), LeBreton KA(3), Harden SM(4), Schuster
SR(5).

Author information:
(1)Colorado State University.
(2)Taylor University.
(3)UCHealth Medical Fitness.
(4)Virginia Tech.
(5)UCHealth Cancer Care and Hematology Clinic-Harmony Campus.

OBJECTIVES: To determine the feasibility and preliminary effectiveness of a group
dynamics-based exercise intervention versus a personal training intervention for
increasing physical activity (PA), physical fitness, and quality of life (QOL) in
post-treatment breast cancer survivors.
SAMPLE & SETTING: 26 women with stage I or II breast cancer who attended
intervention activities at a local academic institution.
METHODS & VRIABLES: Participants were randomly assigned to receive an
eight-week intervention in either a group dynamics-based exercise or a personal
training setting. Both intervention arms received supervised exercise twice per
week, as well as PA education and discussion sessions.
RESULTS: Significant increases were noted in both intervention arms for vigorous
PA, chest press, and leg press. Increases in overall QOL and total PA were
significant only in the group dynamics-based exercise intervention arm.
IMPLICATIONS FOR NURSING: The group dynamics-based exercise intervention produced
similar improvements in PA and physical fitness compared to the personal training
intervention, and it may have facilitated greater improvements in overall QOL.

DOI: 10.1188/19.ONF.185-197
PMID: 30767964

Oncol Nurs Forum. 2019 Mar 1;46(2):217-227. doi: 10.1188/19.ONF.217-227.

Trajectories of Depression and Anxiety in Latina Breast Cancer Survivors.

Crane TE(1), Badger TA(2), Sikorskii A(3), Segrin C(1), Hsu CH(1), Rosenfeld
AG(1).

Author information:
(1)University of Arizona.
(2)University of Arizona Cancer Center.
(3)Michigan State University.

OBJECTIVES: To identify subgroups of Latina breast cancer survivors with unique
trajectories of depression and anxiety and examine predictors associated with
these subgroups.
SAMPLE & SETTING: Secondary analysis of Latina breast cancer survivors (N =
293) from three psychosocial intervention studies.
METHODS & VARIABLES: Depression and anxiety were assessed at intake and at
weeks 8 and 16. Group-based growth mixture modeling was used to identify
subgroups who followed distinct trajectories of depression and anxiety.
Multinomial logistic regression models were used to identify predictors of
trajectory-based subgroup membership.
RESULTS: Three trajectories emerged for depression.
IMPLICATIONS FOR NURSING: Latina women treated for breast cancer are at an
elevated risk for depression and anxiety and follow distinct trajectories of
these symptoms. Psychosocial interventions are needed to manage these symptoms,
particularly for subgroups in which depression and anxiety persist or worsen.

DOI: 10.1188/19.ONF.217-227
PMID: 30767959

Prev Chronic Dis. 2019 Feb 14;16:E20. doi: 10.5888/pcd16.180221.

Higher Breast Cancer Risk Among Immigrant Asian American Women Than Among US-Born
Asian American Women.

Morey BN(1), Gee GC(2), von Ehrenstein OS(2)(3), Shariff-Marco S(4)(5)(6),
Canchola AJ(4)(5), Yang J(4)(5), Allen L(4)(5), Lee SS(7), Bautista R(8), La
Chica T(9), Tseng W(10), Chang P(11), Gomez SL(4)(5)(6).

Author information:
(1)University of California-Riverside, School of Public Policy, 900 University
Ave, 4111 CHASS Interdisciplinary South, Riverside, CA 92521. Email:
brittany.morey@ucr.edu.
(2)University of California-Los Angeles, Fielding School of Public Health,
Department of Community Health Sciences, Los Angeles, California.
(3)University of California, Los Angeles, Fielding School of Public Health,
Department of Epidemiology, Los Angeles, California.
(4)Cancer Prevention Institute of California, Fremont, California.
(5)University of California, San Francisco, School of Medicine, Department of
Epidemiology & Biostatistics, San Francisco, California.
(6)University of California, San Francisco, Helen Diller Family Comprehensive
Cancer Center, San Francisco, California.
(7)Stanford University School of Medicine, Center for Biomedical Ethics,
Stanford, California.
(8)Rise Up Solutions, San Francisco, California.
(9)Hawai’i Public Health Institute, Honolulu, Hawai’i.
(10)University of California, Berkeley, Health Research for Action, Berkeley,
California.
(11)Ravenswood Family Health Center, East Palo Alto, California.

INTRODUCTION: Given rising rates of breast cancer in parts of Asia, immigrant
Asian American women in the United States may have higher rates of breast cancer
than previously anticipated. This study examined breast cancer risk among Asian
American women by nativity and percentage of life lived in the United States,
accounting for established breast cancer risk factors.
METHODS: We analyzed a breast cancer case-control data set of Asian American
women living in the San Francisco Bay Area; this data set included 132 cases of
women with breast cancer selected from a Surveillance, Epidemiology, and End
Results cancer registry and 438 Asian American women without diagnosed breast
cancer matched to cases by age and country of origin. We used logistic regression
to compare 3 Asian American groups: US-born, immigrants who lived 50% or more of
their life in the United States, and immigrants who lived less than 50% of their
life in the United States.
RESULTS: In the minimally adjusted and fully adjusted models, both groups of
immigrant Asian American women had higher risk of breast cancer than US-born
Asian American women. In the fully adjusted model, compared with US-born Asian
American women, immigrant Asian American women who lived more than 50% of their
life in United States were on average 3 times as likely (odds ratio = 3.00; 95%
confidence interval, 1.56-5.75) and immigrants who lived less than 50% of their
life in United States were on average 2.46 times as likely (odds ratio = 2.46;
95% confidence interval, 1.21-4.99) to have breast cancer. We found no difference
in fully adjusted odds ratios of having breast cancer between the 2 immigrant
groups.
CONCLUSION: This study provides preliminary evidence that breast cancer risk
among immigrant Asian American women may be higher than among their US-born
counterparts.

DOI: 10.5888/pcd16.180221
PMID: 30767860

BMC Cancer. 2019 Feb 15;19(1):152. doi: 10.1186/s12885-019-5357-2.

Correction to: Cervical and breast cancer screening uptake among women with
serious mental illness: a data linkage study.

Woodhead C(1), Cunningham R(2), Ashworth M(3), Barley E(4), Stewart RJ(5),
Henderson MJ(1).

Author information:
(1)Institute of Psychiatry, Psychology & Neuroscience, King’s College London,
London, UK.
(2)Department of Public Health, University of Otago, Wellington, New Zealand.
(3)Department of Primary Care and Public Health Sciences, King’s College London,
London, UK.
(4)Facility of Nursing and Midwifery, King’s, College London, London, UK.
(5)Institute of Psychiatry, Psychology & Neuroscience, King’s College London,
London, UK. robert.stewart@kcl.ac.uk.

Erratum for
BMC Cancer. 2016 Oct 21;16(1):819.

Following publication of the original article [1], the authors notified us of an
error in the reported percentages in Table 3.

DOI: 10.1186/s12885-019-5357-2
PMID: 30767774

Anticancer Agents Med Chem. 2019 Feb 13. doi: 10.2174/1871520619666190214103345.
[Epub ahead of print]

Synthesis, Spectroscopic Properties, Crystal Structure And Biological Evaluation
of New Platinum Complexes with 5-methyl-5- (2-thiomethyl)ethyl Hydantoin.

Bakalova AG(1), Buyukliev RT(1), Nikolova RP(2), Shivachev BL(2), Mihaylovac
RA(3), Konstantinov SM(3).

Author information:
(1)Department of Chemistry, Faculty of Pharmacy, Medical University of Sofia,
Dunav -2 Street, 1000 Sofia. Bulgaria.
(2)Institute of Mineralogy and Crystallography, Bulgarian Academy of Science,
Acad. G. Bonchev Street, 107 bl, 1113 Sofia. Bulgaria.
(3)Department of Pharmacology, Pharmacotherapy and Toxicology, Faculty of
Pharmacy, Medical University of Sofia, Dunav -2 Street, 1000 Sofia. Bulgaria.

BACKGROUND: The accidental discovery of cisplatin’s growth-inhibiting properties
a few decades ago led to resurgence of interest in metal-based chemotherapeutics.
A number of well-discussed factors such as severe systemic toxicity and
unfavourable physicochemical properties further limit the clinical application of
the platinating agents. Great efforts have been placed in the development of
alternative platinum derivatives with an extended antitumor spectrum and amended
toxicity profile as compared to the reference drug cisplatin. The rational design
of conventional platinum analogues and the re-evaluation of the empirically
derived «structure-activity» relationships allowed for the synthesis of platinum
complexes with great diversity in structural characteristics, biochemical
stability and antitumor properties.
METHODS: The new compounds have been studied by elemental analyses, IR, NMR and
mass spectral analyses. The structures of the organic compound and one of the new
mixed/ammine Pt(II) complexes were studied by X-ray diffraction analysis. The
cytotoxic effects of the compounds were studied vs. the referent antineoplastic
agent cisplatin against four human tumour cell lines using the standard MTT-dye
reduction assay for cell viability. The most promising complex 3 was investigated
for acute toxicity in male and female H-albino-mice models.
RESULTS: A new organic compound (5-methyl-5-(2-thiomethyl)ethyl hydantoin) L
bearing both S- and N-coordinating sites and three novel platinum complexes, 1, 2
and 3 were synthesized and studied. Spectral and structural characterization
concluded monodentate S-driven coordination of the ligand L to the metal center
in complexes 1 and 2, whereas the same acts as a bidentate N,S-chelator in
complex 3. Ligand L crystallizes in the tetragonal space group I41/a (No 88) with
one molecule per asymmetric unit. While complex 3 crystallizes in the monoclinic
space group P21/c (No 14) with one molecule per asymmetric unit. In the same
complex 3 the platinum ion coordinates an L ligand, a chloride ion and an ammonia
molecule. In the in vitro experiments the tested L and complexes 1 and 2
exhibited negligible cytotoxic activity in all tumor models. Accordingly, complex
3 is twice as potent as cisplatin in the HT-29 cells and is at least as active as
cisplatin on the MDA-MB-231 breast cancer cell line. In the in vivo toxicity
estimation of complex 3 no signs of common toxicity were observed.
CONCLUSION: The Pt(II)-bidentate complex 3 exhibited significant cytotoxic
potential equaling or surpassing that of the reference drug cisplatin in all the
tested tumor models. Negligible anticancer activity on the screened tumor types
has been shown by the ligand L and its Pt(II) and Pt(IV) complexes 1 and 2,
respectively. Our study on the acute toxicity of the most active complex 3 proved
it to be non-toxic in mice models.

DOI: 10.2174/1871520619666190214103345
PMID: 30767754

Nanomedicine (Lond). 2019 Feb;14(4):371-373. doi: 10.2217/nnm-2018-0407. Epub
2019 Jan 18.

Electron microscopy in human diseases: diagnostic and research perspectives.

Scimeca M(1)(2), Montanaro M(3), Bonfiglio R(3), Anemona L(3), Bonanno E(3)(4).

Author information:
(1)Department of Biomedicine & Prevention, University of Rome Tor Vergata, Via
Montpellier 1, Rome 00133, Italy.
(2)San Raffaele University, Via di Val Cannuta 247, 00166 Rome, Italy.
(3)Department of Experimental Medicine & Surgery, University of Rome Tor Vergata,
Via Montpellier 1, Rome 00133, Italy.
(4)’Diagnostica Medica’ & ‘Villa dei Platani’, Neuromed Group, Avellino, 83100,
Italy.

DOI: 10.2217/nnm-2018-0407
PMID: 30767724

Per Med. 2019 Feb 15. doi: 10.2217/pme-2018-0059. [Epub ahead of print]

Functional polymorphism within miR-23a∼27a∼24-2 cluster confers clinical outcome
of breast cancer in Pakistani cohort.

Ahmad M(1), Shah AA(1).

Author information:
(1)Department of Biotechnology, University of Malakand, Chakdara, Pakistan.

AIM: MicroRNAs (miRNAs) are small regulatory RNA molecules that control gene
activity by base pairing with target messenger RNA leading to their cleavage or
translational repression. Previous studies show an involvement of miRNAs in
various diseases including cancer. Members of the Mir-23a cluster (MIR23A,
MIR24-2 and MIR27A) are involved in breast cancer (BC).
METHODS: In the present study, miR-23a/24-2/27a cluster was screened for genetic
mutation in BC patients.
RESULTS: Heterozygous (A/G allele) as well as homozygous (G/G allele) variants
were found in mir-27a gene in screened BC patients. RNA structural analysis
revealed that the single nucleotide polymorphism (SNP) effects the size of the
terminal loop in the precursor miRNA (pre-miRNA).
CONCLUSION: The altered (G allele) hairpin structure observed was two bases
longer than the reference (A allele) hairpin.

DOI: 10.2217/pme-2018-0059
PMID: 30767608

Future Oncol. 2019 Feb 15. doi: 10.2217/fon-2018-0957. [Epub ahead of print]

Current situation and challenges regarding biosimilars in Japan: an example of
trastuzumab biosimilars for breast cancer.

Hara F(1), Tajima K(2), Tanabe K(2).

Author information:
(1)Department of Breast Oncology, National Hospital Organization Shikoku Cancer
Center, Ehime, Japan.
(2)Medical Affairs, Pfizer Japan Inc., Tokyo, Japan.

Biologics have dramatically changed breast cancer treatment, and trastuzumab has
been an essential treatment drug for HER2-positive breast cancer. The
introduction of trastuzumab biosimilar offers the potential to deliver long-term
cost savings plus efficiencies for healthcare systems in Japan. The goal of
biosimilar development is to demonstrate comparability to the original biologic
with a different development concept from that of the original biologic. Hence, a
better understanding of the biosimilar itself is urgently needed for appropriate
adoption and the integration of trastuzumab biosimilars into oncology clinical
practice by all stakeholders. This article focuses on the current situation of
biosimilars and future perspectives in Japan by using the trastuzumab biosimilar
as an example.

DOI: 10.2217/fon-2018-0957
PMID: 30767568

Cancer Med. 2019 Feb 14. doi: 10.1002/cam4.1997. [Epub ahead of print]

Risk of recurrence and bleeding in patients with cancer-associated venous
thromboembolism treated with rivaroxaban: A nationwide cohort study.

Søgaard M(1)(2), Nielsen PB(1)(2), Skjøth F(2)(3), Kjaeldgaard JN(1)(2), Larsen
TB(1)(2).

Author information:
(1)Department of Cardiology, Aalborg University Hospital, Aalborg, Denmark.
(2)Aalborg Thrombosis Research Unit, Department of Clinical Medicine, Faculty of
Health, Aalborg University, Aalborg, Denmark.
(3)Unit for Clinical Biostatistics, Aalborg University Hospital, Aalborg,
Denmark.

BACKGROUND: Rivaroxaban could be an attractive alternative to low molecular
weight heparin for the treatment of cancer-associated venous thromboembolism
(VTE) but the safety and effectiveness remain unclear. We examined risk of
recurrent VTE and major bleeding associated with rivaroxaban treatment of
cancer-associated VTE.
METHODS: Through linkage of nationwide Danish registries, we identified all
adults with cancer-associated VTE initiating treatment with rivaroxaban,
2012-2017. We estimated rates and absolute risk of the primary outcome of
recurrent VTE and major bleeding; all-cause mortality was studied as a secondary
outcome.
RESULTS: We identified 8901 patients with cancer-associated VTE of whom 476
(5.3%) redeemed a prescription for rivaroxaban within 30 days of VTE diagnosis
(mean age 71.5 years, 41% females, 57% with pulmonary embolism). Median time from
cancer diagnosis to rivaroxaban prescription was 31 days (interquartile range
12-73 days). Most frequent cancers were gastrointestinal (26.1%), genitourinary
(23.3%), and hematological cancer (12.6%). Few had distant metastases (7.1%). At
6 months, recurrent VTE occurred in 6.1% (15.1 events per 100 person-years) with
the highest absolute risks for genitourinary cancer (8.1%), gastrointestinal
cancer (7.3%), and breast cancer (6.5%). Major bleeding occurred in 1.9% (5.3
events per 100 person-years), in particular, in genitourinary cancer (4.5%) and
lung cancer (4.2%). Eighty deaths (17.8%) occurred during follow up.
CONCLUSION: In this clinical practice setting, rivaroxaban was rarely used for
cancer-associated VTE. However, among those who received rivaroxaban, the
treatment appeared safe and effective with rates comparable to previous studies
of selected populations.

DOI: 10.1002/cam4.1997
PMID: 30767432

Microsc Res Tech. 2019 Feb 14. doi: 10.1002/jemt.23234. [Epub ahead of print]

Rapid histologic diagnosis using quick fluorescence staining and tissue confocal
microscopy.

Kim H(1), Lee S(1), Kim H(2), Chang HJ(3)(4), Choi Y(2), Yoon HM(1)(5), Kook
MC(4)(5), Jung SY(6), Kwon Y(4)(6), Kang J(7), Yoo H(7), Song I(8), Lee S(9),
Sohn DK(1)(3).

Author information:
(1)Innovative Medical Engineering & Technology, National Cancer Center, Goyang,
South Korea.
(2)Biomarker Branch, National Cancer Center, Goyang, South Korea.
(3)Center for Colorectal Cancer, National Cancer Center, Goyang, South Korea.
(4)Department of Pathology, National Cancer Center, Goyang, South Korea.
(5)Center for Gastric Cancer, National Cancer Center, Goyang, South Korea.
(6)Center for Breast Cancer, National Cancer Center, Goyang, South Korea.
(7)Department of Biomedical Engineering, Hanyang University, Seoul, South Korea.
(8)Nanoscope Systems, Inc., Daejeon, South Korea.
(9)Osong Medical Innovation Foundation, Cheongju, Chungcheongbuk-do, South Korea.

With the development of advanced and minimally invasive surgical techniques, and
in view of the functional and cosmetic aspects, the need for rapid and accurate
diagnosis during surgery is increasing. This study was conducted to develop a
tissue diagnosis method using confocal microscopy after simple tissue staining
that does not require freezing and slicing. At present, fluorescence staining
with confocal microscopy is not generalized for real-time diagnosis during
surgery. In this paper, we propose a fluorescence staining method using Hoechst
33342 and Eosin that does not require tissue freezing and slicing. The proposed
method can be used as part of a rapid tissue diagnosis method that is suitable
for use in the operating room, although further research is required before it
can be applied in clinical practice.

DOI: 10.1002/jemt.23234
PMID: 30767333

Photochem Photobiol. 2019 Feb 15. doi: 10.1111/php.13091. [Epub ahead of print]

Ferrochelatase Deficiency Abrogated the Enhancement of Aminolevulinic
Acid-mediated Protoporphyrin IX by Iron Chelator Deferoxamine.

Palasuberniam P(1), Kraus D(1), Mansi M(1), Braun A(2), Howley R(1), Myers KA(2),
Chen B(1)(3).

Author information:
(1)Department of Pharmaceutical Sciences, Philadelphia College of Pharmacy,
University of the Sciences, Philadelphia, Pennsylvania.
(2)Department of Biological Sciences, Misher College of Arts & Sciences,
University of the Sciences, Philadelphia, Pennsylvania.
(3)Department of Radiation Oncology, Perelman School of Medicine, University of
Pennsylvania, Philadelphia, Pennsylvania.

Aminolevulinic acid (ALA) is a prodrug that is metabolized in the heme
biosynthesis pathway to produce protoporphyrin IX (PpIX) for tumor fluorescence
detection and photodynamic therapy (PDT). The iron chelator deferoxamine (DFO)
has been widely used to enhance PpIX accumulation by inhibiting the
iron-dependent bioconversion of PpIX to heme, a reaction catalyzed by
ferrochelatase (FECH). Tumor response to DFO treatment is known to be highly
variable and some tumors even show no response. Given the fact that tumors often
exhibit reduced FECH expression/enzymatic activity, we examined how reducing FECH
level affected the DFO enhancement effect. Our results showed that reducing FECH
level by silencing FECH in SkBr3 breast cancer cells completely abrogated the
enhancement effect of DFO. Although DFO enhanced ALA-PpIX fluorescence and PDT
response in SkBr3 vector control cells, it caused a similar increase in MCF10A
breast epithelial cells, resulting in no net gain in the selectivity towards
tumor cells. We also found that DFO treatment induced less increase in ALA-PpIX
fluorescence in tumor cells with lower FECH activity (MDA-MB-231, Hs 578T) than
in tumor cells with higher FECH activity (MDA-MB-453). Our study demonstrates
that FECH activity is an important determinant of tumor response to DFO
treatment. This article is protected by copyright. All rights reserved.

DOI: 10.1111/php.13091
PMID: 30767226

Clin Transl Oncol. 2019 Feb 14. doi: 10.1007/s12094-019-02042-w. [Epub ahead of
print]

Elevated expression of GNAS promotes breast cancer cell proliferation and
migration via the PI3K/AKT/Snail1/E-cadherin axis.

Jin X(1)(2), Zhu L(2), Cui Z(2), Tang J(2), Xie M(2), Ren G(3)(4).

Author information:
(1)Department of Endocrine and Breast Surgery, The First Affiliated Hospital of
Chongqing Medical University, No. 1, Youyi Road, Yuanjiagang, Yuzhong District,
Chongqing, 400016, China.
(2)Department of Breast Surgery, The First People’s Hospital of Yibin, Yibin,
Sichuan, China.
(3)Department of Endocrine and Breast Surgery, The First Affiliated Hospital of
Chongqing Medical University, No. 1, Youyi Road, Yuanjiagang, Yuzhong District,
Chongqing, 400016, China. guoshengren65@163.com.
(4)Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First
Affiliated Hospital of Chongqing Medical University, Chongqing, China.
guoshengren65@163.com.

PURPOSE: Although it has been well established that G protein plays pivotal roles
in physiologic or pathologic conditions, including cancer formation, its role in
breast cancer, especially specific subunits, remains largely unknown. Our work
aimed to evaluate the correlation of the G protein alpha subunit (GNAS) with
breast cancer and to investigate the underlying molecular mechanism.
METHODS: The expression of GNAS was determined by breast tumor tissue microarray
of 150 patients with complete follow-up information. The correlation between GNAS
expression and clinical features was assessed. CCK8, EdU incorporation, flow
cytometry, wound healing, transwell, western blot and tumor formation assays were
carried out in nude mice to study the biological function of GNAS and the
underlying molecular mechanism in breast cancer by silencing GNAS using a
specific siRNA.
RESULTS: High GNAS expression showed a close correlation with a reduced overall
survival (p = 0.021), frequent distal metastasis (p = 0.026), advanced clinical
stage (p = 0.001), stronger cell proliferation (ki67+ positive cell rate,
p = 0.0351) and enhanced cancer cell migration, which was further confirmed by in
vitro and in vivo assays and might be dependent on the PI3K/AKT/Snail1/E-cadherin
axis.
CONCLUSION: The data suggested that GNAS promoted breast cancer cell
proliferation and migration (EMT) through the PI3K/AKT/Snail1/E-cadherin
signaling pathway. These findings also indicate that GNAS can serve as a
potential prognostic indicator and novel therapeutic target in breast cancer.

DOI: 10.1007/s12094-019-02042-w
PMID: 30767161

J Community Health. 2019 Feb 14. doi: 10.1007/s10900-019-00622-z. [Epub ahead of
print]

Smoking and Smoking Cessation Among Persons with Tobacco- and
Non-tobacco-Associated Cancers.

Gallaway MS(1), Huang B(2)(3), Chen Q(3), Tucker TC(3)(4), McDowell JK(3), Durbin
E(3)(5), Stewart SL(6), Tai E(6).

Author information:
(1)Division of Cancer Prevention and Control, Centers for Disease Control and
Prevention, National Center for Chronic Disease Prevention and Health, 4770
Buford Highway, MS F76, Atlanta, GA, 30341, Georgia. lnx7@cdc.gov.
(2)Department of Biostatistics, College of Public Health, University of Kentucky,
Lexington, KY, USA.
(3)Kentucky Cancer Registry, College of Medicine, University of Kentucky,
Lexington, KY, USA.
(4)Department of Epidemiology, College of Public Health, University of Kentucky,
Lexington, KY, USA.
(5)Division of Biomedical Informatics, College of Medicine, University of
Kentucky, Lexington, KY, USA.
(6)Division of Cancer Prevention and Control, Centers for Disease Control and
Prevention, National Center for Chronic Disease Prevention and Health, 4770
Buford Highway, MS F76, Atlanta, GA, 30341, Georgia.

PURPOSE: To examine smoking and use of smoking cessation aids among
tobacco-associated cancer (TAC) or non-tobacco-associated cancer (nTAC)
survivors. Understanding when and if specific types of cessation resources are
used can help with planning interventions to more effectively decrease smoking
among all cancer survivors, but there is a lack of research on smoking cessation
modalities used among cancer survivors.
METHODS: Kentucky Cancer Registry data on incident lung, colorectal, pancreatic,
breast, ovarian, and prostate cancer cases diagnosed 2007-2011, were linked with
health administrative claims data (Medicaid, Medicare, private insurers) to
examine the prevalence of smoking and use of smoking cessation aids 1 year prior
and 1 year following the cancer diagnosis. TACs included colorectal, pancreatic,
and lung cancers; nTAC included breast, ovarian, and prostate cancers.
RESULTS: There were 10,033 TAC and 13,670 nTAC survivors. Smoking before
diagnosis was significantly higher among TAC survivors (p < 0.0001). Among TAC
survivors, smoking before diagnosis was significantly higher among persons who:
were males (83%), aged 45-64 (83%), of unknown marital status (84%), had very low
education (78%), had public insurance (89%), Medicaid (85%) or were uninsured
(84%). Smoking cessation counseling and pharmacotherapy were more common among
TAC than nTAC survivors (p < 0.01 and p = 0.05, respectively).
DISCUSSION: While smoking cessation counseling and pharmacotherapy were higher
among TAC survivors, reducing smoking among all cancer survivors remains a
priority, given cancer survivors are at increased risk for subsequent chronic
diseases, including cancer. Tobacco cessation among all cancer survivors (not
just those with TAC) can help improve prognosis, quality of life and reduce the
risk of further disease. Health care providers can recommend for individual,
group and telephone counseling and/or pharmacotherapy recommendations. These
could also be included in survivorship care plans.

DOI: 10.1007/s10900-019-00622-z
PMID: 30767102

Biomed Res Int. 2019 Jan 15;2019:6146972. doi: 10.1155/2019/6146972. eCollection
2019

Effect of Chemotherapeutics and Tocopherols on MCF-7 Breast Adenocarcinoma and
KGN Ovarian Carcinoma Cell Lines In Vitro.

Figueroa D(1), Asaduzzaman M(1), Young F(1).

Author information:
(1)Department of Medical Biotechnology, College of Medicine and Public Health,
Flinders University, Adelaide, SA, 5052, Australia.

The combination of doxorubicin and cyclophosphamide commonly used to treat breast
cancer can cause premature ovarian failure and infertility. α-Tocopherol is a
potent antioxidant whereas γ-tocopherol causes apoptosis in a variety of cancer
models in vitro including breast cancer. We hypothesised that the combination of
doxorubicin (Dox) and 4-hydroperoxycyclophosphamide (4-Cyc) would be more
cytotoxic in vitro than each agent alone, and that α-tocopherol would reduce and
γ-tocopherol would augment the cytotoxicity of the combined chemotherapeutics.
Human MCF-7 breast cancer and KGN ovarian cells were exposed to Dox, 4-Cyc,
combined Dox and 4-Cyc, α-tocopherol, γ-tocopherol, or a combination of Dox and
4-Cyc with α-tocopherol or γ-tocopherol. Cell viability was assessed using a
crystal violet assay according to four schedules: 24h exposure, 24h exposure +
24h culture in medium, 24h exposure + 48h culture in medium, or 72h continuous
exposure. Supernatants from each separate KGN culture experiment (n=3) were
examined using an estradiol ELISA. Dox was cytotoxic to both MCF-7 and KGN cells,
but 4-Cyc only killed MCF-7 cells. γ-Tocopherol significantly decreased MCF-7 but
not KGN cell viability. The combined chemotherapeutics and γ-tocopherol were more
cytotoxic to MCF-7 than KGN cells, and α-tocopherol reduced the cytotoxicity of
the combined chemotherapeutics towards KGN ovarian cells, but not MCF-7 cells.
The addition of both γ-tocopherol and α-tocopherol to the chemotherapeutic
combination of Dox and cyclophosphamide has the potential to increase in vitro
chemotherapeutic efficacy against breast cancer cells whilst decreasing
cytotoxicity towards ovarian granulosa cells.

DOI: 10.1155/2019/6146972
PMCID: PMC6350544
PMID: 30766885

South Asian J Cancer. 2019 Jan-Mar;8(1):18-21. doi: 10.4103/sajc.sajc_56_18.

Stromal expression of CD10 in breast carcinoma and its correlation with
clinicopathological parameters.

Dhande AN(1), Sinai Khandeparkar SG(1), Joshi AR(1), Kulkarni MM(1), Pandya N(1),
Mohanapure N(1), Aggarwal A(1), Patil G(1).

Author information:
(1)Department of Pathology, Smt. Kashibai Navale Medical College and General
Hospital, Pune, Maharashtra, India.

Introduction: Breast cancer is the foremost cause of death in women worldwide
with more than one million cases occurring annually.
Aim: This study was conducted to study the stromal CD10 expression in breast
carcinomas (BCa) and its correlation with various prognostic factors such as
tumor size, histological grade, lymph node status, estrogen receptor (ER),
progesterone receptor (PR), HER2neu, and Ki67 status.
Materials and Methods: Sixty cases of BCa diagnosed between 2013 and 2015 were
included in the study. Stromal expression of CD10 was studied on entire section
of selected BCa blocks for all cases. A technique of manual tissue microarray was
employed for the analysis of expression of immunohistochemical markers ER, PR,
and HER2/Neu and Ki67 in all cases. Results were subjected to statistical
analysis.
Results: Stromal CD10 positivity was seen in 78.3% cases, out of which 53.3% of
cases were strongly positive, and 25.0% cases were weakly positive. Positivity
for ER, PR, HER2, and Ki67 was 31.7%, 33.3%, 65%, and 75%, respectively. Stromal
expression of CD10 was found to be significantly associated with increasing tumor
grade, lymph node status, HER2neu positivity, ER negativity, and Ki67 positivity.
CD10 stromal expression was seen mainly in PR negative BCa cases; however, it was
statistically insignificant. It was noted that CD10 stromal positivity increased
with increasing grade.
Conclusion: CD10 can be used as an independent prognostic marker and should be
included in routine histopathology report. CD10 could act as a potential target
for newer drug development.

DOI: 10.4103/sajc.sajc_56_18
PMCID: PMC6348787
PMID: 30766845

Conflict of interest statement: There are no conflicts of interest.

Hawaii J Med Public Health. 2019 Feb;78(2):39-43.

An Uncommon Pairing of common Tumors: Case Report of Ductal Carcinoma in situ
Within Fibroadenoma.

Marumoto A(1)(2), Steinemann S(1)(2), Furumoto N(1)(2), Woodruff S(1)(2).

Author information:
(1)Department of Surgery, John A. Burns School of Medicine, University of
Hawai’i, Honolulu, HI (AM, SS, NF, SW).
(2)Department of Surgery, Pali Momi Medical Center, Aiea, HI (SW).

Fibroadenomas are common benign tumors of the female breast. In the appropriate
clinical setting, they are often managed expectantly without excision. Rarely,
cancer may arise within a fibroadenoma, and this diagnosis mandates prompt
treatment for malignancy. We present the case of a 70-year-old Samoan woman with
ductal carcinoma in situ (DCIS) arising within a fibroadenoma. Health care
practitioners should be aware of the possibility, particularly in older women, of
finding carcinoma within a fibroadenoma, which informs the rationale for prompt
surgical evaluation and follow up of all breast masses.

PMCID: PMC6369888
PMID: 30766763

Conflict of interest statement: None of the authors identify a conflict of
interest.

Cancer Biol Med. 2018 Nov;15(4):478. doi: 10.20892/j.issn.2095-3941.2018.0438.

Erratum to Analysis of factors related to non-sentinel lymph node metastasis in
296 sentinel lymph node-positive Chinese breast cancer patients.

Maimaitiaili A(1), Wu D(1), Liu Z(1), Liu H(1), Muyiduli X(2), Fan Z(1).

Author information:
(1)Department of Breast Surgery, The First Hospital of Jilin University,
Changchun 130021, China.
(2)Department of Epidemiology & Health Statistics, School of Public Health,
School of Medicine, Zhejiang University, Hangzhou 310058, China.

DOI: 10.20892/j.issn.2095-3941.2018.0438
PMCID: PMC6372918
PMID: 30766758

Cancer Biol Med. 2018 Nov;15(4):468-477. doi:
10.20892/j.issn.2095-3941.2018.0084.

2017 Chinese expert consensus on the clinical application of serum marker for
thyroid cancer.

Gao M(1), Ge M(2), Ji Q(3), Cheng R(4), Lu H(5), Guan H(6), Cui W(7), Gao L(8),
Gao Z(9), Guo L(10), Guo Z(11), Huang T(12), Huang X(13), Lin Y(14), Liu Q(15),
Ni X(16), Qin J(17), Ren L(18), Shan Z(6), Sun H(19), Wang X(1), Xu Z(20), Yu
Y(1), Zhang B(21), Zhao D(22), Zheng Y(23), Zhu J(24), Zheng X(1), Chinese
Association Of Thyroid Oncology Cato China Anti-Cancer
Association(1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20
)(21)(22)(23)(24).

Author information:
(1)Department of Head and Neck Tumor, Tianjin Medical University Cancer Institute
and Hospital; National Clinical Research Center for Cancer, Key Laboratory of
Cancer Prevention and Therapy, Tianjin; Tianjin’s Clinical Research Center for
Cancer, Tianjin 300060, China.
(2)Department of Head and Neck, Zhejiang Cancer Hospital, Hangzhou 310022, China.
(3)Department of Head and Neck Tumor, Fudan University Shanghai Cancer Center,
Shanghai 200433, China.
(4)Department of General Surgery, First Affiliated Hospital of Kunming Medical
University, Kunming 650032, China.
(5)Department of Nuclear Medicine, The Sixth Affiliated Hospital of Shanghai Jiao
Tong University, Shanghai 200025, China.
(6)Department of Endocrinology, The First Hospital of China Medical University,
Shenyang 110001, China.
(7)Department of Clinical Laboratory, Cancer Hospital Chinese Academy of Medical
Science, Beijing 100021, China.
(8)Department of Head and Neck, Sir Run Run Shaw Hospital, Zhejiang University
School of Medicine, Hangzhou 310020, China.
(9)Department of Nuclear Medicine, Union Hospital Tongji Medical College Huazhong
University of Science and Technology, Wuhan 430030, China.
(10)Department of Clinical Laboratory, Fudan University Shanghai Cancer Center,
Shanghai 200433, China.
(11)Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
(12)Department of Thyroid and Breast, Union Hospital Tongji Medical College
Huazhong University of Science and Technology, Wuhan 430030, China.
(13)Department of Otolaryngology, Sun Yat-sen Memorial Hospital, Sun Yat-sen
University, Guangzhou 510120, China.
(14)Department of Nuclear Medicine, Peking Union Medical College Hospital,
Beijing 100730, China.
(15)Department of Head and Neck, Gansu Provincial Cancer Hospital, Lanzhou
730050, China.
(16)Department of Head and Neck, Beijing Children’s Hospital, Capital Medical
University, Beijing 100045, China.
(17)Department of Thyroid, Head and Neck, Henan Cancer Hospital, Zhengzhou
450008, China.
(18)Department of Clinical Laboratory, Tianjin Medical University Cancer
Institute and Hospital; National Clinical Research Center for Cancer, Key
Laboratory of Cancer Prevention and Therapy, Tianjin; Tianjin’s Clinical Research
Center for Cancer, Tianjin 300060, China.
(19)Department of Thyroid, Sino Japanese Union Hospital of Jilin University,
Changchun 130033, China.
(20)Department of Head and Neck, Cancer Hospital Chinese Academy of Medical
Sciences, Beijing 100021, China.
(21)Department of Head and Neck, Peking Union Medical College Hospital, Beijing
100730, China.
(22)Department of General Surgery, The Second Affiliated Hospital of Guizhou
Medical University, Kaili 556099, China.
(23)Department of Head and Neck, Jilin Tumor Hospital, Changchun 130012, China.
(24)Department of Thyroid and Breast, West China School of Medicine, West China
Hospital, Sichuan University, Chengdu 610047, China.

DOI: 10.20892/j.issn.2095-3941.2018.0084
PMCID: PMC6372917
PMID: 30766757

Cancer Biol Med. 2018 Nov;15(4):452-460. doi:
10.20892/j.issn.2095-3941.2018.0270.

Comparison of sentinel lymph node detection performances using blue dye in
conjunction with indocyanine green or radioisotope in breast cancer patients: a
prospective single-center randomized study.

Yuan L(1), Qi X(1), Zhang Y(1), Yang X(1), Zhang F(1), Fan L(1), Chen L(1), Zhang
K(1), Zhong L(1), Li Y(1), Gan S(1), Fu W(1), Jiang J(1).

Author information:
(1)Department of Breast Surgery, Southwest Hospital, Third Military Medical
University (Army Medical University), Chongqing 400038, China.

Objective: This randomized study aimed to compare the clinical efficacy between
the novel dual tracer composed of indocyanine green (ICG) and blue dye (BD) and
the conventional dual tracer composed of radioisotope and BD for sentinel lymph
node (SLN) mapping in patients with breast cancer.
Methods: This study enrolled 471 clinically lymph node-negative patients with
primary breast cancer. All patients underwent mastectomy, and those undergoing
sentinel lymph node biopsy (SLNB) were randomized to receive blue dye plus
radioisotope (RB group) or BD plus ICG (IB group). The detection performances on
SLN identification rate, positive SLN counts, detection sensitivity, and
false-negative rate were compared between the two groups.
Results: In the IB group, 97% (194/200) of the patients who underwent the ICG and
BD dual tracer injection showed fluorescent-positive lymphatic vessels within 2-5
min. The identification rate of SLNs was comparable between the IB group (99.0%,
198/200) and the RB group (99.6%, 270/271) (P = 0.79). No significant differences
were observed in the identification rate of metastatic SLNs (22.5% vs. 22.9%, P >
0.05, RB group vs. IB group, the same below), positive SLN counts (3.72 ± 2.28
vs. 3.91 ± 2.13, P > 0.05), positive metastatic SLN counts (0.38 ± 0.84 vs. 0.34
± 0.78, P > 0.05), SLNB detection sensitivity (94.4% vs. 92.5%, P > 0.05), or
false-negative rate (5.6% vs. 7.5%, P > 0.05) between the two groups.
Conclusions: ICG can be used as a promising alternative tracer for radioisotope
in SLN mapping, and when it is combined with BD in lymphangiography, it offers
comparable detection sensitivity compared to the conventional lymphatic mapping
strategies that are widely used in clinical practice.

DOI: 10.20892/j.issn.2095-3941.2018.0270
PMCID: PMC6372915
PMID: 30766755

Womens Midlife Health. 2018 Apr 27;4:7. doi: 10.1186/s40695-018-0037-y.
eCollection 2018.

Prophylactic salpingo-oophorectomy & surgical menopause for inherited risks of
cancer: the need to identify biomarkers to assess the theoretical risk of
premature coronary artery disease.

Batulan Z(1), Maarouf N(1), Shrivastava V(1), O’Brien E(1)(2).

Author information:
(1)1Department of Cardiac Sciences, Libin Cardiovascular Institute of Alberta,
University of Calgary, Health Research Innovation Centre, GB42, 3280 Hospital Dr
NW, Calgary, AB T2N 4Z6 Canada.
(2)Department of Cardiac Sciences, Libin Cardiovascular Institute of Alberta,
Health Research Innovation Centre, Room GAA16, 3280 Hospital Drive NW, Calgary,
AB T2N 4Z6 Canada.

Background: Some women with genetic risk of breast and/or ovarian cancer (e.g.,
BRCA1/2) opt to undergo prophylactic salpingo-oophorectomy (PSO, or surgical
removal of the ovaries & fallopian tubes) in order to reduce their risk of
cancer. As a consequence, these women experience «surgical menopause» –
accompanied by more severe climacteric symptoms that occur in a much shorter time
frame. While the risk of coronary artery disease (CAD) rises with menopause,
little is known about how the sudden loss of ovarian function from PSO alters the
whole-body physiology, and whether it predisposes women to premature CAD.
Methods/Design: To manage CAD risk there is a prerequisite for reliable
biomarkers that can help guide risk assessment and therapeutic interventions. To
address these needs, this prospective, observational cohort study will evaluate
surrogate markers reflective of CAD health in women experiencing surgical
menopause after PSO. Twenty women representing each of the following groups will
be enrolled over 3 years (total participants = 240): (i) pre-menopausal PSO, (ii)
post-menopausal PSO, (iii) pre-menopausal women undergoing other pelvic surgery,
and (iv) pre-menopausal controls (no surgery). All participants will provide
blood plasma samples pre- and 1, 3, 6, & 12 months post-operatively, with serial
samples collectively assessed for measurements of the study’s primary endpoints
of interest. These include a hormone profile (estradiol, follicle stimulating
hormone (FSH), luteinizing hormone (LH), and progesterone) and both conventional
(lipid profile) and novel biomarkers (Heat Shock Protein 27 (HSP27),
HSP27-antibodies (HSP27 Ab), proprotein convertase subtilisin/kexin 9 (PCSK9),
inflammatory cytokines) of CAD. Another aspect of this study is the measurement
and analysis of retinal vessel diameters – an emerging physiological parameter
reflective of CAD risk. Finally, a patient engagement exercise will result in the
drafting of patient-generated questionnaires that address the well-being and
health concerns of these women as they transition through premature menopause and
work with our research team to identify and discuss their health priorities.
Discussion: The protocol of our planned study investigating the effects of PSO on
CAD is described herein. Characterization of novel CAD markers in women
experiencing surgical menopause will yield new insights into the role of the
functional ovary in modulating lipid parameters and other CAD risk factors such
as HSP27 and HSP27 Ab.

DOI: 10.1186/s40695-018-0037-y
PMCID: PMC6297996
PMID: 30766717

Conflict of interest statement: This research has obtained ethics approval at the
University of Calgary (REB14–2335) and consent from participating PSO women and
controls.The authors declare that they have no competing interests.Springer
Nature remains neutral with regard to jurisdictional claims in published maps and
institutional affiliations.

Toxicol Res. 2019 Jan;35(1):93-101. doi: 10.5487/TR.2019.35.1.093. Epub 2018 Jan
15

Tetrabromobisphenol A Induces MMP-9 Expression via NADPH Oxidase and the
activation of ROS, MAPK, and Akt Pathways in Human Breast Cancer MCF-7 Cells.

Lee GH(1), Jin SW(1), Kim SJ(1), Pham TH(1), Choi JH(1), Jeong HG(1).

Author information:
(1)Department of Toxicology, College of Pharmacy, Chungnam National University,
Daejeon, Korea.

Tetrabromobisphenol A (TBBPA), the most common industrial brominated flame
retardant, acts as a cytotoxic, neurotoxic, and immunotoxicant, causing
inflammation and tumors. However, the mechanism of TBBPA-induced matrix
metalloproteinase-9 (MMP-9) expression in human breast cancer cells is not clear.
In human breast cancer MCF-7 cells, treatment with TBBPA significantly induced
the expression and promoter activity of MMP-9. Transient transfection with MMP-9
mutation promoter constructs verified that NF-κB and AP-1 response elements are
responsible for the effects of TBBPA. Furthermore, TBBPA-induced MMP-9 expression
was mediated by NF-κB and AP-1 transcription activation as a result of the
phosphorylation of the Akt and MAPK signaling pathways. Moreover, TBBPA-induced
activation of Akt/MAPK pathways and MMP-9 expression were attenuated by a
specific NADPH oxidase inhibitor, and the ROS scavenger. These results suggest
that TBBPA can induce cancer cell metastasis by releasing MMP-9 via ROS-dependent
MAPK, and Akt pathways in MCF-7 cells.

DOI: 10.5487/TR.2019.35.1.093
PMCID: PMC6354942
PMID: 30766661

Conflict of interest statement: CONFLICT OF INTEREST None of the authors declares
a conflict of interest.

Evid Based Complement Alternat Med. 2019 Jan 15;2019:9549315. doi:
10.1155/2019/9549315. eCollection 2019.

Screening Five Qi-Tonifying Herbs on M2 Phenotype Macrophages.

Jiang YX(1), Chen Y(2), Yang Y(1), Chen XX(2), Zhang DD(1).

Author information:
(1)Institute of Interdisciplinary Integrative Medicine Research, Shanghai
University of Traditional Chinese Medicine, Cailun Road 1200, Shanghai 201203,
China.
(2)School of Pharmacy, Shanghai University of Traditional Chinese Medicine,
Cailun Road 1200, Shanghai 201203, China.

Tumor-associated macrophages (TAMs) with M2 phenotype play an essential role in
tumor microenvironment (TME) during the progression and development of numerous
cancers and associated with poor prognosis. Thus, regulation of TAMs polarization
emerged as a new strategy for tumor immune therapy. According to Traditional
Chinese Medicine (TCM) theory, herbs with Qi-tonifying character are involved in
improving the defense capacity of immune system. In this study, we screened
extracts and ingredients from five Qi-tonifying herbs exhibiting an inhibitory
effect on M2 polarization of murine macrophages RAW264.7 induced by IL-4 and
IL-13. Among these candidates, total flavonoids from Glycyrrhiza Radix et Rhizoma
(TFRG) and ethanol extract of Ginseng Radix et Rhizoma significantly inhibited
the expression of Arginase-1 (Arg-1) (above 90% at 100μg/mL), one of the
phenotype markers of M2 macrophages. The inhibition of total saponins of Ginseng
Radix et Rhizoma, ethanol extract of Cordyceps, ethanol extract of Acanthopanacis
senticosi Radix et Rhizoma Seu caulis, and ethanol extract of Astragali Radix
reached above 50% at 100μg/mL. The inhibition of ingredients including glabridin,
isoliquiritin apioside, lysionotin, cordycepin, astragaloside IV, and calycosin
reached above 50% at 50μM. Then, we investigated the molecular mechanisms of
TFRG. TFRG abolished the migration of murine breast cancer 4T1 stimulated by the
conditioned medium from M2 macrophages (M2-CM). In addition to Arg-1, TFRG also
antagonized the IL-4/13-mediated mRNA upregulation of the M2 markers including
found in inflammatory zone 1 (FIZZ1), chitinase-3-like protein 3 (YM1), and
mannose receptor (CD206) and upregulated the expression of inducible nitric oxide
synthase (iNOS), one of the M1 markers. The further exploration showed that TFRG
decreased the phosphorylation of STAT6 and increased the expression of miR-155.
Our study provides a series of potential immune regulating natural products from
five Qi-tonifying herbs on M2 phenotype. For instance, TFRG suppressed M2
polarization of macrophages partly by inactivating STAT6 pathway and enhanced the
level of miR-155 to regulate the expressions of M1 and M2 markers.

DOI: 10.1155/2019/9549315
PMCID: PMC6350552
PMID: 30766614

Afr Health Sci. 2018 Dec;18(4):958-964. doi: 10.4314/ahs.v18i4.15.

Breast cancer resistance protein (BCRP) gene expression in a cohort of adult
Egyptian patients with acute myeloid leukemia.

El-Masry MW(1), Gouda HM(1), Shaheen IA(1), Edesa W(2), Hassan NM(3), Ramzy R(3).

Author information:
(1)Department of Clinical and Chemical Pathology, Faculty of Medicine, Cairo
University, Egypt.
(2)Department of Clinical Oncology, National Cancer Institute, Cairo University,
Cairo, Egypt.
(3)Department of Clinical and Chemical Pathology, National Cancer Institute,
Cairo University, Egypt.

Background: Acute myeloid leukemia (AML), an aggressive clonal disease, is
genetically heterozygous. The prognostic role of expression of Breast Cancer
Resistance Protein (BCRP) gene, which behaves as a multidrug transporter, in
adult AML is ambiguous.
Objective: The objective is to assess the level of mRNA expression of BCRP gene
in newly diagnosed cytogenetically normal adult Egyptian AML patients; and to
clarify its potential influence and association between therapeutic
responsiveness and disease free survival.
Methods: The BCRP gene expression was evaluated by quantifying its mRNA using
real time RT-PCR in fifty newly diagnosed cytogenetically normal adult AML
patients and 20 healthy normal controls. The expression was evaluated in relation
to clinical and prognostic factors, response to treatment and the survival rate.
Results: BCRP mRNA was over expressed in adult AML patients compared to controls.
This study showed a positive statistical correlation between BCRP gene expression
and the percent of CD34 expression. Statistical analysis did not reveal any
association between BCRP expression level and chemotherapeutic responsiveness or
disease free survival rate.
Conclusion: The significance of BCRP gene expression and its function in AML is
very complicated, therefore more standardized clinical studies are needed.

DOI: 10.4314/ahs.v18i4.15
PMCID: PMC6354849
PMID: 30766560

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