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Endometriosis is a common gynecological disorder that has been associated with endometrial, breast and epithelial ovarian cancers in epidemiological studies. Since complex diseases are a result of multiple environmental and genetic factors, we hypothesized that the biological mechanism underlying their comorbidity might be explained, at least in part, by shared genetics. To assess their potential genetic relationship, we performed a two-sample mendelian randomization (2SMR) analysis on results from public genome-wide association studies (GWAS). This analysis confirmed previously reported genetic pleiotropy between endometriosis and endometrial cancer. We present robust evidence supporting a causal genetic association between endometriosis and ovarian cancer, particularly with the clear cell and endometrioid subtypes. Our study also identified genetic variants that could explain those associations, opening the door to further functional experiments. Overall, this work demonstrates the value of genomic analyses to support epidemiological data, and to identify targets of relevance in multiple disorders.

Background: Prostate cancer (PCa) shows racial disparity in clinical and genomic characteristics, and Asian patients with PCa often present with more aggressive phenotypes at diagnosis. The ability of TP53 to serve as a prognostic biomarker of PCa has been well studied in Western populations. However, no studies to date have examined the role of TP53 in the disparities of primary hormone-naïve prostate cancer (HNPC) between Chinese and Western populations., Methods: We collected prostate tumors and matched normal tissues or blood samples to perform targeted next-generation sequencing of 94 Chinese primary localized HNPC samples, and correlated these genomic profiles with clinical outcomes. The OncoKB knowledge database was used to identify and classify actionable alterations., Results: The aberrations of PTEN, CDK12, and SPOP in Chinese HNPC samples were similar to those in the Western samples. However, we demonstrated an association of a high frequency of TP53 alterations (21/94) with a relatively higher percentage of alterations in the Wnt signaling pathway (15/94) in Chinese HNPC. Additionally, we highlighted alterations of LRP1B as accounting for a high proportion of PCa and found more frequent alterations in CDH1 in Chinese PCa. Of these, only CDH1 alteration was associated with rapid biochemical recurrence (BCR). However, we verified that TP53 status was at the core of the genomic alteration landscape in Chinese HNPC with putative driver mutations because of the strong connections with other signaling pathways. The mutually exclusive relationship between alterations in TP53 and Wnt/CTNNB1 further molecularly characterizes subsets of prostate cancers. Moreover, the alteration of KMT2C was more likely to co-occur with TP53 alteration, indicating a more aggressive phenotype of PCa, which was associated with sensitivity to treatment with poly ADT-ribose polymerase (PARP) inhibitors., Conclusions: Detection of TP53 alterations has clinical utility for guiding precision cancer therapy for HNPC, especially in the Chinese population.

BRCA1/2 pathogenic variant prevalence in Japanese breast cancer is unclear. Here, we analyzed BRCA1/2 pathogenic variant prevalence with a particular focus on age factors, using the Japanese HBOC consortium database. All registered subjects were Japanese individuals who underwent BRCA1/2 genetic testing from January 1996 to July 2017 according to the Japanese HBOC consortium database. Cases were extracted and analyzed for each evaluation item. Overall BRCA1 and BRCA2 pathogenic variant prevalence was 11.2% and 9.0% in the cohort of 2366 proband patients, respectively. The age at onset of breast cancer for patients with BRCA1/2 pathogenic variants was significantly lower than that for patients without a BRCA1/2 pathogenic variant. In both BRCA1/2 patients, ages at onset were not statistically significantly different between two subtype groups (ER-positive vs. TNBC). We analyzed the BRCA1/2 pathogenic variant prevalence among age groups in patients with no family history of breast or ovarian cancer. In the TNBC group, the rate of genetic variants was more frequent among younger patients. Our results demonstrated that early breast cancer onset is associated with a BRCA1/2 pathogenic variant in the Japanese population. Younger TNBC patients were more likely to have a BRCA1/2 pathogenic variant irrespective of a family history of breast or ovarian cancer.

Purpose: The incidence and predictors of diabetes (DM) in patients with breast cancer (BC) were evaluated. We compared DM incidence and physician access in BC patients to matched controls., Methods: We identified women with stage I-III BC diagnosed from 2005 to 2013 in the SEER-Medicare database, with ≥ 2 years of follow-up after diagnosis, without previous DM claims. Incident DM was determined by ≥ 1 DM claims after BC diagnosis. Multivariable analysis was used to identify factors associated with incident DM. Age- and race-matched non-cancer controls were obtained from a 5% random sample and assigned an index date. Physician and PCP visits per-patient-per-year were compared between cases and controls in the two-year period prior to and after the index date., Results: Among 14,506 eligible BC patients, 3234 (22.3%) developed DM versus 16.5% of controls. Among BC patients, factors associated with incident DM included race (Black OR 1.63 95% CI 1.39-1.93, Hispanic OR 3.03 95% CI 1.92-4.81; vs. Caucasians), SES (Quintile 0 vs. Quintile 4 OR 1.55 95% CI 1.33-1.78), and receipt of chemotherapy (vs. none OR 1.19 95% CI 1.08-1.31). Among cases and controls, respectively, median physician visits per-patient-per-year were 19 and 17 prior to the index date, and 46 and 19 after the index date; median PCP visits were 2 for both groups in both periods., Conclusion: About 22% of BC patients developed DM, more than controls in the same period. While there were differences in healthcare access, there weren't differences in PCP access between groups. This represents an opportunity for better comorbidity management in BC patients.

Purpose: To examine the association between statin use and risk of breast cancer recurrence in a national Danish cohort of postmenopausal breast cancer patients receiving aromatase inhibitors (AI) in the adjuvant setting., Patients and Methods: We enrolled all postmenopausal patients diagnosed with stage I-III estrogen receptor positive breast cancer during the years 2007-2017, assigned adjuvant AI treatment, and registered in both the Danish Breast Cancer Group database and the Danish Cancer Registry. We ascertained incident statin exposure (≥ 1 prescription post-diagnosis) from the Danish National Prescription Registry and modeled statins as a time-varying exposure lagged by 6 months. Follow-up began 7 months after diagnosis and continued to the first event of recurrence, death, emigration, 5 years elapsed, or 25th September 2018. We estimated incidence rates of recurrence at 5 years and used Cox regression models to compute crude and adjusted hazard ratios (HRs) with 95% confidence intervals (95% CI), comparing statin exposure with non-exposure., Results: We enrolled 14,773 eligible patients. During the 5 years of follow-up, there were 32 recurrences in 3163 person-years of follow-up among statin-exposed patients, and 612 recurrences in 45,655 person-years among unexposed patients (incidence rate per 1000 person-years: 10.12 [95% CI 6.92-14.28] and 13.40 [95% CI 12.36-14.51], respectively). In multivariable models, any statin exposure was associated with a reduced rate of 5-year breast cancer recurrence (adjusted HR 0.72 [95% CI 0.50-1.04]). Considering only lipophilic statins as exposure the results were similar (adjusted HR 0.70 [95% CI 0.48-1.02])., Conclusions: Statin use was associated with a reduced risk of breast cancer recurrence among postmenopausal patients diagnosed with early stage breast cancer who received adjuvant AI therapy.

Purpose: It has been hypothesized that selenium (Se) can prevent cancer, and that Se deficiency may be associated with an increased risk of breast cancer. However, findings from epidemiological studies have been inconsistent. The objective of this study was to assess the association between Se intake and risk of breast cancer in the Women's Health Initiative (WHI)., Methods: This study included 145,033 postmenopausal women 50-79 years who completed baseline questionnaires between October 1993 and December 1998, which addressed dietary and supplemental Se intake and breast cancer risk factors. The association between baseline Se intake and incident breast cancer was examined in Cox proportional hazards analysis., Results: During a mean follow-up of 15.5 years, 9487 cases of invasive breast cancer were identified. Total Se (highest versus lowest quartile: HR 1.00, 95% CI 0.92-1.09, P trend  = 0.66), dietary Se (highest versus lowest quartile: HR 0.99, 95% CI 0.89-1.08, P trend  = 0.61), and supplemental Se (yes versus no: HR 0.99, 95% CI 0.95-1.03) were not associated with breast cancer incidence., Conclusions: This study indicates that Se intake is not associated with incident breast cancer among postmenopausal women in the United States. Further studies are needed to confirm our findings by using biomarkers such as toenail Se to reduce the potential for misclassification of Se status.

Second primary breast cancer (SPBC) is becoming one of the major obstacles to breast cancer (BC) control. This study was aimed to determine the trend of SPBC incidence over time and the risk of developing SPBC in site-specific primary cancer survivors in the United States. The Surveillance, Epidemiology, and End Results (SEER) 13 registry (1992-2015) was used to identify SPBC patients with previous malignancies. Standardized incidence ratio (SIR) was computed to compare the incidence rates of the observed cases of SPBC in cancer survivors over the expected cases in the general population. Elevated risk of SPBC was observed in women with previous BC (SIR = 1.74) or thyroid cancer (SIR = 1.17). Women with initial skin melanoma in older age (≥50 years) (SIR = 1.11), or White race (SIR = 1.11) presented an elevated incidence of SPBC than the general female population. Besides, Asian/Pacific Islander (API) women with cancer of corpus uteri, ovary, bladder, or kidney were prone to developing SPBC when compared with the general population, with SIRs of 1.61, 1.35, 1.48, and 1.70, respectively. Male BC patients showed profound risk of developing SPBC (SIR = 34.86). Male leukemia patients also presented elevated risk of developing SPBC (SIR = 2.06). Our study suggests significant increase of SPBC in both sexes in the United States. Elevated risk of SPBC exists in survivors with primary BC, female thyroid cancer, male leukemia, and API female cancer patients with primary genitourinary cancer. Our study is helpful in developing strategies for BC control and prevention on specific first primary cancer survivors with an elevated risk of SPBC., Competing Interests: The authors declare no conflicts of interest.

Prostate cancer remains a leading cause of cancer-related death in men. Concurrently, the incidence of metastatic hormone-sensitive prostate cancer (mHSPC) at diagnosis has significantly risen as a result, in part, of recent advances in imaging. Given the increased utilization of prostate-specific membrane antigen-targeted positron emission tomography imaging and other modalities with improved accuracy in the detection of cancer, combined with changes in screening and other secular trends, more men get diagnosed at an oligometastatic stage in which timely treatment may improve survival. However, the optimal timing of initiation and the specific sequence of systemic agents are not yet clearly defined. Worldwide, both urologists and oncologists may primarily direct the medical management of mHSPC. This collaboration potentially invites differing treatment recommendations dependent upon the treating physician's medical specialty. Ideally, a shared decision-making approach incorporating multidisciplinary tumor board discussions and personalized analysis will provide personalized treatment recommendations to optimize the benefit for mHSPC patients. Here, we conducted a concise review and evaluation of existing literature, and provide one perspective on health care delivery for mHSPC worldwide. PATIENT SUMMARY: Given the improvement in imaging techniques and changes in screening practices, the incidence of metastatic hormone-sensitive prostate cancer will likely continue to rise. An early, multimodal treatment approach involving a multidisciplinary team is critical to delivering the best care to this patient population., (Copyright © 2018. Published by Elsevier B.V.)

Background: The role of female sex hormones in the pathogenesis of malignant melanoma (MM) remains controversial. Although melanocytes appear to be hormonally responsive, the effect of estrogen on MM cells is less clear. Available clinical data does not consistently demonstrate that increased endogenous hormones from pregnancy or increased exogenous hormones from oral contraceptive pills and hormone replacement affect MM prevalence and outcome., Objective: We sought to examine potential associations between in vitro fertilization (IVF) and melanoma., Methods: A literature review was conducted. Primary outcomes were reported as associations between IVF and melanoma risk compared with the general population. Secondary outcomes included associations stratified by type of IVF regimen and subgroup, such as parous versus nulliparous patients., Results: Eleven studies met our inclusion criteria. Five studies found no increased risk for MM among IVF users compared with the general population. Two studies found an increase in MM in clomiphene users, and 4 studies found an increase in MM among patients who were gravid or parous either before or after IVF., Conclusion: The reviewed studies do not reveal consistent patterns of association between IVF and MM among all infertile women. However, the data indicates a potential increased risk for MM in ever-parous patients treated with IVF. High-quality studies including a large number of MM cases that control for well-established MM risk factors are needed to adequately assess the relationship between IVF and MM, particularly among ever-parous women., (Copyright © 2018 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Breast cancer is the most common among women in our country, and its treatment is based on prognostic factors to categorize patients into different risk groups. In this study, the clinical and pathological features that play a role as a prognostic factor in a representative population with breast cancer in México are described., Material and Methods: A descriptive analysis of the clinical and pathological features of women diagnosed with breast cancer, in a period from June 2005 to May 2014; registered in a database and calculated by simple frequencies., Results: A total of 4,411 patients were included, the average age at diagnosis was 53 years, 19.7% were diagnosed by mammography screening program and 80.3% derived from any signs or symptoms. Regarding the stages at diagnosis, 6.8% were carcinoma in situ, 36% at early stages (I and IIA), 45% locally advanced (IIB to IIIC), 7.7% metastatic and 3.9% unclassifiable. A 79% were ductal histology, lobular 7.8% and the rest, other types. Of ductal carcinomas, 9.1% were grade I, 54.1% grade II, and 34.6% grade III. Regarding the biological subtypes, 65.7% were luminal, 10.9% luminal Her positive, 8.7% pure Her 2 positive and 14.6% triple negative., Conclusion: In the present study, we described the clinical and pathologic features of a group of Mexican women with breast cancer that might reflect a national landscape, and represent the prognostic factors to determine groups of risk and treatment decisions., (Copyright © 2016 Academia Mexicana de Cirugía A.C. Publicado por Masson Doyma México S.A. All rights reserved.)

Epidemiological studies have reported inconsistent findings for the association between B vitamins and breast cancer (BC) risk. We investigated the relationship between biomarkers of folate and vitamin B12 and the risk of BC in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Plasma concentrations of folate and vitamin B12 were determined in 2,491 BC cases individually matched to 2,521 controls among women who provided baseline blood samples. Multivariable logistic regression models were used to estimate odds ratios by quartiles of either plasma B vitamin. Subgroup analyses by menopausal status, hormone receptor status of breast tumors (estrogen receptor [ER], progesterone receptor [PR] and human epidermal growth factor receptor 2 [HER2]), alcohol intake and MTHFR polymorphisms (677C > T and 1298A > C) were also performed. Plasma levels of folate and vitamin B12 were not significantly associated with the overall risk of BC or by hormone receptor status. A marginally positive association was found between vitamin B12 status and BC risk in women consuming above the median level of alcohol (OR Q4-Q1  = 1.26; 95% CI 1.00-1.58; P trend  = 0.05). Vitamin B12 status was also positively associated with BC risk in women with plasma folate levels below the median value (OR Q4-Q1  = 1.29; 95% CI 1.02-1.62; P trend  = 0.03). Overall, folate and vitamin B12 status was not clearly associated with BC risk in this prospective cohort study. However, potential interactions between vitamin B12 and alcohol or folate on the risk of BC deserve further investigation., (© 2016 UICC.)

Cardiac glycosides are phytoestrogens and have been linked to the risk of estrogen sensitive cancers such as uterus cancer. However, the association between use of cardiac glycosides and risk of breast cancer remains unclear. We investigated the association between cardiac glycosides use and the risk of breast cancer by systematically reviewing the published literature and performing meta-analyses. A comprehensive literature search was performed using MEDLINE, EMBASE, Web of Science and SCOPUS to identify all relevant articles published up to November 2015. Risk estimates, and accompanying standard errors, for the association between cardiac glycoside use and breast cancer were extracted from identified studies. Meta-analysis models were used to calculate a combined hazard ratio (HR), and 95% confidence interval (CI), and to investigate heterogeneity between studies. In total, nine studies were identified investigating cardiac glycosides use and risk of developing breast cancer. Overall, there was evidence to suggest an association between cardiac glycosides use and breast cancer risk (HR = 1.34; 95% CI 1.25, 1.44; p < 0.001) with little variation in the association between studies (I 2  = 16%, p for heterogeneity = 0.30). Results were little altered when analysis was restricted to studies with high quality scores or cohort studies. Overall, there was a 34% increase in breast risk with use of cardiac glycosides but it is unclear whether this association reflects confounding or is causal. Further observational studies are required to examine this association particularly for estrogen receptor positive breast cancer and to explore the role of potential confounding variables., (© 2016 UICC.)

Purpose: Mucinous carcinoma of the breast accounts for 1 to 4% of all breast cancer. There are two histological subtypes: mixed mucinous carcinoma, where the ductal carcinoma is associated with the colloid component, and pure mucinous carcinoma, with a favorable prognosis, where the mucus surrounds the tumour tissue and constitutes a mechanical barrier limiting cell invasion and making this form less aggressive. Our study aimed to determine retrospectively the main epidemiological, clinical, biological, and therapeutic features, as well as the prognosis of this rare form of breast carcinoma., Materials and Methods: The authors report 32 cases of mucinous carcinoma of the breast diagnosed in Mohammed-VI centre for cancer treatment in Casablanca., Results: The average tumour size was 4.5cm (0.5-7cm). We found ten positive lymph node dissections, seven of them were of mixed mucinous carcinoma with a tumour size ranging between 4 and 7cm. Mucinous carcinoma was pure in 16 cases, mixed in 14 and a neuroendocrine differentiation was found in two cases. Most tumours were of an intermediate histological grade (n=19) with positive hormonal receptors (68%). After a mean follow-up of 30 months, complete remission was maintained in 92% of evaluable patients., Conclusion: Mucinous carcinoma is a rare type of breast cancer, with a favourable prognosis for the pure form., (Copyright © 2016 Société française de radiothérapie oncologique (SFRO). Published by Elsevier SAS. All rights reserved.)

Purpose: Comparing gonadotrophin-releasing hormone (GnRH) antagonists and agonists as androgen deprivation therapy for advanced prostate cancer (PC)., Methods: This article stems from a round-table meeting in December 2014 to compare the properties of GnRH agonists and antagonists in the published literature in order to identify the patient groups most likely to benefit from GnRH antagonist therapy. A broad PubMed and congress abstract search was carried out in preparation for the meeting to ensure that the latest data and opinion were available for the discussions., Results: In randomised, controlled trials, GnRH antagonist therapy provides more rapid suppression of luteinising hormone, follicle-stimulating hormone and testosterone than GnRH agonist treatment. Compared with the GnRH agonist, there is evidence of improved disease control by a GnRH antagonist, with longer interval to prostate-specific antigen progression and greater reduction of serum alkaline phosphatase. In a post hoc analysis of six randomised trials, the risk of cardiac events within 1 year of initiating therapy was significantly lower among men receiving GnRH antagonist than agonist. Pre-clinical laboratory data suggest a number of mechanisms whereby GnRH antagonist therapy may benefit men with pre-existing cardiovascular disease (CVD), the most plausible hypothesis being that, unlike GnRH agonists, GnRH antagonists do not activate T lymphocytes, which act to increase atherosclerotic plaque rupture., Conclusion: When making treatment decisions, clinicians should consider comorbidities, particularly CVD, in addition to effects on PC. GnRH antagonists may be appropriate in patients with significant CV risk, existing osteopenia, lower urinary tract symptoms and significant metastatic disease., Competing Interests: None.

Background: Several studies have indicated that reduction of testosterone levels in patients with prostate cancer undergoing androgen deprivation therapy (ADT) with gonadotropin-releasing hormone (GnRH) agonists can be associated with an increased risk of cardiovascular events. The GnRH antagonists have a different mode of action compared with GnRH agonists and may be preferred in ADT for patients with cardiovascular disease., Objective: This review article discusses potential mechanisms underlying the development of cardiovascular events associated with ADT when using GnRH agonists and explains the differences in mode of action between GnRH agonists and GnRH antagonists. Additionally, relevant studies are presented and practical recommendations for the clinical practice are provided., Material and Methods: A literature search was performed. Full publications and abstracts published in the last 10 years up to September 2015 were considered to be eligible., Results: The GnRH antagonists were associated with a decreased risk of cardiovascular events compared with GnRH agonists in prostate cancer patients undergoing ADT and particularly in patients with cardiovascular risk factors or a history of cardiovascular disease. This decrease may be due to the different mode of action of GnRH antagonists compared with GnRH agonists., Conclusion: Prostate cancer patients with either cardiovascular disease or an increased risk of experiencing a cardiovascular event undergoing ADT should be preferentially treated with GnRH antagonists.

Neuroendocrine carcinoma of the breast is an extremely rare tumor. A standard treatment has yet to be established because only a few cases have been reported in literature. The authors report five cases observed from January 2007 to December 2014 and a review of literature. Four patients underwent quadrantectomy and in two cases axillary nodal dissection and only one to mastectomy with axillary nodal dissection. Tumor size was from T1 to T2 with N0 to N1, according TNM classification. Pathological specimens were stained with hematoxylin and eosin and an immunohistochemical panel of antibodies (Neuron-specific enolase, Chromogranin, Synaptophysin, Estrogen and Progesterone receptors, c-erb and Ki-67). All cases showed markers positivity to Neuron-specific enolase, Chromogranin, Synaptophysin and Estrogen and Progesterone receptors were found. Ki-67 was higher than 40% in four patients. Adjuvant chemotherapy was administrated in patients with Ki-67>10%; every patients were treated with radiotherapy and with hormonal therapy too. Although Neuroendocrine breast tumor is considered a distinct entity, the best treatment seems to be correlate to the size of tumor and to the lymph node status and to Ki-67 index like the common breast cancer., Key Words: Diagnosis, Neuroendocrine breast carcinoma.

Background: The controversy surrounding the relationship between testosterone and prostate cancer has existed for decades. The literature surrounding this topic is confusing and at times contradictory. There is no level-one quality evidence that confirms or refutes the relationship between either high or low serum testosterone levels and the subsequent development of prostate cancer. This commentary aims to review the issues involved and to provide an interpretation as to the causes of the confusion and to provide a framework for ongoing discussion and investigation., Materials and Methods: A Medline and PubMed search was conducted using search terms: testosterone levels and prostate cancer to identify pertinent literature., Results: There is no consistent evidence that a single testosterone level is predictive of prostate cancer risk., Conclusion: The development of prostate cancer is a complex biologic process potentially involving genetics,dietary, life style and hormonal factors. Serum testosterone levels do not accurately reflect the internal prostatic milieu. Finally, if testosterone levels are to be considered in the etiology of prostate cancer they should be measured and interpreted on a chronic basis with multiple measurements over a period of years., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Multiple meningiomas (MMs) or meningiomatosis are defined by the presence of at least 2 lesions that appear simultaneously or not, at different intracranial locations, without the association of neurofibromatosis. They present 1-9 % of meningiomas with a female predominance. The occurrence of multiple meningiomas is not clear. There are 2 main hypotheses for their development, one that supports the independent evolution of these tumors and the other, completely opposite, that suggests the propagation of tumor cells of a unique clone transformation, through cerebrospinal fluid. NF2 gene mutation is an important intrinsic risk factor in the etiology of multiple meningiomas and some exogenous risk factors have been suspected but only ionizing radiation exposure has been proven. These tumors can grow anywhere in the skull but they are more frequently observed in supratentorial locations. Their histologic types are similar to unique meningiomas of psammomatous, fibroblastic, meningothelial or transitional type and in most cases are benign tumors. The prognosis of these tumors is eventually good and does not differ from the unique tumors except for the cases of radiation-induced multiple meningiomas, in the context of NF2 or when diagnosed in children where the outcome is less favorable. Each meningioma lesion should be dealt with individually and their multiple character should not justify their resection at all costs., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Breast cancer (BC) is the most common malignant tumor in women, obesity is associated with increased BC incidence and mortality and high levels of circulating insulin may negatively impact on cancer incidence. In the present study, we investigated whether the strength of several anthropometric and metabolic parameters varies between BC molecular subtypes. Eligible cases were 991 non-metastatic BC patients recruited between January 2009 and December 2013. Anthropometric, clinical and immunohistochemical features were measured. Multivariate logistic regression models were built to assess HER2 positive BC risk, comparing (a) triple positive (TP) with luminal A, luminal B and triple negative (TN) and (b) HER2-enriched group with luminal A, luminal B and TN. We stratified patients in pre- and post-menopause: significant differences emerged for luminal A in relation to age: they were more likely to be older compared to other groups. Among postmenopausal patients, the adjusted multivariate analysis showed that high BMI and high waist circumference were inversely correlated to TP subtype when compared to luminal B (OR=0.48 and OR=0.49, respectively). Conversely, HOMA-IR was a risk factor for TP when compared to luminal A and TN (OR=2.47 and OR=3.15, respectively). Our findings suggest a potential role of higher abdominal fat in the development of specific BC molecular subtypes in postmenopausal women. Moreover, they support a potential role of insulin resistance in the development of HER2 positive BC, although this role appears to be stronger when hormone receptors are co-expressed, suggesting a difference in the etiology of these two BC subtypes., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

For the hundreds of thousands of premenopausal women who are diagnosed annually with endocrine-sensitive breast cancer, treatment strategies are complex. For many, chemotherapy may not be necessary, and endocrine therapy decision making is paramount. Options for adjuvant endocrine regimens include tamoxifen for 5 years, tamoxifen for 10 years, ovarian function suppression (OFS) plus tamoxifen for 5 years, and OFS plus an aromatase inhibitor for 5 years. There are modest differences in efficacy between these regimens, with a benefit from OFS most obvious among patients with higher-risk disease; therefore, choosing which should be used for a given patient requires consideration of expected toxicities and patient preferences. An aromatase inhibitor cannot be safely prescribed without OFS in this setting. Additional research is needed to determine whether genomic tests such as Prosigna and Endopredict can help with decision making about optimal duration of endocrine therapy for premenopausal patients. Endocrine therapy side effects can include hot flashes, sexual dysfunction, osteoporosis, and infertility, all of which may impair quality of life and can encourage nonadherence with treatment. Ovarian function suppression worsens menopausal side effects. Hot flashes tend to be worse with tamoxifen/OFS, whereas sexual dysfunction and osteoporosis tend to be worse with aromatase inhibitors/OFS. Pregnancy is safe after endocrine therapy, and some survivors can conceive naturally. Still, embryo or oocyte cryopreservation should be considered at the time of diagnosis for patients with endocrine-sensitive disease who desire future childbearing, particularly if they will undergo chemotherapy.

The Endocrine Society's first Scientific Statement in 2009 provided a wake-up call to the scientific community about how environmental endocrine-disrupting chemicals (EDCs) affect health and disease. Five years later, a substantially larger body of literature has solidified our understanding of plausible mechanisms underlying EDC actions and how exposures in animals and humans-especially during development-may lay the foundations for disease later in life. At this point in history, we have much stronger knowledge about how EDCs alter gene-environment interactions via physiological, cellular, molecular, and epigenetic changes, thereby producing effects in exposed individuals as well as their descendants. Causal links between exposure and manifestation of disease are substantiated by experimental animal models and are consistent with correlative epidemiological data in humans. There are several caveats because differences in how experimental animal work is conducted can lead to difficulties in drawing broad conclusions, and we must continue to be cautious about inferring causality in humans. In this second Scientific Statement, we reviewed the literature on a subset of topics for which the translational evidence is strongest: 1) obesity and diabetes; 2) female reproduction; 3) male reproduction; 4) hormone-sensitive cancers in females; 5) prostate; 6) thyroid; and 7) neurodevelopment and neuroendocrine systems. Our inclusion criteria for studies were those conducted predominantly in the past 5 years deemed to be of high quality based on appropriate negative and positive control groups or populations, adequate sample size and experimental design, and mammalian animal studies with exposure levels in a range that was relevant to humans. We also focused on studies using the developmental origins of health and disease model. No report was excluded based on a positive or negative effect of the EDC exposure. The bulk of the results across the board strengthen the evidence for endocrine health-related actions of EDCs. Based on this much more complete understanding of the endocrine principles by which EDCs act, including nonmonotonic dose-responses, low-dose effects, and developmental vulnerability, these findings can be much better translated to human health. Armed with this information, researchers, physicians, and other healthcare providers can guide regulators and policymakers as they make responsible decisions.

Obesity is associated with a range of health outcomes that are of clinical and public health significance, including cancer. Herein, we summarize epidemiologic and preclinical evidence for an association between obesity and increased risk of breast and prostate cancer incidence and mortality. Moreover, we describe data from observational studies of weight change in humans and from calorie-restriction studies in mouse models that support a potential role for weight loss in counteracting tumor-promoting properties of obesity in breast and prostate cancers. Given that weight loss is challenging to achieve and maintain, we also consider evidence linking treatments for obesity-associated co-morbidities, including metformin, statins and non-steroidal anti-inflammatory drugs, with reduced breast and prostate cancer incidence and mortality. Finally, we highlight several challenges that should be considered when conducting epidemiologic and preclinical research in the area of obesity and cancer, including the measurement of obesity in population-based studies, the timing of obesity and weight change in relation to tumor latency and cancer diagnosis, and the heterogeneous nature of obesity and its associated co-morbidities. Given that obesity is a complex trait, comprised of behavioral, epidemiologic and molecular/metabolic factors, we argue that a transdisciplinary approach is the key to understanding the mechanisms linking obesity and cancer. As such, this review highlights the critical need to integrate evidence from both epidemiologic and preclinical studies to gain insight into both biologic and non-biologic mechanisms contributing to the obesity-cancer link., (© 2015 Society for Endocrinology.)

This Executive Summary to the Endocrine Society's second Scientific Statement on environmental endocrine-disrupting chemicals (EDCs) provides a synthesis of the key points of the complete statement. The full Scientific Statement represents a comprehensive review of the literature on seven topics for which there is strong mechanistic, experimental, animal, and epidemiological evidence for endocrine disruption, namely: obesity and diabetes, female reproduction, male reproduction, hormone-sensitive cancers in females, prostate cancer, thyroid, and neurodevelopment and neuroendocrine systems. EDCs such as bisphenol A, phthalates, pesticides, persistent organic pollutants such as polychlorinated biphenyls, polybrominated diethyl ethers, and dioxins were emphasized because these chemicals had the greatest depth and breadth of available information. The Statement also included thorough coverage of studies of developmental exposures to EDCs, especially in the fetus and infant, because these are critical life stages during which perturbations of hormones can increase the probability of a disease or dysfunction later in life. A conclusion of the Statement is that publications over the past 5 years have led to a much fuller understanding of the endocrine principles by which EDCs act, including nonmonotonic dose-responses, low-dose effects, and developmental vulnerability. These findings will prove useful to researchers, physicians, and other healthcare providers in translating the science of endocrine disruption to improved public health.

Competing Interests: Disclosures: None

Background: Acne reflects hormone imbalance and is a key component of several systemic diseases. We hypothesized that diagnosis of acne as a teenager might predict subsequent risk of hormone-related cancers., Methods: We followed 99,128 female nurses in the Nurses' Health Study II cohort for 20 years (1989-2009) and used Cox proportional hazards models to estimate the hazard ratios (HRs) of 8 specific cancers (breast, thyroid, colorectal, ovarian, cervical, and endometrial cancers, melanoma, and non-Hodgkin lymphoma) for women with a history of severe teenage acne., Results: After thoroughly adjusting for the previously known risk factors for each cancer, we found that among women with a history of severe teenage acne, the relative risk increased, with a multivariable-adjusted HR of 1.44 (95% confidence interval [CI], 1.03-2.01) for melanoma. We replicated this association in an independent melanoma case-control study of 930 cases and 1026 controls (multivariable-adjusted odds ratio, 1.27; 95% CI, 1.03-1.56). We also found that in both studies the individuals with teenage acne were more likely to have moles (52.7% vs 50.1%, P < .001 in the cohort study; and 55.2% vs 45.1%, P = .004 in the case-control study)., Conclusions: Our findings suggest that a history of teenage acne might be a novel risk factor for melanoma independent from the known factors, which supports a need for continued investigation of these relationships., (© 2015 American Cancer Society.)

It recently has been recognized that men develop colonic adenomas and carcinomas at an earlier age and at a higher rate than women. In the Apc(Pirc/+) (Pirc) rat model of early colonic cancer, this sex susceptibility was recapitulated, with male Pirc rats developing twice as many adenomas as females. Analysis of large datasets revealed that the Apc(Min/+) mouse also shows enhanced male susceptibility to adenomagenesis, but only in the colon. In addition, WT mice treated with injections of the carcinogen azoxymethane (AOM) showed increased numbers of colonic adenomas in males. The mechanism underlying these observations was investigated by manipulation of hormonal status. The preponderance of colonic adenomas in the Pirc rat model allowed a statistically significant investigation in vivo of the mechanism of sex hormone action on the development of colonic adenomas. Females depleted of endogenous hormones by ovariectomy did not exhibit a change in prevalence of adenomas, nor was any effect observed with replacement of one or a combination of female hormones. In contrast, depletion of male hormones by orchidectomy (castration) markedly protected the Pirc rat from adenoma development, whereas supplementation with testosterone reversed that effect. These observations were recapitulated in the AOM mouse model. Androgen receptor was undetectable in the colon or adenomas, making it likely that testosterone acts indirectly on the tumor lineage. Our findings suggest that indirect tumor-promoting effects of testosterone likely explain the disparity between the sexes in the development of colonic adenomas.

Aim: Many men diagnosed with localised prostate cancer will eventually be treated with androgen deprivation therapy (ADT). ADT is associated with adverse effects and its timing is controversial. Data on patterns of use are scarce. We describe patterns of ADT use, defined as castration (medical and surgical) or antiandrogen monotherapy initiated after primary treatment, in a population-based cohort., Methods and Materials: Data were extracted from the population-based Prostate Cancer data Base Sweden (PCBaSe). Totally 45,147 men diagnosed between 1997 and 2009 with clinical stage T1-2, N0-NX, M0-MX and prostate specific antigen (PSA)<50ng/ml without primary ADT were included. Outcomes in the period 2006 through 2010 were analysed using a period analysis approach., Results: The cumulative incidence of castration at 10years after diagnosis was 11.6% (95% confidence interval (CI), 11.0-12.2%). The corresponding proportion of antiandrogen monotherapy was 10.8% (95% CI, 10.2-11.4%). Castration was the dominant therapy among men on deferred treatment. The probability of receiving castration rather than antiandrogen monotherapy increased with age. Estimated median durations of castration ranged from 4years in the deferred treatment high-risk group to 17years in the prostatectomy low-risk group. The main limitation was the lack of information on progression to metastatic disease and PSA at the time for initiation of ADT., Conclusion: When initiated early after curative treatment, the duration of castration can be decades. The findings indicate that more accurate tools are necessary to guide which men should be selected for ADT as secondary treatment., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Purpose of Review: Hormonal treatment of transgender people is becoming a normal part of medicine, though numbers of subjects remain small because of low prevalence. Information on treatment is scattered and this review brings together the latest information on treatment goals and potential side-effects of androgen treatment of female-to-male transsexual subjects., Recent Findings: Androgen treatment of female-to-male transsexuals is usually uneventful, with a good patient compliance. Goals of hormonal treatment are elimination of secondary sex characteristics of the female sex and induction of those of the male sex. Completion takes approximately 2 years. Hormonal treatment is eventually followed by surgical ablation of breasts and removal of uterus and ovaries. Phalloplasty may be considered. Concerns are the sequelae of hypogonadism following surgery, such as loss of bone mass. Contrary to earlier expectations, there is no increase in cardiovascular disease. (Hormone-related) cancers are rare, but vaginal, cervical, endometrial carcinomas have been reported. Cancers of the breasts are of greater concern and have been found in residual mammary tissue after breast ablation. So far, androgen treatment has not raised major safety concerns. Regrets about changing sex have not been reported., Summary: Testosterone treatment of female-to-male transsexuals is effective and well tolerated.

Background: Conservative surgery can be regarded as the standard treatment for most early stage breast tumors. However, a minority of patients treated with conservative surgery will present local or locoregional recurrence. Therefore, it is of interest to evaluate the possible factors associated with this recurrence., Methods: A population-based retrospective study using data from the Tumor Registry of Castellón (Valencia, Spain) of patients operated on for primary nonmetastatic breast cancer between January 2000 and December 2008 was designed. Kaplan-Meier curves and log-rank test to estimate 5-year local recurrence were used. Two groups of patients were defined, one with conservative surgery and another with nonconservative surgery. Cox multivariate analysis was conducted., Results: The total number of patients was 410. Average local recurrence was 6.8%. In univariate analysis, only tumor size and lymph node involvement showed significant differences. On multivariate analysis, independent prognostic factors were conservative surgery (hazard ratio [HR] 4.62; 95% confidence interval [CI]: 1.12-16.82), number of positive lymph nodes (HR 1.07; 95% CI: 1.01-1.17) and tumor size (in mm) (HR 1.02; 95% CI: 1.01-1.06)., Conclusions: Local recurrence after breast-conserving surgery is higher in tumors >2 cm. Although tumor size should not be a contraindication for conservative surgery, it should be a risk factor to be considered.

Aims of the Study: Autologous fat graft injection has been systematically used by our team since 2001 in order to enhance the esthetic outcome of breast reconstruction. However, this technique remains controversial, notably in France. This study evaluated oncologic outcomes at 3 years among 110 patients operated on and monitored by two surgeons., Patients and Methods: 116fat graft injections in 110 patients who required reconstructive breast surgery between January 2001 and December 2011 were included in the analysis of oncologic outcomes. The AJCC (American Joint Committee on Staging) stages were: stage 0 (18 %), stage I (44 %), stage II (26.7 %), and stage III (11.3 %). Mean follow-up was 6.3 years (9 months to 17 years) after initial breast cancer surgery, and 3 years (6 months to 9.5 years) after the last lipofilling procedure., Results: The majority of patients (91.8 %) are alive and recurrence-free. Remote metastases occurred in 8.2 % of patients: one patient had a local and systemic recurrence, one patient had a local, regional and systemic recurrence., Conclusion: Although confirmation is needed from multicenter randomized trials with longer follow-up, a larger group of patients and a control group matched for the cancer status of the lipofilling group, our results support the view that lipofilling has little or no effect on the risk of locoregional recurrence of breast cancer.

Purpose: Time and out-of-pocket (OOP) costs can represent a substantial burden for cancer patients but have not been described for long-term cancer survivors. We estimated these costs, their predictors, and their relationship to financial income, among a cohort of long-term prostate cancer (PC) survivors., Methods: A population-based, community-dwelling, geographically diverse sample of long-term (2-13 years) PC survivors in Ontario, Canada, was identified from the Ontario Cancer Registry and contacted through their referring physicians. We obtained data on demographics, health care resource use, and OOP costs through mailed questionnaires and conducted chart reviews to obtain clinical data. We compared mean annual time and OOP costs (2006 Canadian dollars) across clinical and sociodemographic characteristics and examined the association between costs and four groups of predictors (patient, disease, system, symptom) using two-part regression models., Results: Patients' (N = 585) mean age was 73 years; 77 % were retired, and 42 % reported total annual incomes less than $40,000. Overall, mean time costs were $838/year and mean OOP costs were $200/year. Although generally low, total costs represented approximately 10 % of income for lower income patients. No demographic variables were associated with costs. Radical prostatectomy, younger age, poor urinary function, current androgen deprivation therapy, and recent diagnosis were significantly associated with increased likelihood of incurring any costs, but only urinary function significantly affected total amount., Conclusions: Time and OOP costs are modest for most long-term PC survivors but can represent a substantial burden for lower income patients. Even several years after diagnosis, PC-specific treatments and treatment-related dysfunction are associated with increased costs., Implications for Cancer Survivors: Time and out-of-pocket costs are generally manageable for long-term PC survivors but can be a significant burden mainly for lower income patients. The effects of PC-specific, treatment-related dysfunctions on quality of life can also represent sources of expense for patients.

Purpose/objectives: To examine the trajectory of changes in body composition and metabolic profile in men who receive androgen-deprivation therapy (ADT) for prostate cancer., Design: Prospective longitudinal design with repeated measures., Setting: Urban medical center in the southwestern United States., Sample: 55 men starting radiation therapy for prostate cancer., Methods: Changes in the parameters of metabolic syndrome were estimated with ADT (n=31) and non-ADT (n=24) groups by repeated-measures analysis of variance implemented by general linear mixed-effects models. Models included interactions between groups and follow-up time to test differences between the groups., Main Research Variables: Body composition and metabolic variables., Findings: The ADT group demonstrated a transient increase in waist circumference at the nine-month time point and significant changes in measures of insulin resistance were noted at the three month point. Values for diastolic and systolic blood pressure, plasma glucose, high-density lipoprotein, and triglycerides were not altered for either group. Differences in metabolic variables or measures of body composition did not differ significantly between the groups., Conclusions: The findings demonstrate the development of insulin resistance in men receiving ADT as early as three months after starting ADT., Implications for Nursing: Addressing survivorship concerns can lead to the development of nursing interventions designed to reduce adverse effects associated with ADT.

Risk for breast cancer can be easily and rapidly assessed using validated, quantitative models. Multiple randomized studies show that the selective estrogen response modifiers (SERMs) tamoxifen and raloxifene can safely reduce the risk of invasive breast cancer in both pre- and postmenopausal women. Treatment resulted in a 38% reduction in breast cancer incidence, and 42 women would need to be treated to prevent one breast cancer event in the first 10 years of follow-up. Reduction was larger in the first 5 years of follow-up than in years 5 to 10, but no studies treated patients for longer than 5 years. Thromboembolic events were significantly increased with all SERMs, whereas vertebral fractures were reduced. Tamoxifen provides net benefit to all premenopausal women who are at increased risk, whereas raloxifene reduces risk nearly as much in postmenopausal women and offers increased safety. Both tamoxifen and raloxifene reduce the incidence of in situ cancers. Lasofoxifene reduced the risk of breast cancer by 79% in postmenopausal women with osteoporosis. The MAP3 trial showed a 65% reduction in the annual incidence of invasive breast cancer in postmenopausal women who were at moderately increased risk for breast cancer who took the aromatase inhibitor exemestane. The IBIS-II trial showed a 53% reduction in the risk of invasive breast cancer in postmenopausal women aged 40 to 70 who took the aromatase inhibitor anastrozole. Of the 50 million white women in the United States aged 35 to 79, 2.4 million would have a positive benefit/risk index for chemoprevention.

Small, occult, undiagnosed breast cancers are found at autopsy in up to 15.6 % of women dying from unrelated causes with an average of 7 % from eight separate studies. The mammographic detection threshold of breast tumors ranges from 0.88 to 1.66 cm in diameter based on the patient's age. Tumor growth rates, expressed as "effective doubling times," vary from 10 to >700 days. We previously reported two models, based on iterative analysis of these parameters, to describe the biologic behavior of undiagnosed, occult breast tumors. Our models facilitate interpretation of the Women's Health Initiative (WHI) and antiestrogen breast cancer prevention studies. A nude mouse xenograft model was used to validate our assumption that breast tumors grow in a log-linear fashion. We then used our previously reported occult tumor growth (OTG) and computer-simulated tumor growth models to analyze various clinical trial data. Parameters used in the OTG model included a 200-day effective doubling time, 7 % prevalence of occult tumors, and 1.16 cm detection threshold. These models had been validated by comparing predicted with observed incidence of breast cancer in eight different populations of women. Our model suggests that menopausal hormone therapy with estrogens plus a progestogen (E + P) in the WHI trial primarily promoted the growth of pre-existing, occult lesions and minimally initiated de novo tumors. We provide a potential explanation for the lack of an increase in breast cancer incidence in the subgroup of women in the WHI who had not received E + P prior to randomization. This result may have reflected a leftward skew in the distribution of occult tumor doublings and insufficient time for stimulated tumors to reach the detection threshold. Our model predicted that estrogen alone reduced the incidence of breast cancer as a result of apoptosis. Understanding of the biology of occult tumors suggests that breast cancer "prevention" with antiestrogens or aromatase inhibitors represents early treatment rather than a reduction in de novo tumor formation. Our models suggest that occult, undiagnosed tumors are prevalent, grow slowly, and are the biologic targets of a hormone therapy in menopausal women and of antiestrogen therapy for prevention.

Background: Androgen-deprivation therapy (ADT) for prostate cancer (PCa) may be associated with cardiovascular disease and diabetes. Some data suggest that men with certain conditions may be more susceptible to developing cardiovascular disease than others., Objective: To assess whether the risk of myocardial infarction (MI) or diabetes during ADT is modified by specific baseline comorbidities., Design, Setting, and Participants: We conducted a population-based observational study of 185 106 US men ≥66 yr of age diagnosed with local/regional PCa from 1992 to 2007. We assessed comorbidities monthly over the follow-up period., Outcome Measurements and Statistical Analysis: Cox proportional hazards models with time-varying variables assessing incident diabetes or MI., Results and Limitations: A total of 49.9% of the men received ADT during follow-up. Among men with no comorbidities, ADT was associated with an increase in the adjusted hazard of MI (adjusted hazard ratio [AHR]: 1.09; 95% confidence interval [CI], 1.02-1.16) and diabetes (AHR: 1.33; 95% CI, 1.27-1.39). Risks of MI and diabetes were similarly increased among men with and without specific comorbid illnesses (p>0.10 for all interactions, with one exception). Previous MI, congestive heart failure, peripheral arterial disease, stroke, hypertension, chronic obstructive pulmonary disease, and renal disease were associated with new MI and diabetes, and obesity and rheumatologic disease were also associated with diabetes. Limitations include the observational study design, reliance on administrative data to ascertain outcomes, and lack of information on risk factors such as smoking and family history., Conclusions: Traditional risk factors for MI and diabetes were also associated with developing these conditions during ADT but did not significantly modify the risk attributable to ADT. Strategies to screen and prevent diabetes and cardiovascular disease in men with PCa should be similar to the strategies recommended for the general population., (Copyright © 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Bisphenol A (BPA), initially designed, like diethylstilbestrol, as a synthetic estrogen, has been rapidly and widely used for its cross-linking properties in the manufacture of polycarbonate plastics and epoxy resins. Because of incomplete polymerization and degradation of the polymers by exposure to higher than usual temperatures, BPA leaches out from food and beverage containers, as well as from dental sealants. In humans, free active unconjugated BPA is metabolized by rapid glucurono- or sulfo-conjugation and eliminated via renal clearance. However, exposure to environmental nanomolar concentrations of BPA is ubiquitous and continuous via different routes: oral, air, skin. In rodents, fetal and perinatal exposure to such environmentally relevant doses of BPA has been shown to affect the brain, liver, gut, adipose tissue, endocrine pancreas, mammary gland and reproductive tract and function. Similar concentrations are also able in vitro to impact human malignant breast, prostate, male germ or adipocyte cell lines (with a promoting effect and by interfering with chemotherapy drugs), or to stimulate pancreatic β cell insulin secretion. High levels of BPA have recently been correlated with obesity, diabetes, cardiovascular diseases, polycystic ovarian disease or low sperm count. However, before the real impact of BPA on human health can be clearly assessed, prospective longitudinal epidemiological studies are needed as well as characterization of selective biomarkers to verify long-term exposure and selective imprinting., (Copyright © 2013. Published by Elsevier Masson SAS.)

Aim: Up-regulation of caveolin-1 (CAV1) is associated with aggressive prostate cancer. Among Caucasian and African-American patients, plasma CAV1 levels are elevated in patients with castration-resistant prostate cancer (CRPC), but not in those with hormone-sensitive prostate cancer (non-CRPC), which implies that CAV1 could be a therapeutic target for CRPC. Here, we evaluated associations between plasma CAV1 levels and these types of cancer in Japanese men, and CAV1 expression in PC3 (CRPC) and LNCaP (non-CRPC) cell lines., Materials and Methods: Plasma samples were obtained from 58 patients with prostate cancer: 36 with CRPC and 22 with non-CRPC. Enzyme-linked immuno sorbent assay (ELISA) kits were used to determine CAV1 plasma levels; qRT-PCR and western blots were used to evaluate the expression of CAV1 mRNA and protein in cell lines., Results: Plasma CAV1 levels in patients with CRPC were greatly higher than in those with non-CRPC (1.46±1.37 ng/ml in CRPC; 0.56±0.32 ng/ml in non-CRPC, p<0.004). Western blot and real-time qRT-PCR showed CAV1 protein and mRNA in PC3 cells to be significantly overexpressed compared to its expression in LNCaP cells (p<0.0001)., Conclusion: Our results showed a relationship between CAV1 expression and prostate cancer progression, and support the possibility of CAV1 as a therapeutic target for CRPC.

Purpose Population pharmacokinetics (PK) of sepantronium bromide (YM155) was characterized in patients with non-small cell lung cancer, hormone refractory prostate cancer, or unresectable stage III or IV melanoma and enrolled in one of three phase 2 studies conducted in Europe or the U.S. Method Sepantronium was administered as a continuous intravenous infusion (CIVI) at 4.8 mg/m(2)/day over 7 days every 21 days. Population PK analysis was performed using a linear one-compartment model involving total body clearance (CL) and volume of distribution with an inter-individual random effect on CL and a proportional residual errors to describe 578 plasma sepantronium concentrations obtained from a total of 96 patients by NONMEM Version VI. The first-order conditional estimation method with interaction was applied. Results The one-compartment model with one random effect on CL and two different proportional error models provided an adequate description of the data. Creatinine clearance (CLCR), cancer type, and alanine aminotransferase (ALT) were recognized as significant covariates of CL. CLCR was the most influential covariate on sepantronium exposure and predicted to contribute to a 25 % decrease in CL for patients with moderately impaired renal function (CLCR = 40 mL/min) compared to patients with normal CLCR. Cancer type and ALT had a smaller but nonetheless significant contribution. Other patient characteristics such as age, gender, and race were not considered as significant covariates of CL. Conclusions The results provide the important information for optimizing the therapeutic efficacy and minimizing the toxicity for sepantronium in cancer therapy.

Introduction: association of breast cancer and pregnancy is not common. The objective of this investigation was to evaluate the pregnancy, young age, stage, treatment, prognosis and mortality of women with breast cancer during pregnancy., Methods: retrospective analysis from March 1992 to February 2009, 16 patients were included with breast cancer and pregnancy. They were analized: histological characteristic of tumor, therapeutic response of the oncological treatment, evolution of the pregnancy. From of baby born: Apgar and weight. The woman's mortality with breast cancer during pregnancy was evaluated for age group and for interval of time between late pregnancy and diagnosis posterior of breast cancer and pregnancy., Results: characteristic predominant clinicohistological: stage III (81.2%), T3-T4 (75%), N+ 93.7%, invasive ductal carcinoma (87.5%), histological grade 2-3 (93.7%), receptor estrogeno positive (43.7%); RPpositive (25%); HER-2/neu positive (31.2%). 27 chemotherapy cycles were applied with 5-fluorouracil, epirubicin and cyclophosphamide during the second or third trimester of the pregnancy, there were not severe adverse effects for the mothers and the baby born exposed to chemotherapy. The mean time to disease recurrence was 18.8 months (range, 6-62 months). The rate of mortality for specific age (< 35 years) was of 31.3% (p = 0.358). From the 16 patients, 7 have died and 9 were live without evidence of disease., Conclusions: the advanced stage and the number of affected axillary lymph node more than the age was predictors of worse pronostic influencing the relapse and mortality of the young patients with breast cancer and pregnancy.

Polycystic ovary syndrome (PCOS) is a common endocrinopathy affecting women of fertile age. It is associated with several risk factors and long-term health consequences. Chronic anovulation combined with relative estrogen excess and consequent prolonged stimulatory effect on the endometrium can lead to the pathogenesis of hormonal dependant carcinoma. PCOS is thus traditionally reported to be associated with increased risk of endometrial, as well as breast and ovarian cancers. This article provides a critical literature review of the relationship between PCOS and the incidence of estrogen-dependant gynecological tumours, and it then discusses whether the commonly cited risk factor association can be substantiated by high quality studies which comply with the requirements of "evidence-based medicine."

Background: Limited data are available describing the natural history of patients with HER2-positive and hormone receptor (HR)-positive metastatic breast cancer (MBC). We examined first-line treatment patterns and clinical outcomes in patients with HER2-positive, HR-positive MBC in a real-world setting., Methods: registHER is a prospective, observational cohort of 1,023 patients with HER2-positive MBC diagnosed within 6 months of enrollment and followed until death, disenrollment, or June 2009 (median follow-up time: 27 months). Demographics, first-line treatment patterns, and clinical outcomes were examined for 530 HER2-positive, HR-positive patients. Progression-free survival (PFS) and overall survival (OS) times were examined. Multivariate analyses adjusted for baseline demographic and prognostic factors., Results: HER2-positive, HR-positive patients receiving first-line trastuzumab plus hormonal therapy had significantly longer PFS times than patients who received hormonal therapy only (13.8 vs. 4.8 months; adjusted hazard ratio [HR]: 0.37, 95% confidence interval [CI]: 0.22-0.60); a nonsignificant reduction in OS time was observed (adjusted HR: 0.55, 95% CI: 0.27-1.14). Compared with patients who received first-line trastuzumab plus chemotherapy, patients who received first-line trastuzumab plus chemotherapy and hormonal therapy had longer median PFS times (20.4 months vs. 9.5 months; adjusted HR: 0.53, 95% CI: 0.42-0.68); a statistically significant reduction in risk of death was observed (adjusted HR: 0.50, 95% CI: 0.36-0.70). Sequential use of chemotherapy and hormonal therapy was associated with improved OS times when compared with concurrent use (adjusted PFS HR: 0.81, 95% CI: 0.54-1.21; adjusted OS HR: 0.48, 95% CI: 0.26-0.89)., Conclusions: These real-world data in patients with HER2-positive/HR-positive MBC provide evidence that, with or without chemotherapy, dual targeting of HRs and HER2 receptors is associated with significantly prolonged PFS and OS times.

Introduction: Tamoxifen is associated with a twofold increased risk of thromboembolic events. Third generation aromatase inhibitors (AIs), such as letrozole, anastrozole, and exemestane have therefore replaced tamoxifen in the adjuvant therapy of hormone receptor-positive breast cancer. A retrospective review was performed in patients who underwent delayed microvascular breast reconstruction and received tamoxifen at the time of surgery in order to assess the risk of both minor and major flap complications including thromboembolic events., Patients and Methods: Twenty-nine patients who underwent delayed microsurgical breast reconstruction with autologous tissue between 2006 and 2012 were included in the study. The overall complication rates were compared between patients who did versus those who did not receive tamoxifen at the time of microsurgical breast reconstruction., Results: Breast reconstruction was performed with a DIEP flap in 25 patients and with a TRAM flap in 4 patients. Overall, the complication rate was 37.9% (n=11) consisting of 5 major (including one total flap loss) and 6 minor complications. In patients receiving tamoxifen (n=5), we observed one minor complication and one major complication with a total flap loss due to thrombus formation at the anastomosis site. In one patient pulmonary embolism occurred without association to tamoxifen. The number of thromboembolic events was equivalent in both groups (p=0.642). No increase of major (p=0.858) or minor (p=0.967) complications in the tamoxifen group could be observed. Taking the overall complication rate into account there was no statistically difference between the two groups (p=0.917)., Conclusion: In our study we could not observe an increased risk for thromobembolic events in patients receiving tamoxifen while undergoing autologous microvascular breast reconstruction.

Pulmonary lymphangioleiomyomatosis is an uncommon disease of unknown etiology characterized by the proliferation of abnormal smooth muscle cells in the lungs, leading to parenchymal destruction and progressive respiratory failure. The natural history of this disease remains poorly understood, primarily seen in women of childbearing age. The diagnosis can be difficult because symptoms are nonspecific and very similar to other respiratory diseases like asthma, emphysema and bronchitis. Lymphangioleiomyomatosis may not be diagnosed until a pneumothorax, chylothorax, interstitial lung disease or angiomyolipomas are discovered. The recent advances in genetic and molecular research provide new hope to discover the intricate mechanism of disease and evaluate new therapies. Internists, primary care physicians and pulmonologists should be aware of this condition in order to avoid delay in the diagnosis and institute appropriate therapy. The clinical features, pathophysiology, molecular genetics and medical treatment will be reviewed.