Has oncofertility information for male patients improved? Objective assessment of internet-based fertility preservation resources at NCI cancer centers from 2015 to 2020.

PURPOSE: Fertility preservation is a critical patient counseling component following cancer diagnosis. The aim of this study was to compare change and quality of fertility preservation information available to patients on the websites of National Cancer Institute (NCI)-designated cancer centers over 5 years (2015 to 2020) for both women and men. METHODS: All NCI-designated cancer center websites were queried for information on oncofertility in 2020 publicly available to patients using the methodology and rubric previously employed in 2015. Data was evaluated based on each center's city, county, and state by demographic data obtained from the US Census. Additionally, the yearly number of in vitro fertilization (IVF) cycles performed in the city, county, and state of each NCICC was included using websites of clinics reporting data to the Society for Assisted Reproductive Technology. RESULTS: Significantly NCICCs have a standalone pages for fertility preservation in 2020 compared with 2015 (p = 0.004). There is a statistically significant association between discussion of male fertility and the number of fertility centers in the county and state of the NCICC (p = 0.04 and p = 0.001). NCICCs in counties in the highest quartile of per capita income were significantly more likely to address male fertility (p = 0.03). CONCLUSIONS: Oncofertility information on NCICC websites has improved between 2015 and 2020. The impact of cancer treatment on male fertility, while improved, is still limited, particularly in counties with lower per capita income.

Minnelide, a prodrug, inhibits cervical cancer growth by blocking HPV-induced changes in p53 and pRb.

HPV-induced cervical cancer is one of the prevalent gynecological cancers world-wide. In the present study, we determined the efficacy of Minnelide, a prodrug which is converted to its active form (Triptolide) in vivo against cervical cancer cells. Our studies show that Triptolide inhibited HPV-16 and HPV-18 positive cells at nanomolar concentrations. Tumor cells treated with Triptolide failed to grow in 3-D cultures in a concentration-dependent manner. Triptolide markedly reduced E6 and E7 transcript levels. Further studies revealed that exposure to Triptolide increased the levels of p53 and pRb. As a consequence, Caspase-3/7 activation and apoptosis was induced in cervical cancer cells by Triptolide. Subsequently, we evaluated the efficacy of Minnelide in xenotransplantation models of cervical cancer. Minnelide at very low doses effectively inhibited the growth of established cervical cancers in all the three animal models tested. Furthermore, Minnelide treatment was more effective when combined with platinum-based chemotherapy. These studies show that Minnelide can be used to inhibit the growth of cervical cancer.

Asbestos and ovarian cancer: examining the historical evidence.

Asbestos recently returned to the spotlight when Johnson & Johnson halted sales of baby powder due to lawsuits claiming that the talc in baby powder may have been contaminated with asbestos, which has been linked to the risk of ovarian cancer development. Although talc and asbestos have some structural similarities, only asbestos is considered causally associated with ovarian cancer by the WHO's International Agency for Research on Cancer. While it is useful to understand the types and properties of asbestos and its oncologic biology, the history of its association with ovarian cancer is largely based on retrospective observational studies in women working in high asbestos exposure environments. In reviewing the literature, it is critical to understand the distinction between associative risk and causality, and to examine the strength of association in the context of how the diagnosis of ovarian cancer is made and how the disease should be distinguished from a similar appearing but unrelated neoplasm, malignant mesothelioma. Based on contextual misinterpretation of these factors, it is imperative to question the International Agency for Research on Cancer's assertion that asbestos has a clear causal inference to ovarian cancer. This has important clinical implications in the way patients are conceivably counseled and provides motivation to continue research to improve the understanding of the association between asbestos and ovarian cancer.

Exploration of Global Health Careers Across the Medical Fields.

BACKGROUND: Despite expansion of interest among American medical students in global health (GH), academic medical centers face multiple obstacles to the development of structured GH curricula and career guidance. To meet these demands we sought to provide a systematic analysis of the accounts of GH experts. METHODS: We developed a collaborative, interview-based, qualitative analysis of GH experiences across six career-related themes that are relevant to medical students interested in GH: justification, medical education, economics, research prospects, law and ethics, and work-life balance. Seven GH faculty members were interviewed for 30-90 minutes using sample questions as guidelines. We applied a grounded theory approach to analyze the interview transcripts to discover an emerging theory pertinent to GH trainees. FINDINGS: Regarding justification, 4 respondents defined GH as work with the underserved irrespective of geographic location; 5 respondents found sustainability imperative; and all respondents believe GH creates better physicians. Respondents identified many physician competencies developed through GH medical education, with 5 respondents agreeing that work with underserved populations has transformative potential. Concerning economics, 3 respondents acknowledged GH's popularity among trainees, resulting in increased training opportunities, and 2 respondents emphasized an associated deficiency in program quality. All respondents described career models across specialties. Four respondents noted funding challenges when discussing research prospects. Within the theme of laws and ethics, 4 respondents perceived inadequate accountability, and 6 respondents identified ways to create accountability. Finally, 6 respondents recognized family demands can compromise one's GH career and thus work-life balance. CONCLUSION: Despite diverse perspectives on the meaning and sustainability of GH work, this analysis provides a nascent framework that may inform curricular development for GH trainees. Suggestions are offered for elaborating this framework to fully exploit the transformative potential of GH training in medical education.

Superior in vitro and in vivo activity of trastuzumab-emtansine (T-DM1) in comparison to trastuzumab, pertuzumab and their combination in epithelial ovarian carcinoma with high HER2/neu expression.

BACKGROUND: Epithelial ovarian cancer (EOC) remains the most lethal gynecologic malignancy. The objective of this study was to compare the anti-tumor activity of HER2/neu-targeting monoclonal antibodies, trastuzumab (T), pertuzumab (P), combination of trastuzumab and pertuzumab (T+P) and trastuzumab-emtansine (T-DM1) in EOC with high HER2/neu expression. METHODS: Primary EOC cell lines were established and cell blocks were analyzed for HER2/neu expression. Cytostatic, apoptotic and antibody-dependent cell-mediated cytotoxicity (ADCC) activities of T, P, T+P and T-DM1 were evaluated in vitro. The in vivo antitumor activity was tested in xenograft models with 3+ HER2/neu expression. RESULTS: High (3+) HER2/neu expression was detected in 40% of the primary EOC cell lines. T, P, T+P, and T-DM1 were similarly effective in inducing strong ADCC against primary EOC cell lines expressing 3+ HER2/neu. The combination of T and P was more cytostatic when compared with that of T or P used alone (p<0.0001 and p<0.0001, respectively). T-DM1 induced significantly more apoptosis when compared with T+P (p<0.0001). Finally, T-DM1 was significantly more effective in tumor growth inhibition in vivo in EOC xenografts overexpressing HER2/neu when compared to T alone, P alone and T+P (p=0.04). CONCLUSION: In vitro and in vivo experiments with 3+ HER2/neu expressing EOC revealed limited anti-tumor activity of T or P. T-DM1 showed superior anti-tumor activity to T and P as single agents and as a combination. Our preclinical data support the design of clinical studies with T-DM1 for the treatment of chemotherapy-resistant EOC overexpressing HER2/neu.

Dual-Targeting Nanoparticles for In Vivo Delivery of Suicide Genes to Chemotherapy-Resistant Ovarian Cancer Cells.

Ovarian cancer is the most lethal gynecologic cancer. Claudin-3 and -4, the receptors for Clostridium perfringens enterotoxin (CPE), are overexpressed in more than 70% of these tumors. Here, we synthesized and characterized poly(lactic-co-glycolic-acid) (PLGA) nanoparticles (NPs) modified with the carboxy-terminal-binding domain of CPE (c-CPE-NP) for the delivery of suicide gene therapy to chemotherapy-resistant ovarian cancer cells. As a therapeutic payload, we generated a plasmid encoding for the diphtheria toxin subunit-A (DT-A) under the transcriptional control of the p16 promoter, a gene highly differentially expressed in ovarian cancer cells. Flow cytometry and immunofluorescence demonstrated that c-CPE-NPs encapsulating the cytomegalovirus (CMV) GFP plasmid (CMV GFP c-CPE-NP) were significantly more efficient than control NPs modified with a scrambled peptide (CMV GFP scr-NP) in transfecting primary chemotherapy-resistant ovarian tumor cell lines in vitro (P = 0.03). Importantly, c-CPE-NPs encapsulating the p16 DT-A vector (p16 DT-A c-CPE-NP) were significantly more effective than control p16 DT-A scr-NP in inducing ovarian cancer cell death in vitro (% cytotoxicity: mean ± SD = 32.9 ± 0.15 and 7.45 ± 7.93, respectively, P = 0.03). In vivo biodistribution studies demonstrated efficient transfection of tumor cells within 12 hours after intraperitoneal injection of CMV GFP c-CPE-NP in mice harboring chemotherapy-resistant ovarian cancer xenografts. Finally, multiple intraperitoneal injections of p16 DT-A c-CPE-NP resulted in a significant inhibition of tumor growth compared with control NP in chemotherapy-resistant tumor-bearing mice (P = 0.041). p16 DT-A c-CPE-NP may represent a novel dual-targeting therapeutic approach for the selective delivery of gene therapy to chemotherapy-resistant ovarian cancer cells. Mol Cancer Ther; 16(2); 323-33. ©2016 AACR.

Polymerase ε (POLE) ultra-mutation in uterine tumors correlates with T lymphocyte infiltration and increased resistance to platinum-based chemotherapy in vitro.

OBJECTIVE: Up to 12% of all endometrial-carcinomas (EC) harbor DNA-polymerase-ε-(POLE) mutations. It is currently unknown whether the favorable prognosis of POLE-mutated EC is derived from their low metastatic capability, extraordinary number of somatic mutations thus imparting immunogenicity, or a high sensitivity to chemotherapy. METHODS: Polymerase-chain-reaction-amplification and Sanger-sequencing were used to test for POLE exonuclease-domain-mutations (exons 9-14) 131 EC. Infiltration of CD4+ and CD8+ T-lymphocytes (TIL) and PD-1-expression in POLE-mutated vs POLE wild-type EC was studied by immunohistochemistry (IHC) and the correlations between survival and molecular features were investigated. Finally, primary POLE-mutated and POLE-wild-type EC cell lines were established and compared in-vitro for their sensitivity to chemotherapy. RESULTS: Eleven POLE-mutated EC (8.5%) were identified. POLE-mutated tumors were associated with improved progression-free-survival (P<0.05) and displayed increased numbers of CD4+ (44.5 vs 21.8; P=0.001) and CD8+ (32.8 vs 13.5; P<0.001) TILs when compared to wild-type POLE EC. PD-1 receptor was overexpressed in TILs from POLE-mutated vs wild-type-tumors (81% vs 28%; P<0.001). Primary POLE tumor cell lines were significantly more resistant to platinum-chemotherapy in-vitro when compared to POLE-wild-type tumors (P<0.004). CONCLUSIONS: POLE ultra-mutated EC are heavily infiltrated with CD4+/CD8+ TIL, overexpress PD-1 immune-check-point (i.e., features consistent with chronic antigen-exposure), and have a better prognosis when compared to other molecular subtypes of EC patients. POLE-mutated tumor-cell lines are resistant to platinum-chemotherapy in-vitro suggesting that the better prognosis of POLE-patients is not secondary to a higher sensitivity to chemotherapy but likely linked to enhanced immunogenicity.

SYD985, a Novel Duocarmycin-Based HER2-Targeting Antibody-Drug Conjugate, Shows Antitumor Activity in Uterine Serous Carcinoma with HER2/Neu Expression.

Uterine serous carcinoma (USC) is an aggressive form of endometrial cancer. Up to 35% of USC may overexpress the HER2/neu oncogene at strong (i.e., 3+) levels by IHC while an additional 40% to 50% express HER2/neu at moderate (2+) or low (1+) levels. We investigated the efficacy of SYD985, (Synthon Biopharmaceuticals), a novel HER2-targeting antibody-drug conjugate (ADC) composed of the mAb trastuzumab linked to a highly potent DNA-alkylating agent (i.e., duocarmycin) in USC. We also compared the antitumor activity of SYD985 in head-to-head experiments to trastuzumab emtansine (T-DM1), a FDA-approved ADC, against multiple primary USC cell lines expressing different levels of HER2/neu in in vitro and in vivo experiments. Using antibody-dependent cellular cytotoxicity (ADCC), proliferation, viability, and bystander killing assays as well as propidium iodide-based flow cytometry assays and multiple in vivo USC mouse xenograft models, we demonstrate for the first time that SYD985 is a novel ADC with activity against USC with strong (3+) as well as low to moderate (i.e., 1+/2+) HER2/neu expression. SYD985 is 10- to 70-fold more potent than T-DM1 in comparative experiments and, unlike T-DM1, it is active against USC demonstrating moderate/low or heterogeneous HER2/neu expression. Clinical studies with SYD985 in patients harboring chemotherapy-resistant USC with low, moderate, and high HER2 expression are warranted. Mol Cancer Ther; 15(8); 1900-9. ©2016 AACR.

An update on the current pharmacotherapy for endometrial cancer.

INTRODUCTION: Endometrial cancer (EC) is the most common gynecologic malignancy in the developed world and is increasing in incidence. While the mainstay of treatment for EC is surgery followed by chemotherapy and/or radiation therapy, the available pharmacotherapies are rapidly and constantly evolving. Understanding these new therapies is an important part of the research and clinical care of women with EC. A review of available literature from MEDLINE (1879-2015) was conducted for the historic treatments and current therapies available for endometrial tumors. AREAS COVERED: This article reviews the current conventional therapies and discusses novel therapeutic agents, some of which are available to clinicians while others are currently being investigated in the preclinical setting. EXPERT OPINION: Genomic and immunohistochemical characterization of endometrial cancer may soon be the best approach for the identification of aggressive forms of tumor. Targeted therapies will soon be standard in the management of endometrial cancer.

Surgical site infections in gynecology.

IMPORTANCE: Surgical site infections (SSIs) are preventable, yet nearly 2% of all surgical cases are complicated by an SSI. Each SSI increases the cost of a postoperative hospital stay by more than $10,000. Thus, SSI prevention has become the focus of health care systems and hospitals because it is a reducible health care cost. OBJECTIVE: The objective of this review was to better understand the guidelines and recommendations related to the prevention, diagnosis, and management of SSIs. EVIDENCE ACQUISITION: This study is a thorough review of the most up-to-date peer-reviewed articles and review articles as well as guidelines and recommendations of various professional organizations including the US Centers for Disease Control and Prevention and the American College of Obstetrics and Gynecology. RESULTS: A review of the literature has identified several evidence-based recommendations that physicians should adhere to in an effort to decrease the incidence of SSIs. CONCLUSIONS AND RELEVANCE: By adhering to clinical recommendations and evidence, we can correctly prevent, diagnose, and treat SSIs. In turn, this will improve health outcomes and decrease health care-related costs, thus increasing the value of health care that we provide to patients. Furthermore, we can gain improvements in the quality measures used by hospitals and insurers.