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Purpose: Patients with advanced endometrial cancer (EC) who progress on or after platinum-based therapy and immunotherapy have poor prognosis. We report efficacy and safety of sacituzumab govitecan (SG), a trophoblast cell-surface antigen 2 (Trop-2)-directed antibody-drug conjugate, in patients with advanced EC., Methods: TROPiCS-03 (ClinicalTrials.gov identifier: NCT03964727) is a multicohort, open-label, phase II basket study in patients with metastatic solid tumors. Eligible patients in the EC cohort received SG 10 mg/kg once on days 1 and 8 every 3 weeks. Primary end point was objective response rate (ORR) by investigator's assessment per RECIST v1.1. Secondary end points included clinical benefit rate (CBR; complete and partial response, and stable disease ≥6 months), duration of response (DOR), and progression-free survival (PFS) per investigator assessment, overall survival, and safety. Trop-2 expression of archival or baseline tumor specimens was analyzed by immunohistochemistry., Results: At data extraction date, 41 patients were enrolled. Median follow-up was 5.8 months (range, 0.7-19.3); median previous therapies was three (range, 1-6); and 85% of patients received previous chemotherapy and immunotherapy. ORR was 22% (95% CI, 11 to 38); CBR was 32% (95% CI, 18 to 48). Median DOR was 8.8 months (95% CI, 2.8 to not estimable); median PFS was 4.8 months (95% CI, 2.8 to 9.8). Trop-2 exploratory analysis was conducted retrospectively for 39 patients. Tumor Trop-2 protein was highly expressed in EC, showing limited correlation with efficacy. Grade ≥3 treatment-related adverse events (TRAEs) occurred in 73% of patients. Study drug discontinuation due to TRAEs was 5%. Two deaths occurred, deemed unrelated to SG., Conclusion: Findings from TROPiCS-03 showed encouraging efficacy of SG with a manageable toxicity profile in a heavily pretreated population with advanced EC. Safety findings were consistent with the known SG safety profile.

Advanced-stage endometrial and cervical cancers are associated with poor outcomes despite contemporary advances in surgical techniques and therapeutics. Recent clinical trial results have led to a shift in the treatment paradigm for both malignancies, in which immunotherapy is now incorporated as the standard of care up front for most patients with advanced endometrial and cervical cancers as the standard of care. Impressive response rates have been observed, but unfortunately, a subset of patients do not benefit from immunotherapy, and survival remains poor. Continued preclinical research and clinical trial development are crucial for our understanding of resistance mechanisms to immunotherapy and maximization of therapeutic efficacy. In this setting, syngeneic models are preferred over xenograft models as they allow for the evaluation of the tumor-immune interaction in an immunocompetent host, most closely mimicking the tumor-immune interaction in patients with cancer. Unfortunately, significant disparities exist about syngeneic models in gynecologic malignancy, in which queries from multiple large bioscience companies confirm no commercial availability of endometrial or cervical cancer syngeneic cell lines. Published data exist about the recent development of several endometrial and cervical cancer syngeneic cell lines, warranting further investigation. Closing the disparity gap for preclinical models in endometrial and cervical cancers will support physician scientists, basic and translational researchers, and clinical trialists who are dedicated to improving outcomes for our patients with advanced disease and poor prognosis., (©2024 American Association for Cancer Research.)

Based on findings from The Cancer Genome Atlas and the Proactive Molecular Risk Classifier for Endometrial Cancer algorithm, endometrial carcinoma can now be stratified into 4 prognostically distinct subgroups based on molecular alterations and immunohistochemical (IHC) aberrations. In this study, we describe the de novo adoption and clinical reporting of prognostic subgroup classification based on next-generation sequencing (NGS) and IHC analyses of all endometrial carcinoma resections at a single institution, framed by the Exploration, Preparation, Implementation, and Sustainment model. Results from the first 13 months show 188 tumors underwent analysis by a combination of IHC and a medium-sized (56 analyzed genes) NGS-based assay. All cases were assigned as either POLE ( POLE -mutated) (5.3%), mismatch repair deficient (27.7%), no specific molecular profile (45.7%), or p53 abnormal (21.3%) inclusive of multiple-classifier cases. NGS-based analysis revealed additional distinctions among the subgroups, including reduced levels of PI3K pathway activation in the p53 abnormal subgroup, an increased rate of CTNNB1 activating mutation in the no specific molecular profile subgroup, and lower TP53 mutation variant allele frequencies in POLE and mismatch repair deficient subgroups compared with the p53 abnormal subgroup. Overall, we describe the testing protocol, reporting, and results of a combination of NGS and IHC to prospectively prognosticate endometrial carcinomas at a single tertiary care center., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 by the International Society of Gynecological Pathologists.)

Objectives: The phase 2, multicohort, open-label LEAP-005 study evaluated lenvatinib plus pembrolizumab in patients with previously treated advanced solid tumors. We report outcomes from the ovarian cancer cohort., Methods: Eligible patients had metastatic/unresectable ovarian cancer and had received 3 previous lines of therapy. Patients received lenvatinib 20 mg/day plus pembrolizumab 200 mg every 3 weeks. Treatment continued until progression, unacceptable toxicity, or (for pembrolizumab) completion of 35 cycles. Primary endpoints were objective response rate (ORR) per RECIST version 1.1 and safety. Secondary endpoints included duration of response (DOR), progression-free survival (PFS), and overall survival (OS)., Results: Thirty-one patients were enrolled. 39% had high grade serous ovarian cancer, 23% were platinum-sensitive, 55% were platinum-resistant, 23% were platinum-refractory, and 84% had tumors that had a PD-L1 combined positive (CPS) score ≥1. ORR (95% CI) was 26% (12%-45%) by investigator assessment and 35% (19%-55%) by blinded independent central review (BICR). Per BICR, median DOR was 9.2 (1.5+ to 37.8+) months. ORRs (95% CI) by BICR were 35% (9/26 patients; 17%-56%) for PD-L1 CPS ≥ 1 disease and 50% (2/4 patients; 7%-93%) for PD-L1 CPS < 1 disease. Median (95% CI) PFS by BICR and OS were 6.2 (4.0-8.5) months and 21.3 (11.7-32.3) months, respectively. Treatment-related AEs occurred in 94% of patients (grade 3-4, 77%). One patient died from treatment-related hypovolemic shock., Conclusions: Lenvatinib plus pembrolizumab demonstrated antitumor activity as fourth line therapy in patients with advanced ovarian cancer, and no unanticipated safety signals were identified. Responses were observed regardless of PD-L1 status., (Copyright © 2024 Merck Sharp & Dohme LLC., a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: This study further evaluated the safety and efficacy of the combination of alisertib and sapanisertib in an expansion cohort of patients, including a subset of patients with refractory pancreatic adenocarcinoma, with further evaluation of the pharmacodynamic characteristics of combination therapy., Methods: Twenty patients with refractory solid tumors and 11 patients with pancreatic adenocarcinoma were treated at the recommended phase 2 dose of alisertib and sapanisertib. Adverse events and disease response were assessed. Patients in the expansion cohort were treated with a 7-day lead-in of either alisertib or sapanisertib prior to combination therapy, with tumor tissue biopsy and serial functional imaging performed for correlative analysis., Results: Toxicity across treatment groups was overall similar to prior studies. One partial response to treatment was observed in a patient with ER positive breast cancer, and a patient with pancreatic cancer experienced prolonged stable disease. In an additional cohort of pancreatic cancer patients, treatment response was modest. Correlative analysis revealed variability in markers of apoptosis and immune cell infiltrate according to lead-in therapy and response., Conclusions: Dual targeting of Aurora A kinase and mTOR resulted in marginal clinical benefit in a population of patients with refractory solid tumors, including pancreatic adenocarcinoma, though individual patients experienced significant response to therapy. Correlatives indicate apoptotic response and tumor immune cell infiltrate may affect clinical outcomes.

High-grade serous carcinoma (HGSC) of the fallopian tube, ovary, and peritoneum is the most common type of ovarian cancer and is predicted to be immunogenic because the presence of tumor-infiltrating lymphocytes conveys a better prognosis. However, the efficacy of immunotherapies has been limited because of the immune-suppressed tumor microenvironment (TME). Tumor metabolism and immune-suppressive metabolites directly affect immune cell function through the depletion of nutrients and activation of immune-suppressive transcriptional programs. Tryptophan (TRP) catabolism is a contributor to HGSC disease progression. Two structurally distinct rate-limiting TRP catabolizing enzymes, indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase 2 (TDO2), evolved separately to catabolize TRP. IDO1/TDO2 are aberrantly expressed in carcinomas and metabolize TRP into the immune-suppressive metabolite kynurenine (KYN), which can engage the aryl hydrocarbon receptor to drive immunosuppressive transcriptional programs. To date, IDO inhibitors tested in clinical trials have had limited efficacy, but those inhibitors did not target TDO2, and we find that HGSC cell lines and clinical outcomes are more dependent on TDO2 than IDO1. To identify inflammatory HGSC cancers with poor prognosis, we stratified patient ascites samples by IL6 status, which correlates with poor prognosis. Metabolomics revealed that IL6-high patient samples had enriched KYN. TDO2 knockdown significantly inhibited HGSC growth and TRP catabolism. The orally available dual IDO1/TDO2 inhibitor, AT-0174, significantly inhibited tumor progression, reduced tumor-associated macrophages, and reduced expression of immune-suppressive proteins on immune and tumor cells. These studies demonstrate the importance of TDO2 and the therapeutic potential of AT-0174 to overcome an immune-suppressed TME., Significance: Developing strategies to improve response to chemotherapy is essential to extending disease-free intervals for patients with HGSC of the fallopian tube, ovary, and peritoneum. In this article, we demonstrate that targeting TRP catabolism, particularly with dual inhibition of TDO2 and IDO1, attenuates the immune-suppressive microenvironment and, when combined with chemotherapy, extends survival compared with chemotherapy alone., (© 2024 The Authors; Published by the American Association for Cancer Research.)

Wnt ligand WNT4 is critical in female reproductive tissue development, with WNT4 dysregulation linked to related pathologies including breast cancer (invasive lobular carcinoma, ILC) and gynecologic cancers. WNT4 signaling in these contexts is distinct from canonical Wnt signaling yet inadequately understood. We previously identified atypical intracellular activity of WNT4 (independent of Wnt secretion) regulating mitochondrial function, and herein examine intracellular functions of WNT4. We further examine how convergent mechanisms of WNT4 dysregulation impact cancer metabolism. In ILC, WNT4 is co-opted by estrogen receptor α (ER) via genomic binding in WNT4 intron 1, while in gynecologic cancers, a common genetic polymorphism (rs3820282) at this ER binding site alters WNT4 regulation. Using proximity biotinylation (BioID), we show canonical Wnt ligand WNT3A is trafficked for secretion, but WNT4 is localized to the cytosol and mitochondria. We identified DHRS2, mTOR, and STAT1 as putative WNT4 cytosolic/mitochondrial signaling partners. Whole metabolite profiling, and integrated transcriptomic data, support that WNT4 mediates metabolic reprogramming via fatty acid and amino acid metabolism. Furthermore, ovarian cancer cell lines with rs3820282 variant genotype are WNT4 dependent and have active WNT4 metabolic signaling. In protein array analyses of a cohort of 103 human gynecologic tumors enriched for patient diversity, germline rs3820282 genotype is associated with metabolic remodeling. Variant genotype tumors show increased AMPK activation and downstream signaling, with the highest AMPK signaling activity in variant genotype tumors from non-White patients. Taken together, atypical intracellular WNT4 signaling, in part via genetic dysregulation, regulates the distinct metabolic phenotypes of ILC and gynecologic cancers., Significance: WNT4 regulates breast and gynecologic cancer metabolism via a previously unappreciated intracellular signaling mechanism at the mitochondria, with WNT4 mediating metabolic remodeling. Understanding WNT4 dysregulation by estrogen and genetic polymorphism offers new opportunities for defining tumor biology, precision therapeutics, and personalized cancer risk assessment., (© 2024 The Authors; Published by the American Association for Cancer Research.)

(1) Background: Histone deacetylases (HDACs) play a critical role in epigenetic signaling in cancer; however, available HDAC inhibitors have limited therapeutic windows and suboptimal pharmacokinetics (PK). This first-in-human phase I dose escalation study evaluated the safety, PK, pharmacodynamics (PDx), and efficacy of the oral Class I-targeting HDAC inhibitor bocodepsin (OKI-179). (2) Patients and Methods: Patients ( n = 34) with advanced solid tumors were treated with OKI-179 orally once daily in three schedules: 4 days on 3 days off (4:3), 5 days on 2 days off (5:2), or continuous in 21-day cycles until disease progression or unacceptable toxicity. Single-patient escalation cohorts followed a standard 3 + 3 design. (3) Results: The mean duration of treatment was 81.2 (range 11-447) days. The most frequent adverse events in all patients were nausea (70.6%), fatigue (47.1%), and thrombocytopenia (41.2%). The maximum tolerated dose (MTD) of OKI-179 was 450 mg with 4:3 and 200 mg with continuous dosing. Dose-limiting toxicities included decreased platelet count and nausea. Prolonged disease control was observed, including two patients with platinum-resistant ovarian cancer. Systemic exposure to the active metabolite exceeded the preclinical efficacy threshold at doses lower than the MTD and was temporally associated with increased histone acetylation in circulating T cells. (4) Conclusions: OKI-179 has a manageable safety profile at the recommended phase 2 dose (RP2D) of 300 mg daily on a 4:3 schedule with prophylactic oral antiemetics. OKI-179 is currently being investigated with the MEK inhibitor binimetinib in patients with NRAS-mutated melanoma in the phase 2 Nautilus trial.

Objective: This multi-center cohort study assessed associations between race, TP53 mutations, p53 expression, and histology to investigate racial survival disparities in endometrial cancer (EC)., Methods: Black and White patients with advanced or recurrent EC with Next Generation Sequencing data in the Endometrial Cancer Molecularly Targeted Therapy Consortium database were identified. Clinicopathologic and treatment variables were summarized by race and compared. Overall survival (OS) and progression-free survival (PFS) among all patients were estimated by the Kaplan-Meier method. Cox proportional hazards models estimated the association between race, TP53 status, p53 expression, histology, and survival outcomes., Results: Black patients were more likely than White patients to have TP53-mutated (N = 727, 71.7% vs 49.7%, p < 0.001) and p53-abnormal (N = 362, 71.1% vs 53.2%, p = 0.003) EC. Patients with TP53-mutated EC had worse PFS (HR 2.73 (95% CI 1.88-3.97)) and OS (HR 2.20 (95% CI 1.77-2.74)) compared to those with TP53-wildtype EC. Patients with p53-abnormal EC had worse PFS (HR 2.01 (95% CI 1.22-3.32)) and OS (HR 1.61 (95% CI 1.18-2.19)) compared to those with p53-wildtype EC. After adjusting for TP53 mutation and p53 expression, race was not associated with survival outcomes. The most frequent TP53 variants were at nucleotide positions R273 (n = 54), R248 (n = 38), and R175 (n = 23), rates of which did not differ by race., Conclusions: Black patients are more likely to have TP53-mutated and p53-abnormal EC, which are associated with worse survival outcomes than TP53- and p53-wildtype EC. The higher frequency of these subtypes among Black patients may contribute to survival disparities., Competing Interests: Declaration of Competing Interest Dr. Alvarez Secord discloses that her institution has received clinical trial grant funding from AbbVie, Aravive, Astra Zeneca,Clovis, Eisai, Ellipses Pharma, Tesaro/GSK, I-MAB Biopharma, Immunogen, Merck, OncoQuest, Roche/Genentech, Seagen Inc., VBL Therapeutics, and National Cancer Trial Network to support her effort. She has participated in Advisory Boards (all uncompensated) for AbbVie, Aravive, AstraZeneca, Clovis, GSK/Tesaro, Immunogen, Imvax, Merck, Mersana, Natera, Onconova, OncoQuest, and Regeneron; and Clinical Trial Steering Committees (all uncompensated) for the AXLerate trial (Aravive), AtTEnd trial (Hoffman-LaRoche), Oval Trial (VBL Therapeutics), FLORA-5 trial (CanariaBio), and QPT-ORE-004 (CanariaBio) within the past 36 months. Dr. Strickland discloses he has received consulting fees from Foundation Medicine, Inc., Almac Pharmaceuticals, and Oncoquest Pharmaceuticals. He has received stock or stock options from LapCorp and has other financial interests in LabCorp. Dr. Pothuri discloses she has received research funding from Tesaro/GSK, Clovis Oncology, Merck, Genentech, AstraZeneca, Mersana, Karyopharm, Celsion, Sutro, Takeda, Immunogen, Incyte, Seagen, Toray, VBL Therapeutics, and Onconova. She has received consulting fees from Tesaro/GSK, Merck, AstraZeneca, Eli Lilly, Sutro, Seattle Genetics, Eisai, Natera, and GOG Partners. She has received speaker fees from PeerView and OncLive. She has participated in Advisory Boards for Tesaro/GSK, Eli Lily, Merck, Seattle Genetics, Eisai, AstraZeneca, and GOG Foundation. Dr. Bae-Jump discloses she has received research grant funding from Chimerix, Genentech, Merck, and Epirium. She has received consulting or advisory fees from Eisai. Dr. Thaker discloses her institution has received research grant funding from Merck and GSK. She has participated in advisory boards for GSK, Clovis Oncology, Astra Zeneca, Seagen, Mersana, Immunogen, Verastem, Immunon, Aadi Pharmaceuticals, R-Pharm, Merck, and Novocure. She has participated in data safety monitoring boards (uncompensated) for Iovance, Novocure, and Immunon. Dr. Arend discloses she has consulting or advisory role at Merck, Seagen, Sutro, GSK, VBL Therapeutics, Kiyatec; and research support from Immunogen, GSK, GOG Foundation, Champions Oncology, Exelixis, and Merck. Dr. Ko discloses she has received research grants from the Foundation for Women's Cancer, Feath Therapeutics, National Institutes of Health, National Cancer Institute, Penn Optum Labs, Department of Health and Human Services, and the Winn Bristow Meyers Squibb Diversity in Clinical Trials Award. She serves as a Society of Gynecologic Oncology committee chair. Dr. Jackson discloses she has received speaker fees from OncLive and served as a consultant to Ethicon. She has participated in Advisory Boards for AstraZeneca, Seagen, and Sutro. Dr. Corr discloses he has received research support from Clovis and Immunogen. He has participated in Advisory Boards for GSK, Gilead, Immunogen, Zentalis, Merck, and Imvax. Dr. Wright discloses his institution has received research grant funding from Merck. He received royalties from UpToDate and payment for expert testimony from Medicolegal Consulting Gynecologic Cancer. He serves as a journal editor for American College of Obstetricians and Gynecologists. Dr. Lightfoot discloses she has participated in an Advisory Board for GSK. Dr. Washington discloses she has received the Robert A Winn Career Development Award and ACS iRG URM Grant to support her research. She has received payment for her Great Debates presentation and support for travel from the NRG New Investigator Award. Dr. Herzog discloses he has received consulting fees from AstraZeneca, Caris, Clovis, Eisai, Epsilogen, Genelux, Genentech, GSK, Immunogen, Johnson & Johnson, Merck, Mersana, and Seagen. He has received travel support from Alkermes. He has served an Advisory Board for Corcept and in a leadership role for GOG Foundation. Dr. Salani discloses she has received speaker fees from Merck, Seagen, Regeneron, Eisai, Immunogen, and Mersana. She has received royalties or licensing fees from UpToDate. She serves on the International Gynecologic Cancer Society Executive Committee. Ms. Whelan, Ms. Dillon, Ms. Thomas, Mr. Smitherman, Ms. Powell, and Drs. Haight, Harsono, Ayoola-Adeola, Cosgrove, Newton, Podwika, and Borden have no conflicts of interest., (Copyright © 2023. Published by Elsevier Inc.)

CTNNB1 mutations convey increased risk of recurrence in low-risk endometrial endometrioid carcinoma (EEC). Results from previous high-intermediate risk (HIR) cohorts are mixed. The aims of this study were to correlate CTNNB1 mutational status with clinical outcomes and to evaluate the relationship between CTNNB1 mutations and the 4 prognostic subgroups defined by The Cancer Genome Atlas in HIR EEC. CTNNB1 mutational status was determined by Sanger sequencing of exon 3 of the CTNNB1 gene. Mismatch repair, POLE , p53, and L1 cell-adhesion molecule (L1CAM) status were also evaluated. Descriptive statistics and survival analyses were performed. Eighty-eight cases of HIR EEC were identified, of which 22 (25%) were CTNNB1 mutant ( CTNNB1 -mut) and 66 (75%) were wild-type ( CTNNB1 -WT). Median follow-up was 60 mo. Recurrence occurred in 13/88 (15%) patients. Recurrence rates were not significantly different between patients with CTNNB1- mut and CTNNB1- WT tumors (14% vs. 15%, P =0.86). Recurrence-free survival and overall survival were not significantly different (recurrence-free survival hazard ratio: 0.97, 95% confidence interval: 0.27-3.52, P =0.96; overall survival hazard ratio: 0.23, 95% confidence interval: 0.03-1.71, P =0.15). Mismatch repair deficiency was more prevalent in CTNNB1 -WT compared with CTNNB1 -mut tumors (46% vs. 14%, P =0.01); prevalence of POLE mutations and aberrant p53 were not significantly different. In contrast to patients with low-risk EEC, no differences in recurrence or survival were found in patients with HIR EEC with CTNNB1- mut compared with CTNNB1 -WT tumors., Competing Interests: B.R.C. receives research support from Clovis and is on advisory boards for GSK, Merck, Astrazeneca, and Novocure. The remaining authors declare no conflict of interest., (Copyright © 2022 by the International Society of Gynecological Pathologists.)

Purpose: This phase Ib study evaluated the safety and efficacy of paclitaxel plus navicixizumab, a bispecific antiangiogenic antibody to vascular endothelial growth factor and delta-like ligand 4, against platinum-resistant ovarian cancer., Patients and Methods: This open-label, nonrandomized, dose-escalation and -expansion study included 44 patients with previously treated, recurrent, platinum-resistant grade 2/3 ovarian cancer. Treatment was intravenous navicixizumab (3 mg/kg or 4 mg/kg once every 2 weeks) plus paclitaxel (80 mg/m 2 intravenously on days 0, 7, and 14 of 28-day cycles). The primary and secondary objectives were to evaluate the safety and efficacy of navicixizumab plus paclitaxel. An RNA-based diagnostic panel was retrospectively used to test the hypothesis that tumors with high angiogenesis or immune-suppressed tumor microenvironment (TME) subtypes (biomarker-positive) are more likely to respond to navicixizumab than those with immune-active/-desert TME subtypes (biomarker-negative). RNA expression was analyzed in available pretreatment tumor tissue to classify 33 patients' TME subtypes, and TME panel findings were correlated with tumor response., Results: The dose-escalation cohorts enrolled patients at navicixizumab doses of 3 mg/kg once every 2 weeks (n = 3) and 4 mg/kg once every 2 weeks (n = 2); 3 mg/kg was selected for expansion (n = 39). No dose-limiting toxicities occurred. The most common grade 3/4 treatment-related adverse events were hypertension (40.9%), neutropenia (6.8%), and thrombocytopenia (4.5%). Pulmonary hypertension occurred in 18.2% (grade 1-2). The overall objective response rate was 43.2% (95% CI, 28.3 to 59.0): 33.3% (95% CI, 17.3 to 52.8) in patients previously treated with bevacizumab, 64.3% (95% CI, 35.1 to 87.2) in bevacizumab-naive patients, and 62% (95% CI, 31.6 to 86.1) in biomarker-positive patients. The median duration of response was 6 months (95% CI, 5.4 months to not estimable)., Conclusion: Navicixizumab plus paclitaxel demonstrated promising clinical activity in bevacizumab-treated and -naive patients with platinum-resistant ovarian cancer, with manageable toxicity.

The COVID-19 pandemic has left many individuals suffering from "connection deficit disorder" given changes to the way we work, go to school, socialize, and engage in daily activities. Young adults affected by cancer between the ages of 18-39 have known this connection deficit long before the pandemic. Being diagnosed and treated for cancer during this time can significantly disrupt engagement in important educational, career, social, and reproductive pursuits, and contribute to increased stress, anxiety, depression, and other negative outcomes. Experiencing meaningful connection-with nature, with peers who understand, and with oneself, may help assuage this adverse effect of disconnect. A single arm within-subjects program evaluation was conducted to examine outcomes following participation in immersive, multi-night, mindfulness-based treks in nature in a sample of young adults ( n = 157) and caregivers ( n = 50) affected by cancer from 2016-2021. Pre to post-trek changes included significant ( p < 0.001) self-reported improvements in feeling connected to nature (d = 0.93-0.95), peers (d = 1.1-1.3), and oneself (d = 0.57-1.5); significant ( p < 0.001) improvements on PROMIS Anxiety (d = 0.62-0.78), Depression (d = 0.87-0.89), and Sleep Disturbance (d = 0.37-0.48) short forms; and significant ( p < 0.05) changes in pro-inflammatory biomarkers (d = 0.55-0.82). Connection-promoting experiences like this have the potential to improve health and wellbeing in this population and serve as a model for others.

The role of β-catenin/TCF transcriptional activity in endometrial cancer (EC) recurrence is not well understood. We assessed the impact of Wnt/β-catenin inhibition in EC models. In an analysis of the Cancer Genome Atlas, we confirmed that CTNNB1 mutations are enriched in recurrent low-risk EC and showed that aberrant Wnt/β-catenin pathway activation is associated with recurrence. We studied CTNNB1-wildtype (HEC1B, Ishikawa) and CTNNB1-mutant (HEC108, HEC265, HEC1B-S33Y, Ishikawa-S33Y) EC cell lines. Dose response curves were determined for 5 Wnt/β-catenin pathway inhibitors (Wnt-C59, XAV-939, PyrPam, PRI-724, SM04690). XAV939, Wnt-C59 and PyrPam inhibited function upstream of β-catenin transcriptional activity and were ineffective at inhibiting cell viability. In contrast, PRI724 and SM04690 indirectly inhibited β-catenin transcriptional activity and significantly reduced cell viability in CTNNB1-mutant cell lines. Treatment with SM04690 reduced cell viability (Licor Cell stain) in all EC cell lines, but viability was significantly lower in CTNNB1-mutant cell lines (p < 0.01). Mechanistically, SM04690 significantly inhibited proliferation measured via 5'-bromo-2'-deoxyuridine incorporation and reduced T cell factor (TCF) transcriptional activity. HEC1B, HEC1B-S33Y and HEC265 tumor-bearing mice were treated with vehicle or SM04690. Tumors treated with SM04690 had smaller mean volumes than those treated with vehicle (p < 0.001, p = 0.014, p = 0.06). In HEC1B-S33Y and HEC265 tumors, SM04690 treatment significantly reduced Ki67 H-scores compared to vehicle (p = 0.035, p = 0.024). Targeting the Wnt/β-catenin pathway in CTNNB1-mutant EC effectively inhibited proliferation and β-catenin/TCF transcriptional activity and blunted tumor progression in in vivo models. These studies suggest β-catenin transcriptional inhibitors are effective in EC and particularly in CTNNB1-mutant EC, highlighting a potential therapeutic vulnerability for treatment of CTNNB1-mutant EC., (© 2021 Wiley Periodicals LLC.)

Background: Patients with ovarian cancer who are enrolled on phase 1 trials typically have platinum-resistant and heavily pretreated disease, with a poor prognosis. In the current study, the authors assessed prognostic factors and survival in women with recurrent ovarian cancer who were treated on phase 1 clinical trials., Methods: The authors performed a retrospective analysis of patients treated from 2008 through 2018 at the University of Colorado Cancer Center. Patient characteristics and treatment and toxicity-related survival data were assessed. Descriptive statistics and Cox proportional hazards models were used to identify risk factors associated with survival time., Results: A total of 132 patients were treated on phase 1 clinical trials. Patients had a median age of 59 years (range, 33-88 years) with a median of 5.5 previous chemotherapy lines (range, 1-13 lines). Of the 132 patients, 53 (40%) were treated on multiple phase 1 trials with a median of 1 (range, 0-5) prior phase 1 trial. The overall response rate was 14.7%. The median overall survival was 11.3 months (95% CI, 9.1-13.4 months). Two patients died on trial due to progression of disease whereas no patients died of treatment-related toxicity. Independent risk factors found to be predictive of shorter survival were an elevated cancer antigen 125 (CA 125) level (hazard ratio [HR], 2.8; 95% CI, 1.6-5.2) and albumin <3.5 g/dL (HR, 2.5; 95% CI, 1.65-3.79). A body mass index >25 kg/m 2 was predictive of longer survival (HR, 0.65; 95% CI, 0.44-0.96)., Conclusions: In the current single-institution series, patients with heavily pretreated ovarian cancer who were treated on phase 1 clinical trials experienced a median overall survival of 11.3 months. When available, phase 1 clinical trials represent a reasonable treatment option for patients with heavily pretreated ovarian cancer with a preserved performance status., (© 2020 American Cancer Society.)

Background: There are limited treatment options for patients with metastatic or recurrent cervical cancer. Platinum-based chemotherapy plus the anti-vascular endothelial growth factor antibody bevacizumab remains the mainstay of advanced treatment. Pembrolizumab is Food and Drug Agency approved for programmed death ligand 1 (PD-L1) positive cervical cancer with a modest response rate. This is the first study to report the efficacy and safety of the PD-L1 antibody atezolizumab in combination with bevacizumab in advanced cervical cancer., Methods: We report the results from a phase II, open-label, multicenter study (NCT02921269). Patients with advanced cervical cancer were treated with bevacizumab 15 mg/kg intravenous every 3 weeks and atezolizumab 1200 mg intravenous every 3 weeks. The primary objective was to measure the objective response rate (ORR). Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety., Results: In the total evaluable population (n=10), zero patients achieved an objective response as assessed by Response Evaluation Criteria In Solid Tumors (RECIST) V.1.1, resulting in a confirmed ORR of 0%. Of note, there were two patients who achieved an unconfirmed PR. The DCR by RECIST V.1.1 was 60% (0% complete response, 0% partial response, 60% stable disease). Median PFS was 2.9 months (95% CI, 1.8 to 6) and median OS was 8.9 months (95% CI, 3.4 to 21.9). Safety results were generally consistent with the known safety profile of both drugs, notably with two high-grade neurologic events., Conclusions: The combination of bevacizumab and atezolizumab did not meet the predefined efficacy endpoint, as addition of bevacizumab to PD-L1 blockade did not appear to enhance the ORR in cervical cancer., Competing Interests: Competing interests: DZ reports clinical research support to his institution from Astra Zeneca and Genentech; personal/consultancy fees from Merck, Synlogic Therapeutics, Biomed Valley Discoveries, Trieza Therapeutics, Tesaro, Bristol Myers Squibb, and Agenus; and travel support from Genenetech. These are all outside of the scope of the submitted work. CF reports clinical research support to her institution from Merck, Bristol Myers Squibb and Genentech; personal/consultancy fees from Astra Zeneca, as well as participation in steering committees (compensation waived) for Merck and Genentech. These are outside the scope of the submitted work. AS reports that she is now an employee of Merck and declares Merck stock ownership. ABM reports no conflicts of interest. SF reports clinical research support to his institution from the following: AstraZeneca; Abbisko; Anaeropharma Science; Arrien Pharmaceuticals; BeiGene; BioAtla, LLC; Boehringer Ingelheim; Eli Lilly & Co; Hookipa Biotech GmBH; Huya Bioscience International; IMV, Inc; Innovent Biologics, Co, Ltd; Lyvgen Biopharm, Co, Ltd; MacroGenics; Medivir AB; Millennium Pharmaceuticals, Inc; Nerviano Medical Sciences; NeuPharma, Inc; NIH/NCI; Novartis; OncoMed Pharmaceuticals; Parexel International, LLC; Sellas Life Sciences Group; Soricimed Biopharma, Inc; Tolero Pharmaceuticals. BC reports advisory committees for GSK, Novocure, and Merck. He reports research funding from Clovis. These are all outside the scope of the submitted work. TH reports research funding from Bristol Myers Squibb which is outside the scope of the submitted work., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: The purpose of this study was to evaluate the rational combination of TORC1/2 inhibitor TAK-228 and Aurora A kinase inhibitor alisertib in preclinical models of triple-negative breast cancer (TNBC) and to conduct a phase I dose escalation trial in patients with advanced solid tumors., Experimental Design: TNBC cell lines and patient-derived xenograft (PDX) models were treated with alisertib, TAK-228, or the combination and evaluated for changes in proliferation, cell cycle, mTOR pathway modulation, and terminal cellular fate, including apoptosis and senescence. A phase I clinical trial was conducted in patients with advanced solid tumors treated with escalating doses of alisertib and TAK-228 using a 3+3 design to determine the maximum tolerated dose (MTD)., Results: The combination of TAK-228 and alisertib resulted in decreased proliferation and cell-cycle arrest in TNBC cell lines. Treatment of TNBC PDX models resulted in significant tumor growth inhibition and increased apoptosis with the combination. In the phase I dose escalation study, 18 patients with refractory solid tumors were enrolled. The MTD was alisertib 30 mg b.i.d. days 1 to 7 of a 21-day cycle and TAK-228 2 mg daily, continuous dosing. The most common treatment-related adverse events were neutropenia, fatigue, nausea, rash, mucositis, and alopecia., Conclusions: The addition of TAK-228 to alisertib potentiates the antitumor activity of alisertib in vivo , resulting in increased cell death and apoptosis. The combination is tolerable in patients with advanced solid tumors and should be evaluated further in expansion cohorts with additional pharmacodynamic assessment., (©2020 American Association for Cancer Research.)

Gynecologic malignancies, including ovarian cancer, endometrial cancer, and cervical cancer, affect hundreds of thousands of women worldwide every year. Wnt signaling, specifically Wnt/β-catenin signaling, has been found to play an essential role in many oncogenic processes in gynecologic malignancies, including tumorigenesis, metastasis, recurrence, and chemotherapy resistance. As such, the Wnt/β-catenin signaling pathway has the potential to be a target for effective treatment, improving patient outcomes. In this review, we discuss the evidence supporting the importance of the Wnt signaling pathways in the development, progression, and treatment of gynecologic malignancies.

Importance: Current guidelines recommend a 28-day course of enoxaparin for thromboprophylaxis after surgery for gynecologic cancer. The high cost of this medication and the low adherence rates observed in prior studies provide an opportunity to benefit patients by demonstrating the safety of a more cost-effective, easier to use thromboprophylactic., Objective: To investigate the safety and efficacy of an oral treatment alternative for thromboprophylaxis in postoperative patients with gynecologic cancer., Design, Setting, and Participants: This was a patient-based, multicenter, open-label, blinded, end point, randomized clinical trial conducted May 2015 to March 2019 in outpatient and inpatient gynecologic oncology settings. Women undergoing surgery for suspected or confirmed gynecologic cancer were approached for recruitment. The trial compared rates of major bleeding and clinically relevant nonmajor bleeding events during a 90-day follow-up period in patients taking apixaban or enoxaparin for postoperative thromboprophylaxis using a modified intent-to-treat analysis. Data analysis was performed from October to December 2019., Interventions: Women were randomized to 28 days of apixaban (2.5 mg orally twice daily) or enoxaparin (40 mg subcutaneously daily)., Main Outcomes and Measures: The primary outcome was major bleeding and clinically relevant nonmajor bleeding events. Secondary outcomes included incidence of venous thromboembolic events, adverse events, medication adherence, participant quality of life, and medication satisfaction., Results: Of 500 women recruited for the study, 400 were enrolled and randomized (median age, 58.0 years; range, 18.0-89.0 years); 204 received apixaban and 196 received enoxaparin. Treatment groups did not differ in terms of race/ethnicity, cancer stage, or surgery modality (open vs robotic). There were no statistically significant differences between the apixaban and enoxaparin groups in terms of rates of major bleeding events (1 patient [0.5%] vs 1 patient [0.5%]; odds ratio [OR], 1.04; 95% CI, 0.07-16.76; P > .99), clinically relevant nonmajor bleeding events (12 patients [5.4%] vs 19 patients [9.7%]; OR, 1.88; 95% CI, 0.87-4.1; P = .11), venous thromboembolic events (2 patients [1.0%] vs 3 patients [1.5%]; OR, 1.57; 95% CI, 0.26-9.50; P = .68), adverse events, medication adherence, or quality of life between the groups. Participant satisfaction was significantly greater in the apixaban group with regard to ease of taking the medication (186 patients [98.9%] vs 110 patients [58.8%]; OR, 0.06; 95% CI, 0.01-0.25; P < .001) and pain associated with taking the medication (4 patients [2.1%] vs 92 patients [49.2%]; OR, 9.20; 95% CI, 2.67-31.82; P < .001)., Conclusions and Relevance: These findings suggest that oral apixaban is a potentially safe, less painful, and easier-to-take alternative to subcutaneous enoxaparin for thromboprophylaxis after surgery for gynecologic cancer. The efficacy of apixaban to prevent venous thromboembolic events is hypothesized as being equivalent., Trial Registration: ClinicalTrials.gov Identifier: NCT02366871.

Objectives: Stage I, grade 1 endometrial cancers have low recurrence rates and often do not receive adjuvant therapy. We compared recurrent cases to matched non-recurrent controls to evaluate for molecular markers associated with higher risk of recurrence., Methods: A case-control study including all cases of recurrent stage I, grade 1 endometrioid endometrial cancer at one institution in a ten-year period. Cases were matched to controls by age, BMI, weight and stage. Molecular testing and immunohistochemistry were performed on archival tumor specimens: microsatellite instability (MSI-H), mismatch repair status, POLE mutational status, and next-generation sequencing., Results: 15 stage I, grade 1 endometrial cancer cases with recurrent disease and available tumor specimens were identified. CTNNB1 and MSI-H were present at significantly higher rates in cases than controls (CTNNB1 60% vs. 28%, OR 3.9, 95%CI 1.1-14.7, p = 0.04 and MSI-H 53% vs. 21%, OR 4.4, 95%CI 1.1-17.0, p = 0.03). POLE mutations were found in 0% of cases vs. 7% of controls (p = 0.54). Among specimens demonstrating microsatellite stability (MSS), 100% of cases vs. 26% of controls had CTNNB1 mutations (p < 0.001). CTNNB1 wild type tumors were MSI-H in 100% of cases vs. 19% of controls (p < 0.001)., Conclusions: Compared to controls, CTNNB1 mutation is present at significantly higher rates in recurrent stage I, grade 1 endometrial cancers and is found most commonly in MSS tumors. MSI-H is also present at significantly higher rates in recurrent cases. These markers may be useful for prognostic risk stratification and adjuvant therapy decision-making in this otherwise low-risk population., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objectives: The treatment of choice for locally advanced cervical cancer is definitive chemoradiation (CRT). Hysterectomy is not indicated due to higher-rates of cut-through resections leaving gross disease behind, requiring additional therapy with increasing morbidity and no benefit in overall survival (OS). The objectives of this study were to determine factors associated with cut-through hysterectomies and evaluate OS outcomes., Materials and Methods: The National Cancer Database (NCDB) was queried for patients 18 years and older with clinical Federation of Gynecology and Obstetrics stage IB2 to IVA. All patients underwent upfront hysterectomy and had known margin status. Cut-through hysterectomy was classified as presence of microscopic or macroscopic disease at the margin., Results: A total of 11,638 patients were included; 993 (8.5%) had positive margins. In patients with positive margins, 560 (56.4%) received postoperative CRT and 148 (14.9%) underwent postoperative radiation. Five-year OS was worse for those with cut-through resections when compared with those with negative margins, 66.0% versus 86.7%, respectively (hazard ratios, 3.08; P<0.001). Under multiple logistic regression, African American race (odds ratio [OR], 1.45; P=0.001), older age (OR per year increase, 1.03; P<0.001), patients with government insurance (OR, 1.21; P=0.019), and those treated at community practices (OR, 1.31; P=0.001) were more likely to undergo cut-through hysterectomies., Conclusions: A review of national patterns of care over the past decade confirms women with positive margins after hysterectomy for cervical cancer have significantly worse OS. Disparities in surgical results for women with cervical cancer exist. In response, further causality evaluation and corrective action are warranted to address these inequalities.

Background: Outcomes of women with gynecologic cancer are superior when treated by gynecologic oncologists. The National Surgical Quality Improvement Program (NSQIP) began identifying gynecologic surgeon subspecialty in 2014. We sought to identify characteristics and outcomes of women treated by general gynecologists in comparison with women treated by gynecologic oncologists., Patients and Methods: Patients undergoing hysterectomy for gynecologic malignancy in 2014 and 2015 were abstracted from the NSQIP database. Patient characteristics, morbidities, surgeon specialty, and operative outcomes were captured., Results: 7271 hysterectomies were performed for malignant disease, and 669 were performed by generalists. In comparison with generalists, gynecologic oncologists operated on patients who were older (P < 0.001), more likely to be White [odds ratio (OR) 2.1, P < 0.001], had disseminated cancer (OR 3.1, P < 0.001), had ascites (OR 2.6, P < 0.001), and were classified as American Society of Anesthesiologists (ASA) class ≥ 3 (OR 1.7, P < 0.001). Gynecologic oncologists were also more likely to have hospital readmissions (OR 1.7, P = 0.004) and perform lymph node dissections for endometrial cancer (OR 2.2, P < 0.001). On multivariable analysis, older age [adjusted OR (aOR) 1.0, P = 0.021], White race (aOR 2.0, P < 0.001), presence of disseminated cancer (aOR 2.5, P < 0.001), presence of ascites (aOR 1.8, P = 0.036), and ASA class ≥ 3 (aOR 1.6, P < 0.001) remained independent predictive factors for having a gynecologic oncology surgeon., Conclusions: The majority of gynecologic cancer cases are performed by gynecologic oncologists. Generalists are more likely to operate on minority patients and patients with fewer comorbidities. Further efforts to ensure access to specialized cancer care for all patients are needed.

Objective: In this study, we analyzed patterns of care for patients with locally advanced cervical cancer to identify predictors for upfront surgery compared with definitive chemoradiation (CRT)., Methods: The National Cancer Database was queried for patients aged 18 years or older with Federation of Gynecology and Obstetrics IB2-IIB cervical cancer. All patients underwent either upfront hysterectomy with or without postoperative radiation therapy versus definitive CRT. Logistic regression was used to assess variables associated with modality of treatment (surgery vs CRT)., Results: Of the 9494 patients included, 2151 (22.7%) underwent upfront surgery. Of those undergoing surgery, 380 (17.7%) had positive margins, 478 (22.2%) had positive nodes, and 458 (21.3%) had pathologic involvement of the parametrium. Under multiple logistic regression, rates of surgery significantly increased from 2004 (12.2%) to 2012 (31.2%) (odds ratio [OR] per year increase, 1.15; confidence interval [CI], 1.12-1.17; P < 0.001). Upfront surgery was more commonly performed in urban (OR, 1.21; 95% CI, 1.03-1.41; P = 0.018) and rural counties (OR, 1.79; 95% CI, 1.24-2.58; P = 0.002), for adenocarcinoma (OR, 2.14; 1.88-2.44; P < 0.001) and adenosquamous (OR, 2.69; 2.11-3.43; P < 0.001) histologies, and in patients from higher median income communities (ORs, 1.19-1.37). Upfront surgery was less common at academic centers (OR, 0.73; 95% CI, 0.58-0.93; P = 0.011)., Conclusions: Rates of upfront surgery relative to definitive CRT have increased significantly over the past decade. In the setting of level 1 evidence supporting the use of definitive CRT alone for these women, the rising rates of upfront surgery raises concern for both unnecessary surgical procedures with higher rates of treatment-related morbidity and greater health care costs.

Objectives: Intraoperative frozen section has greater than 90% accuracy for ovarian tumors; however, mucinous histology has been shown to be associated with increased frozen section inaccuracy. Recent data demonstrate that primary ovarian mucinous carcinomas have no lymph node involvement, even when extraovarian disease is present, and therefore may not require lymph node dissection. Our primary objective is to evaluate the accuracy of identifying mucinous histology on frozen section., Methods/materials: A cross-sectional review of mucinous ovarian tumors in surgical patients at one institution from 2006 to 2016 was performed. Cases reporting a mucinous ovarian tumor on frozen section or final pathology were identified. Frozen section results were compared with final diagnosis to calculate concordance rates. Analyses with χ and t tests were performed to identify variables associated with pathology discordance., Results: A total of 126 mucinous ovarian tumors were identified. Of these, 106 were reported as mucinous on frozen section and 103 (97.2%) were concordant on final pathology. Discordant cases included 2 serous and 1 clear cell tumor. Among the 103 mucinous tumors, classification as malignant, borderline, or benign was concordant in 74 (71.8%) of 103 cases, whereas 22 (21.4%) of 103 were discordant and 7 (6.8%) were deferred to final pathology. Lymph node dissection was performed in 33 cases; the only case with lymph node metastasis was a gastrointestinal mucinous adenocarcinoma. Discordance between frozen section and final pathology was associated with larger tumor size and diagnosis other than benign: discordant cases had a mean tumor size of 21.7 cm compared with 14.4 cm for concordant cases (P < 0.001), and 93.5% of discordant cases were borderline or malignant, compared with 30.5% of concordant cases (P < 0.001)., Conclusions: Intraoperative identification of mucinous histology by frozen section is reliable with a concordance rate to final pathology of 97.2%. No lymph node metastases were present in any malignant or borderline primary ovarian cases.

Objective: Preoperative histology is a major component in the perioperative selective lymph node (LN) dissection decision process. Discrepancy between preoperative endometrial sampling and final specimen histopathology is generally accepted. The goals of this project are to determine if discrepancy of histopathology is associated with alteration of adjuvant treatment or outcome., Materials and Methods: We performed a retrospective cross-sectional analysis of all patients undergoing surgery for endometrial cancer at a single institution from 2010 to 2014. All patients had preoperative endometrial sampling. Histopathology discrepancy was evaluated for potential in variation of perioperative LN dissection. Criteria for not performing LN dissection was defined as preoperative endometrioid histology, grade 1 or 2 lesion, myometrial invasion of 50% or less, and primary tumor diameter 2 cm or less., Results: A total of 352 patients were identified; 44 were excluded because of no preoperative pathology or no residual disease on final pathology. Discrepancy of histopathology was noted in 64/308 (20.8%; 95% confidence interval [CI], 16.2%-25.3%) patients. Preoperative endometrioid histology was noted in 272 patients, and 17/272 (6.3%; 95% CI, 3.4%-9.1%) had preoperative sampling reviewed as a grade 1 or 2 endometrioid lesion and final specimen was upgraded to grade 3. Downstaging occurred in 3/272 (1.1%; 95% CI, 0%-2.3%) patients with preoperative grade 3 lesion and final specimen demonstrated grade 1 or 2 disease. All 3 patients' primary tumor diameter was greater than 2 cm and therefore received LN dissection. Histopathological discrepancy that would alter perioperative LN dissection decision based on the aforementioned criteria occurred in 2/272 (0.7%; 95% CI, 0%-1.8%)., Conclusions: Despite a 20% discrepancy of preoperative and postoperative histopathology, discrepancy that would alter a perioperative decision for LN dissection occurs in only 0.7% of cases in this retrospective single-institutional experience. Myometrial invasion and tumor size may be more influential than histology in LN selection criteria.

Objective: Current national guidelines recommend preoperative thoracic imaging for all patients undergoing surgery for endometrial cancer. The objective of this project was to report the incidence of pulmonary metastasis in endometrial cancer patients and describe tumor and patient characteristics to better identify a low-risk population for thoracic involvement. We evaluated the ideal modality of preoperative imaging for both low-risk and high-risk populations based on the risk of pulmonary involvement., Methods: A retrospective cross-sectional study of patients undergoing surgical evaluation for endometrial cancer at a single institution from 2010 to 2014 was performed. Low-risk patients were defined as having a preoperative pathology sample showing grade 1 or 2 endometrioid endometrial cancer and a physical examination not concerning for extrauterine disease spread., Results: A total of 352 patients were evaluated, of which 327 (92.9%) had preoperative thoracic imaging. Twenty-six patients had benign pathology or no preoperative sampling, leaving 301 patients for analysis. There were 228 (75.7%) of 301 patients classified as low-risk by our criteria. There were 20 (8.8%) of 228 low-risk patients with initial imaging concerning for pulmonary metastasis, but follow-up showed no evidence of disease. No low-risk patients (0/228; 95% confidence interval [CI], 0%-0.02%) had pulmonary metastasis. There were 4 (1.3%) of 301 (95% CI, 0%-0.04%) patients diagnosed with pulmonary metastasis based on preoperative imaging, and 4 (1.3%) of 301 (95% CI, 0.01%-0.04%) patients with recurrent pulmonary disease. Median time to pulmonary recurrence was 20 months., Conclusions: The incidence of pulmonary metastasis found on preoperative imaging is exceptionally low in our defined low-risk population. All of the patients with pulmonary involvement either initially or upon recurrence had high-risk features. Given our findings, we would recommend that providers consider chest x-ray as the appropriate screening modality for the low-risk population and chest computed tomography for the high-risk population.

Objective: Cytokeratin 5 (CK5) is an epithelial cell marker implicated in stem and progenitor cell activity in glandular reproductive tissues and endocrine and chemotherapy resistance in estrogen receptor (ER)(+) breast cancer. The goal of this study was to determine the prevalence of CK5 expression in ovarian cancer and the response of CK5(+) cell populations to cisplatin therapy., Materials and Methods: Cytokeratin 5 expression was evaluated in 2 ovarian tissue microarrays, representing 137 neoplasms, and 6 ovarian cancer cell lines. Cell lines were treated with IC(50) (half-maximal inhibitory concentration) cisplatin, and the prevalence of CK5(+) cells pretreatment and posttreatment was determined. Proliferation of CK5(+) versus CK5(-) cell populations was determined using 5-bromo-2'-deoxyuridine incorporation. Chemotherapy-induced apoptosis in CK5(+) versus CK5(-) cells was measured using immunohistochemical staining for cleaved caspase-3., Results: Cytokeratin 5 was expressed in 39.3% (42 of 107) of epithelial ovarian cancers with a range of 1% to 80% positive cells. Serous and endometrioid histologic subtypes had the highest percentage of CK5(+) specimens. Cytokeratin 5 expression correlated with ER positivity (38 of 42 CK5(+) tumors were also ER(+)). Cytokeratin 5 was expressed in 5 of 6 overall and 4 of 4 ER(+) epithelial ovarian cancer cell lines ranging from 2.4% to 52.7% positive cells. Cytokeratin 5(+) compared with CK5(-) cells were slower proliferating. The prevalence of CK5(+) cells increased after 48-hour cisplatin treatment in 4 of 5 cell lines tested. Cytokeratin 5(+) ovarian cancer cells compared with CK5(-) ovarian cancer cells were more resistant to cisplatin-induced apoptosis., Conclusions: Cytokeratin 5 is expressed in a significant proportion of epithelial ovarian cancers and represents a slower proliferating chemoresistant subpopulation that may warrant cotargeting in combination therapy.

Background: This study aimed to assess the safety of robotic surgery for older women undergoing surgery for endometrial cancer., Methods: A retrospective chart review of women undergoing surgery for endometrial cancer between October 2010 and December 2012 was conducted at the authors' institution. This cohort was divided by age (≥65 vs <65 years) and surgical approach (laparotomy vs robotic surgery). Postoperative morbidity and mortality were compared using standard statistical analysis., Results: Of 228 patients identified, 73 (32 %) were 65 years old or older, and 98 (43 %) had undergone robotic surgery. Among the robotic surgery patients, women 65 years old or older had a higher Charlson comorbidity score (7.6 vs 4.9; p < 0.01) and were more likely to undergo pelvic lymphadenectomy (73 vs 39 %; p < 0.01). The complication rates did not differ between the groups except for increased urinary retention in the older group (15 % vs 3 %; p = 0.04). Older patients had a longer hospital stay (2.2 vs 1.3 days; p < 0.01) and a similar rate of discharge home (100 vs 96 %; p = 0.09). For the patients 65 years old or older, robotic surgery was associated with less blood loss (131 vs 235 ml; p = 0.03), a lower rate of ileus (0 vs 15 %; p = 0.04), a lower perioperative surgical complication rate (4 vs 30 %; p = 0.01), a shorter hospital stay (2.2 vs 4.4 days; p < 0.01), and a similar rate of discharge home (96 vs 91 %; p = 0.45) compared with laparotomy., Conclusion: Robotic surgery appears to be associated with less postoperative morbidity than laparotomy for endometrial cancer staging in women 65 years old or older. The complication rates after robotic surgery were similar between the two age groups.

Objective: To determine the effectiveness and safety of an expanded perioperative venous thromboembolism (VTE) prophylaxis strategy in women undergoing complex gynecologic surgery., Methods: We performed a cohort study of 527 patients undergoing major surgery at a single institution over a thirty-month interval during which the gynecologic oncology service implemented an expanded approach to VTE prophylaxis. We compared rates of VTE pre- and post-intervention as well as bleeding and infectious complications., Results: Prior to the intervention, there were 23 VTE events in 345 patients (rate of 6.67%): 8 deep vein thromboses (DVTs) and 15 pulmonary emboli (PEs). Post-intervention, there were 5 VTE events in 182 patients (2.7%): 3 DVTs and 2 PEs (RR=0.4, p=0.056). Time-to-event analysis showed a significantly higher incidence of VTE events in the pre-intervention time frame compared to the post-intervention period (p=0.049). There were no significant differences in bleeding or infection complications between groups., Conclusions: Implementation of a perioperative VTE prophylaxis protocol was safe, feasible and resulted in a clinically significant reduction in symptomatic VTE. Preoperative single-dose unfractionated heparin for all patients, combined with two weeks of thromboprophylaxis in gynecologic cancer patients, may decrease VTE events without increasing bleeding or infection., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The interventional radiologist is often asked to obtain multiple biopsies of gynecological malignancies for genetic profiling. This article reviews the current indications for gynecological biopsy as well as how the information gained contributes to a personalized medicine plan for the individual patient. The specific focus of this review is the current knowledge and practice of molecular profiling for gynecological malignancies.

Metastases to the ovary can be a challenging diagnostic dilemma as they often present similarly to a primary ovarian cancer, and there are many potential sites of origin. We present a case series of 5 patients with known cholangiocarcinoma recurrent in the ovary after completion of initial multimodality therapy including surgical resection of the primary tumor followed by adjuvant chemotherapy.

The purpose of this study was to determine whether or not peripheral blood monocyte esterase deficiency occurring in patients on CAPD was a familial characteristic. The peripheral blood monocyte esterase status of 74 patients on CAPD was determined by a naphthyl acetate esterase staining of cytospin preparations of their mononuclear cells following separation over ficoll. The peripheral blood of first degree relatives and spouses of monocyte esterase deficiency patients was similarly investigated for the deficiency. Three patients bad monocyte esterase deficiency and familiality of the defect was demonstrated in two of their families. The third family was incompletely investigated because of lack of consent. The monocyte esterase deficiency demonstrated in this cohort of patients did not result from their renal failure but was a familial characteristic.