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Background: Enhanced recovery after surgery (ERAS) pathways utilize multimodal analgesia. In pathways already utilizing incisional injection of liposomal bupivacaine (ILB), we assessed the benefit of adding intrathecal opioid analgesia (ITA)., Methods: In this randomized controlled non-inferiority trial in patients undergoing laparotomy for gynecologic malignancy, we allocated patients 1:1 to ILB alone versus ITA + ILB with 150 μg intrathecal hydromorphone. The primary endpoint was the Overall Benefit of Analgesia Score (OBAS) at 24 h following surgery. Secondary endpoints included pain scores, intravenous opioid use, and cost of care., Results: Demographic and surgical factors were balanced for 105 patients. For the primary endpoint, ILB alone was non-inferior to ITA + ILB (median OBAS at 24 h of 4 vs 4; p = 0.70). We observed a significant reduction in the need for intravenous opioids (26% vs 71%; p < 0.001) and total opioid requirements (median 7.5 vs 39.3 mg morphine equivalents, p < 0.001) in the first 24 h. Clinically relevant improvements in pain scores were identified in the first 16 h after surgery favoring ITA + ILB. Total cost of the index episode, pharmacy costs, and costs at 30 days were not statistically different., Conclusions: Using OBAS as the primary endpoint, ILB alone was non-inferior to ITA + ILB. However, important cost-neutral benefits for ITA + ILB in the first 24 h post-operatively included lower pain scores and reduced need for intravenous opioids. These early, incremental benefits of adding ITA to ERAS bundles already utilizing ILB should be considered to optimize immediate post-operative pain., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objectives: To perform a systematic review of published academic literature related to lost, mislabeled, and mishandled surgical and clinical pathology specimens during the preanalytical stage., Methods: The authors used Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines to search PubMed, MEDLINE, Web of Science, and Scopus for relevant articles published from January 1, 1990, to May 1, 2023., Results: The authors screened 1313 articles and identified 44 peer-reviewed, English-language articles published between 1990 and 2021 for inclusion in the final systematic review. Most articles (n = 36) reported results from US-based facilities. Articles primarily focused on general clinical and general surgical pathology. Analysis of the articles revealed that articles reported a range of methodological approaches, including incident reports, implementation analyses, case studies, and commentary recommendations. Most articles focused on mislabeling errors (61.3%) and missing or lost specimens (18.2%), while several articles combined specimen errors (20.5%). Several implementation studies (22.7%) reported using multiple interventions to mitigate errors. Implementation efforts reported between 70% and 100% reduction in pathology errors., Conclusions: The review highlights the limited research on the topic, with an average of 2 articles per year discussing lost, mislabeled, or mishandled specimens. Intervention studies addressed The Joint Commission's patient safety goals for laboratory practice. More research is needed about error incidents and reporting in non-Western countries to gain a more global perspective on the topic., (© The Author(s) 2024. Published by Oxford University Press on behalf of American Society for Clinical Pathology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Cervical adenocarcinoma is the second most common histology of cervical cancer and treatment can involve surgery, radiotherapy, systemic therapy, and any combination of the three. Photon external beam radiation therapy and brachytherapy have been the mainstay of radiation treatment options for cervical cancer. Here, we report a case of a 41-year-old patient who had a prior renal transplant and was diagnosed with early-stage, intermediate-risk adenocarcinoma treated with modified radical hysterectomy plus adjuvant proton-beam therapy and vaginal brachytherapy. Treatment was well tolerated with a disease-free interval of 14-months and preserved renal function., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Dr. Bakkum-Gamez is an editor for Gynecology Oncology Reports and is an inventor of Mayo Clinic intellectual property licensed to Exact Sciences (Madison, WI), and may receive royalties paid to Mayo Clinic]., (© 2024 The Authors.)

Postoperative urinary retention (POUR) is a well-known complication after gynecologic surgery. Our objective was to investigate whether the choice of pharmacologic agent for reversing neuromuscular blockade at the end of a hysterectomy is a risk factor for POUR. Among adult patients undergoing hysterectomy with general anesthesia from 2012 to 2017, those who received aminosteroid nondepolarizing neuromuscular agents followed by pharmacologic reversal were identified, and electronic health records were reviewed. The cohort was dichotomized into two groups by reversal agent: 1) sugammadex and 2) neostigmine with glycopyrrolate. The primary outcome, POUR, was defined as unplanned postoperative bladder recatheterization. A propensity-adjusted analysis was performed to investigate the association between POUR and reversal agent by using inverse probability of treatment weighting to adjust for potential confounders. We identified 1,974 patients, of whom 1,586 (80.3%) received neostigmine-glycopyrrolate and 388 (19.7%) received sugammadex for reversal of neuromuscular blockade. The frequency of POUR was 24.8% (393/1,586) after reversal with neostigmine-glycopyrrolate and 18.3% (71/388) with sugammadex. Results from the propensity-adjusted analysis showed that sugammadex was associated with a lower POUR risk than neostigmine-glycopyrrolate (odds ratio 0.53, 95% confidence interval [CI] 0.37 - 0.76, P < 0.001). A post hoc analysis of sugammadex recipients who received glycopyrrolate for another indication showed a higher POUR risk than among those who did not receive glycopyrrolate (odds ratio 1.86, 95% CI 1.07 - 3.22, P = 0.03). Use of sugammadex to reverse aminosteroid neuromuscular blocking agents is associated with decreased risk of POUR after hysterectomy. A potential mechanism is the omission of glycopyrrolate, which is coadministered with neostigmine to mitigate unwanted cholinergic effects.

Objectives: To determine the cost of two surgical treatment approaches for vulvar Paget's disease and model the cost-effectiveness considering differences in recurrence and reoperation over time., Methods: We assessed cost-effectiveness between excision guided by Mohs micrographic surgery (MMS-E) and traditional wide local excision (WLE). We examined billing data from patients with vulvar Paget's disease who underwent MMS-E (cases, n = 24, 2018-2022) or WLE (controls, n = 64, 1990-2020). We created typical treatment bundles incorporating physician-administered services and facility costs standardized to Medicare reimbursements in 2022 United States Dollars (USD). The primary measure of effectiveness was disease-free years of life. A secondary analysis estimated quality-adjusted life years (QALY). A Markov model simulated treatment pathways over a 10-year time horizon. Transition probabilities were based on institutional recurrence rates (3-year RR 6.7 % for MMS-E vs 34.1 % for WLE). We used a willingness-to-pay threshold of 100,000 USD per QALY., Results: The cost of a single surgical episode was 34,664 USD for MMS-E and 14,969 USD for WLE. In the setting of lower recurrence rates with MMS-E, the incremental cost was 12,789 USD per disease-free year gained. A secondary analysis incorporating QALY showed an incremental cost of 72,820 USD per QALY., Conclusions: MMS-E appears to be a cost-effective treatment for vulvar Paget's disease compared to historic standard of care. Our ability to estimate quality of life gained by avoiding disease recurrence was limited by scant data for this rare condition; thus, future studies incorporating health utility values are needed to facilitate a more comprehensive analysis., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Kelly H Bruce: mentorship through related NIH grant; James P Moriarty: none; Bijan J Borah: Consultant for Boehringer Ingelheim and Exact Sciences Corporation for unrelated projects; Ruchita Dholakia: none; Mary E Lohman: none; Jerry D Brewer: Assistant editor of the Journal of Dermatologic Surgery; Nahid Y Vidal: none; Jamie N Bakkum-Gamez: NIH/NCI grants unrelated to this research, licensing agreements between Mayo Clinic and Exact Science unrelated to this research ($0 in royalties), board member - Foundation for Women’s Cancer; William A Cliby: salary support from a philanthropic named professorship within Mayo Clinic, division member - American Board of Obstetrics and Gynecology., (© 2024 The Author(s).)

Background: Extramammary Paget's disease recurs often after traditional surgical excision. Margin-controlled surgery improves the recurrence rate for male genital disease but is less studied for female anatomy., Objective: This study aimed to compare surgical and oncologic outcomes of margin-controlled surgery vs traditional surgical excision for female genital Paget's disease., Study Design: We conducted a prospective observational trial of patients with vulvar or perianal Paget's disease treated with surgical excision guided by Mohs micrographic surgery between 2018 and 2022. The multidisciplinary protocol consisted of office-based scouting biopsies and modified Mohs surgery followed by surgical excision with wound closure under general anesthesia. Modified Mohs surgery cleared peripheral disease margins using a moat technique with cytokeratin 7 staining. Medial disease margins (the clitoris, urethra, vagina, and anus) were assessed using a hybrid of Mohs surgery and intraoperative frozen sections. Surgical and oncologic outcomes were compared with the outcomes of a retrospective cohort of patients who underwent traditional surgical excision. The primary outcome was 3-year recurrence-free survival., Results: Three-year recurrence-free survival was 93.3% for Mohs-guided excision (n=24; 95% confidence interval, 81.5%-100.0%) compared to 65.9% for traditional excision (n=63; 95% confidence interval, 54.2%-80.0%) (P=.04). The maximum diameter of the excisional specimen was similar between groups (median, 11.3 vs 9.5 cm; P=.17), but complex reconstructive procedures were more common with the Mohs-guided approach (66.7% vs 30.2%; P<.01). Peripheral margin clearance was universally achieved with modified Mohs surgery, but positive medial margins were noted in 9 patients. Reasons included intentional organ sparing and poor performance of intraoperative hematoxylin and eosin frozen sections without cytokeratin 7. Grade 3 or higher postoperative complications were rare (0.0% for Mohs-guided excision vs 2.4% for traditional excision; P=.99)., Conclusion: Margin control with modified Mohs surgery significantly improved short-term recurrence-free survival after surgical excision for female genital Paget's disease. Use on medial anatomic structures (the clitoris, urethra, vagina, and anus) is challenging, and further optimization is needed for margin control in these areas. Mohs-guided surgical excision requires specialized, collaborative care and may be best accomplished at designated referral centers., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: Early identification of human papillomavirus associated oropharyngeal squamous cell carcinoma (HPV(+)OPSCC) is challenging and novel biomarkers are needed. We hypothesized that a panel of methylated DNA markers (MDMs) found in HPV(+) cervical squamous cell carcinoma (CSCC) will have similar discrimination in HPV(+)OPSCC tissues., Materials and Methods: Formalin-fixed, paraffin-embedded tissues were obtained from patients with primary HPV(+)OPSCC or HPV(+)CSCC; control tissues included normal oropharynx palatine tonsil (NOP) and cervix (NCS). Using a methylation-specific polymerase chain reaction, 21 previously validated cervical MDMs were evaluated on tissue-extracted DNA. Discrimination between case and control cervical and oropharynx tissue was assessed using area under the curve (AUC)., Results: 34 HPV(+)OPSCC, 36 HPV(+)CSCC, 26 NOP, and 24 NCS patients met inclusion criteria. Within HPV(+)CSCC, 18/21 (86%) of MDMs achieved an AUC ≥ 0.9 and all MDMs exhibited better than chance classifications relative to control cervical tissue (all p < 0.001). In contrast, within HPV(+)OPSCC only 5/21 (24%) MDMs achieved an AUC ≥ 0.90 but 19/21 (90%) exhibited better than chance classifications relative to control tonsil tissue (all p < 0.001). Overall, 13/21 MDMs had statistically significant lower AUCs in the oropharyngeal cohort compared to the cervical cohort, and only 1 MDM exhibited a statistically significant increase in AUC., Conclusions: Previously validated MDMs exhibited robust performance in independent HPV(+)CSCC patients. However, most of these MDMs exhibited higher discrimination for HPV(+)CSCC than for HPV(+)OPSCC. This suggests that each SCC subtype requires a unique set of MDMs for optimal discrimination. Future studies are necessary to establish an MDM panel for HPV(+)OPSCC., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Messrs. Taylor and Mahoney, and Drs. Van Abel, Routman, Ma, and Kisiel have disclosed inventions of Mayo Clinic intellectual property that are licensed to Exact Sciences (Madison, WI) for which they could earn royalties, paid to Mayo Clinic., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Importance: Requiring personalized genetic counseling may introduce barriers to cancer risk assessment, but it is unknown whether omitting counseling could increase distress., Objective: To assess whether omitting pretest and/or posttest genetic counseling would increase distress during remote testing., Design, Setting, and Participants: Making Genetic Testing Accessible (MAGENTA) was a 4-arm, randomized noninferiority trial testing the effects of individualized pretest and/or posttest genetic counseling on participant distress 3 and 12 months posttest. Participants were recruited via social and traditional media, and enrollment occurred between April 27, 2017, and September 29, 2020. Participants were women aged 30 years or older, English-speaking, US residents, and had access to the internet and a health care professional. Previous cancer genetic testing or counseling was exclusionary. In the family history cohort, participants had a personal or family history of breast or ovarian cancer. In the familial pathogenic variant (PV) cohort, participants reported 1 biological relative with a PV in an actionable cancer susceptibility gene. Data analysis was performed between December 13, 2020, and May 31, 2023., Intervention: Participants completed baseline questionnaires, watched an educational video, and were randomized to 1 of 4 arms: the control arm with pretest and/or posttest genetic counseling, or 1 of 3 study arms without pretest and posttest counseling. Genetic counseling was provided by phone appointments and testing was done using home-delivered saliva kits., Main Outcomes and Measures: The primary outcome was participant distress measured by the Impact of Event Scale 3 months after receiving the results. Secondary outcomes included completion of testing, anxiety, depression, and decisional regret., Results: A total of 3839 women (median age, 44 years [range 22-91 years]), most of whom were non-Hispanic White and college educated, were randomized, 3125 in the family history and 714 in the familial PV cohorts. In the primary analysis in the family history cohort, all experimental arms were noninferior for distress at 3 months. There were no statistically significant differences in anxiety, depression, or decisional regret at 3 months. The highest completion rates were seen in the 2 arms without pretest counseling., Conclusions and Relevance: In the MAGENTA clinical trial, omitting individualized pretest counseling for all participants and posttest counseling for those without PV during remote genetic testing was not inferior with regard to posttest distress, providing an alternative care model for genetic risk assessment., Trial Registration: ClinicalTrials.gov Identifier: NCT02993068.

Lynch syndrome (LS) markedly increases risks of colorectal and endometrial cancers. Early detection biomarkers for LS cancers could reduce the needs for invasive screening and surgical prophylaxis.To validate a panel of methylated DNA markers (MDM) previously identified in sporadic colorectal cancer and endometrial cancer for discrimination of these cancers in LS.In a case-control design, previously identified MDMs for the detection of colorectal cancer and endometrial cancer were assayed by qMSP on tissue-extracted DNA. Results were normalized to ACTB values within each sample. Least absolute shrinkage and selection operator models to classify colorectal cancer and endometrial cancer were trained on sporadic cases and controls and then applied to classify colorectal cancer and endometrial cancer, in those with LS, and cross-validated.We identified colorectal cancer cases (23 with LS, 48 sporadic), colorectal controls (32 LS, 48 sporadic), endometrial cancer cases (30 LS, 48 sporadic), and endometrial controls (29 LS, 37 sporadic). A 3-MDM panel (LASS4, LRRC4, and PPP2R5C) classified LS-CRC from LS controls with an AUC of 0.92 (0.84-0.99); results were similar for sporadic colorectal cancer. A 6-MDM panel (SFMBT2, MPZ, CYTH2, DIDO1, chr10.4479, and EMX2OS) discriminated LS-EC from LS controls with an AUC of 0.92 (0.83-1.0); the AUC for sporadic endometrial cancer versus sporadic controls was nominally higher, 0.99 (0.96-1.0).MDMs previously identified in sporadic endometrial cancer and colorectal cancer discriminate between endometrial cancer and benign endometrium and colorectal cancer and benign colorectum in LS. This supports the inclusion of patients with LS within future prospective clinical trials evaluating endometrial cancer and colorectal cancer MDMs and may provide a new avenue for cancer screening or surveillance in this high-risk population., Prevention Relevance: Lynch syndrome (LS) markedly increases risks of colorectal and endometrial cancers. Early detection biomarkers for LS cancers could reduce the needs for invasive screening and surgery. Methylated DNA markers previously identified in sporadic endometrial cancer and colorectal cancer discriminate between benign and cancer tissue in LS., (©2023 American Association for Cancer Research.)

Purpose: Postoperative venous thromboembolism (VTE) can potentially be associated with significant morbidity, mortality, and healthcare costs. The aim of this study was to determine the utilization of Caprini guideline indicated VTE in elective gynecologic surgery patients and its impact on postoperative VTE and bleeding complications., Methods: This was a retrospective cohort study of elective gynecologic surgical procedures performed between January 1, 2016, and May 31, 2021. Two study cohorts were generated: (1) those who received and (2) those who did not receive VTE prophylaxis based on Caprini score risk stratification. Outcome measures were then compared between the study cohorts and included the development of a VTE up to 90-days postoperatively. Secondary outcome measures included postoperative bleeding events., Results: A total of 5471 patients met inclusion criteria and the incidence of VTE up to 90 days postoperatively was 1.04%. Overall, 29.6% of gynecologic surgery patients received Caprini score-based guideline VTE prophylaxis. 39.2% of patients that met high-risk VTE criteria (Caprini > 5) received appropriate Caprini score-based prophylaxis. In multivariate regression analysis, the American Society of Anesthesiologists (ASA) score (OR 2.37, CI 1.27-4.45, p < 0.0001) and Caprini score (OR 1.13, CI 1.03-1.24, p = 0.008) predicted postoperatively VTE occurrence. Increasing Charlson comorbidity score (OR 1.39, CI 1.31-1.47, P < 0.001) ASA score (OR 1.36, CI 1.19-1.55, P < 0.001) and Caprini score (OR 1.10, CI 1.08-1.13, P < 0.001) were associated with increased odds of receiving appropriate inpatient VTE prophylaxis., Conclusion: While the overall incidence of VTE was low in this cohort, enhanced adherence to risk-based practice guidelines may provide more patient benefit than harm to postoperative gynecologic patients., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objectives: Our objectives were to determine the incidence, timing, and risk factors for venous thromboembolisms (VTEs) in patients with advanced stage epithelial ovarian cancer (EOC) who received neoadjuvant chemotherapy (NACT). We explored the utilization of direct-acting oral anticoagulants (DOACs) for VTE treatment., Methods: This retrospective cohort study included patients with advanced stage EOC receiving NACT followed by interval cytoreductive surgery (ICS) at a single institution. Risk factors were compared between patients with versus without VTE between EOC diagnosis and 180 days after ICS. Bleeding complications were compared between patient who received a DOAC versus non-DOAC., Results: VTE cases occurred amongst 33 of the 154 (21.4%) patients with 4 (2.6%) concurrent with EOC diagnosis, 9 (5.8%) between EOC diagnosis and NACT start, 13 (8.4%) between NACT start and ICS, and 7 (4.5%) within 180 days after ICS. There were no statistically significant differences in risk factors assessed (age, body mass index, functional status, histology, Khorana score, and smoking history) between patients with versus without VTE. Eleven patients (33.3%) received a DOAC for VTE treatment. There were no significant differences in number of intraoperative blood transfusions (p = 0.38), blood loss (p = 0.95), or bleeding complications (p = 0.53) between patients treated with a DOAC versus a non-DOAC., Conclusion: There is a high incidence of VTE events (21.4%) in patients with advanced stage EOC undergoing NACT. Two-thirds of the VTEs may have been prevented with thromboprophylaxis as they occurred between EOC diagnosis and ICS. These data support consideration of thromboprophylaxis in all patients with advanced stage EOC undergoing NACT., (Copyright © 2023 Elsevier Inc. All rights reserved.)

PG545 (Pixatimod) is a highly sulfated small molecule known for its ability to inhibit heparanase and disrupt signaling mediated by heparan-binding-growth factors (HB-GF). Previous studies indicated that PG545 inhibits growth factor-mediated signaling in ovarian cancer (OC) to enhance response to chemotherapy. Here we investigated the previously unidentified mechanisms by which PG545 induces DNA damage in OC cells and found that PG545 induces DNA single- and double-strand breaks, reduces RAD51 expression in an autophagy-dependent manner and inhibits homologous recombination repair (HRR). These changes accompanied the ability of PG545 to inhibit endocytosis of the heparan-sulfate proteoglycan interacting DNA repair protein, DEK, leading to DEK sequestration in the tumor microenvironment (TME) and loss of nuclear DEK needed for HRR. As a result, PG545 synergized with poly (ADP-ribose) polymerase inhibitors (PARPis) in OC cell lines in vitro and in 55% of primary cultures of patient-derived ascites samples ex vivo. Moreover, PG545/PARPi synergy was observed in OC cells exhibiting either de novo or acquired resistance to PARPi monotherapy. PG545 in combination with rucaparib also generated increased DNA damage, increased antitumor effects and increased survival of mice bearing HRR proficient OVCAR5 xenografts compared to monotherapy treatment in vivo. Synergistic antitumor activity of the PG545/rucaparib combination was likewise observed in an immunocompetent syngeneic ID8F3 OC model. Collectively, these results suggest that targeting DEK-HSPG interactions in the TME through the use of PG545 may be a novel method of inhibiting DNA repair and sensitizing cells to PARPis., (© 2023. The Author(s).)

Objective: Alterations in DNA methylation are early events in endometrial cancer (EC) development and may have utility in EC detection via tampon-collected vaginal fluid., Methods: For discovery, DNA from frozen EC, benign endometrium (BE), and benign cervicovaginal (BCV) tissues underwent reduced representation bisulfite sequencing (RRBS) to identify differentially methylated regions (DMRs). Candidate DMRs were selected based on receiver operating characteristic (ROC) discrimination, methylation level fold-change between cancers and controls, and absence of background CpG methylation. Methylated DNA marker (MDM) validation was performed using qMSP on DNA from independent EC and BE FFPE tissue sets. Women ≥45 years of age with abnormal uterine bleeding (AUB) or postmenopausal bleeding (PMB) or any age with biopsy-proven EC self-collected vaginal fluid using a tampon prior to clinically indicated endometrial sampling or hysterectomy. Vaginal fluid DNA was assayed by qMSP for EC-associated MDMs. Random forest modeling analysis was performed to generate predictive probability of underlying disease; results were 500-fold in-silico cross-validated., Results: Thirty-three candidate MDMs met performance criteria in tissue. For the tampon pilot, 100 EC cases were frequency matched by menopausal status and tampon collection date to 92 BE controls. A 28-MDM panel highly discriminated between EC and BE (96% (95%CI 89-99%) specificity; 76% (66-84%) sensitivity (AUC 0.88). In PBS/EDTA tampon buffer, the panel yielded 96% (95% CI 87-99%) specificity and 82% (70-91%) sensitivity (AUC 0.91)., Conclusion: Next generation methylome sequencing, stringent filtering criteria, and independent validation yielded excellent candidate MDMs for EC. EC-associated MDMs performed with promisingly high sensitivity and specificity in tampon-collected vaginal fluid; PBS-based tampon buffer with added EDTA improved sensitivity. Larger tampon-based EC MDM testing studies are warranted., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: To identify high-risk disease in clinicopathologic low-risk endometrial cancer (EC) with high microsatellite instability (MSI-H) or no specific molecular profile (NSMP) and therapeutic insensitivity in clinicopathologic high-risk MSI-H/NSMP EC., Methods: We searched The Cancer Genome Atlas for DNA sequencing, RNA expression, and surveillance data regarding MSI-H/NSMP EC. We used a molecular classification system of E2F1 and CCNA2 expression and sequence variations in POLE , PPP2R1A , or FBXW7 (ECPPF) to prognostically stratify MSI-H/NSMP ECs. Clinical outcomes were annotated after integrating ECPPF and sequence variations in homologous recombination (HR) genes., Results: Data were available for 239 patients with EC, which included 58 MSI-H and 89 NSMP cases. ECPPF effectively stratified MSI-H/NSMP EC into distinct molecular groups with prognostic implications: molecular low risk (MLR), with low CCNA2 and E2F1 expression, and molecular high risk (MHR), with high CCNA2 and E2F1 expression and/or PPP2R1A and/or FBXW7 variants. The 3-year disease-free survival (DFS) rate was 43.8% in the MHR group with clinicopathologic low-risk indicators and 93.9% in the MLR group ( P <.001). In the MHR group, wild-type HR genes were present in 28% of cases but in 81% of documented recurrences. The 3-year DFS rate in patients with MSI-H/NSMP EC with clinicopathologic high-risk indicators was significantly higher in the MLR (94.1%) and MHR/HR variant gene (88.9%) groups than in the MHR/HR wild-type gene group (50.3%, P <.001)., Conclusion: ECPPF may resolve prognostic challenges for MSI-H/NSMP EC by identifying occult high-risk disease in EC with clinicopathologic low-risk indicators and therapeutic insensitivity in EC with clinicopathologic high-risk indicators., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Gonzalez-Bosquet, Weroha, Bakkum-Gamez, Weaver, McGree, Dowdy, Famuyide, Kipp, Halling, Yadav, Couch and Podratz.)

In endometrial cancer, occult high-risk subtypes (rooted in histomorphologically low-risk disease) with insensitivity to adjuvant therapies impede improvements in therapeutic efficacy. Therefore, we aimed to assess the ability of molecular high-risk (MHR) and low-risk (MLR) ECPPF (E2F1, CCNA2, POLE, PPP2R1A, FBXW7) stratification to profile recurrence in early, low-risk endometrioid endometrial cancer (EEC) and insensitivity to platinum-based chemotherapy or radiotherapy (or both) in high-risk EEC. Using The Cancer Genome Atlas endometrial cancer database, we identified 192 EEC cases with available DNA sequencing and RNA expression data. Molecular parameters were integrated with clinicopathologic risk factors and adverse surveillance events. MHR was defined as high (-H) CCNA2 or E2F1 log2 expression (≥2.75), PPP2R1A mutations (-mu), or FBXW7mu; MLR was defined as low (-L) CCNA2 and E2F1 log2 expression (<2.75). We assessed 164 cases, plus another 28 with POLEmu for favorable-outcomes comparisons. MHR and MLR had significantly different progression-free survival (PFS) rates (P < .001), independent of traditional risk factors (eg, TP53mu), except for stage IV disease. PFS of CCNA2-L/E2F1-L paralleled that of POLEmu. ECPPF status stratified responses to adjuvant therapy in stage III-IV EEC (P < .01) and profiled stage I, grade 1-2 cases with risk of recurrence (P < .001). MHR was associated with CTNNB1mu-linked treatment failures (P < .001). Expression of homologous recombination repair (HR) and cell cycle genes was significantly elevated in CCNA2-H/E2F1-H compared with CCNA2-L/E2F1-L (P<1.0E-10), suggesting that HR deficiencies may underlie the favorable PFS in MLR. HRmu were detected in 20.7%. No treatment failures were observed in high-grade or advanced EEC with HRmu (P = .02). Favorable PFS in clinically high-risk EEC was associated with HRmu and MLR ECPPF (P < .001). In summary, MLR ECPPF and HRmu were associated with therapeutic efficacy in EEC. MHR ECPPF was associated with low-risk, early-stage recurrences and insensitivity to adjuvant therapies., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Gonzalez-Bosquet et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Epithelial ovarian cancer is the leading cause of death from gynecologic cancer in the United States, with less than half of patients living >5 years following diagnosis. The NCCN Guidelines for Ovarian Cancer provide recommendations for the diagnosis, evaluation, treatment, and follow-up for patients with ovarian, fallopian tube, and primary peritoneal cancers. These NCCN Guidelines Insights summarize the panel discussion behind recent important updates to the guidelines, including revised guidance on alternative chemotherapy regimens for patients with advanced age and/or comorbidities, a new algorithm for recurrent low-grade serous carcinoma based on developing research and novel therapeutic agents, and updated language regarding tumor molecular analysis applications in ovarian cancer.

Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Objective: Aberrant DNA methylation is an early event in carcinogenesis which could be leveraged to detect ovarian cancer (OC) in plasma., Methods: DNA from frozen OC tissues, benign fallopian tube epithelium (FTE), and buffy coats from cancer-free women underwent reduced representation bisulfite sequencing (RRBS) to identify OC MDMs. Candidate MDM selection was based on receiver operating characteristic (ROC) discrimination, methylation fold change, and low background methylation among controls. Blinded biological validation was performed using methylated specific PCR on DNA extracted from independent OC and FTE FFPE tissues. MDMs were tested using Target Enrichment Long-probe Quantitative Amplified Signal (TELQAS) assays in pre-treatment plasma from women newly diagnosed with OC and population-sampled healthy women. A random forest modeling analysis was performed to generate predictive probability of disease; results were 500-fold in silico cross-validated., Results: Thirty-three MDMs showed marked methylation fold changes (10 to >1000) across all OC subtypes vs FTE. Eleven MDMs (GPRIN1, CDO1, SRC, SIM2, AGRN, FAIM2, CELF2, RIPPLY3, GYPC, CAPN2, BCAT1) were tested on plasma from 91 women with OC (73 (80%) high-grade serous (HGS)) and 91 without OC; the cross-validated 11-MDM panel highly discriminated OC from controls (96% (95% CI, 89-99%) specificity; 79% (69-87%) sensitivity, and AUC 0.91 (0.86-0.96)). Among the 5 stage I/II HGS OCs included, all were correctly identified., Conclusions: Whole methylome sequencing, stringent filtering criteria, and biological validation yielded candidate MDMs for OC that performed with high sensitivity and specificity in plasma. Larger plasma-based OC MDM studies, including testing of pre-diagnostic specimens, are warranted., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Dissemination of ovarian cancer cells can lead to inoperable metastatic lesions in the bowel and omentum that cause patient death. Here we show that LRRC15, a type-I 15-leucine-rich repeat-containing membrane protein, highly overexpressed in ovarian cancer bowel metastases compared with matched primary tumors and acts as a potent promoter of omental metastasis. Complementary models of ovarian cancer demonstrated that LRRC15 expression leads to inhibition of anoikis-induced cell death and promotes adhesion and invasion through matrices that mimic omentum. Mechanistically, LRRC15 interacted with β1-integrin to stimulate activation of focal adhesion kinase (FAK) signaling. As a therapeutic proof of concept, targeting LRRC15 with the specific antibody-drug conjugate ABBV-085 in both early and late metastatic ovarian cancer cell line xenograft models prevented metastatic dissemination, and these results were corroborated in metastatic patient-derived ovarian cancer xenograft models. Furthermore, treatment of 3D-spheroid cultures of LRRC15-positive patient-derived ascites with ABBV-085 reduced cell viability. Overall, these data uncover a role for LRRC15 in promoting ovarian cancer metastasis and suggest a novel and promising therapy to target ovarian cancer metastases., Significance: This study identifies that LRRC15 activates β1-integrin/FAK signaling to promote ovarian cancer metastasis and shows that the LRRC15-targeted antibody-drug conjugate ABBV-085 suppresses ovarian cancer metastasis in preclinical models., (©2021 The Authors; Published by the American Association for Cancer Research.)

Objective: The evaluation of women with perimenopausal abnormal uterine bleeding (AUB) and postmenopausal bleeding (PMB) to detect endometrial cancer (EC) and its precursors is not standardized and can vary widely. Consequently, costs associated with the workup and management undoubtedly vary. This study aimed to quantify costs of AUB/PMB evaluation to understand the healthcare burden associated with securing a pathologic diagnosis., Methods: Women ≥45 years of age presenting to a single institution gynecology clinic with AUB/PMB for diagnostic workup were prospectively enrolled February 2013-October 2017 for a lower genital tract biospecimen research study. Clinical workup of AUB/PMB was determined by individual provider discretion. Costs of care were collected from administrative billing systems from enrollment to 90 days post enrollment. Costs were standardized and inflation-adjusted to 2017 US Dollars (USD)., Results: In total, there were 1017 women enrolled with 5.6% diagnosed with atypical hyperplasia or endometrial cancer (EC). Within the full cohort, 90-day median cost for AUB/PMB workup and management was $2279 (IQR $512-4828). Among patients with a diagnostic biopsy, median 90-day costs ranged from $2203 (IQR $499-3604) for benign or disordered proliferative endometrium (DPE) diagnosis to $21,039 (IQR $19,084-24,536) for a diagnosis of EC., Conclusions: The costs for diagnostic evaluation of perimenopausal AUB and PMB vary greatly according to ultimate tissue-based diagnosis. Even reassuring benign findings that do not require further intervention-the most common in this study's cohort-yield substantial costs. The development of sensitive, specific, and more cost-effective diagnostic strategies is warranted., Competing Interests: Declaration of Competing Interest Dr. Jamie Bakkum-Gamez was funded as noted above by The V Foundation for Cancer Research (T2016–001-03) and National Cancer Institute (grants P30 CA 15083 and Z01CP010124–21). She is also listed as an inventor on intellectual property owned by Mayo Clinic and licensed to Exact Sciences. Bijan Borah is a consultant for Exact Sciences. Dr. Mark Sherman participates in research on developing an early endometrial cancer detection test, which is partly funded by Exact Sciences., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Abnormal uterine bleeding requires the investigation of the endometrium. Histology is typically used but there remains room for the improvement and use of cytology., Methods: Women presenting for clinically indicated office endometrial biopsy were prospectively enrolled. Tao endometrial brushing and office endometrial biopsy were performed, and surgical procedure if clinically indicated. Tao brush cytology specimens were blindly reviewed by up to three pathologists, consensus obtained, and scored as: benign, atypical (favor benign), suspicious, positive for malignancy, or non-diagnostic. Cytology and histology were compared to surgical pathology to determine sensitivity, specificity, positive, and negative predictive values to detect AH (atypical hyperplasia) or EC (endometrial cancer)., Results: Clinical indications of 197 enrolled patients included postmenopausal bleeding (90, 45.7%), abnormal uterine bleeding (94, 47.7%), and abnormal endometrium on ultrasound without bleeding (13, 6.6%). Of the 197 patients, 185 (93.9%) had cytology score consensus and a total of 196 (99.5%) had consensus regarding cytology positivity. Surgical pathology diagnoses (N = 85) were 13 (15.3%) FIGO grade 1 or 2 EC, 3 (3.5%) AH, and 69 (81.2%) benign endometrium. Sensitivity and specificity to detect EC or AH were 93.7% and 100%, respectively, via endometrial biopsy; 87.5% and 63.8%, respectively, via endometrial cytology when scores of malignancy, suspicious, or atypical were considered positive., Conclusions: In a high-risk population, Tao brush endometrial cytology showed high sensitivity to detect AH and EC comparable to biopsy histology when considering scores of malignancy, suspicious, atypical, and non-diagnostic. Revisiting the potential value of endometrial cytology in the contemporary era of endometrial diagnostic workup is warranted., (© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Objective: Emerging technologies may enable detection of endometrial cancer with methods that are less invasive than standard biopsy methods. This study compares patient pain scores among 3 office gynecologic tract sampling methods and explores their potential determinants., Methods: A prospective study including 3 sampling methods (tampon, Tao brush (TB), endometrial biopsy (EB)) was conducted between December 2015 and August 2017 and included women ≥45 years of age presenting with abnormal uterine bleeding, postmenopausal bleeding, or thickened endometrial stripe. Patients rated pain after each sampling procedure using a 100-point visual analog scale (VAS)., Results: Of 428 enrolled, 190 (44.39%) patients underwent all 3 sampling methods and reported a VAS score for each. Nearly half were postmenopausal (n = 93, 48.9%); the majority were parous (172, 90.5%) of which 87.8% had at least one vaginal delivery. Among the 190 patients, the median (IQR) pain score was significantly lower for sampling via tampon (0 [0,2]) compared to TB (28 [12, 52]) or EB (32 [15, 60]) (both p < 0.001, Wilcoxon signed rank test). Among women who underwent tampon sampling, age and pain scores showed a weak positive correlation (Spearman rank correlation, r = 0.14; p = 0.006); EB sampling was associated with a weak inverse correlation between parity and pain scores (r = -0.14; p = 0.016)., Conclusion: Gynecologic tract sampling using a tampon had significantly lower pain than both EB and TB. Pain with tampon sampling was positively correlated with age and pain with EB sampling was inversely correlated with parity. Pain scores for TB and EB were not significantly related to age, menopausal status, or BMI., Competing Interests: Declaration of Competing Interest Dr. Bakkum-Gamez has an intellectual property disclosure filed on endometrial cancer methylated DNA markers with Mayo Clinic Ventures (Rochester, MN) and Exact Sciences (Madison, WI)., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: PI3K-AKT pathway mutations initiate a kinase cascade that characterizes endometrial cancer (EC). As kinases seldom cause oncogenic transformation without dysregulation of antagonistic phosphatases, pivotal interactions governing this pathway were explored and correlated with clinical outcomes., Methods: After exclusion of patients with POLE mutations from The Cancer Genome Atlas EC cohort with endometrioid or serous EC, the study population was 209 patients with DNA sequencing, quantitative gene-specific RNA expression, copy number variation (CNV), and surveillance data available. Extracted data were annotated and integrated., Results: A PIK3CA, PTEN, or PIK3R1 mutant (-mu) was present in 83% of patients; 57% harbored more than 1 mutation without adversely impacting progression-free survival (PFS) (P = .10). PIK3CA CNV of at least 1.1 (CNV high [-H]) was detected in 26% and linked to TP53-mu and CIP2A expression (P < .001) but was not associated with PFS (P = .24). PIK3CA expression was significantly different between those with CIP2A-H and CIP2A low (-L) expression (the endogenous inhibitor of protein phosphatase 2A [PP2A]), when stratified by PIK3CA mutational status or by PIK3CA CNV-H and CNV-L (all P < .01). CIP2A-H or PPP2R1A-mu mitigates PP2A kinase dephosphorylation, and FBXW7-mu nullifies E3 ubiquitin ligase (E3UL) oncoprotein degradation. CIP2A-H and PPP2R1A-mu (PP2A impairment) and FBXW7-mu (E3UL impairment) were associated with compromised PFS (P < .001) and were prognostically discriminatory for PIK3CA-mu and PIK3CA CNV-H tumors (P < .001). Among documented recurrences, 84% were associated with impaired PP2A (75%) and/or E3UL (20%)., Conclusion: PP2A and E3UL deficiencies are seminal biological drivers in EC independent of PIK3CA-mu, PTEN-mu, and PIK3R1-mu and PIK3CA CNV., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Novel endometrial cancer (EC) early-detection approaches may reduce racial disparities in mortality. We conducted six community-based focus groups with White and Black women ( N = 57 participants) in February-March 2020 to explore acceptability of a home-based tampon sampling approach for EC. Participants also completed a survey. Data were analyzed using qualitative content analysis. Awareness of EC and risk factors was low. Acceptability regarding home sampling was high, but participants expressed concerns about instruction complexity and potential risks. Black women reported lower comfort with tampons. Increasing EC awareness, self-efficacy, and familiarization with tampons would advance prospects for at-home sample collection for EC testing., Competing Interests: The authors have no conflicts of interest to declare., (© The Association for Clinical and Translational Science 2021.)

Background: Disparities in the stage at diagnosis of endometrial cancer (EC) account for a significant proportion of the disparities in morbidity and mortality experienced by vulnerable groups in the USA. Evidence suggests that disparities in timeliness of care and treatment play a significant role in stage at diagnosis. Despite an increase in literature on EC disparities, the issue remains largely unchanged. The objectives of this review will be to synthesize the evidence to identify important remaining research questions and inform future interventions to reduce the disparity in stage at diagnosis of EC in the USA., Methods: This scoping review protocol will use the five-step framework developed by Arksey and O'Malley. A literature search will be conducted from January 2000 onwards in PubMed, EMBASE, Scopus, and Cochrane CENTRAL databases. Studies on delays in care of EC will be included if they were published in English and reported findings for the US population. Two reviewers will independently screen all citations, full-text articles, and abstract data. The study methodological quality and bias will be appraised using appropriate tools. A narrative summary of findings will be conducted. Data analysis will involve quantitative (e.g., frequencies) and qualitative (e.g., content and thematic analysis) methods. The literature search, data extraction, and evidence synthesis will be informed by the Pathway to Treatment Model, which divides time to cancer care initiation into appraisal, help-seeking, diagnostic, and pre-treatment intervals. Results will be reported in accordance with the PRISMA statement., Discussion: EC disparities research is currently benefitting form a growing expectation that studies have a real impact on disparities. Patient, healthcare, and disease factors impact the amount of time patients spend in different intervals of the Pathway to Treatment Model, so research and interventions aimed at reducing disparities in EC survival should be designed with cognizance to how these factors impact their target population. Reviews on disparities in stage at diagnosis of EC exist but do not provide a comprehensive picture of the pathway to treatment. This review will seek to provide an expanded bedrock of evidence for future studies to build on as they aim to more actively reduce EC disparities., Trial Registration: Open Science Framework ( osf.io/v2zxy ).

Epithelial ovarian cancer is the leading cause of death from gynecologic cancer in the United States and is the country's fifth most common cause of cancer mortality in women. A major challenge in treating ovarian cancer is that most patients have advanced disease at initial diagnosis. These NCCN Guidelines discuss cancers originating in the ovary, fallopian tube, or peritoneum, as these are all managed in a similar manner. Most of the recommendations are based on data from patients with the most common subtypes─high-grade serous and grade 2/3 endometrioid. The NCCN Guidelines also include recommendations specifically for patients with less common ovarian cancers, which in the guidelines include the following: carcinosarcoma, clear cell carcinoma, mucinous carcinoma, low-grade serous, grade 1 endometrioid, borderline epithelial, malignant sex cord-stromal, and malignant germ cell tumors. This manuscript focuses on certain aspects of primary treatment, including primary surgery, adjuvant therapy, and maintenance therapy options (including PARP inhibitors) after completion of first-line chemotherapy.

During the past decade, the age-adjusted mortality rate for endometrial cancer (EC) increased 1.9% annually with TP53 mutant (TP53-mu) EC disproportionally represented in advanced disease and deaths. Therefore, we aimed to assess pivotal molecular parameters that differentiate clinical outcomes in high- and low-risk EC. Using the Cancer Genome Atlas, we analyzed EC specimens with available DNA sequences and quantitative gene-specific RNA expression data. After polymerase ɛ (POLE)-mutant specimens were excluded, differential gene-specific mutations and mRNA expressions were annotated and integrated. Consequent to TP53-mu failure to induce p21, derepression of multiple oncogenes harboring promoter p21 repressive sites was observed, including CCNA2 and FOXM1 (P < .001 compared with TP53 wild type [TP53-wt]). TP53-wt EC with high CCNA2 expression (CCNA2-H) had a targeted transcriptomic profile similar to that of TP53-mu EC, suggesting CCNA2 is a seminal determinant for both TP53-wt and TP53-mu EC. CCNA2 enhances E2F1 function, upregulating FOXM1 and CIP2A, as observed in TP53-mu and CCNA2-H TP53-wt EC (P < .001). CIP2A inhibits protein phosphatase 2A, leading to AKT inactivation of GSK3β and restricted oncoprotein degradation; PPP2R1A and FBXW7 mutations yield similar results. Upregulation of FOXM1 and failed degradation of FOXM1 is evidenced by marked upregulation of multiple homologous recombination genes (P < .001). Integrating these molecular aberrations generated a molecular biomarker panel with significant prognostic discrimination (P = 5.8×10-7); adjusting for age, histology, grade, myometrial invasion, TP53 status, and stage, only CCNA2-H/E2F1-H (P = .0003), FBXW7-mu/PPP2R1A-mu (P = .0002), and stage (P = .017) were significant. The generated prognostic molecular classification system identifies dissimilar signaling aberrations potentially amenable to targetable therapeutic options., Competing Interests: The authors have declared that no competing interests exist.

Background: Most endometrial cancer cases are preceded by abnormal uterine bleeding, offering a potential opportunity for early detection and cure of endometrial cancer. Although clinical guidelines exist for diagnostic workup of abnormal uterine bleeding, consensus is lacking regarding optimal management for women with abnormal bleeding to diagnose endometrial cancer., Objective: We report the baseline data from a prospective clinical cohort study of women referred for endometrial evaluation at the Mayo Clinic, designed to evaluate risk stratification in women at increased risk for endometrial cancer. Here, we introduce a risk-based approach to evaluate diagnostic tests and clinical management algorithms in a population of women with abnormal bleeding undergoing endometrial evaluation at the Mayo Clinic., Study Design: A total of 1163 women aged ≥45 years were enrolled from February 2013 to May 2019. We evaluated baseline absolute risks and 95% confidence intervals of endometrial cancer and endometrial intraepithelial neoplasia according to clinical algorithms for diagnostic workup of women with postmenopausal bleeding (assessment of initial vs recurrent bleeding episode and endometrial thickness measured through transvaginal ultrasound). We also evaluated risks among women with postmenopausal bleeding according to baseline age (<60 vs 60+ years) as an alternative example. For this approach, biopsy would be conducted for all women aged 60+ years and those aged <60 years with an endometrial thickness of >4 mm. We assessed the clinical efficiency of each strategy by estimating the percentage of women who would be referred for endometrial biopsy, the percentage of cases detected and missed, and the ratio of biopsies per case detected., Results: Among the 593 women with postmenopausal bleeding, 18 (3.0%) had endometrial intraepithelial neoplasia, and 47 (7.9%) had endometrial cancer, and among the 570 premenopausal women with abnormal bleeding, 8 (1.4%) had endometrial intraepithelial neoplasia, and 7 (1.2%) had endometrial cancer. Maximum risk was noted in women aged 60+ years (17.7%; 13.0%-22.3%), followed by those with recurrent bleeding (14.7%; 11.0%-18.3%). Among women with an initial bleeding episode for whom transvaginal ultrasound was recommended, endometrial thickness did not provide meaningful risk stratification: risks of endometrial cancer and endometrial intraepithelial neoplasia were nearly identical in women with an endometrial thickness of >4 mm (5.8%; 1.3%-10.3%) and ≤4 mm (3.6%; 0.9%-8.6%). In contrast, among those aged <60 years with an endometrial thickness of >4 mm, the risk of endometrial cancer and endometrial intraepithelial neoplasia was 8.4% (4.3%-12.5%), and in those with an endometrial thickness of ≤4 mm, the risk was 0% (0.0%-3.0%; P=.01). The most efficient strategy was to perform biopsy in all women aged 60+ years and among those aged <60 years with an endometrial thickness of >4 mm, with the lowest percentage referred to biopsy while still detecting all cases., Conclusion: Existing clinical recommendations for endometrial cancer detection in women with abnormal bleeding are not consistent with the underlying risk. Endometrial cancer risk factors such as age can provide important risk stratification compared with the assessment of recurrent bleeding. Future research will include a formal assessment of clinical and epidemiologic risk prediction models in our study population as well as validation of our findings in other populations., (Published by Elsevier Inc.)

The COVID-19 pandemic has challenged our ability to provide timely surgical care for our patients. In response, the U.S. Surgeon General, the American College of Srugeons, and other surgical professional societies recommended postponing elective surgical procedures and proceeding cautiously with cancer procedures that may require significant hospital resources and expose vulnerable patients to the virus. These challenges have particularly distressing for women with a gynecologic cancer diagnosis and their providers. Currently, circumstances vary greatly by region and by hospital, depending on COVID-19 prevalence, case mix, hospital type, and available resources. Therefore, COVID-19-related modifications to surgical practice guidelines must be individualized. Special consideration is necessary to evaluate the appropriateness of procedural interventions, recognizing the significant resources and personnel they require. Additionally, the pandemic may occur in waves, with patient demand for surgery ebbing and flowing accordingly. Hospitals, cancer centers and providers must prepare themselves to meet this demand. The purpose of this white paper is to highlight all phases of gynecologic cancer surgical care during the COVID-19 pandemic and to illustrate when it is best to operate, to hestitate, and reintegrate surgery. Triage and prioritization of surgical cases, preoperative COVID-19 testing, peri-operative safety principles, and preparations for the post-COVID-19 peak and surgical reintegration are reviewed., Competing Interests: Declaration of competing interest Dr. Warner Huh reports personal fees from LICOR, outside the submitted work and Expert Witness: Skadden (on behalf of Intuitive Surgical). Dr. Bhavana Pothuri reports grants, personal fees and non-financial support outside the submitted work; institutional PI for industry sponsored trials from Tesaro/GSK, AstraZeneca, Merck, Genentech/Roche, and Clovis Oncology. Compensated advisory boards include Tesaro/GSK, AstraZeneca, and Eisai. Dr. Mario Leitao reports personal fees from JnJ/Ethicon, outside the submitted work and Dr. Leitao is an ad hoc speaker for Intuitive Surgical, Inc. Dr. Joshua Kesterson reports personal fees from GSK/Tesaro, personal fees from Clovis Oncology, outside the submitted work. Dr. Jason Wright reports grants from Merck, personal fees from Clovis Oncology, outside the submitted work. Dr. Amer Karam reports personal fees from Clovis Oncology, personal fees from GSK, personal fees from Astra Zeneca, personal fees from UpToDate, outside the submitted work. Dr. S. Diane Yamada reports other from LEAP Therapeutics, outside the submitted work. All other authors have nothing to disclose., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Although endometrial cancer is often diagnosed at an early curable stage, the incidence and mortality from endometrial cancer is rising and minority women are particularly at risk. We hypothesize that delays in clinical presentation contribute to racial disparities in endometrial cancer mortality and treatment-related morbidity. Improved methods for endometrial cancer risk assessment and distinguishing abnormal uterine bleeding and postmenopausal bleeding from physiologic variation are needed. Accordingly, we propose a multipronged strategy that combines innovative patient education with novel early detection strategies to reduce health impacts of endometrial cancer and its precursors, especially among Black women. Futuristic approaches using gamification, smartphone apps, artificial intelligence, and health promotion outside of the physical clinic hold promise in preventing endometrial cancer and reducing morbidity and mortality related to the disease, but they also raise a number of questions that will need to be addressed by future research., (©2020 American Association for Cancer Research.)

Objective: To assess the performance of endometrial thickness (ET) cut-offs for detecting endometrial cancer (EC) in women with postmenopausal bleeding (PMB) and evaluate the clinical utility of additional ultrasound measures such as endometrial volume (EV), vascular flow index (VFI), vascularization index (VI), and uterine artery flow index (FI)., Methods: Clinicaltrials.gov and MEDLINE database via PubMed were queried for studies published between 1/1990 and 3/2016 using specific MeSH terms. Original, peer-reviewed cohort studies reporting EC outcomes and specific ultrasound findings by PMB status were included., Results: Study design, country, clinical setting inclusion/exclusion criteria, aggregate study-level demographic and clinical data were extracted from 44 studies including 17,339 women with PMB and 1341 cases of EC (7.7%). In women with PMB and EC (n = 417), pooled mean ET was 16.4 mm (95% CI, 14.8-18.1 mm). In women with PMB without EC, pooled mean ET was 4.1 mm. 31 studies reported outcomes using different ET cut-off values ranging from 3 to 20 mm. Compared to ≥3 or 4 mm, a cutoff of ≥5 mm had similar sensitivity (96.2, 95%CI 92.3, 98.1) with improved specificity for EC (51.5, 95%CI 42.3-60.7), allowing to reduce the rate of invasive workup for PMB by 17%. EV, VI, VFI, and FI were significantly correlated with EC, but performance of specific cut-offs was not analyzed due to limited data., Conclusion: Among women with PMB mean ET is substantially higher in women with EC compared to those without EC. An ET cutoff of ≥5 mm shows an acceptable tradeoff between sensitivity and specificity for diagnosis of EC., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: To assess the incidence, treatment, and outcomes in patients with invasive vulvar extramammary Paget's disease (EMPD) in a national cohort of patients., Methods: Patients from the Surveillance, Epidemiology and End Results (SEER) database with diagnoses of vulvar EMPD from 1992 to 2016 were included. Demographic, treatment, and outcome data were analyzed., Results: A total of 1268 cases of invasive EMPD were identified. Of those, 69.6% had localized disease, 12.0% regional disease, 1.3% distant disease, and 17.1% were unstaged. The annual incidence of invasive vulvar EMPD was 0.36 per 100,000 person years: rates have increased >2-fold since 1992 (1992: 0.19 per 100,000 person years to 0.50 per 100,000 person years in 2016). Most patients underwent primary surgery (n = 1034; 81.5%). Five-year cancer specific survival (CSS) was 95.5% and was associated with stage. Compared to patients with localized disease, patients with distant metastases had dramatically worse CSS (HR: 85.8 (31.8-248) p < 0.0001). Synchronous cancers (diagnosed within one calendar year of EMPD diagnosis year) were observed in 35 cases (2.8%), and 195 patients (15.4%) developed a secondary malignancy (diagnosed >one year from year of EMPD diagnosis year). The most common synchronous breast, gastrointestinal tract, melanoma and the most common secondary cancers were breast, gastrointestinal tract and genitourinary tract., Conclusions: The incidence of invasive vulvar EMPD has increased over time. CSS is excellent for localized disease, but those with metastatic disease are in need of novel therapies. Approximately 15% will develop a secondary malignancy, indicating that patients with invasive vulvar EMPD should undergo site specific preventative health screens during recurrence surveillance., Competing Interests: Declaration of competing interest The authors have no conflicts of interest., (Copyright © 2020. Published by Elsevier Inc.)

Objectives: This study aimed to assess the association between hormone replacement therapy and the incidence of subsequent malignancies in patients who underwent risk-reducing salpingo-oophorectomy and had mutations predisposing them to Müllerian cancers., Methods: This Institutional Review Board-approved retrospective study was performed at five academic institutions. Women were included if they were age 18-51 years, had one or more confirmed germline highly penetrant pathogenic variants, and underwent risk-reducing salpingo-oophorectomy. Patients with a prior malignancy were excluded. Clinicodemographic data were collected by chart review. Patients with no documented contact for one year prior to study termination were called to confirm duration of hormone use and occurrence of secondary outcomes. Hormone replacement therapy included any combination of estrogen or progesterone., Results: Data were analyzed for 159 women, of which 82 received hormone replacement therapy and 77 did not. In both groups an average of 6 years since risk reduction had passed. The patients treated with hormone replacement therapy did not have a higher risk of subsequent malignancy than those not treated with hormone replacement therapy (6 out of 82 vs. 7 out of 77, P = .68). Patients who received hormone replacement therapy were younger than those who did not receive hormone replacement therapy (39.0 vs. 43.9 years, P < .01) and were more likely to have undergone other risk reductive procedures including mastectomy and/or hysterectomy, though this difference was not statistically significant (69.5% vs. 55.8%, P = .07)., Conclusions: In this multi-institution retrospective study of data from patients with high-risk variant carriers who underwent risk-reducing salpingo-oophorectomy, there was no statistically significant difference in the incidence of malignancy between women who did and did not receive hormone replacement therapy., Competing Interests: Declaration of competing interest The authors of this manuscript certify that they have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: To evaluate the rate of vaginal hysterectomy and outcomes after initiation of a prospective decision-tree algorithm to determine the optimal surgical route of hysterectomy., Methods: A prospective algorithm to determine optimal route of hysterectomy was developed, which uses the following factors: history of laparotomy, uterine size, and vaginal access. The algorithm was implemented at our institution from November 24, 2015, to December 31, 2017, for patients requiring hysterectomy for benign indications. Expected route of hysterectomy was assigned by the algorithm and was compared with the actual route performed to identify compliance compared with deviation. Surgical outcomes were analyzed., Results: Of 365 patients who met inclusion criteria, 202 (55.3%) were expected to have a total vaginal hysterectomy, 57 (15.6%) were expected to have an examination under anesthesia followed by total vaginal hysterectomy, 52 (14.2%) were expected to have an examination under anesthesia followed by robotic-assisted total laparoscopic hysterectomy, and 54 (14.8%) were expected to have an abdominal or robotic-laparoscopic route of hysterectomy. Forty-six procedures (12.6%) deviated from the algorithm to a more invasive route (44 robotic, two abdominal). Seven patients had total vaginal hysterectomy when robotic-assisted total laparoscopic hysterectomy or abdominal hysterectomy was expected by the algorithm. Overall, 71% of patients were expected to have a vaginal route of hysterectomy per the algorithm, of whom 81.5% had a total vaginal hysterectomy performed; more than 99% of the total vaginal hysterectomies attempted were successfully completed., Conclusion: Vaginal surgery is feasible, carries a low complication rate with excellent outcomes, and should have a place in gynecologic surgery. National use of this prospective algorithm may increase the rate of total vaginal hysterectomy and decrease health care costs.

Purpose: GOG-0218, a double-blind placebo-controlled phase III trial, compared carboplatin and paclitaxel with placebo, bevacizumab followed by placebo, or bevacizumab followed by bevacizumab in advanced epithelial ovarian cancer (EOC). Results demonstrated significantly improved progression-free survival (PFS), but no overall survival (OS) benefit with bevacizumab. Blood samples were collected for biomarker analyses., Experimental Design: Plasma samples were analyzed via multiplex ELISA technology for seven prespecified biomarkers [IL6, Ang-2, osteopontin (OPN), stromal cell-derived factor-1 (SDF-1), VEGF-D, IL6 receptor (IL6R), and GP130]. The predictive value of each biomarker with respect to PFS and OS was assessed using a protein marker by treatment interaction term within the framework of a Cox proportional hazards model. Prognostic markers were identified using Cox models adjusted for baseline covariates., Results: Baseline samples were available from 751 patients. According to our prespecified analysis plan, IL6 was predictive of a therapeutic advantage with bevacizumab for PFS ( P = 0.007) and OS ( P = 0.003). IL6 and OPN were found to be negative prognostic markers for both PFS and OS ( P < 0.001). Patients with high median IL6 levels (dichotomized at the median) treated with bevacizumab had longer PFS (14.2 vs. 8.7 months) and OS (39.6 vs. 33.1 months) compared with placebo., Conclusions: The inflammatory cytokine IL6 may be predictive of therapeutic benefit from bevacizumab when combined with carboplatin and paclitaxel. Aligning with results observed in patients with renal cancer treated with antiangiogenic therapies, it appears plasma IL6 may also define those patients with EOC more or less likely to benefit from the addition of bevacizumab to standard chemotherapy., (©2020 American Association for Cancer Research.)

Eleven genes have been identified that increase the lifetime risk of developing ovarian cancer. The cumulative cancer risk of ovarian cancer varies with the mutation type and age. Ovarian cancer risk management options include surgical risk reduction with salpingo-oophorectomy and a newer step-wise approach with interval salpingectomy and delayed oophorectomy. Women should be counseled on the pros and cons of hysterectomy in the setting of reducing the risk of other cancers; eliminating the risk of endometrial cancer in Lynch Syndrome, potential risk of serous/serous-like endometrial cancer in BRCA1 carriers, and elimination of progestogen therapy that may increase breast cancer risk.

Objective: We aimed to assess whether endometrial cancer (EC) can be detected in shed DNA collected with vaginal tampon by analyzing copy number, methylation markers, and mutations., Methods: Tampons were collected prior to hysterectomy from 38 EC patients and 28 women with benign indications. Extracted tampon DNA underwent the following: 1) low-coverage whole genome sequencing (LC-WGS) to assess copy number, 2) pyrosequencing to measure percent promotor methylation of HOXA9, RASSF1, and CDH13 and 3) next generation sequencing (NGS) to identify mutations in 19 genes associated with EC identified through The Cancer Genome Atlas. Sensitivity and specificity for each test and test combinations were calculated., Results: Methylation analysis yielded the highest specificities but lowest sensitivities (37-40% sensitivity; 100% specificity for HOXA9, RASSF1 and HTR1B) while mutation analysis had improved sensitivity (50% sensitivity; 83% specificity). Only one "false positive" result for copy number variants was identified among women with benign surgical indications, which was based on detection of copy number changes, and associated with a leiomyosarcoma that was only recognized at hysterectomy. Considering any of the 3 biomarker classes as a positive, resulted in a sensitivity of 92% and specificity of 86%. Mutation analysis did not add sensitivity to the combination of analysis of copy number and methylation., Conclusions: This study demonstrates a proof-of-principle for non-invasive yet precise detection of endometrial cancer. We propose that with improved biomarker testing, it may be possible to develop a clinically useful test for detecting EC., Competing Interests: Declaration of competing interest Dr. Kisiel and Dr. Bakkum have a pending patent filed on detection of endometrial cancer with Exact Sciences (Madison, WI). In addition, Dr. Kisiel receives royalties on an existing patent with Exact Sciences (Madison, WI)., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: To evaluate endometrial cancer (EC) risk assessment and early detection strategies in high-risk populations, we designed a large, prospective cohort study of women undergoing endometrial evaluation to assess risk factors and collect novel biospecimens for future testing of emerging EC biomarkers. Here we report on the baseline findings of this study., Methods: Women aged ≥45 years were enrolled at the Mayo Clinic from February 2013-June 2018. Risk factors included age, body mass index (BMI), smoking, oral contraceptive and hormone therapy use, and parity. We collected vaginal tampons, endometrial biopsies, and Tao brush samples. We estimated mutually-adjusted odds ratios (OR) and 95% confidence intervals (CI) using multinomial logistic regression; outcomes included EC, atypical hyperplasia, hyperplasia without atypia, disordered proliferative endometrium, and polyps, versus normal endometrium., Results: Subjects included 1205 women with a mean age of 55 years; 55% were postmenopausal, and 90% had abnormal uterine bleeding. The prevalence of EC was 4.1% (n = 49), predominantly diagnosed in postmenopausal women (85.7%). Tampons and Tao brushings were obtained from 99% and 68% of women, respectively. Age (OR 1.14, 95% CI 1.1-1.2) and BMI (OR 1.39, 95% CI 1.1-1.7) were positively associated with EC; atypical hyperplasia (OR 1.07, 95% CI 1.0-1.1; OR 2.00, 95% CI 1.5-2.6, respectively), and polyps (OR 1.06, 95% CI 1.0-1.1; OR 1.17, 95% CI 1.0-1.3, respectively); hormone therapy use and smoking were inversely associated with EC (OR 0.42, 95%, 0.2-0.9; OR 0.43, 95% CI, 0.2-0.9, respectively). Parity and past oral contraception use were not associated with EC., Conclusions: Well-established EC risk factors may have less discriminatory accuracy in high-risk populations. Future analyses will integrate risk factor assessment with biomarker testing for EC detection., (Published by Elsevier Inc.)

Among nearly all gynecologic cancers, knowing whether the cancer has metastasized to lymph nodes impacts the ultimate management of the cancer. Lymph node status assists in cancer staging, prognostication, guidance of surgical intervention and adjuvant therapy, and removal of positive lymph nodes may be therapeutic in some cancers. Surgical staging through lymph node removal and pathologist assessment is standard of care for most gynecologic cancers. This section reviews the anatomic lymphatic drainage patterns of each gynecologic organ and the evolution and current practice of surgical lymph node assessment along the spectrum of gynecologic cancers.

Objective: To compare two published risk stratification models (Milwaukee Model vs. Mayo Criteria) to predict lymphatic dissemination (LD) in endometrioid endometrial cancer (EC)., Methods: Patients with stage I-III EC undergoing surgery from 1/1/2004-9/30/2013 were retrospectively reviewed and classified as low-risk vs at-risk for LD using two independent risk models. LD was defined as positive nodes at surgery or lymph node recurrence within 2 years of surgery after negative lymph node dissection (LND) or when LND was not performed. False positive (FP) and false negative (FN) rates for each risk model were calculated., Results: Among 1103 patients, 81 (7.3%) had LD (72 positive LN and 9 LN recurrences), and most (90.2%) had stage I EC. The Milwaukee Model yielded a low at-risk rate for LD (38.1%) but a high FN rate (13.6%, 95% CI 7.0-23.0). The traditional Mayo Criteria using a cut-off of 2 cm for tumor diameter (TD) had a higher at-risk rate for LD (69.5%) but a FN rate of 0% (95% CI, 0-4.5). Modifying the Mayo Criteria using a TD cutoff of ≤3 cm identified fewer women at-risk (56.8% vs. 69.5%) and had a lower FP rate (53.6% vs. 67.1%), but had a higher FN rate (3.7%, 95% CI, 0.8-10.4)., Conclusions: The Milwaukee Model had the lowest at-risk rate of LD but an unacceptable FN rate. Modifying the Mayo Criteria by increasing the TD cutoff from the traditional ≤2 cm to ≤3 cm would spare an estimated 13.5% of patients LND, but the accompanying FN rate is unacceptably high. The traditional Mayo Criteria for low-risk EC remains the most sensitive in determining which patients LND can be omitted., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Epithelial ovarian cancer is the leading cause of death from gynecologic cancer in the United States, with less than half of patients living >5 years from diagnosis. A major challenge in treating ovarian cancer is that most patients have advanced disease at initial diagnosis. The best outcomes are observed in patients whose primary treatment includes complete resection of all visible disease plus combination platinum-based chemotherapy. Research efforts are focused on primary neoadjuvant treatments that may improve resectability, as well as systemic therapies providing improved long-term survival. These NCCN Guidelines Insights focus on recent updates to neoadjuvant chemotherapy recommendations, including the addition of hyperthermic intraperitoneal chemotherapy, and the role of PARP inhibitors and bevacizumab as maintenance therapy options in select patients who have completed primary chemotherapy.

Objective: To determine the effect of tubal ligation on age at natural menopause, as a marker of long-term ovarian function., Methods: Three preexisting population-based cohorts were included in this cross-sectional study. Data from each cohort was analyzed separately. The cohorts were restricted to women who never smoked and had reached natural menopause, without prior hysterectomy or oophorectomy. The following variables were collected: race, age at menarche, age at menopause, history of hysterectomy or oophorectomy, gravidity and parity, tobacco use, and ever use of hormonal contraception. The type of tubal ligation and age at tubal ligation were manually abstracted in cohort 1. For cohorts 2 and 3, history of tubal ligation was obtained from an institutional form, completed by patient report. The primary outcome, age at natural menopause, was compared between the two groups (those with and without a history of tubal ligation)., Results: Inclusion criteria was met by 555 women from cohort 1, 1,816 women from cohort 2, and 1,534 women from cohort 3. Baseline characteristics did not differ between cohorts. The percentage with tubal ligation was the same in all cohorts: 26.0%, 25.5%, and 25.0%, respectively. Women with a tubal ligation were more likely to have had at least one pregnancy and to have used hormonal contraception compared with women without a tubal ligation. There was no significant difference in age at natural menopause in women who underwent tubal ligation (50.1, 49.9, 50.0 years, respectively) compared with those who did not (50.7, 49.6, 50.0 years, respectively). The type of tubal ligation (cohort 1 only) had no effect on age at menopause., Conclusions: Tubal ligation did not affect age at natural menopause in the three large cohorts included in this study.

Background: Uterine leiomyomas, in contrast to sarcomas, tend to cease growth following menopause. In the setting of a rapidly enlarging uterine mass in a postmenopausal patient, clinical distinction of uterine leiomyoma from sarcoma is difficult and requires pathologic examination., Case Presentation: A 74-year-old woman presented with postmenopausal bleeding and acute blood loss requiring transfusion. She was found to have a rapidly enlarging uterine mass clinically suspicious for sarcoma. An abdominal hysterectomy and bilateral salpingo-oophorectomy were performed. A 15.5 cm partially necrotic intramural mass was identified in the uterine corpus. The tumor was classified as a cellular leiomyoma. RNA sequencing identified a KAT6B-KANSL1 fusion that was confirmed by RT-PCR and Sanger sequencing. After 6 months of follow-up, the patient remains asymptomatic without evidence of disease., Conclusion: Prior studies of uterine leiomyomas have identified KAT6B (previously MORF) rearrangements in uterine leiomyomas, but this case is the first to identify a KAT6B-KANSL1 gene fusion in a uterine leiomyoma. While alterations of MED12 and HMGA2 are most common in uterine leiomyomas, a range of other genetic pathways have been described. Our case contributes to the evolving molecular landscape of uterine leiomyomas.