Consensus on surgical technique for sentinel lymph node dissection in cervical cancer.

OBJECTIVE: The purpose of this study was to establish a consensus on the surgical technique for sentinel lymph node (SLN) dissection in cervical cancer. METHODS: A 26 question survey was emailed to international expert gynecological oncology surgeons. A two-step modified Delphi method was used to establish consensus. After a first round of online survey, the questions were amended and a second round, along with semistructured interviews was performed. Consensus was defined using a 70% cut-off for agreement. RESULTS: Twenty-five of 38 (65.8%) experts responded to the first and second rounds of the online survey. Agreement ≥70% was reached for 13 (50.0%) questions in the first round and for 15 (57.7%) in the final round. Consensus agreement identified 15 recommended, three optional, and five not recommended steps. Experts agreed on the following recommended procedures: use of indocyanine green as a tracer; superficial (with or without deep) injection at 3 and 9 o'clock; injection at the margins of uninvolved mucosa avoiding vaginal fornices; grasping the cervix with forceps only in part of the cervix is free of tumor; use of a minimally invasive approach for SLN biopsy in the case of simple trachelectomy/conization; identification of the ureter, obliterated umbilical artery, and external iliac vessels before SLN excision; commencing the dissection at the level of the uterine artery and continuing laterally; and completing dissection in one hemi-pelvis before proceeding to the contralateral side. Consensus was also reached in recommending against injection at 6 and 12 o'clock, and injection directly into the tumor in cases of the tumor completely replacing the cervix; against removal of nodes through port without protective maneuvers; absence of an ultrastaging protocol; and against modifying tracer concentration at the time of re-injection after mapping failure. CONCLUSION: Recommended, optional, and not recommended steps of SLN dissection in cervical cancer have been identified based on consensus among international experts. These represent a surgical guide that may be used by surgeons in clinical trials and for quality assurance in routine practice.

Preclinical Evaluation of NTX-301, a Novel DNA Hypomethylating Agent in Ovarian Cancer.

PURPOSE: DNA methylation causes silencing of tumor-suppressor and differentiation-associated genes, being linked to chemoresistance. Previous studies demonstrated that hypomethylating agents (HMA) resensitize ovarian cancer to chemotherapy. NTX-301 is a highly potent and orally bioavailable HMA, in early clinical development. EXPERIMENTAL DESIGN: The antitumor effects of NTX-301 were studied in ovarian cancer models by using cell viability, stemness and ferroptosis assays, RNA sequencing, lipidomic analyses, and stimulated Raman spectroscopy. RESULTS: Ovarian cancer cells (SKOV3, IC50 = 5.08 nmol/L; OVCAR5 IC50 = 3.66 nmol/L) were highly sensitive to NTX-301 compared with fallopian tube epithelial cells. NTX-301 downregulated expression of DNA methyltransferases 1-3 and induced transcriptomic reprogramming with 15,000 differentially expressed genes (DEG, P < 0.05). Among them, Gene Ontology enrichment analysis identified regulation of fatty acid biosynthesis and molecular functions related to aldehyde dehydrogenase (ALDH) and oxidoreductase, known features of cancer stem cells. Low-dose NTX-301 reduced the ALDH(+) cell population and expression of stemness-associated transcription factors. Stearoyl-coenzyme A desaturase 1 (SCD), which regulates production of unsaturated fatty acids (UFA), was among the top DEG downregulated by NTX-301. NTX-301 treatment decreased levels of UFA and increased oxidized lipids, and this was blunted by deferoxamine, indicating cell death via ferroptosis. NTX-301-induced ferroptosis was rescued by oleic acid. In vivo, monotherapy with NTX-301 significantly inhibited ovarian cancer and patient-derived xenograft growth (P < 0.05). Decreased SCD levels and increased oxidized lipids were detected in NTX-301-treated xenografts. CONCLUSIONS: NTX-301 is active in ovarian cancer models. Our findings point to a new mechanism by which epigenetic blockade disrupts lipid homeostasis and promotes cancer cell death.

Characterization of pre-operative anemia in patients undergoing surgery by a gynecologic oncologist and association with post-operative complications.

OBJECTIVE: Anemia is prevalent in patients with gynecologic cancers and is associated with increased peri-operative morbidity. We aimed to characterize risk factors for pre-operative anemia and describe outcomes among patients undergoing surgery by a gynecologic oncologist to identify potential areas for impactful intervention. METHODS: We analyzed major surgical cases performed by a gynecologic oncologist in the National Surgical Quality Improvement Program (NSQIP) database from 2014 to 2019. Anemia was defined as hematocrit <36%. Demographic characteristics and peri-operative variables for patients with and without anemia were compared using bivariable tests. Odds of peri-operative complications in patients stratified by pre-operative anemia were calculated using logistic regression models. RESULTS: Among 60 017 patients undergoing surgery by a gynecologic oncologist, 23.1% had pre-operative anemia. Women with ovarian cancer had the highest rate of pre-operative anemia at 39.7%. Patients with advanced-stage cancer had a higher risk of anemia than early-stage disease (42.0% vs 16.3%, p≤0.001). In a logistic regression model adjusting for potential demographic, cancer-related, and surgical confounders, patients with pre-operative anemia had increased odds of infectious complications (odds ratio (OR) 1.16, 95% CI 1.07 to 1.26), thromboembolic complications (OR 1.39, 95% CI 1.15 to 1.68), and blood transfusion (OR 5.78, 95% CI 5.34 to 6.26). CONCLUSIONS: There is a high rate of anemia in patients undergoing surgery by a gynecologic oncologist, particularly those with ovarian cancer and/or advanced malignancy. Pre-operative anemia is associated with increased odds of peri-operative complications. Interventions designed to screen for and treat anemia in this population have the potential for significant impact on surgical outcomes.

Effect of pre-operative warm-up on trainee intraoperative performance during robot-assisted hysterectomy: a randomized controlled trial.

INTRODUCTION AND HYPOTHESIS: The objective was to study the effect of immediate pre-operative warm-up using virtual reality simulation on intraoperative robot-assisted laparoscopic hysterectomy (RALH) performance by gynecology trainees (residents and fellows). METHODS: We randomized the first, non-emergent RALH of the day that involved trainees warming up or not warming up. For cases assigned to warm-up, trainees performed a set of exercises on the da Vinci Skills Simulator immediately before the procedure. The supervising attending surgeon, who was not informed whether or not the trainee was assigned to warm-up, assessed the trainee's performance using the Objective Structured Assessment for Technical Skill (OSATS) and the Global Evaluative Assessment of Robotic Skills (GEARS) immediately after each surgery. RESULTS: We randomized 66 cases and analyzed 58 cases (30 warm-up, 28 no warm-up), which involved 21 trainees. Attending surgeons rated trainees similarly irrespective of warm-up randomization with mean (SD) OSATS composite scores of 22.6 (4.3; warm-up) vs 21.8 (3.4; no warm-up) and mean GEARS composite scores of 19.2 (3.8; warm-up) vs 18.8 (3.1; no warm-up). The difference in composite scores between warm-up and no warm-up was 0.34 (95% CI: -1.44, 2.13), and 0.34 (95% CI: -1.22, 1.90) for OSATS and GEARS respectively. Also, we did not observe any significant differences in each of the component/subscale scores within OSATS and GEARS between cases assigned to warm-up and no warm-up. CONCLUSION: Performing a brief virtual reality-based warm-up before RALH did not significantly improve the intraoperative performance of the trainees.

Borderline With Bad Behavior: An Unusual Low-grade Serous Carcinoma With Dedifferentiation From a Serous Borderline Tumor.

The pathogenesis of serous ovarian tumors has been extensively investigated, with a dualistic model dividing these cancers into 2 groups. Type I tumors, including low-grade serous carcinoma, is characteristic for concurrent presence of borderline tumors, less atypical cytology, relatively indolent biologic behavior, and molecular aberrations related to the MAPK pathway with chromosomal stability. Meanwhile, type II tumors, such as high-grade serous carcinoma, are notable for no significant association with borderline tumors, higher grade cytology, more aggressive biologic behavior, and TP53 mutations along with chromosomal instability. We describe a case of morphologic low-grade serous carcinoma with focally increased cytologic atypia arising in serous borderline tumors involving both ovaries, which demonstrated highly aggressive behavior despite several years of surgical and chemotherapeutic management. Each recurrent specimen contained more uniform higher grade morphology than what was seen in the original specimen. Immunohistochemical and molecular studies in both the original tumor and the most recent recurrence demonstrate identical mutations in the MAPK genes, but with additional mutations in the latter, notably an acquisition of a variant of possible clinical significance in the SMARCA4 gene, which is associated with dedifferentiation and aggressive biologic behavior. This case challenges our current and still evolving understanding of the pathogenesis, biologic behavior, and expected clinical outcome of low-grade serous ovarian carcinomas. It also underscores the need for further investigation into this complicated tumor.

Gender Differences in Letters of Recommendation for Gynecology Surgical Fellowship Applicants: Analysis of One Program's Recruitment Cycle.

STUDY OBJECTIVE: To examine whether there are gender differences in letters of recommendation (LORs) written for residents applying to gynecology surgical fellowships. DESIGN: Retrospective study. SETTING: Single, academic institution. PATIENTS: LORs for applicants to gynecology oncology, urogynecology, and minimally invasive gynecology fellowships during the 2019-2020 application cycle. INTERVENTIONS: Not applicable. MEASUREMENTS AND MAIN RESULTS: We analyzed the linguistic content of the letters for the presence of 4 summary variables and 21 word categories based on previous studies using validated computerized text analysis software. We used multivariable analysis using linear mixed models to compare linguistic characteristics of letters by applicant gender. We performed qualitative content analysis on letters and compared the frequency of code themes by gender. The mixed-method design was planned to allow for analysis of domains not captured in text analysis. Among 680 letters written for 186 applicants, 124 (18.2%) were written for men, and 556 (81.8%) were written for women. There were no differences in the least square mean (standard error) word counts for LORs written for men and women applicants, 465 (20.0) vs 458(9.4) words, p = .74. In multivariable analysis, LORs written for men were found to have higher authentic tone and more risk words (p = .005 and p = .03, respectively). LORs written for women contained more communal (relationship-oriented) words (p = .006). The qualitative analysis demonstrated that ability, interpersonal traits, surgical skills, and research were the most often mentioned themes. Comments about compassion/empathy, leadership potential, teaching, interpersonal skills, and patient rapport were found more often in letters for men. More doubt raisers (words that raise doubt or concern) were present in letters for men, but letters for both genders had similar levels of negative criticism. In contrast, comments on ability, being "drama-free," and self-awareness were found more often in letters for women. CONCLUSION: There were gender differences in LORs written for obstetrics and gynecology surgical subspecialty fellowship applicants indicating the presence of gender bias.

Epigenetic priming enhances antitumor immunity in platinum-resistant ovarian cancer.

BackgroundImmune checkpoint inhibitors (ICIs) have modest activity in ovarian cancer (OC). To augment their activity, we used priming with the hypomethylating agent guadecitabine in a phase II study.MethodsEligible patients had platinum-resistant OC, normal organ function, measurable disease, and received up to 5 prior regimens. The treatment included guadecitabine (30 mg/m2) on days 1-4, and pembrolizumab (200 mg i.v.) on day 5, every 21 days. The primary endpoint was the response rate. Tumor biopsies, plasma, and PBMCs were obtained at baseline and after treatment.ResultsAmong 35 evaluable patients, 3 patients had partial responses (8.6%), and 8 (22.9%) patients had stable disease, resulting in a clinical benefit rate of 31.4% (95% CI: 16.9%-49.3%). The median duration of clinical benefit was 6.8 months. Long-interspersed element 1 (LINE1) was hypomethylated in post-treatment PBMCs, and methylomic and transcriptomic analyses showed activation of antitumor immunity in post-treatment biopsies. High-dimensional immune profiling of PBMCs showed a higher frequency of naive and/or central memory CD4+ T cells and of classical monocytes in patients with a durable clinical benefit or response (CBR). A higher baseline density of CD8+ T cells and CD20+ B cells and the presence of tertiary lymphoid structures in tumors were associated with a durable CBR.ConclusionEpigenetic priming using a hypomethylating agent with an ICI was feasible and resulted in a durable clinical benefit associated with immune responses in selected patients with recurrent OC.Trial registrationClinicalTrials.gov NCT02901899.FundingUS Army Medical Research and Material Command/Congressionally Directed Medical Research Programs (USAMRMC/CDMRP) grant W81XWH-17-0141; the Diana Princess of Wales Endowed Professorship and LCCTRAC funds from the Robert H. Lurie Comprehensive Cancer Center; Walter S. and Lucienne Driskill Immunotherapy Research funds; Astex Pharmaceuticals; Merck & Co.; National Cancer Institute (NCI), NIH grants CCSG P30 CA060553, CCSG P30 CA060553, and CA060553.

Feasibility and Prediction of Adverse Events in a Postoperative Monitoring Program of Patient-Reported Outcomes and a Wearable Device Among Gynecologic Oncology Patients.

PURPOSE: The objective of this study was to test the feasibility of implementing a postoperative monitoring program for women with gynecologic cancers composed of patient-reported outcomes (PROs) and a wearable activity monitor. METHODS: We prospectively enrolled patients undergoing gynecologic cancer surgery to this single-arm study. Enrolled patients completed PROs (Patient-Reported Outcomes Measurement Information System physical function, sleep disturbance, anxiety, fatigue, and pain intensity) at baseline and one-week intervals for 4 weeks. They also wore a wearable accelerometer device that measured steps, heart rate, and intensity of physical activity. The primary outcome was feasibility. The secondary outcome was prediction of unscheduled contacts with the health care system on a given postoperative day. RESULTS: We enrolled 34 women. Three patients were unevaluable. The mean age was 58 years. The mean body mass index was 31 kg/m2; 17 patients were White (54.8%), 12 patients were Black (38.7%), and two patients (6.5%) were Asian. The overall wear time was 83.8%, and patients responded to 80.4% of the PRO instruments. Twenty-two patients (71%) had an unscheduled contact with the health care system postoperatively (median 1.5, 0.0-8.0). The day of an unscheduled health care utilization event was predicted with acceptable discrimination (area under the receiver operating characteristic curve 0.75; 95% CI, 0.67 to 0.81). PROs of fatigue and physical function were most predictive followed by wearable device outputs of lightly active minutes and average daily heart rate. CONCLUSION: Implementation of a postoperative monitoring program of patient-reported outcomes and a wearable device was feasible. The specific day of an unscheduled contact with the health care system was predicted with acceptable discrimination.

FOXK2 promotes ovarian cancer stemness by regulating the unfolded protein response pathway.

Understanding the regulatory programs enabling cancer stem cells (CSCs) to self-renew and drive tumorigenicity could identify new treatments. Through comparative chromatin-state and gene expression analyses in ovarian CSCs versus non-CSCs, we identified FOXK2 as a highly expressed stemness-specific transcription factor in ovarian cancer. Its genetic depletion diminished stemness features and reduced tumor initiation capacity. Our mechanistic studies highlight that FOXK2 directly regulated IRE1α (encoded by ERN1) expression, a key sensor for the unfolded protein response (UPR). Chromatin immunoprecipitation and sequencing revealed that FOXK2 bound to an intronic regulatory element of ERN1. Blocking FOXK2 from binding to this enhancer by using a catalytically inactive CRISPR/Cas9 (dCas9) diminished IRE1α transcription. At the molecular level, FOXK2-driven upregulation of IRE1α led to alternative XBP1 splicing and activation of stemness pathways, while genetic or pharmacological blockade of this sensor of the UPR inhibited ovarian CSCs. Collectively, these data establish what we believe is a new function for FOXK2 as a key transcriptional regulator of CSCs and a mediator of the UPR, providing insight into potentially targetable new pathways in CSCs.

Optimizing a Behavioral Sleep Intervention for Gynecologic Cancer Survivors: Study Design and Protocol.

Sleep difficulties, particularly symptoms of insomnia and circadian disruption, are among the primary complaints of gynecologic cancer survivors before, during, and after treatment. Moreover, difficulty sleeping has been linked to poorer health-related quality of life and elevated symptom burden in this population. Although leading behavioral sleep interventions have demonstrated efficacy among cancer survivors, up to 50% of survivors are non-adherent to these treatments, likely because these interventions require labor-intensive behavior and lifestyle changes. Therefore, there is a need for more effective and acceptable approaches to diminish sleep disturbance among cancer survivors. This manuscript describes the methodology of a two-part study guided by the Multiphase Optimization Strategy (MOST) framework to identify a streamlined behavioral sleep intervention for gynecologic cancer survivors. Three candidate intervention components previously shown to decrease sleep disturbance will be evaluated, including sleep restriction, stimulus control, and systematic bright light exposure. Participants will be adult women with a history of non-metastatic gynecologic cancer who have completed primary treatment and who report current poor sleep quality. Fifteen participants will be recruited for Part 1 of the study, which will utilize qualitative methods to identify barriers to and facilitators of intervention adherence. Results will inform changes to the delivery of the candidate intervention components to promote adherence in Part 2, where 80 participants will be recruited and randomized to one of eight conditions reflecting every possible combination of the three candidate intervention components in a full factorial design. Participants will complete assessments at baseline, post-intervention, and 3-months post-intervention. Part 2 results will identify the combination of candidate intervention components that yields the most efficacious yet efficient 6-week intervention for diminishing sleep disturbance. This is the first known study to apply the MOST framework to optimize a behavioral sleep intervention and will yield a resource-efficient treatment to diminish sleep disturbance, improve health-related quality of life, and decrease symptom burden among gynecologic cancer survivors. ClinicalTrials.gov Identifier: NCT05044975.

Uterine Leiomyosarcoma Associated With Leiomyoma With Bizarre Nuclei: Histology and Genomic Analysis of 2 Cases.

Leiomyoma with bizarre nuclei (LM-BN) is a rare variant of leiomyoma with overall benign clinical course. It has histologic features showing focal or diffuse nuclear atypia surrounded by usual type leiomyoma. Uterine leiomyosarcomas (LMS) are a group of rare and aggressive malignancies with limited treatment options available. The potential association between LM-BN with LMS is largely unknown. In this study, we report 2 cases of uterine smooth muscle tumor with typical histologic and molecular evidence of LM-BN, which are associated with its progression to the malignant counterpart of LMS. We summarize the detailed histologic, morphologic, and genomic characteristics of these 2 sets of cases. Our findings suggest that LMS progressing from preexisting LM-BN can be one of the tumor pathogenesis pathways in uterine leiomyosarcomas.

Treatment of vulvar and vaginal dysplasia: plasma energy ablation versus carbon dioxide laser ablation.

OBJECTIVE: Plasma energy ablation vaporizes tissues similar to carbon dioxide laser ablation, but is not hindered by the unique hazards and regulation of laser technology. We aimed to evaluate the complication rate and effectiveness of plasma versus laser ablation in the treatment of vulvovaginal high-grade squamous intra-epithelial lesions (HSIL). METHODS: We performed a retrospective cohort study of women treated with plasma or carbon dioxide laser ablation for histologically proven HSIL of the vulva or vagina from January 2014 to October 2019 at a single institution. Demographic factors, surgical characteristics, and complications were compared by ablation type using Fisher's exact tests. Recurrence-free survival was evaluated by ablation type using Kaplan-Meier curves, weighted log-rank tests, and Cox proportional hazards ratio estimates. RESULTS: Forty-two women were included; 50% underwent plasma and 50% underwent carbon dioxide laser ablation. Demographic factors were similar between the groups. 50% (n=21) were immunosuppressed, 45.2% (n=19) had prior vulvovaginal HSIL treatment, and 35.7% (n=15) were current smokers. Most women (n=25, 59.5%) were treated for vulvar HSIL, 38.1% (n=16) for vaginal HSIL. Complication rates did not differ by treatment: 9.5% (n=2) for laser ablation versus 4.8% (n=1) for plasma ablation (p=1.0). Over a median follow-up time of 29.3 months (IQR 11.0-45.0 months), recurrence rates were similar: 28.6% in the laser ablation group versus 33.3% in the plasma ablation group (weighted log rank p=0.43; 24-month HR 0.54, 95% CI 0.15 to 2.01). CONCLUSION: Plasma energy ablation of vulvovaginal HSIL has similar complication rates and recurrence risk to carbon dioxide laser ablation. This technique could be considered as an alternative treatment modality for vulvovaginal HSIL and warrants further investigation.

NCCN Guidelines® Insights: Uterine Neoplasms, Version 3.2021.

The NCCN Guidelines for Uterine Neoplasms provide recommendations for diagnostic workup, clinical staging, and treatment options for patients with endometrial cancer or uterine sarcoma. These NCCN Guidelines Insights focus on the recent addition of molecular profiling information to aid in accurate diagnosis, classification, and treatment of uterine sarcomas.

Management and Recommendations for Future Pregnancy in Patients with Early-Stage Endometrial Cancer: A Survey of Gynecologic Oncologists and Reproductive Endocrinology and Infertility Specialists.

Purpose: To determine how young patients with early-stage endometrial cancer are counseled regarding fertility preserving therapy and pregnancy options by gynecologic oncology and reproductive endocrinology and infertility (REI) providers. Methods: Anonymous online survey of Society of Gynecology Oncology (SGO) and the Society for Reproductive Endocrinology and Infertility (SREI) members; data were analyzed using chi-square and t-tests. Results: Twelve percent (169/1433) of SGO and 6.5% (60/927) of SREI members responded to the survey request. Most providers manage fewer than 10 fertility preservation patients annually. All gynecologic oncologists offer conservative management to patients with grade 1 endometrial cancer without evidence of invasion, and 40% would offer it to patients with grade 2 or <50% invasion. Magnetic resonance imaging was the most common method of assessing invasion, and the progesterone intrauterine device was the preferred first-line treatment. Two-thirds of providers would recommend hysterectomy if no endometrial response was noted by 12 months, two-thirds would continue conservative management for more than a year if a partial response was noted, and 70% would recommend hysterectomy after a patient completes childbearing. Comparatively, 60% of REI providers would recommend hysterectomy after childbearing. More gynecologic oncologists than REI providers recommend attempting spontaneous conception and for longer durations before initiating fertility treatments. Conclusion: Heterogeneous management styles exist among and between gynecologic oncology and REI providers for patients with early-stage endometrial cancer desiring future pregnancy. Improved guidelines are needed regarding treatment and monitoring surrounding trials of conception and pregnancy.

HER-2 Amplification in Uterine Serous Carcinoma and Serous Endometrial Intraepithelial Carcinoma.

Human epidermal growth factor receptor 2 (HER-2) targeted therapy shows promising results in HER-2-positive uterine serous carcinoma (USC). HER-2 scoring criteria for USC and its associated noninvasive lesion, serous endometrial intraepithelial carcinoma (SEIC), are not well-established. Here, we compare the breast and gastric (GI) HER-2 immunohistochemistry (IHC) scoring criteria for HER-2 with HER-2/neu fluorescence in situ hybridization (FISH) in 68 tumors (17 USC with SEIC, 30 USC, 18 SEIC, 3 metastatic USC). The majority (97%) of lesions displayed intratumoral HER-2 IHC heterogeneity. Breast or GI IHC scoring criteria were performed equivalently. The breast and GI IHC criteria classified 51% and 47% USC as HER-2 negative (IHC 0/1+), 40% and 45% as equivocal (IHC 2+), and 9% each as HER-2 positive (IHC 3+). A quarter of USC classified as HER-2 negative or positive with the breast (25%, n=7/28) or GI IHC criteria (23%, n=6/26) was discordant by FISH. Specifically, 13% to 14% of IHC 0/1+ USC were FISH amplified; 50% of IHC 3+ USC were FISH negative. The majority (77% to 83%) of SEIC were HER-2 IHC 0/1+, and no SEIC was HER-2 IHC 3+. A minority (4% to 7%) of IHC 0/1+ SEIC were FISH positive. Discordant HER-2 status was observed between half (47%,bn=7/15) of synchronous SEIC and USC. In conclusion, USC displays HER-2 intratumoral heterogeneity, a high IHC/FISH discordance rate, and variation in HER-2 status between the SEIC and invasive components. Caution is required when evaluating HER-2 in small biopsies, which should be repeated on excisions. Both IHC and FISH should be performed on USC until clinical trials correlate HER-2 status with clinical response to HER-2-targeted therapy.

Survival outcomes of acute normovolemic hemodilution in patients undergoing primary debulking surgery for advanced ovarian cancer: A Memorial Sloan Kettering Cancer Center Team Ovary study.

OBJECTIVE: To describe oncologic outcomes after using acute normovolemic hemodilution (ANH) to reduce requirement for allogenic red blood cell transfusions (ABT) in patients undergoing primary debulking surgery (PDS) for advanced ovarian cancer. METHODS: We performed a post-hoc analysis of a recent prospective trial investigating the safety and feasibility of ANH during PDS for advanced ovarian cancer. We report long-term survival outcomes. We compared demographics, clinicopathological characteristics, survival outcomes in this cohort of Stage IIIB-IVB high-grade serous ovarian cancer patients undergoing ANH (ANH group), with a retrospective cohort of all other patients (standard group) undergoing PDS during the same time period (01/2012-04/2017). Standard statistical tests were used. RESULTS: There were no demographic or clinicopathological differences between ANH (n = 33) and standard groups (n = 360), except for higher median age at diagnosis (57 vs. 62 years, respectively; p = 0.044) and shorter operative time (357 vs. 446 min, respectively; p < 0.001) in the standard group. Cytoreductive outcomes (ANH vs. standard): 0 mm, 69.7 vs. 63.9%; gross residual disease (RD) ≤1 cm, 21.2 vs. 26.9%; >1 cm, 9.1 vs. 9.2% (p = 0.78). RD after PDS was the only independent factor associated with worse progression-free survival (PFS) on multivariable analysis (p < 0.001). Patients with BRCA mutations trended towards improved PFS (p = 0.057). Significant factors for overall survival (OS) on multivariable analysis: preoperative CA125 (p = 0.004), ascites (p = 0.018), RD after PDS (p = 0.04), BRCA mutation status (p < 0.001). After adjustment for potential confounders, ANH was not independently associated with PFS or OS [PFS: HR 0.928 (0.618-1.395); p = 0.721; OS: HR 0.588 (95%CI: 0.317-1.092); p = 0.093]. CONCLUSIONS: ANH is an innovative approach in intraoperative management. It was previously proven to decrease need for ABT while maintaining the ability to achieve complete gross resection and associated benefits.

Frizzled-7 Identifies Platinum-Tolerant Ovarian Cancer Cells Susceptible to Ferroptosis.

Defining traits of platinum-tolerant cancer cells could expose new treatment vulnerabilities. Here, new markers associated with platinum-tolerant cells and tumors were identified using in vitro and in vivo ovarian cancer models treated repetitively with carboplatin and validated in human specimens. Platinum-tolerant cells and tumors were enriched in ALDH+ cells, formed more spheroids, and expressed increased levels of stemness-related transcription factors compared with parental cells. Additionally, platinum-tolerant cells and tumors exhibited expression of the Wnt receptor Frizzled-7 (FZD7). Knockdown of FZD7 improved sensitivity to platinum, decreased spheroid formation, and delayed tumor initiation. The molecular signature distinguishing FZD7+ from FZD7- cells included epithelial-to-mesenchymal (EMT), stemness, and oxidative phosphorylation-enriched gene sets. Overexpression of FZD7 activated the oncogenic factor Tp63, driving upregulation of glutathione metabolism pathways, including glutathione peroxidase 4 (GPX4), which protected cells from chemotherapy-induced oxidative stress. FZD7+ platinum-tolerant ovarian cancer cells were more sensitive and underwent ferroptosis after treatment with GPX4 inhibitors. FZD7, Tp63, and glutathione metabolism gene sets were strongly correlated in the ovarian cancer Tumor Cancer Genome Atlas (TCGA) database and in residual human ovarian cancer specimens after chemotherapy. These results support the existence of a platinum-tolerant cell population with partial cancer stem cell features, characterized by FZD7 expression and dependent on the FZD7-ß-catenin-Tp63-GPX4 pathway for survival. The findings reveal a novel therapeutic vulnerability of platinum-tolerant cancer cells and provide new insight into a potential "persister cancer cell" phenotype. SIGNIFICANCE: Frizzled-7 marks platinum-tolerant cancer cells harboring stemness features and altered glutathione metabolism that depend on GPX4 for survival and are highly susceptible to ferroptosis.

Discrepancies between author- and industry-reported disclosures of financial relationships at an annual gynecologic oncology research meeting.

OBJECTIVE: Trillions of dollars pass to physicians from industry-related businesses annually, leading to many opportunities for financial conflicts of interest. The Open Payments Database (OPD) was created to ensure transparency. We describe the industry relationships as reported in the OPD for presenters at the 2019 Society of Gynecologic Oncology (SGO) Annual Meeting and evaluate concordance between author disclosures of their financial interests and information provided by the OPD. METHODS: This is an observational, cross-sectional study. Disclosure data were collected from authors with oral and featured abstract presentations in the 2019 SGO annual conference. These disclosures were compared to data available for each author in the 2018 OPD, which included the amount and nature of industry payments. RESULTS: We examined the disclosures of 301 authors who met inclusion criteria. Of 161 authors who had disclosure statements on their presentations,147 reported "no disclosures," and 14 disclosed industry relationships. The remaining 140 did not list any disclosure information. Sixty percent (184/301) of authors had industry relationships in the 2018 OPD, including 173 of 287 (60.3%) of authors who either reported no disclosures or did not have disclosure data available in their presentations. These transactions totaled over 43 million USD from 122 different companies, with most payments (46%) categorized as "Research or Associated Research." Accurate disclosure reporting was associated with receiving higher payments or research payments, and being a presenting author. CONCLUSIONS: Most authors at the SGO annual conference did not correctly disclose their industry relationships when compared with their entries in the OPD.

Standardization of lower extremity quantitative lymphedema measurements and associated patient-reported outcomes in gynecologic cancers.

Practice changing standardization of lower extremity lymphedema quantitative measurements with integrated patient reported outcomes will likely refine and redefine the optimal risk-reduction strategies to diminish the devastating limb-related dysfunction and morbidity associated with treatment of gynecologic cancers. The National Cancer Institute (NCI), Division of Cancer Prevention brought together a diverse group of cancer treatment, therapy and patient reported outcomes experts to discuss the current state-of-the-science in lymphedema evaluation with the potential goal of incorporating new strategies for optimal evaluation of lymphedema in future developing gynecologic clinical trials.

Controversies in Sentinel Lymph Node Biopsy for Gynecologic Malignancies.

OBJECTIVE: Sentinel lymph node (SLN) biopsy represents an evolution in the advancement of minimally invasive surgical techniques for gynecologic cancers. Prospective and retrospective studies have consistently shown its accuracy in the detection of lymph node metastases for endometrial and cervical cancers. However, consistent with any emerging surgical technique in the early phases of adoption, new questions have arisen regarding its application and impact. This paper served as a scoping review to identify the key controversies that have arisen in the field of SLN biopsy for endometrial and cervical cancers. DATA SOURCES: Several key controversies were identified, and PubMed, the Cochrane Library (cochranelibrary.com) advanced search function, and the National Comprehensive Cancer Network guidelines were searched for supporting evidence. These included search terms such as "the accuracy of SLN biopsy for high grade endometrial cancer or cervical cancers >2-cm," "cost effectiveness of SLN biopsy for gynecologic cancers," "clinical significance of low volume metastases in endometrial cancer," "morbidity of SLN biopsy for endometrial and cervical cancer," and "impact on cancer survival of SLN biopsy for endometrial and cervical cancer." METHODS OF STUDY SELECTION: Studies were selected for review if they included significant numbers of patients, were level I evidence, or were prospective trials. Where this level of evidence failed to exist, seminal observational series that were published in high-quality journals were included. TABULATION, INTEGRATION, AND RESULTS: Similar studies were listed and subcategorized and cross-compared, excluding those that included repeated analyses of the same patient populations. The relevant clinical trials or observational studies were clustered and reviewed for each chosen controversy. Adequate evidence supports the accuracy of SLN biopsy in the staging of high-grade endometrial cancer and cervical cancer, and it seems to be a cost-effective strategy for invasive endometrial cancer. Conclusive evidence was lacking with respect to the oncologic outcomes related to SLN biopsy, the impact on patient morbidity, and whether clinicians should treat isolated tumor cells in SLNs with adjuvant therapy. CONCLUSION: SLN biopsy is an accepted staging strategy for cervical and endometrial cancer surgery; however, controversies remain in how it can be applied with the most safety and efficacy. These ultimately need to be resolved with further clinical trials and observations of larger series of patients.