Cell surface CD55 traffics to the nucleus leading to cisplatin resistance and stemness by inducing PRC2 and H3K27 trimethylation on chromatin in ovarian cancer.

BACKGROUND: Platinum resistance is the primary cause of poor survival in ovarian cancer (OC) patients. Targeted therapies and biomarkers of chemoresistance are critical for the treatment of OC patients. Our previous studies identified cell surface CD55, a member of the complement regulatory proteins, drives chemoresistance and maintenance of cancer stem cells (CSCs). CSCs are implicated in tumor recurrence and metastasis in multiple cancers. METHODS: Protein localization assays including immunofluorescence and subcellular fractionation were used to identify CD55 at the cell surface and nucleus of cancer cells. Protein half-life determinations were used to compare cell surface and nuclear CD55 stability. CD55 deletion mutants were generated and introduced into cancer cells to identify the nuclear trafficking code, cisplatin sensitivity, and stem cell frequency that were assayed using in vitro and in vivo models. Detection of CD55 binding proteins was analyzed by immunoprecipitation followed by mass spectrometry. Target pathways activated by CD55 were identified by RNA sequencing. RESULTS: CD55 localizes to the nucleus of a subset of OC specimens, ascites from chemoresistant patients, and enriched in chemoresistant OC cells. We determined that nuclear CD55 is glycosylated and derived from the cell surface pool of CD55. Nuclear localization is driven by a trafficking code containing the serine/threonine (S/T) domain of CD55. Nuclear CD55 is necessary for cisplatin resistance, stemness, and cell proliferation in OC cells. CD55 S/T domain is necessary for nuclear entry and inducing chemoresistance to cisplatin in both in vitro and in vivo models. Deletion of the CD55 S/T domain is sufficient to sensitize chemoresistant OC cells to cisplatin. In the nucleus, CD55 binds and attenuates the epigenetic regulator and tumor suppressor ZMYND8 with a parallel increase in H3K27 trimethylation and members of the Polycomb Repressive Complex 2. CONCLUSIONS: For the first time, we show CD55 localizes to the nucleus in OC and promotes CSC and chemoresistance. Our studies identify a therapeutic mechanism for treating platinum resistant ovarian cancer by blocking CD55 nuclear entry.

Extended-duration antibiotics are not associated with a reduction in surgical site infection in patients with ovarian cancer undergoing cytoreductive surgery with large bowel resection.

OBJECTIVE(S): To evaluate whether extended dosing of antibiotics (ABX) after cytoreductive surgery (CRS) with large bowel resection for advanced ovarian cancer is associated with reduced incidence of surgical site infection (SSI) compared to standard intra-operative dosing and evaluate predictors of SSI. METHODS: A retrospective single-institution cohort study was performed in patients with stage III/IV ovarian cancer who underwent CRS from 2009 to 2017. Patients were divided into two cohorts: 1) standard intra-operative dosing ABX and 2) extended post-operative ABX. All ABX dosing was at the surgeon's discretion. The impact of antibiotic duration on SSI and other postoperative outcomes was assessed using univariate and multivariable Cox regression models. RESULTS: In total, 277 patients underwent cytoreductive surgery (CRS) with large bowel resection between 2009 and 2017. Forty-nine percent (n = 137) received standard intra-operative ABX and 50.5% (n = 140) received extended post-operative ABX. Rectosigmoid resection was the most common large bowel resection in the standard ABX (89.9%, n = 124) and extended ABX groups (90.0%, n = 126), respectively. No significant differences existed between age, BMI, hereditary predisposition, or medical comorbidities (p > 0.05). No difference was appreciated in the development of superficial incisional SSI between the standard ABX and extended ABX cohorts (10.9% vs. 12.9%, p = 0.62). Of patients who underwent a transverse colectomy, a larger percentage of patients developed a superficial SSI versus no SSI (21% vs. 6%, p = 0.004). CONCLUSION(S): In this retrospective study of patients with advanced ovarian cancer undergoing CRS with LBR, extended post-operative ABX was not associated with reduced SSI, and prolonged administration of antibiotics should be avoided unless clinically indicated.

Carboplatin, paclitaxel, and pembrolizumab followed by pembrolizumab maintenance for primary treatment of incompletely resected epithelial ovarian cancer.

Objective: Incompletely resected epithelial ovarian cancer represents a poor prognostic subset of patients. Novel treatment strategies are needed to improve outcomes for this population. We evaluated a treatment strategy combining platinum-based chemotherapy with pembrolizumab followed by pembrolizumab maintenance therapy in the first-line treatment after incomplete resection of epithelial ovarian cancer patients. Methods: This was a single-arm, non-randomized pilot study of carboplatin, taxane, and immune checkpoint inhibitor, pembrolizumab, followed by 12 months of maintenance pembrolizumab in patients with incompletely resected epithelial ovarian cancer (EOC). Results: A total of 29 patients were enrolled and evaluated for efficacy and safety. The best response to therapy was complete response in 16 (55%) patients, partial response in 9 (31%) patients, and 3 (10%) patients with progression of disease. The median progression-free survival (PFS) was 13.2 months. Grade 3 and 4 toxicities occurred in 20% of patients. In all, 7 patients discontinued therapy due to adverse events. Quality-of-life scores remained high during therapy. Response to therapy did not correlate with PD-L1 tumor expression. Conclusions: Combination platinum-taxane therapy with pembrolizumab did not increase median progression-free survival in this cohort of patients. Key message: EOC is an immunogenic disease, but immune checkpoint inhibitor therapy has yet to impact outcomes. The current study utilized pembrolizumab in combination with standard chemotherapy followed by a maintenance treatment strategy in incompletely resected EOC. Progression-free survival was not extended in this poor prognostic group with combined chemotherapy and immunotherapy. Clinical trial registration: https://clinicaltrials.gov/, identifier NCT 027766582.

Laparoscopic predictability of minimally invasive interval debulking in advanced ovarian cancer: The MIID-SOC trial.

BACKGROUND: We sought to create a laparoscopic-based model to predict the ability to perform a minimally invasive (MIS) cytoreductive surgery in advanced epithelial ovarian cancer patients who have received neoadjuvant chemotherapy (NACT). METHODS: Fifty women were enrolled in a multi-institutional prospective pilot study (NCT03378128). Each patient underwent laparoscopic evaluation of 43 abdominopelvic sites followed by surgeon dictated surgical approach, either continue MIS or laparotomically. However, if the procedure continued MIS, the placement of a hand-assist port for manual palpation was mandated to emulate a laparotomic approach and all 43 sites were re-evaluated. Sensitivity, specificity, positive predictive value, negative predictive value, and overall accuracy were calculated for each site to predict MIS resectability. Each parameter was assigned a numeric value based on the strength of statistical association and a total predictive index score (PIV) was assigned for each patient. Receiver operating characteristic curve analysis was used to assess the ability of the model to predict the MIS approach. RESULTS: Twenty-seven patients (61%) underwent MIS surgery. The following abdominopelvic sites were selected for inclusion in the model: gastrosplenic ligament, rectum, left mesocolon, transverse colon, right colon, cecum, appendix, liver capsule, intrahepatic fossa/gallbladder, ileum/jejunum. Using the PIV, a ROC was generated with an AUC = 0.695. In the final model, a PIV <2 identified patients able to undergo an optimal MIS cytoreductive surgery with an accuracy of 68.2%. The specificity, or the ability to identify patients who would not be able to undergo an optimal MIS interval cytoreductive surgery, was 66.7%. CONCLUSION: This predictive index model may help to guide future inclusion criteria in randomized studies evaluating the MIS approach in advanced epithelial ovarian cancer.

Safety and efficacy of topical artesunate for the treatment of vulvar intraepithelial neoplasia 2/3.

OBJECTIVE: To evaluate the safety, tolerability, and efficacy of topical artesunate ointment for treatment of biopsy-confirmed Human papillomavirus (HPV)-associated Vulvar intraepithelial neoplasia (VIN) 2/3. METHODS: Participants were enrolled on a prospective, IRB-approved, dose-escalation phase I trial testing either 1, 2 or 3 treatment cycles (5 days), every other week, as applicable. Clinical assessments were completed prior to each dose cycle and included exam and review of adverse event (AE) diary cards. HPV testing and colposcopy was completed at 15 and 28 weeks. AEs were assessed according to CTCAE 4.0 criteria. Complete responders (CR) underwent biopsy of the treated site at the 28-weeks while partial (PR) and non (NR)-responders underwent surgical resection or biopsy and ablation. RESULTS: Fifteen patients consented to and began treatment. Per-protocol assessments were completed in 100% at 15- and 80% at 28-weeks. All patients completed prescribed cycles with no grade 3 or 4 AEs. Vulvovaginal burning/ was the most common AE occurring in 93.3%. AEs were grade 2 in 23.7% and included vulvovaginal pruritus (n = 3), swelling (n = 3) and candidiasis (n = 2). The highest ORR was in the 3-cycle group (88.9% with 55.6% CR). HPV-16 was detected either alone (46.7%) or with other subtypes (33.3%) in 80% of lesions and 5 of 8 (62.5%) with CR had complete viral clearance. CONCLUSIONS: Topical artesunate for treatment of high-grade VIN shows high tolerability, low toxicity and evidence for clinical response in this initial small series. The safety and observed responses support further study in a Phase II trial.

Association of Clinical Trial Participation With Improved Overall Survival for Recurrent, Platinum-Resistant Ovarian Cancer.

OBJECTIVE: To investigate whether clinical trial participation is associated with overall survival in patients with platinum-resistant ovarian cancer. METHODS: An IRB-approved, retrospective, single-institution cohort study was performed in patients with platinum-resistant ovarian cancer from January 1, 2009, to December 31, 2017. Platinum resistance was defined as progression within 6 months after completion of platinum chemotherapy. Patients were divided into two cohorts: 1) clinical trial participants for platinum-resistant ovarian cancer or 2) standard of care. The association of trial participation with overall survival from the date of platinum resistance was assessed with univariate and multivariable models. RESULTS: Of 305 eligible patients with recurrent platinum-resistant ovarian cancer, 46 (15.1%) were clinical trial participants. There were no significant differences in age (61.2 years vs 63.3 years, P =.21), body mass index (27.5 vs 27.6, P =.90), race ( P =.61), medical comorbidities ( P >.05), or performance status ( P =.07) for clinical trial participants compared with those receiving standard of care. The majority underwent primary cytoreduction (76.1% vs 69.1%, P =.34) with no differences in residual disease ( P =.43) for clinical trial participants compared with those receiving standard of care. There was no difference in poly-ADP-ribose polymerase inhibitor (21.7% vs 15.1%, P =.26) or bevacizumab (22.2% vs 32.1%, P =.31) use for clinical trial participants compared with those receiving standard of care. On multivariable analysis controlling for comorbidities, stage, and germline mutational status, clinical trial participation was associated with significantly improved overall survival from the date of platinum resistance compared with standard of care (13.8 months vs 10.5 months, adjusted hazard ratio 1.46, 95% CI 1.04-2.05, P =.028). CONCLUSIONS: In this retrospective cohort of patients with platinum-resistant ovarian cancer, clinical trial participation was associated with improved overall survival compared with standard of care therapies. Availability and participation in clinical trials should be prioritized in patients with recurrent, platinum-resistant ovarian cancer.

Efficacy and toxicity of carboplatin and gemcitabine administered on day 1 and day 8 (day1&8) versus day 1-only for platinum-sensitive recurrent epithelial ovarian cancer.

OBJECTIVE: To compare response rate, progression-free survival, overall survival, and toxicity of carboplatin and gemcitabine administered on day 1 and day 8 (day1&8) versus a modified day 1-only regimen in recurrent platinum-sensitive ovarian cancer. METHODS: A retrospective single-institution cohort study was performed in women with recurrent platinum-sensitive ovarian cancer between January 2009 and December 2020 treated with carboplatin and gemcitabine on a 21-day cycle. The impact of dosing schedule on response rate, progression-free survival, overall survival, and toxicities was assessed with univariate and multivariate models. RESULTS: Of 200 patients, 26% (n=52) completed day 1&8, 21.5% (n=43) started day 1&8 but dropped day 8, and 52.5% (n=105) received day 1-only. There were no differences in demographics. Median starting carboplatin and gemcitabine doses were area under curve (AUC) 5 and 600 mg/m2 for day 1-only versus AUC4 and 750 mg/m2 among day 1&8, respectively (p<0.001). A total of 43 patients (45.3%) dropped day 8 primarily due to neutropenia (51.2%) or thrombocytopenia (30.2%). The response rates were 69.3% for day 1&8-completed, 67.5% for day 1&8-dropped, and 67.6% for day 1-only (p=0.92). Median progression-free survival was 13.1, 12.1, and 12.4 months for day 1&8-completed, day 1&8-dropped, and day 1-only, respectively (p=0.29). Median overall survival was 28.2, 33.5, and 34.3 months for the above groups (p=0.42). The rate of grade 3/4 hematologic toxicity (48.9% vs 31.4%, p=0.002), dose reductions (58.9% vs 33.7%, p<0.001), blood transfusions (22.1% vs 10.5%, p=0.025), and treatment with pegfilgrastim (64.2% vs 51%, p=0.059) were higher among day 1&8 versus day 1-only, respectively. CONCLUSIONS: There was no difference in response rate, progression-free survival, or overall survival for day 1&8 versus day 1-only, regardless of whether day 8 was dropped. Day 1&8 was associated with greater hematologic toxicity. A modified day 1-only regimen may represent an alternative to day 1&8 and warrants prospective study.

Longitudinal Analysis of Cancer Risk in Children and Adults With Germline PTEN Variants.

Importance: Identifying hereditary cancer predisposition facilitates high-risk organ-specific cancer surveillance and prevention. In PTEN hamartoma tumor syndrome (PHTS), longitudinal studies remain lacking, and there are insufficient data on cancers in children and young adults, as well as individuals with neurodevelopmental disorders (NDD). Objective: To evaluate lifetime cancer risks, including second malignant neoplasms (SMN), among patients with PHTS. Design, Setting, and Participants: Prospective longitudinal cohort study (September 1, 2005, through January 6, 2022). General population risks from the Surveillance, Epidemiology, and End Results database. Patients with PHTS, molecularly defined as carrying germline PTEN variants, were accrued from community and academic medical centers throughout North America, South America, Europe, Australia, and Asia. Data were analyzed from July 2022 to February 2023. Exposures: Review of physical and electronic medical records, and follow-up through clinical visits or telephone interviews. Main Outcomes and Measures: Lifetime cancer risks in PHTS relative to the general population. Results: A total of 7302 patients were prospectively accrued, 701 of whom had germline PTEN variants (median [IQR] age at consent, 38 [12-52] years; 413 female patients [59%]). Longitudinal follow-up data could be obtained for 260 patients (37%), with a median (IQR) follow-up of 4 (2-8) years. Of the 701 patients, 341 (49%) received at least 1 cancer diagnosis, with 144 (42%) of those having SMN. The study found significantly elevated lifetime risks for breast (91%), endometrial (48%), thyroid (33%), kidney (30%), and colorectal cancers (17%), as well as melanoma (5%). Cancer diagnoses were also observed in children and young adults with PHTS (15%) and in patients with PHTS with neurodevelopmental disorders (11%). Elevated risks (P < .001) of thyroid (age-adjusted standardized incidence ratios [SIR], 32.1; 95% CI, 26.0-39.0), kidney (SIR, 26.5; 95% CI, 18.8-36.3), endometrial (SIR, 26.0; 95% CI, 19.5-34.1), breast (SIR, 20.3; 95% CI, 17.3-23.7), and colorectal (SIR, 7.9; 95% CI, 5.2-11.7) cancers, and melanoma (SIR, 6.3; 95% CI, 3.5-10.5) were observed. Of the 341 patients with PHTS with cancer, 51 (15%) had 1 or more cancers diagnosed at age 29 years or younger, and 16 (31.4%) of those developed SMN at final follow-up. Twenty-three patients with PHTS with NDD and cancer were identified, with 5 (22%) having developed SMN at final follow-up. Individuals with PHTS and NDD showed higher lifetime cancer risks compared with individuals with PHTS but without NDD (hazard ratio, 2.7; 95% CI, 1.7-4.2; P < .001). Conclusions and Relevance: This cohort study found consistently elevated lifetime cancer risks in PHTS. Organ-specific surveillance should continue in patients with PHTS. Additional study is required to ascertain elevated cancer risks in patients with PHTS with NDD.

Low-Grade Ovarian Stromal Tumors with Genetic Alterations of the Wnt/ß-Catenin Pathway That Is Crucial in Ovarian Follicle Development and Regulation.

The Wnt signaling pathway is important in the normal development and regulation of ovarian follicles throughout the lifecycle of females. Dysregulation of the Wnt signaling pathway, genetically or epigenetically, with subsequent activation of ß-catenin has been implicated in tumorigenesis of a spectrum of ovarian neoplasms, from benign to malignant. We review the recent findings of the Wnt signaling pathway involved in regulating normal physiologic processes of the ovarian follicle cycle. We also review the ß-catenin mutations in a family of low-grade ovarian stromal tumors, focusing on characterizing their shared morphological features and the utility of immunohistochemistry of ß-catenin in facilitating the accurate diagnosis of these ovarian stromal tumors. The Wnt signaling pathway is one of the most critical mechanisms in regulating cell proliferation, differentiation, and morphogenesis. The Wnt signaling pathway comprises a diverse group of glycoproteins that serve as ligands and bind to transmembrane Frizzled family receptors. The ligand-receptor interactions activate the pathway and govern the downstream signaling cascades, ultimately affecting the transcriptional control of the cellular cytoskeleton, organelle dynamics, epithelial-mesenchymal interaction, and tissue remodeling in the ovary. Wnt signaling consists of two major pathways: a canonical pathway that is ß-catenin-dependent and a non-canonical Wnt pathway that is ß-catenin-independent. Canonical Wnt signaling is governed by the interaction of ß-catenin with other molecules to regulate cellular decisions related to proliferation and differentiation. Recent studies have demonstrated that the Wnt signaling pathway plays important roles in the development and regulation of ovarian folliculogenesis and oogenesis.

Disruption of the Gut Microbiota Confers Cisplatin Resistance in Epithelial Ovarian Cancer.

Epithelial ovarian cancer (EOC) is the leading cause of gynecologic cancer death. Despite initial responses to intervention, up to 80% of patient tumors recur and require additional treatment. Retrospective clinical analysis of patients with ovarian cancer indicates antibiotic use during chemotherapy treatment is associated with poor overall survival. Here, we assessed whether antibiotic (ABX) treatment would impact growth of EOC and sensitivity to cisplatin. Immunocompetent or immunocompromised mice were given untreated control or ABX-containing (metronidazole, ampicillin, vancomycin, and neomycin) water prior to intraperitoneal injection with EOC cells, and cisplatin therapy was administered biweekly until endpoint. Tumor-bearing ABX-treated mice exhibited accelerated tumor growth and resistance to cisplatin therapy compared with control treatment. ABX treatment led to reduced apoptosis, increased DNA damage repair, and enhanced angiogenesis in cisplatin-treated tumors, and tumors from ABX-treated mice contained a higher frequency of cisplatin-augmented cancer stem cells than control mice. Stool analysis indicated nonresistant gut microbial species were disrupted by ABX treatment. Cecal transplants of microbiota derived from control-treated mice was sufficient to ameliorate chemoresistance and prolong survival of ABX-treated mice, indicative of a gut-derived tumor suppressor. Metabolomics analyses identified circulating gut-derived metabolites that were altered by ABX treatment and restored by recolonization, providing candidate metabolites that mediate the cross-talk between the gut microbiome and ovarian cancer. Collectively, these findings indicate that an intact microbiome functions as a tumor suppressor in EOC, and perturbation of the gut microbiota with ABX treatment promotes tumor growth and suppresses cisplatin sensitivity. SIGNIFICANCE: Restoration of the gut microbiome, which is disrupted following antibiotic treatment, may help overcome platinum resistance in patients with epithelial ovarian cancer. See related commentary by Hawkins and Nephew, p. 4511.

Preoperative assessment using the five-factor modified frailty index: A call for standardized preoperative assessment and prehabilitation services in gynecologic oncology.

OBJECTIVE: To evaluate if the 5-factor modified frailty index (mFI) is associated with postoperative complications, readmissions or non-home discharge in gynecologic cancer patients undergoing surgery. METHODS: Patients with a diagnosis of gynecologic cancer (cervical, uterine, or ovarian cancer) who underwent surgery between 2014 and 2018 were identified through the National Surgical Quality Improvement Program (NSQIP) database. The 5-factor mFI was applied and patients classified into 6 categories (mFI groups 0,1,2, 3, 4 and 5). The incidence of 30-day complications, readmissions and non-home discharge was evaluated. Multivariable logistic regression models were used to determine the association between mFI category and readmissions/ complications. Adjusted probabilities of events were calculated based on patient characteristics. RESULTS: At total of 31,181 gynecologic cancer cases were included in the analysis: N = 2968 (9.4%) cervical, N = 20,862 (66.4%) uterine, and N = 7351 (23.4%) ovarian cancers. Of all patients, 46.1% were in category 0, 36.5% category 1, and 1% category 3-5. Factors associated with increased mFI included older age, African American race, laparoscopic surgery and obesity. A significant dose-response relationship between higher mFI and readmission and 30-day complications was noted on adjusted multivariable analysis (adjusted OR 2.37 (1.65-3.45) and 2.10 (1.59-2.75) for readmissions and complications, respectively, in mFI category 3-5). These associations were consistent within each cancer type. CONCLUSIONS: The 5-factor mFI universally predicts postoperative readmissions, 30-day complications and non-home discharge in patients with gynecologic cancer. Incorporation of mFI into routine preoperative assessment can identify patients for non-surgical treatments, prehabiliatation and short term home assessments.

Assessment of travel distance for hyperthermic intraperitoneal chemotherapy in women with ovarian cancer.

Objective s: To evaluate travel distance in women with advanced or recurrent epithelial ovarian cancer (OC) undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC) and the subsequent impact upon outcomes. Methods: An IRB-approved single-institution prospective registry was queried for women with OC who underwent HIPEC from 1/1/2009-12/1/2020. Demographic, oncologic, and surgical data were recorded. The patient's home zip code was compared to the institutional zip code to determine travel distance using Google Maps. Patients were divided into three strata for analysis: 1) local: ≤50 miles, 2) regional: 51-99 miles, and 3) distant: ≥100 miles and univariate analysis was performed. Results: Of 127 women, the median distance travelled was 57.0 miles (IQR: 20.6, 84.6). There were no significant differences in mild (28.3% vs. 26.3 vs. 24.1%), moderate (21.7% vs. 15.8% vs. 17.2%) or severe postoperative complications (11.7% vs. 5.3% vs. 17.2%) (p = 0.75) for local, regional and distant patients, respectively. There was no difference in progression-free survival (17.4 vs. 22.2 vs. 12.8 months, p > 0.05) or overall survival (57.3 vs. 61.6 vs. 29.2 months, p > 0.05) for local, regional or distant patients, respectively. Conclusions: This study demonstrates that women with OC are willing to travel for HIPEC, with over 50% traveling > 50 miles. Our results suggest that women who travel for HIPEC procedures are not at increased risk for perioperative complications or worse oncologic outcomes than those local to HIPEC centers.

Evaluation of the Effect of Closure Technique on Incidence of Incisional Hernia after Single-Port Laparoscopy in Gynecologic Oncology Surgery.

STUDY OBJECTIVE: To evaluate incidence and risk factors for incisional hernia in women undergoing single-port laparoscopy (SPL) for gynecologic oncology indications with a standardized fascia closure (SC) technique vs historical controls (HC). DESIGN: Retrospective cohort study. SETTING: Single academic institution. PATIENTS: Women who underwent SPL from June 1, 2017, to December 31, 2019, for gynecologic oncology indications with SC were compared with HC who underwent SPL from January 1, 2009, to December 31, 2015. INTERVENTIONS: Data were collected for patient demographics, postoperative outcomes, and incisional hernia development. Univariate analysis and multivariable regression models were built for predictors of incisional hernia. MEASUREMENTS AND MAIN RESULTS: Of 1163 patients, 242 (20.8%) patients had SC, and 921 (79.2%) patients were HC. SC cohort had lower rates of diabetes vs HC (10.3% vs 15.3%; p = .049) but no differences in hypertension (36.8% vs 43.0% p = .081) and obesity (42.6% vs 36.9%, p = .11). A total of 1123 (96.6%) patients did not undergo conversion to multiport laparoscopy or laparotomy, of whom 7.2% (n = 81) of patients developed an incisional hernia; there was no difference in incisional hernia development for SC with SPL (n = 237) vHC with SPL (n = 886) (9.7% vs 6.5%, p = .095). On multivariable analysis, increased body mass index (odds ratio [OR] 1.06; 95% confidence interval [CI] 1.03-1.09, p < .001) and diabetes (OR 2.41; CI 1.34-4.32, p = .003) were associated with incisional hernia, but age (OR 1.00; CI .98-1.02, p = .92), length of surgery (OR 1.00; CI 1.00-1.01, p = .62), and hypertension (OR .89; CI .52-1.53, p = .68) were not. Patients with prior abdominal surgeries (OR 1.92; CI 1.14-3.26, p = .015) and hand-assist surgery (OR 3.17; CI 1.48-6.80, p = .003) were significantly associated with incisional hernia. CONCLUSION: Implementation of an SC protocol did not decrease the rate of incisional hernia vs HC during SPL. Risk of incisional hernia must be considered for SPL planning in patients with complex medical comorbidities and prior abdominal surgery.

Factors Associated With Unplanned Admission in Patients Intended for Same Day Discharge After Minimally Invasive Hysterectomy for Endometrial Cancer.

Objectives. To identify factors that lead to successful same-day discharge compared with unplanned and planned admission after minimally invasive hysterectomy for endometrial cancer. Methods. Patients undergoing laparoscopic or robotic hysterectomy for endometrial cancer between 2016 and 2019 were retrospectively reviewed. 3 groups were created: same-day discarge (SDD), unplanned admission (UA), and planned admission(PA). Demographic/perioperative factors and encounters after discharge were compared. A multivariable logistic regression was performed. Results. 262 patients were included. By year, the success of SDD increased from 59.1% to 82.5%. Patients who underwent SDD compared with admission were younger (62.2 vs 66.2, P = .003) and had a lower Charlson Comorbidity Index (4 vs 5, P < .001). BMI was not significant. Comparing SDD and UA, shorter operative time (100.3 min vs 130.6 min, P = .037) was associated with SDD. Postoperative pain scores were not significant (3.8 vs 4.7, P = .086). The rate of unscheduled encounters within 30 days of discharge was not significantly different. On multivariable analysis, the odds of SDD decreased by 4% with each 1-year increase in age (OR .96, P = .017). Each 1-minute increase in operative time decreased the odds of SDD by 2% (OR .98, P < .001). Intraoperative acetaminophen (OR 2.78, P = .003) and ketorolac (OR 2.27, P = .031) were predictive of SDD. Conclusion. SDD can be safely incorporated into clinical practice in gynecologic oncology patients undergoing minimally invasive hysterectomy, even for patients older than previously reported. Shorter operative time was associated with SDD. The role of perioperative acetaminophen and ketorolac should be further investigated.

Efficacy of hyperthermic intraperitoneal chemotherapy and interval debulking surgery in women with advanced uterine serous carcinoma.

OBJECTIVES: To investigate the efficacy and safety of hyperthermic intraperitoneal chemotherapy (HIPEC) at the time of iterval debulking surgery (IDS) in women with advanced uterine serous carcinoma (USC) following neoadjuvant chemotherapy (NACT). METHODS: An IRB-approved single-institution prospective registry was queried to identify women with incidentally identified USC at the time of IDS + HIPEC for high-grade serous carcinoma. Patient demographic, oncologic, and surgical outcomes data were recorded. Univariate analysis determined progression-free survival (PFS) and overall survival (OS). RESULTS: In total, seven patients were found to have advanced USC after undergoing IDS + HIPEC, with a median age of 64.5 years. The majority had stage IV, (n = 6, 85.7%), MMR proficient (n = 5, 71.4%), p53 mutant (n = 6, 85.1%) USC. The median pre-operative CA125 was 24.0U/mL. HIPEC regimen was cisplatin (n = 3, 42.9%) or cisplatin with paclitaxel (n = 4, 57.1%). All patients underwent optimal cytoreduction, with 71.4% (n = 5) having no gross residual disease. Accordion post-operative complications were mild in 14.3% (n = 1), moderate in 57.1% (n = 4) and severe in 14.3% (n = 1); 14.3% (n = 1) had no complications. The median length of stay was 6.5 days (IQR 4-8 days) with a median time to chemotherapy of 33.0 days. The median PFS was 14.0 months (95% CI 3.5-20.8 months), and the median OS was 27.0 months (95% CI 5.1- not reached). CONCLUSIONS: In this small, prospective series, we demonstrate that IDS + HIPEC is well tolerated in patients with USC and is associated with favorable PFS and OS following NACT. Further prospective investigation is needed to validate these promising findings in larger, heterogeneous cohorts of women with advanced USC who are not candidates for primary surgical management.

PARP inhibitors decrease response to subsequent platinum-based chemotherapy in patients with BRCA mutated ovarian cancer.

To determine the effect of poly-adenosine ribose phosphatase inhibitors (PARPi) on the response to subsequent platinum-based chemotherapy (PBC) in patients with recurrent, platinum-sensitive BRCA-mutated epithelial ovarian, peritoneal, or fallopian cancer (BRCAm EOC). This is a retrospective, single-institution cohort study of patients with BRCAm EOC who received retreatment with PBC. The PFS of patients with BRCAm EOC to 2nd or 3rd PBC with and without a prior PARPi was determined. Additionally, we compared the PFS to subsequent PBC following a prior PARPi for BRCAm and non-BRCAm. One hundred and fifteen patients with BRCAm EOC received a 2nd PBC and 55 received a 3rd PBC. The median PFS was 2.3 and 2.4 times longer, respectively for patients who did not receive a PARPi, (2nd P = 0.005, 3rd P < 0.001). Among 20 PARPi exposed patients with BRCAm EOC the PFS to a 2nd or 3rd PBC was worse at 8.0 months vs. 19.1 months HR 4.01 [2.25,7.16], P < 0.001. Following PARPi exposure the PFS for patients with BRCAm EOC was similar for patients with platinum-free intervals of 6-12, 12-24 and >24 months. Following PARPi exposure the PFS was similar for patients with BRCAm EOC and non BRCAm EOC. Among patients with BRCAm EOC PARPi exposure significantly reduced PFS following 2nd and 3rd PBC. PARPi exposure nullifies established prognostic factors (i.e. platinum-free interval and BRCA mutational status) in platinum-sensitive recurrent ovarian cancer.

Anastomotic leak following interval debulking surgery with or without hyperthermic intraperitoneal chemotherapy in women with advanced epithelial ovarian Cancer.

OBJECTIVE(S): To evaluate the incidence and associated risk factors for anastomotic failure following interval debulking surgery (IDS) with or without hyperthermic intraperitoneal chemotherapy (HIPEC) in women with advanced ovarian cancer. METHODS: We performed a retrospective cohort study in women with stage III/IV high-grade ovarian cancer treated with neoadjuvant chemotherapy followed by IDS with colorectal resection and HIPEC from 2017 to 2020. These patients were compared to a historical control cohort who underwent IDS with colorectal resection without HIPEC from 2009 to 2016. Data was collected for demographics, surgical variables, and perioperative outcomes. The univariate analysis compared progression-free survival and overall survival. RESULTS: 61 women were identified; 21 (34.4%) underwent IDS with HIPEC from 2017 to 2020, and 40 underwent IDS alone from 2009 to 2016. None of the patients who had IDS with HIPEC had protective ileostomy, compared to 10.0% of those who received had IDS alone (n = 4)(p = 0.29). The cumulative incidence of anastomotic leak rate was 8.2% (n = 5). There was no significant difference in anastomotic leak rate for women who underwent IDS with HIPEC (9.5%, n = 2) versus without HIPEC (7.5%, n = 3) (p = 0.99). While there was no difference in PFS (12.2 vs. 13.3 months, log-rank p = 0.31), OS (9.4 vs. 40.6 months, log-rank p = 0.013) was significantly decreased following postoperative anastomotic leak. CONCLUSIONS: In this retrospective series of women with advanced ovarian cancer, HIPEC was not associated with increased risk for anastomotic leak at the time of IDS with colorectal resection and reanastomosis. While further study is needed, HIPEC alone should not preclude colorectal resection or dictate practices for colonic diversion in IDS.

Modified frailty index predicts postoperative complications in women with gynecologic cancer undergoing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.

OBJECTIVE(S): To evaluate the impact of frailty on postoperative complications following cytoreductive surgery (CRS) with hyperthermic intra-peritoneal chemotherapy (HIPEC) in women with advanced or recurrent gynecologic cancer. METHODS: An IRB-approved single-institution prospective registry was queried for women who underwent CRS with HIPEC for advanced or recurrent gynecologic cancer from 1/1/2014-12/31/2020. Frailty was defined as a modified Frailty Index (mFI) score of ≥2. Logistic regression was used to assess the impact of mFI upon the rate of moderate or higher (≥ grade 2) Accordion postoperative complications. RESULTS: Of 141 women, 81.6% (n = 115) were non-frail with mFI of 0-1 and 18.4% (n = 26) were frail with mFI ≥2. The incidence of ≥ grade 2 complications was 21.2% (n = 14) for mFI = 0, 26.5% (n = 13) for mFI = 1, 64.7% (n = 11) for mFI = 2 and 100.0% (n = 9) for patients with mFI ≥3. The incidence of re-operation (1.7% vs. 11.5%, p = 0.044), ICU admission (13.2% vs. 34.6%, p = 0.018), acute kidney injury (6.3% vs. 30.8%, p = 0.001), and respiratory failure (0.9% vs. 19.2%, p < 0.001) were significantly lower amongst non-frail vs. frail women. On multivariable analysis, mFI ≥2 was associated with significantly increased ≥ grade 2 complications versus mFI of 0-1 (OR 9.4, 95% CI 3.3, 26.4, p < 0.001). Age (OR 1.04, 95% CI 1.00, 1.09, p = 0.07), surgical indication (recurrent vs. primary) (OR 0.71, 95% CI 0.30, 1.7, p = 0.44) and Surgical Complexity Score of Intermediate or High vs. Low (OR 1.5, 95% CI 0.67, 3.5, p = 0.31) were not associated with ≥grade 2 complications. CONCLUSIONS: Frailty, defined by the modified frailty index, is predictive of ≥grade 2 postoperative complications following CRS with HIPEC in women with gynecologic cancer. Frailty screening before CRS with HIPEC may assist patient selection and improve postoperative outcomes.

Perioperative outcomes of cytoreductive surgery with hyperthermic intraperitoneal chemotherapy in elderly women with epithelial ovarian cancer: analysis of a prospective registry.

OBJECTIVE: To evaluate perioperative outcomes in elderly versus non-elderly women with advanced or recurrent epithelial ovarian cancer undergoing surgery with hyperthermic intraperitoneal chemotherapy (HIPEC). METHODS: A single-institution prospective registry was analyzed for women with ovarian cancer who underwent surgery with HIPEC from January 2014 to December 2020. Elderly age was defined as ≥65 years at surgery. Complications were defined according to the Accordion scale. Univariate and multivariable analysis was used to compare progression-free survival and overall survival. RESULTS: Of 127 women who underwent surgery with HIPEC, 33.1% (n=42) were ≥65 and 17.3% (n=22) were ≥70 years old. The median age for non-elderly and elderly patients were 55.7±8.3 versus 72.0±5.4 years, respectively (p<0.001). The majority of non-elderly versus elderly patients underwent HIPEC at the time of interval cytoreductive surgery following neoadjuvant chemotherapy (52.9% vs 73.8%, p=0.024). There were no differences in moderate (15.3% vs 26.2%) or severe postoperative complications (10.6% vs 11.9%, p=0.08), acute kidney injury (7.1% vs 16.7%, p=0.12), and length of stay (5.0 vs 5.0 days, p=0.56) for non-elderly versus elderly patients. With a median follow-up of 20 months (95% CI 9.1 to 32.7 months), there was no difference in progression-free survival (18.8 vs 15.7 months, p=0.75) or overall survival (61.6 months vs not estimable, p=0.72) for non-elderly versus elderly patients. Comparing patients 65-69 versus ≥70 years, progression-free survival (33.0 vs 12.5 months, p=0.002) was significantly improved in patients aged 65-69, without difference in overall survival (not estimable vs 36.0 months, p=0.91). On multivariable analysis, age ≥65 did not impact progression-free survival (p=0.74). CONCLUSIONS: In this prospective registry of women with ovarian cancer, perioperative morbidity is not increased for non-elderly versus elderly patients following surgery with HIPEC. While age should not exclude patients from surgery with HIPEC, additional research is needed regarding oncologic benefits in elderly women.

Survey of trends in authorship assignment in gynecologic oncology: Keeping score and playing fair.

Authorship confers credit to those responsible for a publication. In 1985, the International Committee of Medical Journal Editors criteria were founded to standardize authorship assignment. We sought to investigate practices and values in authorship assignment in Society of Gynecologic Oncology (SGO) members. An anonymous online survey was distributed to SGO members from 09/2018-10/2018. Three multivariable logistic regression models were fit to predict ICJME authorship acceptance, assignment and denial. Of 1111 members surveyed, 266 responses were received (23.9%); 30.6% reported prior authorship assignment that did not meet ICMJE criteria, and 18.8% (n = 50) reported a history of accepting authorship not meeting ICJME criteria. Reasons for non-adherence included: inclusion of the author's patients in the study (59.3%), resumé building (45.7%), and networking for career advancement (22.2%). The majority responded that ICJME criteria were generalizable (91.3%), helpful (83.8%), and considered non-adherence as scientific misconduct (66.0%). On multivariable analysis, practice duration of 5-20 years (HR 0.40, 95% CI 0.16, 0.99, p < 0.05) or > 20 years (HR 0.22, 95% CI 0.08, 0.59, p < 0.05) were significant predictors for adherence with ICMJE authorship assignment compared to fellows and those in practice < 5 years. Similarly, practice duration of 5-20 years (HR 10.0, 95% CI 2.0, 49.2, p < 0.05) or > 20 years (HR 25.9, 95% CI 1.06, 3.9, p < 0.05) were significant predictors for denial of authorship assignment compared to fellows and those in practice < 5 years. While the majority of respondents report that ICJME criteria are helpful, adherence to these criteria is a concern, especially in fellows and early-career faculty.