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.

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.

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.

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.

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.

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.

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.

Impact of antibiotic treatment on immunotherapy response in women with recurrent gynecologic cancer.

OBJECTIVE(S): To identify whether antibiotics (ABX) impact immunotherapy (ICI) response rate (RR), progression-free survival (PFS), and overall survival (OS) in women with recurrent endometrial (EC), cervical (CC) and ovarian cancer (OC). METHODS: This retrospective cohort study included women with recurrent EC, CC, and OC treated with ICIs from 1/1/17-9/1/2020. ABX were defined as 30 days before (pABX) or concurrently (cABX) with ICI. The impact of ABX upon PFS and OS was assessed by univariate analysis and multivariable Cox regression. RESULTS: Of 101 women, 52.5% (n = 53) had recurrent EC, 21.4% (n = 22) CC and 25.7% (n = 26) OC. 56.9% (n = 58) received ABX, with 22.8% (n = 23) pABX and 46.5% (n = 47) cABX. While no difference was observed in ICI RR for any ABX vs. none (p = 0.89) and cABX vs. none (p = 0.33), pABX (n = 23) were associated with decreased RR vs. none (n = 78) (Partial Response - 8.7% vs. 30.8%; Complete Response - 4.3% vs. 9.0%; p = 0.002). On univariate analysis, pABX were associated with worsened PFS (2.9 vs. 8.9 months; HR 2.53, 95% CI 1.48-4.31, p < 0.001) and OS (9.3 vs. 19.9 months; HR 2.29, 95% CI 1.22-4.32, p = 0.01). No PFS or OS difference was noted for cABX (PFS - 9.3 vs. 6.0 months; HR 0.70, 95% CI 0.43-1.12; p = 0.14; OS - 13.4 vs. 16.3 months; HR 0.89, 95% CI 0.51-1.54; p = 0.68). On multivariable analysis, pABX were associated with significantly decreased PFS (HR 3.10, 95% CI 1.75-5.49, p < 0.001) and OS (HR 3.03, 95% CI 1.50-6.10, p = 0.002). CONCLUSIONS: In women with recurrent EC, OC, and CC receiving ICI, pABX, but not cABX, are associated with decreased RR, PFS, and OS. Further investigation is warranted to understand predictors of ICI response in women with gynecologic cancer.

Impact of intra-operative factors upon peri-operative outcomes in women undergoing hyperthermic intraperitoneal chemotherapy for gynecologic cancer.

OBJECTIVES: To evaluate the incidence of intra-operative metabolic and electrolyte abnormalities and subsequent impact on peri-operative outcomes in women with gynecologic cancer undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS + HIPEC). METHODS: An IRB-approved single institution retrospective cohort study was performed in women with gynecologic cancer who underwent CRS + HIPEC. Patient demographics, intra-operative electrolyte and metabolic values and peri-operative outcomes were recorded. To assess the association of pH and lactate upon post-operative outcomes, patients were divided in four quartiles for both variables and univariate analysis was performed. RESULTS: 100 consecutive women who underwent CRS + HIPEC from 2017 to 2020 were identified. Intra-operative blood transfusion and pressor support were required in 40% and 86%, respectively. The rate of ICU admission was 17%. Longer operative time (7.0 vs. 5.3 h, p = 0.002), increased blood loss (400.0 vs. 200.0 mL, p = 0.02) and transfusion (70.6% vs. 34.1%, p = 0.005) were associated with ICU admission. Compared to patients in the highest quartile of pH, lower median pH, (7.211 vs. 7.349, p < 0.001) was associated with increased rates of ICU admission, prolonged intubation (36.0% vs. 0.0%, p < 0.05, respectively) and any post-operative complication (72.0% vs. 28.0%, p = 0.01). Similarly, need for prolonged intubation (40% vs. 0%, p = 0.04) and VTE (13.0% vs. 0%, p = 0.01) were increased in women with the highest quartile of lactate levels compared to the lowest (4.7 vs 1.9, p < 0.001). CONCLUSIONS: Intra-operative acidosis is associated with higher incidence of ICU admission and peri-operative complications following CRS + HIPEC in women with gynecologic cancer. These data support the importance of adequate intra-operative resuscitation and timely correction of hemodynamic and metabolic abnormalities.

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.

Patterns of recurrence in women with advanced and recurrent epithelial ovarian cancer treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.

OBJECTIVE(S): To identify recurrence patterns and outcomes in women with advanced or recurrent epithelial ovarian cancer (EOC) after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). METHODS: This is an IRB-approved single-institution cohort study of women who underwent CRS+HIPEC for advanced or recurrent EOC followed in a prospective registry from 1/12/2014-3/1/2020. Recurrence locations were defined as pelvic, upper abdominal (UA) and/or extra-peritoneal (EP). Univariate analysis assessed associations between recurrence location, progression-free survival (PFS), and overall survival (OS). RESULTS: In total, 92 women with EOC underwent interval (56.5%; n=52) or recurrent CRS+HIPEC (43.5%; n=40). For interval CRS+HIPEC, recurrence locations were pelvic in 50.0% (n=15), UA in 23.3% (n=7) and EP in 56.7% (n=17); 40.0% (n=12) were EP alone. Similarly, for recurrent CRS+HIPEC, recurrence locations were pelvic (22.5%, n=9), UA (5.0%, n=2) and EP (60.0%, n=24); 66.7% (n=20) were EP alone. For both interval and recurrent CRS+HIPEC, median PFS was 10.5 vs. 13.0 months for pelvic and UA vs. EP only recurrences (p=0.02). Similarly, median OS was 29.2 months for pelvic and UA and not reached for EP only (p=0.05). For interval CRS+HIPEC, there was no difference in median PFS (10.6 vs. 11.7 months, p=0.68) and OS (27.1 vs. 24.8 months, p=0.96) for pelvic and UA vs EP alone. However, for recurrent CRS+HIPEC, pelvic and UA sites of recurrence were associated with reduced PFS (10.0 vs. 18.1 months, p=0.03) and OS (33.6 months vs. not reached, p=0.02) vs. EP only. CONCLUSIONS: In women with advanced or recurrent EOC undergoing CRS+HIPEC, one-half of patients experience their first recurrence outside of the peritoneal cavity. Providers must be aware of the risk of EP failure in patients treated with CRS+HIPEC.

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.

Short- and long-term outcomes for single-port risk-reducing salpingo-oophorectomy with and without hysterectomy for women at risk for gynecologic cancer.

INTRODUCTION: Risk-reducing salpingo-oophorectomy has been established as one of the most effective strategies in risk reduction for ovarian and breast cancers among women at increased genetic risk. However, there are limited data regarding the single-port laparoscopic platform in the field of risk-reducing surgery. Our objective was to describe outcomes after single-port risk-reducing salpingo-oophorectomy with or without hysterectomy for reduction of ovarian, breast, or endometrial cancer risk. METHODS: A retrospective, single institution (Canadian Task Force Classification II.2) analysis was performed in women at high genetic or familial risk for ovarian/tubal/primary peritoneal cancer or with personal history of breast cancer who underwent single-port laparoscopic risk-reducing salpingo-oophorectomy with or without hysterectomy between October 2009 and December 2015. Data were collected on patient demographics, surgical procedure and characteristics, intra-operative findings, and post-operative outcomes. RESULTS: In total, 187 single-port laparoscopic surgeries were performed with a median follow-up of 204 (IQR 25-749) days. BRCA1/2, Lynch syndrome, or Cowden syndrome was diagnosed in 64.0% of patients. Additionally, 32.1% had a personal history of breast cancer, and 3.2% reported strong family history of ovarian and/or breast cancer. Single-port risk-reducing salpingo-oophorectomy with hysterectomy was performed in 53.5% of patients. The rate of adverse outcomes, including conversion to multiport laparoscopy or laparotomy (1.6%), intra-operative injury (1.6%), deep vein thrombosis (0.5%), urinary tract infection (2.7%), and/or incisional cellulitis (4.3%) were low. Three patients (1.6%) were diagnosed with malignancy on final pathology. All three patients were BRCA1-positive and their CA125 values were significantly lower than those without malignancy (p=<0.0001). CONCLUSIONS: Single-port laparoscopy is a safe option for patients undergoing risk-reducing salpingo-oophorectomy with or without hysterectomy. Standardized pre-operative evaluation criteria are needed to determine absolute risk of incidental malignancy, and the risk of identifying a malignancy should be reiterated to patients during pre-operative counseling.

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.

Trends and Risk Factors for Vaginal Cuff Dehiscence after Laparoscopic Hysterectomy.

STUDY OBJECTIVE: The primary objective was to assess the effect of the route of closure of the vaginal cuff on the incidence of vaginal cuff dehiscence (VCD) in laparoscopic hysterectomy (LH). The secondary objective was to assess patient- and surgical-risk factors associated with VCD, rate of perioperative complications by route of closure, and impact of surgeon volume on complications. DESIGN: Retrospective chart review with case-control component. SETTING: Tertiary care center (main hospital and regional hospitals). PATIENTS: A total of 1278 women underwent LH or robot-assisted hysterectomy in 2016, and met the inclusion criteria. Independently, 26 cases of VCD were identified from 2009 through 2016. INTERVENTIONS: A retrospective comparison of patients with vaginal cuff closure and laparoscopic cuff closure (LCC) undergoing LH or robot-assisted hysterectomy in 2016. Patients with VCD from 2009 through 2016 (n = 26) were matched by route of cuff closure to the next 7 patients who underwent hysterectomies (n = 182), who became controls. MEASUREMENTS AND MAIN RESULTS: In 2016, there were 9 cases of VCD (0.70%). There was no significant difference in VCD between LCC (8/989; 0.81%) and vaginal cuff closure (1/289; 0.35%; p = .41). Seven VCD cases were performed by high-volume surgeons (>30 hysterectomies per year) who were more likely to perform LCC and use barbed suture. There were no significant differences in the rates of perioperative complications or surgeon volume between routes of cuff closure. The case-control patients differed in smoking status (p = .010) and history of prior laparotomy (p = .017). Logistic regression showed that increasing age (odds ratio 0.95; 95% confidence interval, 0.91-0.99) and increasing body mass index (odds ratio 0.98; 95% confidence interval, 0.83-0.97) were protective for VCD. CONCLUSION: VCD is a rare but serious complication of LH. Despite previous studies, we did not find a significant difference in VCD or intra- and perioperative complications by route of cuff closure or surgeon volume. Given the lack of evidence favoring one route of cuff closure, we recommend that, to optimize patient outcomes, surgeons employ the closure technique that they are best accustomed to.

Meta-analysis of Laparoendoscopic Single-site and Vaginal Natural Orifice Transluminal Endoscopic Hysterectomy Compared with Multiport Hysterectomy: Real Benefits or Diminishing Returns?

OBJECTIVE: Because minimally invasive hysterectomy has become increasingly performed by gynecologic surgeons, strategies to further improve outcomes have emerged, including innovations in surgical approach. We sought to evaluate the intraoperative and perioperative outcomes and success rates of laparoendoscopic single-site surgery (LESS) and vaginal natural orifice transluminal endoscopic surgery (vNOTES) hysterectomy in comparison with those of conventional multiport laparoscopic (MPL) hysterectomy. DATA SOURCES: A librarian-led search of PubMed, Scopus, CINAHL, Embase, Web of Science, and the Cochrane Central Register of Controlled Trials was performed for case-control, retrospective cohort, and randomized controlled trials through May 2020. METHODS OF STUDY SELECTION: The inclusion criterion was publications comparing LESS or vNOTES hysterectomy with conventional MPL hysterectomy for the management of benign or malignant gynecologic disease. Four authors reviewed the abstracts and selected studies for full-text review. The manuscripts were reviewed, separately, by 2 authors for final inclusion and assessment of bias using either the risk-of-bias assessment tool or the Newcastle-Ottawa scale. Any disagreement was resolved by discussion with, or arbitration by, a third reviewer. The titles of 2259 articles were screened, and 108 articles were chosen for abstract screening. Full-text screening resulted in 29 studies eligible for inclusion. TABULATION, INTEGRATION, AND RESULTS: Extracted data were placed into REDCap (Vanderbilt University, Nashville, TN), and MPL hysterectomy was compared with single-port hysterectomy using meta-analysis models. The outcomes included estimated blood loss (EBL); operative (OP) time; transfusion; length of hospital stay (LOS); conversion to laparotomy; visual analog scale pain scores at 12 hours, 24 hours, and 48 hours; any complications; and 7 subcategories of complications. Random-effects models were built for continuous outcomes and binary outcomes, and the results are reported as standardized mean difference (SMD) or odds ratio (OR) and their corresponding 95% confidence intervals, respectively. Meta-analysis could not be performed for vNOTES vs MPL, given that only 3 studies met the eligibility criteria. When LESS and MPL were compared, there was a shorter OP time for MPL (SMD = -0.2577, p <.001) and lower rate of transfusion (OR = 0.1697, p <.001), without a significant difference in EBL (SMD = -0.0243, p = .689). There was a nonsignificant trend toward higher risk of conversion to laparotomy in the MPL group (OR = 2.5871, p = .078). Pain scores were no different 12 or 24 hours postoperatively but were significantly higher at 48 hours postoperatively (SMD = 0.1861, p = .035) in the MPL group. There were no differences in overall or individual complications between the LESS and MPL groups. In the vNOTES comparison, 2 studies demonstrated shorter OP times, with reduced LOS and no difference in complications. CONCLUSION: In this meta-analysis, we identified that LESS hysterectomy has comparable and low overall rates of complications and conversion to laparotomy compared with MPL. Notably, the OP time seems longer, and the pain scores at 48 hours may be lower with LESS hysterectomy than with MPL hysterectomy. Limited data suggest that vNOTES hysterectomy may have shorter OP times and improved EBL, transfusion rates, LOS, and pain scores compared with MPL hysterectomy, but further study is needed. There remains a deficit in high-quality data to understand the differences in cosmesis among these surgical approaches. The quality of data for this analysis seems to be low to moderate.

Adjuvant therapy for early stage, endometrial cancer with lymphovascular space invasion: Is there a role for chemotherapy?

OBJECTIVES: Lymphovascular space invasion (LVSI) is an independent risk factor for recurrence and poor survival in early-stage endometrioid endometrial cancer (EEC), but optimal adjuvant treatment is unknown. We aimed to compare the survival of women with early-stage EEC with LVSI treated postoperatively with observation (OBS), radiation (RAD, external beam and/or vaginal brachytherapy), or chemotherapy (CHEMO)+/-RAD. METHODS: This was a multi-institutional, retrospective cohort study of women with stage I or II EEC with LVSI who underwent hysterectomy+/-lymphadenectomy from 2005 to 2015 and received OBS, RAD, or CHEMO+/-RAD postoperatively. Progression-free survival and overall survival were evaluated using Kaplan-Meier estimates and Cox proportional hazards models. RESULTS: In total, 478 women were included; median age was 64 years, median follow-up was 50.3 months. After surgery, 143 (30%) underwent OBS, 232 (48.5%) received RAD, and 103(21.5%) received CHEMO+/-RAD (95% of whom received RAD). Demographics were similar among groups, but those undergoing OBS had lower stage and grade. A total of 101 (21%) women recurred. Progression-free survival (PFS) was improved in both CHEMO+/-RAD (HR = 0.18, 95% CI: 0.09-0.39) and RAD (HR = 0.31, 95% CI: 0.18-0.54) groups compared to OBS, though neither adjuvant therapy was superior to the other. However, in grade 3 tumors, the CHEMO+/-RAD group had superior PFS compared to both RAD (HR 0.25; 95% CI: 0.12-0.52) and OBS cohorts (HR = 0.10, 95% CI: 0.03-0.32). Overall survival did not differ by treatment. CONCLUSIONS: In early-stage EEC with LVSI, adjuvant therapy improved PFS compared to observation alone. In those with grade 3 EEC, adjuvant chemotherapy with or without radiation improved PFS compared to observation or radiation alone.

Sleep, quality of life, and depression in endometrial cancer survivors with obesity seeking weight loss.

PURPOSE: Incidence and mortality rates of uterine cancer are increasing and, obesity, which is also rising, has been associated with uterine cancer development and mortality. A recent study found that poor sleep quality is common among endometrial cancer survivors and those with obesity had more sleep disturbances than those having normal weight. However, it is unclear if higher levels of obesity (Class III, BMI ≥ 40 kg/m2), which are rising rapidly, are differentially associated with sleep as well as depression and quality of life in endometrial cancer survivors. METHODS: We evaluated sleep, depression, and quality of life in 100 Stage I endometrial cancer survivors with obesity seeking weight loss enrolled in a lifestyle intervention (NCT01870947) at baseline. RESULTS: The average age was 60 years and mean BMI was 42.1 kg/m2 with 58% having a BMI ≥ 40 kg/m2. Most survivors (72.3%) had poor sleep quality and most (71.2%) reported sleeping < 7 h/night. Survivors with class III compared with class I obesity had significantly more sleep disturbances and daytime dysfunction; and, those with poor sleep had higher depression and lower quality of life. Survivors with a BMI ≥ 50 kg/m2 (~ 25%) had the highest levels of depression and lowest physical and emotional well-being. CONCLUSIONS: Our results reveal that endometrial cancer survivors with class III compared with class I obesity have poorer sleep quality, higher depression, and lower quality of life. Given the rising rates of obesity and uterine cancer mortality, interventions to combat both obesity and poor sleep are needed.