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.

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.

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.

Incidence and prognostic significance of inguinal lymph node metastasis in women with newly diagnosed epithelial ovarian cancer.

OBJECTIVE(S): To assess incidence and oncologic outcomes in women with advanced epithelial ovarian cancer (EOC) with inguinal lymph node metastasis (ILNM) at diagnosis. METHODS: An IRB-approved, retrospective single-institution cohort study was performed in women with stage III/IV EOC from 2009 to 2017. Patients with inguinal lymphadenopathy (defined as >1 cm in short axis) clinically or radiographically were identified. The impact of ILNM on progression-free survival (PFS) and overall survival (OS) were assessed. RESULTS: Of the 562 women with advanced EOC, 18 (3.2%) had ILNM at diagnosis, accounting for 25.7% of all patients with stage IVB disease (n = 70). Five patients (27.7%) had a known genetic predisposition for EOC, including BRCA1 (11.1%, n = 2), BRCA2 (11.1%, n = 2) and BRIP1 (5.6%, n = 1). The majority of patients underwent optimal primary cytoreductive surgery (CRS), including debulking of inguinal nodal metastasis (83.3%, n = 15), with 50% (n = 9) having no gross residual disease after surgery. There was no difference in PFS (19.9 vs. 19.9 vs. 17.2 months, p = 0.84) or OS (137.2 vs. 52.9 vs. 67.6 months, p = 0.29) in women with stage III/IV with ILNM, stage III/IV without ILNM, and stage IVB disease without ILNM, respectively. Progression-free survival was improved in women with ILNM who underwent an optimal resection to no macroscopic disease vs. non-optimal resection (27.4 vs. 14.3 months, p = 0.019). Median overall survival at the time of analysis did not reach statistical significance (137.2 vs. 57.3 months, p = 0.24). CONCLUSION(S): In this retrospective cohort study, 3.2% of women with advanced EOC presented with ILNM at diagnosis. Although ILNM did not portend worse clinical outcomes compared to all Stage III/IV and Stage IVB patients, respectively, resection to no gross residual disease was associated with improved PFS.

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.

Development and validation of a comprehensive clinical risk-scoring model for prediction of overall survival in patients with endometrioid endometrial carcinoma.

OBJECTIVE: To develop and validate a comprehensive overall survival (OS) risk-scoring model in women with endometrioid endometrial cancer (EC). METHODS: Patients with EC diagnosed from 2004 to 2013 were identified through the National Cancer Database (NCDB). Patients with known lymphovascular space invasion (LVSI) status who were treated surgically (with or without adjuvant therapy) were included. Cox proportional hazards analysis was used to identify prognostic factors for OS. This model was used to assign points based on hazard ratios for risk factors and a risk score was obtained. Recursive partitioning analysis (RPA) was used to categorize patients into risk groups. Results were internally validated in a cohort of patients from our institution (CCF cohort). Risk scores were calculated and assessed in a Cox regression model, and Harrell's c-index was calculated to assess model fit. RESULTS: Among 349,404 women with EEC during the study period, 42,107 fulfilled inclusion criteria. Factors associated with worse OS were age ≥ 60, African American race, Charlson-Deyo score 1 or 2+, higher grade, LVSI, tumor size ≥2 cm, and no lymphadenectomy performed. Six risk groups were identified (scores 0-30) and OS estimated for each risk group. Risk score per 1-point increase in HR were comparable between NCDB and CCF cohorts (HR 1.21 (1.20-1.22 p < 0.001 vs 1.18 (1.12-1.25), p < 0.001), and c-index 0.80 (0.79-0.81) vs. 0.77 (0.68-0.86). Similar analysis was done in stage IA and IB. Adjuvant therapy had a beneficial effect on survival in the majority of stage IB patients, but only one of the six risk groups in stage IA EC. CONCLUSIONS: We report a comprehensive validated OS risk-scoring model for patients with.

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.

Assessing feasibility and perioperative outcomes with minimally invasive surgery compared with laparotomy for interval debulking surgery with hyperthermic intraperitoneal chemotherapy for advanced epithelial ovarian cancer.

OBJECTIVE: To determine peri-operative outcomes in women with advanced epithelial ovarian cancer (EOC) undergoing interval debulking surgery (IDS) with hyperthermic intraperitoneal chemotherapy (HIPEC) via minimally invasive interval debulking surgery (MIS) or laparotomy (LAP). METHODS: A single institution, retrospective cohort study was performed in women with EOC who underwent IDS with HIPEC from 2017 to 2019 via MIS or LAP. Peri-operative outcomes were compared using univariate analysis. RESULTS: In total, 50 eligible women were identified; ten (20.0%) underwent MIS + HIPEC and 40 (80.0%) LAP + HIPEC. The median age of patients in the MIS group was 71.1 vs. 64.2 years in LAP (p = 0.031). There was no significant difference in pre-operative complete radiographic response following NACT (p = 0.18). Notably, there was no difference in the rate of R0 resection (70.0% vs. 77.5%; p = 0.39). There was no significant difference in ICU admission, estimated blood loss, operative time, or use of vasopressors between the cohorts. Similarly, there was no difference in 30-day adverse events for MIS vs. LAP, but length of stay was decreased for those who underwent minimally invasive procedures (3 vs. 4 days, p = 0.016). Time to initiation of chemotherapy following surgery was not significantly different between groups (26.2 days vs 32.0 days, p = 0.090). With median follow-up of 15.1 months, there was no difference in recurrence free survival (median 15.0 vs 17.2 months log-rank, p = 0.30) for MIS vs. LAP. CONCLUSIONS: In this retrospective cohort study, we demonstrate that in women with advanced EOC, HIPEC with MIS at the time of IDS following NACT is feasible. Our institutional experience demonstrates similar rates of R0 cytoreduction, compared to LAP. An MIS approach should not prevent surgeons from utilizing HIPEC where indicated for management of advanced EOC.

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.

The Microbiome and Gynecologic Cancer: Current Evidence and Future Opportunities.

PURPOSE OF REVIEW: We review the emerging evidence regarding the relationship between the microbiota of the gastrointestinal and female reproductive tracts and gynecologic cancer. RECENT FINDINGS: The microbiome has essential roles in maintaining health. In recent years, the microbiota of the gastrointestinal and female reproductive tracts have been linked to many diseases, including gynecologic cancer. Alterations to the bacterial populations in a microbiota, or dysbiosis, have been shown to favor a pro-carcinogenic state through altered immune responses, dysregulated hormone metabolism, and modulation of the cell cycle. Pre-clinical and clinical studies have emerged, demonstrating that specific bacteria or microbial communities may be associated with increased risk for uterine, ovarian, and cervical cancers. Notably, numerous studies have linked a non-Lactobacillus-dominant vaginal microbiota, composed of anaerobic bacteria, with HPV infection, persistence, and development of invasive cervical cancer. Similarly, next-generation high-throughput sequencing techniques have enabled the characterization of unique microbiotas in patients with malignant and benign gynecologic conditions, shedding light on new associations between bacterial species and gynecologic cancers. Harnessing the power of the microbiome for early diagnosis, therapeutic intervention and modulation creates tremendous potential to optimize gynecologic cancer outcomes in the future.

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.