Salpingectomy for the Primary Prevention of Ovarian Cancer: A Systematic Review.

Importance: Most ovarian cancers originate in the fimbriated end of the fallopian tube. This has led to the hypothesis that surgical resection of the fallopian tubes at the time of gynecologic and nongynecologic surgical procedures-referred to as an opportunistic salpingectomy-may prevent the development of epithelial ovarian cancer for women at an average risk of developing the disease. Objective: To compile a comprehensive, state-of-the-science review examining the current landscape of performing bilateral salpingectomy for ovarian cancer prevention. Evidence Review: A systematic review of the literature was performed on March 4, 2022, to identify studies examining salpingectomy for ovarian cancer prevention. This review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) 2020 statement. Four databases were selected: PubMed via the National Library of Medicine's PubMed.gov, Embase via Elsevier's Embase.com, Cochrane Central Register of Controlled Trials (CENTRAL) via Wiley's Cochrane Library, and Northern Light Life Sciences Conference Abstracts via Ovid. A total of 20 gray literature sources, including 1 database, 2 registers, 1 repository, 1 index, 1 archive, 1 preprint server, 1 agency, and 12 organizations, were also searched. Findings: The initial search produced 1089 results; a total of 158 publications were included in the final review. Salpingectomy has been associated with ovarian cancer risk reduction of approximately 80%. Studies have demonstrated that salpingectomy was safe, cost-effective, and was not associated with an earlier age of menopause onset. With widespread implementation, salpingectomy has the potential to reduce ovarian cancer mortality in the US by an estimated 15%. Both physician and patient awareness regarding the adnexa as the origin for most ovarian cancers, as well as the existence of salpingectomy and its potential benefits in reducing ovarian cancer risk, has increased during the past decade. Raising awareness and developing effective implementation strategies are essential. Conclusions and Relevance: The results of this systematic review suggest that bilateral salpingectomy for ovarian cancer prevention was safe and feasible and has the potential to be a cost-effective and cost-saving strategy across the population. Prospective studies to demonstrate long-term survival outcomes and feasibility in nongynecologic surgical procedures are warranted.

The BUMPy road of peritoneal metastases in ovarian cancer.

Ovarian cancer is the most common cause of death due to gynecologic malignancies, with more than 70% of patients presenting with advanced stage disease at the time of diagnosis. The extent and distribution of tumor guide primary treatment selection and clinical management. While primary cytoreductive surgery with complete tumor resection improves survival, patients with extensive peritoneal disease may benefit from neoadjuvant chemotherapy first to reduce tumor burden followed by interval cytoreductive surgery. Imaging plays an essential role in triaging patients including selecting patients who may benefit from neoadjuvant chemotherapy before cytoreductive surgery. Interestingly, there are no universally established criteria to predict resectability and local practices depend on local guidelines and surgeon preferences. Nevertheless, certain anatomical tumor locations are known to be difficult to resect and are associated with suboptimal cytoreduction or require special surgical considerations. This review discusses the recent advances in the initial management of patients with ovarian cancer, a practical approach to the assessment and communication of peritoneal metastases locations on CT and MRI. It also explores recent advances in genomics profiling and radiomics that may influence the initial management of these patients.

Robotic resection of isolated ovarian cancer recurrence in the lesser sac.

In recurrent ovarian cancer patients the addition of surgical cytoreduction is associated with prolonged overall survival compared to chemotherapy treatment alone when complete cytoreduction is achieved (Harter et al., 2021, Shi et al., 2021, Coleman et al., 2019). In the appropriate surgical candidates, a minimally invasive approach may be used to achieve complete cytoreduction of isolated lesions with proper exposure and surgical planning. This video demonstrates safe robotic entry into the lesser sac and resection of recurrent high-grade serous ovarian carcinoma near the pancreatic neck. The patient is a 78-year-old BRCA negative female with a history of a stage IIIC high-grade serous carcinoma. She previously underwent cytoreductive surgery and adjuvant chemotherapy in 2018 and presented 24 months later with a normal CA 125 and CT findings of an isolated lesion near the porta hepatis. An MRI was obtained preoperatively to further characterize the location of the lesion demonstrating a 2.2 × 1.6 cm hypoechoic mass adjacent to the pancreatic neck. Given the patient's prolonged disease-free interval, fitness for surgery and single site of disease, she met strict inclusion criteria for recent studies demonstrating clinical benefit with secondary cytoreduction (Harter et al., 2021, Shi et al., 2021). She was taken for a robotic secondary cytoreduction. At subsequent follow up 7 months later, our patient was still disease free and continues surveillance. In this video, we demonstrate the careful dissection of this isolated lesion from the omental bursa. We review important pre-procedural and anatomic considerations for robotic surgery in the lesser sac.

Predictive validity of American College of Surgeons: National Surgical Quality Improvement Project risk calculator in patients with ovarian cancer undergoing interval debulking surgery.

INTRODUCTION: In gynecologic patients, few studies describe the accuracy of the American College of Surgeons-National Surgical Quality Improvement Project (ACS-NSQIP) pre-operative risk calculator for women undergoing surgery for ovarian cancer. OBJECTIVE: To determine whether the ACS-NSQIP risk calculator accurately predicts post-operative complications and length of stay in patients undergoing interval debulking surgery for advanced stage epithelial ovarian cancer. METHODS: For this multi-institutional retrospective cohort study, pre-operative risk factors, post-operative complication rates, and Current Procedural Terminology codes were abstracted from records of patients with ovarian cancer managed with open interval debulking surgery from January 2010 to July 2015. A power calculation was done to estimate the minimum number of complications needed to evaluate the accuracy of the ACS-NSQIP risk calculator. Predicted risk compared with observed risk was calculated using logistic regression. The predictive accuracy of the ACS-NSQIP risk calculator in estimating post-operative complications or length of stay was assessed using c-statistics and Briar scores. Complications with a c-statistic of >0.70 and Brier score of <0.01 were considered to have high discriminative ability. RESULTS: A total of 261 patients underwent interval debulking surgery, encompassing 21 unique Current Procedural Terminology codes. Readmission (n=25), surgical site infection (n=35), urinary tract infection (n=12), and serious post-operative complications (n=57) met the minimum event threshold (n>10). All predicted complication rates fell within the IQR of the observed incidence rates. However, the ACS-NSQIP calculator demonstrated neither discriminative ability nor accuracy for any post-operative complications based on c-statistics and Brier scores. The calculator accurately predicted length of stay within 1 day for only 32% of patients and could not accurately predict which patients were likely to have a prolonged length of stay (c-statistic=0.65). CONCLUSION: Among patients undergoing interval debulking surgery, the ACS-NSQIP did not accurately discriminate which patients were at increased risk of complications or extended length of stay. The risk calculator should be considered to have limited utility in informing pre-operative counseling or surgical planning.

Impact of residual disease at interval debulking surgery on platinum resistance and patterns of recurrence for advanced-stage ovarian cancer.

OBJECTIVE: To evaluate the impact of size and distribution of residual disease after interval debulking surgery on the timing and patterns of recurrence for patients with advanced-stage epithelial ovarian cancer. METHODS: Patient demographics and data on disease treatment/recurrence were collected from medical records of patients with stage IIIC/IV epithelial ovarian cancer who were managed with neoadjuvant chemotherapy/interval debulking surgery between January 2010 and December 2014. Among patients without complete surgical resection but with ≤1 cm of residual disease, the number of anatomic sites (<1 cm single anatomic location vs <1 cm multiple anatomic locations) was used to describe the size and distribution of residual disease. RESULTS: A total of 224 patients were included. Of these, 70.5% (n=158) had a complete surgical resection, 12.5% (n=28) had <1 cm single anatomic location, and 17.0% (n=38) had <1 cm multiple anatomic locations. Two-year progression-free survival for complete surgical resection, <1 cm single anatomic location, and <1 cm multiple anatomic locations was 22.2%, 17.9% and 7%, respectively (p=0.007). Size and distribution of residual disease after interval debulking surgery did not affect location of recurrence and most patients had recurrence at multiple sites (complete surgical resection: 64.7%, <1 cm single anatomic location: 55.6%, and <1 cm multiple anatomic locations: 71.4%). Controlling for additional factors that may influence platinum resistance and surgical complexity, the rate of platinum-resistant recurrence was similar for patients with complete surgical resection and <1 cm single anatomic location (OR=1.07, 95% CI 0.40 to 2.86; p=0.888), but women with <1 cm multiple anatomic locations had an increased risk of platinum resistance (OR=3.09, 95% CI 1.41 to 6.78 p=0.005). CONCLUSIONS: Despite current classification as 'optimal,' <1 cm multiple anatomic location at the time of interval debulking surgery is associated with a shorter progression-free survival and increased risk of platinum resistance.

Dissection of PIK3CA Aberration for Cervical Adenocarcinoma Outcomes.

Personalized treatment of genetically stratified subgroups has the potential to improve outcomes in many malignant tumors. This study distills clinically meaningful prognostic/predictive genomic marker for cervical adenocarcinoma using signature genomic aberrations and single-point nonsynonymous mutation-specific droplet digital PCR (ddPCR). Mutations in PIK3CA E542K, E545K, or H1047R were detected in 41.7% of tumors. PIK3CA mutation detected in the patient's circulating DNA collected before treatment or during follow-up was significantly associated with decreased progression-free survival or overall survival. PIK3CA mutation in the circulating DNA during follow-up after treatment predicted recurrence with 100% sensitivity and 64.29% specificity. It is the first indication of the predictive power of PIK3CA mutations in cervical adenocarcinoma. The work contributes to the development of liquid biopsies for follow up surveillance and a possibility of tailoring management of this particular women's cancer.

Enhanced Efficacy of Aurora Kinase Inhibitors in G2/M Checkpoint Deficient TP53 Mutant Uterine Carcinomas Is Linked to the Summation of LKB1-AKT-p53 Interactions.

Uterine carcinoma (UC) is the most common gynecologic malignancy in the United States. TP53 mutant UCs cause a disproportionate number of deaths due to limited therapies for these tumors and the lack of mechanistic understanding of their fundamental vulnerabilities. Here we sought to understand the functional and therapeutic relevance of TP53 mutations in UC. We functionally profiled targetable TP53 dependent DNA damage repair and cell cycle control pathways in a panel of TP53 mutant UC cell lines and patient-derived organoids. There were no consistent defects in DNA damage repair pathways. Rather, most models demonstrated dependence on defective G2/M cell cycle checkpoints and subsequent upregulation of Aurora kinase-LKB1-p53-AKT signaling in the setting of baseline mitotic defects. This combination makes them sensitive to Aurora kinase inhibition. Resistant lines demonstrated an intact G2/M checkpoint, and combining Aurora kinase and WEE1 inhibitors, which then push these cells through mitosis with Aurora kinase inhibitor-induced spindle defects, led to apoptosis in these cases. Overall, this work presents Aurora kinase inhibitors alone or in combination with WEE1 inhibitors as relevant mechanism driven therapies for TP53 mutant UCs. Context specific functional assessment of the G2/M checkpoint may serve as a biomarker in identifying Aurora kinase inhibitor sensitive tumors.

Risk of venous thromboembolism for ovarian cancer patients during first-line therapy after implementation of an Enhanced Recovery After Surgery (ERAS) protocol.

OBJECTIVE: To determine incidence and risk factors for VTE for patients with advanced epithelial ovarian cancer undergoing first-line therapy, including cytoreductive surgery, on an Enhanced Recovery After Surgery (ERAS) protocol. METHODS: Medical records were reviewed for patients with FIGO stage IIIA-IVB epithelial ovarian, fallopian tube, or primary peritoneal cancer undergoing primary or interval cytoreductive surgery from March 2017 through September 2019. All patients were enrolled on an ERAS protocol, including 28-day postoperative VTE prophylaxis. Demographic information, medical history, perioperative characteristics, and ERAS compliance were evaluated using univariate and multivariate models. RESULTS: Of 230 patients undergoing cytoreductive surgery via laparotomy, 155 received neoadjuvant chemotherapy and 75 received primary cytoreduction. 38 patients had a VTE during the study period. 13 events (5.7%) were identified at time of diagnosis, 6 (3.9%) during neoadjuvant chemotherapy, 5 (2.2%) within 30 days after surgery, 5 (2.2%) between 30 days and 6 months after surgery, and 9 (3.9%) after the 6-month window. The cumulative incidence of VTE was 6.1% (95% CI, 4.3-8.8%) within 6 months after diagnosis and 8.5% (6.2-11.4%) within 1 year after diagnosis. Estimated blood loss (adjusted HR 1.22 [95% CI, 1.09-1.36], p = 0.001) and history of VTE (7.06 [2.34-21.29], p = 0.001) were independently associated with VTE. CONCLUSION: With implementation of an ERAS protocol, only 1 in 46 patients experienced a VTE within 30 days after surgery. However, overall VTE occurred in 1 in 16 patients during first-line therapy. Strategies to further reduce VTE risk, especially during neoadjuvant chemotherapy and surveillance, should be investigated.

Fragmentation of surgery and chemotherapy in the initial phase of ovarian cancer care and its association with overall survival.

BACKGROUND: Fragmentation occurs when a patient receives care at more than one hospital, and the long-term effects in ovarian cancer are unknown. We examined the association between fragmentation of primary debulking surgery (PDS) and adjuvant chemotherapy (AC) and overall survival (OS). METHODS: The National Cancer Database was used to identify women with stage II-IV epithelial ovarian cancer between 2004 and 2016 who underwent PDS followed by AC. Fragmentation was defined as receipt of AC at a different institution than where PDS was performed. After propensity score weighting, proportional hazard models were developed to estimate the association between fragmented care and OS. RESULTS: Of the 36,300 patients identified, 13,347 (36.8%) had fragmented care. Patient factors associated with fragmentation included older age, higher income, and longer travel distance for PDS; hospital factors included PDS performed at a community center or a facility with lower annual surgical volume (P < 0.05, all). Fragmentation was associated with a 15% risk of 30-day delay to AC (aRR 1.15, 95% CI 1.09-1.22). In a propensity scoring weighted analysis, mortality was reduced when AC was fragmented (HR 0.95, 95% CI 0.92-0.97). Sensitivity analyses indicated fragmentation was associated with improved survival in metropolitan residents. Stratified analyses indicated patients who traveled 50 miles or more with PDS and AC at the same institution had the worst OS. CONCLUSION: Fragmentation of PDS and AC has no adverse effects on long-term survival. Survival outcomes were worst for those who received care at the same institution 50 miles or more away.

Gynecologic oncology treatment modifications or delays in response to the COVID-19 pandemic in a publicly funded versus privately funded North American tertiary cancer center.

OBJECTIVE: To compare gynecologic oncology surgical treatment modifications and delays during the first wave of the COVID-19 pandemic between a publicly funded Canadian versus a privately funded American cancer center. METHODS: This is a retrospective cohort study of all planned gynecologic oncology surgeries at University Health Network (UHN) in Toronto, Canada and Brigham and Women's Hospital (BWH) in Boston, USA, between March 22,020 and July 302,020. Surgical treatment delays and modifications at both centers were compared to standard recommendations. Multivariable logistic regression was performed to adjust for confounders. RESULTS: A total of 450 surgical gynecologic oncology patients were included; 215 at UHN and 235 at BWH. There was a significant difference in median time from decision-to-treat to treatment (23 vs 15 days, p < 0.01) between UHN and BWH and a significant difference in treatment delays (32.56% vs 18.29%; p < 0.01) and modifications (8.37% vs 0.85%; p < 0.01), respectively. On multivariable analysis adjusting for age, race, treatment site and surgical priority status, treatment at UHN was an independent predictor of treatment modification (OR = 9.43,95% CI 1.81-49.05, p < 0.01). Treatment delays were higher at UHN (OR = 1.96,95% CI 1.14-3.36 p = 0.03) and for uterine disease (OR = 2.43, 95% CI 1.11-5.33, p = 0.03). CONCLUSION: During the first wave of COVID-19 pandemic, gynecologic oncology patients treated at a publicly funded Canadian center were 9.43 times more likely to have a surgical treatment modification and 1.96 times more likely to have a surgical delay compared to an equal volume privately funded center in the United States.

Disease Distribution at Presentation Impacts Benefit of IP Chemotherapy Among Patients with Advanced-Stage Ovarian Cancer.

BACKGROUND: Ovarian cancer with miliary disease spread is an aggressive phenotype lacking targeted management strategies. We sought to determine whether adjuvant intravenous/intraperitoneal (IV/IP) chemotherapy is beneficial in this disease setting. METHODS: Patient/tumor characteristics and survival data of patients with stage IIIC epithelial ovarian cancer who underwent optimal primary debulking surgery from 01/2010 to 11/2014 were abstracted from records. Chi-square and Mann-Whitney U tests were used to compare categorical and continuous variables. The Kaplan-Meier method was used to estimate survival curves, and outcomes were compared using log-rank tests. Factors significant on univariate analysis were combined into multivariate logistic regression survival models. RESULTS: Among 90 patients with miliary disease spread, 41 (46%) received IV/IP chemotherapy and 49 (54%) received IV chemotherapy. IV/IP chemotherapy, compared with IV chemotherapy, resulted in improved progression-free survival (PFS; 23.0 versus 12.0 months; p = 0.0002) and overall survival (OS; 52 versus 36 months; p = 0.002) in patients with miliary disease. Among 78 patients with nonmiliary disease spread, 23 (29%) underwent IV/IP chemotherapy and 55 (71%) underwent IV chemotherapy. There was no PFS or OS benefit associated with IV/IP chemotherapy over IV chemotherapy in these patients. On multivariate analysis, IV/IP chemotherapy was associated with improved PFS (HR, 0.28; 95% CI 0.15-0.53) and OS (HR, 0.33; 95% CI 0.18-0.61) in patients with miliary disease compared with those with nonmiliary disease (PFS [HR, 1.53; 95% CI 0.74-3.19]; OS [HR, 1.47; 95% CI 0.70-3.09]). CONCLUSIONS: Adjuvant IV/IP chemotherapy was associated with oncologic benefit in miliary disease spread. This survival benefit was not observed in nonmiliary disease.

Triaging abnormal cervical cancer screening tests using p16INK4a detection by ELISA on fresh cervical samples.

PROBLEM: Cervical cancer screening strategies in the United States include cotesting (human papillomavirus (HPV) with cytology), primary HPV with genotyping and reflex cytology, and cytology alone. An ongoing challenge is the appropriate triage of patients to colposcopy to those at highest risk. We investigated whether incorporation of p16INK4a immunodetection by enzyme-linked immunosorbent assay (ELISA) on fresh cervical samples obtained at the time of screening could improve appropriate referral to colposcopy. METHOD OF STUDY: A derivation group comprised of cervical swabs collected from subjects with high-grade dysplasia or cancer (positive control) and from subjects with negative screening history (negative control). Samples collected from colposcopy were used to evaluate the existing screening strategies individually and with incorporation of p16INK4a ELISA. Histology was used as the gold standard. RESULTS: Among 163 subjects recruited, 138 were included. In the derivation group, mean p16INK4a level was 2.86 ng/mL (n = 31) and 0.58 ng/mL (n = 20) among positive and negative controls respectively (p = 0.002) with an area under the receiver operator characteristic curve of 0.79 (p < 0.001). Among colposcopy subjects, sensitivity/specificity for cotesting, primary HPV, and cytology were 94%/42%, 88%/45%, and 88%/49%, respectively. Incorporation of p16INK4a resulted in similar sensitivity and improved specificity (cotesting+p16 88%/58%, primary HPV+p16 88%/57%, cytology+p16 81%/62%; p = 0.23/p = 0.008) with decrease in colposcopy referrals by 15% to 22% (p = 0.01). CONCLUSIONS: These results demonstrate the feasibility of quantifying p16INK4a by ELISA in fresh cervical samples, and its potential as an adjunct to existing screening strategies in the identification of high grade-dysplasia while reducing the number of colposcopic referrals.

Enhanced Efficacy of Simultaneous PD-1 and PD-L1 Immune Checkpoint Blockade in High-Grade Serous Ovarian Cancer.

Immune therapies have had limited efficacy in high-grade serous ovarian cancer (HGSC), as the cellular targets and mechanism(s) of action of these agents in HGSC are unknown. Here we performed immune functional and single-cell RNA sequencing transcriptional profiling on novel HGSC organoid/immune cell co-cultures treated with a unique bispecific anti-programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) antibody compared with monospecific anti-PD-1 or anti-PD-L1 controls. Comparing the functions of these agents across all immune cell types in real time identified key immune checkpoint blockade (ICB) targets that have eluded currently available monospecific therapies. The bispecific antibody induced superior cellular state changes in both T and natural killer (NK) cells. It uniquely induced NK cells to transition from inert to more active and cytotoxic phenotypes, implicating NK cells as a key missing component of the current ICB-induced immune response in HGSC. It also induced a subset of CD8 T cells to transition from naïve to more active and cytotoxic progenitor-exhausted phenotypes post-treatment, revealing the small, previously uncharacterized population of CD8 T cells responding to ICB in HGSC. These state changes were driven partially through bispecific antibody-induced downregulation of the bromodomain-containing protein BRD1. Small-molecule inhibition of BRD1 induced similar state changes in vitro and demonstrated efficacy in vivo, validating the co-culture results. Our results demonstrate that state changes in both NK and a subset of T cells may be critical in inducing an effective anti-tumor immune response and suggest that immune therapies able to induce such cellular state changes, such as BRD1 inhibitors, may have increased efficacy in HGSC. SIGNIFICANCE: This study indicates that increased efficacy of immune therapies in ovarian cancer is driven by state changes of NK and small subsets of CD8 T cells into active and cytotoxic states.

Neoadjuvant chemotherapy does not disproportionately influence post-operative complication rates or time to chemotherapy in obese patients with advanced-stage ovarian cancer.

OBJECTIVES: To determine whether neoadjuvant chemotherapy (NACT) disproportionately benefits obese patients. METHODS: Data were collected from stage IIIC-IV ovarian cancer patients treated between 01/2010-07/2015. We performed univariate/multivariate logistic regression analyses with post-operative infection, readmission, any postoperative complication, and time to chemotherapy as outcomes. An interaction term was included in models, to determine if the effect of NACT on post-operative complications was influenced by obesity status. RESULTS: Of 507 patients, 115 (22.6%) were obese and 392 (77.3%) were non-obese (obese defined as BMI ≥30). Among obese patients undergoing primary debulking surgery (PDS) vs. NACT, rates of postoperative infection were 42.9% vs. 30.8% (p = 0.12), 30-day readmission 30.2% vs. 11.5% (p < 0.02), and any post-operative complication were 44.4% vs 30.8% (p = 0.133). Among non-obese patients undergoing PDS vs. NACT, rates of post-operative infection were 20.0% vs. 12.9% (p = 0.057), 30-day readmission 16.9% vs. 9.2% (p = 0.02), and any post-operative complication were 19.4% vs 28% (p = 0.044). Obesity was associated with post-operative infection (OR 2.3; 95%CI 1.22-4.33), 30-day readmission/reoperation (OR 2.27; 95%CI 1.08-3.21) and the development of any post-operative complication (OR 2.1; CI 1.13-3.74). However, there was not a significant interaction between obesity and NACT in any of the models predicting post-operative complications. CONCLUSIONS: The decision to use NACT should not be predicated on obesity alone, as the reduction in post-operative complications in obese patients is similar to non-obese patients.

Use of ablation and ultrasonic aspiration at primary debulking surgery in advanced stage ovarian, fallopian tube, and primary peritoneal cancer.

OBJECTIVES: Ovarian cancer patients with miliary disease have the lowest rates of complete surgical resection and poorest survival. Adjunct surgical techniques may potentially increase rates of complete surgical resection. No studies have evaluated the use of these techniques in primary debulking surgery for ovarian cancer patients with miliary disease. The aim of this study was to examine the use of adjunct surgical techniques during primary debulking surgery for patients with advanced epithelial ovarian, fallopian tube, and primary peritoneal cancer with miliary disease. METHODS: Medical records of patients with International Federation of Gynecology and Obstetrics (FIGO) stages IIIC-IVB epithelial ovarian, fallopian tube, or primary peritoneal cancer with miliary disease undergoing primary debulking surgery from January 2010 to December 2014 were reviewed. Adjunct surgical techniques were defined as ultrasonic surgical aspiration, argon enhanced electrocautery, thermal plasma energy, and traditional electrocautery ablation. Patients undergoing surgery with and without these devices were compared with respect to demographics, operative characteristics, postoperative complications, residual disease, progression free survival and overall survival. RESULTS: A total of 135 patients with miliary disease underwent primary debulking surgery, of which 30 (22.2%) patients used adjunct surgical techniques. The most common devices were ultrasonic surgical aspiration (40%) and argon enhanced electrocautery (36.7%). The most common sites of use were diaphragm (63.3%), pelvic peritoneum (30%), bowel mesentery (20%), and large bowel serosa (20%). There were no differences in age, stage, primary site, histology, operative time, surgical complexity, or postoperative complications for patients operated on with or without these devices. Volume of residual disease was similar (0.1-1 cm: 60% with adjunct techniques versus 68.6% without; complete surgical resection: 16.7% with adjunct techniques versus 13.3% without; p=0.67). For patients with ≤1 cm residual disease, median progression free survival (15 versus 15 months, p=0.65) and median overall survival (40 versus 55 months, p=0.38) were also similar. CONCLUSION: Adjunct surgical techniques may be incorporated during primary debulking surgery for patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer with miliary disease; however, these do not improve the rate of optimal cytoreduction.

Racial disparities in brachytherapy administration and survival in women with locally advanced cervical cancer.

OBJECTIVE: Black women have the highest incidence and mortality from cervical cancer in the United States. This study evaluated whether racial disparities in the receipt of brachytherapy (BT) for locally advanced cervical cancer mediate survival differences by race using the National Cancer Database. METHODS: A retrospective cohort study was performed using 16,116 women with stage IB2-IVA cervical cancer treated from 2004 to 2014. Women who did not receive external beam radiation therapy, those with unknown survival data or stage, and those status post hysterectomy or pelvic exenteration were excluded. Multivariate logistic regression was performed to evaluate factors associated with BT use. Using a propensity score adjusted model with inverse probability treatment weighting, adjusted hazard ratios for overall survival were calculated, including an interaction term between BT and race. RESULTS: Of 16,116 patients, 19.2% were black and 55.8% received BT. Black women were significantly less likely to receive BT (AOR 0.87, 95% confidence interval [CI] 0.79-0.96, p = 0.007) and had worse all-cause mortality (median survival 3.9 years [95% CI 3.6-4.6] versus 5.2 years [95% CI 4.9-5.5] for non-black women, p < 0.001). In the adjusted model, black patients had an increased risk of death compared to non-black patients (AHR 1.14, 95% CI 1.05-1.24; p = 0.002) among women who did not receive BT. However, there was no difference in survival by race when both groups received BT (AHR 1.04, 95% CI 0.95-1.13, p = 0.42; p-interaction = 0.005). CONCLUSIONS: Black women with locally advanced cervical cancer are less likely to receive brachytherapy, which mediates survival differences by race. Improving access to brachytherapy may improve overall survival.

A novel classification of residual disease after interval debulking surgery for advanced-stage ovarian cancer to better distinguish oncologic outcome.

BACKGROUND: Complete surgical resection affords the best prognosis at the time of interval debulking surgery. When complete surgical resection is unachievable, optimal residual disease is considered the next best alternative. Despite contradicting evidence on the survival benefit of interval debulking surgery if macroscopic residual disease remains, the current definition of "optimal" in patients undergoing interval debulking surgery is defined as largest diameter of disease measuring ≤1.0 cm, independent of the total volume of disease. OBJECTIVE: To examine the relationship between volume and anatomic distribution of residual disease and oncologic outcomes among patients with advanced-stage epithelial ovarian/fallopian tube/primary peritoneal carcinoma undergoing neoadjuvant chemotherapy then interval debulking surgery. For patients who did not undergo a complete surgical resection, a surrogate for volume of residual disease was used to assess oncologic outcomes. STUDY DESIGN: Patient demographics, operative characteristics, anatomic site of residual disease, and outcome data were collected from medical records of patients with International Federation of Gynecology and Obstetrics stage IIIC and IV epithelial ovarian cancer undergoing interval debulking surgery from January 2010 to July 2015. Among patients who did not undergo complete surgical resection but had ≤1 cm of residual disease, the number of anatomic sites (single location vs multiple locations) with residual disease was used as a surrogate for volume of residual disease. The effect of residual disease volume on progression-free survival and overall survival was evaluated. RESULTS: Of 270 patients undergoing interval debulking surgery, 173 (64.1%) had complete surgical resection, 34 (12.6%) had ≤1 cm of residual disease in a single anatomic location, 47 (17.4%) had ≤1 cm of residual disease in multiple anatomic locations, and 16 (5.9%) were suboptimally debulked. Median progression-free survival for each group was 14, 12, 10, and 6 months, respectively (P<.001). Median overall survival for each group was: 58, 37, 26, and 33 months, respectively (P<.001). CONCLUSION: Following interval debulking surgery, patients with complete surgical resection have the best prognosis, followed by patients with ≤1 cm single-anatomic location disease. In contrast, despite being considered "optimally debulked," patients with ≤1 cm multiple-anatomic location disease have a survival similar to suboptimally debulked patients.

Clinical characteristics and outcomes after bowel surgery and ostomy formation at the time of debulking surgery for advanced-stage epithelial ovarian carcinoma.

OBJECTIVE: There are limited data on clinical outcomes of patients with advanced-stage epithelial ovarian cancer who require ostomy formation at the time of either primary cytoreductive surgery or interval cytoreductive surgery. The objective of this study was to evaluate patients undergoing bowel surgery and ostomy formation after primary or interval surgery. METHODS: Patients with International Federation of Gynecology and Obstetrics (FIGO) stage IIIC-IV epithelial ovarian cancer who underwent cytoreductive surgery between January 2010 and December 2014 were identified retrospectively. Patients with non-epithelial histology, low-grade serous histology or incomplete medical records were excluded. Demographic and clinical data were collected and analyzed. Age, stage, co-morbidity index, pre-operative CA125, pre-operative albumin, and Aletti surgical complexity score were included in a multivariable logistic regression model to assess independent associations with ostomy formation. RESULTS: A total of 554 patients were included in the study. Of these, 261 (47%) underwent primary cytoreduction and 293 (53%) underwent interval cytoreduction. Patients undergoing primary surgery were more likely to undergo bowel resection, compared with interval surgery patients (37.2% vs 14%, p<0.001). Of the 139 (25.1%) patients who underwent bowel surgery, 25 (18%) underwent ostomy formation (11 ileostomies and 14 colostomies). Rates of ostomy formation were similar between the groups (6.1% primary vs 3.1% interval, p=0.10). Patients undergoing ostomy formation were more likely to have longer mean operative time (335 vs 229 min, p<0.001) and undergo small and large bowel resections at the time of cytoreductive surgery (44% vs 14%, p<0.001). Multivariate analysis revealed that a high surgical complexity score was associated with ostomy formation. Of the patients who underwent ostomy formation, 13 (43.3%) underwent stoma reversal including 11 ileostomies and two colostomies. Median time to ostomy reversal was 7 months. CONCLUSION: Bowel surgery is more common among patients undergoing primary surgery as compared with interval surgery, but this does not result in an increased risk of ostomy formation.

Liquid biopsy of HPV DNA in cervical cancer.

BACKGROUND: A blood test to serve as a tumor marker for cervical cancer would be useful to clinicians to guide treatment and provide an early signal for recurrence. The development of droplet digital PCR has enabled the detection of HPV DNA in patient serum, providing a potential marker for cervical cancer. OBJECTIVES: To report on a blood-based test for HPV-specific E7 and L1 genes, which may serve as a tumor marker to guide treatment and detect early recurrence in cervical cancer. STUDY DESIGN: Pre-treatment plasma samples were investigated from 138 Hong Kong Chinese women with primary invasive squamous cell carcinoma and adenocarcinoma of the cervix with tumor samples expressing HPV16 or HPV18. Two genes specific to the human papillomavirus, E7 and L1, were measured in cell free DNA (cfDNA) extracted from plasma using droplet digital PCR. Analysis of detectable E7 and L1 levels was performed to investigate the potential of liquid biopsy of E7 and L1 as a clinically useful molecular biomarker. RESULTS: The majority of patients had HPV16 (71.7%), squamous cell carcinoma (78.3%) and stage IB-II disease (82.6%). HPV E7 and L1 sequences were detected in plasma cfDNA from 61.6% (85/138) of patients. Patients with high viral load (defined as ≥20 E7 or L1 copies per 20 µL reaction volume) had increased risk of recurrence and death at 5 years on univariate analysis but not multivariate analysis. CONCLUSIONS: HPV DNA can be quantitatively detected with the use of cfDNA. This has the potential to provide a clinically useful tumor marker for patients with cervical cancer that can aid in post-treatment surveillance and estimating the risk of disease relapse.

Losartan treatment enhances chemotherapy efficacy and reduces ascites in ovarian cancer models by normalizing the tumor stroma.

In ovarian cancer patients, tumor fibrosis and angiotensin-driven fibrogenic signaling have been shown to inversely correlate with survival. We sought to enhance drug delivery and therapeutic efficacy by remodeling the dense extracellular matrix in two orthotopic human ovarian carcinoma xenograft models. We hypothesized that targeting the angiotensin signaling axis with losartan, an approved angiotensin system inhibitor, could reduce extracellular matrix content and the associated "solid stress," leading to better anticancer therapeutic effect. We report here four translatable findings: (i) losartan treatment enhances the efficacy of paclitaxel-a drug used for ovarian cancer treatment-via normalizing the tumor microenvironment, resulting in improved vessel perfusion and drug delivery; (ii) losartan depletes matrix via inducing antifibrotic miRNAs that should be tested as candidate biomarkers of response or resistance to chemotherapy; (iii) although losartan therapy alone does not reduce tumor burden, it reduces both the incidence and the amount of ascites formed; and (iv) our retrospective analysis revealed that patients receiving angiotensin system inhibitors concurrently with standard treatment for ovarian cancer exhibited 30 mo longer overall survival compared with patients on other antihypertensives. Our findings provide the rationale and supporting data for a clinical trial on combined losartan and chemotherapy in ovarian cancer patients.