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Objective Endometrial biopsy (EMBx) and colonoscopy performed under the same sedation is termed combined screening and has been shown to be feasible and to provide a less painful and more satisfactory experience for women with Lynch syndrome (LS). However, clinical results of these screening efforts have not been reported. The purpose of this study was to evaluate the long-term clinical outcomes and patient compliance with serial screenings over the last 10.5 years. Methods We retrospectively analyzed the data for 55 women with LS who underwent combined screening every 1-2 years between 2002 and 2013. Colonoscopy and endometrial biopsy were performed by a gastroenterologist and a gynecologist, with the patient under conscious sedation. Results Out of 111 screening visits in these 55 patients, endometrial biopsies detected one simple hyperplasia, three complex hyperplasia, and one endometrioid adenocarcinoma (FIGO Stage 1A). Seventy-one colorectal polyps were removed in 29 patients, of which 29 were tubular adenomas. EMBx in our study detected endometrial cancer in 0.9% (1/111) of surveillance visits, and premalignant hyperplasia in 3.6% (4/111) of screening visits. No interval endometrial or colorectal cancers were detected. Conclusions Combined screening under sedation is feasible and less painful than EMBx alone. Our endometrial pathology detection rates were comparable to yearly screening studies. Our results indicate that screening of asymptomatic LS women with EMBx every 1-2 years, rather than annually, is effective in the early detection of (pre)cancerous lesions, leading to their prompt definitive management, and potential reduction in endometrial cancer. [ABSTRACT FROM AUTHOR]

: ObjectiveWe wanted to identify genes up-regulated in ovarian tumors that might serve as early markers for ovarian cancer. One promising focus is the family of genes that encode secreted proteases, which play essential roles in tumor invasion and metastasis. Kallikrein 10 (KLK10) is a member of the kallikrein family of serine proteases which include 15 proteins, including the prostate-specific antigen (PSA), also known as hK3. We investigated whether KLK10 and its related protein, hK10, might serve as equally accurate markers for ovarian carcinoma.: MethodsTranscriptional profiling was performed using RNA isolated from normal ovarian epithelium, ovarian cancer cell lines, and primary ovarian tumors. Microarray data were confirmed by Northern blot analysis of 66 ovarian tumor samples and 6 ovarian cancer cell lines. In situ hybridization and Western blot analysis confirmed the Northern blot findings.: ResultsKLK10 was more highly expressed by primary ovarian tumors than by NOE. Thirty-two of 35 primary serous ovarian carcinoma samples (91.4%) expressed higher levels of KLK10 than NOE did. Eleven of 15 nonserous epithelial ovarian carcinoma samples (73.3%) and 8 of 11 primary peritoneal carcinoma samples (72.7%) also expressed KLK10. Overall, 84.8% of all epithelial ovarian and peritoneal carcinoma tumor samples showed elevated expression of KLK10. Similarly, Western blot analysis demonstrated that levels of the KLK10-related protein, designated hK10, are elevated in primary ovarian tissue lysates, but the protein is undetectable in immortalized ovarian epithelium. Finally, in situ hybridization established that KLK10 mRNA is much more highly expressed by tumor tissue than by normal epithelium and stromal tissues.: ConclusionsOur data support recent immunoassay findings of elevated levels of hK10 in the tumor tissue and serum of ovarian cancer patients. Thus, it is likely that KLK10 and other kallikreins will serve as useful diagnostic and prognostic markers in patients with ovarian carcinoma. [Copyright &y& Elsevier]

To assess the health state utilities of ovarian cancer patients, clinicians, and non-cancer controls regarding surgical complications in ovarian cancer. Utilities for 14 surgical complications were assessed from patients with recently diagnosed or recurrent ovarian cancer, clinicians, and non-cancer controls using the visual analog scale (VAS) and time trade-off (TTO) methods. Health state utilities were converted to a 0-to-1 scale, where 0 represents the least favorable outcome and 1 represents the most favorable outcome. Fifty patients, 50 clinicians, and 50 controls participated. Median VAS scores were lower than TTO scores across all groups (p < 0.01). Patients viewed 'bleeding requiring transfusion' most favorably (VAS utility 0.75), followed in order by less favorable utility scores for hernia, thromboembolism, pleural effusion, abscess, ileus/bowel obstruction, wound infection, bowel obstruction requiring surgery, anastomotic leak requiring drain, temporary ostomy, anastomotic leak requiring surgery, genito-urinary fistula, permanent ostomy, and genito-intestinal fistula (VAS utility 0.2). Overall, clinicians perceived complications more favorably than patients by VAS (overall utility score 0.49 vs 0.43, p < 0.01), but not by the TTO. There were no differences in overall utility scores between patients and controls. Patients who had not experienced certain surgical complications had less favorable scores than patients who did (utility score for ostomy = 0.2 for patients without ostomy vs. 0.7 for patients with ostomy, p = 0.02). This study establishes health state utilities for surgical complications associated with ovarian cancer. These utilities can be used in future cost-effectiveness evaluations to determine quality-adjusted outcomes and may help in counseling patients during the shared decision-making process. • Individuals who have experienced a surgical complication perceived them more favorably than those who did not • Differing views of trade-offs between survival and toxicity by patients and clinicians may affect shared decision making. • Understanding perceptions of surgical morbidity is critical to providing appropriately tailored counseling for patients [ABSTRACT FROM AUTHOR]

Abstract An estimated 2–5% of endometrial cancers and 15–20% of high-grade, non-mucinous epithelial ovarian cancers have an underlying hereditary cause. Appropriate risk assessment, genetic counseling, and germline genetic testing for cancer predisposition genes in both gynecologic cancer patients and their at-risk relatives is essential for effective delivery of tailored cancer treatment and cancer prevention. However, significant disparities exist within medically underserved and minority populations in the United States regarding awareness of, access to, and use of genetic services. The objectives of this review are to summarize the literature on genetic counseling and genetic testing of gynecologic cancer patients, the cascade genetic testing of their families following the identification of a germline mutation associated with susceptibility to cancer, to highlight disparities between populations, and to present some potential remedies. Highlights • Despite increases in the rate of testing for BRCA and Lynch syndrome, many high-risk women remain unidentified. • Underserved populations who do not access genetics services are at risk of missing opportunities for cancer prevention. • Socioeconomic factors, poor communication, concerns about misuse of genetic data contribute to poor use of genetic services. • Research is needed to specifically identify barriers to receipt and use of cancer genetics services. [ABSTRACT FROM AUTHOR]

Abstract: Objective. : Platinum-based chemotherapy exerts its cytotoxic effect by forming DNA adducts and subsequently inhibiting DNA replication. Removing platinum DNA adducts requires the nucleotide excision repair (NER) pathway. The xeroderma pigmentosum (XP) complementation group of genes plays an essential role in the NER pathway. We hypothesized that genetic polymorphisms in XP genes may predict clinical response to platinum chemotherapeutic treatment and survival in women with gynecological cancers. Method. : We genotyped 146 cases of advanced epithelial ovarian cancer for XP gene polymorphisms using the PCR-RFLP method. Kaplan–Meier plots and the log-rank test were used to assess associations between survival and recurrence-free interval and the XP gene polymorphisms. Hazard ratio of response was estimated from an adjusted multivariate Cox proportional hazard model. Results. : Women with a heterozygous variant XPA allele had shorter median survival (21.5 months, P =0.03) and shorter median time to recurrence (11.3 months, P =0.05) than women with the homozygous wild-type allele (37.9 and 13.9 months, respectively). Women with a homozygous variant XPG allele had significantly shorter median survival (8.3 months, P =0.006) compared with women with the homozygous XPG wild-type allele (24.6 months). Polymorphisms in XPC, XPD exon10, and XPD exon23 were associated with a decreased risk of recurrence and death, but were not statistically significant. Conclusions. : This study suggests that NER gene polymorphisms may correlate with recurrence and patient survival. A larger sample size is needed to assess platinum chemotherapy response with these polymorphisms. These findings may help identify subgroups of cancer patients likely to benefit from individualized treatment strategies. Our next study will examine NER gene polymorphisms in cervical cancer patients. [Copyright &y& Elsevier]

Radiation therapy (RT) may improve outcomes for patients with oligometastatic cancer. We sought to determine if there are long-term survivors treated with definitive RT for recurrent or oligometastatic gynecological cancer (ROMGC), and to evaluate the clinical and disease characteristics of these patients. We performed a landmark analysis in 48 patients with ROMGC who survived for ≥5 years following definitive RT of their metastasis. Patient characteristics were extracted from the medical record. DFS was modeled using the Kaplan-Meier method. This cohort included 20 patients (42%) with ovarian cancer, 16 (33%) with endometrial cancer, 11 (23%) with cervical cancer, and one (2%) with vaginal cancer. The sites of ROMGC were the pelvic (46%), para-aortic (44%), supraclavicular (7%), mediastinal (4%), axillary (4%) lymph nodes and the lung (5.5%). Median total RT dose and fractionation were 62.1 Gy and 2.1 Gy/fraction; one patient was treated with SBRT. 32 patients (67%) received chemoradiation; these patients had higher rates of median DFS than those treated with RT alone (93 vs. 34 months, P = 0.05). At median follow-up of 11.7 years, 11 (23%) patients had progression of disease. 20 (42%) patients had died, 9 (19%) died from non-gynecologic cancer and 8 (17%) from gynecologic cancer (three were unknown). 25 (52%) patients were alive and disease-free (10 initially had endometrial cancer [63% of these patients], eight had cervical cancer [73%], six had ovarian cancer [30%], one had vaginal cancer [100%]). Long-term survival is possible for patients treated with definitive RT for ROMG, however randomized data are needed to identify which patients derive the most benefit. • We studied recurrent or oligometastatic gynecological cancer (ROMGC) survivors following receipt of definitive RT. • 48 patients were studied: 20 ovarian cancer, 16 endometrial cancer, 11 cervical cancer, 1 vaginal cancer. • Patients who received chemoradiation had better median DFS than those treated with RT alone (93 vs. 34 months, P = 0.05). • 25 patients (52%) were alive and disease-free at median follow-up of 11.7 years. [ABSTRACT FROM AUTHOR]

We reviewed our institutional data to evaluate toxicity and efficacy outcomes of pembrolizumab/lenvatinib in recurrent endometrial cancer in a "real-world" clinical setting and to compare the impact of reduced lenvatinib starting dose on outcomes. Retrospectively, we reviewed toxicity, treatment responses, and survival outcomes of patients with recurrent endometrial cancer who received ≥1 cycle of pembrolizumab/lenvatinib. We compared subgroups based on lenvatinib starting dose (recommended [20 mg] vs reduced [<20 mg]) and histologic type. We analyzed 70 patients (recommended dose cohort, n = 16; reduced dose cohort, n = 54). The most common starting dose was 14 mg daily. Compared to the reduced dose cohort, the recommended dose cohort had a significantly higher mean number of lenvatinib dose reductions due to side effects (1.1 vs. 0.4; p = 0.003) and significantly shorter median time to treatment toxicity (1.3 vs. 3.7 days; p = 0.0001). Response rates did not differ significantly between the recommended and reduced dose cohorts (28.6% vs. 38.3%, respectively; p = 0.752). Two patients, both in the reduced dose cohort, had complete responses. Patients with carcinosarcoma histology had response and clinical benefit rates of 25% (3 of 12) and 58.3% (7 of 12), respectively. There were no differences between the 2 dose cohorts with respect to progression-free (p = 0.245) or overall survival (p = 0.858). In clinical practice, a lower starting dose of lenvatinib (14 mg daily) in combination with pembrolizumab was safe and efficacious in recurrent endometrial cancer. The combination produced responses in endometrial carcinosarcomas. Larger studies are required to validate these findings. • Recommended 20 mg lenvatinib dosage may be challenging for endometrial cancer patients to tolerate in clinical practice. • Compared to the recommended dose, a reduced lenvatinib starting dose had similar response rates in endometrial cancer. • Compared to the recommended dose, a reduced lenvatinib starting dose had less toxicity with similar survival outcomes. • For endometrial carcinosarcoma (not included in KEYNOTE-146/Study 111), the overall response rate was 25%. [ABSTRACT FROM AUTHOR]

To evaluate the factors associated with response to neoadjuvant chemotherapy (NACT) and the ability to undergo interval tumor reductive surgery (iTRS) in patients with advanced ovarian cancer. We performed a retrospective review from April 2013 to March 2019 of patients with advanced stage ovarian cancer triaged to NACT based on our standard triage algorithm. Clinicopathologic and treatment data were analyzed for factors associated with response to NACT, outcomes at iTRS, and their impact on progression-free survival (PFS). 562 patients met inclusion criteria and triaged to NACT following laparoscopy (n = 132) or without laparoscopy (n = 430). 413 patients underwent iTRS (74%). Factors that correlated with a patient reaching iTRS included increasing age (p < 0.001), higher Charlson comorbidity index (p < 0.001), ECOG status 2 or 3 (<0.001), and laparoscopic assessment (<0.001). Patients with CA-125 ≤ 35 U/mL at iTRS had higher rates of complete gross resection (88% vs. 65%, p < 0.001) and improved PFS (16.8 vs. 12.7 months, p < 0.001). Patients receiving dose-dense paclitaxel (76% vs. 60%, p = 0.004) and CA-125 ≤ 35 U/mL at iTRS (85% vs. 66%, p < 0.001) had higher rates of complete radiographic response. On multivariate analysis, germline BRCA 1/2 mutation (p = 0.001), iTRS vs. no surgery (R0, p < 0.001; ≤1 cm, p < 0.001; >1 cm, p < 0.001), dose-dense chemotherapy (p = 0.01), and CA-125 ≤ 35 U/mL at iTRS (p = 0.001) were independent significant factors affecting PFS. Normalization of CA-125 at the time of iTRS following NACT may serve as a surrogate marker for prognosis in this high-risk population. Our NACT cohort experienced improved response rates and PFS with dose-dense therapy compared to conventional dosing. • Patients undergoing initial laparoscopic triage to NACT were more likely to undergo interval tumor reductive surgery. • Dose-dense therapy was associated with improved progression-free survival in our NACT cohort. • Normalization of CA-125 at the time of interval tumor reductive surgery was associated with improved outcomes. [ABSTRACT FROM AUTHOR]

The ideal number of neoadjuvant chemotherapy (NACT) cycles prior to interval tumor-reductive surgery (iTRS) for advanced ovarian cancer is poorly defined. We sought to assess survival stratified by number of NACT cycles and residual disease following iTRS in patients with advanced ovarian cancer with partial response (PR) or stable disease (SD) following 3–4 cycles of NACT. We retrospectively identified patients with advanced high-grade ovarian cancer (diagnosed 2/1/2013 to 2/1/2018) who received at least 3 cycles of NACT and iTRS and had a PR or SD. The population was divided into four groups based on the number of NACT cycles prior to iTRS and residual disease status after (CGR [complete gross residual] or incomplete resection [any amount of residual disease]): 1) 3–4 NACT cycles/CGR, 2) 3–4 NACT cycles/incomplete resection, 3) > 4 cycles/CGR, and 4) >4 cycles/incomplete resection. Overall survival (OS) and progression-free survival (PFS) were estimated using a Kaplan-Meier product-limit estimator and modeled using univariable and multivariable Cox proportional hazards analysis. The cohort consisted of 265 patients with advanced high-grade ovarian cancer with a median age at diagnosis of 65 years. Most were White (87%), had serous histology (89%), and stage IV disease (57%), with an overall CGR rate of 81%. In a multivariable analysis receipt of >4 NACT cycles was not associated with worse PFS or OS (adjusted hazard ratio [aHR] 1.02, 95% CI 0.74–1.42; aHR 1.12, 95% CI, 0.73–1.72 respectively) than was receipt of 3–4 cycles. Any amount of residual disease was associated with worse PFS and OS regardless of the number of NACT cycles (aHR 1.56, 95% CI 1.09–2.22; aHR 2.38, 95% CI 1.52–3.72 respectively). Residual disease was associated with worse survival outcomes regardless of the number of NACT cycles in patients with PR or SD after NACT for advanced high-grade ovarian cancer. These data suggest that the ability to achieve CGR should take precedence in decision-making regarding the timing of surgery. • Regardless of number of neoadjuvant chemotherapy cycles, residual disease drove survival outcomes. • The ability to achieve no residual disease may take precedence in decision-making about timing of interval surgery. • Surgery may still benefit patients who need additional chemotherapy to achieve a complete gross resection. [ABSTRACT FROM AUTHOR]

Clinical trials demonstrated that PARPi (poly [adenosine diphosphate–ribose]-ADP polymerase inhibitor) therapy is effective in solid tumors. However, long term effects such as therapy-related myelodysplastic syndrome or acute myeloid leukemia (MDS/AML) are poorly described. We sought to quantify whether PARPi therapy is associated with the development of MDS/AML. Medline, Embase, and Cochrane databases were searched (inception to January 6, 2020) and phase 2 and 3 clinical trials that randomized patients with solid tumors to a PARPi or control therapy were included. The PRISMA guidelines were used to extract data independently by multiple authors. We extracted person-time and number of cases of MDS/AML in the PARPi and control arms of each study and pooled results with a random-effects Poisson regression model. The pooled incidence rate ratio (IRR) for MDS/AML among patients randomized to PARPi therapy was compared to those randomized to a control. We identified 14 studies that included 5739 patients. Accounting for intra-study clustering, the risk of MDS/AML was similar in patients who were randomly assigned to receive PARPi compared to controls (IRR 1.32, 95% confidence interval [CI] 0.78–2.26). In the front-line setting, PARPi therapy was associated with developing MDS/AML (IRR 5.43, 95% CI 1.51–19.60). Among patients treated for recurrence, however, the risk of MDS/AML appeared to be similar among patients randomized to PARPi or control treatment. Among studies that included only patients with a BRCA mutation, the risk of MDS/AML was similar in both treatment groups (IRR 0.83, 95% CI 0.45–1.53), but PARPi therapy was associated with MDS/AML in studies with an unrestricted population (IRR 2.43, 95% CI 1.17–5.06). The pooled overall effect was not statistically significant. However, treatment with PARPi was associated with a statistically significant increase in the incidence of MDS/AML among patients receiving front-line cancer therapy and those with limited prior exposure to chemotherapy. • The overall risk of MDS/AML was similar in patients who were randomly assigned to receive PARPi compared to controls. • PARPi use was associated with an increase in risk of MDS/AML in the front-line setting, but not in the recurrent setting. • PARPi use was associated with an increase in risk of MDS/AML in studies with a low proportion of heavily pretreated patients. • Among studies that included a high proportion of heavily pretreated patients, PARPi use was not associated with MDS/AML. [ABSTRACT FROM AUTHOR]

To determine if laparoscopy is a cost-effective way to assess disease resectability in patients with newly diagnosed advanced ovarian cancer. A cost-effectiveness analysis from a health care payer perspective was performed comparing two strategies: (1) a standard evaluation strategy, where a conventional approach to treatment planning was used to assign patients to either primary cytoreduction (PCS) or neoadjuvant chemotherapy with interval cytoreduction (NACT), and (2) a laparoscopy strategy, where patients considered candidates for PCS would undergo laparoscopy to triage between PCS or NACT based on the laparoscopy-predicted likelihood of complete gross resection. A microsimulation model was developed that included diagnostic work-up, surgical and adjuvant treatment, perioperative complications, and progression-free survival (PFS). Model parameters were derived from the literature and our published data. Effectiveness was defined in quality-adjusted PFS years. Results were tested with deterministic and probabilistic sensitivity analysis (PSA). The willingness-to-pay (WTP) threshold was set at $50,000 per year of quality-adjusted PFS. The laparoscopy strategy led to additional costs (average additional cost $7034) but was also more effective (average 4.1 months of additional quality-adjusted PFS). The incremental cost-effectiveness ratio (ICER) of laparoscopy was $20,376 per additional year of quality-adjusted PFS. The laparoscopy strategy remained cost-effective even as the cost added by laparoscopy increased. The benefit of laparoscopy was influenced by mitigation of serious complications and their associated costs. The laparoscopy strategy was cost-effective across a range of WTP thresholds. Performing laparoscopy is a cost-effective way to improve primary treatment planning for patients with untreated advanced ovarian cancer. • Laparoscopy is a cost-effective way to assess disease resectability in patients with newly-diagnosed advanced ovarian cancer. • Laparoscopy was cost-effective even when varying model parameters, such as the cost added by performing laparoscopy. • Laparoscopy is a valuable tool to improve treatment selection in untreated patients with advanced ovarian cancer. [ABSTRACT FROM AUTHOR]

Homologous recombination deficiency (HRD) score is related to chemotherapy response in some cancers, but its role in endometrial cancer in not known. We determined frequency and clinical significance of alterations in the HR pathway in endometrial cancer. 253 endometrioid endometrial adenocarcinoma (EEA) samples from two independent cohorts (discovery and replication) were tested for HRD score using the Myriad HRD assay, microsatellite instability (MSI) and tumor mutation burden (TMB) using a next generation sequencing assay. HRD scores were also generated on endometrial cancer cell lines and in vivo response to olaparib was assessed. ROC curves were employed to determine optimal cutoffs of HRD in relation to survival impact in endometrial cancer and a cutoff of HRD ≥ 4 was suggested for DFS using the discovery cohort. Patients from two independent cohorts with HRD score ≥ 4 trended toward worse survival as compared to those with HRD score < 4. Both cohorts were further separated into four groups according to molecular subtypes (TMB positive; MSI positive; HRD positive; all others). When grouped by molecular subtype, there was a significant difference between groups using an HRD ≥4 cutoff in the initial (p = 0.0024) and replication (p = 0.042) cohorts. The Hec1a model (HRD score = 19) was highly sensitive to olaparib in in vitro and in vivo experiments. High HRD score was associated with worse DFS in our patient cohort. These findings suggest that HRD score may have clinical utility in patients with advanced or recurrent endometrial cancer. • Patients with HRD score ≥ 4 trended toward worse survival as compared to those with HRD score < 4. • When grouped by molecular subtype, there was a significant difference between groups. • Using an HRD ≥4 cutoff in the initial (p = 0.0024) and replication (p = 0.042) cohorts. • The Hec1a model (HRD score = 19) was highly sensitive to olaparib in in vitro and in vivo experiments. • These findings suggest that HRD score may have clinical utility in patients with advanced or recurrent endometrial cancer. [ABSTRACT FROM AUTHOR]

Abstract Objective The universal genetic testing initiative (UGTI) is a quality improvement effort to increase rates of guideline-based genetic counseling (GC) and genetic testing (GT) of patients with potentially hereditary cancers. The UGTI was disseminated to a county hospital gynecologic oncology clinic that serves a diverse, indigent patient population. Methods Using the Model for Improvement quality improvement framework, interventions including integrated GC, clinic tracking, assisted GC referrals, and provider education were tested over 26 months. A retrospective data review included patients with high-grade, non-mucinous epithelial ovarian, fallopian tube, and primary peritoneal cancers (HGOC) and endometrial cancers (EC) diagnosed between 9/1/12–8/31/16. Statistical analyses were performed to describe the population and to evaluate rates of recommendation and use of immunohistochemistry tumor testing (IHC), GC, and GT. Results A cohort of 241 patients (57 HGOC, 184 EC) were included. At the conclusion of the study 84.2% of HGOC patients were referred for GC, 89.6% (43/48) completed GC, and 90.7% (39/43) completed GT. Of EC patients, 81.0% were recommended to have IHC and 62.4% (93/149) completed IHC. Patients with HGOC diagnosed during dissemination of UGTI were significantly more likely to receive a recommendation for GC (p = 0.02) and to complete GT (p = 0.03) than those diagnosed before UGTI. Patients with EC were significantly more likely to complete IHC if diagnosed after UGTI than those diagnosed prior to dissemination (p < 0.001). Conclusions The UGTI can be adapted to increase use of guideline-based cancer genetics services in a diverse, indigent, gynecologic cancer patient population. Highlights • Dissemination of genetics quality improvement to a county hospital was feasible. • Uptake of recommended genetic services increased to >80% by the end of 26 months. • The time between cancer diagnosis and receipt of genetic services decreased. • In this diverse, indigent population, 23% of tested patients had germline mutations. [ABSTRACT FROM AUTHOR]

Abstract Objective Evaluate the impact of clinicopathologic characteristics and adjuvant treatment on survival outcomes in early stage uterine carcinosarcoma patients. Methods We performed a retrospective cohort study of women with stage I or II uterine carcinosarcoma at our institution between March 1990 and June 2016. All pathology had been reviewed and confirmed by gynecologic pathologists. Data were extracted from the electronic medical record. Descriptive and comparative statistics were used to compare clinicopathologic characteristics. Univariable and multivariable analyses were performed for survival outcomes. Results 140 patients were identified. Median age was 67 years (range: 36–91). Median follow-up was 39.1 months (2.9–297.4). The majority of patients had stage IA (67%) versus stage IB (21%) or stage II (11%) disease. The majority of patients (63%) received adjuvant treatment: vaginal brachytherapy only (14%); whole pelvic radiation therapy only (16%); chemotherapy only (n = 13, 9%); combination chemotherapy and vaginal brachytherapy (15%); combination chemotherapy and whole pelvic radiation (9%). 52 patients (37%) received no adjuvant therapy. Median overall survival (OS) was 48.0 months (95% CI 32.7–80.9). On multivariable analysis for OS, advancing age (HR 1.05, 95% CI 1.03–1.08, p < 0.001), higher stage (stage IB: HR 1.64, 95% CI 0.91–2.95, p = 0.10; stage II: HR 3.04, 95% CI 1.51–6.13, p = 0.002), and the presence of a rhabdomyosarcoma component (HR 1.66, 95% CI 1.02–2.70, p = 0.04) were significantly associated with worse OS. Conclusions Advancing age, stage, and the presence of a rhabdomyosarcoma component were all associated with worse OS in patients with early stage uterine carcinosarcoma. New treatment algorithms should incorporate factors aside from stage alone. Highlights • Most early stage uterine carcinosarcoma patients receive adjuvant treatment with radiation and/or chemotherapy. • Recurrence-free and overall survival for uterine carcinosarcoma patients is poor. • Advancing age, stage, and the presence of a rhabdomyosarcoma component were associated with worse overall survival. [ABSTRACT FROM AUTHOR]

Abstract Objective To determine correlation between race and receipt of optimal treatment for ovarian cancer and the impact of this on overall survival. Methods Using SEER-linked Medicare database, women 66 and older diagnosed with advanced ovarian cancer between 2002 and 2011 were identified. Patients with unclear histology, diagnosed on autopsy and without Medicare Parts A and B were excluded. We used Chi-square test for categorical variables, F test for continuous variables, and multivariable logistic regression to identify characteristics associated with receipt of surgery and chemotherapy. Kaplan–Meier analysis was used to compare overall survival rates. Cox Proportional Hazards regression was performed to identify factors associated with 5-year survival. Results 9016 ovarian cancer patients were included. 2638 had primary chemotherapy, 4854 had primary surgery, and 1524 had no treatment. 7653 (84.9%) were white, 572 (6.3%) black, 479 (5.3%) Hispanic, and 312 (3.5%) were of other race/ethnicity. More white patients (57.2%) received both chemotherapy and surgery compared to black (39.9%), Hispanic (48.9%), or other (54.2%) (p <.001). Receipt of either only surgery or chemotherapy, or receipt of neither, resulted in higher risk of death when compared to receipt of both. On multivariable analysis, black (OR 0.58 [0.46–0.73]) and Hispanic (0.69 [0.54–0.88]) patients were less likely to receive both chemotherapy and surgery. Being of black race was significantly correlated with worse overall survival [HR 1.13 (1.03–1.23); p =.02]. Conclusions Non-white women are less likely to receive the standard of care treatment for ovarian cancer and more likely to die from their disease than white women. Highlights • Racial disparities exist among women receiving treatment for ovarian cancer. • Non-white women are less likely to receive both surgery and chemotherapy to treat ovarian cancer than white women. • Non-white women are more likely to die from ovarian cancer than white women. [ABSTRACT FROM AUTHOR]

Abstract The success of targeted and immune therapies in other malignancies has led to an exponential increase in the number of active and pending clinical trials using these therapeutic approaches in patients with gynecologic cancers. These novel investigational agents are associated with unique and potentially life-threatening toxicities and many require special multidisciplinary logistical considerations. The objective of this review is to describe a practical approach for the safe implementation of targeted and immune therapies in academic gynecologic oncology practices based on our experience at M.D. Anderson Cancer Center. Highlights • This review provides a system-based practical approach for the safe implementation of targeted and immune therapies. • Creation of a multidisciplinary EDDIT team can provide shared experience and enhanced patient safety. • Education of providers, staff, trainees, and patients is a key function of the EDDIT team. • Immediate access to expert advice serves to avoid delays in recognition and management of adverse events. [ABSTRACT FROM AUTHOR]

Background Neoadjuvant chemotherapy (NACT) may reduce perioperative morbidity in women undergoing primary treatment for ovarian cancer. We evaluated patterns of use and outcomes in a population-based cohort of elderly women with ovarian cancer (OC). Methods A cohort of patients ≥66 years old diagnosed between 2000 and 2013 with stage III-IV epithelial OC who received surgery and platinum/taxane chemotherapy for primary treatment was identified from the SEER-Medicare database. Propensity-score matching methods were used to examine differences in outcomes. Kaplan–Meier analysis was performed to compare overall survival (OS) in the matched cohort. Results From 2000 to 2013, 22.5% of older women received NACT. The use of NACT increased over time from 16% in 2000 to 35.4% in 2013 (p < .0001). Among women who received PCS, the rate of ostomy creation was higher compared with NACT (23.3% vs. 10.8%, p < .0001). Infectious and other surgical complications were higher among those who had PCS, regardless of stage. Median OS of women III ovarian cancer who underwent PCS was longer compared with NACT (38.8 vs. 28 months, p ≤ .0001). There were no survival differences between NACT and PCS in women with stage IV disease (29.4 vs. 29.8 months, p = .61) or for women aged >80. Conclusion Careful consideration should be given to older patients prior to undergoing PCS. Survival outcomes were similar for patients with stage IV disease, although NACT was associated with decreased perioperative morbidity compared with PCS. Among women with stage III disease, PCS was associated with improved overall survival, but higher rates of perioperative morbidity and acute care. [ABSTRACT FROM AUTHOR]

Objective Risk-reducing salpingo-oophorectomy (RRSO) reduces ovarian cancer risk in BRCA1/2 mutation carriers, but the adverse effects of the associated early-onset surgical menopause are problematic. Despite suggestive evidence, no data demonstrate whether bilateral salpingectomy alone lowers the risk of developing ovarian cancer in BRCA mutation carriers. We conducted a pilot study of bilateral salpingectomy with delayed oophorectomy (BS/DO) in BRCA mutation carriers to determine the safety and acceptability of the procedure . Methods In this prospective, multicenter, non-randomized pilot study, pre-menopausal BRCA1/2 mutation carriers aged 30 to 47 years chose screening, RRSO, or BS/DO. For those undergoing BS/DO, the delayed oophorectomy was recommended at age 40 years for BRCA1 and age 45 years for BRCA2 patients. We compared surgical and psychosocial outcomes between time points and between arms. Results Of the 43 patients enrolled, 19 (44%) chose BS/DO, 12 (28%) chose RRSO, and 12 (28%) chose screening. The cohort was 37% BRCA1 carriers and 63% BRCA2 carriers. One serous tubal intraepithelial carcinoma (STIC) was found in an RRSO patient, and no cases of occult ovarian cancers were found. There were no surgical complications. Twelve months after surgery, responses on the Cancer Worry Scale indicated decreased worry in the BS/DO ( P  < 0.0001) and RRSO ( P  = 0.01) arms, while responses on the State Anxiety Inventory indicated decreased anxiety in the BS/DO arm ( P  = 0.02) compared with preoperative responses. Conclusions In this pilot study, BRCA mutation carriers who underwent bilateral salpingectomy had no intraoperative complications, were satisfied with their procedure choice, and had decreased cancer worry and anxiety after the procedure. [ABSTRACT FROM AUTHOR]

Objective To identify the baseline sleep patterns of endometrial cancer survivors and examine the impact of a physical activity intervention on their sleep quality via retrospective secondary analysis. Methods Early-stage endometrial cancer survivors participated in a 6-month single-arm exercise intervention using printed materials, telephone-based counseling, and pedometers to encourage adherence to exercise guidelines. Participants completed questionnaires evaluating their sleep (PSQI), physical activity (CHAMPS), quality of life (SF-36), and stress (PSS) at baseline and study completion. Results Ninety-five survivors had PSQI data at both time points. Mean age was 57.1 years (range, 25–76). Mean body mass index was 34.3 kg/m 2 . The majority were non-Hispanic white (75%) and had stage I disease (80%). At baseline, most survivors (61%) had poor sleep quality (PSQI > 5), with 24% reporting fairly or very bad sleep. The majority (63%) slept <7 h/night. At least once during the preceding month, 83% had an episode of daytime dysfunction. A pairwise comparison showed that obese survivors had more sleep disturbances than normal weight survivors ( p  = 0.029). No other clinicodemographic factors were associated with sleep. In unadjusted analyses, sleep quality significantly improved in women who increased weekly total or moderate/vigorous physical activity ( p  = 0.004 and p  < 0.050, respectively). This association persisted after adjusting for the potential covariates of age, time since diagnosis, obesity status, disease stage, and treatment ( p  = 0.026). Conclusions Our data demonstrated that poor sleep is common and detrimental to endometrial cancer survivors. Increasing exercise may improve this dysfunction and should be investigated as part of a prospective study. [ABSTRACT FROM AUTHOR]

Objective Genetic counseling (GC) and germline genetic testing (GT) for BRCA1 and BRCA2 are considered standard of care for patients with high-grade, non-mucinous epithelial ovarian, fallopian tube, and primary peritoneal cancers (HGOC). We describe a universal genetic testing initiative to increase the rates of recommendation and acceptance of GC and GT to > 80% for patients with HGOC at our institution. Methods Data from a consecutive cohort of patients seen in our gynecologic oncology clinics between 9/1/2012 and 8/31/2015 for evaluation of HGOC were retrospectively analyzed. Data were abstracted from the tumor registry, medical records, and research databases. Descriptive statistics were used to evaluate patient characteristics and GC, GT, and PARP inhibitor use. Various clinic interventions were developed, influenced by the Plan-Do-Study-Act cycle method, which included physician-coordinated GT, integrated GC, and assisted GC referrals. Results A cohort of 1636 patients presented to the gynecologic oncology clinics for evaluation of HGOC during our study period, and 1423 (87.0%) were recommended to have GC and GT. Of these, 1214 (85.3%) completed GT and 217 (17.9%) were found to have a BRCA1 or BRCA2 mutation. Among BRCA-positive patients, 167 had recurrent or progressive disease, and 56 of those received PARP inhibitor therapy. Conclusions The rates of GC and GT recommendation and completion among patients with HGOC at our institution exceeded 80% following the implementation of a universal genetic testing initiative. Universal genetic testing of patients with HGOC is one strategy to identify those who may benefit from PARP inhibitor therapy. [ABSTRACT FROM AUTHOR]

Objective Sentinel lymph node (SLN) mapping continues to evolve in the surgical staging of endometrial cancer (EC). The purpose of this trial was to identify the sensitivity, false negative rate (FNR) and FN predictive value (FNPV) of SLN compared to complete pelvic and para-aortic lymphadenectomy (LAD) in women with high-risk EC. Methods Women with high-risk EC (grade 3, serous, clear cell, carcinosarcoma) were enrolled in this prospective surgical trial. All patients underwent preoperative PET/CT and intraoperative SLN biopsy followed by LAD. Patients with peritoneal disease on imaging or at the time of surgery were excluded. Patients were evaluable if SLN was attempted and complete LAD was performed. Results 123 patients were enrolled between 4/13 and 5/16; 101 were evaluable. At least 1 SLN was identified in 89% (90); bilateral detection 58%, unilateral pelvic 40%, para-aortic only 2%. Indocyanine green was used in 61%, blue dye in 28%, and blue dye and technetium in 11%. Twenty-three pts. (23%) had ≥ 1 positive node. In 20/23, ≥ 1 SLN was identified and in 19/20 the SLN was positive. Only 1 patient had bilateral negative SLN and positive non-SLNs on final pathology. Overall, sensitivity of SLN was 95% (19/20), FNR was 5% (1/20) and FNPV was 1.4% (1/71). If side-specific LAD was performed when a SLN was not detected, the FNR decreased to 4.3% (1/23). Conclusion This prospective trial demonstrated that SLN biopsy plus side-specific LAD, when SLN is not detected, is a reasonable alternative to a complete LAD in high-risk endometrial cancer. [ABSTRACT FROM AUTHOR]

Objectives The study objective was to analyze the impact of prognostic factors, including treatment modality, on outcome in patients with advanced-stage uterine serous carcinoma (USC). Methods A retrospective review of patients diagnosed with stage III or IV USC between 1993 and 2012 was performed. Summary statistics were used to describe demographic and clinical characteristics. Overall survival (OS) and recurrence free survival (RFS) were estimated by Kaplan-Meier analysis. Cox proportional hazards regression was used to model the association of potential prognostic factors with OS and RFS. Results The study included 260 patients with median follow-up of 26.6 months (range 1–172.8). Median age was 63 years (range 30–88) and 52.3% had stage III disease. In all, 60% were treated with surgery followed by chemotherapy, 18.1% received surgery, chemotherapy, and radiotherapy, 11.5% had surgery and radiotherapy, and 10.4% had neoadjuvant chemotherapy. The overall complete response rate was 68.9%, and the cumulative incidence of recurrence was 82.7%. Treatment that included surgery, chemotherapy, and radiation and stage III disease were associated with improved RFS on multivariate analysis. For OS, therapy with surgery, chemotherapy, and radiation, mixed histology, and stage III disease were associated with better OS on multivariate analysis. Conclusions Patients with advanced-stage USC have a poor prognosis, regardless of clinical factors or treatment received. However, combination therapy that includes chemotherapy and radiation appears to be associated with improved survival in these women. [ABSTRACT FROM AUTHOR]

Objective To assess the impact of body mass index (BMI) and operative approach on surgical morbidity and costs in patients with endometrial carcinoma (EC) and hyperplasia (EH). Methods All women with BMI data who underwent surgery for EC or EH from 2008 to 2014 were identified from MarketScan, a healthcare claims database. Differences in 30-day complications and costs were compared between BMI groups and stratified by surgical modality. Results Of 1112 patients, 35%, 36%, and 29% had a BMI of ≤ 29, 30–39, and ≥ 40 kg/m 2 , respectively. Compared to patients with a BMI of 30–39 and ≤ 29, women with a BMI ≥ 40 had higher rates of venous thromboembolism (3% vs 0.2% vs 0.3%, p < 0.01) and wound infection (7% vs 3% vs 3%, p = 0.02). This increase was driven by the subset of patients who had laparotomy and was not seen in those undergoing minimally invasive surgery (MIS). Median total costs for women with a BMI ≥ 40, 30–39, and ≤ 29 were U.S. $17.3 k, $16.8 k, and $16.6 k respectively (p = 0.53). Costs were higher for patients who had laparotomy than those who had MIS across all BMI groups, with the cost difference being highest in morbidly obese women (≥ 40: $21.6 k vs $14.9 k, p < 0.01; 30–39: $18.9 k vs $16.1 k, p = 0.01; ≤ 29: $19.3 k vs $15 k, p < 0.01). Patients who had complications had higher costs compared to those who did not, with a higher cost difference in the laparotomy group ($27.7 k vs $16.4 k, p < 0.01) compared to the MIS group ($19.9 k vs $15 k, p < 0.01). Conclusions MIS may increase the value of care by minimizing complications and decreasing costs. This may be most pronounced in morbidly obese women. [ABSTRACT FROM AUTHOR]

Objective Metformin reduces cancer incidence and improves overall survival in diabetic patients. In preclinical studies, metformin decreases endometrial cancer (EC) cell growth by activation of AMPK/mTOR inhibition. We sought to determine the effects of metformin on serum/tumor biomarkers in women with EC. Methods In this prospective trial, newly diagnosed EC patients underwent pre-treatment blood draw/endometrial biopsy, were administered oral metformin 850 mg daily for ≥ 7 days, and underwent post-treatment blood draw/definitive surgery. Pre- and post- serum analyses were performed. Tumor samples were evaluated for changes in AMPK, PI3K/AKT pathway, proliferation, and apoptosis by immunohistochemistry. Results Twenty patients completed the trial. Median age and BMI were 57 years (range: 27–67) and 34.5 kg/m 2 (range: 21.9–50.0). Median duration of metformin was 9.5 days (range: 7–24). A majority of women had endometrioid adenocarcinomas (90%) and were early stage (85%). After metformin, there were significant decreases in serum IGF-1 ( p = 0.046), omentin ( p = 0.007), insulin ( p = 0.012), C-peptide ( p = 0.018), and leptin ( p = 0.0035). Compared to baseline, post-treatment tissue showed decreased phospho-AKT in 18/20 patients (90%, p = 0.0002), decreased phospho-S6rp in 14/20 patients (70%, p = 0.057), and decreased phospho-p44/42MAPK in 15/18 patients (83.3%, p = 0.0038). There was no difference in Ki67, phospho-ACC, or caspase 3. Changes did not correlate with BMI, grade, or KRAS mutation. Conclusion In this prospective window of opportunity study, we demonstrated that relevant serum and molecular changes occur in patients with newly diagnosed EC after a short course of metformin. Ongoing clinical trials will help determine the appropriate role for metformin in the treatment of women with EC. [ABSTRACT FROM AUTHOR]

Objective Sexual dysfunction is common in endometrial cancer survivors (ECS). Our group previously tested a six-month exercise intervention in ECS. We performed a secondary analysis to determine intervention's impact on sexual health. Methods We studied 100 post-treatment Stage I-IIIa sedentary ECS who participated in a non-controlled, single-arm, home-based exercise intervention utilizing telephone counseling, printed material, and pedometers. Quality-of-life and physical activity measures were collected at baseline and six months. Sexual function (SF) and sexual interest (SI) scores were extracted from the QLACS questionnaire. Results Baseline SF and SI were lower in survivors with less than a four-year college degree (P < 0.001). Baseline SI was higher in survivors who were married or living with a significant other (P = 0.012). No significant differences in SF or SI were observed based on obesity status, race, time since diagnosis, or treatment type. Post-intervention, mean SF score improved (P = 0.002), 51% of participants had improved SI, and 43% had improved SF. When controlled for age and time since diagnosis, a one-hour increase in weekly physical activity was associated with a 6.5% increased likelihood of improved SI (P = 0.04). Increased physical activity was not associated with improved SF. Conclusions Although causation cannot be determined in this study, the correlation between receipt of an exercise intervention and improved sexual health for ECS is a novel finding. This finding suggests a role for physical activity as a strategy to improve the sexual health of ECS, which our group is examining in a larger prospective study. [ABSTRACT FROM AUTHOR]

Objective Serous tubal intraepithelial carcinoma (STIC) is currently considered the precursor lesion of pelvic (i.e., ovarian or peritoneal) high-grade serous carcinoma. The incidence of STIC has been reported to range from 0.6% to 7% in BRCA mutations carriers. However, the clinical outcome of patients with ‘isolated’ STIC remains elusive. The aim of this study is to review the published literature on isolated STIC to determine outcomes of these patients and present a summary of management strategies. Methods A systematic English-language literature search was conducted in PubMed, MEDLINE-Ovid, Scopus, EBSCOhost, Cochrane Library of articles published from February 2006 to April 2015. Study inclusion criteria for review were the following: risk-reducing salpingo-oophorectomy (RRSO), BRCA mutation carriers, non- BRCA mutation carriers, and benign surgical indication. Exclusion criteria were as follows: the presence of synchronous gynecological cancers, concurrent non-gynecological malignancies, the presence of ovarian intraepithelial lesions, and articles that did not include any clinical information and were restricted to pathology information only. Results A total of 78 patients with isolated STIC were included in our analysis. The median age for all patients was 53.7 years (range; 37–83). Surgical indication was RRSO in 67 patients with BRCA mutations or high-risk personal or family history. In the other 11 patients, an incidental STIC was detected after surgery for non-cancerous indications. Eleven (16.4%) patients received chemotherapy after the diagnosis of STIC. The follow-up time ranged from 2 to 150 months. Three (4.5%) patients with BRCA mutations were diagnosed with primary peritoneal carcinoma (PPC) during the follow-up at 43, 48 and 72 months after RRSO. Conclusions The rate of primary peritoneal carcinoma in patients with BRCA mutations and isolated STIC is 4.5%. The role of adjuvant therapy remains elusive and routine surveillance with tumor markers and imaging is not warranted. [ABSTRACT FROM AUTHOR]

Objective Evaluate rates of chemotherapy and radiotherapy delivery in the treatment of uterine serous carcinoma, and compare clinical outcomes of treated and untreated patients. Methods The National Cancer Database was queried to identify patients diagnosed with uterine serous carcinoma between 2003 and 2011. The impact of chemotherapy on survival was analyzed using the Kaplan–Meier method. Factors predictive of outcome were compared using the Cox proportional hazards model. Results A total of 13,752 patients met the study eligibility criteria. Stage I, II, III, and IV disease accounted for 4355 (31.7%), 1023 (7.4%), 3484 (25.3%), and 2451 (17.8%) of the study population, respectively. 2439 (17.7%) women had unknown stage. Chemotherapy was administered in 4290 (35.4%) patients, radiotherapy to 1673 (12.2%), adjuvant chemo-radiation to 2915 (21.2%), and 4874 (35.4%) of women did not receive adjuvant therapy during the study period. Utilization of chemotherapy became more frequent over time. Over the entire study period, after adjusting for age, period of diagnosis, race, facility location, facility type, insurance provider, socioeconomic status, comorbidity index, lymph node dissection, treatment modality, and stage, there was an association between treatment modality and survival, with the lowest hazard ratio in patients that received chemo-radiation. After adjusting for the same factors in women with stages I and II, chemo-radiation was associated with improved survival compared to patients that received no treatment. Radiotherapy or chemotherapy alone was not associated with improved survival. Conclusion Utilization of chemotherapy is increased in this population over the study period from 2003–2012 and more importantly that survival, particularly in advanced stage patients, is improving. [ABSTRACT FROM AUTHOR]

Objective Pelvic and paraortic lymph nodal regions are frequent sites of relapse in women with endometrial cancer who have not undergone adjuvant external beam radiation. We investigated outcomes after definitive management of nodal relapses of endometrial cancer with intensity modulated radiation therapy (IMRT). Methods Between 2002–2012, 38 patients with endometrial cancer who had no prior external beam radiation were treated definitively using IMRT for regionally confined pelvic or paraortic nodal recurrences. Thirteen (34%) had chemotherapy prior to radiation, and 21 (55%) received concurrent chemotherapy. The nodal basins were typically treated to 45–50 Gy, with a boost to the gross tumor to a median total of 64.7 Gy (range 59–73 Gy). Results The median overall survival from date of recurrence was 46.1 months and the 2-year survival was 71%. Patients who received concurrent chemotherapy had a significantly longer median survival (61.9 months versus 28.7 months, p = 0.034). In-field failures were more frequent in patients who received chemotherapy prior to radiation, had a shorter recurrence-free interval, received a lower radiation dose, and had higher tumor grade. Three patients (8%) experienced grade 3–4 late gastrointestinal (GI) toxicity. Conclusions Long-term survival can be achieved in women with nodal recurrences of endometrial cancer. The use of concurrent chemotherapy and dose escalation with IMRT as feasible may improve survival for women with isolated nodal recurrences of endometrial cancer. [ABSTRACT FROM AUTHOR]

Objective Evaluate rates of chemotherapy and radiotherapy delivery in the treatment of uterine carcinosarcoma, and compare clinical outcomes of treated and untreated patients. Methods The National Cancer Database was queried to identify patients diagnosed with uterine carcinosarcoma between 2003 and 2011. The impact of chemotherapy on survival was analyzed using the Kaplan–Meier method. Factors predictive of outcome were compared using the Cox proportional hazards model. Results A total of 10,609 patients met study eligibility criteria. Stages I, II, III, and IV disease accounted for 2997 (28.2%), 642 (6.1%), 2037 (19.2%), and 1316 (12.4%) of the study population, respectively. Most patients (91.0%) underwent definitive surgery, and lymphadenectomy was performed in 68.7% of the patients. Chemotherapy was administered in 2378 (22.4%) patients, radiotherapy to 2196 (20.7%), adjuvant chemo-radiation to 1804 (17.0%), and 4231 (39.9%) of women did not received adjuvant therapy. Utilization of chemotherapy became more frequent over time. Over the entire study period, after adjusting for race, period of diagnosis, facility location, facility type, insurance provider, stage, age, treatment modality, lymph node dissection, socioeconomic status, and comorbidity index, there was an association between treatment modality and survival. The lowest hazard ratio observed was in patients that received chemo-radiation. The strongest quantitative predictor of death was stage at the time of diagnosis. In addition, surgical treatment, lymph node dissection, most recent time-periods, lower comorbidity index, and higher socioeconomic status were associated with improved survival. Conclusion The overall rates of chemotherapy use have increased over time. Adjuvant chemotherapy and chemo-radiation were associated with improved survival. [ABSTRACT FROM AUTHOR]

The standard management of advanced-stage ovarian cancer has been a subject of debate, and much controversy remains as to whether patients should have primary cytoreductive surgery followed by chemotherapy or neoadjuvant chemotherapy followed by interval cytoreductive surgery. In addition, there is increasing evidence that the patients who ultimately gain the most benefit from surgery are those with no residual disease at the completion of surgery (R0 resection). Therefore, to determine the best therapeutic strategy (primary cytoreductive surgery vs. neoadjuvant chemotherapy) for an individual patient, it is critically important to estimate the likelihood that primary cytoreductive surgery will leave no macroscopic residual disease. A number of studies have evaluated the use of serologic markers, such as CA-125, and imaging modalities, such as computed tomography (CT) or positron emission tomography/CT (PET/CT), to determine which patients are ideal candidates for primary cytoreductive surgery. More recently, laparoscopy has been proposed as a reliable predictor of R0 resection. In this report, we provide a review of the existing literature on the proposed criteria to predict the outcome of cytoreductive surgery and the role of laparoscopy-based scores in the management of advanced ovarian cancer. [ABSTRACT FROM AUTHOR]

Objective: With the growing focus on patient-centered care, patient reported outcomes (PROs) are becoming an important component to clinical trials and quality metrics. The objective of this study was to pilot the collection of patient reported symptom burden in women undergoing surgery in a gynecologic oncology practice. Method: Perioperative patient reported symptom burden was measured for women undergoing laparotomy on the gynecologic oncology service at the University of Texas MD Anderson Cancer Center. Symptoms were assessed using the M.D. Anderson Symptom Inventory (MDASI-OC), a 27 item tool validated for use in patients with ovarian cancer. The MDASI-OC was administered as a preoperative baseline, daily while admitted to the hospital after surgery, twice a week on the first week after discharge and then weekly until 8 weeks postoperatively. Result: 29 patients were evaluable. Seventy-five percent of patients had a diagnosis of ovarian cancer. Of those patients, half underwent a primary debulking surgery and the other half had neoadjuvant chemotherapy prior to interval cytoreductive surgery. In the postoperative inpatient setting, the five symptoms with the highest overall burden were fatigue, pain, abdominal pain, dry mouth and drowsiness. Longitudinal change of the top 5 symptoms during hospitalization did not show any significant difference between those who had neoadjuvant chemotherapy and those who did not. Conclusion: The collection of longitudinal PROs to assess symptom burden is feasible in patients undergoing gynecologic oncology surgery. Patient reported outcomes are a crucial component of patient-centered research and the longitudinal collection and analysis of symptom burden can allow for more meaningful comparisons of surgical technique and perioperative care. [ABSTRACT FROM AUTHOR]

Objective Determine factors impacting the uptake of genetic counseling and results of genetic testing following universal tumor testing for Lynch syndrome in patients with endometrial cancer. Methods The study population consisted of two unselected cohorts of endometrial cancer patients, 408 identified retrospectively and 206 identified prospectively. Immunohistochemistry for mismatch repair protein expression and/or microsatellite instability analysis was performed on these tumors. MLH1 methylation analysis was performed on tumors with loss of MLH1 protein. Tumor studies were considered suggestive of Lynch Syndrome if they showed immunohistochemical loss of MSH2, MSH6 or PMS2, loss of MLH1 without MLH1 promoter methylation, and/or microsatellite instability. Participants with suggestive tumor studies were contacted and offered genetic counseling and testing. Results In the retrospective cohort, 11% had tumor studies suggestive of Lynch syndrome, and 42% was seen for genetic counseling. A germline mutation was detected in 40%, and one had a variant of uncertain significance. In the prospective cohort, 8.7% of patients had tumor testing suggestive of Lynch syndrome; 72% were seen for genetic counseling. Germline mutations were found in 40%, and one had a variant of uncertain significance. Common challenges included timing of re-contact, age, perceived lack of relevance, inability to travel and limited insurance coverage. Conclusions There are several barriers to genetic counseling and testing follow-up after universal tumor testing, and uninformative genetic test results present a management challenge. It is important to consider these limitations when implementing an approach to screening endometrial cancer patients for Lynch syndrome. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Given the emerging evidence for the fimbria as the site of origin for many serous carcinomas in BRCA mutation carriers, consideration is being given in studying prophylactic salpingectomy with delayed oophorectomy (PSDO) as a risk-reducing surgery. We aimed to determine the interest in a study of PSDO among these women. Methods: We evaluated the results of an online survey conducted by Facing Our Risk of Cancer Empowered (FORCE), a patient advocacy group, from October 2010 to August 2012. Premenopausal BRCA mutation carriers with no history of ovarian cancer or prior bilateral salpingo-oophorectomy (BSO) were included. Results: Of the 204 women meeting inclusion criteria, median age was 35years, 92.5% were white, 25.7% were Jewish, and 16.7% had a history of breast cancer. Overall, 34.3% reported interest in a study of salpingectomy, 35.3% were unsure, and 30.4% were not interested in the study. Women noted the possibility of lowering ovarian cancer risk without menopause as a compelling reason to participate (83.8%). Reasons for not participating in a salpingectomy study included surgical complications (46.6%), potential ovarian damage (42.2%), planning BSO soon (32.4%), and surgical costs (32.8%). Acceptable study risks included the need for two surgeries (77.2%), possibility of not lowering ovarian cancer risk (68%), and disruption of ovarian blood supply (66.5%). Conclusions: One-third of BRCA mutation carriers indicated definite interest in a PSDO study. Potential study risks were acceptable to most women. These findings suggest that patient accrual for a clinical trial of prophylactic salpingectomy with delayed oophorectomy is possible. [Copyright &y& Elsevier]

Abstract: Objective: Obesity-associated hyperestrogenism and hyperinsulinemia contribute significantly to the pathogenesis of endometrial cancer. We recently demonstrated that metformin, a drug long used for treatment of type 2 diabetes, attenuates both insulin- and estrogen-mediated proliferative signaling in the obese rat endometrium. In this study, we sought to identify tissue biomarkers that may prove clinically useful to predict tissue response for both prevention and therapeutic studies. We identified CGRRF1 (cell growth regulator with ring finger domain 1) as a novel metformin-responsive gene and characterized its possible role in endometrial cancer prevention. Methods: CGRRF1 mRNA expression was evaluated by RT-qPCR in the endometrium of obese and lean rats, and also in normal and malignant human endometrium. CGRRF1 levels were genetically manipulated in endometrial cancer cells, and its effects on proliferation and apoptosis were evaluated by MTT and Western blot. Results: CGRRF1 is significantly induced by metformin treatment in the obese rat endometrium. In vitro studies demonstrate that overexpression of CGRRF1 inhibits endometrial cancer cell proliferation. Analysis of human endometrial tumors reveals that CGRRF1 expression is significantly lower in hyperplasia, Grade 1, Grade 2, Grade 3, MMMT, and UPSC endometrial tumors compared to normal human endometrium (p<0.05), suggesting that loss of CGRRF1 is associated with the presence of disease. Conclusion: CGRRF1 represents a novel, reproducible tissue marker of metformin response in the obese endometrium. Furthermore, our preliminary data suggests that up-regulation of CGRRF1 expression may prove clinically useful in the prevention or treatment of endometrial cancer. [Copyright &y& Elsevier]

Abstract: Objective: The aims of this study were to implement a patient-administered checklist designed to identify endometrial cancer patients at elevated risk for Lynch syndrome; measure subsequent genetic counseling and testing; and identify differences between those who attended genetic counseling and those who did not. Methods: We developed a 4-item yes/no checklist of personal and family history risk factors for Lynch syndrome-associated endometrial cancer and recommended referral for genetic counseling for patients meeting any of the criteria. Retrospective chart review was performed to determine subsequent genetic counseling and testing outcomes over a 15month period. Results: 6/387 (1.6%) of endometrial cancer patients tested positive for a Lynch syndrome mutation. 4/24 (17%) of endometrial cancer patients who met referral criteria and attended genetic counseling tested positive. 38/70 (55%) of patients who met referral criteria were not seen for genetic counseling. Patients who were diagnosed with endometrial cancer at younger ages, who had primary surgery at our institution, or who met more than one referral criteria were more likely to be seen for genetic counseling. Conclusions: Endometrial cancer patients who met referral criteria and attended genetic counseling comprised a population enriched for Lynch syndrome. This approach allowed Lynch syndrome evaluation resources to be targeted to a population of patients that is high risk and interested in the information. The referral rate of at-risk patients needs to be improved, and allocating resources towards this goal could increase the identification of Lynch syndrome while avoiding some of the pitfalls of universal screening. [Copyright &y& Elsevier]

Abstract: Objective: To prospectively evaluate tumor control, survival, and toxic effects in patients with International Federation of Gynecology and Obstetrics (1988) stage I–IIIA papillary serous carcinoma of the endometrium treated with concurrent chemoradiation and adjuvant chemotherapy. Methods: Thirty-two patients were enrolled from October 2001 through July 2009. Patients underwent full surgical disease staging and postoperative concurrent weekly paclitaxel (50mg/m2) and pelvic RT to 45Gy plus a vaginal cuff boost followed by 4cycles of adjuvant paclitaxel (135mg/m2). Results: Thirty patients (94%) were evaluable (3 with stage IA disease, 11 IB, 3 IC, 1 IIB, and 12 IIIA). Eighteen patients (60%) received all 5 planned courses of concurrent chemotherapy, 10 (33%) received 4 courses, and 2 (7%) received 3 courses. All 30 patients received RT; 27 (90%) received the full dose, 2 received 43.2Gy, and 1 received 39.6Gy owing to toxic effects. Twenty-three patients (77%) completed all 4cycles of adjuvant paclitaxel, 3 (10%) completed 3cycles, 2 (7%) completed 2cycles, and 2 received no adjuvant therapy. Overall survival (OS), progression-free survival (PFS), and local control rates for all patients were 93%, 87%, and 87%, respectively, at 2years and 85%, 83%, and 87%, respectively, at 5years. Six patients developed (20%) grade 3/4 toxicities from the treatment. Four patients (13%) had grade 3 or more severe bowel complications and two patients developed symptomatic pelvic fractures. Conclusions: Treatment with concurrent paclitaxel and pelvic RT followed by 4 courses of systemic paclitaxel produced favorable results in patients with surgically staged I–III UPSC. [Copyright &y& Elsevier]

Abstract: Objective: The low prevalence of ovarian cancer demands both high sensitivity (>75%) and specificity (99.6%) to achieve a positive predictive value of 10% for successful early detection. Utilizing a two stage strategy where serum marker(s) prompt the performance of transvaginal sonography (TVS) in a limited number (2%) of women could reduce the requisite specificity for serum markers to 98%. We have attempted to improve sensitivity by combining CA125 with proteomic markers. Methods: Sera from 41 patients with early stage (I/II) and 51 with late stage (III/IV) epithelial ovarian cancer, 40 with benign disease and 99 healthy individuals, were analyzed to measure 7 proteins [Apolipoprotein A1 (Apo-A1), truncated transthyretin (TT), transferrin, hepcidin, ß-2-microglobulin (ß2M), Connective Tissue Activating Protein III (CTAPIII), and Inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4)]. Statistical models were fit by logistic regression, followed by optimization of factors retained in the models determined by optimizing the Akaike Information Criterion. A validation set included 136 stage I ovarian cancers, 140 benign pelvic masses and 174 healthy controls. Results: In a training set analysis, the 3 most effective biomarkers (Apo-A1, TT and CTAPIII) exhibited 54% sensitivity at 98% specificity, CA125 alone produced 68% sensitivity and the combination increased sensitivity to 88%. In a validation set, the marker panel plus CA125 produced a sensitivity of 84% at 98% specificity (P=0.015, McNemar''s test). Conclusion: Combining a panel of proteomic markers with CA125 could provide a first step in a sequential two-stage strategy with TVS for early detection of ovarian cancer. [Copyright &y& Elsevier]

Abstract: Objective: To determine whether women with low-grade serous ovarian cancer (LGSOC) have personal and family histories of breast and ovarian cancer that are less suggestive of Hereditary Breast and Ovarian Cancer (HBOC), as compared to women with high-grade serous ovarian cancer (HGSOC). Methods: A single institution, case-control retrospective review of medical records was conducted. Personal demographics, personal cancer history, and family history of breast and ovarian cancer of women with LGSOC were collected and compared to controls with HGSOC, which is known to be associated with HBOC. Results: 195 cases of LGSOC and 386 controls with HGSOC were included in the analysis. Women with LGSOC were significantly less likely to have a first- or second-degree relative with breast or ovarian cancer (p =0.0016). Additionally, when the personal and family histories were quantified using the AMyriad BRC mutation prevalence tables, women with LGSOC had lower scores indicative of a less suggestive family history for HBOC (p =0.027). Conclusions: In this study, women with LGSOC had family histories that were less suggestive of HBOC compared to women with HGSOC, especially when the degree of relatedness of affected relatives was taken into account. By beginning to determine if LGSOC is part of the tumor spectrum seen in HBOC, this study is an important step towards refining hereditary cancer risk assessment for women with ovarian cancer. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: Previous studies have suggested that low-grade serous ovarian carcinoma is more chemoresistant to first-line or neoadjuvant chemotherapy than high-grade serous carcinoma. The purpose of this study was to further characterize this chemoresistance in recurrent low-grade serous ovarian carcinoma. Methods: From a 1990–2007 search of the departmental databases at our institution, we identified recurrent low-grade serous ovarian carcinoma patients; abstracted chemotherapy response information from the medical records of those whose disease was: 1) histologically-confirmed, 2) measurable or evaluable, and 3) treated with chemotherapy; and retrospectively reviewed these data. Response was determined based on modified RECIST. Time to progression and overall survival were also calculated. Results: We identified 58 evaluable patients with recurrent low-grade serous ovarian carcinoma who received 108 separate chemotherapy regimens (“patient-regimens”), which produced 4 responses—(1 complete and 3 partial; overall response rate, 3.7%). The overall response rate for the platinum-sensitive cohort was 4.9%, and for the platinum-resistant cohort, 2.1%. Stable disease was observed in 65 (60.2%) of 108 patient-regimens. Median overall survival was 87.1 months. The median time to progression was 29.0 weeks (34.7, platinum-sensitive cohort; 26.4, platinum-resistant cohort) (P =0.32). Conclusions: Compared with high-grade ovarian cancers, recurrent low-grade serous ovarian carcinoma appears relatively chemoresistant. Whether the latter''s high rate of stable disease owes more to the tumor''s biology or the influence of chemotherapy remains unclear. Based on these findings, phase II trials of novel targeted agents in recurrent low-grade serous ovarian carcinoma are warranted. [Copyright &y& Elsevier]

Abstract: Objectives: Few women with ovarian cancer undergo genetic testing for the Breast and Ovarian Cancer susceptibility genes, BRCA1 and BRCA2. With the prospect of BRCA-directed therapeutics, we investigated ovarian cancer patients'' knowledge and willingness to undergo genetic testing. Methods: All ovarian cancer patients seen in the Gynecology Center of a cancer center and a private clinic were asked to complete an anonymous questionnaire regarding knowledge and willingness to undergo BRCA testing. Women who had prior genetic testing were asked not to participate. Data was analyzed using Fisher''s exact test. Results: Two-hundred and thirty seven ovarian cancer patients voluntarily completed the questionnaire. Fifty-five percent (131/237) of participants had not heard of BRCA testing. Of Caucasian respondents, 51% were unaware of BRCA testing, compared to 70% of Hispanic and 88% of African American respondents (p =0.008). Awareness was correlated with education (p <0.001). Eighty-nine percent of participants were willing to be tested if it would directly affect their therapy and 86.9% would be tested to benefit their family. Seventy-four percent of patients would pay 20% of the cost of testing, only 25.1% would pay in full. Conclusions: A majority of women with ovarian cancer are not aware of the availability of BRCA testing. This lack of awareness is more profound in minorities. Despite lack of knowledge, most patients would undergo testing if it would impact their care. However, cost may be a barrier. Given the willingness of patients to undergo testing and the possibility of targeted therapy, clinicians who care for these patients should work to make appropriate genetic counseling referrals. [Copyright &y& Elsevier]

Abstract: Women with germline mutations in the cancer susceptibility genes, BRCA1 or BRCA2, associated with Hereditary Breast/Ovarian Cancer syndrome, have up to an 85% lifetime risk of breast cancer and up to a 46% lifetime risk ovarian cancer. Similarly, women with mutations in the DNA mismatch repair genes, MLH1, MSH2 or MSH6, associated with the Lynch/Hereditary Non-Polyposis Colorectal Cancer (HNPCC) syndrome, have up to a 40–60% lifetime risk of both endometrial and colorectal cancer as well as a 9–12% lifetime risk of ovarian cancer. Genetic risk assessment enables physicians to provide individualized evaluation of the likelihood of having one of these gynecologic cancer predisposition syndromes, as well the opportunity to provide tailored screening and prevention strategies such as surveillance, chemoprevention, and prophylactic surgery that may reduce the morbidity and mortality associated with these syndromes. Hereditary cancer risk assessment is a process that includes assessment of risk, education and counseling conducted by a provider with expertise in cancer genetics, and may include genetic testing after appropriate consent is obtained. This commentary provides guidance on identification of patients who may benefit from hereditary cancer risk assessment for Hereditary Breast/Ovarian Cancer and the Lynch/Hereditary Non-Polyposis Colorectal Cancer syndrome. [Copyright &y& Elsevier]

Abstract: Objective. : STK15 is a serine threonine kinase which assists chromosomal separation and mitotic spindle stability through interaction with the centrosome during mitosis. We hypothesized that STK15 polymorphisms might modulate the risk of uterine cancer. Methods. : We used a hospital-based case–control study to assess the association between STK15 polymorphisms and risk of uterine cancer. Cases and controls were matched on age, race, and smoking status. Two common STK15 single nucleotide polymorphisms (SNPs), F31I (T/A), and V57I (G/A), were genotyped. Odds ratios (OR) and 95% confidence intervals (CI) were obtained using unconditional logistic regression analysis. Results. : A total of 193 women with uterine cancer and 218 controls were genotyped for both SNPs. After adjustment for age, race, and smoking status for the F31I SNP, the homozygous variant genotype (AA) was associated with a significantly increased uterine cancer risk (OR 10.2; 95% CI 2.23–46.5). Individuals with the heterozygous genotype (TA) and a history of tobacco use also exhibited an increased risk for uterine cancer (OR 2.63; 95% CI 1.20–5.76). For the V57I SNP, neither the homozygous (AA) nor the heterozygous (GA) variant genotypes were associated with significantly altered risk for uterine cancer (OR 0.76; 95% CI 0.18–3.25 and OR 0.88; 95% CI 0.52–1.49). Conclusion. : Our study demonstrates that STK15 F31I SNP is associated with an increased risk for uterine cancer. Confirmation of this pilot study is needed in a larger case–control population to evaluate this genetic variant with other known risk factors for uterine cancer. [Copyright &y& Elsevier]

Abstract: Objectives.: Early detection of ovarian cancer should improve overall survival. Multiple serum markers have been evaluated as possible tests to detect early stage disease, but few urine markers have been studied. Mesothelin has been detected in serum from patients with ovarian cancer, but has not been previously reported in urine. Methods.: Mesothelin was assayed in the serum and in the urine from 28 patients with early stage (I/II) invasive epithelial ovarian cancers, 111 with advanced stage (III/IV) invasive disease and 19 with tumors of low malignant potential. Marker values have been compared to those in healthy controls and 115 patients with benign pelvic masses. Thresholds were set to include 95% of mesothelin values for 127 sera and 89 urines from healthy women. Urine values were considered: (1) as assayed; (2) normalized using the ratio of serum to urine creatinine; and (3) normalized using the Cockroft–Gault formula for glomerular filtration rate (GFR). Urines were also assayed for human chorionic gonadotropin (hCG) free beta subunit and beta subunit core fragment and similarly normalized. Results.: Optimal sensitivity for early stage disease was obtained when urine mesothelin was normalized using GFR. A greater fraction of patients with early stage disease was detected with the mesothelin urine assay (42%) than with the serum assay (12%). Similarly, 75% of patients with advanced ovarian cancer had elevated mesothelin in urine compared to 48% in serum. Serum and urine levels of mesothelin correlated for early (p =0.02) and late (p <0.001) disease. Urine mesothelin exhibited greater sensitivity for early stage ovarian cancer than did hCG free beta subunit or beta subunit core fragment and complementarity was not observed. Conclusion.: Urine mesothelin deserves further evaluation as a biomarker for detection of early stage ovarian cancer in combination with other urinary markers. [Copyright &y& Elsevier]

Abstract: Background. : Serous ovarian tumors of low malignant potential (STLMP) frequently coexist with low-grade serous carcinoma of the ovary (LGSC) and, when they recur, frequently do so as LGSC. The purpose of this study was to compare the outcomes of patients with these two tumor types. Methods. : All patients with stages II–IV LGSC (group 1) or with STLMP that recurred as LGSC (group 2) seen at our institution from 1973 to 2003 were identified, and demographic data were obtained. For group 1, progression-free and overall survival times were calculated from the date of primary diagnosis to the date of disease progression/recurrence or the date of last contact/death, respectively. For group 2, progression-free and overall survival times were calculated from the date of first relapse as a LGSC to the date of progression or the date of last contact/death, respectively. The method of Kaplan and Meier was used to estimate survival, and the log-rank test was used to compare differences between survival curves. Results. : We identified 112 patients in group 1 and 41 in group 2. There were no statistically significant differences between the two groups in median age (42.7 vs. 45.4 years [at relapse]; P =0.37), progression-free survival time (19.5 vs. 25 months; P =0.92), or overall survival time (81.8 vs. 82.8 months; P =0.84). Conclusions. : The age at diagnosis, progression-free survival time, and overall survival time associated with newly diagnosed stages II–IV LGSC of the ovary are similar to those of STLMP that recur as LGSC, providing further evidence of an association between these two tumor types. [Copyright &y& Elsevier]

Abstract: Objective. : An HPV (human papillomavirus) vaccine will be available soon. Because vaccination for both boys and girls will be critical to reduce the incidence of this disease, we evaluated the willingness of women to accept the HPV vaccine and to consent to having their children vaccinated. Methods. : A 20-item questionnaire was distributed to women who had children between the ages of 8 and 14 years, the likely age range of the children who will be targeted to receive the vaccine. Results. : 200 women completed surveys. The median age for the respondents was 34.4 years (range, 23–53 years). 77% of the women surveyed would be willing to accept an HPV vaccine for themselves. 67% who had a daughter (n = 156) and 66% who had a son (n = 137) would consent to have their child vaccinated. Those not accepting the vaccine cited the risk of unknown adverse effects or their current lack of sexual activity. Women who would not consent to have their children vaccinated cited the risk of unknown adverse effects and their belief that their children are not sexually active. Male children not directly benefiting from the vaccine were also a reason for not considering the vaccine for sons. A history of an abnormal Papanicolaou smear was not associated with willingness to accept the vaccine. Conclusions. : This pilot study demonstrated a willingness of women to accept the HPV vaccine for themselves and their children. Gynecologists and gynecologic oncologists must focus not only on the diagnosis and treatment of cervical cancer but also on its prevention. [Copyright &y& Elsevier]