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Introduction: Morbidity and Mortality (M&M) rounds can identify adverse events and improve patient safety however adoption in cancer centers is not routine. Herein we report the results of a chemotherapy-specific gynecologic oncology M&M rounds and identify reasons for hospital admission Methods: Between July 2014 and April 2016, all admissions Results: 585 patients were admitted, 78% of whom had ovarian cancer and 43% of whom had recurrent disease. Overall, 47% of admissions were unplanned and these were significantly longer than planned admissions (5.6 vs. 2.4 days, p = 0.0003). Of unplanned admissions, 43% were due to chemotherapy, and 57% were due to disease burden. 74% of patients had received >1 prior line of chemotherapy, and 22% were on clinical trial. The most common causes of unplanned admission were nausea, vomiting or failure to thrive (28.9%), fever (17.9%) and small bowel obstruction (19.9%). Conclusions: There is a high rate of unplanned admission

OBJECTIVE: To describe trends in the use of lymphadenectomy for endometrioid adenocarcinoma of the endometrium between 1998 and 2012. METHODS: A time-trend analysis was conducted using a population-based cancer registry covering 28% of the population of the United States. To quantify differences over the study period time, the frequency of lymphadenectomy and nodal metastasis among women who underwent surgical treatment of endometrioid endometrial adenocarcinoma was compared among consecutive 3- to 4-year periods. Biannual frequency of lymphadenectomy was modeled with Joinpoint regression to identify when potential changes in trends occurred and calculate annual percentage change. RESULTS: A total of 74,365 women who underwent surgery between 1998 and 2012 were analyzed. Frequency of lymphadenectomy increased by 4.2% annually (95% confidence interval [CI] 3.7–4.6) from 1998 to 2007, after which the frequency declined by 1.6% per year (95% CI 0.9–2.2). Between 1998–2000 and 2007–2009, the frequency of lymphadenectomy rose from 48.7% to 65.5% (risk difference 16.8%, 95% CI 15.4–18.1), the proportion of women found to have nodal metastasis increased by 1.1% (95% CI 0.4–1.7), and the frequency of negative lymphadenectomy increased by 15.7% (95% CI 14.3–17.1). The decline in frequency of lymphadenectomy after 2007 was associated a 3.1% (95% CI 2.1–4.1) decline in the rate of negative lymphadenectomy, but no change in the proportion of women found to have nodal metastasis (P=.17). CONCLUSION: The frequency of lymphadenectomy in the surgical treatment of endometrioid endometrial cancer increased by 4.2% annually from 1998 to 2007 and decreased by 1.6% annually from 2007 to 2012. LEVEL OF EVIDENCE: II

ObjectiveThe objectives of this study were to evaluate the rates of chemotherapy and radiotherapy delivery in the treatment of uterine serous carcinoma in the Medicare population and to compare clinical outcomes in treated and untreated patients.MethodsThe linked Surveillance, Epidemiology, and End Results and Medicare databases were queried to identify patients with a diagnosis of uterine serous carcinoma between 1992 and 2009. 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.ResultsA total of 2188 patients met study eligibility criteria. Stages I, II, III, and IV diseases accounted for 890 (41%), 174 (8%), 470 (21%), and 654 (30%) of the study population, respectively. Chemotherapy, radiotherapy, both, or none, were administered as adjuvant therapy in 635 (29%), 536 (24%), 308 (14%), and 709 (32%) of the study population, respectively. Use of chemotherapy became more frequent over time. Over the study period, and after adjusting for race, time of diagnosis, SEER registry, marital status, stage, age, surgery, lymph node dissection, socioeconomic status, and comorbidity index, there was an association between receipt of radiotherapy alone (hazard ratio [HR], 1.3; 95% CI, 1.04–1.67) and not receiving any treatment (HR, 1.5; 95% CI, 1.2–2.01) and worst survival. Survival was not improved over time.ConclusionAlthough adjuvant chemotherapy and combination treatment with chemotherapy and radiation were associated with improved survival in our model, there was no significant improvement in survival over time.

To describe the incidence of thromboembolic events (venous thromboembolism) before and after the diagnosis of epithelial endometrial cancer and to evaluate the effects of these events on survival.We used the National Cancer Institute's Surveillance, Epidemiology, and End Results cancer registries linked to Medicare claim files to identify patients with epithelial endometrial cancer diagnosed between 1992 and 2009. To identify venous thromboembolism events 3 months before diagnosis and up to 24 months after diagnosis, we used International Classification of Diseases, 9th Revision, and Healthcare Common Procedure Coding System codes.A total of 23,122 patients were included; of them 1,873 (8.1%) developed a venous thromboembolism. Patients with low-grade (grades 1 and 2) endometrioid adenocarcinoma had a significantly lower rate of venous thromboembolism 3 months before and 6 months after the diagnosis of cancer (3.6%; 95% confidence interval [CI] 3.3-3.9%) compared with carcinosarcoma (9.2%; 95% CI 7.8-10.8%), clear cell (6.9%; 95% CI 4.8-9.7%), uterine serous cancer (8.1%; 95% CI 7.01-9.3%), and grade 3 endometrioid adenocarcinoma (6.1%; 95% CI 5.4-6.9%) (P.001). On multivariate analysis during the same time period, most recent time periods of diagnosis, carcinosarcoma histology compared with lower grade endometrial cancer, higher stage, African American race, marital status, chemotherapy delivery, and lymph node dissection were associated with increased risk of venous thromboembolism. The median overall survival for women who experienced a venous thromboembolism 3 months before the diagnosis of endometrial cancer was 31 months (95% CI 20-48 months); in women diagnosed with venous thromboembolism 6 months after the cancer diagnosis was 37 months (95% CI 31-44), and in women who did not experienced a venous thromboembolism was 111 months (95% CI 109-114). After adjusting for prognostic factors, there was an association between venous thromboembolism diagnosed 3 months before endometrial cancer (hazard ratio 1.69, 95% CI 1.34-2.13) or 6 months after the diagnosis (hazard ratio 1.57, 95% CI 1.44-1.71) and lower survival.Patients with uterine serous cancer, carcinosarcoma, clear cell carcinoma, and grade 3 endometrioid adenocarcinoma had a higher rate of venous thromboembolism than patients with low-grade endometrioid adenocarcinoma. A diagnosis of venous thromboembolism was associated with decreased survival in elderly patients with endometrial cancer.II.

The aim of this study is to explore the previously unexamined role of the Gynecologic Oncologist as an intraoperative consultant during general gynecologic surgery.Demographic and clinical data were collected on 98 major gynecologic surgeries that included both a general Gynecologist and a Gynecologic Oncologist between October 2010 and August 2014. Data were analyzed using XLSTAT-Prov2014.2.02.Of 794 major gynecologic surgeries, 98 (12.3%) cases that involved an intraoperative consultation were identified. There were 36 (37%) planned consults and 62 (63%) unplanned consults. Significantly more planned consults were during laparoscopy (100% v 58%; p0.01) and significantly more unplanned consults were during laparotomy (42% v 0%; p0.01). The majority of planned consults were for surgical training (86%) and the most common reasons for unplanned consults were adhesions (40%), bowel injury (19%), inability to identify ureter (19%), and cancer (11%). The most common interventions performed during unplanned consults were identification of anatomy (55%), lysis of adhesions (42%), and retroperitoneal dissection (27%). Average surgeon years in practice were significantly lower for unplanned consults (9 v 15; p0.01). A total of 25 major adverse events occurred in 15 cases with the majority occurring in cases with unplanned consults (23% v 3%; p0.01). After controlling for laparotomy, unplanned consultation was not significantly associated with major events (OR=6.67, 95%CI 0.69-64.39; p=0.10).Gynecologic Oncologists play a pivotal role in the support of generalist colleagues during pelvic surgery. In this series, Gynecologic Oncologists were consulted frequently for complex major benign surgeries. It is important to incorporate the skills required of an intraoperative consultant into Gynecologic Oncology fellowship training.

Practitioners may frequently encounter adnexal masses in premenopausal women. Adnexal masses can represent a wide variety of etiologies, and therefore they can represent a diagnostic dilemma. When an adnexal mass is found the initial work up must focus on identifying acute pathology followed by determining the risk of a malignancy. Pelvic ultrasound remains the mainstay for evaluation of adnexal masses in premenopausal patients. If ultrasounds findings are indeterminate magnetic resonance imaging (MRI) is the next imaging modality of choice. The evaluation for malignancy should include serum marker screening. Aspiration of adnexal masses is generally avoided, due to the lack of therapeutic benefit and risk of seeding a tumor. When ultrasound findings are suggestive of benign disease, conservative management, including repeat imaging, should be considered. If the clinical suspicion for malignancy is high referral to a gynecologic oncologist is warranted. In other patients whom the evaluation of their adnexal mass remains unclear surgical excision with care not to disrupt the integrity of the mass should be performed for pathologic diagnosis.

Objective Uterine leiomyosarcoma (LMS) is a relatively rare malignancy that is associated with a poor prognosis. The rarity of LMS has led to a lack of consensus regarding appropriate treatment. The goal of this study was to identify the role that chemotherapy and radiotherapy have played in the treatment of uterine LMS in the United States as well as the effectiveness of adjuvant treatment. Materials/Methods We used the SEER (Surveillance, Epidemiology, and End Results)-Medicare database to gather information on uterine LMS patients older than the age of 66 years diagnosed between 1992 and 2009. Basic demographic and clinical characteristics were collected. A logistic regression model analysis was performed to determine predictors of treatment. Cox proportional hazards models were used to identify clinical parameters and treatment strategies associated with survival differences. Results Our final study group included 230 patients. We found that the rate of use of chemotherapy and radiotherapy in the treatment of patients with uterine LMS increased over the period investigated. However, we identified no significant survival advantage associated with either mode of therapy. The strongest predictor of survival was stage at diagnosis. The logistic regression model analysis revealed that age at diagnosis, treatment year, stage, and underlying health status were all independent predictors of chemotherapy. Age at diagnosis was also a predictor of radiation therapy. Conclusions The increasing rates of chemotherapy and radiotherapy use in this population seem to be unfounded given the lack of survival benefit. Further investigation into alternative treatment regimens is merited. The prognostic significance of stage at diagnosis indicates the importance of improving early detection of uterine LMS.

Objective Uterine serous carcinoma (USC) represents an aggressive subtype of endometrial cancer. We sought to understand Notch pathway activity in USC and determine if pathway inhibition has anti-tumor activity. Methods Patient USC tissue blocks were obtained and used to correlate clinical outcomes with Notch1 expression. Three established USC cell lines were treated with gamma-secretase inhibitor (GSI) in vitro . Mice harboring cell line derived or patient derived USC xenografts (PDXs) were treated with vehicle, GSI, paclitaxel and carboplatin (P/C), or combination GSI and P/C. Levels of cleaved Notch1 protein and Hes1 mRNA were determined in GSI treated samples. Statistical analysis was performed using the Wilcoxon rank sum and Kaplan–Meier methods. Results High nuclear Notch1 protein expression was observed in 58% of USC samples with no correlation with overall survival. GSI induced dose-dependent reductions in cell number and decreased levels of cleaved Notch1 protein and Hes1 mRNA in vitro . Treatment of mice with GSI led to decreased Hes1 mRNA expression in USC xenografts. In addition, GSI impeded tumor growth of cell line xenografts as well as UT1 USC PDXs. When GSI and P/C were combined, synergistic anti-tumor activity was observed in UT1 xenografts. Conclusions Notch1 is expressed in a large subset of USC. GSI-mediated Notch pathway inhibition led to both reduced cell numbers in vitro and decreased tumor growth of USC some xenograft models. When combined with conventional chemotherapy, GSI augmented anti-tumor activity in one USC PDX line suggesting that targeting of the Notch signaling pathway is a potential therapeutic strategy for future investigation.

To investigate racial disparities with respect to adjuvant treatment and survival in patients presenting with malignant ovarian germ cell tumors (OGCT).The National Cancer Database (NCDB) was used to identify women diagnosed with OGCT. Demographic data were abstracted, including stratification by race and histology. Standard univariate and multivariate analyses using logistic regression were performed to describe predictors of adjuvant treatment. Kaplan-Meier and Cox proportional hazards survival methods were used to evaluate racial differences in survival between African American (AA) and white (W) women.The study population included 2196 patients, with 1654 (75.3%) W and 328 (14.9%) AA women. Histologic distribution varied significantly by race (p0.0001), but neither age nor stage at presentation showed racial differences (p=0.086 and p=0.209, respectively). AA received more chemotherapy than W (W: 54.6%, AA: 65.5%, p=0.008), but in multivariate analysis there was no statistically significant difference in any adjuvant treatment modality. Despite similar treatment, and independent of histology, survival varied significantly by race with 91% (CI 0.89-0.93) five year survival in W patients compared to 84% five year survival in AA (CI 0.8-0.89) (p=0.02). These disparities were most pronounced in advanced stage disease, with 5 year survival of 84% (CI 0.79-0.89) in W compared to 61% (CI 0.48-0.78) for AA in stage III (p=0.0002), and 54% (CI 0.42-0.68) compared to 14% (CI 0.03-0.71) for stage IV (p=0.05).AA with OGCT have significantly worse 5 year survival when compared to W patients despite similar rates and modalities of adjuvant treatment.

Ovarian cancer accounts for more deaths in the United States than all other gynecologic malignancies combined. More than two-thirds of patients are still diagnosed, as they always have been, with advanced stage disease. Traditionally, upfront surgery followed by platinum-based chemotherapy has been the treatment of choice. More recently, the paradigm of care has undergone significant revision as our understanding of this heterogeneous disease continues to evolve. As a result, the way we think about, categorize and approach, the treatment of ovarian cancer is changing rapidly. Increasingly, innovations in targeted therapies appear to be the future. The purpose of this review is to provide an update of current controversies in the field, and to highlight new directions in the management of this insidious disease.

To validate whether Surgical Apgar Score can predict post-operative morbidity in patients undergoing hysterectomies for malignancies.We conducted a retrospective cohort study of consecutive hysterectomies performed for cancer at a single academic institution between 2008 and 2010. The Surgical Apgar Score (SAS) was derived as previously reported. Peri-operative complications were as outlined by the American Board for Obstetrics and Gynecology, and then further subdivided into intra-operative and post-operative events. Univariate and multivariate logistic regressions were utilized.A total of 632 patients were identified. Of our cohort, 64% underwent surgery for cancer arising in the uterus, followed by ovary at 28.6% and cervix at 4%. Median patient age was 60 years old with a mean American Society of Anesthesiologists Physical Status Classification System (ASA) score of 2.5 and a median body mass index of 29. Average Surgical Apgar Score was 7.6. As SAS decreased, the risk of peri-operative complications increased (p0.01). On univariate analysis SAS could predict for both intra-operative and post-operative complications. However, on multivariate analyses SAS could not independently predict for any post-operative complications (OR 1.02, CI 0.47-2.17). In a multivariable model incorporating age, ASA class, SAS4, disease site, bowel resection and laparotomy, only ASA class and laparotomy were able to predict for postoperative complication events.Low Surgical Apgar Score significantly associates with morbidity in women undergoing hysterectomy for malignancy, but is unable to predict which patients will have postoperative complications. This renders the SAS less helpful for the creation of peri-operative metrics to guide post-operative care.

Objectives: Universal screening for Lynch syndrome (LS) using immunohistochemistry (IHC) is recommended for patients with new colon cancer. While the sentinel malignancy in women with Lynch syndrome is equally as likely to be endometrial cancer compared to colon cancer, universal screening in endometrial cancer has not been implemented on such a large scale. Our study aims to determine any associations between loss of MMR expression and tumor clinico-pathologic characteristics, as well as the number of germ line mutations identified using IHC at our institution. Methods: A retrospective review of patients who underwent hysterectomy for grade 1 or 2 endometrioid endometrial cancer between August 2012 and January 2014 was performed. Only patients who underwent IHC for deficiencies of MLH1, MSH2, MSH6, and PMS2 were included in this cohort. Patient charts were reviewed and patient demographics, tumor size, grade, invasion, and stainingwere abstracted from electronic medical records. Results: 180 patients underwent hysterectomy for low grade EEC during the study period. Of these, 102 (56.6%) had IHC to evaluate for MMR protein deficiencies. Twenty six (25.5%) tumors had MMR loss detected via IHC, with 19 (18.6%) having deficiencies in MLH1/ PMS2 and 3 (2.9%) in MSH2/MSH6. Loss of single protein expression was observed in 4 patients, with loss of MSH6 expression noted in 2 (2.0%) and loss of MLH1 and PMS2 in 1 (1%) each. MLH1 promoter methylation analysis was performed in 7 (35.0%) of the 20 tumors, showing methylation in 6 (85.7%). One patient with MSH2 and MSH6 loss by IHC was found to have a germline mutation in MSH6. Grade 2 tumors were significantly associated with MLH1 loss on multivariate analysis (OR 5.3, p = 0.012, 95% CI 1.4–19.8). Increasing age was associated with MLH1 and PMS2 loss (OR 1.2, p = 0.021, 95% CI 1.0– 1.3). Younger age was significantly associated with MSH6 loss (OR 0.79, p = 0.025, 95% CI .64–.97). Conclusions: The most common deficiency detected via IHC involves MLH1 and PMS2 loss and is significantly associated with age. Loss of MSH6 is significantly associated with younger age. Large studies with cost-effectiveness analyses must be performed to determine if implementation of a standardized screening regimen is necessary.

Inhibition of the phosphatidylinositol 3-kinase (PI3K) pathway has been shown to induce defective homologous repair in breast carcinoma leading to heightened sensitivity to poly-ADP ribose polymerase (PARP) inhibitors. Our objective was to assess the effects on DNA repair pathways following single agent and combined PI3K and PARP inhibition utilizing endometrial cancer (EnCa) patient derived xenografts (PDX) with and without identified PIK3CA mutations. Under an institutional protocol, tumors from consenting patients with endometrioid carcinoma were collected at the time of primary surgery and genotyped for common oncogenic mutations utilizing the SNaPshot® platform. NOD/SCID mice bearing xenografts derived from two primary human endometrioid endometrial tumors with and without PIK3CA gene mutations (ENCA1 & ENCA2 respectively) were divided into four arm cohorts with equivalent tumor volumes. Vehicle or NVP BKM-120 (30 mg/kg) was administered alone and in combination with veliparib (25 mg/kg) and endometrial xenograft tumor volumes were assessed. Immunoblotting was used to assess downstream PI3K pathway and DNA repair pathway alterations in post treatment samples at specific time points. While NVP BKM120 as a single agent failed to induce significant anti-tumor activity compared to vehicle in either model, decreased pAKT, RAD51 and increased γ-H2AX levels were observed in response to NVP BKM120 alone. PIK3CA mutation status did not affect these molecular alterations. Dual NVP BKM-120 and veliparib therapy significantly impeded tumor growth (p < 0.01) in the ENCA1 model, while in ENCA2, significant tumor regression was observed (p < 0.001). No changes in mouse weight or premature death were observed in the various treatment arms. Combination therapy was associated with reconstitution of baseline RAD51 and increased γ-H2AX levels. In conclusion, these results suggest that PI3K inhibition induces defects in homologous repair mediated by RAD51 and increases reliance on PARP mediated DNA repair mechanisms. Our in vivo data suggest that PI3K inhibition sensitizes endometrial tumors with and without PIK3CA mutations to a PARP inhibitor. Citation Format: Bo Rueda, Celeste Digloria, Tracilyn Hall, Rosemary Foster, Darrell Borger, Whitfield Growdon. PI3K inhibition induces homologous repair defects in endometrioid endometrial cancer patient derived xenografts leading to synergistic anti-tumor activity with PARP inhibitors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2666. doi:10.1158/1538-7445.AM2015-2666

(USC) cell lines with and without HER2/neu gene amplification to afatinib, an EGFR, HER2, and HER4 irreversible tyrosine kinase inhibitor and to test the efficacy of afatinib in the treatment of HER2 amplified USC xenografts. Methods: Eight of fifteen primary USC cell lines (4 with HER2 amplification and 4 without) demonstrating similar in vitro growth rates were treated with scalar concentrations of afatinib. Effects on cell growth, signaling and cell-cycle distribution were determined by flow cytometry assays. Mice harboring xenografts of HER2/neu amplified USC were treated with afatinib by gavage to determine the effect on tumor growth and overall survival. Results: Primary chemotherapy–resistant USC cell lines harboring HER2/neu gene amplification were exquisitely sensitive to afatinib exposure (mean ± SEM IC50 = 0.0056 μM± 0.0006 μM) and significantly more sensitive than HER2/neu non-amplified USC cell lines (mean ± SEM IC50 = 0.563 μM± 0.092 μM, P b 0.0001). Afatinib exposure resulted in abrogation of cell survival, inhibition of HER2/neu autophosphorylation and S6 transcription factor phosphorylation in HER2/neu overexpressing USC and inhibited the growth of HER2 amplified tumor xenografts improving overall survival (p = 0.0017). Conclusions: Afatinib may be highly effective against HER2/neu amplified chemotherapy resistant USC. The investigation of afatinib in patients harboring HER2/neu amplified USC is warranted.