Faculty Bibliography

BACKGROUND:Hospital readmissions are costly, frequent, and increasingly under public scrutiny. With increased financial constraints on the medical environment, understanding the drivers of unscheduled readmissions following gynecologic surgery will become increasingly important to value-driven care. OBJECTIVE:The current study was conducted to identify risk factors for 30-day readmission following hysterectomy for benign and malignant indications. STUDY DESIGN/METHODS:A retrospective cohort study was conducted from 2008 through 2010 of all nongravid hysterectomies at a single tertiary care academic medical center. Clinical, perioperative, and physician characteristics were collected. Multivariable logistic regression models were used to identify predictors of 30-day readmission, stratified by malignant and benign indications for hysterectomy. RESULTS:Among 1649 women who underwent a hysterectomy (1009 for benign indications and 640 for malignancy), 6% were subsequently readmitted within 30 days (8.9% for malignancy vs 4.2% for benign; P < .0001). The mean time to readmission was 13 days (15 days for malignancy vs 10 days for benign; P = .004). The most common reasons for readmission were gastrointestinal (38%) and infectious (34%) etiologies, and 11.6% of readmitted patients experienced a perioperative complication. Among women undergoing hysterectomy for benign indications, a history of a laparotomy, including cesarean delivery (adjusted odds ratio [AOR], 2.12; 95% confidence interval [CI], 1.06-4.25; P = .03), as well as a perioperative complication (AOR, 2.41; 95% CI, 1.00-6.04; P = .05) were both associated with a >2-fold increased odds of readmission. Among women undergoing hysterectomy for malignancy, an American Society of Anesthesiologists Physical Status Classification of III or IV (AOR, 1.92; 95% CI, 1.05-3.50; P = .03), a longer length of initial hospitalization (3 days AOR, 7.83; 95% CI, 1.33-45.99; P = .02), and an estimated blood loss >500 mL (AOR, 3.29; 95% CI, 1.28-8.45; P = .01) were associated with a higher odds of readmission; however, women who underwent a laparoscopic hysterectomy (AOR, 0.32; 95% CI, 0.12-0.86; P = .02) and who were discharged on postoperative day 1 (AOR, 0.16; 95% CI, 0.03-0.82; P = .02) were at a decreased risk of readmission. Physician and operative characteristics were not significant predictors of readmission. CONCLUSION/CONCLUSIONS:This study found that malignancy, perioperative complications, and prior open abdominal surgery, including cesarean delivery, are significant risk factors for consequent 30-day readmission following index hysterectomy. It may be possible to identify patients at highest risk for readmission at the time of hysterectomy, which can assist in developing interventions to reduce such events.

OBJECTIVE:Uterine serous carcinomas (USC) harbor simultaneous HER2 (ERBB2) over-expression and gain of function mutations in PIK3CA. These concurrent alterations may uncouple single agent anti-HER2 therapeutic efficacy making inhibition of the mammalian target of rapamycin (mTOR) a promising option to heighten anti-tumor response. METHODS:Both in vitro and in vivo experiments were conducted to assess proliferation, cell death and anti-tumor activity of ridaforolimus, lapatinib and combination lapatinib, trastuzumab (L/T) and ridaforolimus. With institutional approval, NOD/SCID mice bearing xenografts of non-immortalized, HER2 gene amplified cell lines (ARK1, ARK2) with and without PIK3CA gene mutations were divided into four arm cohorts. Ridaforolimus was administered alone and in combination with L/T. Tumor volumes were assessed and posttreatment analysis was performed. RESULTS:We observed dose dependent in vitro abrogation of downstream target proteins including phospho-AKT and phospho-S6. In both in vivo models, single agent ridaforolimus impaired xenograft tumor growth. Combination ridaforolimus and L/T, however, further improved the observed anti-tumor activity only in the ARK1 model with the PIK3CA gene mutation (E542K). The addition of mTOR inhibition to dual HER2 blockade added no additional anti-tumor effects in the ARK2 xenografts. Western blot and immunohistochemical analysis of downstream pathway alterations following in vivo treatment revealed dual HER2 blockade with ridaforolimus was necessary to induce apoptosis, decrease proliferation and abrogate phospho-S6 protein expression in the PIK3CA mutated model. CONCLUSIONS:These pilot data suggest that PIK3CA gene mutation may be an effective biomarker for selecting those HER2 over-expressing USC tumors most likely to benefit from mTOR inhibition.

OBJECTIVE:To assess if referral of patients with molar pregnancy who then developed postmolar gestational trophoblastic neoplasia (PMGTN) is associated with different outcomes when compared to referral of patients already with a diagnosis of PMGTN. STUDY DESIGN/METHODS:The records of the New England Trophoblastic Disease Center (NETDC) were queried for all patients with molar pregnancy or PMGTN from 1993-2013. Retrospective chart review was performed to extract relevant clinical and demographic data. Parametric and nonparametric tests were utilized to compare variables. RESULTS:From 1993-2013, 429 women with molar disease were evaluated at the NETDC. Of those, 68% were referred with molar pregnancy and 32% were referred with PMGTN. Comparing women with PMGTN who were referred with a molar pregnancy versus referred with PMGTN, the women were of equivalent stage and World Health Organization (WHO) score. Additionally, referral with molar pregnancy or PMGTN did not associate with time to persistence, time to remission, or number of lines of chemotherapy administered. CONCLUSION/CONCLUSIONS:In this trophoblastic disease specialty center in the United States, referral at the time of PMGTN as opposed to at diagnosis of molar pregnancy did not appear to affect the stage or WHO score at diagnosis, the need for multiple chemotherapy lines, or time to remission.

OBJECTIVE:The aim of this study was to review the experience with intraoperative radiation therapy (IORT) in the treatment of gynecologic cancers at the Massachusetts General Hospital. METHODS:From January 1, 1994 to December 31, 2011, 32 patients were treated with IORT at Massachusetts General Hospital. Hospital, pathology, and office medical records and radiation oncology records were reviewed. The Kaplan-Meier method was used to generate disease-free survival and overall survival (OS) data. RESULTS:In 27 patients (84.4), surgical resection margins were microscopically positive. In 5 patients (15.6%), margins were grossly positive. For patients with microscopic disease, 5-year disease-free survival was 40.9% (57 mo), compared with 9.1% (23 mo) for those with gross residual disease (P=0.001). Five-year OS was also statistically improved for patients with microscopic residual disease, when compared with OS among patients with gross residual disease, 77.3% (93 mo) and 54.5% (40 mo), respectively (P=0.001). The risk of distant metastases in patients with gross residual disease was 87%, compared with 28% in patients with microscopic disease (P=0.02). CONCLUSIONS:Volume of residual disease before IORT is an important prognostic indicator. Local recurrence and distant metastases were more common among patients with gross residual disease left in situ at time of IORT. Our institutional experience with IORT further supports the importance of complete surgical resection.

Ovarian, endometrial and cervical cancers are the most prevalent gynecologic cancers in the United States and account for significant mortality. Translational research into these cancers has highlighted the distinctive molecular and genomic profiles of these cancers finding that, even within a disease site, the landscapes and drivers of neoplasia are distinctive. Despite this molecular diversity, activation of the phosphatidylinositol-3-kinase (PI3K) pathway appears to be conserved in subsets of these tumors, suggesting that strategies that antagonize mediators in this signaling cascade could offer anti-tumor efficacy. Extensive pre-clinical and clinical data have demonstrated that single agent targeted therapies lead to modest single agent activity of generally limited duration, even in the setting of innate PI3K pathway activation via mutation or amplification. These findings in the laboratory and clinic have prompted investigations into resistance pathways following PI3K pathway inhibition in order to understand escape pathways and restore tumor cell sensitivity. A next generation of clinical trial investigations will focus on novel combinations in order to define how these important therapeutics can be used in the clinic. This review will present preclinical data that supports the role of the PI3K pathway in ovarian, endometrial and cervical cancers, in addition to discussing the reported clinical trial experience with PI3K pathway inhibition. A specific focus will be on the rationale behind ongoing clinical trials utilizing novel agents in concert with PI3K pathway inhibitors to reverse resistance in populations with and without gain of function alterations in this oncogenic signaling cascade.

BACKGROUND:Pre-clinical studies have demonstrated that natural and synthetic histone deacetylase (HDAC) inhibitors can impede the in vitro and in vivo growth of cell lines from a variety of gynecologic and other malignancies. We investigated the anti-tumor activity of panobinostat (LBH589) both in vitro and in vivo as either a single agent or in combination with conventional cytotoxic chemotherapy using patient-derived xenograft (PDX) models of primary serous ovarian tumors. METHODS:The ovarian cancer cell lines OVCAR8, SKOV3 and their paclitaxel-resistant derivatives OVCAR8-TR and SKOV3-TR were treated with increasing doses of LBH589. The effect of LBH589 on cell viability was assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Serially transplanted primary human high-grade serous ovarian adenocarcinoma tissue was utilized to generate xenografts in 6-week old female NOD/SCID mice. The mice were then randomized into one of 4 treatment groups: (1) vehicle control; (2) paclitaxel and carboplatin (P/C); (3) LBH589; or (4) P/C + LBH589. Mice were treated for 21 days and tumor volumes and mouse weights were obtained every 3 days. These experiments were performed in triplicate with three different patient derived tumors. Wilcoxan rank-sum testing was utilized to assess tumor volume differences. RESULTS:In vitro treatment with LBH589 significantly reduced the viability of both taxol-sensitive and taxol-resistant ovarian cancer cell lines (p < 0.01). In vivo treatment with LBH589 alone appeared tumorstatic and reduced tumor growth when compared to vehicle treatment (p < 0.007) after 21 days. This single agent activity was confirmed in two additional experiments with other PDX tumors (p < 0.03, p < 0.05). A potential additive effect of LBH589 and P/C, manifested as enhanced tumor regression with the addition of LBH589 compared to vehicle (p < 0.02), in one of the three analyzed serous PDX models. CONCLUSIONS:Our findings suggest that pan-HDAC inhibition with panobinostat precludes the growth of ovarian cancer cell lines in vitro and PDXs in vivo. Added benefit of LBH589 to standard P/C therapy was observed in one of three PDX models suggesting improved response in a subset of serous ovarian cancers.

BACKGROUND:Subsets of high grade endometrial cancer (EnCa) over-express HER2 (ERBB2), yet clinical trials have failed to demonstrate any anti-tumor activity utilizing trastuzumab, an approved platform for HER2 positive breast cancer (BrCa). A truncated p95HER2 variant lacking the trastuzumab binding site may confer resistance. The objective of this investigation was to characterize the expression of the p95HER2 truncated variant in EnCa. MATERIALS AND METHODS/METHODS:With institutional approval, 86 high grade EnCa tumors were identified with tumor specimens from surgeries performed between 2000 and 2011. Clinical data were collected and all specimens underwent tumor genotyping, HER2 immunohistochemistry (IHC, HercepTest®), HER2 fluorescent in situ hybridization (FISH), along with total HER2 (H2T) and p95HER2 assessment with VeraTag® testing. Regression models were used to compare a cohort of 86 breast tumors selected for equivalent HER2 protein expression. RESULTS:We identified 44 high grade endometrioid and 42 uterine serous carcinomas (USC). IHC identified high HER2 expression (2+ or 3+) in 59% of the tumors. HER2 gene amplification was observed in 16 tumors (12 USC, 4 endometrioid). Both HER2 gene amplification and protein expression correlated with H2T values. High p95HER2 expression above 2.8RF/mm2 was observed in 53% (n=54) with significant correlation with H2T levels. When matched to a cohort of 107 breast tumors based on HercepTest HER2 expression, high grade EnCa presented with higher p95 levels (p<0.001). CONCLUSIONS:These data demonstrate that compared to BrCa, high grade EnCa expresses higher levels of p95HER2 possibly providing rationale for the trastuzumab resistance observed in EnCa.

OBJECTIVE:To evaluate the mortality outcomes of vaginal sarcomas in a large cohort compared with vaginal squamous cell and adenocarcinomas. METHODS:Women with primary invasive vaginal sarcomas, squamous cell carcinomas, and adenocarcinomas diagnosed between 1988 and 2010 were identified within the National Cancer Institute's Surveillance, Epidemiology, and End Results database. Parametric and nonparametric methods were used to compare the demographic and clinical characteristics of women among the three tumor types as well as between sarcoma histologic subtypes. Overall and cancer-specific mortality outcomes were examined using Kaplan-Meier and multivariable Cox proportional hazards models. RESULTS:The final cohort consisted of 3,121 patients with vaginal squamous cell carcinoma, 720 patients with adenocarcinoma, and 221 patients with sarcoma. Compared with women with squamous cell carcinoma and adenocarcinoma, patients diagnosed with vaginal sarcomas tended to be younger, have larger tumors with less regional extension and lymph node positivity, and be treated primarily with surgery without radiation. In unadjusted analysis, 5-year mortality rates border 30% for all three histologies. After adjusting for other prognostic factors including use of radiation and surgery, patients with vaginal sarcomas had a 69% greater risk of cancer-related mortality compared with patients with squamous cell carcinoma (hazard ratio 1.69, 95% confidence interval 1.26-2.26). Although sarcoma histology failed to associate with mortality risk, age, tumor extension and metastasis, and surgery were poor prognostic factors. CONCLUSION/CONCLUSIONS:Primary vaginal sarcomas are aggressive neoplasms with different presenting characteristics and increased adjusted risk of mortality compared with squamous cell and adenocarcinoma subtypes. LEVEL OF EVIDENCE/METHODS:III.

UNLABELLED:Endometrial cancer is the most common gynecologic cancer in the United States, diagnosed in more than 50,000 women annually. While the majority of women present with low-grade tumors that are cured with surgery and adjuvant radiotherapy, a significant subset of women experience recurrence and do not survive their disease. A disproportionate number of the more than 8,000 annual deaths attributed to endometrial cancer are due to high-grade uterine cancers, highlighting the need for new therapies that target molecular alterations specific to this subset of tumors. Numerous correlative scientific investigations have demonstrated that the HER2 (ERBB2) gene is amplified in 17%-33% of carcinosarcoma, uterine serous carcinoma, and a subset of high-grade endometrioid endometrial tumors. In breast cancer, this potent signature has directed women to anti-HER2-targeted therapies such as trastuzumab and lapatinib. In contrast to breast cancer, therapy with trastuzumab alone revealed no responses in women with recurrent HER2 overexpressing endometrial cancer, suggesting that these tumors may possess acquired or innate trastuzumab resistance mechanisms. This review explores the literature surrounding HER2 expression in endometrial cancer, focusing on trastuzumab and other anti-HER2 therapy and resistance mechanisms characterized in breast cancer but germane to endometrial tumors. Understanding resistance pathways will suggest combination therapies that target both HER2 and key oncogenic escape pathways in endometrial cancer. IMPLICATIONS FOR PRACTICE/CONCLUSIONS:This review summarizes the role of HER2 in endometrial cancer, with a focus on uterine serous carcinoma. The limitations to date of anti-HER2 therapy in this disease site are examined, and mechanisms of drug resistance are outlined based on the experience in breast cancer. Potential opportunities to overcome inherent resistance to anti-HER2 therapy in endometrial cancer are detailed, offering opportunities for further clinical study with the goal to improve outcomes in this challenging disease.

OBJECTIVE:To validate whether Surgical Apgar Score can predict post-operative morbidity in patients undergoing hysterectomies for malignancies. METHODS: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. RESULTS: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 (p<0.01). 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, SAS <4, disease site, bowel resection and laparotomy, only ASA class and laparotomy were able to predict for postoperative complication events. CONCLUSIONS: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.