Faculty Bibliography

BACKGROUND:The objective of this investigation was to characterize the expression landscape of immune regulatory molecules programmed death-ligand-1 (PD-L1, B7-H1) and B7-H4 in a cohort of endometrial tumors across the spectrum of grade and histology. MATERIALS AND METHODS:With institutional review board approval, 70 endometrial tumors from patients with known clinical outcomes were identified representing a spectrum of grade and histology. Immunohistochemistry (IHC) was performed for PD-L1 and B7-H4 and scored. Microsatellite instability (MSI) status was assessed for endometrioid tumors using the institutional IHC assay for expression of the mismatch repair (MMR) genes, MLH1, MSH2, MSH6 and PMS2. RNA sequencing data from the Cancer Genome Atlas was queried for expression levels of CD274 (PD-L1 protein) and VTCN1 (B7-H4) across molecular subtypes of endometrial carcinoma and were correlated with a T cell infiltration index. RESULTS:We identified 40 low grade endometrioid tumors and a cohort of 30 high grade tumors. PD-L1 expression was observed in both high and low grade endometrial tumors (56% vs 35%, p=0.07). In the low grade tumors, PD-L1 expression was associated with MSI status (p<0.01). The high grade cohort had similar rates of PD-L1 expression compared to low grade MSI tumor (56% and 62% respectively), and both were distinct from low grade MSS tumors (22%, p<0.05). High (3+) B7-H4 positive cells were observed in both high and low grade carcinomas (33% and 31% respectively). RNA profiling data from confirmed highest CD274 expression in POLE and MSI tumors that was linearly correlated with T cell infiltration, while VTCN1 expression appeared consistent across molecular subtypes. CONCLUSIONS:While PD-L1 expression correlated with MSI and high grade tumors, B7-H4 expression was independent of grade, histology and immune cell infiltration. The development and testing of multi-agent therapeutics targeting PD-L1 and B7-H4 may be a novel strategy for endometrial tumors.

OBJECTIVE:To compare 3-year survival, length of hospitalization, perioperative mortality, risk of readmission, and residual disease associated with laparoscopic and laparotomic interval debulking surgery among women with epithelial ovarian cancer. METHODS:We used the National Cancer Database to identify a cohort of patients diagnosed with stage IIIC and IV epithelial ovarian cancer between 2010 and 2012 who underwent neoadjuvant chemotherapy and interval debulking surgery. We compared 3-year overall survival, duration of postoperative hospitalization, 90-day postoperative mortality, and residual disease status between women who underwent interval debulking by laparoscopy and by laparotomy. We used the Kaplan-Meier method and Cox regression models in survival analyses. At a significance of .05, this study had 80% power to detect an 8% difference in 3-year survival. The main analysis was intention to treat. RESULTS:We identified 3,071 women meeting inclusion criteria, of whom 450 (15%) underwent surgery initiated laparoscopically. There was no difference in 3-year survival between patients undergoing laparoscopy [47.5%; 95% confidence interval (CI) 41.4-53.5] and laparotomy (52.6%; 95% CI 50.3-55.0; P=.12). Survival did not differ after adjustment for demographic characteristics, facility type, presence of comorbidities, and stage (adjusted hazard ratio, 1.09; 95% CI 0.93-1.28; P=.26). Postoperative hospitalization was slightly shorter in the laparoscopy group (median 4 compared with 5 days, P<.001). Frequency of readmission (5.3% compared with 3.7%; P=.26), death within 90 days of surgery (2.8% compared with 2.9%, P=.93), and suboptimal debulking (20.6% compared with 22.6%, P=.29) did not differ between patients undergoing laparoscopy and laparotomy. CONCLUSION:Ovarian cancer patients selected for laparoscopic interval debulking surgery after neoadjuvant chemotherapy have 3-year survival rates similar to women who undergo interval debulking by laparotomy. Laparoscopy is associated with a modestly shorter postoperative hospitalization, whereas readmission rates and risk of perioperative death are similar for the surgeries.

BACKGROUND:Cervical cancer is the third most common gynecologic malignancy in the United States. Approximately 1-3% of cervical cancers will be diagnosed in pregnant and peripartum women; optimal management in the setting of pregnancy is not always clear. OBJECTIVE:We sought to describe the management of patients with cervical cancer diagnosed in pregnancy and compare their outcomes to nonpregnant women with similar baseline characteristics. STUDY DESIGN:We conducted a retrospective chart review of all patients diagnosed with cervical cancer in pregnancy and matched them 1:2 with contemporaneous nonpregnant women of the same age diagnosed with cervical cancer of the same stage. Patients were identified using International Classification of Diseases, Ninth Revision codes and the Dana-Farber/Massachusetts General Hospital Cancer Registry. Data were analyzed using Stata, Version 10.1 (College Station, TX). RESULTS:In all, 28 women diagnosed with cervical cancer during pregnancy were identified from 1997 through 2013. The majority were Stage IB1. In all, 25% (7/28) of women terminated the pregnancy; these women were more likely to be diagnosed earlier in pregnancy (10.9 vs 19.7 weeks, P = .006). For those who did not terminate, mean gestational age at delivery was 36.1 weeks. Pregnancy complications were uncommon. Complication rates in pregnant women undergoing radical hysterectomy were similar to those outside of pregnancy. Time to treatment was significantly longer for pregnant women compared to nonpregnant patients (20.8 vs 7.9 weeks, P = .0014) but there was no survival difference between groups (89.3% vs 95.2%, P = .08). Women who underwent gravid radical hysterectomy had significantly higher estimated blood loss than those who had a radical hysterectomy in the postpartum period (2033 vs 425 mL, P = .0064), but operative characteristics were otherwise similar. None of the pregnant women who died delayed treatment due to pregnancy. CONCLUSION:Gestational age at diagnosis is an important determinant of management of cervical cancer in pregnancy, underscoring the need for expeditious workup of abnormal cervical cytology. Of women who choose to continue the pregnancy, most delivered in the late preterm period without significant obstetric complications. For women undergoing radical hysterectomy in the peripartum period, complication rates are similar to nonpregnant women undergoing this procedure. Women who died were more likely to have advanced stage disease at the time of diagnosis. This information may be useful in counseling women facing the diagnosis of cervical cancer in pregnancy.

STUDY OBJECTIVE:To assess outcomes of women with cervical cancer undergoing upfront radical hysterectomy (RH) via a minimally invasive surgery (MIS) or a traditional laparotomy (XL) approach at 2 large US academic institutions to determine whether the mode of surgery affects patient outcomes. DESIGN:Retrospective cohort study (Canadian Task Force classification II-1). SETTING:Two academic medical institutions in the United States. PATIENTS:Women undergoing upfront RH for cervical cancer between 2000 and 2013. INTERVENTION:Minimally invasive techniques (laparoscopic and robotic) for RH compared with XL. MEASUREMENTS AND MAIN RESULTS:) and a higher rate of perioperative blood transfusion (3.0% vs 26.2%; p < .001). Length of perioperative hospital stay was significantly shorter in the MIS group (1.9 days vs 4.9 days; p < .001). CONCLUSION:MIS RH does not compromise patient outcomes, including overall survival, rate of recurrence, and the frequency of pelvic lymph node dissection or positivity. Morbidity was decreased in the MIS group, including decreased EBL, fewer blood transfusions, and shorter hospital stay.

OBJECTIVES/OBJECTIVE:The majority of hospital readmissions are unexpected and considered adverse events. The goal of this study was to examine the factors associated with unplanned readmission after surgery for vulvar cancer. METHODS:test and Student's t-test as appropriate for univariate analysis. Multivariate analysis was then performed. RESULTS:Of 363 eligible patients, 35.6% had in situ disease and 64.5% had invasive disease. Radical vulvectomy was performed in 39.1% and 23.4% underwent lymph node assessment. Seventeen patients (4.7%) were readmitted within 30days, with length of stay ranging 2 to 37days and 35% of these patients required a re-operation. On univariate analyses comorbidities, radical vulvectomy, nodal assessment, initial length of stay, and discharge to a post acute care facility (PACF) were associated with hospital readmission. On multivariate analysis, only discharge to a PACF was significantly associated with readmission (OR 6.30, CI 1.12-35.53, P=0.04). Of those who were readmitted within 30days, 29.4% had been at a PACF whereas only 6.6% of the no readmission group had been discharged to PACF (P=0.003). CONCLUSIONS:Readmission affected 4.7% of our population, and was associated with lengthy hospitalization and reoperation. After controlling for patient comorbidities and surgical radicality, multivariate analysis suggested that discharge to a PACF was significantly associated with risk of readmission.

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.

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.

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.