Faculty Bibliography

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.

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.

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:To investigate racial disparities with respect to adjuvant treatment and survival in patients presenting with malignant ovarian germ cell tumors (OGCT). METHODS: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. RESULTS:The study population included 2196 patients, with 1654 (75.3%) W and 328 (14.9%) AA women. Histologic distribution varied significantly by race (p<0.0001), 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). CONCLUSIONS:AA with OGCT have significantly worse 5 year survival when compared to W patients despite similar rates and modalities of adjuvant treatment.

OBJECTIVE:Mucinous endometrial cancer (MEC) is a rare histologic subtype of endometrial cancers. The purpose of this study is to compare the outcomes of patients with MEC with patients with endometrioid endometrial cancers (EEC), and to determine whether there are significant clinicopathologic differences between these tumors. METHODS:Surveillance, Epidemiology, and End Results (SEER) Program data for 1988 to 2009 was reviewed. Demographic and clinical data were compared. The impact of histology on survival was analyzed using the Kaplan-Meier method. Factors predictive of outcome were compared using the Cox proportional hazards model. RESULTS:The study group consisted of 104,659 women, 103,097 (98.5%) had EEC and 1562 (1.5%) MEC. The mean age at diagnosis for EEC and MEC was 62 and 63.4, respectively (P<0.001). MEC tumors were more frequently classified as grade 1 (51.3% vs. 44%; P<0.001). In patients with MEC, a higher rate of pelvic lymph node metastasis (16.3% vs. 10.4%; P<0.001) was noted, but not para-aortic lymph node metastasis (5.1% vs. 4%; P=0.1). After adjusting for race, period of diagnosis, SEER registry, marital status, stage, age, surgery, radiotherapy, grade, histology, and lymph node dissection, there was no difference in survival between MEC and EEC (hazard ratio 0.90; 95% confidence interval, 0.78-1.05). CONCLUSIONS:Mucinous histology does not significantly affect survival when compared with endometrioid histology in endometrial cancer. Patients with MEC were more likely to have positive pelvic lymph nodes at the time of surgery.