Faculty Bibliography

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.

PURPOSE/OBJECTIVE:Uterine serous carcinoma (USC) is an aggressive subtype of endometrial cancer that commonly harbors HER2 gene amplification. We investigated the effectiveness of HER2 inhibition using lapatinib and trastuzumab in vitro and in xenografts derived from USC cell lines and USC patient-derived xenografts. EXPERIMENTAL DESIGN/METHODS:Immunohistochemistry and FISH were performed to assess HER2 expression in 42 primary USC specimens. ARK1, ARK2, and SPEC2 cell lines were treated with trastuzumab or lapatinib. Cohorts of mice harboring xenografts derived from ARK2 and SPEC2 cell lines and EnCa1 and EnCa2 primary human USC samples were treated with either vehicle, trastuzumab, lapatinib, or the combination of trastuzumab and lapatinib. Acute and chronic posttreatment tumor samples were assessed for downstream signaling alterations and examined for apoptosis and proliferation. RESULTS:HER2 gene amplification (24%) correlated significantly with HER2 protein overexpression (55%). All models were impervious to single-agent trastuzumab treatment. Lapatinib decreased in vitro proliferation of all cell lines and in vivo growth of HER2-amplified xenografts (ARK2, EnCa1). In addition, dual therapy with trastuzumab and lapatinib resulted in significant antitumor activity only in ARK2 and EnCa1 tumors. Dual HER2 therapy induced on target alteration of downstream MAPK and PI3K pathway mediators only in HER2-amplified models, and was associated with increased apoptosis and decreased proliferation. CONCLUSIONS:Although trastuzumab alone did not impact USC growth, dual anti-HER2 therapy with lapatinib led to improved inhibition of tumor growth in HER2-amplified USC and may be a promising avenue for future investigation.

Ovarian cancer is the most lethal of all gynecologic malignancies because women commonly present with advanced stage disease and develop chemotherapy refractory tumors. While cytoreductive surgery followed by platinum based chemotherapy are initially effective, ovarian tumors have a high propensity to recur highlighting the distinct need for novel therapeutics to improve outcomes for affected women. The Notch signaling pathway plays an established role in embryologic development and deregulation of this signaling cascade has been linked to many cancers. Recent genomic profiling of serous ovarian carcinoma revealed that Notch pathway alterations are among the most prevalent detected genomic changes. A growing body of scientific literature has confirmed heightened Notch signaling activity in ovarian carcinoma, and has utilized in vitro and in vivo models to suggest that targeting this pathway with gamma secretase inhibitors (GSIs) leads to anti-tumor effects. While it is currently unknown if Notch pathway inhibition can offer clinical benefit to women with ovarian cancer, several GSIs are currently in phase I and II trials across many disease sites including ovary. This review will provide background on Notch pathway function and will focus on the pre-clinical literature that links altered Notch signaling to ovarian cancer progression.

Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is the most common antibody-mediated limbic encephalitis and is associated with underlying ovarian teratoma. Previous studies suggest that expression of NMDAR on teratoma neural tissue initiates an autoimmune response to NMDAR in the brain. As some teratomas of patients with anti-NMDAR encephalitis lack neuronal tissue, we questioned if there could be an alternate mechanism of the disease. We performed immunohistochemical analyses for NMDAR and correlated its expression with histology on 10 control teratomas and 5 teratomas associated with anti-NMDAR encephalitis. Both control and case teratomas expressed NMDAR-bearing neural tissue. All 15 teratomas contained large amounts of NMDAR bearing squamous epithelium; in 2 cases this was the only tissue expressing NMDAR. NMDAR-bearing neural tissue is not the sole source of encephalitis in all patients. Furthermore, we speculate that NMDAR expression by squamous epithelium may contribute to the disease development in some patients.

OBJECTIVE:We report the indications, methods, and complications of percutaneous gastrostomy/gastrojejunostomy (G/GJ) in patients with voluminous ascites. METHODS:Following institutional review board approval, 69 patients (14 male, 55 female, mean age 58±12 years, range 32-89 years) who underwent percutaneous G/GJ with paracentesis were identified from a prospectively acquired database. Electronic medical record data extracted included diagnosis, method of G/GJ insertion, clinical course, and complications, which were graded by The Society of Interventional Radiology (SIR) criteria. Statistics were performed using Graphpad Instat. RESULTS:Sixty-six G and three GJ catheters were placed in 62 patients with malignant and 7 patients with benign disease; 47 procedures were conducted using fluoroscopy and 22 using computed tomography (CT; 10 patients had failed fluoroscopy). Sixty-six patients had 1980±1371 mL (range, 20-5000 mL) ascites drained (more in males, p=0.01) 0.8±1.6 days (range, 0-5 days) prior to placement. Forty-one patients had significantly less ascites (1895±1426 mL; range, 100-5400 mL) drained after G/GJ (p>0.0.5). Mean survival after insertion was 43±57 days (range, 1-252 days) among 38 patients for whom data were available. Fifty-six patients had a mean postprocedure hospital stay of 8.6±8.4 days (range, 0-45 days); 3 were outpatients and 10 patients died in the hospital. Successful gastropexy was confirmed on subsequent cross-sectional imaging in 22 of 25 patients. There were 25 tube maintenance issues that included catheter displacement and leakage, one patient experienced hemorrhage, and there were two deaths. All except one patient had satisfactory gastrostomy function. CONCLUSION/CONCLUSIONS:Effective G/GJ placement is possible in most patients with voluminous ascites provided ascites is drained and gastrocutaneous fistula formation occurs. Caution is advised; placement is generally for fragile terminal patients, and fluoroscopy or CT guidance is required.

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.

OBJECTIVES/OBJECTIVE:The objective of this investigation was to evaluate the risk of nodal metastasis in patients with endometrial cancer, using the Mayo criteria, in a population-based analysis. MATERIALS AND METHODS/METHODS:Data from the SEER registry was reviewed for endometrial cancer cases diagnosed between 1988 and 2010. Patients were considered at low-risk for nodal metastasis if their tumors were histologic grade 1 or 2, myometrial invasion was less than 50%, and tumor size equal to or less than 2 cm. Patients not meeting these criteria were considered at high-risk for nodal involvement. RESULTS:The final study group consisted of 19,329 women with surgically staged endometrial cancer. Of these, 1035 (5.3%) had lymph node involvement. Based on Mayo criteria, 4095 (21.1%) patients were found to be at low-risk and 15,234 (78.9%) at high-risk for nodal metastasis. Low-risk features were associated with a 1.4% risk for lymph node metastasis, compared to 6.4% in patients with high-risk features (p<0.001). When myometrial invasion was removed from the analysis, low-risk pathologic features were associated with a 2.4% risk of lymph node metastasis, compared to 10.4% in patients with high-risk features (p<0.001). CONCLUSIONS:In a population-based analysis, women with low-risk endometrial cancer, as defined by the Mayo criteria, have a low rate of lymph node metastasis.

OBJECTIVE:Alterations in the PI3K pathway are prevalent in endometrial cancer due to PIK3CA mutation and loss of PTEN. We investigated the anti-tumor activity of the PI3K inhibitor NVP BKM-120 (BKM) as a single agent and in combination with standard cytotoxic chemotherapy in a human primary endometrial xenograft model. METHODS:NOD/SCID mice bearing xenografts of primary human tumors with and without PIK3CA gene mutations were divided into two and four arm cohorts with equivalent tumor volumes. BKM was administered alone and in combination with paclitaxel and carboplatin (P/C) and endometrial xenograft tumor volumes were assessed. Tumors from the BKM, P/C, P/C+BKM and vehicle treated mice were processed for determination of PI3K/AKT/mTOR pathway activation. RESULTS:In both single agent experiments, BKM resulted in significant tumor growth suppression starting at days 5-10 compared to the linear growth observed in vehicle treated tumors (p<0.04 in all experiments). Tumor resurgence manifested between days 14 and 25 (p<0.03). When BKM was combined with P/C, this resistance pattern failed to develop in three separate xenograft lines (p<0.05). Synergistic tumor growth suppression (p<0.05) of only one xenograft tumor with no detected PIK3CA mutation was observed. Acute treatment with BKM led to a decrease in pAKT levels. CONCLUSION/CONCLUSIONS:Independent of PIK3CA gene mutation, BKM mediated inhibition of the PI3K/AKT/mTOR pathway in endometrial tumors precludes tumor growth in a primary xenograft model. While a pattern of resistance emerges, this effect appears to be mitigated by the addition of conventional cytotoxic chemotherapy.

OBJECTIVES/OBJECTIVE:The aim of this study is to compare response to chemotherapy and survival between patients with transitional call carcinoma of the ovary (TCCO) and papillary serous ovarian cancer (PSOC). METHODS:We identified women with both pure and mixed TCCO who were treated between 2000 and 2010. Each case was matched to two women with PSOC by age, grade, stage, and year of diagnosis. Correlation between categorical variables was assessed with chi square test. The Kaplan-Meier survival analysis was used to generate overall survival data (OS). Factors predictive of outcome were compared using the log-rank test and Cox proportional hazards model. RESULTS:Eighty-one women diagnosed with TCCO were selected as cases and compared to 162 controls. Women with TCCO had a lower rate of platinum resistance compared to controls (9% vs. 25%; p=0.01). When multivariate logistic regression was used to control for other factors independently associated with platinum resistance, patients with TCCO had a significantly lower risk of platinum resistance compared to PSOC. Median progression-free survival was not significantly different (27 months vs. 22 months; p=0.15) for women with TCCO and PSOC, respectively. Median OS, however, was significantly different at 83 months vs. 52 months for the TCCO and PSOC groups, respectively (p=0.01). A Cox proportional hazards model identified optimal cytoreduction, transitional cell histology, age, stage, and platinum and paclitaxel chemotherapy as independent predictors of OS. CONCLUSIONS:Patients with TCCO are less likely to demonstrate resistance to platinum chemotherapy and have improved overall survival when compared to patients with PSOC.

INTRODUCTION/BACKGROUND:Ovarian cancer (OvCa) is the most lethal gynecologic malignancy in the United States because of chemoresistant recurrent disease. Our objective was to investigate the efficacy of inhibiting the Notch pathway with a γ-secretase inhibitor (GSI) in an OvCa patient-derived xenograft model as a single agent therapy and in combination with standard chemotherapy. METHODS:Immunocompromised mice bearing xenografts derived from clinically platinum-sensitive human ovarian serous carcinomas were treated with vehicle, GSI (MRK-003) alone, paclitaxel and carboplatin (P/C) alone, or the combination of GSI and P/C. Mice bearing platinum-resistant xenografts were given GSI with or without paclitaxel. Gene transcript levels of the Notch pathway target Hes1 were analyzed using RT-PCR. Notch1 and Notch3 protein levels were evaluated. The Wilcoxon rank-sum test was used to assess significance between the different treatment groups. RESULTS:Expression of Notch1 and 3 was variable. GSI alone decreased tumor growth in two of three platinum-sensitive ovarian tumors (p < 0.05), as well as in one of three platinum-sensitive tumors (p = 0.04). The combination of GSI and paclitaxel was significantly more effective than GSI alone and paclitaxel alone in all platinum-resistant ovarian tumors (all p < 0.05). The addition of GSI did not alter the effect of P/C in platinum-sensitive tumors. Interestingly, although the response of each tumor to chronic GSI exposure did not correlate with its endogenous level of Notch expression, GSI did negatively affect Notch signaling in an acute setting. CONCLUSION/CONCLUSIONS:Inhibiting the Notch signaling cascade with a GSI reduces primary human xenograft growth in vivo. GSI synergized with conventional cytotoxic chemotherapy only in the platinum-resistant OvCa models with single agent paclitaxel. These findings suggest inhibition of the Notch pathway in concert with taxane therapy may hold promise for treatment of platinum-resistant OvCa.