Faculty Bibliography

BACKGROUND:Recent evidence links aberrant activation of Hedgehog (Hh) signaling with the pathogenesis of several cancers including medulloblastoma, basal cell, small cell lung, pancreatic, prostate and ovarian. This investigation was designed to determine if inhibition of this pathway could inhibit serous ovarian cancer growth. METHODOLOGY/METHODS:We utilized an in vivo pre-clinical model of serous ovarian cancer to characterize the anti-tumor activity of Hh pathway inhibitors cyclopamine and a clinically applicable derivative, IPI-926. Primary human serous ovarian tumor tissue was used to generate tumor xenografts in mice that were subsequently treated with cyclopamine or IPI-926. PRINCIPAL FINDINGS/RESULTS:Both compounds demonstrated significant anti-tumor activity as single agents. When IPI-926 was used in combination with paclitaxel and carboplatinum (T/C), no synergistic effect was observed, though sustained treatment with IPI-926 after cessation of T/C continued to suppress tumor growth. Hh pathway activity was analyzed by RT-PCR to assess changes in Gli1 transcript levels. A single dose of IPI-926 inhibited mouse stromal Gli1 transcript levels at 24 hours with unchanged human intra-tumor Gli1 levels. Chronic IPI-926 therapy for 21 days, however, inhibited Hh signaling in both mouse stromal and human tumor cells. Expression data from the micro-dissected stroma in human serous ovarian tumors confirmed the presence of Gli1 transcript and a significant association between elevated Gli1 transcript levels and worsened survival. CONCLUSIONS/SIGNIFICANCE/CONCLUSIONS:IPI-926 treatment inhibits serous tumor growth suggesting the Hh signaling pathway contributes to the pathogenesis of ovarian cancer and may hold promise as a novel therapeutic target, especially in the maintenance setting.

Since its advent in the early 1990s, laparoscopic surgical staging for early ovarian cancer has been explored as an option with the potential to offer women equivalent cancer control and survival as provided by laparotomy but with the clear benefits of minimally invasive surgery. A limited but expanding body of literature suggests aggressive surgical staging can be performed with equivalent tissue assessment compared with laparotomy. Given the lack of randomized, controlled trials, the risks and benefits of such a procedure remain ambiguous. This review summarizes the current body of literature regarding the role of laparoscopy in upfront surgical staging of ovarian cancer. This review presents the history, rationale, and established benefits and risks of utilizing this approach in women who present with malignancy that appears confined to the ovary. Although retrospective data confirm the feasibility, safety, and efficacy of laparoscopic staging of early ovarian cancer, more prospective data will be required to confirm equivalent survival in a patient population that has the potential to be cured.

Uterine tumors, whether benign or malignant, are diagnosed in a significant portion of women and are associated with a number of co-morbidities that negatively impact quality of life. Uterine tumors can be derived from the epithelial (endometrial hyperplasia or carcinoma) and mesenchymal (leiomyoma, sarcoma) layers of the uterus. The exact etiologies of the various tumor types are yet to be defined. Collectively their development and progression often results from aberrant steroid hormone exposure or dysregulation of related growth factor signaling and apoptotic pathways, reflecting the role of steroid hormone-dependent signaling and survival pathways in the cycles of cell growth and involution that characterize normal uterine physiology. While molecular analyses of human tumors can identify candidate genetic and epigenetic lesions contributing to uterine tumor initiation and progression, in vivo genetic models are needed to establish the functional significance of such lesions and their contribution to tumorigenesis. For this purpose, genetically-engineered mouse models have proven valuable. Here we review genetically-modified mouse models that develop uterine tumors and compare their pathology, utility/feasibility, and discuss their clinical relevance.

OBJECTIVE:The aim of this study was to evaluate the survival impact of cytoreductive surgery and other prognostic determinants in patients with stage IIIC and IV uterine papillary serous carcinoma (UPSC). METHODS:All patients with FIGO stage IIIC and IV UPSC who underwent surgical staging at the two participating institutions, between January 1, 1995 and December 31, 2007, were identified from the tumor registry database. The Kaplan-Meier method was used to generate overall survival (OS) data. Factors predictive of outcome were compared using the log-rank test and Cox regression analysis. RESULTS:Analysis of 79 patients with stage IIIC-IV disease was performed. Optimal cytoreduction was associated with a median survival of 36 months, compared with 12 months for patients who underwent a suboptimal surgical effort (p=0.001), and a disease-free survival (DFS) of 21 months vs. 10 months (p=0.001), respectively. Regression analysis identified stage (HR=2.4, p=0.03), absence of visible residual disease (HR=0.5, p=0.03), and chemotherapy (HR=0.1, p<0.001) as independent predictors of OS. CONCLUSIONS:Cytoreduction to no gross residual disease and the use of platinum therapy are associated with a significant survival benefit for patients with stage IIIC-IV UPSC. Recommended management for this group of patients should consist of maximal surgical cytoreduction followed by platinum-based chemotherapy, preferably in combination with paclitaxel. Adjuvant radiation therapy should also be considered.

OBJECTIVE:To determine whether any clinical parameters predict the need for multiagent chemotherapy for treatment of low-risk gestational trophoblastic neoplasia (GTN) after the development of methotrexate (MTX) resistance. STUDY DESIGN/METHODS:We retrospectively analyzed clinical data from the New England Trophoblastic Disease Center from women with post-molar GTN between 1973 and 2003. RESULTS:We analyzed data from 150 women (40 with partial mole, 110 with complete mole) who received single-agent MTX for low-risk GTN using FIGO and WHO scoring systems. Of the 45 women who developed MTX resistance, the majority (37/45) of these patients received actinomycin D, with 10 patients ultimately requiring multiagent chemotherapy. The requirement for multiagent chemotherapy following MTX resistance was associated with a beta-hCG > 600 mlU/mL 1 week following initial MTX therapy (p < 0.03). Conversely, a beta-hCG < 600 mlU/mL 1 week following initial MTX therapy was as-sociated with a 93% probability of remission with actinomycin D alone. All patients went into durable remission. CONCLUSION/CONCLUSIONS:The prognosis for patients with low-risk GTN following molar gestation is excellent, with 100% remission rate, though a small but significant proportion (7%) required multiagent chemotherapy. The need for multiagent chemotherapy was associated with beta-hCG levels 1 week following initial MTX therapy.

OBJECTIVE:To identify clinical factors associated with requiring more than a single course of Methotrexate (MTX) to achieve remission among women with low-risk postmolar gestational trophoblastic neoplasia (GTN). METHODS:We studied 150 women with persistent GTN after diagnosis of complete (n=110) or partial mole (n=40) to identify possible predictors of requiring additional treatment after a single treatment of methotrexate (MTX). All women had low-risk disease using FIGO and WHO scoring systems. RESULTS:Seventy women (47%) required additional courses of chemotherapy, of whom 45 (64%) received chemotherapy other than MTX. Multivariate analysis revealed that complete mole histology, presence of metastasis, single day MTX infusion and any increase in serum beta human chorionic gonadotropin (beta-hCG) level 1 week after MTX therapy were independent predictors of requiring additional MTX or alternative chemotherapy. Dilatation and curettage (D+C) within 1 week after the diagnosis of persistence did not affect future chemotherapy requirements (p>0.64). Following complete mole, beta-hCG levels >2000 mIU/mL at 1 week post MTX were associated with a 89% risk of additional cycles chemotherapy including MTX and a 65% risk of alternative chemotherapy. CONCLUSIONS:Metastatic disease, MTX infusion protocol and complete mole histology were independently associated with the need for additional chemotherapy after an initial course of MTX for women with low risk GTN. D+C at persistence did not alter the chemotherapy requirement. Elevated beta-hCG level at 1 week after the initial course of MTX was also an independent factor predicting the need for additional courses of MTX or alternative chemotherapy.

OBJECTIVE:Recent scientific advances have lead to the development of a prophylactic, quadrivalent HPV vaccine conferring. We surveyed Latino and non-Latino women directly to examine what motivates them to vaccinate themselves, their daughters, and their sons. METHODS:A written survey was administered to 86 Latinas and 141 non-Latinas, ages 18-55, and attending a general medicine, gynecology, or pediatric unit at an academic center. The instrument included questions on demographics, knowledge and attitudes toward the HPV vaccine, attitudes toward HPV vaccination for the respondents' daughters and/or sons, and the effect of vaccine acceptability on women's attitudes towards their sexual behavior and cervical cancer screening practices. RESULTS:Acceptance for the HPV vaccine was high, with 73% of non-vaccinated, eligible women stating that they would vaccinate themselves. Cervical cancer prevention was the primary motivation for seeking vaccination. Most respondents reported that vaccination should still be accompanied by cervical cancer screening. Seventy-percent of eligible respondent agreed to vaccinate their daughters (97% of Latino and 68.2% of non-Latino mothers, p=0.0078). Eighty-six percent of eligible participants agreed to vaccinate their sons (92.3% of Latino and 76.9% of non-Latino mothers, p=0.0490). Cervical cancer prevention and anal/penile cancer prevention were the primary motivation reported for accepting the vaccine in their daughters and sons, respectively. Fewer than 20% of eligible respondents cited protection of women against developing cervical cancer as the motivation to vaccinate their son(s). CONCLUSIONS:Among vaccine-eligible women, HPV vaccination acceptance for themselves, their daughters, and potentially their sons is high and primarily motivated by cancer prevention for the individual vaccinated.

MUC4 is a transmembrane glycoprotein more highly expressed in cervical dysplasia than benign cervical epithelium. We sought to determine whether MUC4 expression differs between benign and malignant cervical tissue. Fifty-eight patients with benign, dysplastic, or malignant cervical pathology were identified retrospectively, and representative sections were stained with a mouse monoclonal anti-MUC4 antibody. Semiquantitative analysis was performed on benign, dysplastic, and malignant regions by scoring staining intensity (0: negative, 1: weak, 2: moderate, and 3: strong) and distribution (focal <10%, multifocal=10%-60%, diffuse > or =60%). In samples with benign glycogenated squamous epithelium, only the parabasal cells had MUC4 staining, and 48.5% had an intensity of 2 or 3. All samples with immature squamous metaplasia were positive through the entire epithelial thickness. Cervical intraepithelial neoplasia (CIN) 1 samples had variable staining with an intensity similar to glycogenated squamous epithelium but distribution similar to squamous metaplasia. All CIN 3 (n=21) and invasive squamous cell carcinomas (n=17) had increased MUC4 staining intensity (P<0.001 and P<0.001) and increased diffuse staining (P<0.001 and P<0.001) compared with the limited staining in glycogenated squamous epithelium. In contrast, no differences in staining were observed between benign endocervical glands, adenocarcinoma in situ, and invasive adenocarcinoma. These expression patterns suggest that MUC4 is a lineage marker in benign cervical tissue that may have aberrant expression in squamous dysplasia and carcinoma. Further studies may elucidate the role of MUC4 in the development of squamous cell cervical cancer.

OBJECTIVE:To determine the microvessel density (MVD) at the implantation site of normal placenta (NP) and molar pregnancies and to correlate MVD with clinical data and underlying angiogenic factors. STUDY DESIGN/METHODS:Immunolocalization of CD31, vascular endothelial growth factor and angiopoietin 1 and 2 were performed on NPs, nonpersistent partial moles, persistent partial moles (PPM), nonpersistent complete moles and persistent complete moles (PCM). RESULTS:Significant differences were identified in the MVD between NP and complete mole (CM), and PM and CM (p < 0.001 and p < 0.035, respectively). MVD in PPM and PCM was significantly higher (p = 0.036 and p < 0.001, respectively) when compared to NP. MVD > 100 per high-power field was associated with an increased risk of persistence (p < 0.04). MVD showed a strong correlation with immediate postevacuation hCG levels (p < 0.03). Angiopoietin 2 staining was more heterogeneous, with lower overall expression in molar pregnancies as compared to more homogeneous expression in NP (p < 0.05). CONCLUSION/CONCLUSIONS:MVD is highly correlated with hCG levels, suggesting that hCG may act as an angiogenic factor during implantation of molar pregnancy. MVD at the implantation site may be associated with excessive trophoblastic proliferation or reflect high hCG levels, which places patients at increased risk of persistent neoplasia.

OBJECTIVE:To review our experience with thoracotomy in gestational trophoblastic neoplasia (GTN). STUDY DESIGN/METHODS:Nineteen thoracotomy patients from our database were identified. Thoracotomy was performed for therapeutic reasons in 11 patients and to clarify the diagnosis in eight. RESULTS:Among the 11 patients with chemotherapy-resistant pulmonary tumors, 10 of 11 (90.9%) achieved remission with thoracotomy. Thoracotomy was more likely to be done to clarify diagnosis before 1980 (83%) than after 1980 (23%) (p = 0.04), when it became more likely to be done for therapeutic indications. Ten patients had solitary lung lesions and 9 had multiple lesions. Four patients died (21%), with an average survival after thoracotomy of 149 days; patients had bilateral or multiple lung lesions, median preoperative hCG was 58,000 mIU/mL and all were stage IV. Survivors had lower stage disease, were more likely to have solitary lesions and had lower preoperative hCG levels. CONCLUSION/CONCLUSIONS:There have been several temporal changes in the indications for thoracotomy for GTN. In general, the optimal patient to achieve remission with thoracotomy will have stage III disease, a preoperative hCG of < 1,500 mIU/mL, and a solitary lung nodule resistant to chemotherapy. Likelihood of remission after thoracotomy is high in properly selected patients.