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PurposeThe purpose of this study was to develop an integrated genomic-based approach to personalized treatment of patients with advanced-stage ovarian cancer. We have used gene expression profiles to identify patients likely to be resistant to primary platinum-based chemotherapy and also to identify alternate targeted therapeutic options for patients with de novo platinum-resistant disease.Patients and MethodsA gene expression model that predicts response to platinum-based therapy was developed using a training set of 83 advanced-stage serous ovarian cancers and tested on a 36-sample external validation set. In parallel, expression signatures that define the status of oncogenic signaling pathways were evaluated in 119 primary ovarian cancers and 12 ovarian cancer cell lines. In an effort to increase chemotherapy sensitivity, pathways shown to be activated in platinum-resistant cancers were subject to targeted therapy in ovarian cancer cell lines.ResultsGene expression profiles identified patients with ovarian cancer likely to be resistant to primary platinum-based chemotherapy with greater than 80% accuracy. In patients with platinum-resistant disease, we identified expression signatures consistent with activation of Src and Rb/E2F pathways, components of which were successfully targeted to increase response in ovarian cancer cell lines.ConclusionWe have defined a strategy for treatment of patients with advanced-stage ovarian cancer that uses therapeutic stratification based on predictions of response to chemotherapy, coupled with prediction of oncogenic pathway deregulation, as a method to direct the use of targeted agents.

Using in vitro drug sensitivity data coupled with Affymetrix microarray data, we developed gene expression signatures that predict sensitivity to individual chemotherapeutic drugs. Each signature was validated with response data from an independent set of cell line studies. We further show that many of these signatures can accurately predict clinical response in individuals treated with these drugs. Notably, signatures developed to predict response to individual agents, when combined, could also predict response to multidrug regimens. Finally, we integrated the chemotherapy response signatures with signatures of oncogenic pathway deregulation to identify new therapeutic strategies that make use of all available drugs. The development of gene expression profiles that can predict response to commonly used cytotoxic agents provides opportunities to better use these drugs, including using them in combination with existing targeted therapies.

Objectives: To determine why there has been a decrease in the amount of applicants to Florida-based obstetrics and gynecology (OB/GYN) residency programs, and how this has been affected by the current medical liability climate. Methods: Fourth year Florida medical students were surveyed about their concerns of a career in OB/GYN. The students were then grouped into three categories: students never interested in OB/GYN, students at one point interested in OB/GYN, and students pursuing a career in OB/GYN. The groups were analyzed for differences in their concerns about OB/GYN and the impact it had on their final career decisions. Finally, we addressed the question of whether or not medical liability played a significant role in their career choice. Results: From September to November of 2005, 198 total students were surveyed. Of those surveyed, 10.8% were applying for OB/ GYN, 47.7% had considered OB/GYN but chose another field, and 41.5% never considered OB/GYN as a specialty. The primary and secondary reasons for not choosing OB/GYN were the same in the two groups pursuing different specialties; "more interested in a different specialty" and "desire a specialty with more predictable work hours/lifestyle," respectively. Approximately 27% of those who considered OB/GYN but did not choose it ranked "fear of being sued" first or second, compared with 6.7% of those who never considered it (P < 0.01). Of the 21 students who will pursue careers in OB/ GYN, 85.7% stated they are considering leaving Florida because of high malpractice/litigation. Conclusions: There is a subgroup of students in Florida who were initially interested in OB/GYN but may have been deterred by current medical liability issues. Florida is a state known as being in a professional liability crisis and this survey demonstrates evidence that this has adversely affected students' decisions to pursue OB/GYN.

Epithelial ovarian cancer is the deadliest gynecologic malignancy, yet its molecular etiology remains poorly understood. Evidence is accumulating to support a role for the insulin-like growth factor family in human carcinogenesis, and recently using microarray expression analysis, we demonstrated over-expression of the insulin-like growth factor-2 (IGF-2) gene in advanced stage epithelial ovarian cancers. The purpose of the current study is to further elucidate the role of the IGF-2 gene in ovarian cancer development and progression.Relative expression of IGF-2 was measured in 109 epithelial ovarian cancers and eight normal ovarian surface epithelial (NOSE) samples, using quantitative real-time polymerase chain reaction. Associations with clinicopathological parameters were examined.Expression of the IGF-2 gene was more than 300-fold higher in ovarian cancers compared with normal ovarian surface epithelium samples (P0.001). High IGF-2 expression was associated with advanced stage disease at diagnosis (P0.001), high-grade cancers (P0.05) and sub-optimal surgical cytoreduction (P = 0.08). In multivariate analysis, relative IGF-2 expression was an independent predictor of poor survival.Expression of the IGF-2 gene is significantly higher in ovarian cancers relative to normal ovarian surface epithelium. Further, high IGF-2 gene expression is associated with high grade, advanced stage disease, and is an independent predictor of poor survival in patients with epithelial ovarian cancer. As such, IGF-2 is a molecular marker and potential therapeutic target for the most aggressive epithelial ovarian cancers.

Objective . To assess if the angiogenic factors vascular endothelial growth factor (VEGF) and D-dimer are predictive of persistent disease, early relapse, and survival in patients with ovarian cancer who achieve a complete clinical remission after first-line chemotherapy. Methods . Serum levels of VEGF and D-dimer were assessed by ELISA in 62 patients who completed first-line chemotherapy and underwent second-look laparotomy at Duke University Medical Center. Cox Proportional Hazards Modeling was utilized to determine if VEGF and/or D-dimer levels could predict disease-free and overall survival. The Kaplan–Meier method was used to estimate median survival. The Wilcoxon test was used to determine if a significant difference existed in median VEGF and D-dimer levels between patients with positive and negative second-look operations. Results . Forty (65%) of the 62 women who underwent second-look laparotomy had persistent disease. The median VEGF levels were 264 pg/ml (range 109–896 pg/ml) in the group with negative second looks compared to 390 pg/ml (range 99–1011 pg/ml) in those with positive second-looks ( P = 0.1). High levels of VEGF were marginally associated with the presence of persistent ( P = 0.10) and gross ( P = 0.07) disease at the time of second look laparotomy. After adjusting for CA125, women with high VEGF serum levels had a worse overall survival ( P = 0.004). Conclusions . This study suggests that serum VEGF may be a clinically important marker for persistent disease and is predictive of survival in ovarian cancer patients after first-line chemotherapy.

Background Pelvic retroperitoneal leiomyomas arising from the rectal wall are rare. We present a case of a giant retroperitoneal leiomyoma mimicking bilateral solid adnexal masses in a postmenopausal woman. Case A 54-year-old postmenopausal woman presented with a large abdominopelvic mass. At surgery, the uterus was displaced anteriorly by a large retroperitoneal mass. The rectosigmoid colon was noted to course through the retroperitoneal mass. The patient underwent complete excision of the retroperitoneal mass along with a rectosigmoid resection of the involved colon with primary reanastomosis. Histopathology showed a leiomyoma arising from the muscularis propria of the rectum wall. Conclusion Retroperitoneal masses that extend into the pelvis may mimic adnexal masses and, therefore, represent a rare finding at gynecologic surgery.

The molecular determinants of survival in ovarian cancer are poorly understood. Using expression microarrays, we recently found that high expression of the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) gene is associated with prolonged survival in advanced ovarian cancer. TRAIL has also been shown to synergize with chemotherapeutic agents to induce apoptosis in ovarian cancer cell lines. We therefore sought to confirm the association between TRAIL expression and survival in a larger group of women with ovarian cancer.TRAIL expression was measured using quantitative real-time PCR in 120 epithelial ovarian cancers (11 stage I/II, 109 stage III/IV) and 8 normal ovarian surface epithelial samples.Ovarian cancers demonstrated 10-fold higher mean TRAIL expression than normal ovarian epithelial samples (P0.001). Among ovarian cancers, high TRAIL expression was associated with prolonged survival and was 2.2-fold higher in cancers from patients who lived more than 5 years compared with patients who died within 1 year (P = 0.03).TRAIL expression is higher in ovarian cancers relative to normal ovarian epithelium. High TRAIL expression is associated with favorable ovarian cancer survival, which may be attributable to increased chemosensitivity of cancers that express the most TRAIL. The use of TRAIL to enhance sensitivity of ovarian cancers to therapy represents an appealing molecular therapeutic strategy worthy of further investigation.

Objectives. Weekly paclitaxel alone has moderate activity in the salvage treatment of recurrent ovarian cancer and is associated with a favorable toxicity profile. Combination paclitaxel and carboplatin is a well-established first-line regimen for ovarian cancer. The purpose of this study was to evaluate weekly low-dose paclitaxel and carboplatin in recurrent ovarian or peritoneal cancer. Methods. Patients with recurrent ovarian or peritoneal cancer previously treated with between one and four chemotherapeutic regimens were eligible. Patients had measurable or assessable disease defined by clinical exam, radiographic studies, or serum CA-125 greater than 75 U/ml. One cycle of treatment consisted of carboplatin at an area under the curve of 2 and paclitaxel at 80 mg/m 2 on days 1, 8, and 15 on a 28-day cycle. Clinical responses were defined by established criteria. Results. Twenty-nine patients were included in this intent-to-treat study. The median number of prior treatment regimens was 2 (range 1 to 4). The overall response rate was 82.8% (16 complete clinical responses, 8 partial responses). Among 8 platinum-refractory patients, the response rate was 37.5%, while 21 platinum-sensitive patients had a 100% response rate. Median time to progression was 13.7 months among platinum-sensitive patients and 3.2 months among platinum-refractory patients. Overall median time to progression was 11.5 months and median-duration of response was 9.9 months. Hematologic toxicity was common (32% grade 3 neutropenia, no grade 4 neutropenia, 14.2% grade 3 or 4 thrombocytopenia) and managed by treatment delay, dose reduction of paclitaxel, or discontinuation of carboplatin. Conclusion. Weekly low-dose carboplatin and paclitaxel has significant activity in both platinum-sensitive and platinum-resistant recurrent ovarian cancer with acceptable toxicity that is easily managed by dose adjustment.

Aim Only three cases of vulval trichofolliculoma-like lesion associated with vulvar intraepithelial neoplasia (VIN) have been previously described in the English literature. This is the fourth reported case of trichofolliculoma-like lesion associated with VIN. Case presentation A 39-year-old female presented with a white plaque in the vulva. She had a history of radical hysterectomy for invasive squamous cell carcinoma (SCC) of the cervix 8 years ago and posterior vulvectomy for invasive SCC 2 years ago. The anterior vulval biopsy showed VESf 3 and a dermal trichofolliculoma-like lesion colonised by dysplastic squamous cells. The lesion showed positive immunoperoxidase staining with pl6, as seen in overlying VIN 3. This colonised lesion easily mimics an invasive SCC. Discussion Trichofolliculoma is a rare benign pilar neoplasm of the skin usually found on the scalp, face, or neck. It is an exceedingly rare finding in the genital area. Its histogenesis is unknown. It is not associated with a family history or with other abnormalities. Juxtaposition of trichofolliculoma with VIN 3 in our and previously reported cases is likely to be coincidental. Recognition of benign appendageal tumours in an unusual site allows one to reach the correct diagnosis, and not to misdiagnose them as malignant process.

The authors wish to retract this article because they have been unable to reproduce certain crucial experiments showing validation of signatures for predicting response to chemotherapies, including docetaxel and topotecan.

Nat. Med. 12, 1294–1300 (2006); published online 22 October 2006; corrected after print 10 May and 10 October 2007 and 18 July 2008 In the version of this article initially published, of the 122 samples assayed for sensitivity to daunorubicin for which the authors applied a predictor of adriamycin sensitivity, 27 samples were replicated owing to the fact that the same samples were included in several separate series files in the Gene Expression Omnibus generated in 2004 and 2005, which were the source of the data provided for the study.