Genomic signatures to guide the use of chemotherapeutics.

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.

Growing Teratoma Syndrome in the Setting of Sarcoidosis: A Case Report and Literature Review.

Growing teratoma syndrome (GTS) is rare and can mimic disease recurrence in patients with a history of immature teratoma. Benign hypermetabolic lymphadenopathy found on staging and surveillance computed tomography (CT) and positron emission tomography (PET) may lead to the presumption of metastatic malignancy. We report a case of a 38 year old with mixed mature and immature teratomas who developed new peritoneal masses after adjuvant chemotherapy despite a normalization of tumor markers. In addition to low FDG uptake observed in these peritoneal masses, a PET scan showed hypermetabolic lymphadenopathy and pulmonary and spleen lesions suggesting widespread metastases. Subsequent surgical resection confirmed a mixed pathology with GTS and sarcoidosis. We reviewed the current literature evidence of GTS and sarcoidosis as a benign cause of lymphadenopathy in cancer patients. We emphasize the importance of a tissue diagnosis before instituting therapy for presumed cancer recurrence to avoid potentially fatal diagnostic traps and management errors. A multiple disciplinary team approach is imperative in managing patients with suspected recurrent immature teratomas.

The vascular portion of the cardinal ligament: surgical significance during radical hysterectomy for cervical cancer.

OBJECTIVE: The objective of the study was to analyze the histopathologic content of the vascular portion of the cardinal ligament in patients undergoing radical hysterectomy for cervical cancer. STUDY DESIGN: The vascular portion of the cardinal ligament was completely removed during radical hysterectomy. The maximum cervical diameter and length of the vascular ligament were measured on the fresh specimen. After inking, the pathologist separated and embedded the entire vascular segment from each side. Microscopic examination followed. RESULTS: Eighty-four patients were available for analysis. The mean cervical diameter was 3.9 cm (2-8), whereas the mean vascular segment length on the right and left sides were 4 cm (1-10) and 3.8 cm (1-7), respectively. Mean number of vascular segment lymph nodes were as follows: medial right = 0.7 (0-4), medial left = 0.6 (0-5), lateral right = 0.4 (0-3), and lateral left = 0.6 (0-6). Mean diameter of medial and lateral lymph nodes were 2 mm (0.25-8) and 3.3 mm (0.25-16), respectively. The length of the vascular segment correlated inversely with maximum cervical diameter. Thirty-one percent (26 of 84) had positive pelvic side wall lymph nodes. Fourteen patients had positive vascular segment lymph nodes (1 positive = 7, more than 1 positive = 7). Three of 7 patients had bilateral positive vascular segment lymph nodes; all 7 had microscopic disease in the paravaginal soft tissue, and all 7 had positive pelvic side wall lymph nodes (6 of 7 bilateral). Including the 14 patients, a total of 19 had nodal or nonnodal microscopic disease in the vascular segment. Of these, 7 had disease in the lateral half of the vascular ligament. Histologic sectioning revealed nerve twigs and/or scattered ganglia in the vascular segment but no large nerve trunks. CONCLUSION: Among a population of women with high-risk, early-stage cervical cancer, the lateral vascular segment of the cardinal ligament contained metastatic disease in a substantial number of patients. This segment contains no major nerve trunks. When radical hysterectomy is chosen as primary treatment for such patients, the vascular segment of the cardinal ligament should be completely excised.

Clitoroplasty.

BACKGROUND: Clitoroplasty, especially in an adult, is a rare procedure. The goals of clitoroplasty are to achieve a normal genital appearance and to preserve sensation with a satisfactory sexual response. CASES: We present two cases of acquired clitoromegaly. Case 1 is a 46-year-old woman with clitoromegaly caused by an androgen-producing ovarian tumor. The second case is a 49-year-old woman with clitoromegaly resulting from a prolonged history of self-injected anabolic steroid use. Both women underwent a clitoral reduction procedure with preservation of the neurovascular supply to the glans clitoris. CONCLUSION: Clitoroplasty is an uncommon procedure that is useful in correcting acquired clitoromegaly. The results are cosmetically acceptable, and sexual function can be preserved.

Extended cytoreduction of intraabdominal metastatic ovarian cancer in the left upper quadrant utilizing en bloc resection.

OBJECTIVE: The objective of the study was to describe the development of and experience with a technique for en bloc resection of left upper quadrant intraperitoneal metastatic ovarian cancer. STUDY DESIGN: From May 7, 2002-August 14, 2004, 6 women underwent en bloc resection of extensive tumor contiguously involving the omentum, colon, gastrocolic ligament and spleen. This represents about 5% of all cytoreductive operations performed during that time. Four of the 6 had received neoadjuvant chemotherapy. RESULTS: A description of the technique is included in the text. Two women required partial gastrectomy and partial pancreatectomy. Separate segmental resection or subtotal colectomy was performed in 3 women. Cytoreduction was optimal in all 6 cases. Significant complications occurred in 3 of the women. Disease-free survival ranged from 2-12 months. CONCLUSION: In highly selected patients undergoing cytoreductive surgery for ovarian cancer, en bloc resection of extensive left upper quadrant intraabdominal tumor may be a reasonable method for accomplishing optimal cytoreduction.

High expression of tumor necrosis factor-related apoptosis-inducing ligand is associated with favorable ovarian cancer survival.

PURPOSE: 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. EXPERIMENTAL DESIGN: 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. RESULTS: Ovarian cancers demonstrated 10-fold higher mean TRAIL expression than normal ovarian epithelial samples (P < 0.001). 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). CONCLUSIONS: 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.

Giant pelvic retroperitoneal leiomyoma arising from the rectal wall.

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.

Why are fewer medical students in Florida choosing obstetrics and gynecology?

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.

Cytoreductive surgery for patients with recurrent epithelial ovarian carcinoma.

OBJECTIVE: This study aims to identify favorable preoperative characteristics and examine the impact of secondary cytoreductive surgery on survival for patients with recurrent epithelial ovarian carcinoma. METHODS: Patients who underwent cytoreductive surgery for recurrent epithelial ovarian cancer were identified in our surgical database for the period 1988-2004. Patient charts were reviewed and data collected regarding patient demographics, surgical management, preoperative evaluation, perioperative complications, and oncologic outcome. RESULTS: Eighty-five patients met eligibility criteria. Preoperative factors that correlated with improved survival were disease-free interval of greater than 12 months (p<0.01) and residual disease after primary surgery of <2 cm (p<0.02). Other preoperative factors evaluated but not found significant included radiographic findings, physical findings, previous histology, stage, grade, previous chemotherapy, prior recurrence, and serum CA-125 level. Optimal resection to <1 cm residual disease was achieved in 86% of patients who had secondary cytoreduction. Small bowel and colon resection for cytoreduction occurred in 7% and 51% of patients, respectively. Operative complications occurred in 14% and postoperative complications occurred in 21% of patients. The median survival of patients who were optimally cytoreduced to <1 cm was 30 months compared to 17 months for patients with residual disease>or=1 cm (p<0.05). Operative factors that were evaluated and did not significantly effect survival were location of recurrence, presence of ascites, and extent of recurrence. Recurrent or progressive disease occurred in 75% of patients during follow-up. CONCLUSION: When selecting patients for secondary cytoreduction, the most significant preoperative factors are disease-free interval and success of a prior cytoreductive effort. Once secondary cytoreductive surgery is attempted, the most important factor for improved survival is optimal cytoreduction. Of equal importance is counseling regarding the significant risk for bowel surgery, colostomy, and complications.

An integrated genomic-based approach to individualized treatment of patients with advanced-stage ovarian cancer.

PURPOSE: The 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 METHODS: A 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. RESULTS: Gene 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. CONCLUSION: We 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.

High insulin-like growth factor-2 (IGF-2) gene expression is an independent predictor of poor survival for patients with advanced stage serous epithelial ovarian cancer.

OBJECTIVE: 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. METHODS: 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. RESULTS: Expression of the IGF-2 gene was more than 300-fold higher in ovarian cancers compared with normal ovarian surface epithelium samples (P <0.001). High IGF-2 expression was associated with advanced stage disease at diagnosis (P <0.001), high-grade cancers (P <0.05) and sub-optimal surgical cytoreduction (P = 0.08). In multivariate analysis, relative IGF-2 expression was an independent predictor of poor survival. CONCLUSIONS: 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.

The relationship between serum vascular endothelial growth factor, persistent disease, and survival at second-look laparotomy in ovarian cancer.

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.

Weekly low-dose carboplatin and paclitaxel in the treatment of recurrent ovarian and peritoneal cancer.

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.