Faculty Bibliography

BACKGROUND/AIMS/OBJECTIVE:Stages III and IV ovarian and peritoneal cancer patients are commonly treated with combination chemotherapy after surgical debulking. This phase II trial investigated the use of pegylated liposomal doxorubicin as consolidation chemotherapy for these patients. METHODS:Women with stage III or IV ovarian or primary peritoneal carcinoma demonstrating no clinical evidence of disease after primary therapy were eligible for enrollment. Patients received 4 cycles of 40 mg/m(2) IV of pegylated liposomal doxorubicin every 28 days. RESULTS:Twelve patients were enrolled. There were 6 stage IIIC and 6 stage IV patients. Ten patients received 4 cycles. Two patients had dose limiting skin toxicity manifest as hand-foot syndrome and received only 3 cycles. Forty-six of a planned 48 cycles were administered. Median disease-free survival from registration is 10 months with a mean of 18 months. Median overall survival has not yet been reached. Four patients are disease-free, two have relapsed and six have died from disease progression. CONCLUSION/CONCLUSIONS:Pegylated liposomal doxorubicin is a well-tolerated choice for consolidation chemotherapy in patients with ovarian or primary peritoneal carcinoma.

The goal of this study was to determine whether patterns of expression profiles of p73 isoforms and of p53 mutational status are useful combinatorial biomarkers for predicting outcome in a gynecological cancer cohort. This is the first such study using matched tumor/normal tissue pairs from each patient. The median follow-up was over two years. The expression of all 5 N-terminal isoforms (TAp73, DeltaNp73, DeltaN'p73, Ex2p73 and Ex2/3p73) was measured by real-time RT-PCR and p53 status was analyzed by immunohistochemistry. TAp73, DeltaNp73 and DeltaN'p73 were significantly upregulated in tumors. Surprisingly, their range of overexpression was age-dependent, with the highest differences delta (tumor-normal) in the youngest age group. Correction of this age effect was important in further survival correlations. We used all 6 variables (five p73 isoform levels plus p53 status) as input into a principal component analysis with Varimax rotation (VrPCA) to filter out noise from non-disease related individual variability of p73 levels. Rationally selected and individually weighted principal components from each patient were then used to train a support vector machine (SVM) algorithm to predict clinical outcome. This SVM algorithm was able to predict correct outcome in 30 of the 35 patients. We use here a mathematical tool for pattern recognition that has been commonly used in e.g. microarray data mining and apply it for the first time in a prognostic model. We find that PCA/SVM is able to test a clinical hypothesis with robust statistics and show that p73 expression profiles and p53 status are useful prognostic biomarkers that differentiate patients with good vs. poor prognosis with gynecological cancers.

Ectopic human chorionic gonadotropin production has been described in a wide variety of non-germ cell tumors, particularly in epithelial tumors, but rarely in sarcomas. In this report, we describe the case of 49-year-old woman with a history of "uterine fibroids," who presented with vaginal bleeding and a positive urine pregnancy test. After pregnancy was ruled out by ultrasound, the patient underwent a laparotomy and hysterectomy for a presumptive diagnosis of "fibroids" and was found to have carcinomatosis at the time of the surgery. Therefore optimal debulking of tumors was performed. Two weeks later, the patient developed a small bowel obstruction, which apparently was due to rapid recurrence of tumors in the abdomen, and soon afterwards she died. Microscopically, the resected pelvic mass was composed of highly atypical and pleomorphic spindle cells admixed with many multinucleated giant cells. The tumor had a high mitotic rate along with areas of hemorrhage and necrosis. Immunohistochemically, the tumor cells were positive for vimentin, desmin, smooth muscle actin, and beta-human chorionic gonadotropin, and were negative for epithelial membrane antigen, keratin AE1/3, S-100, CD31, CD117, Ber-EP4, WT-1, estrogen and progesterone receptors. The majority of cells, including the multinucleated giant cells, were strongly immunoreactive for beta-human chorionic gonadotropin. Only three cases of leiomyosarcomas with beta/human chorionic gonadotropin production have been described in the literature, and all three cases had extrauterine origin. Our case, to the authors' best knowledge, is the first uterine leiomyosarcoma with prominent beta/human chorionic gonadotropin production.

OBJECTIVE:This study was undertaken to report on the benign gynecologic conditions occurring among women with an intact uterus at enrollment in the Breast Cancer Prevention Trial of the National Surgical Adjuvant Breast and Bowel Project. STUDY DESIGN/METHODS:The incidence rates of several benign gynecologic conditions were determined and risks were compared among women receiving tamoxifen and those receiving placebo, based on risk ratios (RRs) with 95% CIs. Comparisons included stratification by menopausal status, body mass index, and history of estrogen use. RESULTS:Compared with women taking placebo, premenopausal women taking tamoxifen had a greater incidence of endometrial polyps (RR = 1.9, 95% CI = 1.55-2.41), leiomyomas (RR = 1.3, 95% CI = 1.14-1.55), endometriosis (RR = 1.9, 95% CI = 1.35-2.70), ovarian cysts (RR = 1.5, 95% CI = 1.20-1.78), and gynecologic surgical procedures, including hysterectomy (RR = 1.6, 95% CI = 1.29-1.88). Postmenopausal women taking tamoxifen also had an increased incidence of endometrial polyps (RR = 2.4, 95% CI = 1.76-3.24), leiomyomas (RR = 1.4, 95% CI = 1.04-1.80), endometriosis (RR = 1.9, 95% CI = 1.29-5.58), and gynecologic surgical procedures, including hysterectomy (RR = 2.2, 95% CI = 1.60-3.13), compared with women taking placebo. All women taking tamoxifen also had an increased incidence of simple endometrial hyperplasia without atypia (overall RR = 2.06, 95% CI = 1.64-2.60) compared with those taking placebo. CONCLUSIONS:Our results strongly support the estrogen agonist role of tamoxifen as the causative factor for the increased risk of endometrial polyps, leiomyomas, endometriosis, and endometrial hyperplasia among women taking this agent.

The aging population is the fastest growing segment of our population. Over the last century, the average life expectancy has increased by 25 years. The incidence of ovarian carcinoma, seen primarily in postmenopausal women, is, therefore, expected to increase. The current standard treatment of ovarian cancer has been determined on the basis of prospective, randomised clinical trials carried out by cooperative groups. Sixty-one percent of new cancer cases occur in women >65 years of age. Despite this fact, enrollment in clinical trials has been exceedingly low. In turn, this causes suboptimal treatment for a very fatal disease. The aetiology of this is multifactorial, and strategies for improvement are lacking. Elderly patients may be barred from participation based on physician biases alone. Elderly patients may have limited access to academic centres where clinical trials are conducted or be excluded on the basis of unrealistic inclusion criteria. As physicians, it is our duty to understand the elderly patient and the comorbidities in this age group that may influence the tolerability and toxicity of conventional therapies. Therefore, it is imperative that we make a conscious effort to examine ways in which we may improve enrollment of elderly women with ovarian cancer in clinical trials.

OBJECTIVE:Obstetrician/gynecologists' career satisfaction with certain work-related activities was examined among clinicians who perform deliveries and clinicians who do not. STUDY DESIGN/METHODS:A questionnaire was sent to 1500 member-fellows of the American College of Obstetricians and Gynecologists; 842 members (56%) responded. The questionnaire was designed to distinguish between obstetrician/gynecologists who perform deliveries and clinicians who do not in the areas of satisfaction with specific aspects of career and work-related activities. Data were examined initially by multivariate analysis of variance and subsequently by univariate analysis of variance if the multivariate test was found to be significant. RESULTS:Workload and personal control were the primary factors for which there was a significant difference in satisfaction between clinicians who perform deliveries and clinicians who do not (P<.001). Obstetrician/gynecologists who do not perform deliveries reported working significantly fewer hours per week (P<.001) and had more satisfaction with their work activities than the delivery group overall. Despite lowered satisfaction with certain career aspects among the delivery Group, the highest positive disposition ratings that was given by respondents were for surgery, vaginal delivery, and planned cesarean delivery, with gender differences observed in the level of disposition for these particular activities. The most negative rating was reported for on-call/in-hospital time. CONCLUSION/CONCLUSIONS:Although positive disposition is associated with the activity of vaginal and cesarean delivery overall, 2 primary contributing factors of dissatisfaction that were identified among obstetrician/gynecologists who perform deliveries were increased workload and decreased personal control.

This report summarizes our experience with the combination of mesna, doxorubicin, ifosfamide, and dacarbazine (MAID) for patients with gynecological sarcomas. We reviewed the records of all patients who had received the MAID regimen for a gynecological sarcoma between 1993 and 2000. The MAID regimen was administered intravenously every 4 weeks in the hospital as follows: (1) mesna 1500 mg/m2/day x 4 days; (2) doxorubicin 15 mg/m2/day x 3 days; (3) ifosfamide 1500 mg/m2/day x 3 days; (4) dacarbazine 250 mg/m2/day x 3 days. The results of treatment with MAID were disappointing. Overall, the response rate was 9% with one complete response and one partial response (both in patients with uterine leiomyosarcoma). We did not observe any responses among the patients with carcinosarcomas of either ovarian or uterine origin. The median progression-free interval and survival were 11 months and 29 months, respectively. This regimen was associated with substantial toxicity (including a death from neutropenic sepsis) as well as high cost and inconvenience due to the requirement for inpatient administration. Although our study contains a limited number of patients with a variety of gynecological sarcomas, our review has led us to discontinue using MAID. It remains to be established if any combination chemotherapy regimen is better than single agent treatment.

OBJECTIVE:This study was undertaken to compare the outcomes of patients with endometrial cancer who had primary surgery with gynecologic oncology involvement at university or community hospitals. METHODS:The study population consisted of all patients who had primary surgery for endometrial cancer with involvement of the attending physicians of the Division of Gynecologic Oncology. The patients were divided into two groups based on whether their surgery was performed at a university or community hospital. Demographic and clinical data were abstracted from the medical records. RESULTS:There were no significant differences between the two groups with regard to Quetelet index (kg/m(2)); intervals between biopsy and consultation, consultation and surgery, and biopsy and surgery; estimated blood loss; incidence of operative or hospital complications; frequency of appropriate surgical staging; stage distribution; histology or grade; and hospital stay. Patients at a university hospital were significantly older, had a higher severity index, were more likely to have had a vaginal hysterectomy, and participate in a research protocol. Both the Quetelet index and the severity index were significantly higher for patients who had vaginal hysterectomy than for those who had either laparoscopically assisted vaginal hysterectomy or total abdominal hysterectomy. When analyzed by surgical approach, the frequencies of pelvic and paraaortic lymph node sampling were comparable between the groups. Both the Quetelet and severity indices were significantly higher for patients who did not have lymph node sampling. CONCLUSION/CONCLUSIONS:Involvement of a gynecologic oncologist at the time of primary surgery for endometrial cancer was associated with comparable outcomes in both the university and community hospital setting.

p73 has significant homology to p53. However, tumor-associated up-regulation of p73 and genetic data from human tumors and p73-deficient mice exclude a classical Knudson-type tumor suppressor role. We report that the human TP73 gene generates an NH(2) terminally truncated isoform. DeltaNp73 derives from an alternative promoter in intron 3 and lacks the transactivation domain of full-length TAp73. DeltaNp73 is frequently overexpressed in a variety of human cancers, but not in normal tissues. DeltaNp73 acts as a potent transdominant inhibitor of wild-type p53 and transactivation-competent TAp73. DeltaNp73 efficiently counteracts transactivation function, apoptosis, and growth suppression mediated by wild-type p53 and TAp73, and confers drug resistance to wild-type p53 harboring tumor cells. Conversely, down-regulation of endogenous DeltaNp73 levels by antisense methods alleviates its suppressive action and enhances p53- and TAp73-mediated apoptosis. DeltaNp73 is complexed with wild-type p53, as demonstrated by coimmunoprecipitation from cultured cells and primary tumors. Thus, DeltaNp73 mediates a novel inactivation mechanism of p53 and TAp73 via a dominant-negative family network. Deregulated expression of DeltaNp73 can bestow oncogenic activity upon the TP73 gene by functionally inactivating the suppressor action of p53 and TAp73. This trait might be selected for in human cancers.