Faculty Bibliography

BACKGROUND AND OBJECTIVE/OBJECTIVE:Overactivation of AKT1 and gene amplification of AKT2 are frequently detected in ovarian cancer. Activated AKT kinases provide a cell survival signal that may confer resistance to apoptosis induced by conventional therapies in cancer cells. Therefore, development of potent inhibitors that block AKT pathway is an attractive therapeutic strategy for treating ovarian carcinoma. METHODS:Ovarian cancer cell lines, A2780, MDAH2774, OVCAR-8, Caov-3, and normal murine fibroblasts (NIH3T3) were used. Cells were treated with different doses of a non-peptide small molecule compound, 9-methoxy-2-methylellipticinium acetate (termed API-59-OME) that potentially inhibit AKT pathway. Kinase assays and the phosphorylation of AKT, GSK-3alpha/beta, PDK1, ERK1/2, SGK, p38, FAK, EGFR, JAK2, PKC isoforms, and the cleavage of poly (ADP-ribose) polymerase (PARP) were examined in treated and untreated cell lines. Further, cells treated with API-59-OME were analyzed for induction of apoptosis using sub-G1 profile with propidium iodide staining. RESULTS:API-59-OME inhibited AKT kinase activity but did not inhibit ERK or JNK kinase activities in A2780, MDAH2774, and OVCAR-8 cell lines. API-59-OME did not reduce phosphorylation of other protein kinases in these cell lines. API-59-OME induced apoptosis and the cleavage of PARP in A2780, MDAH2774, and OVCAR-8 ovarian cancer cell lines that express elevated levels of phosphorylated AKT. In contrast, in Caov-3 and NIH3T3 cell lines, which lack constitutive AKT activity, API-59-OME only had minimal effect to induce apoptosis. CONCLUSION/CONCLUSIONS:These data suggest that API-59-OME may be a potent agent to target constitutively activated AKT pathway in ovarian cancer cells.

OBJECTIVE:HSP90 is a cellular chaperone that is overexpressed in many cancers. HSP90 assists in proper folding of a variety of clients, many of which are oncoproteins. HSP90 has been shown to be elevated in endometrial, ovarian, and breast cancer. Furthermore, HSP90 is known to stabilize the oncoprotein Akt; disruptions of the Akt pathway are common in gynecologic malignancies. We sought to evaluate the effectiveness of HSP90 inhibitors in gynecologic cancer. METHODS:We tested two HSP90 inhibitors, 17-AAG and 17-DMAG, against gynecologic cancer cell lines (four endometrial, one cervical, one ovarian, and one breast cancer line). We performed Western blots to determine effects of treatment on levels of HSP90 client proteins and PARP cleavage. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays were used to assess cell viability, and flow cytometry to quantitate cell-cycle distribution and apoptosis. RESULTS:After treatment with 17-AAG or 17-DMAG, we detected no decrease in HSP90 levels. Levels of other oncoproteins did decrease with treatment: phosphorylated and total Akt, and Met. One cell line underwent G(1) arrest, and five showed G(2) arrest. All showed some level of apoptotic cell death, which was confirmed by detection of PARP cleavage. Sensitivity to the drugs varied among cell lines, ranging from 20% to 90% apoptosis after treatment. Our data suggest that 17-DMAG may be more potent than 17-AAG. CONCLUSIONS:HSP90 inhibitors are effective cytotoxic agents in gynecologic cancer cells. Further testing in in vivo model systems is warranted, with the goal of eventual translation to clinical trials in gynecologic oncology patients.

OBJECTIVE:To estimate the utility of fetal echocardiography in the evaluation of the fetus with isolated single umbilical artery. METHODS:A retrospective analysis of fetuses diagnosed with single umbilical artery by sonography was conducted between January 1995 and June 2000 (n = 127). In the 103 patients who had fetal echocardiograms, we examined the frequency of abnormal echocardiographic findings when the initial sonogram demonstrated a normal four-chamber view and cardiac outflow tracts. RESULTS:Approximately 1% of fetal anomaly screens had a diagnosis of single umbilical artery. Of these, 72% were isolated (no other anomalies identified). No fetus in this group had an abnormal echocardiogram. There was one postnatal diagnosis of cardiac disease in this group; it was not predicted by either the four-chamber and outflow tract views or the echocardiogram. Among the group with other anomalies, the four-chamber view predicted every abnormal echocardiogram but one. CONCLUSION/CONCLUSIONS:Fetal echocardiography does not appear to add further diagnostic information to the antenatal evaluation of the fetus with isolated single umbilical artery when normal four-chamber and outflow tract views of the heart have already been obtained.

BACKGROUND:The objectives of the current study were to: 1) characterize the clinical outcome of patients with recurrent micropapillary serous ovarian carcinoma (MPSC) and 2) evaluate the survival impact of secondary cytoreductive surgery and other prognostic variables. METHODS:Twenty-six patients with recurrent MPSC were identified retrospectively from hospital and tumor registry databases. Survival curves were generated from the time of tumor recurrence using the Kaplan-Meier method and statistical comparisons were performed using the log-rank test, logistic regression analysis, and the Cox proportional hazards regression model. RESULTS:The median age of the patients at the time of recurrence was 46 years. The mean progression-free interval was 31.6 months, and 92% of patients had advanced stage disease at the time of the initial diagnosis. Twenty-one patients underwent secondary cytoreductive surgery; tumor debulking was performed in 90.5% of cases and 52.4% of patients required an intestinal resection. Optimal resection (residual disease < or = 1 cm) was achieved in 15 patients (71.4%). Patients undergoing optimal secondary cytoreduction had a median survival time of 61.2 months from the date of disease recurrence, compared with 25.5 months for those patients in whom suboptimal residual disease remained (P < 0.02) and 29.9 months for nonsurgical patients (P < 0.01). On multivariate analysis, optimal secondary cytoreduction was found to be the only independent predictor of survival. Salvage chemotherapy produced an objective response in 25% of patients with measurable disease. The administration of chemotherapy prior to surgical intervention was associated with a trend toward worse survival and a lower likelihood of optimal secondary cytoreduction. CONCLUSIONS:Optimal secondary cytoreductive surgery is feasible in the majority of patients with recurrent MPSC and is an independent predictor of subsequent survival. Surgical intervention should be considered for those patients with recurrent MPSC. [See editorials on pages 675-6 and 677-80, this issue.]

OBJECTIVES/OBJECTIVE:The objectives of this study were to characterize the prognostic features of micropapillary serous ovarian carcinoma (MPSC), examine the clinical impact of surgical staging, and define the role of cytoreductive surgery for patients with advanced disease. METHODS:Fifty-one patients with MPSC were identified from hospital and tumor registry databases. Demographic, operative, pathologic, and follow-up data were abstracted retrospectively. Survival curves were generated using the Kaplan-Meier method, and statistical comparisons were performed using the log rank test, logistic regression analysis, and the Cox proportional hazards regression model. RESULTS:The median age at diagnosis was 45 years, and follow-up extended to a median of 43.0 months. Stage I/II disease was present in 25.5% of patients and no disease-related deaths were observed in this group. Stage III disease was discovered in 29.4% of patients with tumor clinically confined to the ovaries. Stage III/IV disease (74.5% of cases) was associated with median progression-free and overall survival times of 32.8 and 114.2 months, respectively. Menopausal status and the anatomic extent of disease were significantly associated with survival outcome. However, the strongest independent predictor of survival for patients with advanced disease was the amount of residual tumor. Median overall survival for patients with optimal cytoreduction (residual disease </=1 cm) was 115.4 months compared to 43.1 months for those with >1 cm residual tumor (P < 0.0002). CONCLUSIONS:MPSC carries a significant risk of extraovarian spread; however, adequately sampled Stage I/II disease is associated with a favorable prognosis. Optimal cytoreduction is associated with improved survival and should be the primary therapeutic objective for patients with advanced-stage MPSC.

BACKGROUND:Bone marrow transplantation is used in the treatment of a variety of malignancies. One common sequela is graft-versus-host disease (GvHD.) CASE/METHODS:A case of vaginal GvHD in a postmenopausal woman manifested as a 2-cm, cystic, paracervical mass. The patient was followed with consecutive pelvic ultrasounds and pelvic examinations until 27 months after transplantation, when the mass increased in size to 4 x 3 cm. Exploratory laparotomy with total abdominal hysterectomy revealed a 3 x 3-cm phlegmon within the proximal part of the vagina. Presumably, this resulted from vaginal GvHD, causing a midvaginal stricture with obstruction of cervical/uterine effluent. CONCLUSION/CONCLUSIONS:An awareness of the gynecologic manifestations of GvHD is critical for clinicians caring for women undergoing bone marrow transplantation.