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Objective: To determine the impact of weekly paclitaxel consolidation on progression-free survival (PFS) of women undergoing treatment for ovarian cancer., Methods: All women with advanced epithelial ovarian or primary peritoneal carcinoma, treated with paclitaxel consolidation therapy from August 1997 to March 2002, were identified. Patients received weekly paclitaxel infused at a median dose of 80 mg/m(2) (range: 60-80 mg/m(2)) for a maximum of 12 weeks. A chart review was performed to assess disease status and chemotherapy-related toxicities. PFS was calculated from the date of initiation of induction chemotherapy until the date of documented disease recurrence., Results: 31 women received paclitaxel consolidation therapy over the study period (29 stage III and 2 stage IV). 24 women had epithelial ovarian carcinoma and 7 were diagnosed with primary peritoneal carcinoma. The median PFS was 27 months (range: 12-62 months). The overall 2-year survival was 94%, where 17 women (55%) were without evidence of disease and 12 (39%) were alive with disease. The median follow-up was 41 months (range: 15-77 months). Over 337 weeks of consolidation therapy, 1 patient experienced Grade 3 neuropathy and 1 patient developed Grade 3 neutropenia., Conclusion: Consolidation therapy with weekly paclitaxel infusion is a well-tolerated regimen that resulted in a median PFS of 27 months in women who obtained a complete clinical response following induction therapy. Given the lack of side effects and the potential for extending the PFS of those treated, a prospective randomized study of weekly paclitaxel should be considered.

Background: Serous components within endometrial carcinoma are reportedly poor prognosticators. However, to the authors' knowledge the percentage of tumors which must be comprised of a serous component in order to affect outcome is unknown. The authors compared overall survival (OS) in women with endometrial carcinomas comprised of various percentages of uterine serous carcinoma (USC) with that of women with International Federation of Gynecology and Obstetrics (FIGO) Grade 3 endometrioid carcinoma (G3EC) to determine whether outcomes varied between these two poorly differentiated histologies., Methods: Data concerning women with either G3EC or USC who were diagnosed between January 1990 and November 2000 were collected retrospectively. Cases were reviewed to confirm diagnosis and estimate the fraction of tumor comprised of USC. Variables assessed included patient age and race, tumor stage, and lymphovascular space invasion. Associations between variables were tested using the Fisher exact test. The Kaplan-Meier method was used to evaluate OS with comparisons performed using the log-rank test., Results: Fifty-two women with G3EC and 87 women with USC were identified. The OS of women with tumors comprised of > 50% USC was found to be significantly worse compared with women with G3EC (hazard ratio [HR] of 2.4; 95% confidence interval [95% CI], 1.2-5.2). Women with USC were more likely to present with extrauterine disease (odds ratio of 2.2; 95% CI, 1.1-4.5). The 5-year survival rate for women with G3EC was 75% compared with 41% for women with tumors that were > 50% USC (P = 0.01). There was a significant trend toward a worse OS in women with even 10% USC compared with women with G3EC., Conclusions: USC involving > 50% of an endometrial carcinoma was found to be predictive of worse OS compared with the OS of women with G3EC. In patients with early-stage disease, a trend toward a worse prognosis was found to exist when USC comprised even 10% of a tumor. Investigation into the treatment of endometrial carcinoma should include and document tumors with any percentage comprised of USC., ((c) 2004 American Cancer Society)

Objective: Endometrial cancer and breast cancer are two common malignancies found in women. As a result of estrogen dependency, an association is thought to exist between these entities. This study was undertaken to determine if the endometrial carcinomas, which develop in women with a history of breast cancer, were more likely to be of the endometrioid or the serous histology, which is generally considered non-estrogen-dependent., Methods: A retrospective chart review was conducted for the years 1984-2001. All women who were diagnosed at our institution with endometrial carcinoma were identified. The women who also had a prior history of breast cancer were identified and comprise the cohort for this study. Information regarding age at diagnosis, tumor stage, histologic subtype, and tamoxifen exposure were recorded and analyzed., Results: About 1166 women were diagnosed with endometrial cancer during the study period, of whom 54 (4.6%) had a pre-existing diagnosis of breast cancer. Of the 54 women in this study, 41 had tumors of the endometrioid histology and 13 had a tumor of the serous subtype. There was no difference with regards to median age at the time of diagnosis or years of tamoxifen exposure. Women with breast cancer were more likely to develop uterine serous carcinoma (USC) as compared to one of endometrioid histology (OR 2.6; 95% CI 1.29-5.23)., Conclusions: Women with breast cancer who subsequently developed endometrial cancer exhibited a 2.6-fold increased risk of developing a USC as compared to an endometrioid carcinoma. These findings suggest that there may be an underlying genetic predisposition linking breast cancer and USC.

Background: Clear cell adenocarcinoma (CCA) of the vagina and cervix in young women is associated with prenatal exposure to diethylstilbestrol (DES). Parenchymal pulmonary metastases are known to occur following treatment of the primary tumor. Most recurrences present within 2 to 3 years of the initial diagnosis., Case: This is a case report of a solitary endobronchial clear cell adenocarcinoma occurring 15.3 years after the initial diagnosis of DES-induced CCA., Conclusions: This case suggests that management of clear cell cancer survivors should involve long-term follow-up because of the potential for the appearance of a new focus of clear cell adenocarcinoma.

Objective: Gemcitabine has shown therapeutic activity in a variety of malignancies, including ovarian cancer. This review summarizes both published and unpublished data on the use of gemcitabine as a single agent in the treatment of ovarian cancer., Methods: The results of eight clinical trials of gemcitabine in women with advanced (stage III or IV) ovarian cancer whose disease progressed despite previous heavy treatment (one to four previous courses) with platin-based chemotherapy or taxanes were reviewed., Results: Gemcitabine, given as a single weekly infusion of 800-1200 mg/m(2) for 3 consecutive weeks, followed by a week of rest, produced at least a partial remission in 11 to 22% of the patients studied. Median survival was prolonged after gemcitabine therapy, and stable disease was documented in 41 to 52% of patients in four of the eight studies reviewed. Toxicity was minimal and was mostly hematologic., Conclusions: Gemcitabine is obviously active as monotherapy in patients with recurrent stage III or IV ovarian cancer and appears to be very well tolerated.

Objective: To evaluate, in a randomized clinical trial, the role of adjuvant hysterectomy after standardized radiation in improving progression-free survival and survival for patients with "bulky" stage IB cervical cancer., Methods: A total of 256 eligible patients with exophytic or "barrel" shaped tumors measuring > or = 4 cm were randomized to either external and intracavitary irradiation (RT, N = 124) or attenuated irradiation followed by extrafascial hysterectomy (RT + HYST, N = 132). Twenty-five percent of patients had tumors with a maximum diameter of > or =7 cm., Result: Tumor size was the most pronounced prognostic factor followed by performance status 2 and age at diagnosis. Hysterectomy did not increase the frequency of reported grade 3 and 4 adverse effects (both groups, 10%). The majority of these adverse effects were from the gastrointestinal or genitourinary tracts exclusively. There was a lower cumulative incidence of local relapse in the RT + HYST group (at 5 years, 27% vs. 14%). There were no statistical differences in outcomes between regimens except for the adjusted comparison of progression-free survival, although all indicated a lower risk in the adjuvant hysterectomy regimen (unadjusted relative risk [URR] of progression, 0.77, P = 0.07; URR of death, P = 0.26, both one tail)., Conclusion: Overall, there was no clinically important benefit with the use of extrafascial hysterectomy. However, there is good evidence to suggest that patients with 4-, 5-, and 6-cm tumors may have benefitted from extrafascial hysterectomy (URR of progression; 0.58; URR of death, 0.60).

Uterine serous carcinoma (USC) has a propensity for extrauterine spread, and some suggest that this disease be staged as an ovarian cancer, and thus include omental sampling. However, given the primary organ involved, the staging recommendations do not include omental sampling. The aim of this study is to evaluate the role of omental sampling during the surgical staging of USC. We retrospectively identified cases of USC at our institution from January 1990 to June 2000 and abstracted surgical procedures, stage, and sites of metastasis. Fisher's exact test was used to calculate sensitivity, specificity, and positive and negative predictive value. We identified 65 women with USC, of which 52 underwent omental evaluation. Thirty four of the omentums were visually normal and benign on histologic review. Two were visually negative and histologically positive for metastatic serous carcinoma. The remaining 16 specimens were grossly involved with histologic confirmation of disease. The sensitivity of a visually negative omentum is 0.89 (P < 0.0001). Microscopic omental metastasis from USC is rare. When the omentum is involved, thereby upstaging the patient to stage IVB disease, the disease is generally diagnosed by gross visualization. We conclude that omental sampling does not need to be included in the routine surgical staging of USC.

The majority of women diagnosed with epithelial ovarian cancer will have persistent or recurrent disease after initial treatment. We evaluated response and toxicity in women with advanced stage disease given salvage paclitaxel as a low-dose, weekly infusion. We performed a retrospective review of 22 women with advanced stage epithelial ovarian (19 women) or primary peritoneal carcinoma (3 women) who had received low-dose, weekly paclitaxel salvage therapy. All women had refractory, persistent, or recurrent disease following first-line treatment with paclitaxel and platin chemotherapy. Response and toxicity were assessed. Measurable disease present on physical or radiologic exam and serum carbohydrate antigen-125 levels were used to assess disease response. Overall response rate to low-dose, weekly paclitaxel salvage therapy was 50% (27% complete, 23% partial). Median progression-free interval (PFI) in responders was 27 weeks (range, 14-68 weeks). Stabilization of disease occurred in an additional 27% of patients with a median PFI of 22 weeks (range, 15-89 weeks). No difference in response was detected between the 7 women with platin-sensitive disease and the 15 women with platin-resistant disease (P = 0.19). The median dose of paclitaxel was 80 mg/m2 (range, 60-80 mg/m2). During a total of 325 weeks of paclitaxel treatment (median per patient, 12 weeks; range, 6-49 weeks), 13 treatment delays occurred (hematologic indication, 9; nonhematologic indication, 4). No cases of grade 4 hematologic toxicity, sepsis, or worsening neuropathy were documented. Weekly paclitaxel infusion given as salvage therapy results in significant clinical response, even in women previously treated with paclitaxel. The regimen is well tolerated with no cases of grade 4 neutropenia or worsening neuropathy in our population.

Background: Introital stenosis from both bony and soft tissue contracture is an unusual clinical problem not well addressed in the literature., Case: A woman with a history of pelvic irradiation at age 1 for malignancy presented with severe introital stenosis unresponsive to conservative topical and dilatational therapy. She ultimately required staged bony resection of her infantile pelvis and soft tissue reconstruction to reestablish her introital aperture to an adequate and functional size., Conclusion: Introital stenosis from childhood requires a different treatment because development of the pelvis may not have been normal, and bony narrowing may exist in conjunction with soft tissue contracture. A staged multispecialty approach is recommended to treat this interesting variant of introital stenosis.

Purpose: A phase II trial of paclitaxel was initiated in advanced nonsquamous carcinoma of the cervix to determine its activity in patients who had failed standard chemotherapy., Patients and Methods: Eligible patients had at least one measurable lesion. The starting dose of paclitaxel was 170 mg/m(2) (135 mg/m(2) for patients with prior pelvic radiation) given as a 24-hour continuous intravenous infusion with courses repeated every 3 weeks. Dose escalation to 200 mg/m(2) and de-escalation to 110 mg/m(2) were allowed based on adverse effects., Results: In this trial, 42 assessable patients were initially entered onto the study, and 13 responses were seen; four patients had a complete response, and nine patients had a partial response. The overall response rate was 31%. The primary and dose-limiting toxicity was neutropenia., Conclusion: The response rate to paclitaxel exceeds the rates reported using other single agents in nonsquamous carcinoma of the cervix.

Objective: To determine the clinical course of noninvasive uterine papillary serous carcinoma and whether it indicates advanced metastatic disease., Methods: We reviewed the charts of women with noninvasive uterine papillary serous carcinoma who were treated at our institution and abstracted surgical stage, sites of metastases, disease progression, and length of follow-up., Results: There were 595 cases of endometrial adenocarcinoma between January 1990 and February 2000, 69 of which had papillary serous histology. Sixteen were noninvasive tumors. Six were confirmed stage IA by complete surgical staging and ten were associated with metastasis at staging. Two of the six women with stage IA tumors had disease recurrence., Conclusions: Noninvasive papillary serous carcinoma is often widely metastatic. In our experience, approximately two thirds of patients had metastasis, indicating the need for complete surgical staging. Even in those with disease limited to the endometrium, a significant percentage will have disease recurrence.

Objective: Ovarian hemangiomas are very rare with the majority being cavernous hemangiomas. We report a case of a capillary ovarian hemangioma., Methods: A case report of a woman with a capillary ovarian hemangioma with massive ascites and an elevated CA-125 is presented., Results: A 39-year-old woman presented with an enlarged ovary containing two ovarian cysts. Her CA-125 was elevated to 872 U/ml. On surgical exploration, she had 1500 cc of clear yellow ascitic fluid and a 7.9 x 6.5 x 4.5 cm left ovarian mass. Frozen section revealed marked stromal edema with luteinized cells and no evidence of malignancy. Histologically, the tumor was a cellular capillary hemangioma with an anastomosing vascular pattern., Conclusions: This is the first case, reported in the literature, of an ovarian capillary hemangioma presenting with an elevated CA-125 and massive ascites., (Copyright 2000 Academic Press.)

Objective: Malignant transformation of endometriosis has been well documented. Endometrioid adenocarcinoma is the most common malignancy to occur in this setting, although other carcinomas and rarely stromal tumors can be seen. We present the first case in the literature of adenosarcoma, a rare mixed mullerian or mesodermal tumor, arising in extrauterine vaginal endometriosis., Case: A 42-year-old woman underwent multiple medical therapies and surgeries for aggressive endometriosis. A pelvic exenteration was abandoned secondary to severe fibrosis, and low-dose radiotherapy was used to control bleeding from vaginal endometriosis. The pathologic diagnosis of recurrent endometriosis was confirmed multiple times over her 4-year course. Excision of a recurrent vaginal mass revealed adenosarcoma with heterologous elements., Conclusion: It is important to biopsy or excise recurrent endometriosis, as malignant transformation can occur, giving rise to epithelial, stromal, or mixed epithelial-mesenchymal tumors., (Copyright 2000 Academic Press.)

Objectives: In vulvar carcinoma, the expression of Ki-67 has been previously found to correlate with patient outcome. The objective of the study was to determine whether a specific pattern of expression was associated with occult vulvar cancer in patients with vulvar intraepithelial neoplasia (VIN) III and whether patterns of Ki-67 expression correlated with other clinical prognostic factors., Methods: 19 women with only VIN III, 16 women with both vulvar cancer and VIN III, and 15 women with only vulvar cancer were identified. Immunostaining, using a monoclonal antibody for Ki-67, was then performed on representative tissue blocks and slides were assessed for diffuse or localized patterns of expression. For the patients with vulvar cancer, the type of staining was correlated with FIGO stage, tumor grade, lymph nodes status, and associated VIN III., Results: All 35 patients with VIN III exhibited a diffuse staining pattern. In the 31 patients with vulvar carcinoma, 11 (35%) expressed a diffuse staining pattern while 20 (65%) showed a localized pattern. Poorly differentiated tumors were associated with a diffuse staining pattern (P = 0.013, RR 3.59, CI 1.59-7.60). For vulvar carcinoma, there were no statistically significant relationships between Ki-67 expression pattern and stage, associated VIN III, or lymph node involvement., Conclusion: VIN III, regardless of a concomitant vulvar cancer, always expressed a diffuse pattern; thus Ki-67 staining was not useful as a marker for occult cancer. In women with vulvar carcinoma, however, a diffuse Ki-67 expression was significantly associated with poorly differentiated tumors., (Copyright 2000 Academic Press.)

Objective: The aims of this study were to assess the early and late toxicities of multiple-daily-fraction whole pelvic radiation plus concurrent chemotherapy with either hydroxyurea or 5-fluorouracil (5-FU)/cisplatin and to determine the maximum tolerated external radiation dose in conjunction with brachytherapy, when given with either of these drug regimens, as treatment for locally advanced carcinoma of the cervix., Methods: The first study (GOG 8801) of 38 patients utilized hydroxyurea as a single oral dose of 80 mg/kg to a maximum of 6 g at least 2 h prior to a radiation treatment twice every week. In the second study (GOG 8901) of 30 patients, cisplatin and 5-FU were used concomitantly with radiotherapy. Fifty milligrams per square meter of cisplatin was administered on days 1 and 17 of external radiation. 5-FU was given by continuous intravenous infusion at a dose of 1000 mg/m(2)/day for 4 consecutive days on days 2, 3, 4, 5, and 18, 19, 20, and 21 of external radiation therapy. Both studies utilized external radiation given by an accelerated hyperfractionated regimen of 1.2 Gy per fraction, two fractions per day. All patients were treated 5 days per week with a minimum of 4 h between fractions., Results: Acute toxicity was manageable on both protocols but nausea, vomiting, and myelosuppression were more severe with hydroxyurea. Chronic toxicity was primarily enteric and appeared to be dose-related. There was no obvious correlation seen between pelvic failure rates and the radiation dose or between the chemotherapy regimens used., Conclusions: The defined maximal tolerated dose of whole pelvic radiation was 57.6 Gy in 48 fractions which could be delivered in a hyperfractionated setting with concomitant chemotherapy, followed by brachytherapy. Follow-up is now sufficient that further adverse events should be rare., (Copyright 1999 Academic Press.)

Combination chemotherapy using paclitaxel with a platinum-based regimen is currently the standard first-line therapy for ovarian cancer after surgical cytoreduction. Whereas cisplatin-paclitaxel combination chemotherapy has shown significant efficacy over previous drug combinations in ovarian cancer, 20-30% of patients fail to respond to this combination. These patients are deemed cisplatin-paclitaxel resistant, although it is unclear whether the tumors are resistant to one or both drugs. Because the options available to ovarian cancer patients for second-line therapy are limited, and knowing that mechanistic differences exist between cisplatin and paclitaxel, we assessed the efficacy of combination drug therapy on cisplatin-resistant (cisplatinR) ovarian cancer cells. We found that paclitaxel induced apoptosis in cisplatinR cells as well as in the cisplatin-sensitive parental cell lines. In cisplatinR C-13 cells, the concomitant addition of cisplatin blocked paclitaxel-induced apoptosis as determined by DNA fragmentation assays, fluorescence microscopy, and flow cytometry. Paclitaxel-induced multimininucleation was also inhibited when the cells were exposed sequentially to paclitaxel and then cisplatin. Cisplatin did not block paclitaxel-induced stabilization of microtubules or prevent paclitaxel-induced loss of Bcl-2 expression in cisplatinR cells. Conversely, paclitaxel did not inhibit p53 protein accumulation by cisplatin. These results suggest that cisplatin blocks paclitaxel-induced apoptosis at a point downstream of Bcl-2 degradation and independent of microtubule stabilization. Our research shows that cisplatin can inhibit the effectiveness of paclitaxel in cispatinR cell lines. Therefore, the establishment of a clinical protocol to evaluate the efficacy of paclitaxel alone versus another second-line regimen in patients with cisplatin-paclitaxel-resistant ovarian cancer is warranted.

Purpose: In 1986, a protocol comparing primary radiation therapy (RT) plus hydroxyurea (HU) to irradiation plus fluorouracil (5-FU) and cisplatin (CF) was activated by the Gynecologic Oncology Group (GOG) for the treatment of patients with locally advanced cervical carcinoma. The goals were to determine the superior chemoradiation regimen and to quantitate the relative toxicities., Methods: All patients had biopsy-proven invasive squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma of the uterine cervix. Patients underwent standard clinical staging studies and their tumors were found to be International Federation of Gynaecology and Obstetrics stages IIB, III, or IVA. Negative cytologic washings and para-aortic lymph nodes were required for entry. Patients were randomized to receive either standard whole pelvic RT with concurrent 5-FU infusion and bolus CF or the same RT plus oral HU., Results: Of 388 randomized patients, 368 were eligible; 177 were randomized to CF and 191 to HU. Adverse effects were predominantly hematologic or gastrointestinal in both regimens. Severe or life-threatening leukopenia was more common in the HU group (24%) than in the CF group (4%). The difference in progression-free survival (PFS) was statistically significant in favor of the CF group (P = .033). The sites of progression in the two treatment groups were not substantially different. Survival was significantly better for the patients randomized to CF (P = .018)., Conclusion: This study demonstrates that for patients with locally advanced carcinoma of the cervix, the combination of 5-FU and CF with RT offers patients better PFS and overall survival than HU, and with manageable toxicity.

Objective: To determine the impact of margin status on disease recurrence and the incidence of occult cancer in women diagnosed with vulvar intraepithelial neoplasia (VIN) III and treated with surgical excision., Methods: Between 1989 and 1995, 73 women were diagnosed preoperatively with VIN III by vulvar biopsy and were treated with surgical resection. Patients were examined postoperatively, and recurrence was diagnosed when a biopsy of suspicious lesions confirmed VIN III., Results: The mean age was 45 years; 81% of the patients were white, and 18% were black. Eighty-two percent of the women had used tobacco, 56% had prior cervical dysplasia, and 37% had prior genital warts. An underlying squamous vulvar cancer was found in 22% of patients at initial treatment for VIN III. Fifty-nine women had follow-up of at least 7 months. Of these, 66% (39 of 59) had positive surgical margins, 31% (18 of 59) had negative margins and 3% had unknown margins (two of 59). With positive margins, 46% (18 of 39) suffered recurrent disease; with negative margins, only 17% (three of 18) had recurrent disease (P = .03). Multifocal disease and a history of genital warts also correlated with VIN III recurrence (P = .03 for both)., Conclusion: A significant number of women diagnosed initially with VIN III on a vulvar biopsy harbored occult vulvar cancer. Recurrences were almost threefold higher when margins were positive for residual VIN III. We conclude that surgical resection is an appropriate method of treatment of VIN III for both diagnostic and therapeutic purposes.

From January 1993 through January 1996, 37 patients with unresectable squamous carcinoma of the cervix were entered on study and scheduled to receive oral isotretinoin 1 mg/kg per day with subcutaneous alpha interferon 6,000,000 units/day. A course was defined as 4 continuous weeks of therapy. The mean number of four-course cycles delivered was 1.8. One patient was ineligible because of wrong cell type and two were never treated. Thus, 34 patients were evaluable for toxicity. Eight patients were inevaluable for response. Five did not receive a complete 4-week course and three did not have additional tumor measurements; thus 26 were evaluable for response. Prior radiotherapy had been given to 25 patients and prior chemotherapy to 23 patients. There was no grade 4 neutropenia. The incidence of Gynecologic Oncology Group (GOG) grade 3 granulocytopenia and thrombocytopenia was 8.8% and 5.8%, respectively. Six patients (17.6%) developed grade 3 or worse nausea and vomiting. Four (11.7%) patients developed grade 3 neurologic symptoms. There were no complete responses and one partial response. The overall response rate was 3.8% (95% confidence interval, 0.1-19.6%). In this pretreated population, isotretinoin and alpha interferon in the dose and schedule employed exhibit minimal activity.

Background: Tumor hypoxia may be associated with treatment resistance, cell proliferation, and metastatic potential, which contribute to poor prognosis. Complementary techniques for detecting hypoxia, cell growth, and metastases are required to study these relationships., Objectives: The purpose of this study was to demonstrate the clinical feasibility of quantitative hypoxia detection with pimonidazole, a novel hypoxia marker, and to correlate hypoxia with S-phase markers of tumor proliferation., Methods: Pimonidazole binds to thiol-containing proteins specifically in hypoxic cells. Ten patients with cervical carcinoma received 0.5 g/m2 pimonidazole intravenously followed by biopsy of the cervical carcinoma the next day. Hypoxic cells were recognized by immunohistochemical detection of pimonidazole using a mouse monoclonal antibody. Cell proliferation was detected with a commercially available monoclonal antibody for proliferating cell nuclear antigen (PCNA). Assessment of hypoxia and cell proliferation was made qualitatively with light microscopy and quantitatively using point counting and image analysis software methods., Results: No clinical toxic effects were associated with pimonidazole administration. Immunostaining with pimonidazole antibody was observed in 9 of 10 tumors, suggesting that hypoxia is a common occurrence in cervical carcinoma. Quantitatively, tumors that had large numbers of hypoxic cells had the greatest percentage of S-phase cells, but some tumors with smaller amounts of hypoxia also had substantial numbers of S-phase cells., Conclusion: Pimonidazole can be used for qualitative and quantitative assessment of tumor hypoxia., (Copyright 1998 Academic Press.)

Hypoxia in human tumors is associated with poor prognosis, but the molecular mechanisms underlying this association are poorly understood. One possibility is that hypoxia is linked to malignant progression through vascular endothelial growth factor (VEGF) induction and the associated angiogenesis and metastasis. The present clinical study measures hypoxia and VEGF expression on a cell-by-cell basis in human squamous cell carcinomas to test the hypothesis that hypoxia and VEGF protein expression are coupled in human tumors. Eighteen patients with invasive squamous cell carcinoma of the uterine cervix and head and neck have been investigated by a quantitative image analysis of immunostained sections from their tumors. The hypoxia marker pimonidazole was used to measure tumor hypoxia, and a commercially available antibody was used to measure VEGF protein expression. A quantitative immunohistochemical comparison of hypoxia and VEGF protein expression revealed no correlation between the two factors.

Previous clinical investigations using interferons (IFNs) have shown activity against epithelial ovarian cancer. The objective of this study was to determine the maximum tolerated dose of intraperitoneal (ip) IFN-alpha 2b which could be administered in combination with intravenous (iv) cis-platinum plus cyclophosphamide chemotherapy. After comprehensive surgical staging and maximal cytoreduction, previously untreated patients with primary ovarian adenocarcinoma were entered at one of five IFN dose levels. IFN-alpha 2b (5-30 x 10(6) units) was administered ip on Day 1 (+/- Day 8). cis-Platinum (75 mg/m2) plus cyclophosphamide (750 mg/m2) were administered iv on Day 2 with prophylactic hydration and anti-emetics. Courses were repeated every 3 weeks for 8 cycles. Adverse effects were recorded using standard Gynecologic Oncology Group toxicity scales. Fifteen patients with mean age 56 years (range 43-73) were entered and received a combined total of 100 treatment cycles. Catheter-related complications occurred in 8 patients, and in three cases lead to catheter removal and discontinuation of ip therapy. Two patients experienced grade 2-3 nephrotoxicity and 1 experienced grade 2 peripheral neuropathy. There was a single episode of chemical peritonitis. Myelosuppression was the dose-limiting toxicity with grade 3-4 leukopenia complicating 6, 5, 12, 11, and 17 cycles at dose levels 1-5, respectively. No patient completed planned treatment without interruption or dose reduction. Planned cis-platinum dose intensity was most compromised at the fifth IFN-alpha 2b dose level. The maximum tolerated dose of IFN-alpha 2b was determined to be 20 x 10(6) units repeated on Days 1 and 8 of this 21-day cis-platinum plus cyclophosphamide chemotherapy cycle.

Objective: The purpose of this study was to determine and compare the expression of the alpha 2-, alpha 3-, alpha 4- and alpha 5-subunits of the beta 1-family of integrins in both the normal and the carcinomatous cervix., Study Design: A total of 22 solid tissue specimens (18 cancer and 4 normal) were analyzed immunohistochemically. The double-stain technique used an avidin-biotin complex kit to identify the various integrins and alkaline phosphatase-anti-alkaline phosphatase kit to identify the epithelial cells. Staining intensity, the main outcome measured, was graded as absent, weak, moderate, or strong. Statistical analysis was performed with the Wilcoxon rank sum test for nonparametric data., Results: The alpha 2- and alpha 3-integrins stained the normal cervix epithelium more intensely than the stroma (p = 0.03). The alpha 4- and alpha 5-integrins stained both the stroma and the normal epithelium similarly. The alpha 2-integrin was absent in the stroma of all 18 cancer specimens despite being present in the epithelial regions of 14 to 18 cancers. The alpha 3-integrin had a greater staining intensity in the stroma of the cancers than in the epithelial regions (p = 0.002). Both alpha 4- and alpha 5-integrins were absent in the epithelial regions of the cancers but present in the stroma., Conclusions: The distribution and intensity of integrin expression in cervical cancer differ from their expression in the normal cervix. In particular, the fibronectin receptors, alpha 4 and alpha 5, were absent in the epithelial regions of the cervical cancers, and alpha 3 also had diminished expression in the malignant epithelium. These changes correlate well with the changes expected in malignant transformation.

Carcinoma of the endometrium is the most common gynecologic malignancy, expected to account for 33,000 new cases and 6,000 deaths in 1995. Most endometrial cancers occur in postmenopausal women and produce abnormal vaginal bleeding. Some women exhibit the premalignant changes of atypical endometrial hyperplasia before developing an overt carcinoma. Identified epidemiologic risk factors include obesity, diabetes mellitus, use of unopposed exogenous estrogens, estrogen-secreting tumors, and a reproductive history characterized by prolonged estrogenic predominance. Diagnosis can be readily established by outpatient endometrial biopsy. Because clinical estimates of disease extent and spread are subject to substantial error, endometrial cancer is now a surgically staged neoplasm. A well-defined set of surgicopathologic risk factors have been incorporated into the staging scheme. Women with extrauterine disease comprise about 20% of cases and are at greatest risk for tumor recurrence and death from disease. Within the much larger group of women whose tumors are limited to the uterus, recurrence risk can be stratified by cytologic grade, cell type, depth of myometrial invasion, and extension to the cervix. About two-thirds of women have low-risk disease confined to the uterus when these criteria are employed, while the remaining one-third have high-risk subtypes. Recent areas of investigation have focused on molecular and genetic markers. Two clinical observations currently being examined are the poorer survival of Black women with uterine cancer and the apparent association of endometrial lesions with chronic tamoxifen suppression in women with breast carcinomas.

The Gynecologic Oncology Group (GOG), a program of ACOG, is one of 12 cooperative groups conducting clinical trials supported by the National Cancer Institute. Recently, an occurrence of research fraud was found in one of the other cooperative groups. The GOG maintains a quality assessment and assurance program that includes three primary functions: Original source documentation is examined to verify accuracy of treatment modalities, all protocols are regularly scrutinized for consistency and validity, and regular on-site audits are conducted at all institutions. The group endeavors to reassure physicians and their patients that research fraud is not rampant in the cooperative group system and that data published by the cooperative groups are reliable.

The purpose of this report was to review second-line hexamethylmelamine (HMM) chemotherapy of epithelial ovarian cancer to determine if HMM was active in cisplatin-resistant disease. Forty-four women with measurable disease received 100-300 mg/day HMM for 14 days, courses repeated every 4 weeks. There were 6 complete and 3 partial responses for an objective response rate of 20%. Among responding patients disease-free survival was 55% and overall survival was 88% at 3 years. Five of the 6 patients with a complete response remained disease-free at 10-117 months. Only 7/35 (20%) nonresponding patients were alive with mean follow-up of 16 months, and all had persistent cancer. Five women manifesting disease progression during cisplatin or carboplatin were subsequently treated with HMM, and none responded. Seventeen patients developing progressive cancer while receiving HMM were subsequently treated with cisplatin or carboplatin and objective responses occurred in 5 (29%). HMM was an active drug against epithelial ovarian cancer previously treated with cisplatin, but further study is needed to determine its activity against cisplatin-resistant ovarian cancer.

Purpose: Long-term follow-up data of a randomized trial that compared hydroxyurea and the hypoxic-cell radiosensitizer to misonidazole as adjuncts to standard radiation therapy in locally advanced carcinoma of the cervix are reported., Patients and Methods: Three hundred eight women were entered, and all 294 eligible patients are assessable as randomized. Eighty-one percent of patients have been monitored for 5 years or to death., Results: There was an advantage for hydroxyurea in progression-free interval and survival (P = .05 and P = .066, respectively). There was no significant difference in the distribution of sites of failure between the regimens. For the 39% of patients with stages III to IVA disease, the advantage in progression-free interval for hydroxyurea was significant (47.8% v 33.6%). More leukopenia occurred on the hydroxyurea regimen than on the misonidazole regimen., Conclusion: In summary, these data provide stronger evidence than our previous analysis that hydroxyurea is superior to misonidazole as an adjunct to radiation therapy. For patients with locally advanced carcinoma of the cervix, hydroxyurea continues to be the adjunct of choice with radiation.

Objective: The purpose of this study was to determine if computed tomography in cervical cancer staging resulted in treatment modifications leading to improved survival., Study Design: Medical records of 246 consecutive women treated over a 3-year period for primary cervical cancer were reviewed. Frequency of recurrence was the outcome measure of interest and subjected to chi 2 analysis., Results: Only eight patients had improved survival from treatment modifications based on computed tomography findings. Eight patients underwent additional surgical procedures because of computed tomography findings that proved to be erroneous., Conclusions: Considering the high cost and limited benefit, computed tomography for cervical cancer staging is not recommended.

The purpose of this study was to determine the activity and toxicity of hexamethylmelamine chemotherapy in patients with persistent or recurrent epithelial ovarian cancer. Forty-nine women received hexamethylmelamine 100 to 150 mg/day for 14 days, repeated at 4-week intervals. All patients had previously received at least one chemotherapy regimen, and 46 (94%) had received cisplatin. Among 25 patients with clinically measurable disease there were three complete and two partial responses, for an objective response rate of 20%. The mean progression-free interval for responders was 38.6 months versus 9.6 months for nonresponders or patients with nonmeasurable disease (p less than 0.001). Thirteen patients are alive, eight with no clinical evidence for disease. Only four patients discontinued therapy because of toxic reactions. Hexamethylmelamine appears to be a well-tolerated drug with activity against ovarian cancer previously treated with cisplatin.

Amplification of the c-erbB-2 protooncogene has been associated with a poor prognosis in human breast and ovarian cancers. Our study was undertaken to examine whether amplification, rearrangement, or overexpression of c-erbB-2 and other protooncogenes was frequently observed in epithelial ovarian cancers. c-erbB-2 was expressed in 87% of 22 ovarian cancers analyzed, but expression was significantly increased in only one of the 22 tumor specimens. In this case elevated c-erbB-2 expression was associated with dramatic amplification of the gene. In another tumor a 3.8 kb EcoRI fragment was found, in addition to the usual 4.4 and 6.0 kb fragments; this is consistent with a possible gene rearrangement or a restriction fragment length polymorphism. To place these results in perspective, expression of several other protooncogenes has been examined in ovarian carcinomas. The c-fos, c-myc, n-myc, c-fms, and c-Ha-ras protooncogenes were expressed in different fractions of tumors, but expression of l-myc, c-erbB, c-myb, c-sis, and c-mos was not detectable. Aside from c-erbB-2, neither amplification nor rearrangement was observed among the other protooncogenes studied. Expression of c-erbB-2, c-fms, c-myc, n-myc, c-fos, and c-Ha-ras deserves further evaluation as a prognostic factor in ovarian cancer.

The cytokine interleukin-1 (IL-1) can inhibit growth of breast cancer cells in culture and promote cellular differentiation in synergism with other growth factors. A secreted IL-1 receptor antagonist (sIL-1ra) has been described and an intracellular version (icIL-1ra) has been cloned; both antagonists block IL-1-dependent responses. We compared mRNA expression of IL-1 and both receptor antagonists in normal and neoplastic endometrium. RNA was extracted from five benign endometrial and five endometrial cancer whole-tissue specimens, reverse transcribed into cDNA, then amplified by polymerase chain reaction using specific primers for IL-1 alpha, IL-1 beta, sIL-1ra, and icIL-1ra. IL-1 alpha and IL-1 beta were expressed in variable amounts in all tissues; there was no difference in expression between normal and cancer specimens. In contrast, high levels of icIL-1ra were expressed in four of five cancer specimens compared with none of five normal tissues (P = 0.02). There was no expression of sIL-1ra in cancer and normal tissues. These preliminary experiments suggest that IL-1 is ubiquitously expressed in endometrial tissues whereas endometrial cancer preferentially expresses icIL-1ra. IcIL-1ra may regulate IL-1-mediated events such as growth and differentiation in endometrial neoplasia.

Two women presenting with invasive squamous cell cancer of the vulva during pregnancy are reported. The first patient was successfully treated by radical vulvectomy 2 weeks after cesarean section delivery; the second patient died of disseminated cancer despite radical vulvectomy and postoperative radiation therapy. In the second case the diagnosis was not established until 3 months after delivery. Only 12 cases of invasive squamous cell vulvar cancer during pregnancy have been previously reported. Liberal use of punch biopsy for any suspicious vulvar lesions is mandatory to enhance the potential for early diagnosis and successful treatment.

Epithelial ovarian cancers with aneuploid DNA content are associated with a poorer clinical course than diploid tumors. Flow cytometric analysis may further categorize aneuploid tumors based on the relative expression of cell surface histocompatibility (HLA) antigens. Surgical specimens from 20 patients with aneuploid tumors were stained using an indirect immunofluorescence method with primary murine monoclonal antibodies W36/22 (class I HLA surface antigens) and L5.1 (irrelevant antibody), counterstained with propidium iodide (DNA stain), and analyzed with the flow cytometer using a computer program to correct staining intensity for cell size. Patients with high or low class I expression were similar with respect to age, stage, histology, grade, and residual disease following surgical debulking; all patients were treated with cisplatin-based chemotherapy. Women with low class I HLA antigen expression had higher progression rates and death rates than patients with high class I HLA expression. Low class I HLA antigen expression is a poor prognostic factor among patients with aneuploid ovarian cancers.

Class I antigen expression by ovarian epithelial neoplasms was determined by flow cytometric analysis and an immunoperoxidase technique for each specimen. The numbers of class I positive tumors determined by the methods were compared. The more subjective immunohistochemical analysis and the more objective flow cytometric technique revealed similar results as long as strict criteria for the interpretation of results was applied. Most of the tumor specimens revealed a homogeneous Gaussian distribution of green fluorescence, class I antigen expression, by flow cytometry. There were two specimens that exhibited a less than characteristic type of membrane staining. The antigen-antibody reaction product was expressed in the extracellular matrix, as well as on the cell membrane of certain cells. This may represent a defect in antigen expression and, if so, might alter the immune response to these tumors.

Two cases of 5-fluorouracil-induced neurotoxicity from the University of North Carolina are presented. 5-Fluorouracil metabolism is briefly discussed with reference to possible mechanisms for the neurotoxicity. A possible role for thiamine supplementation in the prevention of this unusual complication is supported by our experience.

Clinical stage and pathological characteristics of endometrial cancer cases were related to several aspects of estrogen prescribing. In comparing 256 cases with 321 community control subjects, estrogen use of less than 3 1/2 years' duration did not increase the risk of endometrial cancer for any stage, grade, histological type, or extent of ivasion. With long-term estrogen use (3 1/2 years or more), relative risks were significantly increased (5.2 to 7.6) for the early cancers--those clinically stage IA, histologically grade 1, and invading the endometrium only. These increases were seen with both high-dose (greater than 0.625 mg) and low-dose (less than or equal to 0.625 mg) preparations. Risks were only minimally increased for the more advanced cancers. However, long-duration estrogen use did produce an increased risk of advanced cancer when administration was continuous rather than cyclic.

Thirty-three institutions collaborating in the Gynecologic Oncology Group gathered surgical and pathological data on 1125 patients with primary, previously untreated, histologically confirmed stage I cervical carcinoma with more than 3 mm of invasion who were selected to undergo radical hysterectomy and paraaortic and pelvic lymphadenectomy. Of the 940 eligible, evaluable patients, 732 had squamous carcinoma. Of the study group, 87 (12%) did not undergo radical hysterectomy because of gross disease beyond the uterus or microscopic aortic node involvement documented at exploratory laparotomy. Among the 645 patients undergoing pelvic and paraaortic lymphadenectomy and radical hysterectomy, five risk factors were significantly associated with microscopic pelvic lymph node metastasis: depth of invasion (P = 0.0001), parametrial involvement (P = 0.0001), capillary-lymphatic space invasion (P = 0.0001), tumor grade (P = 0.01), and gross versus occult primary tumor (P = 0.009). The factors identified as independent risk factors for pelvic lymph node metastasis by multivariate analysis were capillary-lymphatic space involvement (P less than 0.0001), depth of invasion (P less than 0.0001), parametrial involvement (P = 0.0005), and age (P = 0.02). The model was used to predict the chance of a patient having nodal metastasis for any combination of risk factors.

Endolymphatic stromal myosis is a neoplasm derived from the endometrial stromal cell. As such it should respond to hormonal manipulation. Reported are positive estrogen and progesterone cytosol receptors in three cases of endolymphatic stromal myosis with disease regression following progestational therapy. Estrogen and progesterone receptor studies are recommended in all cases of endolymphatic stromal myosis. When positive, progestational therapy is appropriate.

In this study, 331 patients with advanced or recurrent squamous cell carcinoma of the cervix no longer amenable to control with surgery or radiotherapy were randomized to receive cisplatin 50 mg/m2 as either a continuous infusion over 24 hr or a more rapid infusion at a rate of 1 mg/min. Antiemetic therapy was standardized for the initial course of both regimens as metoclopramide 60 mg at the time of and at 3 and 6 hours after initiation of cisplatin. The overall frequency of objective regression of disease was 18%; the response rate in each regimen was essentially identical. The continuous infusion regimen was associated with a significantly greater percentage of patients who experienced no nausea and vomiting (34% versus 18%, P = 0.002). Other adverse effects included nephrotoxicity, peripheral neuropathy, myelosuppression, and ototoxicity. Both the frequency and severity of these were essentially the same for each regimen.

An analysis of 41 patients with histologically documented Stage II adenocarcinoma of the endometrium treated between 1969 and 1974 is presented. The 3-year survival for all patients was 46%. Patients treated with radiation therapy alone (tandem, ovoids, and external radiation therapy) had 29% survival while patients treated with radiation therapy and surgery had a 71% survival. For all patients, survival by grade was 80% (Grade I), 36% (Grade II), and 20% (Grade III). Among those patients with recurrent disease, 40% of cases were in the pelvis while 20% were isolated distal recurrences. Patients with stromal invasion of the cervix had a 30% survival while patients without stromal invasion had a 67% survival. An analysis of these data, along with a review of the literature, reveals that 1) hysterectomy plays a critical role in survival, 2) invasion of the cervical stroma would appear to be a requisite criteria for the establishment of Stage II disease, and 3) aggressive radiation therapy with uterine packings (Heyman capsules) should be attempted in those patients who are not surgical candidates.

Among 199 women from 12 to 30 years of age who had been exposed to DES in utero, the colposcopic evaluation of the vagina and cervix was considered normal for only 13.6%. The incidence of colposcopically detected lesions was not related to the trimester of DES exposure, the patient's age, use of oral contraceptives, or presenting symptoms. Areas of punctation, mosaic patterns, white epithelium, and keratosis were not considered areas of adenosis. Cervical bands, hoods, cock's combs, etc., were considered as part of the cervix. Under this definition adenosis of the vagina was diagnosed in only 14.1% of the patients. Eight (4.0%) women were found to have cervical intraepithelial neoplasia (CIN), Grade 3 lesions, and an additional 36 (14.1%) women were found to have CIN, Grade 1 lesions based on the light microscopy evaluation of directed biopsies. There were no cases of clear cell adenocarcinoma. It appears that women with in utero DES exposure may be at a higher risk of developing squamous neoplasia compared with non-DES-exposed women.

Cervical intraepithelial neoplasia (CIN) is so rampant that simpler, effective, and less costly methods of therapy are being evaluated to replace the aggressive surgical therapeutic measures of the past. Cryosurgery is one alternative method. A review is presented of 152 patients in the childbearing age group with biopsy confirmation of CIN II (moderate dysplasia) and CIN III (severe dysplasia and carcinoma in situ). The persistence of CIN 3 months after therapy was deemed a treatment failure. Initial failure rates (24.2% for CIN II and 31.6% for CIN III) were high by this stringent definition. However, follow-up smears, further treatment, and a review of the literature definition of "treatment failure" lowered the failure rate to acceptable levels such that cryosurgery should be utilized in the therapy of cervical intraepithelial neoplasia.

To assess the morbidity of lymph node sampling, medical records were reviewed for all patients with cancers of the uterine corpus and cervix who underwent primary surgical therapy between January 1, 1980 and December 31, 1986. Five hundred fifty-four patients were identified. Of the 292 patients with corpus cancer undergoing total abdominal hysterectomy, lymph node sampling was performed in 65.4%. Operative blood loss, transfusion requirements, and length of hospital stay were not increased significantly (P greater than .05) in women having node sampling. Of the 262 patients with cervical cancer, 72 underwent abdominal hysterectomy, 111 underwent radical hysterectomy, and 79 underwent staging laparotomy, with lymph node sampling performed in 82, 100, and 92% of these groups, respectively. The incidence of perioperative complications in this group was similar to that in the corpus cancer group. Vascular injuries, hematomas, and lymphocysts were more frequent after lymph node sampling. One postoperative death was attributed to complications from node sampling, but there were no other long-term sequelae. The low overall risk associated with lymph node sampling supports its inclusion in the surgical evaluation of gynecologic malignancies.