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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 1,166 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. [Copyright &y& Elsevier]

: ObjectiveTo 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.: MethodsA total of 256 eligible patients with exophytic or “barrel” shaped tumors measuring ≥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 ≥7 cm.: ResultsTumor 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).: ConclusionOverall, 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). [Copyright &y& Elsevier]

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. [Copyright &y& Elsevier]

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.

Introduction: Primary malignant lesions of the vagina represent less than 2% of all gynecologic malignancies. Primary vaginal sarcomas account for about 2% of all malignant vaginal lesions, with leiomyosarcoma being the most common vaginal sarcoma found in adult women., Case: We report a case of primary vaginal leiomyosarcoma occurring in the field of a prior tension-free vaginal tape (TVT) procedure using a Bard Duraderm allograft., Conclusion: This report represents the first report, to our knowledge, of a vaginal sarcoma arising in the field of a Bard Duraderm TVT allograft. Although the product is no longer available for this use, the ongoing studies of the TVT procedure and outcomes should include this potential complication in their review.

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: 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.)

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.)

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.

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.

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.

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.