A randomized comparative trial of carboplatin and iproplatin in advanced squamous carcinoma of the uterine cervix: a Gynecologic Oncology Group study.

A total of 394 patients with advanced, measurable squamous carcinoma of the uterine cervix and no prior chemotherapy were randomized to therapy with either carboplatin or iproplatin. There were 23 patients ineligible for the study and 10 patients who were not evaluable; the remaining 361 patients were evaluable for response and adverse effects. Randomization was well balanced for age, performance status, and prior therapy. Both platinum analogs were given every 28 days with starting doses of 400 mg/m2 for carboplatin (340 mg/m2 if the patient underwent prior radiation) and 270 mg/m2 for iproplatin (230 mg/m2 if the patient underwent prior radiation). These doses are equivalent to cisplatin doses of 75 to 100 mg/m2. Hematologic toxicity was dose-limiting, among which thrombocytopenia was slightly more common than leukopenia. Gastrointestinal toxicity was also prominent with both agents; however, iproplatin was significantly more toxic than carboplatin (P less than .001). Renal, otic, and peripheral nervous system toxicities were absent or infrequent with both analogs. No electrolyte abnormalities were observed. The percentage of planned dosages that were actually administered was 100% of carboplatin doses and 85% of iproplatin doses (P less than .0001). The reduction in iproplatin dose was apparently due to gastrointestinal toxicity. Response rates were similar for both agents (15% for carboplatin, 11% for iproplatin) and appear to be inferior to those noted with the parent compound, cisplatin.

Women with preeclampsia have higher plasma endothelin levels than women with normal pregnancies.

Endothelin, a newly discovered endothelium-derived peptide, has potent vasoactive properties in vivo and in vitro. The actions of endothelin in clinical conditions of hypertension have not yet been defined. This study examined the possible role of endothelin in the vasospasm and hypertension associated with a well-defined syndrome of gestational hypertension, preeclampsia. Our results indicate that the concentration of immunoreactive endothelin is elevated significantly in plasma obtained from women with preeclampsia and rapidly returns to a normal pregnancy value within 48 hours of delivery, as predicted by the prompt clinical resolution of this disorder. The findings suggest that endothelin may contribute to the vasospasm associated with this syndrome and lend further support to the involvement of endothelial cells in the pathophysiology of preeclampsia.

Susceptibility of B-cell lymphoma to human antibodies encoded by the V4-34 gene.

Our previous studies have shown that mAbs derived from the human V4-34 gene bind and kill human B-lymphocytes via membrane disruption. This study demonstrates the cytotoxicity of two V4-34 encoded mAbs, 216 and Z2D2, towards human B-cell lymphoma. In vitro, 216 and Z2D2 are cytotoxic to a variety of B-cell lymphomas obtained from patient biopsies. In vivo, increased survival was observed with both mAbs in a lymphoma model developed in scid mice with human B-cell line Nalm-6. Studies in mice show that these mAbs are well tolerated with minimum side effects. Since 216 and Z2D2 show increased toxicity towards cycling cells, V4-34 mAb-based therapy can be additive with drugs that block cell-cycle progression. Stem cells that are V4-34 mAb ligand negative would not be depleted. Together, these studies recommend an evaluation of the two completely human mAbs in a phase I trial for B-cell lymphoma.

Generation of human monoclonal antibodies to cancer-associated antigens using limited numbers of patient lymphocytes.

A limiting dilution method for the efficient transformation by Epstein-Barr virus (EBV) of human B lymphocytes has been applied to the production of human monoclonal antibodies to ovarian cancer-associated antigens. Limited numbers (e.g., 2 X 10(5)) of EBV-infected B lymphocytes from ovarian cancer patient spleen, lymph node, tumor, ascites and blood were successfully transformed using this method. An immunofiltration assay system was employed to identify EBV transformants secreting IgM antibody which reacted selectively with ovarian cancer patient ascites tumor cells, but not with a mixture of normal cell types. A miniature Western blot assay was utilized to screen for IgG reactivity to protein species in detergent extracts of ovarian cancer tumor cells. EBV-transformed cells selected after screening were then fused with heteromyeloma fusion partner SHM-D33 resulting in efficient recovery of hybridomas secreting MAb of the desired specificity. Human MAbs which selectively react with antigens associated with ovarian cancer tumor cells were obtained.

One-step enrichment of nucleated red blood cells. A potential application in perinatal diagnosis.

We describe a discontinuous triple density gradient to obtain a 25-fold enrichment of nucleated red blood cells from mononuclear cells, granulocytes, and mature red blood cells in a single centrifugation step.

Treatment of high-risk uterine cancer with whole abdominopelvic radiation therapy.

PURPOSE: To evaluate the treatment outcomes in patients with optimally debulked Stage III and IV endometrial adenocarcinoma (ACA) or Stages I-IV uterine papillary serous (UPSC) or clear cell (CCC) carcinoma of the uterus, treated postoperatively with whole abdominopelvic irradiation (WAPI). METHODS AND MATERIALS: Between 1979 and 1998, 48 patients received postoperative WAPI at our institution. Twenty-two patients had FIGO Stage III or Stage IV ACA and 26 patients had FIGO Stages I-IV UPSC or CCC. The median dose was 30 Gy to the upper abdomen and 49.8 Gy to the pelvis. Mean follow-up was 37 months (2.4-135 months). RESULTS: The 3-year estimated disease-free survival (DFS) and overall survival (OS) rates for the entire group were 60% and 77%, respectively. Patients with ACA had 3-year DFS and OS of 79% and 89%, respectively, compared with 47% and 68% in the UPSC/CCC group. Early-stage patients (I and II) with UPSC/CCC had 3-year DFS and OS of 87% compared with 32% and 61% in those with advanced (Stage III and IV) disease. The 3-year actuarial major complication rate was 7%, with no treatment-related deaths. All 4 failures in the ACA group were extra-abdominal and 6 of the 11 in the UPSC/CCC group had an extra-abdominal component. Age and UPSC/CCC histology were significant prognostic factors for DFS and OS. In addition, stage and number of extrauterine sites of disease were significant predictors for DFS in UPSC/CCC. CONCLUSION: WAPI is a safe, effective treatment for patients with optimally debulked advanced-stage uterine ACA or early-stage UPSC/CCC. Survival was significantly worse in advanced-stage UPSC/CCC patients. We recommend future trials of WAPI with concurrent, or subsequent systemic therapy in patients with advanced-stage UPSC or CCC.

FACS analysis of peritoneal lymphocytes in ovarian cancer and control patients.

In this study different lymphocyte populations in the malignant ascites of 10 patients with ovarian carcinoma and in the peritoneal fluid of 8 control patients (tubal ligation and benign conditions) were analyzed. A panel of monoclonal antibodies against the CD markers of lymphocytes was used to stain different populations and the cells were analyzed on a FACS II (fluorescence-activated cell sorter). The mean percentage of B lymphocytes in the peritoneal cavity of the OVCA patients was 0.18 +/- 0.5% and in the control patients 0.05 +/- 0.07%. There was no significant difference between the two groups. In the OVCA group and in the controls the percentage of T lymphocytes (CD5+) was 23.5% and 17.1% respectively with no significant difference between the groups. These results indicate that B lymphocytes are not present in the human peritoneal cavity. The small numbers of B cells found in this study could be due to contamination with peripheral blood. The human peritoneal cavity contains a cell population which differs from that present in peripheral blood. Significant numbers of B lymphocytes have been reported in the peritoneal cavity of mice. The difference between the lymphocyte population of the human peritoneal cavity and that of rodents implies that data on characterization and function of B lymphocytes in the mouse peritoneal cavity would not be applicable to humans.

Human CD5+ B lymphocytes (B-1 cells) decrease in peripheral blood during pregnancy.

Pregnancy is a unique immunologic state where a natural homeostasis exists between antigenically different tissues. Several earlier studies have addressed the fluctuations in the number and/or function of lymphocytes, including B cells during pregnancy, but changes within the subsets of B lymphocytes, conventional (CD5-) and B-1 (CD5+), have not been addressed. Here we demonstrate that the frequency of B-1 cells decreases dramatically during pregnancy, whereas the frequency of conventional B cells remains relatively constant. The missing B-1 cells return to pre-pregnancy levels 8-10 weeks after parturition. The polyreactive autoantibodies secreted by B-1 cells have been implicated in autoimmunity and immune regulation. The possible role of B-1 cells during pregnancy will be discussed in that context.

Modified posterior exenteration for ovarian cancer.

The operative description of a modified posterior exenteration along with operative findings, other operative procedures, postoperative course, and follow-up information are presented for 47 patients (37 primary cytoreduction, ten secondary cytoreduction). All had stage IIIC or IV epithelial ovarian cancer with pelvic disease encasing the reproductive organs, pelvic peritoneum, cul-de-sac, and sigmoid colon. In addition to modified posterior exenteration, all patients had multiple other procedures performed as part of the cytoreductive efforts. Forty-five (95.7%) had optimal (less than 2 cm) cytoreduction and 18 (38.3%) had complete cytoreductive surgery. Thirty-four patients were ultimately rendered continent of feces (25 primarily and nine after colostomy reversal). Nine patients (19.1%) had serious morbidity and one (2.1%) died postoperatively. The median follow-up for those undergoing primary cytoreduction was 13.3 months (6-84). Nineteen (51.4%) were alive at the time of writing, 16 (43.2%) were dead, and two (5.4%) were lost to follow-up. Modified posterior exenteration effectively removes all visible pelvic disease with acceptable mortality. Hence, even patients with the most advanced cases of ovarian cancer may attain optimal cytoreduction and become ideal candidates for adjunctive therapy, with improved survival or a chance for cure.

Clinical practice guidelines in the management of gynecologic malignancies.

The need for guidelines in managing gynecologic cancer is addressed in the first part of this article. Second, the guideline development process that enables the practitioner to judge the validity and usefulness of proffered guidelines is detailed. An important element in this discussion is an exploration of the shortcomings, either real or perceived, of the process. The last section focuses on issues relating to the implementation of guidelines and some of the obstacles that one may encounter as the programs evolve.

Malignant granular cell tumor of the vulva in a 17-year-old: Case report and literature review.

Granular cell tumors are uncommon soft tissue tumors. Although the majority of these tumors are benign, a rare malignant variant exists which is aggressive, with local recurrence rates up to 70% and 3-year survival rates of less than 50%. We present a case of malignant granular cell tumor of the vulva in a 17-year-old, the sixth such case to be reported at this site. She was treated with a left hemivulvectomy and ipsilateral groin node dissection followed by postoperative radiation therapy. She remains free of disease at 16 months. Patients with malignant granular cell tumor or granular cell tumor of malignant potential are best managed with wide local excision and regional lymph node dissection.

Primary leiomyosarcoma of the vagina. A case report and literature review.

Primary vaginal leiomyosarcoma is a rare tumor. We report a unique case of a 27-year-old woman with stage I, high-grade primary leiomyosarcoma of the vagina treated with surgical resection and adjuvant radiation therapy. She returned within 6 months with an abdominal-pelvic recurrence and lung metastases. The patient died of disease 9 months after diagnosis. A comprehensive review of primary vaginal leiomyosarcoma was performed and factors affecting survival were analyzed. A Medline search of the English-language literature revealed 66 previously reported cases. Forty-eight of these had follow-up data. Survival probabilities were calculated using the Kaplan-Meier method, and the effects of age, stage, grade, tumor location, and treatment modality were analyzed. Stage III and IV data were combined. The overall 5-year survival rate was 43%. Patients more than 50 years of age had a 5-year survival rate of 26% compared with 51% for those less than 40 years. Five-year survival for stage I and II tumors was 55% and 44%, respectively. Patients with stage III/IV disease had 25% survival at 18 months. No patient treated primarily with chemotherapy or radiation therapy survived beyond 36 months. In contrast, patients treated primarily with surgery had a 5-year survival rate of 57%. Only stage remained an independent predictor of survival on Cox regression analysis. We continue to recommend surgical resection as primary treatment. Exenteration may be an option for select patients, but ultimately management should continue on a case-by-case basis.

Heavy chain variable gene usage by human B-1 lymphocytes and polyreactive autoantibodies.

To evaluate the role of B-1 cells and polyreactive autoantibodies in the development of adult immune repertoire, it is necessary to assess their immunoglobulin heavy chain variable-gene usage. We thus screened 28 independently derived human polyreactive MAbs from fetal and adult splenic B lymphocytes for their VH-region usage. We demonstrate that the polyreactivity of the IgM antibodies secreted by B-1 cells is not the result of the expression of particular variable region gene families. All six VH families are represented roughly in proportion to their estimated family size. Furthermore, the representation of the six families appears similar in polyreactive MAbs derived from fetal or adult lymphocytes.

Gynecologic factors in sexual dysfunction of the older woman.

Older women may experience sexual dysfunction due to many different causes. Some problems related to menopausal hormonal change may be easily treated with estrogen supplements. Other problems involve intricate interpersonal relations between the woman and her sexual partner and may require a combination of medical therapy and sexual counseling. Gynecologic cancer and cancer treatments are often accompanied by problems in sexual functioning. These problems may then impair relations and self-image, leading to a vicious circle of deteriorating social function. Some recommendations for the clinician follow. The clinician should maintain an attitude of openness to the possibility of sexual concerns in older women. Such concerns should be taken seriously and should not be dismissed as part of aging. Routine periodic health examinations can include a question such as "Do you have any concerns about your sexual life that you would like to discuss?" In follow-up visits for procedures with a high likelihood of causing sexual dysfunction, questions that would open the door to a discussion of sexuality should be asked. Sexual dysfunction should be recognized as a couple-oriented phenomenon. A woman's anxiety about her appearance, postoperative depression, or dyspareunia may be perceived by her partner as a sexual rejection and may initiate a cycle of decreasing contact or may even lead to erectile dysfunction. Sexual counseling should include both partners. When a surgical procedure that will probably have an impact on sexual function is contemplated, provide the patient and her partner with advance counseling. Descriptions of surgery should not be simply a statement of body parts to be removed but should specifically address the anticipated sexual effects. Counseling should include a description of basic anatomy and function of the genital organs. Illustrations and appropriate demonstration during the physical examination should be used to ensure the patient's understanding. Descriptions should be accurate without being either frightening or falsely reassuring. The patient should be counseled about the benefits of including her partner in discussions. Then, when possible, the sexual partner of the patient should be invited to sessions of advance counseling on contemplated procedures. Clinicians should remain open to the possibility that the sexual partner will be a nontraditional one, e.g., an unmarried male partner or another woman. The clinician should be alert to remediable causes of dysfunction. For example, decreased vaginal lubrication may be managed with use of water-soluble lubricants.(ABSTRACT TRUNCATED AT 400 WORDS)

Differential expression of CD40 and CD95 in ovarian carcinoma.

PURPOSE: The role of CD95 (Fas) as a mediator of apoptosis has been well documented. CD40 ligation has been recently shown to initiate apoptosis and modulate CD95 mediated apoptosis in normal and some neoplastic tissues. Here we report the expression of CD95 and CD40 in cryopreserved cell suspensions from ovarian cancer associated ascites, fresh primary and recurrent ovarian carcinoma (OVCA) specimens, and ten established ovarian cancer cell lines. The effect of CD95 and CD40 receptor binding on apoptosis is described in two cell lines. EXPERIMENTAL DESIGN: Ascites specimens, fresh primary and recurrent OVCA specimens were dissociated to single cell suspensions. Expression of CD95 and CD40 was analyzed using flow cytometry. Apoptosis was determined via annexin uptake by flow cytometry following incubation with anti-CD95 antibody, CH11 and trimeric CD40L. RESULTS: Ascites showed the highest expression of both CD95 and CD40. Recurrent OVCA, in contrast, expressed low levels of CD95 and CD40. Primary OVCA showed moderate expression of both receptors. CD40 expression in ascites was significantly greater when compared to solid specimens (p < 0.05). Both CD40 and CD95 were strongly expressed in eight of ten cell lines studied. Binding of CD40L did not influence CD95 mediated apoptosis. CONCLUSIONS: CD40 is ubiquitously expressed in ovarian carcinomas and expression differs between ascites and solid tumor. There may be differential expression of both CD40 and CD95 in recurrent vs primary ovarian carcinoma, which may contribute to increased clinical malignancy of recurrent disease. In contrast to other epithelial malignancies, CD40 ligation does not appear to modulate CD95 mediated apoptosis.

The potential therapeutic role of lymph node resection in epithelial ovarian cancer: a study of 13918 patients.

The aim of the study is to determine the role of lymphadenectomy in advanced epithelial ovarian cancer. The data were obtained from the Surveillance, Epidemiology and End Results (SEER) program reported between 1988 and 2001. Kaplan-Meier estimates and Cox proportional hazards regression models were used for analysis. Of 13 918 women with stage III-IV epithelial ovarian cancer (median age: 64 years), 87.9% were Caucasian, 5.6% African Americans, and 4.4% Asians. A total of 4260 (30.6%) underwent lymph node dissections with a median number of six nodes reported. For all patients, a more extensive lymph node dissection (0, 1, 2-5, 6-10, 11-20, and >20 nodes) was associated with an improved 5-year disease-specific survival of 26.1, 35.2, 42.6, 48.4, 47.5, and 47.8%, respectively (P<0.001). Of the stage IIIC patients with nodal metastases, the extent of nodal resection (1, 2-5, 6-10, 11-20, and >20 nodes) was associated with improved survivals of 36.9, 45.0, 47.8, 48.7, and 51.1%, respectively (P=0.023). On multivariate analysis, the extent of lymph node dissection and number of positive nodes were significant independent prognosticators after adjusting for age, year at diagnosis, stage, and grade of disease. The extent of lymphadenectomy is associated with an improved disease-specific survival of women with advanced epithelial ovarian cancer.

Ovarian cancer in younger vs older women: a population-based analysis.

To compare the clinico-pathologic prognostic factors and survival of younger vs older women diagnosed with epithelial ovarian cancer. Demographic, clinico-pathologic, treatment, and surgery information were obtained from patients with ovarian cancer from the Surveillance, Epidemiology, and End Results Program from 1988 to 2001 and analysed using Kaplan-Meier estimates. Of 28 165 patients, 400 were <30 years (very young), 11 601 were 30-60 (young), and 16 164 were >60 (older) years of age. Of the very young, young, and older patients, 261 (65.3%), 4664 (40.2%), and 3643 (22.5%) had stage I-II disease, respectively (P<0.001). Across all stages, very young women had a significant survival advantage over the young and older groups with 5-year disease-specific survival estimates at 78.8% vs 58.8 and 35.3%, respectively (P<0.001). This survival difference between the age groups persists even after adjusting for race, stage, grade, and surgical treatment. Reproductive age (16-40 years) women with stage I-II epithelial ovarian cancer who received uterine-sparing procedures had similar survivals compared to those who underwent standard surgery (93.3% vs 91.5%, P=0.26). Younger women with epithelial ovarian cancer have a survival advantage compared to older patients.

Uterine papillary serous and clear cell carcinomas predict for poorer survival compared to grade 3 endometrioid corpus cancers.

To compare the survival of women with uterine papillary serous carcinoma (UPSC) and clear cell carcinoma (CC) to those with grade 3 endometrioid uterine carcinoma (G3EC). Demographic, pathologic, treatment, and survival information were obtained from the Surveillance, Epidemiology, and End Results Program from 1988 to 2001. Data were analysed using Kaplan-Meier and Cox proportional hazards regression methods. Of 4180 women, 1473 had UPSC, 391 had CC, and 2316 had G3EC cancers. Uterine papillary serous carcinoma and CC patients were older (median age: 70 years and 68 vs 66 years, respectively; P<0.0001) and more likely to be black compared to G3EC (15 and 12% vs 7%; P<0.0001). A higher proportion of UPSC and CC patients had stage III-IV disease compared to G3EC patients (52 and 36% vs 29%; P<0.0001). Uterine papillary serous carcinoma, CC and G3EC patients represent 10, 3, and 15% of endometrial cancers but account for 39, 8, and 27% of cancer deaths, respectively. The 5-year disease-specific survivals for women with UPSC, CC and G3EC were 55, 68, and 77%, respectively (P<0.0001). The survival differences between UPSC, CC and G3EC persist after controlling for stage I-II (74, 82, and 86%; P<0.0001) and stage III-IV disease (33, 40, and 54; P<0.0001). On multivariate analysis, more favourable histology (G3EC), younger age, and earlier stage were independent predictors of improved survival. Women with UPSC and CC of the uterus have a significantly poorer prognosis compared to those with G3EC. These findings should be considered in the counselling, treating and designing of future trials for these high-risk patients.

Clinical applications of monoclonal antibodies in gynecologic oncology.

The advances of both murine and human monoclonal antibody (MoAb) technology have allowed the development of several antibodies against gynecologic tumors. The goals are to produce effective and specific reagents for both immunodiagnosis and therapy. However, despite an extensive research effort, a clear demonstration of specific cancer-associated antigens in gynecologic malignancies, or of specific immune responses to such antigens has been elusive. Currently, most antibodies found are cross reactive with either oncofetal antigens or some normal adult tissues. Clinical usefulness of these MoAbs as a screening test in radioimaging or in immunotherapy remains to be proven. However, the use of MoAb technology in defined antigens/tumor markers such as beta-human chorionic gonadotropin, and alpha fetal proteins has provided convenient, reproducible and highly specific reagents. More recently, promising antibodies have been shown to detect tumor antigens in serum of patients with ovarian cancer.