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Cervical cancer is a leading cause of cancer deaths in women worldwide. Because of its association with human papilloma virus infection, as well as the ability to screen for premalignant stages of the disease, it is now largely a preventable disease. This article describes the molecular basis for cervical cancer, and presents a clinical overview of current treatment approaches and technological advances, emphasizing the unique aspects of this viral disease as it relates to the immune system and vaccination or other immunotherapeutic strategies. [ABSTRACT FROM AUTHOR]

Objectives: To describe the gastrointestinal (GI) complications associated with the Miami Pouch (MP), a continent ileocolonic urinary reservoir., Methods: A retrospective chart review of patients who underwent a MP from 1988 to 1997 at the University of Miami, School of Medicine, was employed. Data was analyzed in terms of early and late (beyond 6 weeks) GI complications resulting directly from the operation., Results: Seventy-seven patients underwent a MP, a form of continent urinary diversion. Seventy-two patients (93.5%) were previously radiated. The perioperative mortality rate was 11.7%. Twenty (26%) patients developed a GI complication (17 late and 3 early), and 5 (6.5%) were directly as a result of the MP. Twelve recto-vaginal and 1 recto-neo-vaginal fistulas were identified. All but one was considered as late. Three (3.9%) patients developed colo-MP fistulas (3, 5, and 14 months). All three patients failed conservative management and required reoperation. Two patients developed enterocutaneous fistulas (3 and 5 months). One patient developed breakdown of the ileotransverse colon anastomosis on postoperative day 12 and required reoperation with bowel resection and an ileostomy. She expired from intraabdominal sepsis. Finally, 1 patient developed short bowel syndrome secondary to an expanding hematoma in the small bowel mesentery., Conclusions: . The GI complication rate attributed directly to the MP is low (6.5%). Prompt recognition is the key to successful management of these complications. The majority of these complications are considered as late and do not occur in the immediate postoperative period. Conservative management of GI-MP fistulas is not successful and necessitates reoperation.

Objective: The objective was to evaluate the role of human papillomavirus (HPV) in the pathogenesis of papillary squamous cell carcinoma (PSCC) of the cervix and to determine cell proliferative activity and p53 abnormalities in these rare variants of cervical cancer., Methods: Twelve examples of PSCC of the cervix were diagnosed between 1990 and 1999. Formalin-fixed paraffin sections of each tumor were stained by immunoperoxidase method using antibodies to p53 gene product (CM-10) and Ki-67 (MIB-1). In situ hybridization for HPV DNA (ENZO) was used to detect specific sequences of DNA shared by most types of genital HPV, followed by confirmatory PCR analysis. The nuclear staining for Ki-67 was graded as minimal (<10% of cells), moderate (between 10 and 50% of cells), and high (>50% of cells)., Results: Fifty-percent of the tumors showed presence of HPV DNA. Three tumors (25%) showed nuclear accumulation of p53. Moderate and high proliferative activity was observed in four and eight of tumors, respectively. Eight patients presented with stage IB1 tumor (67%), 3 with stage IA1 tumor (25%), and 1 with stage IIIA tumor (8%). Eleven patients (92%) were alive as of last contact with a mean follow-up of 34.2 months (range: 5 days to 84 months)., Conclusion: In this series of patient, PSCC of the uterine cervix had a low rate of HPV DNA in their genome and a low rate of p53 gene abnormality. These genotypic differences may explain the differences between the clinical behavior of PSCC and the common types of squamous cell carcinomas of the cervix.

Purpose: To determine if increasing the dose of paclitaxel increases the probability of clinical response, progression-free survival, or overall survival in women who have persistent or recurrent ovarian cancer, and whether doubling the dose of prophylactic filgrastim accompanying the higher paclitaxel dose decreases the frequency of neutropenic fever., Patients and Methods: Consenting patients with persistent, recurrent, or progressing ovarian cancer, despite first-line platinum therapy (but no prior taxane), were randomly assigned to paclitaxel 135 mg/m2, 175 mg/m2, or 250 mg/m2 over 24 hours every 3 weeks. Patients receiving paclitaxel 250 mg/m2 were also randomly assigned to 5 or 10 microg/kg of filgrastim per day subcutaneously., Results: Accession to the paclitaxel 135-mg/m2 arm was closed early. Among the 271 patients on the other regimens with measurable disease, partial and complete response on paclitaxel 250 mg/m2 (36%) was significantly higher than on 175 mg/m2 (27%, P =.027). This difference was more evident among patients who never responded to prior platinum. However, progression-free and overall survival results were similar. The median durations of overall survival were 13.1 and 12.3 months for paclitaxel 175 mg/m2 and 250 mg/m2, respectively. Thrombocytopenia, neuropathy, and myalgia were greater with paclitaxel 250 mg/m2 (P <.05). The incidence of neutropenic fever after the first cycle of paclitaxel 250 mg/m2 was 19% and 18% on the 5-microg/kg and 10-microg/kg filgrastim dose, respectively (22% for paclitaxel 175 mg/m2 without filgrastim)., Conclusion: Paclitaxel exhibits a dose effect with regard to response rate, but there is more toxicity and no survival benefit to justify paclitaxel 250 mg/m2 plus filgrastim. Doubling the filgrastim dose from 5 to 10 microg/kg did not reduce the probability of neutropenic fever after high-dose paclitaxel.

Objectives: Vaginal reconstruction following pelvic exenteration is an important aspect of the physical and psychological rehabilitation of women after radical surgery for pelvic malignancies. The choice of techniques is vast, and proper patient and surgical selection is important for obtaining satisfactory functional and aesthetic results. The objective of this retrospective study is to review different techniques for vaginal reconstruction and report the complications and patient satisfaction associated with the different procedures., Methods: Between January 1988 and April 2001, 104 pelvic exenterations were performed by the division of gynecologic oncology at the University of Miami, School of Medicine. Twenty-five (24%) patients underwent vulvo-vaginal reconstruction at the time of the exenteration. A retrospective chart review of the 25 patients was performed, and 9 patients were available and contacted for an interview., Results: Twenty-four (96%) patients had received prior definitive radiation therapy. Overall, there were 9 complications (6 major and 3 minor) attributed to vaginal reconstruction, accounting for 36% perioperative morbidity. Seven of the nine (78%) patients interviewed reported successful vaginal intercourse at some point after their operation. All 5 surviving patients in the myocutaneous flap group were very satisfied with their sexual function and were sexually active at the time of their interview., Conclusions: Vaginal reconstruction at the time of pelvic exenteration is an important topic that should be discussed with the patient during the preoperative visit. Although the myocutaneous flaps are associated with longer operative times, they appear to be the preferred type due to decreased postoperative fistulae and better patient satisfaction.

The objective of this study was to determine whether perioperative blood transfusion adversely affected risk of recurrence in 504 evaluable patients with stage I squamous cell carcinoma of the cervix accessioned prospectively in a Gynecologic Oncology Group study. After eliminating patients with advanced-stage disease, wrong cell type, and those without transfusion information available, 504 of 1,125 patients accrued to Gynecologic Oncology Group Protocol 49 were included in this study. Seventy-seven percent of the patients received blood products within 2 weeks of surgery. Either the Pearson chi-square or Fisher exact test assesses the association of categorical clinical-pathologic factors with respect to transfusion status. Cox's proportional hazards model was used to identify and simultaneously evaluate the independent prognostic factors associated with survival and recurrence-free interval (RFI). The number of units transfused was found to be significantly related to RFI and survival using univariate analysis. When adjusted for clinical tumor size, capillary-lymphatic space involvement, and depth of tumor invasion using multivariate analysis, the number of units transfused was no longer statistically significant with respect to either RFI or survival. Recurrence and survival in patients with squamous cell cancer of the cervix could not be shown to be independently related to transfusion status.

During the past quarter-century, progress has occurred in the area of coordinated care of the patient with gynecologic cancer. This progress is the result of the refined surgical techniques and perioperative management of patients requiring intensive care after radical pelvic surgery. Furthermore, the addition of radiation therapy and chemotherapy has made major contributions to the improvement and quality of life for patients with gynecologic cancer. All formal training programs in gynecologic oncology now include appropriate rotations and experience with these newer techniques and treatment modalities. The gynecologic oncologist should be fully equipped to manage primary treatment and most of the complications related to the care of patients with gynecologic neoplasms. Formal training programs in gynecologic oncology have been fundamental in the attainment of this goal and provide the infrastructure for future developments. It is anticipated that continued worldwide surgical studies in the area of gynecologic oncology will improve the well-being of women who may have cancer.

The aging of the population is a social phenomenon that will present a challenge to clinical practice in the 21st century. Women constitute a majority of the elderly population as they outlive males by 5 to 7 years. Ovarian, endometrial, and vulvar cancers are diseases seen more commonly in postmenopausal and elderly women. Cervical cancer continues to be a significant problem in the elderly and is usually detected at a later stage in that population than in younger patients. Accordingly, primary care clinicians ought to possess a thorough knowledge of gynecologic malignancies and should refer women who present with these disorders to a gynecologic oncologist. Ovarian cancer patients treated by a gynecologic oncologist are more likely to undergo proper surgical staging, leading to optimal debulking surgery and improved survival. Age, by itself, should not alter the diagnostic and therapeutic approach to gynecologic malignancy. Elderly patients can safely undergo radical pelvic surgery. Multiagent chemotherapy is also possible in the elderly without excess morbidity, and without compromise of response rates. Radiation therapy for cervical cancer appears to be as effective and is generally well tolerated. The Papanicolaou (Pap) test continues to be the primary screening tool for cervical cancer. Although transvaginal ultrasound seems to be useful in detecting early-stage ovarian cancer, its cost effectiveness for screening the general population remains to be demonstrated. The main considerations in the treatment of ovarian, endometrial, cervical, and vulvar cancer are discussed.

Objective: To determine whether the prevalence of normal endometrial cells in Papanicolaou smears of women with and those without endometrial carcinoma or hyperplasia differs significantly., Methods: Papanicolaou smears of women with biopsy-proved endometrial hyperplasia or carcinoma diagnosed between 1990 and 1998 were reviewed for the presence of normal endometrial cells. Chi-square and a power analysis were used to compare these smears with results of smears from women older than 35 years of age with tissue diagnoses other than hyperplasia or carcinoma. All Papanicolaou smears obtained within the 5 years before endometrial sampling were reviewed. Each patient had at least one smear done within the previous 12 months. Clinical information was available for all patients., Results: Of the 201 women in whom endometrial hyperplasia (n = 103) or carcinoma (n = 98) was diagnosed, 4 (2%) had normal endometrial cells in otherwise negative Papanicolaou smears. Of the 289 women in the comparison group, 15 (5%) had normal endometrial cells in their Papanicolaou smears. The prevalence of normal endometrial cells did not differ significantly between the two groups (P =.071). The study had 80% power to detect a 5% or greater difference between groups., Conclusion: The prevalence of normal endometrial cells in Papanicolaou smears of women with endometrial carcinoma or hyperplasia does not significantly differ from that in women without these conditions. Reporting normal endometrial cells in Papanicolaou smears according to the recommendations of the Bethesda System may lead to unnecessary procedures and patient anxiety.

Objective: This study was conducted to analyze our experience with low (8-12 cm above the anal verge) and very low (<6 cm above the anal verge) colorectal resection and primary anastomosis at the time of radical en bloc resection of pelvic malignancies., Study Design: A retrospective review of 77 patients undergoing supralevator pelvic exenteration with low colorectal resection and primary anastomosis in our gynecologic oncology service was carried out. Data were obtained from patient medical records and from the tumor registry. Univariate statistical analysis of the data was used., Results: The distribution of primary malignancies in this cohort was as follows: 33 (43%) recurrent or primary cervical carcinomas, 27 (35%) primary or recurrent ovarian carcinomas, 7 (9%) recurrent vaginal carcinomas, 4 (5%) endometrial carcinomas, 3 (4%) colon carcinomas, and 3 (4%) cases of stage IV endometriosis. Forty patients underwent total pelvic exenteration, and 37 patients underwent posterior exenteration. Thirty-six patients in the total pelvic exenteration group had a history of pelvic irradiation. Twelve (30%) of these patients had development of breakdown or fistulas of the anastomosis. Six of the 12 patients (50%) had undergone protective colostomy. Thirty-seven patients underwent posterior exenteration with primary anastomosis for ovarian cancer, endometrial cancer, colon cancer, or endometriosis, and only 1 of these had received pelvic irradiation. This patient did not have a protective colostomy, and a rectovaginal fistula developed. In addition, there were 3 other breakdowns in the posterior exenteration group. Finally, the presence of preoperative ascites did not appear to alter the breakdown rate of the anastomosis among the patients with ovarian cancer who underwent cytoreductive surgery., Conclusion: Radical resection of pelvic tissue remains a crucial part of the armamentarium of the gynecologic oncologist. Previous pelvic irradiation appears to be a major risk factor (35% vs 7.5%) for anastomotic breakdown and fistulas, independent of the presence of a protective colostomy. The overall results appear to be better for patients undergoing this procedure as part of a posterior exenteration.

Purpose: To determine if patients with carcinoma of the vulva, with N2/N3 lymph nodes, could undergo resection of the lymph nodes and primary tumor following preoperative chemo-radiation. METHODS AND MATERILAS: Fifty-two patients were entered in the study, but six patients did not meet the criteria of the protocol and were excluded. The remaining 46 patients are the subject of this report. Patients underwent a split course of radiation, 4760 cGy to the primary and lymph nodes, with concurrent chemotherapy, cisplatin/5-FU, followed by surgery., Results: Four patients did not complete the chemo-radiation, because three expired and one refused to complete the treatment. Four patients who completed chemo-radiation did not undergo surgery, because two of them died of non-cancer-related causes, and in the other two patients, the nodes remained unresectable. Following chemo-radiation, the disease in the lymph nodes became resectable in 38/40 patients. Two patients who completed the course of chemo-radiation did not undergo surgery as per protocol because of pulmonary metastasis. One underwent radical vulvectomy and unilateral node dissection and the other radical vulvectomy only. The specimen of the lymph nodes was histologically negative in 15/37 patients. Nineteen patients developed recurrent and/or metastatic disease. The sites of failure were as follows: primary area only, 9; lymph node area only, 1; primary area and distant metastasis, 1; distant metastasis only, 8. Local control of the disease in the lymph nodes was achieved in 36/37 and in the primary area in 29/38 of the patients. Twenty patients are alive and disease-free, and five have expired without evidence of recurrence or metastasis. Two patients died of treatment-related complications., Conclusion: High resectability and local control rates of the lymph nodes were obtained in patients with carcinoma of the vulva with N2/N3 nodes treated preoperatively with chemo-radiation.

Objective: We sought to determine whether there have been any significant changes in professional satisfaction among gynecologic oncologists over the past 30 years., Methods: We mailed surveys to all U.S. gynecologic oncologists belonging to the Society of Gynecologic Oncologists to compile data on demographics, training, motivating factors, overall professional satisfaction, and the effect of managed care. We compared these factors among oncologists who completed training in different years and among different demographic groups. We used calculated confidence intervals to determine statistical significance., Results: We surveyed 767 gynecologic oncologists and received 344 evaluable responses, representing 47% of the total eligible. Results show that neither the factor rated most important in looking for a first job nor the factor rated most important in giving job satisfaction once in a job has changed significantly among gynecologic oncologists over time. In addition, the importance placed on salary has not varied across the fellowship graduate classes, although within each class salary increased in importance from the first job to the current job. Our analysis shows that while male and female gynecologic oncologists are similar in their job satisfaction and practice patterns, men report being sued twice as often as women, and men tend to stay in their first jobs significantly longer than women. We also compare the surveyed academic gynecologic oncologists to the private gynecologic oncologists and show that while overall job satisfaction is similar, their ratings of the factors that provide job satisfaction do differ significantly. Our data show that managed care penetration has increased over time among gynecologic oncology practices and that gynecologic oncologists' job satisfaction ratings tend to decrease with the increase in managed care penetration, although not reaching statistical significance., Conclusions: Our results show that changes in practice styles since the 1960s have not affected overall job satisfaction among gynecologic oncologists. However, several trends in practice styles can be noted, including differences between sexes, academic versus private physicians, and attitudes about managed care. The survey also suggests that there is interest among gynecologic oncologists in continuing to monitor changes in patterns of practice and satisfaction., (Copyright 2000 Academic Press.)

Objective: The aim of this study was to determine the effects on transfusion rates, perioperative complications, and survival of using intraoperative autologous blood transfusions for patients undergoing type III radical hysterectomy and lymphadenectomy., Study Design: A retrospective analysis was conducted on 156 patients treated with type III radical hysterectomy and lymphadenectomy at the University of Miami School of Medicine from 1990 to 1997. One group of patients (n = 50) had intraoperative autologous blood transfusions and the other (n = 106) did not., Results: The group that received intraoperative autologous blood transfusion had a significant reduction in homologous blood transfusions (12% vs 30%; P =.02). Patient demographic data, histologic parameters, and operative factors were similar between the 2 groups. There was a higher percentage of patients with positive pelvic lymph nodes in the group that did not receive intraoperative autologous blood transfusion (10% vs 30%; P =.02). Seven patients in the intraoperative autologous blood transfusion group (14%) died with disease present and all the recurrences in this group were local., Conclusion: The use of intraoperative autologous blood transfusions during type III radical hysterectomy and lymphadenectomy appears to be safe and effective without compromising rates and patterns of recurrence.

Objective: The purpose of this study was to determine the clinical relevance of reporting the presence of normal endometrial cells in the Pap smears of women over the age of 35 years and the significance of this practice as it relates to patient management., Methods: From January 1992 to December 1995, normal endometrial cells were reported in 206 consecutive Pap smears of women over the age of 35 years. Clinical follow-up was available for all patients, including the results of diagnostic procedures whenever performed., Results: Of the 206 women with normal endometrial cells in their Pap smears, 162 presented with the chief complaint of abnormal vaginal bleeding. They were all evaluated by direct endometrial sampling, resulting in detection of 10 endometrial hyperplasias and 7 endometrial carcinomas. The remaining 44 women who were clinically asymptomatic were followed up with only routine annual gynecologic examinations for a minimum of 3 years. All had negative clinical courses., Conclusion: Reporting the presence of normal endometrial cells in Pap smears has little, if any, impact on subsequent patient management. Women who present with abnormal uterine bleeding are worked up for endometrial disease regardless of their Pap smear findings. In clinically asymptomatic patients, practitioners may, and in our experience often do, choose to disregard normal endometrial cells in Pap smear reports. The negative follow-up for the asymptomatic women in our study supports this practice. Therefore, reporting the presence of normal endometrial cells in Pap smears is of no clinical relevance and may, in fact, create a management dilemma for clinicians., (Copyright 1999 Academic Press.)

Objective: The aim of this study was to generate HPV-16 E7 peptide-specific cytotoxic T lymphocytes (CTLs) in vitro for future adoptive immunotherapy of cervical cancer., Methods: Peripheral blood mononuclear cells (PBMC) were isolated from HLA-A2+ healthy donors. The PBMCs were incubated with HPV-16 E7(11-20) peptide and varying cytokines in the primary culture. Restimulation was performed weekly with peptide-pulsed, irradiated autologous PBMCs. Alternatively, the PBMCs were depleted of abundant CD4+ cells and stimulated with HPV-16 E7(11-20) peptide-pulsed dendritic cells. Cytolytic activity was determined by a standard 4-h (51)Cr-release assay., Results: After 6 weeks in culture, we were able to establish peptide-specific CTL lines in one of seven donors by incubating PBMCs with HPV-16 E7(11-20) peptide. When we employed autologous peptide-pulsed dendritic cells to stimulate CD8+ cell-enriched PBMCs, we obtained CTL lines in four of seven donors. The primed CTLs were able to lyse the HLA-A2+ and HPV-16+ cervical cancer cell line Caski. SiHa, an HLA-A2-, but HPV 16+, cervical cancer cell line could be lysed only after transfection with HLA-A2. In addition, a high cytotoxicity (>80%) was obtained against peptide-pulsed, but not unpulsed, targets such as autologous Ebstein-Barr virus-immortalized B cells or allogeneic lipopolysaccaride-stimulated PBMCs. DCs were clearly the most potent of all tested antigen presenting cells to stimulate a CTL response in a proliferation assay., Conclusion: HPV-16 E7 peptide-specific CTLs could be generated in vitro. A practical protocol to expand the CTLs to a sufficient number for an application in a clinical trial is in progress., (Copyright 1999 Academic Press.)

Cervical cancer is generally a locoregional disease. The endopelvic fascia envelops the cervix in anterior-posterior fashion and serves as a natural barrier. Thus, cervical cancer preferentially grows to the parametria and involves the ureters before it infiltrates the bladder or rectum. Disease stage, grade, cell type, tumor volume, depth of stromal invasion, vascular space invasion, and lymph node status are common prognostic indicators. Irregular vaginal bleeding and discharge are the two most frequent complaints. Although cervical cancer is still staged clinically, data continue to accumulate favoring a conversion to surgical staging to improve accuracy and treatment outcome.

Cervical cancer is easily recognized when it presents as a visible lesion, but a problem arises when it adopts unusual presentations. Cervical cancer can develop high in the endocervical canal, beyond the reach of cone biopsy. Copious vaginal discharge from cervical adenocarcinoma may lead to a false-negative Papanicolaou (Pap) smear. Treatment of cervicitis can result in a delay in diagnosis. Successful and timely diagnosis and treatment of cervical cancer requires experience and vigilance. Careful intraoperative palpation of the cervix and uterus can help determine the location and extent of the lesion. Flexibility during surgery is required to utilize intraoperative findings and thus optimize treatment. Pitfalls of cervical cancer diagnosis and treatment with actual case presentations are presented along with other special problems in cervical cancer management such as incidental findings of cervical cancer in hysterectomy specimens, treatment of cervical stump cancers, and unusual cervical cancer cell types.

Purpose: A multicenter trial of chemoradiation therapy to evaluate the feasibility of extended field radiation therapy (ERT) with 5-fluorouracil (5-FU) and cisplatin, and to determine the progression-free interval (PFI), overall survival (OS), and recurrence sites in patients with biopsy-confirmed para-aortic node metastases (PAN) from cervical carcinoma., Methods and Materials: Ninety-five patients with cervical carcinoma and PAN metastases were entered and 86 were evaluable: Stage I--14, Stage II--40, Stage III--27, Stage IVA--5. Seventy-nine percent of the patients were followed for 5 or more years or died. ERT doses were 4500 cGy (PAN), 3960 cGy to the pelvis (Stages IB/IIB), and 4860 cGy to the pelvis (Stages IIIB/IVA). Point A intracavitary (IC) doses were 4000 cGy (Stages IB/IIB), and 3000 cGy (Stages IIIB/IVA). Point B doses were raised to 6000 cGy (ERT + IC) with parametrial boost. Concomitant chemotherapy consisted of 5-FU 1000 mg/m2/day for 96 hours and cisplatin 50 mg/m2 in weeks 1 and 5., Results: Eighty-five of 86 patients completed radiation therapy and 90% of patients completed both courses of chemotherapy. Gynecologic Oncology Group (GOG) grade 3-4 acute toxicity were gastrointestinal (18.6%) and hematologic (15.1%). Late morbidity actuarial risk of 14% at 4 years primarily involved the rectum. Initial sites of recurrence were pelvis alone, 20.9%; distant metastases only, 31.4%; and pelvic plus distant metastases, 10.5%. The 3-year OS and PFI rate were 39% and 34%, respectively, for the entire group. OS was Stage I--50%, Stage II--39%, and Stage III/IVA--38%., Conclusions: Extended field radiation therapy with 5-FU and cisplatin chemotherapy was feasible in a multicenter clinical trial. PFI of 33% at 3 years suggests that a proportion of patients achieve control of advanced pelvic disease and that not all patients with PAN metastases have systemic disease. This points to the importance of assessment and treatment of PAN metastases.

Background: The presence of p53 mutations and associated mutant p53 overexpression has been demonstrated in many cancer systems. Whether the overexpression of mutant p53 represents cause or effect, and whether p53 mutation contributes actively to the malignant phenotype is a matter of controversy. We examined the growth effects of oligonucleotides designed to interfere with p53 expression and/or activity in p53-mutant/overexpressing endometrial cancer cell lines., Methods: Phosphorothioate oligonucleotides were used to target p53-related sequences in two p53-mutant/overexpressing endometrial cancer cell lines (KLE and RL95-2) and a normal fibroblast control. The ATP cell viability assay was used to measure growth effects after 6-day treatments with 27-mer and 14-mer sense (S) or antisense (AS) phosphorothioate oligodeoxyribonucleotides (oligos) targeting the promoter/ATG region of p53 and/or the p53 consensus (CON) DNA binding sequence. These sequences were designed to interfere with p53 expression and activity, respectively. Random sequences of the p53 27- and 14-mer were used as controls for nonspecific oligo effects, and a normal fibroblast cell line was used to compare oligo effects and serve as a negative p53 immunostaining control., Results: Mean +/- SE IC50 (50% growth inhibition) of the S, AS p53, and p53 CON oligos were 4.2 +/- 1.3, 4.7 +/- 0.9, and 7.6 +/- 1.4 microM, respectively, for the two endometrial cell lines combined. The AS and S p53 oligos demonstrated dose-dependent inhibitory effects in both cell lines, while p53 CON produced variable effects alone and in combination with p53 AS. In KLE, a uniform inhibitory dose response was seen with p53 CON oligos. In RL95-2, the approximate IC50 for p53 CON was 0.5-1.0 microM, but at increasing doses above this, an inverse dose response was consistently observed. Combinations of p53 AS and p53 CON oligos produced predominantly synergistic growth inhibition. Although combinations of p53 AS and p53 CON in KLE were synergistic at low doses, antagonistic effects occurred at higher concentrations. Oligos had little effect on normal fibroblast growth, with calculated IC50 > 16 microM. Equimolar combinations of p53 S and AS were antagonistic, indicating that antiproliferative effects were sequence-specific. Random oligos demonstrated some nonspecific inhibitory effects, with >25% growth inhibition at 16 microM and beyond. Immunoperoxidase staining for mutant p53 after exposure to 16 microM concentrations of p53 AS oligos demonstrated reductions in p53 staining but persistent overexpression relative to wild-type (fibroblast) cells., Conclusion: Phosphorothioate oligos directed against p53 sequences in two p53-mutant endometrial cancer cell lines demonstrated antiproliferative effects. Combined anti-p53 and anti-p53 binding site oligos resulted in predominantly synergistic antiproliferative effects. The activity of sense oligos, the variable responses to p53 CON, and the persistent overexpression of mutant p53 at high concentrations of growth-inhibiting anti-p53 oligos suggest that, while promising, the antineoplastic effects of these oligos occur through complex and incompletely understood mechanisms.

Human papillomavirus (HPV) infection is believed to play a central role in cervical carcinogenesis. Specifically, two viral oncoproteins, E6 and E7, possess transforming ability and have been shown to interact with the cellular tumor suppressors p53 and p105, the retinoblastoma (Rb) gene product. To test the hypothesis that E6 and E7 play an active role in the maintenance of the malignant phenotype and may be ideal targets for antigene therapy, we tested the antiproliferative effects of phosphorothioate oligodeoxynucleotides (oligos) targeting HPV-16 E6 and E7 in cervical cancer cell lines and primary tumor explants. The ATP cell viability assay was used to measure growth effects of 27-mer antisense oligos targeting the ATG translational start region of HPV-16 E6 and E7 sequences in HPV-16-positive cell lines SiHa and CaSki and four advanced, primary cervical tumor explants. A random oligo sequence, an HPV-18-positive and HPV-negative cell line, one histologically confirmed endometrial and two ovarian tumors were used as negative controls. HPV type was confirmed by hybrid capture techniques. Cell lines and sterile (staging laparotomy) tumor cells were plated at 5000 cells/0.1 ml and 100,000 cells/0.5 ml in 96-well plates or soft agar, respectively, and incubated at 37 degrees C with a single treatment of oligos at 0-16 microM. E6/E7 combinations at a fixed ratio of 1:1 were used at 0-8 microM for each oligo. Cellular ATP was measured by luciferin/luciferase fluorescence on Day 6. HPV-16 E6 and E7 oligos showed antiproliferative effects in all HPV-16-positive cell lines and primary tumor explants (IC50s 6.9-9.5 microM for cell lines, 9.1-12.1 microM primary cervical tumors), while the HPV-negative C33-A cell line and HPV-18-positive cell line HeLa were relatively insensitive to the HPV-16 oligos (IC50s > 30 microM extrapolated). The endometrial and two ovarian primary tumors were also insensitive to the HPV E6 and E7 oligos (IC50s > 25 microM extrapolated). Random oligos had little effect on cell growth at concentrations up to 16 microM (< 25% inhibition), except in CaSki (@50% inhibition at 16 microM). Combinations of E6 and E7 demonstrated mixed synergistic and antagonistic effects as determined by combination indices (CI) derived from median effect parameters. In the HPV-16-positive primary cervical tumors and the cell line SiHa, E6/E7 combinations were synergistic at low doses (< 25% growth inhibitory dose range) and antagonistic at doses above this. For the HPV-16-positive cell line CaSki, however, E6/E7 combinations were antagonistic at all dose ranges. Phosphorothioate oligos directed against the viral oncogenes E6 and E7 were shown to have antiproliferative effects specific to HPV-containing cancer cells. These specific antiproliferative effects suggest that HPV-16 E6 and E7 sequences play an active role in the malignant growth properties of cervical cancer cells and may be ideal targets for antigene therapy.

The influence of cell type on recurrence-free interval (RFI) and survival after radical hysterectomy for patients with Stage IB carcinoma of the cervix was investigated. Patients with Stage IB carcinoma of the cervix (>3-mm invasion) underwent a radical hysterectomy and pelvic lymphadenectomy. Patients with involved paraaortic nodes or gross extracervical disease were excluded. Of 813 evaluable patients, 645 had squamous, 104 with adenocarcinoma, and 64 had adenosquamous cell type. The time to failure and the following clinical/pathologic characteristics were compared among the three cell types: age, Gynecologic Oncology Group performance status (PS), gross versus occult tumor, histologic grade, depth of invasion, node status, uterine extension, parametrial extension, surgical margins, and capillary-lymphatic space (CLS) involvement. A Cox proportional hazards model was used to compare the patients with adenosquamous and adenocarcinoma to those with squamous while adjusting for prognostic factors. The median age was 40 years (range, 21-87). Pelvic nodes were involved in 119 (15%) of patients. There were no significant differences between cell types in distributions of the following factors: age, PS, positive nodes, depth of invasion, uterine extension, surgical margins, or parametrial extension. There were statistically significant differences between cell types with regards to grade (P < 0.001), gross versus occult primary status (P = 0.016), and CLS involvement (P = 0.005). There was no statistically significant difference detected between cell types in crude comparisons of RFI (P = 0.29); however, there was a difference in survival (P = 0.02) with shorter survival seen in the adenosquamous cell type. After adjusting for CLS involvement, PS, depth of invasion, and clinical tumor size, survival remained worse for patients with adenosquamous primaries when compared to squamous carcinoma (P = 0.02) and adenocarcinoma (P = 0.007). In conclusion, no statistically significant differences were seen in RFI among cell types; however, in patients with Stage I carcinoma of the cervix overall survival after radical hysterectomy may be slightly worse for those with adenosquamous cell type.

Background: This study was performed to identify a statistical combination of independent pathologic and clinical features that best predict 5-year disease free survival (DFS) in patients with early stage cervical carcinoma treated by radical hysterectomy. The main goal of the study was to identify subsets of patients based on risk factors with maximal differences in DFS., Methods: Three hundred and seventy patients were found for whom complete clinical and pathologic material, including cone and cervical biopsies, were available for analysis. Variables studied included age, weight, race, marital status, economic status, tumor size (TS), depth of invasion (DI), lymph-vascular space involvement (LVSI), cell type, tumor grade, lymph node metastasis (LNM), and number of lymph nodes removed. Patients with LNM, parametrial involvement, and positive or close surgical margins were offered postoperative radiation. After excluding patients with microinvasive and small cell carcinoma, data from the remaining 301 patients were submitted to univariate and multivariate analyses to define those variables that best predict DFS., Results: Univariate analysis showed that, ranked by degree of significance, DI, TS, LVSI, LNM, tumor volume (TV) and clinical stage were significant in predicting survival. Significant (P < 0.05) single parameters and other variables considered important were chosen for multivariate analysis, including the creation of a survival tree. With this method, DI (< or = 6 mm and > 2 cm), LVSI, age (> or = 40 yrs), and LNM were found to be the best combination of risk factors to define prognosis., Conclusions: The multivariate survival tree analysis maximally separates patients with early stage invasive carcinoma of the cervix into 3 subgroups with 5-year DFS of 91%, 68%, and 43%, respectively. The authors excluded patients with microinvasive carcinoma (SGO, Society of Gynecologic Oncologists), who have an excellent DFS of 100%, and patients with small carcinoma, who have a poor DFS of 36.4% based on cell type alone, to define independent risk factors that maximally separate the remaining patients by DSF. The survival tree prognostic scoring system is easy to apply, and only requires DI (mm), LVSI (+, -), LNM, and age to assign an individual patient to one of three risk groups.

In 1989, the University of Miami began a program incorporating high-dose-rate (HDR) brachytherapy into the definitive treatment of patients with invasive carcinoma of the cervix. Patients received an average total dose to point A of 5,511 cGy (range 4,280-6,360 cGy) in an average of 57 days (range 39-84 days). An analysis of the first 24 cases found 11 FIGO Stage I-B, four Stage II-A, and nine Stage II-B tumors. At the end of all radiation therapy, 19/24 patients' tumors (79.2%) had undergone a clinical complete response (CR). With median follow-up of 26 months (range 14-63 months), three have relapsed locally, two regionally, and six in extrapelvic sites. Almost two-thirds of all failures occurred in patients with tumors >4 cm, who also took more than 8 weeks to complete their treatment. Overall 2-year actuarial survival for the entire study group is approximately 74%. A univariate analysis determined that clinical stage (P = 0.02), overall treatment time (P = 0.03), tumor size (P = 0.05), and response at the end of therapy (P = 0.005) were significant prognostic factors. Multivariate analysis showed that tumor response to therapy was the most important prognosticator of outcome (P = 0.001). Besides five cases of apical vaginal stenosis, there have been no reported chronic complications in this cohort of patients. A prospectively randomized trial is recommended to compare the efficacy of HDR vs. low-dose-rate brachytherapy in cervical carcinoma.

Background: Accurate evaluation of patients with ovarian carcinoma who have completed primary therapy often requires surgical exploration. Radioimmunoscintigraphy (RIS) represents an evolving technique that may allow noninvasive detection and localization of persistent or recurrent disease in these patients., Methods: Our prospective, blinded study enrolled patients with normal CA 125 levels and no clinical evidence of disease after primary cytoreductive surgery and cytotoxic chemotherapy for ovarian carcinoma. Each patient underwent RIS using Indium-satumomab pendetide (labeled antibody B72.3 to the tumor-associated antigen TAG-72) and abdominal/pelvic computed tomography (CT) prior to reassessment laparotomy., Results: Twenty patients were enrolled from January 1994 to January 1995. Two patients with negative RIS scans refused reassessment laparotomy and were without evidence of disease > 15 months from the study. Twelve of the remaining 18 patients (66.7%) had histologically proven disease at reassessment laparotomy. RIS images indicated the presence of disease in all 12 patients, whereas CT scans detected disease in only 2 patients. In three of five patients, biopsy-proven microscopic disease (no gross disease at the time of laparotomy) was found only in specimens obtained by RIS-directed biopsies. RIS was superior to CT in sensitivity (100% vs. 16.7%), accuracy (72% vs. 33%), and negative predictive value (100% vs. 28.6%) (P < 0.005)., Conclusions: Routine use of CT is of limited value in the assessment of ovarian carcinoma patients with negative physical examinations and normal CA 125 levels. With its high level of sensitivity and negative predictive value, RIS may play a role in the detection of persistent disease in this population and aid in the classification of patients into three distinct groups: those with gross residual disease, small volume or microscopic disease, and no disease. Separation of this heterogenous group without surgery may help guide subsequent consolidation therapy. However, attaining a high level accuracy with RIS, depends on optimizing the method of image acquisition, the timing of scans, and the reconstruction of data.

Background and Methods: Total pelvic exenteration is a salvage procedure done in the effort to eliminate completely pelvic cancer. Low colorectal anastomosis and continent urinary diversion are two new procedures that allow complete pelvic evisceration without the need for external appliances. From 1984 through 1994, 67 patients have undergone rectosigmoid colectomy and low-colorectal anastomosis. Sixteen patients underwent surgery as part of a total pelvic exenteration for recurrent cervical cancer, and 51 patients underwent surgery for either primary or recurrent ovarian carcinoma as part of an optimal debulking procedure. Between 1988 and 1995, 55 patients have received continent urinary diversion with the Miami Pouch. Fifty-two patients underwent surgery for recurrent cervical cancer, two patients for advanced vulvar cancer, and one patient for a vesico-vaginal fistula. All of the patients with recurrent cervical cancer had previously received radiation therapy for gynecologic cancer., Results: Of the 16 patients with recurrent cervical cancer who had a low colorectal anastomosis, 14 had a temporary colostomy. Of these 14 patients, eight had a colostomy takedown and have maintained fecal continence. Of the 51 patients with ovarian cancer who had a low colorectal anastomosis, all achieved fecal continence. With the Miami Pouch, a urinary continence rate of 86% was obtained. Twenty-four (44%) patients had early complications, including ureteral obstruction, ureterocolonic anastomotic leak, reservoir cutaneous fistula, small bowel obstruction, and pyelonephritis. Nineteen (35%) patients had late complications, including ureteral reflux, urinary incontinence, difficult catheterizations, and reservoir stones. There was a perioperative mortality rate of 5%., Conclusions: Low-colorectal anastomosis is an attractive alternative to permanent colostomy, allowing all patients who had the protective colostomies taken down to achieve fecal continence. Continent urinary diversion with the Miami Pouch is also a worthwhile procedure because of its high continence rate. Although survival advantage for either procedure has not been proven, the quality of life of patients undergoing such procedures has been substantially improved because of the avoidance of external appliances. This has been achieved with acceptable morbidity and mortality rates.

Background: This study was performed to identify pathologic and clinical features that best correlate with lymph node metastasis and disease free survival among patients with Stage I and II cervical cancer treated by radical hysterectomy., Methods: Three hundred-seventy patients with complete clinical information and pathologic material, including cone and cervical biopsies, were selected for analysis. Of these patients, 301 with clinical stages I and II disease were the subject of this paper. The results of patients with microinvasive carcinoma of the cervix, as defined by the Society of Gynecologic Oncologists (depth of invasion < or = 3 mm and no lymph node vascular space invasion), were reported previously and excluded from this analysis. Patients with small cell carcinoma of the cervix were found to have a very poor prognosis (disease free 5-year survival of 36%) and were also excluded from this analysis (Sevin BU, Nadji M, Metkoch MW, Lu Y, Averette HE. Unpublished data, 1995). Variables studied were patient age, weight, race, marital status, and economic status; tumor size; depth of invasion; lymph node-vascular space involvement; cell type; tumor grade; lymph node metastasis; and number of lymph nodes removed. The influence of these variables on survival was examined by univariate analysis with use of Cox's regression model and the log rank test for comparison of survival curves., Results: Factors that predict disease free survival, ranked by degree of significance, were depth of invasion, tumor size, lymph node-vascular space invasion, number of positive nodes, tumor volume, clinical stage, and tumor extension to the vagina or surgical margins., Conclusions: Radical hysterectomy and bilateral lymphadenectomy is standard therapy for patients with Stage IB and IIA carcinoma of the cervix. A variety of surgically defined risk factors predict 5-year disease free survival, and many of these factors are related. Identification of independent risk factors requires a multivariate analysis of data.

Gene therapy clinical trials targeting p53 and other genes are underway in nongynecologic cancer systems. To explore the potential for antigene therapy in gynecologic oncology, we examined the in vitro effects of oligonucleotides targeting c-myc and p53 in the ovarian cancer cell lines CAOV-3, SKOV-3, and BG-1. The ATP cell viability assay was used to measure growth effects after 6-day treatments with 27-mer antisense phosphorothioate oligodeoxyribonucleotides (oligos) targeting the Puf/nm23 binding region of c-myc and promoter/ATG region of p53. A random sequence of the p53 27-mer was used as a control, and an untransformed fibroblast cell line was used for comparison. IC50 was defined as the oligo concentration required for 50% growth reduction compared to untreated controls. Synergistic vs antagonistic effects of oligo combinations were quantitated by combination indexes (CI) as calculated from median effect parameters by the methods of Chou and Talalay. Mean +/- SE IC50's of c-myc and p53 antisense oligos in CAOV-3 and SKOV-3 ranged from 1.0 +/- 0.2 to 9.7 +/- 1.3 microM. The IC50's of c-myc oligos were consistently lower than corresponding p53 oligos in all cell lines (P < 0.034, t test). The fibroblast cell line was sensitive to anti-c-myc and combination anti-c-myc/p53 oligos (IC50 = 1.5 +/- 0.6 and 1.4 +/- 0.2 microM, respectively), but not to anti-p53 oligos alone (IC50 > 16 microM). Nonspecific toxicity was observed at concentrations of 16 microM for all cell lines except in BG-1, where maximal growth stimulation occurred at this concentration with anti-p53 oligos. Growth stimulation was also observed in BG-1 with anti-c-myc and anti-c-myc/p53 combinations at intermediate doses, with inhibition at higher doses. While c-myc/p53 combinations in CAOV-3 were synergistic (CI < 0.8), they were antagonistic in SKOV-3 (CI > 3.2). Phosphorothioate oligos directed against c-myc and p53 in different cell lines were shown to have both antiproliferative and stimulatory activity, as single agents and in combination, at concentrations that are achievable in vivo. Because of the complex patterns of effects, further in vitro studies are warranted before considering clinical trials with these agents in gynecologic cancers.

Background: Reports generated from the National Cancer Data Base (NCDB), a joint project of the American College of Surgeons Commission of Cancer and the American Cancer Society, have described trends in demographics, stage, treatment patterns, and survival for a variety of cancers. In this report, the most current (1991) data for ovarian cancer are presented and include some comparisons with 1985/1986 data., Methods: Three calls for data from hospital registries across the United States have yielded 17,114 ovarian cancer cases for 1985, 1986, and 1991 combined. These data represent approximately 23%, 23%, and 43%, respectively, of the annual number of cases of ovarian cancer in the United States for those years., Results: One-fourth of the reported cases of ovarian cancer were diagnosed in women less than 50 years of age. Younger patients (< 40 years) were more likely to have received conservative therapy (unilateral oophorectomy), consistent with their high prevalence (59%) of Stage I disease. The number of patients reported with an unknown American Joint Committee on Cancer (AJCC) stage decreased from 49% in 1985/1986 to 17% in 1991, although the distribution within stages was unchanged. Increases in important staging procedures were reported in 1991, with threefold increase in the proportion of debulking procedures and a 50% increase in omentectomies accompanying hysterectomy compared with 1985/1986. More advanced disease was reported for those of older age, lower income, African Americans, and patients in smaller hospitals. Relative 5-year survival rates were 74% for patients with Stage I disease, 58% for Stage II, 30% for Stage III, and 19% for Stage IV. Asians and Hispanics presented with a relatively high rate of Stage I-II disease (45%) compared with non-Hispanic whites and African Americans (38% and 33%, respectively). Hispanics presented with the most favorable Stage I/IV ratio (1.5) and had an overall 5-year survival of 50% compared with 41% and 37% for non-Hispanic whites and African Americans (Stage I/IV ratios of 1.0 and 0.7, respectively). There was little difference reported in the use of multimodality treatment between 1985/1986 and 1991., Conclusions: A trend toward more complete surgery with full surgical/pathologic staging was observed in 1991, but there was not yet evidence to indicate significant improvements in ovarian cancer survival compared with published figures during the past 10-15 years. Important ethnic and demographic differences in type of surgery and survival were noted but could not be differentiated from differences in tumor stage.

Paclitaxel is an exciting chemotherapeutic agent active in a variety of malignant tumors. This study was designed to explore the radiosensitizing potential of paclitaxel in human cervical cancer cell lines. The cell lines ME180, SiHa, and MS751 were evaluated. Experiments were performed in the proliferative phase of growth. Paclitaxel doses were treated at 0.01x, 0.02x, 0.03x, 0.04x, and 0.05x peak plasma concentration (PPC) in ME180 and 0.001x, 0.002x, 0.003x, 0.004x, and 0.005x PPC in SiHa and MS751. Radiation (RT) doses of cobalt-60 were 0, 2, 4, 6, 8, and 10 Gy. In the combination group RT was given 48 hr after paclitaxel treatment. To allow for median effect analyses, combination doses were kept at a fixed ratio: 0.01x/2 Gy, 0.02x/4 Gy, 0.03x/6 Gy, 0.04x/8 Gy, and 0.05x/10 Gy for ME180 and 0.001x/2 Gy, 0.002x/4 Gy, 0.003x/6 Gy, 0.004x/8 Gy, and 0.005x/10 Gy in MS-751 and SiHa. Adenosine triphosphate bioluminescence was performed on Day 7 after treatment and compared to untreated controls. Dose-response data were fit to the linear quadratic model and mean inactivation dose D was calculated. Data analysis with t test was performed. The median effect principle was used to evaluate the nature of the interaction between the two therapeutic modalities. Paclitaxel increased radiation cytotoxicity in all three cell lines. Mean inactivation D values for RT versus combination were 6.70 (+/- 0.15) and 4.33 (+/- 0.43) (P = 0.004) in ME180, 6.08 (+/- 0.70) and 4.54 (+/- 0.093) (P = 0.033) in MS751, and 7.03 (+/- 0.46) and 5.97 (+/- 0.51) (P = 0.034) in SiHa. The interaction of paclitaxel and RT was found to be supraadditive in ME180 and SiHa and subadditive in MS751. We conclude that paclitaxel has modest radiation-sensitizing effects in cervical cancer cell lines and that further clinical trials should be considered.

Prophylactic oophorectomy is presently the only effective method of ovarian cancer prevention. This study reviews current data on how prophylactic oophorectomy (PO) should be used in different risk groups. It is estimated that 7% of ovarian cancer patients have positive family history, of which 3-9% may end up having hereditary cancer syndromes. Women in direct genetic lineage of family cancer syndromes may have up to 50% lifetime risk of ovarian cancer. Because of such a high risk, PO is indicated for women with familial cancer syndromes after childbearing or the age of 35-40 at the latest. Most women with positive family history of ovarian cancer do not have one of the recognized hereditary cancer syndromes. However, women with one or two affected relatives do have an increased lifetime risk of ovarian cancer from a baseline of 1.6 to 5-7%. This risk is not high enough to warrant PO recommendation for a large number of women. After being properly informed and the patient still desires surgical prevention (i.e., cancer phobia), PO then becomes an indicated procedure. In women without family history of ovarian cancer, the role of PO remains controversial. The decision of PO as a concurrent procedure to other indicated gynecologic surgeries should depend on the individual patient and her ability to comply with lifelong estrogen replacement therapy.

In this study the dose-response curves for doxorubicin, pirarubicin, 5-fluorouracil, 4-hydroperoxy-cyclophosphamide and taxol were obtained in three breast cancer cell lines (MCF-7, T47D and BT-20). The ATP cell viability assay was chosen to evaluate the chemosensitivity profiles and was a reproducible, practicable method to assess drug response in breast cancer cell lines. The IC50 values were calculated on the median effect principle and indicated that taxol was the most active drug tested in this study with a mean IC50 value of 0.02 microM. This in vitro effect correlated well with clinical observations in metastatic breast cancer where taxol proved to be a vary active drug. Pirarubicin was the second most active drug tested with an IC50 value 10 times less compared to that of doxorubicin. The results obtained with the ATP cell viability assay are promising, therefore further testing with drug combination chemotherapy and fresh human breast cancer tumor testing are warranted and ongoing.

Women with a family history of ovarian cancer are at increased risk of ovarian cancer. Prophylactic oophorectomy (PO) remains the only effective method of ovarian cancer prevention. This study reviewed current data on the significance of family history and how prophylactic oophorectomy should be used in different risk groups. Approximately 7% of ovarian cancer patients have a positive family history of whom 3-9% may eventually manifest certain hereditary cancer syndromes. Women in direct genetic lineage of family cancer syndromes have up to a 50% lifetime risk of ovarian cancer. Because of the high risk, PO is indicated for women with familial cancer syndromes after childbearing or between the ages of 35-40 at the latest. The majority of women with a positive family history of ovarian cancer do not have one of the recognized syndromes. Women with one or two affected relatives have an increased lifetime risk of ovarian cancer from a baseline of 1.6 to 5-7%. This risk is not high enough to warrant PO for a large number of women. After being properly informed, the patient still chooses surgical prevention, she then receives PO. For women without a family history of ovarian cancer, the role of PO remains controversial. Assuming an annual incidence of 22,000 new cases of ovarian cancer, it is estimated that at least 1000 may be prevented if PO is diligently practiced during hysterectomy. Despite ovarian and breast cancer prevention, PO would lead to shorter life expectancy if estrogen therapy compliance were less than perfect. Thus, the decision on PO as a concurrent procedure should depend on the individual patient and her ability to comply with lifelong estrogen therapy.

This study evaluates the in vitro sensitivities of 42 ovarian cancer specimens to the new anticancer agent Paclitaxel (taxol, Tx), cisplatin (DDP), and the combination Tx-DDP with the adenosine triphosphate cell viability assay (ATP-CVA). In vitro response is defined by > or = 50% ATP decrease compared to untreated controls 6-7 days after drug treatment with 20% of the peak plasma concentration (PPC). Response rates were 12% to Tx, 19% to DDP, and 27% to Tx + DDP. The mean IC50's of Tx, DDP, and the combination Tx-DDP were (2.6x, 1.0x, and 0.38x PPC, respectively). The mean inhibition of cell viability was significantly greater with drug combinations compared to single drugs. In 7/11 tumors synergistic effects and in 2/11 additive effects were found between Tx and DDP. We conclude that based on ATP-CVA in vitro results, Tx-DDP shows significantly better activity compared to each of the single drugs in ovarian cancer.

Background: Epithelial ovarian carcinoma in women less than or equal to 25 years of age is a rare entity. This study used the database of the National Survey of Ovarian Carcinoma to analyze the disease and survival in women less than or equal to 25 years of age., Methods: Tumor registries of 1230 hospitals were asked to enter the first 25 patients with histologically confirmed ovarian carcinoma from January 1 to December 31, 1983 and from January 1 to December 31, 1988. Data for a total of 12,136 patients were collected. Survival analysis and long-term evaluations were available on patients diagnosed with cancer in 1983. Chi-square analysis was used to compare the frequencies of operations performed in 1983 and 1988., Results: Of 12,136 patients with epithelial ovarian carcinoma, 135 (1.1%) were less than or equal to 25 years of age. The majority of patients had early disease with the following distributions: stage I, 58.5%; stage II, 8.9%; stages III and IV, 28.9%. More patients had early-grade lesions with the following distributions: borderline, 21.5%; Grade 1, 27.4%; Grade 2, 11.1%; Grade 3, 6.7%; and unknown grade, 33.3%. Optimal cytoreduction was achieved in 77% of patients. During the 5-year study period, there was a significant change in the patterns of care toward more conservative surgery. In particular, unilateral salpingooophorectomy increased significantly from 38.2 to 59.7% (P = 0.0237), whereas hysterectomy decreased proportionally from 54.4 to 29.9% (P = 0.0039). The overall 5-year survival rate was 87.3% with the following divisions: stage I, 96.7%; stage II, 90.0%; stage III, 78.5%; and stage IV, 76.4%. Regarding histologic grade, 5-year survival rates were: borderline, 91.6%; Grade 1, 93.7%; Grade 2, 85.7%; Grade 3, 33.3%., Conclusion: Young patients with epithelial ovarian carcinoma appeared to have favorable stage and histologic grade. These factors combined with good performance status and optimal cytoreduction resulted in improved survival from cancer.