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Objective: Stage IB-IIA cervical carcinoma can be equally cured either by radical surgery or radiotherapy (RT). Albeit such policies show the same efficacy, they carry a different morbidity. This is an update after 20 years of a previously published randomized trial of RT vs. surgery in the treatment of stage IB-IIA cervical cancers to assess long-term survival and morbidity and the different pattern of relapse between the 2 modalities., Methods: Between September 1986 and December 1991, women referred for a newly diagnosed stage IB and IIA cervical carcinoma were randomized to radical surgery or RT. The primary outcome measures were long-term survival and complications rate. The secondary outcome was recurrence of the disease., Results: Three-hundred forty-three eligible women were randomized: 172 to radical surgery and 171 to external RT. Minimum follow-up was 19 years. Thirty-three patients (10%) died of intercurrent disease (31 cases) or fatal complications (2 cases). Twenty-year overall survival is 72% and 77% in the 2 treatment groups (p=0.280), respectively. As a whole, 94 recurrences (28%) were observed. Median time to relapse was 13.5 (surgery group) and 11.5 months (radiotherapy group) (p=0.100), respectively. Multivariate analysis confirms that risk factors for survival are histotype (p=0.020), tumor diameter (p=0.008), and lymph node status (p<0.001)., Conclusion: The results of the present study seem to suggest that there is no treatment of choice for early stage cervical carcinoma in terms of survival. Long term follow-up confirms that the best treatment for the individual patient should take into account clinical factors such as menopausal status, comorbidities, histological type, and tumor diameter., Competing Interests: No potential conflict of interest relevant to this article was reported., (Copyright © 2017. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology)

Purpose: Stage I epithelial ovarian cancer (EOC) represents about 10% of all EOCs and is characterized by good prognosis with fewer than 20% of patients relapsing. As it occurs less frequently than advanced-stage EOC, its molecular features have not been thoroughly investigated. We have demonstrated that in stage I EOC miR-200c-3p can predict patients' outcome. In the present study, we analyzed the expression of long non-coding RNAs (lncRNA) to enable potential definition of a non-coding transcriptional signature with prognostic relevance for stage I EOC. Experimental Design: 202 snap-frozen stage I EOC tumor biopsies, 47 of which relapsed, were gathered together from three independent tumor tissue collections and subdivided into a training set ( n = 73) and a validation set ( n = 129). Median follow up was 9 years. LncRNAs' expression profiles were correlated in univariate and multivariate analysis with overall survival (OS) and progression-free survival (PFS). Results: The expression of lnc-SERTAD2 - 3, lnc-SOX4-1, lnc-HRCT1-1 , and PVT1 was associated in univariate and multivariate analyses with relapse and poor outcome in both training and validation sets ( P < 0.001). Using the expression profiles of PVT1, lnc-SERTAD2 - 3 , and miR-200c-3p simultaneously, it was possible to stratify patients into high and low risk. The OS for high- and low-risk individuals are 36 and 123 months, respectively (OR, 15.55; 95% confidence interval, 3.81-63.36). Conclusions: We have identified a non-coding transcriptional signature predictor of survival and biomarker of relapse for stage I EOC. Clin Cancer Res; 23(9); 2356-66. ©2016 AACR ., (©2016 American Association for Cancer Research.)

Background: The objective of this study is to evaluate the safety of fertility-sparing surgery (FSS) for early-stage epithelial ovarian cancer (EOC)., Methods: A retrospective analysis was performed to identify patients treated for early-stage EOC and to compare the clinical outcomes of patients treated with FSS and radical surgery (RS)., Results: A total of 1031 patients were treated at two Institutions, 242 with FSS (group A) and 789 with RS (group B). Median duration of follow-up was 11.9 years. At univariate analyses, FSS was associated with decreased risk of relapse (P=0.002) and of tumour-related death (P=0.001). Multivariate analysis did not confirm the independent positive role of FSS neither on relapse-free interval (RFI) nor on cancer-specific survival (CSS). Tumour grade was associated with shorter RFI (P<0.001) and shorter CSS (P=0.001). The type of treatment did not influence CSS or RFI in any grade group. We also found a significant association between low-grade tumours and younger age., Conclusions: Fertility-sparing surgery is an adequate treatment for patients with stage I EOC. The clinical outcome of patients with G3 tumours, which is confirmed to be the most important prognostic factor, is not determined by the type of treatment received.

Background: Clinical and pathological parameters of patients with epithelial ovarian cancer (EOC) do not thoroughly predict patients' outcome. Despite the good outcome of stage I EOC compared with that of stages III and IV, the risk assessment and treatments are almost the same. However, only 20% of stage I EOC cases relapse and die, meaning that only a proportion of patients need intensive treatment and closer follow-up. Thus, the identification of cell mechanisms that could improve outcome prediction and rationalize therapeutic options is an urgent need in the clinical practice., Patients and Methods: We have gathered together 203 patients with stage I EOC diagnosis, from whom snap-frozen tumor biopsies were available at the time of primary surgery before any treatment. Patients, with a median follow-up of 7 years, were stratified into a training set and a validation set., Results and Conclusions: Integrated analysis of miRNA and gene expression profiles allowed to identify a prognostic cell pathway, composed of 16 miRNAs and 10 genes, wiring the cell cycle, 'Activins/Inhibins' and 'Hedgehog' signaling pathways. Once validated by an independent technique, all the elements of the circuit resulted associated with overall survival (OS) and progression-free survival (PFS), in both univariate and multivariate models. For each patient, the circuit expressions have been translated into an activation state index (integrated signature classifier, ISC), used to stratify patients into classes of risk. This prediction reaches the 89.7% of sensitivity and 96.6% of specificity for the detection of PFS events. The prognostic value was then confirmed in the external independent validation set in which the PFS events are predicted with 75% sensitivity and 94.7% specificity. Moreover, the ISC shows higher classification performance than conventional clinical classifiers. Thus, the identified circuit enhances the understanding of the molecular mechanisms lagging behind stage I EOC and the ISC improves our capabilities to assess, at the time of diagnosis, the patient risk of relapse., (© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose: Epithelial ovarian cancer (EOC) is one of the most lethal gynecologic diseases, with survival rate virtually unchanged for the past 30 years. EOC comprises different histotypes with molecular and clinical heterogeneity, but up till now the present gold standard platinum-based treatment has been conducted without any patient stratification. The aim of the present study is to generate microRNA (miRNA) profiles characteristic of each stage I EOC histotype, to identify subtype-specific biomarkers to improve our understanding underlying the tumor mechanisms., Experimental Design: A collection of 257 snap-frozen stage I EOC tumor biopsies was gathered together from three tumor tissue collections and stratified into independent training (n = 183) and validation sets (n = 74). Microarray and quantitative real-time PCR (qRT-PCR) were used to generate and validate the histotype-specific markers. A novel dedicated resampling inferential strategy was developed and applied to identify the highest reproducible results. mRNA and miRNA profiles were integrated to identify novel regulatory circuits., Results: Robust miRNA markers for clear cell and mucinous histotypes were found. Specifically, the clear cell histotype is characterized by a five-fold (log scale) higher expression of miR-30a and miR-30a*, whereas mucinous histotype has five-fold (log scale) higher levels of miR-192/194. Furthermore, a mucinous-specific regulatory loop involving miR-192/194 cluster and a differential regulation of E2F3 in clear cell histotype were identified., Conclusions: Our findings showed that stage I EOC histotypes have their own characteristic miRNA expression and specific regulatory circuits., (©2013 AACR.)

Background: To assess the long-term oncological outcome and the fertility of young women with early-stage epithelial ovarian cancer (ES/EOC) treated with fertility-sparing surgery (FSS)., Patients and Methods: All patients treated with FSS for ES/EOC in two Italian centers were considered for this analysis. Univariate and multivariate analyses were used to test demographic characteristics and clinical features for the association with overall survival (OS), recurrence-free survival (RFS) and fertility., Results: From 1982 to 2010, 240 patients with malignant ES/EOC were treated with FSS in two tertiary centers in Italy. At a median follow-up of 9 years, 27 patients had relapsed (11%) and 11 (5%) had died of progressive disease. Multivariate analysis found only grade 3 negatively affected the prognosis of patients [hazard ratio (HR) for recurrence: 4.2, 95% confidence interval (CI): 1.5-11.7, P=0.0067; HR for death: 7.6, 95% CI: 2.0-29.3, P=0.0032]. Grade 3 was also significantly associated with extra-ovarian relapse (P=0.006). Of the 105 patients (45%) who tried to become pregnant, 84 (80%) were successful., Conclusions: Conservative treatment can be proposed to all young patients when tumor is limited to the ovaries, as ovarian recurrences can always be managed successfully. Patients with G3 tumors are more likely to have distant recurrences and should be closely monitored.

Background: The role of systematic aortic and pelvic lymphadenectomy (SAPL) at second-look surgery in early stage or optimally debulked advanced ovarian cancer is unclear and never addressed by randomised studies., Methods: From January 1991 through May 2001, 308 patients with the International Federation of Gynaecology and Obstetrics stage IA-IV epithelial ovarian carcinoma were randomly assigned to undergo SAPL (n=158) or resection of bulky nodes only (n=150). Primary end point was overall survival (OS)., Results: The median operating time, blood loss, percentage of patients requiring blood transfusions and hospital stay were higher in the SAPL than in the control arm (P<0.001). The median number of resected nodes and the percentage of women with nodal metastases were higher in the SAPL arm as well (44% vs 8%, P<0.001 and 24.2% vs 13.3%, P:0.02). After a median follow-up of 111 months, 171 events (i.e., recurrences or deaths) were observed, and 124 patients had died. Sites of first recurrences were similar in both arms. The adjusted risk for progression and death were not statistically different (hazard ratio (HR) for progression=1.18, 95% confidence interval (CI)=0.87-1.59; P=0.29; 5-year progression-free survival (PFS)=40.9% and 53.8%; HR for death=1.04, 95% CI=0.733-1.49; P=0.81; 5-year OS=63.5% and 67.4%, in the SAPL and in the control arm, respectively)., Conclusion: SAPL in second-look surgery for advanced ovarian cancer did not improve PFS and OS.

Solid tumors appear to contain a subpopulation of cells (tumor-initiating cells, TICs) that not only drives and sustains tumor growth, but is possibly responsible for recurrence. We isolated, after enzymatic digestion of primary ovarian carcinoma samples, a subpopulation of cells propagating as non-adherent spheres in medium suitable for tumor stem cells. These cells were able to self-renew in vitro, as suggested by PKH-26 staining studies, were tumorigenic and acquired an epithelial morphology when grown in FBS-supplemented medium, losing their tumorigenic potential. Interestingly, the tumorigenic potential of PKH-26 (high) - and PKH-26 (neg) -sorted cells was similar. These TIC-enriched cultures showed higher levels of genes involved in stemness than differentiated cells derived from them and were more resistant to the cytotoxic effects of some drugs but equally sensitive to others. The higher level of ABCG2 efflux pump could explain increased resistance to taxol and VP16, and higher levels of genes involved in nucleotide excision repair partially explain the resistance to cisplatin. These cells express mesenchymal markers, and epithelial transition could be induced when cultured in differentiating conditions, with a loss of invasive potential. These data suggest that ovarian cancer is a stem cell disease and should help elucidate the role of these cells in the aggressive phenotype of this tumor and find new therapeutic strategies to reduce resistance to current chemotherapeutic drugs.

This randomized, open label, phase III clinical trial (1988-1992) compared the efficacy and safety of a dose-dense regimen of single-agent cisplatin with a standard 3-weekly schedule in first-line chemotherapy for advanced epithelial ovarian cancer. Two hundred eighty-five patients were randomly assigned to the experimental dose-dense arm (cisplatin 50 mg/m(2) weekly × nine cycles) or to the control (standard treatment) arm (cisplatin 75 mg/m(2), administered on day 1 every 21 days × six cycles). The primary outcome was progression-free survival (PFS). Secondary outcomes were overall survival (OS), overall response to chemotherapy, and toxicity. Toxicity and response to treatment were compared with the χ(2) test using trend or exact correction. PFS and OS were estimated by Kaplan-Meier analyses and treatment hazard ratios (HRs) with the Cox proportional hazards model. All statistical tests were two-sided. After a median follow-up of 16.8 years, no differences were observed between the two treatments in PFS (experimental arm: 17.2 months; control arm: 18.1 months; HR = 1.08, 95% confidence interval [CI] = 0.83 to 1.40; P = .57) and in OS (experimental arm: 35 months; control arm: 32 months; HR = 0.97, 95% CI = 0.75 to 1.26; P = .97). Thus, increasing dose intensity of cisplatin does not improve PFS or OS compared with standard chemotherapy.

Background: Pelvic lymph nodes are the most common site of extrauterine tumor spread in early-stage endometrial cancer, but the clinical impact of lymphadenectomy has not been addressed in randomized studies. We conducted a randomized clinical trial to determine whether the addition of pelvic systematic lymphadenectomy to standard hysterectomy with bilateral salpingo-oophorectomy improves overall and disease-free survival., Methods: From October 1, 1996, through March 31, 2006, 514 eligible patients with preoperative International Federation of Gynecology and Obstetrics stage I endometrial carcinoma were randomly assigned to undergo pelvic systematic lymphadenectomy (n = 264) or no lymphadenectomy (n = 250). Patients' clinical data, pathological tumor characteristics, and operative and early postoperative data were recorded at discharge from hospital. Late postoperative complications, adjuvant therapy, and follow-up data were collected 6 months after surgery. Survival was analyzed by use of the log-rank test and a Cox multivariable regression analysis. All statistical tests were two-sided., Results: The median number of lymph nodes removed was 30 (interquartile range = 22-42) in the pelvic systematic lymphadenectomy arm and 0 (interquartile range = 0-0) in the no-lymphadenectomy arm (P < .001). Both early and late postoperative complications occurred statistically significantly more frequently in patients who had received pelvic systematic lymphadenectomy (81 patients in the lymphadenectomy arm and 34 patients in the no-lymphadenectomy arm, P = .001). Pelvic systematic lymphadenectomy improved surgical staging as statistically significantly more patients with lymph node metastases were found in the lymphadenectomy arm than in the no-lymphadenectomy arm (13.3% vs 3.2%, difference = 10.1%, 95% confidence interval [CI] = 5.3% to 14.9%, P < .001). At a median follow-up of 49 months, 78 events (ie, recurrence or death) had been observed and 53 patients had died. The unadjusted risks for first event and death were similar between the two arms (hazard ratio [HR] for first event = 1.10, 95% CI = 0.70 to 1.71, P = .68, and HR for death = 1.20, 95% CI = 0.70 to 2.07, P = .50). The 5-year disease-free and overall survival rates in an intention-to-treat analysis were similar between arms (81.0% and 85.9% in the lymphadenectomy arm and 81.7% and 90.0% in the no-lymphadenectomy arm, respectively)., Conclusion: Although systematic pelvic lymphadenectomy statistically significantly improved surgical staging, it did not improve disease-free or overall survival.

Introduction: Benign metastasising leiomyoma refers to a type of lesion characterised by leiomyomatous alterations without any indication of malignancy. It presents as either a singular nodule or multiple nodules of proliferating smooth muscle cells and is generally found in the lungs of women who have undergone a hysterectomy. The purpose of this case report is to contribute to the knowledge of this rare disease by presenting evidence and experience of a patient case. In particular, this report seeks to investigate the therapeutic approaches in order to understand whether a standard of care can be prescribed and whether the use of prophylaxis therapy with progesterone as a follow-up to surgery serves as a reasonable treatment in certain cases diagnosed as benign metastasising leiomyoma., Case Presentation: We present the case of a 52-year-old Caucasian woman who developed a pelvic relapse and a pulmonary localisation of benign metastasising leiomyoma following a hysterectomy for myomatous uterus., Conclusion: Our literature review revealed a single case of the use of chemoprophylaxis as treatment of a benign metastasising leiomyoma. The role of chemoprophylaxis in preventing future recurrences remains unclear. The use of progesterone as an adjuvant therapy for benign metastasising leiomyoma could simply be palliative, with associated psychological benefits, or it could be of therapeutic significance.

To test the feasibility and efficacy of epirubicin and ifosfamide added to first-line chemotherapy with cisplatin and paclitaxel in a phase II randomised clinical trial. Patients with histologically proven epithelial ovarian cancer were randomly assigned to receive first-line polychemotherapy with cisplatin/paclitaxel/epirubicin (CEP) or cisplatin/paclitaxel/ifosfamide (CIP) for six cycles every 21 days. Two hundred and eight patients were randomised between the two treatment arms and the median number of cycles per patient was six. Toxicity was predominantly haematological with both regimens; however, anaemia, leucopaenia, neutropaenic fever and use of granulocyte colony-stimulating factors and transfusion were significantly more frequent in the CIP treatment arm. Response rates were 85% (95% confidence interval (CI) 77-93%) in the CIP arm and 90% (95% CI 84-96%) in the CEP arm; complete response rates were 48 and 52%. After a median follow-up of 82 months, median overall survival (OS) was 51 and 65 months; 5-year survival rates were respectively 43 and 50%. In this clinical trial, both regimens showed good efficacy, but toxicity was heavier with the CIP regimen. Considering that more than 50% of patients were suboptimally debulked after the first surgery, OS seems to be longer than is commonly reported. This unexpected finding might be a consequence of the close surgical surveillance and aggressive chemotherapeutic approach.

No randomised trials have addressed the value of systematic aortic and pelvic lymphadenectomy (SL) in ovarian cancer macroscopically confined to the pelvis. This study was conducted to investigate the role of SL compared with lymph nodes sampling (CONTROL) in the management of early stage ovarian cancer. A total of 268 eligible patients with macroscopically intrapelvic ovarian carcinoma were randomised to SL (N=138) or CONTROL (N=130). The primary objective was to compare the proportion of patients with retroperitoneal nodal involvement between the two groups. Median operating time was longer and more patients required blood transfusions in the SL arm than the CONTROL arm (240 vs 150 min, P<0.001, and 36 vs 22%, P=0.012, respectively). More patients in the SL group had positive nodes at histologic examination than patients on CONTROL (9 vs 22%, P=0.007). Postoperative chemotherapy was delivered in 66% and 51% of patients with negative nodes on CONTROL and SL, respectively (P=0.03). At a median follow-up of 87.8 months, the adjusted risks for progression (hazard ratio [HR]=0.72, 95%CI=0.46-1.21, P=0.16) and death (HR=0.85, 95%CI=0.49-1.47, P=0.56) were lower, but not statistically significant, in the SL than the CONTROL arm. Five-year progression-free survival was 71.3 and 78.3% (difference=7.0%, 95% CI=-3.4-14.3%) and 5-year overall survival was 81.3 and 84.2% (difference=2.9%, 95% CI=-7.0-9.2%) respectively for CONTROL and SL. SL detects a higher proportion of patients with metastatic lymph nodes. This trial may have lacked power to exclude clinically important effects of SL on progression free and overall survival.

Purpose: The PRL-3 phosphatase has been found expressed at higher levels in metastasis than in primary tumors of patients with colorectal cancer. In the present study, we evaluated the expression of PRL-3 in ovarian cancer tissue and its role in ovarian cancer cell growth., Experimental Design: PRL-3 phosphatase expression was evaluated in 84 ovarian tumor samples. PRL-3 expression has been knocked down using specific small interfering RNAs to determine its role in ovarian cancer cell growth in vitro., Results: In ovarian cancers, PRL-3 expression correlates with disease progression, being higher in advanced (stage III) than in early (stage I) tumors. In situ measurements of PRL-3 expression showed that it was confined to the epithelial neoplastic cells. The molecular mechanism underlying PRL-3 overexpression in ovarian cancers is independent from amplification of the corresponding genomic locus. Ovarian cancer cells growing in culture have high levels of expression of this phosphatase. PRL-3-specific knockdown using small interfering RNA severely impaired the growth of cells without affecting the expression of the closely related homologue PRL-1. Intriguingly, the growth of human colon carcinoma cells expressing lower levels of the PRL-3 was not affected by the PRL-3 knockdown., Conclusions: Altogether, these results show that PRL-3 expression is associated with ovarian cancer progression and point to a key role for this phosphatase in the control of ovarian cancer cells growth. This strongly suggests that PRL-3 should be considered as a target for the discovery of new anticancer agents to be tested against this malignancy.

Background: The role of systematic aortic and pelvic lymphadenectomy in patients with optimally debulked advanced ovarian cancer is unclear and has not been addressed by randomized studies. We conducted a randomized clinical trial to determine whether systematic aortic and pelvic lymphadenectomy improves progression-free and overall survival compared with resection of bulky nodes only., Methods: From January 1991 through May 2003, 427 eligible patients with International Federation of Gynecology and Obstetrics (FIGO) stage IIIB-C and IV epithelial ovarian carcinoma were randomly assigned to undergo systematic pelvic and para-aortic lymphadenectomy (n = 216) or resection of bulky nodes only (n = 211). Progression-free survival and overall survival were analyzed using a log-rank statistic and a Cox multivariable regression analysis. All statistical tests were two-sided., Results: After a median follow-up of 68.4 months, 292 events (i.e., recurrences or deaths) were observed, and 202 patients had died. Sites of first recurrences were similar in both arms. The adjusted risk for first event was statistically significantly lower in the systematic lymphadenectomy arm (hazard ratio [HR] = .75, 95% confidence interval [CI] = 0.59 to 0.94; P = .01) than in the no-lymphadenectomy arm, corresponding to 5-year progression-free survival rates of 31.2 and 21.6% in the systematic lymphadenectomy and control arms, respectively (difference = 9.6%, 95% CI = 1.5% to 21.6%), and to median progression-free survival of 29.4 and 22.4 months, respectively (difference = 7 months, 95% CI = 1.0 to 14.4 months). The risk of death was similar in both arms (HR = 0.97, 95% CI = 0.74 to 1.29; P = .85), corresponding to 5-year overall survival rates of 48.5 and 47%, respectively (difference = 1.5%, 95% CI = -8.4% to 10.6%), and to median overall survival of 58.7 and 56.3 months, respectively (difference = 2.4 months, 95% CI = -11.8 to 21.0 months). Median operating time was longer, and the percentage of patients requiring blood transfusions was higher in the systematic lymphadenectomy arm than in the no-lymphadenectomy arm (300 versus 210 minutes, P<.001, and 72% versus 59%; P = .006, respectively)., Conclusion: Systematic lymphadenectomy improves progression-free but not overall survival in women with optimally debulked advanced ovarian carcinoma.

The aim of the study was to evaluate the role of epidoxorubicin plus paclitaxel combination (ET) vs single agent paclitaxel (T), as second-line chemotherapy treatment in advanced ovarian cancer patients in early progression within 12 months after platinum-based chemotherapy. From October 1994 up to June 1999, 234 patients from 34 Italian hospitals were randomised to receive: (A) epidoxorubicin (E) 80 mg m(-2) + paclitaxel (T) 175 mg m(-2) (3 h infusion), every 21 days for 4-6 cycles. (B) Paclitaxel 175 mg m(-2) (3 h infusion) every 21 days for 4-6 cycles. Evaluable for survival analysis were 106 and 106 patients in ET and T arm, respectively. Platinum-based monochemotherapy was the first-line treatment in 43% patients, while polichemotherapy containing anthracyclines was the preferred first-line therapy in 22% patients. The median time from the end of first-line therapy to randomisation was 3 months. Treatment was completed in 87 and 85% of T and ET arm, respectively. Haematological toxicity was significantly more common in ET group (ECOG grade 3-4 neutropenia: 37.4% in ET vs 18.2% in T arm). Neuropathies were similar in both arms (sensory: ECOG grade 2-3: 12.1% in ET vs 14.7% in T arm, motor: 6.1% in ET vs 5.3% in T arm). Objective response was achieved in 37.4% of patients in ET group and in 46.9% of patients in T arm. At a median follow-up of time of 48 months, a total of 180 patients progressed and 163 patients died. Survival analysis showed no difference between ET and T (median time to progression: 6 months for both regimens, median survival: 12 and 14 months for ET and T, respectively; hazard ratio for mortality of ET vs T: 1.17 (95% CI 0.86-1.59; P=0.33). The ET regimen does not seem to be more effective than T in refractory advanced ovarian cancer patients in early progression after platinum-based chemotherapy. Despite an acceptable response rate, the control of disease progression remains poor.

Background: All randomized trials of adjuvant chemotherapy for early-stage ovarian cancer have lacked the statistical power to show a difference in the effect on survival between adjuvant chemotherapy and no adjuvant chemotherapy. They have also not taken into account the adequacy of surgical staging. We performed a prospective unblinded, randomized phase III trial to test the efficacy of adjuvant chemotherapy in patients with early-stage ovarian cancer, with emphasis on the extent of surgical staging., Methods: Between November 1990 and January 2000, 448 patients from 40 centers in nine European countries were randomly assigned to either adjuvant platinum-based chemotherapy (n = 224) or observation (n = 224) following surgery. Endpoints were overall survival and recurrence-free survival, and the analysis was on an intention-to-treat basis. The Kaplan-Meier method was used to perform time-to-event analysis, and the log-rank test was used to compare differences between treatment arms. Statistical tests were two-sided., Results: After a median follow-up of 5.5 years, the difference in overall survival between the two trial arms was not statistically significant (hazard ratio [HR] = 0.69, 95% confidence interval [CI] = 0.44 to 1.08; P =.10). Recurrence-free survival, however, was statistically significantly improved in the adjuvant chemotherapy arm (HR = 0.63, 95% CI = 0.43 to 0.92; P =.02). Approximately one-third of patients (n = 151) had been optimally staged and two-thirds (n = 297) had not. Among patients in the observation arm, optimal staging was associated with a statistically significant improvement in overall and recurrence-free survival (HR = 2.31 [95% CI = 1.08 to 4.96]; P =.03 and HR = 1.82 [95% CI = 1.02 to 3.24] P =.04, respectively). No such association was observed in the chemotherapy arm. In the non-optimally staged patients, adjuvant chemotherapy was associated with statistically significant improvements in overall and recurrence-free survival (HR = 1.75 [95% CI = 1.04 to 2.95]; P =.03 and HR = 1.78 [95% CI = 1.15 to 2.77]; P =.009, respectively). In the optimally staged patients, no benefit of adjuvant chemotherapy was seen., Conclusion: Adjuvant chemotherapy was associated with statistically significantly improved recurrence-free survival in patients with early-stage ovarian cancer. The benefit of adjuvant chemotherapy appeared to be limited to patients with non-optimal staging, i.e., patients with more risk of unappreciated residual disease.

Background: Adjuvant chemotherapy has been suggested as a possible strategy to improve survival in women with early-stage ovarian cancer; however, all randomized studies to date have been too small to answer this question reliably., Methods: We performed a preplanned combined analysis of two parallel randomized clinical trials (International Collaborative Ovarian Neoplasm 1 [ICON1] and Adjuvant ChemoTherapy In Ovarian Neoplasm [ACTION]) in early-stage ovarian cancer that compared platinum-based adjuvant chemotherapy with observation following surgery. Between November 1990 and January 2000, 925 patients (477 in ICON1 and 448 in ACTION) who had surgery for early-stage ovarian cancer were randomly assigned to receive platinum-based adjuvant chemotherapy (n = 465) or observation (n = 460) until chemotherapy was indicated. Kaplan-Meier analysis was used to compare overall and recurrence-free survival by treatment allocation. In subgroup analyses of pretreatment age, tumor stage, histologic cell type, and differentiation grade, the differences in relative size of effect were tested using a chi-square test for interaction or a chi-square test for trend. All tests of statistical significance were two-sided., Results: After a median follow-up of over 4 years, 245 patients had died or had a recurrence (ICON1: 133, ACTION: 112). Overall survival at 5 years was 82% in the chemotherapy arm and 74% in the observation arm (difference = 8% [95% confidence interval (CI) = 2% to 12%]; hazard ratio [HR] = 0.67, 95% CI = 0.50 to 0.90; P =.008). Recurrence-free survival at 5 years was also better in the adjuvant chemotherapy arm than it was in the observation arm (76% versus 65%, difference = 11% [95% CI = 5% to 16%]; HR = 0.64, 95% CI = 0.50 to 0.82; P =.001). Subgroup analyses provided no evidence of a difference in the size of effect of chemotherapy on survival in any pretreatment subcategory., Conclusions: Platinum-based adjuvant chemotherapy improved overall survival and recurrence-free survival at 5 years in this combined group of patients with early-stage ovarian cancer defined by the inclusion criteria of the ICON1 and ACTION trials.

Background: A randomized trial conducted by the Gynecologic Oncology Group (GOG, study #111) in the United States showed a better outcome for patients with advanced ovarian cancer on the paclitaxel-cisplatin regimen than for those on a standard cyclophosphamide-cisplatin regimen. Before considering the paclitaxel-cisplatin regimen as the new "standard," a group of European and Canadian investigators planned a confirmatory phase III trial., Methods: This intergroup trial recruited 680 patients with broader selection criteria than the GOG #111 study and administered paclitaxel as a 3-hour instead of a 24-hour infusion; progression-free survival was the primary end point. Patient survival was analyzed by use of the Kaplan-Meier technique. Treatment effects on patient survival were estimated by Cox proportional hazards regression models. All statistical tests were two-sided., Results: The overall clinical response rate was 59% in the paclitaxel group and 45% in the cyclophosphamide group; the complete clinical remission rates were 41% and 27%, respectively; both differences were statistically significant (P =.01 for both). At a median follow-up of 38.5 months and despite a high rate of crossover (48%) from the cyclophosphamide arm to the paclitaxel arm at first detection of progression of disease, a longer progression-free survival (log-rank P =.0005; median of 15.5 months versus 11.5 months) and a longer overall survival (log-rank P =. 0016; median of 35.6 months versus 25.8 months) were seen in the paclitaxel regimen compared with the cyclophosphamide regimen., Conclusions: There is strong and confirmatory evidence from two large randomized phase III trials to support paclitaxel-cisplatin as the new standard regimen for treatment of patients with advanced ovarian cancer.

Lymph node pathologic status is the most important prognostic factor in vulvar cancer; however, complete inguinofemoral node dissection is associated with significant morbidity. Lymphoscintigraphy associated with gamma-probe guided surgery reliably detects sentinel nodes in melanoma and breast cancer patients. This study evaluates the feasibility of the surgical identification of sentinel groin nodes using lymphoscintigraphy and a gamma-detecting probe in patients with early vulvar cancer. Technetium-99m-labelled colloid human albumin was administered perilesionally in 37 patients with invasive epidermoid vulvar cancer (T1-T2) and lymphoscintigraphy performed the day before surgery. An intraoperative gamma-detecting probe was used to identify sentinel nodes during surgery. A complete inguinofemoral node dissection was then performed. Sentinel nodes were submitted separately to pathologic evaluation. A total of 55 groins were dissected in 37 patients. Localization of the SN was successful in all cases. Eight cases had positive nodes: in all the sentinel node was positive; the sentinel node was the only positive node in five cases. Twenty-nine patients showed negative sentinel nodes: all of them were negative for lymph node metastases. Lymphoscintigraphy and sentinel-node biopsy under gamma-detecting probe guidance proved to be an easy and reliable method for the detection of sentinel node in early vulvar cancer. This technique may represent a true advance in the direction of less aggressive treatments in patients with vulvar cancer.

Purpose: The results of salvage chemotherapy for recurrent or persistent squamous-cell cervical cancer are unsatisfactory. Cisplatin and Ifosfamide are effective compounds in cervical cancer. Paclitaxel has recently been tested with promising results. The aim of this study was to assess the efficacy of a combination of paclitaxel, ifosfamide and cisplatin (TIP) for persistent/recurrent squamous-cell cervical carcinoma in a phase II trial., Patients and Methods: Forty-five women were treated with the TIP regimen. Thirty-one had received prior irradiation. Paclitaxel was given at a dose of 175 mg/m2, ifosfamide at a dose of 5 g/m2, and cisplatin at a dose of 75 mg/m2 (50 mg/m2 in irradiated patients) at three-week intervals., Results: We observed 15 clinical complete responses, 15 partial responses, 9 stable diseases and 6 progressions. The objective response rate was 67% (95% confidence interval: 51%-81%). Ten complete responders underwent subsequent surgery and seven had pathology-defined complete responses (two in irradiated areas). The response rate was 52% in irradiated and 75% in non-irradiated areas. The median survival for non-responders is 6 months, 9+ month for partial responders and 13+ for complete responders. The most relevant side effect was myelotoxicity, with 91% of patients experiencing grade 3-4. One woman had life-threatening toxic effects., Conclusions: This combination is highly effective for salvage treatment in non-irradiated patients. For irradiated women the response rate is higher than that observed with other regimens but further investigation is warranted. The toxicity is relevant but adequate hydration and prolonged infusion of ifosfamide make it acceptable.

Background: Results of salvage therapy in patients with carcinoma of the uterine cervix recurrent after surgery have been dismal even when the disease was apparently confined to the pelvis. Concurrent chemoradiation is one of the several avenues being investigated to improve these results., Patients and Methods: Thirty-five women with recurrent cervical carcinoma were enrolled in the trial. Twenty-eight patients (80%) had disease limited to the central pelvis (ten), lateral pelvis (fourteen) and vagina (four) and seven had paraortic metastases. Patients were treated with a combination of external radiotherapy (50-70 Gy) along with three cycles of 5-fluorouracil (1000 mg/m2/24-hour continuous infusion days 1-4) and carboplatin (75 mg/m2 in bolus days 1-4)., Results: Treatment was well tolerated, with 30 patients (86%) completing the protocol as planned. Acute toxicity was severe but manageable; 11 patients (31%) experienced grades 3-4 acute toxicity. Late morbidity occurred in five patients (14%). Overall response rate was 74% (11 partial responses and 15 complete). After a median follow-up of 27 months (range 18-90), 13 patients (37%) are alive without disease, 4 (11%) are alive with persistent disease and 18 (52%) are dead of their disease. Actuarial two-year survival rate for the series as a whole is 44% and three-year survival is 25%. Stage of the primary disease, site of recurrence, interval from the primary therapy to recurrence, lymph node involvement, ureterohydronephrosis at the time of recurrence and diameter of the relapse are the most significant factors for survival, while complete response is related to diameter and site of relapse and lymph node status at the time of relapse., Conclusion: The acceptable toxicity, high response rate and satisfying survival would suggest that concomitant carboplatin/5-fluorouracil and radiotherapy is a safe and tolerable treatment for recurrent cervical carcinoma. Further studies are needed to demonstrate an eventual survival benefit of this type of chemoradiation over standard radiotherapy alone and to identify the subsets of patients who in particular might benefit from this.

Sarcoma botryoides of the cervix is an extremely rare tumour and seems to be associated with a better prognosis than its vaginal counterpart. Recent studies have suggested that it is possible to limit surgery to local excision in stage I cases. We report three cases of young subjects treated successfully with polypectomy or diathermy loop excision followed by adjuvant chemotherapy. One patient had a local recurrence which was treated with further local excision. All subjects remain alive without evidence of recurrence and with normal menstrual function 36, 38 and 38 months following initial diagnosis. A conservative surgical approach to early cervical sarcoma botryoides is possible. The efficacy of adjuvant chemotherapy and the regimen of choice still need to be investigated.

Background: Several prognostic factors for stage I ovarian carcinoma have been analyzed. Some of them are biological and clinical in nature, but others such as the thoroughness of the staging procedure, the extent of the surgery and the philosophy of treatment, are defined by the human element., Patients and Methods: We reviewed the records of 351 patients with Stage I ovarian cancer who had been treated from 1981 to 1991. For all patients the following information was available: age, size of the tumor, FIGO sub-stage, tumor grade, histologic type, rupture of the tumor, cytology, extent of the staging and of the surgery (hysterectomy and bilateral salpingo-oophorectomy vs. fertility-conserving surgery) and use of adjuvant treatments. The thoroughness of the staging was defined as: optimal staging: total abdominal hysterectomy and bilateral salpingo-oophorectomy or fertility-conserving surgery, peritoneal cytology or washing, omentectomy, multiple peritoneal biopsies, sampling of the retroperitoneal nodes or formal lymphadenectomy, peritoneal staging: all the criteria described above were met with the exception of retroperitoneal sampling, incomplete staging: lack of any of the previously-cited criteria., Results: An optimal staging was performed in 100 patients, a peritoneal staging in 107 and an incomplete staging in 144. Radical surgery was performed in 295 women and fertility-conserving surgery in 56. With a median follow-up of 108 months (range 14-184) 64 patients had recurrence of the tumor. Fifty-three died of the disease, two are currently alive with disease and nine were salvaged by surgery and/or chemotherapy. In a multivariate analysis only the tumor grade and the type of staging were significant independent prognostic factors for both disease-free and overall survival., Conclusions: As described by other authors, we confirm that tumor grade is the single most important biological prognostic factor in early ovarian carcinoma. The thoroughness of the staging impacts significantly on survival, particularly in poorly differentiated carcinomas. Fertility-sparing surgery is not associated with a worse outcome than standard radical surgery.

Background: Neoadjuvant chemotherapy is increasingly being used for the treatment of bulky and locally-advanced cervical cancer. Cisplatin and ifosfamide are known to be effective in cervical cancer, while paclitaxel is one of the promising new drugs for the treatment of this neoplasm., Objective: To assess the toxic effects and antitumor activity of a multidrug neoadjuvant regimen consisting of cisplatin, ifosfamide, and paclitaxel in bulky and locally advanced cervical cancer., Patients and Methods: Thirty-eight patients with pathology-confirmed squamous-cell cervical cancer (27 IB2-IIA, two IIB, eight IIIB, one IVA) were prospectively enrolled in the study. Their treatment consisted of paclitaxel 175 mg/m2 given over three hours on day 1, cisplatin 50 mg/m2 (75 mg/m2 in 10 patients), ifosfamide 5 g/m2 in a 24-hour continuous infusion and mesna 5 g/m2 in a 24-hour continuous infusion on day 2, and mesna 3 g/m2 in a 24-hour continuous infusion on day 3. The course was repeated every three weeks for three courses and all of the patients, except those with disease progression or who were inoperable, were scheduled for radical hysterectomy and pelvic lymphadenectomy., Results: All patients are evaluable for response. Eleven achieved clinical complete responses, 21 had partial responses, five had stable disease and one had progression of disease. Of 34 patients who underwent surgery, six (16%) had pathology-documented complete responses, seven (18%) had partial responses with only microscopic residual disease in the cervix, 19 had sub-optimal partial responses, and two had stable disease, for an overall response rate of 84% (95% confidence intervals (CI): 68.7%-94%). Grade 3-4 neutropenia was recorded for 27 (71%) patients, grade 3-4 thrombocytopenia for four (10.5%), and grade 2 peripheral neuropathy for two (2.5%). At a median follow-up of 16 months (range 7-22), 29 (76%) women are alive without recurrence, seven are alive with persistent/recurrent disease and two have died of their disease., Conclusions: According to pathology examination, this regimen yields a 34% complete and optimal partial response rate with acceptable toxicity, and it should be prospectively compared to other regimens.

Background: The levels and activity of topoisomerase I were determined in 35 biopsies from patients with ovarian cancer., Patients and Methods: The activity was defined by the ability to relax supercoiled DNA plasmid, and levels were determined by Western blotting and immunohistochemistry., Results: We detected topoisomerase I activity in all samples, although at different levels. Enzymatic activity was the same in fresh and frozen tissues. Western blotting analysis detected topoisomerase I in 29 of 35 tumor samples but in the remaining six the levels were below the detection limit. We analyzed the distribution of topoisomerase I in tumor cells and normal infiltrating cells by immunohistochemistry. The enzyme was mainly associated with tumor cells although there were four samples in which tumor cells were negative but in which normal cells, mainly lymphocytes, yielded a positive result., Conclusions: The results indicate that topoisomerase I enzymatic activity is detectable in human ovarian tumors, varying among patients. No correlations were found between the levels of the enzyme and its activity. Because of the high heterogeneity observed, enzymatic activity assays should be combined with immunohistochemical evaluation of Topo I in the tumor and normal cells present in the tissue.

Purpose: To evaluate the toxic effects and antitumour activity of a multidrug regimen with cisplatin, epirubicin and paclitaxel (CEP) as initial therapy in patients with uterine adenocarcinoma., Patients and Methods: Forty-nine patients with histologically-confirmed diagnoses of locally advanced, recurrent or metastatic cervical or endometrial adenocarcinoma entered the study. Treatment consisted of epirubicin (E) given at 70 mg/m2 followed by paclitaxel (P) (175 mg/m2 over three hours) and cisplatin (C) (50 mg/m2), repeated every three weeks. Eligibility criteria also included age < or = 75 years, no previous chemotherapy, no previous radiotherapy to the tumour parameters, bidimensionally-measurable lesions, no previous or ongoing cardiac disease, and renal and liver function within normal limits. Complete blood cell counts were repeated weekly, and tumor response was assessed every three cycles. A maximum of eight courses was administered in responding patients., Results: From January 1996 to January 1997, 30 patients with endometrial adenocarcinoma and 19 with cervical adenocarcinoma entered the study, for a total of 213 cycles of treatment. In patients with endometrial carcinoma the overall clinical and pathological response rates were 73% (95% CI, range 54%-88%) and 35% (95% CI, range 16%-57%) respectively; in patients with locally advanced cervical carcinoma the overall clinical and pathological response rates were 64% and 62%. WHO grade 3-4 neutropenia occurred in 61% of the patients, with one possible toxic death. Retreatment had to be delayed for at least one week because of persisting neutropenia in 34% of the patients. Mild peripheral neuropathy and stomatitis were observed in 46% and 23% of the patients. One patient presented acute congestive heart failure after the third cycle of treatment., Conclusion: The high antitumour activity and the good tolerability of CEP suggest that this regimen should be prospectively compared to standard combinations as initial treatment of advanced endometrial carcinoma.

Background: Conflicting data have been reported about the association between glutathione S-transferase (GST), a family of proteins implicated in detoxification of cytotoxic drugs in human ovarian in vitro models, and response to chemotherapy and prognosis in ovarian cancer patients. The aim of this study was to analyze the possible clinical role of GST activity in a large series of primary ovarian cancer patients., Patients and Methods: The study included a large series of primary untreated ovarian cancer patients who underwent cytoreductive surgery and chemotherapy and who were followed up in a single institution. GST activity levels were assessed in tumor extracts by using a biochemical assay. A cut-off of 250 units of enzymatic activity was chosen according to the receiver operating characteristics (ROC) curve., Results: GST activity levels were distributed in an asymmetrical manner (median: 266 units; range: 4-918 units) and did not seem to be associated with stage, histopathological grading, ascites, or residual tumor after surgery. Higher GST activity levels were found in patients who responded to chemotherapy (median: 298 units, range: 50-691) than in those who responded only partially (median: 227 units, range: 19-747) or not at all to chemotherapy (median: 246 units, range: 4-811) (H = 7.02, P = 0.029). Moreover, the percentage of cases with > 250 units was significantly higher among complete responders (66%) than partial responders (37%) or non-responders (48%) (chi 2 = 7.32; P = 0.025). When multivariate analysis, including clinico-pathological parameters and GST activity status as predictors of response to chemotherapy, was carried out, residual tumor, stage and GST status retained independent predictive value. Patients with high GST activity had more favourable prognosis than those with low GST activity. The median PFS was 42 months for patients with high GST activity compared to 17 months for those with low GST activity (P = 0.037). The median overall survival was 72 months for high-GST-activity and 42 months for low-GST-activity patients (P = 0.043). Substantially similar results were obtained in the subgroup of stage II-III-IV ovarian cancer patients. Multivariate analysis including the clinico-pathological parameters and GST activity status was performed in stage III-IV ovarian cancer patients: Stage IV disease, residual tumor > 2 cm, the presence of ascites and low GST activity status retained independent negative prognostic roles., Conclusion: A direct association between high GST activity and a better clinical outcome in terms of response to chemotherapy and survival has been observed in a large series of primary untreated ovarian cancer patients. These results, which are contrary to the expectations raised by in vitro studies, emphasize the need for caution when translating in vitro-generated hypotheses to the clinical setting.

Objectives: To assess the potential of expectant management for simple ovarian cysts diagnosed by transabdominal or transvaginal ultrasonography. To compare the results of needle aspiration with those achieved with simple observation., Design: Randomised trial., Setting: Hospital department of obstetrics and gynaecology., Subjects: 278 women with simple cysts randomly allocated to simple observation (143) or ultrasound guided fine needle aspiration (135) between 1990 and 1994., Main Outcome Measures: Resolution of cyst or development of malignancy., Results: After six months 269 were available for follow up. The rate of resolution was 46% (59/128) with aspiration and 44.6% (63/141) with observation. Only the diameter of the cyst (P < 0.0001) was a significant independent prognostic factor for resolution in a multivariate analysis. Age and treatment had no significant effect. One woman was subsequently found to have borderline malignant changes on histopathological examination. Her cyst was detected by transabdominal ultrasonography., Conclusions: Expectant management for up to six months does not cause risks for the patients and allows spontaneous resolution in over a third of cases, avoiding the costs and risks of unnecessary surgery. Aspiration does not provide better results than simple observation.

Objective: To evaluate the antitumour activity of paclitaxel in patients with endometrial cancer pretreated with cisplatin, doxorubicin and cyclophosphamide (PAC)., Materials and Methods: Eligible patients had complete initial surgery, expected survival > or = 3 months, performance status < or = 1, measurable or evaluable disease. Paclitaxel was given over three hours at the dose of 175 mg/m2, repeated every 3 weeks. Tumour response was first evaluated after 3 cycles. A maximum of 10 cycles was given in responders., Results: 19 patients entered the study and a total of 105 cycles were administered. Complete and partial responses were achieved in 2 and 5 patients, respectively, for an overall response rate of 37% (95% CI: 16%-62%). The response rate in patients refractory to platinum was 22%. One patient is alive without evidence of disease 16 months after the start of treatment. The most common side effects were mild to moderate myalgia and peripheral neuropathy, which occurred in 31% and 47% of patients, respectively. In only 1 patient treatment had to be discontinued because of severe myalgia., Conclusion: Paclitaxel is active in patients with endometrial cancer pretreated with PAC. Further studies with paclitaxel incorporated in the initial treatment for advanced disease are warranted.

Objective: To evaluate the anti-tumour activity and toxicity of ifosfamide (5 g/m2 continuous infusion) and mitoxantrone (10 mg/m2) given in combination every 3 weeks in patients with ovarian cancer resistant to at least two previous regimens which included platinum., Patients and Methods: Additional eligibility criteria were an ECOG performance status < or = 2 and measurable disease. Of 47 patients entered in the study, 8 were defined as platinum-resistant and 39 as potentially sensitive according to Markman's criteria. Thirty-five patients had also received paclitaxel as last treatment before entering this study. Tumour response was evaluated every three cycles., Results: One complete and 11 partial responses were reported, for an overall response rate of 25% (95% CI: 14%-40%). Three of the partial responders were resistant to platinum. None of the 7 partial responders pretreated with taxol had responded to it. The overall median survival was 11 months. Neutropenia G4 was reported in 18 patients (42%) with hospitalisation because of febrile neutropenia in 3 of them., Conclusions: In patients with ovarian cancer failing at least 2 previous therapies including platinum, the combination of ifosfamide and mitoxantrone has shown an antitumour activity comparable to that of paclitaxel, with acceptable toxicity. Objective responses were reported also in patients failing paclitaxel, suggesting a lack of cross resistance.

Uterine morphology assessed by transvaginal ultrasound and the hemodynamics of intratumoral vessels assessed by color Doppler ultrasound were prospectively correlated with the clinical outcome of 25 patients with trophoblastic tumors. Twenty patients were followed without treatment (observation group) and 16 achieved complete local resolution. The four subjects with local persistence were combined with five patients referred from other institutions and received chemotherapy (treatment group). In the observation group both techniques had 100% accuracy in predicting local resolution or local persistence. Persistence was predicted 1-3 weeks before the increase of beta-human chorionic gonadotropin (beta-hCG) levels, whereas resolution was observed up to 8 weeks before the disappearance of beta-hCG. In one patient normal uterine morphology and vascularization in the presence of elevated hCG levels was associated with extrauterine spread. In the treatment group, normal uterine ultrasound morphology and negative color Doppler results had 100% negative predictive value. False-positive results were observed in two cases. We conclude that ultrasound evidence of abnormal uterine morphology or persistent vascularization on color Doppler examination with persistent hCG levels is indicative of local persistence. Normal uterine morphology with negative color Doppler results may be associated with extrauterine spread.

Background: Cell kinetics could have prognostic significance in human ovarian cancer and might also help in designing optimal therapy. No data are available on the in vivo kinetics of this tumor using bromodeoxyuridine (BrdU) infusion before surgery., Patients and Methods: The kinetic parameters of human ovarian carcinoma were investigated in vivo using BrdU incorporation and bivariate BrdU/DNA flow cytometric (FCM) analysis. Fifty-five previously untreated patients with ovarian cancer (F.I.G.O. clinical stage III and IV) were studied. BrdU (250 mg/sqm) was given i.v. 6 h before surgery and samples of primary tumor and metastasis biopsies were fixed in 70% ethanol. By coupling the BrdU immunoreaction with biparametric FCM analysis, the nuclear DNA content (i.e., ploidy status), the tumor labelling index (LI), the synthesis time (TS) and the potential doubling time of the tumor mass (Tpot) were obtained. BrdU immunodetection was done on histological sections of the same tumors., Results: The majority of the tumors had a DNA aneuploid content (71.5%). The amount of BrdU-positive S-phase cells varied in different tumor samples and when several samples were taken from the same tumor. The proportion of BrdU-negative S-phase cells was large (50% of the total S phase cells) in almost all cases. The mean LI was 6.1% using FCM and 7.2% on visual count of the slide. The mean TS and Tpot were 14.7 h and 12.5 days, respectively. LI and TS were not correlated with clinical tumor stage, histological grading, residual tumor size or DNA ploidy, but Tpot was significantly higher (p < 0.05) in patients with residual tumor size < 2 cm. Univariate analysis showed that Tpot was significantly associated with the response after first-line chemotherapy (p < 0.009). In multivariate analysis only residual tumor size was related to the response., Conclusion: Although this in vivo BrdU technique provides information on the kinetic features of human ovarian cancers, it remains questionable whether this information has any additional value compared to currently used prognostic factors which are assessable clinically and surgically.

Background: While in breast cancer the amplification and overexpression of the erbB2 gene has been reported in numerous studies and found to be correlated to poor prognosis, information about this oncogene with respect to ovarian cancer is still limited. A recent study reported that approximately 30% of tumor biopsies from ovarian cancer patients exhibited erbB2 amplification and overexpression and suggested that the overexpression of this oncogene is an indicator of bad prognosis in ovarian cancer. The purpose of our studies was to investigate amplification of the erbB2 gene, the levels of erbB2 m-RNA and the erbB2 product (p185) in ovarian cancer, and the correlation between these findings and the pathological and clinical features., Results: Amplification of the erbB2 gene was investigated by Southern blot analysis in 75 samples from 62 patients; mRNA levels were evaluated by Northern blot analysis in 58 samples from 48 patients; and p185 was determined by immunohistochemistry in 65 samples from 65 patients. The erbB2 gene was amplified in only one case (1.6%), and a marked increase in erbB2 mRNA was found only in the same case. Staining for p185 was positive in 12 cases (18.5%). The staining was always confined to the cytoplasm except in the case that showed amplification of erbB2 in which p185 was localized in the membrane. No correlation was found between p185 positivity and pathological and clinical features or response to chemotherapy. Western blot analysis showed that the molecular weight of p185 in positive ovarian cancer cells was approximately 10 KDa lower than in breast cancer., Conclusion: In contrast to breast cancer, in ovarian cancer the amplification of erbB2 appears infrequent. The levels of p185 detected by immunohistochemistry were not related to the amplification of the gene or to the increase in mRNA, suggesting the possibility of a longer half-life of the protein in the positive cases. The finding that erbB2 product in ovarian cancer is mostly localised in cytoplasm and not in the membrane as in breast cancer and that it has a lower molecular weight than the p185 in breast cancer suggest that this oncogene plays a different biological role in these two neoplasms.

Aims: To evaluate antitumour activity, toxicity, pharmacokinetics, and the pharmacodynamic relationship with neutropenia of low-dose oral etoposide (E) in patients (pts) with epithelial cancer of the ovary previously treated with cisplatin., Patients and Methods: Eighteen pts receiving 50 mg daily of oral E for 21 days every 4 weeks. CBC with differential repeated every week. E plasma levels determined by HPLC method (sensitivity limit: 0.1 microgram/ml) with evaluation during the first cycle of bioavailability and weekly 24-hour drug concentrations., Results: Among 17 evaluable pts, 1 partial remission of 9 months. Dose-limiting neutropenia of high inter-patient variability. Mean bioavailability value of 75%, ranging from 44% to 100%. No correlation between mean 24-hour E plasma levels and ANC nadir or relative decrease of ANC during the first cycle., Conclusions: Low-dose oral E is ineffective as salvage treatment in epithelial cancer of the ovary. The large variability of neutropenia requires a careful hematological monitoring to avoid severe myelosuppression.

Three human ovarian carcinoma lines (HOC8) derived from the same patient before (P-HOC8) and after (R-HOC8 and Y-HOC8) cycles of chemotherapy were established i.p. in nude mice. The biological characterization showed that these tumor lines had various features in common. Cytological and histopathological characteristics and the expression of tumor-associated antigens OC125 and MOV18 were maintained in the three variants and were comparable to the patient's primary tumor. The HOC8 variants were aneuploid with a chromosome mode number of 80-81. All three tumor lines grew better i.p. than s.c. in nude mice. After i.p. injection the HOC8 lines produced ascites in all the mice, infiltration of pancreas, liver, diaphragm, and lung metastases. The sensitivity to cisplatin was evaluated for HOC8 lines growing in nude mice and mirrored the clinical development of resistance. Treatment with cisplatin of mice transplanted i.p. with P-HOC8 (obtained before the patient received chemotherapy) resulted in a significant increase in survival time; the R-HOC8 and Y-HOC8 lines (obtained after chemotherapy) were less sensitive. HOC8 xenografts, which represent the course of a single patient's disease, are a useful model for investigating the development of drug resistance in ovarian carcinoma.

We quantified and examined the kinetics of DNA interstrand cross links (DNA-ISC) caused by Cis dichlorodiammine platinum (DDP) using the method of alkaline elution in 58 highly purified human ovarian tumours growing in primary culture. A large heterogeneity in both the quantity and kinetics of DDP induced DNA-ISC was observed in cultures derived from neoplasms of different patients and from different lesions of the same patient. In the majority of cases. DNA-ISC lasted for prolonged time intervals after 1 h drug exposure, being significantly repaired only 48 or 72 h following drug washout. The persistence of DNA-ISC is probably due to a prolonged formation of these lesions for up to 24 h as assessed by the change in the repair kinetics that occurred after preventing new DNA-ISC formation by quenching of monoadducts with thiourea. The inefficient repair of DDP monoadducts appears therefore to be a possible reason for the permanence of DNA-ISC. These studies suggest that the long permanence of DNA-ISC in human ovarian cancer could be the basis for the high selectivity of DDP for this human malignancy.