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PURPOSE: Epithelial ovarian tumors (EOT) are among the most lethal of malignancies in women. We have previously identified ZIC2 as expressed at a higher level in samples of a malignant form (MAL) of EOT than in samples of a form with low malignant potential (LMP). We have now investigated the role of ZIC2 in driving tumor growth and its association with clinical outcomes.EXPERIMENTAL DESIGN: ZIC2 expression levels were analyzed in two independent tumor tissue collections of LMP and MAL. In vitro experiments aimed to test the role of ZIC2 as a transforming gene. Cox models were used to correlate ZIC2 expression with clinical endpoints.RESULTS: ZIC2 expression was about 40-fold in terms of mRNA and about 17-fold in terms of protein in MAL (n = 193) versus LMP (n = 39) tumors. ZIC2 mRNA levels were high in MAL cell lines but undetectable in LMP cell lines. Overexpression of ZIC2 was localized to the nucleus. ZIC2 overexpression increases the growth rate and foci formation of NIH3T3 cells and stimulates anchorage-independent colony formation; downregulation of ZIC2 decreases the growth rate of MAL cell lines. Zinc finger domains 1 and 2 are required for transforming activity. In stage I MAL, ZIC2 expression was significantly associated with overall survival in both univariate (P = 0.046) and multivariate model (P = 0.049).CONCLUSIONS: ZIC2, a transcription factor related to the sonic hedgehog pathway, is a strong discriminant between MAL and LMP tumors: it may be a major determinant of outcome of EOTs. Clin Cancer Res; 18(16); 1-12. ©2012 AACR.

Background: Pegylated liposomal doxorubicin (PLD) is an established treatment for relapsed ovarian cancer. Preclinical and clinical evidences in other tumor types suggest that the proteasome inhibitor bortezomib can act synergistically with PLD. Methods: Patients with relapsed ovarian cancer (N = 58), previously treated with platinum (100%) and taxane (95%), received bortezomib, 1.3 mg/m 2 intravenous (days 1, 4, 8, and 11), and PLD, 30 mg/m 2 intravenous (day 1), every 3 weeks. Tumor responses were assessed using Response Evaluation Criteria In Solid Tumors and Gynecologic Cancer Intergroup criteria. An optimal 2-stage design was implemented. Gene expression profiling in peripheral blood was characterized before and during treatment in 10 platinum-sensitive patients enrolled in stage 2 of the study. Results: Median number of bortezomib-PLD cycles was 3.5. Of 38 patients in the platinumsensitive group, 9 responses were observed (median duration, 4.8 months). The platinumresistant group was closed at stage 1 owing to lack of response. Toxicity was moderate and mainly consisted of hematologic, gastrointestinal, and mucositis events. Of the total 58 patients, peripheral neuropathy was reported in 9 patients (none were grade 3). Transcription profiling identified the prevalence of genes associated with ribonucleoprotein complexes, RNA processing, and protein translation. The gene expression changes were more robust in patients who responded or had stable disease compared with patients who had progressive disease. Conclusions: The combination of bortezomib and PLD was well tolerated, but the antitumor activity is insufficient to warrant further investigation in ovarian cancer.

Background: International Federation of Gynecology and Obstetrics stage I epithelial ovarian cancer (EOC) has a significantly better prognosis than stage III/IV EOC, with about 80% of patients surviving at 5 years (compared with about 20% of those with stage III/IV EOC). However, 20% of patients with stage I EOC relapse within 5 years. It is therefore crucial that the biological properties of stage I EOCs are further elucidated. MicroRNAs (miRNAs) have shown diagnostic and prognostic potential in stage III and IV EOCs, but the small number of patients diagnosed with stage I EOC has so far prevented an investigation of its molecular features. We profiled miRNA expression in stage I EOC tumours to assess whether there is a miRNA signature associated with overall and progression-free survival (PFS) in stage I EOC. Methods: We analysed tumour samples from 144 patients (29 of whom relapsed) with stage I EOC gathered from two independent tumour tissue collections (A and B), both with a median follow-up of 9 years. 89 samples from tumour tissue collection A were stratified into a training set (51 samples, 15 of which were from patients who relapsed) for miRNA signature generation, and into a validation set (38 samples, seven of which were from patients who relapsed) for signature validation. Tumour tissue collection B (55 samples, seven of which were from patients who relapsed) was used as an independent test set. The Cox proportional hazards model and the log-rank test were used to assess the correlation of quantitative reverse transcription PCR (qRT-PCR)-validated miRNAs with overall survival and PFS. Findings: A signature of 34 miRNAs associated with survival was generated by microarray analysis in the training set. In both the training set and validation set, qRT-PCR analysis confirmed that 11 miRNAs (miR-214, miR-199a-3p, miR-199a-5p, miR-145, miR-200b, miR-30a, miR-30a*, miR-30d, miR-200c, miR-20a, and miR-143) were expressed differently in relapsers compared with no

Clear cell ovarian carcinoma has a poorer prognosis compared with other histological subtypes.

Topotecan has single-agent activity in recurrent ovarian cancer. It was evaluated in a novel combination compared with standard frontline therapy., Clinical Trial, Phase III, Comparative Study, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't, SCOPUS: ar.j, info:eu-repo/semantics/published

BACKGROUND: The efficacy and tolerability of the regimen containing paclitaxel and cisplatin (TP) in the neo-adjuvant treatment of locally advanced squamous cell cervical cancer are unknown. The TIP regimen (TP plus ifosfamide) showed high efficacy but high toxicity and it is used as an internal control. PATIENTS AND METHODS: In all, 154 patients were randomized to TP (paclitaxel 175 mg/m(2) + cisplatin 75 mg/m(2); n = 80) or TIP (TP + ifosfamide 5 g/m(2); n = 74), three cycles, followed by radical surgery. Pathological response to chemotherapy was classified as optimal [no residual tumor (complete response) or residual disease with < or = 3 mm stromal invasion (PR1)] or suboptimal response. RESULTS: Patient characteristics (TP/TIP): stage IB2 (56%/64%), IIA (18%/14%), IIB (20%/19%), III-IVA (5%/4%) and median age (42 years/45 years). The optimal response rate in the TP group was 25%, 95% confidence interval (CI) = 16% to 37% and 43%, 95% CI = 31% to 55% in the TIP group. Grades 3-4 leukopenia (6%/53%) and neutropenia (26%/76%) were significantly more frequent on TIP. CONCLUSION: TP performance was below expectation since the lower 95% confidence limit of the optimal response rate failed to reach the prespecified minimum requirement of efficacy, i.e. 22%. The TIP regimen confirmed its activity but was associated with higher haematological toxicity than TP.

BACKGROUND: Five percent to 20% of stage I endometrial cancer patients undergoing total abdominal hysterectomy and bilateral salpingo-oophorectomy develop vaginal and pelvic recurrences. Adjuvant radiotherapy can improve locoregional control but not survival. This randomized trial aimed to determine whether a modified radical (Piver-Rutledge class II) hysterectomy can improve survival and locoregional control compared to the standard extrafascial (Piver-Rutledge class I) hysterectomy. METHODS: Eligible patients (n = 520) with stage I endometrial cancer were randomized to class I or class II hysterectomy. Primary endpoint was overall survival. RESULTS: The median length of parametria and vagina removed were 15 and 5 vs. 20 mm and 15 mm for class I and class II hysterectomy, respectively (P > 0.001). Operating time and blood loss were statistically significantly higher for class II hysterectomy. At a median follow-up of 70 months, 51 patients had died. Five-year disease-free and overall survival were similar between arms (87.7 and 88.9% in the class I arm and 89.7 and 92.2% in the class II arm, respectively). The unadjusted hazard ratios for recurrence was 0.91 (95% confidence interval, 0.55-1.51, P = 0.72), and the hazard ratio for death was 0.77 (95% confidence interval, 0.44-1.33, P = 0.35). CONCLUSIONS: Class II hysterectomy did not improve locoregional control and survival compared to class I hysterectomy, but when an adequate vaginal cuff transection is not feasible with class I hysterectomy, a modified radical hysterectomy allows to obtain an optimal vaginal and pelvic control of disease with a minimal increase in surgical morbidity.

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.

Neoadjuvant chemotherapy may represent an alternative to irradiation in locally advanced squamous cell cervical cancer. Aims of this study were to compare a three-drug (paclitaxel, ifosfamide, and cisplatin [TIP]) with a two-drug (ifosfamide and cisplatin [IP]) regimen and to assess the prognostic value of pathologic response on survival. PATIENTS AND METHODS: Patients (n = 219) were randomly assigned to ifosfamide 5 g/m(2) during 24 hours plus cisplatin 75 mg/m(2), or paclitaxel 175 mg/m(2) plus ifosfamide 5 g/m(2) during 24 hours and cisplatin 75 mg/m(2) every 3 weeks for three courses. RESULTS: Grades 3 to 4 neutropenia, anemia, and thrombocytopenia were more frequent with TIP. We recorded four deaths related to toxicity. The optimal pathologic response (OPT) rate (residual disease < 3 mm stromal invasion) was higher with TIP than with IP (48% v 23%; odds ratio, 3.22; 95% CI, 1.69 to 5.88; P = .0003). At a median follow-up of 43.4 months, 79 women experienced disease progression or died (46 in the IP arm, 33 in the TIP arm). Patients receiving TIP experienced a treatment failure rate 25% less than those receiving IP, but this difference was not statistically significant (hazard ratio [HR], 0.75; 95% CI, 0.48 to 1.17; P = .20). Sixty-one patients died (37 in the IP arm, 24 in the TIP arm), and the HR of death was in favor of TIP, although not significantly (HR, 0.66; 95% CI, 0.39 to 1.10; P = .11). In patients assessable for response (n = 189), the average death rates were higher in the group that did not achieve OPT (HR, 5.88; 95% CI, 2.50 to 13.84; P < .0001). CONCLUSION: The TIP regimen is associated with a higher response rate than the IP regimen, without a statistically significant effect on overall survival. OPT was a prognostic factor for survival