Genome-wide analysis of copy number alterations led to the characterisation of PDCD10 as oncogene in ovarian cancer.

Copy Number Alterations (CNAs) represent the most common genetic alterations identified in ovarian cancer cells, being responsible for the extensive genomic instability observed in this cancer. Here we report the identification of CNAs in a cohort of Italian patients affected by ovarian cancer performed by SNP-based array. Our analysis allowed the identification of 201 significantly altered chromosomal bands (70 copy number gains; 131 copy number losses). The 3300 genes subjected to CNA identified here were compared to those present in the TCGA dataset. The analysis allowed the identification of 11 genes with increased CN and mRNA expression (PDCD10, EBAG9, NUDCD1, ENY2, CSNK2A1, TBC1D20, ZCCHC3, STARD3, C19orf12, POP4, UQCRFS1). PDCD10 was selected for further studies because of the highest frequency of CNA. PDCD10 was found, by immunostaining of three different Tissue Micro Arrays, to be over-expressed in the majority of ovarian primary cancer samples and in metastatic lesions. Moreover, significant correlations were found in specific subsets of patients, between increased PDCD10 expression and grade (p < 0.005), nodal involvement (p < 0.05) or advanced FIGO stage (p < 0.01). Finally, manipulation of PDCD10 expression by shRNA in ovarian cancer cells (OVCAR-5 and OVCA429) demonstrated a positive role for PDCD10 in the control of cell growth and motility in vitro and tumorigenicity in vivo. In conclusion, this study allowed the identification of novel genes subjected to copy number alterations in ovarian cancer. In particular, the results reported here point to a prominent role of PDCD10 as a bona fide oncogene.

Multiple genetic alterations within the PI3K pathway are responsible for AKT activation in patients with ovarian carcinoma.

The phosphatidylinositol 3-kinase (PI3K)/AKT pathway is activated in multiple cancers including ovarian carcinoma (OC). However, the relative contribution of the single components within the PI3K pathway to AKT activation in OC is still unclear. We examined 98 tumor samples from Italian OC patients for alterations in the members of the PI3K pathway. We report that AKT is significantly hyperactive in OC compared to normal tissue (n = 93; p<0.0001) and that AKT activation is preferentially observed in the elderly (>58 years old; n = 93; p<0.05). The most frequent alteration is the overexpression of the p110α catalytic subunit of PI3K (63/93, ∼68%); less frequent alterations comprise the loss of PTEN (24/89, 27%) and the overexpression of AKT1 (18/96, 19%) or AKT2 (11/88,12.5%). Mutations in the PIK3CA or KRAS genes were detected at lower frequency (12% and 10%, respectively) whereas mutations in AKT1 or AKT2 genes were absent. Although many tumors presented a single lesion (28/93, of which 23 overexpressed PIK3CA, 1 overexpressed AKT and 4 had lost PTEN), many OC (35/93) presented multiple alterations within the PI3K pathway. Apparently, aberrant PI3K signalling was mediated by activation of the canonical downstream AKT-dependent mTOR/S6K1/4EBP1 pathway and by regulation of expression of oncogenic transcription factors that include HMGA1, JUN-B, FOS and MYC but not by AKT-independent activation of SGK3. FISH analysis indicated that gene amplification of PIK3CA, AKT1 and AKT2 (but not of PI3KR1) and the loss of PTEN are common and may account for changes in the expression of the corresponding proteins. In conclusion, our results indicate that p110α overexpression represents the most frequent alteration within the PI3K/AKT pathway in OC. However, p110α overexpression may not be sufficient to activate AKT signalling and drive ovarian tumorigenesis since many tumors overexpressing PI3K presented at least one additional alteration.

Vaginal cuff dehiscence after hysterectomy: a multicenter retrospective study.

OBJECTIVE: This study estimates the incidence of vaginal cuff dehiscence resulting from different approaches to hysterectomy. STUDY DESIGN: This multicentric study was carried out retrospectively. We retrospectively analyzed 8635 patients; 37% underwent abdominal hysterectomy, 31.2% vaginal hysterectomy, and 31.8% laparoscopic hysterectomy. All the hysterectomies were considered, vaginal evisceration was registered and analyzed for time of onset, trigger event, presenting symptoms, details of prolapsed organs and type of repair surgery. Continuous variables were compared using the one-way analysis of variance between groups as all data followed a Gaussian distribution, as confirmed by the Kolmogorov-Smirnov test. Differences among subgroups were assessed using the Tukey-Kramer multiple comparisons test. Categorical variables were compared with two tailed Chi-square tests with Yates correction or Fisher's exact test, as appropriate. Pearson's linear correlation was used to verify linear relationships between the dehiscence interval and patient's age at surgery. RESULTS: Thirty-four patients (0.39%) experienced vaginal evisceration. The laparoscopic route was associated with a significantly higher incidence of dehiscence (p<0.05). No differences were found between the 6027 patients (69.8%) who had closure of the vaginal cuff and the 2608 (30.2%) who had an unclosed cuff closure technique. CONCLUSION: Vaginal evisceration after hysterectomy is a rare gynecological surgical complication. Sexual intercourse before the complete healing of the vaginal cuff is the main trigger event in young patients, while evisceration presents as a spontaneous event in elderly patients. Surgical repair can be performed either vaginally or laparoscopically with similar outcomes.

Total laparoscopic radical hysterectomy versus abdominal radical hysterectomy with lymphadenectomy in patients with early cervical cancer: our experience.

BACKGROUND: The aim of this study was to retrospectively compare, in a series of 127 consecutive women, the safety, morbidity, and recurrence rate of total laparoscopic radical hysterectomy (TLRH) with lymphadenectomy and abdominal radical hysterectomy with lymphadenectomy (ARH) for early cervical carcinoma. METHODS: A total of 127 consecutive patients with International Federation of Gynecology and Obstetrics stage Ia1 (lymphvascular space involvement), Ia2, and Ib1 early cervical cancer, 65 of whom underwent TLRH and 62 of whom underwent ARH with pelvic lymph node dissection, comprised the study population. The para-aortic lymphadenectomy with the superior border of the dissection being the inferior mesenteric artery was performed in all cases with positive pelvic lymph nodes discovered at frozen section evaluation. RESULTS: The median blood loss in the ARH group (145 ml; range, 60-225 ml) was significantly greater than TLRH group (55 ml; range, 30-80 ml) (P < .01). The median length of hospital stay was significantly greater in the ARH group (7 days; range, 5-9 days) than TLRH group (4 days; range, 3-7 days) (P < .01). The median operating time was 196 min in the TLRH group (range, 182-240 min) compared with 152 min in the ARH group (range, 161-240 min) (P < .01). No statistically significant difference was found between the two groups when the recurrence rate was compared. CONCLUSIONS: Total laparoscopic radical hysterectomy is a safe and effective therapeutic procedure for management of early-stage cervical cancer with a far lower morbidity than reported for the open approach and is characterized by far less blood loss and shorter postoperative hospitalization time, although multicenter randomized clinical trials with longer follow-up are necessary to evaluate the overall oncologic outcomes of this procedure.

Total laparoscopic hysterectomy versus abdominal hysterectomy with lymphadenectomy for early-stage endometrial cancer: a prospective randomized study.

OBJECTIVE: The aim of this study was to compare, in a series of 159 women the feasibility, safety and morbidity of total laparoscopic hysterectomy (LPS) and abdominal hysterectomy with lymphadenectomy (LPT) for early-stage endometrial cancer and to assess disease-free survival and recurrence rate. METHODS: 159 patients with clinical stage I endometrial cancer were enrolled in a prospective randomized trial and treated with LPS or LPT approach. The para-aortic lymphadenectomy was performed in all cases with positive pelvic lymph nodes discovered at frozen section evaluation, in patients with poorly differentiated tumors with myometrial invasion greater than 50% (ICG3), and non-endometrioid carcinomas. RESULTS: The mean operative time was 136 min+/-31 (95% CI 118-181) in the LPS group and 123 min+/-29 (95% CI 111-198) in the LPT group (P<0.01). The mean blood loss was 50 ml+/-12 in the LPS group (95% CI 20-90) and 145 ml+/-35 in the LPT group (95% CI 60-255) (P<0.01). The mean length of hospital stay was 5.1+/-1.2 in the LPT group (95% CI 1-7) and 2.1+/-0.5 in the LPS group (95% CI 1-5) (P<0.01). CONCLUSIONS: Laparoscopy is a suitable procedure for the treatment of patients with early endometrial cancer and may offer the potential benefits of decreased discomfort with decreased convalescence time without compromising the degree of oncological radicality required; however, it does not seem to modify the disease-free survival and the overall survival, although multicenter randomized trials and long-term follow-up are required to evaluate the overall oncologic outcomes of this procedure.

Randomized trial of neoadjuvant chemotherapy comparing paclitaxel, ifosfamide, and cisplatin with ifosfamide and cisplatin followed by radical surgery in patients with locally advanced squamous cell cervical carcinoma: the SNAP01 (Studio Neo-Adjuvante Portio) Italian Collaborative Study.

PURPOSE: 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.