Antonino Ditto

Effects of metformin on gonadotropin-induced ovulation in women with polycystic ovary syndrome

OBJECTIVE To evaluate whether pretreatment with metformin improves FSH-induced ovulation in women with clomiphene-resistant polycystic ovary syndrome (PCOS). DESIGN Randomized prospective trial. SETTING Department of Obstetrics and Gynecology, University of Siena. PATIENT(S) Twenty women with clomiphene citrate-resistant PCOS. INTERVENTION(S) The women were divided randomly into groups A and B (10 subjects each). Group B received 1,500 mg of metformin for at least a month before a single cycle of FSH stimulation. Group A underwent two cycles of FSH stimulation and then received metformin for a month before undergoing a third cycle. MAIN OUTCOME MEASURE(S) The number of FSH ampules, days of treatment, E2 level on the day of hCG, number of follicles > 15 mm, number of hyperstimulation, and the number of cycles with hCG withheld. RESULT(S) The number of follicles > 15 mm in diameter on the day of hCG administration was significantly lower in cycles performed after metformin treatment. The percentage of cycles with hCG withheld because of excessive follicular development was significantly lower in cycles treated with metformin. Plasma levels of E2 were significantly higher in cycles treated with FSH alone than in those treated with FSH and metformin. CONCLUSION(S) By reducing hyperinsulinism, metformin determines a reduction in intraovarian androgens. This leads to a reduction in E2 levels and favors orderly follicular growth in response to exogenous gonadotropins.

Gene expression profiling of advanced ovarian cancer: characterization of a molecular signature involving fibroblast growth factor 2

Epithelial ovarian cancer (EOC) is the gynecological disease with the highest death rate. We applied an automatic class discovery procedure based on gene expression profiling to stages III–IV tumors to search for molecular signatures associated with the biological properties and progression of EOC. Using a complementary DNA microarray containing 4451 cancer-related, sequence-verified features, we identified a subset of EOC characterized by the expression of numerous genes related to the extracellular matrix (ECM) and its remodeling, along with elements of the fibroblast growth factor 2 (FGF2) signaling pathway. A total of 10 genes were validated by quantitative real-time polymerase chain reaction, and coexpression of FGF2 and fibroblast growth factor receptor 4 in tumor cells was revealed by immunohistochemistry, confirming the reliability of gene expression by cDNA microarray. Since the functional relationships among these genes clearly suggested involvement of the identified molecular signature in processes related to epithelial–stromal interactions and/or epithelial–mesenchymal cellular plasticity, we applied supervised learning analysis on ovarian-derived cell lines showing distinct cellular phenotypes in culture. This procedure enabled construction of a gene classifier able to discriminate mesenchymal-like from epithelial-like cells. Genes overexpressed in mesenchymal-like cells proved to match the FGF2 signaling and ECM molecular signature, as identified by unsupervised class discovery on advanced tumor samples. In vitro functional analysis of the cell plasticity classifier was carried out using two isogenic and immortalized cell lines derived from ovarian surface epithelium and displaying mesenchymal and epithelial morphology, respectively. The results indicated the autocrine, but not intracrine stimulation of mesenchymal conversion and cohort/scatter migration of cells by FGF2, suggesting a central role for FGF2 signaling in the maintenance of cellular plasticity of ovary-derived cells throughout the carcinogenesis process. These findings raise mechanistic hypotheses on EOC pathogenesis and progression that might provide a rational underpinning for new therapeutic modalities.

Subcellular Localization of Activated Leukocyte Cell Adhesion Molecule Is a Molecular Predictor of Survival in Ovarian Carcinoma Patients

Purpose: Currently available clinicopathologic prognostic factors are imperfect predictors of clinical course in advanced-stage epithelial ovarian cancer patients. New molecular predictors are needed to identify patients with higher risk of relapse or death from disease. In a retrospective study, we investigated the prognostic impact of activated leukocyte cell adhesion molecule (ALCAM) expression in epithelial ovarian cancer. Experimental Design: We analyzed the effect of cell-anchorage loss on ALCAM cellular localization in vitro and assessed ALCAM expression by immunohistochemistry in a series of 109 well-characterized epithelial ovarian cancer patient samples. Chi-square test, Kaplan-Meier method, and Cox proportional hazard analyses were used to relate ALCAM cellular localization to clinical-pathologic parameters and to overall survival (OS) rate. Results: Loss of epithelial ovarian cancer cell anchorage was associated both in vitro and in vivo with decreased ALCAM membrane expression. In vivo, ALCAM was localized to cell membrane in normal surface ovarian epithelium, whereas in 67% of the epithelial ovarian cancer samples, membrane localization was decreased or even lost, and the molecule was mainly expressed in cytoplasm. Median OS in this group of patients was 58 months, whereas a median OS was not yet reached in patients with ALCAM membrane localization (P = 0.036, hazard ratio [HR] = 2.0, 95% confidence interval [CI] 1.1 to 3.5). In a multivariate Cox regression model including all the available clinicopathologic variables, loss of ALCAM membrane expression was an independent factor of unfavorable prognosis (P = 0.042, HR = 2.15, 95% CI: 1.0 to 4.5). Conclusions: Decreased/lost ALCAM membrane expression is a marker of poorer outcome in epithelial ovarian cancer patients and might help to identify patients who could benefit from more frequent follow-up or alternative therapeutic modalities.

Comparison of two malignancy risk indices based on serum CA125, ultrasound score and menopausal status in the diagnosis of ovarian masses

Objective To evaluate the ability of two malignancy risk indices (RMI 1 and Rh4I 2) incorporating menopausal status, serum CA125 level and ultrasound findings, to discriminate a benign from a malignant pelvic mass.

Diagnostic accuracy of sentinel node in endometrial cancer by using hysteroscopic injection of radiolabeled tracer

OBJECTIVE Retrospective and perspective series have shown the feasibility of sentinel lymph-node (SLN) identification of pelvic nodes in endometrial cancer using a cervical injection of tracers. We designed a perspective study to assess the detection rate and diagnostic accuracy of the SLN procedure by means of hysteroscopic injection of a radiolabeled tracer in endometrial cancer patients. METHODS Patients with endometrial cancer underwent hysteroscopic technetium injection. SLN assessment was performed intraoperatively. A systematic pelvic and paraaortic dissection was carried out thereafter. SLNs were examined by standard and immunochemistry methods. The primary endpoint was estimation of sensitivity and negative predictive value (NPV) of sentinel-node biopsy. RESULTS From 2005 to 2010, 80 consecutive patients entered the study. No severe complications occurred during or after the injection or during surgical SLN biopsy. At least one SLN was detected in 76 of the 80 eligible patients. Fifty nine patients were evaluable according to the study protocol. Ten of these patients (17%) had node metastases. Thirty-three patients (56%) had SLN in the para-aortic area. NPV was 98% (95% CI 89.4-100) and sensitivity 90% (55.5-99.8). CONCLUSIONS SLN detection for endometrial cancer patients has a high sensitivity and NPV when injection is carried out by hysteroscopy. The occurrence of a 56% of sentinel node in paraaortic area may suggest a better sensitivity in this area using hysteroscopic injection compared to cervical injection.

Bone mineral density and biochemical markers of bone turnover in peri- and postmenopausal women.

Abstract. Bone mineral density (BMD) measured by densitometry is the elective parameter for the diagnosis of osteopenia and osteoporosis. Biochemical markers have been proposed as sensitive indicators of high bone turnover and for monitoring response to antiresorptive treatment. We conducted a retrospective study to investigate the values of biochemical markers of bone metabolism with a view to early diagnosis of osteoporosis and monitoring of hormone replacement and calcitonin therapy. The subjects were 415 women, mean age 51 ± 8 years (43–62 years) in peri- and postmenopause, recruited at the Menopause Center of Obstetrics and Gynecology Department of Siena University and divided in five groups. Bone densitometry was performed in all subjects and blood samples were taken for assayed biochemical markers, that is, [osteocalcin (OC), parathyroid hormone (PTH), type 1 procollagen (PICP), and calcitonin (CT)].Three groups of women were divided into two subgroups: those with normal and those with low BMD (<1 SD). Basal concentrations of PCP1, OC, PTH, and CT were compared in the various groups. Two groups of postmenopausal women with BMD below the normal were treated with estrogen replacement therapy and unmodified eel calcitonin.We evaluated whether some of these biochemical markers of bone turnover could help identify women with low BMD and whether they could be useful for monitoring the results of antiresorptive therapies.Markers of bone formation (PICP and OC) make it possible to distinguish women with high turnover who are at risk for osteoporosis from women with low turnover in menopause. A good correlation was also found between changes in levels of these markers and changes in BMD during treatments, which suggests that the PICP and OC would be useful for monitoring response to antiresorptive therapy.

Prognostic indicators in melanoma of the vulva.

Background: The aim of this study was to evaluate the prognostic significance of clinicalpathologic variables in melanoma of the vulva.Methods: From 1979 through 1995, 40 women with a diagnosis of vulvar melanoma underwent radical surgery. Patient age, tumor size and site, histologic type, ulceration, tumor thickness, lymph node status, and number of positive lymph nodes were assessed for prognostic significance by multivariate analysis.Results: Tumor thickness was a significant predictor of lymph node involvement, but not of survival. The most powerful predictors of survival by multivariate analysis were the lymph node status (P 5 .002) and the number of positive lymph nodes (P 5 .00003).Conclusions: The number of positive lymph nodes represents the strongest prognostic factor in melanoma of the vulva. Because of the lack of effective adjuvant therapies, such prognostic indicators might be used to define the timing and extent of the surgical approach.

Surgical treatment of ovarian dermoid cysts

OBJECTIVE To evaluate the efficacy of laparoscopic ovarian cystectomy and to compare the surgical course, post-surgical course and particularly post-surgical pain of the laparoscopic and laparotomic methods. STUDY DESIGN We conducted a surgical study on dermoid cysts at the Gynecology Department of Siena University between 1 January 1992 and 31 December 1996. The selected cases were randomized into two groups based on surgical approach: via laparotomy (n=22) or laparoscopy (n=22). Surgical times, estimated blood loss, post-surgical pain, time in hospital, speed of recovery and complications were compared. RESULTS Mean blood loss was significantly less for laparoscopy (58.64+/-30.17 ml versus 103.84+/-38.45 ml, P<0.05). Mean hospitalization was 6.32+/-1.09 days for laparotomy and 3.18+/-0.39 days for laparoscopy (P<0.05). Post-surgical pain was significantly less in laparoscopy patients (P<0.05). The laparoscopic technique had fewer post-surgical complications. CONCLUSIONS The laparoscopic approach had many advantages. Laparoscopy should be the elective treatment for women with dermoid cysts, because it has many advantages for the patient and lower costs for the national health system.

Evaluation of Treatment of Hyperemesis gravidarum Using Parenteral Fluid with or without Diazepam

Objective: Hyperemesis gravidarum is a relatively unknown disease, and is generally self-limiting. In some women the symptoms are so severe as to threaten the health of the mother and fetus. Therapies proposed for hyperemesis gravidarum are therefore rather empirical. Medical treatment includes parenteral fluid replacement and nutrition, electrolytes, antiemetics, vitamins, sedation and psychological counseling. Diazepam and benzodiazepins have been widely studied in pregnancy but the results are contradictory. The aim of the present study was to investigate the efficacy of parenteral fluids with vitamins, with or without diazepam sedation. Methods: Fifty women with hyperemesis gravidarum were enrolled in the study. They were treated with infusions of normal saline, glucose, vitamins and randomly with diazepam. Results: The results show that the mean stay in the hospital was shorter in the diazepam group: 4.5 ± 1.9 vs. 6 ± 1.6 days (p < 0.05) and readmission to the hospital was 4% in the diazepam group versus 27% in other group (p < 0.05). There was a significant reduction in nausea in the diazepam group (p < 0.05). A significant reduction in vomiting was observed in both groups. No side effects or congenital neonatal malformations were found in the diazepam group. Conclusions: Intravenous administration of fluids and vitamins is the standard treatment for women hospitalized for hyperemesis gravidarum. The addition of diazepam to the treatment is effective in reducing nausea and does not have teratogenic effects.

Implementation of laparoscopic approach for type B radical hysterectomy: a comparison with open surgical operations.

OBJECTIVE To investigate the safety, feasibility and effectiveness of laparoscopic approach in the management patients undergoing modified radical hysterectomy for early stage cervical cancer. METHODS Consecutive data of 157 women who had class II radical hysterectomy, for stage IA2 and stage IB1 <2 cm cervical cancer, were prospectively collected. Data of patients undergoing surgery via laparoscopy (LRH) were compared with those undergoing open surgical operations (RAH). A propensity-matched comparison (1:1) was carried out to minimize as possible selection biases. Post-operative complications were graded per the Clavien-Dindo classification. Five-year survival outcomes were assessed using Kaplan-Meier model. RESULTS After the exclusion of 37 (23.5%) patients on the basis of propensity-matching, 60 patients undergoing LRH were compared with 60 patients undergoing RAH. No between-group differences in baseline, disease and pathological variables were observed (p > 0.05). Patients undergoing surgery via laparoscopy experienced longer operative time than patients undergoing RAH; while LRH correlated whit shorter length of hospitalization and lower blood loss in comparison to RAH. Intra- and post-operative complication rate was similar between groups (p = 1.00). The execution of LRH or RAH did not influence site of recurrence (p > 0.2) as well as survival outcomes, in term of 5-year disease-free (p = 0.29, log-rank test) and overall survivals (p = 0.50, log-rank test). CONCLUSION Laparoscopic approach is a safe procedure, upholds the results of RAH, reducing invasiveness of open surgical operations. Further large prospective investigations are warranted.