Barbara Costantini

The differential effect of the phytoestrogen genistein on cardiovascular risk factors in postmenopausal women: relationship with the metabolic status.

CONTEXT The wide family of the phytoestrogens has become an alternative to the classical hormonal therapy in menopause; nevertheless, some findings are still conflicting. OBJECTIVE To examine the effect of genistein administration on metabolic parameters and vascular reactivity considering the basal endocrine status of the patients. DESIGN AND SETTING A randomized placebo controlled study was conducted at a university hospital. PARTICIPANTS Fifty postmenopausal women participated. INTERVENTIONS Thirty subjects (group A) were randomized to receive 54 mg/d genistein while 20 subjects (group B) were treated with the placebo for 24 wk. In group A, we distinguish two subgroups: 14 normoinsulinemic and 12 hyperinsulinemic patients. MAIN OUTCOME MEASURES Anthropometric measures, hormonal and lipid assays, oral glucose tolerance test with glycemic, insulin, and C-peptide evaluation, indexes of insulin sensitivity and endothelial function, and euglycemic-hyperinsulinemic clamps were performed. RESULTS The insulin basal values significantly decreased in group A, whereas the homeostasis model index of insulin sensitivity and the fasting glucose levels significantly improved compared with placebo group. The genistein administration decreased fasting glucose and area under the curve glucose levels in the normoinsulinemic patients after treatment. In the hyperinsulinemic patients, a significant reduction in fasting insulin, fasting C-peptide, and area under the curve insulin levels as well as an increase in fractional hepatic insulin extraction was shown. In these patients, high-density lipoprotein cholesterol levels were significantly improved. The endothelium-dependent and -independent dilatation improved in the treated group. Normoinsulinemic patients showed both a significantly enhanced flow-mediated and nitrate-mediated dilatation, whereas no significant changes were found in the hyperinsulinemic group. CONCLUSIONS The glycoinsulinemic metabolism and the endothelial function were significantly influenced by genistein. In particular, normoinsulinemic patients showed an improvement in glycemic and vascular reactivity indexes. Conversely, an improvement in the insulin sensitivity indexes was noted in hyperinsulinemic patients.

Cytoreductive surgery plus HIPEC in platinum-sensitive recurrent ovarian cancer patients: A case-control study on survival in patients with two year follow-up

OBJECTIVES To compare survival data in platinum-sensitive recurrent ovarian cancer patients submitted to secondary cytoreduction (SCR) plus hyperthermic intraperitoneal intraoperative chemotherapy (HIPEC) (Cases) and a similar group of women not experiencing HIPEC (Controls). METHODS Case-control study, matching 30 Cases with 37 Controls, with at least 24 months of follow-up. RESULTS Groups were comparable for all characteristics, except for a higher proportion of patients with single-nodule relapses is the Controls (19 vs. 6; p=0.011). Median follow-up time was 46 months in the Cases and 36 months in the Controls. Twenty patients (66.6%) experienced secondary recurrence in the Cases and 37 women (100%) in the Controls (p=0.001). Moreover, 7 (23.3%) and 23 (62.2%) patients died of disease in the Cases and Controls respectively (p=0.003). The duration of secondary response was 26 months in the Cases and 15 months in the Controls (p=0.004). CONCLUSIONS The combination of SCR and HIPEC seems to improve survival rate in patients suffering from platinum-sensitive EOC recurrence with respect to no-HIPEC treatments. This result further supports the need of a randomized trial.

HIPEC in recurrent ovarian cancer patients: Morbidity-related treatment and long-term analysis of clinical outcome

OBJECTIVE To evaluate morbidity and mortality rates associated with the use of hyperthermic intraoperative intraperitoneal chemotherapy (HIPEC) after optimal cytoreduction (CRS) in a large single-institutional series of platinum-sensitive recurrent ovarian cancer patients. Moreover, disease free (DFS) and overall survival (OS) of previously studied patients have been assessed after a longer follow-up period. METHOD From May 2005 to October 2010, recurrent ovarian cancer patients with a platinum-free interval of at least 6 months have been prospectively enrolled in a protocol of CRS plus HIPEC with oxaplatinum (460 mg/m(2)) heated to 41.5 °C for 30 min, followed by 6 cycles of systemic chemotherapy with taxotere 75 mg/m(2) and oxaliplatin 100 mg/m(2). RESULTS Forty-one patients experienced 43 procedures (CRS+HIPEC). An optimal cytoreduction was achieved in all cases (CC-0 95.3%; CC-1 4.7%). A complication rate of 34.8% was registered, with no case of intraoperative death or within 30 days after surgery. Survival curves have been calculated in a group of 25 patients with a minimum follow-up of 18 months, obtaining a median DFS and OS of 24 (range 6-60) and 38 months (range 18-60), respectively. CONCLUSION In recurrent platinum-sensitive ovarian cancer patients, the use of CRS plus HIPEC represents a safe treatment, able to significantly influence the survival rates compared to chemotherapy alone or surgery plus standard chemotherapy.

Quality of life and psychological distress in locally advanced cervical cancer patients administered pre-operative chemoradiotherapy

OBJECTIVE The aim of the study was to analyze the Quality of life (QoL) scores in a single institution series of locally advanced cervical cancer patients (LACC) administered preoperative chemoradiation, compared to early stage disease (ECC) patients undergoing radical surgery. METHODS The following criteria were required in order to enroll patients: age between 18 and 65years at initial diagnosis, at least 12 months from the end of treatment, no evidence of recurrence/second malignancy. The SF-36 questionnaire on general health, and the HADS questionnaire on mental distress were utilized. RESULTS 93 subjects were available for the analysis. At time of analysis, median follow-up was 30 months (range 12-120). LACC patients showed QoL scores comparable to ECC patients with the exception of physical functioning (mean+/-SD=69.0+/-13.1 versus mean+/- SD=85.4+/-16.2, p value=0.0007). In the group of LACC patients, the presence of co-morbidities was significantly associated with the impairment of almost all subscales of QoL. A low education level and the status of unemployment were documented to negatively impact on the vast majority of SF-36 subscale scores. In the multivariate analysis, the presence of co-morbidities, low educational level, age> 50 years, and unemployment maintained their independent negative association with poor QoL scores. The percentage of cases with high levels HADS-anxiety was higher in LACC than ECC patients (27.6% versus 8.6%, p value=0.034). CONCLUSIONS LACC patients administered preoperative chemoradiation showed QoL scores comparable to EEC patients, and a higher proportion of anxiety disorders; low educational level and unemployment status were mainly associated with poor QoL scores.

Upper abdominal surgery in advanced and recurrent ovarian cancer: Role of diaphragmatic surgery

OBJECTIVE Upper abdominal spread of primary and recurrent ovarian cancer is often considered to be a major obstacle to achieve optimal residual disease at the end of surgery. In this study, we investigate the role of diaphragmatic debulking in the natural history of advanced and recurrent epithelial ovarian cancer patients, and the morbidity of this procedure according to clinico-surgical characteristics. METHODS Data from 234 consecutive patients with primary and recurrent advanced ovarian cancer, operated at Catholic University of Rome and Campobasso from January 1, 2005 and December 31, 2008, were retrospectively reviewed. RESULTS Eighty-seven patients (37.2%) underwent a diaphragmatic surgery. Median age was 55 years (range 37-76). Diaphragmatic debulking was performed in 50 out of 120 patients at primary surgery (41.7%), in 16 out of 74 at interval debulking surgery (21.6%) and in 21 out of 40 secondary cytoreductions (52.5%). In the whole study population optimal residual disease at the end of surgery was achieved. The most frequent post-operative complication was pleural effusion, observed in 37 patients (42.5%). Presence of a post-operative pleural effusion was correlated liver mobilization (52.3% vs. 16%; p<0.0027) and large diaphragmatic disease (>5 cm) removal (54.1% vs. 23.5%; p<0.034). CONCLUSIONS Diaphragmatic surgery represents a crucial step in the debulking of advanced and recurrent ovarian cancer patients. Considering the natural history of advanced epithelial ovarian cancer and the rate of patients needing diaphragmatic debulking during primary cytoreduction, interval debulking surgery and secondary cytoreduction, this procedure should be present in the surgical repertoire of a gynecologic oncologist.

Should laparoscopy be included in the work-up of advanced ovarian cancer patients attempting interval debulking surgery?

OBJECTIVES Primary: To investigate whether S-LPS could contribute to a better identification of patients to submit to IDS. Secondary: To identify the most appropriate level of laparoscopic index value (PIV) to identify inoperable patients in this subset of patients. METHODS A prospective single-institutional study including patients with advanced ovarian/peritoneal cancer (FIGO stage IIIC-IV) to be submitted to IDS after NACT. Patients have been considered eligible for surgical exploration in case of complete/partial radiological or serological response; stable disease if primary surgery had been performed in a different hospital; progressive radiological disease in the presence of serological response, young age, and good performance status (ECOG <1); and progressive serological disease with stable clinical and radiological disease. A laparoscopic assessment for each patient has been performed. RESULTS Ninety-eight consecutive AOC patients submitted to NACT have been eligible for the study. With the addition of S-LPS to the RECIST criteria, a surgical exploration is performed in all patients and the percentage of explorative laparotomies drops to about 10%. The use of S-LPS after the GCIG criteria can reduce the risk of both explorative laparotomies from 30% to 13%, and inappropriate unexplorations from 18% to 0%. Moreover, at a PIV >4 the probability of optimally resecting the disease at laparotomy is equal to 0. CONCLUSIONS Present data suggest that S-LPS can play a relevant role to discriminate patients with partially/stable disease or referred from other Institutions after NACT, which can be susceptible of successful IDS.

Metformin improves endothelial function in normoinsulinemic PCOS patients: a new prospective

BACKGROUND Metformin was reported to improve the alterations of endothelial reactivity in normal-weight subjects with polycystic ovary syndrome (PCOS). The aim of the present study was to investigate the mechanisms of action of this drug on the vascular function of this population. METHODS Thirteen normal-weight, normoinsulinemic and normolipemic PCOS women were studied before and after 6 months of metformin treatment (1000 mg/day). The endothelial function was assessed by evaluating the flow-mediated dilatation (FMD) of the brachial artery. We correlated this parameter with the endocrine-metabolic features of the patients. RESULTS Metformin significantly reduced testosterone (1.56 +/- 0.52 after 6 months versus 2.98 +/- 1.00 at baseline) and 17-hydroxyprogesterone (0.03 +/- 0.01 versus 0.06 +/- 0.02 nmol/ml) levels, without affecting gluco-insulinemic parameters. Concomitantly, the basal vessel diameter and the FMD significantly increased (4.12 +/- 0.68 versus 3.2 +/- 0.41 and 5.2 +/- 0.6 versus 3.76 +/- 0.5 mm, respectively), thus documenting an improved endothelial function. CONCLUSIONS Our data confirm the positive effects of metformin on the altered vascular reactivity, a precocious marker of cardiovascular risk, in normoinsulinemic PCOS subjects. This improvement seems to be mediated through hormonal changes, thus highlighting the detrimental role of hyperandrogenemia on the endothelial function, even beyond the metabolic factors. However, a direct effect of metformin on the endothelium should not be excluded.

Ovarian cancer patients with localized relapse: Clinical outcome and prognostic factors

OBJECTIVE We evaluated the clinical outcome and prognostic factors for post-relapse survival (PRS) in a large retrospective series of ovarian cancer patients with localized relapse. PATIENTS AND METHODS The following radiological inclusion criteria were adopted: relapse in single anatomic site and ≤ 3 nodules. All cases were followed for at least 24 months after recurrent disease. RESULTS Two hundred twenty ovarian cancer patients met the inclusion criteria. Serous histotype and G3 tumors were observed in 173 (78.6%) and 151 (77.4%) cases, respectively. All women received platinum-based first-line chemotherapy. Overall, the median follow-up was 46 (8-249) months, and platinum-resistant relapse was documented in 51 women (23.2%). Eighty-one patients (36.8%) recurred in the peritoneum (LPeR), 76 patients (34.5%) in the abdominal lymph nodes (LLNR), and 63 patients (28.7%) in parenchymal organs (LPaR); 142 patients (64.5%) recurred with a single nodule; and 78 patients (35.5%) recurred with 2-3 nodules. Secondary cytoreductive surgery (SCS) was attempted in 73 cases (33.2%), and complete debulking was achieved in all patients. On multivariate analysis, platinum-free interval (PFI, χ(2)=13.457, p value=0.001), complete SCS (median PRS, 69 months vs 25 months, p=0.001), anatomic site of relapse (median PRS, 41months in LPeRs, 63 months in LLNRs and 24 months in LPaRs, p=0.001), and number of nodules (median PRS, 58months in patients with one nodule, 24months in patients with 2-3 nodules, p=0.001) were identified as predictors of PRS. CONCLUSIONS Beside the duration of PFI, the complete SCS, the anatomic site of relapse, and the number of nodules were independent prognostic factor for duration of PRS.

Randomized Study Comparing Use of THUNDERBEAT Technology vs Standard Electrosurgery during Laparoscopic Radical Hysterectomy and Pelvic Lymphadenectomy for Gynecologic Cancer

STUDY OBJECTIVE To compare operative time with use of THUNDERBEAT (TB) vs standard electrosurgery (SES) during laparoscopic radical hysterectomy and pelvic lymphadenectomy to treat gynecologic tumors. DESIGN Evidence obtained from a properly designed, randomized, controlled trial (Canadian Task Force classification I). SETTING Gynecologic Oncology Unit of the Catholic University of the Sacred Heart in Rome, Italy. PATIENTS Fifty patients with early cervical cancer (FIGO stages IA2, IB1, IIA <2 cm) or locally advanced cervical cancer (FIGO stages IB2, IIA >2cm, IIB) who received neoadjuvant treatment (chemotherapy or radiochemotherapy) and demonstrated a complete or partial clinical response and early stage endometrioid endometrial cancer (FIGO stages IB, II) were randomly assigned to undergo TB (arm A) or SES (arm B). INTERVENTION Laparoscopic radical hysterectomy with bilateral pelvic lymphadenectomy, using an easily reproducible technique was performed. MEASUREMENTS AND MAIN RESULTS Fifty patients were available for analysis, with 25 women randomly assigned to TB (arm A) and 25 to SES (arm B). The median operative time was 85 minutes for TB vs 115 minutes for SES (p = .001). At multivariate analysis, endometrial cancer (p = .001) and TB (p = .001) were independently associated with shorter operating time. No differences in perioperative outcomes and postoperative complications were observed between the 2 arms. Patients who underwent TB reported less postoperative pain, both at rest (p = .005) and after the Valsalva maneuver (p = .008), with less additional analgesic therapy other than standard therapy required in patients who underwent SES (p = .02). CONCLUSION TB is associated with shorter operative time and less postoperative pain than is the standard technique (SES) in patients with uterine cancer.

Minimally invasive secondary cytoreduction plus HIPEC for recurrent ovarian cancer: A case series

OBJECTIVE To analyze the feasibility of laparoscopic/robotic secondary cytoreductive surgery and hyperthermic intraperitoneal intra-operative chemotherapy (SCS+HIPEC) in a retrospective series of isolated platinum sensitive recurrent ovarian cancer. METHODS We retrospectively evaluated a consecutive series of ovarian cancer patients with isolated platinum sensitive relapse. Isolated relapse was defined as the presence of a single nodule, in a single anatomic site. In all cases the presence of isolated relapse was assessed at pre-operative FDG-PET/CT scan, and confirmed with staging laparoscopy performed immediately before SCS+HIPEC. RESULTS 84 women with platinum sensitive relapse received SCS+HIPEC during a 4-year period. Among them, 10 cases (11.9%) showed isolated relapse and were treated with laparoscopic/robotic SCS+HIPEC. In all cases complete debulking was achieved. In HIPEC treatment, 9 women received cisplatin at 75 mg/m(2), and the remaining patient oxaliplatin 460 mg/m(2). In 7 patients SCS was performed through the laparoscopic route, and in 3 cases with a robotic approach. The median operative time from skin incision to the end of cytoreductive surgery was 122 min (95-140), estimated blood loss was 50 cm(3) (50-100), and the median length of hospital stay was 4 days (3-7). The interval from surgery to adjuvant chemotherapy was 21 days (19-32). No grade 3/4 surgical, metabolic, or hematologic complications occurred. In all cases post-operative FDG-PET/CT scan was negative, and after a median time of 10 months (6-37) from SCS+HIPEC no secondary recurrence was observed. CONCLUSIONS Minimally invasive SCS+HIPEC can be safely performed in selected ovarian cancer patients with platinum sensitive isolated relapse.