Giorgia Garganese

Prospective validation of a laparoscopic predictive model for optimal cytoreduction in advanced ovarian carcinoma

OBJECTIVE The purpose of this study was to validate the performance of a laparoscopy-based model to predict optimal cytoreduction in advanced ovarian cancer patients. STUDY DESIGN In a consecutive prospective series of 113 advanced ovarian cancer patients, the presence of omental cake, peritoneal and diaphragmatic extensive carcinosis, mesenteric retraction, bowel and stomach infiltration, spleen and/or liver superficial metastasis were investigated by laparoscopy. By summing the scores relative to all parameters, a laparoscopic assessment for each patient (total predictive index value = PIV) has been calculated. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy have been calculated for each PIV. RESULTS The overall accuracy rate of the laparoscopic procedure ranged between 77.3 and 100%. At a PIV >/= 8 the probability of optimally resecting the disease at laparotomy is equal to 0, and the rate of unnecessary exploratory laparotomy is 40.5%. CONCLUSION The proposed laparoscopic model appears a reliable and flexible tool to predict optimal cytoreduction in advanced ovarian cancer.

Possible involvement of hMLH1, p16(INK4a) and PTEN in the malignant transformation of endometriosis.

Endometriosis is a common gynecologic disease, which generally follows a benign course. Notwithstanding, several clinical and histologic studies as well as molecular data show that endometriosis could be a precursor of sporadic endometrioid and clear cell carcinomas at extrauterine loci. Several reports have implicated alterations of the hMLH1 and p16ink4a (p16) genes, in particular hypermethylation of the promoter region, and of the PTEN gene, principally genetic mutations, in endometrial and ovarian cancers and have indicated that these alterations are already present in precancer conditions. In this report, we analyzed the methylation status of hMLH1 and p16 and the protein expression of PTEN and hMLH1 in 46 cases of endometriosis stages III and IV to better define the possible involvement of these genes in the malignant transformation of endometriosis. We found abnormal methylation of hMLH1 in 4 of the 46 cases (8.6%). In addition, these cases had no detectable hMLH1 protein expression. Regarding patients with hMLH1 alterations, 2 were classified as stage IV and 2 showed coexistent endometriosis and carcinoma. Only 1 case of endometriosis (2.17%), classified as atypical, showed abnormal methylation of p16. Reduced PTEN protein expression was detected in 7 of 46 cases (15.21%): 5 were clinically classified as stage IV, and the other 2 presented both cancer and hypermethylated hMLH1. Our preliminary study suggests that reduced expression of both hMLH1 and PTEN may be involved in the malignant evolution of endometriosis and should be used as markers of neoplastic transformation in aggressive endometriosis with elevated tumor markers.

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.

Phase I Study of Gemcitabine and Liposomal Doxorubicin in Relapsed Ovarian Cancer

Twenty-three patients were enrolled in a phase I study conducted to determine the maximum tolerated doses (MTD) of combined liposomal doxorubicin (CAE) and gemcitabine (GEM) in relapsed ovarian cancer patients. A total of 82 courses are evaluable, with a median number of three cycles administered per patient (range 2–8). GEM was administered on days 1 and 8 by 30-min intravenous infusion immediately after CAE given by 60-min intravenous infusion on day 1; cycles were repeated every 21 days. The starting doses were CAE 20 mg/m2 and GEM 600 mg/m2. Following dose levels were 20/800; 20/1,000; 30/800; 30/1,000; 35/800, and 35/1,000 for CAE and GEM, respectively. The MTD was reached at dose level 5, with febrile neutropenia and thrombocytopenia as dose-limiting toxicities. After the MTD, granulocyte-colony stimulating factor was administered in 15% of cycles. Non-hematological toxicity was mild and manageable. All patients are so far evaluable for response. Among them, 5 partial responses (21.7%; 95% confidence interval, CI: 4.9–38.5), 5 disease stabilizations (21.7%, 95% CI: 4.9–38.5) and 13 progressions (56.6%, 95% CI: 36.4–76.8) have been registered. These results warrant further research in a phase II study.

Novel Health Economic Evaluation of a Vaccination Strategy to Prevent HPV-related Diseases The BEST Study

Background:The development of human papillomavirus (HPV)-related diseases is not understood perfectly and uncertainties associated with commonly utilized probabilistic models must be considered. The study assessed the cost-effectiveness of a quadrivalent-based multicohort HPV vaccination strategy within a Bayesian framework. Methods:A full Bayesian multicohort Markov model was used, in which all unknown quantities were associated with suitable probability distributions reflecting the state of currently available knowledge. These distributions were informed by observed data or expert opinion. The model cycle lasted 1 year, whereas the follow-up time horizon was 90 years. Precancerous cervical lesions, cervical cancers, and anogenital warts were considered as outcomes. Results:The base case scenario (2 cohorts of girls aged 12 and 15 y) and other multicohort vaccination strategies (additional cohorts aged 18 and 25 y) were cost-effective, with a discounted cost per quality-adjusted life-year gained that corresponded to &OV0556;12,013, &OV0556;13,232, and &OV0556;15,890 for vaccination programs based on 2, 3, and 4 cohorts, respectively. With multicohort vaccination strategies, the reduction in the number of HPV-related events occurred earlier (range, 3.8–6.4 y) when compared with a single cohort. The analysis of the expected value of information showed that the results of the model were subject to limited uncertainty (cost per patient=&OV0556;12.6). Conclusions:This methodological approach is designed to incorporate the uncertainty associated with HPV vaccination. Modeling the cost-effectiveness of a multicohort vaccination program with Bayesian statistics confirmed the value for money of quadrivalent-based HPV vaccination. The expected value of information gave the most appropriate and feasible representation of the true value of this program.

Cost-Effectiveness Analysis of Universal Human Papillomavirus Vaccination Using a Dynamic Bayesian Methodology: The BEST II Study

BACKGROUND Human papillomavirus (HPV) plays a role in the development of benign and malign neoplasms in both sexes. The Italian recommendations for HPV vaccines consider only females. The BEST II study (Bayesian modelling to assess the Effectiveness of a vaccination Strategy to prevent HPV-related diseases) evaluates 1) the cost-effectiveness of immunization strategies targeting universal vaccination compared with cervical cancer screening and female-only vaccination and 2) the economic impact of immunization on various HPV-induced diseases. OBJECTIVE The objective of this study was to evaluate whether female-only vaccination or universal vaccination is the most cost-effective intervention against HPV. METHODS We present a dynamic Bayesian Markov model to investigate transmission dynamics in cohorts of females and males in a follow-up period of 55 years. We assumed that quadrivalent vaccination (against HPV 16, 18, 6, and 11) is available for 12-year-old individuals. The model accounts for the progression of subjects across HPV-induced health states (cervical, vaginal, vulvar, anal, penile, and head/neck cancer as well as anogenital warts). The sexual mixing is modeled on the basis of age-, sex-, and sexual behavioral-specific matrices to obtain the dynamic force of infection. RESULTS In comparison to cervical cancer screening, universal vaccination results in an incremental cost-effectiveness ratio of €1,500. When universal immunization is compared with female-only vaccination, it is cost-effective with an incremental cost-effectiveness ratio of €11,600. Probabilistic sensitivity analysis shows a relatively large amount of parameter uncertainty, which interestingly has, however, no substantial impact on the decision-making process. The intervention being assessed seems to be associated with an attractive cost-effectiveness profile. CONCLUSIONS Universal HPV vaccination is found to be a cost-effective choice when compared with either cervical cancer screening or female-only vaccination within the Italian context.

Immediate definitive prosthetic reconstruction in patients with ptotic breasts.

AbstractImmediate reconstruction of medium/large ptotic breasts can be performed by using expanders, definitive implants, or autologous flaps. If a skin-sparing mastectomy is feasible, excellent results can be achieved by planning Wise pattern incisions, using definitive implants. The authors suggest the use of a dermal-adipose flap, harvested from the ptotic part of the breast, rotated laterally, and interposed between the serratus fascia and the pectoralis muscle to close the inferolateral part of the pocket. We performed 23 immediate unilateral single-stage breast reconstructions, with simultaneous contralateral reduction. Preoperatively, all breasts showed grade II or III ptosis. There was no case of implant infection or failure of the reconstruction. The median follow-up was 21 months; however, some patients followed up for >4 years; in this period, no case of capsular contracture was observed. This technique has provided good shape, acceptable ptosis consistent with the healthy breast and symmetric scars.

Surgical therapy of vulvar cancer: how to choose the correct reconstruction?

Objective To create a comprehensive algorithmic approach to reconstruction after vulvar cancer ablative surgery, which includes both traditional and perforator flaps, evaluating anatomical subunits and shape of the defect. Methods We retrospectively reviewed 80 cases of reconstruction after vulvar cancer ablative surgery, performed between June 2006 and January 2016, transferring 101 flaps. We registered the possibility to achieve the complete wound closure, even in presence of very complex defects, and the postoperative complications. On the basis of these experience, analyzing the choices made and considering the complications, we developed an algorithm to help with the selection of the flap in vulvoperineal reconstruction after oncologic ablative surgery for vulvar cancer. Results We employed eight types of different flaps, including 54 traditional fasciocutaneous V-Y flaps, 23 rectus abdominis myocutaneous flaps, 11 anterolateral thigh flaps, three V-Y gracilis myocutaneous flaps, three free style perforators V-Y flaps from the inner thigh, two Limberg flaps, two lotus flaps, two deep inferior epigastric artery perforator flap, and one superficial circumflex iliac artery perforator flap. The structures most frequently involved in resection were vulva, perineum, mons pubis, groins, vagina, urethra and, more rarely, rectum, bladder, and lower abdominal wall. Conclusion The algorithm we implemented can be a useful tool to help flap selection. The key points in the decision-making process are: anatomical subunits to be covered, overall shape and symmetry of the defect and some patient features such as skin laxity or previous radiotherapy. Perforator flaps, when feasible, must be considered standard in vulvoperineal reconstruction, although in some cases traditional flaps remain the best choice.

The lymphatic superficial circumflex iliac vessels deep branch perforator flap: A new preventive approach to lower limb lymphedema after groin dissection-preliminary evidence.

Groin dissection is the procedure with the highest risk of lower limb lymphedema.As lymph stasis causes irreversible alterations to the limb over time,therapies should be administered in early stages,or better yet, lymphatic drainage impairment should be prevented.We developed a new preventive approach to lymphedema after groin dissection, and we report our preliminary experience.

Evaluation of dual-timepoint18F-FDG PET/CT imaging for lymph node staging in vulvar cancer

This study aimed to assess the value of dual-timepoint 18F-FDG PET/CT in the prediction of lymph node (LN) status in patients with invasive vulvar cancer (VC) scheduled for inguinofemoral LN dissection. Methods: From April 2013 to July 2015, all consecutive patients with VC scheduled for inguinofemoral LN dissection were prospectively enrolled. All patients underwent a preoperative whole-body 18F-FDG PET/CT scan at 1 h (standard examination) and an additional scan from T11 to the groins at 3 h (delayed examination) after 18F-FDG injection. On both scans, each groin was visually scored 0 or 1 concerning 18F-FDG LN uptake relative to background. Semiquantitative analysis included SUVmax and the corresponding retention index of SUVmax, measured on both scans. The optimal cutoff value of these parameters was defined using a receiver-operating-characteristic analysis. Histopathology was the standard of reference. Results: Thirty-three patients were included, with a total of 57 groins dissected and histologically evaluated. At histopathology, 21 of 57 (37%) groins contained metastatic LNs. Concerning visual score, sensitivity, specificity, negative predictive value, positive predictive value, and accuracy were 95.2%, 75%, 96.4%, 69%, and 82.5% on standard scanning and 95.2%, 77.8%, 96.6%, 71.4%, and 84.2% on delayed scanning, respectively. At receiver-operating-characteristic analysis, sensitivity and specificity were 95.2% and 77.8% on standard and delayed 18F-FDG PET/CT for an SUVmax cutoff of greater than 1.32 and 1.88, respectively, and 95.2% and 80% for a retention index of SUVmax cutoff of greater than 0. Conclusion: Standard 18F-FDG PET/CT is an effective preoperative imaging method for the prediction of LN status in VC, allowing the prediction of pathologically negative groins and thus the selection of patients suitable for minimally invasive surgery. Delayed 18F-FDG PET/CT did not improve the specificity and the positive predictive value in our series. Larger studies are needed for a further validation.