Leonardo D'Urso

The miR-15a – miR-16-1 cluster controls prostate cancer by targeting multiple oncogenic activities

MicroRNAs (miRNAs) are noncoding small RNAs that repress protein translation by targeting specific messenger RNAs. miR-15a and miR-16-1 act as putative tumor suppressors by targeting the oncogene BCL2. These miRNAs form a cluster at the chromosomal region 13q14, which is frequently deleted in cancer. Here, we report that the miR-15a and miR-16-1 cluster targets CCND1 (encoding cyclin D1) and WNT3A, which promotes several tumorigenic features such as survival, proliferation and invasion. In cancer cells of advanced prostate tumors, the miR-15a and miR-16 level is significantly decreased, whereas the expression of BCL2, CCND1 and WNT3A is inversely upregulated. Delivery of antagomirs specific for miR-15a and miR-16 to normal mouse prostate results in marked hyperplasia, and knockdown of miR-15a and miR-16 promotes survival, proliferation and invasiveness of untransformed prostate cells, which become tumorigenic in immunodeficient NOD-SCID mice. Conversely, reconstitution of miR-15a and miR-16-1 expression results in growth arrest, apoptosis and marked regression of prostate tumor xenografts. Altogether, we propose that miR-15a and miR-16 act as tumor suppressor genes in prostate cancer through the control of cell survival, proliferation and invasion. These findings have therapeutic implications and may be exploited for future treatment of prostate cancer.

Control of tumor and microenvironment cross-talk by miR-15a and miR-16 in prostate cancer

The interaction between cancer cells and microenvironment has a critical role in tumor development and progression. Although microRNAs regulate all the major biological mechanisms, their influence on tumor microenvironment is largely unexplored. Here, we investigate the role of microRNAs in the tumor-supportive capacity of stromal cells. We demonstrated that miR-15 and miR-16 are downregulated in fibroblasts surrounding the prostate tumors of the majority of 23 patients analyzed. Such downregulation of miR-15 and miR-16 in cancer-associated fibroblasts (CAFs) promoted tumor growth and progression through the reduced post-transcriptional repression of Fgf-2 and its receptor Fgfr1, which act on both stromal and tumor cells to enhance cancer cell survival, proliferation and migration. Moreover, reconstitution of miR-15 and miR-16 impaired considerably the tumor-supportive capability of stromal cells in vitro and in vivo. Our data suggest a molecular circuitry in which miR-15 and miR-16 and their correlated targets cooperate to promote tumor expansion and invasiveness through the concurrent activity on stromal and cancer cells, thus providing further support to the development of therapies aimed at reconstituting miR-15 and miR-16 in advanced prostate cancer.

POLYTETRAFLUOROETHYLENE GIANT GRANULOMA AND ADENOPATHY: LONG-TERM COMPLICATIONS FOLLOWING SUBURETERAL POLYTETRAFLUOROETHYLENE INJECTION FOR THE TREATMENT OF VESICOURETERAL REFLUX IN CHILDREN

PURPOSE The use of polytetrafluoroethylene as bulking agent for the endoscopic treatment of vesicoureteral reflux in children has raised many concerns about the implant histocompatibility and the risk of migration of polytetrafluoroethylene particles. We report on 3 cases of long-term complications following subureteral polytetrafluoroethylene injection (STING) and an extensive review of the literature is presented. MATERIALS AND METHODS Between January 1993 and December 1995, 3 children (2 males, 1 female; 4, 7 and 6 years old), previously submitted to STING, underwent open surgery for recurrent vesicoureteral reflux. RESULTS In 1 case a hard nodular mass, strictly adherent to the ureteral wall, was a foreign body giant granuloma. All patients demonstrated a heavy multinucleated foreign body reaction around polytetrafluoroethylene particles in the pelvic nodes. CONCLUSIONS Many experimental studies and some clinical observations have demonstrated that polytetrafluoroethylene particles elicit a foreign body granulomatous reaction and have the tendency to migrate. Until the long-term effects of their presence are well known, STING should be carefully evaluated in children and young patients.

Visually Directed Transrectal High Intensity Focused Ultrasound for the Treatment of Prostate Cancer: A Preliminary Report on the Italian Experience

PURPOSE High intensity focused ultrasound is a minimally invasive treatment option for prostate cancer. Data from the literature show promising early oncological outcomes and a favorable side effect profile. This study is a preliminary report of the Italian experience (Perugia and Turin) of patients treated with the Sonablate(R)500 high intensity focused ultrasound device. MATERIALS AND METHODS Between 2004 and 2007, 163 consecutive men with T1-T3 N0M0 prostate cancer underwent high intensity focused ultrasound with the Sonablate 500. Followup included prostate specific antigen tests at 1 month and then every 3 months after treatment, and a random prostate biopsy at 6 months. Failure was defined according to prostate specific antigen nadir, positive findings on followup biopsy and biochemical failure according to Phoenix criteria. RESULTS Median patient age was 72 years old, median baseline prostate specific antigen was 7.3 ng/ml, and disease stage was T1 in 44.1%, T2 in 42.5% and T3a in 13.4% of patients. Median followup was 23.8 months. After high intensity focused ultrasound treatment prostate specific antigen decreased to a median nadir of 0.15 ng/ml. Median prostate specific antigen at 3 and 6 months was 0.30 and 0.54 ng/ml, respectively. At 6 months the negative biopsy rate was 66.1%. There was no biochemical evidence of disease in 71.9% overall. On multivariate analysis prostate specific antigen nadir became the only independent predictor of no biochemical evidence of disease and positive biopsy at a cutoff of 0.40 ng/ml. CONCLUSIONS A favorable outcome of high intensity focused ultrasound is associated with lower baseline prostate specific antigen, lower prostate specific antigen nadir, lower Gleason score and lower tumor stage. As with any novel technology long-term data will be required before this technique gains widespread clinical acceptance.

Endorectal magnetic resonance imaging and magnetic resonance spectroscopy to monitor the prostate for residual disease or local cancer recurrence after transrectal high-intensity focused ultrasound

To assess the role of magnetic resonance imaging (MRI) for evaluating changes in the prostate after transrectal high‐intensity focused ultrasound (HIFU) for treating prostate cancer, correlating the findings with histology to assess its possible role in predicting the outcome, evaluating residual cancer or local recurrence of disease.

Immunologic Aspects of Bovine Injectable Collagen in Humans

This article is also accessible online at: http://BioMedNet.com/karger Collagen-based products have been used for decades in medicine, primarily as resorbable sutures and hemostatic agents. More recently, an injectable collagen, commonly used for soft-tissue augmentation in dermatology, has been applied for the treatment of glottic insufficiency [1, 2], gastroesophageal reflux [3], vesicoureteral reflux [4] and urinary incontinence [5, 6] (table 1). Despite the widespread use of collagen-based devices in medicine, concerns still arise over the possible immunologic sequelae of their use. It is our purpose to provide a review of the literature data regarding this basic aspect of bovine collagen use.

Laparoscopic Microwave Ablation and Enucleation of Small Renal Masses: Preliminary Experience

Advancements in imaging and laparoscopy have led to the expansion of minimally invasive techniques in the ablation of small renal masses (SRMs). We report the results of a study aimed at assessing the efficacy of thermoablative microwave (MW) effects on SRMs and the haemostatic as well as necrotic MW effects on the parenchyma surrounding the neoplasm. From November 2008 to October 2010, 10 patients with SRMs underwent laparoscopy-guided Tru-Cut biopsy, MW tumour ablation, and enucleation. Mean age was 66 yr (range: 46-84 yr). Mean renal tumour diameter was 2.75 cm (range: 1.3-4.2 cm). MW antennas were applied one to three times depending on tumour volume, location, and shape. After MW thermoablation, laparoscopic enucleation was performed to evaluate the histopathologic and haemostatic effects of MW. The mean MW antenna application time was 14.1 min (range: 4-30 min). Enucleation did not require renal pedicle clamping in any of the cases because no significant bleeding took place. Preablation pathology revealed clear cell renal carcinoma of Fuhrman grade I-II in all cases. Postablation pathology showed extensive coagulative necrosis without skipped tumour areas. No intra- or postoperative complications were reported. Histopathologic effects on SRMs provide consistent proof of principle for future studies.

High-intensity focused ultrasound for the treatment of prostate cancer: A prospective trial with long-term follow-up

Abstract Objective. High-intensity focused ultrasound (HIFU) is a minimally invasive treatment for prostate cancer. Data from the literature show promising oncological outcomes with a favourable side-effect profile. The aim of this study was to re-evaluate and bring up to date the follow-up of a previously published, prospective trial on HIFU as the primary treatment for prostate cancer. Materials and methods. Between 2004 and 2007, 163 consecutive men with T1–T3N0M0 prostate cancer underwent HIFU with the Sonablate® 500. Follow-up included prostate-specific antigen (PSA) tests every 3 months after treatment and a random prostate biopsy at 6 months. Failure was defined according to positive findings at the 6 month biopsy and biochemical failure was defined according to the Phoenix criteria. Biochemical-free survival, metastasis-free survival and cancer-specific survival were calculated by Kaplan–Meier curves. Results. Median follow-up was 72.0 months. Of the 160 evaluable patients, 104 (65%) were biochemically disease free; in low- to intermediate-risk disease, on Kaplan–Meier analysis the 8 year biochemical-non-evidence of disease (bNED), metastasis-free survival and cancer-specific survival rates were 69.6%, 81.3%, 100% and 40.5%, 60.6%, 100%, respectively. A PSA nadir below 0.40 ng/ml and risk stratification have an independent predictive value for bNED and metastasis-free survival. Conclusions. A long-term favourable outcome of HIFU is associated with careful patient selection, with low- to intermediate-risk disease being the ideal case. A low postoperative PSA nadir is a predictor of long-term bNED.

Recurrent Pseudodiverticula of Female Urethra: Five-year Experience

OBJECTIVES To report our experience of transvaginal diverticulectomy with pubovaginal sling placement in a series of 32 women with recurrent urethral pseudodiverticula. METHODS A total of 32 women underwent surgical repair from January 2000 to June 2007. Of the 32 women, 12 had undergone other concomitant previous urethral surgery, predominantly for stress urinary incontinence. Transvaginal excision of the diverticulum and concomitant pubovaginal sling placement were performed routinely. The women were evaluated postoperatively for symptom relief, anatomic result, and postoperative continence status at 1, 6, and 12 months and annually thereafter. Pelvic magnetic resonance imaging was repeated after 1 year. RESULTS The mean follow-up was 4.3 years. In all cases, the voiding urethrogram after catheter removal showed a good urethral shape with an absence of urinary leaks. At the postoperative urodynamic investigation, 27 patients had an unobstructed and 5 an equivocal Blaivas-Groutz nomogram. Three patients (20%) reported a persistent degree of stress urinary incontinence, including 2 with grade 1 stress urinary incontinence and 1 with mixed incontinence. Two patients presented with clinically evident diverticulum recurrence, and in 1 patient, an intraurethral diverticulum, was found at the 1-year magnetic resonance imaging examination. CONCLUSIONS A pubovaginal sling added routinely to all diverticulectomy procedures offers significant support to the urethral repair and/or prevention of urinary incontinence, including in recurrent cases, and does not increase the risk of erosion into the urethra or fistula formation.

The Turin Pouch: A New Technique of Ileocecal Cutaneous Continent Urinary Diversion

OBJECTIVE To evaluate the functional results of a new cutaneous continent reservoir, the Turin pouch (TP), consisting of an ileocolonic pouch with an innovative efferent channel (EC). METHODS Since 2006, we have performed the TP on 14 patients in whom the appendix was absent. The distal ileum (10 cm) and right colon (40 cm) were isolated. The cecum and right colon were folded to obtain a U-shaped pouch through a stapler detubularization. An artificial EC was created by separating with a stapler a 5-cm tubularized flap of colonic wall and anastomosing this to the umbilicus. RESULTS After a mean follow-up of 45 months (range, 12-72 months), 13 patients were alive and 1 died of bladder cancer progression. Early and late complications occurred in 3 and 4 patients, respectively. Daytime continence was 100% and nighttime continence was 93%. No patient has reported stenosis or difficulties in catheterization. Urodynamic studies (12 months postoperatively) showed a mean maximal pouch capacity of 520 mL (range, 360-720 mL), mean end-filling pressure of 23 cm H2O (range, 18-30 cm H2O), and mean EC closing pressure of 65 cm H2O (range, 52-75 cm H2O). CONCLUSION The TP offers good functional results and could be applied in patients undergoing continent, heterotopic, urinary diversion.