Giovanni Muto

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.

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.

Stage-specific impact of extended versus standard pelvic lymph node dissection in radical cystectomy

To evaluate the impact of an extended versus a standard pelvic lymph node dissection on disease‐free survival and cancer‐specific survival of patients with non‐metastatic muscle‐invasive urothelial carcinoma of the bladder treated with radical cystectomy.

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.

Effect of complete androgen blockade on pathologic stage and resection margin status of prostate cancer: progress pathology report of the Italian PROSIT study

OBJECTIVES To compare the pathologic stage and surgical margin status in patients undergoing either immediate radical prostatectomy or surgery preceded by 3 or 6 months of neoadjuvant hormonal treatment (NHT) in a prospective, randomized study. METHODS Four hundred thirty-one men with prostate cancer were enrolled in the Italian randomized prospective PROSIT study. The whole-mount sectioning technique was used. By May 1999, the reviewing pathologist had evaluated 303 specimens. One hundred seven patients were untreated before radical prostatectomy was performed, and 114 and 82 patients had been treated for 3 and 6 months, respectively, with complete androgen blockade. RESULTS Pathologic organ-confined disease was found in 63.1% of patients with clinical Stage B disease treated with 6 months of NHT versus 61.0% after 3 months of NHT and 37.5% after immediate surgery. Among patients with clinical Stage C tumors, pathologic staging found organ-confined disease in 62.5%, 32.1%, and 11.1% of patients after 6 months of NHT, 3 months of NHT, and immediate surgery, respectively. Three months of NHT produced a significant increase in negative margins both in patients with clinical Stage B and C disease, but the addition of another 3 months of treatment did not significantly improve this result. A lower degree of benefit was observed in patients with clinical Stage C tumors. CONCLUSIONS This study shows that complete androgen blockade before surgery is beneficial in men with clinical Stage B disease. The effects are more pronounced after 6 months of NHT than after 3 months.

Conservative treatment of iatrogenic urinary fistulas: the value of cyanoacrylic glue.

Once previously attempted conservative maneuvers have failed, iatrogenic persistent urinary fistulas usually require difficult repeated operations. We describe 3 patients in whom cyanoacrylic glue was used to repair endoscopically persistent urinary fistulas occurring after major pelvic surgery. At a mean follow-up of 21 months, all patients were free of urinary leakage and had no evidence of recurrent urinary fistulas. This approach may represent a safe and effective way to repair postoperative urinary fistulas.

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.

Genetic polymorphisms of CYP17A1, vitamin D receptor and androgen receptor in Italian heredo-familial and sporadic prostate cancers.

BACKGROUND Searching for genetic and environmental factors predisposing to prostate cancer, common single-nucleotide polymorphisms in CYP17A1, CYP19A1, VDR genes, and the number of CAG repeats from AR were investigated in Italian heredo-familial prostate cancer (HFPC) patients controlled for dietary intake and life style habits. METHODS We evaluated differences between HFPC and sporadic cancers, in the pattern of common single-nucleotide polymorphisms in CYP17A1, CYP19A1, VDR genes, and the CAG repeat from AR, controlling for dietary intake and lifestyle habits in a regionwide population. Ninety-five patients with HFPC were identified and 378 sporadic prostate cancers were randomly selected as controls. Dietary intake and lifestyle habits were determined through self-administered questionnaires in all patients. Genotyping of polymorphisms for CYP17A1, CYP19A1, VDR, and the CAG repeat from AR was carried out using pyrosequencing. RESULTS HFPC cases were significantly younger than controls, whereas similar proportions of localized tumours, favourable histology, and abnormal prostate serum antigen levels (4-19 ng/ml) were detected in the two groups. A statistically evident gene-gene interaction was found: a 5-fold higher probability [odds ratio (OR)=4.83; 95% confidence interval (CI): 1.37-17.02] of HFPC was observed in the subgroup profiling VDR1 T/T genotypes coupled with VDR2 T/T genotype. Among nutrients, an increase in HFPC risk (OR=3.14; 95% CI: 1.12-8.81) was found only for zinc, when associated with the VDR2 T/T genotype. CONCLUSIONS Significant evidence for positive interactions between VDR1 and VDR2 genotypes was demonstrated, suggesting that high-risk multigenic polymorphism profiles could variously sustain HFPC tumorigenesis.

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.