Vincenzo Mirone

The Management of Peyronie's Disease: Evidence‐based 2010 Guidelines

INTRODUCTION The field of Peyronies disease is evolving and there is need for a state-of-the-art information in this area. AIM To develop an evidence-based state-of-the-art consensus report on the management of Peyronies disease. METHODS To provide state-of-the-art knowledge regarding the prevalence, etiology, medical and surgical management of Peyronies Disease, representing the opinion of leading experts developed in a consensus process over a 2-year period. MAIN OUTCOME MEASURES Expert opinion was based on grading of evidence-based medical literature, widespread internal committee discussion, public presentation, and debate. CONCLUSIONS The real etiology of Peyronies disease and the mechanisms of formation of the plaque still remain obscure. Although conservative management is obtaining a progressively larger consensus among the experts, surgical correction still remains the mainstay treatment for this condition.

Frequency and Determinants of Erectile Dysfunction in Italy

Objective: To analyze the prevalence and risk factors for erectile dysfunction (ED) in Italy in a cross–sectional study.Methods: Eligible for the study were men aged 18 years or more, randomly identified by 143 general practitioners among their registered patients during the period January 1996 to February 1997. ED was defined as the impossibility to achieve and maintain an erection sufficient for satisfactory sexual performance.Results: Of the 2,010 men interviewed, 257 (12.8%) reported ED. The prevalence increased with age, from 2% in men aged 18–39 to 48% in those >70 years (tested for trend, p = 0.0001). A history of cardiopathy, diabetes, hypertension, neuropathy, thrombotic/hemorrhagic stroke, peripheral vascular disorders, pelvic/medullary injury and pelvic surgery/radiation all increased the risk of ED. The association of hypertension and diabetes tends to increase the risk of ED. In comparison with nondiabetic and nonhypertensive men, the odds ratio (OR) was 1.4 (95% confidence interval (CI), 0.7–3.2) for hypertensive men without diabetes, 4.6 (95% CI, 1.6–13.7) for diabetic men without hypertension and 8.1 (95% CI, 1.2–55.0) for men with diabetes and hypertension. In comparison with never smokers, the OR of ED was 1.7 (95% CI, 1.2–2.4) for current smokers and 1.6 (95% CI, 1.1–2.3) for ex–smokers and increased with duration of the habit.Conclusions: The study offers a quantitative estimate of the prevalence of ED and of its main risk factors in Italian men.

A systematic review and meta-analysis on the use of phosphodiesterase 5 inhibitors alone or in combination with α-blockers for lower urinary tract symptoms due to benign prostatic hyperplasia

CONTEXT Several randomized controlled trials (RCTs) on phosphodiesterase type 5 inhibitors (PDE5-Is) have showed significant improvements in both lower urinary tract symptoms (LUTS) and erectile dysfunction (ED) in men affected by one or both conditions, without a significant increase in adverse events. However, the results are inconsistent. OBJECTIVE Perform a systematic review and meta-analysis of available prospective and cross-sectional studies on the use of PDE5-Is alone or in combination with α1-adrenergic blockers in patients with LUTS/benign prostatic hyperplasia (BPH). EVIDENCE ACQUISITION A systematic search was performed using the Medline, Embase, and Cochrane Library databases through September 2011 including the combination of the following terms: LUTS, BPH, PDE5-Is, sildenafil, tadalafil, vardenafil, udenafil, α-blockers, and α1-adrenergic blocker. The meta-analysis was conducted according to the guidelines for observational studies in epidemiology. EVIDENCE SYNTHESIS Of 107 retrieved articles, 12 were included in the present meta-analysis: 7 on PDE5-Is versus placebo, with 3214 men, and 5 on the combination of PDE5-Is with α1-adrenergic blockers versus α1-adrenergic blockers alone, with 216 men. Median follow-up of all RCTs was 12 wk. Combining the results of those trials, the use of PDE5-Is alone was associated with a significant improvement of the International Index of Erectile Function (IIEF) score (+5.5; p<0.0001) and International Prostate Symptom Score (IPSS) (-2.8; p<0.0001) but not the maximum flow rate (Q(max)) (-0.00; p=not significant) at the end of the study as compared with placebo. The association of PDE5-Is and α1-adrenergic blockers improved the IIEF score (+3.6; p<0.0001), IPSS score (-1.8; p = 0.05), and Q(max) (+1.5; p<0.0001) at the end of the study as compared with α-blockers alone. CONCLUSIONS The meta-analysis of the available cross-sectional data suggests that PDE5-Is can significantly improve LUTS and erectile function in men with BPH. PDE5-Is seem to be a promising treatment option for patients with LUTS secondary to BPH with or without ED.

Monotherapy with Tadalafil or Tamsulosin Similarly Improved Lower Urinary Tract Symptoms Suggestive of Benign Prostatic Hyperplasia in an International, Randomised, Parallel, Placebo-Controlled Clinical Trial

BACKGROUND Tadalafil improved lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH; LUTS/BPH) in clinical studies but has not been evaluated together with an active control in an international clinical study. OBJECTIVE Assess tadalafil or tamsulosin versus placebo for LUTS/BPH. DESIGN, SETTING, AND PARTICIPANTS A randomised, double-blind, international, placebo-controlled, parallel-group study assessed men ≥45 yr of age with LUTS/BPH, International Prostate Symptom Score (IPSS) ≥13, and maximum urinary flow rate (Q(max)) ≥4 to ≤15ml/s. Following screening and washout, if needed, subjects completed a 4-wk placebo run-in before randomisation to placebo (n=172), tadalafil 5mg (n=171), or tamsulosin 0.4mg (n=168) once daily for 12 wk. MEASUREMENTS Outcomes were assessed using analysis of covariance (ANCOVA) or ranked analysis of variance (ANOVA) (continuous variables) and Cochran-Mantel-Haenszel test or Fisher exact test (categorical variables). RESULTS AND LIMITATIONS IPSS significantly improved versus placebo through 12 wk with tadalafil (-2.1; p=0.001; primary efficacy outcome) and tamsulosin (-1.5; p=0.023) and as early as 1 wk (tadalafil and tamsulosin both -1.5; p<0.01). BPH Impact Index significantly improved versus placebo at first assessment (week 4) with tadalafil (-0.8; p<0.001) and tamsulosin (-0.9; p<0.001) and through 12 wk (tadalafil -0.8, p=0.003; tamsulosin -0.6, p=0.026). The IPSS Quality-of-Life Index and the Treatment Satisfaction Scale-BPH improved significantly versus placebo with tadalafil (both p<0.05) but not with tamsulosin (both p>0.1). The International Index of Erectile Function-Erectile Function domain improved versus placebo with tadalafil (4.0; p<0.001) but not tamsulosin (-0.4; p=0.699). Q(max) increased significantly versus placebo with both tadalafil (2.4ml/s; p=0.009) and tamsulosin (2.2ml/s; p=0.014). Adverse event profiles were consistent with previous reports. This study was limited in not being powered to directly compare tadalafil versus tamsulosin. CONCLUSIONS Monotherapy with tadalafil or tamsulosin resulted in significant and numerically similar improvements versus placebo in LUTS/BPH and Q(max). However, only tadalafil improved erectile dysfunction. TRIAL REGISTRATION Clinicaltrials.gov ID NCT00970632.

Critical analysis of the relationship between sexual dysfunctions and lower urinary tract symptoms due to benign prostatic hyperplasia

CONTEXT This review focuses on the relationship among sexual dysfunction (SD), lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH), and related therapies. OBJECTIVE We reviewed the current literature to provide an overview of current data regarding epidemiology and pathophysiology of SD and LUTS. Moreover, we analysed the impact of currently available therapies of LUTS/BPH on both erectile dysfunction (ED) and ejaculatory dysfunction and the effect of phosphodiesterase type 5 inhibitors (PDE5-Is) in patients with ED and LUTS. EVIDENCE ACQUISITION We conducted a Medline search to identify original articles, reviews, editorials, and international scientific congress abstracts by combining the following terms: benign prostatic hyperplasia, lower urinary tract symptoms, sexual dysfunction, erectile dysfunction, and ejaculatory dysfunction. EVIDENCE SYNTHESIS We conducted a comprehensive analysis of more relevant general population-based and BPH/LUTS or SD clinic-based trials and evaluated the common pathophysiologic mechanisms related to both conditions. In a further step, the overall impact of current BPH/LUTS therapies on sexual life, including phytotherapies, novel drugs, and surgical procedures, was scrutinized. Finally, the usefulness of PDE5-Is in LUTS/BPH was critically analysed, including preclinical and clinical research data as well as possible mechanisms of action that may contribute to the efficacy of PDE5-Is with LUTS/BPH. CONCLUSIONS Community-based and clinical data demonstrate a strong and consistent association between LUTS and ED, suggesting that elderly men with LUTS should be evaluated for SD and vice versa. Pathophysiologic hypotheses regarding common basics of LUTS and SD as discussed in the literature are (1) alteration of the nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) pathway, (2) enhancement of RhoA-Rho-kinase (ROCK) contractile signalling, (3) autonomic adrenergic hyperactivity, and (4) pelvic atherosclerosis. The most important sexual adverse effects of medical therapies are ejaculation disorders after the use of some α-blockers and sexual desire impairment, ED, and ejaculatory disorders after the use of α-reductase inhibitors. Minimally invasive, conventional, and innovative surgical treatments for BPH may induce both retrograde ejaculation and ED. PDE5-Is have demonstrated significant improvements in both LUTS and ED in men with BPH; combination therapy with PDE5-Is and α1-adrenergic blockers seems superior to PDE5-I monotherapy.

Validation of the 2009 TNM Version in a Large Multi-Institutional Cohort of Patients Treated for Renal Cell Carcinoma: Are Further Improvements Needed?

BACKGROUND A new edition of the TNM was recently released that includes modifications for the staging system of kidney cancers. Specifically, T2 cancers were subclassified into T2a and T2b (< or =10 cm vs >10 cm), tumors with renal vein involvement or perinephric fat involvement were classified as T3a cancers, and those with adrenal involvement were classified as T4 cancers. OBJECTIVE Our aim was to validate the recently released edition of the TNM staging system for primary tumor classification in kidney cancer. DESIGN, SETTING, AND PARTICIPANTS Our multicenter retrospective study consisted of 5339 patients treated in 16 academic Italian centers. INTERVENTION Patients underwent either radical or partial nephrectomy. MEASUREMENTS Univariable and multivariable Cox regression models addressed cancer-specific survival (CSS) after surgery. RESULTS AND LIMITATIONS In the study, 1897 patients (35.5%) were classified as pT1a, 1453 (27%) as pT1b, 437 (8%) as pT2a, 153 (3%) as pT2b, 1059 (20%) as pT3a, 117 (2%) as pT3b, 26 (0.5%) as pT3c, and 197 (4%) as pT4. At a median follow-up of 42 mo, 786 (15%) had died of disease. In univariable analysis, patients with pT2b and pT3a tumors had similar CSS, as did patients with pT3c and pT4 tumors. Moreover, both pT3a and pT3b stages included patients with heterogeneous outcomes. In multivariable analysis, the novel classification of the primary tumor was a powerful independent predictor of CSS (p for trend <0.0001). However, the substratification of pT1 tumors did not retain an independent predictive role. The major limitations of the study are retrospective design, lack of central pathologic review, and the small number of patients included in some substages. CONCLUSIONS The recently released seventh edition of the primary tumor staging system for kidney tumors is a powerful predictor of CSS. However, some of the substages identified by the classification have overlapping prognoses, and other substages include patients with heterogeneous outcomes. The few modifications included in this edition may have not resolved the most critical issues in the previous version.

Efficacy and Safety of Tadalafil Once Daily in the Treatment of Men With Lower Urinary Tract Symptoms Suggestive of Benign Prostatic Hyperplasia: Results of an International Randomized, Double-Blind, Placebo-Controlled Trial

BACKGROUND Tadalafil is being investigated for the treatment of lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH-LUTS). OBJECTIVE To assess efficacy, including onset, and safety of tadalafil on BPH-LUTS and the subjects and clinicians perception of changes in urinary symptoms. DESIGN, SETTING, AND PARTICIPANTS This randomized, double-blind, placebo-controlled, 12-week trial enrolled men ≥45 yr of age with BPH-LUTS for >6 mo, International Prostate Symptom Score (IPSS) ≥13, and maximum urine flow rate (Q(max)) ≥4 to ≤15 ml/s. INTERVENTION Tadalafil 5mg (n=161) or placebo (n=164), once daily. MEASUREMENTS Analysis of covariance (ANCOVA) modeling evaluated change from baseline in continuous efficacy variables. Categoric efficacy variables were analyzed with the Cochran-Mantel-Haenszel test, and between-group differences in treatment-emergent adverse events (TEAEs) were assessed using the Fisher exact test. RESULTS AND LIMITATION: Tadalafil significantly improved IPSS results, from baseline to endpoint, compared to placebo (-5.6 vs -3.6; p=0.004). Reduction in IPSS results was apparent after 1 wk and significant after 4 wk (tadalafil -5.3 vs placebo -3.5; p=0.003). The BPH Impact Index (BII) was not assessed at week 1; however, BII improvement was apparent at 4 wk (tadalafil -1.8 vs placebo -1.2; p=0.029) and continued at 12 wk (tadalafil -1.8 vs placebo -1.3; p=0.057). Tadalafil significantly improved the International Index of Erectile Function-Erectile Function score in sexually active men with erectile dysfunction (ED; 6.7 vs 2.0; p<0.001) at 12 wk (not assessed at week 1). Few subjects reported one TEAE or more (p=0.44). For tadalafil, the most common TEAEs were headache (3.7%) and back pain (3.1%). Tadalafil did not significantly improve Q(max) or reduce postvoid residual volume. CONCLUSIONS Tadalafil 5mg once daily for 12 wk resulted in a clinically meaningful reduction in total IPSS results as early as 1 wk and achieved statistical significance at 4 wk in men with BPH-LUTS. The adverse event profile was consistent with that previously reported in men with ED. TRIAL REGISTRATION This clinical trial is registered on the clinicaltrials.gov website (http://www.clinicaltrials.gov). The registration number is NCT00827242.

Hydrogen sulfide as a mediator of human corpus cavernosum smooth-muscle relaxation

Hydrogen sulfide (H2S) is synthesized by 2 enzymes, cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE). l-Cysteine (l-Cys) acts as a natural substrate for the synthesis of H2S. Human penile tissue possesses both CBS and CSE, and tissue homogenates efficiently convert l-Cys to H2S. CBS and CSE are localized in the muscular trabeculae and the smooth-muscle component of the penile artery, whereas CSE but not CBS is also expressed in peripheral nerves. Exogenous H2S [sodium hydrogen sulfide (NaHS)] or l-Cys causes a concentration-dependent relaxation of strips of human corpus cavernosum. l-Cys relaxation is inhibited by the CBS inhibitor, aminoxyacetic acid (AOAA). Electrical field stimulation of human penile tissue, under resting conditions, causes an increase in tension that is significantly potentiated by either propargylglycine (PAG; CSE inhibitor) or AOAA. In rats, NaHS and l-Cys promote penile erection, and the response to l-Cys is blocked by PAG. Our data demonstrate that the l-Cys/H2S pathway mediates human corpus cavernosum smooth-muscle relaxation.

Combination of Bevacizumab and Docetaxel in Docetaxel-Pretreated Hormone-Refractory Prostate Cancer: A Phase 2 Study

OBJECTIVE Although the taxanes represent the most active agents for the first-line treatment of metastatic hormone-refractory prostate cancer (HRPC), most patients eventually progress while receiving taxane-based treatments. No agents are approved for second-line therapy in HRPC, but common standard practice for the oncologists is to treat patients also after docetaxel failure. METHODS Twenty highly pretreated patients with HRPC received bevacizumab (10mg/kg) and docetaxel (60mg/m(2)) every 3 wk. All patients had bone metastases and eight had measurable lesions. RESULTS Eleven patients (55%) had major prostate-specific antigen (PSA) responses, and 3 (37.5%) had objective responses. Seven major PSA responses were recorded in the same patients who had reported a >50% PSA decrease after first-line docetaxel. However, four major PSA responses were observed in patients previously nonresponsive to docetaxel alone. The treatment was well tolerated. CONCLUSIONS Our results show that the combination of bevacizumab and docetaxel is active and well tolerated. Continued investigation of bevacizumab with cytotoxic chemotherapy is warranted in HRPC.

Phase II Study of Sorafenib in Patients With Sunitinib-Refractory Metastatic Renal Cell Cancer

PURPOSE No previous prospective trials have been reported with sorafenib in patients with sunitinib-refractory metastatic renal cell cancer (MRCC). We conducted a multicenter study to determine the activity and tolerability of sorafenib as second-line therapy after sunitinib progression in MRCC. PATIENTS AND METHODS Between January 2006 and September 2008, 52 patients were enrolled onto this single-arm phase II study. All patients received sorafenib 400 mg orally twice a day until disease progression or intolerable toxicity. The primary end point was objective response rate (complete or partial response) evaluated every 8 weeks by use of the Response Evaluation Criteria in Solid Tumors; secondary end points were toxicity, time to progression (TTP), and overall survival (OS). RESULTS All patients were included in response and safety analyses. Partial responses were observed in 9.6% of patients (five of 52 patients; 95% CI, 5% to 17%) after two cycles. Grade 1 to 2 fatigue, diarrhea, nausea/vomiting, rash, and neutropenia were the most common side effects, noted in 16 (30.8%), 19 (36.5%), 20 (38.5%), 19 (36.5%), and 20 patients (38.5%), respectively. The most common grade 3 toxicity was diarrhea, noted in six patients (11.5%). Median TTP was 16 weeks (range, 8 to 40 weeks), and median OS was 32 weeks (range, 16 to 64 weeks). CONCLUSION Although well tolerated, sorafenib shows limited efficacy in sunitinib-refractory MRCC. Further randomized trials comparing sorafenib with other drugs that target different biologic pathways are needed to define the best second-line treatment option in these patients.