Fabio Castiglione

Intratunical injection of human adipose tissue-derived stem cells prevents fibrosis and is associated with improved erectile function in a rat model of Peyronie's disease.

BACKGROUND Peyronies disease (PD) is a connective tissue disorder of the tunica albuginea (TA). Currently, no gold standard has been developed for the treatment of the disease in its active phase. OBJECTIVE To test the effects of a local injection of adipose tissue-derived stem cells (ADSCs) in the active phase of a rat model of PD on the subsequent development of fibrosis and elastosis of the TA and underlying erectile tissue. DESIGN, SETTING, AND PARTICIPANTS A total of 27 male 12-wk-old Sprague-Dawley rats were divided in three equal groups and underwent injection of vehicle (sham), 0.5-μg [corrected] transforming growth factor (TGF)-β1 in a 50-μl vehicle in either a PD or a PD plus ADSC group in the dorsal aspect of the TA. INTERVENTION The sham and PD groups were treated 1 d after TGF-β1 injection with intralesional treatment of vehicle, and the PD plus ADSC group received 1 million human-labeled ADSCs in the 50-μl vehicle. Five weeks after treatment, six rats per group underwent erectile function measurement. Following euthanasia, penises were harvested for histology and Western blot. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS The ratio of intracavernous pressure to mean arterial pressure (ICP/MAP) upon cavernous nerve stimulation, elastin, and collagen III protein expression and histomorphometric analysis of the penis. Statistical analysis was performed by analysis of variance followed by the Tukey-Kramer test for post hoc comparisons or the Mann-Whitney test when applicable. RESULTS AND LIMITATIONS Erectile function significantly improved after ADSC treatment (ICP/MAP 0.37 in PD vs 0.59 in PD plus ADSC at 5-V stimulation; p=0.03). PD animals developed areas of fibrosis and elastosis with a significant upregulation of collagen III and elastin protein expression. These fibrotic changes were prevented by ADSC treatment. CONCLUSIONS This study is the first to test stem cell therapy in an animal model of PD. Injection of ADSCs into the TA during the active phase of PD prevents the formation of fibrosis and elastosis in the TA and corpus cavernosum.

Is erectile dysfunction a reliable proxy of general male health status? The case for the International Index of Erectile Function-Erectile Function domain.

INTRODUCTION Erectile dysfunction (ED) has emerged progressively as a sentinel marker of cardiovascular disease (CVD). The correlation between ED and the burden arising from multiple comorbid conditions has been incompletely analyzed. AIM Assess whether erectile function, defined with the International Index of Erectile Function-Erectile Function (IIEF-EF) domain score, is associated with health-significant comorbidities scored with the Charlson comorbidity index (CCI). METHODS Clinical and hemodynamic variables of the last 140 consecutive patients who underwent penile color Doppler ultrasonography for new-onset ED were considered. Patients were assessed with a thorough medical and sexual history. Health-significant comorbidities were scored with the CCI. MAIN OUTCOME MEASURE Descriptive statistics and either linear or logistic regression models tested the association among IIEF-EF, hemodynamic parameters, and CCI, which was included in the model both as continuous and categorized variable (0 vs. ≥1). RESULTS Complete data were available for 138 patients (98.6%) (mean age 46.6 years [standard deviation 13.0]; range 21-75 years). CCI was 0, 1, and ≥2 in 94 (68.1%), 23 (16.7%), and 21 (15.25%) patients, respectively. Of all, 35 patients (79.5%) did not have a CVD comorbidity. Mean IIEF-EF was 13.7 (9.3). ED severity was no ED, mild, mild to moderate, moderate, and severe in 12 (9.1%), 28 (20.2%), 12 (9.1%), 23 (16.2%), and 63 (45.5%) patients, respectively. At multivariable linear regression analysis, CCI significantly worsened with increased age (β=0.33; P=0.001) and decreased IIEF-EF values (β=-0.25; P=0.01). At logistic regression analysis, age (odds ratio [OR]: 1.05; P=0.004) and IIEF-EF (OR: 0.95; P=0.04) emerged as significant predictors of categorized CCI. CONCLUSIONS Severity of ED, as objectively interpreted with IIEF-EF, accounts for a higher CCI, which may be considered a reliable proxy of a lower general male health status regardless of the etiology of ED.

One Patient Out of Four with Newly Diagnosed Erectile Dysfunction Is a Young Man—Worrisome Picture from the Everyday Clinical Practice

INTRODUCTION Erectile dysfunction (ED) is a common complaint in men over 40 years of age, and prevalence rates increase throughout the aging period. Prevalence and risk factors of ED among young men have been scantly analyzed. AIM Assessing sociodemographic and clinical characteristics of young men (defined as ≤ 40 years) seeking first medical help for new onset ED as their primary sexual disorder. METHODS Complete sociodemographic and clinical data from 439 consecutive patients were analyzed. Health-significant comorbidities were scored with the Charlson Comorbidity Index (CCI). Patients completed the International Index of Erectile Function (IIEF). MAIN OUTCOME MEASURE Descriptive statistics tested sociodemographic and clinical differences between ED patients ≤ 40 years and >40 years. RESULTS New onset ED as the primary disorder was found in 114 (26%) men ≤ 40 years (mean [standard deviation [SD]] age: 32.4 [6.0]; range: 17-40 years). Patients ≤ 40 years had a lower rate of comorbid conditions (CCI = 0 in 90.4% vs. 58.3%; χ(2) , 39.12; P < 0.001), a lower mean body mass index value (P = 0.005), and a higher mean circulating total testosterone level (P = 0.005) as compared with those >40 years. Younger ED patients more frequently showed habit of cigarette smoking and use of illicit drug, as compared with older men (all P ≤ 0.02). Premature ejaculation was more comorbid in younger men, whereas Peyronies disease was prevalent in the older group (all P = 0.03). At IIEF, severe ED rates were found in 48.8% younger men and 40% older men, respectively (P > 0.05). Similarly, rates of mild, mild-to-moderate, and moderate ED were not significantly different between the two groups. CONCLUSIONS This exploratory analysis showed that one in four patients seeking first medical help for new onset ED was younger than 40 years. Almost half of the young men suffered from severe ED, with comparable rates in older patients. Overall, younger men differed from older individuals in terms of both clinical and sociodemographic parameters.

Metabolic Syndrome and Benign Prostatic Hyperplasia: Evidence of a Potential Relationship, Hypothesized Etiology, and Prevention

Benign prostatic hyperplasia (BPH) is highly prevalent in older men and causes substantial adverse effects on health. The pathogenesis of this disease is not totally clear. Recent reports have suggested a possible relationship between metabolic syndrome (MetS) and BPH. Single components of MetS (obesity, dyslipidemia, hypertension, and insulin resistance) as well as the syndrome itself may predispose patients to a higher risk of BPH and lower urinary tract symptoms (LUTS). This may stem from changes in insulin resistance, increased autonomic activity, impaired nitrergic innervation, increased Rho kinase activity, pro-inflammatory status, and changes in sex hormones that occur in association with MetS. However, the exact underlying mechanisms that regulate the potential relationship between MetS and BPH/LUTS still need to be clarified. Increased physical activity and dietary strategies may help in decreasing the incidence of MetS and its impact on BPH/LUTS. However, differences in the definitions used to address the examined predictors and endpoints preclude the possibility of arriving at definitive conclusions.

Valproic acid prevents penile fibrosis and erectile dysfunction in cavernous nerve-injured rats

INTRODUCTION Bilateral cavernous nerve injury (BCNI) causes profound penile changes such as apoptosis and fibrosis leading to erectile dysfunction (ED). Histone deacetylase (HDAC) has been implicated in chronic fibrotic diseases. AIMS This study will characterize the molecular changes in penile HDAC after BCNI and determine if HDAC inhibition can prevent BCNI-induced ED and penile fibrosis. METHODS Five groups of rats (8-10 weeks, n = 10/group) were utilized: (i) sham; (ii and iii) BCNI 14 and 30 days following injury; and (iv and v) BCNI treated with HDAC inhibitor valproic acid (VPA 250 mg/kg; 14 and 30 days). All groups underwent cavernous nerve stimulation (CNS) to determine intracavernosal pressure (ICP). Penile HDAC3, HDAC4, fibronectin, and transforming growth factor-β1 (TGF-β1) protein expression (Western blot) were assessed. Trichrome staining and the fractional area of fibrosis were determined in penes from each group. Cavernous smooth muscle content was assessed by immunofluorescence to alpha smooth muscle actin (α-SMA) antibodies. MAIN OUTCOME MEASURES We measured ICP; HDAC3, HDAC4, fibronectin, and TGF-β1 protein expression; penile fibrosis; penile α-SMA content. RESULTS There was a voltage-dependent decline (P < 0.05) in ICP to CNS 14 and 30 days after BCNI. Penile HDAC3, HDAC4, and fibronectin were significantly increased (P < 0.05) 14 days after BCNI. There was a slight increase in TGF-β1 protein expression after BCNI. Histological analysis showed increased (P < 0.05) corporal fibrosis after BCNI at both time points. VPA treatment decreased (P < 0.05) penile HDAC3, HDAC4, and fibronectin protein expression as well as corporal fibrosis. There was no change in penile α-SMA between all groups. Furthermore, VPA-treated BCNI rats had improved erectile responses to CNS (P < 0.05). CONCLUSION HDAC-induced pathological signaling in response to BCNI contributes to penile vascular dysfunction. Pharmacological inhibition of HDAC prevents penile fibrosis, normalizes fibronectin expression, and preserves erectile function. The HDAC pathway may represent a suitable target in preventing the progression of ED occurring post-radical prostatectomy.

Landmarks in erectile function recovery after radical prostatectomy.

The description of the nerve-sparing technique of radical prostatectomy by Walsh was one of the major breakthroughs in the surgical treatment of prostate cancer in the 20th century. However, despite this advance and consequent technological refinements to nerve-sparing surgery, a large proportion of men still suffer from erectile dysfunction (ED) as a complication of prostatectomy. A plethora of therapeutic approaches have been proposed to optimize erectile function recovery in these patients. Several preclinical and translational studies have shown benefits of therapies including PDE5 inhibitor (PDE5I) treatment, immunomodulation, neurotrophic factor administration, and regenerative techniques, such as stem cell therapy, in animal models. However, most of these approaches have either failed to translate to clinical use or have yet to be studied in human subjects. Penile rehabilitation with PDE5Is is currently the most commonly used clinical strategy, in spite of the absence of solid clinical evidence to support its use.

When to perform lymph node dissection in patients with renal cell carcinoma: a novel approach to the preoperative assessment of risk of lymph node invasion at surgery and of lymph node progression during follow-up.

To identify preoperatively patients who might benefit from lymph node dissection (LND).

Spinal Cord FAAH in Normal Micturition Control and Bladder Overactivity in Awake Rats

PURPOSE We assessed whether spinal inhibition of the cannabinoid degrading enzyme FAAH would have urodynamic effects in normal rats and rats with bladder overactivity induced by partial urethral obstruction or prostaglandin E2. We also determined the expression of FAAH, and the cannabinoid receptors CB1 and CB2 in the sacral spinal cord. MATERIALS AND METHODS We used 44 rats for functional (cystometry) and Western blot experiments. The FAAH inhibitor oleoyl ethyl amide (3 to 300 nmol) was administered intrathecally (subarachnoidally) or intravenously. The expression of FAAH and CB1/CB2 receptors was determined by Western blot. RESULTS Oleoyl ethyl amide given intrathecally affected micturition in normal rats and rats with bladder overactivity but effects were more pronounced in the latter. In normal rats oleoyl ethyl amide only decreased micturition frequency, while it decreased frequency and bladder pressures in rats with bladder overactivity. Intravenous oleoyl ethyl amide (3 to 300 nmol) had no urodynamic effect. FAAH and CB1/CB2 receptors were expressed in the rat sacral spinal cord. The expression of CB1/CB2 receptors but not FAAH was higher in obstructed than in normal rats. CONCLUSIONS FAAH inhibition in the sacral spinal cord by oleoyl ethyl amide resulted in urodynamic effects in normal rats and rats with bladder overactivity. The spinal endocannabinoid system may be involved in normal micturition control and it appears altered when there is bladder overactivity.

The Number of Cores Taken in Patients Diagnosed with a Single Microfocus at Initial Biopsy is a Major Predictor of Insignificant Prostate Cancer

PURPOSE Patients with a single microfocus of prostate cancer at initial biopsy represent the ideal candidates for active surveillance. We investigate whether the number of cores taken affects the concordance rate between microfocus of prostate cancer and the confirmation of a pathologically insignificant prostate cancer at radical prostatectomy. MATERIALS AND METHODS Data were analyzed from 233 patients with a single microfocus of prostate cancer at initial transrectal prostate biopsy (a single focus of Gleason 6 involving 5% or less of the core) subsequently treated with radical prostatectomy. The chi-square test, cubic spline analyses and logistic regression analyses were used to depict the relationship between the number of cores taken and the probability of confirming the presence of an indolent disease (pathologically confirmed insignificant prostate cancer defined as radical prostatectomy Gleason score 6 or less, tumor volume 0.5 ml or less and organ confined disease). RESULTS Overall 65 patients (27.9%) showed pathologically confirmed insignificant prostate cancer at radical prostatectomy. The rate of pathologically confirmed insignificant prostate cancer was 3.8%, 29.6% and 39.4% in patients who underwent biopsy of 12 or fewer cores, 13 to 18 cores and 19 or more cores, respectively (p <0.001). After adjusting for the available confounders, age (p = 0.04), number of cores taken (p <0.001) and prostate specific antigen density (p <0.02) were independent predictors of pathologically confirmed insignificant prostate cancer. CONCLUSIONS Of patients diagnosed with a single microfocus of prostate cancer the number of biopsy cores taken was a major independent predictor of having pathologically confirmed insignificant prostate cancer at radical prostatectomy. Therefore, when active surveillance is considered as a possible alternative in patients with microfocus of prostate cancer, the number of cores taken should be taken into account in decision making.

Postoperative phosphodiesterase type 5 inhibitor administration increases the rate of urinary continence recovery after bilateral nerve-sparing radical prostatectomy

To investigate the effect of phosphodiesterase type 5 inhibitor on urinary continence recovery after bilateral nerve‐sparing radical prostatectomy.