Temporal gene signature of myofibroblast transformation in Peyronie's disease: first insights into the molecular mechanisms of irreversibility.

BACKGROUND: Transformation of resident fibroblasts to profibrotic myofibroblasts in the tunica albuginea is a critical step in the pathophysiology of Peyronie's disease (PD). We have previously shown that myofibroblasts do not revert to the fibroblast phenotype and we suggested that there is a point of no return at 36 hours after induction of the transformation. However, the molecular mechanisms that drive this proposed irreversibility are not known. AIM: Identify molecular pathways that drive the irreversibility of myofibroblast transformation by analyzing the expression of the genes involved in the process in a temporal fashion. METHODS: Human primary fibroblasts obtained from tunica albuginea of patients with Peyronie's disease were transformed to myofibroblasts using transforming growth factor beta 1 (TGF-ß1). The mRNA of the cells was collected at 0, 24, 36, 48, and 72 hours after stimulation with TGF-ß1 and then analyzed using a Nanostring nCounter Fibrosis panel. The gene expression results were analyzed using Reactome pathway analysis database and ANNi, a deep learning-based inference algorithm based on a swarm approach. OUTCOMES: The study outcome was the time course of changes in gene expression during transformation of PD-derived fibroblasts to myofibroblasts. RESULTS: The temporal analysis of the gene expression revealed that the majority of the changes at the gene expression level happened within the first 24 hours and remained so throughout the 72-hour period. At 36 hours, significant changes were observed in genes involved in MAPK-Hedgehog signaling pathways. CLINICAL TRANSLATION: This study highlights the importance of early intervention in clinical management of PD and the future potential of new drugs targeting the point of no return. STRENGTHS AND LIMITATIONS: The use of human primary cells and confirmation of results with further RNA analysis are the strengths of this study. The study was limited to 760 genes rather than the whole transcriptome. CONCLUSION: This study is to our knowledge the first analysis of temporal gene expression associated with the regulation of the transformation of resident fibroblasts to profibrotic myofibroblasts in PD. Further research is warranted to investigate the role of the MAPK-Hedgehog signaling pathways in reversibility of PD.

Statins synergize with phosphodiesterase type 5 inhibitors but not with selective estrogen receptor modulators to prevent myofibroblast transformation in an in vitro model of Peyronie's disease.

BACKGROUND: Peyronie's disease (PD) is a fibrotic disorder characterized by plaque formation in the tunica albuginea (TA) of the penis, and we have previously shown that inhibition of transformation of TA-derived fibroblasts to myofibroblasts using a combination phosphodiesterase type 5 (PDE5) inhibitors and selective estrogen receptor modulators (SERMs) is effective in slowing the progression of early PD. AIM: The study sought to investigate whether combinations of statins with PDE5 inhibitors or SERMs would affect myofibroblast transformation in vitro. METHODS: Primary fibroblasts were isolated from TA of patients with PD and stimulated with transforming growth factor ß1 in the absence and presence of a range of concentrations of statins, PDE5 inhibitors, SERMs, and their combinations for 72 hours before quantifying α-smooth muscle actin using in-cell enzyme-linked immunosorbent assay. OUTCOMES: The prevention of transforming growth factor ß1-induced transformation of TA-derived fibroblasts to myofibroblasts was measured in vitro. RESULTS: Statins (simvastatin, lovastatin) inhibited myofibroblast transformation in a concentration-dependent manner with half maximal inhibitory concentration values of 0.77 ± 0.07 µM and 0.8 ± 0.13 µM, respectively. Simvastatin inhibited myofibroblast transformation in a synergistic fashion when combined with vardenafil (a PDE5 inhibitor; log alpha >0). Combination of tamoxifen (a SERM) and simvastatin did not show synergy (log alpha <0). When 3 drugs (simvastatin, vardenafil, and tamoxifen) were combined, the effect was not synergistic, but rather was additive. CLINICAL IMPLICATIONS: A combination of a statin with a PDE5 inhibitor might be useful in the clinic to slow the progression of the disease in patients with early PD; however, caution should be taken with such a combination because of the reported myopathy as a side effect. STRENGTHS AND LIMITATIONS: The use of primary human cells from patients with PD is a strength of this study. The mechanisms by which these drug classes exert synergy when used in combination was not investigated. CONCLUSION: This is the first demonstration of an antifibrotic synergy between statins and PDE5 inhibitors.

UK practice for penile prosthesis surgery: baseline analysis of the British Association of Urological Surgeons (BAUS) Penile Prosthesis Audit.

OBJECTIVES: To undertake a prospective multicentre national audit of penile prosthesis practice in the UK over a 3-year period. PATIENTS AND METHODS: Data were submitted by urological surgeons as part of the British Association of Urological Surgeons Penile Prosthesis National Audit. Patients receiving a penile prosthesis (inflatable or malleable) were included as part of a prospective registry over a 3-year period. Data were validated and then analysed using a software package (Tableau). RESULTS: A total of 1071 penile prosthesis procedures were included from 22 centres. The three commonest aetiological factors for erectile dysfunction were diabetes, prostate surgery and Peyronie's disease. Of the recorded data, inflatable penile prostheses were the commonest devices implanted, with 665 devices used (62.1%), whereas malleable prostheses accounted for 14.2% of the implants. Recorded intra-operative complications included urethral injury (0.7%, n = 7), corporal perforation (1.1%, n = 12) and cross-over (0.6%, n = 6). Known postoperative complications were recorded in 9.8% of patients (74/752), with the two most frequently reported being postoperative penile pain (n = 11) and scrotal haematoma (n = 14). CONCLUSION: This baseline analysis is the largest prospective registry of penile prostheses procedures to date. The data show that, over the 3-year collection period in the UK, there are now fewer surgeons performing the procedure, together with a reduction in the number of centres. Peri-operative complications were infrequent, and the rate of implant abortion (e.g. as a result of urethral injury) was very low. Further follow-up data will be required to publish long-term outcomes and patient satisfaction.

Rare Disorders of Painful Erection: A Cohort Study of the Investigation and Management of Stuttering Priapism and Sleep-Related Painful Erection.

BACKGROUND: A chief complaint of men with stuttering priapism (SP) and sleep-related painful erections (SRPE) is bothersome nocturnal erections that wake them up and result in poor sleep and daytime tiredness. SP and SRPE are rare entities that have similarities in their clinical features, but that require different treatment approaches. AIM: The aim of this study was to describe the clinical features, investigations, and effective management options for men with SP and SRPE. METHODS: Retrospective cohort study of 133 men with bothersome nocturnal painful erections that attended a tertiary andrology unit between 2004 and 2018. These men were divided into 3 groups. Group 1 (n = 62) contains men with sickle cell SP; group 2 (n = 40) has men with non-sickle cell SP and group 3 (n = 31) contains men with SRPE. OUTCOME: To determine the effectiveness of medical and surgical treatments for men with SP and SRPE. RESULTS: Hydroxyurea and automated exchange transfusion were the most effective treatment options in the sickle cell SP group. Hormonal manipulation and α-agonist therapies were effective in both SP cohorts (groups 1 and 2). Baclofen was the most effective therapy in men with SRPE. For men who failed medical management, implantation of a penile prosthesis resulted in complete resolution of the symptoms in men with SP (groups 1 and 2). Surgical management (penile prosthesis implantation and embolization) did not improve the patients' symptoms in the SRPE group. CLINICAL IMPLICATIONS: This study differentiates between sickle cell SP, non-sickle cell SP, and SRPE and describes effective treatment options for each group. STRENGTHS & LIMITATIONS: This is the largest cohort study for both SP and SRPE, respectively. Limitations include its retrospective nature and single-center experience. CONCLUSION: Managing men in these 3 groups differently and in accordance with the proposed treatment pathway provides a more structured approach to the management of these rare conditions. Johnson M, McNeillis S, Chiriaco G, et al. Rare Disorders of Painful Erection: A Cohort Study of the Investigation and Management of Stuttering Priapism and Sleep-Related Painful Erection. J Sex Med 2021;18:376-384.

Phosphodiesterase Type 5 Inhibitors and Selective Estrogen Receptor Modulators Can Prevent But Not Reverse Myofibroblast Transformation in Peyronie's Disease.

BACKGROUND: Myofibroblast transformation is a key step in the pathogenesis of Peyronie's disease (PD). Phosphodiesterase type 5 inhibitors (PDE5is) and selective estrogen receptor modulators (SERMs) can prevent the formation of fibrosis in in vitro and in vivo models of PD. However, it is unknown whether these drugs can also reverse established fibrosis. AIM: To investigate whether PDE5is and SERMs can reverse transforming growth factor beta 1 (TGF-ß1)-induced myofibroblast transformation and determine the point of no return. METHODS: In-Cell enzyme-linked immunosorbent assay was used to quantify TGF-ß1-induced myofibroblast transformation of human primary fibroblasts isolated from tunica albuginea (TA) of patients undergoing surgery for treatment of PD. Extracellular matrix production and collagen contraction assays were used as secondary assays. Reverse transcription-quantitative polymerase chain reaction and In-Cell enzyme-linked immunosorbent assay were used to measure drug target expression. PDE5i (vardenafil) and SERM (tamoxifen) were applied at various time points after TGF-ß1. OUTCOMES: Reversibility of myofibroblast transformation and drug target expression were investigated in a time-dependent manner in TA-derived fibroblasts. RESULTS: Vardenafil or tamoxifen could not reverse the myofibroblast traits of alpha-smooth muscle actin expression and extracellular matrix production, whereas only tamoxifen affected collagen contraction after 72 hours of TGF-ß1 treatment. Phosphodiesterase 5A and estrogen receptor (ER)-ß were downregulated after 72 hours, and estrogen receptor -α protein could not be quantified. Tamoxifen could prevent myofibroblast transformation until 36 hours after TGF-ß1 treatment, whereas vardenafil could prevent only 24 hours after TGF-ß1 treatment. This was mirrored by downregulation of drug targets on mRNA and protein level. Furthermore, antifibrotic signaling pathways, peroxisome proliferator-activated receptor gamma and betaglycan (TGFB receptor III), were significantly downregulated after 36 hours of TGF-ß1 exposure, as opposed to upregulation of profibrotic thrombospondin-1 at the same time point. CLINICAL TRANSLATION: This study suggests that using PDE5is and SERMs might only help for early-phase PD and further highlights the need to test drugs at the appropriate stage of the disease based on their mechanism of action. STRENGTHS & LIMITATIONS: The study uses primary human TA-derived fibroblasts that enhances translatability of the results. Limitations include that only 1 example of PDE5i- and SERM-type drug was tested. Time course experiments were only performed for marker expression experiments and not for functional assays. CONCLUSION: This is the first study to demonstrate that timing for administration of drugs affecting myofibroblast transformation appears to be vital in in vitro models of PD, where 36 hours of TGF-ß1 treatment can be suggested as a "point of no return" for myofibroblast transformation. Ilg MM, Stafford SJ, Mateus M, et al. Phosphodiesterase Type 5 Inhibitors and Selective Estrogen Receptor Modulators Can Prevent But Not Reverse Myofibroblast Transformation in Peyronie's Disease. J Sex Med 2020;17:1848-1864.

An analysis of the frequency of Y-chromosome microdeletions and the determination of a threshold sperm concentration for genetic testing in infertile men.

OBJECTIVE: To describe the prevalence of Y-chromosome microdeletions in a multi-ethnic urban population in London, UK. To also determine predictive factors and a clinical threshold for genetic testing in men with Y chromosome microdeletions. PATIENTS AND METHODS: A retrospective cohort study of 1473 men that were referred to a tertiary Andrology centre with male factor infertility between July 2004 and December 2016. All had a genetic evaluation, hormonal profile and 2 abnormal semen analyses. Those with abnormal examination findings also had targeted imaging performed. RESULTS: The prevalence of microdeletions was 4% (n = 58) in this study. These microdeletions were partitioned into the following regions: Azoospermia factors (AZF); AZFc (75%), AZFb+c (13.8%), AZFb (6.9%), AZFa (1.7%), and partial AZFa (1.7%). A high follicle-stimulating hormone level (P < 0.001) and a low sperm concentration (P < 0.05) were both found to be significant predictors for the identification of a microdeletion. Testosterone level, luteinising hormone level and testicular volume did not predict the presence of a microdeletion. None of the men with an AZF microdeletion had a sperm concentration of >0.5 million/mL. Lowering the sperm concentration threshold to this level retained the high sensitivity (100%) and increased the specificity (31%). This would produce significant cost savings when compared to the European Academy of Andrology/European Molecular Genetics Quality Network and European Association of Urology guidelines. The surgical sperm retrieval (SSR) rate after microdissection testicular sperm extraction was 33.2% in men with AZFc microdeletion. CONCLUSIONS: The prevalence of Y-chromosome microdeletions in infertile men appears to vary between populations and countries. A low sperm concentration was a predictive factor (P < 0.05) for identifying microdeletions in infertile males. A threshold for genetic testing of 0.5 million/mL would increase the specificity and lower the relative cost without adversely affecting the sensitivity. The rate of SSR was lower than that previously described in the literature.

Stem-cell regenerative medicine as applied to the penis.

PURPOSE OF REVIEW: Tissue engineering and regenerative medicine has emerged as a new scientific interdisciplinary field focusing on developing new strategies to repair or recreate tissues and organs. This review gathers findings on erectile dysfunction and, Peyronie's disease from recent preclinical and clinical studies under heading of stem-cell regenerative medicine. RECENT FINDINGS: Over the last 2 years, preclinical studies on rat models demonstrated the tangible beneficial role of stem cells and stromal vascular fraction in the context of preventing fibrosis and restoring erectile function in different animal models of Erectile dysfunction and Peyronie's disease. There are not solid evidences in the clinical settings. SUMMARY: Large randomized, double blind clinical trials are needed to prove the efficacy of stem-cell therapy on human patients. Owing to the lack of solid evidences, the stem-cell therapy should be only administrated in a clinical research setting.

Outcomes of inflatable penile prosthesis insertion in 247 patients completing female to male gender reassignment surgery.

OBJECTIVES: To assess the oucomes of penile prosthesis (PP) implantation after total phallic reconstruction secondary to gender dysphoria. PATIENTS AND METHODS: We conducted a retrospective single-centre analysis of 247 consecutive patients. The recruitment period was January 2001 to October 2015. A total of 328 inflatable PPs were implanted. A two-staged inflatable PP implantation was carried out. As a first step, an extraperitoneal reservoir placement was performed simultaneously with the glans sculpture and the insertion of a single large testicular prosthesis into the labia majora. Subsequently, cylinder(s) and pump placement was performed. A Dacron envelope was fitted around the proximal and distal aspect of the cylinder(s) to anchor the device to the pubic bone and to prevent apical protrusion. The outcomes measured were postoperative complications, eventual need for revision surgery, and long-term survival of the implants. Patient and partner satisfaction rates were extrapolated from the administered non-validated questionnaires. The data were analysed using non-parametric tests, multivariate logistic regression analysis, and a Kaplan-Meier survival curve. RESULTS: The mean follow-up was 20 months. In all, 88% of patients were satisfied with the result, although only 77% used their device for sexual intercourse. The overall 5-year device survival was 78%, with no one device being superior. Device infection occurred in 8.5% of patients with an overall revision rate of 43%. According to the multivariate logistic regression analysis, only type of phalloplasty significantly affected the infection risk (P = 0.013). CONCLUSIONS: Implantation of a PP into a neophallus is a complex procedure but yields high satisfaction rates. Nevertheless, complication rates are high and patients must be warned that multiple revisions will be necessary throughout their lifetime.

Efficacy and Safety of MED2005, a Topical Glyceryl Trinitrate Formulation, in the Treatment of Erectile Dysfunction: A Randomized Crossover Study.

BACKGROUND: Current treatments for erectile dysfunction (ED) have some limitations. AIM: This study evaluated the efficacy and tolerability of MED2005, a 0.2% glyceryl trinitrate topical gel, formulated into an enhanced absorption topical delivery system (DermaSys), administered on demand, in the treatment of ED. METHODS: This randomized, double-blinded, placebo-controlled, phase II crossover trial involved 232 men with ED (231 treated, 230 assessed for efficacy) and their partners. After a 4-week run-in period, patients were randomized to 1 of 2 treatment sequences, MED2005-placebo or placebo-MED2005. Each treatment was given for 4 weeks, separated by a 1-week washout interval. Efficacy was assessed by the International Index of Erectile Function (IIEF), the Sexual Encounter Profile, a Global Assessment Questionnaire (GAQ), and specific questions about the onset and offset of action and treatment preferences (patients and partners). OUTCOMES: The primary outcome measure was the IIEF erectile function domain (IIEF-EF) score. Other efficacy assessments were secondary outcomes. RESULTS: The mean baseline IIEF-EF score was 17.1 (SD = 5.7), and this increased to 19.6 (SD = 7.5) after MED2005 treatment and 18.5 (SD = 6.7) after placebo (P = .0132). Overall, 23.1% of patients showed a clinically relevant (≥4-point) increase in IIEF-EF scores after treatment with MED2005 only compared with 14.5% who responded after MED2005 and placebo, 14.0% who responded after placebo only, and 48.4% who did not respond after either treatment (P = .0272). MED2005 also was associated with significant improvements compared with placebo in the other IIEF domains, and this was consistent with patients' and partners' responses to the GAQ. For all assessments, significant effects of MED2005 were seen primarily in patients with mild ED. The start of erection was noticed within 5 and 10 minutes in 44.2% and 69.5%, respectively, of all intercourse attempts with MED2005. Patients and partners showed significant preferences for MED2005 over placebo. The most commonly reported adverse events during MED2005 treatment were headache (patients, n = 18 [7.9%]; partners, n = 3 [1.3%]) and nasopharyngitis (patients, n = 13 [5.7%]; partners, n = 2 [0.9%]). CLINICAL IMPLICATIONS: These findings suggest that topical glyceryl trinitrate could be a useful treatment option in ED. STRENGTHS AND LIMITATIONS: Strengths of this study include the use of a validated outcome measure. Limitations include the use of only 1 dosage. CONCLUSION: Further studies are warranted to investigate the efficacy of topical glyceryl trinitrate to include higher doses, thereby improving clinical significance, especially in cases of moderate and severe ED. Ralph DJ, Eardley I, Taubel J, et al. Efficacy and Safety of MED2005, a Topical Glyceryl Trinitrate Formulation, in the Treatment of Erectile Dysfunction: A Randomized Crossover Study. J Sex Med 2018;15:167-175.

Understanding the Role of Adenosine Receptors in the Myofibroblast Transformation in Peyronie's Disease.

BACKGROUND: Peyronie's disease (PD) is a chronic fibrotic disease of the penis affecting a significant number of men worldwide without effective medical treatments. Myofibroblasts are pivotal in the pathogenesis of PD. Adenosine and adenosine receptors have been suggested to be involved in the pathophysiology of fibrosis. AIM: To understand the role of adenosine receptors in myofibroblast transformation in PD. METHODS: Fibroblasts were isolated from the non-PD tunica albuginea (TA) tissue and PD plaque tissue and were transformed into myofibroblasts using transforming growth factor (TGF)-ß1. Quantification of α-smooth muscle actin and adenosine receptors (adenosine receptor A1 [ADORA1], adenosine receptor A2A, adenosine receptor A2B [ADORA2B], and adenosine receptor A3) was performed using immuno-cytochemistry, in-cell enzyme-linked immuno-sorbent assay (ICE), and real-time reverse transcription quantitative polymerase chain reaction. The effect of various adenosine receptor agonists or antagonists on TGF-ß1-induced myofibroblast transformation was measured using ICE. OUTCOMES: Expression of adenosine receptors in myofibroblasts obtained from human TA and the effect of adenosine receptor ligands on myofibroblast transformation were investigated. RESULTS: The experiments showed that the protein and messenger RNA levels of α-smooth muscle actin in non-PD TA cells and PD plaque-derived cells were significantly higher in cells exposed to TGF-ß1 than those not treated with TGF-ß1. 2 of 4 adenosine receptors (ADORA1 and ADORA2B) were found to be expressed in both cell populations. Among various adenosine receptor agonists/antagonist investigated, only ADORA2B agonist, BAY 60-6583, significantly inhibited myofibroblast transformation in a concentration-dependent manner when applied simultaneously with TGF-ß1 (IC50 = 30 µmol/L). CLINICAL TRANSLATION: ADORA2B agonists may be clinically efficacious in early-stage PD. STRENGTHS & LIMITATIONS: The strength of this study is the use of primary fibroblasts from human TA. Limitation of the study is the high concentrations of the ligands used. CONCLUSION: The effect of an ADORA2B agonist on TGF-ß1-induced myofibroblast transformation shows a novel potential therapeutic target for PD if applied during early, non-stable phase of PD. Mateus M, Ilg MM, Stebbeds WJ, et al. Understanding the Role of Adenosine Receptors in the Myofibroblast Transformation in Peyronie's Disease. J Sex Med 2018;15:947-957.

Safety and effectiveness of collagenase clostridium histolyticum in the treatment of Peyronie's disease using a new modified shortened protocol.

OBJECTIVES: To evaluate the efficacy and safety of collagenase clostridium histolyticum (CCH; Xiapex® , Xiaflex® ) in the treatment of Peyronie's disease (PD) using a new modified treatment protocol that aims at reducing the number of injections needed and reducing patient visits, thus reducing the duration and cost of treatment. PATIENTS AND METHODS: A prospective study of 53 patients with PD who had treatment with CCH at a single centre using a new modified protocol. The angle of curvature assessment after an intracavernosal injection of prostaglandin E1, the International Index of Erectile Function (IIEF) and Peyronie's Disease Questionnaire (PDQ) were completed at baseline and at week 12 (4 weeks after the last injection). The Global Assessment of Peyronie's disease (GAPD) questionnaire was completed at week 12. Under a penile block of 10 mL plain lignocaine 1%, a total of three intralesional injections of CCH (0.9 mg) were given at 4-weekly intervals using a new modified injection technique. In between injections patients used a combination of home modelling, stretching and a vacuum device on a daily basis to mechanically stretch the plaque. Investigator modelling was not performed. RESULTS: The mean (range) penile curvature at baseline was 54 (30-90)°. Of the 53 patients in the study, 51 patients (96.2%) had an improvement in the angel of curvature by a mean (range) of 17.36 (0-40)° or 31.4 (0-57)% from baseline after three CCH injections. The final mean (range) curvature was 36.9 (12-75)° (P < 0.001). There was an improvement in each of the IIEF questionnaire domains, all three PDQ domains and the GAPD. CCH was well tolerated by all patients with only mild and transient local adverse events. CONCLUSION: The new shortened protocol using CCH treatment is safe, effective, and cost efficient. The results of using only three CCH injections according to this modified protocol are comparable to those of the clinical trials that used eight CCH injections.

Sleep disorders in patients with erectile dysfunction.

OBJECTIVE: To assess the prevalence of obstructive sleep apnoea (OSA) in men presenting with erectile dysfunction (ED) at a single centre. PATIENTS AND METHODS: All men attending a specialised andrology outpatient department with a new diagnosis of ED were included in this prospective study. All patients completed three questionnaires: the International Index of Erectile Function (IIEF) and two sleep questionnaires [the Obstructive Sleep Apnoea Screening questionnaire and the Insomnia Severity Index (ISI)]. Their ED management was subsequently undertaken in accordance with local and European guidelines. An OSA diagnosis was made based on a score of ≥3 on the Obstructive Sleep Apnoea Screening questionnaire and those patients were referred for specialist management. RESULTS: Between February and September 2016, 129 patients with ED completed the study questionnaires. In all, 71 patients (55%) had a score of ≥3 on the Obstructive Sleep Apnoea Screening questionnaire, indicating a need for specialist sleep referral. Men who scored ≥3 on the Obstructive Sleep Apnoea Screening questionnaire were significantly older (61.4 vs 46.5 years; P < 0.001) and had a significantly higher body mass index (29.4 vs 26.7 kg/m2 ; P < 0.001) when compared to the control group (OSA score of <3). The sleep apnoea group (OSA score of ≥3) had significantly worse IIEF-ED scores (6.2 vs 9.1; P = 0.018) and ISI scores (7.9 vs 5.5; P = 0.061). CONCLUSION: Men presenting to the andrology clinic with ED are at significant risk of having undiagnosed sleep disorders. This has serious adverse health consequences, as well as being associated with potential dangers at work and travel. The patient compliance was high with 78% completing all three questionnaires. It is feasible to screen this population for sleep disturbance and this should be part of the ED assessment.

Treatment of Peyronie's Disease With Collagenase Clostridium histolyticum and Vacuum Therapy: A Randomized, Open-Label Pilot Study.

BACKGROUND: Collagenase Clostridium histolyticum (CCH) is indicated for the treatment of penile curvature in adult men with Peyronie's disease (PD) with palpable plaque and curvature deformity of at least 30° at the start of therapy. AIM: To evaluate the efficacy and safety of CCH plus vacuum-pump therapy with and without penile modeling for the management of PD. METHODS: Adult men with PD and penile curvature of at least 30° were randomly assigned to receive CCH 0.58 mg plus vacuum therapy alone (n = 15) or with penile plaque modeling (n = 15). Patients received no more than four treatment cycles (cycle = ∼6-week duration), each consisting of two intralesional injections of CCH administered 24 to 72 hours apart. Vacuum therapy was applied twice daily from 14 days after the second injection of each cycle until the following cycle. Modeling was performed 24 to 72 hours after the second injection of each cycle. OUTCOMES: The primary end point was change in penile curvature from baseline to week 36; additional end points included changes in Peyronie's Disease Questionnaire (PDQ) domain scores, composite response (≥20% decrease in penile curvature and decrease in PDQ bother score ≥ 1 point), and global response (small but important, moderate, or much improvement in the Global Assessment of PD). RESULTS: At week 36, improvement in penile curvature from baseline was similar in the two groups (mean change from baseline = -23.7° [SD = 10.9] for CCH + vacuum + modeling and -23.3° [SD = 7.2] for CCH + vacuum; between-group difference = -0.3°, 95% CI = -7.3 to 6.6). Improvements in most PDQ domains, including bother, were observed from baseline to week 36 in the two groups. Most patients were composite (66.7% and 84.6% with CCH + vacuum + modeling and CCH + vacuum, respectively) and global (86.7% and 92.3%, respectively) responders. The most common adverse events were penile contusion, penile swelling, and penile pain. CLINICAL IMPLICATIONS: Vacuum-pump therapy administered alone or in combination with modeling after CCH treatment could improve PD symptoms. STRENGTHS AND LIMITATIONS: This was a pilot study with a small sample and limited follow-up duration. CONCLUSION: CCH and vacuum-pump therapy (alone or combined with modeling) could be an appropriate consideration for men with PD and warrants further investigation. Ralph DJ, Abdel Raheem A, Liu G. Treatment of Peyronie's Disease With Collagenase Clostridium histolyticum and Vacuum Therapy: A Randomized, Open-Label Pilot Study. J Sex Med 2017;14:1430-1437.

Early Effect of Bariatric Surgery on Urogenital Function in Morbidly Obese Men.

INTRODUCTION: Obesity is an independent risk factor for erectile dysfunction (ED) and lower urinary tract symptoms (LUTS). Bariatric surgery has been shown to improve erectile function and urinary symptoms in medium- to long-term studies (3- to 12-month postoperative follow-up). AIM: To investigate the early effect (1 month postoperatively) of bariatric surgery on ED and LUTS, which has not previously been investigated. METHODS: Morbidly obese men (body mass index > 35 kg/m2) undergoing bariatric surgery were asked to complete the International Index of Erectile Function (IIEF) and International Prostate Symptom Score (IPSS) questionnaires before surgery and 1, 3, and 6 months after surgery. MAIN OUTCOME MEASURE: The influence of bariatric surgery on urogenital function, body mass index, fasting blood glucose, and glycated hemoglobin were analyzed using parametric and non-parametric tests for paired samples. RESULTS: Of 30 patients who completed the study, 18 reported ED (IIEF score < 25) and 14 reported moderate or severe LUTS (IPSS ≥ 8) before the operation. Twelve patients had ED and moderate or severe LUTS. IIEF score, IPSS, body mass index, percentage of weight loss, fasting blood glucose, and glycated hemoglobin showed significant and rapid improvement after bariatric surgery starting at the 1-month postoperative time point and improvement continued throughout the study in all patients with ED or moderate to severe LUTS. CONCLUSION: This is the first study showing improvement in erectile and urinary function within 1 month after bariatric surgery, an effect that was parallel to glycemic improvement and weight loss.

Multicenter Investigation of the Micro-Organisms Involved in Penile Prosthesis Infection: An Analysis of the Efficacy of the AUA and EAU Guidelines for Penile Prosthesis Prophylaxis.

INTRODUCTION: Penile prosthesis infections remain challenging despite advancements in surgical technique, device improvements, and adoption of antibiotic prophylaxis guidelines. AIM: To investigate penile prosthesis infection microbiology to consider which changes in practice could decrease infection rates, to evaluate current antibiotic prophylaxis guidelines, and to develop a proposed algorithm for penile prosthesis infections. METHODS: This retrospective institutional review board-exempt multi-institutional study from 25 centers reviewed intraoperative cultures obtained at explantation or Mulcahy salvage of infected three-piece inflatable penile prostheses (IPPs). Antibiotic usage was recorded at implantation, admission for infection, and explantation or salvage surgery. Cultures were obtained from purulent material in the implant space and from the biofilm on the device. MAIN OUTCOME MEASURES: Intraoperative culture data from infected IPPs. RESULTS: Two hundred twenty-seven intraoperative cultures (2002-2016) were obtained at salvage or explantation. No culture growth occurred in 33% of cases and gram-positive and gram-negative organisms were found in 73% and 39% of positive cultures, respectively. Candida species (11.1%), anaerobes (10.5%) and methicillin-resistant Staphylococcus aureus (9.2%) constituted nearly one third of 153 positive cultures. Multi-organism infections occurred in 25% of positive cultures. Antibiotic regimens at initial implantation were generally consistent with American Urological Association (AUA) and European Association of Urology (EAU) guidelines. However, the micro-organisms identified in this study were covered by these guidelines in only 62% to 86% of cases. Antibiotic selection at admissions for infection and salvage or explantation varied widely compared with those at IPP implantation. CONCLUSION: This study documents a high incidence of anaerobic, Candida, and methicillin-resistant S aureus infections. In addition, approximately one third of infected penile prosthesis cases had negative cultures. Micro-organisms identified in this study were not covered by the AUA and EAU antibiotic guidelines in at least 14% to 38% of cases. These findings suggest broadening antibiotic prophylaxis guidelines and creating a management algorithm for IPP infections might lower infection rates and improve salvage success. Gross MS, Phillips EA, Carrasquillo RJ, et al. Multicenter Investigation of the Micro-Organisms Involved in Penile Prosthesis Infection: An Analysis of the Efficacy of the AUA and EAU Guidelines for Penile Prosthesis Prophylaxis. J Sex Med 2017;14:455-463.

Surgical Techniques for Managing Post-prostatectomy Erectile Dysfunction.

PURPOSE OF REVIEW: Due to the increasing numbers of radical prostatectomies (RP) performed for prostate cancer, a substantial number of patients are now suffering from post-operative erectile dysfunction (ED). The aim of this study is to summarize the current literature on surgical techniques for managing post-prostatectomy erectile dysfunction. RECENT FINDINGS: The PubMed database was searched for English-language articles published up to Jan 2017 using the following search terms: "prostatectomy AND erectile dysfunction", "prostatectomy AND penile prostheses", and "prostatectomy AND penile implants". All of the studies that evaluated medical treatment were excluded. In the last few decades, the understanding of the anatomy of the male pelvis and prostate has improved. This has led to significant changes in the nerve-sparing radical prostatectomy techniques, with the aim of preserving post-surgical erectile function (EF). In this scenario, the prostate vascular supply and the anatomy of the neurovascular bundles have a central role. Penile prosthesis implantation is considered the third-line treatment option for RP ED patients, and they have been reported to be a very successful treatment with the highest patient satisfaction rate. Considering the failure of penile rehabilitation, and the lack of evidence for accessory pudendal artery (APA) preservation and nerve graft, nerve-sparing surgery and penile prostheses represent, today, the only methods to permanently and definitively preserve or erectile function after RP.

A prospective multicentric international study on the surgical outcomes and patients' satisfaction rates of the 'sliding' technique for end-stage Peyronie's disease with severe shortening of the penis and erectile dysfunction.

OBJECTIVES: To report the results from a prospective multicentric study of patients with Peyronie's disease (PD) treated with the 'sliding' technique (ST). PATIENTS AND METHODS: From June 2010 to January 2014, 28 consecutive patients affected by stable PD with severe penile shortening and end-stage erectile dysfunction (ED) were enrolled in three European PD tertiary referral centres. The validated International Index of Erectile Function (IIEF) questionnaire, the Sexual Encounter Profile (SEP) Questions 2 and 3, and the Peyronie's disease questionnaire (PDQ) were completed preoperatively by all patients. At the follow-up visits (at 3, 6 and 12 months), the IIEF, the SEP Questions 2 and 3, the PDQ, and the Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS) were completed. The outcome analysis was focused on penile length restoration, and intra- and postoperative complications classified according the Clavien-Dindo Classification. RESULTS: The mean (range) follow-up was 37 (9-60) months. A malleable penile prosthesis (PP) was implanted in seven patients, while an inflatable three-pieces PP was placed in the remainder. In the case of inflatable PP implantation, porcine small intestinal submucosa and acellular porcine dermal matrix were used to cover the tunical defects. While in patients undergoing malleable PP implantation, collagen-fibrin sponge was used. The mean operative time was 145 min in the inflatable PP group and 115 min in the malleable PP group. There were no intraoperative complications. Postoperative complications included profuse bleeding requiring a blood transfusion in one patient (3.5%) on anticoagulation therapy for a mechanical heart valve (Grade II) and PP infection requiring the removal of the device (7%) (Grade III). There were no late recurrences of the shaft deformation. The postoperative functional data showed a progressive improvement in the score of all questionnaires, peaking at 12 months postoperatively. The mean (range) penile lengthening was 3.2 (2.5-4) cm and no patient reported recurrence of the curvature. CONCLUSIONS: The present series suggests that, in the hands of experienced high-volume surgeons, penile length restoration with the use of the ST represents an effective option for end-stage PD associated with ED and severe shortening of the shaft. Larger series and longer follow-up will be required to fully establish the efficacy of this procedure.

Free Flap Phalloplasty For Female To Male Gender Dysphoria.

The Surgical Techniques Section is sponsored in part by Coloplast.

Total Phallic Reconstruction Using the Radial Artery Based Forearm Free Flap After Traumatic Penile Amputation.

INTRODUCTION: Although genital injuries in civilian centers are rare, the scenario is completely different in the battlefield. If the penile distal stump is not adequate for primary reimplantation or it cannot be found, then delayed penile reconstruction needs to be considered. AIM: To report a single-center experience with total phallic reconstruction using radial artery based forearm free flap (RAFFF) after penile traumatic loss. METHODS: We retrospectively reviewed the clinical records of 10 patients who underwent total phallic reconstruction with the use of the RAFFF from September 2001 through August 2015 after traumatic amputation of the penis. MAIN OUTCOME MEASURES: Patients' baseline features, surgical outcomes, complications, and satisfaction are reported. RESULTS: The average age at the time of penile reconstruction was 36 years (range = 27-52 years). The causes of penile loss were self-amputation owing to an acute schizophrenic episode (n = 2), road traffic accident (n = 3), blast injury (n = 3), donkey bite (n = 1), and Fournier gangrene (n = 1). The average time from the trauma to reconstruction with the RAFFF was 7 years (range = 2-15 years). The urethral stump was adequate for primary anastomosis, with phallic neourethra construction in six patients. The remaining patients had complete avulsion of the penis and were voiding though a perineal urethrostomy. In consequence, they required a two-stage urethroplasty. An acute arterial thrombosis of the microsurgical anastomosis occurred in two patients and was managed successfully with immediate exploration. A neourethra stricture and fistula occurred in one patient, which needed revision. All patients who underwent complete urethral reconstruction could void and ejaculate from the tip of the phallus. After a median follow-up of 51 months (range = 1-114 months), all patients were satisfied with the size, cosmetic appearance, and sensation of the phallus. Six patients underwent inflatable penile prosthesis implantation and could engage in penetrative sex. However, revision surgery was needed in three patients (infection, n = 2; mechanical failure, n = 1). CONCLUSION: Despite the high incidence of postoperative complications and the possible need for multiple operations, in expert hands and in large-volume centers, penile reconstruction with the RAFFF after traumatic loss of the penis yields excellent results and allows patients to regain sexual and urinary functions.