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Introduction: The serendipitous discovery of sildenafil (Viagra [sildenafil citrate]) as a treatment for erectile dysfunction (ED) is one of the most fascinating drug development stories of our time. When sildenafil was approved by the U.S. Food and Drug Administration in 1998, it revolutionized the treatment protocol for men with ED, once considered a psychological issue or an inevitable part of aging., Aim: To review the discovery of sildenafil and its role in changing the field of sexual medicine in the context of the epidemiology and history of treatment for ED., Methods: For this narrative review, a literature search was conducted to identify essential articles and was supplemented by author observations from a historical perspective., Main Outcome Measure: A broad overview of ED and its past, current, and future treatments., Results: ED is a prevalent condition for which medical treatment had been limited to genitally localized interventions, including surgery, vacuum pumps, injectable therapies, and intraurethral suppositories. The discovery of sildenafil provided a safe, oral pharmacotherapy for the treatment of ED, sparking greater understanding of the science behind ED and its role in men's overall health., Conclusion: The approval of sildenafil initiated a global conversation about ED that had profound implications for patients, methods of clinical practice, and academic sexual medicine. These changes will catalyze continued advances in ED treatment. Goldstein I, Burnett AL, Rosen RC, et al. The serendipitous story of sildenafil: an unexpected oral therapy for erectile dysfunction. Sex Med Rev 2019;7:115-128., (Copyright © 2018 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.)

Objectives: To clarify the molecular basis of penile erection at the human level and distinguish the mechanisms underlying vasculogenic and post-radical prostatectomy (RP) erectile dysfunction (ED) subtypes., Patients and Methods: Erectile tissue was obtained from men without history of ED who underwent penile surgery for Peyronie's disease (control group, n = 5) and from men with ED who underwent penile prosthesis implantation (n = 17). ED was categorized into vasculogenic (n = 8) and post-RP (n = 9) subtypes. Penile erectile tissue samples were collected for molecular analyses of protein expressions of neuronal and endothelial isoforms of nitric oxide synthase (nNOS and eNOS, respectively), phospho-nNOS (Ser-1412), phospho-eNOS (Ser-1177), phospho-protein kinase B (Ser-473), phosphodiesterase type 5 (PDE5), α-smooth muscle actin, phospho-myosin phosphatase target subunit 1, RhoA/Rho-associated protein kinase (ROCK)-α, ROCK-β, 4-hydroxy-2-nonenal, and nNOS and eNOS uncoupling by Western blot., Results: Vasculogenic ED was characterized by decreased eNOS protein expression and eNOS and nNOS phosphorylation on their activatory sites (Ser-1177 and Ser-1412, respectively), uncoupled eNOS, upregulated PDE5 protein expression, increased ROCK activity, and increased oxidative stress in erectile tissue. Post-RP ED was characterized by decreased nNOS protein expression, increased nNOS phosphorylation on its activatory site (Ser-1412), uncoupled nNOS, downregulated PDE5 protein expression, and increased oxidative stress in erectile tissue., Conclusion: The mechanisms of vasculogenic and post-RP ED in the human penis involve derangements in constitutive nitric oxide synthase function, PDE5 protein expression and ROCK activity, and increased oxidative stress, which conceivably provide a molecular basis for chronically reduced nitric oxide bioavailability and increased smooth muscle contraction contributing to erectile impairment. Selective differences in PDE5 protein expression suggest distinct molecular mechanisms are in play for these ED subtypes., (© 2018 The Authors BJU International © 2018 BJU International Published by John Wiley & Sons Ltd.)

Background: The 8th American Joint Committee on Cancer tumor-node-metastasis (AJCC-TNM) staging system is based on a few retrospective single-center studies. We aimed to test the prognostic validity of the staging system and to determine whether a modified clinicopathological tumor staging system that includes lymphovascular embolization could increase the accuracy of prognostic prediction for patients with stage T2-3 penile cancer., Methods: A training cohort of 411 patients who were treated at 2 centers in China and Brazil between 2000 and 2015 were staged according to the 8th AJCC-TNM staging system. The internal validation was analyzed by bootstrap-corrected C-indexes (resampled 1000 times). Data from 436 patients who were treated at 15 centers over four continents were used for external validation., Results: A survivorship overlap was observed between T2 and T3 patients (P = 0.587) classified according to the 8th AJCC-TNM staging system. Lymphovascular embolization was a significant prognostic factor for metastasis and survival (all P < 0.001). Based on the multivariate analysis, only lymphovascular embolization showed a significant influence on cancer-specific survival (CSS) (hazard ratio = 1.587, 95% confidence interval = 1.253-2.011; P = 0.001). T2 and T3 patients with lymphovascular embolization showed significantly shorter CSS than did those without lymphovascular embolization (P < 0.001). Therefore, a modified clinicopathological staging system was proposed, with the T2 and T3 categories of the 8th AJCC-TNM staging system being subdivided into two new categories as follows: t2 tumors invade the corpus spongiosum and/or corpora cavernosa and/or urethra without lymphovascular invasion, and t3 tumors invade the corpus spongiosum and/or corpora cavernosa and/or urethra with lymphovascular invasion. The modified staging system involving lymphovascular embolization showed improved prognostic stratification with significant differences in CSS among all categories (all P < 0.005) and exhibited higher accuracy in predicting patient prognoses than did the 8th AJCC-TNM staging system (C-index, 0.739 vs. 0.696). These results were confirmed in the external validation cohort., Conclusions: T2-3 penile cancers are heterogeneous, and a modified clinicopathological staging system that incorporates lymphovascular embolization may better predict the prognosis of patients with penile cancer than does the 8th AJCC-TNM staging system. Trial registration This study was retrospectively registered on Chinese Clinical Trail Registry: ChiCTR16008041 (2016-03-02). http://www.chictr.org.cn.

Purpose: The purpose of this guideline is to provide a clinical strategy for the diagnosis and treatment of erectile dysfunction., Materials and Methods: A systematic review of the literature using the Pubmed, Embase, and Cochrane databases (search dates 1/1/1965 to 7/29/17) was conducted to identify peer-reviewed publications relevant to the diagnosis and treatment of erectile dysfunction. Evidence-based statements were based on body of evidence strength Grade A, B, or C and were designated as Strong, Moderate, and Conditional Recommendations with additional statements presented in the form of Clinical Principles or Expert Opinions., Results: The American Urological Association has developed an evidence-based guideline on the management of erectile dysfunction. This document is designed to be used in conjunction with the associated treatment algorithm., Conclusions: Using the shared decision-making process as a cornerstone for care, all patients should be informed of all treatment modalities that are not contraindicated, regardless of invasiveness or irreversibility, as potential first-line treatments. For each treatment, the clinician should ensure that the man and his partner have a full understanding of the benefits and risk/burdens associated with that choice., (Copyright © 2018 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Introduction: Penile structural defects can contribute toward penile prosthesis (PP) surgical complications and suboptimal outcomes. Despite modern improvements in techniques of inflatable PP (IPP) surgeries, suboptimal outcomes arise secondary to unrecognized proximal corporal abnormalities., Aim: To describe a new observation of IPP failure (wobbly penis) secondary to proximal corporal deformities., Methods: We performed a retrospective analysis of the Johns Hopkins institutional database of patients who had IPP surgery from May 2006 to March 2017. All cases requiring surgical revisions secondary to proximal corporal deformities were identified. Exclusion criteria included patients who had incidentally discovered proximal corporal deformities intraoperatively or were documented preoperatively to have had a corporal defect., Main Outcome Measures: Successful reimplantation of a functionally intact PP device., Results: On clinical grounds, we identified 5 patients with properly cycling but unstable prosthetic devices that were associated with proximal corporal dilatation (proximally from the penoscrotal junction). All patients underwent reduction corporoplasty with prosthesis replacements consisting of controlled expansion IPPs. 3 patients had undergone previous device replacements because of intact cycling but unstable and unusable IPP devices, whereas 2 had a single previous device insertion. Mean age at revision was 67 years. Median IPP duration was 17 years. Median number of previous IPP surgeries was 3. All patients reported IPP stability and satisfaction after revision (median follow-up = 6 months)., Conclusions: Proximal corporal deformities could account for IPP failure. This condition can be under-recognized as observed in the present cases of multiple revisions with a normally cycling device that was not usable. Proper recognition of this problem allows the opportunity for surgical correction with reduction corporoplasty. Rajih E, Burnett AL. Penile Wobble Effect: Proximal Corporal Deformities as a Cause of Penile Prosthesis Failure. Sex Med 2018;6:267-271., (Published by Elsevier Inc.)

Penile transplantation using vascularized composite allografts is an emerging technique to treat genital loss. In the United States, this procedure has been performed successfully at Massachusetts General Hospital in a patient who had previously undergone treatment for penile cancer. The Johns Hopkins Medical Institutions has developed a research protocol to perform penile transplantation in patients with genital loss secondary to trauma. The process of selecting the appropriate candidate for genitourinary (GU) vascularized composite allograft surgery is rigorous including extensive physical examination, laboratory testing, imaging and psychological evaluations. After transplantation, limiting the potential complications associated with immunosuppression is critical given that the procedure is intended to improve quality of life and is not life-saving. Ultimately, penile transplant is a surgical intervention which may have numerous applications. Optimization of the pre-operative screening process, surgical technique, and immunosuppressive protocol is required to establish this method as the standard treatment for patients with genital loss and limited reconstructive options., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

cGMP-independent nitric oxide (NO) signaling occurs via S-nitrosylation. We evaluated whether aberrant S-nitrosylation operates in the penis under conditions of cavernous nerve injury and targets proteins involved in regulating erectile function. Adult male Sprague-Dawley rats underwent bilateral cavernous nerve crush injury (BCNI) or sham surgery. Rats were given a denitrosylation agent N-acetylcysteine (NAC, 300 mg/kg/day) or vehicle in drinking water starting 2 days before BCNI and continuing for 2 weeks following surgery. After assessment of erectile function (intracavernous pressure), penes were collected for measurements of S-nitrosylation by Saville-Griess and TMT-switch assays and PKG-I function by immunoblotting of phospho (P)-VASP-Ser-239. Erectile function was decreased (P < 0.05) after BCNI, and it was preserved (P < 0.05) by NAC treatment. Total S-nitrosothiols and total S-nitrosylated proteins were increased (P < 0.05) after BCNI, and these were partially prevented by NAC treatment. S-nitrosylation of sGC was increased (P < 0.05) after BCNI, and it was prevented (P < 0.05) by NAC treatment. S-nitrosylation of eNOS was increased (P < 0.05) after BCNI, and showed a trend towards decrease by NAC treatment. Protein expression of P-VASP-Ser-239 was decreased (P < 0.05) after BCNI, and showed a trend towards increase by NAC treatment. In conclusion, erectile dysfunction following BCNI is mediated in part by S-nitrosylation of eNOS and its downstream signaling mediator GC, while denitrosylation protects erectile function by preserving the NO/cGMP signaling pathway.

Historically, testosterone and prostate cancer have been demonstrated to have a positive association leading providers to forgo testosterone replacement therapy (TRT) in men with concurrent histories of hypogonadism and prostate cancer. This paradigm has been gradually shifting with our evolving understanding of the relationship between testosterone and prostate cancer and the gaining popularity of the saturation model. Newer data suggests improved quality of life for men with hypogonadism after TRT leading to a more tempered view of the effects of this treatment and its risk in prostate cancer. As more reports emerge of TRT in men who have either undergone definitive treatment for prostate cancer or are on active surveillance, some providers see a role for TRT in these patients despite non-consensus in clinical guidelines. It is critical that we examine evidence currently available, while we await more rigorous data to emerge., Competing Interests: The authors have no potential conflicts of interest to disclose., (Copyright © 2018 Korean Society for Sexual Medicine and Andrology.)

Priapism is a disorder in which prolonged penile erection persists uncontrollably, potentially leading to tissue damage. Priapism commonly afflicts patient populations with severely low nitric oxide (NO) bioavailability. Because NO is a primary mediator of erection, the molecular mechanisms involved in priapism pathophysiology associated with low NO bioavailability are not well-understood. The objective of this study was to identify dysregulated molecular targets and signaling pathways in penile tissue of a mouse model of low NO bioavailability that have potential relevance to priapism. Neuronal plus endothelial NO synthase double knockout mice (NOS1/3 -/- ) were used as a model of low NO bioavailability. Priapic-like activity was demonstrated in the NOS1/3 -/- mice relative to wild-type (WT) mice by the measurement of prolonged erections following cessation of electrical stimulation of the cavernous nerve. Penile tissue was processed and analyzed by reverse-phase liquid chromatography tandem mass spectrometry. As a result, 1279 total proteins were identified and quantified by spectral counting, 46 of which were down-regulated and 110 of which were up-regulated in NOS1/3 -/- versus WT (P < 0.05). Ingenuity Pathway Analysis of differentially expressed proteins revealed increased protein kinase A and G-protein coupled receptor signaling in NOS1/3 -/- penises, which represent potential mechanisms contributing to priapism for secondary to low NO bioavailability.

Sickle cell disease (SCD)-associated priapism is characterized by decreased nitric oxide (NO) signaling and downregulated phosphodiesterase (PDE)5 protein expression and activity in the penis. Priapism is also associated with testosterone deficiency, but molecular mechanisms underlying testosterone effects in the penis in SCD are not known. Given the critical role of androgens in erection physiology and NO synthase (NOS)/PDE5 expression, we hypothesized that testosterone replacement to eugonadal testosterone levels reduces priapism by reversing impaired endothelial (e)NOS activity and molecular abnormalities involving PDE5. Adult male transgenic Berkeley sickle cell (Sickle) and wild-type (WT) mice were implanted with testosterone pellets, which release 1.2 μg testosterone/day for 21 days, or vehicle. After 21 days, animals underwent erectile function assessment followed by collection of blood for serum testosterone measurements, penes for molecular analysis, and seminal vesicles as testosterone-responsive tissue. Serum testosterone levels were measured by radioimmunoassay; protein expressions of PDE5, α-smooth muscle actin, eNOS and nNOS, and phosphorylation of PDE5 at Ser-92, eNOS at Ser-1177, neuronal (n) NOS at Ser-1412, and Akt at Ser-473 were measured by Western blot in penile tissue. Testosterone treatment reversed downregulated serum testosterone levels and increased (p < 0.05) the weight of seminal vesicles in Sickle mice to levels comparable to that of WT mice, indicating restored testosterone levels in Sickle mice. Testosterone treatment reduced (p < 0.05) prolonged detumescence in Sickle mice and normalized downregulated P-PDE5 (Ser-92), PDE5, P-eNOS (Ser-1177), and P-Akt (Ser-473) protein expressions in the Sickle mouse penis. Testosterone treatment did not affect P-nNOS (Ser-1412), eNOS, nNOS, or α-smooth muscle actin protein expressions in the Sickle mouse penis. In conclusion, in the mouse model of human SCD, increasing testosterone to eugonadal levels reduced priapic activity and reversed impaired Akt/eNOS activity and PDE5 protein expression in the penis., (© 2017 American Society of Andrology and European Academy of Andrology.)

Objectives: To evaluate neuronal nitric oxide (NO) synthase (nNOS) phosphorylation, nNOS uncoupling, and oxidative stress in the penis and major pelvic ganglia (MPG), before and after the administration of the cAMP-dependent protein kinase A (PKA) agonist colforsin in a rat model of bilateral cavernous nerve injury (BCNI),which mimics nerve injury after prostatectomy., Materials and Methods: Adult male Sprague-Dawley rats were divided into BCNI and sham-operated groups. Each group included two subgroups: vehicle and colforsin (0.1 mg/kg/day i.p.). After 3 days, erectile function (intracavernosal pressure) was measured and penis and MPG were collected for molecular analyses of phospho (P)-nNOS (Ser-1412 and Ser-847), total nNOS, nNOS uncoupling, binding of protein inhibitor of nNOS (PIN) to nNOS, gp91 phox subunit of NADPH oxidase, active caspase 3, PKA catalytic subunit α (PKA-Cα; by Western blot) and oxidative stress (hydrogen peroxide [H 2 O 2 ] and superoxide by Western blot and microdialysis method)., Results: Erectile function was decreased 3 days after BCNI and normalized by colforsin. nNOS phosphorylation on both positive (Ser-1412) and negative (Ser-847) regulatory sites, and nNOS uncoupling, were increased after BCNI in the penis and MPG, and normalized by colforsin. H 2 O 2 and total reactive oxygen species production were increased in the penis after BCNI and normalized by colforsin. Protein expression of gp91 phox was increased in the MPG after BCNI and was normalized by colforsin treatment. Binding of PIN to nNOS was increased in the penis after BCNI and was normalized by colforsin treatment. Protein expression of active Caspase 3 was increased in the MPG after BCNI and was normalized by colforsin treatment. Protein expression of PKA-Cα was decreased in the penis after BCNI and normalized by colforsin., Conclusion: Collectively, BCNI impairs nNOS function in the penis and MPG by mechanisms involving its phosphorylation and uncoupling in association with increased oxidative stress, resulting in erectile dysfunction. PKA activation by colforsin reverses these molecular changes and preserves penile erection in the face of BCNI., (© 2017 The Authors BJU International © 2017 BJU International Published by John Wiley & Sons Ltd.)

Erectile dysfunction (ED) is a significant cause of reduced quality of life in men and their partners. Cavernous nerve injury (CNI) during pelvic surgery results in ED in greater than 50% of patients, regardless of additional patient factors. ED related to CNI is difficult to treat and typically poorly responsive to first- and second-line therapeutic options. Recently, a significant amount of research has been devoted to exploring neuroprotective and neuroregenerative approaches to salvage erectile function in patients with CNI. In addition, therapeutic options such as neuregulins, immunophilin ligands, gene therapy, stem cell therapy and novel surgical strategies, have shown benefit in pre-clinical, and limited clinical studies. In the era of personalized medicine, these new therapeutic technologies will be the future of ED treatment and are described in this review., Competing Interests: The authors declare no conflict of interest.

Purpose: Reconstruction of complex functional structures is increasingly being performed with vascularized composite allotransplantation. Penile transplantation is a novel vascularized composite allotransplantation treatment option for severe penile tissue loss and disfigurement. Three allogeneic human penile transplantations have been reported. We review these cases as well as penile transplant indications, preclinical models and immunosuppression therapy., Materials and Methods: We performed a comprehensive literature review for the years 1970 to 2016 via MEDLINE®, PubMed® and Google with the key words "penis transplantation," "penile rejection," "penile replantation," "penile tissue loss" and "penis vascularized composite allotransplantation." Relevant articles, including original research, reviews and nonscientific press reports, were selected based on contents, and a review of this literature was generated., Results: Three human allogeneic penile transplantations have been performed to date, of which 1 was removed 14 days after transplantation. The second recipient reports natural spontaneous erections and impregnating his partner. All 3 patients were able to void spontaneously through the graft's urethra. The complexity of the transplant is determined by how proximally the penile shaft anastomosis is performed and additional pelvic tissue may be transplanted en bloc if needed., Conclusions: Penile transplantation is a technically demanding procedure with significant ethical and psychosocial implications that can provide tissue and functional replacement, including urinary diversion and natural erections. It is unclear how rejection and immunosuppression may affect graft function. Better models and more preclinical research are needed to better understand and optimize penile transplantation., (Copyright © 2017 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Objective: To investigate detrusor function and cAMP activation as a possible target for detrusor overactivity in an experimental model lacking a key denitrosylation enzyme, S-nitrosoglutathione reductase (GSNOR)., Materials and Methods: GSNOR-deficient (GSNOR -/- ) (n = 30) and wild-type (WT) mice (n = 26) were treated for 7 days with the cAMP activator, colforsin (1 mg/kg), or vehicle intraperitoneally. Cystometric studies or molecular analyses of bladder specimens were performed. Bladder function indices and expression levels of proteins that regulate detrusor relaxation (nitric oxide synthase pathway) or contraction (RhoA/Rho-kinase pathway) and oxidative stress were assessed. For statistical analysis the Student's t-test and one-way analysis of variance were used., Results: GSNOR -/- mice had significantly higher (P < 0.05) voiding and non-voiding contraction frequencies compared to WT mice (Cohen's effect size values d = 1.82 and 2.52, respectively). Colforsin normalised these abnormalities (Cohen's effect size values d = 1.85 and 1.28, respectively). Western blot analyses showed an up-regulation of the RhoA/Rho-kinase pathway reflected by significantly higher (P < 0.05) phosphorylated myosin phosphatase target subunit 1 (P-MYPT-1) expression in GSNOR -/- mouse bladders, which was reversed by colforsin treatment. There was a higher level (P < 0.05) of gp91 phox expression in the bladders of GSNOR -/- mice without significant change after colforsin treatment. Neuronal and endothelial nitric oxide synthase phosphorylation on Ser-1412 and Ser-1177, respectively, did not differ between GSNOR -/- and WT mouse bladders irrespective of colforsin treatment., Conclusion: Impaired denitrosylation is associated with detrusor overactivity, which is linked with upregulated RhoA/Rho-kinase signalling. Colforsin reverses physiological and molecular abnormalities. This study describes a novel model of detrusor overactivity and suggests a possible basis for its treatment., (© 2017 The Authors BJU International © 2017 BJU International Published by John Wiley & Sons Ltd.)

Objective: To provide sexual function and quality of life outcomes in patients with severe penile deficiency who underwent radial forearm flap phalloplasty with and without penile prosthesis implantation., Patients and Methods: Patients with history of severe penile deficiency who underwent microsurgical radial forearm flap phalloplasty with and without penile prosthesis implantation between 2007 and 2014 were identified. They completed a set of web-based validated questionnaires including the International Index of Erectile Function, the Pediatric Penile Perception Score, the Sexual Quality of Life for Men, and several items addressing general quality of life. Outcomes were compared between groups., Results: Nine of the 12 identified patients who had prosthesis after phalloplasty and 4 out of the 7 phalloplasty-only patients completed the survey, resulting in an overall response rate of 68%. Among the phalloplasty-prosthesis patients, 66% reported current sexual activity and 78% reported regular masturbation, whereas 1 of the 4 phalloplasty-only patients reported both. Prosthesis patients scored notably higher in all domains of the International Index of Erectile Function except for sexual desire. In contrast, they demonstrated similar scores of penile perception, as well as general and sexual quality of life., Conclusion: Among patients who have undergone flap phalloplasty, the subsequent placement of penile prosthesis appears to effectively allow for both intercourse and masturbation, resulting in measurable improvements in orgasmic function, intercourse satisfaction, and overall sexual satisfaction. Despite these important benefits, prosthesis placement does not appear to result in improvements in penile perception scores, or general or sexual quality of life., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Insulin-like growth factor-1 receptor (IGF1R) plays a key role in cell growth and transformation. It is overexpressed in several solid tumors. This study evaluates IGF1R immunoexpression in penile squamous cell carcinoma (SCC). Four tissue microarrays were built from formalin-fixed, paraffin-embedded blocks of 112 penile SCC from Paraguay. Membranous IGF1R expression was evaluated by immunohistochemistry using two different approaches. An H-score was calculated in each spot (stain intensity by extent), and a median score per tumor was obtained. The second approach consisted of a score similar to the scoring system that was used for evaluating HER2 immunoexpression. For each case, the highest category obtained at any spot was used for statistical analyses. IGF1R expression was compared by histologic subtype, grade, and human papillomavirus (HPV) status. Median H-score was 22.5. The distribution of IGF1R expression by HER2 approach was as follows: 0 in 33.0% cases, 1+ in 46.4%, 2+ in 14.3%, and 3+ in 6.2%. IGF1R H-scores were associated with basaloid and warty/basaloid subtypes (p = 0.0026) and higher grade (p = 0.00052). Although weaker when using the HER2 approach, the association of IGF1R expression with subtype (p = 0.015) and grade (p = 0.015) remained significant. Furthermore, there was an association between IGF1R expression by HER2 approach and HPV status (p = 0.012). IGF1R was expressed in about two thirds of penile SCC cases, showing a strong positive association with histologic grade, subtype, and HPV status. Considering that grade is a predictor of outcome IGF1R expression may have prognostic relevance and could point to a potential role for IGF1R inhibitors in treating penile SCC.

Penile calciphylaxis is a rare phenomenon of penile necrosis observed in patients with hemodialysis-dependent end-stage renal failure. Multiple treatments have been proposed including conservative management, surgical debridement and penectomy; yet, the prognosis remains extremely poor. Here, we describe a patient with protracted resolution of dry gangrene of the glans, which failed conservative management of wound care and pain management. Radiological studies revealed extensive calcification of abdominal aorta and branching vessels including the penile arteries. Due to intolerable pain, the patient required total penectomy. Earlier surgical intervention guided by findings on radiological studies may improve quality of life in this population.

Background: A successful penile prosthesis implantation (PPI) surgery can be defined by outcomes beyond the absence of complications., Aim: To introduce the concept of failure to cure (FTC) in the context of PPI to more accurately gauge postoperative outcomes after PPI., Methods: Consecutive patients from our sexual function registry who underwent PPI from January 2011 to December 2013 were analyzed. Demographics, previous treatment of erectile dysfunction, comorbidities, social history, postoperative problems (POPs), and surgical outcomes were tabulated. Patients completed the International Index of Erection Function (IIEF) and the Erectile Dysfunction Inventory of Treatment Satisfaction questionnaires. We defined a complication, according to the Clavien-Dindo classification, as any deviation from the ideal postoperative course that is not inherent in the procedure and does not constitute an FTC. FTC was defined as a POP that was not a complication. The χ 2 tests, t-tests, or Wilcoxon rank-sum tests were used., Outcomes: Patient-reported and objective outcomes after PPI., Results: Our enrollment consisted of 185 patients, and we contacted 124 (67%). Of these, 16 (12.9%) had a POP requiring reoperation. Eight patients developed surgical complications (three infections, four erosions, and one chronic pain). Eight patients had FTC (four malpositions and four malfunctions). Factors that correlated with POPs were previous PPI, body mass index higher than 30 kg/m 2 , and previous treatment with intracorporal injections (P < .05 for all comparisons). Patients who had POPs scored significantly lower on the IIEF erectile function and intercourse satisfaction domains (P < .05 for the two comparisons), but not on the orgasmic function, sexual desire, and overall satisfaction domains (P > .05 for all comparisons)., Clinical Implications: POPs after PPI surgery can be more accurately categorized using the Clavien-Dindo classification of surgical complications to more clearly distinguish surgical complications from FTC., Strengths and Limitations: Limitations of our study include its retrospective approach. Our series included a large proportion of patients treated for prostate cancer, which limits the generalizability of our findings. We also had a relatively short median follow-up time of 27 months., Conclusions: Patient-reported outcome assessments can vary greatly from what physicians determine to be successful PPI. An assessment of POPs encompasses more than just complication rates; it also reflects FTC. Even when POPs occur, patients can still derive satisfaction if they are correctively managed. Factors that possibly predispose to POPs include previous PPI surgery, body mass index greater than 30 kg/m 2 , and history of intracorporal injections. Pineda M, Burnett AL. Distinguishing Failure to Cure From Complication After Penile Prosthesis Implantation. J Sex Med 2017;14:731-737., (Copyright © 2017 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.)

Penile transplantation is an emerging option for patients with severe genital defects not amenable to traditional reconstructive options. In this article, we discuss the burgeoning problem of severe male genitourinary trauma in the military, the limitations of traditional reconstructive options in addressing these problems, and the potential for penile transplantation to provide improved outcomes. We also review the preclinical research and limited worldwide experience with penile transplantation to date, including lessons learned, and discuss the many important technical, logistical, and ethical considerations pertaining to penile transplantation that must be addressed to maximize the likelihood of successful implementation., (© 2017 Steunstichting ESOT.)

Introduction: Penile prosthesis implantation is believed to provide a high level of patient satisfaction. The International Index of Erectile Function and the Erectile Dysfunction Inventory of Treatment Satisfaction are two validated questionnaires that have been used to assess this outcome. The lack of a tool specifically validated for patients undergoing penile prosthesis surgery has led to the use of heterogeneous methods to assess patient satisfaction., Aim: To review the assessment of patient satisfaction with penile prosthesis surgery according to several factors., Methods: A literature review was performed through PubMed from January 2000 through February 2016 addressing patient satisfaction after penile prosthesis surgery., Main Outcome Measures: Patient satisfaction according to the characteristics of penile prosthesis devices and different clinical contexts., Results: Forty-eight articles were selected. Of these, 66.2% used non-validated questionnaires to assess patient satisfaction. Device characteristics, patient comorbidities, and partner profile are potential factors that can determine patient satisfaction., Conclusion: Patient satisfaction is a meaningful outcome of penile prosthesis surgery modulated by different conditions. The rigor of this assessment in the literature is limited. The validation of a scale designed for patients with penile prosthesis surgery is needed to optimize clinical practice. Akakpo W, Pineda MA, Burnett AL. Critical Analysis of Satisfaction Assessment After Penile Prosthesis Surgery. Sex Med Rev 2017;5:244-251., (Copyright © 2017 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.)

Although oral phosphodiesterase-5 (PDE5) inhibitors are generally accepted as an effective therapy for erectile dysfunction (ED), men with ED from diabetes or radical prostatectomy respond poorly to these drugs. Many researchers have tried to develop novel therapeutics that target alternative molecular pathways. A group of therapeutics belongs to centrally acting agents that target dopamine and melanocortin receptors. The other one is the peripherally acting agents that target soluble guanylate cyclase, Rho-kinase pathway, and Maxi-K channel, etc. Also, a variety of preclinical studies by the application of biotherapies in the concept of therapeutic angiogenesis or neural regeneration as well as anti-fibrosis to regenerate damaged erectile tissue have been reported. This article will address the current therapeutic targets for ED under clinical or preclinical development, including pharmacotherapy and biotherapy which comprises protein therapy and gene therapy. In spite of numerous clinical trials that target alternative pathways, these agents have yet to reach the market. The results from preclinical studies targeting therapeutic angiogenesis, neural regeneration, and anti-fibrosis are promising., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Background: Penile transplantation is a potential treatment option for severe penile tissue loss. Models of human penile rejection are lacking., Objective: Evaluate effects of rejection and immunosuppression on cavernous tissue using a novel ex vivo mixed lymphocyte reaction (MLR) model., Design, Setting, and Participants: Cavernous tissue and peripheral blood mononuclear cells (PBMCs) from 10 patients undergoing penile prosthesis operations and PBMCs from a healthy volunteer were obtained. Ex vivo MLRs were prepared by culturing cavernous tissue for 48h in media alone, in media with autologous PBMCs, or in media with allogenic PBMCs to simulate control, autotransplant, and allogenic transplant conditions with or without 1μM cyclosporine A (CsA) or 20nM tacrolimus (FK506) treatment., Outcome Measurements and Statistical Analysis: Rejection was characterized by PBMC flow cytometry and gene expression transplant array. Cavernous tissues were evaluated by histomorphology and myography to assess contraction and relaxation. Data were analyzed using two-way analysis of variance and unpaired Student t test., Results and Limitations: Flow cytometry and tissue array demonstrated allogenic PBMC activation consistent with rejection. Rejection impaired cavernous tissue physiology and was associated with cellular infiltration and apoptosis. CsA prevented rejection but did not improve tissue relaxation. CsA treatment impaired relaxation in tissues cultured without PBMCs compared with media and FK506. Study limitations included the use of penile tissue with erectile dysfunction and lack of cross-matching data., Conclusions: This model could be used to investigate the effects of penile rejection and immunosuppression. Additional studies are needed to optimize immunosuppression to prevent rejection and maximize corporal tissue physiology., Patient Summary: This report describes a novel ex vivo model of human penile transplantation rejection. Tissue rejection impaired erectile tissue physiology. This report suggests that cyclosporin A might hinder corporal physiology and that other immunosuppressant agents, such as FK506, might be better suited to penile transplantation., (Copyright © 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Purpose: Urethral carcinoma in situ (CIS) is an uncommon malignancy that is poorly described in the published literature and is often under-recognized in the clinical setting. This short case series reports some challenges associated with the recognition and management of this disease., Methods: A retrospective chart review was done over a 12-year period of patients presenting with urethral cancer to the Johns Hopkins Hospital. Four patients were identified with CIS of the anterior urethra, and their demographic and clinical data were recorded., Results: Three patients presented with meatal lesions that were initially treated as infectious/inflammatory diseases before diagnoses of malignancy were determined following lesion biopsy. The fourth patient presented with painless hematuria and had a cystoscopy and biopsy of urethral polyps. All patients were treated surgically by sequential distal urethrectomy and various reconstructive procedures. Concurrent lymph node dissections were undertaken in two patients who had clinical or radiologic evidence of lymphadenopathy. One patient had persistent disease even after aggressive urethral resection, and he succumbed to his illness 2 years later., Conclusion: This is the largest series of urethral CIS, a disease with potentially serious consequences. A high index of suspicion should be maintained when evaluating and managing these patients.

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., (Copyright © 2017 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.)

Erectile dysfunction (ED) associated with type 2 diabetes mellitus (T2DM) involves dysfunctional nitric oxide (NO) signaling and increased oxidative stress in the penis. However, the mechanisms of endothelial NO synthase (eNOS) and neuronal NO synthase (nNOS) dysregulation, and the sources of oxidative stress, are not well defined, particularly at the human level. The objective of this study was to define whether uncoupled eNOS and nNOS, and NADPH oxidase upregulation, contribute to the pathogenesis of ED in T2DM men. Penile erectile tissue was obtained from 9 T2DM patients with ED who underwent penile prosthesis surgery for ED, and from six control patients without T2DM or ED who underwent penectomy for penile cancer. The dimer-to-monomer protein expression ratio, an indicator of uncoupling for both eNOS and nNOS, total protein expressions of eNOS and nNOS, as well as protein expressions of NADPH oxidase catalytic subunit gp91phox (an enzymatic source of oxidative stress) and 4-hydroxy-2-nonenal [4-HNE] and nitrotyrosine (markers of oxidative stress) were measured by western blot in this tissue. In the erectile tissue of T2DM men, eNOS and nNOS uncoupling and protein expressions of NADPH oxidase subunit gp91phox, 4-HNE- and nitrotyrosine-modified proteins were significantly (p < 0.05) increased compared to control values. Total eNOS and nNOS protein expressions were not significantly different between the groups. In conclusion, mechanisms of T2DM-associated ED in the human penis may involve uncoupled eNOS and nNOS and NADPH oxidase upregulation. Our description of molecular factors contributing to the pathogenesis of T2DM-associated ED at the human level is relevant to advancing clinically therapeutic approaches to restore erectile function in T2DM patients., (© 2017 American Society of Andrology and European Academy of Andrology.)

Purpose: To determine the impact of lymph node density (LND) on survival after inguinal lymph node dissection (ILND) for penile cancer., Materials and Methods: Our institutional penile cancer database was queried for patients who underwent ILND. Clinicopathologic characteristics including LND and total number of positive lymph nodes (LNs) were analyzed to determine impact on recurrence-free survival (RFS) and overall survival (OS). LND, or the percent of positive LN out of total LN, was calculated as a categorical variable at varying thresholds., Results: Twenty-eight patients with complete follow-up were identified. Indications for ILND were stage >T2 in 20 patients (71.4%), palpable adenopathy in 7 (25%), high grade T1 in 1 (3.6%). Median node yield was 17.5 (interquartile range, 12-22), and positive LNs were found in 14 patients (50%). RFS and OS were significantly lower for patients with >15% LN density (median RFS: 62 months vs. 6.3 months, p=0.0120; median OS: 73.6 months vs. 6.3 months, p<0.001). Controlling for age, medical comorbidities, number of positive LN, T stage, pelvic LN status and indication, LN density >15% was independently associated with worse RFS (hazard ratio [HR], 3.6; p=0.04) and OS (HR, 73.6; p=0.002). The c-index for LND was higher than total positive LNs for RFS (0.64 vs. 0.54) and OS (0.79 vs. 0.61)., Conclusions: In this small, retrospective penile cancer cohort, the presence of nodal involvement >15% was associated with decreased RFS and OS, and outperformed total number of positive LN as a prognostic indicator., Competing Interests: The authors have nothing to disclose.

Objective: To assess neurite sprouting and gene expression of neurotrophic factors, nerve markers, and apoptosis in the major pelvic ganglia (MPGs) of rats with type 2 diabetes mellitus (T2DM) as it relates to erectile function., Materials and Methods: Male rats were fed high-fat diet for 2 weeks followed by 2 low-dose injections of streptozotocin (20 mg/kg). In 3 groups (controls, 3-week, or 5-week T2DM), erectile function was measured by ratios of intracavernosal pressure to mean arterial pressure after cavernous nerve stimulation. MPGs were harvested, and gene expressions of neurotrophic factor 3, nerve growth factor, glial cell line-derived neurotrophic factor, brain-derived neurotrophic factor, caspase-1, -3, -9, beta tubulin type III, and neuronal nitric oxide synthase were quantified by quantitative polymerase chain reaction. Additional MPGs were harvested and cultured in Matrigel. Neurite outgrowth from the MPG was evaluated at 48 hours after culture., Results: Erectile function was significantly decreased in all rats with T2DM. Gene expressions of neurotrophic factor 3, nerve growth factor, glial cell line-derived neurotrophic factor, and brain-derived neurotrophic factor were slightly lower at 3 weeks and significantly lower at 5 weeks after T2DM induction. Gene expression of apoptotic markers caspase-1, -3, -9, and neuronal markers beta tubulin type III and neuronal nitric oxide synthase remained unchanged. Rats with T2DM had shorter neurite length and less neurite sprouting than did the control MPG., Conclusion: Early-stage T2DM downregulates neurotrophic factors, induces erectile dysfunction, and impairs MPG neurite outgrowth, suggesting that erectile dysfunction may be prevented by supplementing neurotrophic factors at early-stage T2DM., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Penile squamous cell carcinoma (SCC) is primarily treated by surgical resection. Locally advanced and metastatic diseases require a multidisciplinary treatment approach. However, mortality and morbidity remain high, and novel molecular and immunotherapeutic targets are actively being sought. We investigated the expression of immune-checkpoint markers in penile cancers. Fifty-three invasive penile SCCs diagnosed between 1985 and 2013 were retrieved from our surgical pathology archives. Representative formalin-fixed, paraffin-embedded archival blocks were used for the construction of 2 high-density tissue microarrays. Tissue microarrays were stained with immunohistochemistry for PD-L1, FOXP3, CD8, and Ki-67. PD-L1 was investigated using rabbit monoclonal anti-PD-L1 antibody (Cell Signaling, Boston, MA; E1L3N, 1:100). Overall, 21 (40%) of 53 penile SCCs had positive PD-L1 expression. PD-L1 was expressed by a significant proportion of advanced penile SCC. Forty-four percent (15/34) of stage pT2 or more SCC and 38% (6/16) of tumors with lymph node metastasis were positive for PD-L1. PD-L1 expression did not correlate with patient age, tumor location, histologic subtype, tumor stage, anatomic depth of invasion, or tumor grade. FOXP3 expression in tumoral immune cells was found in 26 (49%) of 53 cases. FOXP3 expression in stromal immune cells correlated with tumor thickness (P = .0086). The ratio of CD8/FOXP3 was greater than 1 in 62% of cases in tumor-infiltrating immune cells and 34% of cases in stromal immune cells. Our current study is the largest to assess expression of PD-L1 in a clinically well-annotated North American cohort of penile SCC. Our findings support a rationale for targeting immune-checkpoint inhibitor pathways in advanced penile SCC., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Sickle cell disease patients display priapism that may progress to erectile dysfunction. However, little is known about the pathophysiological alterations of corpus cavernosum in sickle cell disease., Objective: Thus, this study aimed to evaluate the functional and molecular alterations of sympathetic machinery and nitric oxide-cyclic guanosine monophosphate signaling pathway in Townes transgenic sickle cell disease mice., Methods: Concentration-response curves to contractile (phenylephrine) and relaxant agents (acetylcholine and sodium nitroprusside) were obtained in corpus cavernosum strips from sickle and C57BL/6 (control) mice. Neurogenic contractions and nitrergic relaxations were obtained using electrical-field stimulation. Measurements of endothelial nitric oxide synthase (eNOS), neuronal nitric oxide synthase (nNOS), phosphodiesterase-5 (PDE5) and α1A-, α1B- and α1D-adrenoceptor mRNA expressions and reactive-oxygen species were performed. Tyrosine hydroxylase phosphorylated at Ser-31 and total tyrosine hydroxylase protein expressions in cavernosal tissues were also measured., Results: The neurogenic contractions were higher in the sickle cell disease group, in association with elevated tyrosine hydroxylase phosphorylated at Ser-31 and total tyrosine hydroxylase protein expression, as well as increased tyrosine hydroxylase mRNA expression. Likewise, phenylephrine-induced contractions were greater in the sickle mice, whereas α1A-, α1B- and α1D-adrenoceptor mRNA expression remained unchanged. Cavernosal relaxations to acetylcholine, sodium nitroprusside and EFS were higher in sickle mice, accompanied by decreased eNOS and nNOS, along with lower PDE5 mRNA expression. An increase of about 40% in reactive-oxygen species generation in corpus cavernosum from sickle mice was also detected., Conclusion: Our study shows that decreased nitric oxide bioavailability in erectile tissue due to increased oxidative stress leads to both sympathetic hyperactivity and dysregulation of nitric oxide signaling in corpus cavernosum from Townes sickle mice., Competing Interests: The authors have declared that no competing interests exist.

Competing Interests: The authors have no conflicts of interest to declare.

Patients with sickle cell disease (SCD) display priapism, and dysregulated nitric oxide (NO) pathway may contribute to this condition. However, current therapies offered for the prevention of priapism in SCD are few. The 3-(1,3-dioxoisoindolin-2-yl)benzyl nitrate (compound 4C) was synthesized through molecular hybridization of hydroxyurea and thalidomide, which displays an NO-donor property. This study aimed to evaluate the effects of compound 4C on functional and molecular alterations of erectile function in murine models that display low NO bioavailability, SCD transgenic mice, and endothelial NO synthase and neuronal NO synthase double gene-deficient (dNOS -/ ) mice, focusing on the dysregulated NO-cGMP- phosphodiesterase type 5 (PDE5) pathway and oxidative stress in erectile tissue. Wild-type, SCD, and dNOS -/- mice were treated with compound 4C (100 μmol/kg/d, 3 weeks). Intracavernosal pressure in anesthetized mice was evaluated. Corpus cavernosum tissue was dissected free and mounted in organ baths. SCD and dNOS -/- mice displayed a priapism phenotype, which was reversed by compound 4C treatment. Increased corpus cavernosum relaxant responses to acetylcholine and electrical-field stimulation were reduced by 4C in SCD mice. Likewise, increased sodium nitroprusside-induced relaxant responses were reduced by 4C in cavernosal tissue from SCD and dNOS -/- mice. Compound 4C reversed PDE5 protein expression and reduced protein expressions of reactive oxygen species markers, NADPH oxidase subunit gp91 phox , and 3-nitrotyrosine in penises from SCD and dNOS -/- mice. In conclusion, 3-week therapy with the NO donor 4C reversed the priapism in murine models that display lower NO bioavailability. NO donor compounds may constitute an additional strategy to prevent priapism in SCD., (Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.)

Objective: To review and quantify the association between endogenous and exogenous testosterone and prostate-specific antigen (PSA) and prostate cancer., Methods: Literature searches were performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Prospective cohort studies that reported data on the associations between endogenous testosterone and prostate cancer, and placebo-controlled randomized trials of testosterone replacement therapy (TRT) that reported data on PSA and/or prostate cancer cases were retained. Meta-analyses were performed using random-effects models, with tests for publication bias and heterogeneity., Results: Twenty estimates were included in a meta-analysis, which produced a summary relative risk (SRR) of prostate cancer for an increase of 5 nmol/L of testosterone of 0.99 (95% confidence interval [CI] 0.96, 1.02) without heterogeneity (I² = 0%). Based on 26 trials, the overall difference in PSA levels after onset of use of TRT was 0.10 ng/mL (-0.28, 0.48). Results were similar when conducting heterogeneity analyses by mode of administration, region, age at baseline, baseline testosterone, trial duration, type of patients and type of TRT. The SRR of prostate cancer as an adverse effect from 11 TRT trials was 0.87 (95% CI 0.30; 2.50). Results were consistent across studies., Conclusions: Prostate cancer appears to be unrelated to endogenous testosterone levels. TRT for symptomatic hypogonadism does not appear to increase PSA levels nor the risk of prostate cancer development. The current data are reassuring, although some caution is essential until multiple studies with longer follow-up are available., (© 2016 The Authors BJU International © 2016 BJU International Published by John Wiley & Sons Ltd.)

Reactive oxygen species (ROS) play a critical role in cell signaling and disease pathogenesis. Despite their biological importance, assessment of ROS often involves measurement of indirect byproducts or measurement of ROS from excised tissue. Herein, we describe a microdialysis technique that utilizes the Amplex Ultrared assay to directly measure hydrogen peroxide (H 2 O 2 ) and superoxide in tissue of living, anesthetized rats and mice. We demonstrate the application of this methodology in the penis, adipose tissue, skeletal muscle, kidney, and liver. We provide data demonstrating the impact of important methodological considerations such as membrane length, perfusion rate, and time-dependence upon probe insertion. In this report, we provide a complete list of equipment, troubleshooting tips, and suggestions for implementing this technique in a new system. The data herein demonstrate the feasibility of measuring both in vivo H 2 O 2 and superoxide in the extracellular environment of various rodent tissues, providing a technique with potential application to a vast array of disease states which are subject to oxidative stress., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Introduction: Inflatable penile prosthesis (IPP) surgery has been performed for more than 40 years. IPP infection rates have decreased owing to advances in manufacturing and surgical technique but have remained a devastating complication., Aims: To describe the pathophysiology of infections, examine evidence associating clinical risk factors with IPP infection, assess the benefit of techniques aimed at preventing and managing infection, and discuss future directions., Methods: PubMed and Google Scholar were searched for studies relating to IPP infections., Main Outcome Measures: A comprehensive review of the literature on IPP infections focusing on predisposing factors and ways to prevent and treat., Results: There are two types of IPP infections: those caused by coagulase-negative Staphylococcus species, which present mildly, and those caused by organisms that are more virulent and systemically toxic. Biofilm on devices protects bacteria from immunologic responses and antibiotics. Much research has targeted biofilm. Spinal cord injury, IPP revision, and longer operative times predispose to IPP infection. Other factors, such as diabetes, immunosuppression, and concomitant surgeries, lack sufficient evidence to determine conclusively. Methods that decrease infections include using infused prostheses and adhering to surgical techniques that avoid prolonged wound exposure. Techniques that might prevent IPP infection but lack definitive evidence are using postoperative antibiotics past 24 hours, shaving with clippers, and prepping with chlorhexidine-alcohol. Different treatments for IPP infections exist. Antibiotics should be followed by explantation if no improvement occurs. Device replacement can be immediate or delayed depending on infection severity and other variables such as erosion. Various techniques are proposed to prevent corporal fibrosis after IPP removal., Conclusion: We reviewed studies to determine true risk factors and the techniques that have true impact on infection prevention. Newer studies focusing on prevention and disruption of biofilm will be key in advancing the best outcomes., (Copyright © 2016 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.)

Introduction: Erectile dysfunction (ED) is a common disorder that has many potential etiologies, including hormonal imbalances, psychogenic factors, neurologic disorders, vascular insufficiency, and other risk factors. Cigarette smoking has been well established as a risk factor for cardiovascular disease and stroke, but the relation between smoking and ED is less frequently considered., Aim: To review the current literature that analyzes the association between cigarette smoking and ED., Methods: The PubMed database was searched using the terms erectile dysfunction and smoking and erectile dysfunction and tobacco through December 2015., Main Outcome Measures: Main outcome measures were significant changes in erectile function in relation to smoking status., Results: Eighty-three studies and articles were reviewed. Multiple human studies, animal studies, case series, cross-sectional, and cohort studies analyzed the relation between smoking or nicotine and ED., Conclusion: There is substantial evidence showing that cigarette smoking is a risk factor for ED. Multiple human, animal, case series, cross-sectional, and cohort studies support this conclusion. A positive dose-response relation also is suggested such that increased quantity and duration of smoking correlate with a higher risk of ED. Smoking cessation can lead to recovery of erectile function, but only if limited lifetime smoking exposure exists. Smoking contributes to ED in different ways, especially by causing penile vasospasm and increased sympathetic nervous system tone., (Copyright © 2016 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.)

Background: In sickle cell disease (SCD), hemolysis results in the release and activation of arginase, an enzyme that reciprocally regulates nitric oxide (NO) synthase activity and thus, NO production. Simply supplementing the common substrate L-arginine, however, fails to improve NO bioavailability. In this study, we tested the hypothesis that arginase inhibition would improve NO bioavailability and thereby attenuate systemic and pulmonary vascular endothelial dysfunction in transgenic mice with SCD., Methods: We studied 5-month-old transgenic sickle cell (SC) mice and age matched wild-type (WT) controls. SC mice were treated with the arginase inhibitor, 2(S)-amino-6-boronohexanoic acid (ABH; approximately 400 μg/d) for 4 weeks or left untreated., Results: Vascular arginase activity was significantly higher at baseline in untreated SC mice compared to WT controls (SC versus WT, 346 ± 69.3 vs 69 ± 17.3 pmol urea/mg protein/minute; P = 0.0043; n = 4-5 animals per group). Treatment with ABH may significantly decrease arginase activity to levels near WT controls (SC + ABH 125.2 ± 17.3 pmol urea/mg protein/minute; P = 0.0213). Aortic strips from untreated SC mice showed decreased NO and increased reactive oxygen species (ROS) production (NO: fluorescence rate 0.76 ± 0.14 vs 1.34 ± 0.17 RFU/s; P = 0.0005 and ROS: fluorescence rate 3.96 ± 1.70 vs 1.63 ± 1.20 RFU/s, P = 0.0039; n = 3- animals per group). SC animals treated with ABH for 4 weeks demonstrated NO (fluorescence rate: 1.16 ± 0.16) and ROS (fluorescence rate: 2.02 ± 0.45) levels comparable with age-matched WT controls (n = 3- animals per group). The maximal endothelial-dependent vasorelaxation response to acetylcholine was impaired in aortic rings from SC mice compared with WT (57.7% ± 8.4% vs 80.3% ± 11.0%; P = 0.02; n = 6 animals per group). The endothelial-independent response was not different between groups. In SC mice, the right ventricular cardiac output index and end-systolic elastance were similar (4.60 ± 0.51 vs 2.9 ± 0.85 mL/min/100 g and 0.89 ± 0.48 vs 0.58 ± 0.11 mm Hg/μL), whereas the pulmonary vascular resistance index and right ventricular end-systolic pressure were greater (2.9 ± 0.28 vs 5.5 ± 2.0 mm Hg × min/μL/100 g and 18.9 ± 1.1 vs 23.1 ± 4.0 mm Hg; n = 8 animals per group). Pulse wave velocity (a measure of arterial stiffness) was greater in SC mice compared with WT (3.74 ± 0.54 vs 3.25 ± 0.21 m/s; n = 20 animals per group), arginase inhibition for 4 weeks significantly reduced the vascular SC phenotype to one similar to WT animals (P = 0.0009)., Conclusions: Arginase inhibition improves NO bioavailability and thereby attenuates systemic and pulmonary vascular endothelial dysfunction in transgenic mice with SCD. Therefore, arginase is a potential therapeutic target in the treatment of cardiovascular dysfunction in SCD., Competing Interests: The authors declare no conflicts of interest.

Men with type 2 diabetes mellitus (T2DM) and erectile dysfunction (ED) have greater risk of cardiovascular events than T2DM men without ED, suggesting ED as a predictor of cardiovascular events in diabetic men. However, molecular mechanisms underlying endothelial dysfunction in the diabetic penis explaining these clinical observations are not known. We evaluated whether the temporal relationship between ED and endothelial dysfunction in the systemic vasculature in T2DM involves earlier redox imbalance and endothelial nitric oxidase synthase (eNOS) dysfunction in the penis than in the systemic vasculature, such as the carotid artery. Rats were rendered T2DM by high-fat diet for 2 weeks, followed by an injection with low-dose streptozotocin. After 3 weeks, erectile function (intracavernosal pressure) was measured and penes and carotid arteries were collected for molecular analyses of eNOS uncoupling, protein S-glutathionylation, oxidative stress (4-hydroxy-2-nonenal, 4-HNE), protein expression of NADPH oxidase subunit gp91(phox) , endothelium-dependent vasodilation in the carotid artery, and non-adrenergic, non-cholinergic (NANC)-mediated cavernosal relaxation. Erectile response to electrical stimulation of the cavernous nerve and NANC-mediated cavernosal relaxation was decreased (p < 0.05), while relaxation of the carotid artery to acetylcholine was not impaired in T2DM rats. eNOS monomerization, protein expressions of 4-HNE and gp91(phox) , and protein S-glutathionylation, were increased (p < 0.05) in the penis, but not in the carotid artery, of T2DM compared to non-diabetic rats. In conclusion, redox imbalance, increased oxidative stress by NADPH oxidase, and eNOS uncoupling, occur early in T2DM in the penis, but not in the carotid artery. These molecular changes contribute to T2DM ED, while vascular function in the systemic vasculature remains preserved., (© 2016 American Society of Andrology and European Academy of Andrology.)

Introduction: The biological importance of testosterone is generally accepted by the medical community; however, controversy focuses on its relevance to sexual function and the sexual response, and our understanding of the extent of its role in this area is evolving., Aim: To provide scientific evidence examining the role of testosterone at the cellular and molecular levels as it pertains to normal erectile physiology and the development of erectile dysfunction and to assist in guiding successful therapeutic interventions for androgen-dependent sexual dysfunction., Methods: In this White Paper, the Basic Science Committee of the Sexual Medicine Society of North America assessed the current basic science literature examining the role of testosterone in sexual function and dysfunction., Results: Testosterone plays an important role in sexual function through multiple processes: physiologic (stimulates activity of nitric oxide synthase), developmental (establishes and maintains the structural and functional integrity of the penis), neural (development, maintenance, function, and plasticity of the cavernous nerve and pelvic ganglia), therapeutically for dysfunctional regulation (beneficial effect on aging, diabetes, and prostatectomy), and phosphodiesterase type 5 inhibition (testosterone supplement to counteract phosphodiesterase type 5 inhibitor resistance)., Conclusion: Despite controversies concerning testosterone with regard to sexual function, basic science studies provide incontrovertible evidence for a significant role of testosterone in sexual function and suggest that properly administered testosterone therapy is potentially advantageous for treating male sexual dysfunction., (Published by Elsevier Inc.)

Peyronie's disease (PD) is a debilitating condition of the penis that leads to significant pain, erectile dysfunction, and emotional distress in men. PD is likely underreported due to lack of knowledge of the disease and the absence of well-established available treatments. Surgical treatment can lead to sustained improvements, but is often associated with penile shortening and places the patient at risk for perioperative morbidity. Nonsurgical management has been studied for several years as an alternative to surgery for men with PD. Currently, much of the data on nonsurgical management is conflicting, with only one treatment that has been recently approved by the US Food and Drug Administration. Significant effort has been devoted to advancing non-surgical treatments for PD that can be implemented outside of the operating room. This review aims to describe the research behind current nonsurgical therapies for PD and to highlight the recent advances that have been made within the last three years., Competing Interests: No potential conflict of interest relevant to this article was reported.

Axonal injury due to prostatectomy leads to Wallerian degeneration of the cavernous nerve (CN) and erectile dysfunction (ED). Return of potency is dependent on axonal regeneration and reinnervation of the penis. Following CN injury (CNI), RhoA and Rho-associated protein kinase (ROCK) increase in penile endothelial and smooth muscle cells. Previous studies indicate that nerve regeneration is hampered by activation of RhoA/ROCK pathway. We evaluated the role of RhoA/ROCK pathway in CN regulation following CNI using a validated rat model. CNI upregulated gene and protein expression of RhoA/ROCK and caspase-3 mediated apoptosis in the major pelvic ganglion (MPG). ROCK inhibitor (ROCK-I) prevented upregulation of RhoA/ROCK pathway as well as activation of caspase-3 in the MPG. Following CNI, there was decrease in the dimer to monomer ratio of neuronal nitric oxide synthase (nNOS) protein and lowered NOS activity in the MPG, which were prevented by ROCK-I. CNI lowered intracavernous pressure and impaired non-adrenergic non-cholinergic-mediated relaxation in the penis, consistent with ED. ROCK-I maintained the intracavernous pressure and non-adrenergic non-cholinergic-mediated relaxation in the penis following CNI. These results suggest that activation of RhoA/ROCK pathway mediates caspase-3 dependent apoptosis of nitrergic neurons in the MPG following CNI and that ROCK-I can prevent post-prostatectomy ED.

In August 2015, an expert colloquium commissioned by the Sexual Medicine Society of North America (SMSNA) convened in Washington, DC, to discuss the common clinical scenario of men who present with low testosterone (T) and associated signs and symptoms accompanied by low or normal gonadotropin levels. This syndrome is not classical primary (testicular failure) or secondary (pituitary or hypothalamic failure) hypogonadism because it may have elements of both presentations. The panel designated this syndrome adult-onset hypogonadism (AOH) because it occurs commonly in middle-age and older men. The SMSNA is a not-for-profit society established in 1994 to promote, encourage, and support the highest standards of practice, research, education, and ethics in the study of human sexual function and dysfunction. The panel consisted of 17 experts in men's health, sexual medicine, urology, endocrinology, and methodology. Participants declared potential conflicts of interest and were SMSNA members and nonmembers. The panel deliberated regarding a diagnostic process to document signs and symptoms of AOH, the rationale for T therapy, and a monitoring protocol for T-treated patients. The evaluation and management of hypogonadal syndromes have been addressed in recent publications (ie, the Endocrine Society, the American Urological Association, and the International Society for Sexual Medicine). The primary purpose of this document was to support health care professionals in the development of a deeper understanding of AOH, particularly in how it differs from classical primary and secondary hypogonadism, and to provide a conceptual framework to guide its diagnosis, treatment, and follow-up., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To evaluate insulin-like growth factor-1 receptor (IGF1R) expression in penile cancer and its association with oncologic outcomes., Methods: Tissue microarrays were constructed from 53 patients treated at our institution. Expression of IGF1R was evaluated using a Her2-like scoring system. Overexpression was defined as 1+ or greater membranous staining. Association of IGF1R expression with pathologic features was assessed with comparative statistics, and association with local recurrence, progression to nodal or distance metastases, or death was assessed with Kaplan-Meier survival analysis and Cox proportional hazard regression models., Results: Overall, IGF1R overexpression was seen in 33 (62%) cases. With a median follow-up of 27.8 months, IGF1R overexpression was associated with inferior progression-free survival (PFS) (P  =  .003). In a multivariable model controlling for grade, T stage, perineural invasion, and lymphovascular invasion, IGF1R expression was independently associated with disease progression (hazard ratio 2.3, 95% confidence interval 1.1-5.1, P  =  .03. Comparing patients without IGF1R overexpression to those with overexpression, 5-year PFS was 94.1% vs 45.8%., Conclusion: IGF1R overexpression was associated with inferior PFS in penile cancer. Drugs that target IGF1R and downstream messengers may have a therapeutic benefit in patients that exhibit IGF1R overexpression., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Aims: To characterize the prevalence and impact of nocturnal enuresis and overactive bladder (OAB) symptomatology in the adult sickle-cell disease (SCD) population., Methods: We performed a single-center, cross-sectional study of adult SCD patients from October 2012 to February 2014, using the validated Pfizer OAB short form questionnaire and brief voiding history surveys. Patient responses and scores were compared to that of controls having normal or sickle cell trait hemoglobin genotypes., Results: A group of 239 SCD patients (116 males, 123 females) were compared with 104 normal and 57 sickle cell trait patients. Seven of 239 (2.9%) SCD patients compared to none of the 161 patients without SCD (P = 0.04) reported current nocturnal enuresis. The median age of nocturnal enuresis cessation was higher in SCD patients (12.0, IQR 9.0-15.0 years) compared to that of both normal (7.5, IQR 6.0-9.8 years) and sickle cell trait (7.5, IQR 6.0-8.8 years) groups (P < 0.0001). Ninety-three of 239 (38.9%) SCD patients compared to 17 of 104 (16.3%) normal and 11 of 57 (19.3%) sickle cell trait had scores indicating OAB symptomatology (P < 0.0001). Patients with SCD had higher OAB symptom severity and lower health-related quality of life (HRQL) scores compared to the normal and sickle cell trait groups (P < 0.0001 and P < 0.0001, respectively)., Conclusions: We demonstrate an elevated rate of nocturnal enuresis and OAB symptoms in the adult SCD population. An OAB phenotype may be an under-recognized complication of SCD irrespective of age. Neurourol. Urodynam. 35:642-646, 2016. © 2015 Wiley Periodicals, Inc., (© 2015 Wiley Periodicals, Inc.)