Nitric Oxide Resistance in Priapism Associated with Sickle Cell Disease: Mechanisms, Therapeutic Challenges, and Future Directions.

Patients with sickle cell disease (SCD) display priapism, a prolonged penile erection in the absence of sexual arousal. The current pharmacological treatments for SCD-associated priapism are limited and focused on acute interventions rather than prevention. Thus, there is an urgent need for new drug targets and preventive pharmacological therapies for this condition. This review focuses on the molecular mechanisms linked to the dysfunction of the NO-cyclic guanosine monophosphate (cGMP)-phosphodiesterase type 5 (PDE5) pathway implicated in SCD-associated priapism. In murine models of SCD, reduced NO-cGMP bioavailability in the corpus cavernosum is associated with elevated plasma hemoglobin levels, increased ROS levels that inactive NO, and testosterone deficiency that leads to eNOS downregulation. We discuss the consequences of the reduced cGMP-dependent PDE5 activity in response to these molecular changes, highlighting it as the primary pathophysiological mechanism leading to excessive corpus cavernosum relaxation, culminating in priapism. We also further discuss the impact of intravascular hemolysis on therapeutic approaches, present current pharmacological strategies targeting the NO-cGMP-PDE5 pathway in the penis, and identify potential pharmacological targets for future priapism therapies. In men with SCD and priapism, PDE5 inhibitor therapy and testosterone replacement have shown promising results. Recent preclinical research reported the beneficial effect of treatment with haptoglobin and NO donors. Significant strides have been made in understanding the pathophysiology of SCD-associated priapism. Significance Statement This review discusses the molecular changes that reduce NO-cGMP bioavailability in the penis in SCD and highlights pharmacological targets and therapeutic strategies for the treatment of priapism, including PDE5 inhibitors, hormonal modulators, NO donors, soluble guanylate cyclase stimulators, haptoglobin, hemopexin, and antioxidants.

Clinical outcomes of the Burnett "snake" maneuver shunt modification for ischemic priapism.

BACKGROUND: Major ischemic priapism (IP) is defined as a persistent penile erection for >4 hours. IP may cause serious complications, especially if prompt resolution is not achieved. Therefore, selecting the most effective and usable shunt technique is crucial in IP cases that are refractory to medical therapy. AIM: To compare the effectiveness and complication risks of distal corporoglanular shunt procedures with and without the Burnett "snake" maneuver. METHODS: We conducted a retrospective study of patients who presented with IP and underwent surgical treatment at our institution between 2005 and 2021. The patients were categorized into 2 groups: group 1 (n = 26) underwent distal shunt + Burnett snake maneuver, and group 2 (n = 56) underwent distal shunt-only. Clinical history, parameters of IP, details of medical and surgical treatments, and follow-up information were evaluated. OUTCOMES: Outcomes included differences in IP resolution and recurrence, functional erections, and complications between corporoglanular shunt procedures with and without the Burnett snake maneuver. RESULTS: In group 1, 24 of 26 patients (92.3%) experienced priapism resolution with a single surgical intervention, while this outcome was observed in 30 of 56 patients (53.6%) in group 2 (P < .001). Notably, priapism recurrence was significantly lower in group 1, occurring in 1 of 24 patients (4.2%), as opposed to 8 of 30 patients (26.6%) in group 2 (P < .001). Of the patients with documented sexual function status at follow-up, functional erections (capable of penetration with or without phosphodiesterase 5 inhibitors) were noted in 6 of 14 patients (42.8%) in group 1 and 13 of 26 patients (50%) in group 2 (P = .66). CLINICAL IMPLICATIONS: This study provides valuable insights regarding technical aspects of distal shunt procedures with and without the Burnett snake maneuver for treating major IP episodes. These results can help surgeons with clinical decision making for patients who present with IP. STRENGTH AND LIMITATIONS: Limitations include the single-site retrospective design with potential selection bias, inaccuracies in medical record data, challenges in controlling confounding variables, and the lack of validated questionnaire scores for erectile function evaluation. CONCLUSION: Our study demonstrates that modifying distal shunt procedures using the Burnett snake maneuver significantly improves priapism resolution and effectively prevents further priapism episodes without introducing additional complications or erectile function loss, thereby distinguishing it from distal shunt-only procedures.

Early-onset and uncontrolled diabetes mellitus factors correlate with complications of Peyronie's disease.

BACKGROUND: Peyronie's disease (PD) is a connective tissue disorder that affects the penis and is characterized by abnormal collagen structure in the penile tunica albuginea, resulting in plaque formation and penile deformity. PD's overall prevalence is estimated at 3.2% to 8.9%, with rates as high as 20.3% among men with type 2 diabetes mellitus (DM). However, the characteristics of DM associated with PD complications remain unclear. AIM: To explore clinical associations between DM characteristics and PD complications. METHODS: We conducted a retrospective analysis of patients with DM and PD who presented at our institution between 2007 and 2022. We examined patients' clinical histories, DM- and PD-related clinical parameters, and complications. Penile deformities were assessed through physical examination, photographs, and penile Doppler ultrasound. Patients were categorized into subgroups based on age of DM onset: early (<45 years), average (45-65 years), and late (>65 years). OUTCOMES: Outcomes included effects of DM characteristics on PD development, progression, and severity. RESULTS: In total, 197 patients were included in the evaluation. Early-onset diabetes and elevated hemoglobin A1c (HbA1c) levels exhibited significant correlations with the early development of PD (ρ = 0.66, P < .001, and ρ = -0.24, P < .001, respectively). Furthermore, having DM at an early age was associated with the occurrence of penile plaque (ρ = -0.18, P = .03), and there were no significant differences in plaque dimensions (ρ = -0.29, P = .053). A rise in HbA1c levels after the initial PD diagnosis displayed positive correlations with the formation of penile plaque (ρ = 0.22, P < .006). CLINICAL IMPLICATIONS: These findings emphasize the need for comprehensive assessments and personalized treatment strategies for individuals with DM and PD. Enhanced management approaches can improve outcomes for those facing both challenges. STRENGTHS AND LIMITATIONS: Limitations include the single-site retrospective design with potential selection bias, inaccuracies in medical record data, and challenges in controlling confounding variables. CONCLUSIONS: This study highlights that early-onset diabetes and poor diabetes control, as indicated by a subsequent rise in HbA1c levels following PD diagnosis, are significantly correlated with the onset and severity of PD. Revealing the mechanisms behind these findings will help us develop better management strategies for individuals with DM and PD.

Princeton IV consensus guidelines: PDE5 inhibitors and cardiac health.

BACKGROUND: In 1999, 1 year after the approval of the first oral phosphodiesterase type 5 (PDE5) inhibitor for the treatment of erectile dysfunction (ED), the first Princeton Consensus Conference was held to address the clinical management of men with ED who also had cardiovascular disease. These issues were readdressed in the second and third conferences. In the 13 years since the last Princeton Consensus Conference, the experience with PDE5 inhibitors is more robust, and recent new data have emerged regarding not only safety and drug-drug interactions, but also a potential cardioprotective effect of these drugs. AIM: In March 2023, an interdisciplinary group of scientists and practitioners met for the fourth Princeton Consensus Guidelines at the Huntington Medical Research Institutes in Pasadena, California, to readdress the cardiovascular workup of men presenting with ED as well as the approach to treatment of ED in men with known cardiovascular disease. METHOD: A series of lectures from experts in the field followed by Delphi-type discussions were developed to reach consensus. OUTCOMES: Consensus was reached regarding a number of issues related to erectile dysfunction and the interaction with cardiovascular health and phosphodiesterase-5 inhibitors. RESULTS: An algorithm based on recent recommendations of the American College of Cardiology and American Heart Association, including the use of computed tomography coronary artery calcium scoring, was integrated into the evaluation of men presenting with ED. Additionally, the issue of nitrate use was further considered in an algorithm regarding the treatment of ED patients with coronary artery disease. Other topics included the psychological effect of ED and the benefits of treating it; the mechanism of action of the PDE5 inhibitors; drug-drug interactions; optimizing use of a PDE5 inhibitors; rare adverse events; potential cardiovascular benefits observed in recent retrospective studies; adulteration of dietary supplements with PDE5 inhibitors; the pros and cons of over-the-counter PDE5 inhibitors; non-PDE5 inhibitor therapy for ED including restorative therapies such as stem cells, platelet-rich plasma, and shock therapy; other non-PDE5 inhibitor therapies, including injection therapy and penile prostheses; the issue of safety and effectiveness of PDE5 inhibitors in women; and recommendations for future studies in the field of sexual dysfunction and PDE5 inhibitor use were discussed. CLINICAL IMPLICATIONS: Algorithms and tables were developed to help guide the clinician in dealing with the interaction of ED and cardiovascular risk and disease. STRENGTHS AND LIMITATIONS: Strengths include the expertise of the participants and consensus recommendations. Limitations included that participants were from the United States only for this particular meeting. CONCLUSION: The issue of the intersection between cardiovascular health and sexual health remains an important topic with new studies suggesting the cardiovascular safety of PDE5 inhibitors.

Does climate impact inflatable penile prosthesis infection (IPP) risk? Assessment of temperature and dew point on IPP infections.

BACKGROUND: Variations in climate have been associated with a greater risk of surgical site infections, urinary tract infections, and changes in the skin microbiome; however, limited data exist on the impact of climate on inflatable penile prosthesis (IPP) infections. AIM: We sought to evaluate the impact of climate on the risk of IPP infections in a large international, multicenter cohort. METHODS: We performed a multi-institutional, retrospective study of patients undergoing IPP surgery. We then evaluated whether the month or season, during which surgery was performed, affected device infections. Implant infections were defined as infections requiring device explantation. A univariate logistic regression analysis was undertaken. OUTCOMES: Our primary outcome was implant infection. RESULTS: A total of 5289 patients with a mean age of 62.2 ± 10.8 years received IPP placement. There was a fairly even distribution of implants performed in each season. A total of 103 (1.9%) infections were recorded. There were 32 (31.1%) IPP infections in patients who underwent surgery in the summer, followed by 28 (27.2%) in the winter, 26 (25.2%) in the spring, and 17 (16.5%) in the fall. No statistically significant differences were recorded in terms of season (P = .19) and month (P = .29). The mean daily temperature (P = .43), dew point (P = .43), and humidity (P = .92) at the time of IPP placement was not associated with infection. CLINICAL IMPLICATIONS: These findings provide reassurance to prosthetic urologists that infection reduction strategies do not need to be tailored to local climate. STRENGTHS AND LIMITATIONS: Climate data were not directly recorded for each hospital, but rather based on the monthly averages in the city where the surgery was performed. CONCLUSION: The climate at time of IPP placement and time of year of surgery is not associated with IPP infection risk.

AUA-recommended Antibiotic Prophylaxis for Primary Penile Implantation Results in a Higher, Not Lower, Risk for Postoperative Infection: A Multicenter Analysis.

PURPOSE: Our aim was to determine if the AUA-recommended prophylaxis (vancomycin + gentamicin alone) for primary inflatable penile prosthesis surgery is associated with a higher infection risk than nonstandard regimens. MATERIALS AND METHODS: We performed a multicenter, retrospective study of patients undergoing primary inflatable penile prosthesis surgery. Patients were divided into those receiving vancomycin + gentamicin alone and those receiving any other regimen. A Cox proportional-hazards model was constructed adjusted for major predictors. A subgroup analysis to identify the appropriate dosage of gentamicin was also performed. RESULTS: A total of 4,161 patients underwent primary inflatable penile prosthesis placement (2,411 received vancomycin + gentamicin alone and 1,750 received other regimens). The infection rate was similar between groups, 1% vs 1.2% for standard vs nonstandard prophylaxis. In the multivariable analysis, vancomycin + gentamicin (HR: 2.7, 95% CI: 1.4 to 5.4, P = .004) and diabetes (HR: 1.9, 95% CI: 1.03 to 3.4, P = .04) were significantly associated with a higher risk of infection. Antifungals (HR: 0.08, 95% CI: 0.03 to 0.19, P < .001) were associated with lower risk of infection. There was no statistically significant difference in infection rate between weight-based gentamicin compared to 80 mg gentamicin (HR: 2.9, 95% CI: 0.83 to 10, P = .1). CONCLUSIONS: Vancomycin + gentamicin alone for antibiotic prophylaxis for primary inflatable penile prosthesis surgery is associated with a higher infection risk than nonstandard antibiotic regimens while antifungal use is associated with lower infection risk. A critical review of the recommended antimicrobial prophylactic regimens is needed. Prospective research is needed to further elucidate best practices in inflatable penile prosthesis antimicrobial prophylaxis.

Intravascular hemolysis leads to exaggerated corpus cavernosum relaxation: Implication for priapism in sickle cell disease.

Patients with sickle cell disease (SCD) display priapism. Clinical studies have shown a strong positive correlation between priapism and high levels of intravascular hemolysis in men with SCD. However, there are no experimental studies that show that intravascular hemolysis promotes alterations in erectile function. Therefore, we aimed to evaluate the corpus cavernosum smooth muscle relaxant function in a murine model that displays intravascular hemolysis induced by phenylhydrazine (PHZ), as well as the role of intravascular hemolysis in increasing the stress oxidative in the penis. Corpus cavernosum strips were dissected free and placed in organ baths. Acetylcholine and electrical field stimulation (EFS)-induced corpus cavernosum relaxations in vitro were obtained. Increased corpus cavernosum relaxant responses to acetylcholine and EFS were observed in the PHZ group. Protein expression of heme oxygenase-1 increased in the corpus cavernosum of the PHZ group, but PDE5 protein expression was not modified. Preincubation with the heme oxygenase inhibitor 1 J completely reversed the increased relaxant responses to acetylcholine and EFS in PHZ mice. Protein expression of NADPH oxidase subunit gp91phox, 3-nitrotyrosine, and 4-hydroxynonenal increased in the corpus cavernosum of the PHZ group, suggesting a state of oxidative stress. Basal cGMP production was lower in the PHZ group. Our results show that intravascular hemolysis promotes increased corpus cavernosum smooth muscle relaxation associated with increased HO-1 expression, as well as increased oxidative stress associated with upregulation of gp91phox expression. Moreover, our study supports clinical studies that point to a strong positive correlation between priapism and high levels of intravascular hemolysis in men with SCD.

Urethral bulking with native tissue during artificial urinary sphincter surgery.

The artificial urinary sphincter (AUS) is the "gold standard" surgical treatment for severe stress urinary incontinence.  However, a subset of patients with frail urethras may require technical adjuncts to ensure optimal cuff function.  Our objective is to provide a detailed tutorial of our institution's method for performing urethral bulking with native tissue in patients with frail urethras during AUS surgery. We have found that urethral bulking with native tissue provides a cost-efficient and durable technique for improved AUS cuff coaptation.  Our experience demonstrates adequate short and intermediate term efficacy with limited complications.  These techniques equip surgeons with an alternative surgical approach for appropriate patients receiving AUS surgery who have been previously exposed to pelvic radiation and/or significant surgical morbidity resulting in frail urethral tissue.

Penile Transplantation: Lessons Learned and Technical Considerations.

PURPOSE: Penile vascularized composite allotransplantation is a powerful tool for penile reconstruction. Traditional methods of reconstruction utilizing free tissue and prostheses have well-known complications, can require reoperation and cannot truly emulate the natural form or function of the penis. While vascularized composite allotransplantation may alleviate these difficulties, penile transplantation carries its own ethical, surgical and medical complications. To date, the procedure has only been attempted 5 times. Broader use of this procedure requires unique surgical considerations. We present the first comprehensive, detailed review of this procedure in order to present lessons learned from both our own and the global experience. MATERIALS AND METHODS: A review of published reports of penile transplant methods and outcomes was conducted to compile lessons learned from these cases. RESULTS: Five penile transplant cases have been reported in literature, 4 with published methodology and outcomes data. All 4 detailed unique surgical approaches and postoperative immunosuppressive regimens. Three of these cases resulted in successful sensory and functional outcomes. CONCLUSIONS: Though all 4 analyzed cases employed unique anastomotic and immunosuppressive approaches, 3 resulted in successful recovery of penile urinary and sexual function. Still, specific approaches used by different teams circumvented otherwise common complications, and these differences should guide future research and penile transplant cases.

Association between Previous Pelvic Radiation and All-Cause and Cause-Specific Failure of Replacement Artificial Urinary Sphincters.

PURPOSE: In order to accurately characterize how a history of radiation therapy affects the lifespan of replacement artificial urinary sphincters (AUSs), all possible sources of device failure must be considered. We assessed the competing risks of device failure based on radiation history in men with replacement AUSs. MATERIALS AND METHODS: We identified men who had a replacement AUS in a single institutional, retrospective database. To assess survival from all-cause device failure based on radiation history and other factors, we conducted Kaplan-Meier, Cox proportional-hazards and competing risks analyses. RESULTS: Among 247 men who had a first replacement AUS, men with a history of radiation had shorter time to all-cause device failure (median 1.4 vs 3.5 years for men with radiation vs without radiation history, p=0.02). On multivariable Cox-proportional hazards analysis, previous radiation was associated with increased risk of all-cause device failure (HR: 2.12, 95% CI: 1.30-3.43, p=0.002). On multivariable cause-specific hazards analysis, prior radiation was associated with a higher risk of erosion/infection (HR: 7.57, 95% CI: 2.27-25.2, p <0.001), but was not associated with risk of urethral atrophy (p=0.5) or mechanical failure (p=0.15). CONCLUSIONS: Among men with a replacement AUS, a history of pelvic radiation was associated with shorter time to device failure of any cause. Radiation was also specifically associated with a sevenfold increase in the risk of erosion or infection of replacement AUS, but not with urethral atrophy or mechanical failure. Patients with a replacement AUS should be appropriately counseled on how radiation history may impact outcomes of future revisions.

Low-Intensity Electrostimulation Enhances Neuroregeneration and Improves Erectile Function in a Rat Model of Cavernous Nerve Injury.

BACKGROUND: Neurogenic erectile dysfunction (ED) following radical prostatectomy (RP) is a frequent complication often leading to erectile tissue remodeling and permanent ED. Low-intensity electrostimulation (LIES) has been shown to enhance peripheral nerve regeneration, however, its application on cavernous nerves (CN) has never been investigated. AIMS: To investigate whether LIES enhances CN regeneration, improves erectile function (EF) recovery, and prevents corpora cavernosal remodeling after CN injury, which is a principal factor for ED following RP. METHODS: Adult male Sprague-Dawley rats were divided into Sham, Bilateral Cavernous Nerve Injury (BCNI), and BCNI + LIES (1V, 0.1ms, 12Hz, 1h/day). After 7days, EF was assessed (ICP measurement). Penes and CN were collected for molecular analyses of TGF-ß1, Il-6, CRP, eNOS, ERK and AKT protein levels in corpus cavernosum (CC), and immunohistological analysis of DHE, total collagen and α-SMA in CC and S-100, Tub-III, DAPI, TUNEL, and nNOS in CN. OUTCOMES: Effects of LIES on EF, erectile tissue remodeling and CN structure. RESULTS: EF was decreased (P < .05) 7 days after BCNI and increased (P < .05) by LIES. Intracavernosal reactive oxygen species (DHE) was increased (P < .05) after BCNI and normalized by LIES. Protein expressions of TGF-ß1, IL-6, and CRP were increased in the penis (P < .05) after BCNI and normalized by LIES. The α-SMA and/or total collagen ratio was decreased (P < .05) after BCNI in the penis and normalized by LIES. Protein expression ratio of p-ERK/ERK and p-AKT/AKT did not change after BCNI but increased (P < .05) in LIES group. Myelination and number of nNOS positive cells in the CN were decreased (P < .05) after BCNI and normalized by LIES. The number of apoptotic nerve cells within the dorsal penile nerve was increased (P < .05) after BCNI and decreased (P < .05) by LIES compared to the BCNI group. There were no differences in eNOS expression in the penis between study groups. CLINICAL TRANSLATION: LIES may offer a potential new tool for penile rehabilitation and ED management following RP, potentially enhancing EF recovery and minimizing the side effects of this surgery. STRENGTHS & LIMITATIONS: This study provides evidence of the protective effect of LIES on EF and tissue remodeling following CN injury; nevertheless, this study has been conducted on animals and the translation to humans remains to be demonstrated. Further research to identify the underlying mechanisms of action is required. CONCLUSION: This study demonstrates that LIES of the CN after CN injury protects CN structure, enhances EF recovery, and prevents corpora cavernosal remodeling. Sturny M, Karakus S, Fraga-Silva R, et al. Low-Intensity Electrostimulation Enhances Neuroregeneration and Improves Erectile Function in a Rat Model of Cavernous Nerve Injury. J Sex Med 2022;19:686-696.

Guidelines for Sexual Health Care for Prostate Cancer Patients: Recommendations of an International Panel.

BACKGROUND: Patients with prostate cancer suffer significant sexual dysfunction after treatment which negatively affects them and their partners psychologically, and strain their relationships. AIM: We convened an international panel with the aim of developing guidelines that will inform clinicians, patients and partners about the impact of prostate cancer therapies (PCT) on patients' and partners' sexual health, their relationships, and about biopsychosocial rehabilitation in prostate cancer (PC) survivorship. METHODS: The guidelines panel included international expert researchers and clinicians, and a guideline methodologist. A systematic review of the literature, using the Ovid MEDLINE, Scopus, CINAHL, PsychINFO, LGBT Life, and Embase databases was conducted (1995-2022) according to the Cochrane Handbook for Systematic Reviews of Interventions. Study selection was based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Each statement was assigned an evidence strength (A-C) and a recommendation level (strong, moderate, conditional) based on benefit/risk assessment, according to the nomenclature of the American Urological Association (AUA). Data synthesis included meta-analyses of studies deemed of sufficient quality (3), using A Measurement Tool to Assess Systematic Reviews (AMSTAR). OUTCOMES: Guidelines for sexual health care for patients with prostate cancer were developed, based on available evidence and the expertise of the international panel. RESULTS: The guidelines account for patients' cultural, ethnic, and racial diversity. They attend to the unique needs of individuals with diverse sexual orientations and gender identities. The guidelines are based on literature review, a theoretical model of sexual recovery after PCT, and 6 principles that promote clinician-initiated discussion of realistic expectations of sexual outcomes and mitigation of sexual side-effects through biopsychosocial rehabilitation. Forty-seven statements address the psychosexual, relationship, and functional domains in addition to statements on lifestyle modification, assessment, provider education, and systemic challenges to providing sexual health care in PC survivorship. CLINICAL IMPLICATIONS: The guidelines provide clinicians with a comprehensive approach to sexual health care for patients with prostate cancer. STRENGTHS & LIMITATIONS: The strength of the study is the comprehensive evaluation of existing evidence on sexual dysfunction and rehabilitation in prostate cancer that can, along with available expert knowledge, best undergird clinical practice. Limitation is the variation in the evidence supporting interventions and the lack of research on issues facing patients with prostate cancer in low and middle-income countries. CONCLUSION: The guidelines document the distressing sexual sequelae of PCT, provide evidence-based recommendations for sexual rehabilitation and outline areas for future research. Wittmann D, Mehta A, McCaughan E, et al. Guidelines for Sexual Health Care for Prostate Cancer Patients: Recommendations of an International Panel. J Sex Med 2022;19:1655-1669.

Psychometric Impact of Priapism on Lives of Adolescents and Adults With Sickle Cell Anemia: A Sequential Independent Mixed-Methods Design.

Despite priapism being one of the most frequent complications of sickle cell anemia (SCA) in male individuals, little has been reported about the impact of priapism in this population. The authors used a sequential independent mixed-methods design, which used both international multicenter focus group discussions (n=35) and a quantitative patient-reported outcome measure (n=131) to determine the impact of priapism on men with SCA in Nigeria and the United States. The authors analyzed data from focus groups using an iterative inductive-deductive approach. Comparison of the Priapism Impact Profile data was done using the Kruskal-Wallis H test. Our result showed that priapism, across cultures, is associated with shame and embarrassment. These emotions interfere with timely clinical and family communication about priapism symptoms and complications. Participants were dissatisfied with the quality of care at emergency facilities. The quality of life and physical wellness of men with SCA-related priapism were significantly different for the 3 groups: (1) priapism condition getting better, (2) priapism condition getting worse, and (3) priapism condition remain the same (P=0.002 and P=0.019, respectively). Psychological, sexual, and physical wellbeing are all adversely affected by priapism. Evidence-based methods are necessary for adequate medical, educational, and psychological treatment for recurrent priapism.

The pulley stitch: fixation of penile prosthetic exit tubing.

Proximal positioning of the penile prosthesis cylinder is performed during inflatable penile prosthesis surgery. We describe a technique to secure a prosthetic cylinder during inflatable penile prosthesis implantation. Urologists performing prosthetic surgeries employ a variety of surgical techniques to achieve successful outcomes. A surgical technique that secures the prosthetic device may ultimately mitigate cylinder migration and erosion. This is a simple, cost-effective technique that can be readily incorporated into conventional corporotomy closure procedures. It proves to be a feasible technique for both running and interrupted corporotomy closures. The "pulley stitch" offers an adjunctive technique for prosthesis cylinder positioning and may also help prevent migration of prosthetic devices, and it can be incorporated with corporotomy closure.

TSPO ligand FGIN-1-27 controls priapism in sickle cell mice via endogenous testosterone production.

Priapism, a prolonged penile erection in the absence of sexual arousal, is common among patients with sickle cell disease (SCD). Hypogonadism is also common in patients with SCD. While the administration of exogenous testosterone reverses hypogonadism, it is contraceptive. We hypothesized that the stimulation of endogenous testosterone production decreases priapism by normalizing molecular signaling involved in penile erection without decreasing intratesticular testosterone production, which would affect fertility. Treatment of SCD mice with FGIN-1-27, a ligand for translocator protein (TSPO) that mobilizes cholesterol to the inner mitochondrial membrane, resulted in eugonadal levels of serum testosterone without decreasing intratesticular testosterone production. Normalized testosterone levels, in turn, decreased priapism. At the molecular level, TSPO restored phosphodiesterase 5 activity and decreased NADPH oxidase-mediated oxidative stress in the penis, which are major molecular signaling molecules involved in penile erection and are dysregulated in SCD. These results indicate that pharmacologic activation of TSPO could be a novel, targetable pathway for treating hypogonadal men, particularly patients with SCD, without adverse effects on fertility.

Regimented Phosphodiesterase Type 5 Inhibitor Use Reduces Emergency Department Visits for Recurrent Ischemic Priapism.

PURPOSE: We evaluated the real-world effectiveness of regimented phosphodiesterase type 5 inhibitor dosing on recurrent ischemic priapism outcomes using emergency department visits as a proxy for therapeutic control of the disorder. MATERIALS AND METHODS: We performed a retrospective chart review of patients with recurrent ischemic priapism who were started on regimented phosphodiesterase type 5 inhibitor therapy from May 2006 to January 2020. We compared the number of emergency department visits per month during a 6-month period before treatment, during treatment and after treatment discontinuation. We extracted and categorized priapism outcomes such as priapism frequency and duration. RESULTS: Of 216 patients identified with all cause priapism 114 were diagnosed with recurrent ischemic priapism and 42 were initiated on regimented phosphodiesterase type 5 inhibitor therapy. Treatment effectiveness was analyzed for 24 evaluable patients. Priapism etiology was idiopathic in 12 patients (50%), sickle cell disease in 11 (46%) and drug-induced in 1 (4%). The median length of regimented phosphodiesterase type 5 inhibitor use was 3 months (IQR 2-7). Treatment decreased emergency department visits per month by 4.4-fold (p <0.001), priapism duration tiers (p <0.001) and priapism frequency tiers (p <0.001). Of 24 patients 22 (92%) reported improvement in priapism outcomes, 9 of whom reported resolution of recurrent ischemic priapism episodes. A subgroup analysis of 17 patients with recurrent ischemic priapism relapse after treatment discontinuation showed a significant increase in priapism duration (p <0.001) and frequency (p <0.001) but no significant change in emergency department visits per month (p=0.91). CONCLUSIONS: Regimented phosphodiesterase type 5 inhibitor therapy was an impactful treatment in managing recurrent ischemic priapism according to objective and subjective parameters. This study provides further support for the use of regimented phosphodiesterase type 5 inhibitor dosing as a preventive strategy for recurrent ischemic priapism.

Effect of Erythropoietin on Erectile Function after Radical Prostatectomy: The ERECT Randomized Clinical Trial.

PURPOSE: Erectile dysfunction significantly impacts quality of life for men undergoing radical prostatectomy for prostate cancer. Erythropoietin is a promising neurotrophic factor for neurogenic erectile dysfunction based on preclinical and retrospective data. MATERIALS AND METHODS: ERECT (NCT00737893) is a phase 2, double-blinded, randomized, placebo-controlled trial (July 2017-December 2019) evaluating the impact of perioperative erythropoietin on recovery of erectile function and other patient-reported, health-related quality of life outcomes after bilateral nerve-sparing radical prostatectomy (3, 6, 9, and 12 months). Erythropoietin (20,000 units) or saline placebo was injected subcutaneously the day before, day of, and day after surgery for 3 total doses. RESULTS: Of 63 patients assessed for eligibility, 56 patients were randomized. Arms (29 erythropoietin, 27 placebo) were well balanced (89.3% robotic, median age 55.5 years). International Index of Erectile Function-Erectile Function Domain (IIEF-EF) scores increased from median 12.5 at 3 months to 24.5 at 12 months. Median 2-week serum hemoglobin was higher for the erythropoietin arm compared to placebo (14.7 vs 13.6, p=0.02). There was no statistically significant difference in IIEF-EF scores at 6 months comparing erythropoietin to placebo (p=0.50) or at other time points (mixed model regression coefficient: -1.7, 95% CI -6.1-2.7, p=0.45). Excellent nerve-sparing rating (10/10) was associated with improved IIEF-EF recovery (+5.2, p=0.022). Other patient-reported, health-related quality of life domains as well as oncologic outcome and complications were similar between arms during followup. CONCLUSIONS: In the context of brief perioperative dosing, erythropoietin did not improve recovery of erectile function for men undergoing radical prostatectomy for prostate cancer compared to placebo. Further research to identify effective adjuncts to improve health-related quality of life for these men is needed.

Pedicled Anterolateral Thigh and Radial Forearm Free Flap Phalloplasty for Penile Reconstruction in Patients With Bladder Exstrophy.

PURPOSE: Male patients with exstrophy-epispadias complex have a congenitally short penis. Adolescent and adult patients often desire penile reconstruction to enable penetrative intercourse. When penile lengthening using local tissue and/or skin graft is unsuitable, phalloplasty is performed. We provide updated experiences using radial forearm free flap and pedicled anterolateral thigh flap phalloplasty techniques over a 6-year period in exstrophy-epispadias complex patients. MATERIALS AND METHODS: Consecutive patients who underwent radial forearm free flap or pedicled anterolateral thigh flap phalloplasty between 2013 and 2019 were reviewed. A total of 11 patients were identified, including 8 with classic bladder exstrophy and 3 with cloacal exstrophy. In each case, flap dimensions, donor and recipient vessels and nerves, complications, outcomes and subsequent surgical procedures are reported. RESULTS: A radial forearm free flap was performed in 6 patients and a pedicled anterolateral thigh flap in 5. Flap survival was observed in all cases and 5 patients subsequently received an inflatable penile prosthesis. Among patients undergoing a pedicled anterolateral thigh flap, there was 1 mortality from acute pulmonary embolism, and the other 4 required at least 1 debulking procedure. CONCLUSIONS: Phalloplasty is an important procedure in patients with exstrophy-epispadias complex with severe penile inadequacy. Both techniques have favorable long-term outcomes, although the pedicled anterolateral thigh flap frequently requires a later debulking procedure. The radial forearm free flap is preferred but if the radial forearm is overly thin and the risk of inflatable penile prosthesis extrusion is high, the pedicled anterolateral thigh flap is an acceptable alternative.

Medical treatment of recurrent ischaemic priapism: a review of current molecular therapeutics and a new clinical management paradigm.

OBJECTIVES: To examine the current molecular therapeutics in the medical treatment of recurrent ischemic priapism (RIP). To propose a stepwise clinical management paradigm for the treatment of RIP. METHODS: We performed a literature search using the PubMed database for the terms 'recurrent ischemic priapism' and 'stuttering priapism' up until December 2020. We assessed pre-clinical and clinical studies regarding medical management of RIP and molecular pathophysiology. Case series and randomized trials were evaluated by study quality and patient outcomes to determine a potential clinical management scheme. RESULTS: Recent research has fostered an improved understanding of the underlying molecular pathophysiology of RIP that has paved the way forward for developing new therapeutic agents. Medications targeting neurovascular, hormonal and haematological mechanisms associated with RIP show great promise towards remedying this condition. A host of therapeutic agents operating across different mechanistic directions may be implemented according to a clinical management scheme to potentially optimize RIP outcomes. CONCLUSION: RIP remains a medically neglected condition with current management focused on treating the acute condition rather than modulating the course of disease. Continued research into the molecular mechanisms of RIP and standardized clinical pathways can improve the quality of care for patients suffering from this condition.

NO-Releasing Nanoparticles Ameliorate Detrusor Overactivity in Transgenic Sickle Cell Mice via Restored NO/ROCK Signaling.

Sickle cell disease (SCD) is associated with overactive bladder (OAB). Detrusor overactivity, a component of OAB, is present in an SCD mouse, but the molecular mechanisms for this condition are not well-defined. We hypothesize that nitric oxide (NO)/ ras homolog gene family (Rho) A/Rho-associated kinase (ROCK) dysregulation is a mechanism for detrusor overactivity and that NO-releasing nanoparticles (NO-nps), a novel NO delivery system, may serve to treat this condition. Male adult SCD transgenic, combined endothelial NO synthases (eNOSs) and neuronal NOS (nNOS) gene-deficient (dNOS-/-), and wild-type (WT) mice were used. Empty nanoparticle or NO-np was injected into the bladder, followed by cystometric studies. The expression levels of phosphorylated eNOS (Ser-1177), protein kinase B (Akt) (Ser-473), nNOS (Ser-1412), and myosin phosphatase target subunit 1 (MYPT1) (Thr-696) were assessed in the bladder. SCD and dNOS-/- mice had a greater (P < 0.05) number of voiding and nonvoiding contractions compared with WT mice, and they were normalized by NO-np treatment. eNOS (Ser-1177) and AKT (Ser-473) phosphorylation were decreased (P < 0.05) in the bladder of SCD compared with WT mice and reversed by NO-np. Phosphorylated MYPT1, a marker of the RhoA/ROCK pathway, was increased (P < 0.05) in the bladder of SCD mice compared with WT and reversed by NO-np. nNOS phosphorylation on positive (Ser-1412) regulatory site was decreased (P < 0.05) in the bladder of SCD mice compared with WT and was not affected by NO-np. NO-nps did not affect any of the measured parameters in WT mice. In conclusion, dysregulation of NO and RhoA/ROCK pathways is associated with detrusor overactivity in SCD mice; NO-np reverses these molecular derangements in the bladder and decreases detrusor overactivity. SIGNIFICANCE STATEMENT: Voiding abnormalities commonly affect patients with sickle cell disease (SCD) but are problematic to treat. Clarification of the science for this condition in an animal model of SCD may lead to improved interventions for it. Our findings suggest that novel topical delivery of a vasorelaxant agent nitric oxide into the bladder of these mice corrects overactive bladder by improving deranged bladder physiology regulatory signaling.