Study Protocol for a Randomized Controlled Trial of Low Intensity Shockwave Therapy for the Treatment of Post-Radical Prostatectomy Erectile Dysfunction: "SHARP-ED TRIAL".

Introduction: Erectile Dysfunction (ED) is a common challenge post Radical Prostatectomy (RALP), affecting men's sexual health after undergoing definitive cancer therapy. Despite employing nerve-sparing techniques, ED remains a prevalent issue in this population. Studies indicate that approximately 70%-85% of men experience varying degrees of ED following RALP. The existing treatment landscape for post-RALP-ED presents limitations, and a discernible knowledge gap persists. To address this, our study aims to investigate the efficacy of Shockwave Therapy (SWT) as a potential intervention for managing ED after RALP. Methods: This prospective, randomized, sham-controlled clinical trial aims to recruit 189 eligible patients post-RP and assess the effects of SWT. Comprehensive screening, including medical history, physical examinations, and biochemical evaluations, will be conducted to confirm eligibility. The intervention involves utilizing a device to administer focal shockwaves targeted at cavernosal tissue. Safety measures include continuous monitoring for adverse events and rigorous reporting protocols. The primary endpoint assesses changes in participants' ability to engage in penetrative intercourse from baseline to study completion, while secondary endpoints encompass various measures of erectile function, including questionnaire-based assessments, ultrasound parameters, and clinical outcomes. Results: Statistical analysis, encompassing ANOVA for continuous variables and Fisher's exact test for categorical ones, will evaluate demographic characteristics, baseline data, and primary as well as secondary outcomes for statistical significance. Detailed analysis of trends, subgroup comparisons, and treatment effects will provide a comprehensive understanding of the impact of SWT on post-RP ED. Conclusion: This study protocol represents a rigorous investigation into the potential therapeutic role of SWT in managing post-RP ED. The outcomes from this study aim to contribute valuable insights into the efficacy, safety, and potential improvements in erectile function following SWT, providing significant guidance for future interventions aimed at addressing this challenging condition affecting men's health and quality of life.

A primer on the restorative therapies for erectile dysfunction: a narrative review.

INTRODUCTION: Erectile dysfunction (ED) is a common condition that affects millions worldwide. Patients and urologists alike are seeking alternative therapies that can provide long-lasting results in the treatment of ED. This review provides a comprehensive overview of restorative treatments available for ED, such as platelet-rich plasma, stem cell therapy, and shockwave therapy. OBJECTIVE: The aim of this narrative review is to provide a primer for urologists and general practitioners on the basics of implementing ED restorative therapies in their practice. METHODS: The PubMed, MEDLINE, and Google Scholar databases were searched for articles in the English language through August 31, 2023, that included key terms such as "erectile dysfunction," "restorative therapy," "shockwave therapy," "platelet-rich plasma," "stem cell therapy," and "stromal vascular fraction." Reference lists of selected studies were manually reviewed to find articles not identified by the initial database search. RESULTS: Shockwave therapy has demonstrated effectiveness in treating ED, with devices like the Medispec ED1000 and Storz Duolith showing statistically significant improvements in patient scores for International Index of Erectile Function (IIEF)-Erectile Function scores in clinical trials. In reported studies of platelet-rich plasma injections, a substantial percentage of patients reached a minimal clinically important difference in the IIEF-Erectile Function scale after treatment. Studies of ED treatment with stem cell therapy, while limited and with small sample sizes, have demonstrated encouraging improvements in patient scores for the abridged 5-item version of the IIEF after treatment. CONCLUSION: Shockwave, platelet-rich plasma, and stem cell therapies are important, novel, noninvasive restorative treatments for ED that can provide relief for patients wishing to avoid a more invasive approach. While these therapies have shown promising results in clinical trials, more research is required to establish them as standardized and efficacious options in the management of ED.

Misconceptions of Vaping Among Young Adults.

Background Vaping is growing in popularity worldwide, especially among young adults. To develop effective tobacco prevention interventions, first, there must be an understanding of the attitudes and perceptions of young adults toward the use of vaping. Highlighting perception discrepancies between races may allow physicians to more effectively counsel their patients regarding the risks of vaping. Methodology We conducted an online survey using Amazon Mechanical Turk (MTurk, https://www.mturk.com/) to identify misconceptions about vaping among adults aged 18 to 24 years who currently vape. The survey consisted of 18 questions evaluating reasons for vaping, history of tobacco use, and thoughts on the adverse effects of vaping. The Penn State Electronic Cigarette Dependence Index was implemented to assess dependence. Exclusion criteria comprised respondents who did not vape and were under the age of 18 or over the age of 24. Results A total of 1,009 responses were received with 66% identifying as male (n = 667) and 33% (n = 332) identifying as female. Sixty-nine percent of patients smoked cigarettes or used another form of tobacco previously (n = 692). Of those respondents, 81% indicated that they had since quit using tobacco products (excluding vaping). Switching to vaping was the most common reason for quitting cigarettes or other forms of tobacco, with health concerns and social purposes being the second and third most common reasons provided, respectively. When asked whether vaping had negative health impacts, only 238 (24%) participants strongly agreed with this statement, while a majority (64%) neither agreed nor disagreed or only somewhat agreed. Most participants were white or Caucasian (n = 777). When asked whether smoking or vaping had more severe health implications, 55% of white or Caucasian participants, 41% of Asian participants, and 32% of black or African American participants indicated that vaping was worse than smoking cigarettes. The average Penn State dependence score was 8.7, suggesting medium dependence. Conclusions Our survey sample of 1,006 young adults who vape indicated that the majority did not perceive vaping as significantly harmful. A comprehensive smoking prevention policy, educational interventions, and quit support are needed to enhance awareness among young adults about the health effects associated with vaping. Such interventions should also consider the novel shift toward the replacement of smoking with vaping.

A Phase 2 Randomized, Placebo-controlled Crossover Trial to Evaluate Safety and Efficacy of Platelet-rich Plasma Injections for Peyronie's Disease: Clinical Trial Update.

Intralesional injection of platelet-rich plasma for Peyronie's disease appears to be safe according to early observations from an ongoing clinical trial. Efficacy data remain elusive until completion of the trial.

An evaluation of race-based representation among men participating in clinical trials for prostate cancer and erectile dysfunction.

Background: Inclusion of ethnic/racial minorities in clinical trials is essential to fully assess therapeutic efficacy. It is well-known that populations respond dissimilarly to interventions. Our objective is to analyze the inclusion of minority men in clinical trials for erectile dysfunction (ED). Methods: We searched ClinicalTrials.gov for the disease keyword: "Erectile Dysfunction" and used "Prostate Cancer" for comparison. Completed trials which reported demographic data were included for analysis. Literature was reviewed to determine the prevalence of ED and prostate cancer (PC) among Hispanic, Black, White, and Asian men. The proportion of individuals of each group that participated in trials is divided by the proportion of each group in the disease population to calculate the "Participation to Prevalence Ratio" (PPR). PPRs between 0.8 and 1.2 indicates adequate representation, <0.8 is under-representation and >1.2 is over-representation. Results: A total of 312 trials were assessed: 289 for prostate cancer and 23 for ED. Hispanic men comprised 11.8% of ED trial participants and 4.6% of prostate cancer trial participants, yet represented 18% of ED patients and 7.3% of PC patients. Black/African-American (AA) men accounted for 10.2% of ED trial participants and 9.4% of PC trial participants, but comprise 16% of ED patients, and 16.3% of PC patients. Hispanic and AA men are under-represented in trials for ED and Prostate Cancer (Hispanic ED PPR = 0.66; Hispanic PC PPR = 0.63; AA ED PPR = 0.64; AA PC PPR = 0.58). Conclusion: Our analysis shows that both Hispanic and AA men are underrepresented in both ED and PC clinical trials.

The use of combination regenerative therapies for erectile dysfunction: rationale and current status.

Erectile Dysfunction (ED) is defined as the inability to achieve and maintain an erection sufficient for sexual intercourse. Available treatments for ED provide only symptomatic relief, which is for the most part temporary. Regenerative therapies such as Low Intensity Shockwave, Platelet-Rich Plasma, and Stem Cell therapy can potentially provide a "cure" for ED by reversing the underlying pathology of ED rather than just treating the symptoms. Low Intensity Shockwave therapy is the most evidence based at this point and is thought to act by improving penile blood flow, repairing previous nerve damage, and activating stem cells. Stem Cell therapy takes advantage of the self-replicative potential of stem cells to create new corporal tissue, but also to recruit host cells and angiogenic factors to stimulate endogenous repair. Platelet-Rich Plasma therapy uses concentrated growth factors that already exist within the bloodstream to repair damaged nerves and increase penile blood flow. The use of combination restorative therapy may provide an additive or synergistic benefit greater than any one therapy alone because of its overlapping mechanisms of action on the penis but is a topic that remains to be studied.

The Effect of Transendocardial Stem Cell Injection on Erectile Function in Men With Cardiomyopathy: Results From the TRIDENT, POSEIDON, and TAC-HFT Trials.

BACKGROUND: Despite limited human data, there is a growing interest in the use of stem cell therapy (SCT) for erectile dysfunction (ED). AIM: To determine the effect of transendocardial stem cell injection on erectile function on men with cardiomyopathy and ED. METHODS: We used International Index of Erectile Function (IIEF) scores collected from men enrolled in 3 separate randomized controlled trials: Comparison of Allogeneic vs Autologous Bone Marrow-Derived Mesenchymal Stem Cells Delivered by Transendocardial Injection in Patients With Ischemic Cardiomyopathy (POSEIDON), Transendocardial Mesenchymal Stem Cells and Mononuclear Bone Marrow Cells for Ischemic Cardiomyopathy (TAC-HFT), and Dose Comparison Study of Allogeneic Mesenchymal Stem Cells in Patients With Ischemic Cardiomyopathy (TRIDENT). These trials recruited patients with ischemic cardiomyopathy and ejection fraction less than 50%. Inclusion and exclusion criteria were identical in all 3 trials. The primary intervention in these trials included transendocardial stem cell injection of stem cells or placebo via cardiac catheterization. The follow-up period was 1 year. IIEF data were collected at baseline and at multiple time points in each trial. OUTCOMES: We investigated erectile function over time based on cell dose, cell source (autologous vs allogenic), cell type (mesenchymal stem cells vs bone marrow mononuclear cells), and comparing men who received SCT with those who received placebo. RESULTS: A total of 36 men were identified with complete IIEF data. 8 men received placebo injection, and 28 received SCT. The median age was 66.5 years. Comorbidities were similar among all men. Analysis was performed on men with ED, defined by an IIEF-EF score of 24 or less. In the placebo and all-comer SCT group, the median IIEF-EF score was 5 [1-8] and 5 [1-15] at baseline and was 3.5 [3-5.8] and 7 [1-18] at 12 months (P > .05). When analyzed by cell dose, the IIEF-EF score in men who received 200 million cells increased significantly over 12 months (14 [4-23] to 20 [15-24.5], P = .014.) Similarly, an autologous cell source resulted in a similar increase from baseline to 12 months (14 [3.8-23.3] to 20 [12-22], P = .030). CLINICAL IMPLICATIONS: Erectile function may improve after systemic delivery of SCT in men with ischemic cardiomyopathy and at least mild ED. STRENGTHS & LIMITATIONS: This post hoc analysis is the first to investigate the effect of SCT on erectile function using randomized, placebo-controlled data. Weaknesses include that ED was not a primary end point, and men were not originally recruited based on erectile function. CONCLUSION: Future trials on systemic delivery of SCT for ED should focus on high cell dose and autologous cell source, as these seem to provide the best response in men with at least mild ED. Ory J, Saltzman RG, Blachman-Braun R, et al. The Effect of Transendocardial Stem Cell Injection on Erectile Function in Men With Cardiomyopathy: Results From the TRIDENT, POSEIDON, and TAC-HFT Trials. J Sex Med 2020;17:695-701.

Kidney-derived c-kit+ progenitor/stem cells contribute to podocyte recovery in a model of acute proteinuria.

Kidney-derived c-kit+ cells exhibit progenitor/stem cell properties and can regenerate epithelial tubular cells following ischemia-reperfusion injury in rats. We therefore investigated whether c-kit+ progenitor/stem cells contribute to podocyte repair in a rat model of acute proteinuria induced by puromycin aminonucleoside (PAN), the experimental prototype of human minimal change disease and early stages of focal and segmental glomerulosclerosis. We found that c-kit+ progenitor/stem cells accelerated kidney recovery by improving foot process effacement (foot process width was lower in c-kit group vs saline treated animals, P = 0.03). In particular, these cells engrafted in small quantity into tubules, vessels, and glomeruli, where they occasionally differentiated into podocyte-like cells. This effect was related to an up regulation of α-Actinin-4 and mTORC2-Rictor pathway. Activation of autophagy by c-kit+ progenitor/stem cells also contributed to kidney regeneration and intracellular homeostasis (autophagosomes and autophagolysosomes number and LC3A/B-I and LC3A/B-II expression were higher in the c-kit group vs saline treated animals, P = 0.0031 and P = 0.0009, respectively). Taken together, our findings suggest that kidney-derived c-kit+ progenitor/stem cells exert reparative effects on glomerular disease processes through paracrine effects, to a lesser extent differentiation into podocyte-like cells and contribution to maintenance of podocyte cytoskeleton after injury. These findings have clinical implications for cell therapy of glomerular pathobiology.

Dose Comparison Study of Allogeneic Mesenchymal Stem Cells in Patients With Ischemic Cardiomyopathy (The TRIDENT Study).

RATIONALE: Cell dose and concentration play crucial roles in phenotypic responses to cell-based therapy for heart failure. OBJECTIVE: To compare the safety and efficacy of 2 doses of allogeneic bone marrow-derived human mesenchymal stem cells identically delivered in patients with ischemic cardiomyopathy. METHODS AND RESULTS: Thirty patients with ischemic cardiomyopathy received in a blinded manner either 20 million (n=15) or 100 million (n=15) allogeneic human mesenchymal stem cells via transendocardial injection (0.5 cc per injection × 10 injections per patient). Patients were followed for 12 months for safety and efficacy end points. There were no treatment-emergent serious adverse events at 30 days or treatment-related serious adverse events at 12 months. The Major Adverse Cardiac Event rate was 20.0% (95% confidence interval [CI], 6.9% to 50.0%) in 20 million and 13.3% (95% CI, 3.5% to 43.6%) in 100 million (P=0.58). Worsening heart failure rehospitalization was 20.0% (95% CI, 6.9% to 50.0%) in 20 million and 7.1% (95% CI, 1.0% to 40.9%) in 100 million (P=0.27). Whereas scar size reduced to a similar degree in both groups: 20 million by -6.4 g (interquartile range, -13.5 to -3.4 g; P=0.001) and 100 million by -6.1 g (interquartile range, -8.1 to -4.6 g; P=0.0002), the ejection fraction improved only with 100 million by 3.7 U (interquartile range, 1.1 to 6.1; P=0.04). New York Heart Association class improved at 12 months in 35.7% (95% CI, 12.7% to 64.9%) in 20 million and 42.9% (95% CI, 17.7% to 71.1%) in 100 million. Importantly, proBNP (pro-brain natriuretic peptide) increased at 12 months in 20 million by 0.32 log pg/mL (95% CI, 0.02 to 0.62; P=0.039), but not in 100 million (-0.07 log pg/mL; 95% CI, -0.36 to 0.23; P=0.65; between group P=0.07). CONCLUSIONS: Although both cell doses reduced scar size, only the 100 million dose increased ejection fraction. This study highlights the crucial role of cell dose in the responses to cell therapy. Determining optimal dose and delivery is essential to advance the field, decipher mechanism(s) of action and enhance planning of pivotal Phase III trials. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02013674.