Microvesicles-delivering Smad7 have advantages over microvesicles in suppressing fibroblast differentiation in a model of Peyronie's disease.

BACKGROUND: This study compared the differences of microvesicles (MVs) and microvesicles-delivering Smad7 (Smad7-MVs) on macrophage M1 polarization and fibroblast differentiation in a model of Peyronie's disease (PD). METHODS: Overexpression of Smad7 in rat BMSCs was obtained by pCMV5-Smad7 transfection. MVs were collected from rat BMSCs using ultracentrifugation. In cells, 100 µg/mL of MVs or Smad7-MVs were used to treat the 100 ng/mL of lipopolysaccharide (LPS)-induced RAW264.7 cells or 10 ng/mL of recombinant transforming growth factor-ß1 (TGF-ß1)-induced fibroblasts. The pro-inflammatory cytokines and markers of M1 macrophages were measured in RAW264.7 cells, and the migration and markers of fibroblast differentiation were measured in fibroblasts. In rats, 50 µg of MVs or Smad7-MVs were used to treat the TGF-ß1-induced animals. The pathology of tunica albuginea (TA), the markers of M1 macrophages and fibroblast differentiation in the TA were measured. RESULTS: The MVs or Smad7-MVs treatment suppressed the LPS-induced macrophage M1 polarization and TGF-ß1-induced fibroblast differentiation. Moreover, the Smad7-MVs treatment decreased the fibroblast differentiation compared with the MVs treatment. In the TGF-ß1-induced TA of rats, MVs or Smad7-MVs treatment ameliorated the TA fibrosis by suppressing the macrophage M1 polarization and fibroblast differentiation. There was no significance on the M1-polarized macrophages between the MVs treatment and the Smad7-MVs treatment. Meanwhile, the Smad7-MVs treatment had an edge in terms of suppressing the fibroblast differentiation in the TGF-ß1-induced PD model compared with the MVs treatment. CONCLUSIONS: This study demonstrated that Smad7-MVs treatment had advantages over MVs treatment in suppressing of fibroblast differentiation in a model of PD.

Comparison of Collagenase Clostridium histolyticum to Surgery for the Management of Peyronie's Disease: A Randomized Trial.

PURPOSE: Since Food and Drug Administration approval of collagenase Clostridium histolyticum for Peyronie's disease, there has been significant debate regarding its role and comparable efficacy to surgery. MATERIALS AND METHODS: A randomized, controlled trial was performed of Peyronie's disease men treated with either collagenase C histolyticum + RestoreX penile traction therapy + sildenafil or penile surgery + RestoreX penile traction therapy + sildenafil, with 3-month data presented. Primary objectives were overall satisfaction, subjective changes in erectile function, penile sensation, penile length, and changes in the International Index of Erectile Function-Erectile Function Domain score. Secondary outcomes included objective changes in length, curve, adverse events, and other standardized and nonstandardized questionnaires. RESULTS: A total of 40 men were enrolled, with 38 (collagenase C histolyticum group = 19, surgery group = 19) completing treatment and having 3-month data available. All demographic and clinicopathological variables were similar between groups. Following treatment, 50% of men in the collagenase C histolyticum group reported being very satisfied (vs 21% in the surgery group, P = .08) and noted better subjective erectile function (100% vs 68%, P = .03) and penile length (88% vs 16%, P < .0001), lesser impacts on penile sensation (75% vs 11% no change, P < .001), and similar International Index of Erectile Function-Erectile Function Domain changes (+1.5 vs +2.5, P = .91). Objectively, men in the surgery group had greater curve improvements (84% vs 54%, P < .01) and higher rates of adverse events (50 vs 13 events, P < .001) but decreased penile length (-0.5 cm vs +1.0 cm, P < .01). CONCLUSIONS: At 3 months posttreatment, collagenase C histolyticum + RestoreX penile traction therapy + sildenafil results in lesser curve improvements but greater penile length and fewer adverse events, including impacts on subjective erectile function and sensation, than men treated with surgery.

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

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

The Immunological Microenvironment and the Emerging Role of Stem Cells Therapy in Peyronie's Disease: A Systematic Narrative Review.

Current literature has indicated that Peyronie's disease (PD) could be initiated by microtrauma and the subsequent inflammation episodes that follow. PD could be sorted into acute or chronic status, and it can differ when selecting the clinical therapeutics. PD would cause pain and penile deformity to diseased men and impair their erectile function. Occasionally, surgical revision of the penis might be needed to correct the penile curvature. We find that there are limited effective options of intra-lesion injections for the PD plaques. By searching the databases and screening the literature with the PRISMA 2020 guideline, we observed that several preclinical studies that applied stem cell therapy in treating PD were fruitful in the acute phase. Although in the chronic phase of PD, erectile parameters were not significantly improved, and therefore, future studies might be better elevated in certain aspects, such as the sites selected for harvesting stem cells or changing the centrifugation forces. In this review, we concluded the contemporary understanding of inflammatory microenvironments in PD, the stem cell therapy in PD, and our perspectives on future studies. We concluded that there may be great potential in stem cell therapy for treating both acute and chronic phases PD.

Acute Lower Back Pain after Intralesional Injection of Collagenase Clostridium histolyticum for Peyronie's Disease.

PURPOSE: The safety label for collagenase Clostridium histolyticum was updated to include postinjection acute lower back pain as an adverse event observed with intralesional therapy for Peyronie's disease. Incidence and causality are unknown. We assessed frequencies and temporal associations for this adverse event in a large cohort. MATERIALS AND METHODS: Data on all men undergoing collagenase injections for Peyronie's disease at our institution from October 2015 through December 2020 were retrospectively assessed. The study included 330 patients, 300 completing at least 1 full course (8 injections). Measured outcomes included incidence and timing of back pain, and associations with demographics and comorbidities. RESULTS: Of 330 patients, 19 (5.8%) experienced at least 1 episode of postinjection acute lower back pain. Of 300 who completed at least 1 full course of 8 injections, 4 (1.3%) reported back pain within the 8-injection course. A subset underwent additional rounds (16 or 24 injections). Back pain increased to 8.7% (13/149) during a second round, 6.9% (3/43) during a third. No association was found with age, diabetes or back pain history. Most cases occurred shortly after injection; all were self-limited or resolved with a single dose of ketorolac. CONCLUSIONS: This single-center, retrospective analysis suggests that intralesional collagenase injections for Peyronie's disease may cause acute lower back pain in up to 6% of patients. Patients may benefit from counseling regarding this risk. Incidence rises with additional rounds of treatment. Prospective safety data regarding >8 injections do not exist. No patient had long-term sequelae of back pain.

Predictors of Curvature Improvement in Men With Peyronie's Disease Treated With Intralesional Collagenase Clostridium Histolyticum.

INTRODUCTION: Penile curvature is the most common abnormality that is observed by men with Peyronie's disease (PD). Collagenase Clostridium histolyticum (CCH) has become a standard treatment for PD patients. AIM: To identify predictor factors associated with improvements of penile curvature outcomes in men with PD treated with CCH. METHODS: We retrospectively collected the data of patients with PD treated with CCH up to 8 injections divided into 4 cycles between January 2014 and July 2020. Per protocol, penile curvature was assessed at baseline, and after the second and ford CCH cycle. If after cycle 2, curvature demonstrated no improvement, or penile curvature was significantly improved and the patient was happy, no further treatment was recommended. However, if penile curvature was significantly improved and the patient remained dissatisfied, 4 cycles were completed. Three categories of response were evaluated: improvement (≥10 degrees or ≥20%, either 1 happens), unchanged (±10 degrees or ±20%) or worsened (≥10 degrees or ≥20%, either 1 happens). Logistic regression analyses were performed to evaluate predictive factors associated with penile curvature improvements. OUTCOMES: Degrees of the curvature changes between the baseline and after the cycles of CCH. RESULTS: A total of 114 patients underwent CCH treatment. Median age was 57 years. Median PD duration was 11 months. At baseline, mean curvature was 47 degrees, 65% had dorsal curvature, 53% mid-shaft location, and 15% calcification. After CCH treatment, the mean final curvature was 40 degrees. A total of 44% improved the curvature, 39% had no change while 17% worsened after CCH treatment. Of men who had penile curvature improvement with CCH treatment, the mean curvature decreasing in degrees and percentage were 22 degrees and 41%, respectively. Men with baseline curvature ≤ 30, 31-59, and ≥ 60 degrees, the percentage curvature improvement were 29%, 43%, and 60%, respectively. Baseline curvature was the only significant predictor of penile curvature improvement after CCH (OR 1.33, 95% CI = 1.1, 1.7). CLINICAL IMPLICATIONS: We confirmed baseline penile curvature is the most important predictive factor, and this is the first report describing proportions of penile curvature improvement with CCH treatment. STRENGTHS AND LIMITATIONS: This study has several strengths, including the use of validated instruments. Nonetheless, there are limitations: the retrospective nature of the study, a single institution; and modelling device was not controlled. CONCLUSION: Penile curvature improvement was significantly more common in patients with greater baseline curvature, reaching up to 60% for patients with ≥ 60 degrees. Flores JM, Nascimento B, Punjani N, et al. Predictors of Curvature Improvement in Men With Peyronie's Disease Treated With Intralesional Collagenase Clostridium Histolyticum. J Sex Med 2022;19:1680-1686.

Pre- and Post-Injection Needle Pain in Patients Undergoing First Intracavernosal Injection.

BACKGROUND: Intracavernosal injections (ICI) are a well-established treatment option for men with erectile dysfunction (ED); however, the anticipation of pain with injection remains a significant barrier to the use of ICI. AIM: To evaluate the patient-anticipated degree of pain versus the experienced degree of pain pre- and post-ICI in men undergoing their first injection with an erectile agent. METHODS: We studied 51 patients who underwent their first ICI in our men's health clinic. Anticipated needle-associated pain was judged with a pre-injection score, and pain experienced during the injection was judged with a post-injection score. All patients graded their pre- and post-ICI pain using a standard 10-point scale (0-10). OUTCOMES: Pre- and post-ICI pain was defined with the visual analogue scale (0-10) in men undergoing their first penile injection. RESULTS: Medians and interquartile ranges (IQRs) of the patients' age [65 years (54.5-68.0)], pre-injection pain [5 (4-7)], and post-injection pain [1 (1-2)] were recorded. Most men in the study had erectile dysfunction (68.6%) and/or Peyronie's Disease (64.7%). The average pre-injection prediction pain score was 5.45 ± 2.15; the average post-injection perceived pain score was 1.20 ± 0.73. Thus, there was an average discrepancy of over 4 points in predicted pain vs perceived pain. A paired t-test was performed which showed a statistically significant difference between pre- and post-injection scores (P < .05). A Wilcoxson Signed Rank Test showed statistical significance in the difference between pre- and post-injection pain scores (P < .05). CLINICAL IMPLICATIONS: ICI is a safe, effective treatment for patients with ED and is associated with significantly less pain than is anticipated by patients. STRENGTHS & LIMITATIONS: This is the first report to describe the discrepancy between pre-ICI anticipated pain and post-ICI experienced pain. Limitations include an overall small sample size. CONCLUSION: Patients experience significantly less pain with ICI than they anticipate having. This represents an important factor to consider when counseling patients about available ED treatments. Baird B, Wajswol E, Ericson C et al. Pre- and Post-Injection Needle Pain in Patients Undergoing First Intracavernosal Injection. J Sex Med 2022;19:590-593.

Role of Oxidative Stress in Peyronie's Disease: Biochemical Evidence and Experiences of Treatment with Antioxidants.

BACKGROUND: Peyronie's disease (PD) is a chronic inflammatory condition affecting adult males, involving the tunica albuginea of the corpora cavernosa of the penis. PD is frequently associated with penile pain, erectile dysfunction, and a secondary anxious-depressive state. The etiology of PD has not yet been completely elucidated, but local injury is generally recognized to be a triggering factor. It has also been widely proven that oxidative stress is an essential, decisive component in all inflammatory processes, whether acute or chronic. Current conservative medical treatment comprises oral substances, penile injections, and physical therapy. AIM: This article intends to show how antioxidant therapy is able to interfere with the pathogenetic mechanisms of the disease. METHOD: This article consists of a synthetic narrative review of the current scientific literature on antioxidant therapy for this disease. RESULTS: The good results of the antioxidant treatment described above also prove that the doses used were adequate and the concentrations of the substances employed did not exceed the threshold at which they might have interacted negatively with the mechanisms of the redox regulation of tissue. CONCLUSIONS: We believe new, randomized, controlled studies are needed to confirm the efficacy of treatment with antioxidants. However, we consider the experiences of antioxidant treatment which can already be found in the literature useful for the clinical practice of urologists in the treatment of this chronic inflammatory disease.

Continuing Collagenase Clostridium Histolyticum Injections Among Initial Nonresponders Results in Significant Curvature Improvements in the Majority of Peyronie's Disease Men.

BACKGROUND: It is currently unclear if men with Peyronie's Disease (PD) who achieve minimal benefits with the first 2 series of Collagenase Clostridium Histolyticum (CCH) injections should continue with additional injections. AIM: To analyze curvature improvements from the final two series of CCH injections based on amount of improvement during the first 2 series. METHODS: A prospective registry was analyzed of all men undergoing CCH injections for PD at a single institution. Men were included if they had completed a full 4 series (8 injections) of CCH and had baseline, interval (after 2 series), and/or final (after 4 series) curvature assessments available. Men were stratified into cohorts using baseline-to-interval assessments of ≤10° (or ≤20%) and >10° (or >20%), and improvements were compared using interval-to-final assessments. OUTCOMES: The primary outcome was interval-to-final curvature improvements stratified by ≤10°/>10° or ≤20%/>20% improvements achieved during the baseline-to-interval period. Secondary outcomes included analyses of demographic and pathophysiologic variables to determine associations with significant improvements during the final 2 CCH series. RESULTS: A total of 296 PD men were identified as receiving at least one CCH injection, of whom 175 had baseline-to-interval, 84 interval-to-final, and 115 with baseline-to-final measurements. Mean age was 56.6, PD duration 28.6 months, baseline curvature 63.4°, hourglass deformity 36.2%, and calcification 20%. Mean overall curve improvement was -21.5° (33.1%). Among men who experienced ≤20% improvements after 2 series, the mean subsequent curvature change was -24.6% during the final two series (vs +4.3% of those with >20% initial improvement, P< .001), and they were 2.7x more likely to experience >20% subsequent curve improvements. Thirty-one percent of those who achieved >10° during the first 2 series experienced benefits during the final 2 series compared to 70% of men who had ≤10° improvement initially. No demographic or pathophysiological variables predicted likelihood for improvements during the final 2 series of injections. CLINICAL IMPLICATIONS: Men who fail to achieve significant benefits with 2 series of CCH injections may benefit from completing the final 2 series. STRENGTHS AND LIMITATIONS: Strengths including a relatively large, prospective series. Limitations include a single center, nonrandomization, nonblinded assessments, and restriction to men who completed eight injections. CONCLUSIONS: In the current series, approximately 2/3 of men who fail to achieve >10° or 20% curve improvements with an initial 2 series of CCH injections achieved >10° or 20% improvements with the subsequent 2 series. Alom M, Burgon H, Ziegelmann M, et al. Continuing Collagenase Clostridium Histolyticum Injections Among Initial Nonresponders Results in Significant Curvature Improvements in the Majority of Peyronie's Disease Men. J Sex Med 2021;18:1092-1098.

Predictors of Pursuing Intralesional Xiaflex in Peyronie's Disease Patients.

BACKGROUND: Intralesional collagenase such as Xiaflex (ILX) has become a standard treatment for Peyronie's disease (PD). Many robust studies have demonstrated its clear efficacy in the treatment algorithm. AIM: To examine predictors of the patient decision to pursue ILX in PD patients. METHODS: The study included PD patients (i) with stable disease (ii) who had doppler duplex ultrasonography (DUS) at least 6 months prior to analysis date and (iii) did not choose an operation. All patients received a standard discussion regarding treatment options, specifically, observation, ILX and penile reconstructive surgery (plication, plaque incision and grafting, implant surgery). Patients who opted to use ILX were compared to those who opted against it. Comorbidity, demographic and PD characteristics were recorded at the initial PD visit. All patients completed three validated questionnaires including the PD questionnaire (PDQ), Self-Esteem and Relationship (SEAR) questionnaire and a depression questionnaire (CES-D). Logistic regression was used to determine predictors of ILX use. OUTCOMES: Predictors of ILX utilization. RESULTS: Four hundred and fifty stable PD men had DUS completed 6 months before to allow sufficient time for treatment decision. Of these, 111 (24.7%) patients had ILX treatment and 339 (75.3%) did not. Mean age, relationship status and pain occurrence were similar between groups, but ILX patients had less bother defined as PDQ ≥ 9 (46.8% vs 53.7%, P = .02). ILX patients had more complex curves (79.3% vs 47.8%, P < .01) and more severe instability (32.4% vs 15.3%, P = .01). ILX patients also had higher PDQ domain scores (Psychological 11.5 ± 6.4 vs 7.5 ± 6.2, P < .01; Pain 6.2 ± 6.0 vs 4.3 ± 5.6, P = .02; and Bother 9.8 ± 4.7 vs 6.6 ± 4.8, P < .01). On univariable statistics, significant bother (OR 2.41, 95% CI 1.36-4.28, P<0.01), complex curvature (OR 4.18, 95%CI 2.52-6.93, P < .01), moderate and/or severe instability (OR 1.98, 95%CI 1.18-3.30, P < .01) and PDQ-Bother scores (OR 1.15, 95%CI 1.08-1.22 P < .01) predicted ILX use. On multivariable analysis, instability (OR 2.58, 95%CI 1.02-6.57, P = .05) and significant bother (OR 1.23, 95%CI 1.04-1.45, P = .01) predicted ILX use. CLINICAL IMPLICATIONS: Educates providers as to which patients are more likely to choose ILX. STRENGTHS & LIMITATIONS: Our study has a large sample size and all patients received the same standardized treatment discussion. Our study is limited by the absence of insurance data on all patients, and its retrospective single center design. CONCLUSION: ILX was chosen by the minority of stable PD patients. While moderate to severe instability and significant bother is predictive of ILX use, other demographic factors including relationship status, sexual orientation or pain were not. Punjani N, Nascimento B, Salter C, et al. Predictors of Pursuing Intralesional Xiaflex in Peyronie's Disease Patients. J Sex Med 2021;18:1258-1264.

Lateral herniation during treatment with collagenase Clostridium histolyticum (Xiaflex) for Peyronie's disease.

BACKGROUND: Collagenase Clostridium histolyticum (CCH), also know as Xiaflex, with penile modeling is considered to be the gold standard non-surgical option for management of Peyronie's disease and is known to be safe and efficacious. Corporal rupture is a rare but known adverse event of CCH treatment, however there are limited studies describing corporal herniation without rupture. Here we present a patient who experienced a rare complication following CCH injections for Peyronie's disease: lateral herniation of the tunica albuginea in the setting of a dorsal penile plaque. CASE PRESENTATION: A 58-year-old male presented to our clinic seeking treatment for Peyronie's disease. On exam, he was found to have a palpable dorsal plaque and > 30 degrees leftward curvature of the penis. He was deemed an appropriate candidate for and patient decided to proceed with CCH and modeling. He received 2 cycles of CCH injections (4 total CCH injections) with in-office and at-home penile modeling, per manufacturer's protocol. Two weeks following in-office modeling during his second CCH cycle, the patient reported a painless, soft swelling involving the left side of his penile shaft only occurring with erection. Exam and history were suggestive of lateral herniation rather than corporal rupture. CCH was discontinued. Patient declined further evaluation with penile ultrasound. CONCLUSIONS: This is the first case report detailing lateral herniation with CCH injections. Symptoms and exam that should raise suspicion of corporal herniation are a soft, painless mass with erection.

Conservative Therapy for Peyronie's Disease: a Contemporary Review of the Literature.

PURPOSE OF REVIEW: To analyze the literature on current conservative treatment options for Peyronie's disease (PD). RECENT FINDINGS: Conservative therapy with intralesional collagenase clostridium histolyticum (CCH) is safe and efficacious in either the acute or chronic phases of PD. Combination treatment with penile traction therapy (PTT) can produce even better results. While most PTT devices require extended periods of therapy up to 8 h per day, the RestoreX® device can be effective at 30-90 min per day. A variety of conservative therapies are available for treatment of PD. The available literature does not reveal any treatment benefit of oral therapies. Intralesional therapy is the mainstay conservative treatment of PD. Intralesional CCH therapy is the first Food and Drug Administration-approved intralesional therapy and represents the authors' preference for medical therapy. The most effective conservative management of PD likely requires a combination of therapies.

The Management of Penile Fracture: a Review of the Literature with Special Consideration for Patients Undergoing Collagenase Clostridium Histolyticum Injection Therapy.

PURPOSE OF REVIEW: To review the current literature on acute management of traumatic penile fracture, with a specific discussion of those injuries following collagenase clostridium histolyticum (CCH) injections for the treatment of Peyronie's disease. RECENT FINDINGS: The immediate repair of traumatic penile fracture injury is associated with significantly better prognosis for long-term sexual health. Corporal disruption following CCH administration has several distinct features, and the trend is to manage these patients conservatively in the absence of urethral injury. Traumatic penile fracture repair continues to have excellent results when performed immediately following injury. The post-CCH treatment setting portends increased difficulty during surgical management and can be successfully managed in most cases by conservative measures.

Intralesional low-dose methylprednisolone for the treatment of active phase Peyronie's disease: A single-centre, preliminary prospective non-randomised study.

AIM: There are a few types of drugs that can be used in the active phase of Peyronie's disease. Methylprednisolone is a corticosteroid with a strong anti-inflammatory effect. In this study, we aimed to evaluate the effect of intralesional low-dose methylprednisolone treatment on patients in the active phase of Peyronie's disease. PATIENTS AND METHODS: Forty-eight patients suffering from Peyronie's disease active phase symptoms were included in the study. Methylprednisolone was administered intralesionally for 8 weeks, once per week, at a dose of 40 mg. The injection was applied to the plaques, which causes maximum curvature. Patients were evaluated before and after treatment for plaque size, angle of curvature, and erectile dysfunction according to the International Index of Erectile Function-5 and Peyronie's Disease Questionnaire. RESULTS: The mean age of the patients was 61.1 (43-78) years. The mean duration of the symptoms was 3.4 (0-9) months. The average plaque size before treatment was 13.6 mm (7.1-16.8) and after treatment, this value decreased to 10.8 mm (4.3-14.6) (P: .025). The average scores of Peyronie's Disease Questionnaire elements; symptom severity, penile pain, and bother/discomfort were 12.3, 19.1, and 6.2, respectively, before the treatment. These scores were decreased to 8.9, 9.6, and 4.4, respectively, after treatment. All subgroups of Peyronie's Disease Questionnaire scores were significantly improved after treatment (P: .001, P < .001, P: .045, respectively). No adverse events were observed during or after treatment. CONCLUSION: In order to recover the symptoms and signs, new and easily accessible drugs are required for use in the acute period of Peyronie's disease. In this context, treatment with intralesional low-dose methylprednisolone in acute phase Peyronie's Disease is a promising and safe treatment option.

[Efficacy and safety of local injections treatments for Peyronie's disease: Review of the literature]. / Efficacité et tolérance des traitements locaux en injections pour le traitement de la maladie de La Peyronie : revue de la littérature.

AIM: To assess the efficacy and safety of local injection used to reduce penile curvature in Peyronie's disease. METHODS: A review of the literature was carried out according to the PRISMA guidelines (Preferred Reporting Items for Systematic Reviews and Meta-Analyzes) on the Medline database in April 2020, with the research: "collagenase"[All Fields] OR "Interferon"[All Fields] OR "verapamil"[All Fields] OR "betamethasone"[All Fields] OR "hyaluronic acid"[All Fields] OR "Platelet-Rich Plasma"[All Fields] OR "Stem Cells"[All Fields] AND "peyronie's"[All Fields] AND Controlled Clinical Trial[ptyp]. Only controlled studies with placebo group were included in this review. RESULTS: Of the 35 articles identified, 6 placebo-controlled studies were finally included. Intra-plaque injections of verapamil did not show improvement in penile curvature. Injections of interferon α 2b and clostridium histolyticum collagenase allowed a statistically significant improvement in terms of curvature reduction: 13.5 versus 4.5 degrees P<0.01) and 17 versus 9.3 degrees P<0.0001 respectively. However, interferon α 2b is not available in France for Peyronie's disease and clostridium histolyticum collagenase is no longer authorized since March 1, 2020. No controlled studies are available on corticosteroids, hyaluronic acid, platelet-rich plasma or stem cells injections. CONCLUSION: To correct the deformity in Peyronie's disease in the chronic phase, there is no effective solution currently available in France based on controlled studies. Surgery retains its place for the correction of a curvature of at least 30° associated with a sexual handicap in the stable phase, however at the cost of potential adverse effects. Stem cell or Platelet-Rich Plasma injection might be an injectable therapeutic alternative but need controlled studies.

Long-Term Safety and Curvature Deformity Characterization in Patients Previously Treated with Collagenase clostridium Histolyticum for Peyronie's Disease.

PURPOSE: We assessed the long-term safety and immunogenicity profile of collagenase clostridium histolyticum and characterized penile curvature deformity over time in patients previously treated for Peyronie's disease. MATERIALS AND METHODS: This phase 4 study included men who received collagenase clostridium histolyticum in either 12-month, double-blind, placebo controlled clinical trials (IMPRESS I/II), or one of two 9-month open label studies. Eligible patients received no additional collagenase clostridium histolyticum treatment and were followed once yearly for up to 5 years to assess Peyronie's disease clinical symptoms, patient reported outcomes and safety. RESULTS: Of 280 patients enrolled 204 (73%) completed the study. At baseline 247 patients had already experienced a mean±SD penile curvature decrease from 51.8±15.0 to 31.0±16.1 degrees (improvement of 20.9±16.2 degrees or 39.5%). At year 5 in 180 patients, despite no additional treatment, there was an additional 9.1% improvement in mean penile curvature compared with reference data (4.3±13.4 degrees, 95% CI 2.3-6.2, p <0.02). At baseline 183 patients experienced mean Peyronie's Disease Questionnaire bother domain score improvement from 6.5±3.5 to 3.4±3.3. At year 5 there was additional score improvement to 2.4±2.9 (p=0.0003). Adverse events were reported in 17.5% (49) of patients but no adverse events were considered treatment related. No long-term safety issues were identified up to 5 years after treatment. Long-term immunogenicity profiling showed a decreasing trend in the number of anti-AUX-I and anti-AUX-II seropositive cases at years 4 and 5 after collagenase clostridium histolyticum treatment. CONCLUSIONS: Most patients treated with collagenase clostridium histolyticum continued to have penile curvature and Peyronie's Disease Questionnaire domain score improvements through year 5 without additional collagenase clostridium histolyticum treatment, and no additional safety signals were identified.

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

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

Characteristics of Men With Peyronie's Disease and Collagenase Clostridium Histolyticum Treatment Failure: Predictors of Surgical Intervention and Outcomes.

BACKGROUND: A subset of patients with Peyronie's disease (PD) treated with collagenase clostridium histolyticum (CCH) experience persistent bother and some require surgery. AIM: We characterize patients experiencing persistent bother after CCH treatment and identify associations and predictors of surgical intervention/outcomes. METHODS: We retrospectively identified patients with PD from October 2014 to October 2019 and identified those presenting with persistent bother after CCH treatment by other urologists. Intracavernosal injection and penile Doppler ultrasonography were performed, and subsequent interventions/outcomes were recorded. Baseline characteristics were compared with Student t-test and chi-square test. Predictors of surgical intervention and complications were assessed using multivariable logistic regression. OUTCOMES: The primary outcome was surgery after CCH treatment. Secondary outcomes included worsened erectile function, sensory deficits, and penile length change. RESULTS: Of 573, 67 (11.7%) patients with PD had undergone prior CCH treatment with median 6 injections (range 2-24). Mean post-CCH PD Questionnaire bother score was 10.1 (SD: 3.1), and total International Index of Erectile Function-5 was 15.3 (SD: 8.7). Mean PD duration was 27.8 (SD: 35.7) months, with a mean composite curvature (MCC) of 69.0° (SD: 33.8) measured after injection. Of 67, 44 (65.7%) patients had MCC >60°. Of 67, 52 (77.6%) patients had indent, narrowing, or hourglass and 26 (38.8%) had hinge effect (buckling of the erect penis with axial pressure) on examination. Calcification was identified in 26 of 67 (38.8%) patients, with grade 3 calcifications comprising 6 of 23 (26.1%) patients. Of 67, 33 (49.3%) patients underwent surgery, with 20 (60.1%) undergoing partial plaque excision and grafting with/without tunica albuginea plication, 6 (18.2%) undergoing tunica albuginea plication alone, and 7 (21.2%) undergoing penile prosthesis with plaque incision and grafting. Surgical patients had greater mean curvature (82.6 vs 55.4, P = .001) and were more likely to have hinge (54.5% vs 20.6%, P = .005). On multivariable analysis, MCC ≥60° predicted patient's decision for surgery (odds ratio: 2.99, P < .01, 95% confidence interval: 1.62-4.35). There were no associations between surgical complications and number of injections or CCH-associated adverse events. CLINICAL IMPLICATIONS: Patients presenting with persistent bother after CCH treatment often have narrowing and calcifications (despite calcifications being a contraindication to CCH treatment), and those who have hinge or severe curvature are more likely to undergo surgery with low rates of complications. STRENGTHS/LIMITATIONS: This study's generalizability is limited by selection bias, but useful data are provided for patient counseling. CONCLUSION: Patients with persistent bother after CCH treatment had high rates of indentation/narrowing, plaque calcifications, and MCC >60° at completion of CCH treatment. Surgical intervention is more common with hinge and is safe and feasible in these patients, with low rates of complications. These findings suggest possible negative prognostic factors for CCH treatment, which merit further investigation. Bajic P, Wiggins AB, Ziegelmann MJ, et al. Characteristics of Men With Peyronie's Disease and Collagenase Clostridium Histolyticum Treatment Failure: Predictors of Surgical Intervention and Outcomes. J Sex Med 2020;17:1005-1011.

Management of Peyronie's disease with collagenase Clostridium histolyticum in the acute phase.

INTRODUCTION: Peyronie's disease (PD) can affect men of all ages and is associated with penile pain as well as curvature and erectile dysfunction. Treatment modalities for PD include conservative, less invasive and surgical treatments. Choice of treatment depends on the disease's phase. Injection of collagenase Clostridium histolyticum (CCH) is only the Food and Drug Administration approved treatment for the management of the chronic phase of the disease. Only a few limited studies have evaluated its potential benefits during the acute phase. AIM: To evaluate the current evidence on the use of injectable CCH during the acute or active phase of PD. METHODS: We performed a PubMed database search for articles published between 2015 and 2018 that investigated the use of CCH for the management of the acute phase of PD. Search keywords included "Peyronie's disease", "collagenase Clostridium histolyticum", and "acute phase". MAIN OUTCOME MEASURES: Changes in penile curvature after treatment with injectable CCH. RESULTS: Mean curvature decrease ranged between 15.8° and 22.6° corresponding to 27.4-37.4% decrease from baseline after 2.5-4 cycles, corresponding to 5-8 injections, of CCH treatment in patients during the acute phase of PD. CONCLUSIONS: Intralesional CCH injection therapy during the acute phase of PD can be both safe and effective and clinically significant improvements in penile curvature may be achieved. Larger multi-institutional studies are, however, still needed to confirm these results and validate this additional indication for CCH.

Managing complications of collagenase Clostridium histolyticum (CCH) injection.

PURPOSE: The introduction of collagenase Clostridium histolyticum (CCH) has revolutionized the treatment of Peyronie's disease. The efficacy of this therapy has been well demonstrated and the safety profile is favorable. However, post-injection complications are poorly characterized and management of these complications lacks standardization. METHODS: This review includes literature published in English and indexed in the PubMed®, Embase® or Google Scholar™ databases. What follows is a synopsis of relevant articles, including original research studies, in an attempt to better define CCH complications and their respective management strategies. RESULTS: Adverse effects of therapy are common but generally self-limiting. Penile pain and edema are expected events, and most patients experience hematologic sequelae (bleeding, hematoma, ecchymosis, etc.). The intervention rate for penile hematoma is low. Penile fracture is a morbid complication of therapy that is rare and may be challenging to diagnose given the frequency with which pronounced bruising and swelling are encountered. Imaging is a useful adjunct in situations of diagnostic uncertainty. Alternative injection protocols have been evaluated to limit the cost and morbidity of CCH therapy. Clinical efficacy of these protocols is promising, but prospective evaluation is lacking. CONCLUSIONS: No standardized protocols exist for management of post-injection complications of CCH therapy. The majority of these complications are managed conservatively, but suspected penile fracture should be carefully evaluated and imaging employed when needed. Future prospective studies of alternative injection protocols are warranted to decrease morbidity while maintaining efficacy.