European Association of Urology Guidelines on Penile Size Abnormalities and Dysmorphophobia: Summary of the 2023 Guidelines.

CONTEXT: Recommendations regarding the management of penile size abnormalities and dysmorphophobia are important in guiding evidence-based clinical practice. OBJECTIVE: To present a summary of the 2023 European Association of Urology sexual and reproductive health evidence-based recommendations for the management of penile size abnormalities and dysmorphophobia. EVIDENCE ACQUISITION: A broad and comprehensive scoping exercise covering all areas of the guidelines was performed. Databases searched included Medline, EMBASE, and the Cochrane Libraries. A level of evidence and a strength of recommendation were assigned for each recommendation according to the evidence identified. The evidence cutoff date for the 2023 guidelines is June 1, 2022. EVIDENCE SYNTHESIS: Well-structured studies reporting high level of evidence, with standardized PROMS were deficient on penile size abnormalities and dysmorphohobia. A shared definition for short penis/micropenis was also lacking. Categorisation of penile abnormalities according to congenital, acquired, and dysmorphophobic aetiology is deemed compulsory. A detailed medical and psychosexual history and precise measurements of penile size are essential in the diagnostic pathway. Patients with normal penile size who are seeking penile augmentation should be referred for psychological evaluation for potential dysmorphophobic disorders. Penile length and girth enhancements can be achieved via a multitude of treatments, but a personalised management plan is crucial for satisfactory results. Endocrinological therapies, when indicated, are effective in the prepubertal setting only. Vacuum therapy has a limited evidence base in treatment protocols, although acceptable outcomes have been reported for penile traction therapy. Surgical techniques to enhance penile length and girth have limited evidence and should only be proposed after extensive patient counselling. CONCLUSIONS: Management of penile abnormalities and dysmorphophobia is a complex issue with considerable ethical concerns. The adoption of a structured diagnostic and therapeutic pathway is crucial, as recommended in the guidelines. PATIENT SUMMARY: Requests for medical/surgical treatments to increase penis size have increased dramatically worldwide. Several conservative and surgical treatments are available. However, few patients receive clear information on the benefits and possible harms of these treatments. These guidelines aim to provide a structured path to guide both physicians and patients in the selection of appropriate treatment(s) to increase penis size.

Predictors of Recurrence After Metastasis-directed Therapy in Oligorecurrent Prostate Cancer Following Radical Prostatectomy.

BACKGROUND: Metastasis-directed therapy (MDT) is performed to delay systemic treatments for oligorecurrent disease after primary prostate cancer (PCa) treatment. OBJECTIVE: The aim of this study was to identify the predictors of therapeutic response of MDT for oligorecurrent PCa. DESIGN, SETTING, AND PARTICIPANTS: bicentric, retrospective study, including consecutive patients who underwent MDT for oligorecurrent PCa after radical prostatectomy (RP; 2006-2020) was conducted. MDT encompassed stereotactic body radiation therapy (SBRT), salvage lymph node dissection (sLND), whole-pelvis/retroperitoneal radiation therapy (WP[R]RT), or metastasectomy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: ndpoints were 5-yr radiographic progression-free survival (rPFS), metastasis-free survival (MFS), palliative androgen deprivation treatment (pADT)-free survival, and overall survival (OS) together with prognostic factors for MFS following primary MDT. Survival outcomes were studied by Kaplan-Meier survival and univariable Cox regression (UVA). RESULTS AND LIMITATIONS: A total of 211 MDT patients were included; 122 (58%) developed a secondary recurrence. Salvage lymph node dissection was performed in 119 (56%), SBRT in 48 (23%), and WP(R)RT in 31 (15%) of the cases. Two patients received sLND + SBRT and one received sLND + WPRT. Eleven (5%) patients received metastasectomies. The median follow-up since RP was 100 mo, while follow-up after MDT was 42 mo. The 5-yr rPFS, MFS, androgen deprivation treatment(-free survival, castration-resistant prostate cancer-free survival, CSS, and OS after MDT were 23%, 68%, 58%, 82%, 93%, and 87% respectively. There was a statistically significant difference between cN1 (n = 114) and cM+ (n = 97) for 5-yr MFS (83% vs 51%, p < 0.001), pADT-free survival (70% vs 49%, p = 0.014), and CSS (100% vs 86%, p = 0.019). UVA was performed to assess the risk factors (RFs) for MFS in cN1 and cM+. Alpha was set at 10%. RFs for MFS in cN1 were lower initial prostate-specific antigen (PSA) at the time of RP (hazard ratio [95% confidence interval] 0.15 [0.02-1.02], p = 0.053], pN stage at RP (2.91 [0.83-10.24], p = 0.096), nonpersisting PSA after RP (0.47 [0.19-1.12], p = 0.089), higher PSA at primary MDT (2.38 [1.07-5.24], p = 0.032), and number of positive nodes on imaging (1.65 [1.14-2.40], p < 0.01). RFs for MFS in cM+ were higher pathological Gleason score (1.86 [0.93-3.73], p = 0.078), number of lesions on imaging (0.77 [0.57-1.04], p = 0.083), and cM1b/cM1c (non-nodal metastatic recurrence; 2.62 [1.58-4.34], p < 0.001). CONCLUSIONS: Following MDT, 23% of patients were free of a second recurrence at 5-yr follow-up. Moreover, cM+ patients had significantly worse outcomes in terms of MFS, pADT-free survival, and CSS. The RFs for a metastatic recurrence can be used for counseling patients, to inform prognosis, and potentially select candidates for MDT. PATIENT SUMMARY: In this paper, we looked at the outcomes of using localized, patient-tailored treatment for imaging-detected recurrent prostate cancer in lymph nodes, bone, or viscera (maximum five recurrences on imaging). Our results showed that targeted treatment of the metastatic lesions could delay the premature use of hormone therapy.

Conservative and medical treatments of non-sickle cell disease-related ischemic priapism: a systematic review by the EAU Sexual and Reproductive Health Panel.

Conservative and medical treatments are considered the first step in ischemic priapism (IP) management, although there is no clear evidence regarding their efficacy. We conducted a systematic review on behalf of the EAU Guidelines panel on Sexual and Reproductive health to analyse the available evidence on the efficacy and safety of conservative and medical treatment for non-sickle cell disease-related IP. Databases searched for relevant literature investigating efficacy and safety of conservative measures and medical treatment for IP included Medline, EMBASE, Cochrane Libraries and clinicaltrial.gov published up to September 2021. Overall, 41 retrospective, 3 prospective single-arm studies and 3 randomized controlled trials met the inclusion criteria. Intracavernous injection with sympathomimetic (ICIs) agents were the most frequently utilized treatment with efficacy ranging from 0 to 100% of cases. The combination of ICIs with corporeal aspiration with or without irrigation with saline was successful in 70 to 100% of cases. Oral treatment with ß2 receptor agonist (e.g., terbutaline) showed mild to moderate efficacy. Conservative methods including ice pack, exercise, cold enema and ejaculation depicted lower effectiveness in resolving priapism (1-55%). Longer time interval from the onset to the resolution of IP was associated with higher rate of erectile dysfunction at follow-up (30-70%), especially after 24 h.

Single-cell Transcriptomics Uncover a Novel Role of Myeloid Cells and T-lymphocytes in the Fibrotic Microenvironment in Peyronie's Disease.

BACKGROUND: Peyronie's disease (PD) is an acquired fibrotic disease affecting the penile tunica albuginea that can lead to curvature and deformities, shortening, and erectile dysfunction. Although immunological mechanisms have been suggested for the pathophysiology of PD, these have not been investigated using single-cell transcriptomics. OBJECTIVE: To investigate the immunological signature of plaques from PD patients using immunohistochemistry (IHC) and single-cell RNA sequencing (scRNA-Seq). DESIGN, SETTING, AND PARTICIPANTS: Tunica albuginea biopsy was performed in patients undergoing penile surgery for either PD (n = 12) or plication or penile cancer (control, n = 6). The inclusion criteria for PD patients were stable chronic disease (≥12 mo in duration) and no previous penile surgery or intralesional injection therapy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: IHC was performed on surgical samples from ten patients with PD and five control subjects. An additional two PD and one control sample were used for scRNA-Seq (droplet-based; 10X Genomics). Cell clusters were visualised using heatmaps and t-distributed stochastic neighbour embedding plots (BioTuring v2.7.5). RESULTS AND LIMITATIONS: IHC revealed the presence of myeloid dendritic cells (DCs; CD68+, TLR4+, CD206+), cytotoxic T lymphocytes (CTLs; CD3+, CD8+), and B lymphocytes (CD20+) in PD plaques, which were absent in controls. scRNA-Seq yielded results for 3312 PD and 5658 control cells. Cell clusters contained fibroblasts (COL1A2+), myofibroblasts (COL1A2+, ACTA2+), smooth muscle cells (ACTA2+, DES+), endothelial cells (VWF+), myeloid cells (CD14+), T lymphocytes (CD3D+), and neutrophils (ALPL+). Myeloid cell subclustering showed infiltration of monocyte-derived cells; control tissue contained classical DCs and resident macrophages. Lymphocyte subclustering revealed mucosal-associated invariant T (MAIT) cells and CTLs in PD. Differential gene expression suggests an increase in inflammatory and immune responses in chronic PD. The study is limited by the small scRNA-seq sample size (n = 3) for IHC, mitigated by a larger cohort of historic paraffin-embedded samples (n = 15), which showed largely parallel findings. Owing to tissue stiffness and extracellular matrix adhesion, our single-cell yield was lower for PD than for the control sample. CONCLUSIONS: Our data suggest that even in the chronic PD stage (painless and stable curvature) there is a sustained inflammatory reaction. While vascularisation and collagen production are elevated, the inflammation is driven by specialised monocyte-derived CTL and MAIT cells. These findings could uncover new avenues for medical treatment of PD. PATIENT SUMMARY: We looked at the role of the immune system in patients suffering from Peyronie's disease, a condition causing shortening and curvature of the penis. We found that even in a stable, chronic stage of the disease, there is activation of the immune system. Our results suggest that there is potential for novel treatments for this condition.

European Association of Urology Guidelines on Male Sexual and Reproductive Health: 2021 Update on Male Infertility.

CONTEXT: The European Association of Urology (EAU) has updated its guidelines on sexual and reproductive health for 2021. OBJECTIVE: To present a summary of the 2021 version of the EAU guidelines on sexual and reproductive health, including advances and areas of controversy in male infertility. EVIDENCE ACQUISITION: The panel performed a comprehensive literature review of novel data up to January 2021. The guidelines were updated and a strength rating for each recommendation was included that was based either on a systematic review of the literature or consensus opinion from the expert panel, where applicable. EVIDENCE SYNTHESIS: The male partner in infertile couples should undergo a comprehensive urological assessment to identify and treat any modifiable risk factors causing fertility impairment. Infertile men are at a higher risk of harbouring and developing other diseases including malignancy and cardiovascular disease and should be screened for potential modifiable risk factors, such as hypogonadism. Sperm DNA fragmentation testing has emerged as a novel biomarker that can identify infertile men and provide information on the outcomes from assisted reproductive techniques. The role of hormone stimulation therapy in hypergonadotropic hypogonadal or eugonadal patients is controversial and is not recommended outside of clinical trials. Furthermore, there is insufficient evidence to support the widespread use of other empirical treatments and surgical interventions in clinical practice (such as antioxidants and surgical sperm retrieval in men without azoospermia). There is low-quality evidence to support the routine use of testicular fine-needle mapping as an alternative diagnostic and predictive tool before testicular sperm extraction (TESE) in men with nonobstructive azoospermia (NOA), and either conventional or microdissection TESE remains the surgical modality of choice for men with NOA. CONCLUSIONS: All infertile men should undergo a comprehensive urological assessment to identify and treat any modifiable risk factors. Increasing data indicate that infertile men are at higher risk of cardiovascular mortality and of developing cancers and should be screened and counselled accordingly. There is low-quality evidence supporting the use of empirical treatments and interventions currently used in clinical practice; the efficacy of these therapies needs to be validated in large-scale randomised controlled trials. PATIENT SUMMARY: Approximately 50% of infertility will be due to problems with the male partner. Therefore, all infertile men should be assessed by a specialist with the expertise to not only help optimise their fertility but also because they are at higher risk of developing cardiovascular disease and cancer long term and therefore require appropriate counselling and management. There are many treatments and interventions for male infertility that have not been validated in high-quality studies and caution should be applied to their use in routine clinical practice.

European Association of Urology Guidelines on Sexual and Reproductive Health-2021 Update: Male Sexual Dysfunction.

CONTEXT: The present summary of the European Association of Urology (EAU) guidelines is based on the latest guidelines on male sexual health published in March 2021, with a last comprehensive update in January 2021. OBJECTIVE: To present a summary of the 2021 version of the EAU guidelines on sexual and reproductive health. EVIDENCE ACQUISITION: A literature review was performed up to January 2021. The guidelines were updated, and a strength rating for each recommendation was included based on either a systematic review of the evidence or a consensus opinion from the expert panel. EVIDENCE SYNTHESIS: Late-onset hypogonadism is a clinical condition in the ageing male combining low levels of circulating testosterone and specific symptoms associated with impaired hormone production and/or action. A comprehensive diagnostic and therapeutic work-up, along with screening recommendations and contraindications, is provided. Erectile dysfunction (ED) is the persistent inability to attain and maintain an erection sufficient to permit satisfactory sexual performance. Along with a detailed basic and advanced diagnostic approach, a novel decision-making algorithm for treating ED in order to better tailor therapy to individual patients is provided. The EAU guidelines have adopted the definition of premature ejaculation (PE), which has been developed by the International Society for Sexual Medicine. After the subtype of PE has been defined, patient's expectations should be discussed thoroughly and pharmacotherapy must be considered as the first-line treatment for patients with lifelong PE, whereas treating the underlying cause must be the initial goal for patients with acquired PE. Haemospermia is defined as the appearance of blood in the ejaculate. Several reasons of haemospermia have been acknowledged; the primary goal over the management work-up is to exclude malignant conditions and treat any other underlying cause. CONCLUSIONS: The 2021 guidelines on sexual and reproductive health summarise the most recent findings, and advise in terms of diagnosis and treatment of male hypogonadism and sexual dysfunction for their use in clinical practice. These guidelines reflect the multidisciplinary nature of their management. PATIENT SUMMARY: Updated European Association of Urology guidelines on sexual and reproductive health are presented, addressing the diagnosis and treatment of the most prevalent conditions in men. Patients must be fully informed of all relevant diagnostic and therapeutic options and, together with their treating physicians, decide on optimal personalised management strategies.

Too good for CARMENA: criteria associated with long systemic therapy free intervals post cytoreductive nephrectomy for metastatic clear cell renal cell carcinoma.

PURPOSE: The prospective CARMENA trial surprisingly suggested that patients with upfront metastatic clear-cell renal cell carcinoma (m-ccRCC) would not benefit from cytoreductive nephrectomy (CN). We aimed to identify the m-ccRCC patient subpopulation who would benefit from the continued use of CN. METHODS: We performed a retrospective cohort study on upfront m-ccRCC patients and identified three subgroups: patients treated with vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) only without CN (TKI ONLY), patients undergoing CN immediately followed within 6 months by VEGFR-TKIs (CN > TKI) and patients undergoing CN followed by a considerable therapy-free interval of at least 6 months (CN > AS). Kaplan-Meier survival analysis and Cox proportional hazards regression models were used to compare outcomes and investigate predictive factors. RESULTS: We included 119 patients. Overall survival was 17, 13 and 56 months for the CN > TKI, TKI only and CN > AS subgroups, respectively (p < 0.0001). Oligometastatic disease (HR = 0.33, 95% CI = 0.21-0.54, p < 0.0001), lung as only metastatic site (HR = 0.48, 95% CI = 0.31-0.76, p = 0.001) and having ≤ 2 evaluable International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria (HR = 0.56, 95% CI = 0.32-0.98, p = 0.04) were predictive for systemic therapy free survival after diagnosis. CONCLUSIONS: The CARMENA results only apply for m-ccRCC patients in immediate need for systemic therapy, but not for patients in whom a period of AS can be expected after CN. Patients in whom systemic therapy most likely can be deferred and who are likely to benefit from CN have oligometastatic disease, only present in the lung and few (≤2) evaluable IMDC criteria.

The Cancer of the Bladder Risk Assessment (COBRA) score for estimating cancer-specific survival after radical cystectomy: external validation in a large bi-institutional cohort.

OBJECTIVE: To perform an external validation of the Cancer of the Bladder Risk Assessment (COBRA) score for estimating cancer-specific survival (CSS) after radical cystectomy (RC) in a large bi-institutional cohort of patients. PATIENTS AND METHODS: Patients treated with RC and lymph node dissection (LND) between May 1996 and July 2017 were retrieved from the RC databases of Leuven and Turin. Collected variables were age at RC, tumour stage, lymph node (LN) density, neoadjuvant chemotherapy, the extent of LND, and nodal stage. The primary outcome was CSS visualised using Kaplan-Meier plots. Cox proportional hazard models were used to assess the impact of variables on CSS. We performed a pairwise comparison between the COBRA score levels using a log-rank test corrected by Bonferroni, and developed a simplified COBRA score with three risk categories. To compare models, we assessed concordance indices (C-indices), receiver operating characteristic curves with area under the curve (AUC), calibration plots, and decision curve analysis (DCA). Finally, we compared both COBRA and simplified COBRA models with the established American Joint Committee on Cancer (AJCC) model. RESULTS: A total of 812 patients were included. All COBRA score variables had a significant impact on CSS in a Cox proportional hazard model. However, pairwise comparison of the COBRA subscores could not differentiate significantly between all COBRA score levels. Based on these findings, we developed a simplified COBRA score by introducing three categories within the following COBRA score ranges: low- (0-1) vs intermediate- (2-4) vs high-risk (5-7). A pairwise comparison could discriminate significantly between all COBRA risk categories. When finally comparing COBRA and simplified COBRA models with the AJCC model, AJCC performed better than both. C-indices, AUCs, calibration plots and DCA for AJCC were all better compared with the original and simplified COBRA models. CONCLUSION: We performed an external validation of the COBRA score in a large bi-institutional cohort. We observed that several risk groups had overlapping CSS, demonstrating suboptimal performance of the COBRA score. Therefore, we constructed a simplified model with three COBRA score risk categories. This model resulted in demarcated risk groups with non-overlapping CSS and good predictive accuracy. However, both COBRA score models were outperformed by the AJCC staging system. Therefore, we conclude that the AJCC staging system should remain the current standard for stratifying patients after RC for CSS.

The good, bad, and the ugly of regenerative therapies for erectile dysfunction.

Erectile dysfunction (ED) is a common condition which reduces quality of life of both patients and their partners, and is a significant health care expense every year. Although phosphodiesterase type-5 inhibitors are the current first-line treatment for men with ED, they are limited by their on-demand dosing, intolerance, and variable efficacy in complex patient populations such as men with multiple medical comorbidities or ED after pelvic surgery. Regenerative medicine has been introduced and investigated in andrology as an encouraging strategy to restore diseased erectile tissue structure and function. Novel regenerative therapies for ED are controversial but are perceived to offer a durable and safe tissue restorative approach to act as a long-term solution to this cumbersome disease process. Here, we review platelet-rich plasma, amniotic fluid membranes, low-intensity extracorporeal shockwave therapy, and stem cell therapy as regenerative strategies to treat ED. Most of these approaches have preclinical and occasionally clinical data to support their ongoing investigation; however, none of these treatments are currently supported for use in ED patients outside of clinical trials.

Evolving therapies for Peyronie's disease: how can we work towards new drugs?

Peyronie's disease (PD) is an idiopathic chronic fibrotic disease that causes a penile curvature (PC), subsequent erectile dysfunction (ED) and impaired sexual intercourse in patients. As of yet, there are no reliable non-surgical treatment options available. Intralesional injection with collagenase Clostridum Histolyticum has been FDA approved since 2013, but post-approval studies have not been unanimously positive. Moreover, it renders a curvature improvement of only 30% on average, usually still requiring surgical intervention to remedy PC. Therefore, there is a need for drugs which could prevent surgery altogether. Development of new drugs can either be through a target-based or phenotypic assay-based approach. The current in vivo model for PD is dependent on treatment of primary PD-derived fibroblasts with transforming growth factor-ß1. Moreover, despite the existence of a genetic in vivo PD model, it does not allow for drug screening or testing. While some advances have been made in the past few years, new in vivo and in vivo systems and well-designed studies are urgently needed for the non-surgical treatment of PD.

Prognostic score predicts overall survival following complete urinary tract extirpation.

Purpose: To evaluate the oncological outcome and complications of patients treated with complete urinary tract extirpation (CUTE) in our department, and to identify prognostic factors for survival.Methods: Clinico-pathological data of patients treated with one-step or stepwise CUTE between 1999 and 2017 were collected retrospectively. Complications were classified according to the modified Clavien-Dindo classification (CDC) in the early (≤30 days) and late (>30 days) follow-up. Log-rank test was used to assess independent predictors of overall survival (OS), cancer-specific survival (CSS) and recurrence-free survival (RFS).Results: Twenty-five patients (20 male) underwent CUTE (16 one-step) for BC + unilateral/bilateral UTUC. Minor (CDC 1-2) and major (CDC3-5) complications were observed in 72% and 40% of patients, respectively, in the early postoperative period (≤30 days). Five (20%) patients died in the perioperative period (CDC 5) with a median OS of 52 days (range: 25-77). Median time to last follow-up or death was 30 months (range: 0-161). Median OS was 50 months (95% Confidence Interval [CI]: 22-118 months), while median CCS and RFS were not reached. The 5-year OS, CSS and RFS were 42.7%, 69.6% and 66.7%, respectively. A score for determining which patients would benefit from CUTE was arbitrarily developed, and showed that the patients with a score of 0-2 points (good prognosis) had a better OS than the patients with a poor prognosis (3-4 points) in the log-rank test.Conclusions: Because of lower OS rates, patients with ESRD or with a CUTE score of 3-4 points are probably not ideal candidates for CUTE.

Comparison of postoperative complications of ileal conduits versus orthotopic neobladders.

BACKGROUND: Radical cystectomy (RC) and urinary diversion (UD), with either an ileal conduit (IC) or an orthotopic neobladder (NB), is a complex surgery, in which various complications can occur. In this study, we compared postoperative complication rates after a RC and UD performed for the treatment of muscle-invasive bladder cancer or recurring high-risk non-muscle-invasive bladder cancer in our center. METHODS: We retrospectively included 604 patients that underwent UDs from December 1996 to August 2015. Complications were classified by type and severity according to the Clavien-Dindo classification (CDC). Univariate and multivariate analyses were performed to identify predictive factors of short-term (≤30 d), intermediate-term (31-90 d), and long-term (>90 d) complications. RESULTS: Four hundred and forty-five (74%) and 159 (26%) patients received ICs and NBs, respectively. These groups had significantly different long-term complication rates (IC: 39.7% vs. NB: 49%, P=0.046), but similar short-term (P=0.319) and intermediate-term complication rates (P=0.397). Short-term complications (CDC I-V) were predicted by male gender, age-adjusted Charlson comorbidity index (aCCI) ≥3, and American Society of Anesthesiologists (ASA) score ≥3. Compared to minor short-term complications (CDC I-II), major short-term complications (CDC III-V) were predicted by male gender and a previous abdominal/pelvic surgery, and long-term major complications were predicted by the type of UD (NB). CONCLUSIONS: The increasing risk of short-term complications with increasing aCCI and ASA score can be used when counseling the patients who are planned to undergo a RC with UD. Patients that receive NBs should be informed of the increased risk of reoperations compared to an IC.

Pathophysiology and Future Therapeutic Perspectives for Resolving Fibrosis in Peyronie's Disease.

INTRODUCTION: Peyronie's disease (PD) is a debilitating affliction for the male population, causing severe curvatures to the erect penis and erectile dysfunction in about 50% of men. This deviation of the penis significantly impairs sexual intercourse and causes depression and strains in the relationship. As of today, medical treatment options are few and far between, with surgery remaining as the sole reliable treatment. AIM: To give a general overview regarding fibrosis and the specific role of extracellular matrix, macrophages, and myofibroblasts in PD. Additionally, we will provide an overview of past and present research and how this has shaped our vision concerning the pathophysiology of PD. METHODS: We performed a non-systematic literature review using the search terms "fibrosis," "pathophysiology," "myofibroblast," "extracellular matrix," "Peyronie's disease," and "drug discovery." MAIN OUTCOME MEASURE: We assessed current knowledge regarding fibrosis in PD and the possibility to use this knowledge for new treatment options. RESULTS: Interpreting findings from the most recent next-generation sequencing, in vitro and in vivo PD research, we provide novel insights for the pathophysiology of PD. Using this knowledge, we will attempt to provide future directions for PD research and drug discovery, which is urgently needed, because its treatment has essentially been stagnating for about 30 years. CONCLUSION: Historically, PD has not been studied as widely as kidney, lung, or hepatic fibrosis, and our knowledge of its pathophysiology still remains relatively obscure. Nonetheless, recent breakthroughs using stem cells, next-generation sequencing, and phenotypical screening assays bring us several steps closer to filling the gaps in our knowledge. In the near future, clinical trials will prove essential to translate this plethora of preclinical data into usable tools that can improve the lives of many of our patients. Milenkovic U, Ilg MM, Cellek S, et al. Pathophysiology and Future Therapeutic Perspectives for Resolving Fibrosis in Peyronie's Disease. Sex Med Rev 2019;7:679-689.

Organ-sparing surgical and nonsurgical modalities in primary penile cancer treatment.

PURPOSE OF REVIEW: To provide an overview of the current state of literature on organ-sparing approaches in penile cancer. Surgical as well as nonsurgical approaches can be adapted in the right setting, in an effort to spare patients from the burden of total or subtotal penectomy wherever possible. In this review, we focus on surgical approaches. RECENT FINDINGS: Narrower surgical margins do not seem to affect overall survival rates, neither do local recurrences. This has allowed a paradigm shift towards more sparing approaches locally. Contrary to what was previously thought, margins of a few millimetres suffice for adequate local cancer control. This allows laser therapy, wide local excisions, partial glansectomy and other surgical techniques to be performed in an organ-sparing fashion. Ablative techniques such as brachytherapy and external beam radiotherapy also provide adequate local cancer control. These sparing approaches have an important effect on psychological and functional outcomes; however, they are insufficiently adapted even in larger referral centres. SUMMARY: Organ-sparing techniques should be used in penile cancer surgery whenever possible. Patient selection for the most appropriate technique is key to provide good cosmetic and functional results while remaining oncologically safe.

Antifibrotic Synergy Between Phosphodiesterase Type 5 Inhibitors and Selective Oestrogen Receptor Modulators in Peyronie's Disease Models.

BACKGROUND: Peyronie's disease (PD) is a fibrotic disorder of the penile tunica albuginea, characterised by the formation of a localised fibrous plaque that can lead to deformity and erectile dysfunction. Nonsurgical therapeutic options for PD are limited in efficacy and safety. Myofibroblasts are key cells in the pathogenesis of PD, and inhibition of myofibroblast transformation has been suggested as a therapeutic option. OBJECTIVE: To identify potential drugs using a novel phenotypic assay and then to test them using in vitro and in vivo models of PD. DESIGN, SETTING, AND PARTICIPANTS: We have developed and validated a phenotypic screening assay that measures myofibroblast transformation, by which we tested 21 compounds that were suggested to be efficacious in treating PD. The successful hits from this assay were further tested using in vitro and in vivo models of PD. RESULTS AND LIMITATIONS: The new assay was able to detect transforming growth factor-ß1-induced myofibroblast transformation. Using this assay, phosphodiesterase type 5 inhibitors (PDE5i) and selective oestrogen receptor modulators (SERMs) were identified to significantly inhibit myofibroblast transformation. A PDE5i (vardenafil) and an SERM (tamoxifen) inhibited myofibroblast transformation, collagen gel contraction, and extracellular matrix production in a synergistic fashion. In a rat model of PD, the antifibrotic effect of the combination of vardenafil and tamoxifen was greater than that of each drug alone. This study is limited by not providing a molecular mechanism for the proposed synergy. CONCLUSIONS: This is the first demonstration of a synergistic activity between a PDE5i and an SERM discovered through a phenotypic screening approach. Future clinical trials using a combination of these drugs should be considered during the active phase of PD, given the early evidence of benefit in both in vitro and in vivo models. PATIENT SUMMARY: This report suggests that the combination of a phosphodiesterase type 5 inhibitor and a selective oestrogen receptor modulator may be efficacious in treating Peyronie's disease in its active phase.

Intratunical injection of stromal vascular fraction prevents fibrosis in a rat model of Peyronie's disease.

OBJECTIVE: To investigate whether local injection of autologous adipose stromal vascular fraction (SVF) can prevent the development of fibrosis and elastosis in the tunica albuginea (TA) using a rat model of the acute phase of Peyronie's disease (PD). METHODS: A total of 24 male 12-week-old Sprague-Dawley rats were divided into three equal groups: sham; PD without treatment (transforming growth factor-ß [TGF -ß]); and PD treated with SVF 1 day after disease induction. Sham rats received two injections of vehicle into the TA 1 day apart. TGF -ß rats received TGF- ß1 injection and injection of vehicle 1 day later. SVF rats received TGF-ß1 injection, followed by SVF 1 day later. One month after treatment, all rats underwent measurement of intracavernosal pressure and mean arterial pressure during electrostimulation of the cavernous nerve. The rats were then killed and penises were harvested for histology and Western blot analysis. RESULTS: Erectile function was moderately reduced in the TGF-ß group and was significantly improved after SVF treatment (P < 0.05). PD rats developed areas of fibrosis with a significant upregulation of collagen III, collagen I and elastin protein expression. These fibrotic changes were prevented when treated with SVF. CONCLUSIONS: Local injection of SVF may represent treatment for the acute phase of PD.

Impact of neoadjuvant chemotherapy on short-term complications and survival following radical cystectomy.

OBJECTIVES: To compare perioperative and short-term postoperative complication rates between patients receiving radical cystectomy (RC) after neoadjuvant chemotherapy (NAC) and patients undergoing RC alone. Secondary objectives were to compare overall survival (OS) and cancer-specific survival (CSS). MATERIALS AND METHODS: Clinico-pathological data of all patients who received RC between 1996 and 2015 were retrospectively collected. Only patients with RC for muscle-invasive bladder cancer were included in the final analysis. Short-term (30-day) postoperative complications were assessed by registering the Clavien-Dindo classification (CDC) and dividing into sub-groups: low-grade (LGC) CDC 1-2 and high-grade (HGC) CDC 3-5. To compare populations with similar age, comorbidities and preoperative creatinine, we used a propensity score-adjusted statistical model. Pre- and perioperative predictors of short-term complications were identified using uni- and multivariable models. Survival was assessed using Kaplan-Meier analysis. RESULTS: A total of 491 patients undergoing RC were included, of whom 102 (20.8%) received NAC. After propensity score covariate adjustment, there was no significant difference in postoperative complications between patients undergoing NAC plus RC and RC alone with an overall complication rate of 69% and 66%, respectively. No significant differences in the 30-day HGC rates (11.76% and 11.83%, respectively) were observed. NAC plus RC patients had worse prognostic factors at baseline; nevertheless, after correction for group differences OS and CSS did not differ from RC only group (5-year OS 61.3% vs. 50.2%, and 5-year CSS 61.8% vs. 57.9% respectively, p > 0.05 for all). CONCLUSION: In appropriately selected patients, exposure to NAC is not associated with increased short-term complications.

Simvastatin and the Rho-kinase inhibitor Y-27632 prevent myofibroblast transformation in Peyronie's disease-derived fibroblasts via inhibition of YAP/TAZ nuclear translocation.

OBJECTIVES: To uncover the anti-myofibroblast (MFB) properties of Rho-kinase inhibitor (compound Y-27632) and simvastatin in an in vitro model of Peyronie's disease (PD), a sexually debilitating disease caused by an irreversible fibrotic plaque in the penile tunica albuginea (TA). MATERIALS AND METHODS: Primary human fibroblasts (FBs) were isolated from surgically obtained TA tissue from patients with PD. To induce MFB status, cells were stimulated with 3 ng/mL transforming growth factor-ß1 (TGF-ß1). Increasing doses of Y-27632 and simvastatin were added. Real-time quantitative PCR was used to assess mRNA expression of α-smooth muscle actin (α-SMA), collagen III, elastin and connective tissue growth factor (CTGF) after 72 h. Western blot analysis was used to quantify α-SMA protein contents, and immunofluorescence (IF) was used to visualize MFB differentiation by staining for α-SMA after 72 h. A resazurin-based assay was used to assess cell viability to ensure the anti-MFB effect of the drugs. A mechanistic study was performed using IF staining for YAP/TAZ nuclear translocation. RESULTS: After 72 h of stimulation with TGF-ß1, a six- to 10-fold upregulation of α-SMA could be observed. When treated with Y-27632 or simvastatin, the α-SMA, collagen III, elastin and CTGF mRNA expression was impeded. Additionally, TGF-ß1 stimulation showed a twofold increase in α-SMA protein expression, which was reversed to non-stimulated levels after treatment with Y-27632 and simvastatin. Using IF, stimulated cells were identified as MFB (α-SMA+, Vim+) as opposed to the non-stimulated, Y-27632- and simvastatin-treated cells (α-SMA-, Vim+). The resazurin-based assay confirmed that the cell viability was not compromised by the administered drugs. On stimulation with TGF-ß1, nuclear translocation of YAP/TAZ could be observed, which was prevented by adding the aforementioned compounds. CONCLUSION: Transformation of FBs into the contractile and extracellular matrix-producing MFBs occurs after TGF-ß1 stimulation. In our experiments, Rho-kinase inhibition and simvastatin treatment were shown to prevent this in TGF-ß1-stimulated cells on an RNA and protein level through the inhibition of YAP/TAZ nuclear translocation. Y-27632 and simvastatin could become a novel treatment option in the early treatment of PD.

Intratunical Injection of Human Adipose Tissue-Derived Stem Cells Restores Collagen III/I Ratio in a Rat Model of Chronic Peyronie's Disease.

INTRODUCTION: Previous studies have shown that the injection of adipose tissue-derived stem cells (ADSCs) into the tunica albuginea (TA) during the active phase of Peyronie's disease (PD) prevents the development of fibrosis. AIM: To investigate, using an animal model, whether local injection of human ADSCs (hADSCs) can alter the degree of fibrosis in the chronic phase of PD. METHODS: 27 male, 12-week-old rats were divided into 3 equal groups: sham, PD without treatment, and PD treated with hADSCs 1 month after disease induction. Sham rats underwent 2 injections of vehicle into the TA 1 month apart. PD rats underwent transforming growth factor ß1 (TGFß1) injection and injection of vehicle 1 month later. PD-hADSC rats underwent TGFß1 injection followed by 1 million hADSCs 1 month later. 1 week after treatment, n = 3 animals/group were euthanized, and the penises were harvested for quantitative polymerase chain reaction. 1 month after treatment, the other animals, n = 6 per group, underwent measurement of intracavernous pressure (ICP) and mean arterial pressure (MAP) during electrostimulation of the cavernous nerve. After euthanasia, penises were again harvested for histology and Western blot. MAIN OUTCOME MEASURE: The primary outcome measures included (a) gene expression at one week post-injection; (b) measurement of ICP/MAP upon cavernous nerve stimulation as a measure of erectile function; (c) elastin, collagen I and III protein expression; and (d) Histomorphometric analysis of the penis. Means where compared by analysis of variance (ANOVA) followed by a Student-Newman-Keuls test for post hoc comparisons or Mann-Whitney test when applicable. RESULTS: No significant difference was noted in ICP or ICP/MAP in response to cavernous nerve electrostimulation between the 3 groups at 2.5, 5, and 7.5 V (P > .05 for all voltages). PD animals developed tunical and subtunical areas of fibrosis with a significant upregulation of collagen III protein. The collagen III/I ratio was higher in the PD (4.6 ± 0.92) group compared with sham (0.66 ± 0.18) and PD-hADSC (0.86 ± 0.06) groups (P < .05) These fibrotic changes were prevented when treated with hADSCs. Compared with PD rats, PD-hADSC rats demonstrated a decreased expression of several fibrosis-related genes. CONCLUSION: Injection of hADSCs reduces collagen III expression in a rat model of chronic PD. Castiglione F, Hedlund P, Weyne E, et al. Intratunical Injection of Human Adipose Tissue-Derived Stem Cells Restores Collagen III/I Ratio in a Rat Model of Chronic Peyronie's Disease. Sex Med 2019;7:94-103.

The mechanisms and potential of stem cell therapy for penile fibrosis.

Fibrosis is often caused by chronic tissue injury leading to a persisting inflammatory response with excessive accumulation of extracellular connective tissue proteins. Peyronie's disease, urethral stricture and penile (corpora cavernosa) fibrosis are localized fibrotic disorders of the penile connective tissues that can substantially impair a patient's quality of life. Research over the past few decades has revealed the ability of stem cells to secrete a wide range of paracrine factors, a characteristic that could be exploited therapeutically to prevent and treat several inflammatory and fibrotic diseases. In preclinical studies, mesenchymal stem cells (MSCs) have proven to be the most effective and readily available type of stem cells for therapeutic use. An important advantage of MSCs is their ability to circumvent the immune system and function as immunomodulatory 'drug stores' to influence multiple cell types simultaneously. Many studies using stem cells have been applied exclusively to corpora cavernosa fibrosis owing to its well-established disease models. A plethora of preclinical data suggest the benefit of stem cells for use in penile fibrosis. However, their exact mechanism of action and optimal timing and mode of administration must be determined before clinical translation.