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Objectives: To investigate which phosphodiesterase (PDE) isoforms are expressed in fibroblasts isolated from the tunica albuginea (TA) of patients with Peyronie's disease (PD), and to measure the potency of PDE inhibitors in preventing transformation of these fibroblasts to profibrotic myofibroblasts., Materials and Methods: Fibroblasts isolated from the TA of men undergoing surgery for correction of PD curvature were transformed to myofibroblasts using transforming growth factor beta-1. The expression of 21 PDE isoforms was investigated using quantitative reverse transcriptase-polymerase chain reaction and protein analysis, as were the effects of various PDE inhibitors on prevention of myofibroblast transformation. Intracellular cAMP and cGMP in the presence of PDE inhibitors were quantified using cGMP/cAMP enzyme-linked immunosorbant assay assays., Results: We found that PDE1A, 1C, 4, 5A, 7B and 8B were expressed at mRNA and protein levels. Selective inhibitors of these enzymes prevented myofibroblast transformation in a concentration-dependent manner, with PDE1 inhibitor ITI-214 and PDE4 inhibitors roflumilast and roflumilast N-oxide showing greatest potency. ITI-214 and roflumilast N-oxide increased intracellular cAMP, but not cGMP, in a concentration-dependent manner., Conclusions: This is the first demonstration of the expression of PDE1, 7 and 8 isoforms, and the function of PDE1 and PDE4 in human TA fibroblasts. The ability of inhibitors of these enzymes to prevent myofibroblast transformation suggests that such inhibitors can be developed to treat acute PD., (© 2024 The Author(s). BJU International published by John Wiley & Sons Ltd on behalf of BJU International.)

Injection of exogenous material into the penis and scrotum has been performed for augmentation purposes. Complications include cosmetic dissatisfaction, penile necrosis and lymphoedema. We report the complications and outcomes from a single centre with an updated systematic review of the literature. A retrospective review of all cases presenting with foreign substance injection into the genitalia, over a 10-year period was performed. Thirty-five patients with a mean (standard deviation (SD); range) age of 36.9 (±9.1; 22-61) years at presentation were included. The mean (SD; range) time between injection and presentation was 7.8 (±5.8; 1 day-20 years) years. The most common injected substance was silicone (n = 16, 45.7%) and liquid paraffin (n = 8, 22.9%). The penile shaft (94.3%) was the most injected site. The most common presentations were cosmetic dissatisfaction (57.1%) and pain and/or swelling (45.7%). Surgery was required in 32 (91.4%) cases. Primary procedures included local excision and primary closure (n = 19, 59.4%), circumcision (n = 5, 15.6%), excision with a split skin graft or a scrotal flap reconstruction (n = 5, 15.6%). Three (8.6%) patients presented with necrosis and required acute debridement. Overall, 18 patients had more than 1 procedure, and 8 patients required 3 or more procedures. A systematic search of the literature identified 887 articles of which 68 studies were included for analysis. The most common substance injected was paraffin (47.7%), followed by silicone (15.8%). The majority of patients (77.9%) presented with pain, swelling or penile deformity. 78.8% of the patients underwent surgical treatment, which included excision and primary closure with or without the use of skin grafts (85.1% of all procedures), the use of flaps (12.3%) and penile amputation (n = 2). Complications of foreign body injection into the male genitalia can be serious resulting in necrosis and autoamputation. Surgical intervention is often required to excise abnormal tissue to manage pain and improve cosmesis., (© 2023. The Author(s).)

Extracellular vesicles have emerged as important mediators of cell-to-cell communication in the pathophysiology of fibrotic diseases. One such disease is Peyronie's disease (PD), a fibrotic disorder of the penis caused by uncontrolled transformation of resident fibroblasts to alpha-smooth muscle actin positive myofibroblasts. These cells produce large amounts of extracellular matrix, leading to formation of a plaque in the penile tunica albuginea (TA), causing pain, penile curvature, and erectile dysfunction. We have used primary fibroblasts derived from the TA of PD patients to explore the role of transforming growth factor beta 1 (TGF-β1), a key signalling factor in this process. TGF-β1 treatment elicited a range of responses from the myofibroblasts: (i) they secreted extracellular vesicles (EVs) that were more numerous and differed in size and shape from those secreted by fibroblasts, (ii) these EVs prevented TGF-β1-induced transformation of fibroblasts in a manner that was dependent on vesicle uptake and (iii) they prevented phosphorylation of Erk1/2, a critical component in modulating fibrogenic phenotypic responses, but did not affect TGF-β1-induced Smad-signalling. We posit that this effect could be linked to enrichment of TSG-6 in myofibroblast-derived EVs. The ability of myofibroblast-derived vesicles to prevent further myofibroblast transformation may establish them as part of an anti-fibrotic negative feedback loop, with potential to be exploited for future therapeutic approaches., (© 2024. The Author(s).)

Background: Transformation of resident fibroblasts to profibrotic myofibroblasts in the tunica albuginea is a critical step in the pathophysiology of Peyronie's disease (PD). We have previously shown that myofibroblasts do not revert to the fibroblast phenotype and we suggested that there is a point of no return at 36 hours after induction of the transformation. However, the molecular mechanisms that drive this proposed irreversibility are not known., Aim: Identify molecular pathways that drive the irreversibility of myofibroblast transformation by analyzing the expression of the genes involved in the process in a temporal fashion., Methods: Human primary fibroblasts obtained from tunica albuginea of patients with Peyronie's disease were transformed to myofibroblasts using transforming growth factor beta 1 (TGF-β1). The mRNA of the cells was collected at 0, 24, 36, 48, and 72 hours after stimulation with TGF-β1 and then analyzed using a Nanostring nCounter Fibrosis panel. The gene expression results were analyzed using Reactome pathway analysis database and ANNi, a deep learning-based inference algorithm based on a swarm approach., Outcomes: The study outcome was the time course of changes in gene expression during transformation of PD-derived fibroblasts to myofibroblasts., Results: The temporal analysis of the gene expression revealed that the majority of the changes at the gene expression level happened within the first 24 hours and remained so throughout the 72-hour period. At 36 hours, significant changes were observed in genes involved in MAPK-Hedgehog signaling pathways., Clinical Translation: This study highlights the importance of early intervention in clinical management of PD and the future potential of new drugs targeting the point of no return., Strengths and Limitations: The use of human primary cells and confirmation of results with further RNA analysis are the strengths of this study. The study was limited to 760 genes rather than the whole transcriptome., Conclusion: This study is to our knowledge the first analysis of temporal gene expression associated with the regulation of the transformation of resident fibroblasts to profibrotic myofibroblasts in PD. Further research is warranted to investigate the role of the MAPK-Hedgehog signaling pathways in reversibility of PD., (© The Author(s) 2024. Published by Oxford University Press on behalf of The International Society of Sexual Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Devices such as inflatable penile prostheses (IPP) can be used to achieve erectile rigidity after phalloplasty in assigned female at birth (AFAB) individuals. The approach to inserting an IPP in a neophallus is different and more challenging compared to that of an anatomical penis due to the absence of anatomical structures such as the corpora cavernosa, and the more tenuous blood supply of the neophallus and reconstructed urethra. In addition, the ideal surgical techniques and devices for use in the neophallus have not been defined. This review systematically summarises the literature on the insertion of IPP in the neophallus of individuals AFAB. In particular, the described techniques, types of devices used and peri-operative and patient-reported outcomes are emphasised. An initial search of the PubMed database was performed on 16 September 2022 and an updated search was performed on 26 May 2023. Overall, 185 articles were screened for eligibility and 15 studies fulfilled the inclusion criteria and were included in the analysis. Two studies reported outcomes on the zephyr surgical implant 475 FTM device and the others reported outcomes on the Boston Scientific AMS 600/700 TM CX 3-piece inflatable, AMS Ambicor TM 2-piece inflatable, Coloplast Titan ® or Dynaflex devices. Overall, 1106 IPPs were analysed. The infection rate was 4.2%-50%, with most studies reporting an infection rate of <30%. Mechanical failure or dysfunction occurred in 1.4%-36.4%, explantation was required in 3.3%-41.6%, and implant revision or replacement was performed in 6%-70%. Overall, 51.4%-90.6% of patients were satisfied and 77%-100% were engaging in sexual intercourse. An IPP in a neophallus is an acceptable option to achieve rigidity for sexual intercourse. However, this challenging procedure has good reports of patient and partner satisfaction despite significant risks of complications., Competing Interests: DJR, NC, and WGL are consultants for Coloplast, Boston Scientific. DJR also consultant for Rigicon., (© The Author(s), 2023.)

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 β1 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 β1-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 Author(s) 2023. Published by Oxford University Press on behalf of The International Society of Sexual Medicine.)

Drug repurposing has been shown to bring safe medications to new patient populations, as recently evidenced by the COVID-19 pandemic. We investigated whether we could use phenotypic screening to repurpose drugs for the treatment of Peyronie's disease (PD). PD is a fibrotic disease characterised by continued myofibroblast presence and activity leading to formation of a plaque in the penile tunica albuginea (TA) that can cause pain during erection, erectile dysfunction, and penile deformity. PD affects 3-9% of men with treatment options limited to surgery or injection of collagenase which can only be utilised at late stages after the plaque is formed. Currently there are no approved medications that can be offered to patients presenting with early disease before the formation of the plaque. Drug repurposing may therefore be the ideal strategy to identify medical treatments to address this unmet medical need in early PD. We used primary human fibroblasts from PD patients in a phenotypic screening assay that measures TGF-β1-induced myofibroblast transformation which is the main cellular phenotype that drives the pathology in early PD. A library of FDA-approved 1,953 drugs was screened in duplicate wells at a single concentration (10 μM) in presence of TGF-β1. The myofibroblast marker α-SMA was quantified after 72h incubation. A positive control of SB-505124 (TGF-β1 receptor antagonist) was included on each plate. Hits were defined as showing >80% inhibition, whilst retaining >80% cell viability. 26 hits (1.3%) were identified which were divided into the following main groups: anti-cancer drugs, anti-inflammation, neurology, endocrinology, and imaging agents. Five of the top-ten drugs that increase myofibroblast-transformation appear to act on VEGFR. This is the first phenotypic screening of FDA-approved drugs for PD and our results suggest that it is a viable method to predict drugs with potential for repurposing to treat early PD., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Ilg et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Despite the introduction of effective oral pharmacotherapy for the treatment of erectile dysfunction (ED), penile implants are still the standard care for patients who do not respond well to medical therapy. Since the first inflatable penile implant surgery was performed almost 40 years ago, a variety of improvements in the penile prosthesis design, and advancements in material science, surgical technique, and post-operative care have been developed to increase patients' satisfaction, as well as that of their partners. Penile implants have evolved vastly during that same time frame and now represent the cutting-edge technology, durability, and function. Here, advancements are reviewed with a focus upon recent developments in surgical techniques and device technology.

Objective: Penile reconstruction or phalloplasty following penectomy can be offered where the functional penile length is inadequate for a man to void while standing or to have sexual intercourse. Phalloplasty is usually staged due to the complex surgical techniques required. This narrative review describes the technical concepts and summarises the contemporary outcomes following phalloplasty in this challenging cohort., Methods: A retrospective review of the English literature was performed between January 1946 till November 2021. The data were synthesised and complemented by the expert opinion of the authors with 20 years of experience in this field. The flaps are ideally designed with an integrated urethra or alternatively, a further free flap urethroplasty can be offered. Phalloplasty is further complicated following penectomy by scarring from the previous surgery and the potential loss of structures that would normally be present at the recipient site., Results: There are limited published data with a total of 19 men recorded in the literature. Only the radial artery forearm free flap and anterolateral thigh flap have been described in this cohort of patients. Functional outcomes including standing micturition, sensation in the neophallus, and the ability to orgasm are good. Overall quality of life and satisfaction was also good despite the high risk for long-term complications of the neophallus and donor site., Conclusion: Phalloplasty following penectomy requires microsurgical transfer of a free flap or a pedicled flap to reconstruct a neophallus. An erectile device is inserted at a later stage to facilitate sexual intercourse, if desired. Surgical scarring from penectomy and the potential loss of vasculature that would normally be present at the recipient site may further complicate reconstruction. Surgical and functional outcomes are acceptable based on the limited published experience to date., Competing Interests: The authors declare no conflict of interest., (© 2022 Editorial Office of Asian Journal of Urology. Production and hosting by Elsevier B.V.)

Transmasculine genital gender affirmation surgery (GAS) is evolving rapidly due to social and surgical advances over recent decades. Important innovations include the use of free or pedicled sensate tissue flaps with integrated urethra coupled with an improved understanding of how best to offer inclusive care. Disappointingly, most publications have thus far failed to address standardization, classification systems, and prospective trials to help guide shared decision making. This narrative review highlights contemporary techniques, controversies, and innovations while addressing gaps in the literature and future directions for research., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The aim of this study was to identify potential hazards for the inflatable penile prosthesis (IPP) surgical procedure and from this develop and content validate an IPP intraoperative competency-based assessment tool. A multi-institutional longitudinal prospective observational study was conducted over a 6-month period. Healthcare Failure Mode and Effects Analysis (HFMEA) methodology was used to prospectively risk assess the IPP procedure using a collaborative multidisciplinary team (MDT) approach. International content validation of the developed tool was then undertaken via face-to-face meetings and WebEx seminars. A total of 22 h of observation led to the construction of a detailed process map consisting of 11 stages and 49 sub-stages. HFMEA identified 50 failure modes and 45 failure mode effects, nine failure modes were excluded after analysis leaving 41 key failure modes included in the checklist. The high-risk steps identified were related to corporal dilatation, incorrect sizing of the prosthesis cylinders and incorrect localisation of the superficial inguinal ring for blind reservoir placement. The final content validated IPP assessment tool (PPAT) consisted of 13 processes and 27 sub-processes. We concluded that HFMEA methodology successfully allowed for the identification of key steps within the IPP procedure from which the PPAT was developed. Formal international content validation confirmed that all key procedural steps were included in the PPAT and that completion of all steps would indicate trainee competency in the procedure. Further validation is required before the tool can be used to assess learning curves for the IPP procedure., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)