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Background: Urethral strictures are a common and persistent pathology in urology with significant clinical repercussions. Our aim is to provide an overview of the general aspects of this condition., Methods: A comprehensive review of the literature from PubMed was conducted covering the period from 2020 to 2023. This was complemented by a synthesis of the latest guidelines from the American, European, and French Urological Associations (AUA, EAU, AFU), as well as references from textbooks., Results: Urethral stricture is defined by a narrowing of less than 16 French. The urethra is divided into posterior and anterior parts. The prevalence of urethral stricture is approximately 0.9%. The most common location for strictures is the anterior urethra, particularly its bulbar portion in males. The main causes are idiopathic, iatrogenic, traumatic, inflammatory, and infectious. A better understanding of urethral anatomy and histopathology provides a key element. Urethral reconstruction is based on prior urethral rest, detailed analysis of the stricture characteristics, and the use of grafts and flaps., Conclusion: Urethral strictures remain a broad pathology. Their definition and epidemiology have been clarified. They require a thorough understanding of the anatomy, etiologies, and principles of urethral reconstruction to optimize management., (Copyright © 2024. Published by Elsevier Masson SAS.)

Introduction: Distal anterior urethral strictures (DAUS) affect the meatus, navicular fossa (NF) and penile urethra (PU). The main causes are inflammatory (lichen sclerosous [LS]), traumatic iatrogenic, or idiopathic. Post-hypospadias stenosis is common and constitutes a separate entity, dealt with in a separate article., Method: A summary of North American, European and French recommendations was drawn up, supplemented by a literature search from December 2020 to December 2023, to provide a current overview of strategies adapted to DAUS., Results: Stricture limited to the meatus without LS can be dilated once. From the 1st recurrence or in the presence of LS, only a ventral or dorsal meatoplasty will be effective. In cases of Navicular involvement, an augmentation urethroplasty, respecting the glans penis (aesthetic preservation) will be preferred. Severe cases or recurrences may require replacement urethroplasty in two or more stages. PU stricture should not be treated by endoscopic urethrotomy but by urethroplasty in all cases. A one-stage augmentation technique will be discussed with a staged (2 stages most often) urethroplasty depending on the severity of the obstruction, stricture length, recurrent nature and the presence of LS. Buccal mucosa (jugal, lingual) is the most commonly used material in the form of a free graft. The most complex cases may require a perineal urethrostomy., Conclusion: DAUS present in a variety of ways. They are mainly managed surgically, in one or more stages. It is necessary to master several techniques to adapt to their heterogeneity., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Urethral stricture (US) affects most commonly the anterior portion of the urethra, concretely the bulbar, with a significant incidence in men. Open urethroplasty is the gold standard treatment. However, stricture recurrence (SR) remains a current subject of concern. The aim of the present review is to provide an updated literature summary on surgical urethroplasty techniques for bulbar US and prognostic factors for SR, comparing the different approaches. For short strictures, excision and primary anastomosis (EPA) is the preferred option, with success rates exceeding 90%. Substitution techniques are usually required for longer strictures (>2-3cm). Buccal mucosa graft (BMG) remains the first choice as it complies with ideal features, with no significant differences regarding the site of graft implantation. Stricture length, time since urethroplasty and number of previous urethral interventions are risk factors for failure. Also, surgeon's experience affects technique selection and future outcomes. There seems to be consensus on a higher SR rate following substitution techniques compared to EPA, which appears to be influenced by the stricture length, usually longer in the former group. Furthermore, there is a trend in favor of endoscopic management of SR, except for long and complex recurrences where grafts should be used. In conclusion, multiple urethroplasty techniques are available and selection must be carefully individualized, focusing on stricture characteristics, patient's history, and surgeon's experience. Well-designed studies with clear definitions and follow-up protocols are still necessary to develop standardized guidelines on the management of bulbar US.

Purpose: To create a reproducible and standardized urethral stricture model in rats, evaluating both histomorphologic findings and gene expression data. In studies involving experimental animals, more standardization is needed for the creation of a urethral stricture model., Methods: Sixteen male rats were randomized into two groups. The Sham group (n:8) underwent only a penoscrotal incision, while the stricture group (n:8) had their urethras exposed through a penoscrotal incision, followed by electrocauterization to the corpus spongiosum. On the 15th day, blood and urethral tissues were harvested for histologic and molecular analyses. Histomorphologic, immunohistochemical, and reverse transcription polymerase chain reaction analyses were performed., Results: The stricture group exhibited more severe and intense spongiofibrosis, inflammation, epithelial desquamation, and congestion in vascular structures compared to the controls (p < 0.05). The urethral tissue in the stricture group showed an increased ratio of inflammation parameters, including Collagen 1A1, Collagen 3A1, elastin, Transforming growth factor β1, α Smooth muscle actin, Platelet-derived growth factor α, and Platelet-derived growth factor β. Transforming growth factor β1, Platelet-derived growth factor α, and Platelet-derived growth factor β each correlated highly with the other six parameters (r > 0.60, p < 0.05)., Conclusion: Developing electrocoagulation-induced urethral stricture in rats is a simple, reliable, inexpensive, and reproducible. Reporting histologic data with qualitative and semi-quantitative scoring will enhance data standardization, aiding reader understanding and analysis. Transforming growth factor β and Platelet-derived growth factor play key roles in fibrosis during stricture development. Incorporating these cytokines in urethral stricture animal model studies can demonstrate successful stenosis creation., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Purpose: Anterior urethral stricture disease (aUSD) is a complex, heterogeneous condition that is idiopathic in origin for most men. This gap in knowledge rarely affects the current management strategy for aUSD, as urethroplasty does not generally consider etiology. However, as we transition towards personalized, minimally invasive treatments for aUSD and begin to consider aUSD prevention strategies, disease pathophysiology will become increasingly important. The purpose of this study was to perform a deep phenotype of men undergoing anterior urethroplasty for aUSD. We hypothesized that unique biologic signatures and potential targets for intervention would emerge based on stricture presence/absence, stricture etiology, and the presence/absence of stricture inflammation., Materials and Methods: Men with aUSD undergoing urethroplasty were recruited from one of 5 participating centers. Enrollees provided urethral stricture tissue and blood/serum on the day of surgery and completed patient-reported outcome measure questionnaires both pre- and postoperatively. The initial study had 3 aims: (1) to determine pediatric and adult subacute and repeated perineal trauma (SRPT) exposures using a study-specific SRPT questionnaire, (2) to determine the degree of inflammation and fibrosis in aUSD and peri-aUSD (normal urethra) tissue, and (3) to determine levels of systemic inflammatory and fibrotic cytokines. Two controls groups provided serum (normal vasectomy patients) and urethral tissue (autopsy patients). Cohorts were based on the presence/absence of stricture, by presumed stricture etiology (idiopathic, traumatic/iatrogenic, lichen sclerosus [LS]), and by the presence/absence of stricture inflammation., Results: Of 138 enrolled men (120 tissue/serum; 18 stricture tissue only), 78 had idiopathic strictures, 33 had trauma-related strictures, and 27 had LS-related strictures. BMI, stricture length, and stricture location significantly differed between cohorts ( P < .001 for each). The highest BMIs and the longest strictures were observed in the LS cohort. SRPT exposures did not significantly differ between etiology cohorts, with > 60% of each reporting low/mild risk. Stricture inflammation significantly differed between cohorts, with mild to severe inflammation present in 27% of trauma-related strictures, 54% of idiopathic strictures, and 48% of LS strictures ( P = .036). Stricture fibrosis did not significantly differ between cohorts ( P = .7). Three serum cytokines were significantly higher in patients with strictures compared to stricture-free controls: interleukin-9 (IL-9; P = .001), platelet-derived growth factor-BB ( P = .004), and CCL5 ( P = .01). No differences were observed in the levels of these cytokines based on stricture etiology. However, IL-9 levels were significantly higher in patients with inflamed strictures than in patients with strictures lacking inflammation ( P = .019). Degree of stricture inflammation positively correlated with serum levels of IL-9 (Spearman's rho 0.224, P = .014)., Conclusions: The most common aUSD etiology is idiopathic. Though convention has implicated SRPT as causative for idiopathic strictures, here we found that patients with idiopathic strictures had low SRPT rates that were similar to rates in patients with a known stricture etiology. Stricture and stricture-adjacent inflammation in idiopathic stricture were similar to LS strictures, suggesting shared pathophysiologic mechanisms. IL-9, platelet-derived growth factor-BB, and CCL5, which were elevated in patients with strictures, have been implicated in fibrotic conditions elsewhere in the body. Further work will be required to determine if this shared biologic signature represents a potential mechanism for an aUSD predisposition.

We present the case of a 6-year-old girl who presented with alterations in the voiding stream. On physical examination, a very small urethral meatus was identified at the expense of a membrane. The renovesical ultrasound showed no alterations. An uroflowmetric study was performed, showing a bladder outlet obstruction pattern. The urethral meatus was calibrated and a ventral meatotomy was performed. The histological study of the resected membrane showed a transitional urethral mucosa with chronic focal inflammation and discrete hyperplasia. The patient evolved favorably, with resolution of the symptoms and no notable complications. This is, to the best of our knowledge, the first reported case with a histological study of a congenital meatal urethral stenosis. In the presence of lower urinary tract obstruction, this entity should be considered in the differential diagnosis. Surgical treatment is curative., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Purpose: To determine the prevalence of concomitant squamous metaplasia (SM), the initial histological change from normal urethra to urethral stricture, in bulbar urethral strictures and to investigate the associated clinical factors., Methods: A retrospective review was conducted on 165 male patients with bulbar urethral strictures who underwent excision and primary anastomosis (EPA) between 2010 and 2020, for whom complete clinical data and excised urethral specimens were available. An experienced pathologist histologically evaluated concomitant SM in paraffin sections of the proximal end of the excised urethra blinded to the clinical data. Disease duration was calculated as the period from the initial diagnosis of urethral stricture to the date of EPA. The association between concomitant SM and clinical background was investigated., Results: SM was identified in 86 (52.1%) patients. The median disease duration in patients with SM (38 months) was significantly longer than that in patients without SM (9 months, p < 0.0001). In multivariate analysis, the longer disease duration, non-traumatic stricture etiology, and failure to maintain urethral rest with urinary diversion via a suprapubic tube for more than 90 days were independent factors predicting concomitant SM. No significant difference was observed in success rates of EPA between patients with SM (93.2%) and those without SM (97.5%, p = 0.18)., Conclusions: Reconstructive urologists need to be aware that concomitant SM is frequent in patients with bulbar urethral stricture, especially in those with long disease duration and those who were voiding volitionally during the period of urethral rest., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Urethral cancer after urethral reconstruction is an under-recognized, uncommon disease associated with significant morbidity and mortality. The survival rates of patients with carcinoma of the bulbar urethra are as low as 20%-30%. Stricture recurrence and unrecognized malignant changes present prior to reconstruction are major risk factors for urethral cancer. Skin substitution urethroplasty is subjected to higher rates of recurrence, which lends to the potential for carcinogenesis. We present a case of a 59-year-old male who underwent multi-stage skin substitution urethroplasty who developed urethral carcinoma 20 years later.

Objective: To present a unique series of children with previously repaired anorectal malformations (ARM) with subsequent urethral pathology repaired via a posterior sagittal exposure and highlight the associated technical advantages., Methods: Using a retrospective review of all procedures performed in our pediatric colorectal and pelvic reconstruction program from January 2020 through December 2022, we compiled a case series of patients with a history of ARM and prior posterior sagittal anorectoplasty (PSARP) who had urethral pathology and concurrent indication for redo-PSARP. Clinical features, operative details, and postoperative outcomes were collected., Results: Six male patients presented at a median age of 4.3 years, all born with an ARM of recto-urinary fistula type, of which 3 were recto-prostatic, 1 recto-bladder-neck, and 2 unknown type. In addition to redo-PSARP, 2 underwent remnant of the original fistula excision and 4 had urethral stricture repair. One required post-operative Heineke-Mikulicz anoplasty. Patients underwent cystoscopy 4-6 weeks post-reconstruction, and none showed urethral stricture requiring treatment. Post-procedurally, 5 patients were able to void urethrally and 1 required additional bladder augmentation/Mitrofanoff., Conclusion: Redo-PSARP completely mobilizes the rectum, thereby providing excellent exposure to the posterior urethra for repair. This approach also allows the option of a rectal flap for augmented urethroplasty as well as harvest of an ischiorectal fat pad for interposition., Competing Interests: Declaration of Competing Interest All authors have no disclosures or conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The urogenital tract is a target for many congenital and acquired diseases, both benign and oncogenic. In males, the urethra that transports urine and semen can be obstructed by a fibrotic disease called urethral stricture disease (USD). In severe USD, the whole organ including the vascular embedding, the corpus spongiosum (CS), is affected. Recurrent or severe USD is treated by reconstructive surgery. Tissue engineering may improve the outcome of urethral reconstruction in patients with complicated USD. Currently in urethral reconstruction only the epithelial layer is replaced, no substitution for the CS is provided, while the CS is important for mechanical support and vascularization. To develop a tissue engineering strategy for the CS, it is necessary to know the protein composition of the CS. As the extracellular matrix (ECM) plays an important role in the formation of fibrosis, we analyzed the distribution and localization of ECM components in human healthy and fibrotic CS tissue using immunohistology. The morphology of components of the elastic network were affected in USD. After decellularization a clear enrichment of proteins belonging to the ECM was found. In the proteomic analysis collagens COL15A1 and COL4A2 as well as inter-alpha-trypsin inhibitor ITIH4 were upregulated in fibrotic samples. The glycoproteins Periostin (POSTN), Microfibrillar-associated protein 5 (MFAP5) and EMILIN2 are downregulated in fibrotic tissue. To our knowledge this is the first proteomic study of ECM proteins of the CS in healthy and in USD. With these results a regenerating approach for tissue engineered CS can be developed, including relevant ECM proteins that reduce fibrosis and promote healthy healing in urethral reconstructive surgery., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Linssen 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.)

Objective: Our study aimed to compare surgical success rate (SR) and oral morbidity of augmentation urethroplasty for anterior urethral strictures using autologous tissue-engineered oral mucosa graft (TEOMG) named MukoCell® versus native oral mucosa graft (NOMG)., Methods: We conducted a single-institution observational study on patients undergoing TEOMG and NOMG urethroplasty for anterior urethral strictures >2 cm in length from January 2016 to July 2020. SR, oral morbidity, and potential risk factors of recurrence were compared between groups were analyzed. A decrease of maximum uroflow rate < 15 mL/s or further instrumentation was considered a failure., Results: Overall, TEOMG (n = 77) and NOMG (n = 76) groups had comparable SR (68.8% vs. 78.9%, p = 0.155) after a median follow-up of 52 (interquartile range [IQR] 45-60) months for TEOMG and 53.5 (IQR 43-58) months for NOMG. Subgroup analysis revealed comparable SR according to surgical technique, stricture localization, and length. Only following repetitive urethral dilatations, TEOMG achieved lower SR (31.3% vs. 81.3%, p = 0.003). Surgical time was significantly shorter by TEOMG use (median 104 vs. 182 min, p < 0.001). Oral morbidity and the associated "burden" in patients' quality of life were significantly less at 3 weeks following the biopsy required for TEOMG manufacture, compared to NOMG harvesting and totally absent at 6 and 12 months postoperatively., Conclusions: The SR of TEOMG urethroplasty appeared to be comparable to NOMG at a mid-term follow-up but taking into account the uneven distribution of stricture site and the surgical techniques used in both groups. Surgical time was significantly shortened, since no intraoperative mucosa harvesting was required, and oral complications were diminished through the preoperative biopsy for MukoCell® manufacture., (© 2023 The Authors. International Journal of Urology published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Urological Association.)

Urethral stricture secondary to urethral injury, afflicting both patients and urologists, is initiated by excessive deposition of extracellular matrix in the submucosal and periurethral tissues. Although various anti-fibrotic drugs have been applied to urethral stricture by irrigation or submucosal injection, their clinical feasibility and effectiveness are limited. Here, to target the pathological state of the extracellular matrix, we design a protein-based nanofilm-controlled drug delivery system and assemble it on the catheter. This approach, which integrates excellent anti-biofilm properties with stable and controlled drug delivery for tens of days in one step, ensures optimal efficacy and negligible side effects while preventing biofilm-related infections. In a rabbit model of urethral injury, the anti-fibrotic catheter maintains extracellular matrix homeostasis by reducing fibroblast-derived collagen production and enhancing metalloproteinase 1-induced collagen degradation, resulting in a greater improvement in lumen stenosis than other topical therapies for urethral stricture prevention. Such facilely fabricated biocompatible coating with antibacterial contamination and sustained-drug-release functionality could not only benefit populations at high risk of urethral stricture but also serve as an advanced paradigm for a range of biomedical applications., (© 2023. The Author(s).)

Background: Presently, there's a lack of standardization in animal models used for studying urethral stricture. Transforming Growth Factor Beta 1 (TGF-β1) is known to regulate the deposition of extracellular matrix in both normal and pathological conditions. This factor holds promise as a potential model for simulating urethral stricture., Objective: This study aims to investigate the impact of Transforming Growth Factor Beta 1 (TGF-β1) on Collagen I and Collagen III within the urethral wall of New Zealand Rabbits (Oryctolagus cuniculus) in the context of developing urethral stricture in animal models., Methods: We conducted genuine laboratory experiments using Male New Zealand rabbits (Oryctolagus cuniculus), which were categorized into five groups: control, placebo, and three treatment groups (TGF-β1 injections of 1 µg, 2 µg, 4 µg). After a duration of 6 weeks, we conducted urethrography, histopathological analysis, and assessed the formation of collagen I and collagen III within the urethral wall., Results: Elevating the dosage of TGF-β1 led to a reduction in the average urethral lumen diameter of rabbits (29.3% in the 2µg group and 34% in the 4µg group) compared to the control group. In fact, three rabbits experienced a decrease of ≤ 50% in their urethral lumen diameter. As the doses of TGF-β1 increased, we observed significant increases in the density of collagen I, and collagen III in both the periluminal and peripheral regions of the urethral spongiosum. Additionally, there was a tendency for the collagen I/collagen III ratio to decrease in the periluminal region, with collagen III density surpassing that of collagen I. In the peripheral spongiosa area, notable mean differences were observed between the control group, 1T, and 2T groups, with collagen I density tending to be higher than that of collagen III. Furthermore, the percentage of urethral lumen diameter exhibited a robust negative correlation with periluminal collagen I density (r = -0.672, p = 0.001), peripheral spongiosa collagen I density (r = -0.603, p = 0.005), periluminal collagen III density (r = -0.717, p = 0.001), and an exceptionally strong negative correlation with collagen III density of peripheral spongiosa (r = -0.804, p = 0.000)., Conclusion: TGF-β1 exerts an influence on altering the composition of collagen I and collagen III within the urethral wall of rabbits, leading to a reduction in the diameter of the urethral lumen. Further research is warranted to determine the optimal dose of TGF-β1 required to induce urethral stricture effectively., Competing Interests: The authors have no conflicts of interest to disclose., (© 2023 Paksi Satyagraha, Athaya Febriantyo Purnomo, Hamid Hunaif Dhofi Alluza, I Made Udiyana Indradiputra, Pradana Nurhadi, Kenty Wantri Anita, Yuyun Yueniwati, Happy Kurnia Permatasari, Basuki Bambang Purnomo.)

Objective: To compare the histological properties and stretch of colorectal mucosal grafts (CMG) and buccal mucosal grafts (BMG) and to evaluate the impact of age, medical comorbidity and tobacco use on these metrics., Materials and Methods: Samples of BMGs from patients undergoing augmentation urethroplasty were sent for pathologic review. CMGs were collected from patients undergoing elective colectomy. CMGs were harvested fresh, at full thickness from normal rectum/sigmoid. Patients with inflammatory bowel disease, prior radiation, or chemotherapy were excluded., Results: Seventy two BMGs and 53 CMGs were reviewed. While BMGs and CMGs were both histologically composed of mucosal (epithelium + lamina propria) and submucosal layers, the mucosal layer in CMG had crypts. The outer epithelial layers differed significantly in mean thickness (BMG 573μm vs. CMG 430μm, p=0.0001). Mean lamina propria thickness and submucosal layer thickness also differed significantly (BMG 135μm vs. CMG 400μm, p<0.0001; BMG 1090μm vs. CMG 808μm, p = 0.007, respectively). Mean delta stretch, as to length and width, was greater for CMG (118% x 72%) compared to BMGs (22% x 8%), both p<0.001., Conclusion: CMGs and BMGs significantly differ histologically in layer composition, width and architecture, as well as graft stretch. Given its elastic properties, CMG may be useful in covering large surface areas, but its thin epithelium, thick lamina propria and additional muscularis mucosal layer could impact graft take and contracture., Competing Interests: None declared., (Copyright® by the International Brazilian Journal of Urology.)

Objective: To review and report data on transformation to urethral carcinoma after urethroplasty for urethral stricture disease. Primary urethral carcinoma is a rare entity, and guidelines lack high quality data from which to cite. Urethroplasty is a highly effective treatment for urethral stricture disease, though in rare cases complications may include development of urethral carcinoma., Methods: A systematic PubMed search was performed to identify all articles describing patients with urethral carcinoma after urethroplasty. Data were collected on the following parameters: patient age and sex, indication for urethroplasty, presentation of cancer, imaging, pathology, presence of metastasis, intervention, and outcome., Results: The final cohort included fourteen patients, 13 from previously published cases and one from our institution. The median patient age at presentation was 60, most had endoscopic management prior to urethroplasty, and the majority presented with decreased urinary stream. All patients developed squamous cell carcinoma of the urethra. Patients underwent radical resection, lymph node dissection, chemotherapy, or radiotherapy, often in combination. A majority of patients had died at the time of case report., Conclusion: Development of urethral squamous cell carcinoma, particularly after urethroplasty, is a rarely encountered process. Patients and urologists must have a high index of suspicion and investigate symptoms such as fistula or lower urinary tract symptoms, even if these occur many months or even years after buccal mucosa graft . By compiling previously reported cases and adding an additional case to the literature, we hope that familiarity with this entity will lead to earlier recognition and diagnosis of disease., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Urethral stricture is related to scar tissue fibrosis, but its pathogenesis is still unclear. This study aims to explore the regulatory mechanism of circular RNA (circRNA) in the occurrence and development of urethral stricture. CircRNA microarray was employed to analyze circRNA expression profiles between human urethral scar tissue and normal urethral tissue. The results of circRNA microarray showed that there were 296 differentially expressed genes between urethral scar tissue and normal urethral tissue. The enrichment analysis of Kyoto encyclopedia of genes and genomes showed that these circRNAs were significantly correlated with ECM-receptor interaction. The first nine differentially expressed circRNA were selected to predict the circRNA-miRNA network. RT-qPCR results showed that circ&#95;0047339 was upregulated considerably in urethral scar tissue. Urethral scar fibroblasts were isolated from human urethral scar tissue and cultured in vitro. After silencing circ&#95;0047339, the proliferation of urethral scar cells decreased significantly, and the expressions of Collagen I (COL-1) and α-smooth muscle actin (α-SMA) also reduced. As a competing endogenous RNA, circ&#95;0047339 could increase the expression of TSP-1 by competitively binding miR-4691-5p. In addition, miR-4691-5p mimic transfection could inhibit the proliferation of urethral scar fibroblasts and the presentation of thrombospondin-1 (TSP-1), α-SMA and COL-1, while circ&#95;0047339 overexpression eliminated this inhibition. Our results showed that circ&#95;0047339 might promote the growth and fibrosis of urethral scar fibroblasts through miR-4691-5p/TSP-1 axis, thus promoting the development of urethral stricture., (© 2022. The Author(s).)

Objective: To investigate the effect of pirfenidone for reducing urethral stricture following urethral injury in rats and explore the possible mechanism., Methods: Thirty male SD rats were randomly assigned into negative control group, positive control group and pirfenidone group ( n =10). In pirfenidone and positive control groups, the rats were subjected to incision of the posterior urethral cavernous body followed by daily intraperitoneal injection of pirfenidone (100 mg/kg) and an equivalent volume of solvent, respectively. The rats in the negative control group were given intraperitoneal injections of solvent without urethral injury. At two weeks after modeling, retrograde urethrography was performed for observing urethral stricture, and the injured urethral tissues were harvested for HE staining, Masson staining, immunohistochemical staining and Western blotting for detecting the protein expressions of α-SMA and TGF-β1. The mRNA expressions of the inflammatory factors TNF-α, IL-6, and IL-1β were detected using qRT-PCR., Results: The body weight of the rats in pirfenidone group was significantly decreased compared with that in the other two groups ( P < 0.05). Retrograde urethrography showed significant narrowing of the urethra in the positive control group but not in the pirfenidone group. HE staining of the injured urethral tissues showed obvious proliferation of urethral epithelial cells with narrow urethral cavity and increased inflammatory cells in positive control group. The pathological findings of the urethra were similar between pirfenidone group and the negative control group. Masson staining revealed obviously reduced collagen fibers and regular arrangement of the fibers in pirfenidone group as compared to the positive control group. Compared with those in the negative control group, the expressions of α-SMA and TGF-β1 were significantly increased in the positive control group, and pirfenidone treatment significantly inhibited their expressions ( P < 0.05 or 0.01). Pirfenidone also significantly inhibited the mRNA expressions of TNF-α, IL-6, and IL-1β in the injured urethral tissue ( P < 0.05 or 0.01)., Conclusion: Pirfenidone can prevent urethral fibrosis and stricture after urethral injury possibly by inhibiting the TGF-β1 pathway and inflammatory response.

Background: Rapamycin was shown to reduce transforming growth factor β1 (TGF-β1) expression, inhibit the Mammalian target of rapamycin function, and prevent TGF-β1-induced pulmonary fibrosis. Rapamycin-eluting stents (RES) were successfully used to prevent coronary artery restenosis. Urethral stricture is one of the most challenging problems in urology. Thus, combining the pharmacological effects of rapamycin and the mechanical support of the stent on the urethra may prevent urethral stricture formation. However, the use of RES for urethral stricture treatment has not been studied., Aims: To observe the effects of RES in urethral stricture in a rabbit model., Study Design: Animal experimentation., Methods: Twenty adult male New Zealand rabbits were randomly divided into control, urethral stricture model, bare-metal stent, and RES groups. The rabbits in the control group underwent urethroscopy alone without electrocoagulation. The rabbit model of urethral stricture was established by electrocoagulation using a self-made electrocoagulation device under direct vision using ureteroscopy. After model establishment, the rabbits in the bare-metal stent and RES groups received stent placement by ureteroscopy. On day 30, retrograde urethrography was performed to assess urethral stricture formation, ureteroscopy to remove the stents, and histological examinations to assess the degree of fibrosis. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot analysis were used to evaluate the expression levels of TGF-β1, Smad3, and matrix metalloproteinase 1 (MMP1)., Results: Urethral stricture formation was seen in the model group, whereas not in the bare-metal stent group. The bare-metal stents did not displace but were difficult to remove. In the RES group, RES was dislodged in itself at postoperative day 27 in one rabbit, whereas successfully removed by ureteroscopy in the remaining four rabbits, and urethral stricture formation was not seen on retrograde urethrography after stent removal. Histological examination revealed a large number of dense fibroblasts and blue-stained collagen fibers in the bare-metal stent group, whereas the number of fibroblasts and collagen fibers under the mucosa was reduced in the RES group. RT-qPCR and Western blot analyses showed that the messenger ribonucleic acid (mRNA) and protein expression of TGF-β1and Smad3 was significantly decreased, and mRNA and protein expression of MMP1 was significantly increased in the RES group than that in the model (( P < 0.001) and bare-metal stent groups ( P < 0.001)., Conclusion: RES can effectively prevent electrocoagulation-induced urethral stricture in rabbits. The mechanism may be related to the effect of rapamycin on inhibiting TGF-β1 and Smad3 expression and promoting MMP1 expression in urethral tissues.

Objective: To identify the currently utilised techniques of anterior urethroplasty described in literature for treatment of urethral strictures, assess the effectiveness of the identified techniques based on re-stricture and complication rates, evaluate, and suggest treatment options based on current evidence for urethral strictures at different locations and of different lengths., Methods: A systematic review of the MEDLINE, EMBASE, Scopus and Cochrane Library databases from conception up to September 2020 was performed. Primary outcomes included success rates measured via re-stricture rates and the post-operative maximum urinary flow rate (Qmax). Secondary outcomes included patient reported complication rates., Results: A total of 52 papers, including 7 RCTs, met the inclusion criteria. Forty studies described the use of free graft urethroplasty with a median success rate of 86.5% (IQR = 8.1). The best outcomes were found in dorsal onlay buccal mucosa grafting in the penile urethra (86.6%). Twelve described the use of pedicled flap urethroplasty with a median success rate of 76% (IQR = 14.4). Excision and Primary Anastomosis results were reported in 5 studies and showed an overall highest success rate of 89.7% (IQR = 7.0) but involved the shortest strictures of median lengths of 2.1 cm (IQR = 0.48)., Conclusion: Graft urethroplasty showed optimal outcomes when utilised in penile and bulbar strictures, with dorsal onlay buccal mucosa grafting presenting with the largest evidence base and best outcomes overall. Flap urethroplasty had the highest success rates in panurethral and bulbar strictures, while anastomotic urethroplasty had the greatest success in bulbar and penobulbar strictures., (Copyright © 2021. Published by Elsevier Inc.)

Purpose: To better understand the pathophysiology of lichen sclerosus (LS) urethral stricture disease (USD), we aimed to investigate expression profiles of microRNAs (miRNAs) in tissue samples from men undergoing urethroplasty., Methods: Urethral stricture tissue was collected from 2005-2020. Histologic features diagnostic of LS were the basis of pathologic evaluation. Foci of areas diagnostic for LS or non-LS strictures were chosen for RNA evaluation. In an initial screening analysis, 13 LS urethral strictures and 13 non-LS strictures were profiled via miRNA RT-qPCR arrays for 752 unique miRNA. A validation analysis of 23 additional samples (9 LS and 14 non-LS) was performed for 15 miRNAs. Statistical analyses were performed using SPSS v25. Gene Ontology (GO) analysis was performed using DIANA-mirPath v. 3.0., Results: In the screening analysis 143 miRNAs were detected for all samples. 27 were differentially expressed between the groups (false discovery p-value <0.01). 15 of these miRNAs individually demonstrated an area under the curve (AUC)>0.90 for distinguishing between between LS and non-LS strictures. 11-fold upregulation of MiR-155-5p specifically was found in LS vs. non-LS strictures (p<0.001, AUC = 1.0). In the validation analysis, 13 of the 15 miRNAs tested were confirmed to have differential expression (false discovery p-value <0.10)., Conclusions: To our knowledge this is the first study evaluating miRNA expression profiles in LS and non-LS USD. We identified several miRNAs that are differentially expressed in USD caused by LS vs other etiologies, which could potentially serve as biomarkers of LS USD. The top eight differentially expressed miRNAs have been linked to immune response processes as well as involvement in wound healing, primarily angiogenesis and fibrosis., Competing Interests: The authors have declared that no competing interests exist.

Background/purpose: This study was conducted to present our experience in urethral mucosal graft urethroplasty to repair urethral stricture, as the first experience in our context., Methods: This is a prospective hospital-based study that had been designed to review management outcomes of buccal mucosal graft urethroplasty for anterior urethral stricture from January 2017 to January 2019., Results: The total number of involved patients was 60. The success rate was found to be 90% (n = 54), while 6 (10%) had a recurrence of stricture. Pain and pain combined bleeding from internal suture lines were the only early complication encountered in 50 (83.3%) and 2 (3.3%) patients, respectively. late complications occurred as follows 14 (23.3%) patients had UTI, 12 (20%) had wound infections, 8 (13.3%) had changes in ejaculation, and decrease in intensity of orgasm, and 6 (10%) had erectile dysfunction. One of the long-term complications was graft diverticulum in one case and was treated conservatively (in ventral on lay BMG)., Conclusion: Improvement of the service in limited resources countries like Sudan and was reflected in the excellent outcome of BMG urethroplasty as treatment of anterior urethral stricture (success rate 90%)., (© 2021. The Author(s).)

Purpose: To examine the efficacy of perineal urethrostomy (PU) in patients with anterior urethral stricture., Methods: Patients who underwent PU for anterior urethral stricture between 2013 and 2020 were retrospectively reviewed (n = 56). Surgical success was defined as no need for additional intervention. Uroflowmetry and measurement of residual urine volume (PVR) were examined postoperatively, and the patients were asked to fill out sexual health inventory for men (SHIM) and the validated Urethral Stricture Surgery Patient-reported Outcome Measure questionnaires before and after PU. The overall patient satisfaction was also assessed., Results: PU was successful in 92.9% of patients (n = 52), with a median follow-up of 34 months. Two of four were salvaged by re-do PU, and one was salvaged by forming a composite stoma using a penile skin graft. Thirty-nine patients (69.6%) filled out the questionnaires 6 months after surgery. The mean maximum flow rate, PVR, lower urinary tract symptoms (LUTS)-total score, LUTS-specific quality of life, and EuroQol-visual analog scale scores improved significantly from 3.8 mL/s, 77.6 mL, 12.9, 2.6, and 53.6 at baseline to 17.6 mL/s, 21.3 mL, 4.1, 0.9, and 74.9 postoperatively (p = 0.003, p = 0.004, p = 0.005, p < 0.0001, p < 0.0001, respectively). The SHIM score did not change significantly (from 2.6 at baseline to 2.3 postoperatively; p = 0.59). As for patient satisfaction, 84.6% of patients (33/39) were "satisfied" (46.1%) or "very satisfied" (38.5%) with the outcome., Conclusions: PU had a high surgical success rate, and significantly improved patients' subjective symptoms and achieved a high level of satisfaction., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: Performing 1-stage urethroplasty in patients with urethral strictures caused by lichen sclerosus (LS) is hotly debated among reconstructive urologists due to conflicting reports of success. Therefore, the objective of this study was to determine the pooled incidence of stricture recurrence following 1-stage buccal mucosal graft (BMG) urethroplasty in patients with LS, to determine the impact of surgical technique on recurrence and to compare recurrence risk between patients with and without LS after 1-stage repairs., Materials and Methods: A systematic review was conducted in accordance with PRISMA criteria. The primary outcome was pooled incidence of recurrence, which was calculated using a Der-Simonian-Laird binary random effects model with a Freeman-Tukey arcsine transformation. A total of 21 studies were included, of which 15 provided data for comparative analyses., Results: Pooled data from 625 LS patients revealed a stricture recurrence rate of 10% (95% CI 6-14). Among studies with longer followup (≥24 months), this increased to 18%. Among patients with penile urethral involvement, studies utilizing a penile skin incision had significantly higher pooled recurrence rates than those utilizing penile invagination (p=0.004). Across all studies, there was no evidence to suggest a difference in pooled recurrence rate between patients with and without LS (p=0.36). However, across only long-term studies, recurrence risk was significantly higher for patients with LS (OR 1.83, p=0.05)., Conclusions: One-stage BMG urethroplasty is likely a viable surgical option for patients with LS-related strictures; however, high-quality data are limited. Future multi-institutional, long-term prospective studies are needed to assess durability of 1-stage repair.

Urethral stricture (US) is a common disorder of the lower urinary tract in men caused by fibrosis. The recurrence rate of US is high; however, there are no effective therapies to prevent or treat urethral fibrosis. The pathogenesis of urethral fibrosis involves myofibroblast activation and excessive extracellular matrix (ECM) deposition. The molecular mechanisms underlying this pathological activation are not completely understood. It has been demonstrated that Notch signalling contributes to the development of fibrosis and inflammation. However, whether this contributes to urethral fibrosis remains unclear. In this study, activation of Notch signalling was observed in patients with US. Additionally, it was noted that activation of Notch signalling promoted ECM production and myofibroblast activation in human urethral scar fibroblasts (HUSFs) treated with transforming growth factor (TGF) β1. However, the Notch inhibitor N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT) suppressed activation of Notch signalling as well as proliferation and migration of the TGFβ1-treated HUSFs. Additionally, DAPT ameliorated TGFβ1-induced urethral fibrosis in Sprague Dawley rats by suppressing ECM production, myofibroblast activation and the TGFβ signalling pathway. These findings demonstrate that Notch signalling may be a promising and potential target in the prevention or treatment of urethral fibrosis., (© 2021 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Objective: To identify and explore the various classification systems that have been proposed for anterior urethral stricture disease (AUSD) and to identify the advantages and disadvantages of each., Methods: A comprehensive systematic review was conducted in MEDLINE, EMBASE, SCOPUS and COCHRANE databases with a search strategy created appropriately. Titles and abstracts of search results were screened by two authors and selected for full-text review. Studies exploring urethral stricture classification, clinical scoring or staging systems used in men over the age of 18 with benign anterior urethral stricture disease were included., Results: The search identified 3113 articles, of which 10 were selected for inclusion after scrutiny. Four classification systems were identified. These include ULTRA score, urethral stricture score, cystoscopy-based staging system and Gombe Urethrographic score. These were based on various modalities, including cystoscopy, retrograde urethrogram (RUG) and sonourethrogram (SUG). From the scoring systems identified, the urethral stricture scoring system has multiple external validation studies and is predictive of operative complexity, operative time, recurrence and postoperative complications., Conclusions: Several classification systems have been proposed for AUSD. Each has its advantages and disadvantages. The urethral stricture score has been externally validated and shown to been predictive of surgical outcomes and recurrence. There are no scores that incorporate patient-related outcome measures (PROMs). Many classification systems have yet to provide sufficient external validation. Further external validation studies are needed before the general adoption of a particular system.

Objective: At present, excision and primary anastomosis (EPA) urethroplasty is a highly reliable method of reconstruction for short bulbar urethral strictures. Longer strictures are often managed with grafting techniques to ensure a tension-free repair. Here we report our initial experience with a new, extended anastomotic technique for long bulbar strictures that incorporates plication of the ventral corporal bodies to reduce the distance between the urethral ends and obviates the need for grafting., Methods: We reviewed records for all urethroplasties performed by a single surgeon at our institution between January 2018 and February 2020. We identified a cohort of older patients with complex strictures who underwent Extended Primary Anastomosis with Penile Plication (EPAPP). Patient demographics, stricture characteristics, perioperative 75 parameters, and postoperative outcomes were evaluated., Results: Of 346 urethroplasty records reviewed, 10 patients (2.9%) underwent EPAPP. Mean stricture length was 3.75 ± 1.4 cm. EPAPP patients were older than those repaired by other techniques (mean age 66.6 vs 55.6, P = .024), and most were not sexually active preoperatively. Postoperative voiding cystourethrogram confirmed urethral patency without extravasation in all patients. At a median follow up of 9.7 months (IQR 8.5-11.5) 8 patients remained asymptomatic after EPAPP alone and 2 patients required a single balloon dilation for stricture recurrence., Conclusion: EPAPP is a promising alternative option for the management of long bulbar strictures among appropriately selected patients., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: Our primary objective was to determine the incidence of extravasation on imaging at the time of catheter removal after ventral onlay buccal mucosal graft urethroplasty., Materials and Methods: This is a single center retrospective cohort study of patients who underwent ventral onlay buccal mucosal graft bulbar urethroplasty from 2007 to 2017. Patients with imaging at the time of catheter removal were included. Urethroplasty success was defined as the ability to pass a 17Fr cystoscope at the time of followup cystoscopy., Results: A total of 229 patients met the inclusion criteria, including 110 with a ventral onlay buccal mucosal graft and 119 with an augmented anastomotic urethroplasty with a mean stricture length of 4.4 cm. Imaging consisted of a voiding cystourethrogram in 210 and retrograde urethrogram in 19 patients at a median of 21.7 days after surgery. The incidence of extravasation was 3.1% (7/229). Of patients who had a documented followup cystoscopy (60%, 137/229), those with extravasation on imaging had a worse urethroplasty success rate (60%, 3/5) compared to those who did not (94%, 117/130) (p=0.047). On multivariate analysis those who had 5 or more endoscopic interventions were 9.6 times more likely to demonstrate extravasation (OR 9.6, p=0.0080)., Conclusions: The incidence of radiological extravasation after ventral onlay using a single buccal mucosal graft, with or without augmented anastomotic urethroplasty, is 3.1%. Given this low rate it is reasonable to omit routine imaging at the time of Foley removal in this population. It appears that extravasation may be associated with a worse cystoscopic patency rate but does not lead to more complications.

Purpose: We evaluated the success of minimally invasive management of lichen sclerosus with topical and intraurethral clobetasol, as defined by improvement in patient reported outcome measures and nonprogression to surgery., Materials and Methods: We conducted a review of our prospective ongoing quality improvement study to determine outcomes of our current standard practice for males with penile and urethral biopsy proven lichen sclerosus. Data were collected between 2011 and 2019, and included patient demographic information, medical and surgical histories, and location and extent of lichen sclerosus related pathology. The primary outcomes for this study were voiding function and voiding related quality of life, and were assessed using the AUASS (American Urological Association Symptom Score) and quality of life bother index, respectively., Results: We identified 42 patients with biopsy proven lichen sclerosus related urethral stricture disease. Of these patients 85.7% were treated with intraurethral steroids alone and did not require surgical intervention. Median AUASS significantly improved from 12 to 8, and median quality of life bother index improved from 4 ("mostly dissatisfied") to 2 ("mostly satisfied"). Average stricture length of those with penile urethral disease and bulbar urethral disease was 4.8 cm (SD 3.0) and 16.2 cm (SD 6.5), respectively. Median followup was 8.4 months (IQR 2.6-26.4)., Conclusions: Lichen sclerosus related urethral stricture disease can be effectively managed with intraurethral steroids. This minimally invasive management strategy improves patient reported voiding symptoms and voiding quality of life.

Visualization of the surgically operated tissues is vital to improve surgical model animals including mouse. Urological surgeries for urethra include series of fine manipulations to treat the increasing number of birth defects such as hypospadias. Hence visualization of the urethral status is vital. Inappropriate urethral surgical procedure often leads to the incomplete wound healing and subsequent formation of urethro-cutaneous fistula or urethral stricture. Application of indocyanine green mediated visualization of the urethra was first performed in the current study. Indocyanine green revealed the bladder but not the urethral status in mouse. Antegrade injection of contrast agent into the bladder enabled to detect the urethral status in vivo. The visualization of the leakage of contrast agent from the operated region was shown as the state of urethral fistula in the current hypospadias mouse model and urethral stricture was also revealed. A second trial for contrast agent was performed after the initial operation and a tendency of accelerated urethral stricture was observed. Thus, assessment of post-surgical conditions of urogenital tissues can be improved by the current analyses on the urethral status.

Purpose: To critically evaluate a multi-institutional patient cohort undergoing single-stage distal urethral repair using a novel transurethral buccal mucosa graft inlay urethroplasty technique (TBMGI)., Methods: A retrospective multi-institutional review of consecutive patients with fossa navicularis (FN) strictures treated with a single-stage TBMGI technique at 12 institutions from March 2014-March 2018 was performed. Patient demographics, stricture characteristics, clinical and patient-reported outcomes were analyzed. The primary outcomes were stricture recurrence and complications. Secondary outcomes were change in maximum urinary flow rate (Qmax), PVR, and changes in IPSS, SHIM and global response assessment (GRA) questionnaire responses. Descriptive statistical analysis was used for evaluation of outcomes., Results: Sixty-eight men met inclusion criteria. Median age and stricture length were 60 years (IQR 48-69) and 2 cm (IQR 2-3), respectively. Most common stricture etiology was lichen sclerosus (34%). Median operative time and EBL were 72 min (IQR 50-120) and 20 mL (IQR 10-43), respectively. Fifty-seven men completed ≥ 12-month follow-up. At a median follow-up of 17 months (IQR 13-22), 54 patients (95%) remained stricture-free. Median Qmax improved from 5 to 18 mL/s (p < 0.0001), PVR 76-21 mL (p < 0.0001), and IPSS 15-5 (p < 0.0001); IPSS-QOL score: 5-1 (p < 0.0001). SHIM score did not significantly change following repair (median 22-21 p = 0.85). On GRA assessment, a majority of men reported "marked" (64%) or "moderate" (28%) overall improvement. No patient developed fistula, glanular dehiscence, graft necrosis or chordee., Conclusions: This novel minimally invasive transurethral urethroplasty technique is feasible and has demonstrated generalizable outcomes in a multi-institutional cohort with varying etiologies.

Purpose: To evaluate histological changes in stenotic urethral tissue post-radiation therapy. Treatment of prostate cancer by radiation therapy carries a risk of off-target injury to the membranous urethra causing urethral stenosis. Limited characterization of post-radiation urethral stenosis exists in the literature. We hypothesize that specific histopathologic parameters distinguish this stricture etiology., Methods: Eighty-two consecutive patients with membranous urethral stenosis underwent urethroplasty between 2013 and 2018. Seventy specimens (86.4%) were available for evaluation: 51 from patients without radiation exposure and 19 from patients with history of radiation therapy for prostate cancer. All specimens were reviewed by a pathologist blinded to patient/stricture information. Histological scoring system was used for the quantification of collagen density, collagen organization, hyalinized fibrosis, vascular density, spindle-cell change, necrosis, hemorrhage, fat entrapment, vacuolation, acute and chronic inflammation, and foreign-body giant cells. Differences in histologic outcomes between groups were statistically analyzed., Results: Post-radiation specimens had a higher collagen density (p = 0.01), higher collagen organization (p = 0.001), increased hyalinized fibrosis (p = 0.03), fat entrapment (p = 0.005) and spindle cell change (p = 0.005) when compared to membranous specimens without prior exposure to radiation. Post-radiation specimens also had a significantly decreased vascularity compared to specimens of non-radiated etiology (p = 0.0005). Fibrous connective tissue degenerative change with vacuolation was pronounced in post-radiation specimens and seldom seen in those without radiation (p = 0.0001)., Conclusions: Membranous urethral stenosis following radiation demonstrates specific histologic characteristics including vascular loss and increased scarring (collagen density, organization). This histologic grading system may be used in grading severity of radiation damage, and conceivably adopted for correlation with clinical outcomes.

Purpose: Urethroplasty is the most effective treatment method for anterior urethral strictures, which constitute an important health concern for males. This study aims to investigate factors that may predict treatment failure following urethroplasty for anterior urethral strictures and evaluate outcomes of different urethroplasty techniques., Methods: This retrospective study utilized univariate and multivariate analyses to identify factors affecting treatment success following different urethroplasty techniques performed by a single surgeon on male patients with anterior urethral strictures. Surgical outcomes of different urethroplasty techniques were evaluated individually., Results: Urethroplasty procedures performed on 244 patients with a mean age of 54 years and a mean stricture length of 4.7 cm produced a success rate of 79.1%. Multivariate analyses identified stricture length and number of previous internal urethrotomy procedures as factors predicting urethroplasty success (HR 1.265, 95% CI 1.129-1.416, p < 0.001 and HR 1.188, 95% CI 1.038-1.361, p = 0.013, respectively). The eight surgical techniques used by the surgeon produced success rates that varied between 50% and 86.2%., Conclusion: Urethroplasty can offer satisfactory outcomes for anterior urethral strictures. Accordingly, a longer stricture length and greater number of previous internal urethrotomy procedures were associated with greater risk for urethroplasty failure. Moreover, urethroplasty techniques must be selected based on multifactorial evaluation and performed at experienced centers.

Objective: To develop and validate a clinical classification system for urethral stricture disease (USD) based on the retrograde urethrogram (RUG), physical exam, and stricture-specific patient history., Materials and Methods: Three elements were chosen to be included in the classification system: 1) Length of urethral stricture (L); 2) Stricture segment/location (S); 3) Stricture Etiology (E) (LSE classification system). Each element was divided into clinically relevant sub-categories. A three-step development and validation process then ensued, culminating in an in-person Trauma and Urologic Reconstruction Network of Surgeons (TURNS) meeting, at which the final classification system was unanimously agreed upon by attendees based on interrater reliability data obtained from the classifying of 22 clinical vignettes. A final validation step involved retrospectively classifying cases in the TURNS database to determine if classification influenced surgical technique and was associated with presumed stricture etiology., Results: The final LSE classification system was found to have an interrater reliability of 0.79 (individual components 0.76, 0.70 and 0.93 respectfully). Retrospective classification of the 2162 TURNS strictures revealed the segment (S) to be strongly associated with urethroplasty type (p = 0.0005) and stricture etiology (E) (p = 0.0005)., Conclusion: We developed and validated a novel, easy to use, urethral stricture classification system. The system's ability to aid in directing treatments, predict treatment outcomes, and facilitate collaborative research efforts will require further study., (Published by Elsevier Inc.)

Introduction: To evaluate flexible pediatric cystoscopy (FPC) as an adjunctive procedure to retrograde urethrography (RUG) and voiding cystourethrography (VCUG) in the preoperative setting for male urethral strictures. Since imaging interpretation of stricture length and caliber can be difficult at times, we sought to evaluate diagnostic utility of FPC to predict reconstructive surgery., Materials and Methods: Reconstructive urology databases at Washington University and Columbia University were queried from 2010-2017. A total of 185 anterior urethroplasty patients met inclusion criteria. All surgeries were performed by a single surgeon. There were 102 patients that underwent preoperative FPC (7.5 Fr in diameter). Surgical urethroplasty techniques employed were: ventral or dorsal onlay buccal mucosa graft, fasciocutaneous penile skin flap, excision and primary anastomosis or augmented anastomotic. We analyzed the RUG, VCUG, FPC, and intraoperative details of the urethral strictures by univariate and multivariate statistics., Results: Mean patient age was 47.2 (+/-16.5) years. Of the patients who underwent FPC, 42.2% were narrower than the FPC, and 57.8% were wider. Intraoperative stricture length better correlated with FPC findings compared to RUG/ VCUG (r = 0.834 versus r = 0.766) (p < 0.001). Moreover, inability to pass the FPC through the stricture correlated with the need to perform urethral stricture excision or complete reconstruction of the urethral plate (p = 0.005), rather than onlay urethroplasty., Conclusion: Preoperative FPC is a useful adjunctive tool in the evaluation of urethral strictures. FPC facilitates stricture assessment by accurately correlating with intraoperative stricture length and predicting the need to excise or graft during reconstruction.

Purpose: Urethroplasty of lichen sclerosus strictures has a significantly higher failure rate than strictures due to other causes. We sought to determine predictors of urethroplasty failure in men with lichen sclerosus urethral stricture disease by evaluating protein expression profiles., Materials and Methods: Urethral tissue was excised from patients with lichen sclerosus who were undergoing urethroplasty of urethral stricture disease at a single institution. A tissue microarray was created with cores from each sample. Immunohistochemistry was performed to compare protein expression related to inflammation, cell cycle disruption, oxidative stress, hormone receptor status and infection. Stricture recurrence was defined by the need for a subsequent unanticipated procedure for urethral stricture disease., Results: We evaluated 50 men with lichen sclerosus urethral stricture disease, including 31 with successful reconstruction and 19 with recurrent stricture. Recurrent strictures expressed lower levels of several inflammatory markers and had a lower Ki-67 mitotic index and significantly higher vascular endothelial growth factor levels than nonrecurrent strictures., Conclusions: To our knowledge this is the first study to use tissue protein expression to identify risk factors for urethroplasty failure among men with lichen sclerosus urethral stricture disease. Our findings suggest that recurrent lichen sclerosus strictures demonstrate a suppressed inflammatory response, a decreased cell turnover rate, and poor oxygenation and nutrient delivery. Prospective studies are needed to clarify the role of these pathways in the pathophysiology of lichen sclerosus urethral stricture disease, determine whether preoperative biopsy can predict urethroplasty success, help counsel patients and develop future treatments.

Cowper's syringoceles are uncommon, usually described in children and most commonly limited to the ducts. We describe more complex variants in an adult population affecting with varying degrees of severity, the glands themselves, and the complications they may lead to. One hundred consecutive urethrograms of patients with unreconstructed strictures were reviewed. Twenty-six patients (mean age: 41.1 years) with Cowper's syringoceles who were managed between 2009 and 2016 were subsequently evaluated. Presentation, radiological appearance, treatment (when indicated), and outcomes were assessed. Of 100 urethrograms in patients with strictures, 33.0% demonstrated filling of Cowper's ducts or glands, occurring predominantly in patients with bulbar strictures. Only 1 of 26 patients with non-bulbar strictures had a visible duct/gland. Of 26 symptomatic patients, 15 presented with poor flow. In four patients, a grossly dilated Cowper's duct obstructed the urethra. In the remaining 11 patients, a bulbar stricture caused the symptoms and the syringocele was identified incidentally. Eight patients presented with perineal pain. In six of them, fluoroscopy and magnetic resonance imaging (MRI) revealed complex multicystic lesions within the bulbourethral glands. Four patients developed perineoscrotal abscesses. In the 11 patients with strictures, the syringocele was no longer visible after urethroplasty. In three of four patients with urethral obstruction secondary to a dilated Cowper's duct, this resolved after transperineal excision (n = 2) and endoscopic deroofing (n = 1). Five of six patients with complex syringoceles involving Cowper's glands were excised surgically with symptomatic relief in all. In conclusion, Cowper's syringocele in adults is more common than previously thought and may cause lower urinary tract symptoms or be associated with serious complications which usually require surgical treatment., Competing Interests: None

Objective: To characterize the bulbospongiosus muscle (BSM) in patients with bulbar urethral strictures., Materials and Methods: We studied 21 patients divided into 2 groups: Stricture Group (n = 14; mean age = 62.00 years) with bulbar stricture submitted to open urethroplasty; and Control Group (n = 7; mean age = 60.14 years) with penile strictures (hypospadias cripples, penile cancer and/or penile infection) who were submitted to perineal urethrostomy. Samples of the BSM were dissected and histologic sections were stained by histochemical and immunohistochemical techniques. Histomorphometric analyzes were performed on photomicrographs. Means were statistically compared using the unpaired Student t test and the Mann-Whitney test (P <.05)., Results: The etiology of bulbar urethral stricture was idiopathic in 2 cases (14.29%), post-TURP in 6 (42.86%), post open radical prostatectomy in 5 (35.71%) and post open prostatectomy in 1 case (7.14%). The average length of the stricture was 2.08 cm. The only parameter analyzed with significant difference between the groups was the vessels (significant difference between the control group: 5.11 ± 1.98% and stricture group: 3.57 ± 1.32%, P = .0460). The quantitative analysis of collagen (Control Group: 10.63 ± 5.37% and Stricture Group: 10.83 ± 4.55%, P = .9296); diameter of BSM muscle fibers (Control Group: 41.71 ± 14.63 µm and Stricture Group: 40.11 ± 8.59 µm, P = .76 and elastic system fibers (Control Group; 3.83 ± 1.54% and Stricture Group: 5.43 ± 2.90%, P = .2601) showed no significant difference., Conclusions: Histologic analysis showed a significant decrease of the BSM vessels in urethral stricture, without changes in elastic fibers, collagen, nerves, and muscle fiber diameter. These findings show that the bulbar urethral stricture causes minimal alterations in the structure of the BSM., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: The aim of this study was to estimate the clinical effects of allogeneic acellular dermal matrix (ADM) in the surgical therapy of anterior urethral stricture (AUS)., Methods: We retrospectively collected the clinical data of 49 patients with AUS who underwent urethral repair surgery with ADM in the Department of Urology of the Peking University People's Hospital, and in the First Affiliated Hospital of the People's Liberation Army, from September 2015 to January 2019. The changes in urine flow rate and conditions of urethral mucosal coverage were observed as well as complications and outcomes, and statistical analysis was performed., Results: The average maximum urine flow rates at the 1st, 6th, and 12th month post-surgery were 16.3 ± 1.5, 15.0 ± 1.9, and 14.6 ± 2.1 mL/s, respectively. These values were significantly higher than the preoperative maximum urine flow rate, 1.3 ± 0.5 mL/s (p < 0.05). Cystoscopy was performed in 11 patients 12 months after surgery, with microscopic assessment revealing good urethral epithelial mucosal coverage. Only 2 patients developed infection 2-4 weeks after surgery, while 7 patients developed noninfective urethral restricture 6-10 months after surgery and 1 patient developed urinary fistula 5 months after surgery. All of these statuses improved after receiving appropriate treatment., Conclusions: Use of ADM represents a new option for the surgical management of AUS repair and reconstruction, with positive clinical effects. In addition, it has the advantages of convenient for operation procedures and access, with no need for additional sampling surgery., (© 2020 S. Karger AG, Basel.)

Objective: To examine the most cited literature in urethral reconstruction, review types of work published, and observe research trends., Methods: The Web of Sciences Sci-Expanded Index was used to conduct a search for urethral reconstruction. References were assessed for relevance to urethral reconstruction by 2 independent reviewers and a final list of the top 100 articles ranked by citation count was obtained. For each article, citation count, publication date, corresponding author, origin institution, origin country, topic area, study design, level of evidence, and origin journal were collected., Results: The mean citation count per publication was 108 (median = 94.5; range = 69-366, SD = 43) with a total of 10,874 citations for all papers since 1970. The top 100 articles were published between 1973 and 2011, came from 19 different countries and 16 different journals. Nearly half were case series and most studies were Level III evidence or lower. The United States was the largest contributor to the top 100 with 56 publications, followed by Italy (14), England (12), and Egypt (7). "Outcomes of surgical treatment for urethral stricture disease" was the most prevalent topic area comprising 55 articles in the top 100, with most articles including descriptions or outcomes of novel surgical techniques., Conclusion: In this study, we discovered that the most cited literature in the field of urethral reconstruction is singularly focused and lacking in high levels of evidence. The top 100 cited articles originate primarily from the United States, focus on short-term outcomes after surgical treatment for urethral stricture disease, and are predominantly case series., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The effective treatment of urethral stricture remains a medical problem. The use of proinflammatory cytokines as stimuli to improve the reparative efficacy of mesenchymal stem cells (MSCs) towards damaged tissues represents an evolving field of investigation. However, the therapeutic benefits of this strategy in the treatment of urethral stricture remain unknown. Here, we enriched exosomes derived from human umbilical cord-derived MSCs pretreated with or without tumor necrosis factor alpha (TNF-α) to evaluate their therapeutic effects in an in vivo model of TGFβ1-induced urethral stricture. Male Sprague-Dawley rats received sham (saline) or TGFβ1 injections to urethral tissues followed by incisions in the urethra. Animals in the TGFβ1 injection (urethral fibrosis) cohort were subsequently injected with vehicle control, or with exosomes derived from MSCs cultured with or without TNF-α. After 4 weeks, rats underwent ultrasound evaluation and, following euthanasia, urethral tissues were harvested for histological and molecular analysis. In vitro, the effects of MSC-derived exosomes on fibroblast secretion of collagen and cytokines were studied by enzyme-linked immunosorbent assay (ELISA), quantitative real-time polymerase chain reaction (qRT-PCR), and western blot analysis. Exosomes derived from MSCs pretreated with TNF-α were more effective in suppressing urethral fibrosis and stricture than exosomes from untreated MSCs. We found that miR-146a, an anti-inflammatory miRNA, was strongly upregulated in TNF-α-stimulated MSCs and was selectively packaged into exosomes. Moreover, miR-146a-containing exosomes were taken up by fibroblasts and inhibited fibroblast activation and associated inflammatory responses, a finding that may underlie the therapeutic mechanism for suppression of urethral stricture. Inhibition of miR-146a in TNF-α-treated MSCs partially reduced antifibrotic effects and increased the release of proinflammatory factors of exosomes derived from these cells. Together these findings demonstrate that exosomes derived from TNF-α-treated MSCs are of therapeutic benefit in urethral fibrosis, suggesting that this strategy may have utility as an adjuvant therapy in the treatment of urethral stricture diseases., (© 2019 Wiley Periodicals, Inc.)

Background: Limited data are available on outcomes of the surgical management of inflammatory urethral strictures secondary to infection, a major cause of stricture. Several shortcomings that need to be addressed have been identified in the past., Objective: To determine the impact of stricture length, position and degree of obliterative urethral lumen on the surgical outcomes of corrective procedures for inflammatory anterior urethral strictures., Methods: This retrospective analysis used the records of patients who presented with proven infective anterior urethral strictures at an academic hospital from 2007 to 2010. All patients were followed up after 48 months. Urethroplasty outcomes were analysed according to stricture location and length and effect of urethral obliteration., Results: The median age of the 174 patients in the study was 47 (range 21 - 86) years. Anastomotic urethroplasty was successful in 59/99 (59.6%) patients. Augmented anastomotic urethroplasty was successful in 11/15 (73.3%) patients. Dorsal onlay buccal mucosa graft urethroplasty was successful in 23/32 (71.9%) patients, significantly higher than in 2/9 (22.2%) patients who underwent ventral onlay buccal mucosa graft urethroplasty (p=0.017; hazard ratio 3.4; 95% confidence interval 1.29 - 9.40). The one-stage circular pedicled penile skin-flap urethroplasty was successful in 1/12 (8.3%) patients. Two-stage urethroplasty was successful in 5/7 (71.4%) patients. A primary component analysis of the 73 failed procedures showed that stricture length was the main contributor to failure (eigenvalue 1.79; 45%)., Conclusions: Urethroplasty remains a challenge in inflammatory urethral strictures, where stricture length was the main reason for treatment failure.

Objectives: To identify trends in the management of urethral stricture disease in Australia, assess changes in the standard of care, and examine the availability of genitourinary reconstructive surgery., Methods: Data on eight stricture management procedures were collected online via Medicare Item Reports from the Australian Government Department of Human Services, and then matched to population data from the Australian Bureau of Statistics. A survey was disseminated via the Urological Society of Australia and New Zealand (USANZ) asking whether active members performed urethroplasty and whether this was done in a rural, regional or metropolitan setting., Results: Over a 22-year period, there were 140 540 endoscopic procedures and 5136 urethroplasties, with 27.4 endoscopic procedures per urethroplasty. From 1994 to 2016, the per capita number of passage of sounds and dilatation procedures decreased by 74% and 75%, respectively, with increases in use of optical urethrotomy of 70% and in single-stage urethroplasty of 144%. Overall, the ratio of all endoscopic procedures vs urethroplasty decreased from 58.9 to 16.8. There were as few as 16 surgeons in the USANZ performing urethroplasty, with seven providing this service in regional areas. Seven had formal fellowship training., Conclusion: There has been a clear shift from repetitive endoscopic procedures towards urethroplasty, but the former still make up the majority of interventions. This may be explained by patients not being referred for urethroplasty earlier in the course of disease and there appears to be a gap in genitourinary reconstructive expertise in regional and rural areas., (© 2019 The Authors BJU International © 2019 BJU International Published by John Wiley & Sons Ltd.)

Purpose: Histopathology can provide insights into disease mechanisms but to date it has been poorly described for urethral stricture. The purpose of this study was to comprehensively describe histopathological findings of stricture specimens obtained at the time of anterior urethroplasty., Materials and Methods: All pathological specimens of men who underwent anterior urethroplasty of urethral stricture disease from 2010 to 2017 at a single institution were rereviewed by a single blinded pathologist directed to rule out lichen sclerosus and then describe inflammatory cell type and severity when present. Cohorts comprising strictures with no inflammation, minimal to mild inflammation or moderate to severe inflammation were developed and stricture, patient and surgical outcome characteristics were compared., Results: Histopathology slides from 100 anterior urethroplasty cases were reviewed. Two or more lichen sclerosus characteristics were present in 21% of specimens and 44% of specimens showed chronic inflammation, which was minimal in 20%, mild in 39%, moderate in 39% and severe in 2%. Lymphocytes in 86% of specimens and plasma cells in 12% were the predominant cell types. Patients with inflammatory stricture reported worse overall health. Inflammation was largely absent from isolated bulbomembranous strictures (9%) and more common in lichen sclerosus strictures (100%). The 11% overall failure rate was not affected by the presence (7%) or absence (14%) of inflammation., Conclusions: Chronic inflammation is prevalent in a significant percent of urethral stricture disease specimens. Associations with worse overall health suggest systemic mediators. Absent inflammation in bulbomembranous strictures suggests a unique pathophysiology in this region. The presence of inflammation did not affect surgical outcomes at mid-term followup.

The urethra is part of the lower urinary tract and its main role is urine voiding. Its complex histological structure makes urethral tissue prone to various injuries with complicated healing processes that often lead to scar formation. Urethral stricture disease can affect both men and women. The occurrence of this pathology is more common in men and thus are previous research has been mainly oriented on male urethra reconstruction. However, commonly used surgical techniques show unsatisfactory results because of complications. The new and progressively developing field of tissue engineering offers promising solutions, which could be applied in the urethral regeneration of both men´s and women´s urethras. The presented systematic review article offers an overview of the cells that have been used in urethral tissue engineering so far. Urine-derived stem cells show a great perspective in respect to urethral tissue engineering. They can be easily harvested and are a promising autologous cell source for the needs of tissue engineering techniques. The presented review also shows the importance of mechanical stimuli application on maturating tissue. Sufficient vascularization and elimination of stricture formation present the biggest challenges not only in customary surgical management but also in tissue-engineering approaches.

Objective: To analyze contemporary urethroplasty trends and urethral stricture etiologies over a 7-year study period among urologists from a large multi-institutional surgical outcomes group., Methods: Review of a multi-institutional, prospectively maintained urethroplasty database was performed on 2098 anterior urethroplasties done between 2010 and 2017 by 10 surgeons. Stricture characteristics, including etiology, length, and anatomic location were analyzed and compared to urethroplasty type over the study period using chi-squared analysis to assess for linear trends within the group and by surgeon., Results: Average stricture lengths for bulbar (2.8 ± 1.8 cm), penile (3.6 ± 2.6 cm), and penile-bulbar strictures (8.7 ± 5.0) remained stable. The most common stricture etiology was idiopathic/unknown in all study years (63%). In the bulbar urethra, the group performed significantly (1) fewer excisional repairs (-31%) and more substitutional repairs (+78%); (2) of substitutional repairs, more grafts are being placed dorsally (+95%) vs ventrally (-75%) (3) of the bulbar excisional repairs, more are being performed without transection of the bulbar urethra (+430%); and in the penile urethra (4) the fasciocutaneous flap is in decline (-86%), while single-stage dorsal repairs are increasing (+280%)., Conclusion: Anterior urethroplasty techniques continue to evolve in the absence of robust clinical data or randomized controlled trials, with a general movement in this cohort toward an initial dorsal approach for most strictures. Inter- and intrasurgeon variability in the surgical management of similar strictures was noted, and the feasibility of any future randomized controlled trials, without apparent surgical equipoise, must be questioned., (Copyright © 2019. Published by Elsevier Inc.)

Purpose: We evaluated the pathophysiology of lichen sclerosus and nonlichen sclerosus urethral stricture disease by comparing protein expression related to inflammation, cell cycle disruption, oxidative stress, hormone receptor status and infection., Materials and Methods: Tissue samples were collected from the urethral strictures of 81 patients undergoing urethroplasty. Clinical and demographic data were obtained by chart review. After identifying areas pathognomonic for lichen sclerosus a tissue microarray was created with cores from each sample and immunohistochemistry was performed., Results: Patients had similar baseline demographics and comorbidities. Of the 81 strictures 58 were and 23 were not due to lichen sclerosus. Lichen sclerosus strictures were significantly longer and showed higher levels of inflammation. The proportion of T cells which stained positive for CD8 was significantly higher in strictures due to lichen sclerosus (50% vs 13%, p = 0.004). CCL-4 was expressed significantly more in strictures due to lichen sclerosus (76% vs 42%, p = 0.01). Several other inflammatory markers were only found in strictures due to lichen sclerosus. Block-like p16, a surrogate for high risk human papillomavirus infection, and varicella zoster virus were found only in lichen sclerosus urethral stricture disease samples, although both were rare. Epstein-Barr virus RNA was found in significantly more lichen sclerosus samples (37% vs 10%, p = 0.024)., Conclusions: To our knowledge this is the first study to evaluate protein expression in lichen sclerosus urethral stricture disease. These strictures demonstrate increased inflammation compared to nonlichen sclerosus urethral strictures. Markers of oxidative stress, cell cycle dysregulation and the androgen receptor do not appear to be uniquely associated with lichen sclerosus urethral stricture disease. Positive staining for several viruses in samples of lichen sclerosus urethral stricture disease suggests a possible infectious etiology.

Purpose: To report toxicity outcomes, prostate-specific antigen (PSA) relapse, and cumulative incidence posttreatment biopsy results among patients treated on a prospective dose escalation study using ultra-hypofractionated stereotactic body radiation therapy (SBRT) for patients with low- and intermediate-risk prostate cancer., Methods and Materials: A total of 136 patients were enrolled in a phase 1 dose-escalation study to determine the tolerance of escalating radiation dose levels of SBRT for the treatment of localized prostate cancer. The initial dose level was 32.5 Gy in 5 fractions, and doses were then sequentially escalated to 35 Gy, 37.5 Gy, and 40 Gy. Eligibility criteria included only patients with low and intermediate risk, and the maximum prostate volume was 60 cm 3 . Patients treated with neoadjuvant androgen deprivation were excluded. The median follow-up in survivors for the 4 dose levels was 5.9, 5.4, 4.1, and 3.5 years, respectively., Results: The incidence of acute grade 2 rectal toxicities for dose levels 1 to 4 were 0%, 2.9%, 2.8%, and 11.4% respectively. No grade 3 or 4 acute rectal toxicities were observed. The incidence of acute grade 2 urinary toxicities for dose levels 1 to 4 were 16.7%, 22.9%, 8.3%, and 17.1%, respectively. No grade 3 or 4 acute urinary toxicities were observed. No grade 2 or higher rectal toxicities were observed. The incidence of late grade 2 urinary toxicities for dose levels 1 to 4 was 23.3%, 25.7%, 27.8%, and 31.4%, respectively. Only 1 late grade 3 urinary toxicity (urethral stricture) developed in the 40-Gy dose arm; the stricture was corrected with transurethral resection. No grade 4 late urinary toxicity was observed. The 5-year cumulative incidence of prostate-specific antigen failure for dose levels 1 to 4 was 15%, 6%, 0%, and 0%. The incidence of a 2-year positive posttreatment biopsy was 47.6%, 19.2%, 16.7%, and 7.7%, respectively for the 4 dose arms (P = .013)., Conclusions: SBRT doses ranging from 32.5 to 40 Gy in 5 fractions were well tolerated without severe urinary or rectal toxicities. Biopsy outcomes suggest improved rates of tumor clearance observed with higher doses., (Copyright © 2019 Elsevier Inc. All rights reserved.)