Deep Phenotyping the Anterior Urethral Stricture: Characterizing the Relationship Between Inflammation, Fibrosis, Patient History, and Disease Pathophysiology.

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.

Outcomes of Urethroplasty for Synchronous Anterior Urethral Stricture Utilizing the Trauma and Urologic Reconstruction Network of Surgeons Length, Segment and Etiology Anterior Urethral Stricture Classification System.

OBJECTIVE: To describe the characteristics, management, and functional outcomes of patients with synchronous urethral stricture disease (SUSD) utilizing a multi-institutional cohort. METHODS: Data were collected and assessed from a prospectively maintained, multi-institutional database. Patients who underwent anterior urethroplasty for urethral stricture disease (USD) were included and stratified by the presence or absence of SUSD. USD location and etiology were classified according to the Trauma and Urologic Reconstruction Network of Surgeons Length, Segment and Etiology Anterior Urethral Stricture Classification System. Anterior urethroplasty techniques were recorded for both strictures. Functional failure was compared between groups. RESULTS: One thousand nine hundred eighty-three patients were identified, of whom, 137/1983 (6.9%) had SUSD. The mean primary stricture length for patients with SUSD was 3.5 and 2.6 cm for the secondary stricture. Twelve anterior urethroplasty technique combinations were utilized in treating the 27 different combinations of SUSD. Functional failure was noted in 18/137 (13.1%) patients with SUSD vs 192/1846 (10.4%) patients with solitary USD, P = .3. SUSD was not associated with increased odds of functional failure. S classifications: S1b, P = .003, S2a, P = .001, S2b, P = .01 and S2c, P = .02 and E classifications: E3a, P = .004 and E6, P = .03, were associated with increased odds of functional failure. CONCLUSION: Repair of SUSD in a single setting does not increase the risk of functional failure compared to patients with solitary USD. Increasing S classification, S1b through S2c and E classifications E3a and E6 were associated with increased functional failure. This reinforces the importance of the Trauma and Urologic Reconstruction Network of Surgeons Length, Segment and Etiology Anterior Urethral Stricture Classification System as a necessary tool in large-scale multi-institutional analysis when assessing highly heterogenous patient populations.

Haemorrhagic cystitis: a review of management strategies and emerging treatments.

Haemorrhagic cystitis (HC) is characterised by persistent haematuria and lower urinary tract symptoms following radiotherapy or chemotherapy. Its pathogenesis is poorly understood but thought to be related to acrolein toxicity following chemotherapy or fibrosis/vascular remodelling after radiotherapy. There is no standard of care for patients with HC, although existing strategies including fulguration, hyperbaric oxygen therapy, botulinum toxin A, and other intravesical therapies have demonstrated short-term efficacy in cohort studies. Novel agents including liposomal tacrolimus are promising targets for further research. This review summarises the incidence and pathogenesis of HC as well as current evidence supporting its different management strategies.

Clinical Validation of an Adult-acquired Buried Penis Classification System Based on Standardized Evaluation of the Penis, Abdomen, and Scrotum.

OBJECTIVE: To clinically validate a previously developed adult-acquired buried penis (AABP) classification system that is based on a standardized preoperative physical examination that subtypes patients by their penile skin/escutcheon complex (P), abdominal pannus (A), and scrotal skin (S). METHODS: The Trauma and Urologic Reconstruction Network of Surgeons (TURNS) database was used to create an AABP cohort. Patients were retrospectively classified using the previously described PAS classification system. The frequency of subtypes, surgical methods utilized for AABP repair, and correlations between PAS classification and surgery subtypes were analyzed. RESULTS: The final cohort consisted of 101 patients from 10 institutions. Interrater reliability between two reviewers was excellent (κ = 0.95). The most common subtypes were P2c (contributory escutcheon+insufficient penile skin; 27%) and P2a (contributory escutcheon+sufficient penile skin; 21%) for penile subtypes, A0 (no pannus; 41%) and A1 (noncontributory pannus; 39%) for abdominal subtypes, and S0 (normal scrotal skin with preserved scrotal sulcus; 71%) for scrotal subtypes. AABP repair procedures included escutcheonectomy (n = 59, 55%), scrotoplasty (n = 51, 48%), split-thickness skin grafting (n = 50, 47%), penile skin excision (n = 47, 44%) and panniculectomy (n = 7, 7%). P, A, and S subtypes were strongly associated with specific AABP surgical techniques. CONCLUSION: The PAS classification schema adequately describes AABP heterogeneity, is reproducible among observers, and correlates well with AABP surgery types. Future work will focus on how PAS subtypes affect both surgical and patient-centered outcomes.

Urinary microbiome differences between lichen sclerosus induced and non-lichen sclerosus induced urethral stricture disease.

OBJECTIVE: To describe differences in the urinary microbiome of patients with pathologically confirmed lichen sclerosus (LS) urethral stricture disease (USD) vs non-lichen sclerosus (non-LS) USD pre- and post-operatively. METHODS: Patients were pre-operatively identified and prospectively followed, all underwent surgical repair and had tissue samples obtained to make a pathological diagnosis of LS. Pre- and post-operative urine samples were collected. Bacterial genomic DNA was extracted. Alpha and beta diversity measurements were calculated and compared. A zero-inflated negative binomial model was utilized to compare taxa abundances between disease status and surgery status. RESULTS: Urine samples were obtained from both cohorts, 69 samples in total: 36 samples were obtained pre-operatively and 33 samples were obtained post-operatively. Ten patients provided both a pre-operative and post-operative urine sample. Twenty-six patients had pathological evidence of LS and 33 patients did not. There was a statistically significant difference in alpha diversity between the pre-operative urine samples of patients with non-LS USD and LS USD, (p = 0.01). There was no significant difference in alpha diversity within post-operative urine samples between patients with non-LS USD and LS USD, (p = 0.1). A significant difference was observed in Weighed UniFrac distances with respect to disease and operative status, (p = 0.001 and 0.002). CONCLUSIONS: LS USD have significant alterations in diversity and differential abundance of urine microbiota compared to non-LS USD controls. These findings could be used to guide further investigations into the role of the urinary microbiome in LS USD pathogenesis, severity of presentation, and stricture recurrence.

Biomarkers in Urethral Stricture Disease and Benign Lower Urinary Tract Disease.

Increased understanding of molecular pathophysiology has led to the detection of clinically applicable biomarkers across medicine, which allow for minimally invasive detection, management, and monitoring of disease processes. Although biomarkers have traditionally played a more significant role in malignancy, these goals also pertain to benign disease. Herein, the authors review ongoing research into biomarker investigation and application in urethral stricture disease, benign prostatic hyperplasia, bladder outlet obstruction, and overactive bladder. No biomarkers for these entities are currently in clinical use; however, numerous physiologic pathways provide targets for current and future study.

A multicenter prospective cohort study of endoscopic urethral realignment versus suprapubic cystostomy after complete pelvic fracture urethral injury.

BACKGROUND: Pelvic fracture urethral injury (PFUI) occurs in up to 10% of pelvic fractures. There is mixed evidence supporting early endoscopic urethral realignment (EUR) over suprapubic tube (SPT) placement and delayed urethroplasty. Some studies show decreased urethral obstruction with EUR, while others show few differences. We hypothesized that EUR would reduce the rate of urethral obstruction after PFUI. METHODS: Twenty-six US medical centers contributed patients following either an EUR or SPT protocol from 2015 to 2020. If retrograde cystoscopic catheter placement failed, patients were included and underwent either EUR or SPT placement based on their institution's assigned treatment arm. Endoscopic urethral realignment involved simultaneous antegrade/retrograde cystoscopy to place a catheter across the urethral injury. The primary endpoint was development of urethral obstruction. Fisher's exact test was used to analyze the relationship between PFUI management and development of urethral obstruction. RESULTS: There were 106 patients with PFUI; 69 (65%) had complete urethral disruption and failure of catheter placement with retrograde cystoscopy. Of the 69 patients, there were 37 (54%) and 32 (46%) in the EUR and SPT arms, respectively. Mean age was 37.0 years (SD, 16.3 years) years, and mean follow-up was 463 days (SD, 280 days) from injury. In the EUR arm, 36 patients (97%) developed urethral obstruction compared with 30 patients (94%) in the SPT arm ( p = 0.471). Urethroplasty was performed in 31 (87%) and 29 patients (91%) in the EUR and SPT arms, respectively ( p = 0.784). CONCLUSION: In this prospective multi-institutional study of PFUI, EUR was not associated with a lower rate of urethral obstruction or need for urethroplasty when compared with SPT placement. Given the potential risk of EUR worsening injuries, clinicians should consider SPT placement as initial treatment for PFUI when simple retrograde cystoscopy is not successful in placement of a urethral catheter. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level III.

An Update on Female Urethral Stricture Disease.

PURPOSE OF REVIEW: To provide an overview of female urethral stricture disease and updates on surgical outcomes. RECENT FINDINGS: In a large retrospective case series, women reported significant improvements in urinary symptoms and quality of life following treatment of their urethral stricture. Both vaginal flap and buccal mucosal graft urethroplasty have higher short- and long-term success rates than urethral dilation. Female urethral stricture disease is rare and surgical reconstruction has the highest likelihood of long-term success. Due to the complexity of reconstruction, referral to a reconstructive trained urologist should be considered.

The Outcomes of Pelvic Fracture Urethral Injuries Stratified by Urethral Injury Severity: A Prospective Multi-institutional Genitourinary Trauma Study (MiGUTS).

OBJECTIVE: To determine patient outcomes across a range of pelvic fracture urethral injury (PFUI) severity. PFUI is a devastating consequence of a pelvic fracture. No study has stratified PFUI outcomes based on severity of the urethral distraction injury. METHODS: Adult male patients with blunt-trauma-related PFUI were followed prospectively for a minimum of six months at 27 US medical centers from 2015-2020. Patients underwent retrograde cystourethroscopy and retrograde urethrography to determine injury severity and were categorized into three groups: (1) major urethral distraction, (2) minor urethral distraction, and (3) partial urethral injury. Major distraction vs minor distraction was determined by the ability to pass a cystoscope retrograde into the bladder. Simple statistics summarized differences between groups. Multi-variable analyses determined odds ratios for obstruction and urethroplasty controlling for urethral injury type, age, and Injury Severity Score. RESULTS: There were 99 patients included, 72(72%) patients had major, 13(13%) had minor, and 14(14%) had partial urethral injuries. The rate of urethral obstruction differed in patients with major (95.8%), minor (84.6%), and partial injuries (50%) (P < 0.001). Urethroplasty was performed in 90% of major, 66.7% of minor, and 35.7% of partial injuries (P < 0.001). CONCLUSION: In PFUI, a spectrum of severity exists that influences outcomes. While major and minor distraction injuries are associated with a higher risk of developing urethral obstruction and need for urethroplasty, up to 50% of partial PFUI will result in obstruction, and as such need to be closely followed.

Adult-Acquired Buried Penis Classification and Surgical Management.

In this article, the authors discuss the epidemiology, pathophysiology, and initial work-up for men with adult-acquired buried penis syndrome (AABP). Given the significant heterogeneity of AABP, a classification system is proposed which classifies the condition by the status of the abdominal pannus, the escutcheon, the penile skin and the scrotal skin, and their respective fascial attachments. Classification is achieved by a uniform assessment of anatomy using the proposed standardized preoperative photos. Various surgical strategies to repair AABP are proposed which, importantly, should be in line with the patient-centered goals and also differ widely with the condition.

Complex Lower Genitourinary Fistula Repair: Rectourethral Fistula and Puboprostatic Fistula.

Rectourethral fistula (RUF) and puboprostatic fistula (PPF) are potentially devastating complications that can develop after various pelvic insults, most notable treatment of prostate cancer. Both entities represent surgical challenges given the complex anatomy, risk of injury to adjacent structures, and poor tissue quality and wound healing. While extirpative surgery may be necessary for some patients, meticulous surgical dissection and interposition of healthy muscle allow for fistula repair in a high proportion of appropriately selected patients, especially in RUF. Herein the authors describe the nature, management, and outcomes of RUF and PPF with a full review of the literature.

Patient Risk Factors Associated with Reported Urinary Quality of Life Following Artificial Urinary Sphincter Placement: A Paired Pre and Postoperative Analysis.

OBJECTIVE: To evaluate potential associations between patient risk factors and incontinence related patient-reported outcome measures (PROMs) preandpost artificial urinary sphincter (AUS) implantation. We hypothesize patient risk factors, including prior radiation and diabetes will have a negative association with post AUS PROMs. METHODS: A review of prospectively collected preandpostoperative Incontinence Symptom Index [ISI] and Incontinence Impact Questionnaire-7 (IIQ-7)s from multiple institutions in the Trauma and Urologic Reconstruction Network of Surgeons was performed. Changes in preandpost AUS ISI and IIQ-7 scores were compared for the entire cohort then stratified by patients with prior AUS, obesity, diabetes, prior radiation, and mixed urinary incontinence. RESULTS: A total of 145 patients, 67.2 (SD 10.9) years had complete preandpost AUS questionnaires (median follow up 186 days, IQR 136-362). Post AUS ISI and IIQ-7 scores improved significantly for the group at large. Prior radiation was associated with less improvement in total IIQ-7 scores, -25.5 (31.9) vs -39 (33.0), P = .03. Obesity was associated with a greater reduction in incontinence severity -13.6 (SD 9.1) vs -9.2 (SD 8.9), P<0.01, urge -5.2(SD 4.2) vs -2.5(SD 4.5), P <.01, and total ISI score -29.7(SD19.7) vs -21.2 (SD 19.9), P = .02. Prior AUS, diabetes, and mixed incontinence were not associated with post AUS PROMs outcome. CONCLUSION: Overall, patients reported a significant reduction in incontinence severity, bother, impact, and distress following AUS placement. Prior radiation was associated with less improvement in total IIQ-7 scores. In contrast, obesity demonstrated a greater reduction in ISI severity and urge scores compared to non-obese patients.

The Lived Experience of Patients with Adult Acquired Buried Penis.

PURPOSE: We describe the lived experience of adults with acquired buried penis (AABP) through thematic analysis of patient interviews. We examine the challenges that patients face and the impacts of surgery. MATERIALS AND METHODS: This mixed-methods study utilized validated instruments and semi-structured interviews to capture pre- and postsurgical outcomes. Semi-structured interviews were conducted with open-ended questions to elicit the impact of AABP on a patient's quality of life in several domains including urinary function, sexual function, interpersonal relationships and mental health. Recruitment was completed once we achieved thematic saturation. RESULTS: Twenty patients participated in the study; 11 underwent surgical treatment for AABP. Semi-structured interviewee responses were coded into 12 different themes and 39 subthemes. The most common themes were problems with urinary (19/20, 95%) and sexual function (19/20, 95%). Most participants (16/20, 80%) reported negative impacts of AABP on social life. Interviewees struggled with relationships (8/20, 40%) and mental health (11/20, 55%), often avoiding romantic relationships and reporting fear of rejection with concomitant depression and/or anxiety. The majority (70%, 14/20) experienced difficulties accessing care. Among patients who underwent surgery, the majority discussed improvement in urinary and sexual function (82% [9/11] and 73% [8/11], respectively). Though weight gain was a precipitating factor, weight loss did not result in symptom improvement. Rather, in 4/20 (20%), weight loss made their condition worse. CONCLUSIONS: Patients living with AABP experience profound negative impacts on quality of life including their urinary and sexual function, social life and mental health. Many patients face issues with access to care.

Transurethral reconstruction of fossa navicularis strictures with dorsal inlay buccal mucosa graft urethroplasty.

PURPOSE: To describe a single stage, glans-sparing urethroplasty technique for fossa navicularis strictures using a transurethral dorsal inlay buccal mucosa graft. METHODS: We conducted a retrospective review of a prospectively maintained urethral stricture database to identify all fossa navicularis strictures reconstructed with a single stage, transurethral dorsal inlay buccal mucosa graft urethroplasty (5/2015-6/2020). Primary outcomes were anatomic success, defined as the ability to pass a 17 Fr flexible cystoscope, and functional success, defined as the lack of obstructive voiding symptoms and no need for further procedures. Secondary outcomes were postoperative complications and patient satisfaction. RESULTS: Sixteen patients were included. Mean age was 63.1 years (43.9-75.6) and mean stricture length was 1.7 cm (1.4-2.0). Stricture etiology included internal trauma (62.5%), idiopathic (25.0%), and lichen sclerosus (12.5%). Prior endoscopic procedures were done in 75% of patients. Over a median follow-up of 28.8 months (IQR 17.6-38.0), anatomic success was 15/16 (93.8%) and functional success was 16/16 (100%). The single anatomic recurrence was at 4.2 months postoperatively. No additional procedures were required. Urinary tract infection occurred in 25% (4/16). There were no instances of de novo erectile dysfunction, chordee, or wound infection. All patients would recommend urethroplasty to others and all patients were either very satisfied (83.3%) or satisfied (16.7%) with the procedure. Penile sensitivity was unchanged in 83.3%, increased in 8.3% and decreased in 8.3%. CONCLUSION: Transurethral dorsal inlay buccal mucosa graft urethroplasty is a viable option for reconstruction of fossa navicularis strictures that avoids splitting the glans and results in excellent cosmesis.

Defining Success after Anterior Urethroplasty: An Argument for a Universal Definition and Surveillance Protocol.

PURPOSE: A successful urethroplasty has been defined in different ways across studies. This variety in the literature makes it difficult to compare success rates and techniques across studies. We aim to evaluate the success of anterior urethroplasty based on different definitions of success in a single cohort. MATERIALS AND METHODS: Data were collected from a multi-institutional, prospectively maintained database. We included men undergoing first-time, single-stage, anterior urethroplasty between 2006 and 2020. Exclusion criteria included lack of followup, hypospadias, extended meatotomy, perineal urethrostomy, posterior urethroplasty and staged repairs. We compared 5 different ways to define a "failed" urethroplasty: 1) stricture retreatment, 2) anatomical recurrence on cystoscopy, 3) peak flow rate <15 ml/second, 4) weak stream on questionnaire and 5) failure by any of these measures. Kaplan-Meier survival curves were generated for each of the definitions. We also compared outcomes by stricture length, location and etiology. RESULTS: A total of 712 men met inclusion criteria, including completion of all types of followup. The 1- and 5-year estimated probabilities of success were "retreatment," 94% and 75%; "cystoscopy," 88% and 71%; "uroflow," 84% and 58%; "questionnaire," 67% and 37%; and "any failure," 57% and 23%. This pattern was inconsistent across stricture length, location and etiology. CONCLUSIONS: The estimated probability of success after first-time, anterior urethroplasty is highly dependent on the way success is defined. The variability in definitions in the literature has limited our ability to compare urethroplasty outcomes across studies.

Urethral duplication in an adult male: anatomic variants and operative approach to reconstruction.

Duplicated anterior urethras are a rare congenital anomaly that is exceedingly uncommon among adult patients, as surgical correction is often completed during childhood. We present the case of a 33-year-old man with uncorrected duplicated anterior urethras and urinary retention due to severe urethral stricture disease involving both of his uncorrected duplicated anterior urethras. This report highlights an operative management strategy for reconstruction to create a single, unobstructed urethra that terminates in an orthotopic meatus. Further, we provide an overview of the anatomic variants of urethral duplication.

Minimizing Antibiotic Use in Urethral Reconstruction.

PURPOSE: There are no established guidelines regarding management of antibiotics for patients specifically undergoing urethral reconstruction. Our aim was to minimize antibiotic use by following a standardized protocol in the pre-, peri- and postoperative setting, and adhere to American Urological Association antibiotic guidelines. We hypothesized that prolonged suppressive antibiotics post-urethroplasty does not prevent urinary tract infection and/or wound infection rates. MATERIALS AND METHODS: We prospectively treated 900 patients undergoing urethroplasty or perineal urethrostomy at 11 centers over 2 years. The first-year cohort A received prolonged postoperative antibiotics. Year 2, cohort B, did not receive prolonged antibiotics. A standardized protocol following the American Urological Association guidelines for perioperative antibiotics was used. The 30-day postoperative infectious complications were determined. We used chi-square analysis to compare the cohorts, and multivariate logistic regression to identify risk factors. RESULTS: The mean age of participants in both cohorts was 49.7 years old and the average stricture length was 4.09 cm. Overall, the rate of postoperative urinary tract infection and wound infection within 30 days was 5.1% (6.7% in phase 1 vs 3.9% in phase 2, p=0.064) and 3.9% (4.1% in phase 1 vs 3.7% in phase 2, p=0.772), respectively. Multivariate logistic regression analysis of patient characteristics and operative factors did not reveal any factors predictive of postoperative infections. CONCLUSIONS: The use of a standardized protocol minimized antibiotic use and demonstrated no benefit to prolonged antibiotic use. There were no identifiable risk factors when considering surgical characteristics. Given the concern of antibiotic over-prescription, we do not recommend prolonged antibiotic use after urethral reconstruction.