Significance of inflammatory biomarkers and urethral histology in patients with urethral stricture disease in relation to treatment outcome—a single centre prospective study in the north-eastern part of India

Background Inflammation plays a very important role in defining the urethral stricture. Inflammatory biomarkers may play an important role in predicting the underlying pathophysiology as well as outcome of surgery. Histology of urethral strictures along with histology of urethra proximal and distal to stricture segment may have a role in predicting the outcome of the surgery. The literature discussing this aspect is rare; thus, this novel study aimed to find out the role of inflammatory biomarkers and urethral histology in predicting the outcome of surgery in urethral stricture disease. Methods This prospective study had 105 patients with age more than 15 years with urethral stricture. Baseline characteristics, routine blood tests including inflammatory blood markers (CRP, ESR, HbA1C, fasting insulin, serum ferritin, etc.) were recorded. They underwent various types of surgery, and first biopsy was taken from stricture segment and second biopsy from proximal to stricture segment and third biopsy from distal to stricture segment and evaluated for the presence of features of lichen sclerosus and inflammation. Primary endpoint was to diagnose the role of inflammatory biomarkers and histology of stricture in stricture recurrence. Results Their mean age was 43.3 ± 13.46 years. Mean CRP of 11.54 ± 3.64 in patients with failure and 9.59 ± 2.77 in patients with successful outcome (p 0.025). Other inflammatory biomarkers like HbA1C, fasting insulin, ESR, serum ferritin, NLR had no significant correlation with the outcome. The presence of features of lichen sclerosus like hyperkeratosis and severe inflammation in stricture segment predicted higher likelihood of failure. Histology of proximal and distal segment of urethral stricture had no significant relationship in predicting outcome. Staged urethroplasty with buccal mucosal graft outperformed single-stage urethroplasty in biopsy-proven LS strictures. Conclusions The present study found a negative impact of increased CRP and the presence of features of lichen sclerosus in urethral histology with the outcome of urethral stricture disease. Thus, our study confirms that inflammatory biomarkers (CRP) and histology of stricture segment play a significant role predicting the outcome of surgery.

Differential expression of miRNAs involved in biological processes responsible for inflammation and immune response in lichen sclerosus urethral stricture disease

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.

The use of local therapy in preventing urethral strictures: A systematic review

Background Urethral stricture disease is a common problem amongst men in Western countries often leading to a decreased quality of life. Current endoscopic treatment procedure shows an unsatisfying stricture recurrence rate which could be improved by addition of local therapies. Objectives To provide an overview of both preclinical and clinical studies in order to investigate current level of evidence on the addition of local therapy to improve urethral stricture recurrence rates after endoscopic procedures. Methods We performed a literature search in December 2020 and August 2021 using Cochrane, Embase, PubMed, Scopus and Web of Science and identified articles through combinations of search terms for ‘urethral stricture disease’, ‘stricture formation’ and ‘local interventions’. We used the SYRCLE, RoB-2 and ROBINS-I tools to assess risk of bias across included studies. We did not perform a meta-analysis due to methodological differences between studies. Results We included 32 articles in the qualitative analysis, 20 of which were preclinical studies and 12 clinical studies. Regarding preclinical articles using an animal model, nearly all interventions showed to have a positive effect on either urethral fibrosis, urethral stricture formation and/or fibrotic protein expression levels. Here, immunosuppressants and chemotherapeutics seemed most promising for possible clinical purposes. Regarding clinical studies, mitomycin-C and hyaluronic acid and carboxymethylcellulose showed positive effects on urethral stricture recurrence rates with low to intermediate risk of bias across studies. However, the positive clinical effects of mitomycin-C and steroids seemed to decrease in studies with a longer follow-up time. Conclusion Although local adjuvant use of mitomycin-C or hyaluronic acid and carboxymethylcellulose may carry clinical potential to improve urethral structure recurrence rates after endoscopic procedures, we believe that a large, well-designed RCT with a yearlong follow-up time is necessary to identify the true clinical value.

Retrograde urethrography, sonouretrography and magnetic resonance urethrography in evaluation of male urethral strictures. Should the novel methods become the new standard in radiological diagnosis of urethral stricture disease?

Purpose To verify which of the diagnostic modalities: Voiding cystouretrography (VCUG), Sonouretrography (SUG) or Magnetic resonance uretrography (MRU) is the most accurate in the assessment of urethral strictures in males and in what cases the application of novel imaging techniques benefits most. Methods 55 male patients with a diagnosis of urethral stricture, were enrolled in this prospective study. Initial diagnosis of urethral stricture was based on anamnesis, uroflowmetry and VCUG. Additional imaging procedures—SUG and MRU were performed before the surgery. Virtual models and 3D printed models of the urethra with the stricture were created based on the MRU data. Exact stricture length and location were evaluated by each radiological method and accuracy was verified intraoperatively. Agreement between SUG and MRU assessments of spongiofibrosis was evaluated. MRU images were independently interpreted by two radiologists (MRU 1, MRU 2) and rater reliability was calculated. Results MRU was the most accurate [(95% CI 0.786–0.882), p < 0.0005] with an average overestimation of 1.145 mm (MRU 1) and 0.727 mm (MRU 2) as compared with the operative measure. VCUG was less accurate [(95% CI 0.536–0.769), p < 0.0005] with an average underestimation of 1.509 mm as compared with operative measure. SUG was the least accurate method [(95% CI 0.510–0.776), p < 0.0005] with an average overestimation of 2.127 mm as compared with the operative measure. There was almost perfect agreement of MRU interpretations between the radiologists. Conclusions VCUG is still considered as a ‘gold standard’ in diagnosing urethral stricture disease despite its limitations. SUG and MRU provide extra guidance in preoperative planning and should be considered as supplemental for diagnosing urethral stricture. Combination of VCUG and SUG may be an optimal set of radiological tools for diagnosing patients with urethral strictures located in the penile urethra. MRU is the most accurate method and should particularly be considered in cases of post-traumatic or multiple strictures and strictures located in the posterior urethra.