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Flat urothelial lesions are common and recognition is important for patient management. Over- and undertreatment can be a consequence of misdiagnosis. Reporting the right diagnosis is also important for the follow-up. We describe the most frequent entities with a focus on clinical meaning. Several of these described lesions do not figure in the WHO 2022 classification; therefore knowledge of them is important. We also discuss benign, precursor and malignant lesions and suggest the latest nomenclatures given by international societies. Molecular data, as far as currently known, are included where possible. The aim is to give a practical and precise overview of this complicated topic. [ABSTRACT FROM AUTHOR]

Purpose: Interstitial cystitis/bladder pain syndrome is a chronic urological condition diagnosed in nearly 8 million females in the United States. Whether urinary microbiota play an etiological role remains controversial. Most studies assessed the microbiota of interstitial cystitis/bladder pain syndrome patients with voided or catheterized urine as a proxy for bladder urothelium; however, urine may not be a true reflection of the bladder microbiota. Bladder biopsy tissue may provide a more accurate, and thus more clinically relevant, picture of bladder microbiota. Materials and Methods: Bladder biopsy tissues were obtained from: (1) 30 females with interstitial cystitis/bladder pain syndrome (18-80 years old) via cystoscopically guided cold-cup biopsy following therapeutic bladder hydrodistention, and (2) 10 non–interstitial cystitis/bladder pain syndrome females undergoing pelvic organ prolapse repair. To detect bacteria, technical duplicates of each RNAlater-preserved biopsy were subjected to 16S rRNA gene sequencing. To visualize bacteria, paraformaldehyde-fixed, paraffin-embedded biopsies were subjected to a combined multiplexed fluorescence in situ hybridization and fluorescence immunohistochemistry assay and confocal microscopy. Results: Bacteria were detected by 16S rRNA gene sequencing in at least 1 technical duplicate of most biopsies. The most abundant genus was Staphylococcus, followed by Lactobacillus; Escherichia was common but not abundant. There was no significant difference between interstitial cystitis/bladder pain syndrome patients and controls (P > .05). Combined fluorescence in situ hybridization and immunohistochemistry reproducibly detected 16S rRNA in epithelial cells and shed cells in the urothelium and lesioned areas and capillary walls in the lamina propria of human bladder biopsy tissue. Conclusions: We conclude that urothelial and urinary microbiota are similar but not identical in adult females. [ABSTRACT FROM AUTHOR]

Purpose: Half of patients with muscle-invasive bladder cancer worldwide may not receive curative-intent therapy. Elderly or frail patients are most affected by this unmet need. TAR-200 is a novel, intravesical drug delivery system that provides sustained, local release of gemcitabine into the bladder over a 21-day dosing cycle. The phase 1 TAR-200-103 study evaluated the safety, tolerability, and preliminary efficacy of TAR-200 in patients with muscle-invasive bladder cancer who either refused or were unfit for curative-intent therapy. Materials and Methods: Eligible patients had cT2-cT3bN0M0 urothelial carcinoma of the bladder. TAR-200 was inserted for 4 consecutive 21-day cycles over [ABSTRACT FROM AUTHOR]

Purpose: We sought to evaluate the impact of repeat transurethral resection of bladder tumor prior to radical cystectomy on oncologic outcomes in a contemporary cohort at a tertiary care center. Materials and Methods: An Institutional Review Board approved review of 657 patients diagnosed with muscle-invasive bladder cancer who underwent radical cystectomy at our institution for clinical stage T2 urothelial carcinoma between 2005 and 2017 was performed. Patients with and without repeat transurethral resection of bladder tumor were matched 1-to-1 by propensity score. Matching was done by age, gender, receipt of neoadjuvant chemotherapy, preoperative hydronephrosis, variant histology, lymphovascular invasion, or carcinoma in situ on index transurethral resection of bladder tumor. Results: A total of 548 patients with muscle-invasive bladder cancer were included after matching (2 groups of 274 patients). Kaplan-Meier estimates of recurrencefree and overall survival demonstrated no significant difference based upon performance of repeat transurethral resection of bladder tumor (P = 1.0 and P = .3, respectively). When outcomes were stratified by pathology of repeat transurethral resection of bladder tumor specimens, those with pT0 had superior recurrence-free and overall survival compared to those with residual muscle invasive disease (P < .001 and P = .001, respectively). Notably, more than 60% of patients who were pT0 on repeat transurethral resection of bladder tumor had residual disease at the time of radical cystectomy. Conclusions: Repeat transurethral resection of bladder tumor prior to radical cystectomy, irrespective of receipt of neoadjuvant chemotherapy, was not associated with improved survival outcomes in this propensity score matched muscle-invasive bladder cancer cohort. The absence of residual tumor on pathological evaluation of repeat transurethral resection of bladder tumor specimen was prognostic and was associated with improved survival outcomes. However, a large percentage of patients with pT0 disease on repeat transurethral resection of bladder tumor had residual disease on radical cystectomy pathology. [ABSTRACT FROM AUTHOR]

Background: Bacillus Calmette-Guérin (BCG) has been well recognized as the first-line intravesical therapy for high-risk nonmuscle-invasive bladder cancer (NMIBC). Oncotice, the Tice strain of BCG, serves as a viable alternative to the Connaught strain owing to the worldwide shortage of the latter. We retrospectively compared these two strains in terms of efficacy and adverse effects (AE) in patients who underwent at least one maintenance course after induction. Methods: In this single-institution, retrospective study, patients diagnosed with NMIBC who were administered either Connaught or Tice intravesical therapy were enrolled. Recurrence was defined as the reappearance of urothelial carcinoma. Progression was defined as stage/grade advance, metastasis, or cancer-related death. The primary outcomes were recurrence-free survival (RFS) and progression-free survival (PFS), and the secondary outcome was AE. Results: A total of 76 and 84 patients receiving Tice and Connaught, respectively were enrolled. The median follow-up periods for the Tice and Connaught groups were 32.0 months (range, 7-69 months) and 81.5 months (range, 9-154 months), respectively. Kaplan-Meier method showed no intergroup difference with regard to 3-year RFS and PFS. On Cox multivariate regression analysis, Tice was a significant predictor for inferior PFS (HR = 5.30; 95% CI, 1.11-25.29; p = 0.036). The AE incidence was 38.3% in the Connaught group and 25.0% in the Tice group (p = 0.079). Conclusion: Tice and Connaught were comparable in terms of RFS, PFS, and AE for patients with NMIBC accepting BCG induction and at least one maintenance course in our real-world practice. However, Tice was a predictor of inferior PFS on multivariate analysis. [ABSTRACT FROM AUTHOR]

For descriptive purposes, the urinary tract is divided into upper and lower parts. The kidneys and ureters make up the upper urinary tract with the urinary bladder and urethra forming the lower urinary tract. This article discusses the anatomy of the kidney and ureter highlighting key aspects that are of relevance to their function and to the surgeon. The article also includes a brief account of the anatomy of the suprarenal gland because of the close anatomical relationship between it and the upper urinary tract. [ABSTRACT FROM AUTHOR]

For descriptive purposes, the urinary tract is divided into upper and lower parts. The kidneys and ureters make up the upper urinary tract with the urinary bladder and urethra forming the lower urinary tract. In this article, a detailed description of the surgical and functional anatomy of the urinary bladder is followed by a description of the clinical anatomy of the female and male urethra. There then follows a brief description of the relevant anatomy of the prostate and seminal vesicles. While not strictly involved in the conduction of urine from the bladder to the exterior, the prostate and seminal vesicles are so intimately related (both topographically and functionally) to the urethra and bladder that no account of the lower urinary tract in the male would be complete without them. It is conventional therefore to regard the prostate and seminal vesicles as part of the lower urinary tract. [ABSTRACT FROM AUTHOR]

• Bladder cancer recurrence after TUR remains a challenge, necessitating innovative approaches like Nectin-4 CAR-T cells. • Combining intravesical BCG or ICIs with CAR-T therapy may enhance efficacy against bladder cancer's immune suppression. • Nectin-4 CAR-T cells hold promise in revolutionizing bladder cancer treatment by preventing recurrence. Bladder cancer poses a significant global health challenge, particularly with its prevalence in males and the increasing incidence rates in Europe. While non-muscle invasive bladder cancer can be managed with localized treatments, its recurrence remains a concern. Intravesical Bacillus Calmette-Guérin therapy triggers an immune response against cancer cells, yet recurrences post- transurethral resection of bladder tumor persist. Thus, innovative strategies are needed. We propose the use of Nectin-4 targeted chimeric antigen receptor T cell therapy to prevent non-muscle invasive bladder cancer recurrence and progression. Nectin-4 is expressed in non-muscle invasive bladder cancer, making it an ideal target. CAR-T cells engineered with Nectin-4 receptors can specifically eliminate cancer cells. By directly applying these cells intravesically, the limitations of CAR-T cell access to solid tumors are circumvented. However, challenges persist, such as the immunosuppressive microenvironment of bladder cancer. This can be addressed by combining intravesical Bacillus Calmette-Guérin with CAR-T therapy or utilizing immune checkpoint inhibitors. CAR-T therapy-related toxicities, like cytokine release syndrome, can be managed with IL-6 and IL-1 receptor inhibitors. Our hypothesis suggests that Nectin-4 targeted CAR-T cells have the potential to revolutionize bladder cancer treatment. This therapy could not only eliminate cancer cells but also prevent recurrence and progression by inducing immune memory. Although further research is needed, this innovative approach shows promise in the treatment of non-muscle invasive bladder cancer. [ABSTRACT FROM AUTHOR]

Although primary vesical calculi is an ancient disease, the mechanism of calculi formation remains unclear. In this study, we established a novel primary vesical calculi model with d , l -choline tartrate in mice. Compared with commonly used melamine and ethylene glycol models, our model was the only approach that induced vesical calculi without causing kidney injury. Previous studies suggest that proteins in the daily diet are the main contributors to the prevention of vesical calculi, yet the effect of fat is overlooked. To assay the relationship of dietary fat with the formation of primary vesical calculi, d , l -choline tartrate-treated mice were fed a high-fat, low-fat, or normal-fat diet. Genetic changes in the mouse bladder were detected with transcriptome analysis. A high-fat diet remarkably reduced the morbidity of primary vesical calculi. Higher fatty acid levels in serum and urine were observed in the high-fat diet group, and more intact epithelia in bladder were observed in the same group compared with the normal- and low-fat diet groups, suggesting the protective effect of fatty acids on bladder epithelia to maintain its normal histological structure. Transcriptome analysis revealed that the macrophage differentiation-related gene C–X–C motif chemokine ligand 14 (Cxcl14) was upregulated in the bladders of high-fat diet-fed mice compared with those of normal- or low-fat diet-fed mice, which was consistent with histological observations. The expression of CXCL14 significantly increased in the bladder in the high-fat diet group. CXCL14 enhanced the recruitment of macrophages to the crystal nucleus and induced the transformation of M2 macrophages, which led to phagocytosis of budding crystals and prevented accumulation of calculi. In human bladder epithelia (HCV-29) cells, high fatty acid supplementation significantly increased the expression of CXCL14. Dietary fat is essential for the maintenance of physiological functions of the bladder and for the prevention of primary vesical calculi, which provides new ideas for the reduction of morbidity of primary vesical calculi. With sufficient fatty acid, the bladder epithelial cells secreted more C-X-C motif chemokine ligand 14 (CXCL14), which enhanced the recruitment of macrophages to the crystal nucleus and promoted phagocytosis of budding crystals. [Display omitted] [ABSTRACT FROM AUTHOR]

Purpose: We investigated the pathological response rates and survival associated with 3 vs 4 cycles of cisplatin-based neoadjuvant chemotherapy (NAC) in patients with cT2-4N0M0 muscle invasive bladder cancer. Materials and Methods: In this cohort study we analyzed clinical data of 828 patients treated with NAC and radical cystectomy between 2000 and 2020. A total of 384 and 444 patients were treated with 3 and 4 cycles of NAC, respectively. Pathological objective response (pOR; ypT0-Ta-Tis-T1 N0), pathological complete response (pCR; ypT0 N0), cancer-specific survival and overall survival were investigated. Results: pOR and pCR were achieved in 378 (45%; 95% CI 42, 49) and 207 (25%; 95% CI 22, 28) patients, respectively. Patients treated with 4 cycles of NAC had higher pOR (49% vs 42%, p[0.03) and pCR (28% vs 21%, p[0.02) rates compared to those treated with 3 cycles. This effect was confirmed on multivariable logistic regression analysis (pOR OR 1.46 p[0.008, pCR OR 1.57, p[0.007). On multivariable Cox regression analysis, 4 cycles of NAC were significantly associated with overall survival (HR 0.68; 95% CI 0.49, 0.94; p[0.02) but not with cancer-specific survival (HR 0.72; 95% CI 0.50, 1.04; p[0.08). Conclusions: Four cycles of NAC achieved better pathological response and survival compared to 3 cycles. These findings may aid clinicians in counseling patients and serve as a benchmark for prospective trials. Prospective validation of these findings and assessment of cumulative toxicity derived from an increased number of cycles are needed. [ABSTRACT FROM AUTHOR]

Human urinary tract malformations can cause dysfunctional voiding, urosepsis and kidney failure. Other affected individuals, with severe phenotypes on fetal ultrasound screening, undergo elective termination. Currently, there exist no specific treatments that target the primary biological disease mechanisms that generate these urinary tract malformations. Historically, the pathogenesis of human urinary tract malformations has been obscure. It is now established that some such individuals have defined monogenic causes for their disease. In health, the implicated genes are expressed in either differentiating urinary tract smooth muscle cells, urothelial cells or peripheral nerve cells supplying the bladder. The phenotypes arising from mutations of these genes include megabladder, congenital functional bladder outflow obstruction, and vesicoureteric reflux. We contend that these genetic and molecular insights can now inform the design of novel therapies involving viral vector-mediated gene transfer. Indeed, this technology is being used to treat individuals with early onset monogenic disease outside the urinary tract, such as spinal muscular atrophy. Moreover, it has been contended that human fetal gene therapy, which may be necessary to ameliorate developmental defects, could become a reality in the coming decades. We suggest that viral vector-mediated gene therapies should first be tested in existing mouse models with similar monogenic and anatomical aberrations as found in people with urinary tract malformations. Indeed, gene transfer protocols have been successfully pioneered in newborn and fetal mice to treat non-urinary tract diseases. If similar strategies were successful in animals with urinary tract malformations, this would pave the way for personalized and potentially curative treatments for people with urinary tract malformations. [ABSTRACT FROM AUTHOR]

In a histopathological study of the renal crest (RC) of kidneys of cats with chronic kidney disease (CKD), 58/90 (64%) had epithelial proliferation. Of these, 33 cats had hyperplasia of the collecting duct (CD) epithelium (CDH) alone, eight had hyperplasia of the urothelium covering the RC (RCUH), of which one had concurrent abaxial renal pelvic urothelial hyperplasia (UH), and eight had both CDH and RCUH. CDH or RCUH were present in five cats with marked dysplasia of the CD epithelium (CDD) and four cats with invasive carcinomas, which also had epithelial dysplasia. All nine cats with marked dysplasia or neoplasia of the RC also had substantially altered RC contours due to focal haemorrhage, papillary necrosis or fibrosis. Three of the carcinomas had a strong desmoplastic response. In control cats, both urothelial (RC and renal pelvis) and tubular (CD and distal tubular) cells were immunopositive for cytokeratin (CK; AE1/AE3), tubular epithelial cells were positive for vimentin (Vim) and aquaporin 2 (Aq2), while urothelial cells were positive for p63. PAX8 immunolabelling was difficult to validate. CD and UH labelling was similar to control tissue. While urothelial dysplasia had the same immunolabelling pattern as UH and control tissue, CDD was generally immunonegative for Aq2. As immunolabelling of the four carcinomas did not distinguish between tubular and urothelial origin, with three positive for both Vim and p63, all were broadly designated as RC carcinomas. Overall, proliferative epithelial lesions are common in cats with CKD and form a continuum from simple hyperplasia to neoplasia of the urothelium or CD of the RC. [ABSTRACT FROM AUTHOR]

Urothelial (transitional cell) carcinoma (UC) is the most common type of bladder cancer in humans, dogs and cats, although the incidence in cats is comparatively low. This retrospective study details the histopathological features of UC of the urinary bladder in 38 samples from 35 cats. Of the 38 samples, eight had a papillary architecture and in nine the tumour cells formed tubular or acinar structures. Tumour cell invasion of the bladder wall varied from confinement within the lamina propria or submucosa to transmural or extending to the serosa. The tumour stroma varied from sparse to abundant, with a scirrhous, myxomatous or mucinous appearance in eleven cases, three cases and one case, respectively. The degrees of tumour cell necrosis and inflammation were highly variable. We confirm that the histopathological features of bladder UC in cats have many similarities to the corresponding tumours in dogs and humans. [ABSTRACT FROM AUTHOR]

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Flat urothelial lesions fall into one of four diagnostic categories including urothelial carcinoma in-situ (CIS). There is morphologic overlap between the categories leading to immunohistochemistry (IHC) utilization in difficult cases. The purpose of this study was to examine the frequency, variation and utility of IHC use in bladder biopsy specimens over a 17 year period. A search of "CD44", "p53", and "CK20" keywords was conducted from the pathology files (1/1/2003 to 12/31/2017) on bladder biopsy specimens at our institution. Atypical (AUS), dysplastic (UD) and CIS rates were calculated. A total of 4597 cases were identified. IHC was performed on 345 specimens (7.5%, 345/4597). For cases without IHC (H&E only), the AUS rate was 4.8% (206/4252), UD rate was 9.4% (399/4252), and the CIS rate was 8.4% (359/4252). For IHC cases, the AUS rate was 5.2% (18/345), the UD rate was 8.1% (28/345), and the CIS rate was 11.3% (39/345). There was no statistical difference between the H&E only or IHC rates (p > 0.05). The absolute number IHC orders per year increased until 2011 (60 cases) but drastically declined over the last five years (5 total cases in 2017). The CIS rates have remained relatively constant. We found the AUS, UD and CIS rates were similar regardless of IHC use. Our institution was an early adopter of IHC and it quickly fell out of favor. We agree with the ISUP in that IHC has limited clinical utility for flat urothelial lesions and morphology remains the gold standard. • Examined the frequency and utility of IHC in bladder biopsies over 17 year period. • There were 345 specimens (7.5%, 399/4252) in which IHC was ordered. • Atypical, dysplastic and carcinoma in-situ rates were similar regardless of IHC use. • IHC orders have drastically fallen off in last 5 years (only 5 cases in 2017). [ABSTRACT FROM AUTHOR]

Transitional cell carcinoma (TCC) is the most common canine urinary tract tumour and mimics human invasive TCC. Human TCCs overexpress lipoxygenase (LOX)-5 and the use of target inhibitors has proven effective in inhibiting neoplastic growth. In this study, we investigated the immunohistochemical expression of LOX-5 in normal canine urinary bladder, cystitis and TCC. The comparative expression of LOX-5, cyclo-oxygenase (COX)-1 and COX-2 among the three tissue groups was also examined. Biopsy samples from cases of cystitis and TCC were reviewed from 2012 to 2016; samples of histologically normal bladder were used as controls. Dogs were excluded if they had received glucocorticoids, non-steroidal anti-inflammatory drugs (NSAIDs) and/or chemotherapy prior to tissue collection. LOX-5 was expressed in 95% of TCCs, 23% of cases of cystitis and 10% of controls. LOX-5 and COX-2 immunohistochemistry scores were significantly (P <0.01) higher in TCCs versus cystitis and normal bladders. Results of this study support the rationale for further investigation of the use of NSAIDs with dual anti COX-2 and LOX-5 effect for the treatment of canine TCC. [ABSTRACT FROM AUTHOR]

For descriptive purposes the urinary tract is divided into two parts: the upper urinary tract and the lower urinary tract. The former comprises the kidneys and ureters, while the lower urinary tract consists of the urinary bladder and the urethra. In this article, a detailed description of the surgical and functional anatomy of the urinary bladder is followed by a description of the clinical anatomy of the female and male urethra. There then follows a brief description of the relevant anatomy of the prostate and seminal vesicles. While not strictly involved in the conduction of urine from the bladder to the exterior, the prostate and seminal vesicles are so intimately related (both topographically and functionally) to the urethra and bladder that no account of the lower urinary tract in the male would be complete without them. It is conventional therefore to regard the prostate and seminal vesicles as part of the lower urinary tract. [ABSTRACT FROM AUTHOR]

The urinary tract is divided into upper and lower parts. The kidneys and ureters make up the upper urinary tract while the urinary bladder and urethra constitute the lower urinary tract. This classification while somewhat arbitrary is nevertheless useful and convenient for descriptive purposes. In this article, a detailed description of the topographical and vascular anatomy of the kidney and ureter is followed by a brief account of the anatomy of the suprarenal gland. [ABSTRACT FROM AUTHOR]

Until a recent introduction to checkpoint inhibitors, there were limited second-line chemotherapy options for urothelial carcinoma (UC) patients with disease progression after first-line, platinum-based treatment. Outcomes for patients with advanced disease over the past 30 years have highlighted a need for new and better therapy. In response to evolving interest, durvalumab (MEDI4736) was introduced as a potential treatment for advanced stages of UC. Durvalumab is a selective, high-affinity, human IgG1 kappa monoclonal antibody engineered with a triple mutation to reduce toxicity. This checkpoint inhibitor has shown promise in advanced UC and is currently the topic of much discussion in the cancer research community. This review article will explore the details surrounding durvalumab, while also giving a brief overview of additional immunotherapeutic agents utilized for UC. [ABSTRACT FROM AUTHOR]

Abstract Management of malignant urothelial tumors is often associated with extended costly treatments, some with significant morbidity. Advanced tumors are treated with radical cystectomy with neoadjuvant or adjuvant radiation or chemotherapy. Over and under interpretation of histological findings from biopsies and transurethral resections of urothelial lesions may either incur treatments with significant side effects or miss a possible window of cure, respectively. Herein we reflect our approaches and common diagnostic challenges of urothelial tumors and their mimickers, and highlight the diagnostic pitfalls and key histological and immunohistochemical differentiating features. It is useful to separate mimickers of bladder adenocarcinoma and mimics of urothelial carcinoma as the former can involve the muscularis propria, whereas the latter do not. Glandular mimickers discussed herein include cystitis cystica et glandularis with intestinal (colonic) metaplasia, endocervicosis and endometriosis, and nephrogenic adenoma. Common mimickers of urothelial carcinoma include polypoid cystitis, pseudocarcinomatous urothelial neoplasia, inverted urothelial papilloma, florid proliferation of von Brunn nests, and reactive urothelial metaplasia associated with prostatic infarction. We emphasize where clinical impression and history are important for the correct diagnosis. In some entities assessment of the entire histological picture is critical rather than focusing on isolated findings that out of context may be indistinguishable from cancer. Highlights • Mimickers of urothelial carcinoma • Mimickers of bladder adenocarcinoma • Comprehensive morphological and immunohistochemical approach • Clinical highlights [ABSTRACT FROM AUTHOR]

Objective: To evaluate the changes in urothelial dysfunction protein expressions in bladder after onabotulinumtoxin injection and correlate that with clinical outcomes in spinal cord injury (SCI) patients.Methods: Twenty-six patients with neurogenic detrusor overactivity (NDO) and urinary incontinence due to suprasacral SCI were treated with onabotulinumtoxinA 200U detrusor injection. Urodynamic studies and bladder biopsies were obtained at baseline, 3, and 6 months after treatment. Biopsy tissues were investigated for E-cadherin, zonula occludens-1 (ZO-1), mast cell activity, and urothelial cell apoptosis, sensory protein expression including purinergic receptor P2X3, endothelial NOS, inducible NOS, β3-adrenoceptors, and muscarinic receptors M2 and M3. Differences in functional protein expression between controls and SCI patients and between successful and failed treatment groups were analyzed.Results: SCI patients had significantly lower E-cadherin, higher mast cell activity, increased apoptosis, decreased M3 and eNOS expressions than the controls at baseline. Of the 26 patients, 17 (65%) showed improvement in bladder capacity by >50% at 3 months; however, improvement declined by 6 months after treatment. The urothelial expression of E-cadherin and ZO-1 increased at 3 months but had declined at 6 months. The urothelial sensory protein expression did not change significantly after treatment. M3 receptor density was significantly decreased in SCI patients at baseline and patients with treatment success 3 months after injection (p = 0.01).Conclusion: A single injection of onabotulinumtoxinA 200U improved clinical symptoms but did not significantly alter urothelial sensory protein expression. The results imply that a single 200U onabotulinumtoxinA dose might not be adequate for urothelial dysfunction in NDO. IRB: TCGH 098-53. [ABSTRACT FROM AUTHOR]

Purpose We evaluated the impact of the number of cycles of platinum based, first line chemotherapy (fewer than 6 cycles vs the conventional 6 cycles or more) on the survival of patients with metastatic urothelial carcinoma. Materials and Methods We used the RISC (Retrospective International Study of Invasive/Advanced Cancer of the Urothelium) database. The association of the number of cycles of chemotherapy with overall survival was investigated by Cox multiple regression analysis after controlling for recognized prognostic factors. We excluded patients who received fewer than 3 or more than 9 platinum chemotherapy cycles to reduce confounding factors. The primary analysis was a comparison of overall survival for 3 to 5 vs 6 to 9 cycles using 6-month landmark analysis when 281 death events were observed. Results Of the 1,020 patients in the RISC 472 received cisplatin or carboplatin, of whom 338 and 134, respectively, were evaluable. A total of 157 patients received 3 to 5 cycles (median 4) and 315 received 6 to 9 cycles (median 6). There was no significant difference in overall survival between 3 to 5 and 6 to 9 cycles (HR 1.02, 95% CI 0.78–1.33, p = 0.91). No significant interactions were observed for the type of platinum (p = 0.09) and completed planned chemotherapy (p = 0.56). The limitations of a hypothesis generating, retrospective analysis applied. Conclusions Four cycles of platinum based, first line chemotherapy appeared adequate and did not significantly compromise the survival of patients with advanced urothelial carcinoma. The omission of excessive cycles may avoid unnecessary cumulative toxicity and facilitate a better transition to second line therapy and investigational switch maintenance therapy strategies. These results require prospective validation but they may impact practice in select patients. [ABSTRACT FROM AUTHOR]

Introduction and Objectives. Digital flexible ureteroscopy (FURS) became an important diagnostic and follow-up procedure in upper urinary tract urothelial carcinoma (UTUC). Even so, many characteristics that can suggest nature of a lesion still represent a difficult challenge. The endpoint of the trial was to determine the diagnostic accuracy of NBI assisted digital flexible ureteroscopy versus standard FURS (WL) in upper tract urothelial carcinomas. Materials and Methods. White light (WL) and NBI-assisted digital FURS were performed in 65 patients, admitted for suspicion of UTUC. The inclusion criteria consisted of unilateral hematuria during cystoscopy, abnormal urinary cytology and pyelocaliceal system filling defects according to CT results. Patients with invasive UUT according to CT results were excluded. The investigation protocol included abdominal ultrasound, cytology, contrast CT scan and cystoscopy. The endoscopic examination use digital white light flexible ureteroscopy, followed by the NBI assessment of the renal collecting system urothelium. Results. A total of 78 UTUC lesions (23 pTa, 37 pT1 and 18 CIS) were confirmed by pathology in 65 patients. pTa, pT1 and CIS tumors detection rates were determined for WL combined with NBI mode by comparison to the WL evaluation overall UTUC 78 lesions (100%) versus 67 lesions (85.9%); pTa 23 lesions (100%) versus 17 lesions (73.9%); pT1 37 lesions (100%) versus 35 lesions (94.5%) and CIS 18 lesions (100%) versus 15 lesions (83.3%). Detection rate was improved in WL combined with NBI mode when compared with standard FURS (100% versus 84.4%). A total of 11 (14.1%) UTUC tumors (6 pTa, 2 pT1 and 3 CIS) were solely observed in NBI. Targeted biopsies’ specificity Rate of false-positive results 10.3% vs. 17.8% (WL vs. WL+NBI). Conclusions. NBI was an important tool regarding detection because it is providing a significant diagnostic improvement during digital flexible ureteroscopy. [ABSTRACT FROM AUTHOR]

Several connective tissue cells are present in the human bladder wall; among them, the myofibroblasts (MyF) and the so-called interstitial cells ( IC ) are a matter of investigation either by basic researchers or clinicians. The interest derives from the possibility that these two cell types could regulate the organ function forming a special sensory system in the bladder mucosa. Whereas attention for the myofibroblasts was mainly focused on understanding their role, the so-called IC are debatable starting from their nomenclature. Indeed, the IC should correspond to the previously called fibroblasts-like cells / interstitial Cajal - like cells ( ICLC )/ interstitial cells of Cajal ( ICC ) or PDGFRα positive cells , or CD34 positive cells . Recently a proper name was proposed to give them an identity, i.e. telocyte (TC). To date, this nomenclature is a better term than IC that is quite vague and can be used for all the cells that reside in the connective tissue. Noteworthy, in the bladder mucosa, TC and MyF form a hetero-cellular 3-D network. The detrusor overactivity/overactive bladder (DO/OAB) are pathological conditions characterized by hypersensitivity to filling. It has been hypothesized that erroneous afferent inputs generated in the mucosa affect the efferent pathways and, consequently, the detrusor response. Presently, we review the literature regarding the presence and the potential role of TC and MyF in control conditions and in DO/OAB. On the possibility that the 3D-network made up by these two cell types might play a major role in the genesis of anomalous afferent stimuli will be given attention. [ABSTRACT FROM AUTHOR]

Purpose The prognostic relevance of primary location of urothelial carcinoma on survival has been poorly investigated. Materials and Methods We used prospectively collected data from 3 European Organization for the Research and Treatment of Cancer advanced urothelial carcinoma studies, including 30924 (methotrexate, vinblastine, doxorubicin and cisplatin vs high dose methotrexate, vinblastine, doxorubicin and cisplatin), 30986 (methotrexate, carboplatin and vinblastine vs gemcitabine and cisplatin in patients who were not candidates for cisplatin) and 30987 (gemcitabine and cisplatin-paclitaxel vs gemcitabine and cisplatin in candidates for cisplatin). Patients were grouped by primary tumor location as those with bladder cancer or upper tract urothelial carcinoma. Progression-free and overall survival was tested by tumor location using Cox proportional hazard regression stratified by study and treatment using 2-sided α = 0.05. Results Of the 1,039 patients 878 (85.3%) and 161 (14.7%) had bladder cancer and upper tract urothelial carcinoma, respectively. Patients with bladder cancer had better performance status and were more likely to be male (p = 0.008 and <0.074, respectively). By a median followup of 4.8 years (IQR 4.0–6.7) 733 patients had died and 925 had experienced disease progression. Overall and progression-free survival did not differ significantly between bladder and upper tract urothelial carcinoma cases (p = 0.3 and 0.7, respectively), even after adjusting for the effects of Bajorin risk group by each tumor location. When upper tract urothelial carcinoma was considered separately, patients with primary ureteral tumors had better overall survival than patients with primary bladder cancer (OR = 0.74, p = 0.047). However, this association did not remain significant after adjusting for Bajorin risk group (p = 0.05). Conclusions Primary tumor location had no impact on progression-free or overall survival in patients with locally advanced or metastatic urothelial carcinoma treated with platinum based combination chemotherapy. [ABSTRACT FROM AUTHOR]

Purpose In patients with urothelial carcinoma CIS (carcinoma in situ) generally has a poor prognosis. However, to our knowledge the outcomes of pure/primary CIS and the behavior of CIS concomitant with pTa-pT4 upper tract urothelial carcinoma managed by nephroureterectomy have not been previously specified. We explored the biological and prognostic features of concomitant CIS compared with those of pure/primary CIS. Materials and Methods We queried a multicenter upper tract urothelial carcinoma database. Data from NUOG (Nishinihon Uro-Oncology Group) were analyzed, including patient gender, age, presence of bladder cancer and pT stage. Clinicopathological features were compared between the different subtypes. Cancer specific and overall survival, and the relative excess risk of death were estimated by CIS subtype. Results We identified 163 patients with CIS in the upper urinary tract, of whom pure/primary CIS was noted in 24.5%. In the concomitant CIS cohort the pathological diagnosis of the nonCIS region was pTa, pT1, pT2, pT3 and pT4 in 4.9%, 22.8%, 25.2%, 44.7% and 1.6% of patients, respectively. The sensitivity of a selective urine cytology test was higher in the pure/primary CIS group than in the concomitant CIS group (60.0% vs 37.4%). At a median followup of 32 months 10-year estimated mean cancer specific survival was 92.4 months (range 83.7 to 101.0) in the overall CIS cohort. Ten-year estimated mean cancer specific survival in patients with pure/primary CIS was significantly longer than in patients with concomitant carcinoma in situ (111.8 months, range 101.0 to 122.6 vs 85.89, range 75.3 to 96.5, log rank p = 0.007). Conclusions Patients presenting with concomitant CIS have a worse outcome than those who present with pure/primary CIS, suggesting a need to differentiate these 2 entities in the treatment decision process. [ABSTRACT FROM AUTHOR]

Purpose We tested the effects of tumor size, distribution and grade on progression-free survival in patients with upper tract urothelial carcinoma treated with flexible ureteroscopy with Ho:YAG laser photoablation. Materials and Methods Included in analysis were data on 92 consecutive patients with upper tract urothelial carcinoma treated with Ho:YAG laser photoablation from 2003 to 2015 at a single tertiary care referral center. Stringent followup was offered according to EAU (European Association of Urology) guidelines. Progression during followup was defined by tumor upgrading, distant metastases and/or a relapsing tumor that could not be completely removed with a conservative approach. Kaplan-Meier curves were used to assess the rate of disease progression according to tumor size (1 or less cm vs greater than 1 cm), tumor distribution (unifocal vs multifocal) and tumor grade (low vs high). Cox regression analysis was done to test the impact of clinical and pathological characteristics on the rate of progression-free survival. Results At a median followup of 52 months (IQR 27.8–76.4) the progression-free survival rate was 68% vs 72% in patients with a tumor size of 1 or less vs greater than 1 cm (p = 0.9), 72% vs 69% in patients with unifocal vs multifocal lesions (p = 0.6) and 75% vs 52% in patients with a low vs a high grade tumor (p = 0.03). On multivariable Cox regression analysis tumor grade at first treatment was the only independent predictor of disease progression (HR 5.16, 95% CI 1.19–22.26, p = 0.03). Conclusions High tumor grade independently decreased progression-free survival in patients with upper tract urothelial carcinoma treated with Ho:YAG laser photoablation. Tumor size greater than 1 cm and multifocality did not increase the risk of disease progression in patients treated conservatively with Ho:YAG laser photoablation. [ABSTRACT FROM AUTHOR]

Purpose Patients with Lynch syndrome are at risk for upper tract urothelial carcinoma. We sought to identify the incidence and most reliable means of point of care screening for Lynch syndrome in patients with upper tract urothelial carcinoma. Materials and Methods A total of 115 consecutive patients with upper tract urothelial carcinoma without a history of Lynch syndrome were universally screened during followup from January 2013 through July 2016. We evaluated patient and family history using AMS (Amsterdam criteria) I and II, and tumor immunohistochemistry for mismatch repair proteins and microsatellite instability. Patients who were positive for AMS I/II, microsatellite instability or immunohistochemistry were classified as potentially having Lynch syndrome and referred for clinical genetic analysis and counseling. Patients with known Lynch syndrome served as positive controls. Results Of the 115 patients 16 (13.9%) screened positive for potential Lynch syndrome. Of these patients 7.0% met AMS II criteria, 11.3% had loss of at least 1 mismatch repair protein and 6.0% had high microsatellite instability. All 16 patients were referred for germline testing, 9 completed genetic analysis and counseling, and 6 were confirmed to have Lynch syndrome. All 7 patients with upper tract urothelial carcinoma who had a known history of Lynch syndrome were positive for AMS II criteria and at least a single mismatch repair protein loss while 5 of 6 had high microsatellite instability. Conclusions We identified 13.9% of upper tract urothelial carcinoma cases as potential Lynch syndrome and 5.2% as confirmed Lynch syndrome at the point of care. These findings have important implications for universal screening of upper tract urothelial carcinoma, representing one of the highest rates of undiagnosed genetic disease in a urological cancer. [ABSTRACT FROM AUTHOR]

Purpose We investigated changes in the levels of adenosine triphosphate and nitric oxide in the urothelium of men with detrusor underactivity and benign prostatic hyperplasia. Materials and Methods We prospectively enrolled in study 30 men who planned to undergo surgical treatment for benign prostatic hyperplasia. The 15 patients with a bladder contractility index less than 100 were assigned to the detrusor underactivity group while the 15 with a bladder contractility index more than 100 were assigned to the no detrusor underactivity group. Bladder mucosal specimens were collected at surgical prostate resection, and adenosine triphosphate and endothelial nitric oxide synthase were analyzed in these specimens. The levels of adenosine triphosphate and endothelial nitric oxide synthase were compared between the 2 groups. The correlation of urodynamic parameters with adenosine triphosphate and endothelial nitric oxide synthase was assessed in all patients. Results Mean ± SEM endothelial nitric oxide synthase did not significantly differ between the detrusor underactivity and no underactivity groups (3.393 ± 0.969 vs 1.941 ± 0.377 IU/ml, p = 0.247). However, the mean level of adenosine triphosphate in the detrusor underactivity group was significantly lower than in the no detrusor underactivity group (1.289 ± 0.320 vs 9.262 ± 3.285 pmol, p = 0.011). In addition, in all patients adenosine triphosphate positively correlated with the bladder contractility index (r = 0.478, p = 0.018) and with detrusor pressure on maximal flow (r = 0.411, p = 0.046). Conclusions Adenosine triphosphate was significantly decreased in the urothelium in men with detrusor underactivity and benign prostatic hyperplasia, reflecting the change in detrusor function. [ABSTRACT FROM AUTHOR]

The ability of the urinary bladder to perform its physiological function depends largely on its mechanical characteristics. Understanding the mechanics of this tissue is crucial to the development of accurate models of not just this specific organ, but of the pelvic floor overall. In this study, we tested porcine bladder to identify variations in the tissue's viscoelastic characteristics associated with anatomical locations and swelling. We investigated this relationship using a series of stress-relaxation experiments as well as a modified Maxwell-Wiechert model to aid in the interpretation of the experimental data. Our results highlight that tissue located near the neck of the bladder presents significantly different viscoelastic characteristics than the body of the organ. This supports what was previously observed and is a valuable contribution to the understanding of the location-specific properties of the bladder. We also tested the effect of swelling, revealing that the bladder's viscoelastic behavior is mostly independent of solution osmolarity in hypoosmotic solutions, but the use of a hyperosmotic solution can significantly affect its behavior. This is significant, since several urinary tract pathologies can lead to chronic inflammation and disrupt the urothelial barrier causing increased urothelial permeability, thus subjecting the bladder wall to non-physiologic osmotic challenge. [ABSTRACT FROM AUTHOR]

Purpose PD-L1 is expressed on tumor cells and tumor immune cell infiltrates. In metastatic bladder cancer increased tumor immune cell infiltrate PD-L1 positivity correlated with better overall survival. However, to our knowledge in high grade T1 bladder tumors positivity on tumor cells and tumor immune cell infiltrates, and correlation with outcomes or pathological features remain unknown. Materials and Methods Formalin fixed, paraffin embedded tumor samples from 140 patients with clinically annotated, high grade T1 bladder tumors were retrieved. All patients were initially diagnosed with high grade T1 bladder tumors by transurethral resection, subsequently received bacillus Calmette-Guérin and had a median followup of 7.4 years. PD-L1 positivity on initial transurethral resection was evaluated by immunohistochemistry using a mouse monoclonal antiPD-L1 antibody (405.9A11). Tumor cell PD-L1 positivity was defined as staining of 5% of the tumor cell membrane. Tumor immune cell infiltrate PD-L1 positivity was scored based on the extent of infiltrate and the percent of positive cells. The Fisher exact test was used to assess associations of PD-L1 positivity with disease outcomes, carcinoma in situ presence and the difference between high grade T1 bladder tumors and muscle invasive bladder cancer. Results Among 140 patients with high grade T1 bladder tumors tumor cells and tumor immune cell infiltrate PD-L1 positivity was seen in 6 (4%) and 48 (34.3%), respectively. In a subset of 106 patients with adequate followup PD-L1 positivity did not correlate with disease outcomes on tumor cells (p = 0.3) or on tumor immune cell infiltrates (p = 0.47). PD-L1 positivity also did not correlate with the presence of carcinoma in situ. Tumor cell PD-L1 positivity was significantly less in high grade T1 bladder tumors than in muscle invasive bladder cancer (p <0.001). Conclusions PD-L1 is widely expressed on tumor immune cell infiltrates but not on tumor cells in high grade T1 bladder tumors. We did not find a correlation between PD-L1 positivity and outcomes or carcinoma in situ presence. Tumor cell PD-L1 positivity is significantly lower in high grade T1 bladder tumors than in muscle invasive bladder cancer. [ABSTRACT FROM AUTHOR]

Objective To investigate the underlying pathophysiology in the urothelium of different lower urinary tract diseases (LUTDs) and in patients with overactive bladder (OAB) or hypersensitive bladder (HSB), including chronic inflammation, barrier proteins, and sensory functional receptors. Materials and Methods A total of 156 patients, including 14 with idiopathic OAB, 11 with detrusor overactivity and inadequate contractility (DHIC), 19 with end-stage renal disease (ESRD) and HSB, 26 with spinal cord injury (SCI) and detrusor overactivity (DO), 23 with bladder outlet obstruction (BOO) and DO, 19 with diabetes mellitus (DM) and OAB, 20 with interstitial cystitis (IC), and 24 with ketamine cystitis (KC) were investigated for urothelial dysfunction and sensory protein expressions. Twenty control patients without LUTD were invited and separated into two groups for comparative studies. All participants had urodynamically proven DO or increased bladder sensation on video urodynamic studies. Urothelial dysfunction and functional receptor expressions were investigated and compared between patients with LUTD and controls. Results All patient subgroups had significant increases in mast cell activation and apoptotic cell counts and a decrease in E-cadherin expression. P2X3 expression was significantly decreased in DHIC but was increased in BOO/DO. Urothelial M3 expression was significantly increased in patients with OAB, BOO/DO, DM/OAB, and KC. M2 expression was significantly decreased in DHIC but increased in patients with BOO/DO. β3-AR expression was significantly decreased in patients with OAB and increased in patients with DHIC, ESRD/HSB, DM/OAB, and KC. Patients with OAB and BOO/DO had significantly increased M2/β3-AR. Lower M2/β3-AR was associated with lower voiding efficiency and large postvoid residual (PVR) in DHIC, ESRD/HSB, and SCI/neurogenic detrusor overactivity (NDO). Conclusion Patients with OAB or HSB showed increased urothelial inflammation and lower barrier protein expression. Increased M3/β3-AR or M2/β3-AR in the urothelium was associated with OAB, whereas decreased M3/β3-AR or M2/β3-AR was associated with poor voiding efficiency and large PVR in LUTD. [ABSTRACT FROM AUTHOR]

Purpose We report pathological, functional and oncologic outcomes in patients treated with radical nephroureterectomy following radical cystectomy. Materials and Methods We identified patients who underwent radical cystectomy and then radical nephroureterectomy for metachronous urothelial recurrence at our institution between January 1995 and December 2014. Univariable Cox regression was used to assess the association between overall survival and age, grade, stage, lymph node metastasis and radiographic findings. Results Of the 3,173 patients treated with radical cystectomy 64 underwent subsequent radical nephroureterectomy for metachronous urothelial recurrence. Median age at radical cystectomy was 66 years (IQR 61–74). In the 64 patients who underwent radical nephroureterectomy median time from radical cystectomy to radical nephroureterectomy was 2.7 years (IQR 1.4–4.6). Among 37 patients who underwent ureteroscopy prior to radical nephroureterectomy 29 (78%) had a positive biopsy. Radical nephroureterectomy pathology findings revealed locally advanced disease (pT3/pT4) in 39% of cases and positive node status in 11% compared with locally advanced disease in 17% and positive node status in 6% on radical cystectomy pathology findings. The post-radical nephroureterectomy estimated glomerular filtration rate was less than 60 and less than 30 ml/minute/1.73 m 2 in 96% and 40% of patients, respectively. Median overall survival after radical nephroureterectomy was 3.1 years (95% CI 2.4–4.3). Only lymph node involvement at radical nephroureterectomy was significantly associated with worse overall mortality (HR 2.73, 95% CI 1.04–7.15, p = 0.041). Conclusions The prognosis is poor in patients with panurothelial carcinoma treated with nephroureterectomy following cystectomy with locally advanced disease in a large proportion. Renal function after these procedures diminished and almost all patients were ineligible for cisplatin based chemotherapy. [ABSTRACT FROM AUTHOR]

The bladder presents an attractive target for topical drug delivery. The barrier function of the bladder mucosa (urothelium) presents a penetration challenge for small molecules and nanoparticles. We found that focal mechanical injury of the urothelium greatly enhances the binding and penetration of intravesically-administered cell-penetrating peptide CGKRK (Cys-Gly-Lys-Arg-Lys). Notably, the CGKRK bound to the entire urothelium, and the peptide was able to penetrate into the muscular layer. This phenomenon was not dependent on intravesical bleeding and was not caused by an inflammatory response. CGKRK also efficiently penetrated the urothelium after disruption of the mucosa with ethanol, suggesting that loss of barrier function is a prerequisite for widespread binding and penetration. We further demonstrate that the ability of CGKRK to efficiently bind and penetrate the urothelium can be applied toward mucosal targeting of CGKRK-conjugated nanogels to enable efficient and widespread delivery of a model payload (rhodamine) to the bladder mucosa. [ABSTRACT FROM AUTHOR]

Purpose We evaluated differences in clinicopathological characteristics and oncologic outcomes between patients with upper tract urothelial carcinoma in mainland China and the United States. Materials and Methods We retrospectively compiled clinicopathological and oncologic outcomes data on patients with upper tract urothelial carcinoma treated surgically at tertiary care medical facilities in the United States or China from 1998 to 2015. Baseline demographics, comorbidities and pathological features were evaluated. Oncologic end points, including intravesical recurrence and cancer specific survival, were obtained after excluding patients who received systemic chemotherapy. Multivariable Cox regression was performed to determine predictors of adverse oncologic outcomes for each country. Results A total of 775 patients with upper tract urothelial carcinoma were identified, including 451 in China and 324 in the United States. Median followup was 42 months. American patients were more frequently male (65% vs 44%) and smokers (79% vs 18%), and had a worse mean ASA® (American Society of Anesthesiologists®) score (2.7 vs 2.2) and prior bladder cancer (41% vs 4%, all p <0.001). Chinese patients more often had preoperative hydronephrosis (56% vs 40%), high grade pathology (98% vs 77%), muscle invasion (64% vs 38%) and nodal metastases (26% vs 6%, all p <0.001). American patients had worse overall survival on Kaplan-Meier analysis (p = 0.049). However, country of origin did not predict local relapse or cancer specific survival. Conclusions Patient and disease characteristics of upper tract urothelial carcinoma differed between the Chinese and American cohorts. Chinese patients appeared relatively healthier at presentation but more often exhibited adverse pathological features. While evaluation and management patterns may account for these variations, the pathological findings may reflect a differential underlying pathogenesis of disease. Additional study is warranted to further characterize these differences. [ABSTRACT FROM AUTHOR]

Di-n-butyl phthalate (DBP) is a plasticizer commonly used in industrial production and is present in our daily life. It has been confirmed that DBP causes genitourinary malformations, especially hypospadias. However, the research of hypospadias mainly focusses on the genital tubercle in previous studies. In this study, we found DBP could affect the exocrine function of the vascular endothelium which disturb the development of genital nodules and induced hypospadias. We used cytokine array to find that vascular endothelium-derived NAP-2 may be a major abnormal secreted cytokine with biological functions. The transcriptomic sequencing analysis showed that abnormal activation of the RhoA/ROCK signaling pathway was the main reason for increased NAP-2 secretion. The expression levels of epithelial-mesenchymal transition (EMT) biomarkers and NAP-2 in hypospadias animal models were detected with Immunohistochemistry, Western blot, Immunofluorescence, and ELISA methods. The expression levels of NAP-2, RhoA/ROCK signaling pathway related proteins, reactive oxygen species (ROS) levels in HUVEC cells, EMT biomarkers and migration capacity of urothelial cells cocultured with HUVEC were measured with ELISA, flow cytometry, Western blot or Transwell assay for further cell experiments. The results showed that DBP leaded to NAP-2 oversecretion from vascular endothelium mainly rely on the activation of RhoA/ROCK signaling pathway and ROS accumulation. The RhoA/ROCK inhibitor fasudil could partially decrease ROS production, and both fasudil and N-acetyl- L -cysteine (NAC) could decrease NAP-2 secretion. Meanwhile, the oversecretion of NAP-2 from HUVEC in coculture system promoted EMT and migration capacity of urothelial cells, and TGF-β inhibitor LY219761 could block the aberrant activation of EMT process. Therefore, it could be concluded that DBP increase NAP-2 secretion from vascular endothelium by RhoA/ROCK/ROS pathway, and further promote EMT in urothelial cells through TGF-β pathway. This study provided a novel direction for studying the occurrence of hypospadias and may provide a hypospadias predictive marker in the future. • DBP increased secretion of NAP-2 from vascular endothelium and promoted EMT in genital tubercles. • 2. DBP caused activation of RhoA/ROCK signaling pathway and accumulation of ROS in vascular endothelium. • Fasudil or N-acetyl- L -cysteine could inhibit the secretion of vascular endothelium-derived NAP-2 and EMT of urothelial cells. [ABSTRACT FROM AUTHOR]

Purpose We investigated urothelial integrity, suburothelial inflammation and the expression of sensory proteins in the bladder urothelium of male patients with bladder outlet obstruction and various bladder dysfunctions. Materials and Methods We prospectively enrolled 33 men with urodynamically proven bladder outlet obstruction as the study group. Bladder biopsies were obtained from all study patients and 10 control patients. The expression of E-cadherin, zonula occludens-1, tryptase, apoptosis, TRPV (transient receptor potential vanilloid) 1 and 4, β3 adrenoreceptor, M2 and M3 muscarinic receptors, P2X3 receptor, and inducible/epithelial nitric oxide synthase were compared between study and control patients. Results Study patients had significantly lower expression of E-cadherin, and a higher number of suburothelial mast and apoptotic cells than controls. Additionally, higher expression of P2X3 and M2 muscarinic receptors, and lower expression of M3 muscarinic receptor were detected in study patients. The detrusor underactivity subgroup was characterized by significantly higher expression of β3 adrenoreceptors and lower expression of inducible nitric oxide synthase than in controls. In study patients a significantly positive correlation was noted between voided volume and E-cadherin expression (r = 0.372), volume at first sensation of filling and β3 adrenoreceptor expression (r = 0.386), and detrusor pressure and M2 muscarinic receptor expression (r = 0.496) in the bladder urothelium (each p <0.05). Conclusions Urothelial dysfunction, suburothelial inflammation, cellular apoptosis and alterations in sensory proteins are prominent in bladder dysfunction secondary to bladder outlet obstruction. Impaired urothelial signaling and sensory transduction pathways appear to reflect the pathophysiology of bladder dysfunction and detrusor underactivity in patients with bladder outlet obstruction. [ABSTRACT FROM AUTHOR]

Purpose We investigated the feasibility of using low energy shock waves for intravesical botulinum toxin A delivery. We also evaluated its efficacy for acetic acid induced bladder hyperactivity in rats. Materials and Methods In study 1 magnetic resonance imaging with intravesical administration of Gd-DTPA (Gd-diethylenetriamine pentaacetic acid) contrast medium was performed to visualize increased bladder urothelial permeability after low energy shock waves. In study 2 saline (1 ml) or botulinum toxin A (20 U/1 ml saline) was administered in the bladder with or without low energy shock waves (300 pulses at 0.12 mJ/mm 2 ) and retained for 1 hour on day 1. Continuous cystometrograms were performed on day 8 by filling the bladder with saline followed by 0.3% acetic acid. The bladder was harvested for histology, and SNAP-25, SNAP-23 and COX-2 expression by Western blot or immunostaining. Results Magnetic resonance imaging established bladder urothelial leakage of Gd-DTPA after low energy shock waves, which was not seen in controls. The intercontraction interval was decreased 71.9%, 72.6% and 70.6% after intravesical instillation of acetic acid in saline, saline plus low energy shock wave and botulinum toxin A pretreated rats, respectively. However, rats that received botulinum toxin A plus low energy shock waves showed a significantly reduced response (48.6% decreased intercontraction interval) to acetic acid instillation without compromising voiding function. Rats pretreated with botulinum toxin A plus low energy shock waves showed a decreased inflammatory reaction (p <0.05), and decreased expression of SNAP-23 (p <0.05), SNAP-25 (p = 0.061) and COX-2 (p <0.05) compared with the control group. Conclusions Low energy shock waves increased urothelial permeability, facilitated intravesical botulinum toxin A delivery and blocked acetic acid induced hyperactive bladder. These results support low energy shock waves as a promising method to deliver botulinum toxin A without the need for injection. [ABSTRACT FROM AUTHOR]

For descriptive purposes the urinary tract is divided into two parts: the upper urinary tract and the lower urinary tract. The former comprises the kidneys and ureters, while the lower urinary tract consists of the urinary bladder and the urethra. In this article, a detailed description of the surgical and functional anatomy of the urinary bladder is followed by a description of the clinical anatomy of the female and male urethra. There then follows a brief description of the relevant anatomy of the prostate and seminal vesicles. While not strictly involved in the conduction of urine from the bladder to the exterior, the prostate and seminal vesicles are so intimately related (both topographically and functionally) to the urethra and bladder that no account of the lower urinary tract in the male would be complete without them. It is conventional therefore to regard the prostate and seminal vesicles as part of the lower urinary tract. [ABSTRACT FROM AUTHOR]

Purpose Surgical management of upper tract urothelial carcinoma requires kidney and ureter removal, compromising renal function. Nonsurgical alternatives have potentially prohibitive safety concerns. We examined the feasibility and safety of ablation of the ureter and renal pelvis using endoluminal vascular targeted photodynamic therapy in a porcine model. We also report the efficacy of WST11 vascular targeted photodynamic therapy in a murine model. Materials and Methods After receiving approval we performed a total of 28 endoluminal ablations in the ureters and renal pelvis of 18 swine. Intravenous infusion of WST11 (4 mg/kg) followed by 10-minute laser illumination was done via percutaneous access or a retrograde ureteroscopic approach. Animals were followed clinically with laboratory testing, imaging and histology, which were evaluated at several postablation time points. A murine xenograft was created with the 5637 human urothelial cell carcinoma line to determine sensitivity to this therapy. Results At 24 hours 50 mW/cm laser fluence produced superficial necrosis of the ureter. Deeper necrosis penetrating the muscularis propria or adventitia was produced by treatment with 200 mW/cm in the ureter and the renal pelvis. At 4 weeks superficial urothelium had regenerated over the treatment site. No symptomatic obstruction, clinically relevant hydronephrosis or abnormality of laboratory testing was noted up to 4 weeks. Of the mice 80% had no evidence of tumor 19 days after WST11 vascular targeted photodynamic therapy. Conclusions Urothelial cell carcinoma appears to be sensitive to WST11 vascular targeted photodynamic therapy. The depth of WST11 vascular targeted photodynamic therapy treatment effects can be modulated in a dose dependent manner by titrating light intensity. Moreover, when applied to the porcine upper urinary tract, this treatment modality is feasible via antegrade and retrograde access. [ABSTRACT FROM AUTHOR]

Purpose Attenuated mycobacterium bacillus Calmette-Guérin is widely used as intravesical immunotherapy of nonmuscle invasive urothelial carcinoma. Currently there are limited data on the relationship between bacillus Calmette-Guérin dose intensity and tumor response. We evaluated the dose-response relationship of bacillus Calmette-Guérin to nonmuscle invasive bladder cancer in vitro using urothelial carcinoma cell lines and in vivo using an orthotopic mouse model. Materials and Methods Two human urothelial carcinoma cell lines were used to study the effect of bacillus Calmette-Guérin dose on the tumor cell response. Internalization, activation of signaling pathways, gene transactivation, cell viability, lactate dehydrogenase and HMGB1 release were study end points. An orthotopic tumor model was used to compare the effect of different doses on the antitumor efficacy of bacillus Calmette-Guérin. Results Bacillus Calmette-Guérin internalization by urothelial carcinoma cells increased as a function of time and dose with a plateau at higher doses and/or long exposure times. Intracellular signaling demonstrated a similar direct, dose dependent increase. Cytokine expression by urothelial carcinoma cells as a function of dose was variable. Some genes increased progressively but others showed a decrease at the highest dose. While nonviable cell number increased in proportion to dose, the number of cells undergoing necrotic cell death decreased at higher doses. A higher dose of bacillus Calmette-Guérin (1:200) showed a better antitumor effect than a standard dose (1:50) (p <0.01). Conclusions Bacillus Calmette-Guérin dose has a direct impact on urothelial carcinoma cell biology. Increased dose intensity, particularly in nonresponders, may represent a strategy to increase bacillus Calmette-Guérin treatment efficacy. [ABSTRACT FROM AUTHOR]

Purpose We used targeted mass spectrometry to study the metabolic fingerprint of urothelial cancer and determine whether the biochemical pathway analysis gene signature would have a predictive value in independent cohorts of patients with bladder cancer. Materials and Methods Pathologically evaluated, bladder derived tissues, including benign adjacent tissue from 14 patients and bladder cancer from 46, were analyzed by liquid chromatography based targeted mass spectrometry. Differential metabolites associated with tumor samples in comparison to benign tissue were identified by adjusting the p values for multiple testing at a false discovery rate threshold of 15%. Enrichment of pathways and processes associated with the metabolic signature were determined using the GO (Gene Ontology) Database and MSigDB (Molecular Signature Database). Integration of metabolite alterations with transcriptome data from TCGA (The Cancer Genome Atlas) was done to identify the molecular signature of 30 metabolic genes. Available outcome data from TCGA portal were used to determine the association with survival. Results We identified 145 metabolites, of which analysis revealed 31 differential metabolites when comparing benign and tumor tissue samples. Using the KEGG (Kyoto Encyclopedia of Genes and Genomes) Database we identified a total of 174 genes that correlated with the altered metabolic pathways involved. By integrating these genes with the transcriptomic data from the corresponding TCGA data set we identified a metabolic signature consisting of 30 genes. The signature was significant in its prediction of survival in 95 patients with a low signature score vs 282 with a high signature score (p = 0.0458). Conclusions Targeted mass spectrometry of bladder cancer is highly sensitive for detecting metabolic alterations. Applying transcriptome data allows for integration into larger data sets and identification of relevant metabolic pathways in bladder cancer progression. [ABSTRACT FROM AUTHOR]

Purpose We compared the oncologic outcomes of radical nephroureterectomy, distal ureterectomy and endoscopic surgery for elective treatment of clinically organ confined upper tract urothelial carcinoma of the distal ureter. Materials and Methods From a multi-institutional collaborative database we identified 304 patients with unifocal, clinically organ confined urothelial carcinoma of the distal ureter and bilateral functional kidneys. Rates of overall, cancer specific, local recurrence-free and intravesical recurrence-free survival according to surgery type were compared using Kaplan-Meier statistics. Univariable and multivariable Cox regression analyses were performed to assess the adjusted outcomes of radical nephroureterectomy, distal ureterectomy and endoscopic surgery. Results Overall 128 (42.1%), 134 (44.1%) and 42 patients (13.8%) were treated with radical nephroureterectomy, distal ureterectomy and endoscopic surgery, respectively. Although rates of overall, cancer specific and intravesical recurrence-free survival were equivalent among the 3 surgical procedures, 5-year local recurrence-free survival was lower for endoscopic surgery (35.7%) than for nephroureterectomy (95.0%, p < 0.001) or ureterectomy (85.5%, p = 0.01) with no significant difference between nephroureterectomy and distal ureterectomy. On multivariable analyses only endoscopic surgery was an independent predictor of decreased local recurrence-free survival compared to nephroureterectomy (HR 1.27, p = 0.001) or distal ureterectomy (HR 1.14, p = 0.01). Distal ureterectomy and endoscopic surgery did not significantly correlate to cancer specific or intravesical recurrence-free survival. However, when adjustment was made for ASA ® (American Society of Anesthesiologists ® ) score, distal ureterectomy (HR 0.80, p = 0.01) and endoscopic surgery (HR 0.84, p = 0.02) were independent predictors of increased overall survival, although no significant difference was found between them. Conclusions Because of better oncologic outcomes, distal ureterectomy could be considered the elective first line treatment of clinically organ confined urothelial carcinoma of the distal ureter. [ABSTRACT FROM AUTHOR]

Purpose While bladder outlet obstruction is well established to elicit an inflammatory reaction in the bladder that leads to overactive bladder and fibrosis, little is known about the mechanism by which this is initiated. NLRs (NOD-like receptors) and the structures that they form (inflammasomes) have been identified as sensors of cellular damage, including pressure induced damage, and triggers of inflammation. Recently we identified these structures in the urothelium. In this study we assessed the role of the NLRP3 (NACHT, LRR and PYD domains-containing protein 3) inflammasome in bladder dysfunction resulting from bladder outlet obstruction. Materials and Methods Bladder outlet obstruction was created in female rats by inserting a 1 mm outer diameter transurethral catheter, tying a silk ligature around the urethra and removing the catheter. Untreated and sham operated rats served as controls. Rats with bladder outlet obstruction were given vehicle (10% ethanol) or 10 mg/kg glyburide (a NLRP3 inhibitor) orally daily for 12 days. Inflammasome activity, bladder hypertrophy, inflammation and bladder function (urodynamics) were assessed. Results Bladder outlet obstruction increased urothelial inflammasome activity, bladder hypertrophy and inflammation, and decreased voided volume. Glyburide blocked inflammasome activation, reduced hypertrophy and prevented inflammation. The decrease in voided volume was also attenuated by glyburide mechanistically as an increase in detrusor contraction duration and voiding period. Conclusion Results suggest the importance of the NLRP3 inflammasome in the induction of inflammation and bladder dysfunction secondary to bladder outlet obstruction. Arresting these processes with NLRP3 inhibitors may prove useful to treat the symptoms that they produce. [ABSTRACT FROM AUTHOR]