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Objectives To report our experience of bladder urothelial cell carcinoma (UCC) in children and review contemporary management and follow-up of paediatric UCC. Patients and methods Between 2004 and 2020, five patients (4 boys and 1 girl) were managed at our centre for urothelial cell carcinoma of the bladder. Data was collected by note review for age at presentation, symptoms, clinical findings, investigations, treatment and follow-up. Results All five patients presented with visible haematuria, two had dysuria and one had suprapubic pain. Bladder ultrasound scan (USS) showed exophytic bladder lesions in only 4 patients. Definitive diagnosis and treatment were achieved by cystoscopic excision. Four patients had PUNLMP while one had Grade 3 pTa UCC of the bladder which required further cystoscopic excision and intravesical Mitomycin C (MMC) instillation. All patients were followed up clinically, with renal USS and cystoscopy. We have observed recurrence of the carcinoma in two patients requiring further cystoscopic excision and intravesical MMC. Conclusion Bladder urothelial cell carcinoma in children should be suspected in children presenting with haematuria. If renal USS is normal, cystoscopy should be considered for diagnosis and treatment. Compared to adults, children with bladder UCC often have favourable histopathology and prognosis. Close follow-up is necessary with renal USS and cystoscopy to detect recurrence even in PUNLMP.

Background Receptor activator of NF kappa B (RANK) and its ligand have an essential role in T-cell regulation and the development of bone metastases. The role of RANK expression in muscle-invasive bladder cancer (MIBC) is unknown. Objective To assess the relevance of RANK expression in patients with MIBC. Design, setting, and participants Expression of RANK was assessed via immunohistochemistry of benign urothelium, MIBC tissue, and lymph node metastases from 153 patients undergoing radical cystectomy. Expression data from The Cancer Genome Atlas (TCGA) cohort were analyzed for potential associations with molecular subtypes and outcome. Outcome measurements and statistical analysis RANK expression was correlated with clinical and pathological parameters and to individual data for the clinical course of MIBC. Results and limitations Expression of RANK was significantly higher in both primary tumors (p = 0.02) and lymph node metastases (p = 0.01) compared to normal urothelium. In tumor tissue, RANK expression was significantly lower in patients with locally advanced disease and lymph node involvement compared to those with organ-confined disease (p = 0.0009) and node-negative MIBC (p = 0.0002). In univariable and multivariable analyses, high expression of RANK was associated with a longer time to recurrence (p = 0.0005 and 0.01) and better cancer-specific (p = 0.0004 and 0.007) and overall survival (p = 0.002 and 0.04). High expression of RANK was associated with better outcome for patients with luminal infiltrated tumors in the TCGA cohort. Conclusions RANK expression is increased in bladder cancer tissue compared to benign urothelium, with higher expression in organ-defined compared to locally advanced disease. High RANK expression indicates a favorable prognosis in MIBC. The prognostic role differs in tumors of different molecular subtypes. Patient summary Expression of a protein involved in bone turnover regulation (RANK) is higher in bladder cancer tissue than in benign bladder tissue. However, high levels of RANK on tumor cells indicate favorable prognosis for patients with bladder cancer that invades the muscle layer of the bladder.

Background Among various clinicopathologic factors used to identify low-risk upper tract urothelial carcinoma (UTUC), tumor grade and stage are of utmost importance. The clinical value added by inclusion of other risk factors remains unproven. Objective To assess the performance of a tumor grade- and stage-based (GS) model to identify patients with UTUC for whom kidney-sparing surgery (KSS) could be attempted. Design, setting, and participants In this international study, we reviewed the medical records of 1240 patients with UTUC who underwent radical nephroureterectomy. Complete data needed for risk stratification according to the European Association of Urology (EAU) and National Comprehensive Cancer Network (NCCN) guidelines were available for 560 patients. Outcome measurements and statistical analysis Univariable and multivariable logistic regression analyses were performed to determine if risk factors were associated with the presence of localized UTUC. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of the GS, EAU, and NCCN models in predicting pathologic stage were calculated. Results and limitations Overall, 198 patients (35%) had clinically low-grade, noninvasive tumors, and 283 (51%) had ≤pT1disease. On multivariable analyses, none of the EAU and NCCN risk factors were associated with the presence of non–muscle-invasive UTUC among patients with low-grade and low-stage UTUC. The GS model exhibited the highest accuracy, sensitivity, and negative predictive value among all three models. According to the GS, EAU, and NCCN models, the proportion of patients eligible for KSS was 35%, 6%, and 4%, respectively. Decision curve analysis revealed that the net benefit of the three models was similar within the clinically reasonable range of probability thresholds. Conclusions The GS model showed favorable predictive accuracy and identified a greater number of KSS-eligible patients than the EAU and NCCN models. A decision-making algorithm that weighs the benefits of avoiding unnecessary kidney loss against the risk of undertreatment in case of advanced carcinoma is necessary for individualized treatment for UTUC patients. Patient summary We assessed the ability of three models to predict low-grade, low-stage disease in patients with cancer of the upper urinary tract. No risk factors other than grade assessed on biopsy and stage assessed from scans were associated with better prediction of localized cancer. A model based on grade and stage may help to identify patients who could benefit from kidney-sparing treatment of their cancer.

Background: Few data are available regarding the effectiveness of immune checkpoint inhibitors in advanced upper tract urothelial carcinoma (UTUC) patients. Methods: To provide a real-world experience with anti-PD-1/PD-L1-based therapy in UTUC patients, we involved an Italian network in a multicenter retrospective analysis. Results: A total of 78 UTUC patients were enrolled. The median follow-up was 25.1 months. The median progression-free survival (mPFS) was 2.2 months (95% CI 1.8–2.6), and the median OS (mOS) was 6.0 months (95% CI 3.6–8.4). The Sonpavde score (including performance status > 0, hemoglobin

Background Kidneys with chronic inflammation develop tertiary lymphoid structures (TLSs). Infectious pyelonephritis is characterized by renal pelvis (RP) inflammation. However, the pathologic features of TLSs, including their formation and association with non-infectious nephritis, are unclear. Methods RPs from humans and mice that were healthy or had non-infectious chronic nephritis were analyzed for TLS development, and the mechanism of TLS formation investigated using urothelium or lymphoid structure cultures. Results Regardless of infection, TLSs in the RP, termed urinary tract-associated lymphoid structures (UTALSs), formed in humans and mice with chronic nephritis. Moreover, urine played a unique role in UTALS formation. Specifically, we identified urinary IFN-gamma as a candidate factor affecting urothelial barrier integrity because it alters occludin expression. In a nephritis mouse model, urine leaked from the lumen of the RP into the parenchyma. In addition, urine immunologically stimulated UTALS-forming cells via cytokine (IFN-gamma, TNF-alpha) and chemokine (CXCL9, CXCL13) production. CXCL9 and CXCL13 were expressed in UTALS stromal cells and urine stimulation specifically induced CXCL13 in cultured fibroblasts. Characteristically, type XVII collagen (BP180), a candidate autoantigen of bullous pemphigoid, was ectopically localized in the urothelium covering UTALSs and associated with UTALS development by stimulating CXCL9 or IL-22 induction via the TNF-alpha/ FOS/JUN pathway. Notably, UTALS development indices were positively correlated with chronic nephritis development. Conclusions TLS formation in the RP is possible and altered urine-urothelium barrier-based UTALS formation may represent a novel mechanism underlying the pathogenesis of chronic nephritis, regardless of urinary tract infection.

The human bladder maintains a cycle of filling, storing, and micturating throughout an individual's lifespan. The cycle relies on the ability of the bladder to expand without increasing the intravesical pressure, which is only possible with the controlled relaxation of well-complaint muscles and the congruously organized construction of the bladder wall. A competent bladder outlet, which functions in a synchronous fashion with the bladder, is also necessary for this cycle to be completed successfully without deterioration. In this paper, we aimed to review the contemporary physiological findings on bladder physiology and examine the effects of amino acids on clinical conditions affecting the bladder, with special emphasis on the available therapeutic evidence and possible future roles of the amino acids in the treatment of the bladder-related disorders.

Background A pilot study reported an autologous buccal mucosal cell transplant in humans through the trans-urethral route using the buccal epithelium expanded and encapsulated in scaffold—hybrid approach to urethral stricture (BEES-HAUS), a minimally invasive approach to treat urethral stricture. Although successful outcomes were achieved in that study, for further validation, it is essential to prove that the transplanted buccal epithelium was engrafted over the urothelium through histological examination of the urethra, harvested post-transplant, which is infeasible in humans. Herein, we report the successful creation of an animal model of urethral stricture and the engraftment of epithelial cells derived from autologous buccal mucosal tissue, encapsulated in a thermo-reversible gelation polymer (TGP) scaffold, transplanted by trans-urethral route. Methods An animal model of urethral stricture was created in Japanese white male rabbits using electro-coagulation. Buccal tissue was harvested from the rabbits and subjected to enzyme digestion, followed by 5–7 days of in vitro culture in conventional two-dimensional (2D) culture and in a 3D platform of thermo-reversible gelation polymer (3D-TGP) culture. The cells harvested from the groups were mixed and encapsulated and transplanted with TGP, by transurethral catheterization. Fourteen days later, the urethra was harvested and subjected to histological examination. The buccal biopsy tissue, cells after digestion and cells post-culture were also subjected to histological examination. Urethrogram and endoscopy images were recorded at different time points. Results The stricture was successfully created, with the coagulated area markedly stenosed. Histological staining of the cells after in vitro processing showed that the cells grew with native epithelial and rounded cell morphology in 3D-TGP while they differentiated into fibroblast like-cells in 2D culture. Histological staining of the urethral tissue after transplantation revealed the engraftment of the transplanted buccal mucosal cells, with stratified squamous epithelium over the specialized stratified urothelium in the urethrotomy site. Conclusion We used histology to prove the successful engraftment of TGP-encapsulated buccal mucosal epithelial cells in an animal model of urethral injury with healing of the injured tissue. The model of urethral stricture and cell therapy, using a transurethral approach, recapitulates the previously reported BEES-HAUS approach and lays the foundation for larger multi-centric translational clinical studies., Highlights • An animal model of urethral stricture that closely resembles that occurring in humans could be created. • Trans-urethral transplantation of polymer scaffold encapsulated buccal mucosal epithelial cells could be accomplished. • Successful engraftment of transplanted cells onto urethrotomy site with healing, proven in this first of its kind report.

BACKGROUND/AIM Systemic immune-inflammation index (SII) predicts survival of patients with various malignancies. This study explored the prognostic value of SII in metastatic urothelial carcinoma (MUC) subjects. PATIENTS AND METHODS We evaluated 181 consecutive MUC patients treated with first-line platinum-based therapy. Karnofsky performance status

Objective To present the pathologic analysis of female urethral strictures obtained during reconstructive urethroplasty. Methods Nine separate female urethral tissue specimens were obtained during dorsal vaginal graft urethroplasty by a single surgeon (S.P.P.). Samples were serially sectioned and fixed in 10% formalin 6 to 12 hours before routine processing in paraffin blocks. Serial 5-µm sections were subjected to H&E, Masson trichrome, and elastin staining. End point analysis included evaluation for epithelial hyperplasia and cell type, mucosal edema, degree of fibroblast/inflammatory cell infiltrate, and elastin fiber density and distribution. Results Nine specimens were examined. Six specimens had epithelial linings of stratified squamous epithelium overlying fibrosis (67%), 1 had mixed squamous and urothelial epithelium, and 2 had only urothelial epithelium. Two specimens (29%) showed acute injury with prominent squamous papillary hyperplasia, focal erosion, and patchy mucosal hemorrhage. Areas of urethral stricture were variably thickened, with increased, densely packed collagen fibers and associated mucosal lymphocytic inflammation ranging from mild and patchy to focally dense with lymphoid aggregates. The highest elastin fiber density appeared to be associated with vessels and overlying muscle bundles in the submucosa. Conclusions Further elucidation of histopathologic characteristics may illuminate more appropriate therapeutic pathways for female urethral stricture disease management.

Introduction Microsatellite instability occurs due to a series of mutations in the DNA pairing error repair (Mismatch repair; MMR) genes, which can affect germ cells as occurs in Lynch syndrome, whose patients are at high risk of developing multiple cancers. The loss of MMR protein is commonly determined by immunohistochemical studies. Although the relation between microsatellite instability and urothelial carcinomas has been widely studied, its evaluation is not currently performed in the analysis of urothelial carcinomas. Methods In this study, the microsatellite status of 139 urothelial carcinomas was analyzed and their clinicopathological characteristics were evaluated. We identified that 10.3% (13 patients) of urothelial carcinomas had loss of MMR protein expression (9 MLH1; 5 MSH2; 2 PMS2; 2 PSH6; n = 139). Results Results suggest that these tumors occur more frequently in males, are more frequently located in the bladder or ureters, and present a high tumor grade with a papillary histological pattern that does not infiltrate the lamina propria or, in the case of infiltrating tumors, that grows into perivesical tissues. Conclusions We identified patients with the aforementioned tumor characteristics as patients with a high probability of presenting loss of MMR protein expression, and consider that only these patients should undergo further immunohistochemical and molecular techniques for proper diagnosis. Therefore, we propose that the clinicopathological characteristics found in the present study could become possible markers to determine which cases should undergo additional tests.

BACKGROUND This study aimed to investigate the response to platinum-based chemotherapy rechallenge in patients with pembrolizumab-refractory urothelial carcinoma. PATIENTS AND METHODS We retrospectively reviewed 14 patients with pembrolizumab-refractory urothelial carcinoma. Each patient received a regimen that they had not previously received (paclitaxel plus carboplatin in 10, gemcitabine plus docetaxel and carboplatin in four). Tumor response and adverse events were assessed. We evaluated overall survival from the chemotherapy rechallenge start date until death. RESULTS The median overall survival was 11.2 months. The disease-control rate was 85.7%. Partial responses occurred in the metastases in lymph nodes in three (37.5%) patients, lung in one (25%), peritoneal in three (75%), and liver in three (100%). Neutropenia of grade ≥3 occurred in 13 (92.9%) patients. CONCLUSION The activity of platinum-based chemotherapy rechallenge after pembrolizumab was maintained. Neutropenia was observed in most patients.

Background. Diagnosis of urothelial carcinoma in situ is of great importance because it has prognostic and therapeutic value.We aim to determine the utility of EZH2 and ARID1A as a new tool in the diagnosis of carcinoma in situ.Material and Methods. This retrospective cross-sectional study included Twenty-four specimens of flat urothelial lesions, twenty specimens of CIS, and 10 of normal adjacent urothelium that was taken by cystoscopic resection biopsy procedure. immunohistochemical expression of EZH2 and ARID1A. were evaluated in all studied cases.Results. All normal urothelium specimens showed high nuclear staining for ARID1A and negative nuclear staining for EZH2. High EZH2 expression was observed in 80 % of CIS specimens compared to 20 % of flat urothelial lesions with atypia (p=0.001 ), while high ARID1A expression was observed in 70.8 % of flat urothelial lesions with atypia compared to 25 % of CIS specimens (p=0.001). EZH2 was more accurate and specific in the diagnosis of carcinoma in situ.Conclusion. EZH2 and ARID1A are promising diagnostic markers for urothelial CIS. EZH2 is more accurate and specific than ARID1A in the diagnosis of carcinoma in situ versus other flat urothelial lesions.

Aims The role of hydrodistension in the diagnosis of interstitial cystitis/bladder pain syndrome (IC/BPS) is controversial. This study evaluated the effect of low-pressure hydrodistension on glomerulation formation in female patients diagnosed with the disease. Methods Sixty female patients with the clinical diagnosis of IC/BPS and 30 female controls without the disease underwent cystoscopy and hydrodistension. Cold-cup biopsy was taken from bladder posterior wall at sites with normal cystoscopic appearance before hydrodistension in the IC/BPS group. The tissue samples were processed for histology study. Low-pressure (40 cmH2 O) hydrodistension for 2 min was performed and the appearance of glomerulations was compared between the two groups. High-pressure (80 cmH2 O) hydrodistension for 8 min was then performed as a therapeutic measure for the IC/BPS patients. Further changes to the degree of glomerulations were recorded. Results Histology showed pathological changes in the normal-appearing IC/BPS bladder mucosa including urothelium denudation, inflammatory cell infiltration, stromal edema, fibrosis, and vascular congestion. Low-pressure hydrodistension induced significant glomerulation formation in the patient group (percentage of patients with Grades 0-4: 0%, 8.3%, 40%, 35%, 10%, respectively) while none in the controls. High-pressure hydrodistension further increased the glomerulation grading in the IC/BPS patients. Conclusions Structural changes are present in prehydrodistension IC/BPS bladder wall, which may not be macroscopically detectable. Hydrodistension at low pressure is adequate to disrupt the integrity of such diseased mucosa and offers a more discriminative test in the diagnosis of IC/BPS.

AIMS The therapeutic effect of estrogen on interstitial cystitis/bladder pain syndrome is unclear. We aim to explore the effect of estrogen on bladder overactivity in rats with cyclophosphamide-induced cystitis and its underlying mechanism. METHODS In vivo cystometry was used to determine the effect of estrogen on bladder excitability. The effect of estrogen on the expression of P2X3 receptors in bladder epithelium was detected by real-time polymerase chain reaction and western blot. Effect of P2X3 receptors in bladder urothelium on stretch-released adenosine triphosphate was performed by a Flexcell FX5000 Compression system and an Enzyme-Linked Immunosorbent Assay Kit. RESULTS Estrogen deprivation significantly increased the urinary frequency, while supplementation with diarylpropionitrile (DPN), an estrogen receptor β (ERβ) agonist, alleviated the urinary frequency. 17β-Estradiol and DPN decreased the expression of P2X3 receptors in urothelium cells which was partially inhibited by ERβ antagonist 4-[2-phenyl-5,7-bis(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]phenol. Meanwhile, inhibiting the expression of P2X3 receptors by ERβ agonist or antagonizing the function of P2X3 receptors by selective P2X3 receptor antagonist AF-353 or A-317491 significantly reduced the stretch-released ATP from urothelium cells. CONCLUSIONS Estrogen has a direct effect on the regulation of bladder overactivity in rats with cyclophosphamide-induced cystitis by downregulating the expression of bladder epithelial P2X3 receptors through ERβ and reducing the adenosine triphosphate released from urothelium during bladder filling, thereby inhibiting the generation of the micturition reflex.

It is important to identify prognostic and predictive markers of metastatic urothelial carcinoma (mUC) treated with immunocheckpoint inhibitors. We sought to establish a prognostic marker for patients with mUC treated with pembrolizumab based on only blood test results. We included 165 patients with mUC in the discovery cohort and 103 with mUC who were treated with pembrolizumab in the validation cohort. Multivariate and Cox regression analyses were used to analyse the data. In the discovery cohort, the fibrosis-4 index (hazard ratio [HR]: 2.13, 95% confidence interval [CI] 1.20–3.76, p = 0.010), albumin–bilirubin score (HR 1.91, 95% CI 1.27–2.88, p = 0.002), and neutrophil–lymphocyte ratio (HR: 1.84, 95% CI 1.22–2.79, p = 0.004) were independent significant prognostic factors. We established a ‘FAN score’ that included these three aforementioned items, which were assigned one point each. We divided patients into the 0–1 point (n = 116) and 2–3 points (n = 49) groups. The FAN score was a significant prognostic marker for cancer-specific survival (CSS) (HR 1.48, 95% CI 1.19–1.83, p

Urothelial carcinomas (UC) arise from the urothelium that covers the proximal urethra, urinary bladder, and the upper urinary tract. In daily routine and clinical trials UC originating from different locations are often treated and investigated in the same manner. However, differences between the two locations seem to be apparent and may question in handling them as a single oncologic entity. In this review we discuss similarities and differences between bladder and upper urinary tract UC and consider their potential impact on treatment strategies. Despite similarities of UC in the bladder (BC) and the upper urinary tract (UTUC), clinicopathologic and molecular differences may question to generally assemble both as a single tumor entity. Treatment standards for UTUC are often adopted from BC. However, a specific investigation in the former may still be meaningful as shown by the example of adjuvant cisplatin based chemotherapy. In conclusion, future investigations should prioritize the understanding of the tumor biology of both BC and UTUC. This may reveal which UTUC can be treated according to treatment standards of BC and in which cases, a separate approach may be more appropriate.

To quantify the urinary bladder wall T1 relaxation time (T1) before and after the instillation contrast mixture in rats previously subjected to water avoidance stress (WAS) and/or acute exposure to protamine sulfate (PS). Female Wistar rats were randomized to receive either sham (control) or 1 h of WAS for ten consecutive days before the evaluation of nocturnal urination pattern in metabolic cages. T1 mapping of urinary bladder wall at 9.4 T was performed pre- and post- instillation of 4 mM Gadobutrol in a mixture with 5 mM Ferumoxytol. Subsequently, either T1 mapping was repeated after brief intravesical PS exposure or the animals were sacrificed for histology and analyzing the mucosal levels of mRNA. Compared to the control group, WAS exposure decreased the single void urine volume and shortened the post-contrast T1 relaxation time of mucosa- used to compute relatively higher ingress of instilled Gadobutrol. Compromised permeability in WAS group was corroborated by the urothelial denudation, edema and ZO-1 downregulation. PS exposure doubled the baseline ingress of Gadobutrol in both groups. These findings confirm that psychological stress compromises the paracellular permeability of bladder mucosa and its non-invasive assay with MRI was validated by PS exposure.

Objective In The Paris System for Reporting Urinary Cytology (TPS), the important cytomorphologic features for diagnosing high-grade urothelial carcinoma (HGUC) are a nuclear-to-cytoplasmic (N:C) ratio exceeding 0.7, hyperchromasia, coarse chromatin, and irregular nuclear borders. However, the quantitative cytomorphologic assessment of HGUC cells using SurePath slides is rare. Therefore, we evaluated HGUC cells on SurePath slides quantitatively using a digital image analysis system and compared these data with ThinPrep data. Methods The same urine samples were divided into two aliquots and used to prepare SurePath and ThinPrep slides. We used ImageJ to measure the N:C ratio, hyperchromasia, and irregular nuclear borders for HGUC cells on SurePath and ThinPrep slides. Results The total number of analyzed HGUC cells on SurePath slides was 981, versus 889 on ThinPrep slides. Hyperchromasia and irregular nuclear borders were significantly more severe on SurePath slides than on ThinPrep slides. Conversely, the N:C ratio did not differ between the methods. Additionally, HGUC cells with N:C ratios exceeding 0.7 were present on almost all slides for both methods. Conclusions Our data indicated the reasonableness of using the N:C ratio as the major criterion for the TPS on both SurePath and ThinPrep slides, and an N:C ratio cutoff of 0.7 was suitable for identifying HGUC cells. Meanwhile, the severity of hyperchromasia and irregular nuclear borders differs between the processing methods.

Background This retrospective study was conducted to compare the conventional cytospin method and ThinPrep liquid-based urinary cytology in diagnosing bladder cancer using The Paris System (TPS) of classification. Methods We retrieved files for 2020, at the Cytopathology Department of Laiko Hospital, of urinary cases diagnosed according to TPS. Cytospin and ThinPrep slides were separately reviewed and new diagnoses were rendered, then compared with the original diagnosis and histology when available. Risk of high-grade malignancy (ROHM) for each TPS category was assessed, along with accuracy parameters of each method and their combination. Results The study material comprised 100 cases of void urinary cytology classified as 20 high-grade urothelial carcinoma (HGUC = TPS5) cases, 20 of suspicion for HGUC (SHGUC = TPS4), 25 of atypical urothelial cells (AUC = TPS3), and 35 of negative for HGUC (NHGUC = TPS2). A single inadequate (TPS1) case and 4 of low-grade urothelial neoplasm (TPS6) were excluded as small in number. The ROHM was 95% for HGUC, 55% for SHGUC, 28% for AUC and 5.7% for NHGUC. Agreement with the original diagnosis was 86% for cytospin and 82% for ThinPrep. No significant differences were observed among the two techniques or their combination regarding sensitivity and specificity, with a mild advantage for cytospin. Interobserver reproducibility and repeatability were high. Conclusion No significant differences were found concerning sensitivity and specificity between cytospin and ThinPrep when applying TPS criteria. TPS is a reliable classification scheme for either conventional/cytospin or liquid-based cytology, or their combination.

Summary 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.

Aim: In this study, for the useable of bladder acelluar matrix in urinary tissue engineering, we compared the urodynamic and histopathological results between normal, partial cystectomy and bladder acellular matrix allograft (BAMA) augmented cystoplasty groups in rabbit model. Methods: There were five groups each consisting three rabbits. Urodynamic investigation was applied to all animals at the beging of the study. Then, in the first control group, the rabbits were sacrified and the bladders were removed for histopathological examination. In the second control group the same procedures were realized at the end of 24th week. In the third group, partial cystectomy was performed to the animals and followed for 24 weeks. Partial cystectomy and BAMA augmented cystoplasty were performed to the animals in the 4th and 5th groups. The animals were sacrified at the end of 12th and 24th weeks, respectively. In the 3th, 4th and 5th groups urodynamic investigations were performed before sacrification. Then bladders were underwent for histopathological examination. Results: There was no significant difference in term of bladder capacity between both control and BAMA augmented groups. Detrusor presures were no statistical different in all groups. However bladder capacity has significantly reduced in partial cystectomy group. In histopathological evaluations there were no differences between control and partial cystectomy groups. In BAMA augmented groups urothelium and vascularization were nearly the same as control groups however muscle layer was less organized and was thinner than control groups. Collagen depositon and innervation in BAMA augmented bladder were more prominent than that of the control group. Conclusion: In our animal study; although the detrusor muscle had less organized with more collagen deposition, the BAMA augmented bladders had near normal capacity and compliance with normal detrusor presures.

Current strategies in urinary bladder augmentation include use of gastrointestinal segments, however, the technique is associated with inevitable complications. An acellular biologic scaffold seems to be a promising option for urinary bladder augmentation. The aim of this study was to evaluate the utility of bladder acellular matrix (BAM) for reconstruction of clinically significant large urinary bladder wall defects in a long-term porcine model. Urinary bladders were harvested from 10 pig donors. Biological scaffolds were prepared by chemically removing all cellular components from urinary bladder tissue. A total of 10 female pigs underwent hemicystectomy and subsequent bladder reconstruction with BAM. The follow-up study was 6 months. Reconstructed bladders were subjected to radiological, macroscopic, histological, immunohistochemical, and molecular evaluations. Six out of ten animals survived the 6-month follow-up period. Four pigs died during observation due to mechanical failure of the scaffold, anastomotic dehiscence between the scaffold and native bladder tissue, or occluded catheter. Tissue engineered bladder function was normal without any signs of postvoid residual urine in the bladder or upper urinary tracts. Macroscopically, graft shrinkage was observed. Urothelium completely covered the luminal surface of the graft. Smooth muscle regeneration was observed mainly in the peripheral graft region and gradually decreased toward the center of the graft. Expression of urothelial, smooth muscle, blood vessel, and nerve markers were lower in the reconstructed bladder wall compared to the native bladder. BAM seems to be a promising biomaterial for reconstruction of large urinary bladder wall defects. Further research on cell-seeded BAM to enhance urinary bladder regeneration is required.

The incidence of bladder leiomyoma is estimated at only 0.43% because most bladder tumors arise from the urothelium. Moreover, 30% of them are the extra-vesical type. The symptoms include urinary tract obstruction, bladder irritation, and dysuria, with the possibility of dyspareunia or hematuria depending on the size and location of the tumor. Bladder leiomyomas cannot be diagnosed solely by combining symptoms and imaging techniques. We present a rare case of giant sized extravesical-type bladder leiomyoma with a diameter of 15.5x14.5x14 cm, which was misdiagnosed as a uterine cervical leiomyoma. It caused unilateral ureteral distension without related symptoms. During the 8-year postoperative follow-up, the patient had two healthy full-term pregnancies and no recurrence was observed. We reviewed the literature of the most recent five years and discussed the characteristics of 22 bladder leiomyoma cases. Unlike the literature, the present case is unique due to the giant size of the bladder leiomyoma, its ureteral complications, and long follow-up period. Bladder leiomyomas are rare bladder tumors which should be borne in mind during the differential diagnosis of a pelvic mass. Surgical excision is the most useful procedure for diagnosis and treatment., Mesane leiomyomunun insidansı sadece %0,43 olarak tahmin edilmektedir; çünkü mesane tümörlerinin çoğu üroepitelyumdan kaynaklanmaktadır. Bunun yanı sıra, mesane leiomyomlarının sadece %30’u ekstra-vezikal tiptedir. Üriner sistem obstrüksiyonu, mesane irritasyonu, dizüri, disparoni veya hematüri gibi semptomlar kitlenin boyut ve yerine göre değişebilir. Yalnızca semptom ve görüntüleme tekniklerine dayanarak mesane leiomyomu tanısı konulamayabilmektedir. Preoperatif uterin servikal leiomyom ön tanısı düşünülen, 15,5x14,5x14 cm çapında tek taraflı üreteral distansiyona yol açan, nadir görülen bir ekstravezikal tip mesane leiomyomu olgusunu sunuyoruz. Sekiz yıllık postoperatif takip boyunca, hastanın iki sağlıklı term gebeliği mevcuttu ve nüks izlenmedi. Son beş yılın literatürü gözden geçirilerek 22 mesane leiomyomunun özellikleri sunuldu. Literatürden farklı olarak, mevcut olgu mesane leiomyomunun büyüklüğü, üreteral komplikasyonları ve uzun takip süresi ile benzersizdir. Mesane leiomyomları, pelvik kitlenin ayırıcı tanısında göz önünde tutulması gereken, nadir görülen mesane tümörleridir. Tanı ve tedavi için en faydalı prosedür cerrahi eksizyondur.

PURPOSE: To determine the unique contributions from elevated voiding and storage pressures in the development of fibrosis and the epithelial-to-mesenchymal transition (EMT) in urothelial cells, and how progressive BOO pressure cycling is an important mechanical cue leading to these pathological changes. MATERIALS AND METHODS: Urothelial cells isolated from control, SHAM, 2 (acute)- or 6 (chronic)-week BOO rats treated with an inflammasome inhibitor or no drug. Total RNA was isolated and RT-PCR was conducted with custom primers for pro-fibrotic and EMT genes. In separate experiments, a rat urothelial cell line was exposed to cyclic pressure regimes characteristic of acute and chronic BOO in the presence or absence of an inflammasome inhibitor. Following exposure, RT-PCR was conducted, collagen content was determined and intracellular caspase-1 activity was measured. RESULTS: Urothelial cells isolated from acute and chronic BOO rat models demonstrated expression of pro-fibrotic and EMT genes. Similarly, MYP3 rat urothelial cells subjected to pressure cycling regimes that reflect intravesical pressures in the acute or chronic BOO bladder also demonstrated increased expression of pro-fibrotic and EMT genes, along with elevated soluble collagen. Treatment with inflammasome inhibitors reduced expression of pro-fibrotic genes in the rat model and pressure cycling model but had a limited effect on EMT. CONCLUSION: These results indicate that acute and chronic BOO pressure cycling are essential in the initiation and progression of fibrosis in the bladder via the NLRP3 inflammasome, but also provide new evidence that there is also an alternative NLRP3-independent pathway leading to EMT and fibrosis.

Introduction Urethral or upper urinary tract (UUT) recurrence of urothelial carcinoma (UC) after radical cystectomy (RC) are rare (4-6%), and their diagnosis usually occurs within the first two years. Although it is known that its early detection offers benefit in terms of survival, currently there are no clear recommendations for the detection of recurrence in the remnant urothelium (RU). Our aim is to determine the diagnostic value of urinary cytology for the detection of recurrences in the RU and to estimate its impact as an early diagnostic method on survival. Material and methods Retrospective review of patients who underwent RC for urothelial carcinoma between 2008-2016, with a follow-up of at least 24 months. Results The study included 142 patients. In a median follow-up of 68.5 months, nine patients (6.3%) presented recurrences in the RU (urethra: four, UUT: four, synchronous: one). The sensitivity and specificity of urinary cytology for the diagnosis of UUT recurrences were 20% and 96%, respectively. No significant differences were found between overall survival and cancer-specific survival among patients according to the urinary cytology results. Conclusion Recurrences in the RU after RC are infrequent; our study has shown that urinary cytology offers a low sensitivity for their diagnoses. For these reasons, we do not consider that urinary cytology provides useful information for surveillance of these patients.

Introduction Platinum-based combination chemotherapy is the standard treatment for patients with chemotherapy-eligible metastatic urothelial carcinoma (mUC). Immune-checkpoint inhibitors (ICIs) are currently assessed in this setting. This review aimed to assess the role of ICIs alone or in combination as first-line treatment in chemotherapy-eligible patients with mUC. Methods Multiple databases were searched for articles published until November 2020. Studies were deemed eligible if they compared overall survival (OS), progression-free survival (PFS), objective response rates (ORRs), complete response rates (CRRs), durations of response (DORs) and adverse events (AEs) in chemotherapy-eligible patients with mUC. Results Three studies met our eligibility criteria. ICI combination therapy was associated with significantly better OS and PFS, higher CRR and longer DOR than chemotherapy alone (hazard ratio [HR]: 0.85, 95% confidence interval [CI]: 0.76–0.94, P = 0.002; HR: 0.80, 95% CI: 0.71–0.90, P = 0.0002; odds ratio [OR]: 1.48, 95% CI: 1.12–1.96, P = 0.006; and mean difference: 1.39, 95% CI: 0.31–2.46, P = 0.01, respectively). ICI-chemotherapy combination therapy was also associated with significantly better OS and PFS, higher ORR and CRR and longer DOR than chemotherapy alone. Although OS and PFS benefits of ICI combination therapy were larger in patients with high expression of programmed death-ligand 1 (PD-L1), PD-L1 low expression patients also had a benefit; HR for OS (high PD-L1: HR 0.79 versus low PD-L1: HR 0.89) and PFS (high PD-L1: HR 0.74 versus low PD-L1: HR 0.82). ICI monotherapy was not associated with better oncological outcomes but was associated with better safety outcomes than chemotherapy alone. Conclusions Our analysis indicates a superior oncologic benefit to first-line ICI combination therapies in patients with chemotherapy-eligible mUC over standard chemotherapy. In contrast, ICI monotherapy was associated with favorable safety outcomes compared with chemotherapy but failed to show its superiority over chemotherapy in oncological benefits. PD-L1 status alone cannot help guide treatment decision-making. However, caution should be exercised in interpreting the conclusions drawn from this study, given that there is the heterogeneity of the population of interest, risk of bias and the nature of the studies evaluated whose data remain immature or unpublished.

Summary The current personalized oncology era has witnessed significant efforts to integrate clinical, pathological, and molecular classifications. The growing need for molecular biomarkers to feed personalized oncology, together with the unprecedented wealth of knowledge on the molecular basis of bladder cancer, has led to a novel approach to this disease, incorporating molecularly generated data in clinical practice for locally advanced or metastatic disease. Translational research allows a better understanding of the early events in the development of urothelial carcinoma in the urinary bladder. Thus, mutations in the KMT2D and KDM6A chromatin-modifying genes confer competitive advantages that drive cells to colonize larger regions of the urothelium. Additional mutations in TP53, PIK3CA, FGFR3, or RB1 genes then trigger the process of malignant transformation in the urothelium. In the current review, we provide an overview of what could be the expected transition from the morphology-based classification to a combined, molecularly enriched reporting of clinically meaningful parameters aiming to promote personalized oncology of urothelial carcinoma.

Summary Background PD-1 and PD-L1 inhibitors are active in metastatic urothelial carcinoma, but positive randomised data supporting their use as a first-line treatment are lacking. In this study we assessed outcomes with first-line pembrolizumab alone or combined with chemotherapy versus chemotherapy for patients with previously untreated advanced urothelial carcinoma. Methods KEYNOTE-361 is a randomised, open-label, phase 3 trial of patients aged at least 18 years, with untreated, locally advanced, unresectable, or metastatic urothelial carcinoma, with an Eastern Cooperative Oncology Group performance status of up to 2. Eligible patients were enrolled from 201 medical centres in 21 countries and randomly allocated (1:1:1) via an interactive voice-web response system to intravenous pembrolizumab 200 mg every 3 weeks for a maximum of 35 cycles plus intravenous chemotherapy (gemcitabine [1000 mg/m2] on days 1 and 8 and investigator's choice of cisplatin [70 mg/m2] or carboplatin [area under the curve 5] on day 1 of every 3-week cycle) for a maximum of six cycles, pembrolizumab alone, or chemotherapy alone, stratified by choice of platinum therapy and PD-L1 combined positive score (CPS). Neither patients nor investigators were masked to the treatment assignment or CPS. At protocol-specified final analysis, sequential hypothesis testing began with superiority of pembrolizumab plus chemotherapy versus chemotherapy alone in the total population (all patients randomly allocated to a treatment) for the dual primary endpoints of progression-free survival (p value boundary 0·0019), assessed by masked, independent central review, and overall survival (p value boundary 0·0142), followed by non-inferiority and superiority of overall survival for pembrolizumab versus chemotherapy in the patient population with CPS of at least 10 and in the total population (also a primary endpoint). Safety was assessed in the as-treated population (all patients who received at least one dose of study treatment). This study is completed and is no longer enrolling patients, and is registered at ClinicalTrials.gov , number NCT02853305 . Findings Between Oct 19, 2016 and June 29, 2018, 1010 patients were enrolled and allocated to receive pembrolizumab plus chemotherapy (n=351), pembrolizumab monotherapy (n=307), or chemotherapy alone (n=352). Median follow-up was 31·7 months (IQR 27·7–36·0). Pembrolizumab plus chemotherapy versus chemotherapy did not significantly improve progression-free survival, with a median progression-free survival of 8·3 months (95% CI 7·5–8·5) in the pembrolizumab plus chemotherapy group versus 7·1 months (6·4–7·9) in the chemotherapy group (hazard ratio [HR] 0·78, 95% CI 0·65–0·93; p=0·0033), or overall survival, with a median overall survival of 17·0 months (14·5–19·5) in the pembrolizumab plus chemotherapy group versus 14·3 months (12·3–16·7) in the chemotherapy group (0·86, 0·72–1·02; p=0·0407). No further formal statistical hypothesis testing was done. In analyses of overall survival with pembrolizumab versus chemotherapy (now exploratory based on hierarchical statistical testing), overall survival was similar between these treatment groups, both in the total population (15·6 months [95% CI 12·1–17·9] with pembrolizumab vs 14·3 months [12·3–16·7] with chemotherapy; HR 0·92, 95% CI 0·77–1·11) and the population with CPS of at least 10 (16·1 months [13·6–19·9] with pembrolizumab vs 15·2 months [11·6–23·3] with chemotherapy; 1·01, 0·77–1·32). The most common grade 3 or 4 adverse event attributed to study treatment was anaemia with pembrolizumab plus chemotherapy (104 [30%] of 349 patients) or chemotherapy alone (112 [33%] of 342 patients), and diarrhoea, fatigue, and hyponatraemia (each affecting four [1%] of 302 patients) with pembrolizumab alone. Six (1%) of 1010 patients died due to an adverse event attributed to study treatment; two patients in each treatment group. One each occurred due to cardiac arrest and device-related sepsis in the pembrolizumab plus chemotherapy group, one each due to cardiac failure and malignant neoplasm progression in the pembrolizumab group, and one each due to myocardial infarction and ischaemic colitis in the chemotherapy group. Interpretation The addition of pembrolizumab to first-line platinum-based chemotherapy did not significantly improve efficacy and should not be widely adopted for treatment of advanced urothelial carcinoma. Funding Merck Sharp and Dohme, a subsidiary of Merck, Kenilworth, NJ, USA.

Background The Paris System for Reporting Urinary Cytology (TPS) is a recently developed standardized terminology system. It is well-established that urine cytology has low sensitivity for detecting low-grade urothelial neoplasia (LGUN). Though the majority of tumors are low-grade, surveillance of these lesions is important to monitor for possible progression. Herein, we compared TPS to our veteran integrated system network (VISN) to assess its applicability. We also introduced semi-quantitative scoring to further evaluate cytomorphologic features of high-grade urothelial carcinoma (HGUC). Materials and methods Voided and instrumented urine cytology specimens and concurrent biopsies were reviewed from Sept 2018 – Jan 2020. Cytologic diagnoses reported using the VISN institutional system were reevaluated by staff cytopathologists and categorized according to TPS. A semi-quantitative scoring system to evaluate cytomorphologic features was devised. Results Cytology and surgical specimens from 105 patients were reviewed. The VISN and TPS reporting systems were compared and showed similar sensitivities and specificities for the detection of HGUC. Rates of biopsy-proven LGUN were high for the negative for high-grade urothelial carcinoma category (NHGUC; 27/53, 50.9%) and atypical urothelial cells (AUC; 14/30; 46.7%) compared to suspicious/positive (0/22, 0%) categories. Major and minor criteria as outlined in TPS were evaluated semi-quantitatively. Conclusions Urine cytology has limited sensitivity for LGUN regardless of the cytologic reporting system used. There was a high rate of LGUN following NHGUC/AUC diagnoses in the Veteran population. Coarse chromatin was determined to be the least sensitive criterion for the detection of high-grade lesions and irregular chromatin rim was most specific.

INTRODUCTION Chronic recurrent cystitis (CRC) is a common disease in the female population and a serious medical problem. There are not enough data about etiology of this desiase and effective treatment. OBJECTIVE To increase the accuracy of the differential diagnosis of bacterial and papillomavirus chronic recurrent cystitis. MATERIALS AND METHODS Analysis of endoscopic and morphological diagnostic methods of 118 patients with CRC, which, depending on the etiological factor, were divided into two groups. Group I (n=65) patients with CRC of HPV etiology and Group II (n=53) - CRC of bacterial etiology (E. coli). All patients were examined according to the EAU and RSU recommendations, and an endoscopic examination of the bladder (cystoscopy) was additionally included, followed by morphological examination of biopsy specimen of the urinary bladder. RESULTS The endoscopic picture of bacterial CRC usually is caused by hyperemia of the mucous membrane of the bladder, hyperemia and injection of vessels with the participation of (small-puncture/diapedesic) hemorrhages without signs of proliferative changes. The endoscopic picture in papillomavirus CRC in all patients presented by focal or diffuse, slightly elevated, exophytic, often polypoid formations of a whitish or whitish-gray color, usually localized in the Leto triangle. Morphological analysis of biopsy tissue of the urinary bladder in patients with bacterial cystitis in the mucous and submucous layer showed edema, thickening of the urothelium, capillary abundance, inflammatory infiltration, represented by lymphocytes, plasma cells and leukocytes, among which neutrophilic macrophage leukocytes were predominant. Morphological analysis of the bladder mucosa in all examined patients with signs of HPV-related lesions showed a thickening of the urothelium, squamous metaplasia of the urothelium, chronic inflammation, microcirculatory vascular reaction and edema. An important distinctive pathomorphological sign of HPV within urinary bladder was the presence of koilocytic transformation of urothelium cells due to the cytopathic effect of the virus. CONCLUSIONS Papillomavirus CR has characterized by an infectious-inflammatory process in the bladder paries, with lymphocytic-plasmatic infiltration and coylocytic transformation of the urothelium.

Eosinophils influence antitumor immunity and may predict response to treatment with immune checkpoint inhibitors (ICIs). To examine the association between blood eosinophil counts and outcomes in patients with advanced or metastatic urothelial carcinoma (mUC) treated with ICIs, we identified 2 ICI-treated cohorts: discovery (n=60) and validation (n=111). Chemotherapy cohorts were used as comparators (first-line platinum-based chemotherapy, n=75; second-line or more pemetrexed, n=77). The primary endpoint was overall survival (OS). Secondary endpoints were time on treatment (ToT) and progression-free survival. Univariate and multivariate analyses were performed using Cox proportional hazard models. Associations between changes in eosinophil count at weeks 2/3 and 6 after the start of ICI treatment were analyzed using landmark analyses. Baseline characteristics of the ICI cohorts were similar. In the discovery cohort, an optimal cutoff for pretreatment eosinophil count was determined [Eos-Lo

Purpose To investigate 50 week ultrasound imaging and ultrastructure changes of bladder in diuresis and diabetes rats. Methods Forty-two healthy male Sprague–Dawley rats were randomly divided into control group, sugar-induced diuresis group and streptozotocin-induced diabetes group. The 24 h drinking and urine volume were calculated from 21 to 31 weeks. Using ultrasound to assess bladders after 49 weeks. Bladders were examined by transmission electron microscope after 50 weeks. Results The drinking and urine volume significantly increased in the diuresis and diabetes groups. The bladder morphology and bladder wall thickness increased in the diuresis and diabetes groups. Bladder stones, bladder overdistension and urinary retention were seen in the diuresis and diabetes groups. Urothelium manifested degeneration, denudation and necrosis in the diuresis and diabetes groups. The mitochondrial vacuolar degeneration in the urothelial cells was seen in the diabetes group. The subepithelial vascular endothelial cells hyperplasia with a narrowed lumen were observed in the diabetes group. Abnormal mitochondria were rarely seen in the control group. The mitochondrial vacuolar degeneration in the detrusor was more severe in the diabetes group than in the diuresis group. The detrusor muscle and axon degeneration were observed in the diuresis and diabetes groups. Two rats in the diuresis group share similarities with diabetes group (2/6). Conclusion Long-term diabetes mellitus can cause increments of urinary bladder morphology and bladder wall thickness, urinary retention and bladder stones. Ultrastructural degeneration of the bladder might be the morphological bases of diabetic cystopathy. Supplementary Information The online version contains supplementary material available at 10.1007/s11255-021-02911-w.

Intravesical therapy for the treatment of superficial urinary bladder tumors is promising. However, it is also challenging, due to bladder contraction and relaxation and drug elimination via urination or dilution by urine production. We developed a biodegradable drug-eluting device positioned in the renal pelvis as an alternative strategy for bladder instillation. The urine drains from the renal pelvis into the ureter, collects the eluted drug, and transports it into the bladder. The combination of the renal pelvis and the bladder creates a two-compartment system. The drug is administered into the depot compartment, the renal pelvis, and is instantly and homogeneously distributed into the central compartment, the bladder. This results in an increase in its residence time and in gradual adsorption into the urothelium. The device is inserted through the ureter, followed by upset bulging after reaching the renal pelvis in order to guarantee fixation, while preventing urinary obstruction. The device is made of electrospun poly(lactic-co-glycolic acid) (PLGA) fibers that encapsulate a chemotherapeutic drug, cisplatin (1.17-2.34% w/w). Experimental studies of the stresses developed during the bulging and simulations of the urine flow interaction with the device demonstrated structural longevity and operational safety of the device. Sustained release of 94% of the device content was demonstrated after 1 week in vitro with a flow rate of 30 mL/h. We believe that the drug-eluted device may offer a significant advantage over existing therapies for treatment of nonmuscle invasive bladder cancer.

Objectives This article presents the clinical trial protocol for a phase I open label dose-escalation study to evaluate the tolerability, safety and immunological efficacy of sub-urothelial durvalumab injection in adults with muscle-invasive or high-risk non-muscle-invasive bladder cancer (NMIBC), the SUB-urothelial DUrvalumab injection-1 study (SUBDUE-1). The primary objectives of this study are to assess the safety of sub-urothelial injection of durvalumab using patient reported outcome measures and observed local or systemic adverse events. The secondary objectives are to examine the local immunological efficacy of sub-urothelial administration of durvalumab. Patients and methods The SUBDUE-1 trial will include adult patients with either high-risk NMIBC or MIBC, who are scheduled for radical cystectomy or who have refused or are unsuitable for systemic neoadjuvant chemotherapy. Three fixed total dose levels of durvalumab (25, 75, 150 mg) will be studied to identify a dose suitable to be taken forward into phase II trials. The primary endpoint is to evaluate the safety and tolerability of the trial intervention in terms of the incidence and severity of adverse events and the potential establishment of dose-limiting toxicities. The secondary efficacy endpoints include rates of pT0 status at resection, lymph node status, as well as the change in distribution of tumour-infiltrating lymphocytes and tumour-activated macrophages between pre- and post-injection bladder biopsies. Translational studies will focus on bladder tumour molecular sub-typing, immune infiltrate characterisation, and immune checkpoint protein expression relative to efficacy end-points. Outcome and significance If proven safe and effective, this novel strategy comprising sub-urothelial durvalumab injections aimed at promoting an anti-tumour immune reaction, will provide additional treatment options for reducing tumour recurrence and progression in treatment-naive patients with high-risk NMIBC or in patients with bacille Calmette-Guerin-refractory NMIBC. Local administration of durvalumab may be associated with a reduced rate of immunological side-effects and lower costs when compared to systemic delivery.

Background The benefits of pembrolizumab in patients with advanced urothelial carcinoma (UC) and impaired performance status (PS) remain unknown. This study assessed the safety and efficacy of pembrolizumab in patients with platinum‐refractory UC and Eastern Cooperative Oncology Group PS ≥2 to identify which subgroups may benefit from this drug. Methods This retrospective nationwide cohort study collected clinicopathological information for 755 patients from 59 institutions. The overall response rate (ORR) and overall survival (OS) were compared among the patients with PS 0–1, 2, and 3–4. Multivariate analysis was conducted to identify factors predicting OS in patients with PS ≥2. Results The numbers of patients with PS 0–1, 2, and 3–4 were 602, 98, and 55, respectively; the ORRs in these groups were 29.5, 15.3, and 9.1%, respectively, and the median OS times were 14.3, 3.1, and 2.4 months, respectively. In multivariate Cox regression analysis, a neutrophil–lymphocyte ratio (NLR) ≥3.5 (hazard ratio [HR] = 1.897) and liver metastasis (HR = 2.072) were associated with OS in the PS ≥2 subgroup. The median OS of patients with PS ≥2 without either risk factor was 6.8 months, compared with 3.1 months for patients with one risk factor and 2.3 months for patients with both risk factors. Conclusions PS ≥2 portended worse ORR and OS than PS ≤1 despite a comparable safety profile. Among the patients with impaired PS, patients with NLR, Among patients who received pembrolizumab to treat urothelial carcinoma, those with Eastern Cooperative Oncology Group performance status ≥2 exhibited worse overall response rates and overall survival than those with performance status ≤1 despite their comparable safety profiles. Among the patients with impaired performance status, those with a neutrophil–lymphocyte ratio

Bladder pain syndrome (BPS) is a debilitating disease in humans, particularly women, with patients experiencing chronic, intractable, lower urinary and pelvic pain. Although rodent models have been used, feline idiopathic cystitis (FIC) is a naturally occurring bladder disease of cats that is frequently considered to be the preferred model for BPS. Histologically, FIC is most similar to the non-Hunner BPS subtype. Histology is unnecessary for the clinical diagnosis of FIC but is of great value in elucidating the pathogenesis of this disease so that prevention and therapeutic interventions can be optimized. Further study of the histological features of FIC and BPS is required to determine the significance of Von Brunn's nests, which are invaginations of hyperplastic urothelium that have been associated with irritative bladder stimuli in animals and have been observed in FIC. We review the possible pathogenesis, histopathological similarities and differences between FIC and BPS, and highlight the potential of FIC as a model of BPS.

The time-varying clearance (CL) of the PD-L1 inhibitor atezolizumab was assessed on a population of 1519 cancer patients (primarily with non-small-cell lung cancer or metastatic urothelial carcinoma) from three clinical studies. The first step was to identify the baseline covariates affecting atezolizumab CL without including time-varying components (stationary covariate model). Two time-varying models were then investigated: (1) a model allowing baseline covariates to vary over time (time-varying covariate model), (2) a model with empirical time-varying Emax CL function. The final stationary covariate model included main effects of body weight, albumin levels, tumor size, anti-drug antibodies (ADA) and gender on atezolizumab CL. Both time-varying models resulted in a clear improvement of the data fit and visual predictive checks over the stationary model. The time-varying covariate model provided the best fit of the data. In this model, the main driver for change in CL over time was variations in albumin level with an increase in serum albumin (improvement in a patient’s status) mirroring a decrease in CL. Time-varying ADAs had a small impact (9% increase in CL). None of the covariates impacted atezolizumab CL by more than ± 30% from median. The estimated maximum decrease in CL with time was 22% with the Emax model. The overall impact of covariates on atezolizumab CL did not warrant any change in atezolizumab dosing recommendations. The results support the hypothesis that variation in atezolizumab CL over time is associated with patients’ disease status, as shown with other checkpoint inhibitors.

Recurrent urinary tract infections (RUTI) are one of the most common manifestations of the genitourinary menopausal syndrome and occur in more than 20% of peri- and post-menopausal women. The most common risk factor for RUTI in peri- and post-menopausal women is sex steroid deficiency. The urinary and genital tracts share a common embryonic origin due to the presence of α- and β-estrogen receptors, progesterone and androgen receptors in all structures of the urogenital tract: lower third of the ureters, urinary bladder, vascular plexus, urothelium, pelvic floor muscles, pelvic ligamentous apparatus. Patients with RUTI are treated in two stages: treatment of exacerbations and prevention of relapses. During exacerbations, short courses of antibiotic therapy are administered according to the sensitivity of the bacterial agent. If microbiological testing of urine samples is not possible, antibiotics are selected empirically, taking into account the most common pathogens of a UTI. Vaccine prophylaxis is the leading method of preventing a UTI recurrence. The efficacy and safety of E. coli bacterial extracts have been proven in numerous RCTs. The Uro-Vaxom vaccine reliably reduces the incidence of cystitis recurrence, reduces the need for antibacterial drugs, and therefore improves the quality of life of menopausal women with RUTIs. Vaccine prophylaxis in menopause can be administered as monotherapy or in combination with topical estrogen therapy, which also plays a positive role in the treatment of urinary tract infections.

Upper tract urothelial carcinoma (UTUC) is a rare tumor with an incidence that varies greatly between Eastern and Western countries. Transaldolase 1 (TALDO1) is a rate-limiting enzyme of the pentose phosphate pathway. In humans, aberrant TALDO1 activity has been implicated in various autoimmune diseases and malignancies; however, the function of TALDO1 in UTUC has not been previously investigated. Here we evaluated the clinical significance of TALDO1 expression in 115 paraffin-embedded tumor samples from patients with UTUC using immunohistochemistry. Our results demonstrated that there was an association between high TALDO1 expression and advanced stage (P = 0.011), tumor size (P = 0.005), tumor location (P = 0.047), distant metastases (P = 0.023), local recurrence (P = 0.002), and cancer death (P = 0.003). Using univariate and multivariate analyses, we found that chemotherapy was an independent factor for bladder recurrence-free survival. Late stage (III/IV) and high TALDO1 expression were independent prognostic factors for progression-free and cancer-specific survival. In summary, increased TALDO1 expression in UTUC was significantly correlated with late stage, tumor size, tumor location, distant metastases, local recurrence, and cancer death. Therefore, high TALDO1 expression could be a predictor of poor survival in patients with UTUC. Further studies are necessary to investigate the role of TALDO1 in UTUC development.

Background: Urothelial carcinoma is the common carcinoma of urothelium. Its incidence is high in developed countries but itsoccurrence is increasing in developing countries like Pakistan with mortality rate of 3.8/100,000 in males and 1/100,000 in females.HER2 is a member of the human epidermal growth factor receptor (HER/EGFR/ERBB) family.Amplification or over-expression ofthis oncogene has been shown to play an important role in the development and progression urothelial carcinoma.Objective: To evaluate the relationship between HER2/NEU expression and grades of urothelial carcinoma bladderMaterial and Methods: This was a cross-sectional descriptive study for the period of six months from January to June, 2017conducted at Pathology section Rehman Medical Institute Peshawar. After approval from university Ethical board 63 cases wereselected by purposive sampling.The Tissue samples from diagnosed cases of urothelial carcinoma of urinary bladder were included.Cases of urothelial carcinoma from other sites were excluded. Paraffin embedded tissue blocks were cut and sections stained byH&E to evaluate histopathological features and tumor grades. Immunohistochemical expression of HER2 was determinedapplying standard techniques of immunohistochemistry.Results: Out of total 63 cases, 47 were males and 16 were female with a mean age of 60.7 years (range 14-90 years). There were38 High grade, 23 Low grade and 2 cases of PUNLMP. 36 cases were positive for HER2 expression in which 26(72.2%) were Highgrade, 9(25%) of Low grade and 1(2.7%) of PUNLMP. High grade was more common in HER2 positive cases and this relationshipwas significant (p.05)Conclusion: HER2 is highly expressed in high grades of urothelial carcinoma bladder and this relationship between HER2expression and tumor grades is statistically significant.Keywords: HER2, Urothelial carcinoma, Grades, Immunohistochemistry

Purpose To evaluate the pharmacokinetic properties of UGN-101, a mitomycin-containing reverse thermal gel used as primary chemoablative treatment for low-grade upper tract urothelial carcinoma (UTUC), in a subset of patients participating in a phase 3 clinical trial. Methods Pharmacokinetic parameters (Cmax, Tmax, AUC(0–6), λz, t½, and AUCinf) were evaluated in six participants (male or female, ≥ 18 years) with biopsy-proven, low-grade UTUC who received the first of 6 once-weekly instillations of UGN-101 to the renal pelvis and calyces via retrograde ureteral catheter. Plasma samples were collected prior to instillation and 30 min, 1, 2, 3, 4, 5, and 6 h post-instillation. Safety was assessed by laboratory evaluations, physical exam, and adverse event monitoring. Results The mean age of the six participants was 69 years; most were male (5/6) and Caucasian (5/6). Mean (SD) Cmax was 6.24 (4.11) ng/mL and mean Tmax was 1.79 (1.89) hours after instillation. Mean apparent t½ following instillation was 1.27 (0.63) hours. Mean total systemic exposure to mitomycin up to 6 h post-instillation was 20.30 (19.69) ng h/mL. At 6 h post-instillation, mitomycin plasma concentrations of 5/6 participants were Conclusion The reverse thermal gel formulation of UGN-101 is associated with higher concentration and extended dwell time of mitomycin in contact with the urothelium of the upper urinary tract while limiting systemic absorption of mitomycin. Registration NCT02793128; registered June 8, 2016.

BACKGROUND/AIM We investigated the prognostic nutritional index (PNI), comprised of lymphocytes and albumin, as a potential prognosticator of metastatic urothelial carcinoma (mUC) patients receiving pembrolizumab. PATIENTS AND METHODS Sixty-five patients were retrospectively enrolled and classified as low (

BACKGROUND/AIM To investigate the blood markers for predicting pembrolizumab efficacy in advanced urothelial carcinoma (UC). PATIENTS AND METHODS This study included 91 advanced UC patients. The relationship between prognosis and markers from peripheral blood cell counts, including the neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), monocyte-lymphocyte ratio (MLR), and systemic inflammation response index (SIRI=monocytes × neutrophils/lymphocytes), was evaluated. RESULTS Multivariate analysis indicated that pretreatment NLR and the 1-month-change NLR were both significantly associated with overall survival (OS) after pembrolizumab initiation. When the patients were divided into four groups according to calculated cutoffs using Cox proportional hazard model, the pretreatment NLR

Purpose This study aimed to investigate the effects of miR-29b on renal interstitial fibrosis in the obstructed kidney of mouse with unilateral ureteral obstruction (UUO) via inhibiting phosphatidylinositol 3-kinase/protein kinaseB (PI3K/AKT) signaling pathway. Methods Adult male CD-1 mice were intraperitoneally injected with vehicle or PI3K inhibitor LY294002 (3 mg/kg, 30 mg/kg) daily for 1 or 2 weeks after performing UUO or sham operation. The mice were sacrificed on days 7 and 14 after surgery. The rat proximal tubular epithelial cell (TEC) line NRK-52E was cultured in DMEM and treated with various concentrations angiotensin II (AngII). Obstructed and sham mouse kidneys were analyzed via HE, Masson and immunohistochemistry to assess the degree of renal fibrosis. Real-time quantitative polymerase chain reaction assays (RT-PCR) were performed to investigate changes in the levels of expression of miR-29b and Western blot was used to analyze the activation of PI3K/AKT signaling and expression of E-cadherin, α-smooth muscle actin (α-SMA). Results Histologic analyses of obstructed kidney revealed that LY294002 attenuated the degree of renal fibrosis. In this study, loss of miR-29b accompanied with increased epithelial–mesenchymal transition (EMT) was observed in renal tubules of mice after UUO and cultured NRK-52E cells exposed to AngII. LY294002 also prominently decreased phosphorylation of AKT in vivo and vitro. By RT-PCR and Western blot analysis, LY294002 blocked the PI3K/AKT-induced loss of E-cadherin expression and de novo increase of the expression of α-SMA in a time- and dose-dependent manner. The overexpression of miR-29b markedly reversed the phenotype induced by AngII in NRK-52E cells and the downregulation miR-29b expression with an miR-29b inhibitor resulted in enhanced EMT. In addition, the PI3K/AKT signaling pathway was found to be suppressed in the presence of overexpression of miR-29b by direct hybridization with 3′-untranslated region (3′-UTR) of PIK3R2. Conclusion Our findings suggested that miR-29b significantly prevented tubulointerstitial injury in mouse model of UUO by attenuating renal tubular epithelial cell–mesenchymal transition via repressing PI3K/AKT signaling pathway.

The COVID-19 pandemic has modified the management of urothelial carcinoma (UC). Eighteen months after the onset of the pandemic, a scoping narrative review was able to state that radical cystectomy for UC should not be delayed beyond 10 weeks when neoadjuvant chemotherapy (NAC) was administered and 12 weeks when it was not. NAC should be considered when imminent chemotherapy cannot be performed. Early cystectomy should not be delayed when indicated for patients with high-risk non-MIBC. Patients with non-MIBC should still receive their induction doses of intravesical instillations. Diagnostic cystoscopy should not be deferred in symptomatic patients. Surgical management of upper tract urothelial carcinoma (UTUC) allows for a wider deferral interval.

Background: Aristolochic acids (AA) and arsenic are chemical carcinogens associated with urothelial carcinogenesis. Here we investigate the combined effects of AA and arsenic toward the risk of developing upper tract urothelial carcinoma (UTUC). Methods: Hospital-based (n = 89) and population-based (2,921 cases and 11,684 controls) Taiwanese UTUC cohorts were used to investigate the association between exposure to AA and/or arsenic and the risk of developing UTUC. In the hospital cohort, AA exposure was evaluated by measuring aristolactam-DNA adducts in the renal cortex and by identifying A>T TP53 mutations in tumors. In the population cohort, AA exposure was determined from prescription health insurance records. Arsenic levels were graded from 0 to 3 based on concentrations in well water and the presence of arseniasis-related diseases. Results: In the hospital cohort, 43, 26, and 20 patients resided in grade 0, 1+2, and 3 arseniasis-endemic areas, respectively. Aristolactam-DNA adducts were present in >90% of these patients, indicating widespread AA exposure. A>T mutations in TP53 were detected in 28%, 44%, and 22% of patients residing in grade 0, 1+2, and 3 arseniasis-endemic areas, respectively. Population studies revealed that individuals who consumed more AA-containing herbs had a higher risk of developing UTUC in both arseniasis-endemic and nonendemic areas. Logistic regression showed an additive effect of AA and arsenic exposure on the risk of developing UTUC. Conclusions: Exposure to both AA and arsenic acts additively to increase the UTUC risk in Taiwan. Impact: This is the first study to investigate the combined effect of AA and arsenic exposure on UTUC.

Purpose of review The aim of this review is to highlight the most recent developments in the understanding of kidney damage associated with vesico ureteral reflux. The severe damage, with major adverse long-term sequelae, was thought to be, for the most part, the result of pyelonephritis, predisposed to by vesico ureteral reflux. Recent findings It is now recognized that there are two distinct forms of kidney damage (congenital and acquired), in association with reflux. We examined the most recent research regarding these two conditions. Summary The most recent articles focus on an understanding and the possible interventions for the congenital and acquired abnormalities of the kidney, associated with reflux. Of particular interest in congenital disorders, is the importance of urothelium and gene mutations in normal and aberrant development of the urinary tract. As regards the predisposition to urinary tract infections and kidney scarring, the importance of uromodulin in the defence mechanism preventing infection, and the role of interventions aimed at reducing scarring, such as vitamin A and steroids during the acute phase of the infection, are discussed. A recent article of particular value demonstrated the absence of long-term adverse outcomes during pregnancy, in women investigated for urinary tract infections in childhood.

BACKGROUND Currently, the golden rule for the diagnosis of urothelial carcinoma is biopsy and cystoscopy, unfortionally both are costly, invasive, and uncomfortable. While most urothelial cancers are noninvasive at presentation, it is necessary to find a highly sensitive, noninvasive way to diagnose in its earlier stages, Cytology with immunostaining is a noninvasive, reliable method that might play a role in detecting the earlier stages before its progression and accurate correlation with different stages of these tumors. AIM This study aimed to reach an accurate level in the staging of urothelial carcinoma using CD44, ProExC, Laminin, and Fascin on urinary cytology. DESIGN We include a total of 180 urinary cytology specimens with their surgical biopsies' counterparts, the staging of the surgical specimens were done according to AJCC2017TNM classification, while their counterpart urinary samples were centrifuged and the sediment was used for H&E and immunocytochemical staining with CD44, ProExC, Laminin, and Fascin. RESULTS The diagnosis of Ta-stage tumors was done according to the following immunohistochemical (IHC) profile [positive (+ve) CD44, negative (-ve) proExC, -ve Laminin, and -ve Fascin] with 100% sensitivity, 100% specificity. The diagnosis of Tis stage tumors was done according to IHC profile [-ve CD44, +ve proExC, -ve Laminin, and -ve Fascin] with 100% sensitivity, 93% specificity. The diagnosis of T1 stage tumors according to IHC profile [-ve CD44, +ve proExC, +ve Laminin, and -ve Fascin] with 100% sensitivity, 97% specificity, The diagnosis of T2 and T3 stage tumors was done according to IHC profile [-ve CD44, +ve proExC, +ve Laminin and weak to moderate +ve Fascin] with 100% sensitivity, 92% specificity, while the diagnosis of T4 stage tumors according to the IHC profile [-ve CD44, +ve proExC, +ve Laminin, and intense +ve Fascin] with 100% sensitivity, 100% specificity. CONCLUSION Using (CD44, ProExC, Laminin, and Fascin) on urinary cytology is a simple, reliable, and noninvasive method for the staging of urothelial carcinoma with 99% total accuracy.

Whether pT3 urothelial carcinoma of the renal pelvis (UCRP) and urothelial carcinoma of the ureter (UCU) have the same prognosis is controversial, this study compared the prognosis of pT3 UCRP with that of pT3 UCU. We retrospectively evaluated 954 patients who underwent nephroureterectomy at our institutions between January 1983 and December 2017. All surgical specimens were reviewed by a single genitourinary pathologist. Cases of pT3 UCRP were subclassified as pT3a (urothelial carcinomas extending only to the renal medulla) and pT3b (urothelial carcinomas extending into the renal cortex and/or peripelvic adipose tissue). Fine and Gray's model was used to predict recurrence-free survival (RFS) and cancer-specific survival (CSS). A total of 493 (51.7%) had UCRP and 461 (48.3%) had UCU. Within this group, 202 patients had pT3 UCRP and 146 had pT3 UCU. The pT3 subclassification of UCRP resulted in 79 cases of pT3a and 120 of pT3b. The difference in 5-year CSS among the pT3a UCRP, pT2 UCRP, and pT2 UCU subgroups was not statistically significant (pT3a UCRP vs pT2 UCRP, HR = 0.69, p = 0.56; pT3a UCRP vs pT2 UCU, HR = 0.66, p = 0.31) However, RFS and CSS were significantly higher in the pT3a UCRP group than in the pT3b group (pT3a vs pT3b, HR = 2.59, p = 0.0038 and pT3a vs pT3b, HR = 3.10, p = 0.001). The results suggest that our proposed pT3 subclassification better predicts the prognosis of UCRP patients than does the pT3 of the current AJCC/UICC classification.

Introduction Cytology and cystoscopy are used to detect urothelial carcinoma (UC), but together they still fail to detect some UC cases and are not suitable for screening asymptomatic individuals. Mutations are present in more than 98% of UC, mutations have therapeutic significance, and they can be detected by next generation sequencing (NGS) in urine samples. We review the role of NGS in UC detection. Materials and methods Comprehensive literature review on UC genetics, economics of NGS, and previous reports of UC detection by NGS. Results The raw costs of NGS have decreased to about 14,000 base pairs per penny, making it appear economically feasible to use NGS widely. Reported NGS assays fall short of predicted sensitivity. Decreased sensitivity is attributed to a low frequency of mutant alleles in many urine samples. Attempts to increase the percentage of mutant alleles, by using cell-free urinary DNA, or by using cell sorting and microfluidics, have been unsuccessful or remain unproven. However, cytologic examination can immediately enable NGS: Urine cytologies with sufficient proportions of abnormal cells could be directly triaged to NGS with high sensitivity for UC detection. For cases with a low proportion of abnormal cells, cytologically targeted microdissection of cells for NGS should maintain sensitivity and decrease sequencing costs. Cytologically targeted urothelial cells for NGS could allow a screening test for low grade UC. Conclusions Cytology is immediately poised to allow NGS to improve the diagnosis of UC, allowing NGS to be an ancillary test for atypical cytologies, and potentially allowing a screening test for low-grade UC.