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To present our experience in a single pediatric urology practice over a 10-year period with bladder tumors in the pediatric population in an effort to add to the relatively small amount of existing data. We hope to expand the community's knowledge of presentations, management and natural history of pediatric bladder tumors.We retrospectively queried our electronic medical records for International Classification of Diseases, Tenth Revision (ICD-10) and Current Procedural Terminology (CPT) codes relevant for bladder tumors. Patients with underlying bladder pathology, such as neurogenic bladder, history of bladder exstrophy, and history of bladder augmentation, were excluded.We identified 30 patients with bladder tumors from 2011 to 2021. There were 21 males and 9 females. Age at diagnosis ranged from 16 months to 19 years. Tumors identified were: 11 of various inflammatory subtypes; 4 papillomas; 4 rhabdomyosarcomas; 3 papillary urothelial neoplasms of low malignant potential and 8 of other types. Treatment included transurethral resection of bladder tumor, chemoradiation and laparoscopic partial cystectomy. Twenty nine patients had disease limited to the bladder and 1 had disease outside the bladder. Follow-up ranged from 2 weeks to 13 years (median 19 months). All patients had no evidence of disease at most recent follow-up.Pediatric bladder tumors range from aggressive rhabdomyosarcomas to more benign urothelial lesions. Fortunately, the latter type of tumor is the more prevalent lesion. Knowledge of the treatment options and natural history of these tumors will hopefully be of benefit to clinicians and parents alike.

To highlight the latest changes in prostate cancer (PCa), urothelial carcinoma, upper tract urothelial carcinoma (UTUC) and renal cell carcinoma (RCC) diagnosis and the impact of genetics in this field.Breast cancer1/2 mutations start to play a major role in PCa treatment with regard to personalized medicine. In urothelial carcinoma an overlap between histological pathological and molecular findings exists, fibroblast growth factor receptor alteration are starting to play a major role, programmed death-ligand 1 although problematic is still important in the treatment setting. UTUC is rare, but genetically different from urothelial carcinoma. In the development of RCC, different genetic pathways such as Von Hippel-Lindau, but also tuberous sclerosis 1/2 and others play a major role in tumor development.Over the last years, genetics has become increasingly important role in the diagnosis and the treatment of patients with urological malignancies. The upcoming 5th edition (1) of the WHO still considers conventional surgical pathology as the diagnostic gold standard, but molecular pathology is gaining importance not only for diagnosis, but also in personalized treatment, of prostate, kidney cancer and urothelial carcinomas. Therefore, a close collaboration between surgical urology, pathology and oncology departments is mandatory. In this review, we will discuss the latest evolutions in PCa, urothelial carcinoma, upper urinary tract carcinomas and RCC s in the field of genetics in urology.

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.

Urine cytology offers a rapid and relatively inexpensive method to diagnose urothelial neoplasia. In our setting of a public sector laboratory in South Africa, urothelial neoplasia is rare, compromising pathology training in this specific aspect of cytology. Artificial intelligence-based synthetic image generation-specifically the use of generative adversarial networks (GANs)-offers a solution to this problem.A limited, but morphologically diverse, dataset of 1000 malignant urothelial cytology images was used to train a StyleGAN3 model to create completely novel, synthetic examples of malignant urine cytology using computer resources within reach of most pathology departments worldwide.We have presented the results of our trained GAN model, which was able to generate realistic, morphologically diverse examples of malignant urine cytology images when trained using a modest dataset. Although the trained model is capable of generating realistic images, we have also presented examples for which unrealistic and artifactual images were generated-illustrating the need for manual curation when using this technology in a training context.We have presented a proof-of-concept illustration of creating synthetic malignant urine cytology images using machine learning technology to augment cytology training when real-world examples are sparse. We have shown that despite significant morphologic diversity in terms of staining variations, slide background, variations in the diagnostic malignant cellular elements, the presence of other nondiagnostic cellular elements, and artifacts, visually acceptable and varied results are achievable using limited data and computing resources.

The role of urinary cytology as a diagnostic test for the detection and surveillance of urothelial cancer is crucial. Intravesical bacillus Calmette-Guerin (BCG) is the appropriate therapeutic strategy for patients with high-grade urothelial carcinoma (HGCU) or in situ carcinoma. We investigate how applicable is the Paris System for reporting urinary cytology (TPS) and how accurate is urinary cytology, in patients who undergo intravesical BCG instillations.Our study contains urine samples from patients during the period January 1, 2017 to December 31, 2019. The inclusion criteria were patients with history of urothelial bladder carcinoma who had been treated with intravesical BCG instillation and cytology was followed by histology. We report our results and estimate the risk of high-grade malignancy (ROHM) for each TPS category and cytology accuracy.Four hundred thirty-eight samples corresponding to 146 patients fulfilled the criteria to be included in the study. There were 2 inadequate, 118 negative for high-grade urothelial carcinoma (NHGUC), 14 atypical urothelial cells (AUC), 6 suspicious for high-grade urothelial carcinoma (SHGUC), and 6 cases HGUC. Corresponding histology assessment has shown that the ROHM amounted to 0 for inadequate, 3.4% for NHGUC, 57% for AUC, 100% for SHGUC and HGUC. Sensitivity was 50%, specificity 100%, PPV 100%, NPV 91%, and accuracy 91.7%, considering inadequate, NHGUC and AUC as negative and SHGUC and HGUC as positive result. However, considering AUC a positive result, the accuracy parameters were different; sensitivity 83.3%, specificity 95%, PPV 76.9%, NPV 96.67%, and accuracy 93%.The Paris system for reporting urinary cytology can be safely applied to patients during follow-up after BCG intravesical administration.

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

Intratumoral immune cells were reported to be associated with prognosis of bladder urothelial carcinoma (BUC). However, the role of immune cells related genes in BUC prognosis is less well defined. In the study, we analyzed data retrieved from the Cancer Genome Atlas database and found higher neutrophils and lower T cells infiltration in BUC tumor tissues were significantly correlated with patients' worse prognosis. Additionally, the expression levels of 164 genes were significantly correlated with T cells and neutrophils proportions. A Cox proportional-hazards model integrating 6 genes expression (EMP1, RASGRP4, HSPA1L, AHNAK, SLC1A6, and PRSS8) was identified. The 6-gene signature outperformed other clinical factors in risk prediction and was an independent prognostic factor for BUC. The findings were further conformed in three Gene Expression Omnibus datasets (n=331) and Jiangsu Province Hospital cohort (n = 46). Gene set enrichment analysis revealed that the model was highly involved in some immune-related pathways. A comprehensive nomogram combining the model and other clinical parameters was finally constructed to facilitate clinical application. In conclusion, a T cell and neutrophil-associated 6-gene prognostic model was identified for the survival prediction of BUC patients.

Mitochondrial bioenergetics reprogramming is an essential response of cells to stress. Platelets, an accessible source of mitochondria, have a crucial role in cancer development; however, the platelet mitochondrial function has not been studied in urothelial carcinoma (UC) patients. A total of 15 patients with UC and 15 healthy controls were included in the study. Parameters of platelet mitochondrial respiration were evaluated using the high-resolution respirometry method, and the selected antioxidant levels were determined by HPLC. In addition, oxidative stress was evaluated by the thiobarbituric acid reactive substances (TBARS) concentration in plasma. We demonstrated deficient platelet mitochondrial respiratory chain functions, oxidative phosphorylation (OXPHOS), and electron transfer (ET) capacity with complex I (CI)-linked substrates, and reduced the endogenous platelet coenzyme Q10 (CoQ10) concentration in UC patients. The activity of citrate synthase was decreased in UC patients vs. controls (p = 0.0191). γ-tocopherol, α-tocopherol in platelets, and β-carotene in plasma were significantly lower in UC patients (p = 0.0019; p = 0.02; p = 0.0387, respectively), whereas the plasma concentration of TBARS was increased (p = 0.0022) vs. controls. The changes in platelet mitochondrial bioenergetics are consistent with cell metabolism reprogramming in UC patients. We suppose that increased oxidative stress, decreased OXPHOS, and a reduced platelet endogenous CoQ10 level can contribute to the reprogramming of platelet mitochondrial OXPHOS toward the activation of glycolysis. The impaired mitochondrial function can contribute to increased oxidative stress by triggering the reverse electron transport from the CoQ10 cycle (Q-junction) to CI.

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 Contrasting findings have been reported regarding a possible constitutive expression of inducible nitric oxide synthase (iNOS) in a normal mammalian bladder. The current study was designed to further investigate such putative iNOS expression. MATERIALS AND METHODS The experiments were conducted with paraffin-embedded archival material from the urinary bladder of 6 normal, male Sprague-Dawley rats. In addition, two normal female mice (C57BL/6) were sacrificed and the urinary bladders were harvested. The occurrence of iNOS mRNA was examined by the RNAScope in situ hybridization method. Protein expression of iNOS and 3-nitrotyrosine (the latter used as an indicator of oxidative stress) was investigated by immunohistochemistry. RESULTS No expression of iNOS mRNA was observed in the bladder tissue. iNOS protein and 3-nitrotyrosine were strongly expressed in the urothelium. iNOS was also expressed perinuclearly in the detrusor. CONCLUSIONS Although the RNAScope methodology could not demonstrate mRNA for iNOS in the normal urinary bladder, the results by immunohistochemistry strongly suggest the occurrence of iNOS in particular, in the urothelium. Positive reactivity for 3-nitrotyrosine may indicate ongoing oxidative stress of the urothelium. The finding of perinuclear iNOS immunoreactivity could suggest an intracrine signaling function by iNOS to the nucleus.

Abstract Infections are common in patients with diabetes, but increasing antibiotic resistance hampers successful bacterial clearance and calls for alternative treatment strategies. Hypoxia-inducible factor 1 (HIF-1) is known to influence the innate immune defense and could therefore serve as a possible target. However, the impact of high glucose on HIF-1 has received little attention and merits closer investigation. Here, we show that higher levels of proinflammatory cytokines and CAMP, encoding for the antimicrobial peptide cathelicidin, LL-37, correlate with HIF-1 in type 2 diabetic patients. Chemical activation of HIF-1 further enhanced LL-37, IL-1β, and IL-8 in human uroepithelial cells exposed to high glucose. Moreover, HIF-1 activation of transurethrally infected diabetic mice resulted in lower bacterial load. Drugs activating HIF-1 could therefore in the future potentially have a therapeutic role in clearing bacteria in diabetic patients with infections where antibiotic treatment failed. Key messages • Mohanty et al. “HIF-1 mediated activation of antimicrobial peptide LL-37 in type 2 diabetic patients.” • Our study highlights induction of the antimicrobial peptide, LL-37, and strengthening of the innate immunity through hypoxia-inducible factor 1 (HIF-1) in diabetes. • Our key observations are: 1. HIF-1 activation increased LL-37 expression in human urothelial cells treated with high glucose. In line with that, we demonstrated that patients with type 2 diabetes living at high altitude had increased levels of the LL-37. 2. HIF-1 activation increased IL-1β and IL-8 in human uroepithelial cells treated with high glucose concentration. 3. Pharmacological activation of HIF-1 decreased bacterial load in the urinary bladder of mice with hereditary diabetes. • We conclude that enhancing HIF-1 may along with antibiotics in the future contribute to the treatment in selected patient groups where traditional therapy is not possible.

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.

To study the progression of bladder cancer from non–muscle-invasive to muscle-invasive disease, we have developed a novel toolkit that uses complementary approaches to achieve gene recombination in specific cell populations in the bladder urothelium in vivo, thereby allowing us to generate a new series of genetically engineered mouse models (GEMM) of bladder cancer. One method is based on the delivery of adenoviruses that express Cre recombinase in selected cell types in the urothelium, and a second uses transgenic drivers in which activation of inducible Cre alleles can be limited to the bladder urothelium by intravesicular delivery of tamoxifen. Using both approaches, targeted deletion of the Pten and p53 tumor suppressor genes specifically in basal urothelial cells gave rise to muscle-invasive bladder tumors. Furthermore, preinvasive lesions arising in basal cells displayed upregulation of molecular pathways related to bladder tumorigenesis, including proinflammatory pathways. Cross-species analyses comparing a mouse gene signature of early bladder cancer with a human signature of bladder cancer progression identified a conserved 28-gene signature of early bladder cancer that is associated with poor prognosis for human bladder cancer and that outperforms comparable gene signatures. These findings demonstrate the relevance of these GEMMs for studying the biology of human bladder cancer and introduce a prognostic gene signature that may help to stratify patients at risk for progression to potentially lethal muscle-invasive disease. Significance: Analyses of bladder cancer progression in a new series of genetically engineered mouse models has identified a gene signature of poor prognosis in human bladder cancer.

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 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.

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.

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.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.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-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 urinary bladder is a mechanosensitive organ that accumulates, stores, and expels considerable amounts of fluid. While the neuronal bladder control via the CNS is well defined, the data on the mechanisms of local mechanical sensitivity of the bladder wall are either insufficient or contradictory. Here we compared the mechanical properties of bladder wall of normal rats and rats with modeled type 2 diabetes (T2D).T2D was modeled in 3-month-old Wistar male rats by combined administration of nicotinamide (230 mg/kg) and streptozotocin (65 mg/kg). Cystometry of isolated, denervated whole bladders and stress-strain tensiometry on detrusor smooth muscle (DSM) strips were used to assess the mechanical properties of bladder wall tissues from control and diabetic animals on 10th week after induction.The pressure-volume cystometrograms of both control and T2D bladders featured a quasi plateau between ascending sections. T2D cystometrograms revealed markedly elevated intravesicular pressure (~100% at 1 ml) and a shortened plateau, consistent with decreased bladder wall elasticity and reduced structural bladder capacity versus control. Experiments on urothelium-intact and urothelium-devoid DSM strips have shown that the decrease of bladder walls elasticity in T2D can be explained by the switch of stretched urothelium from inducing DSM relaxation to inducing DSM contraction due to a change in the prevalent release of contractile versus relaxing urothelial factor(s).The decreased elasticity of the bladder walls in T2D results from alterations in urothelium-dependent mechanosensory mechanisms. Elevated intravesical pressure in T2D may contribute to urge incontinence and/or symptoms of upper urinary tract damage.

Cadherin switch (CS) outlined by downregulation of E-cadherin and upregulation of N-cadherin is an established epithelial-mesenchymal transition (EMT) hallmark, being a common signature in wound healing and carcinogenesis. It is intriguing to explore the EMT-associated CS pattern in precancerous phases as well as variably aggressive bladder cancer categories. In this study, we tested CS signified by a reduction in urothelial cells E-cadherin expression and/or aberrant N-cadherin expression in proliferative epithelial changes (PEC) associating inflammation, non-muscle-invasive bladder cancer (NMIBC), and muscle-invasive bladder cancer (MIBC). Immunohistochemical study of both E-cadherin and N-cadherin was performed for 60 cases: 15 PEC, 8 NMIBC, and 37 MIBC. CS patterns were analyzed: abnormal CS patterns were expressed as deviated, hybrid, co-negative, and full CS patterns. E-cadherin expression was significantly preserved in PEC (86.7%) followed by NMIBC (62.5%) and then MIBC (37.8%) (P=0.004), whereas N-cadherin showed obvious aberrant expression in MIBC (51.4%) as compared with PEC (33.3%) and NMIBC (25%). In the MIBC group, abnormal cadherin patterns were the highest (70.3%) and was associated with adverse prognostic indicators. In the context of NMIBC progression to MIBC, combined E and N-cadherin evaluation showed highest sensitivity (70.3%) and NPV (31.3%), whereas aberrant expression of N-cadherin presented highest specificity (75%) and positive predictive value (90.5%). For cancer prediction, combined E-cadherin and N-cadherin evaluation showed the highest sensitivity (64.4%); abnormal E-cadherin offered highest specificity (86.7%), positive predictive value (92.9%), and negative predictive value (40.6%). In posttherapy follow-up setting, a metastable EMT signature in the form of partial CS was noted and might reflect resistant dormant populations.

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

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.

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.

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.

Disruptions to sensory pathways in the lower urinary tract commonly occur and can give rise to lower urinary tract symptoms (LUTS). The unmet clinical need for treatment of LUTS has stimulated research into the molecular mechanisms that underlie neuronal control of the bladder and transient receptor potential (TRP) channels have emerged as key regulators of the sensory processes that regulate bladder function. TRP channels function as molecular sensors in urothelial cells and afferent nerve fibres and can be considered the origin of bladder sensations. TRP channels in the lower urinary tract contribute to the generation of normal and abnormal bladder sensations through a variety of mechanisms, and have demonstrated potential as targets for the treatment of LUTS in functional disorders of the lower urinary tract. Transient receptor potential (TRP) channels have an important role in sensory mechanisms of the lower urinary tract. Vanneste et al. discuss the involvement of TRP channels in normal and abnormal bladder sensations and their potential as therapeutic targets.

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.

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.

The Paris System (TPS) for reporting urine cytology was developed for standardization of diagnosis focusing on the detection of high-grade urothelial carcinoma (HGUC). Probably the most challenging task for TPS is to provide criteria for the atypical urothelial cell (AUC) category. The TPS criteria for AUC include increased nuclear/cytoplasmic (N/C) ratio (0.5) and 1 of the 3 minor criteria including nuclear hyperchromasia (NH), coarse chromatin (CC) and irregular nuclear membrane (INM). We evaluated TPS-AUC diagnostic value and investigated whether other morphologic parameters can improve its criteria.Urine samples with diagnoses of AUC collected during a 6-month period were re-reviewed. Data captured included N/C ratio0.5, NH, CC, INM, and 2 additional criteria including enlarged nuclear size (ENS) and the presence of nucleolus (N). ENS was considered when the nucleus was 2 times larger than the urothelial cell or 3 times larger than lymphocyte.By applying the TPS-AUC criteria, the rate of atypia diagnosis reduced in comparison to Pre-TPS (9% versus 13%, P = 0.02). Among the AUC minor criteria, NH was the best criterion with the highest interobserver agreement (IOA) and correlation with HGUC (k = 0.342, r = 0.61, P0.001) and strong PPV (93.6%). ENS had the highest PPV (95.8%) and, after NH, had the highest IOA and correlation with HGUC (k = 0.29, r = 0.52, P0.001).TPS improves the diagnostic value of urine cytology, particularly in cases with atypia. ENS is a strong criterion for increasing the diagnostic value of AUC and potentially can improve TPS performance as a minor criterion.

Primary adenocarcinoma of the urinary bladder is a rare malignancy with a frequency of less than 2% of all urothelial malignancies. Colonic adenocarcinoma has a much higher prevalence and its infiltration/metastasis in the urinary bladder is a pertinent differential of primary adenocarcinoma of the urinary bladder. However, the distinction of infiltration by colonic adenocarcinoma from synchronous adenocarcinoma in the bladder and colon is not always easy. Here, we report a 42-year-old male, who initially presented with bladder symptoms and subsequently found to have growth in both bladder and colon. A diagnosis of adenocarcinoma was made from the biopsies from both bladder and colon. Further attempts to differentiate synchronous occurrence or secondary involvement from an adjacent organ was made by radiology, and by an immunohistochemistry panel. The loss of MLH1 and PMS2 coupled with histomorphology and radiology helped in the diagnosis of primary colonic adenocarcinoma infiltrating the urinary bladder.

Aim: To develop a survival nomogram for patients with upper tract recurrence (UTR) after resection for localized bladder urothelial carcinoma (BUC). Methods: The data of 361 patients with UTR after resection for BUC registered in the Surveillance, Epidemiology, and End Results database were retrospectively analyzed. The nomogram was established using the Fine and Gray method and its predictive accuracy was assessed using the concordance index. The nomogram was calibrated by comparing the predicted and actual survival. Results: The concordance index of the nomogram was 0.746 (95% CI: 0.733–0.759). Excellent agreement was observed between the predicted and actual survival in all calibration plots. Conclusion: This study describes the first survival nomogram for patients experienced UTR after resection for BUC.

Preoperative immunotherapy with anti-PD1 plus anti-CTLA4 antibodies has shown remarkable pathological responses in melanoma1 and colorectal cancer2. In NABUCCO (ClinicalTrials.gov: NCT03387761 ), a single-arm feasibility trial, 24 patients with stage III urothelial cancer (UC) received two doses of ipilimumab and two doses of nivolumab, followed by resection. The primary endpoint was feasibility to resect within 12 weeks from treatment start. All patients were evaluable for the study endpoints and underwent resection, 23 (96%) within 12 weeks. Grade 3-4 immune-related adverse events occurred in 55% of patients and in 41% of patients when excluding clinically insignificant laboratory abnormalities. Eleven patients (46%) had a pathological complete response (pCR), meeting the secondary efficacy endpoint. Fourteen patients (58%) had no remaining invasive disease (pCR or pTisN0/pTaN0). In contrast to studies with anti-PD1/PD-L1 monotherapy, complete response to ipilimumab plus nivolumab was independent of baseline CD8+ presence or T-effector signatures. Induction of tertiary lymphoid structures upon treatment was observed in responding patients. Our data indicate that combined CTLA-4 plus PD-1 blockade might provide an effective preoperative treatment strategy in locoregionally advanced UC, irrespective of pre-existing CD8+ T cell activity.