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The microenvironments of urinary systems play crucial roles in the development and metastasis of cancers due to their generation of complex temporal and spatial fluidic profiles. Because of their versatility in creating desired biomimetic flow, cone-and-plate bioreactors offer great potential for bladder cancer research. In this study, we construct a biocompatible cone-and-plate device coupled with a torque sensor, enabling the application and real-time monitoring of stable shear stress up to 50 dyne/cm². Under a stable shear stress stimulation at 12 dyne/cm 2 , bladder cancer cell BFTC-905 is arrested at the G1 phase with decreased cell proliferation after 24-hour treatment. This effect is associated with increased cyclin-dependent kinase inhibitors p21 and p27, inhibiting cyclin D1/CDK4 complex with dephosphorylation of serine 608 on the retinoblastoma protein. Consequently, an increase in cyclin D3 and decreases in cyclin A2 and cyclin E2 are observed. Moreover, we demonstrate that the shear stress stimulation upregulates the expression of autophagy-related proteins Beclin-1, LC3B-I and LC3B-II, while caspase cleavages are not activated under the same condition. The design of this system and its application shed new light on flow-induced phenomena in the study of urothelial carcinomas., Competing Interests: Declaration of Competing Interest The authors declare no competing financial interest., (Copyright © 2024 The Authors. Published by Elsevier GmbH.. All rights reserved.)

miR-145-5p is a microRNA whose role in diverse disorders has been verified. This miRNA is encoded by MIR145 gene on chromosome 5. This miRNA is mainly considered as a tumor suppressor miRNA in diverse types of cancers, including bladder cancer, breast cancer, cervical cancer, cholangiocarcinoma, renal cancer, and gastrointestinal cancers. However, few studies have reported up-regulation of this miRNA in some cancers. Moreover, it has been shown to affect pathogenesis of a number of non-malignant conditions such as aplastic anemia, asthma, cerebral ischemia/reperfusion injury, diabetic nephropathy, rheumatoid arthritis and Sjögren syndrome. In the current review, we summarize the available literature about the role of miR-145-5p in these conditions., (Copyright © 2022 Elsevier GmbH. All rights reserved.)

The management of urothelial carcinoma (UC) has rapidly advanced in recent years with new approvals for immune checkpoint inhibitors and antibody-drug conjugates. However, while many UC tumors contain potentially actionable mutations, the role for targeted small molecule inhibitors has been limited. One such target is the fibroblast growth factor receptor (FGFR) family of proteins. Activating mutations and amplifications of FGFR3 are common in UC with higher incidences seen in upper tract as compared to lower tract disease. Consequently, multiple FGFR-directed targeted therapies have been developed and trialed in both UC and other solid tumors harboring FGFR mutations. At current, erdafitinib, an inhibitor of FGFR1-4, is the only approved targeted therapy in metastatic UC following the BLC2001 study, which demonstrated a 49% overall response rate in patients with UC harboring an FGFR3 mutation. Additional FGFR-directed agents also continue to be investigated across multiple disease stages in FGFR-mutated UC including infigratinib, rogaratinib, and AZD4547, among others. Ongoing trials are combining these agents with immune checkpoint inhibitors and chemotherapy regimens. The precision medicine revolution has begun in UC, and FGFR3 inhibitors are leading the charge toward a more personalized, biomarker-driven treatment paradigm., Competing Interests: Declaration of Competing Interest None, (Copyright © 2021 Elsevier Inc. All rights reserved.)

Urinary bladder cancer is a common cancer worldwide. Currently, the modality of treating and monitoring bladder cancer is wide. Nonetheless, the high recurrence rate of non-muscle-invasive bladder cancer after surgical resection is still unsatisfactory. Hereby, our study demonstrated whether the intra-operative and post-operative environments will affect bladder cancer recurrence utilizing in vitro cell line model. Bladder cancer cell lines were submerged in four different irrigating fluids for assessing their tumorigenic properties. Our results showed that sterile water performed the best in terms of the magnitude of cytotoxicity to cell lines. Besides, we also investigated cytotoxic effects of the four irrigating agents as well as mitomycin C (MMC) in normothermic and hyperthermic conditions. We observed that sterile water and MMC had an increased cytotoxic effect to bladder cancer cell lines in hyperthermic conditions. Altogether, our results could be translated into clinical practice in the future by manipulating the intra-operative and post-operative conditions in order to lower the chance of residual cancer cells reimplant onto the bladder, which in turns, reducing the recurrence rate of bladder cancers., (© 2022. The Author(s).)

Background: In patients with genitourinary cancers, the effect of immune checkpoint inhibitors (ICIs) on kidney function is unknown., Patients and Methods: This is a retrospective cohort study of patients with renal cell carcinoma (RCC) and urothelial carcinoma who received ICIs at two major cancer centers between 2012 and 2018. Cumulative incidence and Fine and Gray subdistribution hazard models were performed to determine predictors of the co-primary outcomes, (1) acute kidney injury (AKI) and (2) sustained estimated glomerular filtration rate (eGFR) loss, defined as a >20% decline in eGFR sustained ≥90 days. We also determined the association between immune-related adverse events (irAE) and adverse kidney outcomes among patients surviving ≥1 year., Results: 637 patients were included; 320 (50%) patients had RCC and 317 (50%) patients had urothelial carcinoma. Half of the cohort had eGFR<60 mL/min/1.73 m 2  at baseline. irAEs, AKI, and sustained eGFR loss were common, occurring in 33%, 25% and 16%, respectively. Compared to patients with urothelial carcinoma, patients with RCC were more likely to develop irAEs (aHR 1.61, 95% CI 1.20-2.18) and sustained eGFR loss (aHR 1.97, 95% CI 1.24-3.12), but not AKI (aHR 1.53, 95% CI 0.97-2.41). Among patients surviving ≥1 years, experiencing a non-renal irAE was associated with a significantly higher risk of sustained eGFR loss (aHR 1.71, 95% CI 1.14-2.57)., Conclusion: AKI and sustained eGFR loss are common in patients with genitourinary cancers receiving ICIs. irAEs may be a novel risk factor for kidney function decline among patients receiving ICIs., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: HS, SS, IA, ML, SZ, NR, DC, DEL, KR, CS, MDK, MES have nothing to declare. OR: Research support from Merck. Speaker for activities supported by educational grants from BMS and Merck. Consultant for Merck, Celgene, Five Prime, GSK, Bayer, Roche/Genentech, Puretech, Imvax, Sobi. In addition, Dr. Rahma has a patent “Methods of using pembrolizumab and trebananib” pending. BM: discloses payment for consulting with Bayer, Astellas, Astra Zeneca, Seattle Genetics, Exelixis, Nektar, Pfizer, Janssen, Genentech, Eisai, BMS, Calithera, Dendreon and EMD Serono. He received research support to Dana Farber Cancer Institute (DFCI) from Bristol Myers Squibb, Calithera, Exelixis, Seattle Genetics. GS: Advisory Board: BMS, Genentech, EMD Serono, Merck, Sanofi, Seattle Genetics/Astellas, Astrazeneca, Exelixis, Janssen, Bicycle Therapeutics, Pfizer, Immunomedics; Research Support to Institution: Sanofi, Astrazeneca, Immunomedics; Travel costs: BMS, Astrazeneca; Speaking fees: Physicians Education Resource (PER), Onclive, Research to Practice, Medscape; Writing fees: Uptodate, Editor of Elsevier Practice Update Bladder Cancer Center of Excellence; Steering committee of trials/studies: BMS, Bavarian Nordic, Seattle Genetics, QED (all unpaid), and Astrazeneca, EMD Serono, Debiopharm (paid). SM: Salaried position as a Deputy Editor at UpToDate (Wolters Kluwer). SG: scientific coordinator for the ASCEND trial. XG: Honorarium from Exelixis. XW: Research support to Institution: BMS. MDM - MD Advisory Board for Pfizer, Exelixis, Eisai and Merck. TKC - AstraZeneca, Aveo, Bayer, Bristol Myers-Squibb, Eisai, Exelixis, GlaxoSmithKline, Ipsen, Lilly, Merck, Novartis, Pfizer, Roche, Sanofi/Aventis, Takeda (institutional and personal) related to research, consultancy and advisory boards. TKC is supported in part by the Dana Farber/Harvard Cancer Center Kidney SPORE Program, the Kohlberg Chair at Harvard Medical School and the Trust Family, Michael Brigham, and Loker Pinard Funds for Kidney Cancer Research at DFCI., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Urinary bladder cancer (UBC) is considered one of the most prevalent malignant tumors worldwide. Complementary and integrative approaches for the treatment of bladder cancer, such as the intake of isoflavonoid phytoestrogens, are of increasing interest due to the risk of mortality and long-term morbidity associated with surgical procedures. The biological effects of prunetin, one of the less-studied phytoestrogens, have not yet been examined in this respect. Therefore, this study aimed to explore the efficacy of prunetin on UBC cells (RT-4). METHODS AND RESULTS: The cytotoxicity and nitric oxide synthase activities of prunetin were determined in cell cultures. The expression of apoptosis-related genes was determined with RT-PCR. Cell cycle assays were performed using a flow cytometer and cellular apoptotic rate was measured. The results suggested that prunetin has cytotoxic effects at 21.11 µg/mL on RT-4 cells. Flow cytometry analysis showed that prunetin induced apoptosis and arrested th cell cycle in the G 0 /G 1 phase. Prunetin exposure was associated with increases in CASP3 and TNF-α gene expression in RT-4 cells at doses of 21.11 and 42.22 µg/mL, respectively. Strong nitric oxide inhibition was observed at IC 50 of 5.18 µg/mL under macrophage mediated inflammatory circumstances., Conclusions: Prunetin possesses anti-cancer properties and may be a candidate compound for the prevention of UBC. This is the first study that evaluated prunetin for its in vitro antitumor activities, clarified its possible apoptotic molecular mechanism and provided novel insights into its anti-inflammatory nature and effects on the expression of related key genes., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

Purpose: To study prognostic values of bladder neck involvement (BNI) and survival outcomes in non-muscle-invasive bladder cancer (NMIBC)., Method and Materials: The national Surveillance, Epidemiology, and End Results database (2004-2015) was applied to gain further insight into the prognostic values of BNI and 19,919 patients diagnosed with NMIBC were included in our study. We used the Kaplan-Meier method with the log-rank test and subgroup analyses to evaluate cancer-specific survival (CSS) and overall survival (OS). In addition, the multivariable Cox proportional hazard model and propensity score matching (PSM) were utilized., Results: In all, 3446 patients with BNI and 16,473 patients with sites except for bladder neck were enrolled in our study. Compared with other sites, a tendency toward a higher proportion of higher grade (p < 0.001), bigger tumor size (p < 0.001), and more patients with T1 and Tis stage (p < 0.001) was seen in BNI group. After 1:1 PSM, 3425 matched pairs were selected. Under the survival analyses, the BNI group had a lower survival probability in both OS (p = 0.0056) and CSS analyses (p < 0.0001) in NMIBC patients. However, in the subgroup analysis, only observed in the Ta and T1 stage in terms of CSS (all p < 0.05), and patients with Tis stage failed to show statistical survival differences (p > 0.05). In addition, subgroups stratified by tumor size and grade all revealed poor prognosis of BNI in NMIBC patients. Moreover, better survival outcomes of OS were observed in BNI patients who received radical cystectomy (p = 0.02) or chemotherapy (p < 0.001) multivariable Cox regression after PSM revealed that the BNI group had a higher risk of overall mortality (OM) (BNI vs. other sites hazards ratios [HR]: 1.127, 95% CI: 1.154-1.437, p < 0.001) and cancer-specific mortality (CSM) (BNI vs. other sites HR: 1.127, 95% CI: 1.039-1.223, p < 0.001), while before PSM, similar situations were only existed in CSM (BNI vs. other sites HR: 1.288, 95% CI: 1.154-1.437, p < 0.001)., Conclusions: The prognosis of BNI was poorer than that of the other sites. BNI was an independent risk factor for OM and CSM in patients with NMIBC, especially for those with Ta or T1 stage., (© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

DISCLOSURES : Funding for this summary was contributed by Arnold Ventures, California Health Care Foundation, The Donaghue Foundation, Harvard Pilgrim Health Care, and Kaiser Foundation Health Plan to the Institute for Clinical and Economic Review (ICER), an independent organization that evaluates the evidence on the value of health care interventions. ICER's annual policy summit is supported by dues from AbbVie, Aetna, America's Health Insurance Plans, Anthem, Alnylam, AstraZeneca, Biogen, Blue Shield of CA, Boehringer-Ingelheim, Cambia Health Services, CVS, Editas, Evolve Pharmacy, Express Scripts, Genentech/Roche, GlaxoSmithKline, Harvard Pilgrim, Health Care Service Corporation, HealthFirst, Health Partners, Humana, Johnson & Johnson (Janssen), Kaiser Permanente, LEO Pharma, Mallinckrodt, Merck, Novartis, National Pharmaceutical Council, Pfizer, Premera, Prime Therapeutics, Regeneron, Sanofi, Spark Therapeutics, uniQure, and United Healthcare. Beinfeld, McKenna, Rind, and Pearson are employed by ICER. Touchette received funding from ICER for work on this report and has also received fees from Monument Analytics and AstraZeneca, unrelated to this work. The University of Illinois at Chicago (UIC) and Touchette hold a patent for the model described in this report. The model is included in ICER's Interactive Modeler, for which a fee is paid to UIC and Touchette. Atlas also received funding from ICER for work on this report.

Bladder cancer (BC) is the tenth most common cancer worldwide with a high recurrence rate, morbidity and mortality. Therefore, chemoprevention and improved treatment of BC are of paramount importance. Epidemiological studies suggest that adequate vitamin A intake may be associated with reduced BC risk. In addition, retinoids, natural and synthetic derivatives of vitamin A, are intensively studied in cancer research due to their antioxidant properties and their ability to regulate cell growth, differentiation, and apoptosis. Findings from in vivo and in vitro models of BC show great potential for the use of retinoids in the chemoprevention and treatment of BC. However, translation to the clinical practice is limited. In this narrative review we discuss: (i) vitamin A and retinoid metabolism and retinoic acid signalling, (ii) the pathobiology of BC and the need for chemoprevention, (iii) the epidemiological evidence for the role of dietary vitamin A in BC, (iv) mechanistic insights obtained from in vivo and in vitro models, (v) clinical trials of retinoids and the limitations of retinoid use, (vi) novel systems of retinoid delivery, and (vii) components of retinoid signalling pathways as potential novel therapeutic targets.

Background: Solanum nigrum L. decoction has been used as a folklore medicine in China to prevent the postoperative recurrence of bladder cancer (BC). However, there are no previous pharmacological studies on the protective mechanisms of this activity of the plant. Thus, this study aimed to perform a systematic analysis and to predict the potential action mechanisms underlying S. nigrum activity in BC based on network pharmacology., Methods: Based on network pharmacology, the active ingredients of S. nigrum and the corresponding targets were identified using the Traditional Chinese Medicines for Systems Pharmacology Database and Analysis Platform database, and BC-related genes were screened using GeneCards and the Online Mendelian Inheritance in Man database. In addition, ingredient-target (I-T) and protein-protein interaction (PPI) networks were constructed using STRING and Cytoscape, Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted, and then the pathways directly related to BC were integrated manually to reveal the pharmacological mechanism underlying S. nigrum-medicated therapeutic effects in BC., Results: Seven active herbal ingredients from 39 components of S. nigrum were identified, which shared 77 common target genes related to BC. I-T network analysis revealed that quercetin was associated with all targets and that NCOA2 was targeted by four ingredients. Besides, interleukin 6 had the highest degree value in the PPI network, indicating a hub role. A subsequent gene enrichment analysis yielded 86 significant GO terms and 89 significant pathways, implying that S. nigrum had therapeutic benefits in BC through multi-pathway effects, including the HIF-1, TNF, P53, MAPK, PI3K/Akt, apoptosis and bladder cancer pathway., Conclusions: S. nigrum may mediate pharmacological effects in BC through multi-target and various signaling pathways. Further validation is required experimentally. Network pharmacology approach provides a predicative novel strategy to reveal the holistic mechanism of action of herbs.

A number of urinary bladder urothelial carcinoma (UB UC) mRNA-based classification systems have been reported. It also has been observed that treatment response and prognosis are different for each molecular subtype. In this study, cytokeratin (CK)5/6 and CK20 immunohistochemistry (IHC) were performed, and IHC-based subgroup classification was applied. UB UC was classified into CK5/6 single-positive (SP), CK20 SP, double-positive (DP) and double-negative (DN) subgroups, and transcriptional analysis was performed. The results of gene ontology (GO) terms and functional analysis using differentially expressed genes indicate that, CK5/6 SP and DP subgroups were enriched in cell migration, immune activation, interleukin 6-Janus kinase-signal transducer and activator of transcription 3 (IL6-JAK-STAT3) signaling pathway and tumor necrosis factor-α signaling via the nuclear factor-κB (NF-κB) signaling pathway signature gene. In addition, compared with the other subgroups, the DN subgroup showed inhibited cell movement, cell migration, and cell activation. Furthermore, in survival analysis, the CK5/6 SP subgroup was significantly associated with poor progression-free survival ( p = 0.008). The results of our study indicate that the CK5/6 positive subgroup exhibited high gene expression signature related to aggressive behavior and exhibited worse clinical outcome.

Current organoid models are limited by their inability to mimic mature organ architecture and associated tissue microenvironments 1,2 . Here we create multilayer bladder 'assembloids' by reconstituting tissue stem cells with stromal components to represent an organized architecture with an epithelium surrounding stroma and an outer muscle layer. These assembloids exhibit characteristics of mature adult bladders in cell composition and gene expression at the single-cell transcriptome level, and recapitulate in vivo tissue dynamics of regenerative responses to injury. We also develop malignant counterpart tumour assembloids to recapitulate the in vivo pathophysiological features of urothelial carcinoma. Using the genetically manipulated tumour-assembloid platform, we identify tumoural FOXA1, induced by stromal bone morphogenetic protein (BMP), as a master pioneer factor that drives enhancer reprogramming for the determination of tumour phenotype, suggesting the importance of the FOXA1-BMP-hedgehog signalling feedback axis between tumour and stroma in the control of tumour plasticity.

Robot-assisted radical cystectomy with intracorporeal urinary diversion is one of the most challenging procedures in urological surgery. Over the past 15 years, this procedure has gained in popularity and the number of procedures performed has increased significantly. While ileal conduit remains the most common diversion, orthotopic neobladders are also formed in a few expert centres that have developed their technique for totally intracorporeal neobladder. The objective of this review is to summarise the techniques currently used to perform totally intracorporeal neobladder with a special focus on their functional outcomes, such as continence or sexual function. The techniques described are the Karolinska-modified Studer neobladder, the USC-modified Studer neobladder, the pyramid pouch, the Y-pouch, and the vesica Ileale Padovana, some trying to totally reproduce the steps of open surgery and others trying to simplify them. Functional outcomes vary depending on the technique performed. Standardisation in assessing outcomes is lacking, as well as objective outcome measurements with questionnaires or urodynamic assessments. Current evidence shows acceptable functional outcomes after totally intracorporeal neobladder construction, but larger prospective randomised series with longer follow-up, better defined outcomes, and more objective measurements are needed in the future.

Urinary incontinence of idiopathic nature is a common complication of bladder cancer, yet, the mechanisms underlying changes in bladder contractility associated with cancer are not known. Here by using tensiometry on detrusor smooth muscle (DSM) strips from normal rats and rats with bladder cancer induced by known urothelial carcinogen, N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN), we show that bladder cancer is associated with considerable changes in DSM contractility. These changes include: (1) decrease in the amplitude and frequency of spontaneous contractions, consistent with the decline of luminal pressures during filling, and detrusor underactivity; (2) diminution of parasympathetic DSM stimulation mainly at the expense of m-cholinergic excitatory transmission, suggestive of difficulty in bladder emptying and weakening of urine stream; (3) strengthening of TRPV1-dependent afferent limb of micturition reflex and TRPV1-mediated local contractility, promoting urge incontinence; (4) attenuation of stretch-dependent, TRPV4-mediated spontaneous contractility leading to overflow incontinence. These changes are consistent with the symptomatic of bladder dysfunction in bladder cancer patients. Considering that BBN-induced urothelial lesions in rodents largely resemble human urothelial lesions at least in their morphology, our studies establish for the first time underlying reasons for bladder dysfunction in bladder cancer.

Bladder cancer prognosis is closely linked to the underlying differentiation state of the tumor, ranging from the less aggressive and most-differentiated luminal tumors to the more aggressive and least-differentiated basal tumors. Sequencing of bladder cancer has revealed that loss-of-function mutations in chromatin regulators and mutations that activate receptor tyrosine kinase (RTK) signaling frequently occur in bladder cancer. However, little is known as to whether and how these two types of mutations functionally interact or cooperate to regulate tumor growth and differentiation state. Here, we focus on loss of the histone demethylase UTX (also known as KDM6A) and activation of the RTK FGFR3, two events that commonly cooccur in muscle invasive bladder tumors. We show that UTX loss and FGFR3 activation cooperate to disrupt the balance of luminal and basal gene expression in bladder cells. UTX localized to enhancers surrounding many genes that are important for luminal cell fate, and supported the transcription of these genes in a catalytic-independent manner. In contrast to UTX, FGFR3 activation was associated with lower expression of luminal genes in tumors and FGFR inhibition increased transcription of these same genes in cell culture models. This suggests an antagonistic relationship between UTX and FGFR3. In support of this model, UTX loss-of-function potentiated FGFR3-dependent transcriptional effects and the presence of UTX blocked an FGFR3-mediated increase in the colony formation of bladder cells. Taken together, our study reveals how mutations in UTX and FGFR3 converge to disrupt bladder differentiation programs that could serve as a therapeutic target., Competing Interests: The authors declare no competing interest.

Background: This study aims to determine the relationship between the pre-operative De Ritis ratio (DRR) and bladder cancer (BCa) pathological subtypes. Results & methodology: A total of 248 patients with primary BCa were included. Univariate and multivariate analyses were performed to identify whether DRR can be a risk factor for the presence of carcinoma in situ (C IS ). There was a statistically significant difference between the nonmuscle invasive BCa risk groups and the muscle-invasive BCa group according to the median DRR levels (p < 0.001). DRR was an independent risk factor for the presence of C IS in multivariate analysis (OR: 1.909; 95% CI: 0.030-0.196; p = 0.008). Discussion & conclusion: DRR can be considered as an independent risk factor for the presence of C IS in patients with primary BCa.

The objective was to describe our step-by-step technique for robot-assisted orthotopic "W" ileal neobladder (INB) for urinary diversion following radical cystectomy for oncological purpose, and to report the outcomes of this technique for the first six male patients treated at our center. Patients underwent robot-assisted radical cystoprostatectomy for bladder cancer and had a "W" ileal neaobladder as urinary diversion. Our surgical technique is described step by step and video illustrated. Patients and operative data were collected and reported. The Expanded Prostate Cancer Index Composite Short Form (EPIC-26) self-administered questionnaire was used to assess the urinary, sexual and bowel functions outcomes at 90 days postoperatively. The mean operative time was 475 min [420-525] and mean length of stay was 13 days [11-15]. No major complications occurred (Clavien grade ≥ 3). Regarding the continence four patients reported they leaked urine rarely or never and two patients having urine leak once a day. Two patients did not wear any pad, the four others reported using pad at night. Two patients reported urinary function as not a problem, one as a very small problem, two as a small problem and one as a moderate problem. These results from our six first cases using the technique described here are promising with interesting early functional outcomes. This has to be confirmed on larger cohort and with long-term follow-up.

A 68-year-old woman presented with episodes of headache, palpitations, sweating and poorly controlled hypertension for the past 6 years. These symptoms were, at times, associated with micturition, and there were few episodes of micturition syncope as well. She had elevated 24-hour urinary normetanephrine and was found to have a paraganglioma arising from the urinary bladder infiltrating the sigmoid colon. She underwent laparotomy with excision of the bladder paraganglioma, following which her symptoms subsided. Paragangliomas are extra-adrenal catecholamine-producing tumours. Bladder paragangliomas need to be considered when evaluating hypertensive patients with headache, palpitations or syncope related to micturition., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Limited evidence exists regarding the cost and health-related quality of life (HRQoL) effects of non-muscle-invasive bladder cancer (NMIBC) recurrence and progression to muscle-invasive bladder cancer (MIBC). We examined these effects using evidence from a recent randomized control trial., Material and Methods: The costs and HRQoL associated with bladder cancer were assessed using data from the BOXIT trial (bladder COX-2 inhibition trial; n = 472). The cost and HRQoL effects from clinical events were estimated using generalized estimating equations. The costs were derived from the recorded resource usage and UK unit costs. HRQoL was assessed using the EQ-5D-3L and reported UK preference tariffs. The events were categorized using the TMN classification., Results: Cases of grade 3 recurrence and progression were associated with statistically significant HRQoL decrements (-0.08; 95% confidence interval [CI], -0.13 to -0.03; and -0.10; 95% CI, -0.17 to -0.03, respectively). The 3-year average cost per NMIBC patient was estimated at £8735 (95% CI, 8325-9145). Cases of grade 1, 2, and 3 recurrence were associated with annual cost effects of £1218 (95% CI, 403-2033), £1677 (95% CI, 920-2433), and £3957 (95% CI, 2332-5583), respectively. Progression to MIBC was associated with an average increase in costs of £5407 (95% CI, 2663-8152)., Conclusion: Evidence from the BOXIT trial suggests that patients with NMIBC will both experience decrements in HRQoL and incur significant costs, especially in the event of a grade 3 recurrence or a progression to MIBC., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Bladder cancer is three to four times more common among men than women. The objectives of this study were to explore the association between reproductive and hormonal factors and risk of bladder cancer among women using data from the Prostate, Lung, Colorectal and Ovarian (PLCO) cohort, and to perform a meta-analysis based on cohort studies. After a median of 11.6 years of follow-up, 237 incident bladder cancer cases were identified in PLCO cohort. Compared with menopause at 50-54 years, earlier menopause (< 45 years) was positively but not significantly associated with bladder cancer risk (HR 1.25, 95% CI 0.91-1.71; p = 0.176). In the meta-analysis, parous women had significantly lower bladder cancer risk than nulliparous women (pooled HR 0.79, 95% CI 0.73-0.86). In addition, menopause at an earlier age was significantly associated with a higher risk of bladder cancer (pooled HR 1.22, 95% CI 1.06-1.40). In conclusion, this study indicated a greater risk in bladder cancer among nulliparous women and among women with early menopause. Further studies are needed to understand the underlying mechanisms.

We recorded the survival of 141 patients assessed for radical cystectomy, which included cardiopulmonary exercise testing. The median Kaplan-Meier survival estimates were: 1540 days for the whole cohort; 2200 days after cystectomy scheduled (n = 108); and 843 days without surgery. The mortality hazard remained double that expected for a matched general population, but survival was better in patients scheduled for surgery than those who were not: the mortality hazard ratio (95%CI) after cystectomy was 0.43 (0.26-0.73) the mortality hazard without surgery, p = 0.001. The mortality hazard ratios for the three-variable Bayesian Model Averaging survival model for all 141 patients were: referral for surgery (0.5); haemoglobin concentration (0.98); and efficiency of carbon dioxide output (1.05). Efficiency of carbon dioxide output was the single variable in the postoperative model (n = 108), mortality hazard 1.08 (per unit increase). The ratio of observed to expected peak oxygen consumption associated best with mortality in 33 patients not referred for surgery, hazard ratio 0.001. Our results can inform consultations with patients with invasive bladder cancer and suggest that interventions to increase fitness and haemoglobin may improve survival in patients who do and who do not undergo radical cystectomy., (© 2020 Association of Anaesthetists.)

Objective: This study examined the prevalence of self-perceived burden (SPB) and its association with health-related quality of life (HRQoL) among urologic cancer patients., Methods: This was a prospective, cross-sectional study. A total of 429 respondents diagnosed with urologic cancers (prostate, bladder and renal cancer) from Sarawak General Hospital and Subang Jaya Medical Centre in Malaysia were interviewed by using a structured questionnaire. SPB and HRQoL were measured by the Self-perceived Burden Scale and the Functional Assessment of Cancer Therapy-General 7 Item Scale respectively., Results and Conclusion: Self-perceived burden was experienced by 73.2% of the respondents. Respondents who had a lower education level, a monthly household income

Urothelial cell carcinoma of the bladder is exceedingly rare in pediatric patients. Based on current literature, bladder cancer in this population is thought to be low-grade, noninvasive, and unlikely to recur, suggesting significant biologic differences when compared to the adult population. This is a 15-year-old male diagnosed with low-grade urothelial cell carcinoma with subsequent multifocal recurrence on surveillance cystoscopy managed by induction and maintenance intravesical Bacillus Calmette-Guerin. This case highlights the challenges of management and surveillance of this rare disease., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Previous studies have shown that alterations in the mechanical properties of cells may be associated with the onset and progression of some forms of pathology. In this paper, an experimental study of two types of cells, renal (cancer) and bladder (cancer) cells, is described which used acoustic radiation force (ARF) generated by a high-frequency ultrasound focusing transducer and performed on the operating platform of an inverted light microscope. Comparing images of cancer cells with those of normal cells of the same kind, we find that the cancer cells are more prone to deform than normal cells of the same kind under the same ARF. In addition, cancer cells with higher malignancy are more deformable than those with lower malignancy. This means that the deformability of cells may be used to distinguish diseased cells from normal ones, and more aggressive cells from less aggressive ones, which may provide a more rapid and accurate method for clinical diagnosis of urological disease in the future.

Objective: Between 10 and 20% of bladder cancer patients who are diagnosed with nonmuscle-invasive bladder cancer will progress to muscle-invasive disease. Risk of progression depends on several factors at diagnosis including age, tumour stage, grade, size and number, and the presence or absence of carcinoma in situ. Fluid intake may be related to these factors., Methods: Data of 1123 participants from the West Midlands Bladder Cancer Prognosis Programme were used. Data collection was via a semistructured questionnaire, and case report forms were used to collect clinicopathological data. Fluid intake was measured for six main categories: alcoholic fluids, hot fluids, fruit fluids, milk, fizzy drinks, and water, and converted into quintile variables. Multilevel mixed-effects linear regression was performed for every beverage category per clinicopathological variable and corrected for age, gender, and smoking status., Results: Age at diagnosis was distributed differently amongst those in different total fluid intake quintiles (predicted means 71.5, 70.9, 71.5, 69.9, and 67.4, respectively) and showed a significant inverse linear trend in alcohol (P < 0.01), hot fluids (P < 0.01), and total fluids intake (P < 0.01), in nonmuscle-invasive bladder cancer patients., Conclusion: Our results suggest an inverse association for alcohol intake and total fluid intake with age at diagnosis. These results should be confirmed by future studies, alongside a possible (biological) mechanism that could influence tumour growth, and the effect of micturition frequency.

Objective: To describe the natural history of untreated muscle-invasive bladder cancer (MIBC) and compare the oncological outcomes of treated and untreated patients., Patients and Methods: We utilised a database encompassing all patients with newly diagnosed bladder cancer in Stockholm, Sweden between 1995 and 1996. The median follow-up for survivors was 14.4 years. Overall, 538 patients were diagnosed with bladder cancer of whom 126 had clinically localised MIBC. Patients were divided into two groups: those who received radical cystectomy or radiation therapy, and those who did not receive any form of treatment. Multivariable Cox or competing-risks regressions were adopted to predict metastasis, overall survival (OS), and cancer-specific mortality (CSM), when appropriate. Analyses were adjusted for age at diagnosis, sex, tumour stage, clinical N stage, and treatment., Results: In all, 64 (51%) patients did not receive any definitive local treatment. In the untreated group, the median (interquartile range) age at diagnosis was 79 (63-83) vs 69 (63-74) years in the treated group (P < 0.001). Overall, 109 patients died during follow-up. At 6 months after diagnosis, 38% of the untreated patients had developed metastatic disease and 41% had CSM. The 5-year OS rate for untreated and treated patients was 5% (95% confidence interval [CI] 1, 12%) vs 48% (95% CI 36, 60%), respectively. Patients not receiving any treatment had a 5-year cumulative incidence of CSM of 86% (95% CI 75, 94%) vs 48% (95% CI 36, 60%) for treated patients. Untreated patients had a higher risk of progression to metastatic disease (hazard ratio [HR] 2.40, 95% CI 1.28, 4.51; P = 0.006), death from any cause (HR 2.63, 95% CI 1.65, 4.19; P < 0.001) and CSM (subdistribution HR 2.02, 95% CI 1.24, 3.30; P = 0.004)., Conclusions: Untreated patients with MIBC are at very high risk of near-term CSM. These findings may help balance the risks vs benefits of integrating curative intent therapy particularly in older patients with MIBC., (© 2019 The Authors BJU International © 2019 BJU International Published by John Wiley & Sons Ltd.)

Urothelial cell carcinoma (UCC) is one of the lethal causes of cancer mortality of the genitourinary tract. Carcinogenic epidemiological risk factors exposure and age over 65 years old are associated with UCC risk. Matrix metalloproteinase 11 (MMP11) was suggested as a tumor marker of metastasis and predictor of poor survival in urothelial carcinomas. In this study, we focused on the associations of MMP11 single-nucleotide polymorphisms (SNPs) to UCC susceptibility, clinicopathological characteristics, and prognosis. In this study, real-time polymerase chain reaction was used to analyze five SNPs of MMP11 rs738791, rs2267029, rs738792, rs28382575, and rs131451 in 431 patients with UCC and 650 cancer-free controls. The MMP11 rs28382575 polymorphic "CT" genotype were susceptible to UCC (AOR = 2.045, 95% CI = 1.088 - 3.843; p = 0.026). For MMP11 rs131451, a significant association was found in 166 UCC patients among age ≤ 65 years old who carried MMP11 rs131451 polymorphic "CC" genotype, which is associated with lower risk to develop later tumor T status (T1-T4) (OR = 0.375, 95% CI = 0.159 - 0.887; p = 0.026) compared with the (CT + TT) genotype. Furthermore, patients of UCC with rs738792 polymorphic "CC" genotype were observed to have higher free of relapse (FS) ( p = 0.035), disease specific survival rate ( p = 0.037), and overall survival rate ( p = 0.009) compared with the rs738792 (CT + CC) genotype. In conclusion, our results demonstrated that the MMP11 SNPs are associated with UCC susceptibility, clinical status, and disease survival. The MMP11 polymorphisms may have potential to predict UCC susceptibility and prognosis.

Tumor energy metabolism and angiogenesis play significant roles in tumor genesis and development, while the effect of the tumor microenvironment (TME), which tumors rely on, is always ignored. In this research, we cocultured bladder cancer (BC) T24 cells with tumor-associated human umbilical vein endothelial cells (HUVECs) under normoxic and hypoxic conditions and detected proliferation, migration, oxidative phosphorylation (OXPHOS) and glycolysis to reveal the energy metabolism characteristics and their effect on cell biological behaviors (CBBs) in the TME. Compared with single-cultured cells, both cocultured T24 cells and HUVECs showed poor proliferation and migration in hypoxic environment, and OXPHOS was activated in cocultured T24 cells but weakened in cocultured HUVECs. However, in normoxic environment, cocultured T24 cells grew much faster while cocultured HUVECs grew slower compared with single-cultured cells. Additionally, glycolysis played a crucial role in energy metabolism and was inhibited in cocultured T24 cells but activated in cocultured HUVECs. In normoxic TME, OXPHOS take main responsibility of energy metabolism. T24 cells exhibited increased proliferation and migration with HUVECs support. In hypoxic TME, glycolysis may be the primary energy supply pathway. T24 cells then exhibit suppressed proliferation and migration, while HUVECs tend to promote angiogenesis to adapt to the harsh TME., (© 2019 International Union of Biochemistry and Molecular Biology.)

Background: The new severe acute respiratory syndrome virus (SARS-CoV-2) outbreak is a huge health, social and economic issue and has been declared a pandemic by the World Health Organization. Bladder cancer, on the contrary, is a well-known disease burdened by a high rate of affected patients and risk of recurrence, progression and death., Summary: The coronavirus disease (COVID-19 or 2019-nCoV) often involves mild clinical symptoms but in some cases, it can lead to pneumonia with acute respiratory distress syndrome and multiorgan dysfunction. Factors associated with developing a more severe disease are increased age, obesity, smoking and chronic underlying comorbidities (including diabetes mellitus). High-risk non-muscle-invasive bladder cancer (NMIBC) progression and worse prognosis are also characterized by a higher incidence in patients with risk factors similar to COVID-19. Immune system response and inflammation have been found as a common hallmark of both diseases. Most severe cases of COVID-19 and high-risk NMIBC patients at higher recurrence and progression risk are characterized by innate and adaptive immune activation followed by inflammation and cytokine/chemokine storm (interleukin [IL]-2, IL-6, IL-8). Alterations in neutrophils, lymphocytes and platelets accompany the systemic inflammatory response to cancer and infections. Neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio for example have been recognized as factors related to poor prognosis for many solid tumors, including bladder cancer, and their role has been found important even for the prognosis of SARS-CoV-2 infection. Key Messages: All these mechanisms should be further analyzed in order to find new therapeutic agents and new strategies to block infection and cancer progression. Further than commonly used therapies, controlling cytokine production and inflammatory response is a promising field., (© 2020 S. Karger AG, Basel.)

More than 90% of bladder cancer is composed of transitional cell carcinoma (TCC), being characterized by the development of multiple tumors in the entire urinary tract over time. When cystectomy is conducted, the urinary tract must be reconstructed by various procedures, which can include an orthotopic neobladder using the patient's own intestine formed into a spherical shape anastomosed to the urethra. Using this procedure, patients can void urine from their own urethra even after cystectomy. The incidence of subsequent urethral cancer arising after cystectomy is known to be relatively high; however, if patients with a high risk of urethral recurrence are appropriately excluded, a neobladder can be safely provided for patients. Orthotopic neobladder use is reviewed from an oncological viewpoint and the patient's quality of life after cystectomy for bladder cancer.

A cell is dying when there is no repair after damage. Indeed, the etiology of cancers associates with damaged or unrepaired cells. Cancer results from imbalance between cell's oxidant and antioxidant defenses. This study aimed to review formation of cancer associated to oxidative stress. Tumorgenesis is caused by deregulation of the redox homeostasis by reactive oxygen species that stimulate the formation of tumor by starting an abnormal introduction of signaling nets. Proliferation accompanied by uncontrolled growth could lead to development of mass cancer cells. Kinases/phosphatases, transcription factors, reactive oxygen-nitrogen species and signal transduction are the most important cascades. The biology of tumor is affected by: 1) redox control through growth factor receptor signal, 2) superoxidase production due to small amount of oxygen, 3) infiltrating cytotoxic immune cells, 4) anticancer treatments, 5) repetitive ischemia-reperfusion cycles due to irregular blood supply and 6) inflammation. Keywords: Oxidant; Anti-oxidant; Cancer; Bladder.

Objective: To assess age-based differences in psychological and physical symptoms of bladder cancer (BC) patients at different disease stages., Methods: This was a cross-sectional single-center retrospective study between 2014 and 2017, assessing BC patients at different time points of their disease trajectory, after completing the Edmonton Symptom Assessment System-revised questionnaire. The questionnaire was filled at 3 predefined time points: (a) following diagnosis, (b) after radical cystectomy (RC), and (c) at last follow-up. The Edmonton Symptom Assessment System-revised consists of the physical distress sub-score (PHSDSS), entailing scores of 6 physical symptoms, and the psychological distress sub-score (PDSS), entailing scores of 3 psychological symptoms. Patients were stratified to those younger and older than 65 years. Multivariable linear regression models assessed predictors of increased PDSS and PHSDSS., Results: A total of 232 patients were analyzed. No significant baseline clinical differences were demonstrated between both groups, excepting a higher Charlson comorbidity score (4.85 vs 3.87, P = .004), and a higher rate of muscle-invasive disease (71.7% vs 52.1%, P = .008) in older patients. PHSDSS scores remained similar throughout all time points in both groups. In contrast, younger patients had a significantly higher PDSS score at diagnosis, and after RC. Multivariable models demonstrated that an increased PDSS score (B = 2.372, 95% CI 0.36-4.385) was more likely in younger patients at diagnosis and after RC. An increased PHSDSS (B = 5.118, 95% CI 0.462-9.774) was more likely in younger patients only after RC., Conclusion: Younger BC patients may benefit from access to psychological support services as part of a comprehensive treatment regimen, especially after diagnosis and RC., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Bladder cancer (BC) is a fatal invasive malignancy accounting for approximately 5% of all cancer deaths in humans; however, the underlying molecular mechanisms and potential targeted therapeutics for BC patients remain unclear. We report herein that RAB14 was overexpressed in BC tissues and cells with high metastatic potential and its abundance was significantly associated with lymph node metastasis (P = 0.001), a high-grade tumor stage (P = 0.009), poor differentiation (P < 0.001) and unfavorable prognoses of BC patients (P = 0.003, log-rank test). Interference by RAB14 mediated a reduction in the TWIST1 protein and inhibited cell migration and invasion (P < 0.05). Moreover, silencing RAB14 reduced cell proliferation and induced apoptosis in vitro and suppressed tumorigenesis in a mouse xenograft model. We demonstrated that RAB14-promoted BC cancer development and progression were associated with activation of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase signaling through upregulation of MAPK1/MAPK8 and downregulation of dual-specificity protein phosphatase 6/Src homology 2 domain containing transforming protein/Fos proto-oncogene, AP-1 transcription factor subunit (FOS). We provide evidence that RAB14 acts as a tumor promoter and modulates the invasion and metastatic potential of BC cells via activating the MAPK pathway., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Current pathological nodal staging for bladder cancer is based on lymph node (LN) location but not on the number of positive LNs., Objective: We sought to improve prognostic classification by creating a novel staging system incorporating positive LN burden., Design, Setting, and Participants: We sampled 12515 patients with muscle-invasive bladder cancer (MIBC) from the National Cancer Database (NCDB) and 5928 MIBC patients from the Surveillance, Epidemiology, and End Results (SEER) database for our development and validation cohorts, respectively., Outcome Measurements and Statistical Analysis: Multivariable Cox proportional hazards analysis with restricted cubic splines was used to assess the association between the number of metastatic LNs and overall mortality (OM). A novel staging system was derived by recursive partitioning analysis (RPA) in NCDB and was validated in SEER by assessing discrimination (Harrel's c-index) and calibration (mean absolute prediction error)., Results and Limitations: Mortality risk increased continuously with more metastatic LNs; the effect was most pronounced up to four LNs (hazard ratio [HR] 1.17, 95% confidence interval [CI] 1.12-1.22) and attenuated beyond four nodes (HR 1.03, 95% CI 1.02-1.05). RPA generated a novel staging system predicting mortality by metastatic nodal number with cutpoints at zero (reference), one (HR 1.57, 95% CI 1.46-1.69), two to three (HR 2.03, 95% CI 1.88-2.19), four to seven (HR 2.46, 95% CI 2.25-2.70), and more than seven (HR 3.83, 95% CI 3.38-4.33) positive LNs. Location of LN involvement was not a significant predictor of OM. In external validation, the novel staging system showed good risk discrimination (optimism corrected c-index 0.677, 95% CI 0.672-0.682) and calibration (mean absolute prediction error 0.011 for 5-yr OM). Results are limited by development and validation using secondary data., Conclusions: The number of metastatic LNs predicts mortality better than LN location and may improve pathological nodal staging in MIBC., Patient Summary: This retrospective study found that the number of metastatic lymph nodes more accurately predicts survival than the location of metastatic lymph nodes in patients with muscle-invasive bladder cancer. This finding argues for change to the current bladder cancer staging system., (Copyright © 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Context: Variant histology of muscle-invasive (MIBC) and metastatic (mBC) bladder cancer may define the cancer treatment modality and oncological outcomes., Objective: To determine the prognostic effect and impact of therapy of urothelial and nonurothelial histological variants on the oncological outcomes of MIBC and mBC., Evidence Acquisition: Medline, Embase, Cochrane controlled trial databases, and ClinicalTrials.gov were systematically searched. Patients with histological variants of MIBC or/and mBC from prospective and retrospective comparative studies and single-arm case series published after the year of 2000 were included. Treatment outcomes (overall, recurrence-free, and disease-specific survival) were extracted and reported. Risk of bias (RoB) assessment was performed using Quality in Prognosis Studies tool., Evidence Synthesis: The search yielded 2450 unique articles, of which 41 articles involving a total of 27 672 patients with histological variants were included. Twenty-eight studies had a comparative study design. Two different study settings were seen: large database studies without centralised pathological review and small series with re-review by uropathologists. Although most of the histological variants show similar oncological outcomes after radical cystectomy (RC), signet ring cell, spindle cell, and neuroendocrine tumours showed inferior survival compared with pure urothelial bladder cancer (PUC). Owing to potential misleading interpretations and reporting as well as large heterogeneity between studies, a narrative synthesis approach instead of subgroup analyses was used. Most studies had a moderate RoB., Conclusions: The data about prognosis and treatment of the variant histology are still immature and assessed mostly in cystectomy patients. Based on this systematic review, all patients with MIBC should be treated with RC. Neoadjuvant chemotherapy may be beneficial for patients with micropapillary, plasmacytoid, sarcomatoid, and mixed variants, and especially for patients with neuroendocrine tumours. Metastatic bladder cancer should be treated as PUC., Patient Summary: In this report, we looked at the prognosis and treatment of different bladder cancer histologies. We found that outcomes varied with divergent histologies and appropriate treatment should be based on the histological finding., (Copyright © 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

We prospectively validate the efficacy of the frailty discriminant score (FDS) in individuals with urological cancers, as there has been growing importance in evaluating frailty in clinical practice. A prospective, multicenter study was conducted from February 2017 to April 2019. We enrolled 258 patients with urological cancers and 301 community-dwelling participants who were assessed for frailty. Frailty was assessed using FDS that includes ten items, such as physical, mental, and blood biochemical tests. The primary outcome was the non-inferiority (margin 5%) of FDS in discriminating patients with urological cancers from controls (Ctrl). The sensitivity, specificity, and area under the receiver operating characteristic (AUROC) curve for each predictive test were calculated. The secondary endpoints included the prediction of overall survival between patients with urological cancer who have high and low FDS. FDS was significantly higher in patients with urological cancers than that in the Ctrl. The AUROC curves for individuals with non-prostate cancers (such as bladder cancer, upper tract urothelial carcinoma, and renal cell carcinoma; 0.942) and those with prostate cancer (0.943) were within the non-inferior margin. The overall survival values were significantly lower in patients with higher FDS score than in those with lower FDS score. The study met its primary and secondary endpoints. The FDS is a reliable and valid tool for assessing frailty and prognosis in patients with urological cancers.

Tumor cells rely on aerobic glycolysis as their main energy resource (Warburg effect). Recent research has highlighted the importance of lipid metabolism in tumor progression, and certain cancers even turn to fatty acids as the main fuel. Related studies have identified alterations of fatty acid metabolism in human bladder cancer (BCa). Our microarray analysis showed that fatty acid metabolism was activated in BCa compared with normal bladder. The free fatty acid (FFA) level was also increased in BCa compared with paracancerous tissues. Inhibition of fatty acid oxidation (FAO) with etomoxir caused lipid accumulation, decreased adenosine triphosphate (ATP) and nicotinamide adenine dinucleotide phosphate (NADPH) levels, suppressed BCa cell growth in vitro and in vivo , and reduced motility of BCa cells via affecting epithelial-mesenchymal transition (EMT)-related proteins. Furthermore, etomoxir induced BCa cell cycle arrest at G 0 /G 1 phase through peroxisome proliferator-activated receptor (PPAR) γ-mediated pathway with alterations in fatty acid metabolism associated gene expression. The cell cycle arrest could be reversed by PPARγ antagonist GW9662. Taken together, our results suggest that inhibition of FAO with etomoxir may provide a novel avenue to investigate new therapeutic approaches to human BCa., (© 2019 The Author(s).)

Bladder cancer is the fourth common cancer among men and more than 70% of the bladder cancer is nonmuscle invasive bladder cancer (NMIBC). Because of its high recurrence rate, NMIBC brings to patients physical agony and high therapy costs to the patients' family and society. It is imperative to seek a natural compound to inhibit bladder cancer cell growth and prevent bladder cancer recurrence. Cell proliferation is one of the main features of solid tumor development, and the rapid tumor cell growth usually leads to hypoxia due to the low oxygen environment. In this study we found that sulforaphane, a natural chemical which was abundant in cruciferous vegetables, could suppress bladder cancer cells proliferation in hypoxia significantly stronger than in normoxia ( p < 0.05): 20 μM sulforaphane inhibited bladder cancer cell proliferation by 26.1 ± 4.1% in normoxia, while it inhibited cell proliferation by 39.7 ± 5.2% in hypoxia in RT112 cells. Consistently, sulforaphane inhibited cell proliferation by 29.7 ± 4.6% in normoxia, while it inhibited cell proliferation by 48.3 ± 5.2% in hypoxia in RT4 cells. Moreover, we revealed that sulforaphane decreased glycolytic metabolism in a hypoxia microenvironment by downregulating hypoxia-induced HIF-1α and blocking HIF-1α trans-localization to the nucleus in NMIBC cell lines. This study discovered a food sourced compound inhibiting bladder cancer cells proliferation and provided experimental evidence for developing a new bladder cancer preventive and therapeutic strategy.

Background/aim: Amentoflavone has been shown to be effective against a variety of cancer cells, but its role in bladder cancer remains unclear. Thus, the aim of this study is to evaluate whether amentoflavone may induce toxicity effect of bladder cancer., Materials and Methods: Herein, we evaluated amentoflavone effects in a human bladder cancer cell line TSGH8301 in vitro., Results: Amentoflavone caused significant cytotoxicity in TSGH8301 cells at a concentration as low as 200 μM. FAS/FASL-dependent extrinsic apoptosis and mitochondria-dependent intrinsic apoptosis were observed in amentoflavone-treated cells in a dose-dependent manner. Levels of several proapoptotic proteins, such as FAS, FAS-ligand and BAX (B-cell lymphoma 2 associated X) were increased following amentoflavone treatment. Meanwhile, anti-apoptotic MCL-1 (myeloid cell leukemia sequence 1) and cellular FLICE-inhibitory protein (C-FLIP) protein levels were reduced. Additionally, angiogenesis and proliferation-related proteins, including matrix metalloproteinase (MMP)-2, -9, vascular endothelial growth factor (VEGF), urokinase-type plasminogen actvator (uPA) and cyclin D1 were diminished by amentoflavone., Conclusion: Amentoflavone induced toxicity of bladder cancer by inhibiting tumor progression and inducing apoptosis signaling transduction., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Purpose: The present study aimed to determine whether sarcopenia after radical cystectomy (RC) could predict overall survival (OS) in patients with urothelial bladder cancer (UBC)., Materials and Methods: The lumbar skeletal muscle index (SMI) of 80 patients was measured before and 1 year after RC. The prognostic signifi cance of sarcopenia and SMI decrease after RC were evaluated using Kaplan-Meier analysis and a multivariable Cox regression model., Results: Of 80 patients, 26 (32.5%) experienced sarcopenia before RC, whereas 40 (50.0%) experienced sarcopenia after RC. The median SMI change was -2.2 cm2/m2. Patients with sarcopenia after RC had a higher pathological T stage and tumor grade than patients without sarcopenia. Furthermore, the overall mortality rate was signifi - cantly higher in patients with sarcopenia than in those without sarcopenia 1 year after RC. The median follow-up time was 46.2 months, during which 22 patients died. Kaplan-Meier estimates showed a signifi cant difference in OS rates based on sarcopenia (P=0.012) and SMI decrease (P=0.025). Multivariable Cox regression analysis showed that SMI decrease (≥2.2 cm2/m2) was an independent predictor of OS (hazard ratio: 2.68, confi dence interval: 1.007-7.719, P = 0.048)., Conclusions: The decrease in SMI after surgery might be a negative prognostic factor for OS in patients who underwent RC to treat UBC., Competing Interests: None declared., (Copyright® by the International Brazilian Journal of Urology.)

Objectives: Paragangliomas of the urinary bladder (PUBs) are challenging catecholamine-producing neuroendocrine tumors. We aimed to facilitate their diagnosis and treatment by functional and anatomical classifications., Materials and Methods: Between April 2007 and September 2017, 31 cases from 2 centers were retrieved, in which the patients were pathologically diagnosed with PUB. Besides classifying them into functional and nonfunctional PUBs, functional PUBs were further subclassified into typical functional PUB (with typical symptoms and elevated catecholamines/metabolites levels) and atypical functional PUB. Anatomically, they were classified into submucosal, intramural, and subserosal PUBs., Results: Functionally, these cases comprised 17 (54.8%) functional and 14 (45.2%) nonfunctional PUBs. Functional PUBs had significantly larger diameters than nonfunctional PUBs (P < 0.01). Of the 17 functional PUB cases, 8 were further subclassified into typical functional PUB, of which 4 were diagnosed without cystoscopy. Anatomically, these cases comprised 14 (45.2%) submucosal, 13 (41.9%) intramural, and 4 (12.9%) subserosal PUBs. Intramural and subserosal PUBs had significantly larger diameters and were more likely to be functional than submucosal PUBs (P < 0.05). Cystoscopy failed to detect the tumor in all patients with subserosal PUB. Besides all patients with intramural or subserosal PUB, 1 patient with submucosal PUB underwent partial cystectomy. The remaining 13 patients with submucosal PUB underwent transurethral resection of bladder tumor, 5 of whom required extra surgical intervention., Conclusions: By functional classification, omitting cystoscopy is feasible in the diagnosis of typical functional PUBs. By anatomical classification, intramural, and subserosal PUBs tend to be large and functional. Moreover, negative cystoscopic findings are not sufficient to exclude subserosal PUBs. Finally, not all submucosal PUBs are amenable to transurethral resection of bladder tumor., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Cancer cell invasion is an important characteristic of malignant tumors. Cancer cells overcome the constraints of tight junctions (TJ) to invade other tissues, but less is known about the regulating role of tight junction on bladder cancer (BC) invasion. In order to identify the invasion-regulating function of tight junction component, we investigated the oncogenetic features of zonula occludens-1 associated nucleic acid binding protein (ZONAB), a TJ protein that is usually highly expressed in solid cancers. Expression of ZONAB was found to be up-regulated in human BC cell lines detected by real-time PCR, Western blotting. ZONAB expression was significantly up-regulated in BC cell lines and negatively regulated E-cadherin expression. Overexpression of ZONAB by stable transduction in human BC cell lines promoted invasion detected by transwell invasion assay. Conversely, stable suppression of ZONAB expression by RNA interference (RNAi) in BC cells attenuated invasion. A similar role for ZONAB in promoting invasion and EMT was observed in xenografts. In summary, ZONAB is up-regulated in BC cell lines, which promotes invasion, demonstrating the important role it plays in tumorogenesis and cancer progression.

Purpose: The BCI (Bladder Cancer Index) is a validated, condition specific health questionnaire assessing urinary, bowel and sexual function and quality of life among patients with bladder cancer. We aimed to establish minimally important difference score thresholds that signal clinical importance., Materials and Methods: For 1 year after surgery we followed a prospective cohort of 150 patients who underwent radical cystectomy between 2013 and 2016. Usable data on 138 patients were analyzed. The BCI and the Medical Outcomes Study SF-36 (36-Item Short Form Health Survey) questionnaires were completed prior to cystectomy, and 3, 6 and 12 months postoperatively. Distribution based, minimally important differences were estimated at ⅓ and ½ SD for each index domain across time points. Changes in index domain scores anchored to changes in a SF-36 overall health assessment question were used to estimate anchor based, minimally important differences. Pooled averages are reported between time points and methods., Results: The distribution based, minimally important difference of ⅓ SDs for urinary, bowel and sexual domains ranged between 5.3 and 7.3, 4.6 and 5.6, and 6.0 and 8.9 points, respectively. Ranges of ½ SDs were 8.8 and 10.9, 6.8 and 8.4, and 8.9 and 13.5 points, respectively. The anchor based approach resulted in minimally important difference estimates of 6.2, 7.3 and 6.8 points, respectively. Aggregated results across the 2 approaches resulted in minimally important differences of 6 to 9, 5 to 8 and 7 to 11 points for urinary, bowel and sexual domains, respectively., Conclusions: Using 2 independent approaches to our knowledge we established the first minimally important difference estimates for the BCI. Defining patient reported outcome thresholds is important to interpret changes or differences in BCI scores.

Background: Allyl isothiocyanate (AITC), a volatile and water-insoluble compound present in several cruciferous vegetables, has been shown to possess several biological qualities such as anti-bacterial, anti-fungal, and anti-cancer activity. In this study, water-soluble allyl isothiocyanate nanoparticles (AITC-NPs) were prepared by oil dispersed in water (O/W) microemulsion and complex coacervation techniques and evaluated for their anti-inflammatory activity towards macrophage cell RAW 264.7 and anti-cancer effect on human bladder cancer cell HT1376., Results: The AITC-NPs with a particle size of 9.4 nm were stable during heating up to 110 °C or three freeze-thawing cycles. No significant cytotoxicity was shown on Caco-2 and intestine epithelial IEC-6 cells at AITC-NP doses ranging from 0.25 to 2 g L -1 (8.75-70 mg L -1 AITC). However, at 2 g L -1 dosage, AITC-NPs could inhibit the growth of human bladder cancer cells HT1376 by 90%, while their low dosage at 0.25 g L -1 could inhibit migration ability by 83.7, 71.3, 58.4 and 31.4% after 4, 8, 12, and 24 h of incubation, respectively. Compared to AITC and NPs, AITC-NPs showed a better inhibition on lipopolysaccharide (LPS)-induced TNF-α, IL-6, NO and iNOS production in RAW 264.7 macrophage cells., Conclusion: The results demonstrate the potential of AITC-NPs as therapeutic agents for the treatment of bladder cancer and the enhancement of immune function. © 2018 Society of Chemical Industry., (© 2018 Society of Chemical Industry.)