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The RON receptor tyrosine kinase is critical in the pathogenesis of various cancer types, however, its role in bladder cancer invasive growth is still largely unknown. Here, we found that over 90% of bladder cancer samples exhibit elevated levels of RON expression, with significantly higher expression levels observed in invasive bladder cancer compared to non-invasive bladder cancer. In vitro, RON activation resulted in increased bladder cancer cell migration and invasiveness. Results from mRNA sequencing and transcriptome analysis further demonstrated that MMP12, a downstream molecule of RON, is functionally involved in regulating RON-mediated bladder cancer cell migration and invasiveness. The underlying mechanism appeared to be the RON-mediated inhibition of HIF-2α ubiquitination, which is channeled through the activation of the JNK signaling pathway. Consequently, the activated JNK pathway increased MMP12 expression, ultimately driving bladder cancer cell migration and invasion. As evident in bioinformatics and dual-luciferase reporter assays, the RON mRNA at its 3'-untranslated regions specifically interacted with hsa-miR-659-3p. The binding of hsa-miR-659-3p downregulated the RON gene expression, attenuating the receptor-mediated tumorigenic activities of bladder cancer cells in vitro and in vivo. In conclusion, aberrant RON expression in bladder cancer cells and MMP12 and HIF-2α activities form a functional axis that causes increased bladder cancer cell migration and invasion. The fact that hsa-miR-659-3p downregulates RON expression indicates its critical role in attenuating RON-mediated tumorigenic effect on bladder cancer cells. These findings highlight the importance of RON targeting as a therapeutic means for potential bladder cancer therapy., Competing Interests: Competing interests The authors declare no competing interests. Ethics approval and consent to participate This study involving humans was conducted in compliance with the principles of the Declaration of Helsinki. Informed consent was obtained from all the subjects. Ethics approval for human subjects was provided by the Ethical Committee of the First Affiliated Hospital of Ningbo University, with the approval number: 2022-065A. All animal experiments complied with the National Research Council’s Guide for the Care and Use of Laboratory Animals. Ethics approval for animal work was provided by the Institutional Animal Care and Use Committee (IACUC), ZJCLA, with the approval number: ZJCLA-IACUC-20010178. Consent for publication All authors agree to the content of the manuscript and to publish the paper as co-authors., (© 2024. The Author(s).)

The biological role and precise molecular mechanisms of Notch receptor 3 (NOTCH3) in the malignant progression of bladder cancer (BLCA) remain unclear. In this study, we found that NOTCH3 was significantly upregulated and associated with poor prognosis in BLCA patients. Functional experiments demonstrated that NOTCH3 knockdown inhibited BLCA cell proliferation, migration, invasion and significantly suppressed tumor growth and metastasis in vivo as well. Mechanically, chromatin immunoprecipitation and dual-luciferase reporter assays confirmed that NOTCH3 could promote the transcription of secreted phosphoprotein 1 (SPP1), a potential downstream target gene of NOTCH3, by binding to the CSL elements in the SPP1 promoter. Moreover, we also found that targeting NOTCH3 inhibited BLCA growth and metastasis by suppressing the SPP1-PI3K/AKT axis. Our study highlights the critical role of NOTCH3-SPP1-PI3K/AKT axis in the malignant progression of BLCA, suggesting that NOTCH3 may be a potential therapeutic target for BLCA., Competing Interests: Competing interests The authors declare no competing interests. Ethical Approval and Consent to Participate The study was carried out in accordance with the principles of the Declaration of Helsinki. Informed consent was obtained from all subjects. This study was approved by Ethics Committee of Affiliated Hospital of Qingdao University., (© 2024. The Author(s).)

Background: Bladder cancer (BLCA) is a common malignancy characterized by dysregulated transcription and a lack of effective therapeutic targets. In this study, we aimed to identify and evaluate novel targets with clinical potential essential for tumor growth in BLCA., Methods: CRISPR-Cas9 screening was used to identify transcription factors essential for bladder cancer cell viability. The biological functions of KLF16 in bladder cancer were investigated both in vitro and in vivo. The regulatory mechanism between KLF16 and MYC was elucidated through a series of analyses, including RNA sequencing, quantitative polymerase chain reaction (qPCR), RNA immunoprecipitation, Western blotting, Mass spectrometry, Dual-luciferase reporter assays, Cleavage Under Targets and Tagmentation (CUT&Tag) sequencing, OptoDroplets assays, and RNA stability assay. The clinical relevance of KLF16 and MYC in bladder cancer was evaluated through analyses of public databases and immunohistochemistry., Results: Krüppel-like factor 16 (KLF16) was essential for BLCA cell viability. Elevated expression of KLF16 was observed in bladder cancer tissues, and higher expression levels of KLF16 were correlated with poor progression-free survival (PFS) and cancer-specific survival (CSS) probabilities in BLCA patients. Mechanistically, KLF16 mRNA competed with the mRNA of dual-specificity phosphatase 16 (DUSP16) for binding to the RNA-binding protein, WW domain binding protein 11 (WBP11), resulting in destabilization of the DUSP16 mRNA. This, in turn, led to activation of ERK1/2, which stabilized the MYC protein. Furthermore, KLF16 interacted with MYC to form nuclear condensates, thereby enhancing MYC's transcriptional activity. Additionally, MYC transcriptionally upregulated KLF16, creating a positive feedback loop between KLF16 and MYC that amplified their oncogenic functions. Targeting this loop with bromodomain inhibitors, such as OTX015 and ABBV-744, suppressed the transcription of both KLF16 and MYC, resulting in reduced BLCA cell viability and tumor growth, as well as increased sensitivity to chemotherapy., Conclusions: Our study revealed the crucial role of the KLF16/MYC regulatory axis in modulating tumor growth and chemotherapy sensitivity in BLCA, suggesting that combining bromodomain inhibitors, such as OTX015 or ABBV-744, with DDP or gemcitabine could be a promising therapeutic intervention for BLCA patients., Competing Interests: Declarations Ethics approval and consent to participate This study received approval from the Ethics Committee of Sun Yat-sen University Cancer Center (SYSUCC; Approval No. B2023-168–01). Animal experiments were conducted in strict compliance with the Guide for the Care and Use of Laboratory Animals and the Principles for the Utilization and Care of Vertebrate Animals. Approval for the animal experiments was obtained from the Animal Research Committee of SYSUCC (No. L102012019120I). Consent for publication Not applicable. Competing interests The authors declare that they have no competing interests., (© 2024. The Author(s).)

The redox status is intricately linked to the development and progression of cancer, a process that can be modulated by long non-coding RNAs (lncRNAs). Previous studies have demonstrated that redox regulation can be considered a potential therapeutic approach for cancer. However, the redox-related lncRNA predictive signature specific to bladder cancer (BCa) has yet to be fully elucidated. The purpose of our study is to establish a redox-related lncRNA signature to improve the prognostic prediction for BCa patients. To achieve this, we downloaded transcriptome and clinical data from the Cancer Genome Atlas (TCGA) database. Prognostic redox-related lncRNAs were identified through univariate Cox regression, least absolute shrinkage and selection operator (LASSO) regression, and multivariate Cox regression analysis, resulting in the establishment of two risk groups. A comprehensive analysis corresponding to clinical features between high-risk and low-risk groups was conducted. Eight redox-related lncRNAs (AC018653.3, AC090229.1, AL357033.4, AL662844.4, AP003352.1, LINC00649, LINC01138, and MAFG-DT) were selected to construct the risk model. The overall survival (OS) in the high-risk group was worse than that in the low-risk group (p < 0.001). The redox-related lncRNA signature exhibits superior predictive accuracy compared to traditional clinicopathological characteristics. Gene Set Enrichment Analysis (GSEA) showed that the MAPK signaling pathway and Wnt signaling pathway were enriched in the high-risk group. Compared with the low-risk group, patients in the high-risk group demonstrated increased sensitivity to cisplatin, docetaxel, and paclitaxel. Furthermore, IGF2BP2, a potential target gene of MAFG-DT, was found to be overexpressed in tumor tissues and correlated with overall survival (OS). Our study demonstrated that the predictive signature based on eight redox-related lncRNAs can independently and accurately predict the prognosis of BCa patients., Competing Interests: Declarations Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Background: Plasmacytoid urothelial carcinoma (PUC) is a rare and aggressive subtype that often presents at advanced stages with poor prognosis. This study investigated tumor invasion to better understand tumor behavior and potentially to improve management strategies by comparing the clinicopathologic characteristics of PUC with positive ureter resection margin (+ URM) with PUC with negative URMs (-URM)., Methods: This retrospective analysis used pathology reports from 2017 to 2023 for cases diagnosed with PUC during radical cystectomy (RC). All applicable H&E slides of RC specimens were reviewed. Cases with a plasmacytoid component greater than 25% in the RC specimens were analyzed. Frozen section analyses (FSAs) and permanent section analyses (PSAs) of ureter resection margins were performed., Results: Fifteen patients with a plasmacytoid component greater than 25% in their RC specimens were identified. Compared with -URM PUC cases, +URM PUC cases were located more frequently at the trigone or bladder neck, and all + URM cases exhibited ureter orifice involvement. Among 6 PSA-positive cases, three (50%) cases showed discrepancies with FSA. Three + URM cases exhibited PUC tumor cells along the submucosa and muscularis propria layer, and the 3 remaining cases showed PUC tumor cells along the adventitia. We observed a consistent adventitia invasion in all the discordant cases, with sectioning errors and misinterpretation identified as the primary causal factors., Conclusion: To the best of our knowledge, this is the first study to demonstrate two separate patterns of tumor infiltration along the ureter and to discuss the significance of comparing FSA with PSA in PUC. The significance of comprehensive management strategies for PUC patients, including a thorough evaluation of ureteral margins and accurate interpretation of periureteral fat tissue, is highlighted. Large, well-designed studies are needed to strengthen the evidence and to establish optimal management strategies for patients with PUC., Competing Interests: Declarations Ethics approval and consent to participate The Institutional Review Board at Ewha Womans University Medical Center (2024-03-006) approved this retrospective study. All methods were performed in accordance with the relevant guidelines and regulations, and the ethical standards of the 1964 Helsinki declaration. The requirement for informed consent was waived by the Institutional Review Board due to the retrospective nature of the study. Consent for publication Not applicable. Competing interests The authors declare no competing interests. Clinical trial number Not applicable., (© 2024. The Author(s).)

Most non-muscle invasive bladder cancers have been treated by transurethral resection and following intravesical injection of immunotherapeutic agents. However, the delivery efficiency of therapeutic agents into bladder wall is low due to frequent urination, which leads to the failure of treatment with side effects. Here, we report a urease-powered nanomotor containing the agonist of stimulator of interferon genes (STING) for the efficient activation of immune cells in the bladder wall. After characterization, we perform in vitro motion analysis and assess in vivo swarming behaviors of nanomotors. The intravesical instillation results in the effective penetration and retention of nanomotors in the bladder. In addition, we confirm the anti-tumor effect of nanomotor containing the STING agonist (94.2% of inhibition), with recruitment of CD8 + T cells (11.2-fold compared with PBS) and enhanced anti-tumor immune responses in bladder cancer model in female mice. Furthermore, we demonstrate the better anti-tumor effect of nanomotor containing the STING agonist than those of the gold standard Bacille Calmette-Guerin therapy and the anti-PD-1 inhibitor pembrolizumab in bladder cancer model. Taken together, the urease-powered nanomotor would provide a paradigm as a next-generation platform for bladder cancer immunotherapy., Competing Interests: Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

The overall survival (OS) improvement after the advent of several novel systemic therapies, designed for treatment of metastatic urothelial carcinoma of the urinary bladder (mUCUB), is not conclusively studied in either contemporary UCUB patients and/or non-UCUB patients. Within the Surveillance, Epidemiology, and End Results database, contemporary (2017-2020) and historical (2000-2016) systemic therapy-exposed metastatic UCUB and, subsequently, non-UCUB patients were identified. Separate Kaplan-Meier and multivariable Cox regression (CRM) analyses first addressed OS in mUCUB and, subsequently, in metastatic non-UCUB (mn-UCUB). Of 3443 systemic therapy-exposed patients, 2725 (79%) harbored mUCUB versus 709 (21%) harbored mn-UCUB. Of 2725 mUCUB patients, 582 (21%) were contemporary (2017-2020) versus 2143 (79%) were historical (2000-2016). In mUCUB, median OS was 11 months in contemporary versus 8 months in historical patients (Δ = 3 months; p < .0001). After multivariable CRM, contemporary membership status (2017-2020) independently predicted lower overall mortality (OM; hazard ratio [HR] = 0.68, 95% confidence interval [CI] = 0.60-0.76; p < .001). Of 709 mn-UCUB patients, 167 (24%) were contemporary (2017-2020) and 542 (76%) were historical (2000-2016). In mn-UCUB, median OS was 8 months in contemporary versus 7 months in historical patients (Δ = 1 month; p = .034). After multivariable CRM, contemporary membership status (2017-2020) was associated with HR of 0.81 (95% CI = 0.66-1.01; p = .06). In conclusion, contemporary systemic therapy-exposed metastatic patients exhibited better OS in UCUB. However, the magnitude of survival benefit was threefold higher in mUCUB and approximated the survival benefits recorded in prospective randomized trials of novel systemic therapies., (© 2024 UICC.)

Background: Neoadjuvant chemotherapy followed by radical cystectomy is the standard treatment for cisplatin-eligible patients with muscle-invasive bladder cancer. Adding perioperative immunotherapy may improve outcomes., Methods: In this phase 3, open-label, randomized trial, we assigned, in a 1:1 ratio, cisplatin-eligible patients with muscle-invasive bladder cancer to receive neoadjuvant durvalumab plus gemcitabine-cisplatin every 3 weeks for four cycles, followed by radical cystectomy and adjuvant durvalumab every 4 weeks for eight cycles (durvalumab group), or to receive neoadjuvant gemcitabine-cisplatin followed by radical cystectomy alone (comparison group). Event-free survival was one of two primary end points. Overall survival was the key secondary end point., Results: In total, 533 patients were assigned to the durvalumab group and 530 to the comparison group. The estimated event-free survival at 24 months was 67.8% (95% confidence interval [CI], 63.6 to 71.7) in the durvalumab group and 59.8% (95% CI, 55.4 to 64.0) in the comparison group (hazard ratio for progression, recurrence, not undergoing radical cystectomy, or death from any cause, 0.68; 95% CI, 0.56 to 0.82; P<0.001 by stratified log-rank test). The estimated overall survival at 24 months was 82.2% (95% CI, 78.7 to 85.2) in the durvalumab group and 75.2% (95% CI, 71.3 to 78.8) in the comparison group (hazard ratio for death, 0.75; 95% CI, 0.59 to 0.93; P = 0.01 by stratified log-rank test). Treatment-related adverse events of grade 3 or 4 in severity occurred in 40.6% of the patients in the durvalumab group and in 40.9% of those in the comparison group; treatment-related adverse events leading to death occurred in 0.6% in each group. Radical cystectomy was performed in 88.0% of the patients in the durvalumab group and in 83.2% of those in the comparison group., Conclusions: Perioperative durvalumab plus neoadjuvant chemotherapy led to significant improvements in event-free survival and overall survival as compared with neoadjuvant chemotherapy alone. (Funded by AstraZeneca; NIAGARA ClinicalTrials.gov number, NCT03732677; EudraCT number, 2018-001811-59.)., (Copyright © 2024 Massachusetts Medical Society.)

In the past decade, the treatment of metastatic urothelial cancer (mUC), including bladder cancer (BC), has transformed significantly with the introduction of diverse therapies, such as immune checkpoint inhibitors, targeted therapies, and antibody-drug conjugates. This change is partly due to advancements in genomic understanding, particularly next-generation sequencing, which has identified numerous mutations in UC. Among these therapies, erdafitinib, a pan-fibroblast growth factor receptor (FGFR) inhibitor for specific FGFR2 and FGFR3 alterations, is the only targeted therapy approved till now. In 2019, erdafitinib became pivotal for the treatment of mUC, particularly in patients with specific FGFR alterations. Recent studies have highlighted the benefits of combining erdafitinib with immunotherapy, thereby broadening the treatment options. Ongoing investigations exist on its use in non-muscle-invasive BC and in combination with drugs such as enfortumab vedotin in mUC. Other FGFR-targeted agents are under development; however, overcoming FGFR resistance and ensuring the safety of combination therapies remain major hurdles. FGFR3 mutations are particularly prevalent in BC, a heterogeneous form of UC, and account for a considerable proportion of new cancer diagnoses annually. Approximately half of these cancers have FGFR3 mutations, with gene rearrangements being a common feature. These FGFR3 genomic alterations often occur independently of mutations in other BC oncogenes, such as TP53 and RB1 . This review emphasizes the importance of FGFR inhibition in UC and the optimization of its use in clinical practice. Moreover, it underscores the ongoing efforts to evaluate combination strategies and early treatment testing to enhance the effectiveness of targeted therapies for UC., Competing Interests: The author has no potential conflicts of interest to disclose., (© 2024 The Korean Academy of Medical Sciences.)

Background: Bladder cancer (BC) is a prevalent malignancy characterized by significant cellular heterogeneity. While single-cell multi-omics studies have provided valuable insights, much of the existing data remains underexplored, limiting our understanding of BC's molecular mechanisms. Uncovering the pathogenesis of BC and finding new treatment methods are urgent problems to be solved. This study aims to address this gap by re-analyzing available single-cell datasets to uncover novel insights into BC., Methods: In this study, we retrieved three single-cell transcriptome datasets by searching the Gene Expression Omnibus (GEO) database, focusing on single-cell sequencing of normal mouse bladder within the past 5 years. Through quality control and batch effect elimination, we obtained a total of 24,930 cells including epithelial, stromal, and immune cells. Subgroup analysis, pseudotemporal analysis, cell-cell communication, and transcription factor analysis were conducted specifically on epithelial cells to identify a transitional state during basal cell differentiation. We further compared the expression profiles of key transcription factors in cancer and normal tissues. In addition, we also performed immunohistochemical staining and survival analysis for key transcription factors., Results: Subgroup analysis revealed multiple subtypes of epithelial cells, including basal, umbrella, and intermediate cells. Through pseudotemporal analysis, we discovered the developmental trajectory from basal cells to umbrella cells and further found that Basal&#95;I is a transitional state for basal cell differentiation. Cell-to-cell communication analyses highlighted the pivotal role of Basal&#95;I in cell-cell interactions, and key ligand-receptor pairs associated with cancer progression were also identified. Furthermore, elevated expression levels of key transcription factors in Basal&#95;I were found to be closely associated with the stage and prognosis of BC. Immunohistochemical staining results further confirmed the upregulated expression of these transcription factors in BC., Conclusions: Collectively, we found a transitional state of basal cells in normal bladder epithelial cells in mice, which may be related to the occurrence and development of BC, providing important clues for further understanding of the pathogenesis of BC. Our study provided possible molecular mechanisms or target for the research and treatment of BC., Competing Interests: Declarations Ethics approval and consent to participate All procedures were approved by the Institutional Review Board of Tongji Medical College, Huazhong University of Science and Technology. Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Background: Metastatic urothelial carcinoma (mUC) has a poor prognosis, despite recent therapeutic advancements. Prostaglandin Reductase 1 (PTGR1) is essential for activating acylfulvens, a promising class of drugs for treating a subset of urothelial carcinoma (UC) patients. The efficacy of acylfulvens depends on PTGR1 activity and defects in the nucleotide excision repair (NER) pathway, notably ERCC2 mutations present in 10-15% of bladder tumors. This study identifies patients eligible to be included in acylfulven clinical trials based on the presence of PTGR-1 by immunohistochemistry (IHC) staining, RNA expression level and mutations in the NER pathway. Additionally, it evaluates PTGR-1 expression as a prognostic biomarker., Methods: Three PTGR-1 antibodies were tested in a kidney cancer cell line A498 and in tissues with known PTGR1 expression (liver, tonsils, pancreas, small intestine, etc.). Patients with untreated mUC receiving 1st line platinum from Dec. 2019 to Dec. 2021 in the Capital Region, Denmark, were included retrospectively. FFPE tumor samples were collected, and tissue microarrays (TMAs) were constructed. TMAs were stained with the best-performing PTGR1 antibody, RNA expression was analyzed using Nanostring nCounter PanCancer panel and gene mutations were assessed using a targeted genomic panel (TSO-500). Kaplan-Meier and multivariate Cox regression assessed overall survival and covariate impacts., Results: The AB181131 PTGR1 antibody was the most reliable in validation tissues. Tumors from 71 mUC patients were used to construct the TMA, and 40% of tumors scored positive for PTGR1 by IHC staining. A normalized PTGR1 RNA cutoff at 2,550 normalized counts achieved an AUC of 0.9, defining 35 samples as positive with a sensitivity of 96% and specificity of 85% in relation to IHC-positivity. Differential expression showed a significant upregulation of PTGR1 RNA in PTGR1 IHC-positive cases. NER-deficiency and PTGR1 positivity (mutations in ERCC1, ERCC2, ERCC3, ERCC4) was seen in 9 patients (13%). Median overall survival was 16 months in the cohort. Overall survival (OS) analysis indicates that overexpression of PTGR1 RNA was associated with a reduced median OS (12 months vs. 25 months, p = 0.039, log-rank)., Conclusion: PTGR1 IHC staining pattern using the Abcam AB181131 antibody is highly correlated with PTGR1 RNA expression. 13% in our cohort were identified as NER deficient and PTGR1 positive. Lower levels of PTGR1 indicates better outcome in this cohort., Competing Interests: Declarations Competing interests The authors declare no competing interests. Conflict of interest D.R.S. received educational and research funding from Pfizer and Merck Serono and served on advisory boards for Merck Sharp and Dome (MSD), Bristol Meyers Squibb (BMS), and Johnson and Johnson, unrelated to this study. S.L. No COI to report. B.G.T. Speaker fee from BMS unrelated to this study. L.H.D: No COI to report. L.C.M.: No COI to report. Z.S: Research funding from Lantern Pharma Inc; M.R: received personal fees from AstraZeneca and MSD and served on advisory board of MSD outside the submitted work.; H.P: Research funding from Pfizer and Merck unrelated to this study. K.W.M: Advisory/consulting work for EMD Serono, Pfizer, UroGen, and Riva Therapeutics; has received research support from Pfizer and Novo Ventures; has equity in Riva Therapeutics; has received writing/editor fees from UpToDate; has received speaking fees from OncLive; and is a co-inventor listed on an institutional patent application for analysis of mutational signatures of DNA repair deficiency., (© 2024. The Author(s).)

The progression and outcome of bladder cancer (BLCA) are critically affected by the propensity of tumor metastasis. Our previous study revealed that activation of the mevalonate (MVA) pathway promoted migration of BLCA cells; however, the exact mechanism is unclear. Here we show that elevated expression of MVA pathway enzymes in BLCA cells, correlating with poorer patient prognosis by analyzing single-cell and bulk-transcriptomic datasets. Inhibition of the MVA pathway, either through knockdown of farnesyl diphosphate synthase (FDPS) or using inhibitors such as zoledronic acid or simvastatin, led to a marked reduction in BLCA cell migration. Notably, this effect was reversed by administering geranylgeranyl pyrophosphate (GGPP), not farnesyl pyrophosphate (FPP) or cholesterol, indicating the specificity of geranylgeranylation for cell motility. Moreover, we found that RhoB, a Rho GTPase family member, was identified as a key effector of the impact of the MVA pathway on BLCA metastasis. The post-translational modification of RhoB by GGPP-mediated geranylgeranylation influenced its protein stability through the ubiquitin-proteasome pathway. Additionally, overexpression of RhoB was found to block the membrane translocation of integrin β1 in BLCA cells. In summary, our findings underscore the role of the MVA pathway in BLCA metastasis, providing insights into potential therapeutic targets of this malignancy., (© 2024. The Author(s).)

Purpose: The activity of targeted and immunotherapy for the management of advanced bladder cancer is reviewed., Summary: Platinum-based chemotherapy is standard first-line treatment for advanced bladder cancer. Pembrolizumab is approved alone as first-line therapy for patients who are ineligible for any platinum-based chemotherapy and with enfortumab for patients ineligible for cisplatin-based chemotherapy. Avelumab is approved for maintenance therapy in patients who have not progressed with first-line platinum-containing therapy. Pembrolizumab, avelumab, and nivolumab are approved second-line therapy in patients who experience progression during or after platinum-containing chemotherapy. Erdafitinib is indicated for advanced disease that has susceptible FGFR2 or FGFR3 genetic alterations and has progressed during or after treatment with at least one line of platinum-containing chemotherapy. Enfortumab vedotin and sacituzumab govitecan are antibody-drug conjugates. They are both approved for patients who have received anti-PD-L1 or anti-PD-1 therapy and treatment with platinum-containing chemotherapy. Enfortumab is also indicated for patients who are ineligible to receive cisplatin-based therapy and have received one or more prior lines of therapy., Conclusion: Six targeted and immunotherapeutic agents have been approved for patients with advanced urothelial bladder cancer. They all have demonstrated activity in patients for whom disease has progressed during or after platinum-based therapy. Pembrolizumab, with and without enfortumab, has demonstrated first-line activity, and avelumab is a key maintenance therapy after first-line treatment. The results of additional clinical trials should provide evidence to establish the exact role in therapy of each agent in patients with advanced disease., (© American Society of Health-System Pharmacists 2024. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Purpose: The purpose of this study was to clarify the appropriate cystoscopic interval after nephroureterectomy (NU) for upper tract urothelial carcinoma (UTUC) using a hypothetical model., Methods: A total of 155 patients who underwent NU in 15 years were retrospectively evaluated. Three hypothetical models for surveillance intervals were created: 3 (model 1), 6 (model 2) and 12 months (model 3). We superimposed these models on the actual surveillance of each patient and analyzed the observed timing of recurrence. The time from recurrence to scheduled cystoscopy (timeRCS) was defined as the time from recurrence to estimated cystoscopy. The gap risk ratio was calculated based on the average of timeRCS for model 1 at 0-1 year after surgery., Results: The median follow-up was 20.5 months. Intravesical recurrence was observed in 63 patients (40.6%). The 3-year intravesical recurrence-free survival rate in patients without a history of bladder cancer before NU was significantly higher than in those with a history of bladder cancer (61% vs. 42%, P = 0.034). The medians of timeRCS for models 1, 2, and 3 were 1.9, 2.9, and 8.4 months, respectively. The gap risk ratios for model 1 at 1-3 years, model 2 at 2-3 years for patients with a history of bladder cancer, and model 2 at 1-3 years for patients without a history of bladder cancer were less than 1.0., Conclusion: Model analysis shows that the cystoscopic follow-up interval can be extended depending on the presence or absence of a history of bladder cancer and the time after NU., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: There is lack of evidence regarding the indication for re-transurethral resection of bladder tumor (reTURBT) for Ta high grade (HG) non-muscle invasive bladder cancer (NMIBC). This study aims to evaluate the oncological outcomes of patients with TaHG NMIBC to determine the benefit from performing reTURBT., Methods: We relied on a multicenter cohort of 317 TaHG NMIBC from 12 centers who underwent TURBT and a subsequent complete Bacillus Calmette-Guérin induction from 2009 to 2021. Kaplan Meier analyses estimated recurrence free survival (RFS) and progression free survival (PFS) according to reTURBT. Sub-analyses evaluated PFS in patients with multiple risk factors indicating necessity for reTURBT according to international guidelines (multifocality, size > 3 cm, recurrent cancer, carcinoma in situ, lymph vascular invasion, histological variant, incomplete and absence of muscle layer at index TURBT). Multivariable cox-regression analysis predicted recurrence and progression., Results: Of the 317 patients, 123 (39%) underwent reTURBT, while 194 (61%) did not. Residual disease was detected in 46% of cases, with a 3.2% upstaging rate. Median follow-up was 30 months. The 3-year RFS was higher in patients who underwent reTURBT (79% vs. 58%, p < 0.001), but no significant difference was observed in PFS. ReTURBT reduced the risk of recurrence [multivariable hazard ratio: 0.45, 95% Confidence interval (CI) 0.29-0.71]. Among patients who did not undergo reTURBT, those with ≥ 2 risk factors had lower 3-year PFS (73% vs. 92%, p < 0.001) than those with 0-1 risk factor, whereas no difference in 3-year PFS was observed in patients who underwent reTURBT regardless of the number of risk factors (85% vs. 87%, p = 0.8)., Conclusion: ReTURBT demonstrated efficacy in reducing recurrence among patients with TaHG NMIBC, yet its impact on progression remained uncertain. Our study underscores the importance of adhering to current international guidelines, particularly for patients with multiple risk factors indicating necessity for reTURBT., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Bladder cancer (BCa) poses a significant health challenge, particularly affecting men with higher incidence and mortality rates. Addressing the need for improved predictive models in BCa treatment, this study introduces an innovative 3D in vitro patient-derived bladder cancer tumor model, utilizing decellularized pig bladders as scaffolds. Traditional 2D cell cultures, insufficient in replicating tumor microenvironments, have driven the development of sophisticated 3D models. The study successfully achieved pig bladder decellularization through multiple cycles of immersion in salt solutions, resulting in notable macroscopic and histological changes. This process confirmed the removal of cellular components while preserving the native extracellular matrix (ECM). Quantitative analysis demonstrated the efficacy of decellularization, with a remarkable reduction in DNA concentration, signifying the removal of over 95% of cellular material. In the development of the in vitro bladder cancer model, muscle invasive bladder cancer patients' cells were cultured within decellularized pig bladders, yielding a three-dimensional cancer model. Optimal results were attained using an air-liquid interface technique, with cells injected directly into the scaffold at three distinct time points. Histological evaluations showcased characteristics resembling in vivo tumors derived from bladder cancer patients' cells. To demonstrate the 3D cancer model's effectiveness as a drug screening platform, the study treated it with Cisplatin (Cis), Gemcitabine (Gem), and a combination of both drugs. Comprehensive cell viability assays and histological analyses illustrated changes in cell survival and proliferation. The model exhibited promising correlations with clinical outcomes, boasting an 83.3% reliability rate in predicting treatment responses. Comparison with traditional 2D cultures and spheroids underscored the 3D model's superiority in reliability, with an 83.3% predictive capacity compared to 50% for spheroids and 33.3% for 2D culture. Acknowledging limitations, such as the absence of immune and stromal components, the study suggests avenues for future improvements. In conclusion, this innovative 3D bladder cancer model, combining decellularization and patient-derived cells, marks a significant advancement in preclinical drug testing. Its potential for predicting treatment outcomes and capturing patient-specific responses opens new avenues for personalized medicine in bladder cancer therapeutics. Future refinements and validations with larger patient cohorts hold promise for revolutionizing BCa research and treatment strategies., (© 2024. The Author(s).)

Introduction: Sarcomas with muscle differentiation (for example, rhabdomyosarcoma, leiomyosarcoma, and pleomorphic sarcoma) are uncommon in the adult bladder., Case Presentation: In this case report, we describe a 69-year-old Chinese male patient who presented to the urology outpatient clinic because of intermittent full-course macroscopic hematuria for 10 days. A B ultrasound indicated hypoechoic nodules in the right upper wall of the bladder. Transurethral resection of the bladder tumor and cystoscopic multipoint random biopsy was performed. Postoperative pathological findings showed pleomorphic rhabdomyosarcoma of the adult bladder. Later, he was transferred to the Department of Medical Oncology of our hospital for further postoperative chemotherapy. The chemotherapy regimen used was intravenous chemotherapy of dacarbazine with doxorubicin. The patient in this case has survived for 12 months postoperatively., Conclusion: From this case, our elderly patient with early pleomorphic rhabdomyosarcoma of the urinary bladder received transurethral resection of bladder tumor and postoperative chemotherapy, and there had been no recurrence 12 months postoperatively. The aforementioned treatment modality may offer a favorable prognosis., (© 2024. The Author(s).)

Background: The role of the RING finger protein superfamily in carcinogenesis has been widely studied, but one member of this family, RNF19A, has not yet been thoroughly explored in bladder cancer (BCa)., Methods: The expression levels of RNF19A in BCa samples and cell lines were analysed through data mining of public resources and further experiments. BCa cells in which RNF19A was stably overexpressed or knocked down were generated through lentivirus infection. The effects of RNF19A on cell proliferation, migration, and invasion were explored by performing a series of in vitro experiments, including CCK-8, colony formation, wound healing, and Transwell invasion assays. Using bioinformatics methods and multiple experiments, including western blot, qRT‒PCR, immunoprecipitation, cycloheximide, ubiquitination, and rescue assays, the mechanism underlying the effect of RNF19A on the progression of BCa was investigated., Results: Here, we found that RNF19A expression was reduced in BCa samples and cell lines and that lower RNF19A expression predicted shorter overall survival of BCa patients. Functionally, forced expression of RNF19A suppressed BCa cell proliferation, migration, and invasion by inactivating the AKT/mTOR signalling pathway, whereas silencing RNF19A had the opposite effects. Mechanistically, RNF19A could directly interact with ILK and promote its ubiquitination and degradation. Rescue experiments revealed that forced ILK expression partially rescued the decreased phosphorylation of AKT, mTOR, and S6K1 caused by RNF19A overexpression and that the increased levels of the p-AKT, p-mTOR, and p-S6K1 proteins induced by RNF19A knockdown were eliminated after silencing ILK. Similarly, the effects of RNF19A overexpression or knockdown on the phenotypes of cell proliferation, migration, and invasion could also be restored by forced or decreased ILK expression., Conclusions: RNF19A suppressed the proliferation, migration, and invasion abilities of BCa cells by regulating ILK ubiquitination and inactivating the AKT/mTOR signalling pathway. RNF19A might be a potential prognostic biomarker and promising therapeutic target for BCa., (© 2024. The Author(s).)

Disulfidptosis is a novel programmed cell death mode that has been reported to play a role in oncogenesis. Increasing evidences suggest that the long non-coding RNAs (lncRNAs) play crucial roles in the initiation and progression of bladder cancer (BLCA). However, the role and prognostic value of disulfidptosis-related lncRNAs in BLCA remain unknown.The aim of this study was to construct and validate a disulfidptosis-related lncRNA risk model for predicting the prognosis of BLCA patients. A risk model consisting of 5 disulfidptosis-related lncRNAs was developed to predict the prognosis of BLCA patients. The overall survival (OS) of BLCA patients in the high-risk group was significantly shorter than that in the low-risk group (P < 0.05). The effectiveness of this model was validated using the receiver operating characteristic (ROC) curve analysis, and this model proved superior in prognostic accuracy compared with other clinical features. Furthermore, the tumor immune dysfunction and exclusion (TIDE) score in the high-risk group was significantly higher than that in the low-risk group, suggesting that the high-risk group had a less favorable response to immunotherapy. Simultaneously, patients in the low-risk group exhibited significantly higher sensitivity to CTLA-4 monoclonal antibody therapy compared to those in the high-risk group, suggesting potential benefits of immunotherapy for patients in the low-risk group. The combination of high risk and low tumor mutational burden (TMB) could further shortened the OS of BLCA patients. Lastly, the drug sensitivity analysis revealed that the BLCA cells in the high-risk group showed an increased sensitivity to cisplatin, sunitinib, cetuximab, axitinib, docetaxel, saracatinib, vinblastine and pazopanib compared with those in the low-risk group. According to the Quantitative real time PCR results, we found that five lncRNAs of the risk model were more highly expressed in BCa cell lines than human immortalized uroepithelial cell line. The disulfidptosis-related lncRNA risk model has a valuable effect in assessing the prognosis of BLCA patients., (© 2024. The Author(s).)

Background: Bladder cancer (BCa) is one of the most common urological cancers and remains a leading cause of cancer-related mortality worldwide. Bladder cancer is associated with a range of risk factors, with smoking being one of the most significant contributors. In addition to smoking, exposure to certain chemicals, particularly aromatic amines found in industries such as dye, rubber, leather, and textiles, also increases the risk of bladder cancer. In low-and-middle countries with lower Human Development Index (HDI), data on the underlying causes, incident rate, modes of presentation, treatment, and prognosis of bladder cancer remains unclear and often appear to be inadequate. This study aimed to assess the prevalence, mode of presentation, treatment, and risk factors associated with bladder cancer in Johannesburg, South Africa. By examining these factors, the study seeks to identify possible patterns or predisposing factors that contribute to the development and progression of bladder cancer, which could generate insights that could help to reduce the significant morbidity and mortality associated with this cancer., Methods: This retrospective study analyzed secondary data from 115 patients who were treated in the radiation oncology unit of an academic hospital between January 2010 and December 2020. By reviewing the medical records of these patients, the study aimed to gather comprehensive information on the prevalence of bladder cancer, modes of presentation, treatment approaches, and associated risk factors. Bladder cancer in this study was assessed using a comprehensive analysis of patient data on demographics, risk factors, clinicopathological aspects, and the specific therapies received. A comparison of patients with squamous cell carcinoma (SCC) and transitional cell carcinoma (TCC) of the bladder was conducted as part of this study. This comparison aimed to explore differences in demographic profiles, risk factors, clinicopathological characteristics, and treatment outcomes between these two histological subtypes., Results: A total of 115 patients presenting with bladder cancer symptoms were referred to the academic hospital for evaluation and treatment. The incidence rate of bladder cancer was highest among patients with a mean age of 60.7 ± 14.9. Males constituted 60.9% of the cases, resulting in a male-to-female ratio of 1.6:1. The most common risk factors associated with bladder cancer complications included smoking, being male, black ethnicity and increasing age. Transitional cell carcinoma remained the most prevalent histological subtype at the academic hospital, compared to squamous cell carcinoma (SCC). Patients with transitional cell carcinoma (TCC) were more likely to be older (odds ratio (OR): 1.03, 95% Confidence Interval (CI): 1.01-1.06, p = 0.029), male (OR: 2.60, 95% CI:1.10-6.04, p = 0.030). The study also found that most of the TCC cases were among black patients, though white patients were four times more likely to present with TCC compared to SCC (OR:4.22, 95% CI: 1.43-12.48, p = 0.009)., Conclusion: Bladder cancer is still widespread in LMICs, with lower HDI, with elderly males being at risk. To aggressively prevent mortality and morbidity from bladder cancer, bladder cancer health awareness must be maintained to improving prevention, as well as early detection, management and comprehensive patient care and health services for bladder cancer patients. These findings highlight the importance of targeted screening and prevention strategies for high-risk groups, particularly older males with a history of smoking., (© 2024. The Author(s).)

The therapeutic landscape for metastatic urothelial carcinoma (mUC) has evolved significantly due to the development of innovative combination treatments, including enfortumab vedotin-pembrolizumab (EVP). Despite these advancements, the limited availability of EVP means that platinum-based chemotherapy regimens continue to serve as the primary treatment modality for many patients with mUC. We evaluated the effect of the type of platinum chemotherapy used in combination with immunotherapy (IO) on treatment outcomes in mUC. The meta-analysis showed that cisplatin-gemcitabine plus IO combination and carboplatin-gemcitabine plus IO combination improve progression-free survival compared to platinum-gemcitabine therapy (hazard ratio [HR] = 0.71, 95% CI: 0.62-0.82; P < .0001 and HR = 0.85, 95% CI: 0.73-0.98; P < .03, respectively). However, only the cisplatin-gemcitabine plus IO combination showed overall survival (OS) benefit (HR = 0.80, 95% CI: 0.69-0.93; P < .003). In comparison to the platinum-gemcitabine combination, neither the cisplatin-gemcitabine plus IO nor the carboplatin-gemcitabine plus IO combinations demonstrated an objective response rate (ORR) benefit. In summary, combining cisplatin-gemcitabine with immunotherapy offers significant overall survival benefits in mUC. The exact mechanisms-whether cisplatin's immunomodulatory effects or patient demographic differences-are yet to be determined, necessitating further research to understand these outcomes better., (© The Author(s) 2024. Published by Oxford University Press.)

Background: To examine the agreement of different calculated estimated glomerular filtration rate (eGFR) formulas and measured creatinine clearance (CrCI) at the primary diagnosis of muscle-invasive bladder cancer (MIBC)., Materials and Methods: We performed a multicenter analysis of patients with MIBC, treated with cisplatin-based neoadjuvant chemotherapy (NAC) and radical cystectomy (RC), or with RC alone, between 2011 and 2021. Baseline eGFR was computed using 4 calculated serum equations including Cockcroft-Gault (CG), MDRD, CKD-EPI 2009, and race-free CKD-EPI 2021. To examine the association between calculated eGFR and measured CrCI, subgroup analyses were performed among patients in whom measured 24-hour urine CrCl was determined. Cisplatin-ineligibility was defined as CrCI and/or eGFR < 60 mL/minute per 1.73 m2., Results: Of 956 patients, 30.0%, 33.3%, 31.9%, and 27.7% were found to be cisplatin-ineligible by the CG, MDRD, CKD-EPI, and race-free CKD-EPI equations (P = .052). The concordance between calculated eGFR formulas was rated substantial (Cohen's kappa (k): 0.66-0.95). Among the subgroup (n = 245) with measured CrCl, 37 (15.1%) patients had a CrCI less than 60 mL/minute. Concordance between measured CrCl and calculated eGFR was poor (ĸ: 0.29-0.40). All calculated eGFR formulas markedly underestimated the measured CrCI. Specifically, 78%-87.5% of patients with a calculated eGFR between 40 and 59 mL/minute exhibited a measured CrCI ≥ 60 mL/minute., Conclusions: Comparing calculated eGFR formulas, similar percentages of patients with MIBC were deemed cisplatin-ineligible. However, a significant number of patients could be upgraded by being cisplatin-fit based on measured CrCI, particularly when the calculated eGFR was falling within the gray range of 40-59 mL/minute., (© The Author(s) 2024. Published by Oxford University Press.)

Bladder cancer (BLCA), ranking as the tenth most prevalent malignancy globally, imposes a substantial public health and socio-economic challenge. Despite ongoing efforts by urologists to identify novel molecular subtypes and treatment paradigms, the intrinsic heterogeneity of BLCA continues to obstruct the efficacy of current diagnostic and therapeutic evaluations, leaving a gap in the comprehensive management of BLCA. This necessitates an in-depth investigation into the BLCA tumor microenvironment (TME) to identify pivotal molecules like MFAP3L. Our research concentrated on MFAP3L, commencing with a pan-cancer analysis of its immune profile. We discovered that MFAP3L exhibits a significant negative correlation with numerous immune components and markers in BLCA, a trend not observed in other cancer types. Within the TCGA-BLCA cohort, patients were classified into High-MFAP3L and Low-MFAP3L groups according to their MFAP3L transcript levels. Our exploration into the BLCA TME delved into immune infiltration, molecular subtype patterns, and treatment preferences within these MFAP3L groups. High MFAP3L expression was linked to favorable prognoses, luminal subtypes, and low immune infiltration, inversely associated with various immune molecules and characteristics. Additionally, high MFAP3L expressors exhibited diminished immune checkpoint levels, suggesting enhanced immunotherapy tolerance and sensitivity to oncogenic pathway targeting. Conversely, low MFAP3L expression correlated with poor outcomes, basal subtypes, increased immune infiltration, and heightened gene mutation rates, alongside sensitivity to radiotherapy, EGFR-targeted treatments, and immunotherapy. Hence, MFAP3L emerges as a critical yet underexplored gene in BLCA, offering insights into immune status within the TME and aiding in molecular subtyping and therapeutic decision-making., (© 2024. The Author(s).)

Purpose: To compare the oncological outcomes between standard radical cystectomy (SRC) and organ-sparing cystectomy (OSC) in male patients diagnosed with bladder cancer., Methods: Patients with stage Ta-T3 bladder cancer who underwent OSC or SRC were identified from the Surveillance, Epidemiology, and End Results (SEER) database between 2004 and 2015. The association between preoperative factors and the implementation of OSC was analyzed using logistic regression. Propensity score matching (PSM) was employed to balance baseline characteristics between the two groups. Patients' overall survival (OS) and cancer-specific survival (CSS) were estimated using the Kaplan-Meier method. Subgroup analyses based on the T stage were also conducted., Results: A total of 7264 patients were included, with 96.8% (7033 patients) receiving SRC and 3.2% (231 patients) receiving OSC. Patients with higher T stages and high-grade tumors were less likely to undergo OSC. After PSM, OSC was associated with significantly worse OS and CSS than SRC. Subgroup analysis revealed that OSC did not lead to worse OS and CSS in non-muscle invasive bladder cancer and T2 stage patients, but it resulted in significantly worse outcomes in T3 stage patients., Conclusion: Our study indicates that OSC is associated with poorer oncological outcomes compared to SRC, particularly in patients with advanced-stage tumors. These findings suggest the need for stringent selection criteria for OSC in bladder cancer patients. Given the negative impact on prognosis, stage T3 should potentially be considered a contraindication for OSC. Further evidence is required to confirm these assertions., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: This study examined the efficacy and safety of neoadjuvant chemotherapy combined with immunotherapy in patients with muscle-invasive bladder cancer (MIBC)., Methods: This retrospective cohort study included patients diagnosed with MIBC at the First Affiliated Hospital of Soochow University between January 1, 2020, and December 31, 2023, assigned to either chemotherapy (gemcitabine with cisplatin) or combination (chemotherapy plus toripalimab or tislelizumab) groups based on the neoadjuvant treatment regimen. Key metrics, including pathological downstaging rate (PDR), pathological complete response rate (PCRR), and incidence and severity of adverse events (AEs), were compared between groups., Results: This study included 53 patients (mean age: 67.21 years). In the combination group, 14 patients (51.85%) achieved pathological complete remission (ypT0), and seven (25.93%) achieved partial remission (ypT1), resulting in a PDR and PCRR of 77.78 and 51.85%, respectively. In the chemotherapy group, six patients (23.08%) achieved complete remission, and five (19.23%) achieved partial remission, resulting in a PDR and PCRR of 42.31 and 23.08%, respectively. Differences between groups were statistically significant (p < 0.05). There were no significant differences in pathological downstaging or complete remission rates among subgroups in the combination group (p > 0.05). No serious allergic reactions or fatal AEs were detected in either group, with no grade 4 AEs. Grade 3 AE rates were 22.22 and 20.83% in the combination and chemotherapy groups, respectively, although non-significant (p > 0.05)., Conclusion: Neoadjuvant chemotherapy combined with immunotherapy had enhanced efficacy and manageable safety in patients with MIBC, suggesting its potential for integration into clinical practice., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Yu, Zhang, Chen, Zhang, Ouyang and Zhang.)

Secreted protein, acidic and rich in cysteine-like 1 (SPARCL1) belongs to the SPARC family of matricellular proteins. However, underlying functions of SPARCL1 in bladder cancer (BCa) remain understudied. We performed an integrated search for the expression patterns of SPARCL1 in relation to various clinicopathological features of BCa. We then carried out Gene Ontology (GO) enrichment analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, and gene set enrichment analysis (GSEA). Furthermore, we investigated the correlations between SPARCL1 and immunological features, such as tumour mutation burden (TMB), immune activation processes, immune checkpoint expression, tumour immune dysfunction and exclusion (TIDE) scores, and chemotherapeutic sensitivity in BCa. Our analysis revealed that SPARCL1 was downregulated across multiple cancers. In BCa, elevated SPARCL1 was linked with advanced histopathologic stage, higher T and N stage, and poorer prognosis in the clinical cohort. In vitro experiments demonstrated that increased SPARCL1 expression inhibited cell proliferation, migration, and invasion. Additionally, highly expressed SPARCL1 was linked to elevated immune, stromal and ESTIMATE scores, as well as an increase in naive B cells, M2 macrophages, and resting mast cells. We observed a moderate correlation between SPARCL1 expression and CD163, VSIG4 and MS4A4A, which are markers of M2 macrophages. Furthermore, SPARCL1 expression was positively related to TMB, immune activation processes, TIDE scores, immune checkpoint expression, and chemotherapeutic sensitivity in BCa. Our study highlights the potential involvement of SPARCL1 in macrophage recruitment and polarization and suggests its utility as a biomarker for prognosis in BCa., (© 2024 The Author(s). Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Background: Despite the high recurrence rate of non-muscle-invasive bladder cancer (NMIBC), there are limitations in accurately predicting recurrence after transurethral resection of bladder tumor (TURBT) based on clinicopathological factors alone. However, prediction of recurrence using biomolecular characteristics of bladder tumors has not been applied to clinical practice. The objective of this study was to establish a new gene expression scoring system for identifying patients at high risk of recurrence., Methods: NMIBC and normal bladder samples were subjected to microarray analysis to obtain gene expression profiles. We identified 6 genes that were specifically upregulated in bladder cancer and also in recurrent cases. All patients were randomly grouped into a discovery cohort (n = 59) and a validation cohort (n = 30). Gene expression score (GES) was defined as the mean Z-score of the 6 genes specific for recurrent bladder cancer., Results: The intravesical recurrence rate of the high GES group (n = 38) was higher than the low GES group (n = 21). GES was significantly associated with recurrence-free survival in the validation cohort as well. In prognostic analysis, the European Organization for Research and Treatment of Cancer (EORTC) risk classification was not related to recurrence after TURBT in either univariate or multivariate analysis. On the other hand, the GES we developed was an independent factor for recurrence in NMIBC., Conclusions: A novel gene expression scoring system was shown to predict recurrence in NMIBC patients after TURBT and might be helpful in clinical decision-making for NMIBC patients., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Enfortumab vedotin, a fully human monoclonal antibody-drug conjugate (ADC) directed to Nectin-4, prolonged overall survival (OS) versus standard chemotherapy in patients with previously treated locally advanced or metastatic urothelial carcinoma (mUC) previously receiving a programmed cell death protein 1/ligand 1 (PD-1/L1) inhibitor and platinum-based chemotherapy in the pivotal, phase 3 EV-301 clinical trial, supporting global approvals of enfortumab vedotin monotherapy. This bridging study was the first to evaluate enfortumab vedotin monotherapy in previously treated Chinese patients with locally advanced or mUC., Methods: EV-203 was a multicenter, open-label, phase 2 study (NCT04995419) assessing efficacy, safety/tolerability, pharmacokinetics (PK), and immunogenicity of enfortumab vedotin in 40 Chinese patients (PK analysis set, n = 13) with previously treated locally advanced or mUC. Patients received enfortumab vedotin 1.25 mg/kg (Days 1, 8, and 15). Primary endpoints included confirmed objective response rate (ORR) by the independent review committee (IRC) and PK parameters of ADC, total antibody (TAb), and free monomethyl auristatin E (MMAE). Secondary endpoints included investigator-assessed confirmed ORR; investigator-/IRC-assessed duration of response (DOR), disease control rate (DCR), and progression-free survival (PFS); OS; immunogenicity; and safety/tolerability., Results: As of May 13, 2022, the median follow-up was 6.5 months. Confirmed ORR was 37.5% (n/N = 15/40; 95% CI: 22.7%-54.2%) by IRC and 42.5% (n/N = 17/40; 95% CI: 27.0%-59.1%) by investigator assessment. By IRC, DCR was 72.5% (n = 29), median DOR was not reached, and median PFS was 4.7 months. Median OS was not reached. Endpoints assessed by investigators were consistent with IRC assessments. Two patients discontinued treatment for treatment-related adverse events. No new safety signals were identified. ADC, TAb, and free MMAE were characterized in Chinese patients and consistent with previously characterized populations. The incidence of positive antitherapeutic antibodies postbaseline was 0%., Conclusion: Enfortumab vedotin demonstrated meaningful clinical activity with a manageable safety profile in Chinese patients with previously treated locally advanced or mUC., Trial Registration: ClinicalTrials.gov identifier: NCT04995419., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Purpose: Upper tract urothelial carcinoma (UTUC) and urothelial carcinoma of the bladder (UCB) share histomorphological and therapeutic features but distinct epidemiologic and clinicopathologic characteristics. We examined alterations of chromatin regulatory genes in molecular subtypes, clonal relatedness, and T-cell receptor (TCR) diversity in UTUC and UCB., Materials and Methods: Targeted next-generation sequencing or whole-exome DNA sequencing and TCR sequencing were conducted with 34 UTUC and 49 UCB specimens from 63 patients. Tumors were subtyped based on the expression of CK5 and GATA3. Results of tissue microarray of 78 muscle-invasive bladder cancer (MIBC) samples were used as prognostic factors of different subtypes of MIBC., Results: Chromatin regulatory genes were frequently mutated in both UTUC and UCB. Rapid relapse and progression of non-MIBC are correlated with alterations of KMT2C and EP300. Frequency of alterations in chromatin regulatory genes is higher in UTUC patients with SBS22 and SBS2 signatures and lower in UCB patients with SBS2 and SBS6 signatures. GATA3 and CK5 double-positive patients with higher frequencies of SMARCA4, ARID1A, and EP300 mutations have better prognoses than patients with basal subtypes. Although UTUC and UCB in the same patient can be either clonally related or developed independently, mutated genes in chromatin pathway were enriched in the related clones. Compared to UTUC, UCB had more deleterious mutations in DNA damage repair (DDR) genes, higher levels of tumor mutation burden (TMB) and copy number variations (CNVs), as well as higher TCR clonality and lower TCR diversity., Conclusions: Since genetic alterations of the chromatin pathway genes are important in both UTUC and UCB, they could serve as potential biomarkers for predicting disease progression and therapeutic targets. Differences in mutation frequencies of DDR pathway, TMB, CNV, and TCR might be the contributing factors for the distinct responses to immune checkpoint inhibitor (ICI) between UTUC and UCB., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Purpose: Alterations in DNA damage response (DDR) genes, including ERCC2 , have been correlated with response to neoadjuvant cisplatin-based chemotherapy (NAC) in patients with muscle-invasive bladder cancer (MIBC). The SWOG 1314 (S1314) trial enrolled patients with MIBC who received one of two NAC regimens followed by radical cystectomy. We examined the prevalence of DDR alterations in NAC responders versus nonresponders and correlated DDR alteration status with response., Methods: Pretreatment tumor specimens from 179 evaluable patients underwent next-generation sequencing (Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets assay). Associations were determined between any or only deleterious alterations within nine predefined DDR genes, or any alterations in ERCC2 , and progression-free survival (PFS) and overall survival using Cox regression, and, in a subset of evaluable patients, pathologic response (complete response, pT0, or downstaging to

Purpose: Bladder cancer is a common genitourinary malignant disease worldwide. Dasatinib is a small molecule inhibitor of Src family kinases. We investigated the anticancer effect and putative molecular mechanisms of dasatinib on T24 and cisplatin-resistant T24R2 human bladder cancer cells., Materials and Methods: Cell proliferation was measured using Cell Counting Kit-8 (CCK-8) and colony formation in dasatinib treated bladder cancer cells. Flow cytometry was used to determined cell cycle arrest and apoptosis. The expression of apoptosis and autophagy related proteins were detected by western blot analysis., Results: In bladder cancer cells, dasatinib significantly reduced cell proliferation, colony formation, and induced G1-phase arrest. Dasatinib triggered apoptosis along with an increased expression of apoptosis-related genes (caspases, PARP, and cytochrome c). Down-regulation of Bcl-2 and up-regulation of Bad, which are hallmarks of apoptosis, were found to play a dominant role in mediating the effects of dasatinib treatment. We further showed that dasatinib inhibits p-Src, p-PI3K, p-Akt, and p-mTOR in bladder cancer cells. Dasatinib also increased the expression of markers of autophagy flux such as LC3-II and p62., Conclusions: These results confirmed that dasatinib is a potent chemotherapeutic drug which induces apoptosis and autophagy by suppressing the PI3K/Akt/mTOR pathway in bladder cancer cells., Competing Interests: The authors have nothing to disclose., (© The Korean Urological Association.)

This study investigates the difference in overall survival rates after transurethral resection of bladder tumor between solitary and multiple bladder cancers, aiming to provide guidance for clinical practitioners. A retrospective analysis was conducted on 133 patients with bladder cancer who underwent transurethral resection of bladder tumor from April 2017 to October 2023, of which 112 patients had complete clinical and follow-up data. Clinical and follow-up data were collected, and the overall survival rates after surgery were compared between solitary and multiple bladder cancers. In this study, the recurrence rate after transurethral resection of bladder tumor was 23.21% (26/112), and the overall survival rate was 80.36% (90/112). The overall survival rate after transurethral resection of bladder tumor was 92.11% (35/38) in the solitary bladder cancer group and 74.32% (55/74) in the multiple bladder cancer group, with a statistically significant difference between the 2 groups (P = .025). The proportion of high-grade pathology was 7.89% (3/38) in the solitary bladder cancer group and 25.68% (19/74) in the multiple bladder cancer group after transurethral resection of bladder tumor, with a statistically significant difference between the 2 groups (P = .025). The mean tumor diameter after transurethral resection of bladder tumor was 2.76 ± 1.66 cm in the solitary bladder cancer group and 4.04 ± 3.17 cm in the multiple bladder cancer group, with a statistically significant difference between the 2 groups (P = .023). Univariate and multivariate regression analyses revealed that the number of bladder tumors is a risk factor for overall survival after bladder cancer surgery (P = .004). Multiple bladder cancers have a higher pathological grade, larger tumor diameter, and poorer prognosis after transurethral resection of bladder tumor compared to solitary bladder cancers. The number of bladder tumors is an independent risk factor for overall survival after bladder cancer surgery., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Urothelial cancer is the second most common cancer, and cause of cancer death, related to the genitourinary tract. The goals of imaging for pretreatment staging of urothelial cancer are to evaluate for both local and distant spread of the cancer and assessing for synchronous sites of urothelial cancer in the upper tracts and bladder. For pretreatment staging of urothelial carcinoma, patients can be stratified into one of three groups: 1) nonmuscle invasive bladder cancer; 2) muscle invasive bladder cancer; and 3) upper urinary tract urothelial carcinoma. This document is a review of the current literature for urothelial cancer and resulting recommendations for pretreatment staging imaging. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where peer reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation., (Copyright © 2024 American College of Radiology. Published by Elsevier Inc. All rights reserved.)

Bladder cancer (BCa) and renal cell carcinoma (RCC) are prevalent urologic malignancies (UM) characterized by high morbidity and frequent recurrence. Current diagnostic approaches, often invasive, often indicate an advanced disease stage. And the complex tumor microenvironment often promotes tumor progression and induces resistance to chemotherapy. Current diagnostic and therapeutic modalities often fail to achieve satisfactory outcomes for patients. Exosomes transport diverse cargoes, including cytokines, proteins, lipids, non-coding RNAs, and microRNAs, crucial for intercellular communication. Exosomes have shown potential as biomarkers for UM, participating in tumor progression, especially within the tumor microenvironment (TME), including tumor cell apoptosis, proliferation, migration, invasion, depletion of immune cell function, epithelial-mesenchymal transition (EMT), angiogenesis, and more.In this review, we summarize research advances related to exosomes in UM, focusing on the role of exosomes as biomarkers in bladder and renal cancer, highlighting their significance within the TME., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Background/aim: The aim of our study was to investigate the outcome of colon cancer with bladder invasion after surgical intervention., Patients and Methods: Between 2011 and 2022, a total of 41 patients diagnosed with colon cancer and bladder invasion underwent surgical procedures at Taichung Veterans General Hospital. The impact of various risk factors on overall survival (OS) was assessed using Kaplan-Meier analyses and Cox proportional hazards models., Results: Among the enrolled patients, 21 underwent radical cystectomy, while 20 underwent partial cystectomy. Twelve had tumors located in the rectum, 19 in the sigmoid colon, and 10 in both the rectum and sigmoid colon. The median OS was 71.8 months in stage 2, 50.8 months in stage 3, and 11.2 months in stage 4 (p=0.061). Median OS was 71.8 months in patients with negative surgical margins and 10.5 months in those with positive surgical margins (p=0.003). In multivariate regression analysis, positive surgical margins [hazard ratio (HR)=3.64, 95% confidence interval (CI)=1.28-10.34, p=0.015] and emergency operations (HR=4.57, 95%CI=1.34-15.55, p=0.015) significantly impacted OS., Conclusion: Complete resection of colon cancer with bladder invasion can yield excellent oncologic outcomes. The decision between partial and radical cystectomy should balance surgical margin clearance and the preservation of quality of life. Both surgical margin involvement and emergency operations are independent risk factors for OS., (Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Treatments targeting the immune system only benefit a subset of patients with bladder cancer (BC). Biomarkers predictive of BC progression and response to specific therapeutic interventions are required. We evaluated whether peripheral blood immune subsets and expression of clinically relevant immune checkpoint markers are associated with clinicopathologic features of BC. Peripheral blood mononuclear cells isolated from blood collected from 23 patients with BC and 9 age-matched unaffected-by-cancer control donors were assessed using a 21-parameter flow cytometry panel composed of markers of T, B, natural killer and myeloid populations and immune checkpoint markers. Patients with BC had significantly lower numbers of circulating CD19 + B cells and elevated circulating CD4 + CD8 + T cells compared with the control cohort. Immune checkpoint markers programmed cell death protein 1 (PD-1) and T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) were elevated in the total peripheral immune cell population in patients with BC. Within the BC cohort, PD-1 expression in T and myeloid cells was elevated in muscle-invasive compared with non-muscle-invasive disease. In addition, elevated T, B and myeloid PD-1 cell surface expression was significantly associated with tumor stage, suggesting that measures of peripheral immune cell exhaustion may be a predictor of tumor progression in BC. Finally, positive correlations between expression levels of the various immune checkpoints both overall and within key peripheral blood immune subsets collected from patients with BC were observed, highlighting likely coregulation of peripheral immune checkpoint expression. The peripheral blood immunophenotype in patients with BC is altered compared with cancer-free individuals. Understanding this dysregulated immune profile will contribute to the identification of diagnostic and prognostic indicators to guide effective immune-targeted, personalized treatments., (© 2024 the Australian and New Zealand Society for Immunology, Inc.)

Background/aim: Precise molecular mechanisms underlying resistance to cisplatin-based chemotherapy remain unclear, while the activity of estrogen receptor-β (ERβ) has been suggested to be associated with chemosensitivity in urothelial cancer. We aimed to determine if GULP1, an adapter protein known to facilitate phagocytosis, could represent a downstream effector of ERβ and thereby modulate cisplatin sensitivity in bladder cancer., Materials and Methods: GULP1 expression and cisplatin cytotoxicity were compared in bladder cancer lines. Immunohistochemistry was used to determine the expression of GULP1 and ERβ in two sets of tissue microarray (TMA) consisting of transurethral resection specimens., Results: The levels of GULP1 expression were considerably higher in ERβ-knockdown sublines than in the respective control ERβ-positive sublines. Estradiol treatment reduced GULP1 expression in ERα-negative/ERβ-positive lines, which was restored by the anti-estrogen tamoxifen. Chromatin immunoprecipitation assay revealed the binding of ERβ to the GULP1 promoter in bladder cancer cells. Moreover, GULP1 knockdown sublines were significantly more resistant to cisplatin treatment, but not to other chemotherapeutic agents, including gemcitabine, methotrexate, vinblastine, and doxorubicin. In the first set of TMA (n=129), the expression of ERβ and GULP1 was inversely correlated (p=0.023), and ERβ(-)/GULP1(+) in 51 muscle-invasive tumors was associated with significantly lower risk of disease progression and cancer-specific mortality. Similarly, in the second set (n=43), patients with ERβ(-)/GULP1(+) muscle-invasive disease were significantly (p=0.021) more likely to be responders to cisplatin-based neoadjuvant chemotherapy before radical cystectomy., Conclusion: ERβ activation was found to reduce the expression of GULP1 as a direct downstream target in bladder cancer cells, resulting in the induction of cisplatin resistance., (Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

In clinical practice, the limited efficacy of standard comprehensive therapy for advanced bladder cancer and the lack of targeted treatment options are well recognized. Targeting abnormal epigenetic modifications in tumors has shown considerable potential in cancer therapy. Through drug screening in tumor organoids, we identified that ML324, a histone lysine demethylase 4A (KDM4A) inhibitor, exhibits potent antitumor effects in both in vitro and in vivo cancer models. Mechanistically, Kdm4a demethylates H3K9me3, leading to chromatin opening and increased accessibility of Gabpa to the squalene epoxidase (Sqle) gene promoter, resulting in transcriptional activation. Inhibition of Kdm4a downregulates Sqle transcription, blocking cholesterol synthesis and causing squalene (SQA) accumulation. This process induces reactive oxygen species (ROS) clearance and suppresses JNK/c-Jun phosphorylation, ultimately inducing apoptosis. Furthermore, ML324 treatment significantly inhibited tumor growth in bladder cancer patient-derived xenograft (PDX) models. Our findings reveal the presence of a Kdm4a-Sqle-ROS-JNK/c-Jun signaling axis that regulates oxidative stress balance, offering a novel strategy for targeted therapy in bladder cancer., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Advanced urothelial cancer is a frequently lethal disease characterized by marked genetic heterogeneity 1 . In this study, we investigated the evolution of genomic signatures caused by endogenous and external mutagenic processes and their interplay with complex structural variants (SVs). We superimposed mutational signatures and phylogenetic analyses of matched serial tumours from patients with urothelial cancer to define the evolutionary dynamics of these processes. We show that APOBEC3-induced mutations are clonal and early, whereas chemotherapy induces mutational bursts of hundreds of late subclonal mutations. Using a genome graph computational tool 2 , we observed frequent high copy-number circular amplicons characteristic of extrachromosomal DNA (ecDNA)-forming SVs. We characterized the distinct temporal patterns of APOBEC3-induced and chemotherapy-induced mutations within ecDNA-forming SVs, gaining new insights into the timing of these mutagenic processes relative to ecDNA biogenesis. We discovered that most CCND1 amplifications in urothelial cancer arise within circular ecDNA-forming SVs. ecDNA-forming SVs persisted and increased in complexity, incorporating additional DNA segments and contributing to the evolution of treatment resistance. Oxford Nanopore Technologies long-read whole-genome sequencing followed by de novo assembly mapped out CCND1 ecDNA structure. Experimental modelling of CCND1 ecDNA confirmed its role as a driver of treatment resistance. Our findings define fundamental mechanisms that drive urothelial cancer evolution and have important therapeutic implications., (© 2024. The Author(s).)

Herein, we provide a non-exhaustive selection of the main clinical trials presented in 2023-2024 related to radiation-oncology used in the treatment of urological cancers including prostate cancer (radiotherapy of localized prostate cancer, post-prostatectomy irradiation, reirradiation, biochemical recurrence following local treatment, radiotherapy for metastatic cancer), muscle invasive bladder cancer and primary kidney cancer., (Copyright © 2024 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

Trimodal therapy consisting of transurethral resection of bladder tumors followed by radiotherapy and chemotherapy, has emerged as a valuable therapeutic alternative to radical cystectomy in patients with muscle invasive bladder cancer. Concomitant radiosensitising chemotherapy is a component of trimodality increasing locoregional control compared to radiotherapy alone. The combinations 5-fluorouracil with mitomycin or cisplatin are the best supported in the literature. Gemcitabine appears to be a feasible and promising alternative. There is considerable international heterogeneity in terms of dose, volumes and fractionation. The most commonly used regimens are moderately hypofractionated (55Gy in 20 fractions over 4 weeks) and normofractionated (64Gy in 32 fractions) regimens. Radiotherapy for bladder cancer is an effective and evolving treatment, with current technical developments, and studies of new combinations with systemic treatments underway., (Copyright © 2024 Société française de radiothérapie oncologique (SFRO). Published by Elsevier Masson SAS. All rights reserved.)

Background: Cell death, including apoptosis and necrosis, collectively known as widespread apoptosis. The present study aims to investigate the mechanism of action in widespread apoptosis-related modification patterns in bladder cancer., Methods: Using a clinical genomics database, we obtained transcriptomic data and related clinical information of bladder cancer patients. By employing the least absolute shrinkage analysis, we were able to construct a risk model and single-cell sequencing analysis of differential genes in bladder cancer., Results: Five differentially expressed genes (TMPRSS4, TPST1, FOXD1, ELOVL4, EMP1) associated with widespread apoptosis were identified as features for predicting the prognosis of bladder cancer patients. Survival curve analysis revealed significant differences in prognosis (P<0.05). Additionally, multivariate Cox regression analysis determined the independent risk factor for bladder cancer prognosis as the risk score (P<0.001), with high confidence in the scoring model validated internally (P<0.001). Single-cell sequencing reveals high expression of CDKN2A, ERBB2, and TMPRSS4 in B cells, while HRAS is significantly expressed in fibroblasts., Conclusion: PANscore, as a potential prognostic and immunotherapeutic biomarker, will provide more precise and rational basis for personalized treatment strategies., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

The anticancer and cytotoxic effects of DL-Limonene and R-Limonene are well-documented. However, the role of natural compounds in enhancing the efficacy of platinum-based drugs like Cisplatin (CisPt) remains debated. This study aims to boost Cisplatin's impact on breast (MDA-MB-231) and bladder (5637) cancer cells using DL-Limonene and R-Limonene. Different concentrations of DL-Limonene, R-Limonene, and Cisplatin, combined, were used to treat MDA-MB-231 and 5637 cells in this experimental study. The cell's viability was evaluated using an MTT assay. AnnexinV- PI staining was applied to evaluate the percentage of apoptotic cells. Cytotoxicity results showed that combining DL-Limonene, R-Limonene, and Cisplatin significantly improved outcomes in MDA-MB-231 cells (P < 0.05). Annexin/PI staining revealed apoptosis rates of 74 %, 28 %, 43 %, 81 %, and 91 % for Cisplatin40, R-Limonen1000, DL-Limonen1000, R-Limonen1000/DL-Limonen1000, and the combined treatment, respectively, versus 13 % in the control. The combination also resulted in the greatest reduction of AKT, PI3K, and mTOR gene expression. Our results show that R-Limonene and DL-Limonene enhance Cisplatin's cancer-inhibiting effects in breast and bladder cancer cell lines. These compounds may be promising for combination therapy, potentially allowing for lower doses of chemotherapy and reducing side effects like nephrotoxicity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: This study aimed to describe the life impacts of intravesical therapies for non-muscle invasive bladder cancer (NMIBC) from a patient perspective., Methods: A cross-sectional online survey design was used. Adults with NMIBC (and no other cancer) treated intravesically in the prior 12 months were recruited from US patient online communities. Individuals participating in a clinical trial or treated with erdafitinib were excluded. Participants' treatment experiences were evaluated using a questionnaire comprising (a) custom questions reported on 11-point numerical rating scales and (b) validated patient reported outcome (PRO) measures for bladder symptom burden and work productivity., Results: Among 171 survey participants, most received bacillus Calmette-Guérin (BCG) (83%), intravesical gemcitabine (28%), or gemcitabine + docetaxel (13%) during the past year. Participants generally felt adequately informed about treatment, felt expectation of treatment matched actual experience, and expressed intent to complete the full treatment course and willingness to try different treatments if needed. Participants reported disease symptom burden of 42.6/72 on the NFBlSI-18 scale. Employed participants reported 51% work impairment and 59% overall work productivity loss due to NMIBC., Conclusions: Participants recently treated with intravesical therapies expressed intent to complete the full treatment course and willingness to try new therapies if needed. Participants reported high NMIBC symptom burden and work impairment negatively impacting their well-being, despite receiving intravesical treatment.

Introduction: Urothelial carcinoma is a common malignancy affecting the urinary system, with the spectrum of disease encompassing non-muscle invasive, muscle-invasive and metastatic disease. On a background of almost half a century of immunogenic management with BCG, various immune checkpoint inhibitors, including durvalumab, have now demonstrated clinical efficacy in the treatment of urothelial carcinoma., Areas Covered: This article reviews the available literature on durvalumab in the treatment of urothelial carcinoma for all stages of the disease including mechanisms of action, pharmacokinetics, efficacy and safety and covers a broad portfolio of reported and ongoing trials., Expert Opinion: The management of UC is rapidly evolving, which is reflected in the diverse range of upcoming pivotal trials incorporating durvalumab with additional immunomodulatory agents and therapeutics targeting key oncogenic pathways, each with the potential to change the standard of care. As the complexity of UC management increases, future efforts should be directed at identifying better predictive biomarkers and selecting rational synergistic combinations from the novel treatments available. This will allow the addressing of existing gaps, facilitate the exploitation of new techniques of treatment delivery and ultimately deliver more personalized and efficacious care to the individual patient.

X-ray Photodynamic Therapy (XPDT) is an emerging, deeply penetrating, and non-invasive tumor treatment that stimulates robust antitumor immune responses. However, its efficacy is often limited by low therapeutic delivery and immunosuppressant within the tumor microenvironment. This challenge can potentially be addressed by utilizing X-ray responsive iron-glycol chitosan-polypyrrole nanozymes (GCS-I-PPy NZs), which activate M1 macrophages. These nanozymes increase tumor infiltration and enhance the macrophages' intrinsic immune response and their ability to stimulate adaptive immunity. Authors have designed biocompatible, photosensitizer-containing GCS-I-PPy NZs using oxidation/reduction reactions. These nanozymes were internalized by M1 macrophages to form RAW-GCS-I-PPy NZs. Authors' results demonstrated that these engineered macrophages effectively delivered the nanozymes with potentially high tumor accumulation. Within the tumor microenvironment, the accumulated GCS-I-PPy NZs underwent X-ray irradiation, generating reactive oxygen species (ROS). This ROS augmentation significantly enhanced the therapeutic effect of XPDT and synergistically promoted T cell infiltration into the tumor. These findings suggest that nano-engineered M1 macrophages can effectively boost the immune effects of XPDT, providing a promising strategy for enhancing cancer immunotherapy. The ability of GCS-I-PPy NZs to mediate M1 macrophage activation and increase tumor infiltration highlights their potential in overcoming the limitations of current XPDT approaches and improving therapeutic outcomes in melanoma and other cancers., Competing Interests: Declaration of competing interest All authors declare that no conflicts of interest exist., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Chemotherapy against muscle-invasive bladder cancer is increasingly challenged by the prevalence of chemoresistance. The cholesterol biosynthesis pathway has garnered attention in studies of chemoresistance, but conflicting clinical and molecular findings necessitate a clearer understanding of its underlying mechanisms. Recently, we identified farnesyl-diphosphate farnesyltransferase 1 (FDFT1)-the first specific gene in this pathway-as a tumor suppressor and chemoresistance modulator. Raman spectroscopy revealed higher levels of FDFT1-related metabolites in chemotherapy-sensitive bladder cancer tissue compared to resistant tissue; however, this observation lacks mechanistic insight. FDFT1 expression was reduced in our cisplatin-resistant bladder cancer cells (T24R) compared to parental cisplatin-sensitive cells (T24). Using functional knockdown and ectopic overexpression in T24/T24R cells, we mechanistically demonstrate the pathway through which FDFT1 mediates cisplatin sensitivity in bladder cancer cells. Bioinformatics analysis and rescue experiments showed that microRNA-146b-5p directly targets and downregulates FDFT1, reducing the cisplatin sensitivity of T24 cells, which can be restored by forced FDFT1 expression. Further investigation into the downstream cholesterol pathway revealed that FDFT1 suppression redirects its substrate toward the non-sterol branch of the pathway, as evidenced by the upregulation of non-sterol branch-associated genes and a reduced total cholesterol level in the sterol branch. Since the non-sterol pathway leads to the prenylation of isoprenoids and activation of Ras and Rho family proteins involved in cancer progression and chemoresistance, our findings suggest that redirection of the cholesterol biosynthesis pathway is a key mechanism underlying FDFT1-mediated cisplatin resistance in bladder cancer. The miR-146b-5p/FDFT1 axis represents a promising target for overcoming chemoresistance in bladder cancer., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Nur Akmarina B. M. Said reports financial support was provided by Malaysia Ministry of Higher Education. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper, (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Aging is a major risk factor for cancer, but the precise mechanism by which aging promotes carcinogenesis remains largely unknown. Here, using genetically modified mouse models, we show that p16 high senescent (p16 h -sn) fibroblasts accumulate with age, constitute inflammatory cancer-associated fibroblasts (CAFs) and promote tumor growth in bladder cancer models. Single-cell RNA sequencing of fibroblasts from aged mice revealed higher expression of the C-X-C motif chemokine 12 gene (Cxcl12) in p16 h -sn fibroblasts than in p16 low fibroblasts. Elimination of p16 h -sn cells or inhibition of CXCL12 signaling notebly suppressed bladder tumor growth in vivo. We identified high expression levels of SMOC2, GUCY1A1 (GUCY1A3), CXCL12, CRISPLD2, GAS1 and LUM as a signature of p16 h -sn CAFs in humans and mice, which was associated with age and poor prognosis in patients with advanced and nonadvanced bladder cancer. Here we show that p16 h -sn fibroblasts in the aged bladder create a cancer-permissive niche and promote tumor growth by secreting CXCL12., Competing Interests: Competing interests M.N. is a scientific advisor and shareholder at reverSASP Therapeutics. S.Y. is a co-founder of Celaid Therapeutics. The other authors declare no competing interests., (© 2024. The Author(s).)

Introduction: Few studies have evaluated the potential effects of aging-related conditions like frailty in older adults with cancer on informal caregivers. Our objective was to evaluate the association between the sum total of the aging-related conditions of older adults with non-muscle-invasive bladder cancer (NMIBC) and the strain reported by their informal caregivers., Materials and Methods: We conducted an explanatory sequential mixed methods cross-sectional survey study that recruited 81 dyads of older adults with NMIBC (age ≥ 65 at diagnosis) and their informal caregivers. Our outcome was measured by the Caregiver Strain Index (CSI), a self-reported measure of informal caregivers. Our exposure was the patient's deficit accumulation index (DAI), a validated composite measure of frailty derived from a geriatric assessment. A multivariable negative binomial regression was conducted to model CSI. We conducted qualitative thematic content analysis of responses to open-ended survey questions to understand specific types of caregiver strain and to identify coping strategies., Results: Mean ages of patients and caregivers were 79.4 years and 72.5 years, respectively. Most caregivers were spouses (75.3 %) and lived with the patient (80.2 %). Of patients, 54.3 % were robust, 29.6 % were pre-frail, and 16.1 % were frail. In the multivariable model, we found that patient DAI was significantly associated with CSI (adjusted incidence rate ratio 1.05, 95 % CI 1.02-1.09). The top three sources of strain identified by caregivers were emotional adjustments, medical management, and family adjustments. Coping strategies for each included self-management of emotions, self-education about bladder cancer, and social support, respectively., Discussion: In this cross-sectional study, we found that worsening frailty in an older adult with NMIBC was associated with greater informal caregiver strain. Informal caregivers reported challenges with emotional management, family dynamics, and medical tasks. These findings may inform longitudinal research and interventions to support informal caregivers who provide care for older adults with NMIBC., Competing Interests: Declaration of Competing Interest Matthew E. Nielsen serves as a paid consultant to the American Urological Association and to the American College of Physicians High Value Care Task Force and as a consultant/advisor to Grand Rounds (stock options). Tullika Garg was a Web MD paid consultant in 2020, and currently receives research funding from the Flume Catheter Company, LLC. Through 2021, Dr. Garg's immediate family member was an employee and stockholder of DRPLZ. All other authors report no conflicts., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The pathological assessment of cystectomy specimens is important for accurate prognostic information and to inform adjuvant therapy decisions. However, there is limited evidence regarding the best approach to fixation, dissection, block selection and microscopic assessment of cystectomies. We report the results of an international survey of 212 pathologists and their approach to cystectomy pathology. There is variation at all stages of the specimen journey including in fixation and dissection techniques, and in the approach to evaluating residual tumour. This is particularly evident in the post-neoadjuvant chemotherapy setting where there is variable use of response scoring systems and differing approaches to sampling. We also find variation in the use of digital and molecular pathology in cystectomy specimens. Finally, we have suggested areas for future research in cystectomy pathological assessment., Competing Interests: Declarations All participants gave informed consent to complete the questionnaire and the study received ethical approval from the University of Sheffield (UK) Ethics Committee on 24th July 2023 (approval number: 054611). Competing interests The authors declare no competing interests., (© 2024. The Author(s).)