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Tumor metastasis accounts for over 90% of tumor-related deaths, prompting the development of fluorescently labeled tumor-specific molecular imaging agents for differentiating tumors from normal tissues. However, early detection of metastasis lesions by tracking tumor markers alone has proven to be challenging. Herein, we reported a glycopeptide-based bispecific fluorescence probe (bsProbe) for earlier detection of bladder cancer and metastasis. By simultaneously recognition (tumor & tumor microenvironment) and in vivo self-assembly, the tumor accumulation of bsProbe (12.3% ID/g) was obviously increased by ∼6 fold compared with that in CXCR4 specific fluorescence probe (sProbe), indicating the obvious advantages of bsProbe over existing tumor metastasis detection probes. Additionally, bsProbe substantially broadens the tumor diagnosis window and enhances the detection signal to noise ratio (SNR: approximately 9.5), permitting early diagnosis of lung micro-metastasis (∼1 mm), precise identifying of tumor boundaries and micro-tumors in orthotopic tumor models. More importantly, bsProbe was demonstrated to distinguish malignant from benign specimen with a specificity of 90.48% and sensitivity of 92.22% in 195 clinical specimens of bladder cancer patients. Taken together, this novel synergetic targeting (CD206 × CXCR4) strategy provides an attractive method for earlier detection of bladder cancer and metastasis, which might be further extended to the imaging-guided surgery of clinical invisible tumors., (Copyright © 2024 Science China Press. Published by Elsevier B.V. All rights reserved.)

Background: Bladder cancer (BCa) is one of the most common malignancies of the urinary system and is characterized by a high recurrence rate and significant mortality. Sirtuin 4 (SIRT4), a member of the NAD + -dependent deacetylase and ADP-ribosyltransferase family, is involved in regulating cellular metabolism, DNA repair, and longevity, potentially influencing tumor progression and immune escape. This study aimed to elucidate the role of SIRT4 in BCa., Methods: The correlation between the sirtuin family and immunotherapy sensitivity in BCa patients was analyzed via IMvigor210 data. The clinical significance and immunological role of SIRT4 across multiple cancer types were assessed by evaluating its associations with clinicopathologic features, prognosis, tumor mutation burden (TMB), microsatellite instability (MSI), immune cell infiltration, and immune response genes across 33 datasets from The Cancer Genome Atlas (TCGA). SIRT4 expression was confirmed in BCa tissues, and its functions were examined via proliferation and migration assays. CD8 + T cells were isolated from the peripheral blood of healthy individuals and activated with CD3 and CD28 antibodies and recombinant IL2. Coculture assays involving BCa cells and activated CD8 + T cells, alongside ELISA, were conducted to evaluate the immunological function of SIRT4., Results: SIRT4 was positively associated with the immunotherapy response of BCa patients on the basis of IMvigor210 data. Its expression was downregulated in 11 tumor types but upregulated in 3. SIRT4 was significantly correlated with tumor stage in 2 tumor types and showed varying associations with overall survival, progression-free survival, and disease-specific survival. Additionally, SIRT4 was correlated with TMB in 10 tumor types and with MSI in 8. GSEA indicated that SIRT4 was negatively associated with the immune response in 9 tumor types, excluding BCa. It was positively correlated with immune cell infiltration in 2 tumor types and negatively correlated in 6. The TCGA data revealed that SIRT4 was positively associated with activated NK cell infiltration but negatively associated with M1 macrophages, neutrophils, resting NK cells, and activated memory CD4 T cells. Enrichment analyses revealed positive correlations with various chemokines, immunoinhibitors, immunostimulators, lymphocytes, MHC molecules, and MHC receptors, suggesting that SIRT4 may enhance the immune response in BCa. Further experiments confirmed that SIRT4 was downregulated in BCa tissues compared with adjacent normal tissues. Inhibition of SIRT4 promoted BCa cell proliferation and migration, whereas knockdown of SIRT4 impaired the chemotaxis and tumor-killing ability of CD8 + T cells in the BCa tumor microenvironment., Conclusions: In summary, SIRT4 inhibits the progression and immune escape of BCa, indicating its potential as a novel biomarker and immune checkpoint for immunotherapy., 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.)

Hedyotis diffusa Willd. (HDW), a traditional Chinese medicinal plant, exhibits a variety of pharmacological effects and has anticancer potential for a wide range of cancer types; Ferroptosis is a non-apoptosis-regulated cell death induced by iron accumulation and subsequent lipid peroxidation; and there is currently an increasing interest in the therapeutic role of ferroptosis in cancer. However, the effects of HDW on bladder cancer and its underlying molecular mechanisms remain largely unknown. In this study, a combination of in vivo and in vitro experiments, network pharmacology and data mining methods were used to investigate the effects of HDW on BLCA. The results showed that HDW exerted its anticancer activity by inducing ferroptosis in bladder cancer cells. Subsequently, we demonstrated for the first time that HDW induced ferroptosis in vitro and in vivo. To further explore the possible targets of HDW-induced ferroptosis in bladder cancer, we performed network pharmacological analyses, transcriptomic analyses, and single-cell analyses; through integrative analyses, we identified three key pivotal genes associated with iron death, CAV1, VEGFA, and JUN.Mechanistically, we showed that CAV1, VEGFA and JUN are key determinants of HDW-induced ferroptosis in BLCA. Knockdown of target genes altered the anticancer effects of HDW in 5637 and T24 cells. In conclusion, our data show for the first time that HDW exerts its anticancer effects on BLCA through CAV1, VEGFA and JUN gene-induced ferroptosis. This is expected to provide a promising compound for bladder cancer therapy., 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.)

Bladder cancer, more prevalent in men, has high recurrence rates in non-muscle-invasive forms and is highly lethal upon metastasis in muscle-invasive cases. Transient receptor potential canonical channels (TRPCs), specifically TRPC3, play a role in calcium signaling, influencing cancer cell behavior. This study examines the effects of Pyr3, a TRPC3 inhibitor, and TRPC3 knockdown on both muscle-invasive (T24) and non-muscle-invasive (RT4) bladder cancer cells. Pyr3 treatment reduced cell viability, migration, adhesion, and calcium influx in these cells. Additionally, Pyr3 treatment and siTRPC3 downregulated protein kinase C alpha (PKCα), phospho-PKCα, and protein phosphatase 2A (PP2A) levels. While PKC activator phorbol 12-myristate 13-acetate (PMA) could not restore Pyr3-induced viability loss, it reversed the migration inhibition. In a xenograft model, Pyr3 suppressed T24 cell viability, Ki67, phospho-PKCα, PP2A and TRPC3 expression. These findings suggest that Pyr3 inhibits bladder cancer cell migration through PKC signaling and holds potential as a therapeutic agent for bladder cancer., 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.)

Recent phase 3 randomized controlled trials (RCTs) demonstrate the promising impact of immune checkpoint inhibitor (ICI)-based combination therapies on locally advanced or metastatic urothelial carcinoma (UC). However, comparative data on the efficacy and toxicity of different ICI-based combinations are lacking. This study aims to compare the efficacy of first-line ICI-based combination therapies for locally advanced or metastatic UC using phase 3 RCT data. In November 2023, three databases were searched for RCTs evaluating oncological outcomes in patients with locally advanced or metastatic UC who were treated with first-line ICI-based combination therapies. Network meta-analysis (NMA) was conducted to compare outcomes, including overall survival (OS), progression-free survival (PFS), objective response rates (ORRs), complete response rates (CRRs), and treatment-related adverse events (TRAEs). Subgroup analyses were based on PD-L1 status and cisplatin eligibility. The NMA included five RCTs. Enfortumab vedotin (EV) + pembrolizumab ranked the highest for improving OS (100%), PFS (100%), ORR (96%), and CRR (96%), followed by nivolumab + chemotherapy. EV + pembrolizumab combination superiority held across PD-L1 status and cisplatin eligibility. In patients who are cisplatin-eligible, EV + pembrolizumab significantly improved OS (HR: 0.68, 95%CI 0.47-0.99) and PFS (HR: 0.67, 95%CI 0.49-0.92) compared to nivolumab + chemotherapy. Durvalumab + tremelimumab was the safest combination for severe TRAEs, and EV + pembrolizumab ranked second. Our analyses support EV + pembrolizumab combination as a first-line treatment for locally advanced or metastatic UC. Thus, EV + pembrolizumab may become a guideline-changing standard treatment., Competing Interests: Declarations. Competing interests: Takahiro Kimura is a paid consultant/advisor of Astellas, Bayer, Janssen and Sanofi. Shahrokh F. Shariat received follows: Honoraria: Astellas, AstraZeneca, BMS, Ferring, Ipsen, Janssen, MSD, Olympus, Pfizer, Roche, Takeda Consulting or Advisory Role: Astellas, AstraZeneca, BMS, Ferring, Ipsen, Janssen, MSD, Olympus, Pfizer, Pierre Fabre, Roche, Takeda Speakers Bureau: Astellas, Astra Zeneca, Bayer, BMS, Ferring, Ipsen, Janssen, MSD, Olympus, Pfizer, Richard Wolf, Roche, Takeda The other authors declare no conflicts of interest associated with this manuscript. Ethical approval: N/A. Consent to participate/publish: N/A., (© 2024. The Author(s).)

Introduction: Bladder carcinoma (BC) is the most prevalent malignancy of the urinary system. These cancers are primarily seen in adults > 60 years old and mostly present with microscopic or frank hematuria or obstruction of the urinary system. However, these rare cancers can be found in hernias., Case Presentation: This report discusses a rare, localized bladder urothelial carcinoma (UC) manifestation. The patient had presented with lower abdominal pain several times. However, no accurate diagnosis was made due to the unspecified pain features. After being referred to a radiologic evaluation with ultrasonography, a bladder hernia was detected entering the abdominal wall, and it contained an unusual mass. Further evaluations revealed the malignant feature of the tumor. The abdominal wall hernia was replaced, and a TURP procedure was performed. The resulting sample showed UC without the involvement of the muscle layer., Conclusion: One of the most common malignancies of the urogenital and reproductive systems in male patients is BCs. They are most commonly seen in men older than 60 years old with a history of smoking. The prevalent manifestations of cancer are microscopic or macroscopic hematuria, urinary obstruction, and abdominal pain. A rare but previously reported bladder cancer location is within inguinal or abdominal hernias. The diagnosis of this cancer is not always straightforward, and delays can result in the spread of malignancy and the transition of the patient's clinical condition to a poorer prognosis., Clinical Key Message: The presentation of bladder cancer is not always accompanied by typical symptoms such as hematuria or urinary obstruction. Patients with persistent lower abdominal pain should be evaluated to rule out bladder malignancy. These tumors might be hidden within abdominal or inguinal hernias, and more radiologic accuracy is demanded for their diagnosis., (© 2025 The Author(s). Cancer Reports published by Wiley Periodicals LLC.)

Platinum-based neoadjuvant chemotherapy prior to radical cystectomy is the preferred treatment for muscle-invasive bladder cancer despite modest survival benefit and significant associated toxicities. Here, we profile the global proteome of muscle-invasive bladder cancers pre- and post-neoadjuvant chemotherapy treatment using archival formalin-fixed paraffin-embedded tissue. We identify four pre-neoadjuvant chemotherapy proteomic clusters with distinct biology and response to therapy and integrate these with transcriptomic subtypes and immunohistochemistry. We observe proteomic plasticity post-neoadjuvant chemotherapy that is associated with increased extracellular matrix and reduced keratinisation compared to pre-neoadjuvant chemotherapy. Post-neoadjuvant chemotherapy clusters appear to be differentially enriched for druggable proteins. For example, MTOR and PARP are over-expressed at the protein level in tumours identified as neuronal-like. In addition, we determine that high intra-tumoural proteome heterogeneity in pre-neoadjuvant chemotherapy tissue is associated with worse prognosis. Our work highlights aspects of muscle-invasive bladder cancer biology associated with clinical outcomes and suggests biomarkers and therapeutic targets based on proteomic clusters., Competing Interests: Competing interests: A.C.-S. has consulted for Sustained Therapeutics. D.M.B. serves on the Scientific Advisory Board and has equity in Acrivon Therapeutics. Peter Black has consulted for AbbVie, Astellas Pharma, AstraZeneca, EMD-Serono, Ferring, Pfizer, Janssen Oncology, Bayer, Merck, Sanofi Canada, Bristol-Myers Squibb, Prokarium, Combat, Nonagen, Nanobot, NanOlogy, Photocure, Sumitomo, TerSera, Tolmar, and Verity. He shares a patent with Veracyte which played no role or is linked to the work presented here (Inventors Elai Davicioni, Hussam Al-Deen Ashab, Nicholas Erho, Peter Black; EP 3 571 322 B8 date of publication and mention of the grant patent 07.06.2023). R.S. has consulted for Janssen Oncology. He shares a patent with Veracyte which played no role or is linked to the work presented here (Inventors Elai Davicioni, Hussam Al-Deen Ashab, Nicholas Erho, Peter Black; EP 3 571 322 B8 date of publication and mention of the grant patent 07.06.2023). The rest of authors had no conflict of interest., (© 2025. The Author(s).)

Purpose: To systematically analyze gender-specific differences in recurrence-free survival (RFS), progression-free survival (PFS), cancer-specific survival (CSS), and overall survival (OS) as well as adverse events and quality of Life (QoL) as secondary aims in NMIBC patients undergoing cytostatic intravesical chemotherapy., Methods: A systematic review and meta-analysis were conducted on studies published between 1976 and 2024, following PRISMA guidelines. MEDLINE, Embase and Cochrane Library were used as literature sources. No restrictions were made concerning language, study region or publication type. Data from 12 studies encompassing 1,527 patients were analyzed. Outcomes were assessed using random-effects models, with gender as a primary variable of interest. A risk of bias assessment was done using the ROBINS-I tool or RoB2 as appropriate., Results: The pooled analysis demonstrated no statistically significant gender-specific differences in RFS (HR = 1.0625, 95% CI 0.8094-1.0526) or PFS (HR = 1.0861, 95% CI 0.7038-1.6760). Data on CSS and OS were insufficient for meaningful conclusions. Two included studies analyzed in univariate or multivariate regression gender as risk factor for recurrence or progression, but gender was not a significant risk factor. Adverse events and QoL outcomes were notably underreported, with no gender-specific data available., Conclusions: While this study found no significant gender-based differences in NMIBC outcomes following intravesical chemotherapy, the findings are limited by the small number of studies, underrepresentation of women, and inconsistent reporting of critical outcomes. Future research should prioritize gender-focused analyses and explore the molecular and genetic basis of potential differences to inform precision medicine and equitable care., Competing Interests: Declarations. Conflict of interests: The authors declare no competing interests. Ethics approval: A Statement of Ethics is not applicable because this study is based exclusively on published literature., (© 2025. The Author(s).)

Hyperglycemia and hyperglycosuria, two primary characteristics of diabetes mellitus, may increase the risk of cancer initiation, particularly for bladder cancer. The effectiveness of metformin, a common antidiabetic agent, is determined by its ability to induce growth differentiation factor 15 (GDF15). However, the mechanism of the GDF15 in relation to glucose, which influences the tumor microenvironment in the human bladder, is not fully understood. This study explores the potential roles of GDF15 in response to glucose in the human bladder. High glucose treatment (30 mM) enhanced phosphorylation of AKT at S473 and AMP-activated protein kinase α1/2 (AMPKα1/2) at S485 to block the counteracting effect of metformin on the AMPK activity in bladder cancer and stroma [human bladder stromal fibroblast (HBdSF) and human bladder smooth muscle cell (HBdSMC)] cells compared with normal glucose treatment (5 mM). Metformin modulated the expressions of GDF15, NDRG1, Maspin, and epithelial-to-mesenchymal transition (EMT) markers to attenuate cell proliferation and invasion of bladder cancer cells. Caffeic acid phenethyl ester (CAPE), like metformin, behaves as an inducer of AMPK activity to stimulate GDF15 expression. Knockdown of GDF15 blocked the downregulation of CAPE on the contraction of HBdSMCs. Both CAPE-induced GDF15 expression and the supernatant from bladder cancer cells with overexpressing GDF15 impeded the HBdSF and HBdSMC migration, suggesting that CAPE-upregulated GDF15 blocked the cell migration. These findings reveal that high glucose treatment inhibits the counteracting effects of either metformin or CAPE on the AMPK activity and GDF15 is downregulated by glucose and induced by metformin and CAPE in both stroma and cancer cells. Furthermore, GDF15 is an antitumor gene facilitating communication between stroma and cancer cells in the human bladder. NEW & NOTEWORTHY This study investigates the counteraction of either CAPE or metformin with the AMPK activity increasing GDF15 expression in human bladder cells. The findings are the first study to indicate the secretion of GDF15 from cancer and stroma cells via autocrine or paracrine mechanisms. Our study suggests that GDF15, an antitumor gene in the human bladder induced by AMPK inducers, acts as a communication link between stroma and cancer cells in the human bladder.

Background: FGFR2/3, MTAP and ERBB2 genomic alterations have treatment targets in advanced urothelial carcinoma (aUC). These alterations may affect tumor microenvironment and outcomes with immune checkpoint inhibitors (ICIs) in aUC., Patients and Methods: We identified patients with available genomic data in our multi-institution cohort of patients with aUC treated with ICI. Outcomes (observed response rate [ORR], progression-free and overall survival [PFS, OS]) with ICI were compared between patients with and without FGFR 2/3, MTAP, ERBB2 alterations. We compared ORR using logistic regression and PFS/OS using Cox proportional hazards., Results: Out of 1,514 patients, 276 (18%), 174 (11%) and 208 (14%) patients had known FGFR2/3, MTAP and ERBB2 alteration status, respectively. and were treated with ICI in 1L or 2 + L. In patients with (vs. without) FGFR2/3 alteration, ORR with ICI was 21% vs. 32% (OR 0.54; [95%CI 0.32-0.91]), PFS was significantly shorter in patients with FGFR2/3 alterations (HR = 1.36 [95%CI 1.03-1.80]; P=0.03); OS was not significantly different (HR = 1.22 [95%CI 0.86-1.47]). In patients with (vs. without) MTAP alteration, ORR with ICI was 25% versus 40% (OR 0.52 [95%CI 0.20-1.38]); PFS and OS were nonsignificantly different. In patients with (vs. without) ERBB2 alteration, ORR with ICI was similar (37% vs. 35%; OR 1.06; 95%CI 0.57-1.97); PFS and OS were significantly longer in patients with ERBB2 alteration [HR 0.63 (95%CI 0.41-0.95); P=0.03; HR 0.66, [95% CI 0.44-0.97]), respectively., Conclusion: Our results support further evaluation of FGFR2/3, MTAP and ERBB2 alterations as putative biomarkers in patients with aUC treated with ICI., Competing Interests: Disclosure Rafee Talukder, Dimitra Rafailia Bakaloudi, Dimitrios Makrakis, Leonidas N. Diamantopoulos, Thomas Enright, Jacob Leary, Ruben Raychaudhuri, Nishita Tripathi, Tanya Jindal, Charles B. Nguyen, Roubini Zakopoulou, Aristotelis Bamias, David Marmorejo, David J Pinato, James Korolewicz,Lucia Alonso Buznego, Clara Castro Carballeira, Tyler F. Stewart, Pedro Barata, Vadim S. Koshkin: No conflicts to disclosure. Neeraj Agarwal (lifetime disclosures): No personal COIs since April 15, 2021. Consultancy to Astellas, Astra Zeneca, Aveo, Bayer, Bristol Myers Squibb, Calithera, Clovis, Eisai, Eli Lilly, EMD Serono, Exelixis, Foundation Medicine, Genentech, Gilead, Janssen, Merck, MEI Pharma, Nektar, Novartis, Pfizer, Pharmacyclics, and Seattle Genetics. Research funding to Neeraj Agarwal's institution: Arnivas, Astellas, Astra Zeneca, Bavarian Nordic, Bayer, Bristol Myers Squibb, Calithera, Celldex, Clovis, Crispr, Eisai, Eli Lilly, EMD Serono, Exelixis, Genentech, Gilead, Glaxo Smith Kline, Immunomedics, Janssen, Lava, Medivation, Merck, Nektar, Neoleukin, New Link Genetics, Novartis, Oric, Pfizer, Prometheus, Rexahn, Roche, Sanofi, Seattle Genetics, Takeda, and Tracon. Jason R. Brown: Received funding from EMD–Serono for a Speaker's Bureau. Yousef Zakharia: Advisory Board: Bristol Myers Squibb, Amgen, Roche Diagnostics, Novartis, Janssen, Eisai, Exelixis, Castle Bioscience, Genzyme Corporation, Astrazeneca, Array, Bayer, Pfizer, Clovis, EMD serono, Myovant. Grant/research support from: Institution clinical trial support from NewLink Genetics, Pfizer, Exelixis, Eisai. DSMC: Janssen Research and Development.Consultant honorarium: Pfizer, Novartis. Alexandra Drakaki has served as consultant for Bristol–Myers Squibb, AstraZeneca, RADMETRIX, Seattle Genetics, Janssen, PACT Pharma, Merck, Roche/Genentech, Exelixis, Dyania Health, has received research funding from Kite/Gilead, AstraZeneca, Genentech/Roche, BMS, Merck Sharp & Dohme, Jounce Therapeutics, Infinity Pharmaceuticals, Seattle Genetics/Astellas, and has received travel expenses from Lilly, AstraZeneca and Seattle Genetics. Ignacio Duran: Research Grant to institution: Roche, AstraZeneca, Honoraria: Bristol Myers Squibb, MSD, Ipsen, Roche–Genentech, Janssen, Astellas Pharma, EUSA Pharma, Bayer, Novartis, Gilead, Bayer. Support for attending meetings and/or travel: Merck–Pfizer, Ipsen, Jansen, Bayer, AstraZeneca. Advisory board: Bristol Myers Squibb, MSD, Ipsen, Roche–Genentech, Astellas Pharma, EUSA Pharma, Bayer, Novartis, Eisai, Debio Pharma, Pharmacyclycs, Gilead. Rafael Morales–Barrera has served as consultant/advisor for Sanofi, AstraZeneca, Astellas Pharma and MSD, has been in the speaker's Bureau for Astellas Pharma, Merck/Pfizer and MSD Oncology, and has received travel accommodations from Sanofi, Pfizer, MSD, Astellas Pharma, Astra Zeneca, Bayer, Roche/Genentech. Macarena Rey–Cárdenas: Pfizer, Bayer. Pfizer; Pierre Fabre; Ipsen; BMS; AstraZeneca; MSD; Roche; Kyowa Kirin; Accord. Daniel Castellano: Consulting or Advisory Role: Janseen Oncology, Roche/Genentech, Astellas Pharma, AstraZeneca, Pfizer, Novartis, Ipsen, Bristol–Myers Squibb, MSD Oncology, Bayer, Lilly, Sanofi, Pierre Fabre, Bpehringer Ingelheim. Research funding: Janseen Oncology. Travel, Accomondations, Expenses: Pfizer, Roche, Bristol–Myers Squibb, AstraZeneca Spain. Ajjai Alva: Dr. Ajjai Alva serves as a consultant for Merck, AstraZeneca, Bristol–Myers Squibb, and Pfizer/EMD Serono. Dr. Ajjai Alva receives research funding through the University of Michigan from Merck, Genentech, Prometheus Laboratories, Mirati Therapeutics, Roche, Bayer, Progenics, Astellas Pharma, Arcus Biosciences, AstraZeneca, Bristol–Myers Squibb, and Clovis Oncology. Rana R. McKay: Consulting/Advisory Board – Aveo, AstraZeneca, Bayer, Bristol Myers Squib, Calithera, Caris, Denderon, Exelixis, Esiai, Janssen, Lilly, Merck, Myovant, Novartis, Pfizer, Sanofi, SeaGen, Sorrento Therapeutics, Telix, Tempus. Institutional Research Funding – Bayer, Tempus, AstraZeneca, Oncternal, Exelixis, BMS. Tyler Stewart: Advisory Board/Consulting- Seagen/Astellas, AstraZeneca and received research support from GRAIL. Shilpa Gupta has received personal fees from Bristol Myers Squibb, Merck, Janssen, Seattle Genetics, EMD Sorono and Pfizer, and has received grants from Astellas, BMS and Bristol Myers Squibb. Evan Yu: Consulting fees from Aadi Bioscience, Advanced Accelerator Applications, Bayer, Janssen, Merck, Oncternal. Research funding to institution from Bayer, Blue Earth, Daiichi–Sankyo, Dendreon, Lantheus, Merck, Seagen, Surface, Taiho, Tyra Ali Raza Khaki has received institutional research funding from 23andMe, Janssen, and Pfizer. Petros Grivas: consulting for Aadi Bioscience, Abbvie, Asieris Pharmaceuticals, Astellas, AstraZeneca, Bicycle Therapeutics, Bristol Myers Squibb, CG Oncology, Daiichi Sankyo, EMD Serono, Fresenius Kabi, Gilead, G1 Therapeutics, ImmunityBio, Janssen, MSD, Pfizer, Replimune, Roche, Strata Oncology; research funding: Acrivon Therapeutics, ALX Oncology, Bristol Myers Squibb, EMD Serono, Genentech, Gilead, G1 Therapeutics, Mirati Therapeutics, MSD, QED Therapeutics., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: To compare the oncologic outcomes of patients with nonmetastatic muscle-invasive bladder cancer (MIBC) undergoing complete versus incomplete transurethral tumor resection (TURBT) before radiation therapy., Methods and Materials: Patients with nonmetastatic MIBC who underwent curative-intent radiation therapy between 2002 and 2018 at 10 Canadian institutions were retrospectively evaluated. Inverse probability of treatment weighting was performed using baseline characteristics. Differences in survival outcomes by complete and incomplete TURBT were analyzed., Results: Of the 757 patients included, 66% (498) had documentation of a complete and 34% (259) an incomplete TURBT. Before adjustment, 121 (47%) and 45 (9%) patients who underwent incomplete and complete TURBT, respectively, were diagnosed with cT3-4 tumor (P <.001). After weight-adjustment, all baseline cohort characteristics were balanced (absolute standardized differences < 0.1). The adjusted median follow-up was 27 months. Adjusted survival analyses showed no significant difference in 5-year overall survival (48% vs 52%, 1.03 [0.82-1.29]; P = .8), cancer-specific survival (64% vs 61%, 0.93 [0.70-1.25]; P = .7), metastasis-free survival (43% vs 46%, 0.97 [0.79-1.19]; P = .8), and disease-free survival (32% vs 35%, 0.95 [0.79-1.15]; P = .7) between the 2 groups., Conclusions: Complete TURBT may be associated with clinical organ-confined disease. Extent of TURBT was not independently associated with oncologic outcomes in patients with MIBC treated with radiation therapy., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: A second transurethral resection of bladder tumour (Re-TURBT) is recommended by European Association of Urology (EAU) Guidelines on non-muscle-invasive bladder cancers (NMIBCs) due to the risk of understaging and/or persistent disease following the primary resection. However, in many cases this may be unnecessary, potentially harmful, and significantly expensive constituting overtreatment. The CUT-less trial aims to combine the preoperative staging accuracy of Vesical Imaging-Reporting and Data System (VI-RADS) and the intraoperative enhanced ability of photodynamic diagnosis (PDD) to overcome the primary TURBT pitfalls thus potentially re-defining criteria for Re-TURBT indications., Study Design: Single-centre, non-inferiority, phase IV, open-label, randomised controlled trial with 1:1 ratio., Endpoints: The primary endpoint is short-term BC recurrence between the study arms to assess whether patients preoperatively categorised as VI-RADS Score 1 and/or Score 2 (i.e., very-low and low likelihood of MIBC) could safely avoid Re-TURBT by undergoing primary PDD-TURBT. Secondary endpoints include mid- and long-term BC recurrences and progression (i-ii). Also, health-related quality of life (HRQoL) outcomes (iii) and health-economic cost-benefit analysis (iv) will be performed., Patients and Methods: All patients will undergo preoperative Multiparametric Magnetic Resonance Imaging of the bladder with VI-RADS score determination. A total of 327 patients with intermediate-/high-risk NMIBCs, candidate for Re-TURBT according to EAU Guidelines, will be enrolled over a 3-year period. Participants will be randomised (1:1 ratio) to either standard of care (SoC), comprising primary white-light (WL) TURBT followed by second WL Re-TURBT; or the Experimental arm, comprising primary PDD-TURBT and omitting Re-TURBT. Both groups will receive adjuvant intravesical therapy and surveillance according to risk-adjusted schedules. Measure of the primary outcome will be the relative proportion of BC recurrences between the SoC and Experimental arms within 4.5 months (i.e., any 'early' recurrence detected at first follow-up cystoscopy). Secondary outcomes measures will be the relative proportion of late BC recurrences and/or BC progression detected after 4.5 months follow-up. Additionally, we will compute the HRQoL variation from NMIBC questionnaires modelled over a patient lifetime horizon and the health-economic analyses including a short-term cost-benefit assessment of incremental costs per Re-TURBT avoided and a longer-term cost-utility per quality-adjusted life year gained using 2-year clinical outcomes to drive a lifetime model across the two arms of treatment., Trial Registration: ClinicalTrial.gov identifier (ID): NCT05962541; European Union Drug Regulating Authorities Clinical Trials Database (EudraCT) ID: 2023-507307-64-00., (© 2024 The Author(s). BJU International published by John Wiley & Sons Ltd on behalf of BJU International.)

Background: The National Comprehensive Cancer Network Bladder Cancer Guidelines recommend carboplatin and gemcitabine first-line treatment in patients with cisplatin-ineligible, metastatic urothelial cancer (mUC) -- a Category 1 recommendation. For these patients, the median overall survival is 9.3 months. While carboplatin is purported to offer a more tolerable side-effect profile, many patients still require dose-reductions, dose-delays, and hospitalizations. Given the inability for mUC patients to tolerate this palliative regimen, we aim to determine whether initiating therapy with a lower dose regimen is justified., Methods: A single-institution retrospective analysis was conducted to review eligible patients treated with carboplatin plus gemcitabine from May 2014 through October 2022. Data collected via manual chart review included patient baseline characteristics, chemotherapy doses, reductions, delays, toxicities, and effectiveness., Results: Forty-three patients met inclusion criteria. Nineteen patients (44%) required ≥ 1 dose reduction during therapy. Twenty-six patients (60%) started with a full-dose regimen, and 14 (54%) of those patients required a dose reduction during treatment. Seventeen patients (40%) started with a reduced-dose regimen, and 5 (29%) of those patients required a dose reduction during treatment. No patients received the anticipated 6 cycles at full dose, but 14% completed 6 cycles with dose reductions. One patient (2%) was able to tolerate >80% relative dose intensity of both carboplatin and gemcitabine., Conclusions: Cisplatin-ineligible mUC patients were unable to tolerate full-dose carboplatin and gemcitabine. As this is a palliative regimen, it would be pertinent to consider starting therapy at a reduced dose to minimize treatment interruptions, dose omissions and side effects., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: Papillary urothelial carcinomas are currently graded as either low- or high-grade tumors based on World Health Organization (WHO) 2022 guidelines for genitourinary tumors. However, a minority of tumors are mixed-grade tumors, composed predominantly of low-grade cancer with a minor high-grade component. In the 2022 WHO these cancers are recognized as having outcomes comparable to low-grade cancers, although data to date has been limited., Methods: The pathology records of a large academic institution were searched for mixed-grade, non-muscle invasive papillary carcinomas of the bladder and ureter in order to characterize prognosis of these cancers., Results: Of 136 cancers, the majority (n = 104, 76.5%) were solitary, mixed-grade tumors, while 21 (15.4%) had a concurrent low-grade cancer and 11 (8.1%) had multiple mixed-grade tumors at the time of diagnosis. At follow-up (median 48.3 months, range = 1.3 months-18.1 years), 71 cancers recurred (52.2%): 52 (38.2%) as low- or mixed-grade cancers and 18 (13.2%) as high-grade cancers. There were no instances of stage-progression to >p T2., Conclusions: The clinical outcome of mixed-grade carcinomas was similar to what has been reported for low-grade carcinomas. Based on our results, and prior congruent studies of mixed-grade lesions, these lesions may be regarded as a distinct sub-category with a better prognosis than high-grade tumors., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Purpose: There are few markers to identify those likely to recur or progress after treatment with intravesical bacillus Calmette-Guérin (BCG). We developed and validated artificial intelligence (AI)-based histologic assays that extract interpretable features from transurethral resection of bladder tumor digitized pathology images to predict risk of recurrence, progression, development of BCG-unresponsive disease, and cystectomy., Materials and Methods: Pre-BCG resection-derived whole-slide images and clinical data were obtained for high-risk nonmuscle-invasive bladder cancer cases treated with BCG from 12 centers and were analyzed through a segmentation and feature extraction pipeline. Features associated with clinical outcomes were defined and tested on independent development and validation cohorts. Cases were classified into high or low risk for recurrence, progression, BCG-unresponsive disease, and cystectomy., Results: Nine hundred forty-four cases (development: 303, validation: 641, median follow-up: 36 months) representative of the intended use population were included (high-grade Ta: 34.1%, high-grade T1: 54.8%; carcinoma in situ only: 11.1%, any carcinoma in situ: 31.4%). In the validation cohort, "high recurrence risk" cases had inferior high-grade recurrence-free survival vs "low recurrence risk" cases (HR, 2.08, P < .0001). "High progression risk" patients had poorer progression-free survival (HR, 3.87, P < .001) and higher risk of cystectomy (HR, 3.35, P < .001) than "low progression risk" patients. Cases harboring the BCG-unresponsive disease signature had a shorter time to development of BCG-unresponsive disease than cases without the signature (HR, 2.31, P < .0001). AI assays provided predictive information beyond clinicopathologic factors., Conclusions: We developed and validated AI-based histologic assays that identify high-risk nonmuscle-invasive bladder cancer cases at higher risk of recurrence, progression, BCG-unresponsive disease, and cystectomy, potentially aiding clinical decision making.

Objective: To assess the association of being overweight or obese with Nonmuscle invasive bladder cancer (NMIBC) recurrence, stage progression, and grade progression., Methods: Patients with NMIBC were included and categorized into 3 groups based on their body mass index (BMI): normal weight, overweight, and obese. Recurrence was defined as any histologically proven bladder cancer on subsequent transurethral resection of bladder tumor (TURBT). Progression was defined as upgrading from low to high grade, upstaging to pT1 from pTa, or to muscle-invasion from pT1 disease., Results: A total of 457 patients were analyzed, 135 (29.5%) had normal weight, 192 (42.6%) were overweight, and 130 (28.4%) were obese, with a median BMI of 27.1 (24.4-30.7) Kg/m2. The study found no significant difference in the time to recurrence, stage progression, and grade progression within the BMI categories (P < .05). Additionally, no increased risk was observed in BMI categories (Obesity recurrence HR: 1.067, CI 95%: 0.783-1.453; Obesity stage progression HR: 1.315, 95% CI: 0.635-2.724; Obesity grade progression HR: 0.586, 95% CI: 0.195-1.760)., Conclusions: In our cohort, body weight category showed no association with NMIBC recurrence, stage progression, or grade progression. These findings highlight the need to identify other potential risk factors that could improve NMIBC risk stratification. Further studies are warranted to validate our results and explore additional predictors of NMIBC outcomes., Competing Interests: Disclosure All authors have no conflict of interests to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Extramural venous invasion is an independent prognostic factor in colorectal cancers; the pathological identification of extramural venous invasion in bladder cancer remains unclear. By focusing on high-stage urothelial carcinoma of the bladder, we provide insights into the pathological identification of extramural venous invasion in this particular clinical context. Clinical and demographic details and pathological reports were extracted from electronic medical records. Histological sections were reviewed for the pathological identification of extramural venous invasion. Statistical analysis was done using SPSS version 23 software. Survival analysis was done using Kaplan-Meier method. In patients with available follow-up data, 62% (n = 21) exhibited pathologically evidenced extramural venous invasion, whereas 38% (n = 13) did not. The extramural venous invasion positive group showed trends toward more advanced and pathological staging and a higher occurrence of extra-nodal extension. Positive margins were more frequent in the extramural venous invasion positive group (33%) compared to the extramural venous invasion negative group (8%). However, these differences were not statistically significant. Notably, all instances of recurrence were in the extramural venous invasion positive group of patients. The extramural venous invasion positive group of patients showed a significantly shorter locoregional recurrence-free survival ( P -value of 0.045). However, extramural venous invasion did not emerge as a significant factor in univariate analyses for recurrence-free survival. These findings highlight the potential role of extramural venous invasion as a prognostic factor in bladder cancer but underscore the need for further research with larger cohorts to confirm its significance., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

The tumor microenvironment (TME) modulates therapeutic response and prognosis in patients with bladder cancer (BC). The roles of two phospholipase D (PLD) isoforms, PLD1 and PLD2 (hydrolysis of phosphatidylcholine to phosphatidic acid), in cancer cells have been well-studied in numerous cancer types, but their roles in the TME remain unclear. We used a mouse BC Pld2-KO carcinogenesis model and global transcriptomic analysis to reveal that PLD2 was significantly involved in BC progression through immunosuppressive pathways in the TME. We therefore focused on PLD2 and tumor-associated macrophages (TAMs), which were increased in Pld2-KO mice and further associated with poor prognoses in BC patients. In vitro, we found that Pld2-KO mouse TAMs had significantly enhanced proliferation, correlating closely with increased interleukin-1β (IL-1β) production. These results indicate that PLD2 suppresses BC progression by regulation of IL-1β secretion from TAMs in the TME, suggesting that PLD2 could serve as a potential therapeutic target for modifying the TME in BC., (© 2024 The Author(s). Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Aim: Enfortumab vedotin (EV) represents a novel treatment for patients with locally advanced or metastatic urothelial carcinoma (la/mUC) refractory to platinum-based chemotherapy and PD(L)-1 containing therapies. Real-world data are crucial for informing health policy decisions and validating clinical trial findings., Methods: We conducted a multicentre, retrospective real-world analysis comprising 128 patients with la/mUC from 16 Austrian centres treated with EV from April 2022 to April 2024, presenting the second largest real-world cohort to date. Data were analysed for efficacy and safety parameters., Results: The median age was 69 years, the objective response rate 31% and the disease control rate 47%, with 9% of patients exhibiting a complete remission, 23% a partial remission and 16% a stable disease. After a median follow-up of 6.2 months, the median progression-free survival (mPFS) and the median overall survival (mOS) reached 4.8 and 10.75 months, respectively. Patients with good ECOG PS 0-1, metachronous metastatic disease and absence of liver metastases had significantly better OS. No difference in efficacy was observed in patients who received a reduced dose EV after experiencing adverse events. The safety profile was acceptable, showing grade ≥3 TRAEs in 25.8% of patients., Conclusion: In our real-world population, the administration of EV was feasible and effective, with no new safety signals. Lower efficacy data compared to previous trials might be explained by the use in later therapy lines and in patients with poorer ECOG PS. Our data corroborate the efficacy and safety of EV monotherapy in later lines., Competing Interests: Disclosures The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dora Niedersüß-Beke: serves on advisory boards for Astellas, has received honoraria for lectures from Astellas and has received a funding grant by Astellas for creating and maintaining the registry. Simon Peter Gampenrieder: received consulting fees from Astellas. Franz Stoiber: serves on advisory boards for Astellas, has received honoraria for lectures from Astellas. Sharhrokh Shariat: has received honoraria for lectures from Astellas. Josef Mühlmann: serves on advisory boards for Astellas. Thomas Bauernhofer: has received honoraria for lectures from Astellas. Jasmin Spiegelberg: serves on advisory boards for Astellas. Renate Pichler: serves on advisory boards for Astellas, has received the funding grant by Astellas. The remaining authors have no relevant disclosures., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The Paris System (TPS) diligently detects high-grade urothelial carcinoma (HGUC) and creates a uniform, standardized, reproducible reporting system for urine cytology. However, many centres might still use a common reporting system (CRS). The study aims to compare TPS and CRS for urine cytology with histology correlation., Method: It was a cross-sectional study done from July 2016 to December 2022., Results: The study included 829 urine cytology samples (96% voided urine) from 478 patients. Histology correlation was available for 138 (16.6%) samples of 115 patients. The frequency of NHGUC, AUC, HGUC and SHGUC was 40.6%, 17.4%, 12.2% and 5.5%, respectively, in TPS. In contrast, in CRS, the frequency of NM, AUS, SM and PM was 69.2%, 13.3%, 4.5% and 13.0%, respectively. TPS and CRS had 64% agreement overall with the kappa test (κ-value 0.479, moderate strength). The agreement between TPS and CRS was 39.8% for NHGUC, 10.97% for AUC and 10.85% for HGUC. After combining a few TPS categories, the agreement increased to 87.7% (κ-value 0.7640, good strength). Histological concordance for AUC, HGUC and NHGUC was 75%, 31.8% and 31.3% in TPS, and it was 50% and 33.3% for AUS and PM, respectively, in CRS. The sensitivity and specificity of TPS and CRS against histology were 37.5% vs. 26.0%, p = 0.0005 and 76.5% vs. 85.3%, p = 0.0083, respectively., Conclusion: TPS and CRS have moderate strength of agreement for urine cytology. TPS was more sensitive than CRS. It may be easy for institutes to transition to a newer TPS system if they still use a CRS., (© 2024 Wiley Periodicals LLC.)

Introduction: The phase 3 KEYNOTE-361 trial of first-line pembrolizumab with or without chemotherapy versus chemotherapy alone in patients with locally advanced or metastatic urothelial carcinoma (la/mUC) completed enrollment before the approval of postchemotherapy maintenance avelumab for patients without progressive disease. This post hoc analysis evaluated the outcomes of patients who received chemotherapy alone in KEYNOTE-361 by retrospective eligibility for subsequent maintenance therapy., Patients and Methods: Patients in the chemotherapy alone arm were retrospectively categorized as maintenance eligible (received ≥4 cycles of chemotherapy and did not die or experience disease progression within 10 weeks of chemotherapy completion), maintenance ineligible (received <4 cycles of chemotherapy or had progressive disease or died within 0-10 weeks after completion of ≥4 cycles of chemotherapy), and indeterminate eligibility for maintenance therapy (if neither maintenance eligible or ineligible). End points included progression-free survival per Response Evaluation Criteria in Solid Tumors version 1.1 by blinded independent central review and overall survival from randomization (start of chemotherapy)., Results: Median follow-up was 31.7 months (range, 22.0-42.3). Among 342 patients who received chemotherapy alone, 172 (50.3%) were maintenance eligible, 108 (31.6%) were maintenance ineligible, and 62 (18.1%) had indeterminate eligibility for maintenance therapy. The median progression-free survival was 9.0 months (95% CI 8.4-10.4) in maintenance-eligible patients, 5.1 months (4.2-6.0) in maintenance-ineligible patients, and 2.3 months (1.9-3.8) in the indeterminate group; median overall survival was 23.3 months (95% CI 19.4-26.1), 10.2 months (9.1-11.6), and 5.5 months (3.7-8.5), respectively., Conclusion: This post hoc analysis suggests that a majority of patients with untreated la/mUC who initiated chemotherapy in a clinical trial may have been considered eligible for maintenance therapy and had favorable survival outcomes compared with those considered maintenance ineligible., Competing Interests: Disclosure R. Mamtani reports research grants or contracts to his institution from Astellas and MSD and consulting fees from Astellas, Bristol Myers Squibb, Merck & Co, Inc, and Seagen outside the submitted work. N. Matsubara reports research grants or contracts to his institution from AbbVie, Amgen, Astellas, AstraZeneca, Bayer, Chugai, Eisai, Eli Lilly, Janssen, MSD, Pfizer, PRA Health Science, Roche, Taiho, Takeda, and Seagen; personal payment or honoraria from Sanofi; and support for attending meetings and/or travel from Pfizer outside the submitted work. A. Montesa Pino reports consulting fees from Advanced Accelerator Applications, Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Ipsen, Janssen, Merck & Co, Inc, MSD, Novartis, and Pfizer; support for attending meetings and/or travel from Bayer, Ipsen, Merck & Co, Inc, and Pfizer; and participation on a data safety monitoring board or advisory board of Advanced Accelerator Applications, Ipsen, and Merck & Co, Inc outside the submitted work. U. Anido Herranz reports payments for lectures from Ipsen and Merck & Co, Inc outside the submitted work. M. A. N. Şendur reports consulting fees and payments or honoraria from Astellas, AstraZeneca, Bristol Myers Squibb, Gilead, Janssen, Lilly, MSD, Novartis, Pfizer, Roche, and Takeda. G. Gravis reports research grants or contracts to his institution from Bristol Myers Squibb and Janssen; payments or honoraria to his institution for lectures, presentations, speaker's bureaus, manuscript writing, or educational events from Advanced Accelerator Applications, Alliance Merck-Pfizer, Amgen, Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, Ipsen, Janssen, MSD, Pfizer, and Sanofi; support for attending meetings and/or travel from AstraZeneca, Bayer, Bristol Myers Squibb, Ipsen, Janssen, MSD, and Pfizer; and participation on a data safety monitoring board or advisory board of Advanced Accelerator Applications, Alliance Merck-Pfizer, AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, Ipsen, Janssen, and Pfizer outside the submitted work. O. Huillard reports payments or honoraria to his institution for lectures, presentations, speaker's bureaus, manuscript writing or educational events from Advanced Accelerator Applications, Bristol Myers Squibb, Eisai, Ipsen, Janssen, MSD, Novartis, Pfizer, and Sanofi; and support for attending meetings and/or travel from Advanced Accelerator Applications and Ipsen outside the submitted work. R. Gafanov reports funding for the present manuscript from MSD; research grants or contracts to him and his institution from Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Ipsen, Jannsen, Pfizer, and Roche; payments or honoraria to him and his institution for lectures, presentations, speaker's bureaus, manuscript writing or educational events from Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Ipsen, Jannsen, Pfizer, and Roche; support for attending meetings and/or travel from Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Ipsen, Jannsen, Pfizer, and Roche; and participation on a data safety monitoring board or advisory board of Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Ipsen, Jannsen, Pfizer, and Roche outside the submitted work. F. Joly reports grants or contracts to her institution for ISS protocol from Ipsen; consulting fees paid to her for membership of scientific board of Esai Co, Ltd., Ipsen, and Pfizer; payment for lectures from Ipsen and Pfizer; and support for congress attendance from Esai Co, Ltd. and Ipsen. J. Bedke reports receiving medical writing support and local principal investigator payments to his institution for the present manuscript from MSD; local principal investigator payments to his institution from Astellas, AstraZeneca, Bristol Myers Squibb, Eisai, Ipsen, MSD, Nektar, Novartis, Pfizer, Roche, and Seagen; consulting fees from Apogepha, Astellas, AstraZeneca, Bristol Myers Squibb, Eisai, Ipsen, Janssen, Merck Serono, MSD, Pfizer, and Roche; payment or honoraria to him and his institution for lectures, presentations, speaker's bureaus, manuscript writing or educational events from Astellas, Bristol Myers Squibb, Ipsen, Merck Serono, MSD, Pfizer, Roche, and Seagen; support for attending meetings and/or travel from Ipsen and Merck & Co, Inc; payments to his institution for participation on a steering committee of Bristol Myers Squibb, MSD, and Seagen and participation on a data safety monitoring board or advisory board of MSD and Pfizer, outside the submitted work. K. Imai, B. Homet Moreno, and J. Z. Xu are employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc, Rahway, NJ, USA, and have stock in Merck & Co, Inc, Rahway, NJ, USA. A. Alva reports funding to his institution for the present manuscript from MSD and research grants or contracts to his institution from MSD. T. Powles reports grants or contracts from Astellas, AstraZeneca, Bristol Myers Squibb, Eisai, Exelixis, Gilead, Ipsen, Johnson & Johnson, Merck Serono, MSD, Novartis, Pfizer, Seattle Genetics, and Roche; consulting fees from Astellas, AstraZeneca, Bristol Myers Squibb, Eisai, Exelixis, Incyte, Ipsen, Johnson & Johnson, Mashup, Merck Serono, MSD, Novartis, Pfizer, Roche, and Seattle Genetics; and payment or honoraria for lectures, presentations, speaker's bureaus, manuscript writing or educational events from Astellas, AstraZeneca, Bristol Myers Squibb, Eisai, Exelixis, Incyte, Ipsen, Johnson & Johnson, Mashup, Merck Serono, MSD, Novartis, Pfizer, Roche, and Seattle Genetics; support for attending meetings and/or travel from Astellas, AstraZeneca, Gilead, Ipsen, MSD, Pfizer, and Roche; participation on a data safety monitoring board or advisory board of Astellas, AstraZeneca, Bristol Myers Squibb, Eisai, Exelixis, Ipsen, Johnson & Johnson, Merck Serono, MSD, Novartis, Pfizer, Roche, and Seattle Genetics; and other financial or nonfinancial interests as principal investigator for AstraZeneca, Eisai, MSD, Novartis, Pfizer, and Roche/Genentech, outside the submitted work. H. J. Lee, A. Sella, and Y.-H. Chang declare no competing interests., (Copyright © 2024. Published by Elsevier Inc.)

Introduction: KEYNOTE-361 evaluated first-line pembrolizumab with and without platinum-based chemotherapy versus chemotherapy alone in advanced or metastatic urothelial carcinoma. The primary end points of progression-free survival (PFS) or overall survival (OS) were not met. Exploratory analysis of efficacy by platinum agent (cisplatin or carboplatin) is reported., Patients and Methods: Eligible patients were randomly assigned 1:1:1 to receive pembrolizumab 200 mg intravenously every 3 weeks for ≤35 cycles with or without chemotherapy (gemcitabine with investigator's choice of either cisplatin or carboplatin) or chemotherapy alone. This exploratory subset analysis evaluated PFS and objective response rate (ORR) per RECIST v1.1 by blinded independent central review and OS for cisplatin- or carboplatin-based chemotherapy with versus without pembrolizumab for patients assigned to chemotherapy-containing arms of KEYNOTE-361., Results: Of 1010 patients enrolled, 703 were assigned to receive a chemotherapy-containing regimen (n = 312 cisplatin based; n = 391 carboplatin based). Median follow-up was 31.3 months. For cisplatin-based arms, with versus without pembrolizumab, median OS was 20.1 versus 16.4 months (HR 0.88, 95% CI, 0.67-1.15) and median PFS was 8.5 versus 7.1 months (HR 0.67, 0.51-0.89). ORR was 64.1% versus 48.7%, respectively. For carboplatin-based arms, with versus without pembrolizumab, median OS was 15.5 versus 12.3 months (HR 0.84, 95% CI, 0.67-1.06) and median PFS was 8.0 versus 6.7 months (HR 0.86, 0.68-1.09). ORR was 47.2% versus 41.8%, respectively. Among patients in the cisplatin-based versus carboplatin-based chemotherapy alone arms, 55.8% versus 41.8% received a subsequent antiprogrammed cell death protein 1/ligand 1 therapy. The addition of pembrolizumab did not significantly increase the incidence of adverse events reported., Conclusion: Results suggest trends toward OS and PFS improvements with the addition of pembrolizumab to gemcitabine-platinum doublet over gemcitabine-platinum alone regardless of whether cisplatin or carboplatin was the chosen platinum agent. OS may have been influenced by active subsequent therapies., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: This study explored prognostic differences between radical cystectomy (RC), tri-modality treatment (TURBt combined with radiotherapy and chemotherapy, TMT), electrocautery (EC) and partial cystectomy (PC) for T2N0M0 MIBC., Materials and Methods: Using SEER data (2004-2015, 2018-2020), we identified T2N0M0 MIBC patients treated with RC, TMT, EC, or PC. Propensity score matching (PSM, 1:1, caliper=0.1) minimized confounding. Kaplan-Meier analysis and Cox regression identified independent prognostic factors, stratified by tumor size and age., Result: This study included 6526 patients with T2N0M0 MIBC. Among them, 348(5.33%) underwent PC, 309(4.73%)underwent EC, 1833(28.09%)received TMT, and 4036(61.84%) RC. After 1:1 propensity score matching, RC showed improved CSS (HR=0.67, 95%CI 0.47-0.95 , and PC also benefited (HR=0.97, 95%CI 0.69-1.36) compared to EC. While TMT showed a worse end (HR=1.41, 95%Cl 1.03-1.92) compared to EC. Cox analysis was used to stratify tumor size and age for subgroup analysis. Results for tumor size subgroups were aligned with PSM findings. In the age-stratified subgroups, patients aged <67 years, both RC (HR=0.54, P=0.107) and TMT(HR=0.91, P=0.785) showed better prognoses compared to EC treatment, while PC treatment showed worse prognoses compared to EC treatment (HR=1.23, P=0.542).; for 68-77 years, RC(0.64, P=0.1436) and PC(HR=0.46, P=0.0283)had advantages, and PC is more recommended. For >78 years, RC had superior CSS over EC and PC, whereas TMT had the poorest prognosis., Conclusion: In clinical T2N0M0 MIBC, overall, RC outperformed focal-tumor therapy and PC, irrespective of tumor size. However, considering age, we recommend PC treatment for patients aged 68-77 and EC for those aged >78 years., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Photodynamic therapy (PDT) and radiotherapy using ionizing radiation (IR) are promising options for organ-preserving treatment of bladder cancer (BCa). A combination therapy (IR+PDT) could be beneficial for BCa treatment., Purpose: For PDT, we used the near-infrared photosensitizer tetrahydroporphyrin-tetratosylate (THPTS) showing high therapeutic efficacy. Treatment responses were analyzed in BCa organoids., Methods: Organoids consisting of BCa cells lines, bladder fibroblasts and muscle cells were treated with IR (9 Gy) and/or PDT using THPTS (25, 50 μM; 20 J/cm 2 ). Cytotoxicity was determined by microscopy, cell-based assays and histology. The cell death mode was analyzed by applying specific inhibitors followed by immunofluorescence or qPCR analyses of cell death markers. A matrix-based co-culture model was used to study T cell migration into the environment of treated organoids., Results: PDT and/or IR resulted in concentration-dependent reduction of metabolic activity, organoid diameter and integrity. Higher cytotoxicity of IR+PDT vs. monotherapies was observed after 72 h. Non-malignant organoids showed no cytotoxic effects. While apoptosis, necroptosis and ferroptosis were clearly involved in cell death of T-24 cells, cytotoxicity in RT-112 cells was probably provoked by apoptosis, ferroptosis and pyroptosis. IR+PDT resulted in significant migration of Jurkat cells into ECM-embedded organoids within 3 days after treatment., Conclusion: Treatment with IR+PDT showed tumor-selective cytotoxicity with additive or synergistic effects in BCa organoids. Thereby, IR+PDT led to multimodal cell death depending on the cellular context. Migration of T cells into the organoid environment illustrates the immunogenic potential of IR+PDT. Therefore, it might be a promising approach for organ-preserving BCa treatment., Competing Interests: Declaration of competing Interest The authors declare no conflicts of interest., (Copyright © 2024. Published by Elsevier B.V.)

Aims: Loss of heterozygosity in chromosome 9p21, common in urothelial carcinoma (UC), typically involves deletion of CDKN2A and MTAP genes. MTAP loss is emerging as a promising therapeutic target and predictive biomarker in UC. This single-centrre retrospective study examined the incidence of CDKN2A deletions and MTAP loss in muscle-invasive bladder cancer (MIBC) and metastatic urothelial carcinoma (mUC), investigating their correlations with clinical, pathological, and genomic features, as well as patient outcomes., Methods: Fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) were performed on 302 MIBC specimens and 63 biopsy-proven metachronous urothelial metastases to assess CDKN2A deletions and MTAP protein expression., Results: CDKN2A homozygous deletion (HD), identified in 30.3% of MIBCs, and MTAP loss, found in 28.8% of MIBCs, were both significantly associated with the luminal-URO subtype, FGFR3 mutations, and normal/wildtype p53 IHC (P < 0.05). Loss of MTAP expression was significantly correlated with CDKN2A HD, with 84.0% sensitivity, 92.3% negative predictive value (NPV), 96.3% specificity, and 91.9% positive predictive value (PPV). MTAP expression was 100% concordant between primary tumours and nodal metastases. Patients with MTAP loss had a higher incidence of visceral metastases (50%) compared to bone/soft tissue (35.7%) and nodes (14.3%). Mean progression-free survival and overall survival were shorter for patients with MTAP loss, although not statistically significant., Conclusion: Our findings highlight CDKN2A HD and MTAP loss as prevalent genetic alterations in MIBC and mUC, particularly within the luminal-URO subtype and FGFR3-mutated, p53-normal/wildtype tumours. MTAP IHC can serve as a surrogate marker for 9p21.3 HD, highlighting its clinical relevance and potential as a therapeutic target and predictive biomarker in MIBC., (© 2024 The Author(s). Histopathology published by John Wiley & Sons Ltd.)

Background: Muscle-invasive bladder cancer continues to lack reliable diagnostic and prognostic biomarkers. Recently, tumor vaccines targeting specific molecules have emerged as a promising treatment in inhibiting tumor progression, which was rekindled under the background of coronavirus disease-2019 pandemic. However, the application of mRNA vaccine targeting muscle-invasive bladder cancer-specific antigens remains limited, and there has been a lack of comprehensive studies or validations to identify suitable patient subgroups for vaccination. This study aims to explore novel muscle-invasive bladder cancer antigen signatures to identify patients most likely to benefit from vaccination., Methods: Gene expression profiles of muscle-invasive bladder cancer samples, along with corresponding clinical data, were retrieved from the Cancer Genome Atlas Program. The least absolute shrinkage and selection operator model was applied to develop signatures for stratifying muscle-invasive bladder cancer patients. Prognostic accuracy of each factor was assessed using receiver operating characteristic analysis. Tumor Immune Estimation Resource was employed to visualize the relationship between the proportion of antigen-presenting cells and the expression of selected genes. The CIBERSORT and WGCNA R packages were used to identify differences in immune infiltration levels across muscle-invasive bladder cancer subgroups. Additionally, the STRING database and Cytoscape were used to construct the protein-protein interaction network. CCK-8 and colony formation assays were employed in invitro experiments., Results: A total of 49 potential tumor antigens were identified. Using least absolute shrinkage and selection operator Cox regression, 14 tumor antigens were selected to develop a risk evaluation signature. The risk score signature can serve as a valuable tool for predicting the outcomes of muscle-invasive bladder cancer patients. Based on differential clinical, molecular, and immune-related gene profiles, muscle-invasive bladder cancer patients were classified into 2 subtypes: the immune "cold" subtype (immune score 1) and the immune "hot" subtype (immune score 2). The immune score signature, developed using a logistic score model, effectively distinguishes between patients more likely to belong to immune score 1 or 2. Notably, patients with a high risk score exhibited a higher proportion of immune score 2 compared to those with a low risk score. Additionally, the prognostic accuracy was significantly enhanced when the risk score and immune score were combined. Different tumor subtypes displayed distinct immune landscapes and signaling pathways. Moreover, novel tumor antigens associated with oxidative stress were identified., Conclusion: The risk score and immune score signatures based on tumor antigens have identified potential effective neo-antigens for the development of mRNA vaccines targeting muscle-invasive bladder cancer. Patients with low risk score and immune score 1 subtype are more likely to benefit from mRNA vaccination. Additionally, this study highlights the critical role of oxidative stress in modulating the efficacy of the mRNA vaccine., Competing Interests: Conflict of Interest/Disclosure The authors declare no potential conflicts of interest in terms of the research, authorship, and/or publication of this article., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Cisplatin-based chemotherapy is the recommended therapy for muscle-invasive bladder cancer (MIBC). However, the efficacy of MIBC for chemotherapy is only about 40%. Therefore, predictors of therapy response are urgently needed. Neutrophils form neutrophil extracellular traps (NETs), a network structure, and growing evidence indicated that it could be a prognostic and predictive marker in cancer. In MIBC, the predictive role of NETs in chemotherapy resistance is unclear. We used the Least Absolute Shrinkage and Selection Operator (LASSO) logistic regression analyses to develop a NETs-associated signature score (NETs-score) for therapeutic response prediction in the discovery cohort (GSE169455). Then the NETs score-based risk stratification was verified in two validation cohorts (Taber et al.'s cohort, our institutional cohort). In the training cohort, high NETs-score was associated with poor chemotherapy response (AUC = 0.781) and reduced recurrence-free survival (RFS) (hazard ratio [HR] = 2.07, 95% confidence interval [CI]: [1.26-3.40], p = 0.003) in MIBC patients. The NETs-score was also demonstrated to be a predictive factor for the efficacy of neoadjuvant chemotherapy in the validation cohort (AUC = 0.731). The accuracy of the NETs-score was superior to other chemotherapy response predictors such as Ba/Sq expression subtype (AUC = 0.711), BRCA2 mutation (AUC = 0.692) and ERCC2 mutation (AUC = 0.548). Furthermore, in our center cohort, the expression level of H3Cit showed a significant difference between the response and no-response group (p = 0.01). Through immunohistochemical validation, NETs was an independent predictor of MIBC neoadjuvant chemotherapy efficacy as determined by the multivariate logistic regression analysis (OR = 5.94, 95% CI: 1.20-45.50, p = 0.045). Patients with high levels of NETs predicted poor response to neoadjuvant chemotherapy. This study was the first to reveal the correlation between the level of NETs in MIBC and the efficacy of chemotherapy, which may provide a theoretical basis regarding NETs inhibitors., (© 2024 Wiley Periodicals LLC.)

Background and Objective: The 2024 US Food and Drug Administration approval of erdafitinib for the treatment of metastatic urothelial carcinoma (mUC) with FGFR3 alterations ushered in the era of targeted therapy for bladder cancer. In this review, we summarize the effects of FGFR pathway alterations in oncogenesis, clinical data supporting FGFR inhibitors in the management of bladder cancer, and the challenges that remain., Methods: Original articles relevant to FGFR inhibitors in urothelial cancer between 1995 and 2024 were systematically identified in the PubMed and MEDLINE databases using the search terms "FGFR" and "bladder cancer". An international expert panel with extensive experience in FGFR inhibitor treatment was convened to synthesize a collaborative narrative review., Key Findings and Limitations: Somatic FGFR3 alterations are found in up to 70% of low-grade non-muscle-invasive bladder cancers; these activate downstream signaling cascades and culminate in cellular proliferation. Beyond a link to lower-grade/lower-stage tumors, there is little consistency regarding whether these alterations confer prognostic risks for cancer recurrence or progression. FGFR3-altered tumors have been linked to a non-inflamed tumor microenvironment, but paradoxically do not seem to impact the response to systemic immunotherapy. Several pan-FGFR inhibitors have been investigated in mUC. With the introduction of novel intravesical drug delivery systems, FGFR inhibitors are poised to transform the therapeutic landscape for early-stage UC., Conclusions and Clinical Implications: With deepening understanding of the biology of bladder cancer, novel diagnostics, and improved drug delivery methods, we posit that FGFR inhibition will lead the way in advancing precision treatment of bladder cancer., (Copyright © 2024 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Context.—: Localized amyloidosis of the bladder is rare and often mimics bladder malignancy. It is typically associated with the extracellular deposition of monoclonal light chains, either κ or λ. The cause is unknown, but it is thought to be due to chronic inflammation/cystitis., Objective.—: To highlight the importance of localized urinary bladder amyloidosis as a rare mimicker of urothelial malignancy and elucidate its clinical, histopathologic, and cytopathologic manifestations., Design.—: Cases of urinary bladder amyloidosis diagnosed during 2000-2023 were retrieved retrospectively from pathology archives. Electronic medical records, including cystoscopy findings and pathology slides including Congo red stain, were reviewed., Results.—: Here we present 6 patients with localized urinary bladder amyloidosis. Four of the 6 patients were women, with ages ranging from 46 to 69 years, and a mean age of 58 years. Five of 6 patients presented with hematuria, while in 1 patient, bladder amyloidosis was discovered incidentally. Cystoscopy findings invariably were concerning for malignancy, with raised erythema in 5 patients and fungating mass protruding into the bladder lumen in 1 patient. Bladder biopsies and urine cytology were negative for malignancy in all cases. Congo red-positive amyloid deposits involved lamina propria with sparing of the detrusor muscle. In 5 cases, the deposits were typed as derived from the λ light chain, whereas no information was available for 1 patient. Subsequent clinical workup ruled out systemic amyloidosis., Conclusions.—: These cases of urinary bladder amyloidosis highlight the importance of considering rare amyloidosis in the differential diagnosis of hematuria and cystoscopy with a lesion mimicking malignancy., Competing Interests: The authors have no relevant financial interest in the products or companies described in this article., (© 2025 College of American Pathologists.)

Background: Few Bladder Cancer (BC) studies have examined the role of area-level variables. The purpose of this study was to examine racial differences in BC survival to elucidate if insurance status and contextual covariates could explain Black disadvantage in survival., Method: Using the Fine-Gray subdistribution hazard models (sHR), five-year survival time was calculated from the date of diagnosis until the last day of follow-up or the date of death due to BC in Florida 2000-2014 (n = 32,321). Non-BC deaths were considered a competing risk. In all models, individual-level clinical and demographic variables were adjusted for and we included the exposures of interest for Carcinoma-in-Situ (CIS) and Non-Muscle-Invasive BC(NMIBC), separately., Results: In CIS-Patients, living in neighborhoods with higher levels of segregation was associated with 50 % to 2-fold increase in sHR (medium level segregation sHR= 1.50, 95 % CI: 1.06-2.13; high level segregation sHR= 2.07, 95 % CI: 1.25-3.43). Uninsured CIS patients had more than 2-fold increased sHR compared to those with private insurance (sHR=2.34, 95 % CI: 1.05-5.24). In NMIBC patients, living in areas with level of poverty resulted in 10 % the hazard of death increased when compared to low poverty (high poverty sHR=1.11, 95 % CI: 1.01-1.21). Uninsured and Medicaid covered NMIBC patients had an increased sHR (uninsured sHR=2.05, 95 % CI: 1.62-2.59; Medicaid sHR=1.36, 95 % CI: 1.11-1.67). For both CIS and NMIBC patients, the Black/White survival gap decreased when insurance and contextual variables were included., Conclusion: This study identified BC survival rates were different for Black and White patients in Florida and found that those observed gaps were, to some extent, linked to broader social factors. We recommend that future cancer studies examining racial disparities incorporate area-level variables to offer a more nuanced understanding of these complex disparities., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: Neoadjuvant cisplatin-based chemotherapy followed by radical surgery is the standard treatment for muscle-invasive urothelial carcinoma (MIUC). The Checkmate-274 and AMBASSADOR trials have demonstrated improvements in disease-free survival (DFS) with adjuvant immunotherapy. Consequently, this meta-analysis aimed to assess the effectiveness of strategies involving checkpoint inhibitors in managing high-risk MIUC., Patients and Methods: We searched PubMed, Embase, Cochrane, ClinicalTrials.gov, EAU24, and ASCO GU abstracts for randomized controlled trials (RCTs) comparing adjuvant PD-1 and PD-L1 inhibitors against control (placebo or observation) for MIUC. Outcomes included DFS, grade ≥3 adverse events (AEs), and overall survival (OS). Heterogeneity was assessed using I2 statistics, employing a random-effects model for analysis., Results: In a cohort of 2220 patients from three RCTs, 1,113 (50.14%) underwent adjuvant immunotherapy. This treatment significantly increased DFS (HR 0.76; 95% CI, 0.65-0.90; P < .01), particularly in lower tract tumors (HR 0.71; 95% CI, 0.56-0.91; P < .01). No substantial DFS improvement surfaced in the upper tract subgroup (P = .28) (p-interaction = .01). PD-L1 status (p-interaction = .83) and previous neoadjuvant chemotherapy (p-interaction = .11) did not significantly affect outcomes. However, immunotherapy correlated with higher grade ≥3 AEs (RR 1.47; P < .01), with no notable difference in OS (P = .07)., Conclusions: Adjuvant PD-1/PD-L1 inhibitors notably enhance MIUC DFS, particularly in lower tract tumors, regardless of PD-L1 status. These findings support immunotherapy, especially anti-PD1, as a valuable adjuvant treatment strategy for high-risk MIUC patients., Competing Interests: Disclosure The authors have stated that they have no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Abnormal expression and function of histone deacetylases (HDACs) are closely associated with the development of bladder cancer (BCa). Systematic elucidation of the role of HDACs in BCa is expected to improve BCa prognosis and treatment strategies., Methods: We explored the correlation and expression patterns of HDAC family genes in BCa. Consensus clustering was employed to categorize BCa into subtypes based on HDAC expression profiles. Differential analysis, pathway enrichment analysis, and drug responsiveness evaluation were conducted to characterize HDAC subtypes. Then, a prognostic model based on HDAC cluster related genes was constructed and validated across multiple cohorts., Results: We identified distinct HDAC expression patterns and correlations with immune cell infiltration and enrichment of pathways in cancer, highlighting their role in BCa. Consensus clustering revealed 2 HDAC gene subtypes. Gene cluster 1 showed worse survival, higher clinical stage, and lower immune cell infiltration compared to gene cluster 2. Additionally, pathway enrichment analysis revealed differences in tumor-promoting pathways between the clusters. Moreover, gene cluster 1 exhibited higher resistance to Rho kinase inhibitor drugs. Multi-omic analysis unveiled unique mutation and CNV profiles between the clusters, indicating distinct molecular features. Furthermore, a HDAC gene-related prognostic model demonstrated robust predictive accuracy and identified EMP1 as a key prognostic gene associated with poor survival and enriched metastatic pathways., Conclusion: Our study provides comprehensive insights into the landscape of HDACs in BCa, elucidating their roles in tumor heterogeneity, immune modulation, drug responsiveness, and molecular features. EMP1 is a potential therapeutic target and prognostic marker for BCa., Competing Interests: Disclosure The authors have stated that they have no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Real-world outcomes, especially patterns of failure, are limited for patients with muscle-invasive bladder cancer (MIBC) treated with trimodality therapy (TMT). We aim to evaluate patterns of failure after TMT for MIBC in a typical heterogeneous population., Methods: In the national Veterans Affairs database, patients with urothelial histology, MIBC (T2-4a/N0-3/M0) who underwent definitive intent TMT between 2000-2018. Successful TMT was defined as ≥ 50% definitive radiation dose and ≥ 1 cycle chemotherapy. Endpoints of any recurrence, metastatic (nonbladder) recurrence (MR), and local (bladder) recurrence (LR) evaluated in multivariable Fine-Gray models. Times to recurrence calculated from radiation start date., Results: In 347 patients with MIBC treated with TMT, 65% of patients were deemed ineligible for surgery while 35% were surgically eligible but elected for TMT. Median follow-up time was 77 months. Median overall survival was 32.4 months (95% CI: 28.2-36.7). 154 (44%) patients had no recurrence. 130 (37%) patients developed MR, median time 9.9 months. 117 (34%) patients developed LR, median time 8.7 months. In multivariable models, lymph node positive (LN+) disease (HR:3.31, 95% CI: 1.45-7.55, P < .01) and pretreatment hydronephrosis (HR:1.62, 95% CI:1.11-2.36, P = .01) were associated with higher rates of MR. No patient, tumor, or treatment variables were associated with LR., Conclusions: Across a multi-institutional and heterogeneous population, TMT is an effective treatment for many real-world patients with MIBC. However, a notable proportion of patients develop MR and/or LR which emphasizes the need for post-treatment surveillance and improved treatment pathways. Identified high risk features (LN+ disease, pretreatment hydronephrosis) and other markers should be further investigated to delineate the patients at high risk of TMT failure who therefore may potentially benefit from augmented treatment, such as additional systemic therapy., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: 1L PBC has historically been recommended for patients with la/mUC. Maintenance avelumab is recommended for patients without disease progression following 1L PBC. Real-world data on the proportion of patients eligible for maintenance avelumab are limited, and outcomes among patients ineligible for maintenance avelumab are uncertain. This study assessed the proportion of patients with la/mUC initiating 1L PBC who were maintenance-avelumab eligible and real-world outcomes following 1L PBC by maintenance-avelumab eligibility., Methods: A retrospective, observational study was conducted using a longitudinal electronic health record-derived database comprising de-identified patient-level structured and unstructured data including adults with Ia/mUC who received ≥1 dose of 1L PBC (April 2020-January 2022). The proportion of patients eligible for maintenance avelumab (real-world stable disease, partial response, or complete response following 1L PBC) was estimated and median overall survival (mOS) assessed for maintenance avelumab-eligible and -ineligible patients., Results: Of 336 patients with Ia/mUC treated with 1L PBC (55.4% received cisplatin-based treatment 44.6% carboplatin-based treatment); 181 (54%) were maintenance-avelumab eligible; and 138 (41%) maintenance-avelumab ineligible (17 [5%] were nonevaluable). Of 181 maintenance-avelumab-eligible patients, 67 (37.0%; 19.9% of all 1L PBC-treated patients) received maintenance avelumab. mOS (95% CI) among all 1L PBC-treated patients was 15.0 (12.2-19.6) months and among maintenance-avelumab-ineligible patients was 8.0 (6.7-10.3) months; whereas among maintenance-avelumab-eligible patients (including 37% who received maintenance avelumab), mOS was 27.6 (23.4-not reached) months., Conclusions: In this study, approximately half of 1L PBC-treated patients were maintenance-avelumab eligible, and one-fifth received it. Real-world OS remains short for the overall 1L PBC-treated population. These results support the use of treatment-guideline preferred 1L treatment options that demonstrate survival benefit for all patients with la/mUC, and are available to patients irrespective of their eligibility for cisplatin, or response to PBC., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To report real-world outcomes for high-risk non-muscle-invasive bladder cancer (HRNMIBC), including bacillus Calmette-Guérin (BCG) and radical cystectomy (RC), as randomised comparisons of these have not been possible., Methods: We detail consecutive participants screened for the BRAVO randomised controlled trial comparing RC with BCG (International Standard Randomised Controlled Trial Number [ISRCTN]12509361). Patients were prospectively registered and case-note review used for outcomes. The primary outcome was overall survival. Secondary outcomes included recurrence, progression, metastasis, and bladder cancer-specific survival., Results and Limitations: A total of 193 patients were screened, including 106 (54.9%) who received BCG, 43 (22.3%) primary RC, 37 (19.2%) 'other' treatment and seven (3.6%) hyperthermic intravesical mitomycin C. All-cause death occurred in 55 (28.5%) patients at median (interquartile range [IQR]) of 29.0 (19.5-42.0) months. In multivariable analysis, overall mortality was more common in older patients (hazard ratio [HR] 2.63, 95% confidence interval [CI] 1.35-5.13; Cox P = 0.004 for age >70 years), those recruited from district hospitals (HR 0.53, 95% CI 0.3-0.95; P = 0.032) and those who did not undergo RC as their first treatment (HR 2.16, 95% CI 1.17-3.99; P = 0.014). In all, 17 (8.8%) patients died from bladder cancer (BC) at median (IQR) of 22.5 (19-36.25) months. In multivariable analysis, BC-specific mortality was more common in older patients (HR 4.87, 95% CI 1.1-21.6; P = 0.037) and those with Tis/T1 disease (HR 2.26, 95% CI 1.23-4.16; P = 0.008) but did not vary with initial treatment., Conclusions: Patients with HRNMIBC are at high-risk of mortality. Those choosing RC as their initial treatment have lower risks of mortality than others, although this may reflect fitness and selection., (© 2024 The Author(s). BJU International published by John Wiley & Sons Ltd on behalf of BJU International.)

Purpose: We evaluate the efficacy and safety of UGN-102 chemoablation for the primary treatment of patients with recurrent low-grade intermediate-risk nonmuscle-invasive bladder cancer., Materials and Methods: ENVISION is an ongoing, multinational, single-arm, phase 3 study in patients with a biopsy-proven recurrence of untreated low-grade intermediate-risk nonmuscle-invasive bladder cancer. Patients received 6 weekly intravesical instillations of UGN-102 (mitomycin; outpatient setting) and were evaluated at 3 months. Patients achieving complete response (CR; negative cystoscopic examination, cytology, and for-cause biopsy) were surveilled regularly until recurrence, progression, or death. Patients who remain disease-free will be followed up to 5 years, and further results will be reported in the future., Results: Of 240 patients enrolled, 228 (95%) received all 6 planned doses; 191 (80%; 95% CI, 73.9-84.5) achieved CR at 3 months, with an 82% (95% CI, 75.9-87.1) probability of response 12 months later. Median duration of response was not estimable over a median 13.9-month follow-up period. The most common adverse events (≥5.0% of patients) were dysuria, hematuria, UTI, pollakiuria, fatigue, and urinary retention; generally mild/moderate and resolved/resolving. Serious adverse events were observed in 29/240 (12.1%); 2 were treatment related (urinary retention/urethral stenosis), and both resolved., Conclusions: Primary chemoablation with UGN-102 in patients with recurrent low-grade intermediate-risk nonmuscle-invasive bladder cancer resulted in an 80% CR rate. Patients achieving a CR had an 82% likelihood of remaining disease-free 1 year later. The benefit-risk profile was favorable, supporting UGN-102 as a nonsurgical alternative for transurethral resection of bladder tumors in this patient population. Limitations of this study included lack of tumor sizing after the diagnostic biopsy., Trial Registration: ClinicalTrials.gov Identifier: NCT05243550.

Background: In recent years, our understanding of the genesis and development of urothelial carcinomas (UC) has expanded considerably thanks to advancing molecular classifications. These advances have led to significant changes in the 5th edition of the WHO classification of tumors of the urinary tract and male genitalia. The new findings allow both the introduction of modern diagnostic approaches and a return to proven methods in the evaluation of precursor lesions and non-invasive carcinomas., Aims: This article is intended to provide a summarized overview of the various precursor lesions and pathways of urothelial carcinoma., Results and Discussion: The changes and clarifications in the 5th edition of the WHO classification reflect the progress made in the molecular and morphological characterization of urothelial carcinomas. These adjustments provide an improved basis for diagnosis and treatment and emphasize the importance of differentiated molecular profiles for the classification and treatment of UC. Despite all this, conventional histology remains the gold standard for the diagnosis and classification of non-invasive carcinomas and precursor lesions., Competing Interests: Einhaltung ethischer Richtlinien. Interessenkonflikt: F. Lange gibt an, dass kein Interessenkonflikt besteht. A. Hartmann: Honorare von Abbvie, AstraZeneca, Biontech, BMS, Boehringer Ingelheim, Cepheid, Diaceutics, Ipsen, Janssen, Lilly, MSD, Nanostring, Novartis, Roche, 3DHistotech; Beratungsgebühren von Abbvie, AstraZeneca, Biontech, BMS, Boehringer Ingelheim, Cepheid, Diaceutics, Gilead, Illumina, Ipsen, Janssen, Lilly, MSD, Nanostring, Novartis, Qiagen, QUIP GmbH, Roche, 3DHistotech; Forschungsförderung von AstraZeneca, Biontech, Cepheid, Gilead, Illumina, Janssen, Nanostring, Qiagen, QUIP GmbH, Roche. M. Eckstein: Honorare und Reisekosten von MSD, AstraZeneca, Janssen-Cilag, Cepheid, Roche, Astellas, Diaceutics, Owkin, BMS; Forschungsförderung von AstraZeneca, Janssen-Cilag, STRATIFYER, Cepheid, Roche, Gilead, Owkin, QUIP GmbH; Beratungsgebühren von Diaceutics, MSD, AstraZeneca, Janssen-Cilag, GenomicHealth, Owkin, BMS. Für diesen Beitrag wurden von den Autor/-innen keine Studien an Menschen oder Tieren durchgeführt. Für die aufgeführten Studien gelten die jeweils dort angegebenen ethischen Richtlinien., (© 2024. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Background: After failure of first-line chemotherapy, standard of care for advanced urothelial cancer (aUC) is immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1 pathway. Several prognostic models (Bajorin and Bellmunt scores) have been evaluated, but only in the context of chemotherapy., Objective: To study whether the variables in these scores and new emerging clinical and biological criteria have an impact on the probability of objective response in aUC treated with ICIs in 2nd-line setting and beyond., Materials and Methods: Between October 2016 and March 2023, we included 168 patients treated with ICIs in 2nd-line setting or more in 2 French centers. Variables of interest were selected after a literature review and collected retrospectively. Analyses used log-rank test and multivariate models (binary logistic and Cox regressions)., Results and Limitations: Median age at diagnosis was 68 years. Patients presented with bladder tumors in 73.8% and upper urinary tract tumors in 26.2%. 63.7% of patients had received only one line of chemotherapy before ICIs. Median follow-up after starting ICIs was 8.9 months. The variables statistically associated with objective response were: - The presence of locally advanced or lymph node-only disease compared with visceral involvement (adjusted Odds Ratio 0.19, 95% confidence interval [0.06-0.55], P = .002) and bone-only involvement (aOR 0.22 [0.08-0.64], P = .005) - The absence of antibiotic therapy the month before/after ICIs initiation (aOR 0.31 [0.12-0.84], P = .021). Limitations included retrospective design and small number of patients included., Conclusion: This real-life study from 2 French centers found a higher likelihood of objective response: - In the absence of antibiotic therapy at ICIs initiation: - In locally advanced or lymph node-only disease, in contrast to visceral or bone-only disease. Our results suggest that negative impact of antibiotic therapy on the response to ICIs needs to be further investigated to optimize the management of these patients., Competing Interests: Disclosure The authors declare no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: To quantify the oncological risks of bladder-sparing therapy (BST) in patients with Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle-invasive bladder cancer (NMIBC) compared to upfront radical cystectomy (RC)., Patients and Methods: Pre-specified data elements were collected from retrospective cohorts of patients with BCG-unresponsive NMIBC from 10 international sites. After Institutional Review Board approval, patients were included if they had BCG-unresponsive NMIBC meeting United States Food and Drug Administration criteria. Oncological outcomes were collected following upfront RC or BST. BST regimens included re-resection or surveillance only, repeat BCG, intravesical chemotherapy, systemic immunotherapy, and clinical trials., Results: Among 578 patients, 28% underwent upfront RC and 72% received BST. The median (interquartile range) follow-up was 50 (20-69) months. There were no statistically significant differences in metastasis-free survival, cancer-specific survival, or overall survival between treatment groups. In the BST group, high-grade recurrence rates were 37% and 52% at 12 and 24 months and progression to MIBC was observed in 7% and 13% at 12 and 24 months, respectively. RC was performed in 31.7% in the BST group and nodal disease was found in 13% compared with 4% in upfront RC (P = 0.030)., Conclusion: In a selected cohort of patients, initial BST offers comparable survival outcomes to upfront RC in the intermediate term. Rates of recurrence and progression increase over time especially in patients treated with additional lines of BST., (© 2024 The Author(s). BJU International published by John Wiley & Sons Ltd on behalf of BJU International.)

Background: Therapeutic modalities used in bladder lesions/neoplasms (electrocautery, fulguration, and laser) could produce morphologic alterations leading to diagnostic challenges. While often seen on histology, they can present in urine cytology as atypia or even raise the concern for malignancy. Herein, we present clinicopathologic findings of four patients with cautery artifact in urine cytology., Methods: The authors' lists and a computerized search of urine cytology with features of thermal cautery artifact were collated. Slides and clinicopathologic variables (prior specimens, concurrent and follow-up surgical specimens, age, sex, manner of urine collection, cystoscopy, and treatment procedure during cystoscopy) were reviewed., Results: Four cases were identified. Procedures performed during cystoscopy included laser therapy (n = 2), postbiopsy cauterization (n = 1), and fulguration (n = 1). All cases showed spindled cells with delicate bipolar cytoplasm, "cigar-shaped" nuclei, smooth to slightly irregular nuclear membranes, and arranged singly and loosely cohesive to lamellar stacks. Few atypical well-preserved, undistorted cells were identified in 2/4. The concurrent biopsies showed superficial cellular fragments with thermal artifact (n = 1) and rare atypical cells (n = 2). Follow-up biopsies in two cases had high-grade urothelial carcinoma both of which were diagnosed as atypical urothelial cells on cytology., Conclusion: Thermal cautery artifact in urine cytology is rare and can be seen following laser, electrocautery, and fulguration. The spindling artifact can render some degree of difficulty in assessing for the presence of urothelial atypia both in cytology and biopsy. Familiarity with these cytologic features, knowledge of the treatment procedure, attention to the cytologic findings of well-preserved cells and repeat sampling in cases with atypical urothelial cells in patients with history of malignancy is essential., (© 2024 The Author(s). Diagnostic Cytopathology published by Wiley Periodicals LLC.)

Non-muscle-invasive bladder cancer (NMIBC) often recurs and can progress to MIBC due to resistance to treatments like intravesical chemotherapy or Bacillus Calmette-Guérin (BCG). Therefore, we established the Gemcitabine-Resistant Cells (GRCs) to study the molecular evolution under external pressure. A 63-gene Chemoresistance-Motility (CrM) signature was created to identify stage-specific traits of GRCs. This signature was tested on 1846 samples using log-rank tests and Cox regression to evaluate clinical utility. Early and intermediate resistance stages showed increased cell motility and metastatic potential. FAK, PI3K-AKT, and TGFβ pathways were activated first, followed by MAPK signaling. Single-cell analysis and experiments utilizing the CrM signature confirmed interaction with cancer-associated fibroblasts (CAFs). The high-CrM groups mainly included NMIBC patients with poor prognosis (progression-free survival analysis by log-rank test based on UROMOL cohort, p < 0.001), T1-high grade, high European Association of Urology (EAU) risk score, and also included MIBC patients with a history of metastases. Additionally, relative ineffectiveness was observed for BCG (the chi-square test based on BRS cohort, p = 0.02) and immune checkpoint inhibitors (ICIs) in patients with high-CrM. In addition, we identified five drugs that can be used with gemcitabine in these patients, including doxorubicin, docetaxel, paclitaxel, napabucacin, and valrubicin, and verified their efficacy. This study provides insights into NMIBC progression to MIBC via molecular evolution. The CrM signature can assess NMIBC prognosis and BCG treatment response, suggesting alternative treatments. Furthermore, these results need to be prospectively validated., 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 The Authors. Published by Elsevier B.V. All rights reserved.)

Promoting ferroptosis in tumor cells has emerged as a promising strategy for cancer therapy. Nonetheless, the heightened antioxidant activity within tumor cells hampers this approach, diminishing its effectiveness and fostering drug resistance. In this study, a new type of sulfasalazine (SAS) loaded nanoframe self-etched Pt-Co nanodendrites (Pt/Co-BNN@SAS) was developed, presenting a novel avenue for inducing ferroptosis in tumor cells by depleting glutathione (GSH) for cancer treatment. Pt/Co-BNN exhibits notable peroxidase (POD) activity, catalyzing the production of abundant oxygen radicals through the consumption of hydrogen peroxide (H 2 O 2 ) and the concurrent depletion of GSH. Simultaneously, the liberated sulfasalazine (SAS) from Pt/Co-BNN@SAS effectively obstructs system xc - , impeding the absorption of cystine by tumor cells and thereby expediting GSH depletion. The expeditious reduction of GSH markedly stimulates the accumulation of lipid peroxides (LPO) and suppresses glutathione peroxidase 4 (GPX4), consequently triggering ferroptosis in bladder cancer cells and inhibiting the migration ability of bladder cancer cells effectively. This research contributes to a more profound comprehension of nano-drug-biological interactions and provides a prospective outlook on treating bladder cancer by instigating ferroptosis in tumor cells through GSH depletion., 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 B.V.)

Objective: Recent preclinical and retrospective clinical evidence shows that androgen receptor (AR)-mediated signals have significant roles in development of non-muscle invasive bladder cancer (NMIBC). Here, we conducted a single-center, phase I study to assess the feasibility and efficacy of enzalutamide in patients having recurrent NMIBC with marker tumors. Patients with NMIBC who cannot achieve complete transurethral resection (TUR) or with recurrence within a year after the TUR, were enrolled. The patients were administered oral enzalutamide at 160 mg dose, once daily for four weeks. Clinical response at the end of the treatment was evaluated using cystoscopy., Results: Of the six patients enrolled, two experienced multiple recurrences. All the patients received the planned administration of enzalutamide. Enzalutamide was tolerable and all patients were able to complete the planed treatment, although four patients experienced mild treatment-related adverse events (AEs), but AEs with grade 2 or more were not observed. As for efficacy, three patients showed no change while the remaining three showed disease progression. Immunohistochemical analysis did not showed the strong staining of AR in the latest tumors. This is the first clinical study on enzalutamide treatment for NMIBC patients. In this study, four weeks of enzalutamide administration was well tolerated, however showed no clinical response for non-strong staining of AR., Trial Registration: University Hospital Medical Information Network UMIN000026520 (date registration: 2017/3/13)., Competing Interests: Declarations. Ethics approval and consent to participate: The protocol was approved by the Internal Review Board of the Tsukuba University Hospital (approval number: H28-260). Patients provided written, informed consent that included the right to opt out at any time. This trial was registered at the University Hospital Medical Information Network Clinical Trials Registry (UMIN000026520). Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Objective: Given the increasing significance of digital health literacy (DHL) and health literacy (HL) in promoting informed decision-making and healthy behaviors, this study aimed to assess the influence of self-reported HL and DHL on treatment adherence and quality of life among patients who underwent transurethral resection of bladder tumors (TUR-BT) for primary non-muscle invasive bladder cancer (NMIBC)., Materials & Methods: This single-center observational study involved patients who underwent TUR-BT for NIMBC at a tertiary hospital from May 2022 to February 2024. Before the procedure, the patients' DHL and HL were evaluated using the European Health Literacy Survey Questionnaire short version and the eHealth Literacy Scale. Six months after surgery, we surveyed patients' QoL using the EORTC QLQ-C30. In line with recommendations from the European Association of Urology guidelines, adherence to the treatment plan was assessed along with a follow-up cystoscopy examination for each patient., Results: Multivariate analysis revealed that poorer DHL and HL were significantly associated with older age (p < 0.001), lower educational attainment (p < 0.001), and lack of internet access (p < 0.001). Conversely, higher DHL and HL levels were positively correlated with increased treatment adherence, as measured by cystoscopy completion (p < 0.001). Additionally, logistic regression analysis demonstrated significant associations between improved DHL and HL scores and better global health status (DHL, p = 0.022; HL, p = 0.008), higher emotional status (p < 0.001 for both), and social functioning (p < 0.001 for both). Notably, there were no significant differences in the symptom scale scores between the DHL and HL groups., Conclusion: To the best of our knowledge, this is the first study to explore the specific effect of HL/DHL on QoL and adherence in this patient population. Our research suggests that there may be a link between self-reported levels of DHL/HL and treatment adherence as well as QoL among patients with NIMBC., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Background: The progression of bladder cancer (BC) from non-muscle-invasive bladder cancer (NMIBC) to muscle-invasive bladder cancer (MIBC) significantly increases disease severity. Although the tumor microenvironment (TME) plays a pivotal role in this process, the heterogeneity of tumor cells and TME components remains underexplored., Methods: We characterized the transcriptomes of single cells from 11 BC samples, including 4 NMIBC, 4 MIBC, and 3 adjacent normal tissues. Bulk RNA-seq data were used to validate the clinical features of characteristic cells, and protein levels of these cells were further confirmed through immunohistochemistry (IHC) and multiplex immunofluorescence., Results: Bladder cancer progression was associated with distinct transcriptomic features in the TME. Tumor cells in MIBC displayed enhanced glycolytic activity and downregulation of chemokines and MHC-II molecules, reducing immune cell recruitment and facilitating immune evasion. This highlights glycolysis as a potential therapeutic target for disrupting tumor progression. We identified a T cell exhaustion pathway from naive CD8 + T cells (CD8 + TCF7) to terminally exhausted CD8 + STMN1 cells, with progressively declining immune surveillance. Targeting intermediate exhaustion states may restore T cell function and improve anti-tumor immunity. Macrophages polarized toward a pro-tumorigenic phenotype, while VEGFA + mast cells promoted angiogenesis in early-stage BC, suggesting their role as potential targets for therapeutic intervention in NMIBC. Furthermore, conventional dendritic cells (DCs) transformed into LAMP3 + DCs, contributing to an immunosuppressive microenvironment and enabling immune evasion., Conclusion: This study reveals dynamic changes in the TME during BC progression, including enhanced glycolysis, T cell exhaustion, and immune cell remodeling, which contribute to immune evasion and tumor progression. These findings identify critical pathways and cell populations as potential therapeutic targets, offering new strategies to improve treatment outcomes in BC patients., Competing Interests: Declarations. Ethics approval and consent to participate: All scRNA-seq data of patients were approved by the Institutional Review Board of Tongji Medical College, Huazhong University of Science and Technology (IRB: S116). Consent for publication: Not applicable. Competing interests: The authors have no competing interests., (© 2025. The Author(s).)

Objective: This systematic review was conducted to synthesize current research on the role of repeated transurethral resection of the bladder (re-TURB) and the emerging use of magnetic resonance imaging (MRI) in discerning patient suitability for safely foregoing this procedure., Evidence Acquisition: Employing a methodical literature search, we consulted several bibliographic databases including PubMed, Science Direct, Scopus, and Embase. The review process adhered strictly to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA 2020) guidelines., Evidence Synthesis: We evaluated data from 667 patients (mean age 65.8 years; age range 59-75 years) who underwent MRI prior to potential re-TURB. The gap between initial TURB and MRI was reported as 42 days in one study, while the interval between MRI and subsequent cystoscopy, with or without biopsy, varied from 21 days to 3 months. Initial TURB pathology for non-muscle invasive bladder cancer (NMIBC) patients identified stage Ta in 177 (42.5%) and T1 in 246 (57.5%) patients across three studies. High-grade and low-grade pathologic classifications were reported in 377 (64.5%) and 207 (35.5%) patients respectively in two studies. The VI-RADS scoring system's sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for the detection of bladder cancer recurrence were 89%, 85.5%, 82.7%, and 96%, respectively. A total of 365 patients (54.7%) underwent re-TUR. Among NMIBC patients, re-TUR pathology revealed Ta in 22 cases (5.4%) and pT1 in 179 cases (44%) with VI-RADS 1-2, while no cases of Ta (0%) and 37 cases of T1 (9%) were reported with VI-RADS 4-5, as documented in two studies. Notably, only 69 patients (10.7%) were identified as having MIBC across all studies., Conclusion: MRI is demonstrating reliability as a diagnostic tool for non-muscle invasive bladder cancers. The VI-RADS scoring system appears to be a promising approach in selecting patients for re-TURB. DW-MRI may serve as a primary diagnostic examination for patient follow-up post-TURB., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2025. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: Bladder cancer is a malignant neoplasm with increasing incidence rates. LncRNAs play an important role in cancer, including development, prognosis, and response to therapies. It is known that lncRNA SBF2-AS1 was associated with cell proliferation and worse prognosis in various tumor types, but its role remains incompletely understood in bladder cancer. In this context, our objective was to evaluate the effect of lncRNA SBF2-AS1 silencing on bladder cancer cells., Methods: J82 and UM-UC-3 high-grade bladder tumor cells were treated with two siRNAs specific for SBF2-AS1 to evaluate cytotoxicity, clonogenic survival, morphology, cell migration, and cell cycle progression., Results: Expression inhibition of SBF2-AS1 resulted in cytotoxicity, morphological changes, and decreased clone formation and cell migration. Cell cycle alterations were not observed., Conclusion: Our study revealed that SBF2-AS1 plays an oncogenic role and holds promise as a potential target for the treatment of bladder cancer., 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 Transitional cell bladder carcinoma (tcBC) is the predominant form of bladder cancer, making up around 95% of reported cases. Prognostic factors for older individuals with tcBC differ from those affecting younger patients. The main purpose of this study was to establish a prognostic competing risk model for elderly patients with tcBC. MATERIAL AND METHODS We conducted a retrospective analysis using data from the SEER database, randomly assigning patients to training and validation groups. We applied proportional subdistribution hazard (SH) to assess risk factors for cancer-related mortality (CSM). A competitive risk model was created to predict cancer-specific survival in elderly patients with tcBC. Model validation involved evaluating the area under the receiver operating curve, the consistency index, and a calibration curve. The Kaplan-Meier (K-M) curve was then used to compare mortality risk between high-risk and low-risk groups identified by the model. RESULTS This study randomly assigned 61 293 patients from the SEER database into training (42 905 patients) and validation (18 388 patients) groups in a 7: 3 ratio. Using a proportional subdistribution hazards model, we identified prognostic risk factors such as age, race, sex, marital status, TNM staging, grade, and metastatic status in brain, bone, liver, and lung. We developed a competitive risk model to predict 5-year cancer-specific survival (CSS) in elderly tcBC patients, achieving consistency index (C-index) values of 0.814 and 0.815 for the training and validation groups, respectively. Kaplan-Meier (K-M) analysis revealed 5-year survival probabilities of 35.1% (high-risk) and 42.2% (low-risk) in the training group, with similar rates of 35.7% and 42.0% in the validation group, both showing statistically significant differences (log-rank P<0.01). CONCLUSIONS We successfully established a competitive risk model for forecasting cancer-specific survival in elderly tcBC patients, primarily relying on these identified risk factors. The validation outcomes indicate the model's accuracy and dependability, making it a highly efficient predictive instrument. This tool enables making personalized clinical decisions for both medical professionals and patients.

Urinary Bladder Cancer (UBC) ranks among the most prevalent cancers worldwide, has a high recurrence rate and unpredictable treatment responses. Thus, biomarkers are urgently needed. Extracellular vesicles (EVs) are released from both cancer- and immune cells and provide a snapshot of the originating cell. They are abundant in urine and are therefore candidate biomarkers for UBC. Isolated urinary EVs from 39 UBC patients were compared with EVs from healthy controls, prostate cancer patients and whole urine. Samples were from bladder urine at time of both transurethral resection of the bladder tumour (TURB) and cystectomy, as well as urine taken from the ureter at cystectomy. EVs were isolated by tangential flow filtration and differential ultracentrifugation and their protein composition was detected by Proximity Extension Assay (PEA; Olink, immuno-oncology panel). In UBC patients, the proteomic signature of bladder urine EVs differed from ureter urine EVs from the same individuals, and from bladder urine derived EVs of both healthy and prostate cancer controls. Pairwise comparison was performed with matched whole urine revealing proteins solely detected in isolated vesicles. Additionally, a distinct signature was identified in bladder urine EVs correlating with muscle invasiveness, and a trained classifier could predict UBC with 92 % accuracy. Some differentially expressed proteins, HO-1 and MMP7, were analysed by bead-based flow cytometry, where HO-1 was detected on the EV surface. Taken together, these results strengthen the rationale of using EVs as non-invasive biomarkers and prognostic tools for UBC., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Susanne Gabrielsson has a patent on B cell derived exosomes in immune therapy and is part of the Scientific Advisory Board of Anjarium Biosciences. The other authors don't have any additional competing interests., (Copyright © 2024. Published by Elsevier B.V.)

Purpose: As Bladder EpiCheck ® (BE) is a promising urinary biomarker for diagnosis and follow up of non-muscle-invasive bladder cancer (NMIBC), there are no studies evaluated this tool for second transurethral resection (TUR) indication. We aim to evaluate the performance of BE in predicting residual tumor before second TUR in NMIBC and its effects on clinical decision making., Methods: A total of 50 patients who were diagnosed with NMIBC and indicated for a second TUR were included in the study prospectively. The urine sample taken one day before the second TUR operation was evaluated with BE and the results were compared with second TUR pathologies., Results: The mean age was 65.3 and 45 of the patients were male. Specificity and negative predictive value of BE in primary tumor stage Ta were 100% and 87.5% while in primary tumor stage T1 were 71.4% and 68.2%, respectively. The specificity and negative predictive value of BE were 77.8% and 75%, respectively, in patients with high grade primary tumor. When all NMIBC were evaluated, the specificity and negative predictive value of BE were found to be 78.6% and 73.3% for second TUR, respectively. As an independent predictor of residual tumor in this group, positivity rates of BE were higher in T1 (p < 0.037) and high grade (p < 0.002) tumors., Conclusions: BE may be useful in detecting residual tumor before second TUR and benefit in clinical decision making with high specificity and negative predictive value. These results encourage the use of BE to reduce number of unnecessary second TUR procedures. It may improve cost effectivity and quality of life as high numbered studies are needed to support these views and to incorporate BE into clinical practice., Competing Interests: Declarations. Ethics approval: The protocol for this research has been approved by Clinical Research Ethics Commitee of the University of Health Sciences, Istanbul Bagcilar Training and Research Hospital, decision number 2019.10.2.01.074. All methods were carried out in accordance with relevant guidelines and regulations of Helsinki declaration. Consent to participate: Written informed consent was obtained from the participants included in the study. Competing interests: The authors declare no competing interests., (© 2025. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)