BackgroundPatients with non–muscle-invasive bladder cancer (NMIBC) face high recurrence rates and a substantial risk of progression to muscle invasive disease. Although observational studies suggested a link between body size and NMIBC outcomes, inconsistent evidence leaves its role as a modifiable prognostic factor uncertain. We investigated the associations of body size and related metabolic and inflammatory traits with NMIBC outcomes using genetically predicted values in a Mendelian randomization (MR) framework. MethodsWe used data from our genome-wide association study (GWAS) consortium for NMIBC outcome (N 5,008). Causal associations of body-mass index (BMI), waist-hip ratio (WHR), WHR adjusted for BMI (WHRadjBMI), and selected metabolic and inflammatory traits (fasting insulin, insulin-like growth factor-1 (IGF-1), leptin, adiponectin, and C-reactive protein (CRP)) with recurrence and progression were studied using (1) individual data MR based on genetic risk scores (GRS) with Cox proportional hazards models and (2) summary data MR. ResultsGRS for all body size traits showed no statistically significant association with NMIBC recurrence or progression. Higher genetically predicted fasting insulin was associated with increased recurrence risk, whereas higher genetically predicted CRP was associated with reduced recurrence risk; none of these markers showed associations with progression. Results from individual and summary data MR analyses were concordant, and sensitivity analyses supported the robustness of the findings. ConclusionOur results do not support the hypothesis that body size measures BMI and WHR are modifiable determinants of NMIBC prognosis. Additional research into uncovering a potential causal relation between fasting insulin and NMIBC outcome is warranted.

BACKGROUND AND OBJECTIVE:Cystoscopy is a core component of haematuria investigations; however, it is invasive and resource intensive. GALEAS Bladder is a DNA-based diagnostic urine test that measures mutations in 23 bladder cancer (BC)-associated genes. OBJECTIVE:We aimed to assess the diagnostic performance of GALEAS Bladder in real-world patients with haematuria and its utility as a molecular triage tool in this setting. METHODS:Patients referred for urgent investigation of haematuria were prospectively enrolled across seven UK National Health Service urology departments between October 2024 and June 2025. Urine samples were collected prior to cystoscopy and analysed by GALEAS Bladder. Assay results were compared with cystoscopy and biopsy/transurethral resection of bladder tumour findings. KEY FINDINGS AND LIMITATIONS:Cystoscopic findings and GALEAS Bladder results were available for 964 participants (575 visible and 294 non-visible haematuria, 95 unknown), including 77 (8.0%) newly diagnosed with pathology-confirmed BC. The assay detected 71 of the 77 BCs, including all 17 muscle-invasive BCs and 35 of the 36 high-grade BCs, with negative predictive value >99% (95% confidence interval [CI] 98-100), positive predictive value 50% (95% CI 42-58), positive likelihood ratio (LR) 11.5, and negative LR 0.09. Decision curve analysis showed net benefit over cystoscopy for all referrals. Limitations include observational study design over a limited timeframe and absence of subsequent diagnoses for participants with positive GALEAS Bladder test results without cystoscopically visible tumour. CONCLUSIONS AND CLINICAL IMPLICATIONS:GALEAS Bladder is a clinically implementable molecular urine test that detects new cases of BC with high negative predictive value and favourable LRs in patients undergoing urgent investigation of haematuria. These data show that GALEAS Bladder can be used now to triage patients with haematuria to immediate or deferred cystoscopy.

Background Cystoscopy is a core component of haematuria investigations but is invasive and resource-intensive. GALEAS™ Bladder is a DNA-based diagnostic urine test that measures alterations in 23 bladder cancer-associated genes. Objective To assess the diagnostic performance and clinical utility of GALEAS™ Bladder as a molecular triage tool in real-world haematuria investigation pathways. Methods Patients referred for urgent investigation of haematuria were prospectively enrolled across seven UK NHS Urology Departments between October 2024 and June 2025. Urine samples were collected prior to cystoscopy and analysed using the GALEAS™ Bladder assay (Nonacus Clinical Services, UK). Assay results were compared with cystoscopy findings. Key Findings and Limitations Cystoscopic findings and GALEAS™ Bladder results were available for 964 participants, including 77 (8.0%) newly-diagnosed with pathology-confirmed BC. The assay demonstrated an overall sensitivity of 92.2% (95% CI: 84.0-96.4%), specificity of 92.0% (95% CI: 90.0-93.6%), and negative predictive value (NPV) of 99.3% (95% CI: 98.4-99.7%) for the diagnosis of BC. For the diagnosis of high-grade BCs, sensitivity was 97.2% (95% CI: 85.8-99.5%) with an NPV of 99.9% (95% CI:99.3-100.0%). Limitations include an absence of subsequent diagnoses for participants with positive GALEAS™ Bladder test results in the absence of cystoscopically-visible tumour. Conclusions and Clinical Implications GALEAS™ Bladder is a clinically implementable molecular urine test with very high sensitivity and specificity for the diagnosis of new cases of BC in patients undergoing urgent investigation of haematuria, especially for high-grade BCs. Clinical adoption could permit the molecular triage of haematuria patients to immediate or deferred cystoscopy. ### Competing Interest Statement DGW and RTB co-developed the GALEAS™ Bladder urine test with Nonacus Ltd (UK). RTB is a paid consultant for Cystotech ApS (Denmark) and an unpaid charity trustee for Action Bladder Cancer UK (UK). LS, RKH, SC, RS, MP, MS and VH are employees of Nonacus. ### Funding Statement Nonacus Ltd ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: IRBs of Royal Berkshire Hospital waived ethical approval for this work IRBs of Leeds General Infirmary Hospital waived ethical approval for this work IRBs of Kingston & Richmond NHS Foundation Trust waived ethical approval for this work IRBs of Western General Hospital, The University of Edinburgh waived ethical approval for this work IRBs of University Hospitals of Leicester waived ethical approval for this work IRBs of Dorset County Hospital waived ethical approval for this work IRBs of Manchester Royal Infirmary waived ethical approval for this work I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors

Non-muscle invasive bladder cancer (NMIBC) is a biologically and clinically heterogeneous disease, accounting for approximately 75% of bladder cancer cases. Over the past decade, multiple RNA-based molecular classification systems for NMIBC have been proposed, demonstrating associations with tumor stage, grade, prognosis, and treatment response. However, unlike muscle-invasive bladder cancer, a unified consensus classification for NMIBC is lacking, limiting clinical translation and cross-study comparability. To address this gap, the first NMIBC Consensus Classification Meeting was convened in November 2024 at Erasmus University Medical Center, bringing together 13 international experts from seven countries representing major NMIBC molecular classification efforts. This report summarizes the discussions, comparative evaluation of existing classification systems, and the agreed strategy towards developing a consensus molecular model. The meeting focused on harmonizing heterogeneous transcriptomic datasets, integrating RNA sequencing and microarray platforms, and assessing the applicability of classification models across tumor stages (Ta/T1) and grades. Key features, strengths, and limitations of the Lund Taxonomy, Leeds, Birmingham, UROMOL, and Rotterdam (BCG response) subtypes were critically examined. Building on prior experience from the muscle-invasive bladder cancer consensus, participants agreed on a centroid-based clustering framework using rigorously defined core samples to derive stable consensus subtypes and a single-sample classifier with associated probability scores. A large, curated dataset encompassing approximately 2500 NMIBC samples from published cohorts will facilitate model development and validation. The resulting consensus classification aims to improve biological understanding, facilitate reproducibility across studies, and enable future evaluation of prognostic and therapeutic relevance, including response to intravesical BCG therapy.

Background:The latest bladder cancer (BC) urine tests based on multiple genomic and/or epigenomic markers detect BC with high sensitivity and specificity. The GALEAS Bladder (GB) gene panel covers several actionable mutations, including in FGFR3. Objective:To modify GB to detect FGFR3 fusions as well as single nucleotide variants and assess its potential as a urine-based companion diagnostic. We also study tissue-urine concordance and associations between FGFR3 genomic alterations and FGFR3 expression. Methods:Probes were added to GB covering the 3'-region of FGFR3. The new panel was used to analyse genomic DNA extracted from 158 frozen primary BCs. Mutation concordance was also analysed in 107 tumour-urine pairs. Associations between FGFR3 mutations and expression were analysed in 608 FFPE BCs with the Decipher Bladder transcriptome assay. Results and limitations:FGFR3-TACC3 fusions were found in 3/3 positive controls and 4/158 frozen BCs. Fusions were also detectable in genomic DNA from FFPE tumour and urine cell pellet DNA. All fusions were corroborated by PCR and Sanger sequencing. FGFR3 mutation status in urine was 94.4% concordant (95% CI 87.7-97.7%); GB detected mutations in urine with 92.1% sensitivity (95% CI 81.7-97.0%) at 97.7% specificity (95% CI 86.5-99.9). All FGFR3 mutations were associated with increased FGFR3 expression. This is a proof-of-principle study, rather than definitive evidence of utility as a companion diagnostic, with the need for fusion detection validation in larger patient cohorts. Conclusions:In addition to BC detection, a modified version of GB demonstrates feasibility for tissue and urine-based detection of FGFR3 fusions.

BACKGROUND AND AIMS:Bladder cancer (BC) is a global health burden, with an estimated 614,000 new cases and 220,000 deaths in 2022. While diet influences BC progression, the association between dietary inflammatory potential and BC prognosis remains unclear. This study investigated the association using the empirical dietary inflammatory pattern (EDIP) score in the Bladder Cancer Prognosis Programme (BCPP) cohort. METHODS:We included 1016 newly diagnosed BC patients (2005-2011) and assessed baseline and 3-month post-treatment EDIP scores using food frequency questionnaires. Multivariate Weibull regression models analyzed the associations between pre- and post-treatment EDIP and its dynamic changes with progression-free survival (PFS), overall survival (OS) and cancer specific survival (CSS). RESULTS:A higher baseline EDIP score (more pro-inflammatory diet) was significantly associated with poorer outcomes in muscle-invasive BC (MIBC) patients (PFS: HRcontinuous EDIP= 1.82, 95% CI: 1.11-3.00; OS: HRcontinuous EDIP= 2.03, 95% CI: 1.21-3.41) and those aged >70 years (PFS: HR Q5 vs Q1= 1.51, 95% CI: 1.06-2.17; OS: HR Q5 vs Q1= 1.99, 95% CI: 1.26-3.13). Post-treatment EDIP alone showed no significant associations with BC prognosis. However, in non-muscle-invasive BC (NMIBC) patients, a shift from low to high post-treatment EDIP increased poor PFS risk (HRLow/High= 1.57, 95% CI: 1.06-2.32), and persistently high EDIP elevated poor OS risk (HRHigh/High= 2.02, 95% CI: 1.03-3.97) versus consistently low EDIP. No significant EDIP-related associations with CSS were observed. CONCLUSION:Pro-inflammatory diets at diagnosis may worsen PFS and OS in MIBC patients and those aged >70 years. Dynamic post-treatment EDIP changes may impact NMIBC prognosis, highlighting the need for personalized dietary strategies tailored to BC subtype and age to improve survival.

Hepatocyte growth factor activator inhibitor type-1 (HAI-1) plays pivotal roles in epithelial integrity and tumour biology. Although implicated in various malignancies, its expression profile and prognostic value in bladder cancer (BC) remain incompletely defined. High levels of HAI-1 ectodomain in urine have previously been reported to be associated with poor prognosis in BC patients. This study aimed to determine the relationships between tissue and urine levels of HAI-1 and clinical outcomes in BC. This study used immunohistochemistry to measure HAI-1 expression across 770 BCs of all stages and grades. HAI-1 expression was scored on the basis of the percentage of positive cancer cells, subcellular localisation, and staining intensity. Additionally, HAI-1 (SPINT1) mRNA expression was compared with protein levels in tissue and urine. HAI-1 was highly expressed in low-grade, early-stage disease with strong membranous staining. Reduced overall HAI-1 expression, loss of membranous staining and increased cytoplasmic staining correlated with higher stage and grade and shorter survival. SPINT1 mRNA levels were positively correlated with membranous HAI-1 staining intensity (p = 0.005). Urinary levels of HAI-1 were negatively associated with the fraction of HAI-1 positive cancer cells and membranous staining intensity (p < 0.05). A positive correlation was observed between SPINT1 expression and urinary HAI-1 levels (p < 0.05). The Urobasal A subtype had lower urinary HAI-1 ectodomain levels than other subtypes. HAI-1 expression may serve as a biomarker of tumour differentiation and prognosis in BC. Increased ectodomain shedding into the urine, rather than increased expression, likely explains the higher urine HAI-1 levels seen in more aggressive tumours.

BACKGROUND:Patients with non-muscle invasive bladder cancer (NMIBC) frequently experience recurrence and may progress to muscle-invasive disease. Although several common germline variants associated with bladder cancer risk have been identified, their prognostic value in NMIBC remains unclear. We performed an updated genome-wide association study (GWAS), incorporating additional cohorts and analysing multiple NMIBC recurrences, to identify germline genetic variants associated with recurrence and progression. METHODS:We analysed eight cohorts (N = 5009) from the Netherlands, UK, Canada, and Spain. Cohort-specific GWAS were conducted using Cox regression for recurrence-free survival (RFS) and progression-free survival (PFS), including recurrent-event analysis and gene-based analyses. Analyses included chromosome X and were stratified by sex and Bacillus Calmette-Guérin (BCG) treatment. Previously reported variants for bladder cancer risk and prognosis were also evaluated. RESULTS:We observed 4237 recurrences, of which 2145 were first recurrences, and 742 cases of progression in stage and/or grade. No genome-wide significant associations were identified in the overall population, chromosome X, or sex-stratified analyses. In BCG-treated patients, two loci reached genome-wide significance for RFS, with the strongest signal for rs72744118, an intron variant in DISP-1 (HR = 0.43; 95% CI (0.32, 0.56), p = 5.8 × 10-10). Gene prioritization identified 101 candidate genes from SNP associations (p < 1 × 10-6) and colocalization analyses, of which 16 genes showed nominally significant association between gene expression and NMIBC outcome in UROMOL. CONCLUSIONS:In the largest GWAS of NMIBC prognosis to date, we prioritized a set of 16 genes. Future research should independently validate the prognostic and functional roles of identified genes.

Pentadecanoic acid (PEA), an odd-chain fatty acid derived from diet by the gut microbiome, has garnered increasing attention for its systemic health-promoting properties. Its potential role in bladder cancer (BC) occurrence and invasion, however, remains unclear. Large-scale cohorts’ analyses were performed to assess the association between dietary PEA and BC occurrence and invasion. In vitro and in vivo experiments, including EJ and T24 BC cell assays and a BBN-induced mouse model, were conducted to experimentally assess the impact of PEA on BC. Serum proteomics, gut microbiome, and targeted fecal lipidomics analyses were employed to explore the underlying mechanisms. Dietary PEA was negatively associated with BC occurrence and invasion in cohort analyses. PEA suppressed EJ and T24 BC cell migration, invasion, and proliferation, while inhibiting BC development in a BBN-induced mouse model. In vivo serum proteomics identified differentially expressed lipid-related proteins (e.g., Apoe and Apob) following PEA treatment, implicating its modulation of lipid metabolism pathways. Considering the essential role of the gut-bladder axis, the gut microbiome analysis exhibited that PEA markedly altered bacteria (e.g., g_Alistipes) and fungi (e.g., o_Erysiphales, g_Teberdinia, and g_Gibberella), with concomitant lipid metabolism changes. Furthermore, targeted fecal lipidomics demonstrated the shifts in key lipids, such as phosphatidylethanolamines (PE) involved in essential lipid clusters, suggesting regulation by gut microbiome linked to BC development. Collectively, our findings demonstrate that PEA mitigates BC by reshaping the gut microbiome and modulating lipid metabolism, providing new insights into its molecular and therapeutic potential. This study aims to investigate the effects of PEA on BC occurrence and invasion using multi-dimensional approaches. We found PEA showing the protective effect on BC based on large-scale cohorts, in vitro and in vivo experiments. This observation may be mediated by the gut microbiome’s involvement in the lipid-metabolism pathway, potentially highlighting a gut-bladder axis in BC. Abbreviations: PEA, pentadecanoic acid; BC, bladder cancer; BCPP, Bladder Cancer Prognosis Programme; CCK-8, Cell Counting Kit-8; DIA MS, Data-Independent Acquisition Mass Spectrometry; 16S rRNA, 16S ribosomal RNA; ITS, Internal Transcribed Spacer; LC-MS/MS, Liquid Chromatography-Tandem Mass Spectrometry; PE, phosphatidylethanolamine.

Urine-based tumour DNA detection enables non-invasive profiling of urological malignancies and may also inform on distant cancers via trans-renal cell-free DNA. However, limited large-scale validation and standardization of urinary cell-free DNA biomarkers constrain their clinical use, highlighting the need for a reporting framework. We therefore propose the ‘minimal urine methods in experiments’ (MUMIE) framework. Urine-based tumour DNA detection enables non-invasive profiling of urological malignancies and may inform on distant cancers via trans-renal cell-free DNA (cfDNA). Here the authors propose the ‘minimal urine methods in experiments’ (MUMIE) framework to enhance validation and standardization of urinary cfDNA biomarkers.

Non-invasive urine tests for bladder cancer (BC) could reduce dependence on flexible cystoscopy for diagnosis and surveillance. Most recent developments in urine testing are based on targeted detection of genomic and/or epigenomic markers. We hypothesised that long-read whole-genome sequencing of urinary DNA with direct methylation profiling may allow accurate BC detection and insights into disease biology. However, the feasibility of such an approach has not yet been reported. We applied long-read whole-genome sequencing with direct methylation detection to urine cell pellet DNA (ucpDNA) from 21 haematuria clinic patients: 13 BCs and 8 non-BCs. The modkit Hidden Markov Model algorithm was used to define differentially methylated regions across the genome. The ability to discriminate between BC and non-BC, and the cellular pathways affected were tested using PCA, h-clust and GSEA. We observed global hypomethylation and cancer-specific patterns of promoter hypermethylation in urine from BC patients. Sequencing of a single ucpDNA sample per flow cell yielded read depths of 18-34x; furthermore, BC methylation patterns were also evident with 2–5x multiplex sequencing. Copy number changes were also evident in ucpDNAs from BC patients. A limitation of the study is the small number of samples analysed; however, the detection of cancer-specific events demonstrates the feasibility of the approach, both in single and multiplexed flow-cell runs. Even at low-read depths, genome-wide methylation patterns in urinary DNA reflect the presence of BC, potentially permitting rapid, non-invasive and cost-effective BC detection.

Bladder cancer is a common malignancy of the urinary tract [1], with occupational exposure the second most common modifiable risk factor after smoking [2]. Individuals involved in bomb disposal may be at risk of bladder cancer as explosive compounds such as nitro-aromatics can be derivatives of benzene or amines [3, 4]. Such individuals include ammunition technicians (AT) within the British Army (the mainstay of high-threat bomb disposal in the UK), where the risk of bladder cancer remains unknown and the association between exposure to explosives and bladder cancer is undetermined. As a profession, AT personnel are exposed to potential carcinogens found in bulk explosives, their precursors, their detonation and degradation products, and the residue from the combustion of pyrotechnic compositions, ammunition, and associated packaging [5]. Pathways to exposure include inhalation, absorption, and ingestion. Hence, we sought to investigate the association between exposure to explosives and bladder cancer risk within the AT profession. With ethical approval (University of Wales Trinity Saint David ethics reference EC1273 PG2), we used a questionnaire to survey the veteran AT network given security implications associated with the participation of serving individuals. The questionnaire (which can be made available upon request) was based upon up-to-date epidemiological evidence of risk factors [2] and sought to elucidate cancer occurrences. Veteran ATs with known contact details were approached on social media by the Felix Fund Bomb Disposal Charity between 1 March and 31 May 2024. The veteran cohort comprised 688 AT who had served within one particular Explosive Ordnance Disposal (EOD) squadron since 1970, representing 30% of the 2300 soldiers known to have trained and served to date (the largest possible sample size available). In this EOD squadron, AT personnel would have been exposed to all modalities of ammunition management prior to appointment, which includes manufacture, storage, inspection, maintenance, and disposal. Given the vast array of explosives managed by the ATs, it was necessary to limit the scope of the survey. As such, nitro and nitramine explosives were highlighted as representative groups given that they are the most common explosives encountered within the global ordnance, munitions and explosives stockpile [6]—all serving and veteran ATs are exposed to them. Responses to the survey were extracted and tabulated using descriptive statistics (Table 1). Standardised incidence ratios (SIRs) and 95% CIs for bladder cancer were then calculated by comparing the incidence in the AT cohort with the UK general population [7]. We received 203 responses to the survey (30% of those 688 veterans approached). Of all cancers diagnosed within respondents, bladder cancer accounted for 27% (prostate, 22%; testicular, 4%; colon/bowel, 13%; throat, 4%; ureteric, 2%; myelodysplastic syndrome, 2%; and skin, 24%). In respondents with a bladder cancer diagnosis, a higher proportion reported weekly exposure to nitro-aromatic explosives during their career (67%) than in other cancer (24%) and no cancer respondents (16%); a similar relationship was observed for weekly exposure during EOD tasks (42%, 21% and 28%, respectively). Using the whole cohort of 688 to compare bladder cancer incidence with the UK general population, SIRs showed increased occurrence of bladder cancer amongst AT (SIRs for age 50–59 years: 7.27, 95% CI 2.33–22.55; age 60–69 years: 3.42, 95% CI 1.30–9.10). Three-quarters of bladder cancers were diagnosed below the age of 70 years, representing an SIR of 5.03 (95% CI 2.62–9.67) vs the UK general population below the age of 70 years [7]. Pathological details were known for 10/12 respondents with bladder cancer —all these tumours were high-grade non-muscle-invasive bladder cancer (NMIBC; five) or muscle-invasive bladder cancer (MIBC; five). This is the first UK study to quantify the association between exposure to certain groups of explosives and bladder cancer (BC). SIRs indicate an excess of BC occurrence, representing 27% of cancer diagnoses in ATs, a considerable excess compared to the UK general population [7]. Smoking is another contributor to BC risk, and BC cases from this study were either ex-smokers (50%) or non-smokers (50%) compared with other cancer cases (3% smokers, 61% ex-smokers, 36% non-smokers) and the no cancer group (2% smokers, 54% ex-smokers, 44% non-smokers). Hence, smoking does not appear to be the principal cause of the BC excess amongst this group. In addition, two younger diagnoses (age <40 years) may be linked to schistosomiasis (one veteran) or other causes (one, length of service <5 years). Male preponderance was expected given that females did not join the AT profession until 2001. This small dataset does not permit robust multivariate analyses of risk factors and is indicative. Future studies should collect detailed information on a larger number of participants, as well as potential confounders, to provide more precise CIs. However, the difference in BC risk between AT respondents and the UK general population appears to be profound. If we were to assume that the remainder of the 2300 veteran/non-veteran AT who have served in the squadron were within the no cancer group, our findings still demonstrate an excess of BC (SIRs for age 50–59 years: 2.17, 95% CI 1.17–4.05; age 60–69 years: 1.02, 95% CI 0.28–3.68). However, we are unable to account for attrition due to death in service, from cancer, or other diseases within that cohort. When assessing the types of explosive exposures, weekly exposure to nitro-explosives during disposal was 2.8-times more frequent for those diagnosed with BC compared to those diagnosed with other cancers. This suggests that exposure to ammunition at end of useful service life, degraded/unsafe ammunition, or the products of detonation (gaseous, particulate, or within the soil medium of demolition areas [8]) is indicative of increased risk. These procedures align with activities subjectively characterised as higher risk by AT military heads of service, as many nitro-explosive precursors and their metabolites are closely related to known bladder carcinogens (e.g., aromatic amines and polycyclic aromatic hydrocarbons). Notably, ATs also deal with homemade explosives, synthesised from a variety of harmful chemical precursors, as well as military or commercial explosives. This survey presents the first quantitative data for a small but vital profession to the UK's national security and highlights an urgent need for further investigations into military exposure to explosives and the risk of BC. Regular exposure to nitro-explosives is associated with high incidence rates, especially for those AT between the ages of 50 and 69 years, with a median length of 25 years from first exposure to BC diagnosis. Therefore, safe exposure levels should be established by duty holders to inform the protection and post-exposure monitoring of all military personnel. Although the AT profession is inherently dangerous, the longer-term risks for veterans worldwide should not be ignored. Since completion of this initial survey, two further AT veterans have been diagnosed with BC, taking the number of known cases amongst 688 individuals to 14. Gareth Collett is an unpaid charity trustee for the Felix Fund Bomb Disposal Charity and former head of the UK Bomb Disposal Profession. Richard T. Bryan receives research funding from Cancer Research UK (CRUK), Wellcome Trust (UK) and Janssen (European Union), is a paid consultant for Informed Genomics Limited (UK) and Cystotech (Denmark) and is an unpaid charity trustee for Action Bladder Cancer UK (UK). Mieke Van Hemelrijck receives funding from CRUK, the European Organisation for Research and Treatment of Cancer (EORTC, Belgium), Bayer (Germany), National Institute for Health Research (UK), Medical Research Council (UK), Guy's Cancer Charity (UK), Royal Marsden Cancer Charity (UK), and Movember Foundation (Australia). She is an unpaid member of the Board of the EORTC.

PURPOSETransurethral resection of bladder tumor (TURBT) is the initial staging procedure for new bladder cancers (BCs). For muscle-invasive bladder cancers (MIBCs), TURBT may delay definitive treatment. We investigated whether definitive treatment can be expedited for MIBC using flexible cystoscopic biopsy and multiparametric magnetic resonance imaging (mpMRI) for initial staging.PATIENTS AND METHODSWe conducted a prospective open-label, randomized study conducted within 17 UK hospitals (registered as ISRCTN 35296862). Participants with suspected new BC were randomly assigned 1:1 to TURBT-staged or mpMRI-staged care, with minimization factors of sex, age, and clinician visual assessment of stage. Blinding was not possible. Patients unable/unwilling to undergo mpMRI or with previous BC were ineligible. The study had two stages with separate primary outcomes of feasibility and time to correct treatment (TTCT) for MIBC, respectively.RESULTSBetween May 31, 2018, and December 31, 2021, 638 patients were screened, and 143 participants randomly assigned to TURBT (n = 72; 55 males, 15 MIBCs) or initial mpMRI (n = 71; 53 males, 14 MIBCs). For feasibility, 36 of 39 (92% [95% CI, 79 to 98]) participants with suspected MIBC underwent mpMRI. The median TTCT for participants with MIBC was significantly shorter with initial mpMRI (n = 12, 53 days [95% CI, 20 to 89] v n = 14, 98 days [95% CI, 72 to 125] for TURBT, log-rank P .02). There was no detriment for participants with non-MIBC (median TTCT: n = 30, 17 days [95% CI, 8 to 25] for mpMRI v n = 28, 14 days [95% CI, 10 to 29] for TURBT, log-rank P = .67). No serious adverse events were reported.CONCLUSIONThe mpMRI-directed pathway led to a 45-day reduction in TTCT for MIBC. Incorporating mpMRI ahead of TURBT into the standard pathway was beneficial for all patients with suspected MIBC.

BACKGROUND AND OBJECTIVE:Intravesical therapy is central to managing non-muscle-invasive bladder cancer (NMIBC); yet, recurrence and progression remain common, underscoring the need for new treatments. This systematic review evaluates clinical trials of novel intravesical therapies for all risk categories of NMIBC. METHODS:A comprehensive literature search was conducted to identify the clinical trials assessing the effectiveness, safety, and tolerability of intravesical therapies for NMIBC. The search focused on studies published from 2020 to 2024, including trials on bacillus Calmette-Guérin (BCG)-unresponsive/refractory disease as well as on BCG-naïve and intermediate-risk patients. Mechanisms of action and drug delivery methods were summarized. No statistical syntheses were performed due to limited comparative data. KEY FINDINGS AND LIMITATIONS:Out of 2998 studies identified, 36 reported on efficacy and safety, and six provided patient-reported outcomes (PROs). Intravesical therapies included BCG-based therapies, chemotherapy combinations, chemical-drug conjugates, thermogels, hyperthermic chemotherapy, osmotic pumps, and gene therapy. Initial response rates ranged from 42% to 85% for BCG-unresponsive/refractory patients and from 65% to 100% for treatment-naïve patients. The 12-mo recurrence-free survival rates ranged from 22% to 83% and 39% to 92%, respectively. Progression and severe toxicity (grade ≥3) were rare (0-17% and 0-20%, respectively). PROs were stable. The limitations included early-phase studies, heterogeneous outcome assessments, and a need for research on long-term durability, comparative effectiveness, quality of life, and cost. CONCLUSIONS AND CLINICAL IMPLICATIONS:This systematic review highlights the promising efficacy and tolerability of novel intravesical therapies for NMIBC. However, further research is needed to refine treatment strategies and assess long-term outcomes, quality of life, and economic factors. Future studies should include multiarm, multistage designs with a focus on patient-centered outcomes.