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Background: Urothelial bladder cancer (UBC) is characterised by a high risk of recurrence. Patient monitoring is currently based on iterative cystoscopy and on urine cytology with low sensitivity in non-muscle-invasive bladder cancer (NMIBC). Telomerase reverse transcriptase (TERT) is frequently reactivated in UBC by promoter mutations. Methods: We studied whether detection of TERT mutation in urine could be a predictor of UBC recurrence and compared this to cytology/cystoscopy for patient follow-up. A total of 348 patients treated by transurethral bladder resection for UBC were included together with 167 control patients. Results: Overall sensitivity was 80.5% and specificity 89.8%, and was not greatly impacted by inflammation or infection. TERT remaining positive after initial surgery was associated with residual carcinoma in situ . TERT in urine was a reliable and dynamic predictor of recurrence in NMIBC ( P <0.0001). In univariate analysis, TERT positive-status after initial surgery increased risk of recurrence by 5.34-fold ( P =0.0004). TERT positive-status was still associated with recurrence in the subset of patients with negative cystoscopy ( P =0.034). Conclusions: TERT mutations in urine might be helpful for early detection of recurrence in UBC, especially in NMIBC.

Non-muscle-invasive bladder cancer (NMIBC) is a highly recurrent tumor despite intravesical immunotherapy instillation with the bacillus Calmette-Guérin (BCG) vaccine. In a prospective longitudinal study, we took advantage of BCG instillations, which increase local immune infiltration, to characterize immune cell populations in the urine of patients with NMIBC as a surrogate for the bladder tumor microenvironment. We observed an infiltration of neutrophils, T cells, monocytic myeloid-derived suppressor cells (M-MDSCs), and group 2 innate lymphoid cells (ILC2). Notably, patients with a T cell-to-MDSC ratio of less than 1 showed dramatically lower recurrence-free survival than did patients with a ratio of greater than 1. Analysis of early and later time points indicated that this patient dichotomy existed prior to BCG treatment. ILC2 frequency was associated with detectable IL-13 in the urine and correlated with the level of recruited M-MDSCs, which highly expressed IL-13 receptor α1. In vitro, ILC2 were increased and potently expressed IL-13 in the presence of BCG or tumor cells. IL-13 induced the preferential recruitment and suppressive function of monocytes. Thus, the T cell-to-MDSC balance, associated with a skewing toward type 2 immunity, may predict bladder tumor recurrence and influence the mortality of patients with muscle-invasive cancer. Moreover, these results underline the ILC2/IL-13 axis as a targetable pathway to curtail the M-MDSC compartment and improve bladder cancer treatment.

Collagen type 4 alpha 1 (COL4A1) and collagen type 13 alpha 1 (COL13A1) produced by urothelial cancer cells support the vital oncogenic property of tumor invasion. We investigated the diagnostic and prognostic capability of COL4A1 and COL13A1 in voided urine and compared the observed values with those of fragments of cytokeratin‐19 (CYFRA21‐1), nuclear matrix protein 22 (NMP‐22), and voided urine cytology in bladder cancer (BCa). We collected voided urine samples from 154 patients newly diagnosed with BCa, before surgery and from 61 control subjects. Protein levels of COL4A1, COL13A1, CYFRA21‐1, and NMP‐22 in urine supernatants were measured using enzyme‐linked immunosorbent assays. Diagnostic performance and optimal cut‐off values were determined by receiver operating characteristic analysis. Urine levels of COL4A1, COL13A1, the combined values of COL4A1 and COL13A1 (COL4A1 + COL13A1), and CYFRA21‐1 were significantly elevated in urine from patients with BCa compared to the controls. Among these biomarkers, the optimal cut‐off value of COL4A1 + COL13A1 at 1.33 ng/mL resulted in 57.4%, 83.7%, 56.1%, 80.7%, and 91.7% sensitivity for low‐grade tumors, high‐grade tumors, Ta, T1, and muscle invasive disease, respectively. We evaluated the prognostic value of preoperative urine levels in 130 non‐muscle invasive BCa samples after the initial transurethral surgery. A high urinary COL4A1 + COL13A1 was found to be an independent risk factor for intravesical recurrence. Although these data need to be externally validated, urinary COL4A1 and COL13A1 could be a potential diagnostic and prognostic biomarker for BCa. This easy‐to‐use urinary signature identifies a subgroup of patients with a high probability of recurrence and progression in non‐muscle invasive and muscle invasive BCa. This study demonstrated the diagnostic and prognostic performance of urinary collagens in comparison with those of CYFRA21‐1, NMP‐22, and voided urine cytology in bladder cancer. This easy‐to‐use urinary signature identifies a subgroup of patients with high probability of recurrence and progression in non‐muscle invasive disease..

Abstract Context Urine steroid metabolomics, combining mass spectrometry-based steroid profiling and machine learning, has been described as a novel diagnostic tool for detection of adrenocortical carcinoma (ACC). Objective, Design, Setting This proof-of-concept study evaluated the performance of urine steroid metabolomics as a tool for postoperative recurrence detection after microscopically complete (R0) resection of ACC. Patients and Methods 135 patients from 14 clinical centers provided postoperative urine samples, which were analyzed by gas chromatography–mass spectrometry. We assessed the utility of these urine steroid profiles in detecting ACC recurrence, either when interpreted by expert clinicians or when analyzed by random forest, a machine learning-based classifier. Radiological recurrence detection served as the reference standard. Results Imaging detected recurrent disease in 42 of 135 patients; 32 had provided pre- and post-recurrence urine samples. 39 patients remained disease-free for ≥3 years. The urine “steroid fingerprint” at recurrence resembled that observed before R0 resection in the majority of cases. Review of longitudinally collected urine steroid profiles by 3 blinded experts detected recurrence by the time of radiological diagnosis in 50% to 72% of cases, improving to 69% to 92%, if a preoperative urine steroid result was available. Recurrence detection by steroid profiling preceded detection by imaging by more than 2 months in 22% to 39% of patients. Specificities varied considerably, ranging from 61% to 97%. The computational classifier detected ACC recurrence with superior accuracy (sensitivity = specificity = 81%). Conclusion Urine steroid metabolomics is a promising tool for postoperative recurrence detection in ACC; availability of a preoperative urine considerably improves the ability to detect ACC recurrence.

The acidic tumor microenvironment is associated both with the progression and drug resistance of cancer. We aimed to investigate the effects of alkalization therapy performed concurrently with chemotherapy on the survival of advanced pancreatic cancer patients (study registration: UMIN 000035659). Twenty-eight patients with metastatic or recurrent pancreatic cancer were assessed in this study. Alkalization therapy consisted of an alkaline diet with supplementary oral sodium bicarbonate (3.0-5.0 g/day). The mean urine pH was significantly higher after the alkalization therapy (6.85±0.74 vs. 6.39±0.92; p<0.05). The median overall survival from the start of alkalization therapy of the patients with high urine pH (>7.0) was significantly longer than those with low urine pH (≤ 7.0) (16.1 vs. 4.7 months; p<0.05). An alkalization therapy may be associated with better outcomes in advanced pancreatic cancer patients treated with chemotherapy.

Repeat transurethral resection of bladder tumor (re‐TURBT) is commonly recommended for patients with non–muscle‐invasive bladder cancer (NMIBC) with high‐risk features, although many individuals may undergo unnecessary procedures that increase morbidity without clear benefit. Urinary tumor DNA (utDNA) has emerged as a promising biomarker, and we evaluated the performance of a multidimensional utDNA assay (utLIFE) in this context. In a retrospective cohort of 161 patients who underwent re‐TURBT between May 2020 and May 2025, urine samples collected 2–6 weeks after initial TURBT were analyzed using utLIFE, which integrates shallow whole‐genome sequencing and targeted sequencing of 155 genes with machine learning–based classification. Residual tumor was identified in 35% of patients, and utLIFE demonstrated high diagnostic accuracy, with sensitivity of 80.7%, specificity of 96.2%, and overall accuracy of 90.7%, markedly outperforming urine cytology. A positive utLIFE result was the strongest independent predictor of residual disease (OR = 77.5, 95% CI: 22.4–268.2, p < 0.001). During a median follow‐up of 32.5 months, recurrence occurred in 20.5% of patients; recurrence was defined as urothelial tumor relapse within the urinary tract and did not include distant metastasis. utLIFE positivity was significantly associated with shorter recurrence‐free survival (HR = 16.4, 95% CI: 2.7–101.8, p = 0.003). Longitudinal testing further revealed that utDNA positivity frequently preceded cystoscopic evidence of recurrence by several months. These findings highlight the strong diagnostic and prognostic value of utDNA in identifying residual disease and predicting recurrence, supporting its potential role in refining postoperative management strategies for NMIBC.

ObjectivesWith the advent of novel genomic and transcriptomic technologies, new urinary biomarkers have been identified and tested for bladder cancer (BCa) surveillance. To summarize the current status of urinary biomarkers for the detection of recurrence and/or progression in the follow-up of non-muscle invasive BCa patients, and to assess the value of urinary biomarkers in predicting response to intravesical Bacillus Calmette–Guerin (BCG) therapy.Methods and materialsA medline/pubmed© literature search was performed. The performance of commercially available and investigational biomarkers has been reviewed. End points were cancer detection (recurrence), cancer progression, and response to BCG therapy.ResultsThe performance requirements for biomarkers are variable according to the clinical scenario. The clinical role of urinary biomarkers in the follow-up of non-muscle invasive BCa patients remains undefined. The FDA-approved tests provide unsatisfactory sensitivity and specificity levels and their use is limited. Fluorescence in situ hybridization (FISH) has been shown to be useful in specific scenarios, mostly as a reflex test and in the setting of equivocal urinary cytology. FISH and immunocytology could conceivably be used to assess BCG response. Recently developed biomarkers have shown promising results; upcoming large trials will test their utility in specific clinical scenarios in a manner similar to a phased drug development strategy.ConclusionsCurrent commercially available urinary biomarker-based tests are not sufficiently validated to be widely used in clinical practice. Several novel biomarkers are currently under investigation. Prospective multicenter analyses will be needed to establish their clinical relevance and value.

Purpose To prospectively evaluate prognostic capabilities of non-muscle invasive bladder cancer (NMIBC) biomarkers for predicting disease recurrence or progression after radical TURB (transurethral resection of bladder tumor). Methods Evaluated biomarkers included blood: plasminogen activator inhibitor 1 (PAI-1), soluble urokinase plasminogen activator receptor (suPAR), interleukin 8 (IL-8) and urine: IL-8, vascular endothelial growth factor (VEGF) and apolipoprotein E (APOE). Blood and urine samples acquired before TURB for NMIBC from 223 subjects were analysed. The primary outcome was tumor recurrence or progression. Results After 3 months follow-up with cystoscopy or TURB– 92 patients were tumor free (Group 1). In 131 subjects (Group 2) a recurrence of NMIBC ( n  = 120) or progression to muscle invasive bladder cancer (MIBC) ( n  = 11) has been observed. No major clinical differences between these two groups were spotted. The group 2 has presented with significantly higher concentrations of blood IL-8 and suPAR as well as urine VEGF and APOE. The serum IL-8 and urinary VEGF showed the highest prognostic abilities with AUROC of 0.611 (95% CI: 0.534–0.687, p  = 0.0044) and 0.632 (95% CI: 0.557–0.707, p  = 0.0006), respectively. Multivariable machine learning models which included all investigated biomarkers and European Organisation for Research and Treatment of Cancer (EORTC) risk scores have allowed to discriminate the two patient entities with AUROC of 0.84 (95% CI: 0.73–0.95, p  < 0.0001). Conclusions The assessed biomarkers alone have shown unsatisfactory prognostic capabilities to be used for prognostication of outcomes after TURB. More complex multivariable prediction models may improve their prognostic performance. Trial registration The study was retrospectively registered at clinicaltrails.gov with National Clinical Trial number (NCT): NCT06235853.

To improve treatment outcomes in real practice, useful biomarkers are desired when predicting postoperative recurrence for renal cell carcinoma (RCC). We collected data from patients who underwent definitive surgery for RCC and for benign urological tumor at our department between November 2016 and December 2019. We evaluated the differences in pre‐ and postoperative urinary metabolites with our precise quantitative method and identified predictive factors for RCC recurrence. Additionally, to clarify the significance of metabolites, we measured the intracellular metabolite concentration of three RCC cell lines. Among the 56 patients with RCC, nine had a recurrence (16.0%). When comparing 27 patients with T1a RCC and 10 with benign tumor, a significant difference was observed between pre‐ and postoperative concentrations among 10 urinary metabolites. In these 10 metabolites, multiple logistic regression analysis identified five metabolites (lactic acid, glycine, 2‐hydroxyglutarate, succinic acid, and kynurenic acid) as factors to build our recurrence prediction model. The values of area under the receiver operating characteristic curve, sensitivity, and specificity in this predictive model were 0.894%, 88.9%, and 88.0%, respectively. When stratified into low and high risk groups of recurrence based on this model, we found a significant drop of recurrence‐free survival rates among the high risk group. In in vitro studies, intracellular metabolite concentrations of metastatic tumor cell lines were much higher than those of primary tumor cell lines. By using our quantitative evaluation of urinary metabolites, we could predict postoperative recurrence with high sensitivity and specificity. Urinary metabolites could be noninvasive biomarkers to improve patient outcome. Although the postoperative recurrence rate for nonmetastatic renal cell carcinoma (RCC) has been reported to be approximately 30%, there was no marker to predict recurrence. In this study, we evaluated urinary metabolites to identify new noninvasive biomarkers, and established a recurrence prediction model with high sensitivity and specificity by our accurate quantitative measurement system. Additionally, we undertook an in vitro study to investigate their intracellular concentrations in three RCC cell lines to understand their clinical significance.

Cystoscopy is the gold standard for surveillance of non‐muscle invasive bladder cancer (NMIBC), but the procedure is invasive and has suboptimal accuracy. The aim of this study was to investigate the potential of analyzing urine samples for the presence of urine tumor DNA (utDNA) to replace cystoscopy for surveillance of bladder cancer recurrence. In this longitudinal, prospective, and observational study, 47 patients were followed for recurrence for 2 years, involving analysis of utDNA using the BladMetrix DNA methylation biomarker test at each cystoscopy. In total, utDNA was detected in 21/23 recurrences (91% sensitivity), including 5/5 T1, T2, and carcinoma in situ (CIS) tumors (100%) and 10/12 Ta tumors (83%), with < 1% false‐negative test results. Importantly, utDNA analysis showed the potential to reduce the number of cystoscopies by 55%, benefitting 79% of the patients. Eleven of 23 recurrences (48%) were detected earlier with utDNA than with cystoscopy, and distinct patterns of residual utDNA post‐surgery indicated minimal residual disease (MRD) or field effect in 6% and 15% of the patients, respectively. In conclusion, utDNA analysis shows high sensitivity to detect tumor recurrence, potential to reduce the number of cystoscopies, and promise to guide patient‐specific surveillance regimens. In this longitudinal study, we followed 47 bladder cancer patients over 2 years for recurrence, using a urine tumor DNA test (BladMetrix) in parallel to cystoscopy. The urine test detected 91% of the recurrences with < 1% false negative test results. Importantly, the urine test showed potential to reduce cystoscopies by 55%, and to indicate minimal residual disease and field effect.