Search Results (207)

Background: Circulating tumor DNA (ctDNA) analysis has emerged as a promising tool for real-time disease monitoring in muscle-invasive bladder cancer (MIBC). This narrative review summarizes current clinical evidence regarding ctDNA across disease stages. Methods: We examine recent translational and clinical findings, incorporating key prospective data from practice-changing trials, as well as insights into minimal residual disease (MRD) detection, treatment escalation and de-escalation strategies, and systemic barriers to adoption. Results: Postoperative ctDNA positivity consistently identifies patients with molecular residual disease (MRD) who face a substantially higher risk of recurrence and mortality, frequently preceding radiographic relapse by several months. Prospective evidence now validates ctDNA as a predictive biomarker to guide adjuvant immunotherapy escalation, while sustained ctDNA negativity correlates with high long-term disease-free survival. Beyond plasma ctDNA, emerging multi-compartment liquid biopsies—integrating urinary tumor DNA (utDNA)—demonstrate enhanced sensitivity, particularly in bladder-sparing and local surveillance settings. Furthermore, integrating genomic ctDNA profiling with novel post-transcriptional layers like epitranscriptomics offers a functional framework to capture tumor adaptation under therapeutic pressure. However, clinical translation remains constrained by a lack of assay harmonization, variable analytical sensitivity, and the need for standardized intervention thresholds. Conclusions: Longitudinal liquid biopsies are rapidly shifting MIBC management from static, stage-based paradigms toward dynamic, molecularly informed precision oncology. While ctDNA-guided strategies show robust clinical utility, prospective interventional validation and technical standardization are required before widespread routine integration. Full article

Background: The fibrovascular stalk is characteristic of papillary bladder tumors and may be visualized on MRI as the inchworm sign. Contrast-enhanced ultrasound (CEUS) may depict the same structure dynamically by demonstrating pedicle perfusion before tumor enhancement. We hypothesized that CEUS would be more sensitive than the MRI inchworm sign for detecting a histologically confirmed fibrovascular stalk and that stalk presence would be associated with non-muscle-invasive bladder cancer without completely excluding detrusor muscle invasion. Methods: This retrospective study assessed 80 consecutive patients with one focal bladder lesion; 69 patients with technically adequate imaging and an adequate TURBT reference standard were included in the final paired analysis. Dedicated retrospective rereads of anonymized stored CEUS cine loops and complete mpMRI datasets were independently performed by two experienced readers per modality, who were blinded to the other imaging modality, histopathology, and each other’s assessments. A blinded pathologist assessed fibrovascular stalk presence and detrusor muscle invasion. Paired performance was evaluated using exact McNemar testing. Results: Histopathology identified a stalk in 48 lesions. CEUS detected 46 of 48 stalks, and MRI detected 36, corresponding to sensitivities of 95.8% and 75.0%, specificities of 90.5% and 81.0%, and accuracies of 94.2% and 76.8%, respectively. Interobserver agreement was 94.2% for both signs, with almost-perfect agreement for the CEUS vascular stalk sign (κ = 0.86) and the MRI inchworm sign (κ = 0.88). For MIBC detection, overall CEUS impression and VI-RADS 4–5 showed sensitivities of 66.7% and 87.5% (paired p = 0.063), specificities of 88.9% and 68.9% (paired p = 0.004), and accuracies of 81.2% and 75.4% (paired p = 0.424), respectively. Conclusions: However, the two signs are not operationally equivalent because the MRI inchworm sign additionally requires preservation of the underlying muscular layer, a criterion that may have contributed to its lower observed sensitivity. The stalk strongly favored non-muscle-invasive disease but did not exclude detrusor invasion. CEUS provides complementary perfusion information, whereas MRI-based VI-RADS remains central to local staging. Full article

Introduction: To investigate the diagnostic and prognostic value of commonly used immunohistochemical markers regarding high-grade disease, muscle-invasion bladder cancer (MIBC) and survival in bladder cancer. Methods: A total of 477 patients diagnosed with bladder cancer at Peking University Cancer Hospital between 2009 and 2024 were included. The immunohistochemical markers included CK7, CK20, GATA3, Uroplakin 3, CK5/6, P40, P63, Syn, CD56, CGA, Vimentin, S100, LCA, Ki67, P53, Her2, EGFR, PD-L1, PD-1 tumor, PD-1 stroma, and Pan-TRK. Logistic analyses were used to determine the diagnostic value of the markers for high-grade disease and MIBC. Cox regression analyses were used to determine the prognostic value of the markers for survival. Results: We found Ki67 positivity (p < 0.001) and Her2 positivity (p = 0.001) might have an association with high-grade disease, while no marker demonstrated diagnostic value for MIBC. Patients with CK7 positivity (p = 0.012), Uroplakin 3 positivity (p = 0.004), and PD-1 (stroma) positivity (p = 0.037) had better overall survival (OS) than those with negative expression, while Cox regression analyses showed only CK7 positivity (p = 0.025) and Uroplakin 3 positivity (p = 0.008) had prognostic value for better OS. However, considering there were only 2 CK7-negative patients, the sample size might be insufficient to demonstrate its prognostic value. Conclusions: These results suggest that Ki67 positivity and Her2 positivity might have association with high-grade disease, and Uroplakin 3 positivity might have prognostic value for better OS. However, these conclusions require further clarification through larger-scale studies in the future. Full article

Bladder cancer (BC) is a common urological malignancy that lacks the non-invasive biomarkers that would make it suitable for early diagnosis. Human alpha-satellite DNA (hASAT) is a tandemly repeated centromeric/pericentromeric DNA family associated with chromosomal stability and cancer-related genomic instability. We quantified extracellular hASAT (ec-hASAT) in plasma circulating cell-free DNA by nanoplate-based digital PCR in a pilot cohort including 29 BC-negative samples, 10 patients with non-muscle-invasive BC (NMIBC), and 7 patients with muscle-invasive BC (MIBC). Plasma ec-hASAT copy number was higher in patients with BC than in the BC-negative group (Mann–Whitney U test, p = 6.61 × 10⁻⁷). BC-negative samples ranged from 225 to 11,864 copies/µL plasma, whereas BC samples ranged from 1138 to 16,097 copies/µL plasma. ROC analysis yielded an AUC of 0.944 for discriminating BC from BC-negative samples. At an exploratory threshold of 2000 copies/µL plasma, sensitivity was 94.1% (16/17; exact 95% CI, 71.3–99.9%) and specificity was 89.7% (26/29; exact 95% CI, 72.6–97.8%). These preliminary data support plasma ec-hASAT as a candidate minimally invasive biomarker for BC detection, including NMIBC, and justify validation in larger prospective cohorts. Full article

Bladder preservation has emerged as an established treatment option for selected patients with muscle-invasive bladder cancer (MIBC), offering durable oncologic control with the potential to maintain native bladder function and quality of life. Over the past several decades, prospective trials and large institutional experiences have refined trimodality therapy (TMT)—maximal transurethral resection followed by definitive radiation therapy with concurrent radiosensitizing systemic therapy—and clarified principles of patient selection, treatment delivery, surveillance, and salvage. Randomized evidence supports combined-modality therapy as the backbone of bladder preservation, and contemporary comparative analyses suggest outcomes comparable to radical cystectomy in appropriately selected populations. This review synthesizes the clinical foundations of bladder preservation, including radiobiologic considerations, advances in radiation technique, and patterns of recurrence following TMT. We discuss outcomes in higher-risk populations, including locally advanced and node-positive disease, and examine the evolving integration of systemic therapies. The emergence of immune checkpoint inhibitors and antibody–drug conjugates in urothelial carcinoma has reshaped the systemic treatment landscape and raises important questions regarding patient selection, sequencing, and the potential expansion of organ-preserving strategies. Finally, we outline future directions—including response-adaptive approaches, advances in image-guided and adaptive radiotherapy, and ctDNA-enabled risk stratification—while emphasizing the need for prospective validation and multidisciplinary collaboration to refine and optimize bladder-preserving care. Full article

Background/Objectives: Neoadjuvant cisplatin-based chemotherapy (NAC) followed by radical cystectomy (RC) is a standard treatment for cisplatin-eligible patients with muscle-invasive bladder cancer (MIBC), yet baseline tools to refine prognostic stratification remain limited. We aimed to develop and internally validate a clinicopathological nomogram integrating the neutrophil-to-lymphocyte ratio (NLR) to estimate event-free survival (EFS) in patients with MIBC treated with NAC. Methods: We retrospectively analyzed 210 patients with cT2–T4aN0–1M0 MIBC treated with cisplatin-based NAC at two Spanish institutions between 2010 and 2021. Candidate predictors included demographic, clinicopathological, and routine laboratory variables. A multivariable Cox model with backward selection based on the Akaike information criterion (AIC) was used to derive the final model, and internal validation was performed using 1000 bootstrap resamples. Results: Sex, age, prior non–muscle-invasive bladder cancer (NMIBC), and NLR were retained in the final nomogram. The model showed moderate discrimination, with a Harrell’s c-index of 0.60 and an optimism-corrected c-index of 0.58. The nomogram stratified patients into low-, intermediate-, and high-risk groups, with median EFS not reached, 47.5 months, and 18.0 months, respectively. High-risk patients also showed lower pathological complete response (pCR) rates. Conclusions: This exploratory nomogram integrates an accessible systemic inflammatory marker with baseline clinical variables to identify patients with poorer outcomes despite NAC. External validation in contemporary cohorts is warranted before clinical implementation. Full article

Nectin-4 has emerged as a clinically relevant target in muscle-invasive bladder cancer (MIBC), primarily because of its role in antibody–drug conjugate-based therapies. However, the broader biological context of Nectin-4 expression and its association with tumor-promoting signaling pathways in MIBC remain insufficiently characterized. In this single-institution study, Nectin-4 expression (H-score 0–300) was assessed by immunohistochemistry in two independent MIBC cohorts. Associations between Nectin-4 expression and key markers related to growth signaling, metabolic regulation, and inflammation were analyzed alongside clinicopathological characteristics. Nectin-4 expression was significantly higher in malignant tissue than in non-malignant tissue (p = 0.0016 and p = 0.0302, respectively). Nectin-4 expression was not associated with demographic or clinicopathological parameters; however, a trend toward lower expression in more advanced disease stages was observed. Significant positive correlations were identified between Nectin-4 expression and protein kinase B (p = 0.0004), cytoplasmic (p = 0.0115) and membranous somatostatin receptor 2 (p = 0.0125), insulin receptor substrate 1 (p = 0.03), and interleukin-1 receptor antagonist (IL-1RA; p = 0.0045). In contrast, a negative correlation was observed with the IL-1β/IL-1RA ratio (p = 0.0246). Although Nectin-4 expression was not significantly associated with cancer-specific or overall survival, a trend toward shorter relapse-free survival was observed in patients with lower Nectin-4 expression (p = 0.0531). In multivariate analysis, patient age, but not Nectin-4 expression, emerged as an independent prognostic factor. Although Nectin-4 expression does not appear to have independent prognostic value, its biological associations suggest that it reflects an integrated tumor-related signaling context. These findings support further investigation of Nectin-4 as part of rational, biology-driven therapeutic strategies in bladder cancer. Full article

Background. Accurate prediction of pathologic complete response (pCR) to neoadjuvant chemotherapy (NAC) in muscle-invasive urothelial bladder cancer (MIBC) remains an unmet clinical need. The neutrophil-to-platelet/hemoglobin-to-lymphocyte (NPLH) ratio, a composite hematologic index that reflects both systemic inflammation and nutritional oxygen-carrying capacity, has not been previously evaluated as a predictor of NAC response in this setting. Methods. We retrospectively analyzed 114 consecutive patients with MIBC (cT2–T4, N0–N3) who received accelerated MVAC (aMVAC) NAC followed by radical cystectomy at a single academic center. Pretreatment NPLH (calculated as [neutrophils × platelets]/[hemoglobin × lymphocytes]) was assessed as a predictor of pCR (ypT0N0) and tumor regression grade (TRG). Receiver operating characteristic (ROC) curve analysis, Mann–Whitney U test, and logistic regression were used. NPLH performance was compared to NLR and PLR. Results. pCR was achieved in 35 patients (30.7%). Median NPLH was significantly lower in pCR vs. non-pCR patients (33.9 [IQR 23.1–42.4] vs. 47.6 [IQR 30.7–90.4]; p = 0.0007). NPLH yielded an AUC of 0.700 (bootstrap 95% CI 0.596–0.794) for pCR prediction, numerically superior to NLR (AUC 0.645 [0.542–0.741]) and PLR (AUC 0.643 [0.533–0.747]); DeLong test: NPLH vs. NLR p = 0.079, NPLH vs. PLR p = 0.090. At the optimal cut-off of 44.5, NPLH demonstrated 80.0% sensitivity and 57.0% specificity. pCR rates declined progressively across NPLH quartiles: 48.3% (Q1) to 10.3% (Q4). On multivariate logistic regression, log-transformed NPLH was the only independent predictor of pCR (parsimonious model, OR 0.292, 95% CI 0.131–0.652; p = 0.003; EPV = 17.5). A positive correlation was observed between NPLH and TRG score (Spearman r = 0.284; p = 0.0022), with significant differences between TRG 1 and TRG 3 subgroups (p = 0.0036). Conclusions. Pretreatment NPLH is an independent predictor of pCR to aMVAC in MIBC and is numerically superior to NLR and PLR (DeLong p = 0.079). Consisting exclusively of standard complete blood count parameters, NPLH is readily available and inexpensive. This single-center exploratory study is hypothesis-generating and requires prospective external validation before clinical implementation. Full article

The failure of therapy in muscle invasive bladder cancer (MIBC) is primarily attributed to tumor heterogeneity and therapy resistance. We propose a novel approach targeting interleukin-13 receptor subunit alpha 2 (IL-13Rα2), which is expressed on bladder cancer (BC) cells but absent in normal urothelial cells. We investigated the therapeutic effects of WPD101a immunotoxin (IL-13-DT390) on IL-13Rα2-expressing BC cells in relation to BC cell phenotype and functional characteristics in vitro using both 2-dimensional (2D) and 3-dimensional (3D) models. Cell phenotype and IL-13Rα2 expression were assessed using flow cytometry, immunofluorescence, and Western blot analysis. The biological effects of WPD101a were evaluated by measuring cell viability and proliferation using the MTT, sulforhodamine B (SRB), CellTiter-Glo and Live/Dead assays. Apoptosis was assessed using Annexin V/propidium iodide (PI) staining, and quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis of CASP genes expression. We found that the reference BC cell lines TCC-SUP, JMSU-1 and UM-UC-3 express IL-13Rα2 at various level in contrast to RT-4, HCV-29 and 5637 cells. Cells expressing IL-13Rα2 were sensitive to WPD101a at lower concentrations in the 2D model (0.1 ng/mL) compared to the 3D model (1.0 ng/mL). IL-13Rα2-negative cells remain resistant to the immunotoxin. WPD101a induces apoptosis in BC cells expressing IL-13Rα2 as confirmed by the presence of apoptotic cells, increase the proportion of cells in the subG1 phase, and by the effector CASP3, CASP7, and initiator CASP8, CASP9 genes expression. This study confirmed receptor-dependent cytotoxic effects of WPD101a and the ability and specificity to inhibit growth and apoptosis induction in MIBC cells expressing IL-13Rα2. Full article

Background: Most bladder cancer cases present as non-muscle-invasive bladder cancer (NMIBC), with the course of multiple recurrences leading to stage progression to muscle-invasive bladder cancer (MIBC) in 10–20% of cases, which is associated with higher morbidity and mortality. Accurate histopathologic classification of bladder cancer remains important for patient management. Methods: This retrospective–prospective observational cohort study was conducted on 244 transurethral resection specimens. Immunohistochemistry assessed CK5/6, CK20, and apoptosis-inducing factor (AIF) using three representations: intensity, percentage of positive cells, and multiplicative score. Discrimination between NMIBC (pTa/pT1) and MIBC (≥pT2), and between low-grade (LG) and high-grade (HG) tumors, was evaluated using ROC/AUC analysis and logistic regression. The main analysis focused on cross-sectional marker performance in primary/non-recurrent tumors. Recurrent tumors were analyzed only as an exploratory subgroup. Tumors were also categorized into basal, luminal, mixed/double-positive, and double-negative phenotypes using thresholds of 10% for CK5/6 and CK20. Results: For stage discrimination, all three markers showed modest separation. The best-performing representation was CK5/6 intensity (AUC 0.641; lower in MIBC). For grade discrimination, the AIF score showed the highest performance (AUC 0.729, higher in HG). Combining markers improved model performance (NMIBC vs. MIBC: AUC 0.784; strict LG vs. HG: AUC 0.778). Using the 10% cutoff in non-recurrent tumors, mixed/double-positive tumors had the lowest MIBC proportion (6.0%) and double-negative tumors the highest (46.7%). Conclusions: CK5/6, CK20, and AIF provide modest discrimination between stages, with lower CK5/6 and CK20, and higher AIF, in MIBC. The AIF score shows the highest separation between grades and may serve as a useful non-proliferation marker for grading, particularly when interpreted alongside CK5/6 and CK20 in a simple immunohistochemical panel. Full article

Background: Muscle-invasive bladder cancer (MIBC) is an aggressive disease with heterogeneous responses to neoadjuvant chemotherapy and emerging chemo-immunotherapy combinations. Reliable biomarkers to predict treatment responsiveness before therapy initiation are needed to guide patient selection. Objective: The objective of this study was to identify genomic and immune-related features associated with immune-active tumor phenotypes in MIBC using The Cancer Genome Atlas bladder cancer cohort (TCGA-BLCA). Methods: A retrospective bioinformatics analysis of TCGA-BLCA data was performed, evaluating gene expression, somatic mutations, tumor mutational burden (TMB), DNA damage response (DDR) gene status, and immune infiltration signatures. Immune enrichment metrics were derived from transcriptomic data. In the absence of direct treatment response data, a surrogate immune response classification was applied. Associations were analyzed using descriptive statistics and Firth’s penalized logistic regression. Results: Tumors classified as immune-high phenotype group based on immune-related features exhibited significantly higher global immune infiltration, including increased ImmuneScore and enrichment of cytotoxic and innate immune cells. In multivariable analysis, ImmuneScore was the only independent predictor of inferred responsiveness (p = 0.003). Conclusions: Global immune infiltration showed the strongest association with immune-active tumor phenotypes among the features examined in this TCGA-based analysis. These exploratory findings suggest that immune profiling may warrant further investigation as a component of tumor characterization in MIBC, pending validation in cohorts with clinical treatment and outcome data. Full article

Background: Immunohistochemistry (IHC) plays a central role in subtyping of muscle-invasive bladder cancer (MIBC), yet conventional semi-quantitative scoring lacks objectivity and scalability. Automated digital pathology offers potential solutions, but requires robust, marker-specific validation against expert consensus scoring. Methods: We developed and internally validated an automated digital pathology pipeline for continuous IHC H-score quantification using QuPath (v0.6.0-arm64). Tissue microarrays (TMAs) were generated from transurethral resection of bladder tumor (TURBT) specimens from a cohort of patients with MIBC treated at Vancouver General Hospital. Cell detection was performed using StarDist (v0.9), followed by automated intensity-based H-score calculation for four epithelial IHC marker stains (CK14, CK20, CK5/6, and Uroplakin II). H-scoring was then restricted to tumor epithelium by object-level classification using a supervised tumor/non-tumor classifier trained on pathologist-reviewed annotations. Automated scores were compared with consensus scores from three blinded pathologists using Pearson correlation, linear regression, intraclass correlation coefficients (ICC), and Bland–Altman analysis. Results: Automated H-scores demonstrated strong agreement with pathologist consensus across all four markers. CK14 showed near-perfect agreement (ICC ≈ 0.99) with minimal bias and narrow limits of agreement. CK20 also showed high agreement (ICC ≈ 0.95). CK5/6 and Uroplakin II demonstrated slightly lower agreement (ICC ≈ 0.92 to 0.93) with mild proportional bias. Across markers, the automated pipeline preserved a broad H-score range, with range ratios of 0.96 to 0.99. Conclusions: This study establishes a robust, methods-forward pipeline for automated continuous IHC H-scoring in MIBC. The internally validated framework provides a scalable foundation for external cohort testing and future clinical outcome-associated biomarker analyses. Full article

Background and Objectives: Pathological upstaging from non-muscle-invasive bladder cancer (NMIBC) to muscle-invasive disease (MIBC) at radical cystectomy (RC) compromises preoperative risk stratification and may deprive patients of the survival benefit conferred by neoadjuvant chemotherapy. This study aimed to define the frequency and independent predictors of pathological upstaging in a contemporary single-institution cohort, and to characterise its impact on recurrence-free, disease-specific, and overall survival. Materials and Methods: We conducted a retrospective review of a prospectively maintained database of all patients who underwent RC and pelvic lymphadenectomy for urothelial bladder cancer at our institution between January 2009 and December 2023. Upstaging was defined as the final pathological stage ≥ pT2 or pN+ from a clinical stage of <T2N0M0. Clinicopathological factors were evaluated for their association with upstaging using chi-squared, Fisher’s exact, and logistic regression analyses. Survival outcomes—recurrence-free survival (RFS), disease-specific survival (DSS), and overall survival (OS)—were estimated by the Kaplan–Meier method and compared using the log-rank test. Multivariable Cox proportional hazards regression identified independent prognostic factors. Results: Of 1002 patients who underwent RC during the study period, complete clinicopathological data were available for 826. Primary clinical stage at presentation was MIBC (≥T2) in 448 (54.2%) and NMIBC (<T2) in 378 (45.8%). Among NMIBC patients, 102 (27.0%) were upstaged to MIBC at final pathology. Multivariable logistic regression identified concomitant carcinoma in situ (CIS) (p = 0.042), variant histology—predominantly squamous differentiation (p = 0.003)—and urethral involvement (p = 0.003) as independent predictors of upstaging. Upstaged patients had significantly worse 5-year RFS (p < 0.001), DSS (p = 0.01), and OS (p < 0.001) compared with patients who remained NMIBC. No statistically significant difference in survival was observed between patients upstaged at RC and those presenting with primary MIBC. Conclusions: Pathological upstaging occurs in more than a quarter of patients undergoing RC for NMIBC and confers a survival penalty equivalent to that of primary MIBC. Concomitant CIS, variant histology, and urethral involvement identify those at highest risk. These patients warrant aggressive preoperative counselling, expedited surgical planning, and consideration of perioperative systemic therapy. Full article

Background/Objectives: Radical cystectomy (RC) for muscle-invasive bladder cancer (MIBC) is associated with high morbidity. Frailty is an important determinant of surgical outcomes; however, its association with the composite outcome Days Alive and Out of Hospital (DAOH) has not been examined following RC. We assessed the impact of preoperative frailty on 90-day DAOH in older patients undergoing RC for MIBC. Methods: We conducted a retrospective cohort study including 408 consecutive patients aged ≥65 years undergoing RC at a tertiary referral center between 2018 and 2023. Frailty was assessed using the record-based Multidimensional Prognostic Index (r-MPI), classifying patients as non-frail (MPI1), moderately frail (MPI2), or severely frail (MPI3). The primary outcome was 90-day DAOH; secondary outcomes included length of stay (LOS), postoperative complications, delirium, and mortality. DAOH was dichotomized at the cohort median. Associations with low DAOH were analyzed using modified Poisson regression with robust variance estimation. Results: Median 90-day DAOH decreased progressively with increasing frailty: MPI1: 81 days (IQR 76–83), MPI2: 73 days (IQR 62–80), MPI3: 67 days (IQR 52–76); p < 0.01. In multivariable analysis, frailty was independently associated with low DAOH (MPI2: RR 2.46, 95% CI 1.94–3.11; MPI3: RR 3.37, 95% CI 2.55–4.46), whereas age and comorbidity were not. Increasing frailty was consistently linked to worse postoperative outcomes, including longer LOS, higher complication burden and severity, and more frequent delirium. Ninety-day postoperative complication-related mortality increased markedly with frailty (MPI1: 1.6%, MPI2: 11.9%, MPI3: 12.1%; p < 0.01). Conclusions: Preoperative frailty is a strong independent predictor of low 90-day DAOH and adverse postoperative outcomes following RC in older patients. Full article

Trimodality therapy (TMT)—maximal transurethral resection of bladder tumor (TURBT) followed by concurrent chemoradiotherapy—can offer oncologic outcomes comparable to radical cystectomy (RC) in carefully selected muscle-invasive bladder cancer (MIBC) patients while preserving the bladder and, possibly, the quality of life. Systematic reviews and long-term series support durable bladder-intact survival in responders, yet there is still a significant percentage of patients who exhibit incomplete response or invasive intravesical recurrence requiring salvage RC. This review covers computational genomics, transcriptomics, immune contexture, radiogenomics, and digital pathology approaches for predicting response in order to avoid preventable TMT failures. We discuss clinically relevant endpoints (complete response, invasive recurrence, bladder-intact survival, and salvage RC), patient selection (carcinoma in situ, hydronephrosis, debulking feasibility, and histology), and DNA damage response (DDR) biology—highlighting ERCC2 and related pathways as determinants of chemo-radiation sensitivity. We then review reproducible transcriptomic subtype classifiers and immune deconvolution methods, emphasizing translational constraints and reporting standards. Finally, we propose an integrated hypothetical modeling framework (calibration, external validation, and decision-curve thresholds) to guide recommendations for upfront RC versus bladder preservation with intensified surveillance and timely salvage RC. Full article