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Background: This study assessed the topography and lateralization of lymph node (LN) metastases in muscle-invasive bladder cancer (MIBC) patients using super-extended pelvic lymph node dissection (sePLND) with sentinel lymph node dissection (SLND). Methods: We analyzed 54 MIBC patients who underwent cystectomy with sePLND and SLND. Tumor location was classified using cystoscopy. Nanocolloid-Tc-99m was injected peritumorally. Preoperative SPECT/CT lymphoscintigraphy and an intraoperative gamma probe were used for SLN detection. Results: A total of 1414 LNs, including 192 SLNs, were resected from 54 patients. Metastases were found in 72 LNs from 22 patients (41%). The obturator fossa was the primary site for LN metastases (37.5%). SLNs were most common in the external iliac region (34.4%). In 36% of the patients with positive LNs, metastases were identified only through sePLND. In 9% of the patients, metastases were found solely in the pararectal region, identified through SLND. Tumor lateralization correlated with ipsilateral positive LNs, but 20% of the patients had contralateral metastases. Conclusions: The pararectal region may be the exclusive site for positive LNs in MIBC. The obturator fossa is the most prevalent region for LN metastases. Unilateral PLND should be avoided due to the risk of contralateral metastases. Combining sePLND with SLND improves staging.

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PURPOSE: To report the oncological outcomes and the tolerance between 6 instillations and more than 6 cycles of hyperthermic intravesical chemotherapy(HIVEC) in patients with non-muscle invasive bladder cancer(NMIBC). METHODS: This is a multicenter retrospective study from a national database including 9 expert centers. All patients treated with HIVEC between 2016 and 2023 for NMIBC were included. Patients were classified into two groups according to the total number of HIVEC instillations, including induction plus maintenance. Kaplan-Meier curves were computed to present survival outcomes. RESULTS: 261 patients with a median follow-up of 25.5 months were included. 199(76.2%) and 62(23.8%) were treated by 6 and more than 6 cycles of HIVEC, respectively. The 2-years RFS(40.2% vs. 34.4%,p = 0.3) and the 2-years PFS(86% vs. 87%,p = 0.85) were similar between group treated with 6 and more than 6 instillations. 2-years CSS and OS were also similar between both groups. Univariate Cox regression showed no association between the number of bladder instillation and RFS (HR = 1.2 95%CI[0.8-1.84], p = 0.3) or PFS (HR = 0.8 95%CI[0.29-2.02], p = 0.2). In the group treated with more than 6 cycles, 2-years RFS and 2-years PFS were similar between patients who received induction plus maintenance compared to those treated with induction only. Finally, hematuria and urinary burning were significantly higher in the group treated by more than 6 cycles (21% vs. 8.5%(p < 0.01),and 29% vs. 17% (p = 0.03), respectively). Serious side effects(grade ≥ 3) are rare(3.1%) and similar in both groups. CONCLUSIONS: Results show no significant difference in two years RFS, PFS, CSS and OS according to number of instillations received, while toxicity profile seems better in the group receiving six instillations only.

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BACKGROUND: Bladder cancer (BC) is very common among cancers of urinary system. It was usually categorized into two types: non-muscle invasive bladder cancer (NMIBC) and muscle invasive bladder cancer (MIBC). NMIBC and MIBC groupings are heterogeneous and have different characteristics. OBJECTIVES: The study was aimed to find some hub genes and related signal pathways which might be engaged in the progression of BC and to investigate the relationship with clinical stages and its prognostic significance. METHODS: GSE37317 datasets were acquired from Gene Expression Omnibus (GEO) database. GEO2R on-line tool was selected to screen the differentially expressed genes (DEGs) of the two different types of BC. Then, Gene Ontology (GO) enrichment and KOBAS-Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of these DEGs were conducted. A protein-protein interaction (PPI) network was employed to help us screen hub genes and find significant modules. Finally, we made analysis of gene expression and survival curve by GEPIA and Kaplan-Meier plotter database. RESULTS: 224 DEGs were screened in total, with 110 showing increased expression and 114 demonstrating decreased expression. GO and KEGG pathway enrichment analysis showed that DEGs were mostly involved in collagen fibril organization, extracellular matrix (ECM) structural constituent, bHLH transcription factor binding, AGE-RAGE signaling pathway and TGF-beta signaling pathway. Only 3 hub genes (DCN, JUN, THBS1) displayed significantly higher expression compared to those in the healthy controls. These hub genes were also strongly related to clinical stages as well as overall survival (OS) of BC patients. CONCLUSIONS: Taken together, most of hub genes involved in the progression of BC were related to ECM and EMT. In addition, 3 hub genes (DCN, JUN, THBS1) were strongly related with clinical stages and OS of BC patients. This study can enhance our comprehension of the progression of NMIBC and identify novel potential targets for MIBC.

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Mycobacterium bovis Bacillus Calmette-Guerin (BCG) is the primary treatment for non-muscle-invasive bladder cancer (NMIBC), known to stimulate inflammatory cytokines, notably interferon (IFN)-γ. We observed that prolonged IFN-γ exposure fosters adaptive resistance in recurrent tumors, aiding immune evasion and tumor proliferation. We identify HLA-E and NKG2A, part of a novel NK and T cell checkpoint pathway, as key mediators of resistance in BCG-unresponsive NMIBC. IFN-γ enhances HLA-E and PD-L1 expression in recurrent tumors, with an enrichment of intra-tumoral NKG2A-expressing NK and CD8 T cells. CXCL9+ macrophages and dendritic cells and CXCL12-expressing stromal cells likely recruit CXCR3/CXCR4-expressing NK and T cells and CXCR7+ HLA-EHIGH tumor cells. NK and CD8 T cells remain functional within BCG-unresponsive tumors but are inhibited by HLA-E and PD-L1, providing a framework for combined NKG2A and PD-L1 blockade strategy for bladder-sparing treatment of BCG-unresponsive NMIBC.

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BACKGROUND: To develop a prognostic model to manage patients with muscle-invasive bladder cancer (MIBC) undergoing radical cystectomy (RC) and chemotherapy. PATIENTS AND METHODS: Clinicopathologic characteristics and survival data were collated from a North American database to develop a model. Genomic and clinicopathologic data were also obtained from European and Asian databases to externally validate the model. Patients were classified as either "primary" or "progressive" MIBC according to non-muscle invasive stage history. Optimized cancer-specific survival (CSS) models, based on MIBC types, were constructed using Cox's proportional hazard regression. Differences of biological function and tumor immunity, between two risk-based groups stratified according to the prognostic model, were estimated. RESULTS: There were 2631 participants in the American cohort, 291 in the European cohort and 142 in the Asian cohort. Under Cox's regression analysis, tumor stage, lymph node stage, age, ethnicity, and MIBC types were independent CSS predictors (all p < 0.05). The constructed nomogram, which integrated these variables, improved the predictive power. This model had good discrimination and calibration. Patients were categorized into high- or low-risk groups according to the total points calculated. Kaplan-Meier curves revealed that patients in the high-risk group had poorer survival (p < 0.001). This was confirmed with two external validation cohorts (both with p < 0.001). Higher stromal scores and increased M0 and M2 macrophage numbers were observed in samples from the high-risk group, whereas regulatory T cells had lower infiltration in these populations (all with p < 0.05). CONCLUSIONS: This MIBC type-based nomogram provides accurate CSS predictions, which could help improve patient management and clinical decision-making.

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Muscle invasive bladder cancer (MIBC) is an aggressive disease with a high risk of metastasis. Bladder preservation with trimodality therapy (TMT) is an option for well-selected patients or poor cystectomy candidates. Cone beam computed tomography (CBCT)-guided online adaptive radiotherapy (oART) shows promise in improving the dose to treatment targets while better sparing organs at risk (OARs). The following series presents two cases in which the capabilities of a CBCT-guided oART platform were leveraged to meet clinical challenges. The first case describes a patient with synchronous MIBC and high-risk prostate cancer with challenging target-OAR interfaces. The second recounts the case of a patient with a history of low dose rate (LDR) brachytherapy to the prostate who was later diagnosed with MIBC and successfully treated with CBCT-guided oART with reduced high-dose volume bladder targeting. To date, both patients report minimal side effects and are without disease recurrence. These cases illustrate how CBCT-guided online adaptive systems may efficiently aid radiation oncologists in treating patients with more complex clinical scenarios who desire bladder-sparing therapy.

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Background: Neoadjuvant chemotherapy with radical cystectomy (RC) is the preferred first-line treatment for localized muscle-invasive bladder cancer (MIBC). Due to the concern about morbidity associated with RC, the elderly population considers bladder preservation alternatives. Guidelines suggest partial cystectomy (PC) can be considered a viable option in carefully selected individuals. We used the National Cancer Database (NCDB) to compare the overall survival (OS) among octogenarians treated with PC and RC. Methods: Using NCDB, we retrospectively evaluated individuals aged 80 years and above diagnosed with localized MIBC (cT2-4aN0M0) with tumor size less than 5 cm and urothelial histology between 2004 and 2018. Our primary cohort was divided into the RC cohort, which included patients who underwent RC with or without chemotherapy/radiotherapy, and the PC cohort, which included those who underwent PC. After propensity-matching, we compared the OS. Results: Of 94,104 patients with MIBC, 2,528 octogenarians met our selection criteria. Among them, 313 were treated with PC, and 2,215 were treated with RC. A total of 151 (48.2%) PC patients had pelvic lymph node dissection, while 1,967 (88.8%) RC patients had lymph node dissection (P<0.001). The OS for matched PC and RC was 33.4 and 29.9 months, respectively (P=0.68). In T2 tumors, the OS for PC and RC was 37 and 33.5 months, respectively (P=0.52); for T3 tumors, the OS was 22.3 and 24.4 months, respectively (P=0.98). Conclusions: Our study compared PC and RC in octogenarians with localized MIBC and observed that PC is safe and not inferior to RC in carefully selected octogenarians. The role of PC needs further exploration by comparing or integrating with strategies like concurrent chemoradiation to improve the oncological and survival outcomes.

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The most common histological variants of bladder cancer include urothelial, squamous, and adenocarcinoma. In high-grade, invasive urothelial carcinoma, divergent differentiation can be observed, including glandular, squamous, trophoblastic, and small-cell types. Urothelial sarcomatoid carcinoma is characteristic of advanced carcinomas and is considered a possible common end route for all epithelial carcinomas. Adenocarcinoma of the bladder refers exclusively to true glandular carcinomas. Hybrid tumors are extremely rare and consist of more than one tumor type within the total tumor mass. Penile metastases are extremely uncommon, and there are no reported cases of metastatic adenocarcinoma of the bladder in the literature.

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Background: More muscle-invasive bladder cancer (MIBC) patients are now eligible for bladder-preserving therapy (BPT), underscoring the need for precision medicine. This study aimed to identify prognostic predictors and construct a predictive model among MIBC patients who undergo BPT. Methods: Data relating to MIBC patients were obtained from the Surveillance, Epidemiology and End Results (SEER) database from 2004 to 2016. Eleven features were included to establish multiple models. The predictive effectiveness was assessed using receiver operating characteristic (ROC) curves, calibration plots, decision curve analysis (DCA) and clinical impact curve (CIC). SHapley Additive exPlanations (SHAP) were used to explain the impact of features on the predicted targets. Results: The ROC showed that Catboost and Random Forest (RF) obtained better predictive discrimination in both 3- and 5-year models [test set area under curves (AUC) =0.80 and 0.83, respectively]. Furthermore, Catboost showed better performance in calibration plots, DCA and CIC. SHAP analysis indicated that age, M stage, tumor size, chemotherapy, T stage and gender were the most important features in the model for predicting the 3-year cancer-specific survival (CSS). In contrast, M stage, age, tumor size and gender as well as the N and T stages were the most important features for predicting the 5-year CSS. Conclusions: The Catboost model exhibits the highest predictive performance and clinical utility, potentially aiding clinicians in making optimal individualized decisions for MIBC patients with BPT.

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BACKGROUND: The tumoricidal complex alpha1-oleate targets bladder cancer cells, triggering rapid, apoptosis-like tumor cell death. Clinical effects of alpha1-oleate were recently observed in patients with non-muscle invasive bladder cancer (NMIBC), using a randomized, placebo-controlled study protocol. AIMS: To investigate if there are dose-dependent effects of alpha1-oleate. MATERIALS AND METHODS: Here, patients with NMIBC were treated by intravesical instillation of increasing concentrations of alpha1-oleate (1.7, 8.5, or 17 mM) and the treatment response was defined relative to a placebo group. RESULTS: Strong, dose-dependent anti-tumor effects were detected in alpha1-oleate treated patients for a combination of molecular and clinical indicators; a complete or partial response was detected in 88% of tumors treated with 8.5 mM compared to 47% of tumors treated with 1.7 mM of alpha1-oleate. Uptake of alpha1-oleate by the tumor triggered rapid shedding of tumor cells into the urine and cell death by an apoptosis-like mechanism. RNA sequencing of tissue biopsies confirmed the activation of apoptotic cell death and strong inhibition of cancer gene networks, including bladder cancer related genes. Drug-related side effects were not recorded, except for local irritation at the site of instillation. DISCUSSION AND CONCLUSIONS: These dose-dependent anti-tumor effects of alpha1-oleate are promising and support the potential of alpha1-oleate treatment in patients with NMIBC.

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OBJECTIVE: To investigate the influence of statins on the survival outcomes of patients with non-muscle-invasive bladder cancer (NMIBC) treated with adjuvant intravesical bacille Calmette-Guérin (BCG) immunotherapy. PATIENTS AND METHODS: A retrospective cohort of consecutive patients with NMIBC who received intravesical BCG therapy from 2001 to 2020 and statins prescription were identified. Overall survival (OS), cancer-specific survival (CSS), recurrence-free survival (RFS), and progression-free survival (PFS) were analysed between the Statins Group vs No-Statins Group using Kaplan-Meier method and multivariable Cox regression. RESULTS: A total of 2602 patients with NMIBC who received intravesical BCG were identified. The median follow-up was 11.0 years. On Kaplan-Meier analysis, the Statins Group had significant better OS (P < 0.001), CSS (P < 0.001), and PFS (P < 0.001). Subgroup analysis indicated statins treatment started before BCG treatment had better CSS (P = 0.02) and PFS (P < 0.01). Upon multivariable Cox regression analysis, the 'statins before BCG' group was an independent protective factor for OS (hazard ratio [HR] 0.607, 95% confidence interval [CI] 0.514-0.716), and CSS (HR 0.571, 95% CI 0.376-0.868), but not RFS (HR 0.885, 95% CI 0.736-1.065), and PFS (HR 0.689, 95% CI 0.469-1.013). CONCLUSIONS: Statins treatment appears to offer protective effects on OS and CSS for patients with NMIBC receiving adjuvant intravesical BCG.

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BACKGROUND: Prior research has demonstrated a discrepancy between pathologic and clinical staging in individuals with muscle-invasive bladder cancer (MIBC) following neoadjuvant chemotherapy (NAC). These findings were the major reasons for the under-usage of the bladder preservation strategy. Hence, we aim to explore the reliable markers in identifying pathological complete response (ypCR) status in MIBC patients who achieved clinical complete response (cCR) after NAC. METHODS: Between January 2016 and April 2023, 161 consecutive MIBC patients treated with NAC and achieved cCR were enrolled in the study. Patient clinicopathologic information was documented. Multivariate binary logistic regression was used for determining adjusted odds ratios (OR) and 95% confidence intervals (CI). It considered statistically significant when a P < .05. RESULTS: Of the 161 MIBC patients with cCR after NAC, 64.0% (103/161) achieved ypCR after RC. The independent factors for ypCR status were the origin of MIBC (secondary vs. Primary) with odds ratios (OR) of 0.433 (P = .027), the pathological type (pure vs. mixed) with OR of 3.556 (P = .003), concurrent carcinoma in situ (yes vs. no) with OR of 0.360 (P = .016), and lymphovascular invasion (yes vs. no) with OR of 0.271 (P = .007). CONCLUSION: This study demonstrated that primary MIBC, pure UC pathological type, absence of concurrent CIS, and LVI were significant predictors of ypCR in MIBC patients who achieved cCR after NAC and before surgery. These findings may contribute to the decision-making process of bladder preservation strategy in selected patients.

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BACKGROUND: The National Cancer Institute SEER Program regularly publishes bladder-cancer specific survival statistics. However, this data is for all bladder cancers, and information for non-muscle invasive bladder cancer (NMIBC) is difficult to obtain. OBJECTIVE: To quantify 5-year overall and bladder cancer-specific survival in a cohort of Department of Veterans Affairs (VA) patients diagnosed with NMIBC. METHODS: We identified VA patients diagnosed with NMIBC who underwent a transurethral resection from 2003-2013. The patient demographics and Charlson Comorbidity Index were categorized. We acquired the patients' date of death from the Veterans Health Administration's Death Ascertainment File and their cause of death from the Mortality Data Repository. We calculated Kaplan Meier estimates of survival. RESULTS: A total of 27,008 patients were included; median age was 69 and almost all were male (99%). The median comorbidity score was 4. The most prevalent comorbidity indicators included Chronic Pulmonary Disease (48%), cancer other than Bladder (41%), and diabetes (40%). This cohort was found to have a 5-year overall survival of 68% (99% CI 67% -69%) and a 5-year bladder cancer-specific survival of 93% (99% CI 92% -94%). CONCLUSIONS: The 5-year bladder cancer-specific survival in patients diagnosed with non-muscle invasive bladder cancer is substantially higher than the 5-year overall survival. This difference may be related to the severity and number of comorbidities that patients in this population must manage. This warrants further research into the necessity of currently recommended high-intensity cancer surveillance for individuals with NMIBC.

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BACKGROUND: Accurately assessing 5-year recurrence rates is crucial for managing non-muscle-invasive bladder carcinoma (NMIBC). However, the European Organization for Research and Treatment of Cancer (EORTC) model exhibits poor performance. PURPOSE: To investigate whether integrating multiparametric MRI (mp-MRI) with clinical factors improves NMIBC 5-year recurrence risk assessment. STUDY TYPE: Retrospective. POPULATION: One hundred ninety-one patients (median age, 65 years; age range, 54-73 years; 27 females) underwent mp-MRI between 2011 and 2017, and received ≥5-year follow-ups. They were divided into a training cohort (N = 115) and validation/testing cohorts (N = 38 in each). Recurrence rates were 23.5% (27/115) in the training cohort and 23.7% (9/38) in both validation and testing cohorts. FIELD STRENGTH/SEQUENCE: 3-T, fast spin echo T2-weighted imaging (T2WI), single-shot echo planar diffusion-weighted imaging (DWI), and volumetric spoiled gradient echo dynamic contrast-enhanced (DCE) sequences. ASSESSMENT: Radiomics and deep learning (DL) features were extracted from the combined region of interest (cROI) including intratumoral and peritumoral areas on mp-MRI. Four models were developed, including clinical, cROI-based radiomics, DL, and clinical-radiomics-DL (CRDL) models. STATISTICAL TESTS: Student's t-tests, DeLong's tests with Bonferroni correction, receiver operating characteristics with the area under the curves (AUCs), Cox proportional hazard analyses, Kaplan-Meier plots, SHapley Additive ExPlanations (SHAP) values, and Akaike information criterion for clinical usefulness. A P-value <0.05 was considered statistically significant. RESULTS: The cROI-based CRDL model showed superior performance (AUC 0.909; 95% CI: 0.792-0.985) compared to other models in the testing cohort for assessing 5-year recurrence in NMIBC. It achieved the highest Harrell's concordance index (0.804; 95% CI: 0.749-0.859) for estimating recurrence-free survival. SHAP analysis further highlighted the substantial role (22%) of the radiomics features in NMIBC recurrence assessment. DATA CONCLUSION: Integrating cROI-based radiomics and DL features from preoperative mp-MRI with clinical factors could improve 5-year recurrence risk assessment in NMIBC. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 3.

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Lymphoepithelioma-like carcinoma of the bladder (LELC-B) is a rare histologic subtype characterized by strong immune cell (IC) infiltrates. A better prognosis and favorable response rates to immune checkpoint inhibitors have been described. We aimed to characterize the molecular profiles and IC infiltration of LELC-B for a better understanding of its therapeutic implications. We identified 11 muscle-invasive bladder cancer cases with pure and mixed LELC-B. Programmed cell death ligand-1 (PD-L1) expression and mismatch repair proteins were evaluated using immunohistochemistry. We calculated the tumor mutational burden and characterized mutational profiles using whole-exome DNA sequencing data. Transcriptomic signatures were detected using the NanoString nCounter PanCancer IO360 Panel. Multiplex immunofluorescence of tumor microenvironment (PD-L1, PanCK, α-SMA, vimentin, CD45, and Ki67) and T cells (CD4, CD3, PD-1, CD163, CD8, and FoxP3) was used to quantify cell populations. All LELC-B cases were highly positive for PD-L1 (median tumor proportion score/tumor cell, 70%; range, 20%-100%; median combined positive score, 100; range, 50-100) and mismatch repair proficient and negative for Epstein-Barr virus infection. IC infiltrates were characterized by a high CD8+ T-cell count and high PD-1/PD-L1 expression on immune and tumor cells. LELC-B showed upregulation of signaling pathways involved in IC response. Most common mutations were found in chromatin remodeling genes causing epigenetic dysregulation. All LELC-B cases showed high tumor mutational burden with a median of 39 mutations/Mb (IQR, 29-66 mutations/Mb). In conclusion, LELC-B is a highly immunogenic tumor, showing strong upregulation of PD-1/PD-L1 and making immune checkpoint inhibitors a promising treatment option.

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INTRODUCTION: Robot-assisted radical cystectomy (RARC) has gained momentum in the management of muscle invasive bladder cancer (MIBC). Predictors of RARC outcomes are not thoroughly studied. We aim to investigate the implications of preoperative hydronephrosis on oncological outcomes. PATIENTS AND METHODS: This study analysed data from the Asian RARC consortium, a multicentre registry involving nine Asian centres. Cases were divided into two groups according to the presence or absence of pre-operative hydronephrosis. Background characteristics, operative details, perioperative outcomes, and oncological results were reviewed. Outcomes were (1) survival outcomes, including 10-year disease-free survival (DFS) and overall survival (OS), and (2) perioperative and pathological results. Multivariate regression analyses were performed on survival outcomes. RESULTS: From 2007 to 2020, 536 non-metastatic MIBC patients receiving RARC were analysed. 429 had no hydronephrosis (80.0%), and 107 (20.0%) had hydronephrosis. Hydronephrosis was found to be predictive of inferior DFS (HR = 1.701, p = 0.003, 95% CI = 1.196-2.418) and OS (HR = 1.834, p = 0.008, 95% CI = 1.173-2.866). Subgroup analysis demonstrated differences in the T2-or-above subgroup (HR = 1.65; p = 0.004 in DFS and HR = 1.888; p = 0.008 in OS) and the T3-or-above subgroup (HR = 1.757; p = 0.017 in DFS and HR = 1.807; p = 0.034 in OS). CONCLUSIONS: The presence of preoperative hydronephrosis among MIBC patients carries additional prognostic implications on top of tumour staging. Its importance in case selection needs to be highlighted.

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This study aims to evaluate the prognostic utility of Activity-dependent neuroprotective protein (ADNP) expression in Circulating Tumor Cells (CTCs) inpatients with Non-muscle-invasive Bladder Cancer (NMIBC) undergoing Transurethral Resection of Bladder Tumor (TURBT). A prospective cohort of 74 bladder cancer patients and 22 non-cancer controls were enrolled. The expression of ADNP mRNA was detected by immunomagnetic beads-droplet digital PCR. The ADNP mRNA expression was evaluated in patients with high-risk NMIBC and those with indeterminate invasion depth post 2nd TURBT. Primary cultured bladder cancer cells and PBMCs from healthy donors were immunofluorescence stained. Our findings suggest that baseline ADNP mRNA level in CTCs shows potential as a prognostic marker for NMIBC with a sensitivity of 83.33% and a specificity of 73.58%. In comparison to baseline, ADNP mRNA expression increased post 2nd TURBT in 5 patients, where 2 experienced recurrence. Meanwhile, among the 12 patients with decreased levels, only one patient relapsed. A considerable limitation of this study entails the small sample size. The Immuno-magnetic beads-ddPCR technique provided a viable method for ADNP mRNA detection in CTCs from bladder cancer patients. The preoperative ADNP mRNA level in CTCs was identified as a prognostic indicator for NMIBC. Longitudinal monitoring of ADNP mRNA in CTCs of bladder cancer patients shows promise in evaluating treatment responses and predicting prognosis.

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Bladder cancer (BC) is the second most common type of cancer of the urinary system. Approximately 75% of the cases are non-muscle invasive bladder cancer (NMIBC), which has a high recurrence and progression rate. Current diagnosis and surveillance methods present challenges, including risks to the patients. For this reason, urinary biomarkers have been proposed as alternatives to the methods. The goal of this mini-review is to describe urinary mRNA-based biomarkers available in current literature for NMIBC tumors, using the PubMed database. The search included the following keywords: "biomarkers" AND "bladder cancer" AND "urine" and "RNA" and "non-muscle". The search yielded 11 original researchers utilizing mRNA-based urinary biomarkers. Although there is a wide variety of biomarkers described, the cohorts of the studies were not exclusively NMIBC, which is the subtype of BC that would mostly benefit from the introduction of a good follow-up biomarker, highlighting the need for randomized interventional trials for NMIBC.

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BACKGROUND AND OBJECTIVE: There has been a recent surge in the development of agents for bacillus Calmette-Guérin-unresponsive (BCG-U) non-muscle-invasive bladder cancer (NMIBC). Critical assessment of these agents and practical recommendations for optimal selection of patients and therapies are urgently needed, especially in the absence of randomized trials on bladder-sparing treatment (BST) options. METHODS: A global committee of bladder cancer experts was assembled to develop recommendations on BST for BCG-U NMIBC. Working groups reviewed the literature and developed draft recommendations, which were then voted on by International Bladder Cancer Group (IBCG) members using a modified Delphi process. During a live meeting in August 2023, voting results and supporting evidence were presented, and recommendations were refined on the basis of meeting discussions. Final recommendations achieved >75% agreement during the meeting, and some were further refined via web conferences and e-mail discussions. KEY FINDINGS AND LIMITATIONS: There is currently no single optimal agent for patients with BCG-U disease who seek to avoid radical cystectomy (RC). BST selection should be personalized, taking into account individual patient characteristics and preferences, tumor attributes, and efficacy/toxicity data for the agents available. For patients with BCG-U carcinoma in situ (CIS), gemcitabine/docetaxel (GEM/DOCE), nadofaragene firadenovec (NFF), and nogapendekin alfa inbakicept-pmln (NAI) + BCG are recommended; because of its systemic toxicity, pembrolizumab should only be offered after other options are exhausted. For patients with BCG-U papillary-only tumors, GEM/DOCE, NFF, NAI + BCG, single-agent chemotherapy, hyperthermic mitomycin C, and pembrolizumab are recommended. Given the modest efficacy of available options, clinical trial participation is encouraged. For unapproved agents with reported data, IBCG recommendations await the final results of pivotal trials. CONCLUSIONS AND CLINICAL IMPLICATIONS: The IBCG consensus recommendations provide practical guidance on BST for BCG-U NMIBC.