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Open research questions in Bladder and Urothelial Cancer Treatments

42 unresolved questions extracted from the limitations and future-work sections of 409 Bladder and Urothelial Cancer Treatments papers in our library. Each links back to the study that raised it.

What the literature leaves open

  • The potential prognostic significance of CAR as a biomarker in patients with bladder cancer who underwent radical cystectomy should be further investigated in prospective studies involving larger patient cohorts and extended follow-up periods.

    Preoperative C-reactive protein-to-albumin ratio as a prognostic marker of histopathological characteristics and survival outcomes following radical cystectomy · 2026 · DOI

  • These findings support incorporating squamous differ- entiation into risk stratification models and clinical trial eligibility criteria, and they underscore the need for further research into molecular mechanisms and targeted therapies for squamous histologies in bladder cancer. Nevertheless, given the limited sample size of pure SCC in our institutional cohort, further studies with larger SCC cohorts are warranted to confirm these results.

    The prognostic impact of squamous differentiation in bladder cancer after radical cystectomy: a propensity score-matched comparative analysis of pure urothelial carcinoma, urothelial carcinoma with squamous differentiation, and squamous cell carcinoma · 2026 · DOI

  • Though this resulted in substantial uncer- tainty in the cisplatin PD, it provides a clear demonstration of the interpretability of the results from this workflow, directly indicating when individual data were insufficient.

    Innovative In Vitro-In Silico Platform for Dose–Response Modeling in Canine Bladder Cancer: A 3D Organoid- and Mathematics-Based Approach · 2026 · DOI

  • Results: Intravesical BCG was associated with decreased sperm concentration and motility, in some cases with progression to oligospermia and abnormal sperm morphology including "amorphous" heads, bent necks, and short tails—although results were inconsistent.

    The Impacts of Intravesical Bacillus Calmette–Guérin (BCG) Therapy on Male Fertility in Non-Muscle-Invasive Bladder Cancer (NMIBC): A Narrative Review · 2026 · DOI

  • This review therefore emphasizes several translational issues that are often underreported: lesion-level versus patient-level inference, the distortive effect of TURBT-based labels, the need to evaluate false-negative consequences in VI-RADS 3 tumors, and the distinction between diagnostic support and broader pathway redesign.

    Artificial Intelligence-Enhanced Multiparametric MRI and VI-RADS in Bladder Cancer: Current Evidence, Clinical Opportunities and Barriers to Translation · 2026 · DOI

  • The potential biological functions of these fragments remain to be clarified. First, our research focused on full-length ELN; however, the degra- dation fragments known as elastin-derived peptides (EDPs), which are typically generated by elastase-me- diated cleavage, were not investigated in vivo. Second, we primarily examined the effects of ELN on T cells and macrophages; the respons- es of other immune populations within the TME, such as DCs and neutrophils, were not explored in this study.

    ELN orchestrates prometastatic and immunosuppressive niche in bladder cancer via TGFB1 autocrine signaling · 2026 · DOI

  • This study has several limitations that should be considered. Given its retrospective design, selection bias and residual confounding cannot be fully excluded. Although baseline characteristics were generally comparable between groups, differences related to case selection, surgeon preference, and evolving clinical practice over time cannot be fully excluded. The robotic approach was introduced later during the study period, resulting in shorter follow-up and poten- tial era-related effects, including changes in perioperative management and learning curve influences. In particular, the higher proportion of T3 disease in the robotic cohort may reflect temporal trends or case selection patterns, which could have contributed to the observed findings in subgroup analyses. In addition, perioperative management, including the use of intravesical chemotherapy, was not standardized and may have varied over time, introducing further hetero- geneity. The relatively small number of events, especially within post-hoc subgroup analyses, also limits statistical power and warrants cautious interpretation. Importantly, the observed association between robotic surgery and reduced IVR should not be interpreted as causal, as unmeasured technical and perioperative factors may have influenced the results. Despite these limitations, this study provides additional real-world evidence supporting the role of minimally inva- sive nephroureterectomy in UTUC. Both laparoscopic and robotic approaches achieved comparable oncologic out- comes while maintaining acceptable perioperative safety. The lower rate of IVR observed in patients with pathologi- cal T3 disease undergoing robotic surgery is of interest; nev- ertheless, this finding should be regarded as exploratory and hypothesis-generating. Further validation in larger, prefer- ably prospective studies with standardized perioperative management is required before definitive conclusions can be drawn.

    Robotic versus laparoscopic radical nephroureterectomy for upper tract urothelial carcinoma: comparable oncologic outcomes with reduced intravesical recurrence in pathological T3 disease · 2026 · DOI

  • Emerging innovations in intravesical drug delivery may further refine NMIBC management by reducing reliance on patient compliance and minimizing variability in instillation technique. Thermosensitive hydrogels that transition from liquid to gel at body temperature have demonstrated prolonged intravesical residence times and sus- tained urothelial exposure in preclinical bladder models.16 Similarly, nanoparticle-based formulations of BCG and chemotherapeutic agents have been explored as a means of controlled intravesical drug release, potentially extending therapeutic exposure while reducing peak-related toxicity.17 Drug-eluting platforms, adapted from ureteral and vascular stent technologies, represent another investigational approach to achieving sustained mucosal contact without repeated catheterization.18 While promising, these technologies remain largely 6 Khan et al. Beyond the Rotisserie Urology Research and Practice 2026;52:1-8 preclinical or early-phase and require prospective validation before clinical adoption. Advances in intravesical imaging may also inform future procedural optimization. Techniques such as intravesical fluorescence map- ping and ultrasound-enhanced microbubble dispersion have been investigated as methods to visualize agent distribution and blad- der wall contact in real time.19 If validated, such approaches could help identify suboptimal drug coverage related to bladder anatomy or instillation technique, thereby guiding individualized procedural adjustments rather than uniform protocols. From a clinical research standpoint, there remains a need for well- designed, multicenter studies examining intravesical delivery parameters across agents beyond BCG. In particular, comparative trials evaluating catheter removal versus clamped Foley strategies for intravesical chemotherapy (e.g., mitomycin-C, gemcitabine) are warranted, incorporating oncologic outcomes, patient-reported tol- erability, and health-economic endpoints. In parallel, remote moni- toring strategies—including telehealth-based dwell-time tracking and patient-reported outcome tools—may offer pragmatic solutions to improve adherence and safety, especially in settings where pro- longed in-clinic observation is impractical.20 Tumor Grade, Risk Stratification, and Emerging Analytic Tools Current NMIBC management frameworks rely primarily on tumor stage to guide treatment selection and surveillance intensity. While stage remains essential for anatomical classification and procedural planning, tumor grade reflects intrinsic biological aggressiveness and is a critical determinant of recurrence and progression risk. High-grade NMIBC, even when superficially staged, is associated with substantially worse oncologic outcomes compared with low-grade disease, under- scoring the importance of accurate histopathologic assessment.21,22 Recent advances in digital pathology and computational analyt- ics have generated interest in the use of artificial intelligence (AI) to augment traditional risk stratification. Early studies suggest that machine-learning models applied to histopathologic images, molec- ular profiles, and longitudinal clinical data may improve prediction of recurrence and progression beyond conventional clinicopathologic variables.23 At present, however, most AI-driven models in NMIBC remain investigational, with limited external validation and uncer- tain generalizability across practice settings. Rather than replacing established staging systems, emerging ana- lytic tools may ultimately complement existing frameworks by refin- ing risk estimates and informing surveillance or treatment intensity. Future integration of such approaches will require rigorous prospec- tive validation, transparent model development, and clear demon- stration of clinical utility before incorporation into routine NMIBC care. Within this context, procedural optimization of intravesical ther- apy—grounded in evidence and patient-centered practice—remains a foundational component of effective bladder cancer management.

    Beyond the Rotisserie: Dispelling the Myths of Intravesical Therapy and Pioneering a Precision Future for Bladder Cancer · 2026 · DOI

  • Our study is subject to several limitations. First, the dataset was imbalanced (13% positive cases), which can negatively impact model performance by causing bias toward the majority class. To address this, we applied class-weighting techniques, assigning higher penalties to misclassifications in the minority class (positive) compared with the majority class (negative), thereby encouraging the model to better distinguish between them. Second, the analysis was based on a small dataset of 252 patients. While including more patients, and in particular more positive cases, would increase the credibility of our results, this study represents one of the largest prospective patient cohorts with longitudinal monitoring after RC, which adds to its value despite its size. Third, variability in sensor wearing time may have introduced errors in activity measurement, although we mitigated this by filtering out monitoring phases with insufficient data and aggregating data across phases. Missingness in RPM data represents another limitation. Missing data arose primarily from not wearing the device and device loss in shipping during the COVID-19 pandemic. Such missingness may introduce bias and reduce statisti- cal power, especially if it is not missing at random. That said, missingness was treated as features in the CP+RPM model and suggested added value to the mortality predic- tion. Additionally, the baseline models (nomogram and CP-only model) are unaffected by missing data because they rely exclusively on clinical-pathological variables. In the future, prospective validation with predefined data collection protocols and external cohorts will be conducted to confirm model robustness and clinical usefulness prior to real-world deployment. Ideally, the model would be validated using external data. However, this type of dataset is extremely rare due to the complexity and heterogeneity of the patient population and the clinical burden of data collection. The dataset used in this study was itself collected across multiple centers, providing a degree of institutional and clinical diversity. Nevertheless, the total number of patients remained small, which precluded holding out an independent external cohort without substan- tially compromising model training and evaluation. In the future, we will include an external validation dataset for this AI RPM model evaluation.

    Artificial Intelligence Remote Patient Monitoring for Predicting Overall Survival for Patients Undergoing Radical Cystectomy for Bladder Cancer: Exploratory Analysis of the Prospective Trial · 2026 · DOI

  • BACKGROUND: Number of studies has been performed to investigate the association of NAD (P) H quinine oxidoreductase 1 (NQO1) rs1800566 polymorphism with risk of bladder and prostate cancers, but presented inconsistent results.

    Association of NAD(P)H Quinine Oxidoreductase 1 rs1800566 Polymorphism with Bladder and Prostate Cancers – a Systematic Review and Meta-Analysis · 2020 · DOI

  • However, this paper concerns clinically important problems, but while both the incidence of bladder cancer is high and EORTC tables still need to be validated in contemporary series of patients, in my opinion, the authors leave us with some unaddressed and unexplained issues.

    Who needs numbers more: patients or doctors? · 2013 · DOI

  • OBJECTIVES: The A148T polymorphism of CDKN2A gene is observed in various neoplasms with the incidence rate of 3-35%, however, rather little is known either about the frequency of its occurrence or of its significance in urinary bladder carcinoma.

    Significance of CDKN2A gene A148T variant in patients with bladder cancer · 2011 · DOI

  • However, its clinical specificity in populations without hematuria has not been fully evaluated.

    Specificity of a Urine-Based PENK Methylation Test (EarlyTect Bladder Cancer) in Patients With Benign Urologic Conditions and Healthy Controls · 2026 · DOI

  • Filamin C (FLNC) has been reported implicated in various cancers, but its role in BC remains unclear.

    Filamin C activates MAPK/ERK signaling to facilitate epithelial-mesenchymal transition in bladder cancer · 2026 · DOI

  • Molecular correlates of IVR after UTUC surgery are poorly understood, while therapeutic targets for UTUC and diagnostic markers for IVR are lacking.

    Genomic characterization of upper urinary tract urothelial carcinoma and clonal evolution of intravesical recurrences · 2026 · DOI

  • Although early mortality rates are comparable, cutaneous ureterostomy may offer a safer profile for high-risk individuals, though long-term comparative studies with multivariable adjustment are warranted.

    Cutaneous ureterostomy versus ileal conduit as urinary diversion in patients with muscle-invasive bladder cancer undergoing radical cystectomy: A comparative analysis of high-risk cases · 2026 · DOI

  • The heterogeneity analyses indicated substantial variation among some direct comparisons, probably due to small sample sizes, whereas heterogeneity could not be assessed…

    Comparison of the efficacy of different orthotopic neobladder reconstruction techniques following radical cystectomy for bladder cancer: a network meta-analysis · 2026 · DOI

  • For patients with muscle-invasive disease, more aggressive therapy with radical cystectomy and urinary diversion or trimodal therapy with maximal endoscopic resection, radiosensitizing chemotherapy, and radiation is warranted to curb the risk of metastasis and disease-specific mortality.

    Bladder Cancer · 2020 · DOI

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42 open questions have been extracted from the limitations and future-work passages of 409 Bladder and Urothelial Cancer Treatments papers in our library. Each one below links back to the study that raised it, so you can read the original claim in context.

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