The immunotherapy-related analysis was validated only in the public IMvigor210 cohort of metastatic urothelial carcinoma

The gap

Evidence profile

Sourced from the future work and inline gaps of the source papers, classified as general, drawn from work published between 2025 and 2026, spanning 3 journals. Those papers have been cited 17 times in total.

Supporting evidence — 4 representative gaps

• Artificial Intelligence-Enhanced Multiparametric MRI and VI-RADS in Bladder Cancer: Current Evidence, Clinical Opportunities and Barriers to Translation (2026) · Cancers · doi

  The next phase of the field should move from isolated retrospective classifiers to prospectively evaluated clinical systems. Future studies should predefine the intended use case—reader support, equivocal-lesion triage, response assessment, or prognostic enrichment—and should evaluate lesion-level, patient-level, and pathway-level end- points separately. Calibration, uncertainty, subgroup performance, and failure analysis should be reported alongside discrimination metrics in line with modern AI reporting standards [20,21,26]. Methodologically, that means site-held-out and temporal validation, stronger pathol- ogy linkage, and explicit analysis of how performance changes as segmentation becomes more automated [25,46,47,49]. Clinically, it means pathway-based trials asking whether AI-enhanced mpMRI reduces time to correct treatment, improves management of equivocal disease, or supports safer response-adapted bladder preservation [18,24,43]. Biologically, it means linking imaging to radiogenomics and multi-omics so that risk estimates reflect more than anatomy alone [35,36,50,54]. The systems most likely to matter are not simply the most accurate in curated datasets, but the ones that remain stable across centers and improve real decisions in difficult cases.

  generalfuture work
  Keywords: level means systems equivocal lesion response pathway performance next phase field move isolated retrospective classifiers
• Circulating Tumor DNA in Upper Tract Urothelial Carcinoma: A Framework for Precision Perioperative Management (2026) · Cancers · doi

  Future clinical trial designs should prioritize the integration of ctDNA as a central, pre-specified component rather than a secondary or exploratory endpoint. In UTUC, where therapeutic decision-making is often constrained by limited evidence and heterogeneous risk profiles, biomarker-driven trials may offer a critical path forward. Clinical trials specif- ically enrolling ctDNA-positive patients following nephroureterectomy and randomizing them to adjuvant systemic therapy versus observation would provide the most definitive evidence of clinical utility and determine whether MRD-guided intervention improves sur- vival outcomes and other clinically meaningful endpoints. Such designs could potentially establish ctDNA as a predictive biomarker capable of identifying patients most likely to benefit from treatment escalation. Several ongoing urothelial carcinoma trials are currently evaluating ctDNA-guided therapeutic strategies and may provide important insights relevant to future UTUC-specific trial development. However, dedicated prospective studies specifically designed for UTUC remain limited. Future UTUC-specific studies should prospectively enroll patients with https://doi.org/10.3390/cancers18101651 Cancers 2026, 18, 1651 13 of 16 high-risk localized disease, incorporate predefined ctDNA time points, and evaluate paired plasma ctDNA and utDNA approaches. Stratification by renal pelvis versus ureteral pri- mary, Lynch syndrome/MMR status, FGFR3 alterations, renal function, and perioperative systemic therapy may further refine biologic interpretation. Given the rarity of UTUC, adaptive and collaborative trial designs will likely be important, although safeguards addressing false-positive and false-negative ctDNA results remain essential. Adaptive trial designs could allow escalation or de-escalation of therapy based on ctDNA dynamics, reflecting a more personalized and biology-driven approach to cancer care. For example, patients with persistent ctDNA positivity after initial therapy could be prospectively evaluated for combination regimens or novel agents, whereas those demonstrating early ctDNA clearance might be candidates for treatment de-escalation or abbreviated therapy duration within prospective clinical trials. This approach aligns with a broader shift toward response-adapted oncology, where therapeutic intensity is continuously refined based on evolving tumor biology rather than fixed treatment algo- rithms. Platform trials incorporating multiple therapeutic arms such as immunotherapy, ADCs, and targeted therapies could be particularly valuable in UTUC, allowing for efficient evaluation of ctDNA-guided strategies across diverse treatment modalities. Importantly, given the relative rarity of UTUC, multi-institutional and international collaboration will be pivotal to achieve adequate patient accrual, increase statistical power, and ensure that findings are generalizable across populations. Beyond its role in guiding perioperat

  generalfuture work
  Keywords: ctdna utuc trials therapy clinical trial designs therapeutic patients treatment escalation future guided rather limited
• Construction of a risk model based on folate metabolism-related genes to predict prognosis and immunological characteristics of stomach adenocarcinoma (2026) · Discover Oncology · doi

  Moreover, the immunotherapy-related analysis was validated only in the public IMvigor210 cohort of metastatic urothelial carcinoma; therefore, this represents a cross-cancer exploratory validation rather than disease-specific confirmation in STAD, and the generalizability of the immunotherapy findings remains to be further verified in real-world STAD immunotherapy cohorts. Therefore, future studies are warranted to validate the model in large-scale prospective clinical cohorts, thereby excluding potential data selection bias and cohort heterogeneity.

  generalinline gaps
  Keywords: immunotherapy cohort stad cohorts related validated public imvigor metastatic urothelial carcinoma represents cross cancer exploratory
• Advances in Therapy for Urothelial and Non-Urothelial Subtype Histologies of Advanced Bladder Cancer: From Etiology to Current Development (2025) · Biomedicines · cited 17× · doi

  - Increased risk of misclassification due to overlapping histopathological features. - Difficulty in achieving accurate diagnoses. - Different subtypes respond uniquely to chemotherapy, immunotherapy, and targeted therapies. - Biological behavior influences therapeutic outcomes. - Limitations of General Trials: Including subtype patients in general urothelial carcinoma trials may dilute results and fail to provide meaningful data. - Advantages of Specialized Trials: Dedicated international trials focusing on subtypes can generate robust and meaningful data to improve patient outcomes. - Implementation Challenges: While there are logistical challenges such as multicenter collaboration, funding, and patient recruitment, the benefits outweigh the difficulties. - Need for International Efforts: Addressing unmet needs associated with subtypes requires collaboration from international genitourinary oncology community. - Design of Specialized Clinical Trials: It is important to design and implement clinical trials specifically targeting these subtypes. - Industry Partnerships and Funding: Partnerships with industry and securing adequate funding are essential for advancing research initiatives. - Ultimate Goal: These efforts aim to establish evidence-based targeted treatment protocols for aggressive cancer subtypes, significantly improving patient outcomes. - Advancements in Molecular Characterization: Rapid progress in molecular characterization of bladder cancer is expected to utilize molecular subtyping for prognosis assessment and personalized therapies. - Integrated Classification System: Need for system combining molecular subtyping with traditional histology-based approaches. - Enhance predictive accuracy and personalized treatment strategies: Such an integrated framework can lead to more accurate predictions and enhanced personalized treatment strategies. Approximately 30% of tumor subtypes reclassified in ABACUS-2 trial [102] Sarcomatoid tumors: 62% pathological response to immunotherapy vs. squamous cell carcinomas: 8% [131] - Emphasize importance of central pathology reviews - Utilize advanced tools such as artificial intelligence in digital pathology [130] - Develop subtype-specific treatment protocols - Establish treatment strategies based on distinct signaling pathways and genetic mutations [133] “UNITED study” showing variable response rates to enfortumab vedotin based on subtype predominance [132] - Conduct dedicated international trials focusing on specific subtypes - Ensure multicenter collaboration and adequate funding for robust studies - Strengthen collaboration within international genitourinary oncology community - Build partnerships with industry and secure appropriate funding to advance research initiatives Biomedicines 2025, 13, 86 25 of 31 Author Contributions: Conceptualization, W.-A.K. and W.S.P.; writing—original draft preparation, W.-A.K.; writing—review and editing, all authors; supervision, W.-A.K., H.K.S., G.S., M.-K.L. and W.S.P. All authors have read and agreed to the published version of the manuscript. Funding: This work was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (2022R1F1A061069) and the Technology Innovation Program (20008924) funded by the Ministry of Trade, Industry, and Energy (MOTIE, Korea). Institutional Review Board Statement: Not applicable. Informed Consent Statement: Not applicable. Data Availability Statement: No new data were created. Conflicts of Interest: The authors declare no conflicts of interest.

  generalfuture work
  Keywords: subtypes trials funding international treatment collaboration industry based molecular outcomes subtype patient partnerships personalized strategies

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