Bladder cancer is one of the most prevalent malignancies, and the mechanisms underlying its progression and the role of the tumor microenvironment (TME) are unclear. Recent advancements in single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics (ST) enable detailed analysis of the cellular heterogeneity, gene expression, and cell-cell interactions in bladder diseases. We conducted a comprehensive search for recent articles that have investigated bladder diseases using scRNA-seq and ST. scRNA-seq and ST have led to significant discoveries in bladder disease research. These technologies have enabled the identification of multiple molecular subtypes within individual tumors and of the mechanisms of treatment resistance. Additionally, molecular differences based on gender have been explored, explaining the heterogeneity of the incidence and progression of bladder cancer. These findings deepen our understanding of the pathology of bladder diseases and highlight the transformative potential of scRNA-seq and ST in identifying novel biomarkers and therapeutic targets. Integrating scRNA-seq and ST has considerably enhanced our understanding of tumor heterogeneity and the tumor microenvironment within tissues. These insights may lead to the development of personalized therapies and the improvement of patient outcomes. Several challenges, such as technical limitations and access difficulties, need to be addressed for the future clinical application of these technologies.

Radical cystectomy (RC) with urinary diversion (UD) is associated with substantial morbidity. Enhanced recovery after surgery protocols, increased robotic usage, and improvements in urinary diversion have been evaluated for their effects on health-related Quality of Life (HRQoL), however, results are mixed. How psychosocial traits inherent to the patient influence HRQoL outcomes is unknown in this population. This study aimed to evaluate resilience and its correlation with HRQoL in a cohort of patients undergoing RC for bladder cancer. Patients with bladder cancer undergoing RC with UD at the University of Kansas Medical Center were screened for prospective enrollment in this clinical trial (NCT06337305). The validated Connor-Davidson Resilience Scale 25 (CD-RISC), the Functional Assessment of Cancer Therapy-Bladder-Cystectomy (FACT-BL-Cys), and the PROMIS 29-v2.0 were administered preoperatively, 2-3 weeks postoperatively, and at 90 days postoperatively. Patient demographics, pathology, and complication data were collected. Between November 2020 and August 2022, 52 patients completed the survey data. Patients were stratified based on baseline resilience score. The higher resilience group scored 85.7, 85.0, and 81.9 compared to 64.9, 70.4, and 72.0 at the three time points which all remained statistically significant. Participant resilience scores using the CD-RISC did not correlate with quality-of-life measures using the PROMIS or FACT-Bl-Cys at baseline or two weeks but did correlate at 90 days (p < 0.01). Resilience did not correlate with the patient's pathology stage or 90-day complication data. Patients with higher baseline resilience maintain higher levels throughout the perioperative period and correlate with QOL.

Enfortumab vedotin (EV) and Sacituzumab govitecan (SG) are antibody-drug conjugates (ADCs) with demonstrated activity in advanced bladder cancer. A subset of bladder tumors harbors a DNA repair deficiency in either the homologous recombination (HR) or nucleotide excision repair (NER) pathway that has the potential to impact sensitivity to specific classes of therapeutics. Define the impact of HR or NER deficiency on sensitivity to ADC payloads alone or in combination with DNA repair targeted agents in bladder cancer. Isogenic cell pairs with versus without HR or NER deficiency were profiled using DNA repair and drug sensitivity assays. Sensitivity to the ADC payloads monomethyl auristatin E (MMAE) and SN-38 alone or in combination with small molecule inhibitors of poly(ADP-ribose) polymerase (PARP), ATR, or USP1 were measured using cell viability assays. BRCA2 loss was sufficient to confer an HR deficient phenotype and increase sensitivity to cisplatin and PARP inhibition in bladder cancer cell lines. HR deficiency, but not NER deficiency, increased sensitivity to MMAE and SN-38 in bladder cancer cells. The combination of SN-38 and PARP inhibition displayed synergistic cell killing independent of HR or NER status. HR and NER deficiency have distinct impacts on sensitivity to cisplatin and ADC payloads in bladder cancer preclinical models.

Several phase III randomized controlled trials (RCTs) have shown the importance of perioperative systemic therapy, especially for the efficacy of immune checkpoint inhibitors (ICIs) in both neoadjuvant and adjuvant settings for muscle-invasive bladder cancer (MIBC). To synthesize the growing evidence on the efficacy and safety of systemic therapies for MIBC utilizing the data from RCTs. Three databases and ClinicalTrials.gov were searched in October 2024 for eligible RCTs evaluating oncologic outcomes in MIBC patients treated with systemic therapy. We evaluated pathological complete response (pCR), disease-free survival (DFS), progression-free survival (PFS), event-free survival (EFS), overall survival (OS), and adverse events (AEs). Thirty-three RCTs (including 14 ongoing trials) were included in this systematic review. Neoadjuvant chemotherapy improved OS compared to radical cystectomy alone. Particularly, the VESPER trial demonstrated that dd-MVAC provided oncological benefits over GC alone in terms of pCR rates, OS (HR: 0.71), and PFS (HR: 0.70). Recently, the NIAGARA trial showed that perioperative durvalumab plus GC outperformed GC alone in terms of pCR rates, OS (HR: 0.75), and EFS (HR: 0.68). Despite the lack of data on overall AE rates in the VESPER trial, differential safety profiles in hematologic toxicity were reported between dd-MVAC and durvalumab plus GC regimens. In the adjuvant setting, no study provided the OS benefit from adjuvant chemotherapy. However, only adjuvant nivolumab had significant DFS and OS benefits compared to placebo. Neoadjuvant chemotherapy remains the current standard of care for MIBC. Durvalumab shed light on the promising impact of ICIs added to neoadjuvant chemotherapy. Nivolumab is the only ICI recommended as adjuvant therapy in patients who harbored adverse pathologic outcomes. Ongoing trials will provide further information on the impact of combination therapy, including chemotherapy, ICIs, and enfortumab vedotin, in both neoadjuvant and adjuvant settings.

Bladder cancer (BC), one of the most prevalent and aggressive urological malignancies, poses significant challenges in diagnosis, treatment, and recurrence management. Patient-derived organoid provides new directions for the precision diagnosis and treatment of bladder cancer. To make a comprehensive summary of the current bladder cancer organoid studies. A comprehensive database search was conducted to provide an in-depth overview of the current state of bladder cancer organoid models, with a focus on their applications in basic research, clinical translation, and therapeutic discovery. We summarized the current bladder cancer organoid studies, highlighting their advantages, such as genetic fidelity and high-throughput drug screening capabilities. Additionally, we also address the challenges, including their limited representation of the tumour microenvironment and technical complexity. Finally, we discuss future directions, including the integration of immunotherapy, the development of co-culture systems, and the exploration of non-invasive sampling methods and organoid-on-chip systems. Traditional pre-clinical models have inherent limitations in mimicking the complexity of human tumours. The emergence of organoid technology has offered a groundbreaking approach to address this challenge, providing an innovative tool for studying tumour biology, genetic alterations, drug screening, and personalized medicine in bladder cancer.

In current clinical practice, the use of switch maintenance avelumab is recommended for patients with locally advanced and metastatic urothelial carcinoma who experience favorable responses to first-line chemotherapy. We aimed to evaluate the potential advantages of platinum-based chemotherapy (Pl-CT) rechallenge after maintenance avelumab. A retrospective analysis involving 383 patients treated with first-line Pl-CT between 2015 and 2023 was conducted. Subsequent treatment strategies included Pl-CT or enfortumab vedotin (EV) following maintenance avelumab or pembrolizumab, and their benefit was evaluated. Pl-CT rechallenge following maintenance avelumab did not show significant benefits, demonstrating lower response rates and shorter progression-free survival compared to EV. Conversely, both Pl-CT and EV following pembrolizumab showed similar efficacy. These findings suggest that in the current clinical landscape, EV might be a more preferable option than Pl-CT rechallenge subsequent to avelumab maintenance therapy, thereby influencing treatment decisions for metastatic urothelial carcinoma.

The practice patterns and efficacy of ddMVAC administered with split-dose cisplatin for patients with muscle-invasive bladder cancer (MIBC) remains largely undefined. To characterize the application and overall survival (OS) in patients with MIBC receiving conventional ddMVAC versus split-dosed ddMVAC and to examine the predictive variables in those receiving split-dosed cisplatin. Using data from the CancerLinQ Discovery database, we identified 626 patients with bladder cancer between 2000-2023 with receipt of ddMVAC. The primary outcome was OS by receipt of split-dose versus conventional ddMVAC. A secondary outcome of interest assessed predictors of receipt of split-dose ddMVAC. Use of split-dose versus conventional ddMVAC was compared using chi-square tests. Univariate and multivariable OS were estimated using Cox proportional hazards models. Predictors of receipt of split dose versus conventional ddMVAC were estimated using logistic regression models. Most patients with MIBC are treated with standard dose ddMVAC. In multivariate analysis, no statistically significant difference in OS was observed between split-dose and conventional ddMVAC (HR 1.3, CI 0.78-2.18, p = 0.316). We demonstrate a notable decline in the use of split-dose cisplatin over time. Baseline GFR and performance status were not predictors of split-dosing in this cohort. Most patients with MIBC received conventional ddMVAC with decreasing frequency of split-dose cisplatin use over time. We did not observe a difference in OS between patients with MIBC who received standard versus split-dose cisplatin.

Metabolomic research and metabolomics-based biomarkers predicting treatment outcomes in bladder cancer remain limited. We explored the serum metabolites potentially associated with the risk of recurrence after intravesical Bacillus Calmette-Guérin (BCG) therapy. Two independent cohorts, a discovery cohort (n = 23) and a validation cohort (n = 40), were included in this study. Blood was collected before the induction of BCG therapy (pre-BCG blood; both discovery and validation cohorts) and after six doses of BCG (post-BCG blood; only discovery cohort). Metabolome analysis of serum samples was conducted using capillary electrophoresis time-of-flight mass spectrometry. The endpoint was intravesical recurrence-free survival, which was analysed using Kaplan-Meier estimates, the log-rank test, and the Cox proportional hazard model. Of the 353 metabolites quantified, nine (2.5%) and four (1.1%) were significantly upregulated and downregulated, respectively. The heatmap of hierarchical clustering analysis and principal coordinate analysis for the fold changes and in serum metabolites differentiated 10 recurrent cases and 13 non-recurrent cases in the discovery cohort. A metabolome response-based scoring model using 16 metabolites, including threonine and N6,N6,N6-trimethyl-lysine effectively stratified the risk of post-BCG recurrence. Additionally, pre-BCG metabolome-based score models using six metabolites, octanoylcarnitine, S-methylcysteine-S-oxide, theobromine, carnitine, indole-3-acetic acid, and valeric acid, were developed from the discovery cohort. Univariate and multivariate analyses confirmed a high predictive accuracy in the validation and combination cohorts. We demonstrated that numerous types of serum metabolites were altered in response to intravesical BCG and developed high-performance score models which might effectively differentiated the risk of post-BCG tumour recurrence.

Bladder cancer in the setting of previous a kidney transplant (KT) is challenging to manage due to complex medical and surgical considerations. To provide a comprehensive evaluation of the scope of management of bladder cancer in KT patients, and describe the controversies surrounding these management options. A systematic review of studies reporting management of KT patients with bladder cancer and involving ≥3 patients was performed. A narrative review was also performed for various aspects of management such as pathophysiology, surgical considerations, intravesical therapy, immunosuppression and oncological surveillance. Bladder cancer incidence in KT recipients is 2.8-4.1 times higher than the general population, and there is a notable association with aristolochic acid nephropathy as well as BK virus oncogenesis. Regarding surgical treatment, transurethral resection is preferred for non-muscle invasive tumors, and intravesical BCG for intermediate- and high-risk patients appears to be underutilized despite its safety and associated reduction in recurrence. Radical cystectomy with limited pelvic lymph node dissection, urinary diversion, and consideration of bilateral nephroureterectomy appears to be the safest method of oncological control in muscle-invasive tumors. A switch in immunosuppressive regimens to mTOR inhibitors may be considered in lieu of its antitumor effects. Routine surveillance in KT patients with risk factors for bladder cancer is challenging and may be warranted especially in the Asian population which has a higher rate of urothelial malignancy. This review provides a thorough summary of management strategies for bladder cancer in the setting of previous KT.