Bladder Cancer最新文献

Purpose: This study aims to identify specific genotypes within the UK Biobank (UKB) cohort contributing to a genetic predisposition for bladder cancer (UBC). It highlighted the impact of environmental exposures and the broader role of certain genes in UBC development, offering a comprehensive understanding of the genetic basis for UBC susceptibility.

Experimental design: Leveraging the rich data from the UKB- a longitudinal study involving participants across the UK-the primary outcome was the presence of UBC, determined using ICD-10 and ICD-9 codes. The study employed rigorous Genome-Wide Association Study (GWAS) protocols, Phenome-Wide Association (PheWAS) frameworks, and gene-level pleiotropy analyses. Quality control measures were applied, such as single-nucleotide polymorphisms (SNP) missingness and minor allele frequency thresholds. Polygenic Risk Score (PRS) evaluations were also conducted based on the Mavaddat score using UKB's high-density genome-wide SNP dataset.

Results: Our GWAS identified significant associations between UBC risk and genetic variants, notably in the PSCA and TERT genes. The UGT1A polymorphism was found to be protective against UBC, particularly in heavy smokers. The PheWAS framework linked UBC-predisposition polymorphisms to other conditions, such as prostate cancer.

Conclusions: Our GWAS identified significant associations between UBC risk and genetic variants across loci, including PSCA, TERT, TACC3 and TMEM129. The protective effect of the UGT1A variant against UBC, especially concerning tobacco exposure, suggests the potential for genetic-based preventive strategies in UBC management.Patient summary In our study of a large group from the United Kingdom (UK), we explored genetic factors that might increase the likelihood of developing UBC. We discovered that certain genetic changes offer protection against UBC, particularly in individuals exposed to tobacco smoke. Understanding these genetic factors could improve strategies for preventing and treating UBC.

Purpose: This study aimed to evaluate the impact of lymphovascular invasion (LVI) and histologic subtypes on prognosis following Bacillus Calmette-Guérin (BCG) therapy in high-grade non-muscle invasive bladder cancer (NMIBC).

Methods: We retrospectively analyzed 245 patients who underwent transurethral resection of bladder tumor (TURBT) for high-grade Ta, T1, or carcinoma in situ (CIS) and received BCG therapy between January 2010 and December 2020. Effects of LVI and histologic subtypes on recurrence-free survival (RFS) and progression-free survival (PFS) were assessed using Kaplan-Meier and Cox regression analyses.

Results: At median follow-up of 48.5 months, LVI was detected in 25.7% of patients and histologic subtypes in 36.3%. During follow-up, disease recurrence occurred in 98 patients (40.0%) and progression in 45 patients (18.4%). In multivariate analysis, LVI (HR: 2.28, 95% CI: 1.68-3.10, p < 0.001) and histologic subtypes ≥1% (HR: 1.95, 95% CI: 1.45-2.62, p < 0.001) were independent risk factors for recurrence. Similarly, LVI (HR: 2.85, 95% CI: 1.98-4.11, p < 0.001) and histologic subtypes ≥1% (HR: 2.34, 95% CI: 1.67-3.28, p < 0.001) were independent risk factors for progression. Patients with concurrent LVI and histologic subtypes demonstrated highest risk of progression (HR: 4.15, 95% CI: 2.85-6.05, p < 0.001) with 5-year PFS rate of 45.2%.

Conclusion: In high-grade NMIBC patients receiving BCG therapy, LVI and histologic subtypes are strong independent risk factors for disease recurrence and progression. Patients with both factors have highest risk and may require more aggressive treatment strategies including consideration of early radical cystectomy. These findings support the importance of detailed pathological assessment in treatment selection for BCG-treated NMIBC patients.

Background: The presence of cancer in pelvic lymph nodes removed during radical surgery for muscle-invasive bladder cancer (MIBC) is a key determinant of patient outcome. It would be beneficial to predict node status preoperatively to tailor the use of neoadjuvant chemotherapy and extent of lymph node dissection. Of 12 published node status predictors based on tumor RNA expression signatures, none have been successfully validated in subsequent reports. Objective: We aimed to validate all published node status predictors and evaluate new prediction models in MIBC. Methods: Gene expression data and node status from two MIBC cohorts were used to test 12 published node-predictive signatures. The overlap in differential expression was examined across the two datasets, and new prediction models were tested in cross-validation and by application to the independent cohort. Results: Published node status predictors performed either no better, or only slightly better than chance in the two independent validation datasets (maximum AUC 0.59 and 0.65, and maximum balanced accuracy 0.54 and 0.57). Among very few genes and signatures differentially expressed in the same direction in both data sets we identified upregulation of interferon-response signatures in node negative cases. Transcriptomic predictors trained in one dataset performed poorly when applied to the independent dataset (AUC 0.60-0.62). Conclusions: In this systematic evaluation, neither the 12 published signatures nor our own models reached an adequate performance for clinical node status prediction in independent data. This indicates that the biological determinants of nodal spread are poorly captured by bulk tumor RNA expression profiles.

Small cell carcinoma of the bladder (SCCB) is a rare, aggressive malignancy that accounts for less than 1% of all bladder cancers. In this report, we highlight the clinical manifestations of SCCB (including epidemiology, cystoscopic and imaging findings), summarize insights into the molecular mechanisms underlying its pathophysiology, detail current methods of staging, review local and systemic treatment, and explore novel agents currently in clinical development. Most of the regimens used for SCCB treatment are extrapolated from small cell lung cancer, a more common cancer that shares the neuroendocrine and aggressive clinical phenotype of SCCB. Greater preclinical research can help to elucidate pertinent similarities and differences between SCCB and other neuroendocrine cancers as well as reveal new therapeutic targets, while increased participation of patients with SCCB in clinical trials may provide additional treatment options for patients with this aggressive cancer.

Background: The recommended treatment for high-risk non-muscle invasive bladder cancer (NMIBC) is intravesical instillations of Bacillus Calmette-Guérin (BCG). Despite completing BCG therapy, up to 40% of patients experience disease recurrence within five years. T cell exhaustion has been associated with poor outcome following treatment with BCG.

Objective: In this study, we investigated whether T cell exhaustion, characterized by tumor protein expression of PD-1 and PD-L1 in paired samples obtained before and after BCG treatment could provide further insight into BCG response and help predict outcome in patients with NMIBC.

Methods: Tumor samples from 104 patients with NMIBC were collected before and after BCG. Sections from tissue microarrays were stained using immunohistochemistry to analyze the protein expression of PD-1 and PD-L1. Data was analyzed using digital pathology software.

Results: High PD-1 expression was associated with higher tumor stage and grade pre-BCG (p = 0.001 and p = 0.002) and with tumor stage post-BCG (p = 0.005). PD-L1 was associated with higher tumor stage in pre- and post-BCG samples (p = 0.006 and p = 0.048). Patients with low expression of PD-1 and PD-L1 in the pre-BCG tumor had a superior high-grade recurrence-free survival (HG-RFS) compared to patients with high PD-1 (p = 0.008) and PD-L1 (p = 0.006) expression.

Conclusion: Protein expression of the exhaustion markers PD-1 and PD-L1 in pre-BCG tumor samples were correlated to higher stage and grade as well as worse HG-RFS, indicating that T cell exhaustion may play an important role in resistance to BCG treatment.

Bladder cancer (BC) is a significant global health concern, with non-muscle invasive bladder cancer (NMIBC) comprising 75% of cases at diagnosis. High-risk NMIBC (HR-NMIBC) poses a significant therapeutic challenge due to its high recurrence and progression rates despite Bacillus Calmette-Guerin (BCG) therapy. Radical cystectomy remains the gold standard for BCG-unresponsive cases but is often met with considerable morbidity and patient reluctance. This has driven research into alternative bladder-sparing therapies (BSTs). Emerging BSTs include immune checkpoint inhibitors like pembrolizumab and novel agents such as nadofaragene firadenovec and nogapendekin alfa inbakicept (IL-15). These therapies have demonstrated promising response rates in clinical trials, offering potential for disease management while preserving bladder function. Gene therapies and targeted agents like CG0070 and EG-70 are also gaining traction for their innovative mechanisms. However, most data are derived from early-phase, single-arm studies, necessitating larger, randomised trials for validation. Device-assisted strategies, including hyperthermic and electromotive drug delivery systems, show potential to enhance intravesical therapy efficacy. Despite advancements, challenges remain in balancing efficacy, safety, and cost-effectiveness within diverse healthcare settings. This narrative review highlights the evolving landscape of BSTs for HR-NMIBC, emphasising the need for robust clinical evidence to refine patient selection and optimise outcomes.

Trimodality therapy (TMT), consisting of maximal transurethral resection of bladder tumor (TURBT) followed by concurrent chemoradiotherapy, has emerged as a bladder-sparing alternative to radical cystectomy for select patients with muscle-invasive bladder cancer (MIBC). While each component of TMT plays a critical role, maximal TURBT is foundational to its success. This review examines the importance of maximal TURBT in optimizing oncological outcomes in TMT, discusses its technical nuances, and explores the evidence supporting its role in achieving durable local control and improving survival outcomes in MIBC.

Background: During surveillance of high-risk non-muscle invasive bladder cancer (HR-NMIBC), occult disease can be missed by standard cystoscopy.

Objective: To determine the utility of enhanced restaging procedures.

Methods: We retrospectively reviewed 297 patients with HR-NMIBC who underwent enhanced restaging procedures during the first surveillance following induction intravesical therapy between 2010-2021. Patients were stratified by number of induction treatments with unique agents (161, 63, and 73 patients with 1, 2, and 3+ treatments) and analyzed using exact logistic regression models. Enhanced restaging procedures included standard cystoscopy (white-light cystoscopy with bladder wash cytology) plus additional components including blue-light cystoscopy, mapping bladder biopsies, retrograde pyelograms, upper tract cytologies, and prostatic urethral biopsies.

Results: When standard cystoscopy was negative, blue light cystoscopy detected occult bladder cancer in 6.0%, 7.4%, and 19% of patients in the 1, 2, and 3+ treatment groups. History of CIS was associated with increased detection with blue light (p = 0.03). Extravesical (upper tract or prostatic urethral) cancer was detected by additional restaging components in 0.6%, 1.7%, and 15% of patients with 1, 2, and 3+ intravesical treatments. On multivariable analysis, receipt of 3+ intravesical inductions increased the odds of having at least one additional restaging component identify cancer (HR 3.76; p < .01).

Conclusions: Blue light cystoscopy improves surveillance of HR-NMIBC, particularly in those with CIS. Additional restaging procedures improved detection of extravesical disease in patients with heavier pre-treatment history. Risk-adapted utilization of enhanced restaging procedures requires further study.