Muscle-invasive Bladder Cancer Research Articles

VI-RADS-based Algorithm for Bladder Cancer Management Randomized Retrospective Study

To evaluate if VI-RADS can distinguish between non-muscle-invasive bladder cancers (NMIBC), muscle-invasive bladder cancer (MIBC), and high-risk non-muscle-invasive bladder cancers (HR-NMIBCs). It is unclear if the Vesical Imaging-Reporting and Data System (VI-RADS) can replace repeated transurethral resection of bladder tumour (Re-TURBT) as in the new VI-RADS-based algorithm. Sensitivity, specificity, and positive (PPV) and negative (NPV) predictive values of the VI-RADS score were calculated for mpMRI performance in patients undergoing TURBT and HR-NMIBC patients for only Re-TURBT. Of 283 cases, when VI-RADS≥3 lesions were considered muscle-invasive, its sensitivity was 95.7% and specificity was 92.5%. PPV and NPV were 86.6% and 97.7%, respectively. The area under the curve (AUC) was 0.942 (p <.001). Of 89 patients undergoing post-Re-TURBT, 41 (46%) were tumour-free, 47 (50.5%) showed permanent HR-NMIBC, and 3 (2.2%) were upgraded to MIBC. Per the new VI-RADS-based approach, 73 (41%) of the 178 HR-NMIBCs with VI-RADS≤ 2 would not undergo Re-TURBT. Of the 75 patients with VI-RADS ≥ 4, 6 (6) with HR-NMIBCs (8%) would not undergo Re-TURBT. When incomplete resections were excluded, 35 (60.3%) of the patients had complete resection, 23 (39.7%) had residual disease, and complete resection would not have been performed in these patients, and 2 (100%) still had residual disease. The new VI-RADS-based algorithm helped VI-RADS ≥ 4 patients by switching to radical treatment. Since the residual disease is high in cases with VI-RADS ≤ 2, even if incomplete resections are excluded, TURBT should be continued.

Intra-arterial chemotherapy combined with BCG immunotherapy is more effective than intra-arterial chemotherapy plus intravesical chemotherapy or standard BCG immunotherapy in preventing the recurrence and progression of high-risk non–muscle-invasive bladder cancer

BackgroundUp to 45% of patients with high-risk non–muscle-invasive bladder cancer (NMIBC) will not benefit from adjuvant intravesical instillation. We aimed to introduce intra-arterial chemotherapy (IAC) to existing intravesical treatment and evaluate its feasibility and safety. Materials and methodsWe collected data from 170 patients who had been diagnosed with high-risk NMIBC and underwent transurethral resection of bladder tumor (TURBT) over the last 5 years. Twenty-seven patients were excluded according to specific exclusion criteria. The remaining 143 patients were divided into 3 groups according to their treatment: intravesical instillation of Bacillus Calmette – Guerin (BCG), BCG+ intra-arterial chemotherapy (IAC), and intravesical chemotherapy (IVC)+IAC groups. All groups received standard intravesical instillation of BCG or chemotherapeutic agents. In contrast, both the BCG+IAC and IVC+IAC groups received four courses of IAC (injection of cisplatin [60 mg/m2] and epirubicin [50 mg/m2] in the internal iliac arteries via Seldinger's percutaneous technique). ResultsThe median follow-up time was 47 months, ranging from 20 to 60 months. The restricted mean survival time (RMST), which represents the recurrence and progression rate of the BCG+IAC group, differed significantly when compared with the BCG group (P = 0.029 and 0.004, respectively) and the IVC+IAC group (P = 0.004 and 0.006, respectively). Kaplan-Meier plots revealed that the recurrence and progression-free survival of the BCG+IAC group were significantly higher than the BCG and IVC+IAC groups (P = 0.033 and 0.028, respectively). In contrast, the BCG and IVC+IAC groups showed similar RMST (P = 0.156 and 0.935, respectively), recurrence (P = 0.627), and progression-free (P = 0.931) survival. A small proportion of patients (20%) suffered from the adverse effects of IAC while 65% suffered from adverse reactions to intravesical instillation. Most adverse effects were ranked as grade I or II according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. ConclusionAnalysis showed that tumor recurrence and progression rate in the BCG+IAC group was lower than the BCG and IVC+IAC groups while patients in the IVC+IAC group suffered from milder adverse effects in cystitis and flu-like symptoms. Our findings may provide a new perspective for urologists when treating patients with high-risk NMIBC.

Adjuvant intravesical therapy in intermediate-risk non-muscle-invasive bladder cancer.

To evaluate the impact of adjuvant therapy on oncological outcomes in patients with intermediate-risk non-muscle-invasive bladder cancer (NMIBC), as due to the poorly-defined and overlapping diagnostic criteria optimal decision-making remains challenging in these patients. In this multicentre study, patients treated with transurethral resection of bladder tumour for Ta disease were retrospectively analysed. All patients with low- or high-risk NMIBC were excluded from the analysis. Associations between adjuvant therapy administration with recurrence-free survival (RFS) and progression-free survival (PFS) rates were assessed in Cox regression models. A total of 2206 patients with intermediate-risk NMIBC were included in the analysis. Among them, 1427 patients underwent adjuvant therapy, such as bacille Calmette-Guérin (n = 168), or chemotherapeutic agents, such as mitomycin C or epirubicin (n = 1259), in different regimens up to 1 year. The median (interquartile range) follow-up was 73.3 (38.4-106.9) months. The RFS at 1 and 5 years in patients treated with adjuvant therapy and those without were 72.6% vs 69.5% and 50.8% vs 41.3%, respectively. Adjuvant therapy was associated with better RFS (hazard ratio [HR] 0.79, 95% confidence interval [CI] 0.70-0.89, P < 0.001), but not with PFS (P = 0.09). In the subgroup of patients aged ≤70 years with primary, single Ta Grade 2 <3 cm tumours (n = 328), adjuvant therapy was not associated with RFS (HR 0.71, 95% CI 0.50-1.02, P = 0.06). While in the subgroup of patients with at least one risk factor including patient age >70 years, tumour multiplicity, recurrent tumour and tumour size ≥3 cm (n = 1878), adjuvant intravesical therapy was associated with improved RFS (HR 0.78, 95% CI 0.68-0.88, P < 0.001). In our study, patients with intermediate-risk NMIBC benefit from adjuvant intravesical therapy in terms of RFS. However, in patients without risk factors, adjuvant intravesical therapy did not result in a clear reduction in the recurrence rate.

SUBDUE-1: sub-urothelial immunotherapy to balance effectiveness and safety in Bacillus Calmette-Guérin-unresponsive non-muscle invasive bladder cancer?

SUBDUE-1: sub-urothelial immunotherapy to balance effectiveness and safety in Bacillus Calmette-Guérin-unresponsive non-muscle invasive bladder cancer?

Grade Heterogeneity in High-Grade Urothelial Carcinomas: Does It Have an Impact on the Survival of Patients With Intermediate/High-Risk Nonmuscle-Invasive Bladder Cancer Who Received Adequate Adjuvant Bacillus Calmette-Guérin Therapy? Erratum.

Grade Heterogeneity in High-Grade Urothelial Carcinomas: Does It Have an Impact on the Survival of Patients With Intermediate/High-Risk Nonmuscle-Invasive Bladder Cancer Who Received Adequate Adjuvant Bacillus Calmette-Guérin Therapy? Erratum.

Performance and Clinical Implications of VI-RADS in detecting muscle invasion in bladder tumors: A prospective observational study

ABSTRACT Introduction: Bladder cancer staging is pivotal for guiding therapeutic decisions. In this study, the primary objective was to assess the diagnostic accuracy of multiparametric magnetic resonance imaging (mpMRI), The study aimed to classify bladder tumors as either nonmuscle-invasive bladder cancers or muscle-invasive bladder cancers (MIBC) using the Vesical Imaging Reporting and Data System (VI-RADS) scoring. A secondary objective of the study focused on the accuracy of biparametric magnetic resonance imaging (bpMRI) in comparison to mpMRI. Methods: Thirty-three patients with bladder tumors were enrolled and underwent both mpMRI and bpMRI scoring assessments. VI-RADS scores were assigned and subsequently compared with histopathological findings posttransurethral resection of bladder tumor., Statistical measures included sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy for VI-RADS scores at cutoff thresholds of ≥4 and 5. Results: MpMRI at a VI-RADS cutoff of ≥4 yielded an 83.33% sensitivity and 100% specificity, with a diagnostic accuracy of 90.91%. At a cutoff of 5, sensitivity was 100%, specificity was 77.27%, and diagnostic accuracy was 84.85%. bpMRI at a cutoff of ≥4 showed an 80% sensitivity and 100% specificity, with diagnostic accuracy matching mpMRI at 90.91%. Conclusions: This prospective analysis demonstrates that VI-RADS scoring with mpMRI provides reliable diagnostic accuracy for bladder cancer staging. mpMRI exhibits high sensitivity and specificity at a cutoff of ≥ 4, making it a robust tool for MIBC detection. bpMRI is an effective alternative in select patients. The study validates the use of VI-RADS scoring in clinical practice for effective treatment planning.

Long-term oncologic outcomes and complications of robot-assisted radical cystectomy for the treatment of urothelial carcinoma of the bladder

IntroductionTo report the long-term outcomes of robot-assisted radical cystectomy (RARC) for the treatment of muscle invasive and high-risk non-muscle invasive bladder cancer. MethodsWe reviewed a single tertiary center database of RARC from 2004 to 2020. Concomitant extended pelvic lymph node dissection and extracorporeal urinary diversion were performed. Cox regression analysis and the Kaplan-Meier method were used to identify factors associated with and report time-to-event estimations of recurrence-free survival and overall survival. Clavien-Dindo complications were identified, categorized, and substratified by time from surgery within 90-days and between 90-days and >5-years postoperatively. ResultsA total of 510 patients with median follow-up of 57.1 months (IQR 21.8–103.6) were included. Continent diversion was performed in 259 (51%) patients. Of the 340 (67%) ≥cT2 patients, 153 (45%) received cisplatin-based neoadjuvant chemotherapy. Recurrence was identified in 157 (31%) patients, and 118 (23%) died from bladder cancer. The overall complication rate was 52% with 267 (41%) major grade ≥ III events. Infectious (25%) and genitourinary (22%) complications were the most common irrespective of the time interval beyond 90-days. The risk of recurrence or death were increased by extravesical disease (HR 1.91 and 1.97, respectively) and lymph node positivity (HR 4.58 and 2.42, respectively) in multivariable analysis (all, P < 0.001). The estimated 5-, and 10-year recurrence-free and overall survival rates were 69% and 64% and 61% and 44%, respectively. ConclusionsRARC is a durable treatment that optimizes the probability of cure for patients requiring extirpation for bladder cancer. Targeting the modifiable complications of radical surgery may further improve the risk/benefit ratio of RARC.

Prognostic Value of Tumour Infiltrating T-Lymphocytes (Tils) with Special Preference to CD8 Positive T-Lymphocyte in Muscle Invasive Urothelial Bladder Cancer

Prognostic Value of Tumour Infiltrating T-Lymphocytes (Tils) with Special Preference to CD8 Positive T-Lymphocyte in Muscle Invasive Urothelial Bladder Cancer

SY13-1 Emerging treatment for high risk non-muscle invasive bladder cancer: from BCG to immune checkpoint inhibitors and beyond

SY13-1 Emerging treatment for high risk non-muscle invasive bladder cancer: from BCG to immune checkpoint inhibitors and beyond

Trends in the use of immediate postoperative intravesical chemotherapy following transurethral resection of bladder tumors

PurposeThe use of immediate postoperative intravesical chemotherapy (IVC) following transurethral resection of bladder tumor (TURBT) has been shown to reduce the rate of recurrence of nonmuscle invasive bladder cancer. Historically, utilization of IVC following TURBT has been low. We sought to determine the rate of immediate postoperative IVC following TURBT, as well as assess factors that may influence its use. MethodsWe utilized the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database to assess the rates of IVC between the years 2016 to 2021. All patients who underwent TURBT based on appropriate procedure codes were initially included. Patients with an additional procedure code for the administration of IVC were identified. ResultsFrom 2016 to 2021, 50,295 patients underwent TURBT for bladder cancer. There were 21,544 (43%) small, 18,135 (36%) medium, and 10,616 (21%) large tumors treated. In total, 2,833 (5.6%) patients received IVC. Use of IVC was associated with surgery performed in an elective setting, those who did not receive preoperative blood transfusion, and shorter operative time. Receipt of chemotherapy was more common in the later years examined. ConclusionsThe rate of use of IVC remains very low. Ongoing study and improvement initiatives are in place, though these predominantly are assessing academic centers. Further study and quality improvement should be performed and include community practice settings.

Patterns of Failure after Definitive Trimodality Therapy for Muscle-Invasive Bladder Cancer

Patterns of Failure after Definitive Trimodality Therapy for Muscle-Invasive Bladder Cancer

Total extra-peritoneal approach to radical cystectomy with ureterostomy: A novel technique for the elderly and frail

ObjectivesRadical cystectomy with urinary diversion is the gold standard treatment for bladder cancer (high-risk/muscle invasive). The transperitoneal approach is associated with significant gastrointestinal complications like ileus. In the elderly and frail with a single functional kidney, we describe an extraperitoneal technique of radical cystectomy, with a ureterostomy, to be performed without general anesthesia. Materials and methodsThe elderly, frail, and high-risk candidates for general anesthesia, with a prior history of nephroureterectomy with a second primary muscle-invasive bladder cancer, were chosen. All patients underwent the described procedure under combined spinal and epidural anesthesia. The posterior dissection was retrograde, caudal to cranial, with the peritoneum being opened only for resection of the dome. A cutaneous ureterostomy was fashioned on the side of the functional kidney. Peri-operative parameters were assessed for early recovery in this high-risk group. ResultsThe mean age was 82 years (range: 73–91), with Charleson Comorbidity Index 5, and were all deemed unfit for neoadjuvant chemotherapy. With a median duration of 127.5 minutes, an average blood loss of 225ml, and no patient requiring general anesthesia; early ambulation, early return of bowel function, and a lesser hospital stay (7 days) with minimal morbidity were achieved. Negative surgical margins were achieved in all cases, with a mean harvest of 29 lymph nodes. Only 1 patient developed stomal stenosis. The cause-specific survival (CSS) is 100% at 2 years. ConclusionsThe highlighting features are the early return of bowel function (flatus passage on day 1) and the avoidance of the cardio-pulmonary complications of general anesthesia. The extraperitoneal cystectomy offers a promising alternative in this select group and warrants further studies to extrapolate this technique for bilateral urinary drainage.

Development and validation of a recurrence risk assessment model for high-grade bladder cancer based on TCGA and GEO.

Bladder cancer is one of the most commonly diagnosed urinary cancers worldwide. Although muscle-invasive bladder cancer (MIBC) accounts for only 25% of bladder cancer cases, it has a high recurrence rate and poor prognosis, especially among high-grade cases. Despite the existence of some molecular markers, there is a clear clinical need for a robust recurrence prediction model that can assist in patient management and therapeutic decision-making. Therefore, we aimed to use public databases to develop such an effective assessment model. We developed a recurrence risk assessment model for high-grade bladder cancer based on the clinical information of 217 cases from The Cancer Genome Atlas (TCGA) and profiles of 87 samples from GSE31684 in the Gene Expression Omnibus (GEO) database. Edge R was used to analyze differences between RNAs of bladder cancer in the TCGA database, with thresholds of P<0.05 and |log2(fold change)| >1; least absolute shrinkage and selection operator (LASSO) Cox regression models were used to screen the RNAs significantly related to recurrence with minimum λ. Survival receiver operating characteristic (ROC) and area under the curve (AUC) was used to assess the predictive accuracy of the model in the training and validation sets of GSE31684. There were 2,876 differential RNAs obtained from TCGA data. Among a total of 284 RNAs identified as significantly related to recurrence of bladder cancer, 49 were obtained by LASSO regression, and 30 were finally obtained by multifactor risk regression to construct a risk assessment model. The model was found to predict the prognosis of bladder cancer recurrence well, with an AUC of 0.911 in the TCGA training set and an adjusted AUC value of 0.839 in the GEO validation set. The recurrence assessment model is a relatively accurate recurrence prediction tool for high-grade bladder cancer and could provide a guidance for the treatment of bladder cancer.

The Role of Maximal TURBT in Muscle-Invasive Bladder Cancer: Balancing Benefits in Bladder Preservation and Beyond.

Radical cystectomy with lymph node dissection and urinary diversion is the gold-standard treatment for non-metastatic muscle-invasive bladder cancer (MIBC). However, in patients who refuse cystectomy, or in whom cystectomy carries a high risk, bladder-preserving therapies remain potential options. Bladder preservation therapies can include maximal debulking transurethral resection of bladder tumor (TURBT), concurrent chemoradiation therapy, followed by cystoscopy to assess response. At this time, maximal TURBT is recommended for patients prior to the initiation of chemoradiation therapy or in patients with residual bladder tumors after the completion of chemoradiation therapy. That being said, TURBT carries significant risks such as bladder perforation, bleeding, and infection, ultimately risking delayed systemic treatment. Hence, understanding its role within trimodal therapy is crucial to avoid undue suffering in patients. Herein, we review the current literature on the impact of debulking TURBT in non-metastatic MIBC.

Characterizing Psychological Resources and Resilience in Patients With Bladder Cancer: Associations With Frailty and Quality of Life.

Resilience, the ability to maintain or restore baseline function after a stressor, remains unexplored in patients with bladder cancer. Our objective was to demonstrate the feasibility of prospectively characterizing baseline resilience, related psychological resources, and frailty in patients with bladder cancer and evaluate associations with quality-of-life and mental health outcomes over time. We enrolled patients with bladder cancer (N = 67, September 2020-July 2021) into a prospective, observational, cohort study. At intake, patients completed validated assessments of frailty domains and psychological resources (resilience, psychological capital, self-compassion, and thriving, collectively PsyResources). Validated quality-of-life surveys were completed at 2 weeks, 3 months, and 6 months after treatment selection. Correlation matrices were constructed to quantify correlations between baseline PsyResources and frailty measures (reported with Spearman correlation coefficient [ρ]). Associations between PsyResources and quality-of-life outcomes were evaluated with linear regression. The median age was 71 years (83.6% male), and 77.6% had muscle-invasive bladder cancer (cN+: 21%, M1: 7.6%). Baseline PsyResources were inversely correlated with the Geriatric Depression Scale (ρ = -0.50 to 0.65, P < .0001). Higher baseline PsyResources were associated with improved global symptoms and emotional function and decreased anxiety and depression over time (B: -0.17 to -2.5; P < .05). We present the first prospective characterization of baseline PsyResources in patients with bladder cancer. We observed positive correlations with improved mental health and quality-of-life outcomes over time. Ongoing work is exploring the relationship between resilience, frailty domains, and their role in functional recovery after treatment. Future work is needed to understand associations between PsyResources and treatment tolerance, recovery trajectories, and oncologic outcomes.

Muscle-Invasive Bladder Cancer in Non-Curative Patients: A Study on Survival and Palliative Care Needs.

To assess the survival outcomes of patients diagnosed with muscle-invasive bladder cancer (MIBC) who are not candidates for curative treatment and to identify the factors influencing these outcomes. We conducted an analysis of patients diagnosed with MIBC who were either unable or unwilling to undergo curative therapy. We evaluated overall survival (OS) and cancer-specific survival (CSS) and examined their associations with various clinical variables. Additionally, we assessed emergency department visits and palliative procedures. The study included 142 patients with a median age of 79.4 years and a Charlson Comorbidity Index of 9.8. At diagnosis, 59.2% of the patients had localized disease, 23.2% had metastatic disease, and 49.3% presented with hydronephrosis. Curative treatment was excluded due to comorbidities in 40.1% of cases and advanced disease stage in 36.6%. The 1-year and 2-year OS rates were 42.8% and 23.6%, respectively, with a median survival of 10.6 months. The 1-year and 2-year CSS rates were 49.6% and 30.2%, respectively, with a median survival of 11.9 months. Worse survival outcomes were associated with advanced disease stage and the presence of hydronephrosis. Patients excluded from curative treatment solely due to age had a relatively better prognosis. On average, patients visited the emergency department three times: 19% underwent palliative transurethral resection of the bladder tumor, 14.8% received radiotherapy to control hematuria, and nephrostomy tubes were placed in 26.1% of cases. Patients with MIBC who are unable or unwilling to undergo curative treatment have a median overall survival of less than one year, with worse outcomes observed in those with advanced disease stage and hydronephrosis.

Evaluation of serum fibronectin levels and fibronectin gene polymorphism in patients receiving intravesical BCG therapy for non-muscle invasive bladder cancer and its prognostic value

BackgroundBladder cancer continues to be a significant health issue, leading to ongoing research into novel biomarkers and treatment strategies. This study aims to evaluate the potential of serum fibronectin levels and fibronectin gene polymorphisms as biomarkers for predicting the recurrence and treatment response in patients with NMIBC undergoing intravesical BCG therapy.MethodsBetween June 2022 and December 2022, data of 73 patients who applied to the Mersin University Urology Clinic due to NMIBC and were followed and treated in our clinic, receiving intravesical BCG treatment, when necessary, as well as 56 individuals without any malignancy, were prospectively examined. Serum fibronectin levels were measured using the enzyme-linked immunosorbent assay method. PCR testing was applied for the fibronectin gene RS10202709 and RS 35,343,655 gene polymorphisms by using Real-Time PCR.ResultsThe mean serum fibronectin level in the patient group was 76.794 ± 66.998ng/ml. Simultaneously, it was 50.486 ± 25.156ng/ml in the control group, and these differences in serum fibronectin levels were statistically significant(p = 0.003). Out of the 73 patients included in the study, recurrence of bladder cancer was observed in 53 of them. They were divided into two groups based on the recurrence times: early recurrence and late recurrence. The mean fibronectin level in the early recurrence group was 102 ± 86.1 ng/ml, while it was 44.7 ± 11.8 ng/ml in the late recurrence group. Emphasize the significance of the higher fibronectin levels in the early recurrence group by stating, patients with early recurrence exhibited significantly higher serum fibronectin levels compared to those with late recurrence (p < 0.001), suggesting a potential role for fibronectin as a prognostic biomarker.ConclusionsThe statistically higher concentrations of serum fibronectin levels in patients with bladder cancer observed in our study are a noteworthy finding. These findings suggest that serum fibronectin levels could serve as a valuable prognostic biomarker for early recurrence in NMIBC patients, although their predictive value for BCG treatment response remains limited.

Young age and adequate BCG are key factors for optimal BCG treatment efficacy in non-muscle-invasive bladder cancer

ObjectiveTo investigate the impact of ageing on survival outcomes in Bacillus Calmette–Guérin (BCG) treated non-muscle invasive bladder cancer (NMIBC) patients and its synergy with adequate BCG treatment.MethodPatients with NMIBC who received BCG treatment from 2001 to 2020 were divided into group 1 (< = 70 years) and group 2 (> 70 years). Overall Survival (OS), Cancer-Specific Survival (CSS), Recurrence-Free Survival (RFS), and Progression-Free Survival (PFS) were analyzed using the Kaplan–Meier method. Multivariable Cox regression analysis was used to adjust potential confounding factors and to estimate Hazard Ratio (HR) and 95% Confidence Interval (CI). Subgroup analysis was performed according to adequate versus inadequate BCG treatment.ResultsOverall, 2602 NMIBC patients were included: 1051 (40.4%) and 1551 (59.6%) in groups 1 and 2, respectively. At median follow-up of 11.0 years, group 1 (< = 70 years) was associated with better OS, CSS, and RFS, but not PFS as compared to group 2 (> 70 years). At subgroup analysis, patients in group 1 treated with adequate BCG showed better OS, CSS, RFS, and PFS as compared with inadequate BCG treatment in group 2, while patients in group 2 receiving adequate BCG treatment had 41% less progression than those treated with inadequate BCG from the same group.ConclusionsBeing younger (< = 70 years) was associated with better OS, CSS, and RFS, but not PFS. Older patients (> 70 years) who received adequate BCG treatment had similar PFS as those younger with adequate BCG treatment.

MTAP protein status is highly concordant with CDKN2A fluorescent in situ hybridization and allows stratification of the luminal subtype in muscle-invasive bladder cancer.

Loss of heterozygosity in chromosome 9p21, common in urothelial carcinoma (UC), typically involves deletion of CDKN2A and MTAP genes. MTAP loss is emerging as a promising therapeutic target and predictive biomarker in UC. This single-centrre retrospective study examined the incidence of CDKN2A deletions and MTAP loss in muscle-invasive bladder cancer (MIBC) and metastatic urothelial carcinoma (mUC), investigating their correlations with clinical, pathological, and genomic features, as well as patient outcomes. Fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) were performed on 302 MIBC specimens and 63 biopsy-proven metachronous urothelial metastases to assess CDKN2A deletions and MTAP protein expression. CDKN2A homozygous deletion (HD), identified in 30.3% of MIBCs, and MTAP loss, found in 28.8% of MIBCs, were both significantly associated with the luminal-URO subtype, FGFR3 mutations, and normal/wildtype p53 IHC (P < 0.05). Loss of MTAP expression was significantly correlated with CDKN2A HD, with 84.0% sensitivity, 92.3% negative predictive value (NPV), 96.3% specificity, and 91.9% positive predictive value (PPV). MTAP expression was 100% concordant between primary tumours and nodal metastases. Patients with MTAP loss had a higher incidence of visceral metastases (50%) compared to bone/soft tissue (35.7%) and nodes (14.3%). Mean progression-free survival and overall survival were shorter for patients with MTAP loss, although not statistically significant. Our findings highlight CDKN2A HD and MTAP loss as prevalent genetic alterations in MIBC and mUC, particularly within the luminal-URO subtype and FGFR3-mutated, p53-normal/wildtype tumours. MTAP IHC can serve as a surrogate marker for 9p21.3 HD, highlighting its clinical relevance and potential as a therapeutic target and predictive biomarker in MIBC.

Integrating Genetic Alterations and Histopathological Features for Enhanced Risk Stratification in Non-Muscle-Invasive Bladder Cancer.

Urothelial carcinoma presents as non-muscle-invasive bladder cancer (NMIBC) in ~75% of primary cases. Addressing the limitations of the TNM and WHO04/16 classification systems, this study investigates genetic alterations, the mitotic activity index (MAI), and immunohistochemistry (IHC) markers CK20, p53, and CD25 as better prognostic biomarkers in NMIBC. Using the Oncomine™ Focus Assay for targeted next-generation sequencing (NGS), 409 single-nucleotide variations (SNVs) and 193 copy number variations (CNVs) were identified across 287 patients with TaT1 tumors. FGFR3 and PIK3CA alterations were significantly more prevalent in Ta tumors, while T1 tumors had significant ERBB2 alterations. Low-grade (LG) tumors were enriched with FGFR3 alterations, while high-grade (HG) tumors were significantly associated with ERBB2 alterations, as well as FGFR1 and CCND1 amplifications. FGFR3 alterations were linked to shorter recurrence-free survival (RFS; p = 0.033) but improved progression-free survival (PFS; p < 0.001). Conversely, ERBB2 alterations (p < 0.001), ERBB3 mutations (p = 0.044), and both MYC (p < 0.001) and MYCN (p = 0.011) amplifications were associated with shorter PFS. Survival analysis of gene sets revealed inverse associations between PIK3CA and ERBB2 (p = 0.003), as well as PIK3CA and MYC (p = 0.005), with PFS. In multivariate Cox regression, MAI was the strongest predictor for PFS. Integrating genetic alterations and histopathological features may improve risk stratification in NMIBC.