High-risk Non-muscle-invasive Bladder Cancer Patients Research Articles

Abstract B004: Deep learning unveils molecular footprints in histology: predicting molecular subtypes from bladder cancer histology slides

Abstract Introduction: Transurethral resection followed by intravesical bacillus Calmette-Guerin (BCG) is the standard of care for high-risk non-muscle-invasive bladder cancer (HR-NMIBC) patients. However, ≈20% of HR-NMIBC patients progress to muscle-invasive or metastatic disease, which is associated with a high-risk of death. Early identification of patients who are unlikely to benefit from BCG treatment could benefit from an early radical cystectomy or bladder-sparing alternatives. Previously, we showed that molecular subtyping or HR-NMIBC identified BCG response subtypes (BRS 1/2/3). BRS3 tumors were associated with a poor response to BCG and a high-risk of progression. However, molecular subtyping relies on resource-intensive and costly sequencing methods such as next-generation sequencing, and microarray analysis. We employed deep learning (DL) to predict BRS3 vs BRS1/2 molecular subtypes from digitized histology slides. Methods: Haematoxylin and eosin (H&E)-stained slides were digitized, and quality control was performed. The areas where the RNA was extracted were annotated pixel-wise by a trained pathology assistant, using QuPath. Image tiles of 512 × 512 pixels at 10X, 20X, and 40X magnifications were extracted with a 25% overlap. For classification, BRS1 and BRS2 images were grouped, while BRS3 images were categorized separately. After applying Macenko normalization, tiles were split based on individual patients into a 75/25 training/validation ratio via stratified 4-fold cross-validation. Four DL models (DenseNet, Inception, ShuffleNet, ResNet) were trained to classify tiles into BRS3 and BRS1/2, with tile labels based on the patient’s subtype. Patient-level classification was performed using majority voting from tile predictions. Model efficacy was gauged using the area under the ROC curve (AUC). Results: Out of 245 H&E slides, 45 were discarded after quality control. From 200 patients – with a 70:30 distribution between BRS1&2 and BRS3 The DenseNet model at 10x magnification was the best-performing model, achieving the highest AUC compared to all other models and magnifications. On the image tile level, the best DenseNet achieved an average AUC of 0.65 with a standard deviation of 0.03 across the four folds of the validation set. At the patient-level prediction, the best DenseNet reached an average AUC of 0.80 and a standard deviation of 0.05 on the validation set. Conclusion: Our study demonstrates that deep learning classifies BSR3 from BSR1 and 2 subtypes from H&E slides. This method holds potential to identify BRS3 HR-NMIBC patients who may benefit from alternative treatments than BCG. With further refinement, this deep learning strategy can become a key tool in histology, aiding in swift, affordable, and efficient subtype identification. Hence, this method has the potential to bridge the gap between molecular techniques and clinical practice. Future research should prioritize evaluating the model on an external test cohort and consider predicting additional molecular markers to fine-tune prediction outcomes. Citation Format: Farbod Khoraminia, Flouros C de Jong, Farhan Akram, Geert Litjens, Maarten D.J. Jansen, Alberto Nakuama Gonzalez, Danique Lichtenburg, Andrew Stubbs, Nadieh Khalili, Tahlita C.M. Zuiverloon. Deep learning unveils molecular footprints in histology: predicting molecular subtypes from bladder cancer histology slides [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2024 May 17-20; Charlotte, NC. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(10_Suppl):Abstract nr B004.

Tumor microenvironment-modulating oncolytic adenovirus combined with GSK-3β inhibitor enhances antitumor immune response against bladder cancer

Bladder cancer is a common type of cancer around the world, and the majority of patients are diagnosed with non-muscle-invasive bladder cancer (NMIBC). Although low-risk NMIBC has a good prognosis, the disease recurrence rate and development of treatment-refractory disease remain high in intermediate- to high-risk NMIBC patients. To address these challenges for the treatment of NMIBC, a novel combination therapy composed of an oncolytic adenovirus (oAd) co-expressing interleukin (IL)-12, granulocyte-macrophage colony-stimulating factor (GM-CSF), and relaxin (RLX; HY-oAd) and a clinical-stage glycogen synthase kinase (GSK)-3β inhibitor (9-ING-41; elraglusib) was investigated in the present report. Our findings demonstrate that HY-oAd and 9-ING-41 combination therapy (HY-oAd+9-ING-41) exerted superior inhibition of tumor growth compared with respective monotherapy in a syngeneic NMIBC tumor model. HY-oAd+9-ING-41 induced high-level tumor extracellular matrix (ECM) degradation and a more potent antitumor immune response than the respective monotherapy. In detail, HY-oAd+9-ING-41 induced superior accumulation of intratumoral T cells, prevention of immune cell exhaustion, and induction of tumor-specific adaptive immune response compared to either monotherapy. Collectively, these results demonstrate that the combination of HY-oAd and 9-ING-41 may be a promising approach to elicit a potent antitumor immune response against bladder cancer.

Effect of sequential gemcitabine and epirubicin therapy on high-risk non-muscle invasive bladder cancer following transurethral bladder tumour resection

Purpose: To investigate the efficacy of sequential gemcitabine and epirubicin therapy on high-risk non-muscle invasive bladder cancer (NMIBC) after transurethral resection of bladder tumour (TURBT). Methods: The records of 100 high-risk NMIBC patients, who underwent TURBT at the Tongling People's Hospital, Tongling City, China between January 2020 and March 2023 were retrospectively analyzed. A total of 46 patients, treated with epirubicin after operation, were assigned to control group, while 54 patients, treated with both gemcitabine and epirubicin, were included in the study group. DKK-1 and YKL-4 levels were assayed by immunomagnetic bead‐based liquid chip technology and enzyme-linked immunosorbent assay, respectively. Furthermore, treatment efficacy was determined and compared between the two groups. Results: There were no significant differences in the pre-treatment DKK-1 and YKL-40 levels between the two groups (p > 0.05). However, both groups experienced a significant drop in post-treatment levels, with significantly lower post-treatment levels in the study group (p < 0.05). There were no significant differences in catheter retention time and hospitalization time between the two groups (p > 0.05). The study group achieved a significantly better overall response rate than the control group. The pre-treatment SF-36 scores of the two groups were similar, while their post-treatment SF-36 scores increased significantly (p < 0.05). Conclusion: Sequential therapy with gemcitabine and epirubicin is effective in the therapy of high-risk NMIBC after TURBT. It significantly lowers DKK-1 and YKL-40 levels, improves postoperative quality of life and reduces the postoperative recurrence rate without increasing adverse reactions and affecting the catheter retention and hospitalization times. A more comprehensive analysis is required to obtain improved outcomes.

Performance of the EORTC and CUETO Models to Predict Recurrence and Progression in High-risk Non-muscle-invasive Bladder Cancer Patients.

To evaluate the performance of the European Organization for Research and Treatment of Cancer (EORTC) and the Spanish Urological Club for Oncological Treatment (CUETO) risk scoring models in non-muscle-invasive bladder cancer (NMIBC) patients defined as high risk according to European Association of Urology guidelines and managed based on current recommendations. Data from 187 high-risk NMIBC patients treated at a tertiary center between July 2010 and November 2021 were analyzed retrospectively. One- and five-year recurrence- and progression-free survival were assessed for each patient using the EORTC and CUETO risk scores. The patients were divided into four risk groups according to their risk scores as low, medium-low, medium-high and high risk, as indicated in the models. Discriminative ability was evaluated with the Harrell's concordance index (c-index). Both risk scoring models overestimated the risk of recurrence and progression at one and five years. Only the prediction of recurrence at five years in the high risk group according to the CUETO model was compatible with our cohort. CUETO (c-indices for recurrence and progression were 0.802 and 0.834, respectively) exhibited better discrimination than EORTC (0.722 for recurrence and 0.752 for progression) in the prediction of disease recurrence and progression. The CUETO model was superior to the EORTC model in predicting recurrence and progression and stratifying patients with different prognoses in our high-risk NMIBC patient population treated according to current guideline recommendations. However, both models overestimated the probability of disease recurrence and progression. Only the probability of recurrence at five years in the high-risk group of the CUETO model was compatible with our cohort.

Photodynamic diagnosis-assisted transurethral resection of bladder tumor for high-risk non-muscle invasive bladder cancer improves intravesical recurrence-free survival (BRIGHT study).

In a primary analysis of data from the BRIGHT study (UMIN000035712), photodynamic diagnosis-assisted transurethral resection of bladder tumor (PDD-TURBT) using oral 5-aminolevulinic acid hydrochloride reduced residual tumors in high-risk non-muscle invasive bladder cancer (NMIBC). We aimed to evaluate the effectiveness of PDD-TURBT for intravesical recurrence after a second transurethral resection for high-risk NMIBC. High-risk NMIBC patients initially treated with PDD-TURBT (PDD group) were prospectively registered between 2018 and 2020. High-risk patients with NMIBC who were initially treated with white-light TURBT (WL group) were retrospectively registered. Intravesical recurrence-free survival after the second transurethral resection was compared between the PDD and WL groups using propensity score matching analysis. In total, 177 patients were enrolled in the PDD group, and 306 patients were registered in the WL group. After propensity score matching (146 cases in each group), intravesical recurrence within 1 year was significantly less frequent in the PDD group than in the WL group (p = 0.004; hazard ratio [HR] 0.44, 95% confidence interval [CI]: 0.25-0.77). In subgroup analysis, PDD-TURBT showed a particularly high efficacy in reducing intravesical recurrence within 1 year, especially in cases of tumors measuring less than 3 cm (p = 0.003; HR 0.31, 95% CI: 0.14-0.67), absence of residual tumor at second transurethral resection (p = 0.020; HR 0.37, 95% CI: 0.16-0.86), and no postoperative intravesical Bacillus Calmette-Guérin therapy (p < 0.001; HR 0.27, 95% CI: 0.13-0.58). PDD-TURBT may reduce short-term intravesical recurrence in patients with high-risk NMIBC.

PD-L1 Expression in High-Risk Non-Muscle-Invasive Bladder Cancer Is Influenced by Intravesical Bacillus Calmette-Guérin (BCG) Therapy.

In the expanding landscape of immune checkpoint inhibitors (CPI) in high-risk (HR) non-muscle-invasive bladder cancer (NMIBC), the role of programmed death ligand 1 (PD-L1) as prognostic and predictive is increasingly significant. However, data evaluating its variability and susceptibility to Bacillus Calmette-Guérin (BCG) therapy in HR NMIBC patients is scarce. This retrospective study analyzed 126 HR NMIBC tissue samples from 63 patients (38× BCG-treated, 25× BCG-naïve) at two time points to assess PD-L1 expression using the 'combined positivity score' (CPS) with the 22C3 DAKO antibody method and correlated it with clinicopathological parameters. A CPS > 10 defined PD-L1 positivity. The impact of initial PD-L1 status and its change over time on time-to-recurrence, progression-free survival, and overall survival (TTR, PFS, OS) was analyzed using Kaplan-Meier and Cox proportional hazard models. BCG treatment significantly increased PD-L1 expression (5.31 vs. 0.22, p = 0.0423), with PD-L1 positive cases rising post-treatment in the BCG group and remaining unchanged in BCG-naïve patients. Multivariate analysis including T-stage, CIS, grading, tumor size, multifocality, age, and sex revealed a significant correlation between PD-L1 status change to positivity and improved TTR (p = 0.03). Our findings demonstrate a potential modulation of the PD-L1 status by an intravesical BCG therapy. However, its prognostic value appears limited.

A Multi-Gene Signature of Non-Muscle-Invasive Bladder Cancer Identifies Patients Who Respond to Immunotherapies Including Bacillus Calmette-Guérin and Immune Checkpoint Inhibitors.

Approximately 75% of bladder cancer cases originate as non-muscle-invasive bladder cancer (NMIBC). Despite initial diagnosis, NMIBC commonly recurs, with up to 45% advancing to muscle-invasive bladder cancer (MIBC) and metastatic disease. Treatment for high-risk NMIBC typically includes procedures like transurethral resection and, depending on recurrence risk, intravesical chemotherapy or immunotherapy such as Bacillus Calmette-Guérin (BCG). However, persistent shortages of BCG necessitate alternative first-line treatments. We aim to use a multi-gene signature in high-risk NMIBC patients to determine whether patients may benefit from immune checkpoint inhibitors (ICIs) as an alternative to BCG and to evaluate their clinical utility. The multi-gene signature obtained from the three independent NMIBC cohorts was applied to stratify the UROMOL2016 cohort (n = 476) using consensus clustering. Each subtype was distinguished by biological pathway analysis. Validation analysis using a machine learning algorithm was performed in six independent cohorts including the BRS (n = 283) cohort treated with BCG and the IMvigor210 (n = 298) clinical trials treated with PD-L1 inhibitors. Based on consensus cluster analysis, NMIBC patients in the UROMOL2016 cohort were classified into three classes exhibiting distinguished characteristics, including DNA damage repair (DDR). Survival analysis showed that the NMIBC-DDR class had the highest rates of disease progression (progression-free survival, p = 0.002 by log-rank test) in the UROMOL cohort and benefited from BCG and ICIs (respectively, p = 0.02 and p = 0.03 by log-rank test). This study suggests that the multi-gene signature may have a role in identifying high-risk NMIBC patients and improving the responsiveness of ICIs. Additionally, we propose immunotherapy as a new first-line treatment for patients with high-risk NMIBC because of the shortage of BCG supply. It is important to help more patients prioritize cancer immunotherapy.

RC48-ADC versus BCG in adjuvant treatment of high-risk non-muscle-invasive bladder cancer with HER2 over-expression: A real-world retrospective study.

644 Background: Bladder cancer ranks as the tenth most prevalent malignancy globally, with non-muscle invasive bladder cancer (NMIBC) accounting for approximately 75% of cases. Patients diagnosed with high-risk NMIBC (HR-NMIBC) face a grim prognosis, characterized by a 5-year disease progression rate of up to 40%. Currently, the standard treatment for HR-NMIBC involves transurethral resection of bladder tumor (TURBT) followed by adjuvant intravesical Bacillus Calmette-Guérin (BCG) therapy. However, BCG infusion therapy is associated with prolonged duration, substantial costs, and a high frequency of toxic side effects. RC48-ADC, a novel humanized anti-HER2 antibody conjugated with monomethyl auristatin E, has shown promising efficacy with a manageable safety profile in patients with locally advanced or metastatic urothelial carcinoma (mUC) in a Phase II clinical trial (NCT03507166). Therefore, investigating the therapeutic potential of RC48-ADC in HR-NMIBC patients holds significant clinical importance. Methods: We conducted a retrospective analysis on patients diagnosed with HR-NMIBC exhibiting HER2 overexpression (≥ HER2 2+) who underwent adjuvant therapy with either RC48-ADC, a HER2-targeting antibody-drug conjugate, or BCG, at West China Hospital of Sichuan University between 2019 and 2023. The primary study endpoint was the twelve-month recurrence-free survival (RFS) rate, with safety assessments as secondary endpoints. Results: A total of thirty patients diagnosed with HR-NMIBC displaying HER2 overexpression were included in the study. Following TURBT, eleven patients received adjuvant therapy with RC48-ADC, while nineteen received adjuvant therapy with BCG. The median follow-up duration for patients receiving RC48-ADC and BCG adjuvant therapy was 7.3 and 16.43 months, respectively. Among patients treated with RC48-ADC, the twelve-month RFS rate was 100%, with one out of the 11 patients experiencing relapse after 14.2 months of RC48-ADC adjuvant therapy. In the BCG-treated group, the twelve-month RFS rate was 57.6%. However, Kaplan-Meier analysis revealed no statistically significant difference between these two groups (P=0.22). In the RC48-treated group, the most commonly reported treatment-related adverse events (TRAEs) included alopecia (45.5%), arthralgia (18.2%), and nausea (18.2%). A total of 27.7% of patients experienced grade 3 TRAEs, including alopecia, rash, and hypoesthesia, with no observations of grade 4 or grade 5 TRAEs. Conclusions: RC48-ADC has demonstrated promising efficacy with a manageable safety profile as an adjuvant therapy in patients with HR-NMIBC. RC48 may be an alternative adjuvant therapy for BCG in terms of the 12-month recurrence-free survival rate.

Effects of intravenous chemotherapy after TURBT for high-risk nonmuscle invasive bladder cancer: results of a retrospective study.

This study compared the efficacy and safety of intravenous chemotherapy combined with intravesical chemotherapy versus intravesical chemotherapy alone for high-risk nonmuscle invasive bladder cancer (HRNMIBC) patients after transurethral resection of the bladder tumor (TURBT) surgery. A retrospective analysis was performed on 349 HRNMIBC cases admitted to TangDu hospital between January 2014 and June 2019. After TURBT, 262 patients received intravesical chemotherapy alone, whereas 87 patients underwent intravesical chemotherapy in combination with intravenous chemotherapy. The recurrence rate and progression rate were assessed by Chi-square test, the prognostic factors for tumor recurrence were predicted by univariable and multivariable Cox hazards analyses, recurrence-free survival (RFS) and progression-free survival (PFS) were calculated using the Kaplan-Meier method. In this study, the recurrence rate was 24.7% (19/77) in the intravenous chemotherapy combined group and 41.6% (102/245) in the intravesical chemotherapy group, while the progression rate was 6.5% (5/77) and 14.3% (35/245) in the two groups respectively. The two groups differed significantly in recurrence rate (p = 0.007) while the progression rate did not show a significant difference (p = 0.071). Multivariable analyses revealed that additional intravenous chemotherapy treatment was an independent prognostic factor for tumor recurrence in the cohort (hazard ratio [HR], 0.495, 95% confidence interval [CI], 0.275-0.892, p = 0.019). Kaplan-Meier curves showed significant differences in RFS and PFS between the two groups, with a log-rank P value of p < 0.005 and p = 0.045, respectively. Grade 3/4 toxicity was reported in 2 of 77 patients in the intravenous chemotherapy combined group, including nausea/vomiting 1.3% (1/77) and hypoleukemia 1.3% (1/77). Intravenous chemotherapy of gemcitabine and cisplatin combined with intravesical chemotherapy after TURBT can effectively reduce the postoperative recurrence rate, most toxicities were minor and reversible, and it may be considered as a new choice for HRNMIBC patients.

The efficacy of hyperthermic intravesical chemotherapy in high-risk non-muscle-invasive bladder cancer patients with BCG intolerance.

Some patients with high-risk non-muscle-invasive bladder cancer (NMIBC) are unable to receive adequate BCG instillations due to intolerance. In this study we aimed to investigate the efficacy and tolerability of hyperthermic intravesical chemotherapy (HIVEC®) treatment using Mitomycin C (MMC) in BCG-intolerant NMIBC patients. Retrospectively collected data from a total of 22 high-risk papillary NMIBC patients who received adjuvant HIVEC therapy for BCG intolerance were analyzed. The primary outcomes of the study were recurrence-free survival (RFS), time to recurrence, progression-free survival (PFS), and time to progression following initial TURB. Detection of histologically confirmed urothelial carcinoma during follow-up was considered as recurrence, while detection of muscle-invasive disease was defined as progression. The secondary outcome was adverse events of HIVEC treatment. The median follow-up was 32.2 (IQR: 17.8-42.8) months. The RFS and PFS rates were 81.8% and 95.4%, respectively. The mean time to tumor recurrence and progression was 29.2 ± 14.3 and 16.7 months, respectively. Adverse events occurred in 50% of patients, and 95% of adverse events were mild to moderate. This study demonstrated that adjuvant HIVEC with MMC is an effective and safe alternative bladder sparing treatment in BCG intolerant high risk papillary NMIBC patients.

Intravesical BCG in bladder cancer induces innate immune responses against SARS-CoV-2.

BCG is the most efficient adjuvant therapy for high-risk, non-muscle-invasive bladder cancer (NMIBC). Both innate and adaptive immune responses have been implicated in BCG-mediated effects. BCG vaccination can boost innate immune responses via trained immunity (TI), resulting in an increased resistance to respiratory viral infections. Here we evaluated for the first time whether intravesical application of BCG triggers increased immunity against SARS-CoV-2 in patients with high-risk NMIBC. Serum and peripheral blood mononuclear cells (PBMCs) from heparinized whole blood samples of 11 unvaccinated SARS-CoV-2-naïve high-risk NMIBC patients were collected at baseline and during BCG treatment in a pre-COVID-19 era. To examine B-cell or T cell-dependent adaptive immunity against SARS-CoV-2, sera were tested for the presence of SARS-CoV-2 neutralizing antibodies. Using a SARS-CoV-2 peptide pool, virus-specific T cells were quantified via IFNγ ELISpot assays. To analyze innate immune responses, mRNA and protein expression levels of pro- and anti-inflammatory cytokines were measured after a 24-hour stimulation of PBMCs with either BCG or SARS-CoV-2 wildtype. ATAC- sequencing was performed to identify a potential epigenetic reprogramming in immune cells. We neither identified SARS-CoV-2 neutralizing antibodies nor SARS-CoV-2- reactive T cells, indicating that intravesical BCG did not induce adaptive immunity against SARS-CoV-2. However, a significant increase in mRNA as well as protein expression of IL-1β, IL-6 and TNFα, which are key cytokines of trained immunity, could be observed after at least four intravesical BCG instillations. Genomic regions in the proximity of TI genes (TLR2, IGF1R, AKT1, MTOR, MAPK14, HSP90AA1) were more accessible during BCG compared to baseline. Although intravesical BCG did not induce adaptive immune responses, repetitive intravesical instillations of BCG induced circulating innate immune cells that produce TI cytokines also in response to SARS-CoV-2.

The Management of Bacillus Calmette-Guérin (BCG) Failure in High-Risk Non-muscle Invasive Bladder Cancer: A Review Article.

Non-muscle invasive bladder cancer (NMIBC) is a common urological malignancy, and bacillus Calmette-Guérin(BCG) therapy is the gold standard treatment in intermediate and high-risk groups. However, BCG failure occurs in a significant proportion of patients, emphasizing the need for effective alternative treatment modalities to address this burden. These treatments include immunotherapy, enhanced drug delivery, targeted therapy, device-assisted chemotherapy, vaccine therapy, and gene therapy, which show varying degrees of safety and efficacy. The objective of this review is to summarize the current evidence and ongoing research on these emerging therapies, offering insight into their potential for improving patient outcomes and quality of life. Although radical cystectomy remains the standard of care for high-risk NMIBC patients unresponsive to BCG, novel treatment modalities hold promise for the future management of this challenging patient population.

Effect of regional versus general anesthesia on recurrence of non-muscle invasive bladder cancer: a systematic review and meta-analysis of eight retrospective cohort studies

BackgroundRegional anesthesia appears to reduce cancer recurrence, but the optimal anesthesia modality for non-muscle invasive bladder cancer (NMIBC) were still under debate. Therefore, we sought to assess the effect of regional and GA only upon the recurrence and long-term prognosis of NMIBC through this meta-analysis.MethodsWe performed an extensive literature search of PubMed, Embase, Web of Science, the Cochrane Library and China National Knowledge Infrastructure (up to October 30, 2022) to identify eligible articles on the possible impact of different anesthetic modalities for the recurrence rate of NMIBC.ResultsEight studies comprising 3764 participants, including 2117 subjects with RA and 1647 with GA, were finally enrolled. Cancer recurrence rate was significantly lower in subjects with RA than those with GA (RR 0.84, 95%CI 0.72–0.98, P = 0.03). We didn’t detect the differences between GA and RA in the time of recurrence (SMD 2.07, 95% CI -0.49–4.63, P = 0.11) and cancer progression (RR 1.14, 95%CI 0.71–1.84, P = 0.59). Results from subgroup analysis demonstrated that spinal anesthesia could significantly decrease the incidence of cancer recurrence in comparison with general anesthesia (RR 0.80, 95%CI 0.72–0.88, P < 0.001) and high-risk NMIBC patients who received RA tended to have less recurrence (HR 0.55, 95%CI 0.39–0.79, P = 0.001) than those receiving GA.ConclusionsRA, especially spinal anesthesia, may be effective in reducing the recurrence rate after transurethral resection of NMIBC. More prospective experimental and clinical studies are needed to validate our findings.Trial registrationINPLASY registration INPLASY2022110097.

The efficacy and safety outcomes of lower dose BCG compared to intravesical chemotherapy in non-muscle-invasive bladder cancer: A network meta-analysis.

This study aimed to assess both efficacy and safety outcomes of lowering the dose of BCG compared to intravesical chemotherapies in non-muscle-invasive bladder cancer (NMIBC) patients using a systematic review, meta-analysis, and network meta-analysis approach. A comprehensive literature search was performed through Pubmed®, Web of Science™, and Scopus® in December 2022 to identify randomized controlled trials comparing the oncologic and/or safety outcomes of reduced dose intravesical BCG and/or intravesical chemotherapies according to the Preferred Reporting Items for Systematic Review and Meta-analyses (PRISMA) statement. The outcomes of interest were risk of recurrence, progression, treatment-related adverse events, and discontinuation. Overall, 24 studies were eligible for quantitative synthesis. Among 22 studies that adopted induction followed by maintenance intravesical therapy, with reference to the lower-dose BCG, epirubicin was associated with a significantly higher risk of recurrence (Odds ratio [OR]: 2.82, 95% CI: 1.54-5.15), but not other intravesical chemotherapies. There were no significant differences in risk of progression among the intravesical therapies. On the other hand, standard-dose BCG was associated with a higher risk of any AEs (OR: 1.91, 95% CI: 1.07-3.41) but other intravesical chemotherapies had a comparable risk of AEs compared to lower-dose BCG. The discontinuation rate did not significantly differ between lower-dose and standard-dose BCG (OR: 1.40, 95% CI: 0.81-2.43) as well as other intravesical. According to the surface under the cumulative ranking curve, gemcitabine, and standard-dose BCG were preferable to lower-dose BCG in terms of recurrence risk; gemcitabine was also preferable to lower-dose BCG in terms of risk of AEs. In patients with NMIBC, lowering the dose of BCG decreases the risks of AEs and discontinuation rate compared to standard-dose BCG, but there is no difference in these endpoints compared to other intravesical chemotherapies. Standard-dose of BCG is preferred for all intermediate and high-risk NMIBC patients based on oncologic efficacy; however, lower-dose BCG and intravesical chemotherapies, especially gemcitabine, could be considered a reasonable alternative to BCG in selected patients who suffer from significant AEs or in case standard-dose BCG is not available.

Abstract 5570: Development of prognostic index based on twenty-three genes for predicting superficial-to-invasive progression of non-muscle invasive bladder cancer patients

Abstract Background: Although recent advances in high-throughput technology and data-driven approach have provided many insights into non-muscle invasive bladder cancer (NMIBC), previous studies are still limited in their ability to predict the clinical behavior of NMIBC. Here, using deep learning method with long term follow-up data, we identified a prognostic gene set consisting of a small gene group for precisely predicting NMIBC heterogeneity. Methods: We sought to identify progression-associated genes in patients with NMIBC using Cox regression analysis and verified their predictive values using a fully connected neural network (FNN) algorithm in five independent cohorts comprising more than 800 NMIBC patients. Based on these genes, a prognostic index (PI) in NMIBC progression was also developed. The association between the PI and prognosis of NMIBC patients was evaluated using Kaplan-Meier plots and log-rank tests. Results: Gene expression profiling in NMIBC patients identified a prognostic gene set consisting of 1,789 genes for predicting NMIBC progression in a patient cohort (training set, n = 103). Their prognostic significances were validated based on FNN algorithm in other four independent cohorts (validation sets, n = 722). Pathway enrichment analysis revealed a twenty-three gene signature including known prognostic transcription factors such as FOXM1 and E2F1 along with novel genes. We incorporated these genes into the PI system, which was a significant prognostic indicator of NMIBC progression. The PI system was shown to be an independent risk factor by a multivariate analysis and subset stratification according to stage and grade (each P &amp;lt; 0.001). The subset analysis also revealed that the PI system could identify patients who would benefit from BCG immunotherapy. Conclusions: The twenty-three gene-based PI represents a promising diagnostic tool for the identification of high-risk NMIBC patients who would display different clinical behaviours as well as response to BCG immunotherapy. Citation Format: Jae-Yoon Kim, Seong-Hwan Park, Seon-Young Kim, Seok Joong Yoon, Seon-Kyu Kim. Development of prognostic index based on twenty-three genes for predicting superficial-to-invasive progression of non-muscle invasive bladder cancer patients. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5570.

Bladder tumor Resection Weight as a Prognostic Factor for Recurrence and Progression in Patients With High-Risk Non-Muscle Invasive Bladder Treated With BCG.

Predicting outcomes of patients with high-risk non-muscle invasive bladder cancer (HR-NMIBC) is critical. Here, we evaluate whether bladder tumor resection weight might serve as a prognostic factor for recurrence and progression of HR-NMIBC patients treated with Bacillus Calmette-Guérin (BCG). In this retrospective, single-centre study in the UK, we analysed a consecutive cohort of HR-NMIBC patients who have received adequate intravesical BCG immunotherapy between 2009 and 2019. Univariable and multivariable Cox proportional hazards models were used to assess the association of resection weight and established predictors with recurrence and progression. A total of 187 HR-NMIBC patients were analysed. The median resection weight was 1.4g (range: 0.2-28.5g). Within a median follow-up of 41 months, 58 (31%) tumors recurred and 19 (10%) progressed. Fifty-four patients (29%) died from any cause and 16 (9%) died from bladder cancer. Both the risk of recurrence (P=.007) and progression (P=.019) increased with rising resection weight. On the multivariable analysis, a resection weight of ≥ 2g and ≥ 3g conferred a 4.35-fold and a 9.03-fold increased risk of bladder cancer recurrence (P < .001) and progression (P < .001), respectively. The addition of resection weight improved the C index of multivariable standard prognostic models to a clinically significant extent (+ 3.8% for recurrence,+4.3% for progression). In our HR-NMIBC patient cohort treated with BCG, bladder tumor resection weight was associated with disease recurrence and progression. Its addition improves discrimination of standard prognostic factors. Measurement may therefore be considered for routine clinical practice.

PD29-03 COMPARISON OF REDUCED AND FULL BCG DOSING IN THE TREATMENT OF NON-MUSCLE INVASIVE BLADDER CANCER

You have accessJournal of UrologyCME1 Apr 2023PD29-03 COMPARISON OF REDUCED AND FULL BCG DOSING IN THE TREATMENT OF NON-MUSCLE INVASIVE BLADDER CANCER Matthew Buck, Andrew Salib, Edward Kloniecke, Rishabh Simhal, Anne Calvaresi, Costas Lallas, Leonard Gomella, and Joseph Izes Matthew BuckMatthew Buck More articles by this author , Andrew SalibAndrew Salib More articles by this author , Edward KlonieckeEdward Kloniecke More articles by this author , Rishabh SimhalRishabh Simhal More articles by this author , Anne CalvaresiAnne Calvaresi More articles by this author , Costas LallasCostas Lallas More articles by this author , Leonard GomellaLeonard Gomella More articles by this author , and Joseph IzesJoseph Izes More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003315.03AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: The BCG shortage era has prompted the need for rethinking of the classic treatment paradigm for non-muscle invasive bladder cancer (NMIBC). Among other approaches, reduced BCG dosage protocols have been implemented across various institutions with conflicting evidence on their efficacy. We retrospectively evaluated patients at out institution with NMIBC and hypothesized that reduced dose protocols would have no significant impact on the development of BCG-relapsing disease, BCG-refractory disease, or progression to muscle invasive bladder cancer. METHODS: We evaluated 300 patients treated at our institution during the BCG shortage era (01/2017–05-2021). After obtaining institutional IRB approval, we retrospectively reviewed the charts of 300 patients and recorded pathology at diagnosis, size of tumor at initial resection, BCG induction dose (25 mg vs. 50 mg), BCG maintenance dose (25 mg vs 50 mg), pathology and date of recurrence. We evaluated baseline differences between full and reduced dose groups utilizing chi-squared tests, t-test, and ANOVA where appropriate. We then compared time to recurrence between the two dosing strategies with log-rank tests and Cox proportional hazards models. RESULTS: 203 patients with complete data were treated with BCG during the period of the study (115 high risk, 73 intermediate risk). Patients who received a lower induction dose of were more likely to develop a recurrence during the study period (log-rank test, p<0.001, Figure 1). On multivariable Cox proportional-hazards modelling, those who received reduced dose BCG were more likely to experience a recurrence during the study period (HR: 1.88, 95% CI 1.08–3.26) while adjusting for number of inductions, maintenance dosing, and AUA risk category. CONCLUSIONS: In this cohort of mainly high-risk NMIBC patients, those treated with reduced induction dose of BCG were more likely to experience a recurrence within the study period. Additional research and prospective trials can shed light on which patients are able to safely be treated with reduced dose BCG in the shortage era. Source of Funding: Institutional funding. © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e824 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Matthew Buck More articles by this author Andrew Salib More articles by this author Edward Kloniecke More articles by this author Rishabh Simhal More articles by this author Anne Calvaresi More articles by this author Costas Lallas More articles by this author Leonard Gomella More articles by this author Joseph Izes More articles by this author Expand All Advertisement PDF downloadLoading ...

MP08-07 IS PELVIC LYMPH NODE DISSECTION NECESSARY IN NMIBC PATIENTS UNDERGOING RC?

You have accessJournal of UrologyCME1 Apr 2023MP08-07 IS PELVIC LYMPH NODE DISSECTION NECESSARY IN NMIBC PATIENTS UNDERGOING RC? Qiang Lv, Xiao Yang, Qiang Cao, and Juntao Zhuang Qiang LvQiang Lv More articles by this author , Xiao YangXiao Yang More articles by this author , Qiang CaoQiang Cao More articles by this author , and Juntao ZhuangJuntao Zhuang More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003223.07AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Radical cystectomy (RC) combined with pelvic lymph node dissection (PLND) is the principle for muscle invasive bladder cancer (MIBC), but it is unclear whether PLND is necessary for high-risk non-muscle invasive bladder cancer (NMIBC). METHODS: From January 2021, patients diagnosed as high-risk NMIBC without swollen lymph nodes (or lymph nodes ≤8mm) on MRI/CT were prospectively enrolled, and randomly received RC+PLND or RC alone (NCT: 05123625). Perioperative clinical data, 90-day complications, and medical expenses, et al were recorded. The endpoint was progression-free survival (PFS) and overall survival (OS). All statistical analyses were performed in SPSS26.0 and R software (version 3.6.3). RESULTS: As of September 19, 2022, a total of 63 patients were enrolled, with 40 patients received ileal conduit, 5 patients received orthotopic neobladder, and 18 received ureteral cutaneous diversion. Among all patients, 26 cases were in RC+PLND group, with the age of 65.5 (IQR: 57.25-72.75) years. Laparoscopic surgery was performed in 15 cases, robotic-assisted in 10 cases, and open surgery in 1 case due to excessive bleeding. Pathological stage was Ta/ Tis: 6 cases and T1: 20 cases. None positive lymph node was found. There were 37 cases in RC only group, with the age of 66 (IQR: 59-73) years. Laparoscopic surgery was performed in 7 cases, and robotic-assisted in 30 cases. Pathological stage was Ta/Tis: 6 cases and T1: 31 cases. The operation time of RC group was significantly shorter than that of RC+PLND group (241±63 min vs. 335±83 min, p < 0.001), and the intraoperative blood loss was significantly lower than that of RC+PLND group (p=0.026). The average daily postoperative drainage volume of patients in RC group was significantly less than that in RC+PLND group (p=0.002), and the time from postoperative to discharge was shorter (8.0±2.4 vs. 11.2±6.3 days, p=0.019). Within 90 days after operation, the incidence of Clavien-Dindo grade II-III complications in RC group were lower than that in RC+PLND group (2.7% vs 19.2%, p=0.073). At the median follow-up of 9.5 (IQR: 6.9-12.8) months, there was no significant difference in PFS and OS between the two groups (Figure 1). CONCLUSIONS: For high-risk NMIBC patients, combined PLND has no survival benefit but increases the incidence of complications. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e95 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Qiang Lv More articles by this author Xiao Yang More articles by this author Qiang Cao More articles by this author Juntao Zhuang More articles by this author Expand All Advertisement PDF downloadLoading ...

PD13-04 DEVELOPMENT OF A NOVEL GENE EXPRESSION SCORING SYSTEM FOR RECURRENCE IN NON-MUSCLE-INVASIVE BLADDER CANCER AFTER TRANSURETHRAL RESECTION OF BLADDER TUMOR

You have accessJournal of UrologyCME1 Apr 2023PD13-04 DEVELOPMENT OF A NOVEL GENE EXPRESSION SCORING SYSTEM FOR RECURRENCE IN NON-MUSCLE-INVASIVE BLADDER CANCER AFTER TRANSURETHRAL RESECTION OF BLADDER TUMOR Emina Kayama, Motohide Uemura, Yusuke Kirihana, Akifumi Onagi, Seiji Hoshi, Tomoyuki Koguchi, Tomohiko Yanagida, Fusao Murakami, and Yoshiyuki Kojima Emina KayamaEmina Kayama More articles by this author , Motohide UemuraMotohide Uemura More articles by this author , Yusuke KirihanaYusuke Kirihana More articles by this author , Akifumi OnagiAkifumi Onagi More articles by this author , Seiji HoshiSeiji Hoshi More articles by this author , Tomoyuki KoguchiTomoyuki Koguchi More articles by this author , Tomohiko YanagidaTomohiko Yanagida More articles by this author , Fusao MurakamiFusao Murakami More articles by this author , and Yoshiyuki KojimaYoshiyuki Kojima More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003260.04AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Non-muscle-invasive bladder cancer (NMIBC) frequently recurs after transurethral resection of bladder tumor (TURBT). However, clinical prognostic factors do not always accurately predict tumor recurrence. Therefore, we developed a new gene expression scoring system that is practical for distinguishing between high- and low-risk NMIBC that recur after TURBT. METHODS: We included 89 patients (median age 75) diagnosed with NMIBC after initial TURBT without prior or concurrent upper tract urothelial carcinoma at our institution between 2008 and 2019. This study obtained the approval of the institutional ethics board and the patient's consent. Variations in the expression signature of 14,400 genes within each patient were measured by our microarray analysis which has no mRNA amplification bias, not requiring validation by quantitative reverse transcriptase PCR. A hierarchical cluster analysis was performed to identify a set of genes that discriminates between high- and low-risk NMIBC. RESULTS: Eleven genes were extracted that predict tumor recurrence after TURBT. The cumulative equivalent of the 11 genes (microarray score) was obtained from each sample, and the optimal cutoff score was calculated to be 1.29 (area under the curve 0.83). A Kaplan-Meier curve showed the 5-year recurrence-free survival (RFS) rate was 38.2% in the “high microarray score group” (microarray score ≥1.29, n=39), which was significantly lower than in the “low microarray score group” (82.6%, p=0.002, Figure 1). The 5-year RFS rate in patients with single, Ta low grade tumor <3 cm in diameter without CIS (n=15) was 90.0%, which was higher than in the rest (55.2%); however, no significant difference was observed (p=0.063). Multivariate Cox regression analysis showed that a microarray score ≥1.29 was an independent factor for disease recurrence (hazard ratio 3.89, p=0.005), but clinical factors were not. CONCLUSIONS: Our novel gene expression scoring system proved to be more useful in predicting recurrence in patients with NMIBC after TURBT than clinical prognostic factors. This scoring system may enable individualized strategic management of high-risk NMIBC patients. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e406 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Emina Kayama More articles by this author Motohide Uemura More articles by this author Yusuke Kirihana More articles by this author Akifumi Onagi More articles by this author Seiji Hoshi More articles by this author Tomoyuki Koguchi More articles by this author Tomohiko Yanagida More articles by this author Fusao Murakami More articles by this author Yoshiyuki Kojima More articles by this author Expand All Advertisement PDF downloadLoading ...

Study of real-world treatment patterns and adherence to bacillus Calmette-Guerin (BCG) in the context of guideline recommendations for patients with high-risk non-muscle invasive bladder cancer (NMIBC).

470 Background: Intravesical BCG is considered a first-line (1L) treatment for high-risk NMIBC patients. Since the presence of carcinoma in situ (CIS) in NMIBC is associated with increased disease progression rates and poor clinical outcomes, BCG is prioritized in clinical guidelines for NMIBC patients with CIS. However, BCG’s US shortage may negatively affect clinical outcomes in patients. This study evaluated the adequacy of BCG treatment patterns among NMIBC patients, including a subgroup with CIS. Methods: Adults with NMIBC treated with BCG were selected from de-identified IBM MarketScan Commercial, Medicare, and Medicaid Databases (1/1/2010-2/28/2021). Treatment patterns were assessed from the first BCG claim (triggering the start of 1L treatment) until the end of the patient’s observation. Consistent with real-world literature, adequate BCG induction was defined as ≥5 BCG claims within 70 days of the first BCG claim whereas adequate BCG induction and maintenance was defined as ≥7 BCG claims within 274 days of the first BCG claim. Proportions of patients with adequate BCG induction and maintenance were compared between CIS subgroup and overall NMIBC cohorts using chi square tests. Results: Of 5,803 NMIBC patients treated with 1L BCG, 1,182 (20.4%) had documentation of CIS. Overall and CIS cohorts had similar mean age (67 years; range 18-101 years). After 1L BCG, 56.6% and 71.8% of the overall and CIS cohorts had another treatment (P&lt;.001; table). While 86.9% and 90.0% of the overall and CIS cohorts had adequate BCG induction (P=0.003), only 41.5% and 50.8% had adequate BCG maintenance (P&lt;.001). More patients in the CIS versus overall cohort had a cystectomy (13.9% vs 9.7%; P&lt;.001). Conclusions: In this study, most NMIBC patients treated with BCG received adequate induction; however, BCG maintenance was inadequate and most patients had another treatment following 1L BCG. Patients with CIS were more likely to have cystectomy after BCG, suggesting higher risk of progression in this subgroup. Results of this study further emphasize a need for additional available treatment options that are safe, efficacious, and tolerable. [Table: see text]