Cases Of Non-muscle Invasive Bladder Cancer Research Articles

The Role of Immunohistochemistry as a Surrogate Marker in Molecular Subtyping and Classification of Bladder Cancer

Background/Objectives: Bladder cancer (BC) is a highly heterogeneous disease, presenting clinical challenges, particularly in predicting patient outcomes and selecting effective treatments. Molecular subtyping has emerged as an essential tool for understanding the biological diversity of BC; however, its implementation in clinical practice remains limited due to the high costs and complexity of genomic techniques. This review examines the role of immunohistochemistry (IHC) as a surrogate marker for molecular subtyping in BC, highlighting its potential to bridge the gap between advanced molecular classifications and routine clinical application; Methods: We explore the evolution of taxonomic classification in BC, with a particular focus on cytokeratin (KRT) expression patterns in normal urothelium, which are key to identifying basal and luminal subtypes. Furthermore, we emphasise the need for consensus on IHC markers to reliably define these subtypes, facilitating wider and standardised clinical use. The review also analyses the application of IHC in both muscle-invasive (MIBC) and non-muscle-invasive bladder cancer (NMIBC), with particular attention to the less extensively studied NMIBC cases. We discuss the practical advantages of IHC for subtyping, including its cost effectiveness and feasibility in standard pathology laboratories, alongside ongoing challenges such as the requirement for standardised protocols and external validation across diverse clinical settings; Conclusions: While IHC has limitations, it offers a viable alternative for laboratories lacking access to advanced molecular techniques. Further research is required to determine the optimal combination of markers, establish a consensus diagnostic algorithm, and validate IHC through large-scale trials. This will ultimately enhance diagnostic accuracy, guide treatment decisions, and improve patient outcomes.

Prospective Assessment of VI-RADS with Muscle Invasion in Urinary Bladder Cancer and Its Implication on Re-Resection/Restaging TURBT Patients.

Bladder cancer (BCa) diagnosis relies on distinguishing muscle-invasive bladder cancer (MIBC) from non-muscle-invasive bladder cancer (NMIBC) forms. Transurethral resection of the bladder tumor (TURBT) is a standard procedure for initial staging and treatment. The Vesical Imaging-Reporting and Data System (VI-RADS) enhances diagnostic accuracy for muscle invasiveness through advanced imaging techniques, potentially reducing reliance on repeat TURBT and improving patient management. We aimed to evaluate the role of VI-RADS in predicting muscle invasiveness in BCa and its potential to predict adverse pathology in high-risk NMIBC to avoid unnecessary repeat TURBT procedures. In this prospective study, we included 62 patients over the age of 18years who underwent TURBT. In a secondary phase, patients selected for restaging TURBT (re-TURBT) were included, but those with T2 tumors or low-risk NMIBC were excluded. Multiparametric magnetic resonance imaging (MRI) examinations were scored by a radiologist using the VI-RADS 5 method, while a pathologist analyzed TURBT and re-TURBT samples for accurate staging. Statistical analysis evaluated the role of VI-RADS in BCa staging. The VI-RADS score was the only predictive factor for muscle invasion in multivariate analysis. Setting the VI-RADS score at >3 resulted in the highest sensitivity, specificity, and diagnostic accuracy, with values of 67.0%, 89.0%, and 78%, respectively. The receiver operating characteristic area under the curve score for VI-RADS for muscle invasion was 85% for stage Ta, 61% for stage T1, and 88% for stage T2, which shows the utility of VI-RADS in the predictiveness of MIBC/NMIBC. VI-RADS is effective in stratifying BCa patients by predicting muscle invasiveness and identifying NMIBC cases that may not need repeat TURBT.

P106 ENZYMES INVOLVED IN THE CATABOLISM OF TRYPTOPHAN IN THE PROGNOSIS OF BLADDER CANCER

Bladder cancer (BC) ranks third among the most common carcinomas in Brazil. Tumor immunology opens up perspectives for treatment, where the enzyme indoleamine 2,3-dioxygenase-1 (IDO1) stands out for degrading the amino acid tryptophan, initiating a cascade that culminates in the generation of catabolites (derived from kynurenine). These catabolites, in different associations, determine degrees of local immunosuppression. These catabolites are generated by other enzymes that have not yet been studied in BC. We analyzed the expression of enzymes involved in tryptophan catabolism in order to correlate them with the stage, recurrence, and progression of BC. Analysis of published microarray databases was performed using the NCBI (National Center of Biotechnology Information) and accessed through GEO Datasets (Gene Expression Omnibus). The descriptor “Bladder cancer” was used. Series that provided analysis of normal bladder tissue (Normal) versus BC, including cases of non-muscle invasive BC (CBNMI) and muscle invasive BC (CBMI), recurrence and progression. Statistical analysis was performed using the GEO2R and ROC curve was used. The transcripts were: Tryptophan 2,3-dioxygenase (TDO2), Indoleamine 2,3-dioxygenase (IDO1), Kynurenine Formamidase (AFMID), Kynureninase (KNYU), Kynurenine-oxoglutarate-transaminase 1 (KYAT1), and Kynurenine Monooxygenase (KMU). GSE13507 series was selected, with ten Normal samples and 165 BC samples, including 104 CBNMI and 61 CBMI cases. CBNMI was predicted by KYNU, AFMID, and KYAT1 (AUC of 0.625, 0.589, and 0.638, respectively; p<0.05), while for CBMI were, IDO1, TDO2, and KMO (AUC of 0.662, 0.633, and 0.601, respectively; p<0.05). No enzyme was found to be important in predicting progression; however, the IDO1 enzyme was predictive of recurrence (AUC of 0.366; p<0.05). A relationship between the two IDO1/KYNU was established, which improved the prediction of stage for CBNMI (AUC of 0.733, p<0.05), non-progression (AUC of 0.619, p<0.05), and non-recurrence (AUC of 0.626, p<0.05). The expression of enzymes involved in tryptophan catabolism may aid in the prognosis of BC. It is likely that these enzymes are involved in tumor immunomodulation, which will be explored in future studies.

Adjuvant or rescue disitamab vedotin (RC48-ADC) for high-risk non-muscle invasive bladder cancer with HER2 overexpression: A phase II multi-center study.

TPS4625 Background: Non-muscle invasive bladder cancer (NMIBC) comprises approximately three-quarters of newly diagnosed cases of bladder cancer. Based on the risk of disease progression, NMIBC is categorized into low, intermediate, and high risk, with high-risk NMIBC patients facing a 5-year disease progression rate of up to 40%. The current standard treatment for high-risk NMIBC involves transurethral resection of the bladder tumor (TURBT) combined with intravesical Bacillus Calmette-Guérin (BCG) instillation as adjuvant therapy. In cases of BCG instillation treatment failure, the standard approach is radical cystectomy. Multiple studies have reported HER2 positivity in 20-44% of NMIBC cases, and HER2 overexpression (immunohistochemistry ≥2+) is closely linked to the progression and adverse prognosis of bladder cancer. Consequently, HER2 may serve as a novel therapeutic target for bladder cancer. Disitamab Vedotin (DV; RC48-ADC) is an antibody-drug conjugate (ADC) comprising a fully humanized HER2-directed monoclonal antibody conjugated to monomethyl auristatin E (MMAE) via a protease-cleavable mc-vc linker. Results from a Phase II clinical trial (NCT03507166) suggest that Disitamab Vedotin exhibits favorable efficacy and safety in HER2-positive metastatic urothelial carcinoma patients who have previously failed chemotherapy. This clinical trial aims to investigate the efficacy and safety of RC48-ADC as adjuvant or rescue therapy for high-risk NMIBC with HER2 overexpression and to explore molecular biomarkers predicting the efficacy of RC48-ADC. Methods: This multicenter, Phase II clinical trial will enroll two cohorts: Cohort A, consisting of 52 patients undergoing first-line adjuvant therapy, and Cohort B, with 25 patients receiving rescue therapy after BCG instillation failure, both exhibiting HER2 overexpression in high-risk NMIBC. Following the Simon two-stage optimal design, the first stage will involve enrolling 19 patients in Cohort A and 12 patients in Cohort B. After safety and baseline assessments, both cohorts will undergo six cycles of treatment with RC48-ADC (120 mg intravenous infusion every two weeks), totaling 12 weeks of treatment. Primary endpoints include safety, 12-month recurrence-free rate (Cohort A), and 3-month clinical complete response rate (Cohort B). Secondary endpoints encompass the 6-month recurrence-free rate (Cohort A), duration of response (Cohort B), recurrence-free survival, progression-free survival, overall survival, and quality of life (assessed through eEuroQoL EQ-5D and FACT-BI). Additionally, exploratory endpoints will investigate the relationship between biomarkers in tumor tissues, blood, and urine, and treatment efficacy. Clinical trial information: NCT05996952 .

A cohort profile of the Graham Roberts study cohort.

The Graham Roberts Study was initiated in 2018 and is the first Trials Within Cohorts (TwiCs) study for bladder cancer. Its purpose is to provide an infrastructure for answering a breadth of research questions, including clinical, mechanistic, and supportive care centred questions for bladder cancer patients. All consented patients are those aged 18 or older, able to provide signed informedconsent and have a diagnosis of new or recurrent bladder cancer. All patients are required to have completed a series of baseline questionnaires. The questionnaires are then sent out every 12 months and include information on demographics and medical history as well as questionnaires to collect information on quality of life, fatigue, depression, overall health, physical activity, and dietary habits. Clinical information such as tumor stage, grade and treatment has also been extracted for each patient. To date, a total of 125 bladder cancer patients have been consented onto the study with 106 filling in the baseline questionnaire. The cohort is made up of 75% newly diagnosed bladder cancer patients and 66% non-muscle invasive bladder cancer cases. At present, there is 1-year follow-up information for 70 patients, 2-year follow-up for 57 patients, 3-year follow-up for 47 patients and 4-year follow-up for 19 patients. We plan to continue recruiting further patients into the cohort study. Using the data collected within the study, we hope to carry out independent research studies with a focus on quality of life. We are also committed to utilizing the Roberts Study Cohort to set up and commence an intervention. The future studies and trials carried out using the Roberts Cohort have the potential to identify and develop interventions that could improve the prevention, diagnosis, and treatment of bladder cancer.

A HER2-targeted Antibody-Drug Conjugate, RC48-ADC, Exerted Promising Antitumor Efficacy and Safety with Intravesical Instillation in Preclinical Models of Bladder Cancer.

More than half of non-muscle-invasive bladder cancer (NMIBC) patients eventually relapse even if treated with surgery and BCG without optional bladder-preserving therapy. This study aims to investigate the antitumor activity and safety of a HER2-targeted antibody-drug conjugate, RC48-ADC, intravesical instillation for NMIBC treatment. In this preclinical study, itis revealed that human epidermal growth factor receptor 2 (HER2) expression scores of 1+, 2+, and 3+ are recorded for 16.7%, 56.2%, and 14.6% of NMIBC cases. The antitumor effect of RC48-ADC is positively correlated with HER2 expression in bladder cancer (BCa) cell lines and organoid models. Furthermore, RC48-ADC is revealed to exert its antitumor effect by inducing G2/M arrest and caspase-dependent apoptosis. In an orthotopic BCa model, tumor growth is significantly inhibited by intravesical instillation of RC48-ADC versus disitamab, monomethyl auristatin E, epirubicin, or phosphate-buffered saline control. The potential toxicity of intravesical RC48-ADC is also assessed by dose escalation in normal nude mice and revealed that administration of RC48-ADC by intravesical instillation is safe within the range of effective therapeutic doses. Taken together, RC48-ADC demonstrates promising antitumor effects and safety with intravesical administration in multiple preclinical models. These findings provide a rational for clinical trials of intravesical RC48-ADC in NMIBC patients.

Factors Related to Overactive Bladder-like Symptoms in Bladder Cancer.

The aim of the present study was to investigate the factors related to overactive bladder (OAB)-like symptoms in patients with bladder cancer. This study included 59 patients who underwent transurethral resection of bladder tumor (TURBT). OAB-like symptoms were identified based on the Overactive Bladder Symptom Score (OABSS) and International Prostate Symptom Score (IPSS) questionnaires. The main outcome measures were elucidation of bladder cancer-related factors that might induce OAB-like symptoms. Non-muscle invasive bladder cancer (NMIBC) was observed in 50 patients, and carcinoma in situ (CIS) was observed in 14 patients. OABSS total score, IPSS total score, and quality of life index were 5±3, 12±7 and 3±1, respectively. The OABSS question 1 score, indicating pollakisuria, was significantly higher in NMIBC patients with CIS than in those without CIS (presence of CIS vs. absence of CIS=1.0±0.6 : 0.5±0.6, p=0.02). IPSS question 4 score, indicating urgency (r=0.31, p=0.01), and OABSS question 4 score, indicating urgency incontinence (r=0.29, p=0.03), correlated significantly with the maximum bladder tumor diameter. Multivariate regression analysis demonstrated that presence of CIS in NMIBC cases correlated significantly with pollakisuria (p=0.02), and that maximum diameter of the bladder tumor correlated significantly with both urgency (p=0.04) and urgency incontinence (p=0.01). CIS induced pollakisuria in NMIBC. Larger diameter bladder tumors induced both urgency and urgency incontinence. Patients with bladder cancer who present with pollakisuria might have CIS.

Associations of dietary isothiocyanate exposure from cruciferous vegetable consumption with recurrence and progression of non–muscle-invasive bladder cancer: findings from the Be-Well Study

BackgroundHigh recurrence and progression rates are major clinical challenges for non–muscle-invasive bladder cancer (NMIBC). Dietary isothiocyanates (ITCs), phytochemicals primarily from cruciferous vegetables (CV), show strong anticancer activities in preclinical BC models, yet their effect on NMIBC prognosis remains unknown. ObjectivesThis study aimed to investigate the associations of dietary ITC exposure at diagnosis with NMIBC recurrence and progression. MethodsThe study analyzed 1143 participants from the Be-Well study, a prospective cohort of newly diagnosed NMIBC cases in 2015–2019 with no prior history of BC. Dietary ITC exposure was indicated by self-reported CV intake, estimated ITC intake, urinary metabolites, and plasma ITC–albumin adducts. Cox proportional hazards regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for recurrence and progression, and unconditional logistic regression models were used to calculate odds ratios (ORs) and 95% CIs for delayed and multiple recurrence. ResultsOver a mean follow-up of 25 mo, 347 (30%) developed recurrence and 77 (6.7%) had disease progression. Despite no significant associations with the overall risk of recurrence, urinary ITC metabolites (OR: 1.96; 95% CI: 1.01, 4.43) and dietary ITC intake (OR: 2.13; 95% CI: 1.03, 4.50) were associated with late recurrence after 12-mo postdiagnosis compared with before 12-mo postdiagnosis. Raw CV intake was associated with reduced odds of having ≥2 recurrences compared with having one (OR: 0.34; 95% CI: 0.16, 0.68). Higher plasma concentrations of ITC–albumin adducts were associated with a reduced risk of progression, including progression to muscle-invasive disease (for benzyl ITC, HR: 0.40; 95% CI: 0.17, 0.93; for phenethyl ITC, HR: 0.40; 95% CI: 0.19, 0.86). ConclusionsOur findings indicate the possible beneficial role of dietary ITCs in NMIBC prognosis. Given the compelling preclinical evidence, increasing dietary ITC exposure with CV intake could be a promising strategy to attenuate recurrence and progression risks in patients with NMIBC.

Abstract P038: Transcriptome-wide association study identifies novel genes associated with bladder cancer risk

Abstract Background: Genome-wide association studies (GWAS) have identified several common germline variants associated with bladder cancer risk. However, the genetic architecture of bladder cancer risk is still largely unknown. Therefore, we conducted a transcriptome-wide association study (TWAS) to identify gene expression patterns associated with bladder cancer risk. Methods: Individual-level genotype data from bladder cancer cases and controls was accessed from dbGaP (phs000346.v2.p2). We included 3,630 muscle invasive and non-muscle invasive bladder cancer cases and 3,356 controls from the Spanish Bladder Cancer Study (1,145 cases and 1,083 controls) and the New England Bladder Cancer Study (Maine and Vermont, 2,485 cases and 2,273 controls) with imputed genotype data for 22 million single-nucleotide polymorphisms (SNPs). We used PrediXcan to predict gene expression in whole blood using reference data from the Depression Genes and Networks (DGN). Covariate-adjusted logistic regression was used to estimate the associations between gene expression and bladder cancer risk. Results were validated using data from 280 non-muscle invasive bladder cancer cases and 353 controls of the New Hampshire Bladder Cancer Study. Results: We identified five genes associated with bladder cancer risk, including a previously reported locus (1p13.3: GSTM1) and four other loci (4p16.3: FAM53A, 7q22.3: RP11-325F22.2, 8p23.1: RP11-297N6.4, 11q24.1: JHY). Among them, higher predicted expression of GSTM1 in whole blood was associated with lower risk of bladder cancer (Discovery dataset OR = 0.78, 95% CI = 0.67, 0.92; Validation dataset OR = 0.58, 95% CI = 0.34, 0.98). Higher predicted expression of FAM53A (Discovery OR = 1.34, 95% CI = 1.08, 1.68; Validation OR = 3.79, 95% CI = 1.76, 8.29), RP11-325F22.2 (Discovery OR = 1.34, 95% CI = 1.09, 1.65; Validation OR = 2.11, 95% CI = 1.05, 4.30), RP11-297N6.4 (Discovery OR = 1.78, 95% CI = 1.22, 2.60; Validation OR = 6.32, 95% CI = 1.74, 23.34) and JHY (Discovery OR = 1.94, 95% CI = 1.30, 2.91; Validation OR = 6.78, 95% CI = 1.85, 25.76) in whole blood was associated with higher risk of bladder cancer. Conclusion: Our TWAS identified five genes associated with bladder cancer risk: GSTM1, a previously reported locus associated with bladder cancer risk, is related to metabolic detoxification. Four novel loci were identified: FAM53A (related to neural tube development and was previously reported to be related to breast cancer progression), JHY (related to axoneme structure), RP11-325F22.2 (lincRNA), and RP11-297N6.4 (lncRNA). These loci require further validation and may help to reveal the underlying mechanism of the relationship between gene expression and bladder cancer risk. Citation Format: Siting Li, Jiang Gui, Margaret R. Karagas, Michael N. Passarelli. Transcriptome-wide association study identifies novel genes associated with bladder cancer risk. [abstract]. In: Proceedings of the AACR Special Conference: Precision Prevention, Early Detection, and Interception of Cancer; 2022 Nov 17-19; Austin, TX. Philadelphia (PA): AACR; Can Prev Res 2023;16(1 Suppl): Abstract nr P038.

A prospective descriptive 1-year study in France of all BCG therapy dispensations for non-muscle-invasive bladder cancer.

To describe the clinico-pathological characteristics of non-muscle-invasive bladder cancer (NMIBC) treated in metropolitan France over 1 year when bacille Calmette-Guérin (BCG) was subject to a national quota, and to document, in the context of recurrent shortages of intravesical BCG for NMIBC, the real-life indications for adjuvant treatment. Between February 2021 and February 2022, the French National Agency for the Safety of Medicines (ANSM) asked the French Association of Urology to propose a science-based quota solution for BCG using a clinical score. The ANSM then asked the distributor of the drug, MEDAC, to collect the scores for all patients for whom BCG was requested by healthcare institutions and to prioritize the requests for patients with the highest scores. Tumour stage, grade, size, number, time to recurrence, carcinoma insitu, age, accessibility of alternative treatments (total cystectomy, radio-chemotherapy, thermo-chemotherapy) and BCG treatment progress (initiation or maintenance) were documented for each intravesical BCG prescription. A descriptive analysis of the data collected during the quota year was performed. During the 1-year quota, 25 878 requests for BCG were made for 19 024 patients, 60.5% of whom were aged ≥70 years. Requests for induction and maintenance treatment accounted for 12 704 (49.1%) and 13 174 prescriptions (50.9%), respectively. NMIBC treated with BCG maintenance therapy was more frequently high-risk NMIBC (91.7% vs 90.2%; P < 0.0001) than NMIBC for which induction therapy was requested. The number of cases of NMIBC leading to BCG adjuvant treatment was estimated at 12 704 cases/66 062 188 inhabitants over 1 year in metropolitan France. Our data suggest that the incidence of NMIBC at high risk of recurrence and progression is underestimated in reference epidemiological studies. These results should help to better define future care needs.

Clinical utility of vesical imaging-reporting and data system (VI-RADS) in non-muscle invasive bladder cancer (NMIBC) patients candidate for en-bloc transurethral resection: A prospective study.

To assess accuracy of vesical imaging-reporting and data system (VI-RADS) 5-point score in detection of muscle invasive bladder cancer and avoiding second look transurethral resection of the tumors (TURBT). Additionally, to assess safety and efficacy of bipolar en-block transurethral urethral resection of bladder tumor. Patients with bladder mass up to 5 cm were included in the study. VI-RADS 5-point score was done preoperative for all cases and postoperatively before second look TURBT. Patients were followed up for 12 months. In all, 80 cases were eligible for the study. Preoperative VI-RADS score at cutoff of 3 had sensitivity of 89.3 %, specificity 83.3 %, postive predective value (PPV) 92.6 %, negative predictive value (NPV) 76.9 %, accuracy of 87.5 %, while at cutoff 2 sensitivity was 82.1%, specificity 91.7%, PPV 95.8%, NPV 68.8%, accuracy of 85.0%. Operative time 28.8 ± 9.4 minutes, hemoglobin drop 0.3 ± 0.05 g/dl, catheterization time 2.8 ± 0.8 days, hospital stay 1.4 ± 0.4 days. No complications occurred. Recurrence in field of resection 3.75%. Detrusor muscle was available in 76 cases (95%). Postoperative VI-RADS score at cutoff of 3 had sensitivity of 78.6%, specificity 77.8%, PPV 84.6%, NPV 70.0%, accuracy of 78.3%. At cutoff 2 VI-RADS score sensitivity was 71.4%, specificity 77.8%, PPV 83.3%, NPV 63.6%, accuracy of 73.9%. VI-RADS 5-point score showed high sensitivity and specificity in preoperative discrimination of non-muscle invasive bladder cancer (NMIBC) from muscle invasive bladder cancer cases and in avoiding unnecessary second look TURBT. Bipolar en-block TURBT technique is both safe and efficacious in resecting NMIBC cases with low recurrence rate.

Glycoprotein α-Subunit of Glucosidase II (GIIα) is a novel prognostic biomarker correlated with unfavorable outcome of urothelial carcinoma

BackgroundUrothelial carcinoma (UC) is among the most prevalent malignancies. The muscle-invasive bladder cancer (MIBC) shows an invasive feature and has poor prognosis, while the non-muscle invasive bladder cancer (NMIBC) shows a better prognosis as compared with the MIBC. However, a significant proportion (10%–30%) of NMIBC cases progress to MIBC. Identification of efficient biomarkers for the prediction of the course of UC remains challenging nowadays. Recently, there is an emerging study showed that post-translational modifications (PTMs) by glycosylation is an important process correlated with tumor angiogenesis, invasion and metastasis. Herein, we reported a data-driven discovery and experimental validation of GANAB, a key regulator of glycosylation, as a novel prognostic marker in UC.MethodsIn the present study, we conducted immunohistochemistry (IHC) assay to evaluate the correlation between the expression levels of GANAB protein and the prognosis of UC in our cohort of 107 samples using whole slide image (WSI) analysis. In vitro experiments using RNAi were also conducted to investigate the biological functions of GANAB in UC cell lines.ResultsWe observed that positive GANAB protein expression was significantly correlated with poor prognosis of UC in our cohort, with p-value of 0.0017 in Log-rank test. Notably, tumor cells at the invasive front of the tumor margin showed stronger GANAB expression than the tumor cells inside the tumor body in UCs. We further validated that the elevated expression levels of GANAB were significantly correlated with high grade tumors (p-values of 1.72 × 10–10), advanced stages (6.47 × 10–6), and elevated in luminal molecular subtypes. Moreover, knocking-down GANAB using RNAi in UM-UC-3 and T24 cells inhibited cell proliferation and migration in vitro. Knockdown of GANAB resulted in cell cycle arrest at G1 phase. We demonstrated that GANAB mediated HIF1A and ATF6 transcriptional activation in the ER stress signaling, and regulated the gene expression of cell cycle-related transcriptional factors E2F7 and FOXM1.ConclusionsThe elevated expression of GANAB is a novel indicator of poorer prognosis of UC. Our data suggests that GANAB is not only a new and promising prognostic biomarker for UC, but also may provide important cues for the development of PTM-based therapeutics for UC treatment.

Novel intravesical bacterial immunotherapy induces rejection of BCG-unresponsive established bladder tumors

BackgroundIntravesical BCG is the gold-standard therapy for non-muscle invasive bladder cancer (NMIBC); however, it still fails in a significant proportion of patients, so improved treatment options are urgently needed.MethodsHere, we...

Bladder cancer prospective cohort study on high-risk non-muscle invasive bladder cancer after photodynamic diagnosis-assisted transurethral resection of the bladder tumor (BRIGHT study).

ObjectivesTransurethral resection of bladder tumor with photodynamic diagnosis has been reported to result in lower residual tumor and intravesical recurrence rates in non‐muscle invasive bladder cancer. We aimed to evaluate the usefulness of photodynamic diagnosis‐transurethral resection of bladder tumor combined with oral 5‐aminolevulinic acid hydrochloride for high‐risk non‐muscle invasive bladder cancer.MethodsHigh‐risk non‐muscle invasive bladder cancer patients with an initial photodynamic diagnosis‐transurethral resection of bladder tumor (photodynamic diagnosis group) were prospectively registered between 2018 to 2020. High‐risk non‐muscle invasive bladder cancer cases with a history of initial white‐light transurethral resection of bladder tumor (white‐light group) were retrospectively registered. Propensity score‐matching analysis was used to compare residual tumor rates, and factors that could predict residual tumors at the first transurethral resection of bladder tumor were evaluated.ResultsAnalyses were conducted with 177 and 306 cases in the photodynamic diagnosis and white‐light groups, respectively. The residual tumor rates in the photodynamic diagnosis and white‐light groups were 25.7% and 47.3%, respectively. Factor analysis for predicting residual tumors in the photodynamic diagnosis group showed that the residual tumor rate was significantly higher in cases with a current/past smoking history, multiple tumors, and pT1/pTis. When each factor was set as a risk level of 1, cases with a total risk score ≤1 showed a significantly lower residual tumor rate than cases with a total risk score ≥2 (8.3% vs 33.3%, odds ratio 5.46 [1.81–22.28]).ConclusionsIn high‐risk non‐muscle invasive bladder cancer cases, the odds of a residual tumor after initial photodynamic diagnosis‐transurethral resection of bladder tumor were 0.39‐fold that of the odds of those after initial white‐light transurethral resection of bladder tumor. A risk stratification model could be used to omit the second transurethral resection of bladder tumor in 27% of the cases.

Reduction of residual tumors by photodynamic diagnosis-assisted TURBT using 5-aminolevulinic acid for high-risk nonmuscle-invasive bladder cancer (BRIGHT study).

489 Background: High-risk non-muscle invasive bladder cancer (NMIBC) has high tumor residual rate of 40–60% after TURBT, and second TUR is strongly recommended. Photodynamic diagnosis-assisted TURBT (PDD-TURBT) using 5-aminolevulinic acid (5-ALA) has been reported to reduce residual tumors and intravesical recurrence. The purpose of this study is to investigate the residual tumor-reducing effect of PDD-TURBT for high-risk NMIBC and to explore the possibility that second TUR could be omitted by PDD-TURBT. Methods: We conducted an investigator-initiated multicenter prospective observational study (BRIGHT study; UMIN000035712) involving patients who underwent PDD-TURBT using 5-ALA and second TUR for high-risk NMIBC (high-grade UC or pT1 or concurrent CIS). The primary endpoint was tumor residual rate and the secondary endpoint was recurrence-free survival, which were compared with historical data (conventional TURBT) using propensity score-matching (PSM; caliper: 0.2). Assuming that the difference between the two groups was 20%, the planned number of cases was statistically set to 200 PDD-TURBT cases and 300 historical data cases, and the registration period was 2 years from January 2019 to December 2020, and the follow-up period was 2 years after second TUR. Results: In this study, 188 patients in the PDD-TURBT group and 313 patients in the historical group were enrolled, and 177 patients and 306 patients were included in the final analysis, respectively. After PSM adjustment, 167 patients in both groups were compared, and no significant differences were observed in age, gender, history of bladder cancer, tumor diameter, number of tumors, history of upper tract urothelial cancer, and period from initial TURBT to second TUR. The tumor residual rate was 25.8% in the PDD-TURBT group compared with 47.3% in the historical group, showing a significant decrease (odds ratio 0.39 [95% CI: 0.24–0.63]; p = 0.000064). Logistic regression analysis revealed that significant factors predicting residual tumors in PDD-TURBT were current or past smoking history, multiple tumors, and non-pTa (pT1 or pTis) tumors. Focusing on these three factors, patients with 0–1 of these three factors have a significant less tumor residual rate compared with patients with 2–3 factors (8.33% vs. 33.3%; odds ratio 5.46 [95% CI: 1.81–22.3]; p = 0.00052). Conclusions: PDD-TURBT for high-risk NMIBC significantly reduced the tumor residual rate at the second TUR compared to the conventional TURBT. PDD-TURBT using 5-ALA may enable to omit second TUR in some high-risk NMIBC cases. Clinical trial information: UMIN000035712.

Cruciferous Vegetable Intervention to Reduce the Risk of Cancer Recurrence in Non-Muscle-Invasive Bladder Cancer Survivors: Development Using a Systematic Process.

BackgroundBladder cancer is one of the top 10 most common cancers in the United States. Most bladder cancers (70%-80%) are diagnosed at early stages as non–muscle-invasive bladder cancer (NMIBC), which can be removed surgically. However, 50% to 80% of NMIBC cases recur within 5 years, and 15% to 30% progress with poor survival. Current treatments are limited and expensive. A wealth of preclinical and epidemiological evidence suggests that dietary isothiocyanates in cruciferous vegetables (Cruciferae) could be a novel, noninvasive, and cost-effective strategy to control NMIBC recurrence and progression.ObjectiveThe aim of this study is to develop a scalable dietary intervention that increases isothiocyanate exposure through Cruciferae intake in NMIBC survivors.MethodsWe worked with a community advisory board (N=8) to identify relevant factors, evidence-based behavior change techniques, and behavioral theory constructs used to increase Cruciferae intake in NMIBC survivors; use the PEN-3 Model focused on incorporating cultural factors salient to the group’s shared experiences to review the intervention components (eg, the saliency of behavioral messages); administer the revised intervention to community partners for their feedback; and refine the intervention.ResultsWe developed a multicomponent intervention for NMIBC survivors consisting of a magazine, tracking book, live telephone call script, and interactive voice messages. Entitled POW-R Health: Power to Redefine Your Health, the intervention incorporated findings from our adaptation process to ensure saliency to NMIBC survivors.ConclusionsThis is the first evidence-based, theoretically grounded dietary intervention developed to reduce bladder cancer recurrence in NMIBC survivors using a systematic process for community adaptation. This study provides a model for others who aim to develop behavioral, community-relevant interventions for cancer prevention and control with the overall goal of wide-scale implementation and dissemination.

Intravesical immunotherapy with a GM-CSF armed oncolytic vesicular stomatitis virus improves outcome in bladder cancer

A significant proportion of non-muscle invasive bladder cancer cases will progress to muscle invasive disease. Transurethral resection followed by Bacillus Calmette Guerin immunotherapy can reduce this risk, while cystectomy prior to muscle invasion provides the best option for survival. Currently, there are no effective treatments for Bacillus Calmette Guerin refractory disease. A novel oncolytic vesicular stomatitis virus containing the human GM-CSF transgene (VSVd51-hGM-CSF) was rescued and tested as a potential bladder-sparing therapy for aggressive bladder cancer. The existing variant expressing mouse GM-CSF was also used. Measurement of gene expression and protein level alterations of canonical immunogenic cell death associated events on mouse and human bladder cancer cell lines and spheroids showed enhanced release of danger signals and immunogenic factors following infection with VSVd51-m/hGM-CSF. Intravesical instillation of VSVd51-mGM-CSF into MB49 bladder cancer bearing C57Bl/6 mice demonstrated enhanced activation of peripheral and bladder infiltrating effector immune cells, along with improved survival and reduced tumor volume. Importantly, virus-mediated anti-tumor immunity was recapitulated in bladder cancer patient-derived organoids. These results suggest that VSVd51-hGM-CSF is a promising viro/immunotherapy that could benefit bladder cancer patients.

Preoperative abdominal fat distribution and systemic immune inflammation were associated with response to intravesical Bacillus Calmette-Guerin immunotherapy in patients with non-muscle invasive bladder cancer

To investigate the predictors of response to intravesical Bacillus Calmette-Guerin (BCG) immunotherapy for intermediate and high-risk non-muscle invasive bladder cancer (NMIBC) patients. We retrospectively analyzed the clinicopathological data of 184 intermediate and high risk NMIBC cases receiving transurethral resection of bladder tumor (TURBT) and intravesical BCG immunotherapy from December 2014 to April 2021at our center. All patients were divided into BCG responders and non-responders. Multivariate Logistic regression analysis was performed to identify the independent predictors of response to intravesical BCG immunotherapy. Univariate and multivariate Cox regression analyses were applied to explore the independent prognostic factors of recurrence-free survival (RFS). Receiver operating characteristic (ROC) curve and Kaplan-Meier survival analysis were also utilized. The RFS of BCG responders was significantly increased compared with BCG non-responders. Multivariate Cox regression analysis demonstrated that low grade, pTa stage, non-CIS, lower relative visceral fat area (rVFA) and lower systemic immune inflammation index (SII) were independent prognostic factors of increased RFS after intravesical BCG immunotherapy. Multivariate Logistic regression analysis demonstrated that pTa stage, low grade, non-CIS, low rVFA, and low SII were independent predictors of response to intravesical BCG immunotherapy. Kaplan-Meier survival analysis indicated that the RFS of patients in low rVFA group or low SII group was significantly increased in comparison with those in high rVFA group or high SII group. ROC curve analysis showed that the area under ROC (AUC) of including SII and rVFA was significantly increased, indicating that the inclusion of preoperative SII and rVFA could significantly improve the predictive efficiency. Low grade, pTa stage, non-CIS, preoperative lower rVFA and lower SII were vital independent predictors of response to intravesical BCG immunotherapy and were associated with preferable prognosis in NMIBC patients. The inclusion of preoperative SII and rVFA could significantly improve the predictive efficiency.

P53 Expression analysis in Low Grade and High Grade Urothelial Bladder Carcinoma and the Association with Tumor Stages

BackgroundUrothelial carcinoma is the most common bladder malignancy in men. Risk factors include smoking, chemicals exposure, radiation,schistosoma hematobium infection. P53 mutation is the most common mutation in urothelial bladder carcinoma that cause p53 proteinaccumulation which are detected through immunohistochemical examination. The aim of this study is to analyze the differencesbetween p53 expression in low and high grade urothelial and the carcinomas association of p53 expression with tumor stage.MethodsThis was a cross sectional study with 47 cases (22 cases of low grade and 25 cases of high grade) urothelial carcinoma in AnatomicalPathology Department Faculty Medicine of Universitas Indonesia/Cipto Mangunkusumo Hospital (FKUI/RSCM) in 2009-2017. Allcases stained with p53 antibody with immunohistochemical methods with positive cut off ≥20%.ResultsP53 positive expression are found in 33 samples, 20 cases of high grade and 13 cases in low grade; 22 cases of Nonmuscle invasivebladder cancer and 11 cases of Muscle invasive bladder cancer.ConclusionThe expression of p53 in low grade and high grade urotelial carcinoma of the bladder and its association with tumor stage showed nosignificant difference.

Upregulation of Fatty Acid Transporters is Associated With Tumor Progression in Non-Muscle-Invasive Bladder Cancer.

As patients with non-muscle-invasive bladder cancer (NMIBC) show a high degree of heterogeneity in tumor recurrence or progression, many clinicians demand a detailed risk stratification. Although modified fatty acid metabolism in cancer cells is reported to reflect malignant phenotypes such as metastasis, the impact of fatty acid transporters on NMIBC has never been investigated. This study examined the clinicopathologic implications of fatty acid transporters such as fatty acid transport protein 4 (FATP4), cluster of differentiation 36/fatty acid translocase (CD36/FAT), and long chain acyl CoA synthetase 1 (ACSL1) in 286 NMIBC cases. This study revealed that FATP4, CD36, and ACSL1 were overexpressed in 123 (43.0%), 43 (15.0%), and 35 (12.2%) NMIBC cases, respectively. High FATP4 in tumor cells was associated with high grade (p = 0.004) and high stage (p = 0.039). High CD36 was related to high grade (p < 0.001), high stage (p = 0.002), and non-papillary growth type (p = 0.004). High ACSL1 showed an association with high grade (p < 0.001), high stage (p = 0.01), non-papillary growth type (p = 0.002), and metastasis (p = 0.033). High FATP4 was an independent factor predicting short overall survival (OS) (hazard ratio = 3.32; 95% confidence interval, 1.07–10.31; p = 0.038). In conclusion, upregulation of FATP4, CD36, and ACSL1 might promote the NMIBC progression and could be exploited in clinical risk stratification and targeted therapy.