Urinary mRNA-based biomarkers for non-muscle-invasive bladder cancer: a mini-review.

Bladder cancer (BC) is the second most common type of cancer of the urinary system. Approximately 75% of the cases are non-muscle invasive bladder cancer (NMIBC), which has a high recurrence and progression rate. Current diagnosis and surveillance methods present challenges, including risks to the patients. For this reason, urinary biomarkers have been proposed as alternatives to the methods. The goal of this mini-review is to describe urinary mRNA-based biomarkers available in current literature for NMIBC tumors, using the PubMed database. The search included the following keywords: "biomarkers" AND "bladder cancer" AND "urine" and "RNA" and "non-muscle". The search yielded 11 original researchers utilizing mRNA-based urinary biomarkers. Although there is a wide variety of biomarkers described, the cohorts of the studies were not exclusively NMIBC, which is the subtype of BC that would mostly benefit from the introduction of a good follow-up biomarker, highlighting the need for randomized interventional trials for NMIBC.

Experimental and New Approaches for Bladder Preservation in Intermediate and High-Risk Non-Muscle-Invasive Bladder Cancer (NMIBC).

About 75% of bladder cancers are detected as non-muscle invasive. High-risk patients have high progression risk. Although the standard is transurethral resection of bladder tumor plus full dose intravesical BCG for one to 3 years, due to the high risk of progression, radical cystectomy may be considered in specific cases. Although radical cystectomy is still the best approach for high-grade NMIBC from an oncological perspective, its high morbidity and impact on quality of life motivate studies of new strategies that may reduce the need for cystectomy. We carried out a mini-review whose objectives were: 1 - to identify bladder-sparing alternatives that are being studied as possible treatment for patients with intermediate and high-risk NMIBC; 2 - understand the evidence that exists regarding success rate, follow-up, and side effects of different strategies. Several studies have sought alternatives for bladder preservation, including immunotherapy, intravesical chemotherapy, chemo-hyperthermia, antibody-drug conjugates, viral genetic therapy, and others with promising results. The selection of an optimal therapy for high-risk NMIBC that can reduce the need for cystectomy, with low toxicity and high efficacy, is of paramount importance and remains an issue, however, several known medications are being tested as bladder-preserving alternatives in this scenario and have shown promise in studies.

A Th2-score in the tumor microenvironment as a predictive biomarker of response to Bacillus Calmette Guérin in patients with non-muscle invasive bladder carcinoma: A retrospective study.

Intravesical Bacillus Calmette Guerin (BCG) is the gold standard therapy for intermediate/high-risk non-muscle invasive bladder cancer (NMIBC). However, the response rate is ~60%, and 50% of non-responders will progress to muscle-invasive disease. BCG induces massive local infiltration of inflammatory cells (Th1) and ultimately cytotoxic tumor elimination. We searched for predictive biomarker of BCG response by analyzing tumor-infiltrating lymphocyte (TIL) polarization in the tumor microenvironment (TME) in pre-treatment biopsies. Pre-treatment biopsies from patients with NMIBC who received adequate intravesical instillation of BCG (n = 32) were evaluated retrospectively by immunohistochemistry. TME polarization was assessed by quantifying the T-Bet+ (Th1) and GATA-3+ (Th2) lymphocyte ratio (G/T), and the density and degranulation of EPX+ eosinophils. In addition, PD-1/PD-L1 staining was quantified. The results correlated with BCG response. In most non-responders, Th1/Th2 markers were compared in pre-and post-BCG biopsies. ORR was 65.6% in the study population. BCG responders had a higher G/T ratio and a greater number of degranulated EPX+ cells. Variables combined into a Th2-score showed a significant association with higher scores in responders (p = 0.027). A Th2-score cut-off value >48.1 allowed discrimination of responders with 91% sensitivity but lower specificity. Relapse-free survival was significantly associated with the Th2-score (p = 0.007). In post-BCG biopsies from recurring patients, TILs increased Th2-polarization, probably reflecting BCG failure to induce a pro-inflammatory status and, thus, a lack of response. PD-L1/PD-1 expression was not associated with the response to BCG. Our results support the hypothesis that a pre-existing Th2-polarized TME predicts a better response to BCG, assuming a reversion to Th1 polarization and antitumor activity.

Should continuous bladder irrigation be recommended when single instillation of intravesical chemotherapy cannot be used after transurethral resection in low-risk non-muscle invasive bladder cancer?

Reducing the recurrence rate in patients with low-risk non-muscle invasive bladder cancer patients is a critical concern in the urologic community. The gold standard treatment is single instillation (SI) of intravesical chemotherapy after transurethral resection of bladder tumor (TURBT), but unfortunately, it is underused. Continuous bladder irrigation (CBI) after TURBT is an alternative strategy to SI for the prevention of bladder tumor implantation and recurrence. The aim of this review was to present the evidence that supports CBI after TURBT when SI is not possible.

Mutational Landscape of Bladder Cancer in Mexican Patients: KMT2D Mutations and chr11q15.5 Amplifications Are Associated with Muscle Invasion.

Bladder cancer (BC) is the most common neoplasm of the urinary tract, which originates in the epithelium that covers the inner surface of the bladder. The molecular BC profile has led to the development of different classifications of non-muscle invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC). However, the genomic BC landscape profile of the Mexican population, including NMIBC and MIBC, is unknown. In this study, we aimed to identify somatic single nucleotide variants (SNVs) and copy number variations (CNVs) in Mexican patients with BC and their associations with clinical and pathological characteristics. We retrospectively evaluated 37 patients treated between 2012 and 2021 at the National Cancer Institute-Mexico (INCan). DNA samples were obtained from paraffin-embedded tumor tissues and exome sequenced. Strelka2 and Lancet packages were used to identify SNVs and insertions or deletions. FACETS was used to determine CNVs. We found a high frequency of mutations in TP53 and KMT2D, gains in 11q15.5 and 19p13.11-q12, and losses in 7q11.23. STAG2 mutations and 1q11.23 deletions were also associated with NMIBC and low histologic grade.

Comparative Analysis of Very Reduced vs Full Dose BCG Treatment for High-Risk Non-Muscle Invasive Bladder Cancer: A Contemporary Experience from Chile.

BACKGROUND: Adjuvant bacillus Calmette-Guérin (BCG) is recommended for high-risk (HR) non-muscle invasive bladder cancer (NMIBC), but BCG shortages have led to exploration of reduced-dose regimens and shortened maintenance durations out of necessity, with limited data on treatment efficacy in Latin America. OBJECTIVE: Oncological outcomes of HR-NMIBC patients treated with reduced (RD,1/4th dose) vs full dose (FD) BCG instillations of Danish Strain 1331 BCG. METHODS: We performed a retrospective study of HR-NMIBC patients treated with BCG between 2003 and 2022 at our center in Santiago Chile. We stratified patients according to either RD (1/4th dose) or FD BCG. Univariate and multivariable Cox regression models were used to predict recurrence. Kaplan-Meier method was used to calculate survival estimates. RESULTS: Of a total of 200 patients, 116 (58%) had RD and 84 (42%) FD BCG. Median follow-up was 57 months (IQR: 29-100). Patients who received FD BCG had a lower risk of recurrence (HR: 0.41, 95% CI 0.22-0.74) and high-grade (HG)-recurrence (HR: 0.30, 95% CI 0.15-0.61; p = 0.001). More patients in the RD vs FD group progressed to MIBC (10/84 vs 2/116; p = 0.18). Additionally, patients were less likely to stop BCG treatment in the RD group compared to the FD group due to toxicity (5% vs 11%, p = 0.14). CONCLUSIONS: A 1/4th dose of Danish Strain 1331 BCG treatment was associated with worse recurrence free rate and HG-recurrence rate in our cohort. Patients with RD had lower discontinuation treatment rates due to a reduced toxicity profile. These findings would suggest that RD BCG would compromise oncological outcomes in HR-NMIBC patients.

Effect of Re-TUR time on recurrence and progression in high-risk non-muscle-invasive bladder cancer.

OBJECTIVE: We aimed to investigate the significance of time to re-staging transurethral resection (re-TUR) on recurrence and progression rates in patients with high-risk non-muscle-invasive bladder cancer as a prospective randomized study. METHODS: The patients were randomly separated into three groups according to Re-TUR timing. In Groups 1, 2, and 3, the time interval between initial and re-TUR was 14-28 days, 29-42 days, and 43-56 days, respectively. Cox regression analysis was used to assess the effect of time from initial TUR to re-TUR on oncological outcomes. RESULTS: Twenty patients in Group 1 (14-28 days), 22 patients in Group 2 (29-42 days), and 29 patients in Group 3 (43-56 days) completed the study. Kaplan-Meier plots showed no differences in recurrence-free survival (RFS) and progression-free survival (PFS) rates between the three groups. Cox regression analysis demonstrated that only tumor number was found to be a prognostic factor on RFS rates. CONCLUSION: Our prospective study demonstrated that time laps from initial TUR to re-TUR did not significantly affect on RFS and PFS rates.

OBJETIVO: Nuestro objetivo fue investigar la importancia del tiempo para volver a estadificar la resección transuretral (re-RTU) en las tasas de recurrencia y progresión en pacientes con cáncer de vejiga no músculo invasivo de alto riesgo como un estudio prospectivo aleatorizado. MÉTODO: Los pacientes se separaron aleatoriamente en 3 grupos de acuerdo con el tiempo de Re-TUR. En el grupo 1, 2 y 3, el intervalo de tiempo entre la RTU inicial y la nueva fue de 14 a 28 días, 29 a 42 días y 43 a 56 días, respectivamente. Cox para evaluar el efecto del tiempo desde la RTU inicial hasta la nueva RTU sobre los resultados oncológicos. RESULTADOS: Veinte pacientes del grupo 1, 22 pacientes del grupo 2, 29 pacientes del grupo 3 completaron el estudio. Los gráficos de Kaplan-Meier no mostraron diferencias en las tasas de SLR y SLP entre los tres grupos. El análisis de regresión de Cox demostró que solo se encontró que el número de tumores era un factor pronóstico en las tasas de RFS. CONCLUSIÓN: Nuestro estudio prospectivo demostró que los lapsos de tiempo desde la RTU inicial hasta la nueva RTU no afectaron significativamente las tasas de SLR y SLP.

Protective role of intravesical BCG in COVID-19 severity.

OBJECTIVES: To establish the role of BCG instillations in the incidence and mortality of COVID-19. PATIENTS AND METHODS: NMIBC patients in instillations with BCG (induction or maintenance) during 2019/2020 were included, establishing a COVID-19 group (with a diagnosis according to the national registry) and a control group (NO-COVID). The cumulative incidence (cases/total patients) and the case fatality rate (deaths/cases) were established, and compared with the national statistics for the same age group. T-test was used for continuous variables and Fisher's exact test for categorical variables. RESULTS: 175 patients were included. Eleven patients presented CIS (11/175, 6.3%), 84/175 (48.0%) Ta and 68/175 (38.9%) T1. Average number of instillations = 13.25 ± 7.4. One hundred sixty-seven patients (95.4%) had complete induction. Forty-three patients (cumulative incidence 24.6%) were diagnosed with COVID-19. There is no difference between COVID-19 and NO-COVID group in age, gender or proportion of maintenance completed. COVID-19 group fatality rate = 1/43 (2.3%). Accumulated Chilean incidence 70-79 years = 6.3%. Chilean fatality rate 70-79 years = 14%. CONCLUSIONS: According to our results, patients with NMIBC submitted to instillations with BCG have a lower case-fatality rate than the national registry of patients between 70 and 79 years (2.3% vs. 14%, respectively). Intravesical BCG could decrease the mortality due to COVID-19, so instillation schemes should not be suspended in a pandemic.

EORTC Risk Model to Predict Progression in Patients With Non-Muscle-Invasive Bladder Cancer: Is It Safe to Use in Clinical Practice?

PURPOSE: To evaluate the validation of European Organization for Research and Treatment of Cancer (EORTC) risk tables to predict progression in Brazilian patients with non-muscle-invasive bladder cancer (NMIBC). PATIENTS AND METHODS: Two hundred five consecutively and prospectively selected patients with NMIBC who underwent transurethral resection were analyzed during 12 years. Six parameters were analyzed: tumor grade, size, and number, pT stage, previous recurrence rate, and carcinoma-in-situ. Time to progression, risk score, and progression probabilities were calculated and compared to probabilities obtained from the EORTC model. The C index was calculated, and accuracy was analyzed for external validation. RESULTS: A total of 152 patients had complete follow-up data, 36 died, and 17 were lost to follow-up. One hundred thirty-seven patients had primary tumors and 68 had recurrent tumors. Progression to muscle-invasive disease occurred in 42 patients (20.5%). Significant characteristics related to progression were male gender, pT1 stage, lesion size ≥ 3 cm, high grade of disease, and no combined intravesical therapy. Mean time to progression was 26.9 months; the 1-year progression rate was 3.4% and the 5-year rate was 19.1%. The C index was 0.86 at 1 year and 0.78 at 5 years. For calibration, 1- and 5-year progression rates were lower than the values predicted by EORTC risk tables, mainly in high-risk groups. Although the EORTC model overestimated the short- and long-term risk of progression, an overlapping of the confidence intervals between both populations was detected. CONCLUSION: The EORTC model successfully stratified progression risks in a Brazilian cohort, although it overestimated progression rates. This scoring system is useful in predicting progression of NMIBC; however, updating new risk markers is essential to improve risk classification and prediction of progression.