Induction and maintenance of sequential intravesical gemcitabine/docetaxel for intermediate and high-risk non-muscle invasive bladder cancer with different dosage protocols.

INTRODUCTION: The combination of sequential intravesical gemcitabine and docetaxel (Gem/Doce) chemotherapy has been considered a feasible option for BCG (Bacillus Calmette-Guérin) treatment in non-muscle invasive bladder cancer (NMIBC), gaining popularity during BCG shortage period. We seek to determine the efficacy of the treatment by comparing Gem/Doce induction alone vs induction with maintenance, and to evaluate the treatment outcomes of two different dosage protocols. METHODS: A bi-center retrospective analysis of consecutive patients treated with Gem/Doce for NMIBC between 2018 and 2023 was performed. Baseline characteristics, risk group stratification (AUA 2020 guidelines), pathological, and surveillance reports were collected. Kaplan-Meier survival analysis was performed to detect Recurrence-free survival (RFS). RESULTS: Overall, 83 patients (68 males, 15 females) with a median age of 73 (IQR 66-79), and a median follow-up time of 18 months (IQR 9-25), were included. Forty-one had an intermediate-risk disease (49%) and 42 had a high-risk disease (51%). Thirty-seven patients (45%) had a recurrence; 19 (23%) had a high-grade recurrence. RFS of Gem/Doce induction-only vs induction + maintenance was at 6 months 88% vs 100%, at 12 months 71% vs 97%, at 18 months 57% vs 91%, and at 24 months 31% vs 87%, respectively (log-rank, p < 0.0001). Patients who received 2 g Gemcitabine with Docetaxel had better RFS for all-grade recurrences (log-rank, p = 0.017). However, no difference was found for high-grade recurrences. CONCLUSION: Gem/Doce induction with maintenance resulted in significantly better RFS than induction-only. Combining 2 g gemcitabine with docetaxel resulted in better RFS for all-grade but not for high-grade recurrences. Further prospective trials are necessary to validate our results.

Treatment of Low-grade Intermediate-risk Nonmuscle-invasive Bladder Cancer With UGN-102 ± Transurethral Resection of Bladder Tumor Compared to Transurethral Resection of Bladder Tumor Monotherapy: A Randomized, Controlled, Phase 3 Trial (ATLAS).

PURPOSE: Low-grade intermediate-risk nonmuscle-invasive bladder cancer is a chronic illness commonly treated by repetitive transurethral resection of bladder tumor. We compared the efficacy and safety of intravesical chemoablation with UGN-102 (a reverse thermal gel containing mitomycin), with or without subsequent transurethral resection of bladder tumor, to transurethral resection of bladder tumor alone in patients with low-grade intermediate-risk nonmuscle-invasive bladder cancer. MATERIALS AND METHODS: This prospective, randomized, phase 3 trial recruited patients with new or recurrent low-grade intermediate-risk nonmuscle-invasive bladder cancer to receive initial treatment with either UGN-102 once weekly for 6 weeks or transurethral resection of bladder tumor. Patients were followed quarterly by endoscopy, cytology, and for-cause biopsy. The primary end point was disease-free survival. All patients were followed for adverse events. RESULTS: Trial enrollment was halted by the sponsor to pursue an alternative development strategy after 282 of a planned 632 patients were randomized to UGN-102 ± subsequent transurethral resection of bladder tumor (n=142) or transurethral resection of bladder tumor monotherapy (n=140), rendering the trial underpowered to perform hypothesis testing. Patients were predominantly male and ≥65 years of age. Tumor-free complete response 3 months after initial treatment was achieved by 92 patients (65%) who received UGN-102 and 89 patients (64%) treated by transurethral resection of bladder tumor. The estimated probability of disease-free survival 15 months after randomization was 72% for UGN-102 ± transurethral resection of bladder tumor and 50% for transurethral resection of bladder tumor (hazard ratio 0.45). The most common adverse events (incidence ≥10%) in the UGN-102 group were dysuria, micturition urgency, nocturia, and pollakiuria. CONCLUSIONS: Primary, nonsurgical chemoablation with UGN-102 for the management of low-grade intermediate-risk nonmuscle-invasive bladder cancer offers a potential therapeutic alternative to immediate transurethral resection of bladder tumor monotherapy and warrants further investigation.

International Bladder Cancer Group Intermediate-risk Nonmuscle-invasive Bladder Cancer Scoring System Predicts Outcomes of Patients on Active Surveillance.

PURPOSE: We sought to determine if the International Bladder Cancer Group IR-NMIBC (Intermediate-risk Nonmuscle-invasive Bladder Cancer) scoring system can predict the requirement of delayed transurethral resection of bladder tumor in low-grade nonmuscle-invasive bladder cancer managed by active surveillance. MATERIALS AND METHODS: We prospectively studied recurrent low-grade Ta/T1 nonmuscle-invasive bladder cancer patients managed with active surveillance with the following characteristics: low-grade papillary nonmuscle-invasive bladder cancer, ≤5 apparent low-grade nonmuscle-invasive bladder tumors, tumor diameter ≤1 cm, absence of gross hematuria, and negative urinary cytology. Subsequent transurethral resection of bladder tumor was offered to patients who no longer met the inclusion criteria or patient choice. The ability of the International Bladder Cancer Group IR-NMIBC scoring system to predict receipt of subsequent transurethral resection of bladder tumor was determined. Multivariable Cox proportional hazards analysis was used to determine factors associated with subsequent transurethral resection of bladder tumor. RESULTS: A total of 163 patients with low-grade Ta/T1 nonmuscle-invasive bladder cancer were included for analysis. After a median follow-up of 33 months (IQR: 21-46), transurethral resection of bladder tumor was performed on 109 patients. At landmark time point of 24 months, patients with 0 risk factors were over 2-fold more likely to continue active surveillance compared to patients with ≥3 risk factors (59% vs 24%). Multivariable Cox regression suggested that the International Bladder Cancer Group IR-NMIBC scoring system was associated with subsequent transurethral resection of bladder tumor (1-2 risk factors [HR: 1.66, 95% CI: 0.96-2.90, P = .072], ≥3 risk factors [HR: 3.21, 95% CI: 1.70-6.09, P < .001]) after adjusting for age, T stage, and sex. CONCLUSIONS: The International Bladder Cancer Group IR-NMIBC scoring system can predict the risk of subsequent transurethral resection of bladder tumor in patients with low-grade nonmuscle-invasive bladder cancer on active surveillance.

Multi-DECT image-based intratumoral and peritumoral radiomics for preoperative prediction of muscle invasion in bladder cancer.

OBJECTIVES: To assess the predictive value of intratumoral and peritumoral radiomics based on Dual-energy CT urography (DECTU) multi-images for preoperatively predicting the muscle invasion status of bladder cancer (BCa). MATERIAL AND METHODS: This retrospective analysis involved 202 BCa patients who underwent DECTU. DECTU-derived quantitative parameters were identified as risk factors through stepwise regression analysis to construct a DECT model. The radiomic features from the intratumoral and 3 mm outward peritumoral regions were extracted from the 120 kVp-like, 40 keV, 100 keV, and iodine-based material-decomposition (IMD) images in the venous-phase and were screened using Mann-Whitney U test, Spearman correlation analysis, and LASSO. Radiomics models were developed using the Multilayer Perceptron for the intratumoral, peritumoral and intra- and peritumoral (IntraPeri) regions. Subsequently, a nomogram was created by integrating the multi-image IntraPeri radiomics and DECT model. Model performance was evaluated using area-under-the-curve (AUC), accuracy, sensitivity, and specificity. RESULTS: Normalized iodine concentration (NIC) was identified as an independent predictor for the DECT model. The IntraPeri model demonstrated superior performance compared to the intratumoral and peritumoral models both in 40 keV (0.830 vs. 0.766 vs. 0.763) and IMD images (0.881 vs. 0.840 vs. 0.821) in the test cohort. In the test cohort, the nomogram exhibited the best predictability (AUC=0.886, accuracy=0.836, sensitivity=0.737, and specificity=0.881), outperformed the DECT model (AUC=0.763, accuracy=0.754, sensitivity=0.632, and specificity=0.810) in predicting muscle invasion status of BCa with a statistically significant difference (p < 0.05). CONCLUSION: The nomogram, incorporating IntraPeri radiomics and NIC, serves as a valuable and non-invasive tool for preoperatively assessing the muscle invasion status of BCa.

Impact of variant histology in the prognosis of non­muscle invasive bladder cancer with low­tumor burden: A propensity score­matched analysis with conventional urothelial carcinoma.

Bladder cancer (BCa) with variant histology (VH) is associated with an increased risk of recurrence and progression, as well as worse survival. However, the available literature does not provide the prognostic value of VH based on its tumor burden in non-muscle invasive BCa (NMIBC). The purpose of the present study was to investigate the prognosis of VH in NMIBC with low-tumor volume compared with conventional urothelial carcinoma (UC) with a similar tumor burden. The present single-center study analyzed patients diagnosed with NMIBC and retrospectively characterized them based on their VH status. Propensity scores for VH status were calculated to match patients with VH with those with conventional UC (1:3). The VH group was further divided into two subgroups based on pathological aggressiveness: Aggressive and highly aggressive variants. Oncological outcomes were compared among the three groups. Among the 494 patients with NMIBC, 60 (12.1%) had VH. Patients with VH had a higher tumor stage and grade and more multiple tumors (all P<0.05). In the matched cohort, >80% had tumors <3 cm, and >65% had solitary tumors. During a median follow-up of 42.5 months (range, 4.0-122.0 months), 35.1% (85/240) experienced recurrence and 5.4% (13/240) progressed to muscle-invasive disease. Prognosis did not differ between patients with aggressive or highly aggressive variants and those with conventional UC, including 5-year recurrence-free and pathologic progression-free survival (log-rank, P=0.510 and 0.257, respectively). Intravesical Bacillus Galmette-Guerin was the only factor associated with reduced recurrence (P<0.001). In conclusion, NMIBC with low-tumor burden and VH have similar oncologic outcomes to conventional UC with a similar tumor burden, indicating that bladder-sparing methods currently used for high-risk conventional NMIBC may be effective for managing low-tumor burden NMIBC with VH.

COL6A1 expression as a potential prognostic biomarker for risk stratification of T1 high grade bladder cancer: Unveiling the aggressive nature of a distinct non-muscle invasive subtype.

PURPOSE: T1 high grade (T1HG) bladder cancer (BC) is a type of non-muscle invasive BC (NMIBC) that is recognized as an aggressive subtype with a heightened propensity for progression. Current risk stratification methods for NMIBC rely on clinicopathological indicators; however, these approaches do not adequately capture the aggressive nature of T1HG BC. Thus, new, more accurate biomarkers for T1HG risk stratification are needed. Here, we enrolled three different patient cohorts and investigated expression of collagen type VI alpha 1 (COL6A1), a key component of the extracellular matrix, at different stages and grades of BC, with a specific focus on T1HG BC. MATERIALS AND METHODS: Samples from 298 BC patients were subjected to RNA sequencing and real-time polymerase chain reaction. RESULTS: We found that T1HG BC and muscle invasive BC (MIBC) exhibited comparable expression of COL6A1, which was significantly higher than that by other NMIBC subtypes. In particular, T1HG patients who later progressed to MIBC had considerably higher expression of COL6A1 than Ta, T1 low grade patients, and patients that did not progress, highlighting the aggressive nature and higher risk of progression associated with T1HG BC. Moreover, Cox and Kaplan-Meier survival analyses revealed a significant association between elevated expression of COL6A1 and poor progression-free survival of T1HG BC patients (multivariate Cox hazard ratio, 16.812; 95% confidence interval, 3.283-86.095; p=0.001 and p=0.0002 [log-rank test]). CONCLUSIONS: These findings suggest that COL6A1 may be a promising biomarker for risk stratification of T1HG BC, offering valuable insight into disease prognosis and guidance of personalized treatment decisions.

Insights into the Interplay between the Urinary Microbiome and Bladder Cancer: A Comprehensive Review.

New insights in the urinary microbiome have led to a better understanding being built of the shifts in bacterial representations from health to disease; these hold promise as markers for diagnosis and therapeutic responses. Although several efforts have been made to identify a "core urinary microbiome", different fingerprints have been identified in men and women that shift with age. The main bacterial groups overall include Firmicutes, Actinobacteria, Fusobacteria, and Bacteroidetes. Although patients with bladder cancer have a microbiome that is similar to that of healthy individuals, differences have been observed at the species level with Fusobacterium nucleatum and Ralstonia, and at the genus level with Cutibacterium. Different bacterial representations may influence extracellular matrix composition, affecting tumor metastatic spreading and tumorigenic metalloproteinase expression. Furthermore, gene expression affecting targets of immune therapy, such as PD-L1, has been associated with changes in bacterial representations and therapeutic response to BCG. This comprehensive review aims to examine the influence of the urinary microbiome in bladder cancer.

Surgeon experience in second-look transurethral resection of bladder cancer - a prospective study.

INTRODUCTION AND OBJECTIVES: Transurethral resection of bladder tumor (TURBT) is crucial in the treatment of bladder tumors and when incorrectly performed can cause staging mistakes. To avoid these errors, a second resection is recommended in selected cases. The aim of this study is to evaluate the surgeon's ability to predict histologically complete primary resection of newly diagnosed bladder tumors avoiding the need for a second TURBT. METHODS: This is a prospective, observational study involving 47 consecutive patients with newly diagnosed bladder tumors who had previously undergone primary TURBT, and met EAU criteria for second-look TURBT. Second-look TURBT specimens were analyzed for routine histological assessment and compared with the surgeon's impression of the tumor at initial resection. RESULTS: Of 91 patients submitted to primary TURBT, 47 met the criteria for second-look TURBT. Second-look specimens revealed residual disease in 20.9% of patients and 3 (6.4%) of patients showed upstaging disease. The sensitivity of a senior to detect disease on second-look TURBT in relation to muscle invasion was 75%, and the specificity was 85%. CONCLUSIONS: Second-look TURBT is crucial in the treatment of bladder cancer and cannot be replaced by a surgeon's opinion, so international recommendations should be followed. Supervision of less experienced surgeons is a cornerstone.

Comparative Effectiveness of Bacillus Calmette-Guérin and Sequential Intravesical Gemcitabine and Docetaxel for Treatment-naïve Intermediate-risk Non-muscle-invasive Bladder Cancer.

BACKGROUND AND OBJECTIVE: Sequential intravesical gemcitabine/docetaxel (Gem/Doce) has emerged as a potential alternative to bacillus Calmette-Guérin (BCG) for the treatment of non-muscle-invasive bladder cancer (NMIBC). Our aim was to determine the comparative effectiveness of BCG and Gem/Doce for patients with intermediate-risk (IR) NMIBC, composed mainly of high-grade (HG) Ta disease. METHODS: Patients with IR-NMIBC who received either BCG or Gem/Doce during 2013-2023 were included. Maintenance BCG (as per the Southwest Oncology Group protocol) and monthly Gem/Doce maintenance for 1 yr were offered to patients with no evidence of recurrence after induction. Routine surveillance with cystoscopy was performed according to the American Urological Association guidelines. The Kaplan-Meier method was used to assess high-grade and any-grade recurrence-free survival (RFS). Cox regression analysis was performed to find predictors of recurrence. KEY FINDINGS AND LIMITATIONS: Of 483 patients, 127 had IR-NMIBC; 66 patients received BCG and 61 received Gem/Doce. Median age was 69 yr (interquartile range [IQR] 61-76) for the BCG group and 72 yr (IQR 62-76) for the Gem/Doce group. Median follow-up was 53.1 mo (IQR 25.3-71.2) for the BCG group and 20.2 mo (IQR 8.28-33.1) for the Gem/Doce group. The 2-yr high-grade RFS rates for primary high-grade tumors for BCG versus Gem/Doce groups were 81% versus 61%, with corresponding any-grade RFS rates of 60% versus 41%. Induction with Gem/Doce predicted any-grade recurrence (hazard ratio [HR] 1.87, 95% confidence interval [CI] 1.1-3.2) and high-grade recurrence for primary high-grade tumors (HR 3.4 95% CI 1.27-9.13), while receipt of maintenance therapy decreased the risk of any-grade recurrence (HR 0.4, 95% CI 0.22-0.72). This study is limited by its retrospective design. CONCLUSIONS AND CLINICAL IMPLICATIONS: For patients with IR-NMIBC, BCG was associated with superior any-grade RFS and high-grade RFS for primary high-grade tumors. Maintenance therapy was associated with better RFS when receiving Gem/Doce. Standardization and longer maintenance therapy protocols should be considered for Gem/Doce treatment. PATIENT SUMMARY: We compared outcomes for patients who received two different in-bladder treatments for intermediate-risk bladder cancer. Bacillus Calmette-Guérin (BCG) led to better outcomes than gemcitabine + docetaxel (Gem/Doce). Monthly maintenance therapy improved recurrence-free survival for patients who received Gem/Doce. We conclude that maintenance therapy is essential for patients receiving Gem/Doce to avoid bladder cancer recurrence after treatment.

Longitudinal Tumor-informed Circulating Tumor DNA Status Predicts Disease Upstaging and Poor Prognosis for Patients Undergoing Radical Cystectomy.

BACKGROUND AND OBJECTIVE: Decision-making on the use of neoadjuvant and adjuvant treatment for patients with bladder cancer undergoing radical cystectomy (RC) currently depends on assessment of clinical and pathological features, which lack sensitivity. Circulating tumor DNA (ctDNA) has emerged as a possible novel prognostic biomarker in the field. Our aim was to assess whether ctDNA status before RC is predictive of pathological and oncological outcomes. We also evaluated the dynamic changes in ctDNA status after RC in relation to recurrence-free survival (RFS). METHODS: We analyzed data for patients who underwent RC during 2021-2023 for whom prospective tumor-informed ctDNA analyses were conducted before and after RC. RFS was evaluated using the Kaplan-Meier method. Predictors for disease recurrence were assessed using Cox proportional-hazards models. Pathological outcomes associated with detectable ctDNA before RC were assessed in univariable and multivariable regression analyses. KEY FINDINGS AND LIMITATIONS: We included 112 patients in the analysis. Median follow-up was 8 mo (interquartile range 4-13). ctDNA was detected before RC in 59 patients (53%) and was associated with poor RFS (log-rank p < 0.0001). Detectable ctDNA before RC was associated with poor outcomes regardless of clinical stage (

Orthotopic Mouse Models of Urinary Bladder Cancer.

BACKGROUND/AIM: Urinary bladder cancer has various etiologies and tends to recur and then progress to a higher grade. When muscles are invaded, the response to conventional therapy is poor and the quality of life deteriorates rapidly. Here, we summarize and compare two representative methods used to create the syngeneic mouse models required for immunological research. MATERIALS AND METHODS: In this study, we utilized six-week-old female C3H/HeNCrl mice and the mouse bladder tumor cell line MBT-2. The first method involved transurethral catheterization with poly-L-lysine pretreatment (catheter group), while the second method involved transperitoneal incision and direct injection of tumor cells into the bladder wall (open group). Mouse postoperative status was monitored on a weekly basis using magnetic resonance imaging (MRI). RESULTS: The catheter group had a tumor development rate of 47% (7 out of 15 mice), with only 1 mouse developing an intravesical tumor. In contrast, the open group had a higher tumor formation rate of 69% (47 out of 68 mice), with 27 mice showing intravesical tumor formation. Notably, with a lower cell count, urinary obstruction events were observed 2 weeks post-inoculation, which is one week later than the higher cell count group. CONCLUSION: In this study, we conducted a comparative analysis between the transurethral catheterization method and the transperitoneal incision and direct injection method in animal bladder tumor models. Our findings provide evidence of the consistent effectiveness in constructing a stable model within the open group. Well-designed orthotopic animal models are essential.

Cytomorphologic visualization of circulating tumor cells in urinary bladder cancer patients using ScreenCell™ technology: Potential as a simple cytology test.

Circulating tumor cells (CTC) are a recent technique which is a potentially important prognostic factor in many solid tumors. There are many techniques of detecting CTCs, but they usually implement costly techniques like EpCAM targeted detection, fluorescence-based diagnosis, or magnetic bead based positive or negative selection. The diagnostic utility of simple cytomorphological diagnosis after routine staining of CTCs have been rarely studied. We aimed to detect CTCs in 24 patients clinically suspected to have Urinary Bladder Cancer using a simple but efficient patented filtration technology (ScreenCell™), followed by optical microscopic visualization after routine May-Grunwald-Giemsa (MGG) staining. The detected CTCs were then tested for association with the histologic type, lamina propria invasion, deep muscle invasion and the T-stage. Out of the 24 patients tested, one was found to have papilloma, nine had low grade urothelial carcinoma, 13 had high grade urothelial carcinoma and one had poorly differentiated adenocarcinoma. Of these, two LGUC, eight HGUC and one adenocarcinoma had detectable CTC. Presence of CTCs had a statistically significant association with Lamina propria invasion (P = .006) and T-stage (P = .02), and a trend toward significance for differentiating LGUC from HGUC (P = .10). These results suggest that cytomorphological detection of CTC is likely to be clinically useful in diagnosis and prognostication of urinary blader cancers. These findings need to be confirmed on studies with larger sample sizes.

Prognostic Role of Preoperative Neutrophil-To-Lymphocyte Ratio (NLR) and Recurrence at First Evaluation after Bacillus Calmette-Guérin (BCG) Induction in Non-Muscle-Invasive Bladder Cancer.

We investigated the prognosis of BCG induction-only treatment and non-complete response (CR) at the first 3-month evaluation and examined factors associated with CR. In total, 209 patients with moderate- and high-risk NMIBC who received BCG induction-only treatment between 2008 and 2020 were retrospectively analyzed. Recurrence-free survival (RFS) and progression-free survival (PFS) were assessed based on the initial NMIBC stage. PFS and associated factors of non-CR compared to CR were also assessed. Initial T1 high-grade (HG) (n = 93) had poorer RFS and PFS after BCG induction-only treatment than Ta low-grade (LG) (p = 0.029, p = 0.002). Non-CR (n = 37) had a different neutrophil-to-lymphocyte ratio (NLR) (2.81 ± 1.02 vs. 1.97 ± 0.92) and T staging from CR (p < 0.001, p = 0.008). T1HG recurrence was associated with a worse PFS compared to non-T1HG (13.7 months vs. 101.7 months, p < 0.001). There was no difference in PFS between T1HG and T1LG. T1 and NLR were predictors of response at 3 months in multivariable analysis (p = 0.004, p = 0.029). NLR was also found to be an associated factor with RFS and PFS of bladder cancer (p < 0.001, p < 0.001). BCG induction-only treatment was effective for high-risk TaLG but not for T1HG. T1HG recurrence at 3 months after BCG induction has a poor prognosis for bladder cancer. Preoperative NLR and T1 were predictors of non-CR, and NLR was also associated with the long-term prognosis of bladder cancer.

Increased risk of bladder cancer recurrence due to bacillus Calmette-Guérin shortage in Brazil

SUMMARY OBJECTIVE: Our study aimed to evaluate the impact of bacillus Calmette-Guérin shortage on recurrence and progression in patients with non-muscle invasive bladder cancer in a Brazilian cohort. METHODS: We retrospectively reviewed the clinicopathological data of 409 patients who had their first transurethral resection of the bladder tumor for intermediate or high-risk non-muscle invasive bladder cancer between June 2014 and May 2021 in a tertiary public hospital in Brazil. Patients included had non-muscle-invasive urothelial carcinoma of the bladder resected completely for the first time, regardless of bacillus Calmette-Guérin use. Low-risk disease patients were excluded from the analysis. Demographic, clinicopathological, and bacillus Calmette-Guérin use data were collected from our database. Recurrence and progression data were obtained from patient records or through telephone interviews. Recurrence-free survival and progression-free survival were calculated from the date of transurethral resection of the bladder tumor until the events of recurrence, progression, last office visit, or phone interview. RESULTS: Within a median follow-up period of 26.7 months, 168 (41.1%) patients experienced a recurrence in a median time of 27 months (95%CI 16.1-38). Bacillus Calmette-Guérin was administered to 57 (13.9%) individuals after transurethral resection of the bladder tumor. Patients with ≥3 lesions (p<0.001), those with lesions >3 cm (p=0.02), and those without bacillus Calmette-Guérin treatment (p<0.001) had shorter recurrence-free survival. According to a Cox multivariate regression model, bacillus Calmette-Guérin use was independently associated with a reduced recurrence rate, with an HR of 0.43 (95%CI 0.25-0.72). Out of the patients studied, 26 (6.4%) experienced progression. T1 stage (p<0.001) and high-grade (p<0.001) were associated with shorter progression-free survival. Bacillus Calmette-Guérin did not influence bladder cancer progression. In the Cox multivariate analysis, high-risk disease was independently associated with progression (p<0.001). CONCLUSION: Our study confirms that non-muscle invasive bladder cancer exhibits a high recurrence rate. The use of adjuvant bacillus Calmette-Guérin in intermediate and high-risk patients significantly reduces this rate. Furthermore, the bacillus Calmette-Guérin shortage could have negatively impacted these patients.