Bacillus Calmette-Guérin Instillation Research Articles

Temporal dynamics of immune cell patterns in bladder cancer patients receiving Bacillus Calmette-Guérin therapy.

Bacillus Calmette-Guérin (BCG) is capable of enhancing the infiltration of immune cells into the tumour. However the temporal dynamics of immune cell patterns in patients receiving BCG instillation remains unclear. Ninety-six patients who underwent intravesical BCG therapy, comprising 46 responders and 50 non-responders, were retrospectively enroled to explore the evolving immune landscape. This study involved a detailed examination of sequential samples collected before, during, and after BCG treatment to assess BCG's influence on the immune microenvironment, employing techniques such as immunohistochemistry, fluorescent multiplex immunohistochemistry, and mass spectrometry techniques. Our study found that initial BCG instillation leads to enhanced immune cell infiltration, correlating with treatment efficacy, with responders exhibiting more pronounced increases. Non-responders experience a rise in immune cell infiltration and PD-L1 expression during the first instillation, which returns to baseline after treatment. In non-responders, BCG re-challenge fail to further increase immune cell infiltration into the tumour or improve patient outcomes. Strikingly, proteomics data revealed that GBP1 expression was induced by BCG treatment in non-responders. Our findings demonstrated the induction of tumour PD-L1 expression by BCG in non-responders, and therefore provide insights for the combination of BCG and anti-PD1/anti-PD-L1 therapy.

The role of TERT C228T and KDM6A alterations and TME in NMIBC treated with BCG

We aimed to investigate the genomic and tumor microenvironmental (TME) profiles in non-muscle invasive bladder cancer (NMIBC) and explore potential predictive markers for Bacillus Calmette–Guérin (BCG) treatment response in high-risk NMIBC patients (according to European Association of Urology (EAU) risk stratification). 40 patients with high-risk NMIBC (cTis-T1N0M0) who underwent en bloc resection followed by BCG instillation were retrospectively enrolled. Surgical samples were subjected to Next Generation Sequencing (NGS) and multiplex immunofluorescence (mIF) assay. Genomic profiling revealed high prevalences of alterations in TERT (55%), KDM6A (32.5%), FGFR3(30%), PIK3CA (30%), TP53(27.5%) and ARID1A (20%). TME analysis showed different proportions of macrophages, NK cells, T cells subsets in tumoral and stromal compartment. Multivariate analysis identified TERT C228T and alteration in KDM6A as two independent factors associated with inferior RFS. The study comprehensively depicted the genomic and TME profiles in NMIBC and identified potential predictive biomarkers for BCG treatment.

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

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

No clinical benefit from sequential combination of mitomycin C plus bacillus Calmette-Guérin (BCG) than BCG alone in the adjuvant treatment of high risk non muscle invasive bladder cancer: result of a planned interim analysis of a prospective randomized trial.

The aim of this study was to evaluate whether the sequential use of Mitomycin C (MMC) and Bacillus Calmette-Guérin (BCG) is superior to BCG alone in reducing the risk of disease recurrence in patients with non-muscle invasive bladder cancer (NMIBC) with high risk of progression. Prospective randomized trial was conducted from March 2021 to March 2023 and included 72 patients with high risk NMIBC. Trial registration number: NCT03790384; EUDRACT Number: 2017-004540-37. Thirty-one patients underwent to BCG alone and forty-one to MMC plus BCG during the induction course. The BCG schedule comprised six weekly instillation of 81 mg Connaught strain BCG as the induction course, followed by a further three-monthly instillation at three, six and twelve months, as the maintenance course. Forty mg of MMC were administered the day prior to each weekly BCG instillation in BCG plus MMC arm. A planned interim analysis was carried out in June 2023, at the end of the 12mo follow-up period. Six out of thirteen 6/31(19.3%) and 10/41 (24.4%) patients experienced recurrence in BCG and BCG plus MMC group (P=0.611), respectively. BCG plus MMC did not improve Disease Free Interval (HR: 1.23 95% CI:0.46-3.50; P=0.640). Patients receiving sequential treatment experienced similar AEs (P>0.05) and more urinary symptoms (P<0.05). This interim pre-planned analysis suggested absence of clinical advantages in terms of disease recurrence rate when MMC is administered one day prior to BCG during induction course.

Epirubicin and Non-Muscle Invasive Bladder Cancer Treatment: A Systematic Review.

(1) Background: Intravesical chemotherapy is the standard of care in intermediate-risk non-muscleinvasive bladder cancer (NMIBC). Different agents are used across the world based on availability, cost, and practice patterns. Epirubicin (EPI), one of these agents, has been used by many centers over many decades. However, its true differential efficacy compared to other agents and its tolerability are still poorly reported. We aimed to assess the differential efficacy and safety of intravesical EPI in NMIBC patients. (2) Methods: This study aimed to systematically review the efficacy and safety profile of Epirubicin (EPI) in the management of non-muscle invasive bladder cancer (NMIBC) compared to other adjuvant therapies. A systematic search of the PUBMED, Web of Science, clinicaltrials.gov, and Google Scholar databases was conducted on 31 December 2023, using relevant terms related to EPI, bladder cancer, and NMIBC. The inclusion criteria targeted studies that evaluated patients treated with EPI following the transurethral resection of bladder tumors (TURBT) for NMIBC and compared oncological outcomes such as recurrence and progression with other adjuvant therapies, including Mitomycin C (MMC), Gemcitabine (GEM), and Bacillus Calmette-Guérin (BCG). Additionally, studies investigating the safety profile of EPI administered intravesically at room temperature and under hyperthermia, as well as oncological outcomes associated with hyperthermic intravesical EPI administration, were included. (3) Results: Eleven studies reported adverse events after adjuvant intravesical instillations with EPI; the most frequently reported adverse events included cystitis (34%), dysuria, pollakiuria, hematuria, bladder irritation/spasms, fever, nausea and vomiting, and generalized skin rash (2.3%). Nine studies compared EPI to BCG in terms of recurrence and progression rates; BCG instillations showed a lower recurrence rate compared to EPI, with limited or non-significant differences in progression rates. Two studies found no significant differences between EPI and MMC regarding progression and recurrence rates. One study showed statistically significant lower recurrence and progression rates with GEM in high-risk NMIBC patients. Another study found no significant differences between EPI and GEM regarding recurrence and progression. (4) Conclusions: EPI exhibits similar oncological performances to Gemcitabine and Mitomycin C currently used for adjuvant therapy in NMIBC. Novel delivery mechanisms such as hyperthermia are interesting newcomers.

Comparative efficacy of Bacillus Calmette-Guérin instillation and radical cystectomy treatments for high-risk non-muscle-invasive urothelial cancer classified as high-grade T1 in initial and repeat transurethral resection of bladder tumor.

To compare the differential therapeutic effects of Bacillus Calmette-Guérin (BCG) instillation and radical cystectomy (RC) for high-risk non-muscle-invasive urothelial cancer (NMIBC) classified as high-grade T1 in initial and repeat transurethral resection of bladder tumors (TURBT) and to construct a prediction model. We retrospectively analyzed the clinical data of patients with malignant bladder tumors treated at the First Affiliated Hospital of Soochow University from January 2016 to December 2017 and compared the differences in 1-year, 2-year, 3-year, 5-year, and comprehensive overall survival (OS) and progression-free survival (PFS) between BCG instillation treatment and RC treatment. Survival curves were drawn to show differences in OS and PFS between the two groups. Concurrently, univariate and multivariate COX analyses were performed to identify risk factors affecting OS and PFS, and a nomogram was created. In total, 146 patients were included in the study, of whom 97 and 49 were in the BCG and RC groups, respectively. No statistical differences were observed in the 1- and 2-year OS and PFS between the two groups, whereas significant statistical differences were found in the 3-year, 5-year, and comprehensive OS and PFS. Survival curves also confirmed the statistical differences in OS and PFS between the BCG and RC groups. Multivariate COX analysis revealed that the treatment method, concomitant satellite lesions, and albumin-to-alkaline phosphatase ratio (AAPR) were independent risk factors affecting OS and PFS. The nomogram that was further plotted showed good predictive ability for OS and PFS. For patients who exhibit high-level T1 pathology after both initial and repeat TURBT, especially those with low AAPR, and concomitant satellite lesions, choosing RC as a treatment method offers a better prognosis.

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 .

Cumulative incidence of and risk factors for BCG infection after adjuvant BCG instillations.

To investigate the cumulative incidence proportion of disseminated or local Bacillus Calmette-Guérin (BCG) infections after adjuvant BCG instillations in patients with non-muscle-invasive bladder cancer (NMIBC). We analysed the timing and occurrence of BCG infections and absolute and relative risk in relation to patient characteristics available in the Swedish nationwide database 'BladderBaSe 2.0'. The cumulative incidence proportion of a BCG infection was indicated by a reported diagnosis of tuberculosis (TB) in the patient registry or filing a prescription for tuberculostatic drugs. The cumulative incidence proportion was 1.1% at the 5-year follow-up in 5033 patients exposed to adjuvant BCG instillations. The incidence rate was highest during the first 2 years after start of BCG instillations. Women had a lower risk than men (hazard ratio 0.23, 95% confidence interval 0.07-0.74). Age and calendar time at diagnosis, comorbidity, tumour risk group, previous medication with corticosteroids, immunosuppressive drugs, or time between transurethral resection of the bladder tumour and commencing the adjuvant BCG instillation were not associated with risk. These data further supports that the overall risk of a BCG infection after BCG-instillation treatment for NMIBC is low. The great majority of infections occur in the first 2 years, calling for an awareness of the diverse symptoms of BCG infection during this period. We provide evidence for male sex as a risk factor; however, the statistical precision is low and with a risk of selection bias, making it difficult to rule out the other suggested risk factors without further studies with different approaches.

Phase 3 KEYNOTE-676 cohort A: Bacillus Calmette-Guérin (BCG) with or without pembrolizumab for high-risk (HR) non–muscle-invasive bladder cancer (NMIBC) that persists/recurs after BCG induction.

TPS722 Background: Intravesical instillation of BCG is a standard-of-care treatment for patients with HR NMIBC, but up to 50% of patients later experience disease recurrence or progression to muscle-invasive bladder cancer (MIBC) despite BCG treatment. In the phase 2 KEYNOTE-057 study (NCT02625961), pembrolizumab monotherapy was shown to have antitumor activity in patients with HR BCG–unresponsive NMIBC who had carcinoma in situ (CIS) with or without papillary tumors and in patients with only papillary tumors. In cohort A of the randomized, phase 3 KEYNOTE-676 trial (NCT03711032), pembrolizumab plus BCG versus BCG alone is being evaluated in patients with persistent/recurrent HR NMIBC after first BCG induction. Methods: Key eligibility criteria include adults with histologically confirmed HR NMIBC (T1, high-grade Ta, and/or CIS) that is persistent/recurrent following 1 adequate course of BCG induction therapy, have no concurrent extravesical disease or history of extravesical disease that recurred within 2 years, have an ECOG PS score of 0 to 2, and have undergone cystoscopy/TURBT ≤12 weeks before randomization. Approximately 430 patients will be randomly assigned 1:1 to receive pembrolizumab 200 mg intravenously every 3 weeks plus BCG or BCG alone. BCG (50 mg) will be administered by intravesical instillation as induction therapy once weekly for 6 weeks and then as maintenance therapy once weekly for 3 weeks at weeks 13 and 25, then every 24 weeks (Q24W) thereafter. Treatment will continue for approximately 2 years (pembrolizumab) or 3 years (BCG), or until confirmed persistent/recurrent HR NMIBC or disease progression to MIBC or metastatic bladder cancer, unacceptable toxicity, or withdrawal. Randomization to treatment will be stratified by PD-L1 combined positive score (≥10 or ˂10), histology (CIS or non-CIS), and NMIBC disease history (persistence/recurrence 0 to ≤6 months or recurrence ˃6 to ≤12 months or recurrence ˃12 to ≤24 months). Response will be assessed by local cystoscopy and blinded independent central review of urine cytology and biopsy (as applicable) every 12 weeks for years 1 to 2 and Q24W for years 3 to 5. Computed tomography urography will occur every 72 weeks through year 5, then every 104 weeks thereafter. The primary end point is complete response rate in patients with CIS. Secondary end points are duration of response in patients with CIS, event-free survival, recurrence-free survival, time to cystectomy, overall survival, disease-specific survival, safety and tolerability, and patient-reported outcomes. Enrollment incohort A of KEYNOTE-676 is ongoing in Asia, Australia, Europe, and North America. Clinical trial information: NCT03711032 .

BCG immunotherapy promotes tumor-derived T-cell activation through the FLT3/FLT3LG pathway in bladder cancer.

Bladder instillation therapy is a common treatment for superficial or nonmuscle invasive bladder cancer. After surgery or reresection, chemotherapy drugs (epirubicin) or medications such as Bacillus Calmette-Guérin (BCG) are used for bladder instillation therapy, which can reduce the risk of bladder cancer recurrence and progression. However, the specific mechanism by which BCG stimulates the antitumor response has not been thoroughly elucidated. Additionally, although BCG immunotherapy is effective, it is difficult to predict which patients will have a positive response. In this study, we explored the BCG-induced immune response and found that high levels of Fms-related receptor tyrosine kinase 3 ligand (FLT3LG) were expressed after BCG treatment. This FLT3LG can directly act on CD8+ T cells and promote their proliferation and activation. The use of FLT3 inhibitors can neutralize the antitumor effects of BCG. In vitro experiments showed that FLT3LG can synergize with T-cell receptor activators to promote the activation of tumor-derived T cells. This study partially elucidates the mechanism of CD8+ T-cell activation in BCG immunotherapy and provides a theoretical basis for optimizing BCG instillation therapy in bladder cancer.

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

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. Oncological outcomes of HR-NMIBC patients treated with reduced (RD,1/4th dose) vs full dose (FD) BCG instillations of Danish Strain 1331 BCG. 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. 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). 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.

Comparison of hyperthermic intravesical chemotherapy and Bacillus Calmette-Guerin therapy in high-risk non-muscle invasive bladder cancer: a matched-pair analysis.

To compare adjuvant hyperthermic intravesical chemotherapy (HIVEC) with mitomycin C and standard Bacillus Calmette-Guerin (BCG) therapy in terms of oncological outcomes and adverse events in patients with high-risk non-muscle-invasive bladder cancer (NMIBC). The data of patients with high-risk papillary NMIBC treated with adjuvant intravesical BCG instillations or HIVEC in our institution between June 2017 and August 2022 were analyzed retrospectively. Twenty-four patients who received HIVEC were matched 1:1 with patients receiving BCG therapy based on tumor characteristics (tumor stage and grade), age, gender, smoking status, and the number of tumors (single or multiple). HIVEC and standard BCG treatments were compared in terms of recurrence-free survival (RFS), progression-free survival (PFS), and adverse events. Forty-eight patients (24 in the BCG group and 24 in the HIVEC group) were included in the study. The median follow-up times of the BCG and HIVEC groups were 32 [interquartile range (IQR): 28.0-47.8] and 28 (IQR: 16.7-41.8) months, respectively (p = 0.11). There was no significant difference between the groups in terms of the 24-month RFS (BCG 83% vs HIVEC 88%, p = 0.64) and the 24-month PFS (BCG 100% vs HIVEC 94%, p = 0.61). Regarding the safety profile, at least one adverse event occurred in 13 (54%) of the patients in the BCG group and 12 (50.0%) of those in the HIVEC group (p = 0.77). This study demonstrated that HIVEC with mitomycin C has a similar oncological efficacy and safety profile to standard BCG therapy in high-risk NMIBC.

Quality of Life in Patients with High-grade Non-muscle-invasive Bladder Cancer Undergoing Standard Versus Reduced Frequency of Bacillus Calmette-Guérin Instillations: The EAU-RF NIMBUS Trial.

Adverse events induced by intravesical bacillus Calmette-Guérin (BCG) to treat high-grade non-muscle-invasive bladder cancer (NMIBC) often lead to treatment discontinuation. The EAU-RF NIMBUS trial found a reduced number of standard-dose BCG instillations to be inferior with the standard regimen. Nonetheless, it remains important to evaluate whether patients in the reduced BCG treatment arm had better quality of life (QoL) due to a possible reduction in toxicity or burden. To evaluate whether patients in the EAU-RF NIMBUS trial experienced better QoL after a reduced BCG instillation frequency. A total of 359 patients from 51 European sites were randomized to one of two treatment arms between December 2013 and July 2019. The standard frequency arm (n=182) was 6 weeks of BCG induction followed by 3 weeks of maintenance at months 3, 6, and 12. The reduced frequency arm (n=177) was BCG induction at weeks 1, 2, and 6, followed by maintenance instillations at weeks 1 and 3 of months 3, 6, and 12. Analyses were performed using an intention-to-treat analysis and a per-protocol analysis. QoL was measured using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 version 3.0 (QLQ-C30 v.03) prior to the first and last instillations of each BCG cycle. Group differences were determined using linear regression corrected for QoL at baseline. Differences in QoL over time were tested for significance using a linear mixed model. Side effects were recorded by the treating physician using a standardized form. Chi-square tests were used to compare the side-effect frequency between the arms. There were no significant differences in the means of each QoL scale between the two arms. There were also no significant changes over time in all QoL domains for both arms. However, differences in the incidence of general malaise at T1 (before the last induction instillation), frequency, urgency, and dysuria at T7 (before the last maintenance instillation) were detected in favor of the reduced frequency arm. Reducing the BCG instillation frequency does not improve the QoL in NMIBC patients despite lower storage symptoms. In this study, we evaluated whether a reduction in the number of received bacillus Calmette-Guérin instillations led to better quality of life in patients with high-grade non-muscle-invasive bladder cancer. We found no difference in the quality of life between the standard and the reduced bacillus Calmette-Guérin instillation frequency. We conclude that reducing the number of instillations does not lead to better quality of life in patients with high-grade non-muscle-invasive bladder cancer.

Impact of age >70 years on oncological outcomes in patients with non-muscle-invasive bladder cancer treated with Bacillus Calmette-Guérin.

To evaluate the impact of age on oncological outcomes in a large contemporary cohort of patients with non-muscle-invasive bladder cancer (NMIBC) treated with adequate Bacillus Calmette-Guérin (BCG). We performed an Institutional Review Board-approved retrospective study analysing patients with NMIBC treated with adequate BCG at our institution from 2000 to 2020. Adequate BCG was defined as per United States Food and Drug Administration (FDA) guidelines as being receipt of at least five of six induction BCG instillations with a minimum of two additional doses (of planned maintenance or of re-induction) of BCG instillations within a span of 6 months. The study's primary outcome was to determine if age >70 years was associated with progression to MIBC cancer or distant metastasis. The cumulative incidence method and the competing-risk regression analyses were used to investigate the association of advanced age (>70 years) with progression, high-grade (HG) recurrence and cancer-specific mortality (CSM). Overall, data from 632 patients were analysed: 355 patients (56.2%) were aged ≤70 years and 277 (43.8%) were >70 years. Age >70 years did not adversely affect either cumulative incidence of progression or HG recurrence (P = 0.067 and P = 0.644, respectively). On competing-risk regression analyses, age >70 years did not emerge as an independent predictor of progression or HG recurrence (sub-standardised hazard ratio [SHR] 1.57, 95% confidence interval [CI] 0.87-2.81, P = 0.134; and SHR 1.05, 95% CI 0.77-1.44, P = 0.749). Not unexpectedly, patients in the older group did have higher overall mortality (P < 0.001) but not CSM (P = 0.057). Age >70 years was not associated with adverse oncological outcomes in a large contemporary cohort of patients receiving adequate intravesical BCG for NMIBC. BCG should not be withheld from older patients seeking for bladder sparing options.

Phase I/II randomized clinical trial of in-clinic acupuncture prior to BCG in patients with high-risk non-muscle invasive bladder cancer.

4590 Background: Acupuncture can reduce pain and urinary urgency and frequency. Treatment-related dose-limiting dysuria and irritative bladder symptoms are common in patients receiving intravesical Bacillus Calmette-Guerin (BCG) for the treatment of non muscle-invasive bladder cancer (NMIBC). We evaluated the feasibility, safety, and tolerability of weekly in-clinic pre-procedure acupuncture among patients receiving induction BCG. Methods: Patients with high-risk NMIBC undergoing induction BCG were randomized 2:1 to a standardized acupuncture protocol (Acu) or an attention waitlist control. Acu patients received acupuncture prior to each of 6 weekly BCG instillations. Feasibility was assessed via recruitment, retention, and intervention adherence. Acupuncture safety and tolerability were assessed via physician-reported CTCAE v5.0 and adverse events (AEs). Secondary endpoints included BCG treatment adherence, patient-reported BCG-related toxicity, and bladder cancer-specific and generic quality of life (QOL), assessed with the EORTC-QLQ-NMIBC-24 and -C30 surveys. Subjective assessments of acupuncture acceptability were assessed through patient exit surveys. Results: Between 1/21 and 7/22, 43 patients were randomized to Acu (n=28) vs. Control (n=15). Median age was 70.3 years and 76% were male. Week 7 follow-up surveys were completed by 93% of patients; 6 patients withdrew early due to disease progression, refractory gross hematuria, or for patient preference. Acupuncture was successfully delivered prior to each BCG treatment in Acu patients with no acupuncture-related AEs or interruptions to induction BCG. BCG-attributed AEs were reported by 91% Acu and 100% Control patients, including pain (28% vs. 43%, respectively, p=0.34) and urinary symptoms (62% vs. 79%, respectively, p=0.31). Comparing Acu with Controls, change in QOL over the study period demonstrated greater improvements in median urinary symptoms (9.5, IQR 0.0-19.0 vs. 0.0, IQR -14.3-7.1, p=0.02) and a trend towards improvement in median pain scores (16.7, IQR 0.0-16.7 vs. 8.3, IQR 0.0-33.3 p=0.68) among patients in the Acu arm. 96% of Acu patients reported that acupuncture was “very/extremely helpful” and 91% would recommend acupuncture to other patients. Conclusions: Acupuncture prior to induction BCG treatments is feasible and safe. In this Phase I/II trial, we observed reductions in pain and a trend towards improved urinary function scores over successive treatments among patients undergoing in-clinic pre-BCG instillation acupuncture. Patients receiving acupuncture reported high degrees of satisfaction with treatments. Future larger randomized controlled trials are needed to further characterize the efficacy of acupuncture with respect to pain, urinary symptoms and impact on QOL, and continuation of maintenance therapy during BCG treatment. Clinical trial information: NCT04496219 .

Topical instillation of BCG immunotherapy for biopsy-proven primary upper urinary tract carcinoma in situ: A single institution series and systematic review.

Primary upper tract carcinoma in situ (UTcis) is a rare disease whose diagnosis and natural history are poorly understood. Radical nephroureterectomy is the standard of care but in imperatives or selected cases, topical instillations of Bacillus Calmette-Guérin (BCG) may represent a good alternative. The aim of this study was to report the histologic response to BCG instillations for the treatment of biopsy-proven UTcis and to systematically assess the current evidence on topical BCG instillation for the treatment of UTcis. This is a retrospective analysis of patients with biopsy-proven UTcis treated with BCG instillation between 1995 and 2020 in an expert center. The initial diagnosis was performed by a standardized random biopsy scheme during ureterorenoscopy (URS) in patients with positive cytology but negative CT and bladder biopsies. BCG course consisted of 6 weekly instillation of 81 mg Immucyst (Sanofi Pasteur MSD AG, Baar, Switzerland). Administration techniques were single-J, double-J and nephrostomy tube. The primary outcome was the rate of complete histological response at the 3-month 2nd-look-URS. Kaplan-Meier analysis curves assessed recurrence- and progression-free survival. A total of 22 patients (23 renal units) were included. Twenty-one (91.3%) patients completed the planned 6-week instillation cycle. Only one major complication was recorded (renal tuberculosis). Twenty patients had a 3-month 2nd-look-URS, with a complete histological response achieved in 17/20 cases (85%). After a median time of follow-up of 40 months (30-62), 8/20 patients harbored disease recurrence, including 5 cases of disease progression (≥pT2). The main limitations are the retrospective and non-comparative design of the study. Our systematic review (CRD42022324876) identified 15 studies (289 renal units). UTcis suffers from the lack of a standardized definition, and considerable heterogeneity has been found in making the diagnosis and assessing the response to treatment. Our study is the first to propose a histological diagnosis of UTcis as well as a histological re-evaluation of the response to treatment. Topical instillations of BCG appear to be a promising alternative, avoiding radical treatment in the majority of cases.

Miliary Pulmonary Tuberculosis After Intravesical BCG Instillation in a Patient with High-Grade Bladder Cancer

Intravesical administration of Bacillus Calmette-Guerin (BCG) vaccine is used in the treatment of superficial bladder cancer. In clinical practice, intravesical BCG immunotherapy after transurethral tumor resection is a highly effective treatment option in preventing tumor recurrence and progression in medium and high risk superficial bladder tumors. Since patients are given live tuberculosis (TB) bacillus, serious side effects such as pneumonia, sepsis and even death can be seen. Lung involvement occurs in less than 1% of patients and most commonly presents as interstitial pneumonia or miliary TB. Miliary TB is difficult to diagnose and is usually based on high clinical suspicion, as Mycobacterium bovis is not isolated in most cases. Treatment is not completely standardized. However, in severe cases, a combination of antituberculosis drugs and corticosteroids is recommended. In this report, a case of miliary tuberculosis, a very rare complication after instillation of BCG into the bladder in a patient with a diagnosis of superficial bladder cancer, was presented. A 73-year-old male patient diagnosed with bladder tumor underwent transurethral resection of bladder tumor, and then weekly intravesical injection of BCG-MEDAC for six weeks had no adverse effects. Three weeks of intravesical BCG supplementation was planned for the patient who had no signs of recurrence when checked three months later by cystoscopy. Two hours after the first dose, the patient, who applied to the emergency department with the complaint of chills and shivering, was hospitalized for further follow-up and treatment. Afterwards, repeat cultures were taken from the patient whose fever continued on the seventh day of treatment with broad-spectrum antibiotics (meropenem and teicoplanin). In addition, when abdominal and thorax computed tomography (CT) were performed, multiple miliary nodular lesions were detected in both lungs and were evaluated in favor of miliary TB. With these findings, the patient was started on miliary TB therapy [isoniazid (INH), rifampicin (RIF), ethambutol (EMB) and streptomycin (STM)] targeting Mycobacterium bovis, since it was an infection that developed after BCG injection. In the third week of the treatment, the patient's fever was under control, and he was discharged on the 25th day of his hospitalization because of significant improvement in infection markers [C-reactive protein(CRP)-procalcitonin]. At the end of two months, there was clear regression of pulmonary abnormalities on control thorax CT. In conclusion, miliary TB developing after intravesical BCG instillation is a very rare condition, the cause of which is not fully understood, the etiology of fever can be easily missed, and the diagnosis is difficult. In addition, this case is presented to draw attention to a critical disease that requires long treatment and follow-up and requires attention.

Abstract 2127: TERT C228T and KDM6A alterations are potential predictive biomarkers in non-muscle-invasive bladder cancer treated with intravesical Bacillus Calmette-Guérin instillation

Abstract Introduction: Bacillus Calmette-Guérin (BCG) is the standard of care for high-risk non-muscle-invasive bladder cancer (NMIBC) following transurethral resection. However, patients often have heterogeneous responses. Even among those who initially respond well to BCG, 10-20% relapse. Identification of reliable biomarkers predicting the efficacy of BCG remains an unmet need. En bloc resection is a novel technique representing a substantial advancement in the surgical management of NMIBC. We sought to investigate genomic and tumor microenvironmental (TME) profiles in NMIBC and explore potential predictive markers for BCG treatment following en-block resection. Methods: A total of 40 patients with high-risk NMIBC (cTis-T1N0M0) were retrospectively enrolled who underwent en bloc resection followed by BCG instillation. Surgical samples were subjected to NGS sequencing using a 520-gene panel (Burning Rock Biotech, Guangzhou) and multiplex immunofluorescence (mIF) assay. Results: The cohort had a median age of 63 years, and 80% were male. After a median follow-up of 21.8 months, 19/40 patients relapsed with a one-year relapse-free survival (RFS) rate of 57.5%. All tumors were microsatellite stable and showed a median TMB of 7.98muts/Mb. Genomic profiling revealed a high prevalence of alterations in TERT (55%), KDM6A (32.5%), KMT2D (32.5%), FGFR3(30%), PIK3CA (30%), TP53(27.5%), KMT2C (25%), and ARID1A (20%). TME analysis showed higher proportions of M1 macrophages and CD56 dim NK cells in the tumoral compartment and more intense infiltration of CD8+ T cells, exhausted CD8+T, CD56 bright NK cells, and M2 macrophages in the stromal compartment. Multivariate analysis identified TERT C228T mutation (HR=3.28 [95%CI:1.225-8.79], p=0.0181) and alteration in KDM6A (HR=2.94 [95%CI:1.040-8.29], p=0.042) as two independent factors associated with inferior RFS. Patients with concomitant TERT C228T and KDM6A alteration had the shortest RFS (median RFS:5.83months) compared with those who were free of (median RFS: NR) or harbored either one of the two alterations (median RFS:9.13months) (p=0.0022). We also found that tumoral infiltration of CD8+T cells was positively associated with RFS (HR=0.29 [95%CI:0.097-0.885], p=0.0208). Conclusion: The study comprehensively depicted the genomic and TME profiles in NMIBC and identified potential predictive biomarkers for BCG treatment. Our findings may facilitate the stratification of patients and better guide the clinical decision-making on the management of NMIBC. Citation Format: Qi-Dong Xia, Yao-Bing Chen, Jian-Xuan Sun, Chen-Qian Liu, Jin-Zhou Xu, Zhi-Peng Yao, Ye An, Meng-Yao Xu, Si-Han Zhang, Xing-Yu Zhong, Na Zeng, Si-Yang Ma, Hao-Dong He, Heng-Long Hu, Jia Hu, Yi Lu, Lin Shao, Si-Qi Li, Zheng Liu, Shao-Gang Wang. TERT C228T and KDM6A alterations are potential predictive biomarkers in non-muscle-invasive bladder cancer treated with intravesical Bacillus Calmette-Guérin instillation [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 2127.

Manejo del carcinoma in situ de tramo urinario superior diagnosticado por biopsia ureteroscópica: ¿es el bacilo de Calmette-Guérin una alternativa a la nefroureterectomía?

IntroductionRadical nephroureterectomy (RNU) still represents the gold standard treatment for upper tract urothelial carcinoma (UTUC); however, since the 1980s attempts have been made to treat upper urinary tract CIS (UT-CIS) conservatively. The aim of this study was to compare the outcome of patients with primary UT-CIS treated in our center by means of RNU vs. bacillus Calmette-Guérin (BCG) instillations. MethodsThis retrospective study included patients with diagnosis of primary UT-CIS between 1990 and 2018. All patients had histological confirmation of UT-CIS in the absence of other concomitant UTUC. Histological confirmation was obtained by ureteroscopy with multiple biopsies. Patients were treated with RNU, distal ureterectomy, or BCG instillations. Clinicopathological features and outcomes were compared between the RNU and BCG groups. ResultsA total of 28 patients and 29 renal units (RUs) were included. Sixteen (57.1%) patients (17 RUs) received BCG. BCG was administered via a nephrostomy tube in 4 patients, a single-J ureteral stent in 5, and a Double-J stent in 7. Complete response and persistence or recurrence were detected in ten (58.8%) and seven (41.2%) RUs treated with BCG, respectively. Eight (27.6%) RUs underwent RNU, with contralateral recurrence detected in four (50%), and 4 (13.8%) RUs underwent distal ureterectomy. No differences were found in recurrence-free survival (p=0.841) and cancer-specific survival (p=0.77) between the RNU and BCG groups. ConclusionsAlthough RNU remains the gold standard treatment for UT-CIS, our results confirm that BCG instillations are also effective. Histological confirmation of UT-CIS is mandatory before any treatment.

MP08-18 ASYMPTOMATIC BACTERIURIA DOES NOT INCREASE THE RISK OF INFECTIVE COMPLICATIONS IN PATIENTS WITH NON-MUSCLE-INVASIVE BLADDER CANCER UNDERGOING INTRAVESICAL BACILLUS CALMETTE-GUERIN IMMUNOTHERAPY

You have accessJournal of UrologyCME1 Apr 2023MP08-18 ASYMPTOMATIC BACTERIURIA DOES NOT INCREASE THE RISK OF INFECTIVE COMPLICATIONS IN PATIENTS WITH NON-MUSCLE-INVASIVE BLADDER CANCER UNDERGOING INTRAVESICAL BACILLUS CALMETTE-GUERIN IMMUNOTHERAPY Antti Nummi, Pertti Nurminen, Olli Kesti, Mikael Högerman, Otto Ettala, Peter Boström, Antti Kaipia, Jukka Sairanen, and Riikka Järvinen Antti NummiAntti Nummi More articles by this author , Pertti NurminenPertti Nurminen More articles by this author , Olli KestiOlli Kesti More articles by this author , Mikael HögermanMikael Högerman More articles by this author , Otto EttalaOtto Ettala More articles by this author , Peter BoströmPeter Boström More articles by this author , Antti KaipiaAntti Kaipia More articles by this author , Jukka SairanenJukka Sairanen More articles by this author , and Riikka JärvinenRiikka Järvinen More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003223.18AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Asymptomatic bacteriuria (ABU) is common in patients with non-muscle-invasive bladder cancer (NMIBC). Even though ABU is not considered as an absolute contraindication for bacillus Calmette-Guérin (BCG) administration, many urologists prefer sterile urine or use prophylactic antibiotics prior BCG instillation, aiming to prevent acute urinary tract infection (UTI), bacterial sepsis and BCG infection. However, the use of antibiotics may potentially lead to multidrug-resistant bacterial strains, while the clinical benefit is not clear. The aim of this study was to determine whether ABU increases the risk of infective complications and whether it is justified to screen asymptomatic patients for bacteriuria before BCG instillations. METHODS: We analyzed retrospectively patients who received ≥1 BCG instillations as treatment of NMIBC in our institutions during 2009-2018. Patients had submitted urine specimen 1-7 days prior every BCG instillation. Urine cultures were recorded as no growth or the presence of bacteriuria. ABU was classified as having any positive urine culture but no dysuria or fever. Antibiotic prophylaxis prior BCG administration was recorded. Our primary endpoints were admission to hospital because of UTI, BCG toxicity and BCG infections within 2 weeks of BCG instillation. RESULTS: We analyzed 802 patients and 12 882 BCG instillations. ABU was recorded with 2 200 (17%) instillations. Antibiotics were used in 519 (21%) instillations in bacteriuria group. Hospital admission was recorded after 8 (0.3%) and 37 (0.4%) instillations in the bacteriuria and in the no growth group, respectively (p=0.9). There was no significant difference in hospital admissions between the groups with or without antibiotic prophylaxis (p=0.4). CONCLUSIONS: BCG instillation with ABU is safe and does not increase the risk of developing a symptomatic UTI or severe BCG complications. By consequence, our results do not support routine screening of asymptomatic patients for bacteriuria prior intravesical BCG treatment. Antibiotic prophylaxis should only be used with consideration. Symptomatic UTI remains contraindication for BCG instillation. Source of Funding: Finnish Association of Urology © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e101 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Antti Nummi More articles by this author Pertti Nurminen More articles by this author Olli Kesti More articles by this author Mikael Högerman More articles by this author Otto Ettala More articles by this author Peter Boström More articles by this author Antti Kaipia More articles by this author Jukka Sairanen More articles by this author Riikka Järvinen More articles by this author Expand All Advertisement PDF downloadLoading ...