BACKGROUND: In patients with non-invasive urothelial carcinoma of the prostatic urethra (PUC), treatment with Bacillus Calmette-Guérin (BCG) could be beneficial.
OBJECTIVE: To assess the response rates to BCG in the different tumor stages, to describe the clinical impact of transurethral resection of the prostate (TURP) before BCG treatment, and to review the side effects of BCG treatment for PUC.
METHODS: A systematic search was conducted using the PubMed database to identify original studies between 1977 and 2019 reporting on PUC and BCG.
RESULTS: Of a total of 865 studies, ten were considered for evidence synthesis. An indication for BCG treatment was found in non-stromal invasive stages (Tis pu, Tis pd) and in stromal infiltrating cases (T1) of primary and secondary PUC when transitional cell carcinoma was the histology of origin. Studies including patients treated with TURP before BCG showed a better local response in the prostatic urethra with a higher disease free survival (DFS) (80-100% vs. 63-89%) and progression free survival (PFS) (90-100% vs. 75-94%) than patients in studies in which no TURP was performed. However, this difference in recurrence and progression in the prostate neither affected the total PFS (57-75% vs. 58-93%), nor the disease specific survival (70-100% vs. 66-100%).
CONCLUSIONS: The use of resection loop biopsies of the prostatic urethra in appropriate cases during the primary work-up for suspected PUC, as well as the use of the current TNM classification for PUC, need to be improved. BCG therapy for non-stromal invasive stages of PUC show a good local response. Local response is further improved by a TURP before BCG therapy, although the overall prognosis does not seem to be affected. Further evidence for BCG treatment in the rare cases of stromal invasive PUC is needed. Specific side effects of BCG treatment for PUC are not reported.

Kidney-sparing surgery (KSS) for upper urinary tract urothelial carcinoma (UTUC) is a promising alternative to radical nephroureterectomy, especially for low-risk cases. However, due to the established risk of ipsilateral UTUC recurrence caused by the implantation of floating neoplastic cells after endoscopic resection, adjuvant endocavitary (endoureteral) instillations have been proposed. Instillation therapy may be also used as primary treatment for UTUC. The two most studied drugs that have been evaluated in both the adjuvant and primary setting of endocavitary instillation are mitomycin C and Bacillus Calmette-Guerin. The current paper provides an overview of the endocavitary treatments for UTUC, focusing on methods of administration, novel formulations, oncologic outcomes (in terms of endocavitary recurrence and progression), as well as on complications. In particular, the role of UGN-101 as a primary chemoablative treatment of primary noninvasive, endoscopically unresectable, low-grade, UTUC has been analysed. The drug achieved a complete response rate of 58% after the induction cycle, with a durable response independently of the maintenance cycle. The cumulative experience on the role of UUT instillation therapy appears encouraging; however, no definitive conclusions can be drawn about its therapeutic benefit. Given the current state of the art, any decision to administer adjuvant endoureteral therapy for UTUC should be carefully weighed against the potential adverse events. Nevertheless, newer investigations that improve visualization during ureteroscopy, genomic characterization, novel drugs and innovative strategies of improved drug delivery are under evaluation. The landscape of KSS for the treatment of the UTUC is evolving and seems promising.

BACKGROUND: Bacillus Calmette-Guerin (BCG) is the standard adjuvant treatment for intermediate and high-risk non-muscle invasive bladder cancer (NMIBC) following transurethral resection of the bladder (TURB). However, the optimal dose, strain, and schedule of BCG remain unclear.
OBJECTIVE: To evaluate the impact of BCG dose reduction on oncological outcomes and toxicity in patients with non-muscle invasive bladder cancer.
METHODS: We performed a systematic review of the literature in PubMed, EMBASE, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov databases. Selected studies were analyzed for Meta Analysis using PRISMA criteria. The study focused on disease recurrence, progression, and toxicity. We also compared the oncological outcomes of the different BCG strains.
RESULTS: A total of 2963 patients in 13 randomized controlled trials were included. In recurrence analysis, we found a non-significant difference between the full dose and any dose reduction of BCG (RR = 1.17, [1.06-1.28], I2 = 0%, p = 0.7). In terms of progression, the difference was also non-statistically significant (RR: 1.12 [0.89 - 1.41], I2 = 0%, p = 0.93). In the toxicity analysis, there were more local (RR: 0.81 [0.67-0.99] I2 = 76%; p < 0.01) and systemic (RR: 0.53 [0.34-0.82] I2 = 83%; p < 0.01) side effects in the full dose group than in the dose reduction group. There were no statistically significant differences in oncological outcomes between the analyzed BCG strains.
CONCLUSIONS: Dose reduction did not affect the oncological outcomes of patients with NMIBC who received adjuvant therapy with BCG. On the other hand, dose reduction showed a significant trend towards fewer systemic and local side effects. Further studies comparing oncological and toxicity outcomes using different strains are needed.

UNASSIGNED: This is a summary of two studies that looked at the safety and effectiveness of a potential new treatment, N-803 (Anktiva), in combination with a standard treatment bacillus Calmette-Guerin (BCG) for people with non-muscle invasive bladder cancer (NMIBC).One study was a Phase 1b study that tested increasing doses of N-803 in combination with the same dose of BCG in people with NMIBC who had never received BCG previously (BCG-naive). The other study is a Phase 2/3 study of N-803 and BCG in people with NMIBC whose cancer wasn\'t eliminated by BCG alone (BCGunresponsive).
UNASSIGNED: In the Phase 1b study, the nine participants were split into three groups of 3 participants who received a dose of 100, 200, or 400 μg N-803 along with a standard 50 mg dose of BCG. In the Phase 2/3 study, one group (cohort A) of participants with carcinoma in situ (CIS) disease and another group (cohort B) with papillary disease were treated with 400 μg N-803 plus 50 mg BCG. There was also a cohort C that received only 400 μg N-803. Treatments were delivered directly into the bladder once a week for 6 weeks in a row.
UNASSIGNED: N-803 plus BCG eliminated NMIBC in all nine BCG-naive participants and the effects were long-lasting, with participants remaining NMIBC-free for a range of 8.3 to 9.2 years.As reported in 2022, cancer was eliminated in 58 of 82 (71%) participants with BCG-unresponsive CIS disease and the effect was also long-lasting. Importantly, approximately 90% of the successfully treated participants avoided surgical removal of the bladder. In cohort B participants with papillary disease, 40 of 72 (55.4%) were cancer-free 12 months after treatment. N-803 used alone was only effective in 2 of 10 participants. In both studies, the combination of N-803 and BCG was found to be associated with very few adverse events.Based on results from the Phase 2/3 study, the U.S. Food and Drug Association (FDA) approved the use of N-803 plus BCG for the treatment of BCG-unresponsive bladder CIS with or without Ta/T1 papillary disease.Clinical Trial Registration: NCT02138734 (Phase 1b study), NCT03022825 (Phase 2/3 study).
Addition of the IL-15 superagonist N-803 to BCG therapy produces a high rate of success in eliminating non-muscle invasive bladder cancer in both BCG-naive and BCG-unresponsive patients, with long-lasting effects that allow patients to avoid surgical removal of the bladder.

The Mycobacterium tuberculosis bacterial pathogen is responsible for the ongoing global tuberculosis (TB) epidemic. Bacille Calmette-Guérin (BCG), the only currently approved TB vaccine, is successful in preventing disseminated disease in newborns. However, it has a variable efficacy against pulmonary TB in adults. This protective effect of the vaccine varies greatly among different populations and geographical areas, which the increased exposure of particular populations to non-tuberculous mycobacteria (NTM) is considered as one of the reasons for this issue. Numerous studies have shown that exposure to NTM species causes the host immune system to be improperly primed. It has also been suggested that NTM species may be blamed for reduction in BCG vaccine effectiveness against M. tuberculosis. The increased exposure of certain populations to NTM has diverse effects on BCG efficacy. Moreover, the exposure to NTM can induce opposite effects on BCG efficacy depending on the NTM exposure route and survivability. A detailed understanding of the impact of NTM exposure on the efficacy of the BCG vaccine is essential for ongoing efforts to develop new TB vaccines as it may ultimately be a crucial success factor. The aim of this study was to review the findings of the studies focusing on the effects of NTM on BCG vaccine efficacy in animal models.

First described by Wallis et al. in 2001 for the assessment of TB drugs, the direct mycobacterial growth inhibition assay (MGIA) offers a tractable ex vivo tool measuring the combined influences of host immunity, strain virulence and intervention effects. Over the past 13 years, we have led efforts to adapt the direct MGIA for the assessment of TB vaccines including optimisation, harmonisation and validation of BCG vaccine-induced responses as a benchmark, as well as assay transfer to institutes worldwide.
We have performed a systematic review on the primary published literature describing the development and applications of the direct MGIA from 2001 to June 2023 in accordance with the PRISMA reporting guidelines.
We describe 63 studies in which the direct MGIA has been applied across species for the evaluation of TB drugs and novel TB vaccine candidates, the study of clinical cohorts including those with comorbidities, and to further understanding of potential immune correlates of protection from TB. We provide a comprehensive update on progress of the assay since its conception and critically evaluate current findings and evidence supporting its utility, highlighting priorities for future directions.
While further standardisation and validation work is required, significant advancements have been made in the past two decades. The direct MGIA provides a potentially valuable tool for the early evaluation of TB drug and vaccine candidates, clinical cohorts, and immune mechanisms of mycobacterial control.
https://www.crd.york.ac.uk/prospero/, identifier CRD42023423491.

BACKGROUND: Mendelian susceptibility to mycobacterial diseases (MSMD) is a rare clinical syndrome characterized by vulnerability to weakly virulent mycobacterial species, including Bacillus Calmette-Guérin (BCG) vaccines and environmental mycobacteria.
OBJECTIVE: We sought to perform a systematic review of the genetic, immunologic, and clinical findings for reported patients with MSMD.
METHODS: We searched PubMed, Web of Science, and Scopus databases for publications in English relating to MSMD. All full texts were evaluated for eligibility for inclusion. Two reviewers independently selected the publications, with a third reviewer consulted in cases of disagreement.
RESULTS: A primary systematic search and searches of other resources identified 16,155 articles. In total, 158 articles from 63 countries were included in qualitative and quantitative analyses. In total, 830 patients-436 males (52.5%), 369 females (44.5%), and 25 patients of unknown sex (3.0%)-from 581 families were evaluated. A positive family history was reported in 347 patients (45.5%). The patients had a mean age of 10.41 ± 0.42 (SEM) years. The frequency of MSMD was highest in Iran, Turkey, and Saudi Arabia. Lymphadenopathy was the most common clinical manifestation of MSMD, reported in 378 (45.5%) cases and multifocal in 35.1%. Fever, organomegaly, and sepsis were the next most frequent findings, reported in 251 (30.2%), 206 (24.8%), and 171 (20.8%) cases, respectively. In total, 299 unique mutations in 21 genes known to be involved in MSMD were reported: 100 missense (34%), 80 indel-frameshift (insertion or deletion, 27%), 53 nonsense (18%), 35 splice site (12%), 10 indel-in frame (2.7%), 6 indel (2%), and 15 large deletion/duplication mutations. Finally, 61% of the reported patients with MSMD had mutations of IL12RB1 (41%) or IFNGR1 (20%). At the time of the report, 177 of the patients (21.3%) were dead and 597 (71.9%) were still alive.
CONCLUSIONS: MSMD is associated with a high mortality rate, mostly due to impaired control of infection. Preexposure strategies, such as changes in vaccination policy in endemic areas, the establishment of a worldwide registry of patients with MSMD, and precise follow-up over generations in affected families, appear to be vital to decrease MSMD-related mortality.

Introduction: Intravesical Bacillus Calmette-Guérin (BCG) immunotherapy is the standard of care for high-risk and intermediate-risk non-muscle-invasive bladder cancer (NMIBC) as well as for Carcinoma in situ (CIS). Evidence supports that the different BCG strains, despite genetic variability, are equally effective clinically for preventing the recurrence and progression of papillary NMIBC. The available evidence regarding possible differences in clinical efficacy between various BCG strains in CIS is lacking. Methods: We reviewed the literature on the efficacy of different BCG strains in patients with CIS (whether primary, secondary, concomitant, or unifocal/multifocal), including randomized clinical trials (RCTs), phase II/prospective trials, and retrospective studies with complete response rates (CRR), recurrence-free survival (RFS), or progression-free survival (PFS) as endpoints. Results: In most studies, being RCTs, phase II prospective trials, or retrospective studies, genetic differences between BCG strains did not translate into meaningful differences in clinical efficacy against CIS, regardless of the CIS subset (primary, secondary, or concurrent) or CIS focality (unifocal or multifocal). CRR, RFS, and PFS were not statistically different between various BCG strains. None of these trials were designed as head-to-head comparisons between BCG strains focusing specifically on CIS. Limitations include the small sample size of many studies and most comparisons between strains being indirect rather than head-to-head. Conclusions: This review suggests that the clinical efficacy of the various BCG strains appears similar, irrespective of CIS characteristics. However, based on the weak level of evidence available and underpowered studies, randomized studies in this space should be encouraged as no definitive conclusion can be drawn at this stage.

Aim: We aimed to review the evidence of reducing the dose or number of BCG instillations in non-muscle invasive bladder cancer (NMIBC) patients. Material & methods: A literature search was done according to Preferred Reporting Items for Meta-Analyses statement. Results: Overall, 15 and 13 studies were eligible for qualitative and quantitative synthesis, respectively. In patients with NMIBC, lowering either the dose or number of BCG instillations increases the risk of recurrence, but not the risk of progression. Lowering the dose of BCG decreases the risk of adverse events compared with standard-dose BCG. Conclusion: Standard-dose and -number of BCG is preferred for NMIBC patients based on oncologic efficacy; however, low-dose BCG could be considered in selected patients who suffer from significant adverse events.
Doctors use a medicine called BCG to treat a kind of bladder cancer that hasn\'t spread to other parts of the body. But because there isn\'t enough of this medicine, scientists are looking at giving smaller amounts. They found that smaller amounts of the medicine have fewer side effects, but they also found that they might not work as well to stop the cancer from coming back. So, the regular amount of BCG is still the best option for most patients, but smaller amounts might be okay for some people who are worried about side effects. However, more research is needed to make sure it\'s safe and effective.

To assess the oncologic outcomes and the safety profile of a reduced-dose versus full-dose BCG regimen in patients with non-muscle-invasive bladder cancer (NMIBC).
We performed a systematic review according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). The PubMed, Embase, and Web of Science databases were searched in January 2022 for studies that analyzed oncological outcomes and compared between reduced- and full-dose BCG regimens.
Seventeen studies including 3757 patients met our inclusion criteria. Patients who received reduced-dose BCG had significantly higher recurrence rates (OR 1.19; 95%CI, 1.03-1.36; p = 0.02). The risks of progression to muscle-invasive BC (OR 1.04; 95%CI, 0.83-1.32; p = 0.71), metastasis (OR 0.82; 95%CI, 0.55-1.22; p = 0.32), death from BC (OR 0.80; 95%CI, 0.57-1.14; p = 0.22), and all-cause death (OR 0.82; 95%CI, 0.53-1.27; p = 0.37) were not statistically different. When restricting the analyses to randomized controlled trials, we found similar results. In subgroup analysis, reduced dose was associated with a higher rate of BC recurrence in studies that used only an induction regimen (OR 1.70; 95%CI, 1.19-2.42; p = 0.004), but not when a maintenance regimen was used (OR 1.07; 95%CI, 0.96-1.29; p = 0.17). Regarding side effects, the reduced-dose BCG regimen was associated with fewer episodes of fever (p = 0.003), and therapy discontinuation (p = 0.03).
This review found no association between BCG dose and BC progression, metastasis, and mortality. There was an association between reduced dose and BC recurrence, which was no longer significant when a maintenance regimen was used. In times of BCG shortage, reduced-dose regimens could be offered to BC patients.