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This overview of the 2024 European Association of Urology guidelines offers valuable insights into risk factors, diagnosis, classification, prognostic factors, treatment, and follow-up of non–muscle-invasive bladder cancer patients. These guidelines are designed for effective integration into clinical practice. This publication represents a summary of the updated 2024 European Association of Urology (EAU) guidelines for non–muscle-invasive bladder cancer (NMIBC), TaT1, and carcinoma in situ. The information presented herein is limited to urothelial carcinoma, unless specified otherwise. The aim is to provide practical recommendations on the clinical management of NMIBC with a focus on clinical presentation. For the 2024 guidelines on NMIBC, new and relevant evidence was identified, collated, and appraised via a structured assessment of the literature. Databases searched included Medline, EMBASE, and the Cochrane Libraries. Recommendations within the guidelines were developed by the panel to prioritise clinically important care decisions. The strength of each recommendation was determined according to a balance between desirable and undesirable consequences of alternative management strategies, the quality of the evidence (including the certainty of estimates), and the nature and variability of patient values and preferences. Key recommendations emphasise the importance of thorough diagnosis, treatment, and follow-up for patients with NMIBC. The guidelines stress the importance of defining patients' risk stratification and treating them appropriately. This overview of the 2024 EAU guidelines offers valuable insights into risk factors, diagnosis, classification, prognostic factors, treatment, and follow-up of NMIBC. These guidelines are designed for effective integration into clinical practice. [ABSTRACT FROM AUTHOR]

Purpose: Chronic granulomatous disease (CGD) is an inherited immunodeficiency caused by pathogenic variants of genes encoding the enzyme complex NADPH oxidase. In countries where tuberculosis (TB) is endemic and the Bacillus Calmette–Guérin (BCG) vaccine is routinely administered, mycobacteria are major disease-causing pathogens in CGD. However, information on the clinical evolution and treatment of mycobacterial diseases in patients with CGD is limited. The present study describes the adverse reactions to BCG and TB in Mexican patients with CGD. Methods: Patients with CGD who were evaluated at the Immunodeficiency Laboratory of the National Institute of Pediatrics between 2013 and 2024 were included. Medical records were reviewed to determine the clinical course and treatment of adverse reactions to BCG and TB disease. Results: A total of 79 patients with CGD were included in this study. Adverse reactions to BCG were reported in 55 (72%) of 76 patients who received the vaccine. Tuberculosis was diagnosed in 19 (24%) patients. Relapse was documented in three (10%) of 31 patients with BGC-osis and six (32%) of 19 patients with TB, despite antituberculosis treatment. There was no difference in the frequency of BCG and TB disease between patients with pathogenic variants of the X-linked CYBB gene versus recessive variants. Conclusions: This report highlights the importance of considering TB in endemic areas and BCG complications in children with CGD to enable appropriate diagnostic and therapeutic approaches to improve prognosis and reduce the risk of relapse. [ABSTRACT FROM AUTHOR]

What is this summary about? 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). What happened in the studies? 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. What were the key takeaways? 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) Tweetable Abstract 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 [ABSTRACT FROM AUTHOR]

Background: The predictive accuracy of the preoperative neutrophil-to-lymphocyte ratio (NLR) on the prognosis of patients with non-muscle-invasive bladder cancer (NMIBC) with intravesical Bacillus Calmette–Guérin immunotherapy (BCG) after transurethral resection of the bladder tumor (TURBT) remains unknown. Therefore, the current study performed a systematic review and meta-analysis to examine the relationship between preoperative NLR and the prognosis of patients with NMIBC with intravesical BCG immunotherapy. Methods: For this systematic review and meta-analysis, articles were retrieved from PubMed, Cochrane Library, Web of Science, and Embase databases from their inception to 14 May 2024. The role of NLR in predicting recurrence and progression in NMIBC was determined using pooled hazard ratios (HRs) and 95% confidence intervals (CIs). Results: Seven articles were included in this meta-analysis, involving 4,187 patients. An elevated NLR was significantly associated with recurrence (HR = 2.67, 95% CI = 1.34–5.32, P < 0.001) and progression (HR = 1.72, 95% CI = 1.13–2.60, P = 0.004) in patients with NMIBC with intravesical BCG immunotherapy. Conclusion: This meta-analysis demonstrated that elevated preoperative NLR levels were significantly associated with recurrence and disease progression in patients with NMIBC who underwent intravesical BCG immunotherapy after TURBT. Systematic review registration: https://inplasy.com/inplasy-2024-7-0058/ , identifier 202470058. [ABSTRACT FROM AUTHOR]

Granulomatous prostatitis (GP) is a rare form of chronic prostatitis with reported incidence of 0.65–1.5%. Radiological features of GP overlap with those of prostate adenocarcinoma. The following magnetic resonance imaging characteristics can suggest the diagnosis in an appropriate clinical setting: Diffuse or focal nodular low T2 signal, high signal on diffusion-weighted imaging with corresponding low apparent diffusion coefficient signal, and post-contrast imaging with lesion enhancement or rim-enhancing in the setting of caseous necrosis or abscess formation. Even with suspicion on imaging, the overlapping imaging features with prostate adenocarcinoma necessitate biopsy for confirmatory diagnosis. Here, we report a case of a 70-year-old man with GP in the setting of prior intravesicle bacillus Calmette–Guérin administration. [ABSTRACT FROM AUTHOR]

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Trained immunity (TI) is functional memory displayed by innate immune cells (IICs). TI facilitates rapid, non-specific responses to pathogens upon secondary challenge. It is driven by immunological signaling and metabolic rewriting via epigenetic alteration, triggered by recognition of certain stimuli. Recently, immune checkpoint inhibitors have come into common use in clinical oncology settings, and genetically engineered cytotoxic T cells comprise a potent cancer treatment strategy. However, the contributions of TI in the tumor microenvironment (TME) are only beginning to be uncovered. Accumulating evidence that various microorganisms and vaccines convey tumoricidal ability suggest that TI may become a useful anti-cancer tool. The expected roles of TI in tumor therapy are the 1) promotion of proinflammatory cytokine section, 2) enhancement of phagocytosis, 3) quick expansion and recruitment of cancer-specific cytotoxic T cells to the TME through neoantigen presentation, 4) reversal of immunosuppression in the TME, and 5) removal of pathogens associated with carcinogenesis or tumor development. Medium- to long-term TI durability may reduce the risk of tumor development. Recent findings on TI usher in new aspirations for cancer treatment.

BACKGROUND: 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. OBJECTIVE: To evaluate whether patients in the EAU-RF NIMBUS trial experienced better QoL after a reduced BCG instillation frequency. DESIGN SETTING AND PARTICIPANTS: 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. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: 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. RESULTS AND LIMITATIONS: 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. CONCLUSIONS: Reducing the BCG instillation frequency does not improve the QoL in NMIBC patients despite lower storage symptoms. PATIENT SUMMARY: 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.

Abstract Background The COVID-19 pandemic had a profound impact on healthcare systems and services, including routine immunization (RI). To date, there is limited information on the effects of the COVID-19 pandemic on RI in West African countries such as Sierra Leone, which had already experienced public health emergencies that disrupted its healthcare system. Here, we describe the impact of the COVID-19 pandemic on the RI of key antigens in Sierra Leone. Methods We used vaccination data from the District Health Information System for BCG, measles-rubella 1 and 2, and pentavalent 1 and 3 antigens. We compared 2019, 2020, 2021, and 2022 annual coverage rates for the selected antigens at the national and district levels. We used the Pearson chi-square test to assess the difference between annual coverage rates between 2019 and 2020, 2020–2021, and 2021–2022. Results National coverage rates for all antigens declined in 2019–2020, notably measles-rubella 1 and pentavalent 3 (-5.4% and − 4.9%). Between 2020 and 2021, there was an overall increase in coverage (+ 0.2% to + 2.5%), except for measles-rubella 2 (-1.8%). Measles-rubella antigens rebounded in 2021–2022, while others decreased between − 0.5 and − 1.9% in coverage. Overall, all district-level coverage rates in 2022 were lower than those in 2019. Most districts decreased between 2019 and 2022, though a few had a continuous increase; some had an increase/recovery between 2020 and 2021; some districts had recovered 2019 levels by 2022. Conclusion The COVID-19 pandemic impacted Sierra Leone’s national BCG, measles-rubella, and pentavalent antigen immunization, which were not fully restored in 2022. Most districts experienced notable coverage declines during the pandemic, though a few reached or surpassed 2019 rates in 2022. Examining pandemic impact can benefit from a focus beyond the national level to identify vulnerable regions. Sierra Leone’s post-pandemic RI reestablishment needs targeted strategies and continual investments for equitable access and coverage, as well as to prevent vaccine-preventable diseases.

Photothermal immunotherapy emerges as a promising strategy for treating tumors. However, the majority of current photothermal immunotherapy approaches do not yet show significant potential for clinical translation. In this study, lyophilized polydopamine (PDA) nanoparticles combined with Bacillus Calmette–Guérin (BCG) are investigated for photothermal immunotherapy against colorectal cancer. By simply mixing with two lyophilized powders, PDA nanoparticles can covalently bond onto BCG to form BCG@PDA. This combination demonstrates a potent photothermal cytotoxic effect on tumor cells by utilizing PDA nanoparticles. In addition, a heightened immune response triggered by the BCG vaccine, as evidenced by the secretion of important pro‐inflammatory cytokines and the activation of antigen‐presenting cells, is observed. In vivo testing on a murine colon cancer model demonstrates that the combined treatment significantly inhibits tumor growth. Further, the lyophilized PDA nanoparticles can be stored at −20 °C for up to 1 year with stable photothermal properties. Therefore, this study not only presents a reliable method for storing the therapeutic PDA nanoparticles but also demonstrates the potential application of BCG@PDA in photothermal immunotherapy for colorectal cancer. [ABSTRACT FROM AUTHOR]

Purpose of Review: Intravesical Bacillus Calmette-Guérin (BCG) is used as adjuvant therapy for intermediate-risk and high-risk non-muscle invasive bladder cancer (NMIBC). While it is generally well-tolerated, approximately 2.9% of patients receiving intravesical BCG discontinue immunotherapy as a result of genitourinary infection. We conducted a comprehensive systematic review of the contemporary literature to understand the presentation, evaluation, and treatment of post-BCG cystitis. This systematic literature review was performed in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA). Recent Findings: Post-BCG cystitis is categorized into two groups: chemical cystitis and bacterial cystitis. Chemical cystitis presents as irritative voiding symptoms and spontaneously resolves, while bacterial cystitis requires further treatment. Early, localized symptoms may be improved by NSAIDs and bladder relaxants if urgency is a predominant symptom. In some cases, BCG cystitis resolved with conservative medical treatment. In BCG cystitis that persists, the standard treatment is isoniazid, rifampin, and ethambutol. If not responsive to medical treatment, radical cystectomy is an option. Summary: Intravesical BCG remains the recommended treatment to decrease the risk of progression and recurrence of NMIBC. An untoward adverse effect is post-BCG cystitis, which can result in significant distress to patients. Future studies are warranted to evaluate various measures to decrease the incidence of post-BCG cystitis and increase BCG therapy completion rate. [ABSTRACT FROM AUTHOR]

Obtaining information about cellular interactions is fundamental to the elucidation of physiological and pathological processes. Proximity labeling technologies have been widely used to report cellular interactions in situ; however, the reliance on addition of tag molecules typically restricts their application to regions where tags can readily diffuse, while the application in, for example, solid tissues, is susceptible. Here, we propose an "in‐situ‐tag‐generation mechanism" and develop the GalTag technology based on galactose oxidase (GAO) for recording cellular interactions within three‐dimensional biological solid regions. GAO mounted on bait cells can in situ generate bio‐orthogonal aldehyde tags as interaction reporters on prey cells. Using GalTag, we monitored the dynamics of cellular interactions and assessed the targeting ability of engineered cells. In particular, we recorded, for the first time, the footprints of Bacillus Calmette‐Guérin (BCG) invasion into the bladder tissue of living mice, providing a valuable perspective to elucidate the anti‐tumor mechanism of BCG. [ABSTRACT FROM AUTHOR]

Background: The COVID-19 pandemic had a profound impact on healthcare systems and services, including routine immunization (RI). To date, there is limited information on the effects of the COVID-19 pandemic on RI in West African countries such as Sierra Leone, which had already experienced public health emergencies that disrupted its healthcare system. Here, we describe the impact of the COVID-19 pandemic on the RI of key antigens in Sierra Leone. Methods: We used vaccination data from the District Health Information System for BCG, measles-rubella 1 and 2, and pentavalent 1 and 3 antigens. We compared 2019, 2020, 2021, and 2022 annual coverage rates for the selected antigens at the national and district levels. We used the Pearson chi-square test to assess the difference between annual coverage rates between 2019 and 2020, 2020–2021, and 2021–2022. Results: National coverage rates for all antigens declined in 2019–2020, notably measles-rubella 1 and pentavalent 3 (-5.4% and − 4.9%). Between 2020 and 2021, there was an overall increase in coverage (+ 0.2% to + 2.5%), except for measles-rubella 2 (-1.8%). Measles-rubella antigens rebounded in 2021–2022, while others decreased between − 0.5 and − 1.9% in coverage. Overall, all district-level coverage rates in 2022 were lower than those in 2019. Most districts decreased between 2019 and 2022, though a few had a continuous increase; some had an increase/recovery between 2020 and 2021; some districts had recovered 2019 levels by 2022. Conclusion: The COVID-19 pandemic impacted Sierra Leone's national BCG, measles-rubella, and pentavalent antigen immunization, which were not fully restored in 2022. Most districts experienced notable coverage declines during the pandemic, though a few reached or surpassed 2019 rates in 2022. Examining pandemic impact can benefit from a focus beyond the national level to identify vulnerable regions. Sierra Leone's post-pandemic RI reestablishment needs targeted strategies and continual investments for equitable access and coverage, as well as to prevent vaccine-preventable diseases. [ABSTRACT FROM AUTHOR]

Purpose: Aimed to investigate the role of multiparametric magnetic resonance imaging (mp-MRI) in the diagnosis of granulomatous prostatitis caused by intravesical Bacillus Calmette–Guérin (BCG). Methods: In this prospective, single-center study, 10 male patients who were given intravesical BCG due to intermediate- and high-risk bladder cancer were included. Before transurethral resection of bladder tumors (TURB), all patients were evaluated by mp-MRI, serum prostate-specific antigen (PSA), and digital rectal examination (DRE). Serum PSA levels and DRE findings were evaluated before and after intravesical BCG treatment. Prostate mp-MRI was performed for patients with elevated levels of serum PSA and/or with abnormal DRE findings. Then, MRI fusion + systematic prostate biopsy was performed. Demographic data of the patients before and after intravesical BCG were compared. Results: The average age of the patients was 66.9 years (55–87 years). While PSA was 1.7 ng/ml before intravesical BCG treatment, it was 4.3 ng/ml after intravesical BCG treatment (p = 0.005). PSA density (PSAD) was 0.04 and 0.10 before and after the treatment, respectively (p = 0.012). DRE findings of all patients were normal before the treatment. However, abnormal findings were detected in 80% of them after the treatment (p = 0.008). PI-RADS ≥ 3 lesions were found to be significantly higher in all patients after intravesical BCG (p = 0.004). Conclusion: Granulomatous prostatitis is a rare complication of intravesical BCG. High PSA, abnormal DRE, and PI-RADS ≥ 3 lesions detected after intravesical BCG should suggest granulomatous prostatitis and unnecessary biopsies may be avoided. [ABSTRACT FROM AUTHOR]

Bladder cancer (BCa) exhibits significant sex disparities, and intravesical Bacillus Calmette-Guerin (BCG) is a widely used treatment for non-muscle invasive bladder cancer (NMIBC). A comprehensive evaluation of intravesical BCG, including the safety profile and adverse events (AEs), is essential. In particular, exploring the sex differences is crucial. We conducted a pharmacovigilance data analysis using real-world big data from the Food and Drug Administration Adverse Event Reporting System (FAERS) database. In our study, we analyzed 3,374 cases of intravesical BCG for signal mining. We detected 353 signals at the Preferred Term (PT) level and 10 signals at the System Organ Class (SOC) level when compared to the full FAERS database. When comparing between intravesical BCG and other administration routes, we identified 14 signals at the PT level and 8 signals at the SOC level. Intravesical BCG exhibited lower immune-related AEs (irAEs) risk than anti-PD-1/PD-L1 treatment, but antibiotics increased the risk. Notably, AEs associated with intravesical BCG exhibited significant sex differences. Female patients showed a higher susceptibility to developing allergic diseases such as Reiter’s syndrome and Arthralgia, while male patients were more prone to infectious diseases. Additionally, we highlighted that male patients had higher fatality rates, whereas female patients experienced higher rates of recurrence and irAEs. We have compiled an overview of AEs associated with intravesical BCG. These findings enhance understanding of safety profiles and risks, enabling informed decisions prioritizing patients.

BackgroundThe predictive accuracy of the preoperative neutrophil-to-lymphocyte ratio (NLR) on the prognosis of patients with non-muscle-invasive bladder cancer (NMIBC) with intravesical Bacillus Calmette–Guérin immunotherapy (BCG) after transurethral resection of the bladder tumor (TURBT) remains unknown. Therefore, the current study performed a systematic review and meta-analysis to examine the relationship between preoperative NLR and the prognosis of patients with NMIBC with intravesical BCG immunotherapy.MethodsFor this systematic review and meta-analysis, articles were retrieved from PubMed, Cochrane Library, Web of Science, and Embase databases from their inception to 14 May 2024. The role of NLR in predicting recurrence and progression in NMIBC was determined using pooled hazard ratios (HRs) and 95% confidence intervals (CIs).ResultsSeven articles were included in this meta-analysis, involving 4,187 patients. An elevated NLR was significantly associated with recurrence (HR = 2.67, 95% CI = 1.34–5.32, P < 0.001) and progression (HR = 1.72, 95% CI = 1.13–2.60, P = 0.004) in patients with NMIBC with intravesical BCG immunotherapy.ConclusionThis meta-analysis demonstrated that elevated preoperative NLR levels were significantly associated with recurrence and disease progression in patients with NMIBC who underwent intravesical BCG immunotherapy after TURBT.Systematic review registrationhttps://inplasy.com/inplasy-2024-7-0058/, identifier 202470058.

Background: Bacillus Calmette-Guérin (BCG) immunotherapy is a standard treatment for high-risk non-muscle invasive bladder cancer (NMIBC) after tumor resection. However, not all patients respond to BCG therapy. Reliable prognostic markers are needed to predict treatment outcomes. Objectives: This study reviewed the prognostic value of systemic immune-inflammation index (SII) and related markers in BCG response. Methods: A systematic literature search was conducted in PubMed, Web of Science, and Scopus databases from inception to October 2023 for studies on SII index, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and monocyte-to-lymphocyte ratio (MLR) in bladder cancer patients receiving BCG therapy. Four retrospective studies involving 1124 patients met the inclusion criteria and were included in qualitative synthesis. Three studies were included in the meta-analysis of progression-free survival (PFS) and recurrence-free survival (RFS). Data on study characteristics and demographics, follow-up duration, cancer stage/grade, and pre-treatment marker levels were extracted. Hazard ratios (HRs) were pooled using a random effects model. Results: Elevated pre-treatment SII was associated with significantly worse PFS (HR: 3.72, 95% CI: 1.74-7.98, P672.75 was an independent predictor of BCG failure (OR: 2.229, 95% CI: 1.172-4.238, P=0.015). NLR, PLR, and MLR also showed potential prognostic value with area under the curve (AUC) values ranging from 0.592 to 0.663 for predicting non-response to BCG therapy. Specifically, NLR>3.0435, PLR>123.4398, and MLR>0.1995 were significantly associated with non-response to BCG (P

Objective. Intravesical administration of bacillus Calmette-Guérin is standard adjuvant treatment of non-muscle invasive bladder cancer. In spite of the fact that this immunotherapy is locoregional, there are still risk of some complications. Methods. We describe two cases of systemic BCG infection after intravesical administration of BCG vaccine in patients with early stage of bladder cancer. Results. Both patients suffered from systemic BCG infection manifesting as BCG pneumonitis. After standard therapy with antituberculotic agents, both of them fully recovered. Conclusion. BCG infection can occur as a rare but potentially serious complication of this treatment procedure. Gravity of this side effect and its specific therapy require prompt and right diagnosis.

Abstract Introduction The introduction of a national evaluation of newborn screening for Severe Combined Immunodeficiency (SCID) in England triggered a change to the selective Bacillus Calmette-Guerin (BCG) vaccination programme delivery pathway, as this live attenuated vaccine is contraindicated in infants with SCID. The neonatal BCG vaccination programme is a targeted programme for infants at increased risk of tuberculosis and used to be offered shortly after birth. Since September 2021 the BCG vaccine is given to eligible infants within 28 days of birth, when the SCID screening outcome is available. We explore the experiences of those implementing the new pathway, and how they made sense of, engaged with, and appraised the change. Methods A mixed-methods evaluation was conducted between October 2022 and February 2023. This involved national online surveys with BCG commissioners and providers and qualitative semi-structured interviews with commissioners, providers, and Child Health Information System stakeholders in two urban areas. Survey data was analysed using descriptive statistics and interview data was analysed thematically. The data was triangulated using Normalization Process Theory as a guiding framework. Results Survey respondents (n = 65) and qualitative interviewees (n = 16) revealed that making sense of the new pathway was an iterative process. Some expressed a desire for more direction on how to implement the new pathway. The perceived value of the change varied from positive, ambivalent, to concerned. Some felt well-prepared and that improvements to data capture, eligibility screening, and accountably brought by the change were valuable. Others were concerned about the feasibility of the 28-day target, reductions in vaccination coverage, increased resource burden, and the outcome of the SCID evaluation. New collaborations and communities of practice were required to facilitate the change. Three main challenges in implementing the pathway and meeting the 28-day vaccination target were identified: appointment non-attendance; appointment and data systems; and staffing and resourcing. Feedback mechanisms were informal and took place in tandem with implementation. Conclusion The new NHS neonatal BCG service specification has created an effective structure for monitoring and managing the BCG vaccination programme, but further work is required to support delivery of the 28-day vaccination target and improve uptake rates.

Objective: To evaluate the prognostic value of T1 substaging in patients treated with bacillus Calmette‐Guérin (BCG) or immediate radical cystectomy (iRC). Materials and Methods: We performed an institutional review board‐approved retrospective study analysing non‐muscle‐invasive bladder cancer (NMIBC) patients with pT1 disease treated with either BCG or iRC between 2000 and 2020. Lamina propria (LP) invasion characteristics were extracted from the pathology report. The Kaplan–Meier method was used to calculate overall survival (OS), cancer‐specific survival (CSS) and metastasis‐free survival (MFS). Multivariable Cox models were used to determine the association between progression‐free survival (PFS) and characteristics in the BCG cohort. A logistic regression model explored the relationship between T1 substaging and upstaging to >pT2 at iRC. Results: A total of 411 T1 high‐grade patients were identified. LP invasion characteristics were as follows: not specified: 115 (28%); focal/superficial (F/S): 147 (35.8%); and extensive/multifocal (E/M): 149 (36.2%). Overall, 303 patients (73.7%) received BCG, and 108 patients (26.3%) underwent iRC. The median (interquartile range) follow‐up was 53 (32–96) months. Patients with E/M LP invasion were significantly more likely to undergo iRC (34% vs. 19%; P = 0.003). Patients with E/M LP invasion showed poorer MFS and CSS compared to those with F/S LP invasion when treated with BCG but not when treated with iRC. Among BCG‐treated patients, progression occurred in 41 patients and E/M LP invasion was independently associated with progression after BCG (hazard ratio 5.3, 95% confidence interval [CI] 2.2–13.1; P < 0.001). T1 substaging was not associated with upstaging at RC (odds ratio 3.15, 95% CI 0.82–12.12; P = 0.095). Conclusions: Extensive/multifocal LP invasion was associated with poor PFS, MFS and CSS in patients treated with BCG. T1 substaging provides valuable prognostic information and should be reported in pathology reports. [ABSTRACT FROM AUTHOR]

Vaccination after birth provides protection against pathogen infection and immune related disorders in healthy children. The detailed effects of vaccination on neonatal immunity, however, remain largely unknown. Here, we reported that vaccination using Bacillus Calmette‐Guérin (BCG) diminished the immunosuppressive function of myeloid‐derived suppressor cells in neonatal mice, an immature myeloid population. A combination of single‐cell transcriptome, metabolite profiling, and functional analysis demonstrated that upregulation of mTOR/HIF1a signalling and the enhanced glycolysis explained the effects of BCG on neonatal myeloid cells. Pharmalogical inhibition of glycolysis or mTOR signalling efficiently rescued the effects of BCG on neonatal myeloid cells. These observations suggest that BCG facilitates the maturation of myeloid cells in early life, which may contribute to its beneficial effects against immune disorders later in life. [ABSTRACT FROM AUTHOR]

Objective. Intravesical administration of bacillus Calmette-Guérin is standard adjuvant treatment of non-muscle invasive bladder cancer. In spite of the fact that this immunotherapy is locoregional, there are still risk of some complications. Methods. We describe two cases of systemic BCG infection after intravesical administration of BCG vaccine in patients with early stage of bladder cancer. Results. Both patients suffered from systemic BCG infection manifesting as BCG pneumonitis. After standard therapy with antituberculotic agents, both of them fully recovered. Conclusion. BCG infection can occur as a rare but potentially serious complication of this treatment procedure. Gravity of this side effect and its specific therapy require prompt and right diagnosis. [ABSTRACT FROM AUTHOR]

Simple Summary: The mainstay of treatment for non-muscle invasive bladder cancer is transurethral resection of the tumor followed by intravesical treatment for intermediate- or high-risk disease. Duration and type of intravesical treatment depend on specific characteristics of the tumor and the patient's disease course. Patients with non-muscle invasive bladder cancer are closely monitored with frequent surveillance cystoscopies following treatment. This type of cancer has a low progression rate; however, it has a high rate of recurrence with the current recommended treatments. Therefore, patients often find themselves having to undergo multiple resections and rounds of intravesical treatment throughout their lifetime. This is not only burdensome for patients but also costly for the healthcare system. Given the high recurrence with the standard treatment options, it is important to continue investigating novel therapies. The goal of this review article is to outline the most recent therapies available or in clinical trials for the treatment of non-muscle invasive bladder cancer. The landscape of treatment for non-muscle invasive bladder cancer is rapidly changing. A complete and careful transurethral resection is the mainstay of initial treatment and is followed by intravesical therapy in intermediate or high-risk cases. The standard of care is intravesical BCG. Many alternative or additive approaches to this are being explored. We divided this review into three relevant spaces to consider these novel treatment approaches: (1) low-risk disease, for which intravesical therapy is not usually considered, (2) BCG-naïve disease (i.e., considering alternatives to the standard therapy), and (3) BCG-unresponsive disease. We performed a review of published literature and summarized ongoing trials in the United States. Novel approaches that we explored include surgical techniques for resection, alterations in dwell time for intravesical therapy, delivery method and schedule of intravesical therapies, new intravesical therapy agents, and systemic therapies (especially immunotherapy). These are thoroughly outlined throughout this review article, and the numerous modalities being studied demonstrate significant promise for the future treatment of the expanding space of NMIBC. [ABSTRACT FROM AUTHOR]

Introduction: The aim of the study was to examine whether disinfection of bacillus Calmette-Guerin-containing urine with etaprocohol® (ethanol 76.9–81.4 vol % and isopropanol as an additive) is safer than disinfection with sodium hypochlorite. Method: In prospective research, safety and efficacy was analyzed in 5 patients in the etaprocohol® disinfection group and 5 patients in the sodium hypochlorite disinfection group. The primary endpoint was the temperature change after disinfection and the secondary endpoint was the unpleasantness of the odor caused by disinfection. Additionally, concentration of gas produced was also examined. Sensory tests were taken from staff who performed urine disinfection and the odor generated by disinfection was evaluated. As a safety protocol, post-BCG-treated urine is cultured to verify the negativity for mycobacteria. Results: Mycobacteria were disinfected in all cases. The temperature rise following disinfection was significantly higher in the sodium hypochlorite group. The sensory test outcomes were significantly worse in the group disinfected with sodium hypochlorite. The concentration of gas generated immediately after disinfection in both groups reached the maximum value and declined quickly. Conclusions: Disinfection of bacillus Calmette-Guerin-containing urine with etaprocohol® was safer than disinfection with sodium hypochlorite, and an equivalent disinfection effect was achieved. [ABSTRACT FROM AUTHOR]

Introduction: Bacillus Calmette–Guérin (BCG) vaccination induces long-lasting effects on the adaptive and innate immune systems and prevents development of experimental autoimmune encephalomyelitis and possibly also inflammatory disease activity in multiple sclerosis (MS). Objective: The objective is to examine if BCG given in early adulthood decreases MS risk. Methods: From 791,369 (52% females) Norwegians participating in a national tuberculosis screening program from 1963 to 1975, we collected information on BCG vaccination and tuberculosis disease status. Later, MS disease was ascertained through both the Norwegian MS Registry and Biobank and the Norwegian Death Registry. We used logistic regression models to assess the relationship between BCG vaccination and MS risk. Results: In those BCG vaccinated, mean age at vaccination was 15.6 (standard deviation (SD) = 5.5) years. A total of 2862 (65% females) MS cases were retrieved. Overall, we found no association between MS risk and BCG vaccination. Compared to non-BCG-vaccinated individuals with no signs of tuberculosis infection, odds ratio (OR) for MS was 1.00 (95% confidence interval (CI) = 0.80–1.25) in the BCG-vaccinated group. In those not BCG vaccinated because of latent tuberculosis infection, the corresponding OR was 0.86 (95% CI = 0.66–1.13). Conclusion: We found no evidence of BCG vaccination or latent tuberculosis infection in young adulthood being linked to MS risk. [ABSTRACT FROM AUTHOR]

Bacillus Calmette-Guérin (BCG) is the standard of care for patients with high-risk non-muscle-invasive bladder cancer (NMIBC) after transurethral resection of bladder tumor (TURBT). BCG in combination with programmed cell death-1 (PD-1) inhibitors may yield greater anti-tumor activity compared with either agent alone. CREST is a phase III study evaluating the efficacy and safety of the subcutaneous PD-1 inhibitor sasanlimab in combination with BCG for patients with BCG-naive high-risk NMIBC. Eligible participants are randomized to receive sasanlimab plus BCG (induction ± maintenance) or BCG alone for up to 25 cycles within 12 weeks of TURBT. The primary outcome is event-free survival. Secondary outcomes include additional efficacy end points and safety. The target sample size is around 1000 participants. Non-muscle-invasive bladder cancer (NMIBC) is the most common type of bladder cancer. Most people have surgery to remove the cancer cells while leaving the rest of the bladder intact. This is called transurethral resection of a bladder tumor (TURBT). For people with high-risk NMIBC, a medicine called Bacillus Calmette-Guérin (BCG) is placed directly inside the bladder after TURBT. A 'high risk' classification means that the cancer is more likely to spread or come back after treatment. Some people's cancer does not respond to BCG or returns after BCG treatment. Researchers are currently looking at whether BCG combined with other immunotherapies may prevent cancer growth more than BCG on its own. Immunotherapy helps the immune system recognize and kill cancer cells. Sasanlimab is an immunotherapy medicine that is not yet approved to treat people with NMIBC. It is given as an injection under the skin. In this CREST study, researchers are looking at how safe and effective sasanlimab plus BCG is for people with high-risk NMIBC. Around 1000 people are taking part in CREST. They must have had TURBT 12 weeks or less before joining the study. Researchers want to know how long people live without certain events occurring, such as bladder cancer cells returning. A plain language summary of this article can be found as Supplementary Material. Clinical Trial Registration:NCT04165317; 2019-003375-19 (EudraCT) (ClinicalTrials.gov) CREST is a phase III study evaluating the subcutaneous PD-1 inhibitor sasanlimab in combination with BCG versus current standard-of-care BCG monotherapy for patients with high-risk non-muscle-invasive bladder cancer (NMIBC). [ABSTRACT FROM AUTHOR]

Introduction: The introduction of a national evaluation of newborn screening for Severe Combined Immunodeficiency (SCID) in England triggered a change to the selective Bacillus Calmette-Guerin (BCG) vaccination programme delivery pathway, as this live attenuated vaccine is contraindicated in infants with SCID. The neonatal BCG vaccination programme is a targeted programme for infants at increased risk of tuberculosis and used to be offered shortly after birth. Since September 2021 the BCG vaccine is given to eligible infants within 28 days of birth, when the SCID screening outcome is available. We explore the experiences of those implementing the new pathway, and how they made sense of, engaged with, and appraised the change. Methods: A mixed-methods evaluation was conducted between October 2022 and February 2023. This involved national online surveys with BCG commissioners and providers and qualitative semi-structured interviews with commissioners, providers, and Child Health Information System stakeholders in two urban areas. Survey data was analysed using descriptive statistics and interview data was analysed thematically. The data was triangulated using Normalization Process Theory as a guiding framework. Results: Survey respondents (n = 65) and qualitative interviewees (n = 16) revealed that making sense of the new pathway was an iterative process. Some expressed a desire for more direction on how to implement the new pathway. The perceived value of the change varied from positive, ambivalent, to concerned. Some felt well-prepared and that improvements to data capture, eligibility screening, and accountably brought by the change were valuable. Others were concerned about the feasibility of the 28-day target, reductions in vaccination coverage, increased resource burden, and the outcome of the SCID evaluation. New collaborations and communities of practice were required to facilitate the change. Three main challenges in implementing the pathway and meeting the 28-day vaccination target were identified: appointment non-attendance; appointment and data systems; and staffing and resourcing. Feedback mechanisms were informal and took place in tandem with implementation. Conclusion: The new NHS neonatal BCG service specification has created an effective structure for monitoring and managing the BCG vaccination programme, but further work is required to support delivery of the 28-day vaccination target and improve uptake rates. [ABSTRACT FROM AUTHOR]

Objectives: Excellent anticancer effect for solid tumors with microsatellite instability (MSI)‐high by anti‐PD‐1 antibody has been reported. In this study, we investigated the clinical impact of MSI status in bladder cancer. Methods: This study included 205 Japanese patients who underwent transurethral resection for bladder cancer between 2005 and 2021. The prevalence rates of microsatellite stable (MSS), MSI‐low (MSI‐L), and MSI‐high (MSI‐H) were determined using molecular testing. We examined the association of MSI status (MSS versus MSI‐L/H) with clinicopathological characteristics and oncological outcomes. Results: MSI‐L/H tumors were associated with higher T‐category in non‐muscle invasive bladder cancer (NMIBC). Additionally, MSI‐L/H tumors were associated with a higher risk of intravesical recurrence in NMIBC patients treated with intravesical bacillus Calmette‐Guérin (BCG) but not with non‐BCG therapy. Conclusions: This study suggested that the MSI status might serve as a predictive marker for intravesical recurrence after BCG intravesical therapy in NMIBC and highlighted an unmet need for an alternative treatment in patients with MSI‐L/H tumors. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the efficiency and safety of combined local bladder hyperthermia and intravesical chemotherapy (IVC) for the treatment of patients with pT1 stage bladder cancer. Method: A total of 189 patients with pT1 who underwent transurethral resection of bladder cancer (TURBT) were retrospectively reviewed. After TURBT, the patients with low‐grade urothelial carcinoma (UC) were treated with either an IVC with pirarubicin (THP) protocol or chemo‐thermotherapy (CHT) with THP protocol, whereas patients with high‐grade UC were treated with either an intravesical immunotherapy (IVI) with bacillus Calmette–Guerin (BCG) protocol or CHT protocol, patients' characteristics, tumor biological features, and follow‐up data were analyzed and compared between CHT and IVC group in low‐grade UC, CHT, and IVI group in high‐grade UC, respectively. Results: The median follow‐up time was 24 months. In patients with low‐grade UC, the median recurrence free survival (RFS) interval and costs of treatment in CHT group were significantly higher than those in IVC group (p =.01, p <.001, respectively), CHT was associated with higher RFS compared with IVC by Kaplan–Meier analysis, and three patients in IVC group upgraded to high grade when tumor recurred, whereas no cases were found upgraded in CHT group, p =.38. In patients with high‐grade UC, tumor recurrence rates at 12 (p =.004) and 24 months (p =.004) after TURBT, rate of complications (p =.04)—especially for hematuresis (p =.03) and irritation symptoms (p =.04)—the median costs of treatment (p <.001) in CHT group were significantly lower than those in IVI group, RFS interval, health‐related quality of life) at 12 and 24 months after TURBT in CHT group was significantly higher than those in IVI group (p <.001, p =.002, and p <.001, respectively), and CHT was associated with higher RFS compared with IVI by Kaplan–Meier analysis. The rate of patients upstaged to pT2 in CHT group seemed lower than that in IVI group, but there was no significantly statistical difference (14.3% vs. 24%, p =.58). Conclusion: CHT has a beneficial prophylactic effect in patients with pT1 bladder cancer, especially in patients with high‐grade UC, which is much more effective and safer than BCG, meanwhile it costs less compared with BCG. [ABSTRACT FROM AUTHOR]

Intravesical therapy (IVT) is the standard of care to decrease risk of recurrence and progression for high‐grade nonmuscle‐invasive bladder cancer. However, post‐IVT recurrence remains common and the ability to risk‐stratify patients before or after IVT is limited. In this prospectively designed and accrued cohort study, we examine the utility of urinary comprehensive genomic profiling (uCGP) for predicting recurrence risk following transurethral resection of bladder tumor (TURBT) and evaluating longitudinal IVT response. Urine was collected before and after IVT instillation and uCGP testing was done using the UroAmp™ platform. Baseline uCGP following TURBT identified patients with high (61%) and low (39%) recurrence risk. At 24 months, recurrence‐free survival (RFS) was 100% for low‐risk and 45% for high‐risk patients with a hazard ratio (HR) of 9.3. Longitudinal uCGP classified patients as minimal residual disease (MRD) Negative, IVT Responder, or IVT Refractory with 24‐month RFS of 100%, 50%, and 32%, respectively. Compared with MRD Negative patients, IVT Refractory patients had a HR of 10.5. Collectively, uCGP enables noninvasive risk assessment of patients following TURBT and induction IVT. uCGP could inform surveillance cystoscopy schedules and identify high‐risk patients in need of additional therapy.

Purpose: 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). Materials and methods: 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. Results: 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). Conclusion: This study demonstrated that HIVEC with mitomycin C has a similar oncological efficacy and safety profile to standard BCG therapy in high-risk NMIBC. [ABSTRACT FROM AUTHOR]

Bladder cancer is one of the most common malignant tumours of the urogenital system, with high morbidity and mortality. In most cases, surgery is considered the first choice of treatment, followed by adjuvant chemotherapy. However, the 5‐year recurrence rate is still as high as 65% in patients with non‐invasive or in situ tumours and up to 73% in patients with slightly more advanced disease at initial diagnosis. Various treatment methods for bladder cancer have been developed, and hundreds of new immunotherapies are being tested. To date, only a small percentage of people have had success with new treatments, though studies have suggested that the combination of immunotherapy with other therapies improves treatment efficiency and positive outcomes for individuals, with great hopes for the future. In this article, we summarize the origins, therapeutic mechanisms and current status of research on immunotherapeutic agents for bladder cancer. [ABSTRACT FROM AUTHOR]

Bacille Calmette-Gueérin (BCG) is a live strain of Mycobacterium bovis (M.bovis) for use as an attenuated vaccine to prevent tuberculosis (TB) infection, while it could also lead to an infection in immunodeficient patients. M.bovis could infect patients with immunodeficiency via BCG vaccination. Disseminated BCG disease (BCGosis) is extremely rare and has a high mortality rate. This article presents a case of a 3-month-old patient with disseminated BCG infection who was initially diagnosed with hemophagocytic syndrome (HPS) and eventually found to have X-linked severe combined immunodeficiency (X-SCID). M.bovis and its drug resistance genes were identified by metagenomics next-generation sequencing (mNGS) combined with targeted next-generation sequencing (tNGS) in blood and cerebrospinal fluid. Whole exome sequencing (WES) revealed a pathogenic variant in the common γ-chain gene (IL2RG), confirming X-SCID. Finally, antituberculosis therapy and umbilical cord blood transplantation were given to the patient. He was successfully cured of BCGosis, and his immune function was restored. The mNGS combined with the tNGS provided effective methods for diagnosing rare BCG infections in children. Their combined application significantly improved the sensitivity and specificity of the detection of M.bovis. [ABSTRACT FROM AUTHOR]

Objectives: We aimed to compare the efficacy and adverse events of Bacillus Calmette-Guérin (BCG) versus Mitomycin C (MMC) in high-risk Non-Muscle-Invasive Bladder Cancer (NMIBC) patients. Methods: This randomized controlled study was conducted over 24 months in four hospitals in Egypt. A sample of 90 patients was randomly assigned to either treatment group, with procedures including baseline examinations, a single postoperative instillation of chemotherapy, a 6-week induction cycle of the assigned drug, and regular follow-up cystoscopies and upper urinary tract imaging. Treatment results and side effects were monitored, with data analyzed via Statistical Package for Social Sciences (SPSS). Results: No significant differences were observed in mean age or tumor characteristics (p > 0.05). However, adverse reactions were significantly higher in the BCG group, including cystitis (40% vs. 17.78%, p = 0.020), hematuria (24.44% vs. 4.44%, p = 0.007), overall local reactions (75.56% vs. 26.67%, p < 0.001), fever (13.33% vs. 2.22%, p = 0.049), and fatigue (17.78% vs. 2.22%, p = 0.014). The MMC group had a slightly higher recurrence rate (28.89% vs. 17.78%, hazard ratio 1.89, 95% CI: 0.78–4.55, p = 0.15) with a shorter median time to recurrence (six vs. 12 months). Progression rates were similar (8.89% MMC vs. 4.44% BCG, p = 0.398). Conclusion: Although BCG and MMC have comparable efficacy in managing high-risk NMIBC, BCG demonstrated a higher rate of adverse reactions. Decision-making should consider this balance, patient preferences, and health status. Further research is needed for the validation and exploration of these findings. [ABSTRACT FROM AUTHOR]

BCG instillations are considered to be the standard of care therapy for superficial urothelial bladder carcinoma. Although serious adverse events are uncommon, the presence of high fever for at least two days in conjunction with systemic and/or local organ manifestations (except for urogenital symptoms), with the exclusion of other causes, suffice for the diagnosis of a disseminated BCG infection. Microbiologic detection of the pathogen is not necessary for diagnosis, as the detection of granuloma is more often successful and sufficient. Therapy for this infection includes oral Isoniazid, Rifampicin and Ethambutol for six months. [ABSTRACT FROM AUTHOR]

Intravesical therapy (IVT) is the standard of care to decrease risk of recurrence and progression for high‐grade nonmuscle‐invasive bladder cancer. However, post‐IVT recurrence remains common and the ability to risk‐stratify patients before or after IVT is limited. In this prospectively designed and accrued cohort study, we examine the utility of urinary comprehensive genomic profiling (uCGP) for predicting recurrence risk following transurethral resection of bladder tumor (TURBT) and evaluating longitudinal IVT response. Urine was collected before and after IVT instillation and uCGP testing was done using the UroAmp™ platform. Baseline uCGP following TURBT identified patients with high (61%) and low (39%) recurrence risk. At 24 months, recurrence‐free survival (RFS) was 100% for low‐risk and 45% for high‐risk patients with a hazard ratio (HR) of 9.3. Longitudinal uCGP classified patients as minimal residual disease (MRD) Negative, IVT Responder, or IVT Refractory with 24‐month RFS of 100%, 50%, and 32%, respectively. Compared with MRD Negative patients, IVT Refractory patients had a HR of 10.5. Collectively, uCGP enables noninvasive risk assessment of patients following TURBT and induction IVT. uCGP could inform surveillance cystoscopy schedules and identify high‐risk patients in need of additional therapy. [ABSTRACT FROM AUTHOR]

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Introduction: The attenuation of BCG has led to the loss of not only immunogenic proteins but also lipid antigens. Methods: Thus, we compared the macrophage and T-cell responses to nonpolar lipid extracts harvested from BCG and Mycobacterium tuberculosis (Mtb) to better understand the role of BCG lipids in the already known diminished responses of the vaccine strain. Results: Relative to Mtb, nonpolar lipid extract from BCG presented a reduced capacity to trigger the expression of the genes encoding TNF, IL-1b, IL-6 and IL-10 in RAW 264.7 macrophages. Immunophenotyping of PBMCs isolated from healthy individuals revealed that lipids from both BCG and Mtb were able to induce an increased frequency of CD4+ and CD8+ T cells, but only the lipid extract from Mtb enhanced the frequency of CD4-CD8-double-negative, γσ+, CD4+HLA-DR+, and γσ+HLA-DR+ T cells relative to the nonstimulated control. Interestingly, only the Mtb lipid extract was able to increase the frequency of CD4+ memory (CD45RO+) T cells, whereas the BCG lipid extract induced a diminished frequency of CD4+ central memory (CD45RO+CCR7-) T cells after 48 h of culture compared to Mtb. Discussion: These findings show that the nonpolar lipids of the BCG bacilli presented diminished ability to trigger both proinflammatory and memory responses and suggest a potential use of Mtb lipids as adjuvants to increase the BCG vaccine efficacy. [ABSTRACT FROM AUTHOR]

Simple Summary: Carcinoma in situ of the bladder is an aggressive type of non-muscle invasive bladder cancer characterized as a flat, high-grade tumour confined to the urothelial layer. Non-muscle invasive bladder cancer comprises approximately 75% to 80% of all bladder cancers, with Carcinoma in situ found in about 10% of cases. Intravesical instillations of Bacillus Calmette-Guérin immunotherapy is the standard of care for high-risk and intermediate-risk papillary non-muscle invasive bladder cancer as well as for Carcinoma in situ. Evidence supports that the different Bacillus Calmette-Guérin strains, despite genetic variability, are equally effective clinically for preventing the recurrence and progression of papillary non-muscle invasive bladder cancer. The available evidence regarding possible differences in clinical efficacy between various Bacillus Calmette-Guérin strains specifically against Carcinoma in situ is lacking. We therefore reviewed the literature on this topic. We found that the clinical efficacy of the various Bacillus Calmette-Guérin strains against Carcinoma in situ appears similar. However, our conclusions should be considered with caution as most studies were underpowered, and none of the trials were designed as head-to-head comparisons. Randomized studies should be encouraged in this space to draw definitive conclusions. 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. [ABSTRACT FROM AUTHOR]

Objective: 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). Patients and Methods: 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). Results: 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). Conclusion: 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. [ABSTRACT FROM AUTHOR]

Tuberculosis is a major cause of morbidity and mortality in developing countries including India. The Bacille Calmette-Guerine (BCG) vaccine has been in use for prevention of tuberculosis since 1921. Although BCG is safe, it causes minor adverse reactions such as pain, swelling, redness and rarely suppurative lymphadenitis, BCG osteomyelitis and at times even disseminated disease. The term BCG lymphadenitis applies when lymph nodes have become large enough to be easily palpable and a cause of concern for the parents. Here we report thirteen cases of BCG lymphadenitis with age ranging from 4 month to 2.5 years, eight males and the other five female, all presented with left axillary swelling with no history of constitutional symptoms and without family history of tuberculosis. Routine investigations including chest X-ray were normal. In all the cases, there was history of BCG vaccination prior to appearance of swelling, which did not regress on medical management. Ipsilateral regional lymphadenitis being the most common complication of BCG vaccination a high index of clinical suspicion for BCG adenitis should be kept in mind for patients who are recently vaccinated. [ABSTRACT FROM AUTHOR]

Bladder field cancerization may affect tumor biology and disease recurrence rates. Urinary measurements have potential for real-time assessment of treatment response and bladder disease status. Field cancerization is characterized by areas of normal tissue affected by mutated clones. Bladder field cancerization may explain the development and recurrence of bladder cancer and may be associated with treatment outcomes. To investigate the predictive and prognostic roles of field cancerization in patients with high-risk non–muscle-invasive bladder cancer (NMIBC) treated with bacillus Calmette-Guérin (BCG). We conducted comprehensive genomic and proteomic analyses for 751 bladder biopsies and 234 urine samples from 136 patients with NMIBC. The samples were collected at multiple time points during the disease course. Field cancerization in normal-appearing bladder biopsies was measured using deep-targeted sequencing and error correction models. Endpoints included the rates of recurrence and progression. Cox regression and Wilcoxon rank-sum and Fisher's exact tests were used. A high level of field cancerization was associated with high tumor mutational burden (p = 0.007), high tumor neoantigen load (p = 0.029), and high tumor-associated CD8 T-cell exhaustion (p = 0.017). In addition, high field cancerization was associated with worse short-term outcomes (p = 0.029). Nonsynonymous mutations in bladder cancer–associated genes such as KDM6A , ARID1A , and TP53 were identified as early disease drivers already found in normal-appearing bladder biopsies. Urinary tumor DNA (utDNA) levels reflected the bladder tumor burden and originated from tumors and field cancerization. High levels of utDNA after BCG were associated with worse clinical outcomes (p = 0.027) and with disease progression (p = 0.003). High field cancerization resulted in high urinary levels of proteins associated with angiogenesis and proliferation. Limitations include variation in the number of biopsies and time points analyzed. Field cancerization levels are associated with tumor development, immune responses, and clinical outcomes. utDNA measurements can be used to monitor disease status and treatment response. Molecular changes in the tissue lining the bladder result in tumor recurrence. Urinary measurements may be used to monitor bladder cancer status and treatment responses. [ABSTRACT FROM AUTHOR]

Bacillus Calmette-Guérin (BCG) therapy is an adjuvant treatment for urothelial carcinomas of the upper urinary tract (UTUC). BCG therapy can result in various side effects. We present a case of a 67-year-old female with a history of UTUC who developed disseminated tuberculosis following BCG instillation into the upper urinary tract after conservative management. This complex clinical scenario required a multidisciplinary approach, including antibiotic therapy, immunoglobulin infusion, and tailored tuberculosis treatment. The case underscores the importance of vigilance, early detection, and tailored interventions in managing disseminated tuberculosis arising from BCG therapy and rare complications like hemophagocytic syndrome.

Lung tuberculosis (TB) remains a heavy burden on public health worldwide. This review discusses mainly the mechanisms of the development of pulmonary fibrosis in an experimental TB model in mice. The involvement of individual components of the extracellular matrix, the activity of matrix metalloproteinases, and the role of their tissue inhibitors in the fibrosis development. The current TB therapy activates fibrosis along with anti-mycobacterial action. The paper describes the authors’ results of experimental use of the liposome-encapsulated dextrazid (LЕDZ) combined with isoniazid (INH) which has both antifibrotic and anti-mycobacterial effects to be considered for future treatment.

Background: 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. Objective: To evaluate whether patients in the EAU-RF NIMBUS trial experienced better QoL after a reduced BCG instillation frequency. Design, setting, and participants: 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. Outcome measurements and statistical analysis: 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. Results and limitations: 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. Conclusions: Reducing the BCG instillation frequency does not improve the QoL in NMIBC patients despite lower storage symptoms. Patient summary: 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.

Objective: Bacillus Calmette-Guérin (BCG) instillation is the standard adjuvant treatment for intermediate- and high-risk non-muscle-invasive bladder cancer after transurethral resection. Nevertheless, its toxicity often causes bladder complications. On follow-up cystoscopy, post-BCG bladder lesions can be pathologically benign, urothelial carcinoma recurrence, or other types of bladder malignancy. Only a small number of case reports have been published on post-BCG bladder lesions. Their clinical features, natural course, and management remain unknown. Methods: We retrospectively studied cystoscopic videos and medical records of BCG-treated bladder cancer patients at our center. During a long-term follow-up, we took biopsies on tumor-like lesions and described their changes. In addition, we summarized previous studies on post-BCG bladder lesions by systematic literature searching and review. Results: We described a series of three cases with post-BCG bladder lesions mimicking tumor recurrence from a total of 38 cases with follow-up data for more than 5 years. Those lesions could last, grow, or disappear spontaneously, and remain pathological benign for years. In systematic review, we identified and analyzed a total of 15 cases with post-BCG bladder lesions with detailed clinical information. Eleven of the 15 were benign and have a good prognosis with nephrogenic adenoma being the most common pathological type. Conclusion: Based on previous studies and our experience, benign lesions after BCG instillation cannot distinguish with cancer recurrence by cystoscopy alone, even under narrow band imaging mode. Nonetheless, given most of them have a good prognosis, random biopsy or transurethral resection might be spared in the patients with long-term negative biopsy and urine cytology.

Background: Data for bladder-sparing treatment (BST) in bacillus Calmette-Guerin (BCG)-unresponsive non–muscle-invasive bladder cancer (NMIBC) patients report short-term outcomes limited to 1–2 yr. Objective: To assess long-term survival outcomes of BCG-unresponsive NMIBC patients treated with BST. Design, setting, and participants: BCG-unresponsive NMIBC patients diagnosed between January 2000 and September 2021 from an institutional NMIBC registry were evaluated. Intervention: Long-term survival outcomes for patients receiving BST, early radical cystectomy (RC), and delayed RC were compared. Outcome measurements and statistical analysis: The primary endpoints were overall survival (OS) and cancer-specific survival (CSS). Results and limitations: In total, 114 patients with a median follow-up of 71.2 mo (interquartile range: 32.6–132.2) were analyzed. There were no significant differences in OS (hazard ratio [HR]: 1.40, 95% confidence interval [CI]: 0.68–2.89, p = 0.4) or CSS (HR: 0.88, 95% CI: 0.22–3.55, p = 0.9) between patients undergoing early RC (n = 38) and BST (n = 76). At 60 mo, BST patients had a high-grade recurrence-free rate, muscle-invasive disease/metastasis progression-free rate, and avoidance of RC rate of 37%, 83%, and 58%, respectively. Current smoker status (HR: 4.44, 95% CI: 1.41–13.97, p = 0.011) was the only variable predictive of high-grade recurrence following a multivariable analysis. The median time to RC from BCG-unresponsive date was 2.1 and 11.7 mo for those undergoing early RC and delayed RC (after BST), respectively. Patients treated with early RC had a higher incidence of cT1 disease (53% vs 36%, p = 0.049) and lymphovascular invasion (LVI; 11% vs 0%, p = 0.011) compared to patients treated with BST. Survival outcomes were similar between groups: 10-yr OS—58% versus 50% (HR: 1.40, 95% CI: 0.68–2.89, p = 0.4), and 10-yr CSS—81% versus 85% (HR: 0.88, 95% CI: 0.22–3.55, p = 0.9). Conclusions: An analysis of long-term survival of BCG-unresponsive NMIBC patients receiving BST suggests that it may be safe in patients without LVI and/or variant histology and nonsmokers. Survival outcomes for patients treated with BST may not be inferior to those receiving early RC. Patient summary: Bladder-sparing treatment can be offered to appropriately selected patients who have bacillus Calmette-Guerin (BCG)-unresponsive non–muscle-invasive bladder cancer. Long-term outcomes may not be inferior to those for patients who opt for early radical cystectomy.

Despite the widespread use of the Bacillus Calmette–Guérin (BCG) vaccine, Mycobacterium tuberculosis (MTB) continues to be a global burden. Vaccination has been proposed to prevent and treat tuberculosis (TB) infection, and several of them are in different phases of clinical trials. Though vaccine production is in progress but requires more attention. There are several TB vaccines in the trial phase, most of which are based on a combination of proteins/adjuvants or recombinant viral vectors used for selected MTB antigens. In this review, we attempted to discuss different types of TB vaccines based on the vaccine composition, the immune responses generated, and their clinical trial phases. Furthermore, we have briefly overviewed the effective delivery systems used for the TB vaccine and their effectiveness in different vaccines.

IntroductionThe attenuation of BCG has led to the loss of not only immunogenic proteins but also lipid antigens.MethodsThus, we compared the macrophage and T-cell responses to nonpolar lipid extracts harvested from BCG and Mycobacterium tuberculosis (Mtb) to better understand the role of BCG lipids in the already known diminished responses of the vaccine strain.ResultsRelative to Mtb, nonpolar lipid extract from BCG presented a reduced capacity to trigger the expression of the genes encoding TNF, IL-1b, IL-6 and IL-10 in RAW 264.7 macrophages. Immunophenotyping of PBMCs isolated from healthy individuals revealed that lipids from both BCG and Mtb were able to induce an increased frequency of CD4+ and CD8+ T cells, but only the lipid extract from Mtb enhanced the frequency of CD4-CD8-double-negative, γσ+, CD4+HLA-DR+, and γσ+HLA-DR+ T cells relative to the nonstimulated control. Interestingly, only the Mtb lipid extract was able to increase the frequency of CD4+ memory (CD45RO+) T cells, whereas the BCG lipid extract induced a diminished frequency of CD4+ central memory (CD45RO+CCR7-) T cells after 48 h of culture compared to Mtb.DiscussionThese findings show that the nonpolar lipids of the BCG bacilli presented diminished ability to trigger both proinflammatory and memory responses and suggest a potential use of Mtb lipids as adjuvants to increase the BCG vaccine efficacy.