Bacillus Calmette-Guérin Research Articles

Adherence to First-Line Intravesical Bacillus Calmette-Guérin Therapy in the Context of Guideline Recommendations for US Patients With High-Risk Non-muscle Invasive Bladder Cancer

Background: Bacillus Calmette-Guérin (BCG) can reduce recurrence and delay progression among patients with high-risk non–muscle invasive bladder cancer (NMIBC), but is associated with a substantial emotional, physical, and social burden. Objectives: This study evaluated the adequacy of first-line intravesical BCG treatment among high-risk NMIBC patients in the United States, including the subgroup with carcinoma in situ (CIS) of the bladder. Methods: Adults with high-risk NMIBC treated with BCG were selected from de-identified MarketScan® Commercial, Medicare, and Medicaid Databases (1/1/2010-2/28/2021). Adequacy of BCG induction and maintenance was evaluated from the first BCG claim until the end of the patient’s observation, using a previously published claims-based algorithm (induction: ≥5 instillations within 70 days; induction and maintenance: ≥7 instillations within 274 days of first instillation) and a definition based on the landmark Southwest Oncology Group (SWOG) trial (induction: ≥5 instillations without gaps >7 days; followed by ≥2 instillations at month 3, 6, and every 6 months thereafter). Proportions of patients with adequate BCG induction and maintenance were reported overall and compared between those with and without CIS. Results: Of 5803 high-risk NMIBC patients treated with first-line BCG (mean age, 67.3 years; 20.6% female), 930 (16.0%) had CIS. After first-line BCG, 56.6% received another treatment. Although 86.9% had adequate BCG induction based on the claims-based algorithm (SWOG, 73.6%), only 41.5% had adequate BCG induction and maintenance (SWOG, 1.6%). Similar trends were observed for patients with and without CIS, with higher adherence to guidelines for patients with CIS (adequate induction using claims-based algorithm: 90.3% vs 86.2%; adequate induction and maintenance: 50.8% vs 39.7%, all P < .001). A greater proportion of CIS patients than non-CIS patients had cystectomy (CIS, 14.4%, non-CIS, 8.5%; P < .001) after first-line BCG. Discussion: Among patients with NMIBC treated with first-line intravesical BCG, most received adequate BCG induction but less than half had adequate BCG maintenance. BCG treatment was also inadequate for patients with CIS, with only half of patients receiving adequate BCG maintenance and a higher proportion undergoing cystectomy following first-line BCG. Conclusions: Results emphasize the need for additional treatment options for patients with NMIBC.

Self-Adjuvanting Adenoviral Nanovaccine for Effective T-Cell-Mediated Immunity and Long-Lasting Memory Cell Activation against Tuberculosis.

An enhanced vaccine is immediately required to swap the more than 100 year-old bacillus Calmette-Guerin (BCG) vaccine against tuberculosis. Here, trimethyl chitosan-loaded inactivated Mycobacterium smegmatis (MST), along with potent adenovirus hexon protein (AdHP), and toll-like receptor (TLR)-1/2 as a nanovaccine, was developed against tuberculosis (TB). The nanoformulation increased the bioavailability of MST and elicited the targeting ability. Nanovaccines have a size range of 183.5 ± 9.5 nm with a spherical morphology and uniform distribution. The nanovaccine exhibited a higher release of antigen in acidic pH, and this is mainly due to protonation of ionizable groups in polymeric materials. The nanovaccine facilitated the effective cellular uptake of bone-marrow-derived dendritic cells and progressive endosomal escape in a shorter period. In vitro analyses indicated that the nanovaccine activated cytokine and T-cell production and also assisted in humoral immunity by producing antibodies. The nanovaccine was able to induce more cellular and humoral memory cells and a better protective immune response. Nanomaterials effectively delivered the MST, AdHP, and TLR1/2 antigens to the major histocompatibility complex class I and II pathways to generate protective cytotoxic CD8+ and CD4+ T-cells. In vivo experiments, compared with free MST and BCG, showed that mice immunized with the nanovaccine induced more specific CD4+, CD8+, and memory T-cell activations. Overall, the fabricated nanovaccine was able to control the release of antigens and adjuvants and enhance memory cell activation and humoral immunity against TB.

Myeloid-Derived Suppressor Cells in Bladder Cancer: An Emerging Target.

Bladder cancer remains a prevalent and challenging malignancy. Myeloid-derived suppressor cells (MDSCs) have emerged as key contributors to the immunosuppressive tumor microenvironment, facilitating tumor progression, immune evasion, and resistance to therapies. This review explores the role of MDSC in bladder cancer, highlighting their involvement in immune regulation; tumor progression; and resistance to therapies such as bacillus Calmette-Guérin (BCG) therapy, chemotherapy, and immune checkpoint inhibitors (ICIs). We also discuss their potential as biomarkers and therapeutic targets, with current evidence suggesting that targeting MDSCs, either alone or in combination with existing treatments such as BCG and ICIs, may enhance anti-tumor immunity and improve clinical outcomes. However,, challenges remain, particularly regarding the identification and therapeutic modulation of MDSC subpopulations. Further research is warranted to fully elucidate their role in bladder cancer and to optimize MDSC-targeted therapies.

Unveiling the dimension of regional disparities: Assessing the disruption of immunisation services by COVID-19 in Bangladesh.

The coronavirus disease 2019 (COVID-19) pandemic disrupted essential health care services worldwide, including those related to immunisation. National data from Bangladesh shows that child immunisation may have been adversely affected by the pandemic but regional evidence is limited. We therefore aimed to explore the regional differences in the indirect effects of COVID-19 on child immunisation in Bangladesh. We extracted data from the District Health Information Software (DHIS2) spanning the period from January 2017 to December 2021. We examined three essential immunisation indicators: Bacille Calmette-Guérin (BCG), pentavalent third dose, and measles vaccinations. We examined both the yearly and monthly trends to explore fluctuations in the number of immunisations to pinpoint specific periods of service utilisation regression. Segmented regression with Poisson distribution was implemented given the count-based outcome. We reported incidence rate ratios (IRRs) with 95% confidence intervals (CIs) in different regions in 2020 and 2021 compared to the reference period (2017-19). We initially observed a notable decline in vaccine administration in April 2020 compared to the pre-pandemic period of 2017-19 with a drop of approximately 53% for BCG vaccines, 55% for pentavalent third doses, and 51% for measles vaccines followed by May 2020. The second half of 2020 saw an increase in vaccination numbers. There were noticeable regional disparities, with Sylhet (IRR = 0.75; 95% CI = 0.67-0.84 for pentavalent administration, IRR = 0.79; 95% CI = 0.71-0.88 for measles administration) and Chattogram (IRR = 0.77; 95% CI = 0.72-0.83 for BCG administration) experiencing the most significant reductions in 2020. In April 2020, Dhaka also experienced the largest decline of 67% in measles vaccination. In 2021, most divisions experienced a rebound in BCG and pentavalent administration, exceeding 2019 levels, except for Chittagong, where numbers continued to decline, falling below the 2019 figure. Our findings highlight the impact of the COVID-19 pandemic on childhood immunisation across regions in Bangladesh. Sylhet, Chattogram, and Dhaka divisions experienced the most significant reductions in immunisation services during 2020. This underscores the importance of targeted interventions and regional strategies to mitigate the indirect effects of future challenges on essential health care services, particularly childhood immunisation, in Bangladesh.

Microbiome and bladder cancer: the role of probiotics in treatment.

Bladder cancer (BCa) remains a significant global health challenge, with increasing interest in the role of the bladder microbiome in its pathogenesis, progression and treatment outcomes. The complex relationship between bladder cancer and the microbiome, as well as the potential impact of probiotics on treatment effectiveness, is currently under investigation. Research suggests that the microbiota may influence BCa recurrence prevention and enhance the efficacy of the Bacillus Calmette-Guérin (BCG) vaccine. Recent studies reveal differences in the bladder microbiome between individuals without bladder cancer and those with the disease. In the healthy bladder, Streptococcus and Lactobacillus are consistently identified as the most prevalent genera. However, in men, the predominant bacterial genera are Staphylococcus, Corynebacterium and Streptococcus, while in women with bladder cancer, Gardnerella and Lactobacillus are dominant. Probiotics, particularly Lactobacillus spp., can exhibit anti-tumor properties by competing with pathogenic strains involved in carcinogenesis or by producing regulatory substances. They regulate cancer signaling, induce apoptosis, inhibit mutagenic activity, downregulate oncogene expression, induce autophagy, inhibit kinases, reactivate tumor suppressors and prevent metastasis. These mechanisms have shown promising results in both preclinical and some clinical studies.

Performing national independence through medical diplomacy: tuberculosis control and socialist internationalism in Cold War Vietnam.

This article explores medical diplomacy as a means of navigating distinct but related nation-building and internationalist projects during the Cold War. It examines how medical professionals from the Democratic Republic of Vietnam (DRV) utilized their expertise to bolster foreign relations and assert national independence. This article focuses on how three tuberculosis (TB) specialists - Đặng Đức Trạch, Phạm Ngọc Thạch and Phạm Khắc Quảng - adopted, adapted and circulated techniques of TB control, including a modified version of bacillus Calmette-Guérin (BCG) vaccine. Amidst these endeavours, these medical-doctors-cum-diplomats navigated various forms of internationalism while soliciting medical assistance. Their roles within the DRV's state apparatus were prominently showcased from the 1950s to the 1970s, particularly at international gatherings such as the conferences of Ministers of Health of the Socialist Countries (MOHOSC). Because of the political complexities inherent in socialist internationalism, these conferences provided a crucial platform for dialogue among socialist nations when other avenues were limited. Consequently, the DRV's medical experts cultivated goodwill and garnered political support, despite encountering mixed results in their TB control initiatives.

Mendelian Susceptibility to Mycobacterial Disease with Signal Peptide Peptidase-like 2A (SPPL2A) Deficiency: A Case Report

Mendelian susceptibility to mycobacterial disease (MSMD) is a rare genetic disorder characterized by immunodeficiency, leading to increased susceptibility to mycobacterial infections. Studies have identified several genes that are associated with MSMD in the interferon-gamma/interleukin (IL)-12/IL-23 signaling pathway. One of these genes is signal peptide peptidase-like 2A (SPPL2A), which is very rare, and defects in this gene have been reported only in 3 patients with MSMD. This case report presents the rare SPPL2A deficiency with an abnormal presentation, which adds to the limited number of these genetic defects. This report presents the case of a 1-year-old boy who developed Bacillus Calmette-Guerin infection (BCGitis), lymphadenopathy, and an arm abscess that required surgical drainage following BCG vaccination. The patient had hypogammaglobulinemia, normal B-cell counts, normal CD4 counts, low CD8 counts, and SPPL2A deficiency, which is related to MSMD. The patient received a second line of anti-tuberculosis agents. SPPL2A deficiency is associated with MSMD and can cause severe BCGitis and disruption of immunoglobulin production.

Effect of standardized patient simulation with BCG vaccination on nursing students' skills, knowledge and satisfaction, and self-confidence: A randomized controlled study

AimTo examine the effect of standardised patient simulation training on nursing students' skills and knowledge in administering the Bacillus Calmette-Guérin vaccine, as well as their satisfaction and self-confidence. BackgroundThe Bacillus Calmette-Guérin vaccine is administered by nurses to prevent tuberculosis. However, there have been reports of complications arising from inadequate knowledge and skills related to Bacillus Calmette-Guérin vaccine administration. DesignA randomised controlled experimental design. MethodThis experimental study was conducted between October 2022 and January 2023 at a university, Medical Training and Simulation Centre. The fourth-year nursing students enrolled in their intern term were asked to participate in this experimental study. Participants were allocated to the intervention group (n=45) and the control group (n=45). The control group received only theoretical training and then BCG application on the model. The socio-demographic survey was conducted to collect demographic data. The Bacillus Calmette-Guérin Vaccine Knowledge Form, Bacillus Calmette-Guérin Vaccine Administration Checklist, and the student satisfaction and self-confidence scale in learning were used. The intervention group received simulation training using a standardized patient. All students' knowledge and skills were measured before and 3 months after the theoretical training. ResultsSimulation training using standardized patients significantly increased nursing students' Bacillus Calmette-Guérin vaccine knowledge (intervention group=21.57±5.12; control group=15.33±5.61), skills (intervention group=20.88±4.29; control group=10.22±4.56), confidence and satisfaction (intervention group=4.61±0.30; control group=4.17±0.3) compared with the control group (p < 0.05). ConclusionTraining with standardized patient techniques provides students the opportunity to practice realistically in a safe environment, enabling repetitive practice, which enhances self-confidence and satisfaction.

Evaluating the effect of BCG vaccination for non-specific protection from infection in senior citizens during the COVID-19 pandemic: A randomised clinical trial

The Bacillus Calmette-Guérin (BCG) vaccine may induce non-specific protection against unrelated infections. We tested the effect of BCG on the risk of infections among Danish senior citizens. Single-blinded randomised controlled trial including 1676 volunteers >65 years. Participants were randomised 1:1 to BCG or placebo and followed for 12 months. The primary outcome was acute infection leading to medical contact. Secondary outcomes were verified SARS-CoV-2 infection, self-reported respiratory symptoms, and all-cause hospitalisation. Data was analysed using Cox regression models, estimating hazard ratios (HR) with 95% confidence intervals (CI). The incidence of acute infection was 52.1 and 58.2 per 100 person-years for BCG and placebo, respectively (HR=0.89, 95% CI=0.78-1.02). There was no effect of BCG on SARS-CoV-2 infections (0.97, 0.75-1.26) or all-cause hospitalisations (1.10, 0.80-1.50), but BCG was associated with more respiratory symptoms (1.21, 1.10-1.33). BCG reduced the incidence of acute infections among participants <75 years (0.82, 0.70-0.95) but not among those >75 years (1.14, 0.88-1.47). In participants, who were COVID-19 vaccinated before enrolment, BCG was associated with lower incidence of acute infections (0.65, 0.50-0.85). BCG did not reduce risk of acute infections among Danish seniors overall, but the effect was modified by age group and COVID-19 vaccination. ClinicalTrials.gov (NCT04542330) and EU Clinical Trials Register (EudraCT number 2020-003904-15). Full trial protocol is available at ClinicalTrials.gov. In a randomised clinical trial among Danish senior citizens, BCG vaccination did not reduce the overall risk of acute infection, but BCG was associated with reduced risk in participants <75 years and participants who received COVID-19 vaccines prior to enrolment.

Differential Urinary Microbiome and Its Metabolic Footprint in Bladder Cancer Patients Following BCG Treatment.

Recent studies have identified a urinary microbiome, dispelling the myth of urine sterility. Intravesical bacillus Calmette-Guérin (BCG) therapy is the preferred treatment for intermediate to high-risk non-muscle-invasive bladder cancer (BCa), although resistance occurs in 30-50% of cases. Progression to muscle-invasive cancer necessitates radical cystectomy. Our research uses 16S rRNA gene sequencing to investigate how the urinary microbiome influences BCa and its response to BCG therapy. Urine samples were collected via urethral catheterization from patients with benign conditions and non-muscle-invasive BCa, all of whom underwent BCG therapy. We utilized 16S rRNA gene sequencing to analyze the bacterial profiles and metabolic pathways in these samples. These pathways were validated using a real metabolite dataset, and we developed predictive models for malignancy and BCG response. In this study, 87 patients participated, including 29 with benign diseases and 58 with BCa. We noted distinct bacterial compositions between benign and malignant samples, indicating the potential role of the toluene degradation pathway in mitigating BCa development. Responders to BCG had differing microbial compositions and higher quinolone synthesis than non-responders, with two Bifidobacterium species being prevalent among responders, associated with prolonged recurrence-free survival. Additionally, we developed highly accurate predictive models for malignancy and BCG response. Our study delved into the mechanisms behind malignancy and BCG responses by focusing on the urinary microbiome and metabolic pathways. We pinpointed specific beneficial microbes and developed clinical models to predict malignancy and BCG therapy outcomes. These models can track recurrence and facilitate early predictions of treatment responses.

Characterization of Fibroblast Growth Factor Receptor Alterations and Activation in Patients with High-Risk Non-Muscle Invasive Bladder Cancer.

The GARNER study investigated fibroblast growth factor receptor (FGFR) alteration (ALT) frequency and the clinical outcome relationship with Bacillus Calmette-Guérin (BCG) treatment in high-risk non-muscle invasive bladder cancer (HR-NMIBC). An FGFR predictive response signature (FGFR-PRS) was discovered that identifies patients with an activated FGFR pathway who could potentially benefit from FGFR-targeted therapy beyond those who are FGFR ALT (+). Pre-treatment tumor samples and clinical data were analyzed from 582 BCG-treated HR-NMIBC patients. FGFR-PRS was discovered using a separate BC dataset and applied to the GARNER and other BC cohorts. FGFR-PRS was also applied to in vitro data from UC cell lines treated with FGFR-active agents. 31% of pre-treatment GARNER HR-NMIBC tumors were FGFR ALT (+) but this was not significantly associated with BCG response. For the subset of patients with paired pre- and post-BCG treatment samples, nearly one-third pre-treatment ALT (+) patients were ALT (-) post-treatment. FGFR-PRS identified patients with an activated FGFR pathway and identified approximately 2-fold additional patients compared to ALT status alone, and this increase was similar across tumor stage. A positive relationship between tumor growth inhibition and FGFR-PRS score was shown in BC in vitro models treated with FGFR-active agents. These data provide support for FGFR-targeted therapy use in FGFR ALT (+) HR-NMIBC and describe tumors with shared FGFR pathway-activated biology that are FGFR ALT (-) but FGFR-PRS (+). The latter suggests a broader potential patient population for FGFR-targeted therapy, which will require subsequent validation in patients treated with FGFR-targeted therapy.

Determinants of under-five mortality in informal settlements in Nairobi, Kenya from 2002 to 2018

BackgroundChildhood mortality persists as a significant public health challenge in low and middle-income countries and is uneven within countries, with poor communities such as urban informal settlements bearing the highest burden. There is limited literature from urban informal settlements on the risk factors of mortality. We assessed under-five mortality and associated risk factors from the period 2002 to 2018 in Nairobi urban informal settlements.MethodsWe used secondary data from the Nairobi Urban Health and Demographic Surveillance System (NUHDSS), a longitudinal surveillance platform that routinely collects individual and household-level data in two informal settlements (Viwandani and Korogocho) in Nairobi, Kenya. We used Kaplan-Meier curves to estimate overall survival and the Cox proportional hazard model with a frailty term to evaluate the impact of risk factors on survival time.ResultsOverall under-five survival rate was 96.8% and this improved from 82.6% (2002-2006) to 95% (2007-2012) and 98.4% (2012-2018). There was a reduced risk of mortality among children who had BCG vaccination, those born to a married mother or a mother not engaging in any income-generating activity (both from 2007 to 2011), children from singleton pregnancy, children born in Viwandani slum and ethnicity of the child.ConclusionUnder-five mortality is still high in urban informal settlements. Targeted public health interventions such as vaccinations and interventions empowering women such as single mothers, those with multiple pregnancies, and more impoverished slums are needed to further reduce under-five mortality in urban informal settlements.

Expert consensus of multi-disciplinary collaboration on bladder-preserving treatment for bladder cancer in China (2024 edition)

Bladder cancer is one of the common malignant tumors in urology. According to statistics, there will be 613 791 new cases of bladder cancer in the world in 2022, and the number of new cases of bladder cancer in China will be approximately 92 900, accounting for approximately 15% of new cases of bladder cancer in the world, ranking 11th in the spectrum of malignant tumors in China, among which there are approximately 73 200 new cases in males, ranking 8th in the spectrum of male malignant tumors. Bladder urothelial cancer accounts for approximately 90% of all bladder malignant tumors. It can be divided into non-muscle-invasive bladder cancer and muscle-invasive bladder cancer according to whether it invades the bladder muscle layer. Radical cystectomy is the standard treatment for muscle invasive bladder cancer patients and bacillus calmette-guerin (BCG) unresponsive high-risk non-muscle invasive bladder cancer patients. Nevertheless, due to the patient's underlying diseases and the deterioration of the quality of life caused by surgery, many patients refused or are not suitable for radical cystectomy. Therefore, it is vital to find a bladder-preserving treatment that can achieve cure other than radical cystectomy. Bladder-preserving therapy that balances tumor control and quality of life serves as an alternative and supplement to radical cystectomy. This consensus is based on contemporary evidence-based medicine, combined with native clinical practice and experiences of bladder preservation in a multidisciplinary treatment manner. To some extent, this consensus serves as a guidance for bladder preservation of bladder cancer in China. The consensus aims to discuss issues including organizational structure and workflow of multidisciplinary treatment, the selection of patients for bladder-preserving therapy, treatment options and regimens, efficacy evaluation, follow-up, as well as regimen choices of recurrence after bladder-preserving therapy.

Reliability of mpMRI in diagnosing cancer prostate following intravesical BCG for bladder cancer.

Detecting carcinoma prostate (CaP) after intravesical Bacillus Calmette Guerin (BCG) immunotherapy for non-muscle invasive bladder cancer (NMIBC) poses diagnostic challenges. Granulomatous prostatitis (GP) has an incidence of 0.8%-3.3% in post-intravesical BCG patients and 6% incidence in a PIRADS 5 lesion on multiparametric MRI (mpMRI). Patients with GP after intravesical BCG may have clinical, biochemical, and radiological features similar to CaP. In our study, we evaluate the reliability of mpMRI in diagnosing CaP after intravesical BCG therapy. We reviewed the NMIBC patients treated with intravesical BCG therapy between 2017 and 2023 and investigated those who underwent mpMRI and MR fusion biopsy in suspicion of CaP. A total of 120 patients had intravesical BCG immunotherapy, and 10 patients met our selection criteria. We performed a descriptive analysis of these patients and assessed the sensitivity and specificity of mpMRI in diagnosing CaP. The sensitivity of mpMRI in detecting CaP was 100%, and the specificity was 28.6%. Similarly, the negative predictive value for detecting CaP was 100%, and the positive predictive value was 37.5%. Among patients evaluated with mpMRI, a PIRADS 4 or 5 lesion was seen in 8 (80%) patients, and there was no lesion in 2 (20%) patients. The mpMRI detected 1 lesion in 6 patients (60%) and 2 (20%) in 2 patients. The lesions had a PIRADS score of 4 and 5 in 6 (60%) and 2 (20%) patients, respectively. Among these lesions, 8 (80%) were in the peripheral zone and 2 (20%) in the transition zone. In the MR fusion biopsy of these 10 patients, 7 (70%) had granulomatous prostatitis, and 3 (30%) had CaP. In our study on evaluating the reliability of mpMRI in diagnosing CaP among post-intravesical BCG patients, we noted that although PIRADS in mpMRI had high sensitivity in identifying prostate lesions, its specificity for detecting CaP is limited.

Assays for Assessing Mycobacterium avium Immunity and Evaluating the Effects of Therapeutics.

In Europe and North America, the prevalence of pulmonary nontuberculous mycobacteria (NTM) is increasing. Most pulmonary NTM infections are caused by the Mycobacterium avium complex (MAC). Sadly, the treatment of pulmonary MAC is suboptimal with failure rates ranging from 37% to 58%. Therefore, there is a need to develop new therapeutics. Developing new immunotherapies and studying their interaction with standard or new drugs requires reliable assays. Four different assays including CFSE-based flow cytometry, in vitro protection assays, IFN-γ ELISPOT, and murine infection models were optimized using a reference strain of MAC (ATCC 700898) to help with the development of immunotherapies for MAC. Expansion of proliferating and IFN-γ producing human T cells is optimal after 7 days of stimulation with MAC at a multiplicity of infection (MOI) of 0.1, achieving a stimulation index of 26.5 ± 11.6 (mean ± SE). The in vitro protection assay for MAC works best by co-culturing T cells expanded for 7 days with MAC (MOI 1)-infected autologous macrophages. Aerosol MAC infection of mice allows measurement of the effects of the BCG vaccine and clarithromycin. IFN-γ ELISPOT assays with live MAC (MOI 3) stimulation of splenocytes from mice immunized with BCG help identify differences between unimmunized mice and mice immunized with BCG. In conclusion, multiple assays are available for use to identify MAC-specific effector T cells, which will help in the development of new therapeutics or vaccines against pulmonary MAC.

Recurrent Visceral Leishmaniasis in a Case With Interleukin-12 Receptor Beta-1 Deficiency.

In this study, we present the case of a children who was followed up for recurrent visceral leishmaniasis and diagnosed with IL-12Rβ1 deficiency. A female patient who received Bacille Calmette-Guérin (BCG) vaccine 2 months after birth and developed visceral leishmaniasis at the age of 91 months was subsequently diagnosed with IL-12Rβ1 deficiency. The patient's diagnosis and treatment process were examined retrospectively. IL-12Rβ1 deficiency is an autosomal recessive disease characterized by susceptibility to recurrent and/or severe infections caused by weakly pathogenic mycobacteria and salmonella. Infections with other intramacrophagic organisms may also occur, although rarely. Based on this information, it is believed that the mutation in the IFN-γ/IL-12 axis in our patient predisposed her to recurrent Leishmania infections. This study adds to the limited literature on IL12RB1 deficiency as a cause of VL. Patients diagnosed with VL should be evaluated immunologically, as recurrent Leishmania infections may occur in those with IL-12Rβ1 defects.

Predicting Response to Intravesical BCG in High-Risk NMIBC Using an Artificial Intelligence-Powered Pathology Assay: Development and Validation in an International 12-Center Cohort.

There are few markers to identify those likely to recur or progress after treatment with intravesical bacillus Calmette-Guérin (BCG). We developed and validated artificial intelligence-based histologic assays that extract interpretable features from transurethral resection of bladder tumor digitized pathology images to predict risk of recurrence, progression, development of BCG-unresponsive disease, and cystectomy. Pre-BCG resection-derived whole-slide images and clinical data were obtained for high-risk NMIBC cases treated with BCG from 12 centers and were analyzed through a segmentation and feature extraction pipeline. Features associated with clinical outcomes were defined and tested on independent development and validation cohorts. Cases were classified into high or low risk for recurrence, progression, BCG-unresponsive disease, and cystectomy. Nine hundred forty-four cases (development: 303, validation: 641, median follow-up: 36 months) representative of the intended use population were included (high-grade Ta: 34.1%, high-grade T1: 54.8%; carcinoma in situ only: 11.1%, any carcinoma in situ: 31.4%). In the validation cohort, "high recurrence risk" cases had inferior high-grade recurrence-free survival vs "low recurrence risk" cases (HR, 2.08, P < .0001). "High progression risk" patients had poorer progression-free survival (HR, 3.87, P < .001) and higher risk of cystectomy (HR, 3.35, P < .001) than "low progression risk" patients. Cases harboring the BCG-unresponsive disease signature had a shorter time to development of BCG-unresponsive disease than cases without the signature (HR, 2.31, P < .0001). AI assays provided predictive information beyond clinicopathologic factors. We developed and validated AI-based histologic assays that identify high-risk NMIBC cases at higher risk of recurrence, progression, BCG-unresponsive disease, and cystectomy, potentially aiding clinical decision making.

Overall burden and impact on health-related quality of life associated with intravesical treatment of patients with non-muscle invasive bladder cancer in the United States

Background This study aimed to describe the life impacts of intravesical therapies for non-muscle invasive bladder cancer (NMIBC) from a patient perspective. Methods A cross-sectional online survey design was used. Adults with NMIBC (and no other cancer) treated intravesically in the prior 12 months were recruited from US patient online communities. Individuals participating in a clinical trial or treated with erdafitinib were excluded. Participants’ treatment experiences were evaluated using a questionnaire comprising (a) custom questions reported on 11-point numerical rating scales and (b) validated patient reported outcome (PRO) measures for bladder symptom burden and work productivity. Results Among 171 survey participants, most received bacillus Calmette-Guérin (BCG) (83%), intravesical gemcitabine (28%), or gemcitabine + docetaxel (13%) during the past year. Participants generally felt adequately informed about treatment, felt expectation of treatment matched actual experience, and expressed intent to complete the full treatment course and willingness to try different treatments if needed. Participants reported disease symptom burden of 42.6/72 on the NFBlSI-18 scale. Employed participants reported 51% work impairment and 59% overall work productivity loss due to NMIBC. Conclusions Participants recently treated with intravesical therapies expressed intent to complete the full treatment course and willingness to try new therapies if needed. Participants reported high NMIBC symptom burden and work impairment negatively impacting their well-being, despite receiving intravesical treatment.

6684 Multi-Dose BCG Vaccination for Protection Against COVID-19 Disease and Other Respiratory Infections in Subjects with Type 1 Diabetes Late in the US Pandemic

Abstract Disclosure: W. Kühtreiber: None. E. Hostetter: None. G.E. Wolfe: None. M. Vaishnaw: None. R. Goldstein: None. E. Bulczynski: None. N. Hullavarad: None. J.E. Braley: None. H. Zheng: None. D.L. Faustman: None. A Phase II clinical trial previously reported that multiple doses of the bacillus Calmette-Guerin (BCG) vaccine, originally developed for tuberculosis prevention, could protect at-risk individuals with type 1 diabetes (T1D) against COVID-19 disease and infectious diseases early in the pandemic in the United States (US) (Cell Rep Med 2022). As SARS-CoV-2 evolved, COVID-19 disease became more transmissible, but less lethal. In a new, Phase III, randomized, double-blinded, placebo-controlled trial, we tested whether at-risk individuals with T1D given multi-dose, intradermal BCG would be protected against COVID-19 and other infectious diseases (2:1 randomization; BCG: n=93; placebo: n=48). The trial was conducted late in the COVID-19 pandemic during sequential dominance of Beta, Gamma, Delta and Omicron variants. All participants were US citizens and were negative for prior BCG vaccination and negative for tuberculosis. Two co-primary endpoints were protection from COVID-19 disease and platform protection from all infectious diseases. From April 2021 to November 2022, Tokyo-strain BCG vaccination provided significant protection against COVID-19 disease (p=0.023) and strong platform protection against all infectious diseases (p&amp;lt;0.0001). Over the 19-month course of the study, commercial COVID-19 vaccines were rolled out. An observational analysis of the placebo control group (i.e., no BCG vaccination) showed that COVID-19 mRNA vaccination alone provided no protection from COVID-19 disease in the enrolled population (p=0.43). BCG vaccination efficacy against COVID-19 and infectious disease in T1D was unaffected by concurrent COVID-19 vaccinations (observational analysis). These data suggest that BCG has efficacy against a range of SARS-CoV-2 variants, in contrast to current COVID-19 vaccines, which have narrow efficacy against specific viral variants. Further, it shows that individuals with T1D represent a vulnerable population for whom BCG appears to be the only effective vaccine against COVID-19 disease and confirms that, in the US, BCG vaccination protects against infectious disease as well. Presentation: 6/3/2024

6519 BCG Clinical Trial Programs in Advanced Type 1 Diabetes - 2024 Update

Abstract Disclosure: W.M. Kühtreiber: None. B. Thach: None. H. Hayashi: None. L. Adams: None. N. Hullavarad: None. D.A. Mounier: None. K. Le: None. E. Bulczynski: None. J.L. Dorsey: None. N. Kartsounis: None. J. Braley: None. H. Zheng: None. D.L. Faustman: None. The bacillus Calmette-Guerin (BCG) vaccine, originally developed a century ago to prevent tuberculosis infection, has today advanced in multiple clinical trials for the treatment of the type 1 diabetes (T1D), other forms of autoimmunity and infectious disease. At our institution, over 500 individuals with type 1 diabetes have been enrolled in ongoing BCG clinical protocols to test BCG’s ability to lower HbA1c, reduce insulin requirements and stabilize day-to-day fluctuations in blood sugars; 300 have been treated with BCG. In a completed randomized, placebo-controlled Phase I trial in adults with established T1D, long-term follow up continues to show that HbA1c values are durably lowered for 8+ years after multi-dose BCG treatment. In two open-label clinical trials in adults with juvenile-onset diabetes, a 10-15% reduction of HbA1c was observed after multi-dose BCG treatment. A randomized, double-blinded Phase II trial in adults with longstanding T1D has followed all patients in the BCG-treated (n=100) and placebo groups (n=50) for five years and is pending read-out. The primary outcome of all the trials is HbA1c lowering. Two new, randomized, double-blinded pediatric trials are testing the potential benefits of BCG vaccination with active enrollment ongoing. One is testing BCG in children ages 12 to 18 with more than 2 years since T1D diagnosis. The other is enrolling children ages 8 to 18 with less than 1 year since T1D diagnosis. BCG vaccine therapy may provide a safe and affordable medical intervention in individuals with longstanding T1D and works decades after disease onset by changing glucose metabolism within lymphocytes, independently of the pancreas. Presentation: 6/3/2024