Bacillus Calmette-Guérin Research Articles

Cost effectiveness analysis of nadofaragene firadenovec for the treatment of high-risk, bacillus Calmette-Guerin–unresponsive, non-muscle invasive bladder cancer from a US third-party payer perspective.

4598 Retraction The abstract by Yang et al entitled, “Cost effectiveness analysis of nadofaragene firadenovec for the treatment of high-risk, bacillus Calmette-Guerin–unresponsive, non-muscle invasive bladder cancer from a US third-party payer perspective,” ( Journal of Clinical Oncology 42, no. 16_suppl 4598; DOI 10.1200/JCO.2024.42.16_suppl.4598) published on May 29, 2024, has been retracted. The authors wish to retract this article as it is undergoing additional review and further updates are expected. They could not rule out that the current results may be incorrect, inaccurate, or misleading. It is important to provide the best estimate of nadofaragene’s cost effectiveness vs pembrolizumab in this space for healthcare decision making whereas uncertainty remains at this time. The authors are no longer able to endorse the work. This abstract was retracted on August 26, 2024. Background: Bladder cancer is the second most common cancer in the urinary tract in the United States (US), with 75% restricted to the superficial layers of the bladder and termed as non-muscle invasive bladder cancer (NMIBC). Bacillus Calmette-Guerin (BCG) is the standard of care for high risk NMIBC patients; however, bladder preserving treatments are limited after BCG failure. Nadofaragene firadenovec, an interferon-alfa-2b encoding gene therapy, is approved for the treatment of high-risk BCG-unresponsive NMIBC with carcinoma in situ (CIS) with or without papillary tumors (CIS ± Ta/T1). This study assessed cost-effectiveness of nadofaragene firadenovec compared to pembrolizumab from a US third-party payer perspective. Methods: A Markov model was developed to estimate total costs, quality-adjusted life-years (QALYs), and corresponding incremental cost per QALY ratios (ICER) over a lifetime time horizon for patients treated with nadofaragene firadenovec or pembrolizumab. In the absence of head-to-head data comparing nadofaragene firadenovec to pembrolizumab, the model population was based on Phase 3 trial for nadofaragene firadenovec (NCT02773849, data cut: July 8, 2019) and included adult patients (mean age of 71.0 years; 11.7% female) with high-risk, BCG unresponsive NMIBC with CIS ± Ta/T1. Pembrolizumab data was informed by the published KeyNote-057 trial (NCT02625961, data-cut: May 25, 2020). The model consisted of 7 mutually exclusive health states with a three-month model cycle: NMIBC disease-free, NMIBC recurrence, MIBC, metastatic disease, cystectomy, post-cystectomy, and death. Drug costs, adverse events (AEs) costs, and health state associated medical costs were included and discounted at 3% annually. The nadofaragene firadenovec and pembrolizumab prices were informed by 2023 U.S. pricing compendia. Sensitivity analyses were performed. Results: Compared to pembrolizumab, nadofaragene firadenovec resulted in an ICER of $123,725 per QALY gained. The incremental cost was $24,194 (nadofaragene firadenovec: $374,280; pembrolizumab: $350,086) and the incremental QALYs were 0.196 (nadofaragene firadenovec: 4.560; pembrolizumab: 4.364). The cumulative drug acquisition and administration costs for nadofaragene firadenovec and pembrolizumab were $181,134 and $141,954 respectively, and AE costs were $248 and $2,749 and medical costs associated with health states were $192,898 and $205,382, respectively. The ICERs for nadofaragene firadenovec remained cost-effective across a majority of the sensitivity analyses and simulations. Conclusions: The analysis suggests that nadofaragene firadenovec is cost-effective compared to pembrolizumab for the treatment of high-risk, BCG unresponsive NMIBC with CIS ± Ta/T1 at a willingness to pay of $150,000/QALY.

A phase 1/2 study of EG-70 (detalimogene voraplasmid) intravesical monotherapy for patients with BCG-unresponsive non-muscle invasive bladder cancer with carcinoma in situ.

TPS4626 Background: High-risk non-muscle-invasive bladder cancer (NMIBC) is treated with adjuvant intravesical Bacille Calmette-Guérin (BCG). However, approximately 50% of patients experience recurrence and/or progression after BCG treatment and are considered unresponsive. EG-70 (detalimogene voraplasmid) is an investigational drug product that was specifically engineered for intravesical administration to elicit local stimulation of anti-tumor immune responses in the bladder and drive durable efficacy in patients with BCG-unresponsive NMIBC, while mitigating the risk of systemic toxicities from immune stimulation. The phase 1 (dose-escalation) part of the first-in-human LEGEND (NCT04752722) phase 1/2, open-label, multicenter study of EG-70 in patients with high-risk BCG-unresponsive NMIBC with carcinoma in situ (CIS) is complete: intravesical instillation of EG-70 was well tolerated with an overall complete response (CR) rate of 73%; and the recommended phase 2 dose (RP2D) was identified. Here we describe the ongoing phase 2 part of the study, which opened to enrollment in May 2023. Methods: Patient eligibility criteria: age ≥18 years; ECOG PS 0−2; BCG-unresponsive NMIBC with CIS, with or without resected coexisting papillary tumors, ineligible for, or have elected not to undergo, cystectomy; satisfactory bladder function with ability to retain study drug for ≥60 minutes. Prior checkpoint inhibitor treatment is allowed if completed within 30 days before study entry. Patients are treated with EG-70 at the RP2D (800 µg in 50 mL) by intravesical administration on weeks 1, 2, 5, and 6 of a 12-week cycle, for 4 cycles in one of two cohorts: BCG-unresponsive (Cohort 1); BCG-naïve or BCG-incompletely treated (Cohort 2). Patients in either cohort who exhibit stable disease (SD) or CR at week 12 will continue treatment until week 24; patients with progressive disease (PD) will discontinue treatment. Patients who experience or maintain CR at week 24 will receive additional cycles every 12 weeks until week 48; patients with SD or PD at week 24 will discontinue treatment. Patients with PD at any time after week 24 will discontinue treatment. Phase 2 primary objective: evaluate efficacy (CR rate at week 48) and safety of EG-70. Secondary objectives: evaluate progression-free survival, CR rate at 12, 24, 36 and 48 weeks, and duration of response. The study is being conducted in accordance with the International Conference on Harmonisation Good Clinical Practice guidelines and with the principles of the Declaration of Helsinki. All patients provide written informed consent. The ongoing, registration-enabling phase 2 portion of the LEGEND study is anticipated to recruit approximately 100 patients from sites in North America, Europe, and the Asia-Pacific region. Clinical trial information: NCT04752722 .

Outcomes of childhood TB in countries with a universal BCG vaccination policy.

<sec id="st1"><title>BACKGROUND</title>TB remains an important cause of childhood morbidity and mortality. Underdiagnosis, underreporting and limited data on the outcomes of childhood TB have led to an underestimation of its impact.</sec><sec id="st2"><title>METHODS</title>This was a systematic review to characterise childhood TB outcomes. Studies reporting relevant epidemiological data on children between 0 and 14 years of age, with a particular focus on treatment outcomes, from countries with universal bacilli Calmette-Guérin (BCG) vaccination and conducted between 2000 and 2020 were selected. Random effects meta-analysis was performed in R software.</sec><sec id="st3"><title>RESULTS</title>We identified 1,806 references and included 35 articles. Among children with TB, the overall proportion of unfavourable outcomes was 19.5% (95% CI 14.4-25.8) and pooled case-fatality ratio was 6.1% (95% CI 4.3-8.4). The proportion of deaths observed among children between 0 and 4 years old was 6.6% (95% CI 4.9-8.7) and 4.6% (95% CI 3.1-6.9) in older children. TB and HIV co-infected children presented a case-fatality ratio of 15.1% (95% CI 7.9-27.0).</sec><sec id="st4"><title>CONCLUSIONS</title>Despite the efforts made in the last decades, treatment outcomes in childhood TB are still worrisome. Efforts to fill existing gaps and design health policies targeting vulnerable populations, such as children, should be intensified to tackle the global TB burden.</sec>.

Treatment patterns with intravesical bacillus Calmette-Guérin (BCG) in patients with non-muscle-invasive bladder cancer (NMIBC): A real-world data analysis.

Treatment patterns with intravesical bacillus Calmette-Guérin (BCG) in patients with non-muscle-invasive bladder cancer (NMIBC): A real-world data analysis.

Factors Influencing Bladder Perforation during Transurethral Resection of Bladder Cancer: A Comprehensive Analysis.

Bladder perforation (BP) is one of the important complications during transurethral resection of bladder tumour (TURBT). Additionally, multiple factors can contribute to BP. Here, we investigated the rates of BP, specifically in variant histology of bladder cancer (BC), and examined the clinical follow-up of relevant patients. Of the 797 patients who underwent TURBT between 2015 and 2023, they were divided into two groups according to BP during the operation. Group 1 (n = 744) consisted of patients without BP, whereas Group 2 (n = 53) consisted of patients with BP. Demographic, operative, postoperative and follow-up data were investigated and analysed. Groups were examined in terms of causes of BP. Significance was set at p < 0.05. A significantly higher rate of BP was found in patients operated with bipolar energy (p = 0.027) than in their counterparts. In multivariable analysis, the presence of the obturator reflex during TURBT was significantly associated with an increased risk of BP (p < 0.001). We observed a statistically significant increase in the rate of BP in patients with a history of previous intravesical Bacillus Calmette-Guérin (BCG) therapy (p = 0.023). Variant histology was reported in 32 patients (4%). However, we could not find any statistically significant relationship between the development of BP and the variant histology of BC (p = 0.641). Multiple factors can affect BP during TURBT. Understanding the factors associated with BP is crucial for improving patient safety and outcomes. According to the results of the present study, the energy source, the presence of obturator reflex during TURBT and intravesical BCG therapy may increase BP. Nevertheless, the presence of variant histology was not significantly associated with BP.

Adjuvant or rescue disitamab vedotin (RC48-ADC) for high-risk non-muscle invasive bladder cancer with HER2 overexpression: A phase II multi-center study.

TPS4625 Background: Non-muscle invasive bladder cancer (NMIBC) comprises approximately three-quarters of newly diagnosed cases of bladder cancer. Based on the risk of disease progression, NMIBC is categorized into low, intermediate, and high risk, with high-risk NMIBC patients facing a 5-year disease progression rate of up to 40%. The current standard treatment for high-risk NMIBC involves transurethral resection of the bladder tumor (TURBT) combined with intravesical Bacillus Calmette-Guérin (BCG) instillation as adjuvant therapy. In cases of BCG instillation treatment failure, the standard approach is radical cystectomy. Multiple studies have reported HER2 positivity in 20-44% of NMIBC cases, and HER2 overexpression (immunohistochemistry ≥2+) is closely linked to the progression and adverse prognosis of bladder cancer. Consequently, HER2 may serve as a novel therapeutic target for bladder cancer. Disitamab Vedotin (DV; RC48-ADC) is an antibody-drug conjugate (ADC) comprising a fully humanized HER2-directed monoclonal antibody conjugated to monomethyl auristatin E (MMAE) via a protease-cleavable mc-vc linker. Results from a Phase II clinical trial (NCT03507166) suggest that Disitamab Vedotin exhibits favorable efficacy and safety in HER2-positive metastatic urothelial carcinoma patients who have previously failed chemotherapy. This clinical trial aims to investigate the efficacy and safety of RC48-ADC as adjuvant or rescue therapy for high-risk NMIBC with HER2 overexpression and to explore molecular biomarkers predicting the efficacy of RC48-ADC. Methods: This multicenter, Phase II clinical trial will enroll two cohorts: Cohort A, consisting of 52 patients undergoing first-line adjuvant therapy, and Cohort B, with 25 patients receiving rescue therapy after BCG instillation failure, both exhibiting HER2 overexpression in high-risk NMIBC. Following the Simon two-stage optimal design, the first stage will involve enrolling 19 patients in Cohort A and 12 patients in Cohort B. After safety and baseline assessments, both cohorts will undergo six cycles of treatment with RC48-ADC (120 mg intravenous infusion every two weeks), totaling 12 weeks of treatment. Primary endpoints include safety, 12-month recurrence-free rate (Cohort A), and 3-month clinical complete response rate (Cohort B). Secondary endpoints encompass the 6-month recurrence-free rate (Cohort A), duration of response (Cohort B), recurrence-free survival, progression-free survival, overall survival, and quality of life (assessed through eEuroQoL EQ-5D and FACT-BI). Additionally, exploratory endpoints will investigate the relationship between biomarkers in tumor tissues, blood, and urine, and treatment efficacy. Clinical trial information: NCT05996952 .

Bacillus Calmette-Guerin (BCG) utilization and treatment (Tx) patterns in Chinese patients (pts) with non-muscle invasive bladder cancer (NMIBC): Results from a national urologist survey.

Bacillus Calmette-Guerin (BCG) utilization and treatment (Tx) patterns in Chinese patients (pts) with non-muscle invasive bladder cancer (NMIBC): Results from a national urologist survey.

The impact of living conditions and health interventions on tuberculosis, Denmark, 1876 to 2022.

BackgroundDenmark possesses an exceptional historical data collection on tuberculosis (TB) from 1876 to the present, providing a unique opportunity to assess TB epidemiology over 147 years in Denmark.AimOur aim was to describe the TB disease burden in Denmark in relation to historical events, living conditions and health interventions during the past 147 years.MethodsWe performed a nationwide register-based ecological study including all persons with TB in Denmark from 1876 through 2022, correlating the TB incidence to social, economic and health indicators.ResultsIn Denmark, the overall TB incidence and mortality declined markedly over the past 147 years, only marginally influenced by specific TB interventions such as sanatoria, Bacillus Calmette-Guèrin (BCG) vaccination, mass screenings and antibiotics. Parallel to this decline, the country experienced improved living conditions, as illustrated by decreased infant mortality and increased life expectancy and wealth. In 1978, Denmark became a low-incidence country for TB with risk groups predominantly affected, and with a continuous change in demographics towards fewer Danish-born cases and relatively more migrant cases.ConclusionsThe decline over time in TB incidence and mortality in Denmark preceded specific TB interventions and can, first of all, be attributed to improved living conditions. TB has now become a rare disease in Denmark, predominantly occurring in particular risk groups. Future elimination of TB will require a combination of specific health interventions in these risk groups combined with a continued focus on improving socioeconomic status and living conditions.

Antitumor mechanisms of OncoTherad (MRB-CFI-1) nanoimmunotherapy involving monoamine oxidases: Clinical implications in BCG-unresponsive non-muscle invasive bladder cancer.

e14597 Background: Bacillus Calmette-Guérin (BCG) immunotherapy has been the gold standard treatment for non-muscle invasive bladder cancer (NMIBC) for nearly half a century. However, many high-risk patients experience recurrence, including those who progress and eventually become unresponsive to BCG. The emergence of new immunotherapeutic agents has revolutionized the treatment of various tumor types, including urothelial carcinoma. In this context, our research group has developed OncoTherad (MRB-CFI-1) immunotherapy, which has shown promising results in cancer treatment, particularly in NMIBC. Given the inherent complexity of the immune response, patient selection and the development of biomarkers to guide the identification of individuals who will derive the greatest benefit from a specific immunotherapy remain crucial. Over the past years, several studies have demonstrated the upregulation of monoamine oxidases (MAOs) in tumor progression and metastasis. Therefore, the objectives of this present study were to characterize the effects of OncoTherad (MRB-CFI-1) on the modulation of MAOs (MAO-A and MAO-B) in the bladder of patients with BCG-unresponsive NMIBC. Methods: A total of 40 bladder biopsies from patients with BCG-unresponsive NMIBC treated with OncoTherad (MRB-CFI-1) were collected and analyzed from Paulínia Municipal Hospital (HMP). These samples were then divided into two groups (n=20 per group): Group 1 (biopsy before OncoTherad treatment) and Group 2 (biopsy after OncoTherad treatment). Subsequently, the samples underwent immunohistochemical analyses for MAO-A and MAO-B. The retrospective anonymous study was approved by the local ethics committee (Clinical Trial: RBR-6swqd2). Results: Our results demonstrated high immunoreactivities for both MAO-A and MAO-B in the bladder tumor microenvironment prior to OncoTherad (MRB-CFI-1) treatment, confirming that the pattern reported in literature studies can also be observed in NMIBC. Total immunoreactivities for MAO-A did not differ statistically between bladder biopsies of Groups 1 and 2, indicating that this treatment does not interfere with the action of MAO-A in bladder tissue. In contrast, immunoreactivities for MAO-B were significantly lower (p&lt;0.05) in the Group 2 when compared to Group 1 suggesting that this immunotherapy reversed the immunosuppressive state and tumor progression induced by MAO-B. Conclusions: Taken together, our results support the use of MAO-B as a biomarker for clinical response to OncoTherad (MRB-CFI-1) immunotherapy.

Lycopene alleviates BCG-induced depressive phenotypes in mice by disrupting 5-HT3 receptor – IDO1 interplay in the brain

The 5-HT3 receptor and indoleamine 2,3-dioxygenase 1 (IDO1) enzyme play a crucial role in the pathogenesis of depression as their activation reduces serotonin contents in the brain. Since molecular docking analysis revealed lycopene as a potent 5-HT3 receptor antagonist and IDO1 inhibitor, we hypothesized that lycopene might disrupt the interplay between the 5-HT3 receptor and IDO1 to mitigate depression. In mice, the depression-like phenotypes were induced by inoculating Bacillus Calmette-Guerin (BCG). Lycopene (intraperitoneal; i.p.) was administered alone or in combination with 5-HT3 receptor antagonist ondansetron (i.p.) or IDO1 inhibitor minocycline (i.p.), and the behavioral screening was performed by the sucrose preference test, open field test, tail suspension test, and splash test which are based on the different principles. Further, the brains were subjected to the biochemical analysis of serotonin and its precursor tryptophan by the HPLC. The results showed depression-like behavior in BCG-inoculated mice, which was reversed by lycopene administration. Moreover, prior treatment with ondansetron or minocycline potentiated the antidepressant action of lycopene. Minocycline pretreatment also enhanced the antidepressant effect of ondansetron indicating the regulation of IDO1 activity by 5-HT3 receptor-triggered signaling. Biochemical analysis of brain samples revealed a drastic reduction in the levels of tryptophan and serotonin in depressed animals, which were restored following treatment with lycopene and its combination with ondansetron or minocycline. Taken together, the data from molecular docking, behavioral experiments, and biochemical estimation suggest that lycopene might block the 5-HT3 receptor and consequently inhibit the activity of IDO1 to ameliorate BCG-induced depression in mice.

Interim results from a phase II study of tislelizumab combined with radiotherapy as bladder-preserving treatment for patients with high-risk non-muscle-invasive bladder cancer (HR NMIBC) unresponsive to bacillus Calmette-Guerin (BCG).

Interim results from a phase II study of tislelizumab combined with radiotherapy as bladder-preserving treatment for patients with high-risk non-muscle-invasive bladder cancer (HR NMIBC) unresponsive to bacillus Calmette-Guerin (BCG).

Neuropathological lesions in intravenous BCG-stimulated K18-hACE2 mice challenged with SARS-CoV-2

In the wake of the COVID-19 pandemic caused by SARS-CoV-2, questions emerged about the potential effects of Bacillus Calmette-Guérin (BCG) vaccine on the immune response to SARS-CoV-2 infection, including the neurodegenerative diseases it may contribute to. To explore this, an experimental study was carried out in BCG-stimulated and non-stimulated k18-hACE2 mice challenged with SARS-CoV-2. Viral loads in tissues determined by RT-qPCR, histopathology in brain and lungs, immunohistochemical study in brain (IHC) as well as mortality rates, clinical signs and plasma inflammatory and coagulation biomarkers were assessed. Our results showed BCG-SARS-CoV-2 challenged mice presented higher viral loads in the brain and an increased frequency of neuroinvasion, with the greatest differences observed between groups at 3–4 days post-infection (dpi). Histopathological examination showed a higher severity of brain lesions in BCG-SARS-CoV-2 challenged mice, mainly consisting of neuroinflammation, increased glial cell population and neuronal degeneration, from 5 dpi onwards. This group also presented higher interstitial pneumonia and vascular thrombosis in lungs (3–4 dpi), BCG-SARS-CoV-2 mice showed higher values for TNF-α and D-dimer values, while iNOS values were higher in SARS-CoV-2 mice at 3–4 dpi. Results presented in this study indicate that BCG stimulation could have intensified the inflammatory and neurodegenerative lesions promoting virus neuroinvasion and dissemination in this experimental model. Although k18-hACE2 mice show higher hACE2 expression and neurodissemination, this study suggests that, although the benefits of BCG on enhancing heterologous protection against pathogens and tumour cells have been broadly demonstrated, potential adverse outcomes due to the non-specific effects of BCG should be considered.

Immune Response to the Recombinant Apa Protein from Mycobacterium tuberculosis Expressed in Streptomyces lividans After Intranasal Administration in Mice. Induction of Protective Response to Tubercle Bacillus Aerosols Exposure

Identifying and evaluating potential vaccine candidates has become one of the main objectives to combat tuberculosis. Among them, mannosylated Apa antigen from Mycobacterium tuberculosis and the non-mannosylated protein expressed in Escherichia coli, have been studied. Although both proteins can induce a protective response in mice, it has been considered that native protein can be dispensed. In this work, we study the protective response induced by Apa expressed in E. coli and in Streptomyces lividans. The latter, like native is secreted as a double band of 45/47 kDa, however, only its 47 kDa band is mannosylated. Both antigens and BCG were intranasal administrated in mice, and animals were then challenged by aerosol with M. tuberculosis H37Rv. The results showed that both, Apa from S. lividans and E. coli conferred statistically significantly protection to animals compared to controls. The cytokine immune response was studied by an immunoassay after animals’ immunization, revealing that Apa from S. lividans induced a statistically significant proliferation of T cell, as well as the expression of IFN-γ, IL-1β, IL-17 and IL-10. In contrast, non-proliferation was obtained with non-mannosylated protein, but induction of IL-12 and IL-17 was observed. Together, these results demonstrate that both proteins were able to modulate a specific immune response against M. tuberculosis, that could be driven by different mechanisms possibly associated with the presence or not of mannosylation. Furthermore, stimulation of cells from BCG-vaccinated animals with the proteins could be an important tool, to help define the use of a given subunit-vaccine after BCG vaccination.

Potential biomarkers for evaluating the BCG vaccination response based on humoral immunity

BackgroundThe current prophylactic tuberculosis vaccine Bacille Calmette-Guérin (BCG), was derived in the 1920s, but the humoral immune responses induced by BCG vaccination have not been fully elucidated to date. In this study, our aim was to reveal the profiles of antibody responses induced by BCG vaccination in adults and identify the potential biomarkers for evaluating the BCG vaccination response. MethodsProteome microarrays were performed to reveal the serum profiles of antibody responses induced by BCG vaccination in adults. ELISA was used to validate the potential biomarkers in validation cohort (79 healthy controls and 58 BCG-vaccinated subjects). Then combined panel was established by logistic regression analysis based on OD values of potential biomarkers. ResultsMultiple antigens elicited stronger serum IgG or IgM antibody responses in BCG vaccinated subjects than healthy subjects at 12 weeks post BCG vaccination; among the antigens, Rv0060, Rv2026c and Rv3379c were further verified using 137 serum samples and presented the moderate performance in assessment of the BCG vaccination response by receiver operating characteristic analysis. Furthermore, a combined panel exhibited an improved AUC of 0.923, and the sensitivity and specificity were 77.59 % and 91.14 %, respectively. In addition, the antibody response against Rv0060, Rv2026c and Rv3379c was related to the clinical background to a certain extent. ConclusionsThe novel antigens identified in our study could offer better knowledge towards developing a more efficacious vaccine based on humoral immune responses, and they could be potential biomarkers in assessments of BCG vaccination responses.

Determination of immunisation status of children between 2-5 years of age who attending to teaching institute with concern to both national immunization schedule and optional vaccines

Background: In order to know the causes for non-immunisation, search for societal reasons for primary immunisation along with evaluating coverage. Aim of this current study is to determine the immunisation status of children between 2-5 years of age who are attending teaching health care centre with concern to both National Immunisation Schedule and Optional vaccines. Methods: Study analysed the children's immunisation status, factors affecting their immunisation coverage, and reasons for partial or incomplete immunisation. The information was obtained from the parents using a questionnaire. Information such as socio-demographic variables, immunisation status, causes of their partial immunisation and lack of immunisation. The "vaccination card and the recall" approach was used to determine the recipient's immunisation status. Results: Study found that 70.4% of children had received all recommended vaccinations. Lack of information and ignorance are significant contributors to under-immunization. Other statistically significant contributing factors for the low immunisation coverage include female gender, rural background, low socioeconomic status, born at home, lower mother age, and being from a joint household. BCG vaccination coverage was higher than pentavalent vaccine coverage, probably because of multiple doses needed. Only 77% of kids received vitamin A solution. Conclusions: Paediatrician should mention the next vaccination date and dose at each appointment in order to lower the vaccination dropouts. Parents should be informed regarding the date of vaccination of their child through SMS message, calls, and social media groups.

Efficacy of BCG for non-muscle invasive bladder cancer following nephroureterectomy for upper tract urothelial carcinoma

PurposeTo evaluate the efficacy of intravesical (IVe) Bacillus Calmette-Guerin (BCG) to treat non-muscle invasive bladder cancer (NMIBC) recurrences in patients who have previously undergone nephroureterectomy for upper tract urothelial carcinoma (UTUC). MethodsWe performed a single institution retrospective review of patients who underwent nephroureterectomy for UTUC from 2009 to 2021. Patients who subsequently developed NMIBC treated with transurethral resection followed by IVe BCG were included in the study group. A control cohort was formed by retrospective review of patents with primary NMIBC treated with BCG during the same period. Patients in the control cohort were matched by stage of bladder cancer at a 2:1 ratio of control to study subjects. Demographic data, pathology of bladder tumors prior to and following BCG, use of maintenance BCG (mBCG), time to recurrence, time to progression, progression to cystectomy, and progression to metastatic disease were collected on all patients. Descriptive statistics were utilized to compare the 2 groups. The primary outcome was progression to muscle invasive disease. Secondary outcomes included intravesical recurrence free survival, disease free survival, and progression to metastatic disease. Univariable and multivariable logistic regression analysis was performed to elucidate independent variables associated with bladder tumor recurrence. Multivariable Cox regression analysis was used to assess the impact of prior UTUC on time to bladder tumor recurrence. ResultsOne-hundred and ninety-one patients underwent nephroureterectomy at our institution from 2009 to 2021 for UTUC. Twenty-five patients were identified to have subsequently developed NMIBC recurrences treated with inductions BCG. The control group was comprised of 50 patients with primary NMIBC matched by stage of bladder cancer for which BCG was indicated in the study group. Median (interquartile range [IQR]) follow-up was significantly longer in the control group relative to the study group (64.8 [50.1-85.6] vs 25 months [17-35]; P = 0.001). There were no significant differences in demographics between the study and control groups. The rate of progression to muscle invasive disease was 17% vs 0% in the study group and control group respectively (P = 0.0521). History of UTUC was associated with increased risk of intravesical bladder tumor recurrence post BCG on multivariable analysis (HR 2.5; P = 0.017) and Kaplan Meier survival analysis (P = 0.039). The mean time to bladder tumor recurrence after treatment with BCG was significantly worse in the study group at (7.9 vs. 23.9 months; P = 0.0322). Similarly, the rate of progression to metastatic disease was worse in the study group (24% vs 2%; P = 0.0047). Overall disease-free survival was also noted to be significantly worse on Kaplan Meier survival analysis in the study group (P = 0.0074). No statistically significant differences in the stage grade of bladder tumor recurrence, grade of bladder tumor recurrence, or rate of progression to cystectomy were identified. ConclusionsOur study suggests reduced efficacy of BCG for NMIBC in patients with a history of UTUC. Patients in this population should be counseled accordingly. Research into alternative treatments for bladder tumor recurrence and more aggressive prophylactic regimens after nephroureterectomy for prevention of bladder tumor recurrence in this population is encouraged.

Early experience with sequential intravesical gemcitabine and docetaxel for micropapillary variant non-muscle invasive bladder cancer

BackgroundGuidelines lack clear recommendations regarding conservative management of micropapillary (MP) variant non-muscle invasive bladder cancer (NMIBC). Bladder-sparing therapy using intravesical Bacillus Calmette-Guerin (BCG) has been reported although there are concerns regarding recurrence and progression with this approach. Due to the ongoing BCG shortage, we have utilized sequential intravesical gemcitabine and docetaxel (Gem/Doce) as primary therapy for NMIBC, including some cases with limited MP urothelial carcinoma (MPUC). To compare oncologic outcomes of patients with non-muscle invasive MPUC and conventional UC treated with Gem/Doce. MethodsA secondary analysis of 138 patients with high-risk NMIBC treated with intravesical Gem/Doce from January 2011 to December 2021 was performed. Oncologic outcomes were compared in patients with or without MPUC using the Kaplan-Meier method. ResultsMedian follow-up (f/u) for all patients was 23 months (IQR 13–34). There were 129 patients with pure UC and 9 with MPUC. In those with MPUC, all were high-grade (HG), 8/9 were stage T1, 7/9 had a focal MP component (extent < 10%), 3/9 had concomitant CIS, and 2/9 had lymphovascular invasion. All MPUC tumors were re-resected, and 4 had T0, 3 had T1 HG, 1 had Ta HG, 1 had carcinoma in situ (CIS); none had residual MP or LVI tumors before Gem/Doce treatment. The 24-month high-grade recurrence-free survival was 89% and 80% in patients with MPUC and pure UC, respectively. Survival outcomes did not significantly differ between patients with and without MPUC. Four patients with MPUC experienced recurrent NMIBC after Gem/Doce, and all were treated successfully with rescue sequential intravesical valrubicin and docetaxel (Val/Doce). Pathology of these four recurrent patients revealed more aggressive histologic features in the original tumor including: multifocal tumor (3/4), T1 HG disease (4/4), concomitant CIS (2/4), and moderate MP variant extent (30%) (1/4). No patient with MPUC underwent cystectomy, experienced progression, or died at last follow-up (median f/u of 43 months). ConclusionsGem/Doce with Val/Doce rescue appears to have activity against carefully selected non-muscle invasive MPUC with favorable histology. Larger prospective trials are needed to validate these results.

Revisiting Bacille Calmette‐Guérin revaccination strategies: timing of immunization, Mycobacterium tuberculosis and non‐tuberculous mycobacteria infections, strain potency and standardization of randomized controlled trials

AbstractThe persistent threat of tuberculosis (TB) on a global scale hasprompted a reevaluation of preventive strategies, with a particular focus onthe Bacille Calmette‐Guérin (BCG) vaccine's role in revaccination. Theresurgence underscores an urgent need for enhanced measures, prompting acritical examination of BCG revaccination strategies. Drawing from the researchof Paulo Cesar Pereira dos Santos and a synthesis of randomized controlledtrials (RCTs), this review identifies key considerations for refining BCGrevaccination's efficacy against Mycobacterium tuberculosis (MTB) andTB. The main body of this review integrates four principal domains essentialfor optimizing BCG revaccination: the timing of revaccination, the assessmentof various BCG strains, the evaluation of the vaccine's effectiveness on MTBand non‐tuberculous mycobacteria (NTM) strains, and the enhancement of RCTmethodologies. Determining the optimal revaccination timing is paramount forbolstering immunity, especially in regions with high TB prevalence. Theanalysis of different BCG strains provides insights into strain‐specificimmunogenicity, informing vaccine deployment strategies. Additionally,understanding the vaccine's impact on a range of mycobacterial infections iscrucial for its broader application in various microbial contexts. The reviewemphasizes the refinement of RCT designs to ensure robust and consistentoutcomes, facilitating the reproducibility of results in diverse settings. Itproposes a strategy that not only suggests modifications to revaccinationpractices to increase global TB prevention effectiveness but also calls forcontinuous research to improve BCG revaccination methodologies. The paperadvocates for a standardized, evidence‐driven approach to global TB preventionthat takes into account regional epidemiological differences. In conclusion,this review significantly contributes to the discourse on TB prevention,advocating for evidence‐based, standardized approaches that could potentiallytransform the role of BCG revaccination in global TB prevention efforts. Thefindings support current initiatives aimed at developing policies based onsolid evidence, ensuring the scientific integrity and practical relevance ofBCG revaccination strategies.

Childhood vaccination trends during 2019 to 2022 in Tanzania and the impact of the COVID-19 pandemic

ABSTRACT The COVID-19 pandemic has significantly disrupted healthcare systems at all levels globally, notably affecting routine healthcare services, such as childhood vaccination. This study examined the impact of these disruptions on routine childhood vaccination programmes in Tanzania. We conducted a longitudinal study over four years in five Tanzanian regions: Mwanza, Dar es Salaam, Mtwara, Arusha, and Dodoma. This study analyzed the trends in the use of six essential vaccines: Bacille Calmette-Guérin (BCG), bivalent Oral Polio Vaccine (bOPV), Diphtheria Tetanus Pertussis, Hepatitis-B and Hib (DTP-HepB-Hib), measles-rubella (MR), Pneumococcal Conjugate Vaccine (PCV), and Rota vaccines. We evaluated annual and monthly vaccination trends using time-series and regression analyses. Predictive modeling was performed using an autoregressive integrated moving average (ARIMA) model. A total of 32,602,734 vaccination events were recorded across the regions from 2019 to 2022. Despite declining vaccination rates in 2020, there was a notable rebound in 2021, indicating the resilience of Tanzania’s immunization program. The analysis also highlighted regional differences in vaccination rates when standardized per 1000 people. Seasonal fluctuations were observed in monthly vaccination rates, with BCG showing the most stable trend. Predictive modeling of BCG indicated stable and increasing vaccination coverage by 2023. These findings underscore the robustness of Tanzania’s childhood immunization infrastructure in overcoming the challenges posed by the COVID-19 pandemic, as indicated by the strong recovery of vaccination rates post-2020. We provide valuable insights into the dynamics of vaccination during a global health crisis and highlight the importance of sustained immunization efforts to maintain public health.

Late in the US pandemic, multi-dose BCG vaccines protect against COVID-19 and infectious diseases

The Bacillus Calmette-Guérin vaccine has many off-target benefits, including protection from diverse infectious diseases. As SARS-CoV-2 evolved, COVID-19 disease became more transmissible and less lethal. In this Phase III double-blinded, placebo-controlled trial conducted late in the pandemic, we tested at-risk US adults with type 1 diabetes if multi-dose BCG protected against COVID-19 and other infectious disease, co-primary outcomes. From April 2021 to November 2022, Tokyo-strain BCG vaccines provided significant protection against COVID-19 disease (p= 0.023) and strong platform protection against all infectious diseases (p<0.0001). Over the course of the study, commercial COVID-19 vaccines were rolled out, most of which were mRNA-based. In contrast to the protection afforded by BCG, as reported by others, COVID-19 mRNA vaccine alone provided no protection from COVID-19 disease (p= 0.43). BCG vaccination efficacy was unaffected by concurrent COVID-19 vaccinations; COVID-19 vaccines neither helped nor hindered BCG protection.