A bispecific glycopeptide spatiotemporally regulates tumor microenvironment for inhibiting bladder cancer recurrence.

Up to 75% of bladder cancer patients suffer from recurrence due to postoperative tumor implantation. However, clinically used Bacillus Calmette-Guerin (BCG) treatment failed to inhibit the recurrence. Here, we report a bispecific glycopeptide (bsGP) that simultaneously targets CD206 on tumor-associated macrophages (TAMs) and CXCR4 on tumor cells. bsGP repolarizes protumoral M2-like TAMs to antitumor M1-like that mediated cytotoxicity and T cell recruitment. Meanwhile, bsGP is cleaved by the MMP-2 enzyme to form nanostructure for the long-term inhibition of CXCR4 downstream signaling, resulting in reduced tumor metastasis and promoted T cell infiltration. In orthotopic bladder tumor models, bsGP reduced the postoperative recurrence rate to 22%. In parallel, the recurrence rates of 89 and 78% were treated by doxycycline and BCG used in clinic, respectively. Mechanistic studies reveal that bsGP reduces the matrix microenvironment barrier, increasing the spatially redirected CD8+ T cells to tumor cells. We envision that bis-targeting CD206 and CXCR4 may pave the way to inhibit tumor metastasis and recurrence.

[Knockdown of Wnt7a inhibits BCG induced autophagy in mouse alveolar epithelial cells].

Objective To investigate the regulatory effect of wingless gene 7a (Wnt7a) on Bacille Calmette Guerin (BCG) induced autophagy in alveolar epithelial cells. Methods The alveolar epithelial cells of TC-1 mice were treated with interfering Wnt7a lentivirus and BCG alone or together in four groups, namely, small interfering RNA control (si-NC) group, si-NC combined with BCG group, Wnt7a small interfering RNA (si-Wnt7a) group, and si-Wnt7a combined with BCG group. The expressions of Wnt7a, microtubule associated protein 1 light chain 3 (LC3), P62, and autophagy related gene 5 (ATG5) were detected by Western blot analysis, and the distribution of LC3 was detected by immunofluorescence cytochemical staining. Results Compared with those in the si-NC group, Wnt7a, ATG5 and LC3 expressions increased and green fluorescent spots of LC3 significantly increased in the BCG infected TC-1 cells; the expressions of Wnt7a, LC3, P62, and ATG5 and green fluorescent spots of LC3 significantly decreased in the si-Wnt7a combined with BCG group comparing with those in the si-NC combined with BCG group. Conclusion Knocking down Wnt7a inhibits BCG induced autophagy in mouse alveolar epithelial cells.

The impact of circadian rhythm on Bacillus Calmette-Guérin vaccination effects on SARS-CoV-2 infections.

Background and objective: A recent study has suggested that circadian rhythm has an important impact on the immunological effects induced by Bacillus Calmette-Guérin (BCG) vaccination. The objective of this study was to evaluate whether the timing of BCG vaccination (morning or afternoon) affects its impact on severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infections and clinically relevant respiratory tract infections (RTIs). Methods: This is a post-hoc analysis of the BCG-CORONA-ELDERLY (NCT04417335) multicenter, placebo-controlled trial, in which participants aged 60 years and older were randomly assigned to vaccination with BCG or placebo, and followed for 12 months. The primary endpoint was the cumulative incidence of SARS-CoV-2 infection. To assess the impact of circadian rhythm on the BCG effects, participants were divided into four groups: vaccinated with either BCG or placebo in the morning (between 9:00h and 11:30h) or in the afternoon (between 14:30h and 18:00h). Results: The subdistribution hazard ratio of SARS-CoV-2 infection in the first six months after vaccination was 2.394 (95% confidence interval [CI], 0.856-6.696) for the morning BCG group and 0.284 (95% CI, 0.055-1.480) for the afternoon BCG group. When comparing those two groups, the interaction hazard ratio was 8.966 (95% CI, 1.366-58.836). In the period from six months until 12 months after vaccination cumulative incidences of SARS-CoV-2 infection were comparable, as well as cumulative incidences of clinically relevant RTI in both periods. Conclusion: Vaccination with BCG in the afternoon offered better protection against SARS-CoV-2 infections than BCG vaccination in the morning in the first six months after vaccination.

Multisystem inflammatory syndrome in children associated with Bacille Calmette-Guérin scar: a case presentation.

BACKGROUND: During Coronavirus disease of 2019 (COVID-19) pandemic, the WHO reported a noticeable increase in Kawasaki disease prevalence in countries where Kawasaki disease is rare. This newly seen disease, unlike typical Kawasaki disease, tends to appear at a later age, has prominent gastrointestinal findings, higher rates of myocarditis and coronary artery involvement and a greater need for admission to the intensive care unit (ICU). Induration of the Bacillus Calmette-Guerin (BCG) scar is a rare finding seen in multisystem inflammatory syndrome (MIS-C). This is the second reported case of erythema and induration of the BCG scar in a 1-year-old boy with MIS-C. CASE PRESENTATION: The Arabic boy presented with high resistant fever, nausea/vomiting, diarrhea, erythematous lips, and conjunctivitis. He later developed induration of his BCG scar, diffuse rash and desquamation on fingers and toes. He had a history of COVID-19 exposure as his IgG antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were positive. Based on his clinical findings and repeated lab results, he was diagnosed with MIS-C with Kawasaki features and treated with intravenous immune globulin (IVIG) followed by methylprenisolone and aspirin. CONCLUSIONS: Reaction at the BCG inoculation site is not a diagnostic criteria for Kawasaki, but it is seen clinically in 30-50% of the patients. We report the case of a 1-year-old boy diagnosed with MIS-C presenting with erythema and induration of BCG scar. Further studies are needed to explore this clinical presentation, especially in the countries that have BCG vaccination programs, and to determine the mechanisms of MIS-C.

Effects of Ballistocardiogram Peak Detection Jitters on the Quality of Heart Rate Variability Features: A Simulation-Based Case Study in the Context of Sleep Staging.

Heart rate variability (HRV) features support several clinical applications, including sleep staging, and ballistocardiograms (BCGs) can be used to unobtrusively estimate these features. Electrocardiography is the traditional clinical standard for HRV estimation, but BCGs and electrocardiograms (ECGs) yield different estimates for heartbeat intervals (HBIs), leading to differences in calculated HRV parameters. This study examines the viability of using BCG-based HRV features for sleep staging by quantifying the impact of these timing differences on the resulting parameters of interest. We introduced a range of synthetic time offsets to simulate the differences between BCG- and ECG-based heartbeat intervals, and the resulting HRV features are used to perform sleep staging. Subsequently, we draw a relationship between the mean absolute error in HBIs and the resulting sleep-staging performances. We also extend our previous work in heartbeat interval identification algorithms to demonstrate that our simulated timing jitters are close representatives of errors between heartbeat interval measurements. This work indicates that BCG-based sleep staging can produce accuracies comparable to ECG-based techniques such that at an HBI error range of up to 60 ms, the sleep-scoring error could increase from 17% to 25% based on one of the scenarios we examined.

Wearable Dual-Signal NH3 Sensor with High Sensitivity for Non-invasive Diagnosis of Chronic Kidney Disease.

NH3 gas in human exhaled breath contains abundant physiological information related to human health, especially chronic kidney disease (CKD). Unfortunately, up to now, most wearable NH3 sensors show inevitable defects (low sensitivity, easy to be interfered by the environment, etc.), which may lead to misdiagnosis of CKD. To solve the above dilemma, a nanoporous, heterogeneous, and dual-signal (optical and electrical) wearable NH3 sensor mask is developed successfully. More specifically, a polyacrylonitrile/bromocresol green (PAN/BCG) nanofiber film as a visual NH3 sensor and a polyacrylonitrile/polyaniline/reduced graphene oxide (PAN/PANI/rGO) nanofiber film as a resistive NH3 sensor are constructed. Due to the high specific surface area and abundant NH3 binding sites of these two nanofiber films, they exhibit good NH3 sensing performance. However, although the visual NH3 sensor (PAN/BCG nanofiber film) is simple without the need of any detecting facilities and quite stable when temperature and humidity change, it shows poor sensitivity and resolution. In comparison, the resistive NH3 sensor (PAN/PANI/rGO nanofiber film) is of high sensitivity, fast response, and good resolution, but its electrical signal is easily interfered by the external environment (such as humidity, temperature, etc.). Considering that the sensing principles between a visual NH3 sensor and resistive NH3 sensor are significantly different, a wearable dual-signal NH3 sensor containing both a visual NH3 sensor and resistive NH3 sensor is further explored. Our data prove that the two sensing signals in this dual-signal NH3 sensor mask can not only work well without interference with each other but also complement each other to improve the sensing accuracy, indicating its potential application in non-invasive diagnosis of CKD.

Berberine governs NOTCH3/AKT signaling to enrich lung-resident memory T cells during tuberculosis.

Stimulation of naïve T cells during primary infection or vaccination drives the differentiation and expansion of effector and memory T cells that mediate immediate and long-term protection. Despite self-reliant rescue from infection, BCG vaccination, and treatment, long-term memory is rarely established against Mycobacterium tuberculosis (M.tb) resulting in recurrent tuberculosis (TB). Here, we show that berberine (BBR) enhances innate defense mechanisms against M.tb and stimulates the differentiation of Th1/Th17 specific effector memory (TEM), central memory (TCM), and tissue-resident memory (TRM) responses leading to enhanced host protection against drug-sensitive and drug-resistant TB. Through whole proteome analysis of human PBMCs derived from PPD+ healthy individuals, we identify BBR modulated NOTCH3/PTEN/AKT/FOXO1 pathway as the central mechanism of elevated TEM and TRM responses in the human CD4+ T cells. Moreover, BBR-induced glycolysis resulted in enhanced effector functions leading to superior Th1/Th17 responses in human and murine T cells. This regulation of T cell memory by BBR remarkably enhanced the BCG-induced anti-tubercular immunity and lowered the rate of TB recurrence due to relapse and re-infection. These results thus suggest tuning immunological memory as a feasible approach to augment host resistance against TB and unveil BBR as a potential adjunct immunotherapeutic and immunoprophylactic against TB.

Epidemiology of the koch phenomenon of infants after bacillus calmette-Guerin vaccination by interferon-γ release assay status, Japan, 2013-2019.

Background: The epidemiology of infants who exhibited the Koch-like phenomenon after Bacillus Calmette-Guérin vaccination and who subsequently tested positive in interferon-γ release assay (IGRA) was compared to that of those who tested negative. The reports of pediatricians on the phenomenon to the health authorities of Japan were retrieved and analyzed. Methods: In 2013-2019, 790 infants with such events were reported with IGRA test results available, of whom 81 (10.3%) tested positive and 709 (89.7%) negative. Results: The infants who were IGRA positive did not show an increasing trend (P = 0.06, P = 0.60), whereas those who were IGRA negative showed a significantly increasing trend (P = 0.42, P = 0.0002). The infants who were IGRA positive did not exhibit seasonality, whereas those who were IGRA negative had a higher number of cases in winter than in summer. The rates of infants who were IGRA positive per 10 million live births showed a significant correlation with the tuberculosis (TB) notification rates by prefecture (P = 0.41, P = 0.004), whereas those who were IGRA negative did not (P = 0.04, P = 0.78). Conclusion: The IGRA-positive infants were distributed quite differently from those who were IGRA negative and appeared more likely to be infected with TB. Reports of pediatricians on the Koch-like phenomenon should continuously be collected as the reports reflect a risk of TB infection including TB outbreaks among infants in Japan. The reports should include IGRA test results as IGRA is more specific than tuberculin skin testing. Infants with IGRA-positive results should be followed up for 2-3 years to determine their final outcomes.

Nadofaragene Firadenovec: First Approval.

Nadofaragene firadenovec (nadofaragene firadenovec-vncg; Adstiladrin®) is a non-replicating adenoviral vector-based gene therapy developed by Ferring Pharmaceuticals for the treatment of high-risk Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle invasive bladder cancer (NMIBC). Nadofaragene firadenovec constitutes vector DNA that encodes for interferon (IFN)-α2b and is the first approved gene therapy in bladder cancer. The production of IFN-α2b by transfected urothelial cells is associated with anticancer activity, including immunostimulatory, antiangiogenic and apoptotic effects. In December 2022, nadofaragene firadenovec received its first global approval in the USA for the treatment of high-risk BCG-unresponsive NMIBC with carcinoma in situ (CIS) with or without papillary tumours in adults. This article summarizes the milestones in the development of nadofaragene firadenovec leading to this first approval for this indication.

In vitro and in silico evaluations of actinomycin X2and actinomycin D as potent anti-tuberculosis agents.

Background: Multidrug-resistant tuberculosis (MDR-TB) is one of the world's most devastating contagious diseases and is caused by the MDR-Mycobacterium tuberculosis (MDR-Mtb) bacteria. It is therefore essential to identify novel anti-TB drug candidates and target proteins to treat MDR-TB. Here, in vitro and in silico studies were used to investigate the anti-TB potential of two newly sourced actinomycins, actinomycin-X2 (act-X2) and actinomycin-D (act-D), from the Streptomyces smyrnaeus strain UKAQ_23 (isolated from the Jubail industrial city of Saudi Arabia). Methods: The anti-TB activity of the isolated actinomycins was assessed in vitro using the Mtb H37Ra, Mycobacterium bovis (BCG), and Mtb H37Rv bacterial strains, using the Microplate Alamar Blue Assay (MABA) method. In silico molecular docking studies were conducted using sixteen anti-TB drug target proteins using the AutoDock Vina 1.1.2 tool. The molecular dynamics (MD) simulations for both actinomycins were then performed with the most suitable target proteins, using the GROningen MAchine For Chemical Simulations (GROMACS) simulation software (GROMACS 2020.4), with the Chemistry at HARvard Macromolecular Mechanics 36m (CHARMM36m) forcefield for proteins and the CHARMM General Force Field (CGenFF) for ligands. Results: In vitro results for the Mtb H37Ra, BCG, and Mtb H37Rv strains showed that act-X2 had minimum inhibitory concentration (MIC) values of 1.56 ± 0.0, 1.56 ± 0.0, and 2.64 ± 0.07 µg/mL and act-D had MIC values of 1.56 ± 0.0, 1.56 ± 0.0, and 1.80 ± 0.24 µg/mL respectively. The in silico molecular docking results showed that protein kinase PknB was the preferred target for both actinomycins, while KasA and pantothenate synthetase were the least preferred targets for act-X2and act-D respectively. The molecular dynamics (MD) results demonstrated that act-X2 and act-D remained stable inside the binding region of PknB throughout the simulation period. The MM/GBSA (Molecular Mechanics/Generalized Born Surface Area) binding energy calculations showed that act-X2 was more potent than act-D. Conclusion: In conclusion, our results suggest that both actinomycins X2 and D are highly potent anti-TB drug candidates. We show that act-X2is better able to antagonistically interact with the protein kinase PknB target than act-D, and thus has more potential as a new anti-TB drug candidate.

[Levofloxacin combined with cellulase can eradicate bacille Calmette-Guerin biofilm infection].

OBJECTIVE: To investigate the inhibitory effects of levofloxacin (LEV) combined with cellulase against bacille CalmetteGuerin (BCG) biofilms in vitro. METHODS: The mature growth cycle of BCG biofilms was determined using the XTT method and crystal violet staining. BCG planktonic bacteria and BCG biofilms were treated with different concentrations of LEV and cellulose alone or jointly, and the changes in biofilm biomass were quantified with crystal violet staining. The mature BCG biofilm was then treated with cellulase alone for 24 h, and after staining with SYTO 9 and Calcofluor White Stain, the number of viable bacteria and the change in cellulose content in the biofilm were observed with confocal laser scanning microscopy. The structural changes of the treated biofilm were observed under scanning electron microscopy. RESULTS: The MIC, MBC and MBEC values of LEV determined by broth microdilution method were 4 µg/mL, 8 µg/mL and 1024 µg/mL, respectively. The combined treatment with 1/4×MIC LEV and 2.56, 5.12 or 10.24 U/mL cellulase resulted in a significant reduction in biofilm biomass (P < 0.001). Cellulase treatments at the concentrations of 10.24, 5.12 and 2.56 U/mL all produced significant dispersion effects on mature BCG biofilms (P < 0.001). CONCLUSION: LEV combined with cellulose can effectively eradicate BCG biofilm infections, suggesting the potential of glycoside hydrolase therapy for improving the efficacy of antibiotics against biofilmassociated infections caused by Mycobacterium tuberculosis.

Evaluating the cost-utility of intravesical Bacillus Calmette-Guérin versus radical cystectomy in patients with high-risk non-muscle-invasive bladder cancer in the UK.

AIMS: Approximately 75% of bladder cancer (BC) cases present as non-muscle-invasive BC (NMIBC). In patients with high-risk NMIBC, the mainstay treatment is intravesical Bacillus Calmette-Guérin (BCG), with immediate radical cystectomy (RC) as an alternative treatment option. The aim of the present study was to evaluate the cost-utility of BCG versus RC in patients with high-risk NMIBC from the UK healthcare payer perspective. MATERIALS AND METHODS: A six-state Markov model was developed that covered controlled disease, recurrence, progression to muscle-invasive BC, metastatic disease, and death. The model included adverse events of BCG and RC and monitoring and palliative care. Drug costs were obtained from the British National Formulary. Intravesical delivery, RC, and monitoring costs were sourced from the National Tariff Payment System and the literature. Utility data were obtained from the literature. Analyses were run over a 30-year time horizon, with future costs and effects discounted at 3.5% per annum. One-way and probabilistic sensitivity analyses were performed. RESULTS: The base case analysis comparing BCG with RC showed that BCG would increase life expectancy by 0.88 years versus RC, from 7.74 to 8.62 years. BCG resulted in an increase of 0.76 quality-adjusted life years (QALYs) versus RC, from 5.63 to 6.39 QALYs. Patients incurred lower lifetime costs if treated with BCG (£47,753) than with RC (£64,264). Cost savings were mainly driven by the lower cost of BCG versus RC, and palliative care costs. Sensitivity analyses showed that results were robust to assumptions. LIMITATIONS: The evidence base informing efficacy estimates of BCG is heterogeneous as different BCG administration schedules were reported in the literature, while incidence and cost data on some BCG-associated adverse events were sparse. CONCLUSIONS: Intravesical BCG led to increased QALYs and reduced costs versus RC for patients with high-risk NMIBC from the UK healthcare payer perspective.

Intravesical Bacillus Calmette-Guérin (BCG) is a recommended immunotherapy option for patients with high-risk non-muscle invasive bladder cancer (NMIBC) who have undergone transurethral resection of bladder tumor (TURBT). BCG is known for its high efficacy and good safety profile. However, current evidence on its effectiveness against other comparators such as radical cystectomy (RC) is limited, mainly because different BCG schedules are used, particularly with regard to maintenance therapy. Given this lack of evidence, we conducted the first cost-utility analysis which considers adequate BCG therapy relative to RC for the UK. We developed a Markov model that captured the effects of the intravesical BCG and RC on NMIBC, in addition to incidences of adverse events associated with either treatment. Costs of the two treatments, their administration, maintenance, and of treatments for adverse events were modelled alongside the quality-of-life effects of NMIBC, adverse events, and palliative care. We used published clinical data and UK cost data to inform our model. Our results show that BCG was associated with higher quality-adjusted life expectancy than RC and lower total costs from the healthcare system perspective. These results imply that adequate BCG immunotherapy is likely valuable for the National Healthcare System in terms of its effects on patients and indeed cost-saving relative to RC.

Bacterial Communication Coordinated Behaviors of Whole Communities to Cope with Environmental Changes.

Bacterial communication plays an important role in coordinating microbial behaviors in a community. However, how bacterial communication organizes the entire community for anaerobes to cope with varied anaerobic-aerobic conditions remains unclear. We constructed a local bacterial communication gene (BCG) database comprising 19 BCG subtypes and 20279 protein sequences. BCGs in anammox-partial nitrification consortia coping with intermittent aerobic and anaerobic conditions as well as gene expressions of 19 species were inspected. We found that when suffering oxygen changes, intra- and interspecific communication by a diffusible signal factor (DSF) and bis-(3'-5')-cyclic dimeric guanosine monophosphate (c-di-GMP) changed first, which in turn induced changes of autoinducer-2 (AI-2)-based interspecific and acyl homoserine lactone (AHLs)-based intraspecific communication. DSF and c-di-GMP-based communication regulated 455 genes, which covered 13.64% of the genomes and were mainly involved in antioxidation and metabolite residue degradation. For anammox bacteria, oxygen influenced DSF and c-di-GMP-based communication through RpfR to upregulate antioxidant proteins, oxidative damage-repairing proteins, peptidases, and carbohydrate-active enzymes, which benefited their adaptation to oxygen changes. Meanwhile, other bacteria also enhanced DSF and c-di-GMP-based communication by synthesizing DSF, which helped anammox bacteria survive at aerobic conditions. This study evidences the role of bacterial communication as an "organizer" within consortia to cope with environmental changes and sheds light on understanding bacterial behaviors from the perspective of sociomicrobiology.

Trained Immunity, BCG and SARS-CoV-2 General Outline and Possible Management in COVID-19.

The Bacillus Calmette-Guérin (BCG) vaccine has been in use for over 100 years. It protects against severe, blood-borne forms of tuberculosis. Observations indicate that it also increases immunity against other diseases. The mechanism responsible for this is trained immunity, an increased response of non-specific immune cells in repeated contact with a pathogen, not necessarily of the same species. In the following review, we present the current state of knowledge on the molecular mechanisms responsible for this process. We also seek to identify the challenges facing science in this area and consider the application of this phenomenon in managing the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic.

[Development of a flow cytometry method for detection of bovine multi-cytokines].

This study aims to develop a method to detect bovine multi-cytokines based on flow cytometry. Previously we have prepared and screened monoclonal antibodies against bovine cytokines IFN-γ, IL-2, TNF-α, IP-10 and MCP-1. These bovine cytokine monoclonal antibodies were fluorescently labeled, and the combination of antibody and cell surface molecules were used to develop the method for detecting bovine multi-cytokines. Subsequently, the developed method was used to determine the cytokine expression profile of Mycobacterium bovis BCG infected bovine peripheral blood mononuclear cells in vitro, and evaluate the cytokine expression level of peripheral blood CD4+ T cells of tuberculosis-positive cattle. The bovine multi-cytokine flow cytometry detection method can effectively determine the cytokine expression of BCG-infected bovine peripheral blood T lymphocytes. Among them, the expression levels of IFN-γ, IL-2, and TNF-α continue to increase after 40 hours of infection, while the expression levels of IP-10 and MCP-1 decreased. The combined detection of IFN-γ, IL-2, and TNF-α on CD4+ T lymphocytes in peripheral blood of cattle can effectively distinguish tuberculosis-positive and tuberculosis-negative samples. This method may facilitate evaluating the level of cellular immune response after bovine pathogen infection and vaccine injection.

Dosis reducida vs. dosis completa de BCG en el cáncer de vejiga: revisión sistemática y metaanálisis / Reduced- vs full-dose BCG in bladder cancer: a systematic review and meta-analysis

Objetivo Evaluar los resultados oncológicos y el perfil de seguridad de un régimen de Bacilo Calmette-Guérin (BCG) de dosis reducida frente a uno de dosis completa en pacientes con cáncer de vejiga no músculo infiltrante (CVNMI). Material y métodos Se realizó una revisión sistemática de acuerdo con la declaración Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Se realizaron búsquedas de estudios que analizaran los resultados oncológicos entre los regímenes de BCG con reducción de dosis y dosis completa en las bases de datos PubMed, Embase y Web of Science en enero del 2022. Resultados Diecisiete estudios que incluían a 3.757 pacientes cumplieron los criterios de inclusión. Los pacientes que recibieron reducción de dosis de BCG tuvieron tasas de recidiva significativamente mayores (OR 1,19; IC del 95%, 1,03-1,36; p = 0,02). Los riesgos de progresión a un cáncer de vejiga (CV) músculo infiltrante (OR 1,04; IC 95%, 0,83-1,32; p = 0,71), de metástasis (OR 0,82; IC 95%, 0,55-1,22; p = 0,32), de muerte por CV (OR 0,80; IC 95%, 0,57-1,14; p = 0,22) y de muerte por cualquier causa (OR 0,82; IC 95%, 0,53-1,27; p = 0,37) no fueron estadísticamente diferentes. Al restringir los análisis a ensayos controlados aleatorizados, se encontraron resultados similares. En el análisis de subgrupos, la reducción de dosis se asoció con una mayor tasa de recidiva de CV en los estudios que utilizaron solo un régimen de inducción (OR 1,70; IC 95%, 1,19-2,42; p = 0,004), lo cual no se observó cuando se empleó un régimen de mantenimiento (OR 1,07; IC 95%, 0,96-1,29; p = 0,17). En cuanto a los efectos secundarios, el esquema reducido de BCG se asoció con menos episodios de fiebre (p = 0,003) y de interrupción del tratamiento (p = 0,03). Conclusión Esta revisión no encontró ninguna asociación entre la dosis de BCG y la progresión, la metástasis y la mortalidad del CV (AU)

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

Comparison of Sequential Intravesical Gemcitabine and Docetaxel vs Bacillus Calmette-Guérin for the Treatment of Patients With High-Risk Non-Muscle-Invasive Bladder Cancer.

Importance: Due to the ongoing bacillus Calmette-Guérin (BCG) shortage, sequential intravesical gemcitabine and docetaxel has been increasingly used as first-line therapy for high-risk non-muscle-invasive bladder cancer (NMIBC). However, data directly comparing these 2 therapies are lacking. Objective: To compare the outcomes of patients with high-risk NMIBC treated with gemcitabine and docetaxel vs BCG. Design, Setting, and Participants: This retrospective cohort study was conducted from January 1, 2011, to December 31, 2021. The median (IQR) duration of follow-up was 23 (12-33) months for patients receiving gemcitabine and docetaxel and 49 (27-79) months for patients receiving BCG. All patients were treated at the University of Iowa tertiary care center. A total of 312 patients with high-risk treatment-naive NMIBC were included; 174 patients were treated with BCG therapy and 138 were treated with gemcitabine and docetaxel therapy. Exposures: After undergoing complete transurethral resection of bladder tumor, patients received either sequential intravesical gemcitabine, 1 g, and docetaxel, 37.5 mg, or 1 vial of BCG. Induction treatments were administered once per week for 6 weeks. Maintenance regimens were initiated if the patient was disease free at the first follow-up visit. Main Outcomes and Measures: The primary outcome was high-grade recurrence-free survival (RFS). Survival probabilities were estimated using the Kaplan-Meier method. Cox regression models were used to evaluate the association of covariates with outcomes. Adverse events were reported using the Common Terminology Criteria for Adverse Events, version 5. Results: Among 312 patients, the median (IQR) age was 73 (66-79) years; 255 patients (81.7%) were male and 292 (93.6%) were White. Baseline clinicopathological characteristics such as sex, smoking status, and pretreatment tumor pathology were similar between treatment groups. High-grade RFS estimates were 76% (95% CI, 69%-82%) at 6 months, 71% (95% CI, 64%-78%) at 12 months, and 69% (95% CI, 62%-76%) at 24 months in the BCG group and 92% (95% CI, 86%-95%) at 6 months, 85% (95% CI, 78%-91%) at 12 months, and 81% (95% CI, 72%-87%) at 24 months in the gemcitabine and docetaxel group. Multivariable Cox regression analyses controlled for age, sex, treatment year, and presence of carcinoma in situ revealed that treatment with gemcitabine and docetaxel was associated with better high-grade RFS (hazard ratio, 0.57; 95% CI, 0.33-0.97; P = .04) and RFS (hazard ratio, 0.56; 95% CI, 0.34-0.92; P = .02) than treatment with BCG. Induction therapy for BCG was associated with greater treatment discontinuation than induction therapy for gemcitabine and docetaxel (9.2% vs 2.9%; P = .02). Conclusions and Relevance: In this cohort study, gemcitabine and docetaxel therapy was associated with less high-grade disease recurrence and treatment discontinuation than BCG therapy. These findings suggest that, while awaiting results from an ongoing randomized clinical trial during the current BCG shortage, use of gemcitabine and docetaxel can be considered for recommendation in updated practice guidelines.

Severe persistent mycobacteria antigen stimulation causes lymphopenia through impairing hematopoiesis.

Miliary tubersculosis (TB), an acute systemic blood disseminated tuberculosis mainly caused by Mycobacterium tuberculosis (M. tuberculosis), can cause signs of lymphopenia in clinical patients. To investigate whether/how persistent mycobacteria antigen stimulation impairs hematopoiesis and the therapeutic effect of interleukin-7 (IL-7), a mouse model of Mycobacterium Bovis Bacillus Calmette-Guérin (BCG) intravenous infection with/without an additional stimulation with M. tuberculosis multi-antigen cocktail containing ESAT6-CFP10 (EC) and Mtb10.4-HspX (MH) was established. Consistent with what happened in miliary TB, high dose of BCG intravenous infection with/without additional antigen stimulation caused lymphopenia in peripheral blood. In which, the levels of cytokines IFN-γ and TNF-α in serum increased, and consequently the expression levels of transcription factors Batf2 and IRF8 involved in myeloid differentiation were up-regulated, while the expression levels of transcription factors GATA2 and NOTCH1 involved in lymphoid commitment were down-regulated, and the proliferating activity of bone marrow (BM) lineage- c-Kit+ (LK) cells decreased. Furthermore, recombinant Adeno-Associated Virus 2-mediated IL-7 (rAAV2-IL-7) treatment could significantly promote the elevation of BM lymphoid progenitors. It suggests that persistent mycobacteria antigen stimulation impaired lymphopoiesis of BM hematopoiesis, which could be restored by complement of IL-7.