Administration Of Bacillus Calmette-Guérin Research Articles

Granulomatous lymphadenitis in Taiwan: Unraveling infantile peak and Bacillus Calmette-Guérin lymphadenitis

BackgroundGranulomatous lymphadenitis, a histopathological diagnosis, often indicates infections, such as those caused by mycobacterial and fungal agents. MethodsWe conducted an analysis of 1098 granulomatous lymphadenitis cases, examining age distribution, lymph node locations, and laterality. Molecular detection of Bacillus Calmette-Guérin (BCG) was performed on archived formalin-fixed paraffin-embedded tissue specimens. ResultsOur analysis revealed a bimodal age distribution, notably with a minor peak in infants. These infantile cases predominantly featured axillary involvement, frequently occurring on the left side. Positive rates of BCG identification decreased with age: <1 year, 71%; 1–2 year, 33%; 2–3 year, 13%; 3–4 year, 0%. Remarkably, only one of the 14 cases with molecularly confirmed BCG lymphadenitis had comments regarding BCG in the pathological report. Compared with patients born after 2016 (BCG at 5–8 months), those born before 2016 (BCG at birth) developed BCG lymphadenitis at a wider age range with right skewness (before 2016, 13 ± 11 months [range, 3–33 months] vs. after 2016, 10 ± 2 months [range, 8–13 months]). Four of the 14 BCG-positive cases had congenital heart disease. Seven patients received anti-tuberculosis drugs following surgical excision. No surgical complications were reported. ConclusionsBCG lymphadenitis constitutes a distinctive minor peak within the spectrum of granulomatous lymphadenitis in Taiwan. Pathologists should consider the possibility of BCG infection, especially in cases of infantile axillary, supraclavicular, neck lymphadenopathies on the left side. Moreover, BCG administration at 5–8 months may reduce delayed-onset BCG lymphadenitis.

Longitudinal Transcription Profiling of Bladder Cancers Dictate the Response to BCG Treatment and Disease Progression.

Although the intravesical instillation of Bacillus Calmette-Guerin (BCG) is widely used as adjuvant treatment for nonmuscle-invasive bladder cancers, the clinical benefit is variable across patients, and the molecular mechanisms underlying the sensitivity to BCG administration and disease progression are poorly understood. To establish the molecular signatures that predict the responsiveness and disease progression of bladder cancers treated with BCG, we performed transcriptome sequencing (RNA-seq) for 13 treatment-naïve and 22 post-treatment specimens obtained from 14 bladder cancer patients. To overcome disease heterogeneity, we used non-negative matrix factorization to identify the latent molecular features associated with drug responsiveness and disease progression. At least 12 molecular features were present, among which the immune-related feature was associated with drug responsiveness, indicating that pre-treatment anti-cancer immunity might dictate BCG responsiveness. We also identified disease progression-associated molecular features indicative of elevated cellular proliferation in post-treatment specimens. The progression-associated molecular features were validated in an extended cohort of BCG-treated bladder cancers. Our study advances understanding of the molecular mechanisms of BCG activity in bladder cancers and provides clinically relevant gene markers for evaluating and monitoring patients.

Current Understanding of Bacillus Calmette-Guérin-Mediated Trained Immunity and Its Perspectives for Controlling Intracellular Infections.

The bacillus Calmette-Guérin (BCG) is an attenuated bacterium derived from virulent Mycobacterium bovis. It is the only licensed vaccine used for preventing severe forms of tuberculosis in children. Besides its specific effects against tuberculosis, BCG administration is also associated with beneficial non-specific effects (NSEs) following heterologous stimuli in humans and mice. The NSEs from BCG could be related to both adaptive and innate immune responses. The latter is also known as trained immunity (TI), a recently described biological feature of innate cells that enables functional improvement based on metabolic and epigenetic reprogramming. Currently, the mechanisms related to BCG-mediated TI are the focus of intense research, but many gaps are still in need of elucidation. This review discusses the present understanding of TI induced by BCG, exploring signaling pathways that are crucial to a trained phenotype in hematopoietic stem cells and monocytes/macrophages lineage. It focuses on BCG-mediated TI mechanisms, including the metabolic-epigenetic axis and the inflammasome pathway in these cells against intracellular pathogens. Moreover, this study explores the TI in different immune cell types, its ability to protect against various intracellular infections, and the integration of trained innate memory with adaptive memory to shape next-generation vaccines.

Intravenous administration of BCG in mice promotes natural killer and T cell-mediated antitumor immunity in the lung

Intravesical administration of Bacillus Calmette-Guérin (BCG) was one of the first FDA-approved immunotherapies and remains a standard treatment for bladder cancer. Previous studies have demonstrated that intravenous (IV) administration of BCG is well-tolerated and effective in preventing tuberculosis infection in animals. Here, we examine IV BCG in several preclinical lung tumor models. Our findings demonstrate that BCG inoculation reduced tumor growth and prolonged mouse survival in models of lung melanoma metastasis and orthotopic lung adenocarcinoma. Moreover, IV BCG treatment was well-tolerated with no apparent signs of acute toxicity. Mechanistically, IV BCG induced tumor-specific CD8+ T cell responses, which were dependent on type 1 conventional dendritic cells, as well as NK cell-mediated immunity. Lastly, we also show that IV BCG has an additive effect on anti-PD-L1 checkpoint inhibitor treatment in mouse lung tumors that are otherwise resistant to anti-PD-L1 as monotherapy. Overall, our study demonstrates the potential of systemic IV BCG administration in the treatment of lung tumors, highlighting its ability to enhance immune responses and augment immune checkpoint blockade efficacy.

Subcutaneous Bacillus Calmette-Guérin Administration Induces Innate Training in Monocytes in Preweaned Holstein Calves.

The bacillus Calmette-Guérin (BCG) vaccine, administered to prevent tuberculosis, is a well-studied inducer of trained immunity in human and mouse monocytes. We have previously demonstrated that aerosol BCG administration induces innate training in calves. The current study aimed to determine whether s.c. BCG administration could induce innate training, identify the cell type involved, and determine whether innate training promoted resistance to bovine respiratory syncytial virus (BRSV) infection, a major cause of bovine respiratory disease in preweaned calves. A total of 24 calves were enrolled at 1-3 d of age and blocked by age into two treatment groups (BCG, n = 12; control, n = 12). BCG was given s.c. to preweaned calves. The control calves received PBS. We observed a trained phenotype, demonstrated by enhanced cytokine production in response to invitro stimulation with LPS (TLR-4 agonist) in PBMCs and CD14+ monocytes from the BCG group 2 wk (IL-1β, p = 0.002) and 4 wk (IL-1β, p = 0.005; IL-6, p = 0.013) after BCG administration, respectively. Calves were experimentally infected via aerosol inoculation with BRSV strain 375 at 5 wk after BCG administration and necropsied on day 8 postinfection. There were no differences in disease manifestation between the treatment groups. Restimulation of bronchoalveolar lavage fluid cells isolated on day 8 after BRSV infection revealed enhanced IL-1β (p = 0.014) and IL-6 (p = 0.010) production by the BCG group compared with controls. In conclusion, results from our study show that s.c. administration of the BCG vaccine can induce trained immunity in bovine monocytes and influence cytokine production in the lung environment after BRSV infection.

Fever of Unknown Origin in a Patient Administered With Bacillus Calmette-Guérin (BCG) to Treat Urothelial Vesical Carcinoma in Situ

Koch’s Bacillus bovis (Mycobacterium bovis) was made avirulent by special culture conditions, i.e., 230 passages on medium containing potatoes treated with bile salts. It has been used mainly to prevent tuberculosis. The vaccine was named after the bacteriologist Albert Calmette and the veterinarian Camille Guérin, i.e., Bacillus Calmette-Guérin (BCG). These researchers worked at the Pasteur Institute in Lille and launched the vaccine in 1921.Recently, BCG was used also for its non-specific immunostimulant action. Intravesical administration of BCG is an adjunctive therapy for the treatment of bladder cancer, which does not invade the muscle wall.We will discuss the clinical case of a patient who had fever of unknown origin for about 2 months and was resistant to treatment with multiple lines of antibiotics.

MP08-18 ASYMPTOMATIC BACTERIURIA DOES NOT INCREASE THE RISK OF INFECTIVE COMPLICATIONS IN PATIENTS WITH NON-MUSCLE-INVASIVE BLADDER CANCER UNDERGOING INTRAVESICAL BACILLUS CALMETTE-GUERIN IMMUNOTHERAPY

You have accessJournal of UrologyCME1 Apr 2023MP08-18 ASYMPTOMATIC BACTERIURIA DOES NOT INCREASE THE RISK OF INFECTIVE COMPLICATIONS IN PATIENTS WITH NON-MUSCLE-INVASIVE BLADDER CANCER UNDERGOING INTRAVESICAL BACILLUS CALMETTE-GUERIN IMMUNOTHERAPY Antti Nummi, Pertti Nurminen, Olli Kesti, Mikael Högerman, Otto Ettala, Peter Boström, Antti Kaipia, Jukka Sairanen, and Riikka Järvinen Antti NummiAntti Nummi More articles by this author , Pertti NurminenPertti Nurminen More articles by this author , Olli KestiOlli Kesti More articles by this author , Mikael HögermanMikael Högerman More articles by this author , Otto EttalaOtto Ettala More articles by this author , Peter BoströmPeter Boström More articles by this author , Antti KaipiaAntti Kaipia More articles by this author , Jukka SairanenJukka Sairanen More articles by this author , and Riikka JärvinenRiikka Järvinen More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003223.18AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Asymptomatic bacteriuria (ABU) is common in patients with non-muscle-invasive bladder cancer (NMIBC). Even though ABU is not considered as an absolute contraindication for bacillus Calmette-Guérin (BCG) administration, many urologists prefer sterile urine or use prophylactic antibiotics prior BCG instillation, aiming to prevent acute urinary tract infection (UTI), bacterial sepsis and BCG infection. However, the use of antibiotics may potentially lead to multidrug-resistant bacterial strains, while the clinical benefit is not clear. The aim of this study was to determine whether ABU increases the risk of infective complications and whether it is justified to screen asymptomatic patients for bacteriuria before BCG instillations. METHODS: We analyzed retrospectively patients who received ≥1 BCG instillations as treatment of NMIBC in our institutions during 2009-2018. Patients had submitted urine specimen 1-7 days prior every BCG instillation. Urine cultures were recorded as no growth or the presence of bacteriuria. ABU was classified as having any positive urine culture but no dysuria or fever. Antibiotic prophylaxis prior BCG administration was recorded. Our primary endpoints were admission to hospital because of UTI, BCG toxicity and BCG infections within 2 weeks of BCG instillation. RESULTS: We analyzed 802 patients and 12 882 BCG instillations. ABU was recorded with 2 200 (17%) instillations. Antibiotics were used in 519 (21%) instillations in bacteriuria group. Hospital admission was recorded after 8 (0.3%) and 37 (0.4%) instillations in the bacteriuria and in the no growth group, respectively (p=0.9). There was no significant difference in hospital admissions between the groups with or without antibiotic prophylaxis (p=0.4). CONCLUSIONS: BCG instillation with ABU is safe and does not increase the risk of developing a symptomatic UTI or severe BCG complications. By consequence, our results do not support routine screening of asymptomatic patients for bacteriuria prior intravesical BCG treatment. Antibiotic prophylaxis should only be used with consideration. Symptomatic UTI remains contraindication for BCG instillation. Source of Funding: Finnish Association of Urology © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e101 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Antti Nummi More articles by this author Pertti Nurminen More articles by this author Olli Kesti More articles by this author Mikael Högerman More articles by this author Otto Ettala More articles by this author Peter Boström More articles by this author Antti Kaipia More articles by this author Jukka Sairanen More articles by this author Riikka Järvinen More articles by this author Expand All Advertisement PDF downloadLoading ...

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

AimsApproximately 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 methodsA 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.ResultsThe 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.LimitationsThe 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.ConclusionsIntravesical BCG led to increased QALYs and reduced costs versus RC for patients with high-risk NMIBC from the UK healthcare payer perspective.

Effect of BCG on Respiratory Complications Caused by COVID-19: A Scoping Review.

Bacillus Calmette-Guérin (BCG) has been shown to have protective effects against respiratory viruses. We conducted a scoping review of the literature to clarify the available evidence regarding the effect of BCG therapy in preventing respiratory complications of coronavirus disease 2019 (COVID-19). We searched PubMed, Embase, CENTRAL, Scopus, and Web of Science for related studies up to October 2022. In total, 35 publications and trials were included. One animal study, two observational studies, and six finalized trials measured the effect of BCG administration on respiratory complications of COVID-19. The remaining publications included eight unfinished trials, 12 ecological studies, and six observational studies that did not directly measure respiratory complications but assessed overall mortality of the disease and were included as an adjunct to our study. All trials involved vaccinating adults to protect them against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection, and measured respiratory symptoms or the need for intensive respiratory support as the primary or secondary aim of the study. One trial that exclusively included at-risk adults between 18 and 60 years old showed a decreased chance of respiratory complications as the secondary outcome of the study. Another trial that exclusively evaluated this effect on the elderly (60 years and older) as the primary aim of the study reported no protective effect against respiratory complications. The remaining literature provided mostly inconclusive evidence. The majority of the literature on the protective effect of BCG against respiratory complications of COVID-19 is inconclusive.

Highlights of the 3rd international BCG symposium: 100th anniversary of the first administration of BCG

2021 was the year of the 100th anniversary of the first administration of the Bacillus Calmette-Guérin (BCG) to a human being. It was the start of a long journey of the world's most widely used vaccine and the oldest vaccine still in use. More than 4 billion children have been vaccinated with BCG for protection against tuberculosis. However, over the years it became apparent that BCG also has beneficial non-specific effects. As such, it provides protection against various heterologous infectious and non-infectious diseases and is used to treat non-muscle-invasive bladder cancer. As BCG was developed at the Institut Pasteur de Lille by Albert Calmette and Camille Guérin, the Institute has celebrated this important anniversary with an international scientific symposium on all aspects of BCG, held from November 17 to 19, 2021 at the Institut Pasteur de Lille. It covered BCG against tuberculosis and described novel vaccine approaches, the effect of BCG against heterologous infections, including BCG and COVID-19, the effect of BCG against cancer, and BCG against auto-immune and inflammatory diseases. To discuss these areas, the symposium gathered close to 200 participants from all five continents, 2/3 on-line. This article presents the highlights of this 3rd International Symposium on BCG.

Abstract 3540: Effect of route of Bacillus Calmette Guerin administration on the immune microenvironment and growth of bladder tumors

Abstract Background: Bladder cancer is the fifth most common cancer in North America. The standard of care for high-risk non-muscle invasive bladder cancer (NMIBC) involves intravesical immunotherapy with Bacillus Calmette Guérin (BCG). However, it is possible that the efficacy of this modality of BCG administration is suboptimal, as most patients do not respond fully to this immunotherapy. Furthermore, our current understanding of the immunotherapeutic effect of BCG is incomplete. Using a mouse model of NMIBC, we compared the tumor immune microenvironment (TiME) following intravesical versus intravenous administration of BCG, as well as changes in tumor volume and mice survival. Methods: Female C57Bl/6 mice (6-8 weeks old) were catheterized and instilled with 2.5x105 MB49 bladder cancer cells after poly-L-lysine treatment. Beginning on day 7, mice were treated with intravenous (IV) or intravesical BCG (8 mg/ml) or saline once weekly for three weeks. Ultrasound was performed weekly to monitor tumor growth. Similarly, a cohort of non-tumor bearing mice was treated with poly-L-lysine on day one followed by three weekly intravesical instillations of BCG. In both cohorts, mice were sacrificed on day 23 and bladders were harvested, enzymatically dispersed to generate single-cell suspensions for analysis by flow cytometry, or snap frozen for transcriptomic analysis using NanoString nCounter Platform. Results: Mice receiving IV BCG had better survival and their bladder tumors were significantly smaller compared with mice receiving intravesical BCG. This reduction in tumor size was associated with a significantly increased proportion of CD8+ T cells and a significantly reduced proportion of inflammatory monocytes in bladder tumors from mice treated with IV BCG compared with intravesical BCG. Whole tumor transcriptome analysis revealed alterations in various signalling pathways associated with route of BCG administration. Our results demonstrate similar trends in the distribution of immune populations in the TiME following intravesical saline and IV BCG treatment, as well as following IV saline and intravesical BCG treatment. We also found that the TiME after intravesical BCG treatment has more immune cells which are predominantly immature myeloid cells. Moreover, our results indicate that intravesical BCG treatment leads to a significant population of immature myeloid cells in the bladders of non-tumor bearing mice. Conclusion/Significance: These results provide evidence that the route of BCG administration is an important determinant of the TiME composition and may influence anti-tumor responses. Understanding the link between the TiME and BCG therapy may facilitate the development of new approaches to improve outcomes and reduce recurrence rates in patients with NMIBC. Citation Format: Aline Atallah, Arielle Grossman, Jean-Francois Pare, Robert Siemens, Tiziana Cotechini, Charles H. Graham. Effect of route of Bacillus Calmette Guerin administration on the immune microenvironment and growth of bladder tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3540.

Abstract 2058: Effect of route of Bacillus-Calmette Guerin administration on systemic immune responses in a murine model of non-muscle invasive bladder cancer

Abstract Background: Bladder cancer is the 5th most common cancer worldwide, with the most common type being non-muscle invasive bladder cancer (NMIBC). Treatment for high grade NMIBC includes resection of the bladder tumor followed by repeated intravesical administration of Bacillus-Calmette Guérin (BCG), the live-attenuated form of Mycobacterium bovis. Unfortunately, 60-70% of patients will experience disease recurrence. Our current understanding is that BCG acts within the local bladder tumor microenvironment and draining lymph nodes, leading to the activation of a systemic immune response. Using a murine model of NMIBC, here we investigated whether different routes of BCG administration alter the systemic immune response to BCG and affect tumor size. Methods: To establish syngeneic orthotopic bladder tumors in a mouse model, female C57Bl/6 mice were catheterized and 2.5 x 105 mouse bladder cancer cells (MB49) were instilled into the bladder. Beginning on day 7, mice received either intravesical, intravenous (IV) or intraperitoneal (IP) BCG (8 mg/ml) or saline once weekly for three weeks and bladders were imaged through ultrasound. At endpoint (day 23), tumors, tumor draining lymph nodes (tdLNs), spleen, and bone marrow were harvested and stored. Immune composition of the various lymphoid organs was evaluated using polychromatic flow cytometry. Ex vivo responsiveness to lipopolysaccharide (LPS) was assessed in bone marrow cells by measuring cytokine levels in culture supernatants. Results: Mice treated with IV BCG had significantly smaller tumor volumes when compared to intravesical BCG treatment. Ex vivo LPS stimulation of bone marrow from BCG-treated mice, regardless of administration route, led to increased release of pro-inflammatory cytokines compared with saline controls. IP and IV BCG treatment skewed immune microenvironments of secondary lymphoid organs towards a cytotoxic phenotype compared with intravesical BCG treatment. Within the lymphoid compartment of tdLNs, the proportion of CD8+ T cells was significantly increased while the proportion of CD4+ T cells was significantly decreased in mice treated with IV and IP BCG compared with intravesical BCG. Conversely, the proportion of CD11b+ dendritic cells (DCs) was significantly increased in tdLNs from mice receiving intravesical BCG compared with BCG administered IV or IP. Within the spleen, the proportion of CD8+CD11b- DCs were significantly increased in the DC compartment following IP BCG treatment compared to other treatment routes. Conclusion: This provides evidence that route of BCG administration affects the immune composition of secondary lymphoid organs that may be associated with anti-tumor responses. A better understanding of the mechanism of BCG immunotherapy will lead to novel approaches to optimize anti-tumor immune responses and, consequently, improved patient outcomes. Citation Format: Arielle Grossman, Aline Atallah, Tiziana Cotechini, Jean-Francois Pare, Robert Siemens, Charles H. Graham. Effect of route of Bacillus-Calmette Guerin administration on systemic immune responses in a murine model of non-muscle invasive bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2058.

Innate Memory Following Intravenous BCG in Neonatal Pigs

Abstract In adults and rodents, Bacillus Calmette-Guerin (BCG) inoculation alters innate immune cells via epigenetic and metabolic modifications resulting in heightened responses to subsequent microbial exposure (innate memory). Neonatal BCG vaccination can correlate to improved disease resistance in some human populations, but studies with human infants are extremely limited. Pigs are a relevant biomedical model for human disease and offer a path to directly asses neonatal innate memory to improve disease resilience. BCG administration in a weaned (3 week old) pig model elicited monocyte memory only with intravenous (IV) but not subcutaneous administration. Therefore, to evaluate induction of innate memory in neonates, 3–5 day old piglets received intravenous (IV) BCG or mock and ex vivo monocyte memory was assessed. At 3 and 6 weeks post-BCG, monocytes from the IV-BCG group had elevated TNF but not IL-1β production in response to LPS stimulation ex vivo, indicating neonatal BCG exposure induced innate memory. Interestingly, broncho-alveolar lavage cells from IV-BCG group had minimal differences compared to mock group in response to LPS, suggesting IV-BCG alters responses in peripheral monocytes differently than tissue resident myeloid-lineage cells. Overall, IV-BCG administration induced monocyte memory in neonatal pigs, highlighting piglets as a valuable model for continued study on the utility of BCG induced innate memory to improve disease resilience. This work was funded by USDA-NIFA AFRI grant # 2019-07511 as part of the joint USDA-NIFA-NIH Dual Purpose with Dual Benefit: Research in Biomedicine and Agriculture Using Agriculturally Important Domestic Animal Species Program and USDA-ARS CRIS project 5030-32000-225-000D

Vitamin B6 Antidepressant Effects Are Comparable to Common Antidepressant Drugs in Bacillus-Calmette-Guerin Induced Depression Model in Mice.

Objective: Bacillus-Calmette-Guerin (BCG) inoculation in mice produces an acute period of illness followed by a chronic depressive-like behavior period that lasts for few weeks. The aim was to evaluate vitamin B6 antidepressant effect in comparison with common antidepressants. Method : BCG (0.2 ml/mouse) single dose was intraperitoneally inoculated in male mice. Vitamin B6 (100 mg/kg), fluoxetine, imipramine, or venlafaxine (10 mg/kg each) were intraperitoneally injected for 14 consecutive days following BCG administration. Illness was evaluated following inoculation and depressive-like behaviors were assessed on days 7 and 14. Results: Illness was induced by BCG since mice lost weight and locomotor activity was reduced. Illness was prevented by vitamin B6 similar to antidepressant drugs. Despair was measured by immobility time during the forced swim test and BCG increased it compared to control (193 ± 3s vs 151 ± 7s, P < 0.01) on day 7, and (200 ± 5s vs 147 ± 6s, P < 0.001) on day 14. Vitamin B6, like antidepressants, reduced despair. BCG clearly induced anhedonia evaluated by sucrose preference test (47.5%), and it was soothed by B6 and the antidepressants. Novelty-suppressed feeding test evaluated long term depressive behavior after 14 days. BCG increased the latency to first feeding (222 ± 41s vs control 87 ± 2.6s, P < 0.001) and reduced food consumption per body weight (13 ± 1 mg/g vs control 19 ± 2 mg/g, P < 0.001) while B6 like antidepressants reduced latency and improved food consumption. Conclusion: Vitamin B6 efficiently prevented BCG sickness and depression that was comparable to common antidepressant drugs. Therefore, B6 supplement for preventing depression in high-risk individuals is suggested for further clinical research.

Investigation of the causes of BCG refractory in patients treated with intracavitary BCG as secondary treatment in superficial bladder tumors with transurethral resection.

Non-muscle invasive bladder cancers (NMIBC) tend to recur and progress over time. Bacillus Calmette-Guerin (BCG) is an effective therapy for the treatment of NMIBC in that it reduces both recurrence and progression rates. The present study investigates the causes of BCG failure, with emphasis on those attributable to application errors by the practitioner and/or patient. The demographic and histopathological characteristics of 115 patients who underwent TUR-B for primary bladder tumors and who underwent intracavitary BCG in the postoperative period in the Urology Clinic of the İzmir Katip Çelebi University Atatürk Training and Research Hospital between January 2014 and January 2019, were analyzed retrospectively. BCG-refractory patients were compared with non-BCG refractory patients after BCG administration. The extent of the tumor, and the involvement of the tumor in the bladder trigone and/or the bladder neck were found to increase significantly the likelihood of BCG refractory. When the micturition times of both groups were compared after instillation, the differences between the groups were found to be statistically significant. In the BCG-refractory patient group, the micturition time after instillation was shorter due to the tumor involvement in the trigone/bladder neck. Some modifiable factors originating from the patient and the tumoral characteristics were found to have an effect on BCG failure. It was further determined that the time until micturition after BCG administration is an important parameter to be considered in the prevention of application deficiencies. We believe these factors should be subjected to careful consideration during patient selection and follow-up.

Abstract P008: Effect of route of Bacillus Calmette Guérin administration on the tumor immune microenvironment in a mouse model of non-muscle invasive bladder cancer

Abstract Background: Bladder cancer is the fifth most common cancer in North America, with up to 80% of cases being non-muscle invasive bladder cancer (NMIBC). The standard of care for high-risk NMIBC involves intravesical immunotherapy with Bacillus Calmette Guérin (BCG), a live attenuated bacterium. Unfortunately, most patients do not respond fully to this therapy, resulting in recurrences that sometimes progress to invasive disease. Moreover, our understanding of how BCG exerts its immunotherapeutic effect is incomplete. Using a mouse model of NMIBC, we compared the bladder tumor immune microenvironment (TiME) following intravesical versus intravenous (IV) administration of BCG. Methods: Female C57Bl/6 mice (6-8 weeks old) were catheterized and 2.5 × 105 MB49 bladder cancer cells were instilled into the bladders after poly-L-lysine treatment. On day 7 post cancer cell instillation, mice with equal tumor volumes were randomized to receive three weekly intravesical or IV administrations of saline or BCG (2 mg/50 μl). Similarly, following catheterization, 50 μl of poly-L-lysine was administered into the bladders of control non-tumor bearing mice, which was then followed by three weekly intravesical instillations of BCG (2 mg/50 μl). In both cohorts, mice were sacrificed on day 23 and bladders were harvested and enzymatically dispersed to generate single-cell suspensions for analysis by polychromatic flow cytometry. Results: Compared with intravesical BCG treatment, the TiME of mice treated with BCG intravenously was associated with a significantly higher proportion of CD11b− CD3+, CD3−, and CD4− lymphoid cells, as well as a significantly lower proportion of immature myeloid cells. Furthermore, compared with saline IV treatment, BCG administered IV resulted in a significantly larger CD4− T cell population. There were no significant differences in the TiME of intravesically BCG-treated vs intravesically saline-treated tumor-bearing mice. However, compared with control non-tumor-bearing mice treated with saline intravesically, bladders of non-tumor-bearing mice treated intravesically with BCG had a significantly higher proportion of leukocytes, which were predominantly immature myeloid cells. Conclusion/Significance: These results provide evidence that the route of BCG administration is an important determinant of the composition of the TiME in bladder cancer. Understanding the link between the TiME and BCG therapy may facilitate the development of new approaches to improve outcomes and reduce recurrence rates in patients with NMIBC. This knowledge may also help optimize BCG treatment regimen to avoid unnecessary therapy and induce an optimal anti-tumor immune response. Citation Format: Aline Atallah, Arielle Grossman, William Tran, Jean-Francois Paré, Tiziana Cotechini, Charles H. Graham. Effect of route of Bacillus Calmette Guérin administration on the tumor immune microenvironment in a mouse model of non-muscle invasive bladder cancer [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr P008.

Clinical features of tuberculous pseudoaneurysm and risk factors for mortality

ObjectivesThe objective of this study was to determine the clinical features of tuberculous aneurysms and risk factors for mortality. MethodsWe reviewed all case reports of tuberculous aneurysms in the English literature from January 2000 to December 2020. The clinical features and possible risk factors for mortality were recorded and analyzed. ResultsIn total, 174 cases of tuberculous aneurysms were identified. The morbidity of men was more than twice that of women. Male patients (51.47 ± 20.67 years) were older than female patients (39.52 ± 20.23 years; P < .05). The rupture rate in women (69.2%) was higher than that in men (48.8%). Tuberculosis (TB)-induced aneurysms often spontaneously ruptured 1.41 to 3.01 months after the onset of TB symptoms without any treatment, and Bacillus Calmette-Guerin (BCG)-induced aneurysms often spontaneously ruptured 10.51 to 26.49 months after BCG administration. The morbidity of large artery aneurysms was nearly twice that of middle artery aneurysms. However, middle artery aneurysms were more likely to rupture (75.4%) than large artery aneurysms (43.5%; P < .05). The rupture rate of BCG-induced aneurysms (37.0%) was lower than that of TB-induced aneurysms, regardless of whether there was a TB history (56.7%) or not (57.7%). Symptoms of TB occurred in 63.2% of patients, but only 8.6% of patients had both symptoms of TB and aneurysmal mass effects. Pain was the most common atypical clinical manifestation (50.0%). The Cox proportional hazards regression analysis and Kaplan-Meier estimator showed that rupture and no combined therapy were risk factors for mortality. ConclusionsTuberculous aneurysms seemingly shared the same demographic characteristics as common aneurysms. The clinical features of TB-induced aneurysms were different from those of BCG-induced aneurysms in terms of the aneurysm location and rupture rate. Tuberculous aneurysms may occur at any site of the cardiovascular system with a preponderance for large arteries. The changeable clinical manifestations were important index for diagnosis, but focusing only on clinical manifestations may lead to a missed diagnosis. The combination of anti-TB medications and surgery before aneurysm rupture may provide the best prognosis.

Single-cell transcriptomic profiles reveal changes associated with BCG-induced trained immunity and protective effects in circulating monocytes.

Bacillus Calmette-Guérin (BCG) vaccine is one of the most widely used vaccines worldwide. In addition to protection against tuberculosis, BCG confers a degree of non-specific protection against other infections by enhancing secondary immune responses to heterologous pathogens, termed "trained immunity." To better understand BCG-induced immune reprogramming, we perform single-cell transcriptomic measurements before and after BCG vaccination using secondary immune stimulation with bacterial lipopolysaccharide (LPS). We find that BCG reduces systemic inflammation and identify 75 genes with altered LPS responses, including inflammatory mediators such as CCL3 and CCL4 that have a heightened response. Co-expression analysis reveals that gene modules containing these cytokines lose coordination after BCG. Other modules exhibit increased coordination, including several humanin nuclear isoforms that we confirm induce trained immunity invitro. Our results link invivo BCG administration to single-cell transcriptomic changes, validated in human genetics experiments, and highlight genes that are putatively responsible for non-specific protective effects of BCG.

Associating Graphene Oxide Derivatives to Treat Non-Muscle Invasive Bladder Cancer (NMIBC)

According to estimates, there were 17,670 bladder cancer-associated deaths in the USA by 2019. Intravesical Bacillus Calmette-Guerin (BCG) instillation is used to treat non-muscle invasive bladder cancer (NMIBC). However, more than 40% of BCG administration cases fail to avoid NMIBC relapse and progression. Our aim is to use synthesized GO derivatives to enable the transport of doxorubicin (DOX), a conventional cancer drug, and siRNA to reduce VEGF. Several platforms were tested, and their effects on NMIBC progression were assessed in vivo based on histo- and immune analyses. siRNA and GO were covalently bonds to polyethyleneimine (PEI) and polyethylene glycol (PEG) (GO-PEG-PEI/siRNA). DOX bond to oxidized GO was also synthesized. Hybrids were administered in vivo (rats) against NMIBC. Histopathology results have shown that hybrids have reduced bladder cancer. The GO-COOH-DOX/GO-PEG-PEI/siRNA potentiated tumor aggressiveness (60%) reduction in animals that did not show signs of lesions. Immunohistochemistry results have shown that the GO hybrid reduced VEGF expression, increased endostatin levels, and low p53 levels were observed. Data analyzed in the current study have shown that hybrid graphene oxides were capable of reducing VEGF expression and have great potential to treat NMIBC.

Good old BCG - what a century-old vaccine can contribute to modern medicine.

Good old BCG - what a century-old vaccine can contribute to modern medicine.