Bacille Calmette-Guérin Strain Research Articles

Maternal Bacille Calmette-Guérin Scars and Mortality Risk for Male and Female Newborns: Observational Study From Guinea-Bissau.

Maternal priming with bacille Calmette-Guérin (BCG) has been associated with reduced mortality in male offspring. We investigated this association in a cohort of healthy BCG-vaccinated neonates. This observational study within a randomized controlled trial comparing different BCG strains was conducted in Guinea-Bissau from 2017 to 2020. As part of trial inclusion procedures, on the day of discharge from the maternity ward, maternal BCG scar status was evaluated by visual inspection, followed by offspring BCG and polio vaccination. Through mortality data collected at telephone interviews at 6 weeks and 6 months of age, we assessed all-cause mortality risk in Cox proportional hazards models adjusted for maternal schooling and BCG strain, providing adjusted mortality rate ratios (aMRRs). In total, 64% (11 070/17 275) of mothers had a BCG scar, which was not associated with admission risk, admission severity, or all-cause mortality for females and the overall sample. By 6 months of age, the mortality rate (MR) was 4.1 (200 deaths/4919 person-years) for the maternal BCG scar cohort and 5.2 (139/2661) for no maternal scar (aMRR, 0.86; 95% Confidence Interval [CI], .69-1.06). In males, 6-month MRs were 4.3 (109 deaths/2531 person-years) for maternal BCG scar vs 6.3 (87/1376) for no scar (aMRR, 0.74; 95% CI, .56-.99). In females, 6-month MRs were 3.8 (91 deaths/2388 person-years) vs 4.0 (52/1286), respectively (aMRR, 1.04; 95% CI, .74-1.47; for interaction with sex, P = .16). While we cannot rule out an association in females, being born to a mother with a BCG scar reduced the risk of death during early infancy for BCG-vaccinated males, reproducing findings from previous studies.

Mycobacterium Tuberculosis Complex in Children Clinical, Radiological Features, Management, Outcome and Susceptibility Pattern

Introduction Mycobacterium tuberculosis complex MTC is a major cause of morbidity and mortality globally. The Bacille Calmette-Guérin (BCG) vaccine is most commonly used worldwide. Disseminated BCG disease is one of the vaccine complications that may occur in immunocompromised children. Methods Retrospective study from January 2009 to December 2022. Results We evaluated 66 patients with microbiologically documented M. tuberculosis complex. Immunocompetent were 28 while 38 were immunocompromised. Our data include 46 patients with BCG-related infections. The majority of 26 patients were diagnosed with disseminated BCGiosis, and local BCGitis was found in 20 out of 46. Remaining 20 patients constitute non-BCG-related infections. Chest radiography done in 58 patients and 10.6% had abnormal findings specific for TB. Other image was mainly done for disseminated BCGiosis. The overall acid-fast bacillus AFB smear was positive in 42.4%, polymerase chain reaction (PCR) positive in 75.8% and positive cultures in 97%. Susceptibility of all samples showed high resistance of pyrazinamide 78.2%, and INH 57.8%, while low resistance to RIF and ethambutol. A further subanalysis of the non-BCG group only showed a drop of resistance to 30% for the related group; all strains were pyrazinamide resistant in the same line with the fact that BCG strain is intrinsically resistant to pyrazinamide, all our patients were 100% resistant. We observed four medications showed some advantage over three-drug regimens with respect to mortality in immunocompromised group. The overall outcome in all patients showed 10.6% mortality. Majority were in disseminated BCGiosis, in which 19.2% died. Conclusion: Our center is the main referral hospital in the kingdom with a large number of patients that will help in understanding local data more. Performance of smear and PCR showed variation in relation to different TB diagnoses and sensitivity patterns, giving us insight into different MTB complex strain characteristics that would help in treatment. Sensitivity pattern data will help in keeping updated treatment protocol locally. We recommend managing disseminated BCGiosis with at least four antimycobacterial agents.

Safety and Immunogenicity of Recombinant Bacille Calmette-Guérin Strain VPM1002 and Its Derivatives in a Goat Model.

A more effective vaccine against tuberculosis than Bacille Calmette-Guérin (BCG) is urgently needed. BCG derived recombinant VPM1002 has been found to be more efficacious and safer than the parental strain in mice models. Newer candidates, such as VPM1002 Δpdx1 (PDX) and VPM1002 ΔnuoG (NUOG), were generated to further improve the safety profile or efficacy of the vaccine. Herein, we assessed the safety and immunogenicity of VPM1002 and its derivatives, PDX and NUOG, in juvenile goats. Vaccination did not affect the goats' health in regards to clinical/hematological features. However, all three tested vaccine candidates and BCG induced granulomas at the site of injection, with some of the nodules developing ulcerations approximately one month post-vaccination. Viable vaccine strains were cultured from the injection site wounds in a few NUOG- and PDX- vaccinated animals. At necropsy (127 days post-vaccination), BCG, VPM1002, and NUOG, but not PDX, still persisted at the injection granulomas. All strains, apart from NUOG, induced granuloma formation only in the lymph nodes draining the injection site. In one animal, the administered BCG strain was recovered from the mediastinal lymph nodes. Interferon gamma (IFN-γ) release assay showed that VPM1002 and NUOG induced a strong antigen-specific response comparable to that elicited by BCG, while the response to PDX was delayed. Flow cytometry analysis of IFN-γ production by CD4+, CD8+, and γδ T cells showed that CD4+ T cells of VPM1002- and NUOG-vaccinated goats produced more IFN-γ compared to BCG-vaccinated and mock-treated animals. In summary, the subcutaneous application of VPM1002 and NUOG induced anti-tuberculous immunity, while exhibiting a comparable safety profile to BCG in goats.

ESX-5-targeted export of ESAT-6 in BCG combines enhanced immunogenicity & efficacy against murine tuberculosis with low virulence and reduced persistence

Tuberculosis (TB) is the leading infectious cause of death globally. The only licensed TB vaccine, Bacille Calmette–Guérin (BCG), has low efficacy against TB in adults and is not recommended in people with impaired immunity. The incorporation of the Mycobacterium tuberculosis (Mtb) secretion system ESX-1 into BCG improves immunogenicity and protection against TB in animal models, which is associated with the secretion of the ESX-1-dependent protein ESAT-6. However, the resulting strain, BCG::ESX1Mtb, has been deemed unsafe as a human vaccine, due to prolonged persistence and increased virulence in immunocompromised mice. In this study, we describe a new recombinant BCG strain that uncouples the beneficial aspects of ESAT-6 secretion from the detrimental ESX-1effects on virulence and persistence. The strain was constructed by fusing the ESAT-6-encoding gene esxA to the general secretion signal for the mycobacterial type VII secretion pathway protein PE25. This new strain, BCG::ESAT6-PE25SS, secretes full-length ESAT-6 via the ESX-5 secretion system, which in contrast to ESX-1 is also present in BCG. In vivo testing revealed that ESX-5-targeted ESAT-6 export, induces cytosolic contact, generates ESAT-6-specific T cells and enhances the protective efficacy against TB disease, but is associated with low virulence and reduced persistence in immunocompetent and immunocompromised mice. Additionally, compared to BCG::ESX1Mtb and parental BCG, mucosal administration of BCG::ESAT6-PE25SS is associated with more rapid clearance from the lung. These results warrant further studies to evaluate BCG::ESAT6-PE25SS as a potential live attenuated vaccine candidate for TB.

A 20-year retrospective study of osteoarticular tuberculosis in a pediatric third level referral center

PurposeThe objective of the present study is to describe the clinical, diagnostic, radiological and therapeutic aspects of osteoarticular tuberculosis (OATB) in patients in a tertiary pediatric hospital, to know if the diagnosis of OATB in pediatrics is a challenge due to its insidious clinical presentation.MethodsA retrospective, descriptive study of the cases of Tuberculosis (TB) in children was carried out. A total of 159 cases met the condition for the analysis.ResultsThe most frequent TB modality was extrapulmonary in 85%. Out of this, only 29% was OATB. The mean age was 4.9 years (range 8 months–16 years). Eighty-six per cent of cases received Bacille Calmette-Guérin (BCG) vaccination at birth. Median time of symptoms prior to diagnosis was 8 months. Microbiological confirmation was achieved only in five cases, with a high sensitivity to the antimicrobial treatment. Mycobacterium bovis BCG strain Tokio 172 was confirmed in three cases. Mortality rate was 0% during the time of studyConclusionOur study describes the epidemiological characteristics of OATB cases in Mexican children. This data revealed a high prevalence of bone and joint TB infection. Pediatric OATB should be considered in cases with lytic bone lesions, fever and local pain. In countries with BCG immunization program, M. bovis should not be forgotten as an etiological agent. The low detection rate with one technique approach highlights the urgent need for more sensitive test to diagnose OATB in children.

BCG skin reactions by 2 months of age are associated with better survival in infancy: a prospective observational study from Guinea-Bissau

IntroductionReceiving Bacille Calmette-Guérin (BCG)-Denmark vaccine at birth has been associated with ~40% reductions in all-cause neonatal mortality. We evaluated determinants of BCG skin reaction characteristics by age 2 months and...

Bacille Calmette-Guérin Vaccine Strain Modulates the Ontogeny of Both Mycobacterial-Specific and Heterologous T Cell Immunity to Vaccination in Infants.

Differences in Bacille Calmette-Guérin (BCG) immunogenicity and efficacy have been reported, but various strains of BCG are administered worldwide. Since BCG immunization may also provide protection against off-target antigens, we sought to identify the impact of different BCG strains on the ontogeny of vaccine-specific and heterologous vaccine immunogenicity in the first 9 months of life, utilizing two African birth cohorts. A total of 270 infants were studied: 84 from Jos, Nigeria (vaccinated with BCG-Bulgaria) and 187 from Cape Town, South Africa (154 vaccinated with BCG-Denmark and 33 with BCG-Russia). Infant whole blood was taken at birth, 7, 15, and 36 weeks and short-term stimulated (12 h) in vitro with BCG, Tetanus and Pertussis antigens. Using multiparameter flow cytometry, CD4+ T cell memory subset polyfunctionality was measured by analyzing permutations of TNF-α, IL-2, and IFN-γ expression at each time point. Data was analyzed using FlowJo, SPICE, R, and COMPASS. We found that infants vaccinated with BCG-Denmark mounted significantly higher frequencies of BCG-stimulated CD4+ T cell responses, peaking at week 7 after immunization, and possessed durable polyfunctional CD4+ T cells that were in a more early differentiated memory stage when compared with either BCG-Bulgaria and BCG-Russia strains. The latter responses had lower polyfunctional scores and tended to accumulate in a CD4+ T cell naïve-like state (CD45RA+CD27+). Notably, BCG-Denmark immunization resulted in higher magnitudes and polyfunctional cytokine responses to heterologous vaccine antigens (Tetanus and Pertussis). Collectively, our data show that BCG strain was the strongest determinant of both BCG-stimulated and heterologous vaccine stimulated T cell magnitude and polyfunctionality. These findings have implications for vaccine policy makers, manufacturers and programs worldwide and also suggest that BCG-Denmark, the first vaccine received in many African infants, has both specific and off-target effects in the first few months of life, which may provide an immune priming benefit to other EPI vaccines.

Clinical features and outcomes of Bacille Calmette-Guérin (BCG)-induced diseases following neonatal BCG Tokyo-172 strain immunization

BackgroundBacille Calmette-Guérin (BCG) vaccination at birth may cause mild and benign local adverse effects (AE). More serious AE are rarely reported. ObjectiveTo describe clinical features and outcomes of BCG (Tokyo-172 strain)-induce diseases (BCG-ID) that required medical attention at a tertiary care center in Bangkok, Thailand. MethodWe retrospectively reviewed medical records from January 2007 to December 2016 that were selected by ICD-10 codes. The inclusion criteria were the patients under 3 years of age who developed lymphadenitis, osteitis, or disseminated infections of which BCG was a possible pathogen. Cases were classified into suspected (clinically compatible without laboratory confirmation), probable (suspected cases with M. tuberculosis complex identified), and confirmed BCG-ID (probable cases with molecular confirmation of M. bovis BCG strain). Results95 children were identified; 57 (60.0%) were male, and the median age at presenting symptom was 3.5 (range: 0.6–28.7) months. Of these, 25 (26.3%) were suspected, 49 (51.6%) were probable, and 21 (22.1%) were confirmed BCG-ID. Overall, 87 (92%) children had regional lymphadenitis corresponding to the BCG site, 5 (5%) had osteitis, and 3 (3%) had disseminated BCG. Of those with lymphadenitis, average size was 2.2 (range 0.7–5) cm. in diameter and 53% (46/87) had pulmonary involvement. Five children with immunodeficiency; three had disseminated BCG and two had lymphadenitis. Eight (9.2%) patients with lymphadenitis underwent needle aspiration; 57 (65.5%) had surgical excision. All children with BCG osteitis underwent surgical intervention in combination with anti-tuberculosis treatment. One patient with osteitis experienced long-term leg length discrepancy. ConclusionRegional lymphadenitis was the most common feature of BCG-ID requiring medical attention. That none of the BCG osteitis were immunocompromised hosts suggested the potential virulence of BCG in neonates. A systematic national surveillance and reporting system is needed to develop accurate estimates of population incidence and support development of effective vaccine policy.

Safety and efficacy of various strains of bacille Calmette–Guérin in the treatment of bladder tumors in standard clinical practice

BackgroundThe natural progression of bladder tumors (nonmuscle-invasive bladder cancer [NMIBC]) is recurrence with a high rate of progression. Bacille Calmette–Guérin (BCG) has been shown effective in reducing these rates, but there are few comparative studies between strains. Material and methodsAn observational, prospective and multicentre registry studied 433 patients with a 12-month follow-up visit from 961 registered patients, assessing disease-free survival (DFS), progression-free survival (PFS) cancer-specific survival (CSS) and adverse effects. We studied the Tice, Russian, Tokyo, Connaught and RIVM strains. ResultsThe sociodemographic data, NMIBC history, comorbidities, size, number, stage, grade, associated carcinoma in situ and transurethral resection were well balanced. DFSThere were 85 relapses (19.6%). The median DFS time was 20months. When comparing the various strains, we detected no statistically significant differences (log-rank test; p=0.93). LPS: There were 33 cases of progression (7.62%). When comparing the various strains, we detected no statistically significant differences (log-rank test; p=0.69). CSS: Seven patients died (1.68%). When comparing the various strains, we detected no statistically significant differences (log-rank test; p=0.93).In terms of safety, 33.3% of the patients presented some type of adverse effect, mostly lower urinary symptoms (no urinary tract infections) <48h, >48h and haematuria. According to the Common Toxicity Criteria of the European Organisation for Research and Treatment of Cancer, 92.7% of the patients were grade 1. There were no statistically significant differences between the strains. ConclusionsIn this intermediate analysis, the risk of recurrence, progression, specific death and safety were independent of the BCG strain employed.

Eficacia y seguridad de distintas cepas de BCG en el tratamiento del tumor vesical en práctica clínica habitual

BackgroundThe natural progression of bladder tumours (nonmuscle-invasive bladder cancer [NMIBC]) is recurrence with a high rate of progression. Bacille Calmette-Guérin (BCG) has been shown effective in reducing these rates, but there are few comparative studies between strains. Material and methodsAn observational, prospective and multicentre registry studied 433 patients with a 12-month follow-up visit from 961 registered patients, assessing disease-free survival (DFS), progression-free survival (PFS) cancer-specific survival (CSS) and adverse effects. We studied the Tice, Russian, Tokyo, Connaught and RIVM strains. ResultsThe sociodemographic data, NMIBC history, comorbidities, size, number, stage, grade, associated carcinoma in situ and transurethral resection were well balanced.DFS: There were 85 relapses (19.6%). The median DFS time was 20months. When comparing the various strains, we detected no statistically significant differences (log-rank test; P=.93). LPS: There were 33 cases of progression (7.62%). When comparing the various strains, we detected no statistically significant differences (log-rank test; P=.69). CSS: Seven patients died (1.68%). When comparing the various strains, we detected no statistically significant differences (log-rank test; P=.93).In terms of safety, 33.3% of the patients presented some type of adverse effect, mostly lower urinary symptoms (no urinary tract infections) <48h, >48h and haematuria. According to the Common Toxicity Criteria of the European Organisation for Research and Treatment of Cancer, 92.7% of the patients were grade1. There were no statistically significant differences between the strains. ConclusionsIn this intermediate analysis, the risk of recurrence, progression, specific death and safety were independent of the BCG strain employed.

ITPKC and SLC11A1 Gene Polymorphisms and Gene-Gene Interactions in Korean Patients with Kawasaki Disease.

PurposeKawasaki disease (KD) is an acute systemic vasculitis. Both the etiology of KD and the erythema of Bacille Calmette-Guérin (BCG) injection sites observed in the disease are poorly understood. We investigated the association between KD and single nucleotide polymorphisms (SNPs) in two candidate genes: inositol 1,4,5-triphosphate 3-kinase (ITPKC), a well-studied KD-associated gene, and solute carrier 11a1 (SLC11A1), which is associated with the hypersensitive reaction to the BCG strain in Koreans.Materials and MethodsAssociations between KD and SNPs in two genes were evaluated. Potential associations between BCG injection site erythema and SNPs in two genes were also evaluated. Gene-gene interactions between ITPKC and SLC11A1 in KD and BCG injection site erythema were also analyzed.ResultsThree tagging SNPs in ITPKC and five tagging SNPs in SLC11A1 were genotyped in 299 KD patients and 210 control children. SNP rs28493229 in ITPKC was associated with KD and coronary artery complications. SNP rs77624405 in SLC11A1 was associated with KD. Comparisons of KD patients with and without BCG injection site erythema revealed that SNP rs17235409 in SLC11A1 was associated with erythema; no erythema-associated SNPs in ITPKC were identified. Interactions between ITPKC rs28493229_GG and SLC11A1 rs17235409_GA and between ITPKC rs10420685_GG and SLC11A1 rs17235409_AA were strongly associated with BCG injection site erythema.ConclusionThis study identified several important polymorphisms in the ITPKC and SLC11A1 genes in Koreans. The genetic variants identified in this study affected KD and erythema of BCG injection sites independently and through gene-gene interactions. Also, the effects of the polymorphisms were age-dependent.

A novel recombinant BCG-expressing pro-apoptotic protein BAX enhances Th1 protective immune responses in mice

One-third of the world's population is infected with Mycobacterium tuberculosis (MTB). The protective efficacy of bacille Calmette Guérin (BCG) vaccine against tuberculosis (TB) in adults is highly controversial even though the BCG vaccine has been available for more than 90 years. Because BCG is effective against infantile tuberculosis meningitis and miliary tuberculosis in young children and provides cost-effective prevention from tuberculosis for developing countries, it would be desirable to modify the existing BCG vaccine to provide more comprehensive protection. In our study, we constructed a novel recombinant BCG strain expressing pro-apoptotic BAX (rBCG::BAX) and demonstrated that it significantly induced the apoptosis of macrophages infected with rBCG::BAX both in vitro and in vivo. In addition, it significantly enhanced Ag85B-specific IFN-γ enzyme-linked immunospot responses, IFN-γ secretion, IL-2 secretion and the ratio of Ag85B-specific IgG2b/IgG1, and it significantly decreased Ag85B-specific IL-4. Furthermore, it presumably facilitated antigen presentation by inducing a significant up-regulation in the expression of MHC-II and B7.1 (CD80) co-stimulatory molecules on macrophages. In conclusion, these results suggest that the rBCG::BAX strain elicited predominantly a Th1 protective immune responses and might be a potential tuberculosis vaccine candidate for further study.

The Development and Impact of Tuberculosis Vaccines

Vaccination is expected to make a major contribution to the goal of eliminating tuberculosis worldwide by 2050. But developing a new effective vaccine will require innovation in scientific research, a proactive approach to clinical trials of new vaccine candidates, and application of vaccines as part of an integrated approach to disease control.

Conjunctival vaccination of the brushtail possum (Trichosurus vulpecula) with bacille Calmette-Guérin

AIM: To determine the efficacy of conjunctival vaccination of captive brushtail possums (Trichosurus vulpecula) with bacille Calmette-Guérin (BCG), as measured by immunological responses to vaccination and response to intratracheal challenge with Mycobacterium bovis. METHODS: Nine adult male brushtail possums were vaccinated by the instillation of a suspension of BCG strain Pasteur 1173P2 into the conjunctival sac of each eye. Each drop contained approximately 2.5 × 105 colony forming units (cfu). At 8 weeks post-vaccination (pv) the vaccinated possums and 10 unvaccinated possums were challenged by intratracheal instillation of approximately 100 cfu of M. bovis. Cellular immune responses to bovine purified protein derivative (PPD) antigen were measured using the lymphocyte proliferation assay (LPA). Possums surviving to 50–51 days after challenge were euth anised and subjected to detailed post-mortem examination, including histopathology, to assess protection against tuberculosis. Sections of lung and spleen were cultured for M. bovis. RESULTS: No conjunctival inflammation or other adverse reactions to the administration of the vaccine were evident macroscopically. The vaccinated group showed a systemic cellular immune response to bovine PPD antigen at 4 and 8 weeks pv, and the response at 8 weeks was significantly greater than at 4 weeks (p<0.05). Conjunctival vaccination induced significant levels of protective immunity, measured as less mass of tuberculous lesions in lung (p<0.05) and less dissemination of disease in vaccinated compared with unvaccinated possums (p<0.05). CONCLUSIONS: Conjunctival vaccination with BCG induced a significant level of protective immunity against M. bovis infection in possums. This route of vaccination, together with intranasal aerosol vaccination, could be utilised in the delivery of an aerosolised vaccine using a device that sprays the vaccine suspension into the eyes and nose of possums.

Intravesical bacille calmette-guérin versus mitomycin c in superficial bladder cancer: formal meta-analysis of comparative studies on tumor progression

Objectives To compare the therapeutic efficacy of intravesical bacille Calmette-Guérin (BCG) with mitomycin C (MMC) on progression of Stage Ta and T1 bladder carcinoma. Methods Combined published and unpublished data from comparative studies on BCG versus MMC in superficial bladder carcinoma were analyzed, considering possible confounding factors. Odds ratios (ORs) and 95% confidence intervals (CIs) were used as the primary effect size estimate. Tumor progression was defined as progression to a higher tumor stage or the development of metastatic disease. Results In nine eligible clinical trials, 1277 patients were treated with BCG and 1133 with MMC. Within the overall median follow-up of 26 months, 7.67% of the patients in the BCG group and 9.44% of the patients in the MMC group developed tumor progression. In all nine individual studies and in the combined results, no statistically significant difference in the ORs for progression between the BCG and MMC-treated groups was found (combined OR = 0.77; 95% CI 0.57 to 1.03; P = 0.081). In the subgroup with BCG maintenance, the combined result of the five individual studies showed a statistically significant superiority of BCG over MMC (OR = 0.66; 95% CI 0.47 to 0.94; P = 0.02). In the four studies without BCG maintenance, the combined result indicated no statistically significant difference between the two treatments (OR = 1.16; 95% CI 0.65 to 2.07; P = 0.612). Potential confounders, such as tumor risk status, duration of follow-up, BCG strain, BCG and MMC treatment regimen, and year of publication did not significantly influence these results. Conclusions The results demonstrated statistically significant superiority for BCG compared with MMC for the prevention of tumor progression only if BCG maintenance therapy was provided.

Danish bacille Calmette-Guérin vaccine-induced disease in human immunodeficiency virus-infected children.

An analysis of isolates of Mycobacterium tuberculosis complex was performed to determine the prevalence of bacille Calmette-Guérin (BCG) disease among human immunodeficiency virus (HIV)-infected children. Speciation was done with polymerase chain reaction; 183 isolates from mycobacterial cultures for 49 HIV-infected patients were analyzed. The Danish Mycobacterium bovis BCG strain was isolated from 5 patients. No cases of Tokyo M. bovis BCG strain disease were detected. All patients were asymptomatic at birth, <12 months of age, and severely immunodeficient at presentation. Four patients had regional axillary adenitis ipsilateral to the vaccination site, and 2 had pulmonary BCG disease. Two patients with regional BCG disease had simultaneous pulmonary M. tuberculosis infection. Although chest radiographic features were similar to those seen in patients with tuberculosis, BCG disease should be considered in HIV-infected infants with right axillary adenitis ipsilateral to the vaccination site. Young, symptomatic, HIV-infected infants are at risk for BCG-related complications. Controlled, population-based studies are needed to assess the risk of BCG in HIV-infected children.

Modified Microbe May Boost TB Vaccine

In its war against bacterial infections, one of medicine's longtime allies has been a member of the enemy: bacille Calmette-Guérin (BCG). The mycobacterium has been widely used as a vaccine against the tuberculosis (TB) organism. But BCG's protective effect varies greatly and wanes as people age. Now reinforcements may be on the way. Researchers have engineered a BCG strain to express mammalian cytokines, intercellular messengers that rally the immune system.

Five-year results of a phase ii study with low-dose bacille calmette-guérin therapy in high-risk superficial bladder cancer

Objectives Numerous studies have shown bacille Calmette-Guérin (BCG) to be an effective prophylactic and therapeutic agent for superficial transitional cell carcinoma of the bladder. The high-grade T1 lesion treated by transurethral resection alone is reported to progress to muscle invasion in 30% to 50% of the patients. Until now, optimal treatment schedule and optimal dose have not been defined. As suggested by Pagano's group, we used BCG in a lower dose than hitherto usual in our high-risk cancer patients. Methods Five years ago, we treated 32 Stage T1 cancer patients who were described as at high risk based on the criteria of histologic grade 3 in 21 patients, grade 2, but multiple in 11 patients, and with carcinoma in situ in 17 patients. Follow-up ranged from 51 to 63 months, with a mean of 57 months. We used BCG strain Pasteur Paris 75 mg weekly for 6 weeks and then maintenance therapy monthly for the first year and every 3 months for the second year. Complete remission was defined as negative cystoscopy, biopsy, and cytology. Results After a single 6-week course of BCG, 25 patients had negative cytology and biopsy findings after 3 months; 2 other patients needed a second 6-week cycle of BCG, for an overall response rate of 80%. Five patients underwent cystectomy because of multiple recurrences and tumor progression. After 2 years of follow-up, but under continuing maintenance therapy, 3 additional patients had tumor recurrences and also underwent cystectomy. Now, after 5 years' follow-up, the overall progression rate to cystectomy was 25% (8 of 32 patients), but none of the patients had progression to metastasis. Treatment-related toxicity did not appear to be lower at a lower dose of BCG. Conclusions Low-dose BCG therapy is also an effective treatment in high-risk T1 bladder cancer (especially with maintenance therapy and short-term evaluations of the patients always by the same controlling physician) to prevent progression and recurrence and to preserve bladder function.