Dose Of Bacillus Calmette-Guerin Research Articles

Bacillus Calmette-Guerin vaccine-mediated neuroprotection is associated with regulatory T-cell induction in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease

We previously showed that, in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease (PD), vaccination with bacillus Calmette-Guerin (BCG) prior to MPTP exposure limited the loss of striatal dopamine (DA) and dopamine transporter (DAT) and prevented the activation of nigral microglia. Here, we conducted BCG dose studies and investigated the mechanisms underlying BCG vaccination's neuroprotective effects in this model. We found that a dose of 1 × 10(6) cfu BCG led to higher levels of striatal DA and DAT ligand binding (28% and 42%, respectively) in BCG-vaccinated vs. unvaccinated MPTP-treated mice, but without a significant increase in substantia nigra tyrosine hydroxylase-staining neurons. Previous studies showed that BCG can induce regulatory T cells (Tregs) and that Tregs are neuroprotective in models of neurodegenerative diseases. However, MPTP is lymphotoxic, so it was unclear whether Tregs were maintained after MPTP treatment and whether a relationship existed between Tregs and the preservation of striatal DA system integrity. We found that, 21 days post-MPTP treatment, Treg levels in mice that had received BCG prior to MPTP were threefold greater than those in MPTP-only-treated mice and elevated above those in saline-only-treated mice, suggesting that the persistent BCG infection continually promoted Treg responses. Notably, the magnitude of the Treg response correlated positively with both striatal DA levels and DAT ligand binding. Therefore, BCG vaccine-mediated neuroprotection is associated with Treg levels in this mouse model. Our results suggest that BCG-induced Tregs could provide a new adjunctive therapeutic approach to ameliorating pathology associated with PD and other neurodegenerative diseases.

Side Effects of Bacillus Calmette-Guérin (BCG) in the Treatment of Intermediate- and High-risk Ta, T1 Papillary Carcinoma of the Bladder: Results of the EORTC Genito-Urinary Cancers Group Randomised Phase 3 Study Comparing One-third Dose with Full Dose and 1 Year with 3 Years of Maintenance BCG

BackgroundAlthough bacillus Calmette-Guérin (BCG) has proven highly effective in non–muscle-invasive bladder cancer (NMIBC), but it can cause severe local and systemic side effects. ObjectivesThe objective was to determine whether reducing the dose or duration of BCG was associated with fewer side effects. Efficacy comparisons of one-third dose versus full dose BCG given for 1 yr versus 3 yr have previously been published. Design, setting, and participantsAfter transurethral resection, patients with intermediate- and high-risk NMIBC without carcinoma in situ were randomised to one-third dose or full dose BCG and 1 yr or 3 yr of maintenance. Outcome measurements and statistical analysisLocal and systemic side effects were recorded at every instillation and divided into three time periods: during induction, during the first year after induction, and during the second and third years of maintenance. Results and limitationsOf the 1316 patients who started BCG, 826 (62.8%) reported local side effects, 403 (30.6%) reported systemic side effects, and 914 (69.5%) reported local or systemic side effects. The percentage of patients with at least one side effect was similar in the four treatment arms (p=0.41), both overall and in the different time periods. The most frequent local and systemic side effects were chemical cystitis in 460 (35.0%) patients and general malaise in 204 patients (15.5%); 103 patients (7.8%) stopped treatment because of side effects. No significant difference was seen between treatment groups (p=0.74). In the 653 patients randomised to 3 yr of BCG, 35 (5.4%) stopped during the first year, and 21 (3.2%) stopped in the second or third year. ConclusionsNo significant differences in side effects were detected according to dose or duration of BCG treatment in the four arms. Side effects requiring stoppage of treatment were seen more frequently in the first year, so not all patients are able to receive the 1–3 yr of treatment recommended in current guidelines.This study was registered at ClinicalTrials.gov with identifier NCT00002990 (http://clinicaltrials.gov/ct2/show/record/NCT00002990).

Does age really matter in the choice of treatment for bladder cancer?

Sir, We would like to congratulate Noon et al (2013) on their work on the effect of patients' age on the outcome of surgery for bladder cancer (BC). In their elegant paper, the authors compared the risks of competing mortality and demonstrated that older patients with BC had significantly worse cause-specific mortality than younger ones. To evaluate outcomes with respect to patient age, they compared treatments by stratifying cohorts of high-risk BC patients according to age and demonstrated that intravesical bacillus Calmette-Guerin (BCG) for high-risk disease was used less frequently in the oldest patients. They concluded that clinicians should consider offering more aggressive treatment in older patients. In order to confirm these findings and recommendations concerning the use of BCG in the elderly, we would like to share our experience of the effect of age on the outcomes of high-risk BC therapy. Analysing our extensive series of such patients treated at Padova University Hospital from 1995 to 2010, we focused on cases with primary high-risk BC (Ta-T1 HG and carcinoma in situ), who received immunotherapy with BCG as first treatment after complete transurethral resection of the cancer. BCG was demonstrated to be the most efficacious available treatment before radical cystectomy for these kinds of BC patients (Holmang, 2013). We performed 6 weekly inductions of intravesical instillations of BCG and, after endoscopic evaluation, a monthly maintenance cycle for 1 year. We used a low dose of BCG (27 mg), as reported in our historical study that first demonstrated the efficacy of this low dosage (Pagano et al, 1991), with significant reduction of side effects. To obtain comparable data, we excluded patients who had previously undergone other types of chemotherapy (e.g., Mitomycin C, Epirubicin) or other therapies (thermotherapy, partial surgery). We included in our study only patients with bladder transitional cell carcinoma, excluding those with other histologic neoplasms or synchronous cancers of the upper urinary tract. Analysing only cases with a follow-up of at least 24 months, we selected 343 patients (mean age 63.6 years, 28–88), 293 men and 50 women. To evaluate whether age is a predictive factor of outcome of BCG treatment, we focused specifically on the response to immunotherapy treatment, evaluating disease-free survival (DFS: considered as the absence of recurrence of BC after BCG therapy) after a follow-up of 60 months, time to recurrence, progression of disease (defined as upstaging of BC) and interruption of treatment due to side effects. Using Fisher's exact test, the Kruskall–Wallis test and Kaplan–Meier analysis (Figure 1), we found that the percentage of DFS was not statistically different in any of the examined age groups (<50, 50–59, 60–69, 70–79, ⩾80 years; P=0.94). No difference was found with regard to gender (P=0.23). Time to recurrence and progression of BC were also similar in the various age cohorts, with P=0.73 and 0.77, respectively. Even in the cases with severe side effects, age did not influence the percentages in the various patient groups. Figure 1 Kaplan–Meier curve for disease-free survival according to age groups. Our data indicate that, in patients with primary high-risk BC suitable for BCG treatment, age is not a factor predictive of recurrence or progression of disease. In addition, as emphasised by Noon et al (2013), our findings confirm that, when BCG therapy is indicated, it should also be performed in the elderly, because age does not seem to be a criterion indicating other less efficacious therapies.

BCG-Mediated Bladder Cancer Immunotherapy: Identifying Determinants of Treatment Response Using a Calibrated Mathematical Model

Intravesical Bacillus Calmette Guérin (BCG) immunotherapy is considered the standard of care for treatment of non-muscle invasive bladder cancer; however the treatment parameters were established empirically. In order to evaluate potential optimization of clinical parameters of BCG induction therapy, we constructed and queried a new mathematical model. Specifically, we assessed the impact of (1) duration between resection and the first instillation; (2) BCG dose; (3) indwelling time; and (4) treatment interval of induction therapy – using cure rate as the primary endpoint. Based on available clinical and in vitro experimental data, we constructed and parameterized a stochastic mathematical model describing the interactions between BCG, the immune system, the bladder mucosa and tumor cells. The primary endpoint of the model was the probability of tumor extinction following BCG induction therapy in patients with high risk for tumor recurrence. We theoretically demonstrate that extending the duration between the resection and the first BCG instillation negatively influences treatment outcome. Simulations of higher BCG doses and longer indwelling times both improved the probability of tumor extinction. A remarkable finding was that an inter-instillation interval two times longer than the seven-day interval used in the current standard of care would substantially improve treatment outcome. We provide insight into relevant clinical questions using a novel mathematical model of BCG immunotherapy. Our model predicts an altered regimen that may decrease side effects of treatment while improving response to therapy.

Efficacy of combined intravesical immunotherapy and chemotherapy for non-muscle invasive bladder cancer

Intravesical immunotherapy using attenuated bacillus Calmette–Guérin (BCG) strains and intravesical chemotherapy are the modalities most commonly used to treat intermediate- or high-risk patients with non-muscle invasive bladder cancer. BCG has been shown to decrease recurrence rates by up to 67% compared with tumor resection alone, but intensive BCG maintenance regimens are poorly tolerated in a large proportion of patients. Intravesical chemotherapy also decreases the risk of recurrence for these patients, but has diminished efficacy compared with BCG. If BCG dose reduction can be achieved with combined intravesical immunotherapy and chemotherapy, this regimen may improve compliance and thus optimize treatment for these patients by limiting side effects from BCG monotherapy, while at the same time improving oncologic efficacy via the separate anti-tumor mechanisms of these agents. The authors discuss the most recent data regarding combining these agents in an alternating or sequential regimen.

Protection of Eurasian badgers ( Meles meles) from tuberculosis after intra-muscular vaccination with different doses of BCG

Mycobacterium bovis infection is widespread in Eurasian badger ( Meles meles) populations in Great Britain and the Republic of Ireland where they act as a wildlife reservoir of infection for cattle. Removal of infected badgers can significantly reduce the incidence of bovine tuberculosis (TB) in local cattle herds. However, control measures based on culling of native wildlife are contentious and may even be detrimental to disease control. Vaccinating badgers with bacillus Calmette-Guerin (BCG) has been shown to be efficacious against experimentally induced TB of badgers when administered subcutaneously and orally. Vaccination may be an alternative or complementary strategy to other disease control measures. As the subcutaneous route is impractical for vaccinating wild badgers and an oral vaccine bait formulation is currently unavailable, we evaluated the intramuscular (IM) route of BCG administration. It has been demonstrated that the IM route is safe in badgers. IM administration has the practical advantage of being relatively easy to perform on trapped wild badgers without recourse to chemical immobilisation. We report the evaluation of the efficacy of IM administration of BCG Danish strain 1331 at two different doses: the dose prescribed for adult humans (2–8 × 10 5 colony forming units) and a 10-fold higher dose. Vaccination generated a dose-dependent cell-mediated immune response characterised by the production of interferon-γ (IFNγ) and protection against endobronchial challenge with virulent M. bovis. Protection, expressed in terms of a significant reduction in the severity of disease, the number of tissues containing acid-fast bacilli, and reduced bacterial excretion was statistically significant with the higher dose only.

1655 INTRAVESICAL GEMCITABINE VERSUS BACILLUS CALMETTE-GUERIN ( BCG) IN TREATMENT OF NON-MUSCLE INVASIVE BLADDER CANCER: SHORT TERM COMPARATIVE STUDY

You have accessJournal of UrologyBladder Cancer: Superficial1 Apr 20111655 INTRAVESICAL GEMCITABINE VERSUS BACILLUS CALMETTE-GUERIN ( BCG) IN TREATMENT OF NON-MUSCLE INVASIVE BLADDER CANCER: SHORT TERM COMPARATIVE STUDY Lotfy Bendary, Salem Khalil, Ashraf Shahin, and Nashwa Nawar Lotfy BendaryLotfy Bendary Zagazig, Egypt More articles by this author , Salem KhalilSalem Khalil Zagazig, Egypt More articles by this author , Ashraf ShahinAshraf Shahin Zagazig, Egypt More articles by this author , and Nashwa NawarNashwa Nawar Zagazig, Egypt More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2011.02.1765AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES There is still some controversy about the best agent to be used for intravesical therapy after TURBT.So the aim of this study is to compare the efficacy and safety of intravesical instillation of the new drug (Gemcitabine) versus (BCG) in treatment of non-muscle invasive TCC of the bladder. METHODS During the period from January 2006 to June 2008, 80 patients with primary Ta-T1 TCC of the bladder without CIS were the subject of the study. Their mean age was (56.2 ± 11.18 years). After complete TURBT patients were randomized to receive Gemcitabine or BCG (40 patients for each group). Both groups received 6 weekly intravesical instillation after 2 weeks from resection. BCG dose was 6×108 colony forming units in 50 ml of normal saline. Gemcitabine dose was 2000 mg dissolved in 50 ml normal saline. The follow up period ranged from 3-18 months (mean 10.8 ±2.7 months). The end point of the study for any patient was either completing a period of 18 months of follow up without recurrence or progression , or appearance of recurrence and / or progression at any time during the period of follow up. RESULTS Ta group showed recurrence in 26.31% of the BCG group and in 22.22% of the Gemcitabine group, with no statistically significant difference between both groups (P =0.92), progression occurred in one patient of either group. T1 tumors showed recurrence in 33.33% of patients in the BCG group and in 27.27% patients of the Gemcitabine group with insignificant statistical difference(P =0.66), progression occurred in 9.5%,9.1% respectively with no statistically significant difference (P=1.0). The overall recurrence for the BCG group was 30% compared to 25% for the gemcitabine group with insignificant statistical difference (p=0.61) while the overall progression for the BCG group and the Gemcitabine group was equal(p=1.0). As regard safety, Gemcitabine was better tolerated than BCG with better safety profile. Dysuria was present in 35% in the BCG group compared to 12.5% in the gemcitabine group with statistically significant difference (P< 0.05) and urinary frequency was present in 45% of the BCG group compared to 10% in the gemcitabine group with highly significant statistical difference (P <0.001). CONCLUSIONS After complete TUR-BT, at short term follow up, intravesical Gemcitabine was as effective as BCG in prevention of recurrence and progression of non-muscle invasive TCC of the bladder, even with a better safety profile and minimal toxicity. Further studies are needed to confirm these findings in a large number of patients with a longer follow up period. © 2011 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetailsCited byGontero P, Oderda M, Mehnert A, Gurioli A, Marson F, Lucca I, Rink M, Schmid M, Kluth L, Pappagallo G, Sogni F, Sanguedolce F, Schiavina R, Martorana G, Shariat S and Chun F (2018) The Impact of Intravesical Gemcitabine and 1/3 Dose Bacillus Calmette-Guérin Instillation Therapy on the Quality of Life in Patients with Nonmuscle Invasive Bladder Cancer: Results of a Prospective, Randomized, Phase II TrialJournal of Urology, VOL. 190, NO. 3, (857-862), Online publication date: 1-Sep-2013. Volume 185Issue 4SApril 2011Page: e664-e665 Advertisement Copyright & Permissions© 2011 by American Urological Association Education and Research, Inc.MetricsAuthor Information Lotfy Bendary Zagazig, Egypt More articles by this author Salem Khalil Zagazig, Egypt More articles by this author Ashraf Shahin Zagazig, Egypt More articles by this author Nashwa Nawar Zagazig, Egypt More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

1740 RETROSPECTIVE STUDY OF DIFFERENT OPTIONS IN THE MANAGEMENT OF NON-MUSCLE INVASIVE BLADDER CANCER T1G3: MAINTENANCE BCG IS HERE TO STAY

You have accessJournal of UrologyBladder Cancer: Superficial1 Apr 20111740 RETROSPECTIVE STUDY OF DIFFERENT OPTIONS IN THE MANAGEMENT OF NON-MUSCLE INVASIVE BLADDER CANCER T1G3: MAINTENANCE BCG IS HERE TO STAY Juan Palou, Eduardo Solsona, J. Angulo, Jesús María Fernández, Miguel Unda, and L.M. Piñeiro Juan PalouJuan Palou Barcelona, Spain More articles by this author , Eduardo SolsonaEduardo Solsona Valencia, Spain More articles by this author , J. AnguloJ. Angulo Madrid, Spain More articles by this author , Jesús María FernándezJesús María Fernández Madrid, Spain More articles by this author , Miguel UndaMiguel Unda Madrid, Spain More articles by this author , and L.M. PiñeiroL.M. Piñeiro Madrid, Spain More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2011.02.2067AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES The management of T1G3 non-muscle invasive bladder cancer (NMIBC) has evolved during the last 20 years but recurrence and progression remain the main concerns. The introduction of intravesical Bacillus Calmette-Guerin (BCG) with different doses and number of doses is still under debate. Good first TUR and Re-TUR has become standart of care in high grade NMIBC in order to improve clinical staging and otucomes by decreasing understaging and residual disease. To evaluate, in a large retrospective series of patients, the differences in recurrence, progression to invasive disease and cancer specific survival according to the different treatments received in the different periods before and after the introduction of BCG. METHODS This is a retrospective analysis of 1039 patients with primary and recurrent stage T1G3 NMIBC including 945 males (mean age of 66.5, b9.8 years, range 21–89). All underwent a complete TUR with multiple bladder biopsies, with muscle present in the specimen. All of them were treated conservatively as follows: 1) no BCG, 2) Re-TUR only, 3) BCG Connaught 27 mgrs induction course, 4) BCG Connaught 81 mgrs induction course, 5) BCG Connaught 81 mgrs induction course + maintenance. There were no differences on the distribution in the groups except that patients with CIS and recurrent tumours were treated more frequently with BCG (p<0.001). We evaluate the time to first recurrence, progression to a higher stage (T2 or greater, or metastatic disease), disease specific mortality. Time to event was estimated with Kaplan Meier and then compared using the logrank test and the multivariate Cox proportional hazards regression model. RESULTS The following results were observed with a median followup of 62±39 months. CONCLUSIONS BCG treatment with maintenance offers the best results in recurrence, progression and disease specific survival in patients with stage T1G3 bladder cancer. Full dose BCG is better than one third dose related to the same parameters. There is an important difference in recurrence rate between the patients treated with or wihout BCG. Full dose BCG treatment reduces progression to invasive disease. Disease specific mortality is better in those patients treated with BCG. Despite being a retrospective study, the large number of patients offers an overview of the impact of the different conservative modalities in patients with T1G3 NMIBC. © 2011 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 185Issue 4SApril 2011Page: e698-e699 Advertisement Copyright & Permissions© 2011 by American Urological Association Education and Research, Inc.MetricsAuthor Information Juan Palou Barcelona, Spain More articles by this author Eduardo Solsona Valencia, Spain More articles by this author J. Angulo Madrid, Spain More articles by this author Jesús María Fernández Madrid, Spain More articles by this author Miguel Unda Madrid, Spain More articles by this author L.M. Piñeiro Madrid, Spain More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Quel traitement d’entretien par instillations endovésicales de BCG pour les tumeurs de vessie n’infiltrant pas le muscle ?

Intravesical Bacillus Calmette-Guerin (BCG) is the standard treatment after transurethral resection for intermediate or high-risk non muscle-invasive bladder cancer. The objective is to prevent tumor recurrence and progression with muscle invasion. To improve immunotherapy efficacy, an induction course followed by maintenance BCG cycles is strongly recommended. The SWOG schedule is today considered as the gold standard, consist of three weekly instillations of BCG at 3 and 6 months, and every 6 months for 3 years. However, less than 20% of the patients are able to complete the 3-year maintenance-dosing schedule because of BCG side effects. Prophylactic ofloxacin could lead to a reduction of 18.5% of grade II and III toxicity. Alternative schedules have been currently evaluated to improve the tolerance of maintenance treatment with endo-vesical instillations of BCG. Thus, low dose BCG during maintenance therapy does not appear to affect the recurrence-free survival and/or the risk of tumor progression. In contrast, the optimal number of instillations of BCG maintenance therapy remains to be defined.

Assessment of immune response to repeat stimulation with BCG vaccine using in vitro PBMC model

BackgroundTuberculosis (TB) is one of the most prevalent cause of death due to a single pathogen. Bacillus Calmette Guérin (BCG) is the only vaccine available for clinical use that protects against miliary TB; however, this vaccine has shown variable levels of efficacy against pulmonary TB. In India, a single dose of BCG vaccine is given and there are few countries where repeated doses of BCG are given. The incidence of TB in India is very high inspite of primary vaccination in neonatal period and therefore requires consideration for repeated immunization.MethodsTo improve BCG immunogenicity, we have evaluated specific antimycobacterial immune responses (anti-BCG IgG and IFN-γ), T cell activity-ADA, CD4 and CD8 T cell count, and CD4/CD8 ratio in a peripheral blood mononuclear cells (PBMC) model using boost immunization protocols with the BCG vaccine. PBMC were induced with a repeat dose of BCG at 24 and 72 hrs of cell culture.ResultsAt the end of the experimental time, supernatant was collected to estimate anti-BCG IgG titer, interferon γ, ADA activity, CD 4 and CD8 T cell count, and CD4/CD8 ratio. We demonstrated that PBMC induced with a repeat dose of BCG showed an increased specific anti-mycobacterial immune responses, T cell activity, and ADA activity as compared to PBMC induced with BCG alone or without BCG induction.ConclusionThe repeat BCG stimulation of PBMC obtained from BCG vaccinated individuals shows enhanced immune activation with respect to increased anti-BCG titre, IFN-γ and ADA activity without concomitant increase in CD4 and CD8 cells. This study provides some basic data in future experiments in animal models with respect to repeat BCG vaccination.

318 ANTI-ANGIOGENIC EFFECTS OF THE SUPERANTIGEN STAPHYLOCOCCAL ENTEROTOXIN B (SEB) AND BACILLUS CALMETTE-GUERIN (BCG) IMMUNOTHERAPY IN THE SUPERFICIAL BLADDER CANCER (SBC)

You have accessJournal of UrologyUrothelial Cancer: Medical & Surgical Therapy1 Apr 2010318 ANTI-ANGIOGENIC EFFECTS OF THE SUPERANTIGEN STAPHYLOCOCCAL ENTEROTOXIN B (SEB) AND BACILLUS CALMETTE-GUERIN (BCG) IMMUNOTHERAPY IN THE SUPERFICIAL BLADDER CANCER (SBC) Leonardo O. Reis, Valéria H.A. Cagnon, Ubirajara Ferreira, Athanase Billis, and Wagner J. Fávaro Leonardo O. ReisLeonardo O. Reis More articles by this author , Valéria H.A. CagnonValéria H.A. Cagnon More articles by this author , Ubirajara FerreiraUbirajara Ferreira More articles by this author , Athanase BillisAthanase Billis More articles by this author , and Wagner J. FávaroWagner J. Fávaro More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2010.02.382AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES The angiogenic phenotype can be defined as an effect of balance between angiogenic and anti-angiogenic factors. Vascular endothelial growth factor (VEGF) is important regulator of cancer cell growth and metastases. Endostatin is one of angiogenic inhibitors which plays an important role in suppressing tumor growth. However, the endostatin anti-angiogenic mechanisms on urothelial tissue are unclear. Thus, the aim of this work was to characterize the anti-angiogenic effects of the BCG, SEB and BCG plus SEB treatments in the SBC of rats. METHODS Fifty 7-week-old female Fisher 344 rats were anesthetized and 10 of them received 0.3 ml dose of saline (Control group). Other 40 rats received 1.5 mg/kg dose of n-methyl-n-nitrosourea (MNU), intravesically every other week for 7 weeks. After MNU treatment, the 40 rats were divided into 4 groups: The MNU group; The SEB group received 10 μg/ml dose of SEB intravesically for 8 weeks; The BCG group received 106 UFC dose of BCG for 8 weeks; The BCG-SEB group received simultaneous BCG and SEB treatments. After 15 weeks, all bladders were collected for immunological analyses of the VEGF receptor (VEGFR), endostatin, matrix metalloproteinase 9 (MMP-9), insulin like growth factor receptor 1 (IGFR-1), Ki-67 (cellular proliferation) and apoptosis. RESULTS The apoptosis and cellular proliferation indexes were increased in all treatment groups. However, these processes were decreased in the BCG, SEB and BCG-SEB groups in relation to the MNU group. These indexes were similar to the normal status in the BCG-SEB group. Intensified VEGFR, IGFR-1 and MMP-9 immunoreactivities were verified in the MNU group; moderate in the BCG and SEB groups; and weak in the BCG-SEB and Control groups. Weak endostatin immunoreactivity was seen in the blood vessels of the MNU, BCG and SEB groups, moderate in the BCG-SEB group and intense in the Control group. CONCLUSIONS The associated BCG-SEB treatment was more effective in restoring apoptosis and cellular proliferation balance than BCG or SEB treatments. VEGFR, MMP-9 and IGFR-1 reactivities were an important pathway in cellular proliferation, and can be considered fundamental elements involved in bladder carcinogenesis. Furthermore, the decreased cellular proliferation and neoplastic features were correlated with increased endostatin and decreased VEGFR reactivities, mainly, in the BCG-SEB group. Finally, the association between BCG and SEB may be effective in treating bladder cancer focusing on angiogenic homeostasis. Campinas, Brazil© 2010 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 183Issue 4SApril 2010Page: e126 Advertisement Copyright & Permissions© 2010 by American Urological Association Education and Research, Inc.MetricsAuthor Information Leonardo O. Reis More articles by this author Valéria H.A. Cagnon More articles by this author Ubirajara Ferreira More articles by this author Athanase Billis More articles by this author Wagner J. Fávaro More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

The Safety and Efficacy of Different Doses of Bacillus Calmette Guérin in Superficial Bladder Transitional Cell Carcinoma

Objectives To conduct a trial using three different doses of bacillus Calmette-Guérin (BCG) to determine whether lowering the dose of BCG could reduce toxicity without compromising its efficacy in the treatment of superficial bladder cancer. Methods From July 2002 to June 2005, 152 patients with superficial bladder cancer entered the trial. The patients were randomized to receive three different doses of BCG: 40, 80, and 120 mg. There were no significant differences in clinical and pathologic characteristics among the three groups. Twenty-four patients could not be followed to the end of the study because of poor compliance. At completion of the study, 40 patients could be evaluated in group A (40 mg), 48 in group B (80 mg), and 40 in group C (120 mg). Results After treatment patients were evaluated for a mean follow-up period of 36 months (range 18 to 52 months). No significant difference in recurrence rate (20% versus 25% versus 20% respectively; P >0.05) was observed among the groups, and no progression of the disease was seen. Significant differences were observed among groups A, B, and C in local toxicity (30% versus 41.7% versus 70%, respectively; P <0.01). Systemic toxicity was more common in group C compared with groups B and A (P <0.01). Conclusions Reduction in the dose of intravesical BCG can reduce the toxicity associated with the treatment of superficial bladder cancer without affecting the efficacy of therapy.

A Multicentre, Randomised Prospective Trial Comparing Three Intravesical Adjuvant Therapies for Intermediate-Risk Superficial Bladder Cancer: Low-Dose Bacillus Calmette-Guerin (27 mg) versus Very Low-Dose Bacillus Calmette-Guerin (13.5 mg) versus Mitomycin C

ObjectiveThe primary aim was to search for lower doses of Bacillus Calmette-Guerin (BCG) that are effective and have lower toxicity. MethodsA low dose of BCG 27mg was compared with BCG 13.5mg, using mitomycin C (MMC) 30mg as the third arm of comparison. A total of 430 patients with intermediate-risk superficial bladder cancer were randomised into three groups. Instillations were repeated once a week for 6 wk followed by another six instillations given once every 2 wk during 12 wk. ResultsThere was a significantly longer disease-free interval for BCG 27mg versus MMC 30mg (p=0.006). There were no statistically significant differences between BCG 27mg and BCG 13.5mg (p=0.165) or between BCG 13.5mg and MMC 30mg (p=0.183). Cox proportional hazards regression showed that disease-free interval in the multivariate analysis was significantly better for primary disease and treatment with BCG 27mg.There were no significant differences among the three groups with regards to time to progression and cancer-specific survival time. Local and systemic toxicity were higher in both BCG treatment groups. ConclusionsOne third of the standard dose, BCG 27mg, seems to be the minimum effective dose as adjuvant treatment for intermediate-risk superficial bladder cancer, being more effective than MMC 30mg. One sixth of the standard dose, BCG 13.5mg, has the same efficacy as MMC 30mg but it is more toxic.

The safety and immunogenicity of Bacillus Calmette-Guérin (BCG) vaccine in European badgers ( Meles meles)

European badgers ( Meles meles) are a wildlife reservoir for Mycobacterium bovis ( M. bovis) in Great Britain (GB) and the Republic of Ireland and therefore constitute a potential source of infection for cattle. Reduction of badger densities in the Republic of Ireland has resulted in an associated reduction in the risk of a herd break-down with bovine tuberculosis and a study to determine whether this is also the case in GB has been running since 1997. If badgers are a significant source of M. bovis infection for cattle, vaccinating badgers with Bacillus Calmette-Guérin (BCG) might prove to be a long term, cost-effective strategy for controlling bovine tuberculosis whilst preserving badger populations. As a first step towards BCG vaccination of wild badgers, it was necessary to demonstrate safety of the vaccine in captive badgers. Therefore, captive badgers were vaccinated with a commercial source of BCG that is already licensed for administration to humans in GB—BCG Danish SSI. Using a protocol prescribed by the Veterinary Medicines Directorate (VMD) of GB, badgers were vaccinated with two consecutive doses of BCG via either the subcutaneous (s.c.) or intra-muscular (i.m.) routes. The first dose was high, ranging from 16 to 22 × 10 7 colony-forming units (CFU), and was followed 15 weeks later by a lower dose in the range of 4–7 × 10 5 CFU. Local reaction at the site of injection and general responses (body temperature, haematology and blood serum chemistry), behaviour and excretion of BCG were monitored for 28 weeks from the time of the first vaccination. The only side-effect observed was the occurrence of localised swelling at the site of BCG injection that disappeared 48 days after i.m. vaccination but persisted longer in the group vaccinated by the s.c. route. Immunological responses were measured at regular intervals. Strong cellular responses were observed 13 days after the first vaccination, which persisted for 76 days. The lower dose induced a weaker and shorter-lived response.

Vaccination-relatedMycobacterium bovisBCG Infection

Vaccination-related<i>Mycobacterium bovis</i>BCG Infection

Radical cystectomy after bacillus Calmette-Guérin for high-risk Ta, T1, and carcinoma in situ: Defining the risk of initial bladder preservation

Objectives To critically evaluate the survival of patients with high-grade Ta or T1 urothelial cancer (UC) or carcinoma in situ of the bladder who have received bacillus Calmette-Guérin (BCG) and who have undergone radical cystectomy. Methods We retrospectively reviewed our single-surgeon database of those patients who underwent cystectomy and previously received BCG. We evaluated the baseline characteristics, pathologic outcomes, and survival data. Results Of 313 patients who underwent cystectomy between January 1992 and March 2004, 90 (29%) received BCG before bladder removal. The mean time from the first BCG course to the date of cystectomy was 27.9 months. The mean duration of follow-up from cystectomy was 32.1 months. The risk of progression to muscle invasion for those who underwent cystectomy less than or more than 1 year from the time of their first BCG dose was 59% and 36%, respectively ( P = 0.05). The disease-specific survival rate was 81% versus 80% for those who underwent early versus delayed cystectomy ( P = 0.9). Conclusions Patients with high-grade UC are at risk of dying from this cancer, even if they ultimately undergo cystectomy. Patients who receive BCG should be appropriately counseled that they remain at risk for disease progression and death from UC. It is difficult to ascertain the proper time to proceed with cystectomy if an initial bladder conservation approach is used.

A randomized trial comparing low dose (40 or 80 mg) with standard dose (120 mg) of bacillus Calmette-Guerin for superficial bladder cancer

Objective: Intravesical bacillus Calmette-Guerin (BCG) therapy is considered to be the most effective therapy for high-risk superficial cancer of bladder. Reduction in dose has been tried to decrease the toxicity following instillations of BCG while maintaining efficacy. This study compares the efficacy and toxicity of three different doses of modified Danish 1331 strain of BCG in patients with high risk superficial bladder cancers. Materials and Methods: A prospective randomized study was undertaken between January 2000 to March 2005 to include all patients with superficial bladder cancer who received BCG after fulfilling one or more of the appropriate criteria (grade above 1, stage above Ta, size >1 cm, multiple or recurrent). One hundred and six patients received 40 mg, 80 mg or 120 mg Danish 1331 strain BCG weekly for six weeks. The recurrence rates, tumor progression, toxicity and long-term outcome of three different doses of BCG were studied. No maintenance therapy was given. Results: Of the 106 patients, 28 received 40 mg, 37 received 80 mg and 41 received 120 mg of intravesical BCG for six weeks. The mean follow-up was three years (range one to six years). Overall, 77.4% patients responded to a single cycle of BCG, with a recurrence rate of 32.1% in 40 mg, 13.5% in 80 mg and 24.3% in the 120 mg groups. Median time to recurrence was seven months, eight months and nine months in the three groups respectively. Overall, six patients (5.6%) developed disease progression, two (7.1%) in the 40 mg, one (2.7%) in the 80 mg and three (7.3%) in the 120 mg arm. Kaplan - Meier analysis for time to recurrence ( P =0.1839) and time to progression ( P =0.595) was not significantly different in the three treatment arms. Adverse effects were seen in 55.6% patients with most being of class 1 severity. Significantly less patients developed severe adverse effects in the 40 mg group as compared to the higher dose groups. Conclusions: We conclude that 40 mg dose of intravesical BCG is as effective as the standard dose in reducing the risk of recurrence and progression. Moreover this dose is associated with significantly less toxicity.

Factores pronósticos en la recidiva y progresión del cáncer superficial vesical. Grupos de riesgo (Parte I)

IntroductionWe have carried out a retrospective study on a series of superficial bladder tumours, analyzing the clinical- pathological factors that can determine the subsequent evolution of the tumour as for recurrence and progression. Material and MethodsThey were revised on the whole 473, of which finally 419 superficial bladder tumours were useful for the study (223 primary tumours and 196 recurrent). Studies are carried out univariate and multivariate on 24 variables of each tumour referred to the characteristics and to the evolution of the tumour. ResultsWe find significant differences in the free time to recurrence, diminishing it in the tumours that recurred in less than 12 months, in multiple tumours (3 or more tumours) and in bladder dome tumours. Also statistically significant differences existed when were studied two homogeneous groups of surgeons, while the treatment with bladder instillations increased it. The time to progression, diminishes in: Tumours that had recurred prematurely (in 6 months), tumours over 3 cm, high grade tumours and when two groups of surgeons were studied, we also find that the maintenance therapy with BCG (bacillus Calmette-Guerin) showed a greater time to progression versus induction therapy. DiscussionThe independent factors to explain smaller free time till superficial recurrence were: recurrence in the 1º year, multiplicity, surgical technique, not employment of bladder washes, treatment with low dose of BCG and use of intravesical therapy with induction therapy versus maintenance. About the progression, we objectify that the factors with greater influence in the progression were, recurrence in the first 6 months, grade (grade 2 and grade 3 + Tis) and treatment with maintenance therapy versus induction.

HAS A 3-FOLD DECREASED DOSE OF BACILLUS CALMETTE-GUERIN THE SAME EFFICACY AGAINST RECURRENCES AND PROGRESSION OF T1G3 AND TIS BLADDER TUMORS THAN THE STANDARD DOSE? RESULTS OF A PROSPECTIVE RANDOMIZED TRIAL

We determined if a third of the dose of intravesical bacillus Calmette-Guerin (BCG) has the same efficacy than a standard dose for decreasing the risk of recurrence and progression after transurethral resection in patients with superficial high risk (stages T1G3 and carcinoma in situ) bladder cancer. Also, we evaluated toxic side effects. A total of 155 patients with a mean age +/- SD of 67 +/- 10.1 years with superficial bladder cancer, including stages T1G3 in 90, a Tis primary tumor in 23 and associated Tis disease in 42, were enrolled and randomly assigned to be treated after transurethral resection of all visible lesions with intravesical BCG, Connaught strain (weekly x 6 and fortnightly x 6 thereafter) with the standard dose of 81 mg or with the decreased dose of 27 mg. Median followup was 61 months (range 3 to 102). Disease recurred in 32 patients (39%) treated with the standard dose and in 33 (45%) treated with the decreased dose. Median time to recurrence was not attained in the standard dose arm and it was 63 months in the decreased dose arm. Kaplan-Meier estimates for time to recurrence did not reveal differences between the 2 doses (p = 0.405). Tumor progressed in 20 patients (24.7%) with the standard dose and in 19 (26%) with the decreased dose. Four patients (6.1%) with Tis had local extension into the prostatic urethra and ducts, including 3 (8.3%) treated with the standard dose and 1 (3.4%) treated with the decreased dose. Median time to progression was not attained in either arm. Kaplan-Meier estimates for time to progression did not differ significantly (p = 0.7997). Deferred cystectomy for progression was performed in 7 patients (8.4%) treated with the standard dose and in 7 (9.5%) of those treated with the decreased dose. Subgroup analysis by patient age, tumor status, number, size and T stage (T1G3 vs Tis) did not differ significantly. The groups did not differ in disease specific mortality, which was 12.2% in the standard dose arm and 16.4% in the decreased dose arm. Mean disease specific survival +/- SE was 86.96 +/- 4.14 and 83.73 +/- 4.73 months, respectively. Our results suggest that a 3-fold decreased dose of intravesical BCG is as effective as the standard dose against progression in patients with high risk stages T1G3 and Tis superficial bladder carcinoma but with significantly less toxicity.

Interim results from a national multicenter phase II trial of combination bacillus Calmette-Guerin plus interferon alfa-2b for superficial bladder cancer: O’Donnell MA, Lilli K, Leopold C, National Bacillus Calmette-Guerin/Interferon Phase 2 Investigator Group, Department of Urology, University of Iowa, Iowa City, IA

Interim results are provided from a large multicenter trial of combination bacillus Calmette-Guerin (BCG) plus interferon (IFN) alfa-2b for BCG naive (BCG-N) and previous BCG failure (BCG-F) cases of superficial bladder cancer. A total of 490 patients enrolled from May 1999 to May 2000 with a median of 24 months of followup were analyzed. The BCG-N group (259) was treated with a 6-week induction course of standard dose BCG plus 50 million units of IFN followed by 3, 3-week maintenance cycles of reduced dose BCG (1/3 to 1/10) plus 50 million units IFN at 3, 9 and 15 months after induction. The BCG-F group (231) was treated similarly except induction therapy began at a decreased (1/3 to 1/10) BCG dose. The simple tumor recurrence rates for BCG-N and BCG-F groups were 40% and 52%, and the Kaplan-Meier estimates for disease freedom at 24 months were 57% and 42%, respectively. Progression to muscle invasion occurred in 5% and 4.3% while metastasis occurred in 2.3% and 2.6%, respectively. In each group 3.9% of patients underwent cystectomy and 2 patients in each group died of bladder cancer. Serious adverse events occurred in 5.5% with infection related serious adverse events being less prevalent in the BCG-F group (2.6% vs 5.4%). Toxicity related dropout, treatment delay and/or further BCG dose reduction, and need for symptomatic drugs were similar. Moderate to severe local side effects during induction were higher in the BCG-F group (6.2% vs 16.9%) but equilibrated during maintenance therapy. Systemic reactions were rare. This multicenter trial provides a benchmark for the efficacy and safety of combination BCG and IFN as up front and salvage therapy. The incremental value of IFN cannot be determined from this study.