Bacillus Calmette-Guerin Group Research Articles

Attenuation of oxidative stress and neurotoxicity involved in the antidepressant-like effect of the MK-801(dizocilpine) in Bacillus Calmette-Guerin-induced depression in mice.

Background The emerging line of research suggests that neuro-inflammation and oxidative stress are linked to the development of depression-like behavior. The tryptophan metabolizing enzyme, indolamine 2,3-dioxygenase (IDO), serves as an important interface between chronic inflammation and depression. IDO is induced by pro-inflammatory cytokines and diverts tryptophan towards the kynurenine pathway, decreasing serotonin synthesis. Further, the metabolites of kynurenine pathway increase brain oxidative stress and also cause N-methyl-D-aspartate (NMDA) receptor-mediated exitotoxicity. The resulting oxidative damage and dysfunction in glutamatergic neurotransmission alters the network connectivity of the brain, which may be the further mechanism for emergence of depression-like symptoms. Methods A depression-like illness was induced in mice by injecting Bacillus Calmette-Guerin (BCG) suspended in isotonic saline at a dose of 107 CFU I.P. The mice were then divided into different groups and were administered MK-801 or normal saline for the next 21 days, after which a battery of behavior and biochemical tests were conducted to assess them. Results The BCG group had significantly reduced sucrose preference index and an increase in immobility time in forced swim test (FST) and Tail Suspension Test (TST) as compared to the saline group. There was also a significant increase in the brain MDA levels and a decline in the brain GSH levels. The hippocampal tissue from the BCG group had significantly more comet cells than the saline group. The NMDA receptor antagonist, MK-801, was able to reverse the BCG-induced depression-like behaviour. MK-801 also showed significant decrease in brain oxidative stress but failed to show significant protection against BCG-induced neurotoxicity observed in comet assay. Conclusions The NMDA receptor antagonist, MK-801, mitigated BCG-induced, depressive-like behavior in mice by improving the sucrose preference and decreasing the duration of immobility time in TST and FST. The overall improvement in depression-like behavior was accompanied by a reduction in brain oxidative stress and comet cells, thus suggesting the antioxidant and neuroprotective action of MK-801.

Safety and efficacy of intensive instillation of low-dose pirarubicin vs. bacillus Calmette-Guérin in patients with high-risk non-muscle-invasive bladder cancer

ObjectivesTo evaluate the safety and efficacy of intensive intravesical instillation of low-dose pirarubicin (THP) for 6 times vs. bacillus Calmette-Guérin (BCG) without maintenance therapy after transurethral resection of bladder tumor (TURBT) in patients with primary high-risk non-muscle-invasive bladder cancer (NMIBC). Materials and MethodsWe retrospectively evaluated 370 patients with primary high-risk NMIBC who underwent TURBT from November 1993 to April 2019. The patients were divided into 2 groups: patients treated with intravesical instillation of BCG without maintenance therapy (BCG group) and intensive intravesical instillation of low-dose (20 mg) THP for 6 times within 10 days after TURBT (THP group). Safety was assessed using the Common Terminology Criteria for Adverse Events version 5.0. Background-adjusted multivariate analyses were performed to evaluate the effect of intensive intravesical instillation of low-dose THP on oncological outcomes, including intravesical recurrence-free survival (RFS), upper urinary tract RFS, muscle-invasive bladder cancer-free survival, metastasis-free survival, cancer-specific survival, and overall survival. ResultsOf the 370 patients with primary high-risk NMIBC, 180 (49%) and 190 (51%) were stratified into the BCG and THP groups, respectively. The incidence rate of adverse events of any grade in the BCG group was significantly higher than that in the THP group (P < 0.001). In the background-adjusted multivariate analyses, no significant differences were observed in oncological outcomes between the BCG and THP groups. ConclusionsIntensive intravesical instillation of low-dose THP for 6 times may be one of the treatment options in view of safety and efficacy after TURBT in patients with primary high-risk NMIBC.

MP73-05 BCG-UNRESPONSIVE NMIBC, COMPARISON OF 2 ND -LINE INTRAVESICAL INSTILLATION THERAPY

You have accessJournal of UrologyBladder Cancer: Non-invasive IV (MP73)1 Apr 2020MP73-05 BCG-UNRESPONSIVE NMIBC, COMPARISON OF 2ND-LINE INTRAVESICAL INSTILLATION THERAPY Gal Rinott Mizrahi*, Yuval Freifeld, Ido Orlin, Ilona Pilosov, Boris Friedman, and Yoram Dekel Gal Rinott Mizrahi*Gal Rinott Mizrahi* More articles by this author , Yuval FreifeldYuval Freifeld More articles by this author , Ido OrlinIdo Orlin More articles by this author , Ilona PilosovIlona Pilosov More articles by this author , Boris FriedmanBoris Friedman More articles by this author , and Yoram DekelYoram Dekel More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000959.05AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Intravesical instillation of live attenuated bacillus Calmette-Guérin (BCG) is the gold standard treatment for intermediate and high-risk Non-Muscle-Invasive Bladder Cancer (NMIBC), with proven effects on reducing recurrence, progression, and death. However, it is not effective in all patients, and recurrence after adequate BCG therapy can lead to progression and to a life-threatening disease. For this reason, the current recommendation for BCG-unresponsive disease is early radical cystectomy. In practice, most patients at that point prefer less aggressive treatment or are un-fit for radical surgery and therefore are treated with 2nd-line intravesical instillations. The objective of the current study is to compare 2nd line treatments for BCG-unresponsive disease. METHODS: This is a retrospective study based on a single institutional database. The study population included patients with BCG-unresponsive disease treated in our department during 2008-2016. BCG-unresponsive disease was defined as persistence or progression within 12 months of adequate BCG therapy. For each patient data regarding 2nd line therapy and oncologic outcome was obtained. RESULTS: Of 315 patients treated with BCG during the defined period, 68 patients had BCG-unresponsive disease. Presentation of unresponsive disease was with muscle invasive/metastatic disease in 25% of patients and with NMIBC in 75% of patients (n=51). In the NMIBC group 6 patients had early cystectomy, 21 were treated with re-induction BCG and 23 were treated with Thermo-chemotherapy Mitomycin C (SYNERGO). Response to 2nd line treatment was observed in 33.3% and 39.1% in the BCG and SYNERGO groups respectively. Immediate progression to muscle invasive/metastatic disease was observed in 19% and 26.1% in the BCG and SYNERGO groups respectively. In each group 3 patients further progressed to metastatic disease during follow-up. CONCLUSIONS: We found a response rate to 2nd line intravesical instillation therapy in BCG-unresponsive disease of 35% with no significant difference between re-induction with BCG or SYNERGO. Progression to muscle invasive/metastatic disease was observed in 35% of patients with no significant difference between groups. These results emphasize the need to present to patients with BCG-unresponsive disease, the poor prognosis of their disease and encourage strongly towards early cystectomy. For patient who refuse or are un-fit, there is no significant differences between re-induction with BCG or SYNERGO. Source of Funding: non © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 203Issue Supplement 4April 2020Page: e1122-e1123 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Gal Rinott Mizrahi* More articles by this author Yuval Freifeld More articles by this author Ido Orlin More articles by this author Ilona Pilosov More articles by this author Boris Friedman More articles by this author Yoram Dekel More articles by this author Expand All Advertisement PDF downloadLoading ...

MP72-10 THE OUTCOME OF PATIENTS WITH HIGH-RISK NON-MUSCLE INVASIVE BLADDER CANCER IN SWEDEN

You have accessJournal of UrologyBladder Cancer: Non-invasive III (MP72)1 Apr 2020MP72-10 THE OUTCOME OF PATIENTS WITH HIGH-RISK NON-MUSCLE INVASIVE BLADDER CANCER IN SWEDEN Eugen Wang*, Ulf Larsson, Truls Gårdmark, and Per-Uno Malmström Eugen Wang*Eugen Wang* More articles by this author , Ulf LarssonUlf Larsson More articles by this author , Truls GårdmarkTruls Gårdmark More articles by this author , and Per-Uno MalmströmPer-Uno Malmström More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000952.010AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: At the time of bladder cancer detection, about 2/3 are non-muscle invasive bladder cancer (NMIBC). The high-risk NMIBC tumor types (TaG3, T1G2,T1G3 or/and Tis) present an increased risk of progression to deep-growing cancer and metastasis. Our aim was to identify this group of patients in the Bladder Cancer Data Base Sweden (BladderBaSe) and analyze the cancer specific survival after different managements. METHODS: BladderBaSe was created in 2015. This database links information from the Swedish National Register of Urinary Bladder Cancer (SNRUBC) from 1997 to 2014, with a number of national health care and demographic registers through the use of the personal identification numbers. The national register has detailed data on 97% of the bladder cancer cases diagnosed in Sweden. In 1997-2014 in Sweden, a total of 26808 patients were diangosed with NMIBC, of whom 10209 were high-risk cancer with median age 71 and 80 % male. 5660 patients were treated with TURBT only, 3862 had inital Bacillus Calmette-Guérin (BCG). Radical cystectomy was performed in 687 patients initially while 399 had delayed cystectomy after BCG. RESULTS: Characteristics of patients with high risk NMIBC is shown in table 1. During the follow-up 5 years, the cancer specific survival chance was higher for the BCG group (85 %) than it was for the initial radical cystectomy (75 %) or TURBT only group (65 %). (Fig.1). In a Cox proportional hazards model younger patients, lower cancer stage, initial treatment with BCG and treatment in high volume university hospital was associated with better survival. CONCLUSIONS: Initial BCG installation with or without delayed cystectomy improved cancer specific survival more than initial cystectomy in high-grade T1 bladder cancer in this population registry. However selection criteria could be a cause for confounding and will be further studied. Source of Funding: Schmekel fund in Urological research © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 203Issue Supplement 4April 2020Page: e1077-e1077 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Eugen Wang* More articles by this author Ulf Larsson More articles by this author Truls Gårdmark More articles by this author Per-Uno Malmström More articles by this author Expand All Advertisement PDF downloadLoading ...

BCG instillation versus radical cystectomy for high-risk NMIBC with squamous/glandular histologic variants

This study aims to evaluate the effect of Bacillus Calmette-Guérin (BCG) instillation and radical cystectomy on high-risk NMIBC with squamous or glandular variants. We retrospectively reviewed the data of high-risk (T1 or CIS or HG or TaG1/G2 with multiple, recurrent, large tumor) NMIBC patients from January 2000 to December 2017. Comparative analysis of radical cystectomy, intravesical BCG, and observation groups was conducted in high-risk NMIBC with squamous or glandular histologic variants. Among the 1263 high-risk NMIBC patient, 62 (4.9%) were reported squamous or glandular histologic variants. Thirty patients underwent BCG instillation and 15 patients were subjected to radical cystectomy. Statistically significant differences were found between the three treatment groups in terms of underlying hypertension (p = 0.031), T stage (p = 0.022) and tumor multiplicity (p = 0.019). Similar 5-year OS (p = 0.893) and CSS (p = 0.811) were observed in each of BCG instillation and radical cystectomy group. BCG instillation showed survival benefit in both OS (p = 0.019) and CSS (p = 0.038) than in the observation group. In high-risk patients diagnosed with NMIBC bladder cancer with squamous or glandular histologic variants, both intravesical BCG and radical cystectomy showed survival gain. In conclusion, BCG instillation represents an appropriate treatment option in high-risk NMIBC with squamous or glandular histologic variant.

Definitive BCG immunotherapy versus radical cystectomy in intermediate or high-risk nonmuscle invasive bladder cancer patients: A retrospective study.

At present, intravesical Bacillus Calmette-Guerin (BCG) immunotherapy is recommended for prophylaxis purposes after transurethral resection of bladder tumor, but has chances of recurrence. Radical cystectomy reduces the risk of recurrence in bladder cancer patients, but may have chances of postoperative complications. The objective of the study was to test the hypothesis that radical cystectomy has overtreatment and definitive BCG immunotherapy has undertreatment in intermediate or high-risk nonmuscle invasive bladder cancer patients. Data regarding biopsies, ultrasound, the computed tomography scan, adopted treatment strategy, treatment-emergent adverse effect, and a follow-up period of 312 patients with confirmed nonmuscle invasive bladder cancer (pTa, pTis, or pT1 stage; intermediate or high-risk cancer) were reviewed. Patients who had received definitive intravesical BCG immunotherapy were included in BCG group (n = 210) and those who underwent radical cystectomy were included in RXC group (n = 87). Clinical decision-making for treatment strategies was evaluated for both groups. Cystitis was frequently observed in all patients who received BCG immunotherapy. In RXC group, ileus was frequently observed in all patients in early days after the operation. During 2 years of the follow-up period, biopsies, ultrasound, and the computed tomography scan reported that BCG group had fewer numbers of negative cancer patients after treatment than the RXC group after surgery (P < .0001). Total expenditure for BCG immunotherapy was higher than radical cystectomy (22,945 ± 945 ¥/patient vs 17,985 ± 545 ¥/patient; P < .0001). Definitive BCG immunotherapy had undertreatment and radical cystectomy had overtreatment for intermediate or high-risk invasive bladder cancer patients (level of evidence III).

EXPRESSION OF IMMUNOGLOBULIN, GRANZYME-B AND PERFORIN AGAINST Ag85A AND Ag85B PROTEINS OF MYCOBACTERIUM TUBERCULOSIS IN BALB/C MICE.

Background:Ag85 is a protein that may maintain survival of M. tuberculosis in intracellular parts of host cells and is considered as a virulence factor. The expression of Ag85 protein can stimulate proliferation and differentiation of B- cells and T-cells in patients with tuberculosis. This research aimed to determine the ability of Ag85A and Ag85B proteins in activating the response of antibodies, granzyme-B and perforin in Balb/c mice.Materials and Methods:Twenty-five male Balb/c mice were assigned into five groups. Group I was treated with adjuvant, group II with Bacillus Calmette-Guerin (BCG) vaccine, group III with a combination of BCG and Ag85A, group IV with a combination of BCG and Ag85B and group V with a combination of BCG, Ag85A and Ag85B. Concentrations of immunoglobulin G, granzyme-B and perforin were examined using ELISA and the number of CD8+ T-cells and NK T-cells were checked by flow cytometry.Results:The highest concentration of immunoglobulin G was found in group V with 62.49±5.4327 ng/ml. The highest mean number of CD8+ T-cells, NK T-cells, granzyme-B and perforin was found in group IV with 4.32%, 1.03%, 35.11±1.7789 pg/ml and 6.19±0.2235 pg/ml, respectively. The results of One-Way ANOVA test showed that there were significant differences in immunoglobulin responses, with p<0.05. The expressions of granzyme-B and perforin were higher in mice treated with combination of BCG and recombinant proteins.Conclusions:Ag85 protein can be combined with the BCG vaccine to improve protection against M. tuberculosis infection.

Recombinant BCG With Bacterial Signaling Molecule Cyclic di-AMP as Endogenous Adjuvant Induces Elevated Immune Responses After Mycobacterium tuberculosis Infection.

Bacillus Calmette-Guerin (BCG) is a live attenuated vaccine against tuberculosis (TB) and remains the most commonly used vaccine worldwide. However, BCG has varied protective efficiency in adults and has safety concerns in immunocompromised population. Thus, effective vaccines are necessary for preventing the prevalence of TB. Cyclic di-AMP (c-di-AMP) is a bacterial second messenger which regulates various cellular processes and host immune response. Previous work found that c-di-AMP regulates bacterial physiological function, pathogenicity and host type I IFN response. In this study, we constructed a recombinant BCG (rBCG) by overexpressing DisA, the diadenylate cyclase of Mycobacterium tuberculosis (Mtb), and observed the physiological changes of rBCG-DisA. The immunological characteristics of rBCG-DisA were investigated on humoral and cellar immune responses in a mice infection model. Our study demonstrated that overexpression of DisA in BCG does not affect the growth but reduces the length of BCG. rBCG-DisA-immunized mice show similar humoral and cellar immune responses in BCG-immunized mice. After Mtb infection, the splenic lymphocytes from both BCG and rBCG-DisA-immunized mice produced more IFN-γ, IL-2, and IL-10 than the un-immunized (UN) mice, while the cytokine levels of the rBCG-DisA group increased significantly than those of the BCG group. The transcription of IFN-β, IL-1β and autophagy related genes (Atgs) were up-regulated in macrophages after treated with c-di-AMP or bacterial infection. The productions of IL-6 were increased after Mtb challenge, especially in the rBCG-DisA-immunized mice. Strikingly, H3K4me3, the epigenetic marker of innate immune memory, was found in both two immunized groups, and the rBCG-DisA group showed stronger expression of H3K4me3 than that of BCG. In addition, the pathological changes of rBCG-DisA immunized mice were similar to that of BCG-immunized mice. The bacterial burdens in the lungs and spleens of BCG- and rBCG-DisA-immunized mice were significantly decreased, but there was no significant difference between the two immunized groups. Together, these results suggested that compared to BCG, rBCG-DisA vaccination, induces stronger immune responses but did not provided additional protection against Mtb infection in this study, which may be related to the innate immunity memory. Hence, c-di-AMP is a promising immunomodulator for a further developed BCG as a better vaccine.

Immunization using male germ cells and gametes as rich sources of cancer/testis antigens for inhibition of 4T1 breast tumors' growth and metastasis in BALB/c mice

Recently cancer/testis antigens (CTA) have gained lots of attention as targets of immune therapy. However, the therapeutic efficacy of the CTAs single-antigen vaccines is not satisfying due to tumor heterogenicity. Therefore, many studies have focused on the enhancement of their efficacy by utilizing rich sources of tumor-associated antigens for anti-cancer vaccination. In the present study, the testicular germ cells and sperm cells as well-known sources of cancer/testis antigens were investigated for anti-4T1 breast cancer vaccination in BALB/c mice. The testicular germ cells (TGCs) and sperm cells were isolated from male BALB/c mice. The definite number of cells were homogenized and mixed with Bacillus Calmette–Guerin (BCG) for vaccination of female BALB/c mice. The treatment groups underwent 3 times of immunizations with one-week intervals and one week after the last injection, all groups were injected with 4T1 cancer cells. The TGCs + BCG (259.7 ± 39 mm3) and Sperm + BCG (426 ± 52 mm3) groups exhibited a significant decrease in the tumors' volume in comparison with BCG (641.3 ± 102 mm3) and no-treatment (788.1 ± 117 mm3) groups. Therefore, the TGCs + BCG immunized mice had the smallest tumors in comparison with all groups (P < 0.05). Also, the vital organs of TGCs + BCG (lungs: 6.8 ± 2, liver: 10.1 ± 2) immunized mice exhibited lowest metastatic burden in comparison with the Sperm + BCG (lungs: 13.5 ± 3, liver: 21.1 ± 4), BCG (lungs: 24.3 ± 4, liver: 33 ± 4), and no-treatment (lungs: 26.5 ± 6, liver: 37.3 ± 3) groups. These observations were inconsistent with the tumor-bearing mice survival evaluations as the TGCs + BCG group had longer mean survival time (79.6 ± 12 days) in comparison with other groups (no-treatment: 49.8 ± 8, BCG: 50.5 ± 10, BCG + Sperm: 64.6 ± 7 days). Therefore, TGCs can be a potential source of antigens for the anti-breast cancer immunization and more investigations are necessary.

Efficacy of Immediate Postoperative Instillation of Chemotherapy for Primary Non-Muscle-Invasive Bladder Cancer in Real-World Clinical Practice.

Non-muscle-invasive bladder cancer (NMIBC) can be treated using transurethral resection (TUR), but high incidence of intravesical recurrence remains a clinical challenge. Single immediate postoperative instillation of chemotherapy (IPIOC) is controversial for NMIBC patients with intermediate recurrence risk. The aim of the present study was to report the efficacy and toxicity of IPIOC, particularly in intermediate-risk NMIBC patients, in the real-world setting. We retrospectively analyzed 363 consecutive patients with primary NMIBC who underwent radical TUR at Kyoto University Hospital between 2007 and2016. In low-risk patients, recurrence-free survival (RFS) was significantly better for IPIOC than non-IPIOC (2-year RFS: 89.3% vs. 59.4%; P= .001). In intermediate-risk patients, IPIOC was associated with significantly longer RFS compared with non-IPIOC (2-year RFS: 85.5% vs. 58.2%; P= .011). IPIOC and bacillus Calmette-Guérin (BCG) were independent predictors for post-TUR recurrence (non-IPIOC vs. IPIOC: hazard ratio [HR], 2.33; 95% confidence interval [CI], 1.14-4.88; P= .02; non-BCG vs. BCG: HR, 2.22; P= .045, 95% CI, 1.02-5.30). In the high-risk group, only BCG was an independent prognostic factor of recurrence in a multivariate Cox proportional hazards model (HR, 2.55; P= .006, 95% CI, 1.32-4.87). There were no significant differences between the BCG-only group and the IPIOC with BCG group in Grade 3 or more local (16 patients [21%] vs. 21 patients [24%]; P= .61) or systemic (3 patients [4%] vs. 6 patients [7%]; P= .40) toxicity rates. Our study showed the efficacy of IPIOC for the prevention of intravesical recurrence in primary intermediate-risk NMIBC patients regardless of BCG therapy.

Efficacy comparison of intravesical instillation of gemcitabin and bacillus calmette guerin in patients with high-risk non-muscle invasive bladder cancer

Objective To compare clinical efficacy of intravesical instillation of gemcitabine(GEM) and bacillus calmette guerin(BCG) for high-risk non-muscle invasive bladder cancer(NMIBC). Methods From September 2015 to June 2017, clinical data of 208 NMIBC patients underwent transurethral resection of bladder tumor were prospective analyzed.All patients were assigned into GEM group(n=135)and BCG group(n=73). Recurrence, progression and side effects between two groups were followed up. Results Recurrence rate of BCG group was significantly lower than GEM group(38.5% vs.21.9%, P=0.015). However, there was no significant difference(P=0.257) in tumor progression between GEM (20.0%) group and BCG group (13.7%), and adverse effects of GEM was significantly lower than BCG group (14.1% vs.27.4%, P=0.019). Conclusions BCG is superior to GEM in preventing recurrence, but there is no significant difference in tumor progression, adverse effects of BCG is higher than GEM group. Key words: Urinary Bladder Neoplasms; BCG Vaccine; Chemotherapy, Cancer, Regional Perfusion

Clinical impact of Bacillus Calmette-Guérin (BCG) Therapy on prognosis in patients with carcinoma in situ (CIS) of the upper urinary tract: A retrospective comparison with nephroureterectomy.

417 Background: Clinical benefit of bacillus Calmette-Guérin (BCG) therapy for the management of upper urinary tract carcinoma in situ (CIS) remain unclear. We investigated safety and long-term oncological outcome of BCG therapy for upper urinary tract CIS compared with nephroureterectomy. Methods: We treated consecutive 490 patients with upper urinary tract carcinoma Aomori, Japan. We retrospectively reviewed the post-treatment course of 60 patients with CIS of the upper urinary tract who had undergone either a radical nephroureterectomy (RNU group) or BCG therapy (BCG group). Clinical effectiveness, safety, and oncological outcomes were compared between the groups. Multivariate Cox regression analysis via inverse propensity treatment weighted (IPTW) methods was performed to identify the impact of BCG therapy on prognosis. Results: The number of patients in RNU and BCG groups were 22 and 38, respectively. Median follow-up was 59 months in this cohort. There was no significant difference in background of patients including age, sex, performance status between the groups. The reason of selection for BCG therapy were bilateral CIS of upper urinary tract (50%), solitary kidney (26%), and others (24%). The cytology became negative in 30 (79%) patients after 6-week course of BCG. BGC related adverse events were observed 92% of patients. Most common events were cystitis (76%) followed by fever (50%). Two patients experienced grade 3 sepsis after BCG therapy. 13 patients (43%) experienced tumor recurrence after BCG therapy. There were no significant differences in recurrence-free survival, cancer-specific survival, and overall survival between the RNU and BCG groups. Multivariate analysis revealed BCG therapy did not worse the prognosis of those patients. Conclusions: Although mild adverse events were frequented in BCG therapy for CIS of the upper urinary tract, it might be a useful alterative in patients with CIS of the upper urinary tract who are ineligible for radical nephroureterectomy. Further prospective studies are needed to confirm the benefits of BCG therapy for CIS of the upper urinary tract.

Efficacy of Bladder Instillations with Mitomycin or Bacillus Calmette–Guérin in Patients with T1 High-Grade Bladder Cancer

Objectives: To evaluate the efficacy of instillations with mitomycin C (MMC) or bacillus Calmette–Guérin (BCG) in patients with T1 high-grade bladder cancer (BC). Patients and Methods: From 2007 to 2015, 186 patients admitted to Taichung Veteran General Hospital with new diagnosis of T1 high-grade BC receive transurethral resection of the bladder tumor (TURBT) and 6 weekly adjuvant instillation following. Histological stage followed the WHO grading system. End point evaluation was recurrence and progression to muscle invasive BC. Results: A total of 118 patients received 6 weekly intravesical instillation chemotherapy with MMC and 68 with BCG. Above all, 93 patients received immediate intravesical MMC after TURBT. The mean follow-up period was 46.78 ± 19.05 months in the MMC group versus 50.13 ± 24.18 months in the BCG group (P = 0.512). The BCG group showed better outcomes with longer 5-year recurrence-free survivals (64.6% vs. 50.0%, P of log rank = 0.008*) and progression-free survivals (94.1% vs. 87.3%, P of log rank = 0.023*). The treatment efficacy of BCG in comparison to MMC was further adjusted in uni-multivariate analysis model (recurrence: Hazard ratio [HR] =0.511, 95% confidence interval [CI] = 0.304–0.858, P= 0.011*; progression: HR = 0.216, 95% CI = 0.068–0.683, P= 0.009*). We also explore smoker, multiple lesions, and tumor diameter &gt;3 cm to be risk factors for recurrence. Conclusions: For patients with T1 high-grade nonmuscle invasive BC, the adjuvant therapy with BCG, as opposed to MMC, resulted in better outcomes based on recurrence and progression with tolerable complications. For immediate single instillations, in comparison, the efficacy was lower in preventing tumor recurrence and progression in the current stage.

Effects of intravesical therapy with platelet-rich plasma (PRP) and Bacillus Calmette-Guérin (BCG) in non-muscle invasive bladder cancer.

This study describes the effects of a promising therapeutic alternative for non-muscle invasive bladder cancer (NMIBC) based on Bacillus Calmette-Guerin (BCG) intravesical immunotherapy combined with Platelet-rich plasma (PRP) in an animal model. Furthermore, this study describes the possible mechanisms of this therapeutic combination involving Toll-like Receptors (TLRs) 2 and 4 signaling pathways. NMIBC was induced by treating female Fischer 344 rats with N-methyl-N-nitrosourea (MNU). After treatment with MNU, the animals were distributed into four experimental groups: Control (without MNU) group, MNU (cancer) group, MNU + PRP group, MNU + BCG group and MNU + PRP + BCG group. Our results demonstrated that PRP treatment alone or associated with BCG triggered significant cytotoxicity in bladder carcinoma cells (HTB-9). Animals treated with PRP associated to BCG clearly showed better histopathological recovery from the cancer state and decrease of urothelial neoplastic lesions progression in 70% of animals when compared to groups that received the same therapies administered singly. In addition, this therapeutic association led to distinct activation of immune system TLRs 2 and 4-mediated, resulting in increased MyD88, TRIF, IRF3, IFN-γ immunoreactivities. Taken together, the data obtained suggest that interferon signaling pathway activation by PRP treatment in combination with BCG immunotherapy may provide novel therapeutic approaches for non-muscle invasive bladder cancer.

Immunogenicity of heparin-binding hemagglutinin expressed by Pichia pastoris GS115 strain.

Objective(s):Heparin-binding hemagglutinin (HBHA), a mycobacterial cell surface protein, mediates adhesion to nonphagocytic cells and the dissemination of Mycobacterium tuberculosis (M. tuberculosis) from the site of primary infection. Superior expression systems are required to obtain abundant M. tuberculosis proteins for the purpose of diagnosing M. tuberculosis infection or for the immunization. Here, HBHA was expressed by Pichia pastoris (P. pastoris) GS115 strain , and the immunogenicity of HBHA was evaluated.Materials and Methods:The HBHA gene of M. tuberculosis was cloned into the pPIC9K plasmid, which was good for electroporation into P. pastoris GS115 strain. Unlabeled HBHA protein was purified using a Sepharose CL-6B column, and its expression was confirmed using anti-HBHA polyclonal antibody from mouse serum. We injected C57BL/6 mice with HBHA/ dimethyldioctadecylammonium/trehalose 6,6’-dibehenate (HBHA/DDA/TDB) to investigate the immunogenicity of this potential vaccine.Results:The results demonstrated that HBHA/DDA/TDB has the ability to induce high levels of HBHA-specific IgG antibody and its subclasses, as well as interferon-gamma, compared with injection of phosphate-buffered saline, DDA/TDB alone and Bacillus Calmette-Guérin (BCG) controls (P<0.05). Moreover, the ratio of IgG2a/IgG1 of the HBHA/DDA/TDB group was higher than that of the BCG group (P<0.05).Conclusion:HBHA with no label has excellent immunogenicity, and is suitable for evaluating the effectiveness to prevent M. tuberculosis infection.

Intravesical Gemcitabine versus Intravesical Bacillus Calmette-Guérin for the Treatment of Non-Muscle Invasive Bladder Cancer: An Evaluation of Efficacy and Toxicity.

Intravesical Bacillus Calmette-Guérin (BCG) remains the standard adjuvant treatment for non-muscle invasive bladder cancer (NMIBC) following transurethral resection; however, BCG failure and related toxicities are common. To compare the efficacy and toxicity of intravesical BCG and gemcitabine in the treatment of NMIBC. Retrospective data were collected in the region of Canberra, Australia from January 2010 to December 2015. The survival cutoff was December 2016. Primary end point was disease-free survival (DFS) and secondary end point was toxicity. After optimal transurethral resection all patients received weekly intravesical BCG or gemcitabine for 6 weeks and maintenance treatment according to their risk. The recurrence was defined as histology proven tumor recurrence (any grade), or appearance of carcinoma in situ. One hundred and three patients were evaluable, 52 treated with BCG and 51 with gemcitabine with a median age of 77 and 78, and were mostly male. Approximately half of each received maintenance therapy. The groups were well balanced, apart from some difference in cancer risk groups. Twenty-one percent in the BCG group and 29% in the gemcitabine group had received prior BCG. Median follow up was 15.0 months. Median DFS was 19.6 months for BCG, whereas median DFS was not reached with gemcitabine. There was a trend toward improved DFS with gemcitabine in multivariate analysis, HR: 0.49 (95% CI: 0.22-1.06, p = 0.07). Adverse events were significantly less frequent with gemcitabine (7 versus 44%, p ≤ 0.05). There were four cases of systemic BCG infection. Intravesical gemcitabine was associated with a trend toward better DFS with significantly lower toxicity when compared with BCG. Intravesical BCG remains the standard first-line adjuvant therapy; however, intravesical gemcitabine could be a reasonable alternative in cases where BCG is contraindicated and for patients who are intolerant or refractory to BCG. A prospective phase 3 trial is needed to confirm the benefits of gemcitabine over BCG.

In vivo evaluation of the efficacy of Sophora moorcroftiana alkaloids in combination with Bacillus Calmette-Guérin (BCG) treatment for cystic echinococcosis in mice.

Human cystic echinococcosis is a widespread, chronic, endemic, helminthic zoonosis caused by larval tapeworms of the species Echinococcus granulosus. At present, there is no rational and effective therapy for patients with echinococcosis. The present study evaluated whether the combination of alkaloids from Sophora moorcroftiana seeds (SMSa2) and Bacillus Calmette-Guérin (BCG) was effective in the treatment of experimental echinococcosis. After 20 weeks of secondary infection with protoscoleces, mice were randomly allocated to five groups and treated for 6 weeks by daily intragastric administration of albendazole (ABZ, 100 mg/kg), SMSa2 (100 mg/kg), BCG (abdominal subcutaneous injection at 5 × 106 CFU), SMSa2 + BCG (100 mg/kg SMSa2 and 5 × 106 CFU BCG) or normal saline (untreated group), respectively. The results indicated a significant reduction in the weight of hydatid cysts in the SMSa2 + BCG group compared with the untreated, SMSa2 and BCG groups. The rate of inhibition of hydatid cyst growth in the SMSa2 + BCG group (76.1%) was obviously increased compared with that in the SMSa2 (25.7%) and BCG (26.6%) groups, respectively. Compared with the untreated control, the SMSa2 + BCG group showed a non-significant increase in serum interleukin-4 (IL-4). Furthermore, the serum levels of interferon-γ (IFN-γ) between the untreated and SMSa2 + BCG groups were not statistically different. Therefore, the combination of alkaloids from S. moorcroftiana seeds and BCG can reduce cyst burden and is an effective therapeutic regimen against echinococcosis.

Neonatal BCG vaccination and atopic dermatitis before 13 months of age: A randomized clinical trial.

Studies have suggested that Bacillus Calmette-Guérin (BCG) vaccination may reduce the risk of allergic diseases, including atopic dermatitis. The Danish Calmette Study was conducted 2012-2015. Within 7 days of birth new-borns were randomised 1:1 to BCG or no BCG. Exclusion criteria were gestational age <32 weeks, birth weight <1000 g, known immunodeficiency or no Danish-speaking parent. Data were collected through telephone interviews and clinical examinations until 13 months. Clinical atopic dermatitis was diagnosed in 466/2,052 (22.7%) children in the BCG group and 495/1,952 (25.4%) children in the control group (RR = 0.90 [95% confidence intervals 0.80-1.00]). The effect of neonatal BCG vaccination differed significantly between children with atopic predisposition (RR 0.84 (0.74-0.95)) and children without atopic predisposition (RR 1.09 [0.88-1.37]) (test of no interaction, P = .04). Among children with atopic predisposition, the number-needed-to-treat with BCG to prevent one case of atopic dermatitis was 21 (12-76).

Neonatal BCG has no effect on allergic sensitization and suspected food allergy until 13months.

Vaccination with Bacillus Calmette-Guérin (BCG) is used in many countries as protection against tuberculosis. Studies have suggested that BCG may also have non-specific effects, reducing non-tuberculosis mortality, morbidity, and atopic manifestations. In this study, we evaluated the effect of neonatal BCG vaccination on allergic sensitization and suspected food allergy at 13months of age. The Danish Calmette Study was conducted from 2012 to 2015 at three Danish hospitals. Within 7days of birth, the 4262 newborns of 4184 included mothers were randomized 1:1 to BCG or to a no-intervention control group. Exclusion criteria were gestational age <32weeks, birth weight <1000g, known immunodeficiency, or no Danish-speaking parent. Follow-up information was collected through telephone interviews at 3 and 13months of age. Subgroups of participants were offered blood sampling at 13months of age. By 13months of age, the parents and/or general practitioners of 5.6% (117/2089) of the children in the BCG group and 6.1% (126/2061) of the control group suspected food allergy, resulting in a risk ratio comparing BCG-vaccinated children with control children of 0.91 (95% CI 0.71-1.16). Among 1370 blood samples, sensitization (Phadiatop Infant >0.35kUA/L) was found in 55 of 743 (7.4%) children in the BCG group and 50 of 627 (8.0%) of the control group (risk ratio 0.94 [0.65-1.36]). In this randomized clinical trial, neonatal BCG had no significant effect on suspected food allergy or on sensitization at 13months of age.

Immunization with Bacillus Calmette-Guérin (BCG) alleviates neuroinflammation and cognitive deficits in APP/PS1 mice via the recruitment of inflammation-resolving monocytes to the brain

The immune system plays a crucial role in the progression of Alzheimer's disease (AD). Recently, immune-dependent cascade induced by systemic immune activation has been verified to play a beneficial role in AD mouse models. Here, we tested whether Bacillus Calmette-Guérin (BCG) immunization alters AD pathology and cognitive dysfunction in APP/PS1 AD mouse model, and with 4Aβ1-15 vaccination as positive control. It was found that BCG treatment reversed the cognitive decline to the extent observed in 4Aβ1-15 group, but did not reduce the β-amyloid (Aβ) burden in the brain. Then, we demonstrated the enhanced recruitment of inflammation-resolving monocytes across the choroid plexus and perivascular spaces to cerebral sites of plaque pathology in APP/PS1 mice immunized with BCG. Furthermore, elevated splenocyte Foxp3+ regulatory T cell levels in the control APP/PS1 mice were down-regulated back to the wild-type (WT) levels by BCG treatment but not 4Aβ1-15 vaccination. In addition, BCG treatment induced the production of more circulating interferon (IFN)-γ than the controls and 4Aβ1-15 vaccination. Though the similar reductions in brain levels of pro-inflammatory cytokines were observed in the BCG and 4Aβ1-15 groups compared to the controls, only BCG had the great effect in upregulating cerebral anti-inflammatory cytokine levels as well as elevating the expression of neurotrophic factors in the brain of APP/PS1 mice. Thus, it is suggested that BCG exerts a beneficial immunomodulatory effect in APP/PS1 mice through mitigation of systemic immune suppression, induction of IFN-γ response and alleviation of the neuroinflammatory response.