The Effects of Oral Liposomal Glutathione and In Vitro Everolimus in Altering the Immune Responses against Mycobacterium bovis BCG Strain in Individuals with Type 2 Diabetes.

Tuberculosis (TB) caused by Mycobacterium tuberculosis (M. tb) still remains a devastating infectious disease in the world. There has been a daunting increase in the incidence of Type 2 Diabetes Mellitus (T2DM) worldwide. T2DM patients are three times more vulnerable to M. tb infection compared to healthy individuals. TB-T2DM coincidence is a challenge for global health control. Despite some progress in the research, M. tb still has unexplored characteristics in successfully evading host defenses. The lengthy duration of treatment, the emergence of multi-drug-resistant strains and extensive-drug-resistant strains of M. tb have made TB treatment very challenging. Previously, we have tested the antimycobacterial effects of everolimus within in vitro granulomas generated from immune cells derived from peripheral blood of healthy subjects. However, the effectiveness of everolimus treatment against mycobacterial infection in individuals with T2DM is unknown. Furthermore, the effectiveness of the combination of in vivo glutathione (GSH) supplementation in individuals with T2DM along with in vitro treatment of isolated immune cells with everolimus against mycobacterial infection has never been tested. Therefore, we postulated that liposomal glutathione (L-GSH) and everolimus would offer great hope for developing adjunctive therapy for mycobacterial infection. L-GSH or placebo was administered to T2DM individuals orally for three months. Study subjects' blood was drawn pre- and post-L-GSH/or placebo supplementation, where Peripheral Blood Mononuclear Cells (PBMCs) were isolated from whole blood to conduct in vitro studies with everolimus. We found that in vitro treatment with everolimus, an mTOR (membrane target of rapamycin) inhibitor, significantly reduced intracellular M. bovis BCG infection alone and in conjunction with L-GSH supplementation. Furthermore, we found L-GSH supplementation coupled with in vitro everolimus treatment produced a greater effect in inhibiting the growth of intracellular Mycobacterium bovis BCG, than with the everolimus treatment alone. We also demonstrated the functions of L-GSH along with in vitro everolimus treatment in modulating the levels of cytokines such as IFN-γ, TNF-α, and IL-2 and IL-6, in favor of improving control of the mycobacterial infection. In summary, in vitro everolimus-treatment alone and in combination with oral L-GSH supplementation for three months in individuals with T2DM, was able to increase the levels of T-helper type 1 (Th1) cytokines IFN-γ, TNF-α, and IL-2 as well as enhance the abilities of granulomas from individuals with T2DM to improve control of a mycobacterial infection.

Clinical trial of high dose hyperthermic intravesical mitomycin C for intermediate and high-risk non-muscle invasive bladder cancer during BCG shortage.

PURPOSE: Intravesical Bacillus Calmette-Guérin (BCG) is the gold standard for intermediate and high-risk non-muscle invasive bladder cancer (NMIBC), but availability is limited by global shortages. We present the first North American clinical experience using intravesical hyperthermia (HIVEC) with high-dose mitomycin C (MMC) during BCG shortage. MATERIALS AND METHODS: Single arm intermediate size expanded access protocol for high dose HIVEC MMC in patients with intermediate and high-risk NMIBC during BCG shortage. Patients received 120 mg intravesical MMC using the Combat BRS to achieve 43°C HIVEC. Primary outcome was a safety assessment of adverse events, with recurrence-free survival and a descriptive analysis of hematologic impacts as secondary outcomes. RESULTS: Fourteen patients were treated from May 2019 to June 2020, 4 (29%) intermediate and 10 (71%) high risk. The cohort is heavily pretreated, only 2 (14%) BCG naïve and median 6 BCG instillations (IQR 5.25, 8.25), with median 3.5 recurrences per patient (IQR 1.00, 5.25) 67% with >1 per year. Patients underwent a median 6 instillations (IQR 3.25, 9.25) which were well tolerated in 11/14 (79%). Seven patients (50%) experienced 10 adverse events, all grades 1 or 2. Most common was MMC allergy (4/14, 29%), followed by bladder spasm (3/14, 21%). Two had recurrences at median 11 months follow up, but both discontinued HIVEC after only 2 treatments. CONCLUSIONS: High dose MMC HIVEC is a safe and well-tolerated substitute for BCG during global shortages. The higher rate of systemic effects implies increased drug delivery, which may improve efficacy.

Increased Bacillus Calmette-Guérin Treatment Intensity Associated With Improved Outcomes in Elderly Patients With Non-Muscle-invasive Bladder Cancer in United States Clinical Practice.

OBJECTIVE: To characterize Bacillus Calmette-Guérin (BCG) treatment patterns and associated outcomes in a large cohort of patients with non-muscle-invasive bladder cancer (NMIBC). METHODS: Our retrospective analysis of patients aged ≥66 years with stage 0-1 urothelial bladder carcinoma diagnosed between 2000 and 2012 in the United States Surveillance, Epidemiology, and End Results-Medicare database estimated proxies for recurrence and secondary events and both all-cause and bladder cancer-specific mortality. Proportional hazards models were used in conditional landmark analyses to compare adequate (≥5 induction instillations and ≥2 maintenance instillations) and inadequate BCG, stratified by National Comprehensive Cancer Network risk group. RESULTS: Of 39,532 patients who met the selection criteria, 16,225 (41.0%) received BCG; of them, 4602 (28.4%; 11.6% overall) received adequate treatment. Adequately treated patients were slightly younger and healthier than inadequately treated patients. Half of patients with intermediate- and high-risk NMIBC did not receive BCG; few received adequate treatment. At the 12-month landmark, adequate BCG treatment was associated with decreased risks of recurrence and of cancer-specific and all-cause mortality in patients with intermediate- and high-risk disease. CONCLUSION: We observed lower than expected use of adequate BCG treatment in patients with intermediate- to high-risk NMIBC despite evidence of improved outcomes, which suggested that practice patterns may not be in line with management recommendations in this population.

Curcumin-A Viable Agent for Better Bladder Cancer Treatment.

Although the therapeutic armamentarium for bladder cancer has considerably widened in the last few years, severe side effects and the development of resistance hamper long-term treatment success. Thus, patients turn to natural plant products as alternative or complementary therapeutic options. One of these is curcumin, the principal component of Curcuma longa that has shown chemopreventive effects in experimental cancer models. Clinical and preclinical studies point to its role as a chemosensitizer, and it has been shown to protect organs from toxicity induced by chemotherapy. These properties indicate that curcumin could hold promise as a candidate for additive cancer treatment. This review evaluates the relevance of curcumin as an integral part of therapy for bladder cancer.

Effect of nitric oxide inhibition in Bacillus Calmette-Guerin bladder cancer treatment.

BACKGROUND: Bacillus Calmette-Guerin (BCG) is the standard treatment for patients with high-risk non-muscle invasive bladder cancer (BC). Despite its success, about 30-50% of patients are refractory. It was reported that inducible nitric oxide synthase (iNOS) tumor expression is presented in 50% of human BC, associated with bad prognosis and BCG failure. OBJECTIVE: to evaluate in human bladder tumors the association between iNOS expression and the tumor microenvironment focusing on the immunosuppressive protein S100A9. Also, investigate in a preclinical murine MB49-BC model the tumor immunoresponse induced by BCG in combination with the nitric oxide production inhibitor l-NAME. RESULTS: In human bladder tumors, we detected a positive association between iNOS and S100A9 tumor expression, suggesting a relationship between both immunomodulatory proteins. We also found a positive correlation between iNOS tumor expression and the presence of S100A9+ tumor-infiltrating cells, suggesting an immunosuppressive tumor microenvironment induced by the nitric oxide production. Using the subcutaneous murine BC model, we show that similarly to the human pathology, MB49 tumors constitutively expressed iNOS and S100A9 protein. MB49 tumor-bearing mice presented an immunosuppressive systemic profile characterized by fewer cytotoxic cells (CD8+ and NK) and higher suppressor cells (Treg and myeloid-derived suppressor cells -MDSC-) compared to normal mice. BCG treatment reduced tumor growth, increasing local CD8+-infiltrating cells and induced a systemic increase in CD8+ and a reduction in Treg. BCG combined with l-NAME, significantly reduced tumor growth compared to BCG alone, diminishing iNOS and S100A9 tumor expression and increasing CD8+-infiltrating cells in tumor microenvironment. This local response was accompanied by the systemic increase in CD8+ and NK cells, and the reduction in Treg and MDSC, even more than BCG alone. Similar results were obtained using the orthotopic BC model, where an increase in specific cytotoxicity against MB49 tumor cells was detected. CONCLUSION: The present study provides preclinical information where NO inhibition in iNOS-expressing bladder tumors could contribute to improve BCG antitumor immune response. The association between iNOS and S100A9 in human BC supports the hypothesis that iNOS expression is a negative prognostic factor and a promising therapeutic target.

[Safety of Hyperthermic IntraVEsical Chemotherapy (HIVEC) for BCG Unresponsive Non-Muscle Invasive Bladder Cancer Patients]. / Tolérance de la thermo-chimiothérapie par HIVEC® chez les patients réfractaires au BCG.

INTRODUCTION: There is increasing evidence that Hyperthermic Intravesical Chemotherapy is an effective treatment for non-muscle invasive bladder cancer (NMIBC). HIVEC (COMBAT BRS system) is an innovative hyperthermia delivering device. The aim of our study is to evaluate tolerance and safety of HIVEC in patients with BCG-refractory NMIBC. MATERIALS AND METHODS: In this study, we included 22 patients between January 2017 and April 2018. The treatment consisted in a weekly instillation of Hyperthermic Mitomycin for a total of 6 weeks, with a follow-up every 3 months. In order to evaluate the tolerance, patients filled a questionnaire before each instillation. We analyzed collected data to evaluate safety and efficiency of the treatment after one year. RESULTS: Among 22 patients included, no patient suffered from severe side effects. The minor side effects reported were : urinary urgency (40,1 %), urinary pain (40,1%), macroscopic hematuria (4,5%). The IPSS score didn't significantly varied before and after instillations (mean IPSS: 10.8 versus 10.1, p=0.77). The mean follow-up was 11.2 months. The recurrence rate was 27,3% with an average time to recurrence of 7.36 months. Two patients (9.1%) presented a progression to muscle-invasive disease. Four patients (18,2%) had a radical cystectomy. CONCLUSION: Hyperthermic Mitomycin using the HIVEC® device is a rather safe and well tolerated treatment. Efficiency remains partial as 27.3% of patients experienced recurrence during the first year. These data should be confirmed by prospective multicentric studies.

High-grade T1 Urothelial Carcinoma: Where Do We Stand?

PURPOSE OF REVIEW: Bladder cancer is a deadly and common malignancy, with 24% of new cases presenting as T1 disease. High-grade T1 in particular represents a difficult entity to treat due to its clinical variability and known risks of recurrence, progression, and cancer-specific mortality. The differences in guidelines from major urologic organizations underscore this variability, and the past year has seen another BCG shortage, further complicating management. Advances have been made in the molecular and genomic characterization of high-grade T1, and new clinical trials are available to investigate alternative therapies. In this review, we summarize the variations in guidelines, alternatives to BCG, emerging molecular and genomic discoveries, and recent clinical trials. RECENT FINDINGS: Adherence to guidelines for non-muscle-invasive bladder cancer in the community among practicing urologists remains low, in part due to the variations in available guidelines. In the era of a BCG shortage, decreased dosing schedules and alternative intravesical options are increasingly being used. New biomarkers are being discovered to better risk-stratify patients, with future therapies aimed at targeting aggressive disease. HGT1 urothelial carcinoma remains a highly variable and aggressive disease, but we are making significant progress in better characterizing the clinical and molecular factors that influence recurrence and progression, to better guide management.

Care Quality and Variability in the Use of Intravesical Therapy for Initial Treatment of Nonmuscle Invasive Bladder Cancer Within a Large, Diverse Integrated Delivery System.

OBJECTIVES: To examine treatment variability, disparities, and quality among newly diagnosed nonmuscle invasive bladder cancer (NMIBC) patients, and to identify factors associated with treatment use in a large, diverse integrated delivery system. METHODS: Retrospective cohort study of 5386 NMIBC patients diagnosed between January 2001 and June 2015 within Kaiser Permanente Southern California. Electronic health data were used to identify treatment outcomes and patient, provider, and tumor characteristics. Outcomes were use of (1) postoperative intravesical chemotherapy, (2) induction Bacille Calmette-Guérin (BCG) immunotherapy, and (3) any intravesical therapy. Multivariable odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using generalized linear mixed models with a binary outcome and urologist as a random effect. RESULTS: From 2001 to 2015, 41% of newly diagnosed NMIBC patients were treated with intravesical therapy. Postoperative chemotherapy use increased significantly over this period (OR per-year = 1.16, 95% CI: 1.07-1.25). BCG use was strongly associated with tumor characteristics: patients with high-grade or carcinoma in situ tumors were more likely to receive BCG (OR = 10.10, 95% CI: 8.39-12.16). Few treatment differences were found by sex or race/ethnicity, but were observed by age. Wide treatment variability across urologists was observed, with some urologists never using intravesical therapy as part of initial treatment while others almost always used it. Differences across urologists accounted for more variability in postoperative chemotherapy (intraclass correlation coefficient = 0.52) than BCG immunotherapy (intraclass correlation coefficient = 0.11) use. CONCLUSION: Substantial variability in initial treatment of NMIBC was observed across urologists, accounting for tumor, patient, and provider characteristics. Results suggest a considerable opportunity for quality improvement programs to reduce unwanted treatment variability and improve care for patients.

Infant cortisol stress-response is associated with thymic function and vaccine response.

Stress can impair T cell-mediated immunity. To determine if infants with high stress responses had deficits in T-cell mediated immunity, we examined the association of pain-induced cortisol responsiveness with thymic function and vaccine responses in infants. This study was performed among 306 (male = 153 and female = 153) participants of a randomized, controlled trial examining the effect of neonatal vitamin A supplementation on immune function in Bangladesh (NCT01583972). Salivary cortisol was measured before and 20 min after a needle stick (vaccination) at 6 weeks of age. The thymic index (TI) was determined by ultrasonography at 1, 6, 10 and 15 weeks. T-cell receptor excision circle and blood T-cell concentrations were measured at 6 and 15 weeks. Responses to Bacillus Calmette-Guérin (BCG), tetanus toxoid, hepatitis B virus and oral poliovirus vaccination were assayed at 6 and 15 weeks. Cortisol responsiveness was negatively associated with TI at all ages (p < .01) in boys only, was negatively associated with naïve helper T-cell concentrations in both sexes at both 6 (p = .0035) and 15 weeks (p = .0083), and was negatively associated with the delayed-type hypersensitivity (DTH) skin test response to BCG vaccination at 15 weeks (p = .034) in both sexes. Infants with a higher cortisol response to pain have differences in the T-cell compartment and a lower DTH response to vaccination. Sex differences in the immune system were seen as early as 6 weeks of age in these healthy infants.

Disseminated Mycotic Aneurysms following Intravesical Bacillus Calmette-Guérin Therapy for Bladder Cancer: Case Discussion and Systematic Treatment Algorithm.

Numerous case reports have highlighted the relationship between bacillus Calmette-Guérin (BCG) therapy and development of systemic mycotic aneurysms but none have established a management algorithm in patients with suspected vascular dissemination of Mycobacterium bovis. Delay in diagnosis of this disease process will lead to delays in initiation of antimycobacterium treatment to prevent dissemination into other arterial beds and potentially complicate effective surgical treatment leading to aneurysmal rupture and other devastating vascular consequences. Given the increasing number of reported cases in the literature and the ongoing, standard of care utilization of BCG for bladder cancer, we believe that a systematic approach to the management of patients with suspected BCG-related mycotic aneurysms should be set in place to prevent misdiagnosis and delays in treatment. In this report, we discuss the presentation, work-up, and report our treatment algorithm of a patient who developed diffuse peripheral mycotic aneurysms following BCG therapy for bladder cancer.

Intravesical Bacillus Calmette Guerin Combined with a Cancer Vaccine Increases Local T-Cell Responses in Non-muscle-Invasive Bladder Cancer Patients.

PURPOSE: Treatments with cancer vaccines may be delivered as combination therapies for better efficacy. Addition of intravesical immunostimulation with bacteria promotes vaccine-specific T cells in the bladder and tumor-regression in murine bladder cancer models. Here, we determined whether an adjuvanted cancer vaccine can be safely administered with concomitant standard intravesical Bacillus-Calmette-Guérin (BCG) therapy and how vaccine-specific immune responses may be modulated in patients with non-muscle-invasive bladder cancer (NMIBC). EXPERIMENTAL DESIGN: In a nonrandomized phase I open-label exploratory study, 24 NMIBC patients, apportioned in three groups, received 5 injections of a subunit cancer vaccine (recMAGE-A3 protein+AS15) alone or in two combinations of intravesical BCG-instillations. Safety profiles were compared between the three treatment groups, considering single vaccine injections or BCG instillations and concomitant interventions. Immune responses in blood and urine were compared between treatment groups and upon BCG instillations. RESULTS: The mild adverse events (AE) experienced by all the patients were similar to AE previously reported for this vaccine and standard BCG treatment. AEs were not increased by the double interventions, suggesting that BCG did not exacerbate the AE caused by the MAGE-A3 vaccine and vice-versa. All patients seroconverted after MAGE-A3 vaccination. In half of the patients, vaccine-specific T cells were induced in blood, irrespective of BCG treatment. Interestingly, such T cells were only detected in urine upon BCG-induced T-cell infiltration. CONCLUSIONS: Cancer vaccines, including strong adjuvants, can be safely combined with intravesical BCG therapy. The increase of vaccine-specific T cells in the bladder upon BCG provides proof-of-principle evidence that cancer vaccines with local immunostimulation may be beneficial. Clin Cancer Res; 23(3); 717-25. ©2016 AACR.

Association of BCG, DTP, and measles containing vaccines with childhood mortality: systematic review.

OBJECTIVES:  To evaluate the effects on non-specific and all cause mortality, in children under 5, of Bacillus Calmette-Guérin (BCG), diphtheria-tetanus-pertussis (DTP), and standard titre measles containing vaccines (MCV); to examine internal validity of the studies; and to examine any modifying effects of sex, age, vaccine sequence, and co-administration of vitamin A. DESIGN:  Systematic review, including assessment of risk of bias, and meta-analyses of similar studies. STUDY ELIGIBILITY CRITERIA:  Clinical trials, cohort studies, and case-control studies of the effects on mortality of BCG, whole cell DTP, and standard titre MCV in children under 5. DATA SOURCES:  Searches of Medline, Embase, Global Index Medicus, and the WHO International Clinical Trials Registry Platform, supplemented by contact with experts in the field. To avoid overlap in children studied across the included articles, findings from non-overlapping birth cohorts were identified. RESULTS:  Results from 34 birth cohorts were identified. Most evidence was from observational studies, with some from short term clinical trials. Most studies reported on all cause (rather than non-specific) mortality. Receipt of BCG vaccine was associated with a reduction in all cause mortality: the average relative risks were 0.70 (95% confidence interval 0.49 to 1.01) from five clinical trials and 0.47 (0.32 to 0.69) from nine observational studies at high risk of bias. Receipt of DTP (almost always with oral polio vaccine) was associated with a possible increase in all cause mortality on average (relative risk 1.38, 0.92 to 2.08) from 10 studies at high risk of bias; this effect seemed stronger in girls than in boys. Receipt of standard titre MCV was associated with a reduction in all cause mortality (relative risks 0.74 (0.51 to 1.07) from four clinical trials and 0.51 (0.42 to 0.63) from 18 observational studies at high risk of bias); this effect seemed stronger in girls than in boys. Seven observational studies, assessed as being at high risk of bias, have compared sequences of vaccines; results of a subset of these suggest that administering DTP with or after MCV may be associated with higher mortality than administering it before MCV. CONCLUSIONS:  Evidence suggests that receipt of BCG and MCV reduce overall mortality by more than would be expected through their effects on the diseases they prevent, and receipt of DTP may be associated with an increase in all cause mortality. Although efforts should be made to ensure that all children are immunised on schedule with BCG, DTP, and MCV, randomised trials are needed to compare the effects of different sequences.

Sleeping Beauty and the Story of the Bacille Calmette-Guérin Vaccine.

Mycobacterium bovis BCG is the only available vaccine for protection against tuberculosis (TB). While BCG protects children from severe disease, it has little impact on pulmonary disease in adults. A recombinant BCG vaccine BCG ΔureC::hly (strain VPM1002) is in advanced clinical trials and shows promise for improved vaccine safety but little change in efficacy in animal models. A second-generation recombinant BCG vaccine with an additional deletion of the nuoG gene (BCG ΔureC::hly ΔnuoG) shows improved efficacy in a mouse model compared to that of VPM1002. BCG was first used in humans in 1921 and, like Sleeping Beauty pricked by the spinning wheel, we have slept for 100 years, showing a reluctance to invest in clinical development or in biomanufacturing capacity for TB vaccines. The advance of recombinant BCGs should awaken us from our sleep and call us to invest in new-generation TB vaccines and to protect the biomanufacture of our current BCG vaccine.

The future of neonatal BCG.

We hypothesise that neonatal BCG (Bacillus Calmette-Guérin) might be used to adapt to a new phase in the history of human births. Among most mammals, the placenta is not effective at transferring antibodies to the fetus: antibodies are transferred immediately after birth via the colostrum. Among humans (and other mammals with hemochorial placentas) the transplacental transfer of antibodies (namely IgG) is effective. In humans, foetal concentrations of IgG sub-classes approximate to maternal concentrations at 38weeks and continue to increase thereafter. These facts explain inter-species differences regarding the basic needs of neonates. Among most mammals, the early colostrum is, strictly speaking, vital. Among humans, the main questions are about the bacteriological environment in the birthing place and how familiar it is to the mother. Today, most human beings are born in unfamiliar bacteriological environments characterized by a low microbial diversity. The effects of clinical environments may be amplified by the use of antibiotics and birth by caesarean, i.e. by-passing the bacteriologically rich perineal zone. There is already an accumulation of data confirming that the maturation of a balanced Th1/Th2 immune response is affected by the mode of delivery. There is also an accumulation of epidemiological studies detecting risk factors in the perinatal period for health conditions such as type 1 diabetes (and other autoimmune diseases), atopy, autism and obesity. In such a context there are reasons to plan randomized controlled trials with long term follow-up of the effects of BCG given immediately after birth, as a modulator of Th-1/Th-2 responses. A follow-up period in the region of 6-10years would be long enough to evaluate the prevalence of several nosologically well defined diseases. These studies would be ethically acceptable, since BCG is the only infancy vaccine that has been evaluated through randomised controlled trials with long term follow-up. Furthermore, whatever the standard of living of the populations and the research protocols, concordant results suggest that BCG has positive non-specific long term effects on health. Meanwhile, some simple adaptive practices are possible, such as, after a caesarean section, wrapping the neonate in clothes recently worn by the mother and, occasionally, putting the neonate in the arms of a person who is cohabiting with the mother.

Developments in Intralesional Therapy for Metastatic Melanoma.

BACKGROUND: Locoregional advanced melanoma poses a complex clinical challenge that requires a multidisciplinary, patient-centered approach. Numerous agents have been studied for their suitability as intralesional therapy in the past decades, but few have successfully completed phase 3 clinical trial testing. METHODS: The relevant medical literature was searched for articles regarding use of intralesional therapies in metastatic melanoma. Therapies with data from phase 2 or higher studies were selected for review. This review also summarizes the mechanisms of action, adverse-event profiles, and clinical data for these agents. RESULTS: Intralesional therapies demonstrate promising effects in select patients with advanced melanoma. The optimal approach should be individually tailored and consist of a combination of intralesional therapies, regional perfusions, systemic immunotherapies, targeted therapies, and surgery, if necessary. CONCLUSIONS: Due to its relatively good local response rates and tolerable adverse-event profile, intralesional therapy may be a treatment option for select patients with unresectable, locally advanced or metastatic melanoma.

Efficacy and safety of a new device for intravesical thermochemotherapy in non-grade 3 BCG recurrent NMIBC: a phase I-II study.

PURPOSE: We report for the first time the activity and safety of Unithermia(®) (Elmedical Ltd, Hod-Hasharon, Israel), a novel device for administration of MMC-C with hyperthermia (HT), that employs conductive heating, in a series of non-grade 3 non-muscle-invasive bladder cancer (NMIBC) that failed Bacillus Calmette-Guerin (BCG). METHODS: Patients with non-grade 3 NMIBC recurring after at least a full induction course of BCG were eligible for this phase I-II prospective single-arm study. Six weekly instillations with Unithermia(®) were scheduled following complete TUR. Primary end points were treatment safety and response rate (RR), and the latter defined as the absence of any unfavourable outcome at 12 months. Any grade 3 and/or muscle-invasive (T > 1) recurrence was considered disease progression. Kaplan-Meier estimation of the time to recurrence and progression, cancer-specific survival and overall survival was taken as secondary end points. RESULTS: Thirty-four eligible patients entered the study between January 2009 and April 2011. RR was documented in 20/34 (59%). Among the 14/34 (41%) non-responders, four developed G3 disease, one developed carcinoma in situ, and one progressed to muscle-invasive bladder cancer, with an overall 18% progression rate at 1 year. At a median follow-up of 41 months, recurrence and progression rates were 35.3 and 23.5%, respectively. Toxicity did not go beyond grade 2 except in five cases. CONCLUSIONS: Initial experience with MMC-HT with Unithermia(®) showed an interesting activity and safety profile in non-grade 3 NMIBC recurring after BCG, suggesting a role as second-line therapy in this selected subgroup of NMIBC.

Hyperthermia for non-muscle invasive bladder cancer.

Recurrent non muscle invasive bladder cancer (NMIBC) represents a therapeutic challenge, especially in the case of Bacillus Calmette Guerin (BCG)-failures. Chemohyperthermia (CHT) has been tested as adjuvant therapy in selected categories of patients with promising results. The aim of this systematic review is to explore the current role of CHT and its future perspectives. The review process was carried out following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria. After the selection process, 30 articles were used in this review. Treatment with CHT is safe and quite well tolerated. CHT seems to be effective in low and intermediate risk bladder cancer. Moreover CHT could be offered to selected categories of high risk patients and BCG failures NMIBC. Further trials are needed in order to better identify the categories of patients which could benefit from this therapy and to standardise the right schedule of treatment.

Early BCG vaccine to low-birth-weight infants and the effects on growth in the first year of life: a randomised controlled trial.

BACKGROUND: Randomised trials have shown that early Bacille Calmette-Guérin (BCG) vaccine reduces overall neonatal and infant mortality. However, no study has examined how BCG affects growth. We investigated the effect on infant growth of early BCG vaccine given to low-birth-weight (LBW) infants. METHODS: Two-thousand three hundred forty-three LBW infants were randomly allocated 1:1 to "early BCG" (intervention group) or "late BCG" (current practice). Furthermore, a subgroup (N = 1717) were included in a two-by-two randomised trial in which they were additionally randomised 1:1 to vitamin A supplementation (VAS) or placebo. Anthropometric measurements were obtained 2, 6, and 12 months after enrolment. RESULTS: Overall there was no effect of early BCG on growth in the first year of life. The effect of early BCG on weight and mid-upper-arm circumference at 2 months tended to be beneficial among girls but not among boys (interaction between "early BCG" and sex: weight p = 0.03 and MUAC p = 0.04). This beneficial effect among girls was particularly seen among the largest infants weighing 2.0 kg or more at inclusion. CONCLUSION: Though BCG vaccination is not recommended to be given to LBW infants at birth in Guinea-Bissau, early BCG had no negative effect on infant growth and may have had a beneficial effect for girls. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov (NCT00146302).

Antiandrogen Therapy with Hydroxyflutamide or Androgen Receptor Degradation Enhancer ASC-J9 Enhances BCG Efficacy to Better Suppress Bladder Cancer Progression.

Recent studies suggest that the androgen receptor (AR) might play important roles in influencing bladder cancer progression, yet its clinical application remains unclear. Here, we developed a new combined therapy with Bacillus Calmette-Guérin (BCG) and the AR degradation enhancer ASC-J9 or antiandrogen hydroxyflutamide (HF) to better suppress bladder cancer progression. Mechanism dissection revealed that ASC-J9 treatment enhanced BCG efficacy to suppress bladder cancer cell proliferation via increasing the recruitment of monocytes/macrophages that involved the promotion of BCG attachment/internalization to the bladder cancer cells through increased integrin-α5ß1 expression and IL6 release. Such consequences might then enhance BCG-induced bladder cancer cell death via increased TNFα release. Interestingly, we also found that ASC-J9 treatment could directly promote BCG-induced HMGB1 release to enhance the BCG cytotoxic effects for suppression of bladder cancer cell growth. In vivo approaches also concluded that ASC-J9 could enhance the efficacy of BCG to better suppress bladder cancer progression in BBN-induced bladder cancer mouse models. Together, these results suggest that the newly developed therapy combining BCG plus ASC-J9 may become a novel therapy to better suppress bladder cancer progress.