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BackgroundTo explore the necessity of maintenance, efficacy of low-dose and superiority of various combination therapies of Bacillus Calmette-Guérin (BCG) in treatment of superficial bladder cancer (BCa).MethodsComprehensive searches of electronic databases (PubMed, Embase, and the Cochrane Library) were performed, then a systematic review and cumulative meta-analysis of 21 randomized controlled trials (RCTs) and 9 retrospective comparative studies were carried out according to predefined inclusion criteria.ResultsSignificantly better recurrence-free survivals (RFS) were observed respectively in patients who received BCG maintenance, standard-dose and BCG plus epirubicin therapy comparing to those received induction, low-dose and BCG alone. BCG maintenance therapy was also associated with significantly better progression-free survival (PFS), but there were more incidences of adverse events. Pooled results showed no remarkable advantage of BCG combined with Mitomycin C or with interferon α-2b in improving oncologic outcomes. Sensitivity-analyses stratified by study-design and tumor stage led to very similar overall results and often to a decrease of the between-study heterogeneity. Our data confirmed that non-RCT only affected strength rather than direction of the overall results.ConclusionsAll patients with superficial BCa should be encouraged to accept BCG maintenance therapy with standard-dose if well tolerated. Patients can benefit from BCG combined with epirubicin but not from BCG combined with Mitomycin C or interferon α-2b.

ObjectiveHuman murine double minute 2 protein (MDM2) is mainly a negative regulator of p53 tumor suppressor pathway. We aimed to investigate the association between MDM2 SNP309 polymorphism and bladder cancer risk.MethodsA total of 535 bladder cancer patients and 649 health controls were recruited for our study. MDM2 SNP309 T>G polymorphism was genotyped by polymerase chain reaction-ligase detection reaction method. Logistic regression was used to analyze the relationship between the genotype and susceptibility of bladder cancer. Kaplan–Meier estimates and log-rank test were obtained to analyze the association between the genotype and risk of recrudesce in nonmuscle-invasive bladder cancer patients. A multivariable Cox proportional hazards model was fitted to identify independent prognostic factors. To further investigate the association, we conducted a meta-analysis including six studies.ResultsThe frequency of the MDM2 SNP309 T>G polymorphism showed no significant difference between cases and controls (all P>0.05). In the stratification analysis, the results showed that G allele carriers were prone to have a significant decrease in risk of low-grade bladder cancer (adjusted odds ratio: 0.613, 95% confidence interval: 0.427–0.881), and G variant was associated with a significantly reduced risk of recurrence in nonmuscle-invasive bladder cancer patients with or without chemotherapy (P<0.05). The results of the meta-analysis showed that G allele and GG genotype of MDM2 SNP309 polymorphism were significantly associated with increased risk of bladder cancer in Caucasians (both P<0.05), and no association was observed in total populations and Asians (P>0.05).ConclusionMDM2 SNP309 T>G polymorphism has no influence on bladder cancer risk in Asians, but this single nucleotide polymorphism may be associated with genetic susceptibility of bladder cancer among Caucasians.

Abstract. Bacillus Calmette-Guérin (BCG) reduces the recurrence and progression of non-muscle invasive bladder cancer. The present study aimed to investigate the impact of a recombinant hIFN-α2b-secreting BCG (rBCG) on the mouse bladder MB49 cell line and an orthotopic mouse model of bladder cancer. MB49 cells were cultivated in the presence or absence of rBCG, BCG or BCG+hIFN-α2b. Cellular morphology and viability were assessed by microscopy and CCK-8 assay, respectively. Apoptosis was assessed by acridine orange, Hoechst 33258 staining and flow cytometry. MHC-I expression was assessed by flow cytometry. MB49 cells were transplanted into the bladders of C57BL/6 mice administered BCG, rBCG or BCG+hIFN-α2b. Local tissue Fas expression and T cell subsets were assessed by immunohistochemistry. Peripheral blood TNF-α and IL-12 levels were measured by ELISA, and circulating T lymphocyte subsets by flow cytometry. BCG, rBCG and BCG+hIFN-α2b increased the distortion and death of MB49 cells, yet rBCG reduced the proliferation and enhanced apoptosis most substantially. Apoptosis was increased after a 24-h co-culture with rBCG or BCG+hIFN-α2b. Mice administered rBCG survived longer than mice administered BCG (p<0.001), yet this result was not significantly different from mice administered BCG+hIFN-α2b. The average bladder weight was reduced by administration of rBCG (p<0.001). Fas expression and peripheral blood mTNF-α and mIL-12, cell counts of polymorphonuclear leukocytes, monocytes, T lymphocytes and CD4 + /CD8 + ratios were significantly increased by all BCG treatments (p≤0.05), yet monocyte and T lymphocyte counts were higher in mice administered rBCG than in mice treated with BCG or BCG+hIFN-α2b (p=0.000). These results indicate that in an orthotopic murine bladder cancer model rBCG possesses superior antitumor activity to BCG+hIFN-α2b.

Nuclear factor-kappa B (NF-κB), a cell survival signal, is involved in carcinogenesis. Polymorphism of NF-κB1 is associated with cancer by several studies. This study aims to perform a comprehensive meta-analysis of studies and determine the association between the NF-κB1-94ins/del ATTG promoter polymorphism and cancer. Twenty-five case-control studies (7,281 cases and 10,039 controls) were included. We used odds ratios (ORs) to assess the strength of the association, and 95 % confidence intervals (CIs) to identify precision of the estimate. Overall, NF-κB1-94ins/del ATTG promoter polymorphism was significantly associated with decreased susceptibility to cancer in overall population under homozygote (for DD vs. WW: OR = 0.74, 95 % CI = 0.58-0.96), recessive (for DD vs. WD+WW: OR = 0.82, 95 % CI = 0.69-0.99), dominant (for DD+WD vs. WW: OR = 0.84, 95 % CI = 0.71-1.00), and allele (for D vs. W: OR = 0.88, 95 % CI = 0.78-0.98) model. Subgroup analysis for ethnicity found that NF-κB1-94ins/del ATTG promoter polymorphism was significantly associated with decreased susceptibility to cancer in Asians (for DD vs. WW: OR = 0.54, 95 % CI = 0.40-0.74; for WD vs. WW: OR = 0.75, 95 % CI = 0.69-0.81; for DD vs. WD+WW: OR = 0.70, 95 % CI = 0.55-0.90; for DD+WD vs. WW; OR = 0.66, 95 % CI = 0.56-0.78; for D vs. W: OR = 0.75, 95 % CI = 0.65-0.86), but the association was not found in Caucasians. The findings suggest that NF-κB1-94ins/delATTG promoter polymorphism is significantly associated with decreased susceptibility to cancer in overall and Asian population.