The Efficacy of Combined Therapy of Regorafenib with Detoxicating and Stasis Softening Chinese Herbal Spleen Tonics in Mid-/Late-Stage Hepatocellular Carcinoma.

Objective: To explore the efficacy of combined therapy of Regorafenib with detoxicating and stasis softening Chinese herbal spleen tonics (DSS-splenic tonics) in mid-/late-stage hepatocellular carcinoma. Methods: Retrospective observational data of 120 patients were obtained, 60 of which received combined therapy of DSS-splenic tonics and regorafenib. Adverse event, overall survival (OS), and time-to-progress (TTP) were analyzed. Synergistic effect of DSS-spleen tonics was found and validated in human hepatocellular carcinoma HCCLM3 cell line and xenograft mouse models. Results: Combination of regorafenib and DSS-splenic tonics also slightly extended the TTP and OS compared with treatment of regorafenib alone, suggesting DSS-splenic tonics has synergistic effect with regorafenib. Both Regorafenib and DSS-spleen tonics exerted inhibitory effect on cell viability and invasion capability of HCCLM3 cells, and combining both could enhance the antitumor effect. At molecular level, we found that VEGF, HIF-1α, MVD, and VEGF2 were all suppressed by regorafenib and DSS-splenic tonics. These results suggest that DSS-spleen tonics function synergistically with regorafenib in HCC by enhancing the regulation of regorafenib on VEGF, MMP-2, HIF-1α, and MVD, and may diminish angiogenesis during HCC progression. Conclusion: DSS-spleen tonics could exert synergistic antitumor effect with regorafenib via targeting VEGF.

Association of three common BARD1 variants with cancer susceptibility: a system review and meta-analysis.

BARD1 has been shown to play tumor suppressive roles in human cancer. We performed this meta-analysis and firstly evaluated the association between three common BARD1 polymorphisms (Arg378Ser, Val507Met and Pro24Ser) and cancer susceptibility. We performed this meta-analysis following PRISMA guidelines. A comprehensive search of PubMed, EMBASE, Cochrane Library, OVID and Web of Science databases was done from database inception to August 2014. Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were combined to measure the association between BARD1 polymorphisms and cancer risk. On the basis of 10 studies about BARD1 polymorphisms and cancer, we found that BARD1 Val507Met (G/A) polymorphism was associated with decreased cancer susceptibility (allelic model: OR = 0.76, 95% CI: 0.66-0.87, P < 0.00001; dominant model: OR = 0.77, 95% CI: 0.65-0.91, P < 0.00001; recessive model: OR = 0.64, 95% CI: 0.55-0.74, P < 0.00001; homozygote comparison: OR = 0.58, 95% CI: 0.49-0.70, P < 0.00001; heterozygote comparison: OR = 0.85, 95% CI: 0.74-0.99 , P = 0.0008). BARD1 Pro24Ser (C/T) polymorphism was also associated decreased cancer risk in allelic model (OR = 0.72, 95% CI: 0.60-0.88, P = 0.0009), dominant model (OR = 0.70, 95% CI: 0.56-0.87, P = 0.004), recessive model (OR = 0.70, 95% CI: 0.56-0.87 , P = 0.004), homozygote comparison (OR = 0.55, 95% CI: 0.39-0.78, P = 0.0007) and heterozygote comparison (OR = 0.75, 95% CI: 0.62-0.91, P = 0.004). And in our sensitivity analysis, when deleting the study performed by Capasso in 2009, we found that BARD1 Arg378Ser polymorphism was associated with decreased cancer risk in allelic model (OR = 0.81, 95% CI: 0.67-0.97, P = 0.02), dominant model (OR = 0.72, 95% CI: 0.56-0.91, P = 0.007) and heterozygote comparison (OR = 0.72, 95% CI: 0.57-0.91, 0 = 0.006). In conclusion, BARD1 Arg378Ser, Val507Met and Pro24Ser may be associated with decreased cancer risk. More studies with larger samples and gene-environment interactions are needed to confirm our findings.