Tetsuya Beppu

Predictive factors for distant recurrence of HCV‐related hepatocellular carcinoma after radiofrequency ablation combined with chemoembolization

Background  Radiofrequency ablation (RFA) therapy for hepatocellular carcinoma has enabled good local control to be possible. However, after successful local control, distant recurrences frequently occur in the remnant liver.

High incidence of tumors in diabetic thrombin activatable fibrinolysis inhibitor and apolipoprotein E double-deficient mice

Summary.  Background: Activation of the complement system has been implicated in tumor growth. The antifibrinolytic protein, activated thrombin‐activatable fibrinolysis inhibitor (TAFIa), can modulate the activation of the complement system by inactivating the anaphylatoxins C3a and C5a. The apolipoprotein‐E (ApoE) genotype has been associated with carcinogenesis. Objective: The aim of this study was to evaluate whether TAFIa can affect the development of cancer in the ApoE‐deficient mouse model. Methods: TAFI and ApoE double‐knockout mice were generated. A group of mice was treated with the diabetogenic and carcinogenic compound streptozotocin (stz). Mice treated with saline, single knockout mice and wild‐type (wt) mice served as controls. Results: Six months after treatment with stz, mice were sacrificed. Hepatic tumors were found in male double‐knockout mice treated with stz but none was found in control animals that were not treated with stz or in single knockout of ApoE or wt animals. There was no significant difference in coagulation system activation between the groups of mice. The plasma concentrations of C5a, factor D and transforming growth factor‐β1 were increased in TAFI/ApoE double‐deficient mice treated with stz compared with the mice of the same genotype treated with saline. Conclusion: Apo‐E deficiency alone was not associated with tumors but the lack of TAFI appears to make the mice permissive for tumor formation in ApoE mice.

Su2049 Radiofrequency Ablation Therapy for the Treatment of Metastatic Lung Tumor From Primary Hepatocellular Carcinoma

Background: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide. The prevalence of HCC varies widely in different regions of the world. The impact of specific causes of chronic liver disease to HCC prevalence is well-established. In contrast, the contribution of the underlying genetic architecture to the risk of HCC remains undefined. Genome wide association studies have identified genetic polymorphisms associated with increased susceptibility to HCC. Our aim was to characterize evolutionary trends in the genetic profile of HCC. We hypothesized that negative selection would reduce susceptibility to genetic polymorphisms that increase risk of HCC. Methods: SNPs identified from genome wide association studies with an increased risk of HCC associated with HBV (rs17401966) or HCV (rs9275572, rs2596542) were analyzed. Genetic risk was determined from the risk odds ratio and the frequency of the risk alleles across 53 indigenous human populations across all continents using the Human Genome Diversity Project and ALFRED databases. The fixation index (Fst ) was used to describe the degree of population differentiation (low 1.5) as a measure of gene flow and similarity across subpopulations. A genetic risk score for HCC was determined based on the combined risk of five SNPs associated with increased risk of HCC [rs1800562, rs2596542, rs2267716, rs9275572 and rs17401966]. The frequency of each risk allele and the genetic risk score were correlated with geographic location and with temporal and spatial patterns of human migration. Results: A moderate increase in differentiation was noted for rs2596542 (Fst = 0.106) and rs17401966 (Fst =0.116). Both of these SNPs show an increase in allelic frequency with the most recent human migrations from East Asia, to Oceania and the Americas. In contrast, rs9275572 lacked differentiation (Fst=0.09) with stable allelic expression across populations. The percentile genetic risk score for HCC was greatest in populations from Africa (e.g. Mbuti pygymies 100, San 97), and decreased with subsequent migration into Europe and Asia through to East Asia (e.g. Lahu 1, Yi 1.5). However, a major increase was noted with most recent migrations into Oceania and the Americas (e.g. Karitiana 93.9). Conclusions: Population based studies of genomic variations provide insight into the role of migration on genetic risk for hepatocarcinogenesis. There are differences in directional differentiation of HCC risk alleles across human populations, indicating that susceptibility to HCC can be modified by factors other than genetic drift. Variations in allelic frequency of HCC associated SNPs can contribute to population-based differences in HCC prevalence, and need to be considered for developing regional strategies for screening and surveillance for HCC.