Background: Activation of the phosphatidylinositol 3-kinase (PI3K) through mutational inactivation of PTEN tumour suppressor gene is common in diverse cancer types, but rarely reported in gastric cancer. Recently, mutations in PIK3CA, which encodes the p110α catalytic subunit of PI3K, have been identified in various human cancers, including 3 of 12 gastric cancers. Eighty percent of these reported mutations clustered within 2 regions involving the helical and kinase domains. In vitro study on one of the "hot-spot" mutants has demonstrated it as an activating mutation. Methods: Based on these data, we initiated PIK3CA mutation screening in 94 human gastric cancers by direct sequencing of the gene regions in which 80% of all the known PIK3CA mutations were found. We also examined PIK3CA expression level by extracting data from the previous large-scale gene expression profiling study. Using Significance Analysis of Microarrays (SAM), we further searched for genes that show correlating expression with PIK3CA. Results: We have identified PIK3CA mutations in 4 cases (4.3%), all involving the previously reported hotspots. Among these 4 cases, 3 tumours demonstrated microsatellite instability and 2 tumours harboured concurrent KRAS mutation. Data extracted from microarray studies showed an increased expression of PIK3CA in gastric cancers when compared with the non-neoplastic gastric mucosae (p < 0.001). SAM further identified 2910 genes whose expression levels were positively associated with that of PIK3CA. Conclusion: Our data suggested that activation of the PI3K signalling pathway in gastric cancer may be achieved through up-regulation or mutation of PIK3CA, in which the latter may be a consequence of mismatch repair deficiency.

Background: There are limited therapeutic options for hepatocellular carcinoma (HCC), the most common liver malignancy worldwide. Recent studies have identified the Frizzled-7 receptor (FZD7), important for activation of Wnt-mediated signaling, as a potential therapeutic target for HCC and other cancers.Methods: We hypothesized that the extracellular domain of FZD7 (sFZD7) would be a clinically more relevant therapeutic modality than previously studied approaches to target FZD7. We expressed and purified sFZD7 from E. coli, and tested its functional activity to interact with Wnt3, its ability to inhibit Wnt3-mediated signaling, and its potential for combinatorial therapy in HCC.Results: sFZD7 pulled down Wnt3 from Huh7 cells, and decreased β-catenin/Tcf4 transcriptional activity in HCC cells.In vitro, sFZD7 dose-dependently decreased viability of three HCC cell lines (HepG2, Hep40, and Huh7, all with high FZD7 and Wnt3 mRNA), but had little effect on normal hepatocytes from three donors (all with low level FZD7 and Wnt3 mRNA). When combined with doxorubicin, sFZD7 enhanced the growth inhibitory effects of doxorubicin against HCC cellsin vitro, and against Huh7 xenograftsin vivo. Reduced expressions of c-Myc, cyclin D1, and survivin were observedin vitroandin vivo. Additionally, sFZD7 altered the levels of phosphorylated AKT and ERK1/2 induced by doxorubicin treatmentin vitro, suggesting that several critical pathways are involved in the chemosensitizing effect of sFZD7.Conclusions: We propose that sFZD7 is a feasible therapeutic agent with specific activity, which can potentially be combined with other chemotherapeutic agents for the improved management of HCC.

Liver disease and liver cancer associated with childhood-acquired chronic hepatitis B are leading causes of death among adults in China. Despite expanded newborn hepatitis B vaccination programs, approximately 20% of children under age 5 years and 40% of children aged 5 to 19 years remain unprotected from hepatitis B. Although immunizing them will be beneficial, no studies have examined the cost-effectiveness of hepatitis B catch-up vaccination in an endemic country like China. We examined the cost-effectiveness of a hypothetical nationwide free hepatitis B catch-up vaccination program in China for unvaccinated children and adolescents aged 1 to 19 years. We used a Markov model for disease progression and infections. Cost variables were based on data published by the Chinese Ministry of Health, peer-reviewed Chinese and English publications, and the GAVI Alliance. We measured costs (2008 U.S. dollars and Chinese renminbi), quality-adjusted life years, and incremental cost-effectiveness from a societal perspective. Our results show that hepatitis B catch-up vaccination for children and adolescents in China is cost-saving across a range of parameters, even for adolescents aged 15 to 19 years old. We estimate that if all 150 million susceptible children under 19 were vaccinated, more than 8 million infections and 65,000 deaths due to hepatitis B would be prevented. Conclusion : The adoption of a nationwide free catch-up hepatitis B vaccination program for unvaccinated children and adolescents in China, in addition to ongoing efforts to improve birth dose and newborn vaccination coverage, will be cost-saving and can generate significant population-wide health benefits. The success of such a program in China could serve as a model for other endemic countries. (Hepatology 2009.)

Background: Hepatocellular carcinoma (HCC) is an aggressive cancer, and is the third leading cause of cancer death worldwide. Standard therapy is ineffective partly because HCC is intrinsically resistant to conventional chemotherapy. Its poor prognosis and limited treatment options make it critical to develop novel and selective chemotherapeutic agents. Since the Wnt/β-catenin pathway is essential in HCC carcinogenesis, we studied the inhibition of Wnt-1-mediated signaling as a potential molecular target in HCC.Results: We demonstrated that Wnt-1 is highly expressed in human hepatoma cell lines and a subgroup of human HCC tissues compared to paired adjacent non-tumor tissues. An anti-Wnt-1 antibody dose-dependently decreased viability and proliferation of Huh7 and Hep40 cells over-expressing Wnt-1 and harboring wild type β-catenin, but did not affect normal hepatocytes with undetectable Wnt-1 expression. Apoptosis was also observed in Huh7 and Hep40 cells after treatment with anti-Wnt-1 antibody. In these two cell lines, the anti-Wnt-1 antibody decreased β-catenin/Tcf4 transcriptional activities, which were associated with down-regulation of the endogenous β-catenin/Tcf4 target genes c-Myc, cyclin D1, and survivin. Intratumoral injection of anti-Wnt-1 antibody suppressedin vivotumor growth in a Huh7 xenograft model, which was also associated with apoptosis and reduced c-Myc, cyclin D1, and survivin expressions.Conclusion: Our results suggest that Wnt-1 is a survival factor for HCC cells, and that the blockade of Wnt-1-mediated signaling may offer a potential pathway-specific therapeutic strategy for the treatment of a subgroup of HCC that over-expresses Wnt-1.

Background: An estimated 862 000 to 2.4 million people have chronic hepatitis B infection (CHB). Hepatitis B screening is recommended for pregnant women and populations with increased CHB risk. However, diagnosis rates remain low, with only 33% of people with CHB aware of their infection. This study aimed to assess the cost-effectiveness of universal adult screening for CHB.Methods: We used a Markov model to calculate the costs, population health impact, and cost-effectiveness of 1-time universal screening and CHB monitoring and treatment compared with current practice. Sensitivity analysis was performed on model parameters to identify thresholds for cost-saving or cost-effectiveness based on a willingness to pay of $50 000/quality-adjusted life-year. The analysis assumed testing would be performed during routine healthcare visits and that generic tenofovir or entecavir would be dispensed for treatment. Testing costs were based on Medicare reimbursement rates.Results: At an estimated 0.24% prevalence of undiagnosed CHB, universal hepatitis B surface antigen (HBsAg) screening in adults aged 18–69 years is cost-saving compared with current practice if antiviral treatment drug costs remain below $894/year. Compared with current practice, universal screening would avert an additional 7.4 cases of compensated cirrhosis, 3.3 cases of decompensated cirrhosis, 5.5 cases of hepatocellular carcinoma, 1.9 liver transplants, and 10.3 hepatitis B virus–related deaths at a saving of $263 000/100 000 adults screened.Conclusions: Universal HBsAg screening of adults in the US general population for CHB is cost-effective and likely cost-saving compared with current CHB screening recommendations.