TET1 upregulation drives cancer cell growth through aberrant enhancer hydroxymethylation of HMGA2 in hepatocellular carcinoma.

Ten-eleven translocation 1 (TET1) is an essential methylcytosine dioxygenase of the DNA demethylation pathway. Despite its dysregulation being known to occur in human cancer, the role of TET1 remains poorly understood. In this study, we report that TET1 promotes cell growth in human liver cancer. The transcriptome analysis of 68 clinical liver samples revealed a subgroup of TET1-upregulated hepatocellular carcinoma (HCC), demonstrating hepatoblast-like gene expression signatures. We performed comprehensive cytosine methylation and hydroxymethylation (5-hmC) profiling and found that 5-hmC was aberrantly deposited preferentially in active enhancers. TET1 knockdown in hepatoma cell lines decreased hmC deposition with cell growth suppression. HMGA2 was highly expressed in a TET1high subgroup of HCC, associated with the hyperhydroxymethylation of its intronic region, marked as histone H3K4-monomethylated, where the H3K27-acetylated active enhancer chromatin state induced interactions with its promoter. Collectively, our findings point to a novel type of epigenetic dysregulation, methylcytosine dioxygenase TET1, which promotes cell proliferation via the ectopic enhancer of its oncogenic targets, HMGA2, in hepatoblast-like HCC.

A case of a giant glucagonoma with parathyroid hormone-related peptide secretion showing an inconsistent postsurgical endocrine status.

A 53-year-old woman was admitted because of a giant pancreatic tumor. Hypercalcemia and a high serum parathyroid hormone-related peptide (PTHrP) level were observed. A hypoglycemic attack occurred during pancreatectomy, and the surgical specimen revealed a PTHrP-secreting glucagonoma. Liver metastases developed 1 and 5.5 years later, and bone metastases appeared 6 years after surgery. Her serum PTHrP concentrations remained normal after surgery, despite re-elevation of the serum glucagon concentration after recurrence. The clinical course of this case illustrates the process of development of neuroendocrine tumors secreting two or more hormones.

Clinical features and risk factors of extrahepatic seeding after percutaneous radiofrequency ablation for hepatocellular carcinoma.

AIM: To clarify the clinical features of and risk factors for extrahepatic seeding, a major complication following radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC). METHODS: Our prospective database of 351 nodules in 257 patients with HCC who had undergone RFA between April 2001 and April 2008 was reviewed. The following variables were assessed to identify the risk factors for extrahepatic seeding: age, sex, viral markers, Child-Pugh class, tumor size, number of tumors, RFA indication (tumor size ≤3 cm, number of tumors ≤3), tumor biopsy prior to RFA, degree of histological differentiation, tumor markers, tumor location, number of sessions, and combined transcatheter arterial chemoembolization. RESULTS: The median follow-up period was 36.5 months, during which the rate of seeding after was 5.1% and the 5-year cumulative seeding rate was 8.4%. The survival rate after neoplastic seeding was 21% at 5 years. Univariate analysis of the risk factors for neoplastic seeding showed significant differences in tumor size, RFA indication, subcapsular lesion, number of sessions, tumor biopsy prior to RFA, and des-gamma-carboxy prothrombin value. However, multivariate analysis showed that the only independent risk factor was RFA indication. CONCLUSIONS: The prognosis of patients with neoplastic seeding was poor. In particular, RFA performed for HCC not satisfying the RFA indication showed a high risk of seeding, and careful consideration should be given to the optimal treatment method and avoiding direct puncture of subcapsular tumors.

[The usefulness and limitations of the new Japanese criteria for severity assessment in acute pancreatitis].

New Japanese criteria for severity assessment in acute pancreatitis were introduced in October 2008. The new criteria are simpler than the previous ones, and are also expected to be more useful for the severity assessment. We retrospectively analyzed the clinical factors in our patients to predict prognosis, and evaluated the usefulness and limitations of the new criteria. There were few missing data in the new criteria compared with the previous criteria. The areas under the receiver operating characteristic (ROC) curves for mortality prediction were 0.870 for the new criteria and 0.884 for the previous criteria. However, there were more patients whose disease severity on admission were underestimated using the new criteria and who finally progressed to worse stages including death. This evidence strongly suggests the lower sensitivity of the new criteria in mortality prediction. Repeated assessment of severity after admission will be indispensable in the proper treatment of patients with acute pancreatitis.

[A case of HIV coinfected with hepatitis B virus treated by entecavir].

A 45-year-old male active homosexual was given a diagnosis of HIV-1 and acute hepatitis B in August 2007. Since his liver function became rapidly impaired, anti-HBV therapy with oral administration of entecavir (ETV) was started, and resulted in a favorable outcome. However, serum concentration of HIV-RNA decreased by log 1.26 within 60 days, which strongly suggested the inhibition of HIV proliferation by ETV. To prevent the appearance of mutated HIV, novel therapeutic strategies should be established in HIV/HBV-coinfected patients.