Sarcopenia, IMF deposition, and visceral adiposity independently predict mortality in patients with HCC. Body composition rather than BMI is a major determinant of prognosis in patients with HCC.

OBJECTIVES:Radiofrequency ablation (RFA) is widely performed for hepatocellular carcinoma (HCC). However, there has been no report on 10-year outcome of RFA. The objective of this study was to report a 10-year consecutive case series at a tertiary referral center.METHODS:We performed 2,982 RFA treatments on 1,170 primary HCC patients and analyzed a collected database.RESULTS:Final computed tomography images showed complete tumor ablation in 2,964 (99.4%) of 2,982 treatments performed for the 1,170 primary HCC patients. With a median follow-up of 38.2 months, 5- and 10-year survival rates were 60.2% (95% confidence interval (CI): 56.7–63.9%) and 27.3% (95% CI: 21.5–34.7%), respectively. Multivariate analysis demonstrated that age, antibody to hepatitis C virus (anti-HCV), Child-Pugh class, tumor size, tumor number, serum des-γ-carboxy-prothrombin (DCP) level, and serum lectin-reactive α-fetoprotein level (AFP-L3) were significantly related to survival. Five- and 10-year local tumor progression rates were both 3.2% (95% CI: 2.1–4.3%). Serum DCP level alone was significantly related to local tumor progression. Five- and 10-year distant recurrence rates were 74.8% (95% CI: 71.8–77.8%) and 80.8% (95% CI: 77.4–84.3%), respectively. Anti-HCV, Child-Pugh class, platelet count, tumor size, tumor number, serum AFP level, and serum DCP level were significantly related to distant recurrence. There were 67 complications (2.2%) and 1 death (0.03%).CONCLUSIONS:RFA could be locally curative for HCC, resulting in survival for as long as 10 years, and was a safe procedure. RFA might be a first-line treatment for selected patients with early-stage HCC.

Mutations in the PIK3CA gene, which encodes the p110A catalytic subunit of phosphatidylinositol 3-kinase (PI3K), have been reported in human cancers, including colorectal cancer. Most of the mutations cluster at hotspots within the helical and kinase domains. Whereas H1047R, one of the hotspot mutants, is reported to have elevated lipid kinase activity, the functional consequences of other mutations have not been examined. In this study, we examined the effects of colon cancer-associated PIK3CA mutations on the lipid kinase activity in vitro, activation of the downstream targets Akt and p70S6K in vivo and NIH 3T3-transforming ability. Of eight mutations examined, all showed increased lipid kinase activity compared with wild-type p110A. All the mutants strongly activated Akt and p70S6K compared with wild-type p110A as determined by immunoblotting using phospho-specific antibodies. These mutants also induced morphologic changes, loss of contact inhibition, and anchorage-independent growth of NIH 3T3 cells. The hotspot mutations examined in this study, E542K, E545K, and H1047R, all had high enzymatic and transforming activities. These results show that almost all the colon cancer-associated PIK3CA mutations are functionally active so that they are likely to be involved in carcinogenesis. (Cancer Res 2005; 65(11): 4562-7)

Pancreatic ductal adenocarcinoma (PDAC), one of the most lethal neoplasms, is characterized by an expanded stroma with marked fibrosis (desmoplasia). We previously generated pancreas epithelium-specific TGF-β receptor type II (Tgfbr2) knockout mice in the context of Kras activation (mice referred to herein as Kras+Tgfbr2 KO mice) and found that they developed aggressive PDAC that recapitulated the histological manifestations of the human disease. The mouse PDAC tissue showed strong expression of connective tissue growth factor (Ctgf), a profibrotic and tumor-promoting factor, especially in the tumor-stromal border area, suggesting an active tumor-stromal interaction. Here we show that the PDAC cells in Kras+Tgfbr2 KO mice secreted much higher levels of several Cxc chemokines compared with mouse pancreatic intraepithelial neoplasia cells, which are preinvasive. The Cxc chemokines induced Ctgf expression in the pancreatic stromal fibroblasts, not in the PDAC cells themselves. Subcutaneous grafting studies revealed that the fibroblasts enhanced growth of PDAC cell allografts, which was attenuated by Cxcr2 inhibition. Moreover, treating the Kras+Tgfbr2 KO mice with the CXCR2 inhibitor reduced tumor progression. The decreased tumor progression correlated with reduced Ctgf expression and angiogenesis and increased overall survival. Taken together, our data indicate that tumor-stromal interactions via a Cxcr2-dependent chemokine and Ctgf axis can regulate PDAC progression. Further, our results suggest that inhibiting tumor-stromal interactions might be a promising therapeutic strategy for PDAC. IntroductionPancreatic cancer is the fourth and fifth leading cause of cancer death in the United States and Japan, respectively (1, 2). It is one of the most lethal cancers, with 5-year survival rate of less than 5% that is partially attributed to the difficulty of early diagnosis. Moreover, even with a successful resection, 5-year survival is still less than 20%. The poor outcome after resection may be due to the frequent aggressive character of pancreatic tumor cells, which are often able to efficiently invade, disseminate, and metastasize (3, 4).The most common type of human pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC). Previous studies have suggested a multistep progression model of PDAC that includes a preinvasive state termed pancreatic intraepithelial neoplasia (PanIN). PDAC is thought to result from progression of PanIN lesions through accumulation of specific genetic alterations (5). Activation of a point mutation of the KRAS proto-oncogene and inactivation of tumor suppressor genes, including P16 INK4A , P53, and SMAD4 (also known as deleted in pancreatic adenocarcinoma 4 [DPC4]), have been shown to increase in frequency with progression of the PanIN stages. Notably, at the invasive stage, the mutations and deletions

Dysregulated DNA methylation followed by abnormal gene expression is an epigenetic hallmark in cancer. DNA methylation is catalyzed by DNA methyltransferases, and the aberrant expression or mutations of DNA methyltransferase genes are found in human neoplasm. The enzymes for demethylating 5-methylcytosine were recently identified, and the biological significance of DNA demethylation is a current focus of scientific attention in various research fields. Ten-eleven translocation (TET) proteins have an enzymatic activity for the conversion from 5-methylcytosine to 5-hydroxymethylcytosine (5-hmC), which is an intermediate of DNA demethylation. The loss-of-function mutations of TET2 gene were reported in myeloid malignancies, suggesting that impaired TET-mediated DNA demethylation could play a crucial role in tumorigenesis. It is still unknown, however, whether DNA demethylation is involved in biological properties in solid cancers. Here, we show the loss of 5-hmC in a broad spectrum of solid tumors: for example, a significant reduction of 5-hmC was found in 72.7% of colorectal cancers (CRCs) and 75% of gastric cancers compared to background tissues. TET1 expression was decreased in half of CRCs, and a large part of them was followed by the loss of 5-hmC. These findings suggest that the amount of 5-hmC in tumors is often reduced via various mechanisms, including the downregulation of TET1. Consistently, in the in vitro experiments, the downregulation of TET1 was clearly induced by oncogene-dependent cellular transformation, and loss of 5-hmC was seen in the transformed cells. These results suggest the critical roles of aberrant DNA demethylation for oncogenic processes in solid tissues. (Cancer Sci 2012; 103: 670-676) P atterns of DNA methylation, histone modification and chromatin structure are profoundly altered in human cancers.(1-5) In particular, aberrant promoter hypermethylation leading to inappropriate transcriptional silencing of genes, especially tumor suppressor genes, is often found in various types of human neoplasm, including colorectal and gastric cancers.(6-9) DNA methylation is catalyzed by DNA methyltransferases (DNMTs), and it is reported that the increased level of DNMT1 is correlated with the histological grade or poor prognosis of human cancers. (10)(11)(12) In addition, a recent report demonstrated somatic mutations in the DNMT3A gene from acute myeloid leukemia patients. (13) Global loss of methylated DNA in paternal genome after fertilization suggests active DNA demethylation pathway in mammalian cells, although the molecular mechanism has been unknown for a long time. The recent discovery of ten-eleven translocation (TET) proteins those are capable of converting from 5-methylcytosine to 5-hydroxymethylcytosine (5-hmC) gave a breakthrough to the epigenetic research field. (14)(15)(16)(17)(18)(19) Following studies showed that the activationinduced cytidine deaminase family convert cytosine to uracil and 5-hmC to 5-hydroxymethyluracil, (20,21) and that TET1 mediates further oxidation of 5-h...