Angiogenesis is a critical step in the development and progression of hepatocellular carcinoma (HCC). Myeloid lineage cells, such as macrophages and monocytes, have been reported to regulate angiogenesis in mouse tumor models. TIE2, a receptor of angiopoietins, conveys pro-angiogenic signals and identifies a monocyte/macrophage subset with pro-angiogenic activity. Here, we analyzed the occurrence and kinetics of TIE2-expressing monocytes/macrophages (TEMs) in HCC patients. This study enrolled 168 HCV-infected patients including 89 with HCC. We examined the frequency of TEMs, as defined as CD141CD161TIE21 cells, in the peripheral blood and liver. The localization of TEMs in the liver was determined by immunofluorescence staining. Micro-vessel density in the liver was measured by counting CD341 vascular structures. We found that the frequency of circulating TEMs was significantly higher in HCC than non-HCC patients, while being higher in the liver than in the blood. In patients who underwent local radio-ablation or resection of HCC, the frequency of TEMs dynamically changed in the blood in parallel with HCC recurrence. Most TEMs were identified in the perivascular areas of tumor tissue. A significant positive correlation was observed between micro-vessel density in HCC and frequency of TEMs in the blood or tumors, suggesting that TEMs are involved in HCC angiogenesis. Receiver operating characteristic analyses revealed the superiority of TEM frequency to AFP, PIVKA-II and ANG-2 serum levels as diagnostic marker for HCC. Conclusion: TEMs increase in patients with HCC and their frequency changes with the therapeutic response or recurrence. We thus suggest that TEM frequency can be used as a diagnostic marker for HCC, potentially reflecting angiogenesis in the liver.

The polymorphisms in the interleukin (IL)-28B (interferon-lambda [IFN]-k3) gene are strongly associated with the efficacy of hepatitis C virus (HCV) clearance. Dendritic cells (DCs) sense HCV and produce IFNs, thereby playing some cooperative roles with HCVinfected hepatocytes in the induction of interferon-stimulated genes (ISGs). Blood dendritic cell antigen 3 (BDCA3) 1 DCs were discovered as a producer of IFN-k upon Toll-like receptor 3 (TLR3) stimulation. We thus aimed to clarify the roles of BDCA3 1 DCs in anti-HCV innate immunity. Seventy healthy subjects and 20 patients with liver tumors were enrolled. BDCA3 1 DCs, in comparison with plasmacytoid DCs and myeloid DCs, were stimulated with TLR agonists, cell-cultured HCV (HCVcc), or Huh7.5.1 cells transfected with HCV/ JFH-1. BDCA3 1 DCs were treated with anti-CD81 antibody, inhibitors of endosome acidification, TIR-domain-containing adapter-inducing interferon-b (TRIF)-specific inhibitor, or ultraviolet-irradiated HCVcc. The amounts of IL-29/IFN-k1, IL-28A/IFN-k2, and IL-28B were quantified by subtype-specific enzyme-linked immunosorbent assay (ELISA). The frequency of BDCA3 1 DCs in peripheral blood mononuclear cell (PBMC) was extremely low but higher in the liver. BDCA3 1 DCs recovered from PBMC or the liver released large amounts of IFN-ks, when stimulated with HCVcc or HCV-transfected Huh7.5.1. BDCA3 1 DCs were able to induce ISGs in the coexisting JFH-1-positive Huh7.5.1 cells. The treatments of BDCA3 1 DCs with anti-CD81 antibody, cloroquine, or bafilomycin A1 reduced HCVcc-induced IL-28B release, whereas BDCA3 1 DCs comparably produced IL-28B upon replication-defective HCVcc. The TRIF-specific inhibitor reduced IL-28B release from HCVcc-stimulated BDCA3 1 DCs. In response to HCVcc or JFH-1-Huh7.5.1, BDCA3 1 DCs in healthy subjects with IL-28B major (rs8099917, TT) released more IL-28B than those with IL-28B minor genotype (TG). Conclusion: Human BDCA3 1 DCs, having a tendency to accumulate in the liver, recognize HCV in a CD81-, endosome-, and TRIF-dependent manner and produce substantial amounts of IL-28B/IFN-k3, the ability of which is superior in subjects with IL-28B major genotype. (HEPATOLOGY 2013;57:1705-1715 H epatitis C virus (HCV) infection is one of the most serious health problems in the world. More than 170 million people are chronically infected with HCV and are at high risk of developing liver cirrhosis and hepatocellular carcinoma. Genomewide association studies have successfully identified the genetic polymorphisms (single nucleotide polymorphisms, SNPs) upstream of the promoter region of the

Systemic IDO activity is enhanced in chronic hepatitis C patients in correlation with the degree of liver inflammation and fibrosis. In response to inflammatory stimuli, DCs from the patients tend to induce Tregs, with some of this action being dependent on IDO.

Fatal chemotherapy-induced hepatitis B virus reactivation (HBV-R) is a well-described serious complication observed in patients with lymphoma and resolved HBV infection. The aim of the present study was to determine the predictive factors of the development of chemotherapy-induced HBV-R. A total of 77 consecutive newly diagnosed patients with lymphoma and resolved HBV infection, who received chemotherapy from 2007 through 2015 were analysed retrospectively. Significant predictive factors associated with HBV-R were identified based on the data from these patients. Ten patients developed HBV-R during and following chemotherapy, and two of these 10 patients developed HBV-associated hepatitis flares. There was a significant negative correlation between anti-hepatitis B core (HBc) titres prior to chemotherapy and time to HBV-R (P=0.016, R=−0.732). Univariate and multivariate logistic regression analyses demonstrated that anti-HBc and anti-hepatitis B surface (HBs) titres at baseline were significant predictive factors for HBV-R. In addition, patients with high anti-HBc titres at baseline (above 10 S/CO) were significantly more likely to experience HBV-R than patients with low anti-HBc and high anti-HBs titres (above 28 mIU/ml), who did not experience complete reactivation (P<0.0001). Furthermore, patients with low anti-HBs titres were significantly more likely to experience HBV-R than those with high anti-HBs titres (P=0.031). All HBV-R episodes among the patients with high anti-HBc titres occurred within 3 months following the initiation of chemotherapy. The combination of anti-HBc and anti-HBs titres, as opposed to either titre alone, at baseline in patients with lymphoma may serve as a surrogate marker for the occurrence of HBV-R under the influence of chemotherapy.

Background and study aims: Sessile serrated adenoma/polyps (SSA/Ps) have a different potential than traditional adenomatous polyps for developing into malignant colorectal cancer. However, little is known about the coexistent cancer rate. Here, we evaluate the frequency of carcinoma in serrated polyps removed by endoscopic resection (ER). Patients and methods: This was a retrospective single-center cohort study of consecutive patients with colorectal polyps who underwent ER from March 2003 to October 2014. We determined the frequency of serrated polyps among all resected colorectal polyps and analyzed the clinicopathological findings as well as the frequency and characteristics of coexistent carcinoma in the serrated polyps resected by ER based on pathology reports. Results: A total of 21,048 polyps from 15,326 patients were identified, including 15,984 traditional adenomatous polyps (75.9 %), 621 SSA/Ps (3.0 %), 136 traditional serrated adenomas (TSAs) (0.6 %), 1,121 hyperplastic polyps (5.3 %), and 3,186 polyps of other types (15.1 %). The clinical and endoscopic findings of SSA/Ps revealed a male predominance (68.6 %), with 61.7 % of the polyps located in the proximal colon. Males accounted for 77.2 % of all patients with TSAs, and 77.2 % of these polyps were located in the distal colon. The mean sizes of the SSA/Ps and TSAs were 8.8 and 10.7 mm, respectively. Among the SSA/Ps, 8 (1.3 %) cases had coexistent carcinoma, and 1 (0.7 %) patient with TSA showed coexistent carcinoma. In the patients with SSA/Ps, female sex and a tumor size ≥ 10 mm were predictive factors for coexistent carcinoma. Conclusions: The frequency of SSA/Ps with carcinoma was lower than that for traditional adenoma. Female sex and tumor size ≥ 10 mm were significant predictive factors for coexistent carcinoma.