Purpose. It has been reported that Th2 cytokines downregulate antitumor immunity, while activation of type T cells promotes antitumor immunity. The aim of this paper was to evaluate host immunity in liver cirrhosis (LC) patients with advanced hepatocellular carcinoma (aHCC) receiving sorafenib therapy. Methods. Forty-five adult Japanese LC patients received sorafenib for aHCC between 2009 and 2011 at our hospital. Sorafenib was administered at a dose of 200–800 mg/day for 4 weeks. Blood samples were collected before and after treatment. Results. Eleven patients were treated with sorafenib at 200 mg/day (200 group), 27 patients received sorafenib at 400 mg/day (400 group), and 7 patients were given sorafenib at 800 mg/day (800 group). There was no significant change in the percentage of Th1 cells after treatment in any group. However, the percentages of Th2 cells and regulatory T cells were significantly decreased after treatment in the 400 group and 800 group compared with before treatment, although there was no significant change after treatment in the 200 group. Conclusions. These results indicate that treatment with sorafenib might induce Th1 dominance and prevent the escape of tumor cells from the host immune system in LC patients with aHCC.

These findings suggest that treatment with sorafenib at doses ≥400 mg/day might promote TNF-related or Fas-related apoptosis by increasing the circulating level of TNF-alpha or decreasing that of sFas.

It is considered difficult to make a definitive diagnosis of focal nodular hyperplasia (FNH) of <3 cm when using conventional diagnostic imaging modalities. Typical FNH imaging findings are: i) central scar formation, ii) nutrient vessels extending radially from the center and iii) the presence of Kupffer cells. In a clinical setting, identification of a spoke-wheel pattern formed by nutrient vessels extending radially is a key feature in the diagnosis of FNH. In this study, we investigated the detection rate of spoke-wheel patterns of FNH <3 cm using arrival time parametric imaging (At-PI) technology with Sonazoid-enhanced ultrasonography (US). Five patients with FNH <3 cm who had undergone Sonazoid-enhanced US at the Toho University Omori Medical Center between February 2008 and March 2009 were included in the study. The mean tumor diameter was 20.2±7.2 mm. Lesions were enhanced with 0.5 ml Sonazoid US contrast agent and a video of the procedure was saved and used for At-PI analysis of contrast agent dynamics in FNH. Three ultrasonographic specialists examined the images and made a diagnosis of FNH based on the findings of spoke-wheel patterns. Similarly, micro-flow imaging (MFI) was performed to evaluate the contrast agent dynamics in FNH. Using MFI, FNH was diagnosed in 3 of the 5 cases by the three specialists, whereas At-PI enabled the identification of spoke-wheel patterns in all 5 cases. At-PI using Sonazoid-enhanced US is superior for detecting spoke-wheel patterns of FNH <3 cm.

Tivantinib, a mesenchymal-epithelial transition factor (cMET) inhibitor, is a molecular targeting drug that kills hepatocellular carcinoma (HCC) cells. Tivantinib alone does not affect the overall survival of patients with HCC, and combination treatment with tivantinib and other therapies has not been evaluated. This study was conducted to clarify the effect of the tivantinib in regulating breast cancer therapy-resistant protein (BCRP), a key transporter of 5-fluorouracil (5-FU), and dihydropyridine dehydrogenase (DPYD), a major metabolic enzyme of 5-FU. To this end, cMET gene expression was determined by RT-PCR in HepG2 (human hepatoma) cells. The transcriptional start sites of BCRP were determined by 5′-rapid amplification of cDNA ends (5′-RACE). BCRP and DPYD mRNA levels were determined by real-time RT-PCR, and promoter activities were measured by dual-luciferase assays. Results show that hepatocyte growth factor (HGF) upregulated the mRNA level of BCRP, but not DPYD, in HepG2 cells. The upregulation of BCRP expression by HGF was down-regulated by tivantinib. We also identified two transcriptional start sites (E1α, E1β) in BCRP by 5′-RACE. The transcriptional activity of the region 287 to E1α of BCRP was upregulated by HGF, which was decreased by tivantinib, whereas activity of the region 297 to E1βo f BCRP was not affected by tivantinib. Therefore, tivantinib regulates BCRP expression upstream of exon 1α. Combination treatment of tivantinib and 5-FU should be further evaluated for HCC therapy.

PurposeArrival time parametric imaging (At-PI) using contrast-enhanced ultrasonography (CEUS) is a procedure for evaluating liver disease progression in chronic hepatitis C infection (CHC). We investigated At-PI diagnostic efficacy in predicting development of collateral veins.MethodsIn total, 171 CHC patients underwent CEUS and upper gastrointestinal (UGI) endoscopy before liver biopsy. Conventional US was performed before CEUS to identify paraumbilical veins (PV) or splenorenal shunts (SRS). After intravenous perflubutane, contrast dynamics of liver segments 5–6 and the right kidney were saved as raw data. At-PI image ratio of red (ROR) pixels to the entire liver was analyzed. Receiver operating characteristic (ROC) curves were generated to investigate the utility of At-PI for collateral vein identification.ResultsConventional US revealed PV in two patients and SRS in five patients; UGI endoscopy detected esophageal varices (EV) in eight patients. Diagnostic capability of At-PI for detecting PV, SRS, and EV was satisfactory, and high for PV and SRS [PV; area under the ROC curve (AUROC) 0.929, cutoff value 77.9%, SRS; AUROC 0.970, cutoff value 82.0%, EV; AUROC 0.883, cutoff value 66.9%].ConclusionsEvaluation of hepatic arterialization by At-PI was useful for predicting collateral vein development in CHC patients.