Host Immunity Influences the Efficacy of Combined Intra-Arterial Chemotherapy for Advanced Hepatocellular Carcinoma in Liver Cirrhosis Patients.

BACKGROUND/AIMS: It has been reported that Th2 cytokines down-regulate antitumor immunity, while activation of Th1 cells promotes such immunity. The aim of this study was to assess changes of host immunity in relation to efficacy in patients with liver cirrhosis (LC) and advanced hepatocellular carcinoma (aHCC) treated by combined intra-arterial chemotherapy (CIAC). METHODOLOGY: Forty-three adult Japanese LC patients who had aHCC received CIAC. Blood samples were collected before and after CIAC. RESULTS: Eleven of the 43 patients showed a partial response (group PR) and 21 patients had stable disease (group SD), but 11 patients showed no response (group PD). There were no significant differences of Th1 or Th2 cells between before and after CIAC in each group. However, groups SD and PD had higher levels of Th2 cells than in group PR before and after CIAC. The percentage of regulatory T (Treg) cells in group PD was significantly increased after CIAC compared with before CIAC, whereas groups PR and SD showed significant decrease after CIAC. CONCLUSIONS: The percentage of Th2 cells is useful for predicting the response to CIAC and the percentage of Treg cells is useful for assessment of efficacy in LC patients with aHCC receiving CIAC.

Influence of etiology on host immunity in liver cirrhosis patients with advanced hepatocellular carcinoma receiving intra-arterial chemotherapy.

BACKGROUND/AIMS: We have shown that continuous intra-arterial combination chemotherapy (IACC) might be more effective for advanced HCC (aHCC) in patients with HCV-related (C-LC) or alcoholic (A-LC) liver cirrhosis (LC) patients than in patients with HBV-related LC (B-LC). This study retrospectively assesses the difference of etiology on host immunity in LC patients with aHCC treated by IACC. METHODOLOGY: Forty-seven adult LC patients with aHCC were treated by IACC between 2005 and 2008, with inoperable tumors according to CT findings. IACC (LV at 12 mg/hr, CDDP at 10 mg/hr, and 5-FU at 250 mg/22 hr) was delivered via the proper hepatic artery every 5 days for 4 weeks using a catheter connected to a subcutaneously implanted drug delivery system. The control group comprised 13 healthy volunteers. RESULTS: Twelve of the 47 patients with aHCC had B-LC, 27 had C-LC, and 8 had A-LC. In the B-LC group, 1 out of 12 patients had a Japan Integrated Staging (JIS) score of 2, 4 had a JIS score of 3, 7 had a JIS score of 4, and no patients had a JIS score of 5, while the respective numbers were 6, 9, 10 and 2 in the C-LC group, and 1, 1, 5 and 1 in the A-LC group. The response rates were 37.0%, 37.5% and 8.3% in the C-LC, A-LC and B-LC group, respectively. In the C-LC group, the percentage of Th1 cells before and after chemotherapy was significantly higher than in the control group. In the B-LC group, the percentage of Th2 cells after chemotherapy was significantly higher than that in the control group. However, there were no significant differences of Th1 and Th2 cells between the A-LC group and the control group. CONCLUSIONS: These results indicate that IACC was more effective for aHCC in A-LC patients with normal Th1/Th2 balance and in C-LC patients without Th2 dominance than in B-LC patients who showed Th2 dominance after chemotherapy.

Sorafenib prevents escape from host immunity in liver cirrhosis patients with advanced hepatocellular carcinoma.

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.

Usefulness of arrival time parametric imaging in evaluating the degree of liver disease progression in chronic hepatitis C infection.

OBJECTIVE: To determine whether the degree of liver disease progression in chronic hepatitis C infection can be evaluated by arrival time parametric imaging using contrast-enhanced sonography with Sonazoid (perfluorobutane; GE Healthcare, Oslo, Norway). METHODS: In this study, 60 patients with liver disease in chronic hepatitis C infection were examined and compared with 10 healthy volunteers who served as controls. A recommended dose of the sonographic contrast agent Sonazoid was intravenously infused, and the S5 or S6 region of the liver and right kidney were observed concurrently while movies of the procedure were saved. Arrival time parametric images of liver parenchymal blood flow were created, with red pixels to indicate an arrival time of 0 to 5 seconds and yellow pixels to indicate an arrival time of 5 to 10 seconds. From the obtained images, the ratio of the red area to the entire enhanced area of the liver was calculated using image-processing software. Each participant was subsequently subjected to liver biopsy for liver fibrosis staging according to Metavir scores, and the determined fibrosis stage was compared with the ratio of red. The serum albumin level, platelet count, and prothrombin time were also compared with the ratio of red for each participant. RESULTS: The ratio of red increased significantly as liver fibrosis stage advanced (P < .01 for F1 versus F2; P < .01 for F1 versus F3; P < .01 for F1 versus F4; and P < .01 for F2 versus F4). As the ratio of red increased, significant decreases were observed in the serum albumin level (r = -0.29; P = .027), platelet count (r = -0.46; P = .0003), and prothrombin time (r = -0.46; P = .0002). CONCLUSIONS: Arrival time parametric imaging using Sonazoid-enhanced sonography enables noninvasive evaluation of the degree of progression of liver disease in chronic hepatitis C infection and is thus considered clinically useful.

Importance of branched-chain amino acids in patients with liver cirrhosis and advanced hepatocellular carcinoma receiving hepatic arterial infusion chemotherapy.

PURPOSE: The aim of this retrospective cohort study was to clarify the effect of a branched-chain amino acids (BCAA) on the liver function and the prognosis of Child-Pugh class (C-P) A and B liver cirrhosis (LC) patients with advanced hepatocellular carcinoma (aHCC) undergoing hepatic arterial infusion chemotherapy (HAIC). METHODS: Ninety-two adult Japanese patients with LC and aHCC underwent HAIC. They were in C-P A or B, and they showed multiple partial responses or stable disease. We excluded 11 patients classified as C-P C and 47 patients who showed no response. The patients were divided into an HAIC group receiving HAIC alone (n = 43) and a BCAA group treated with HAIC plus BCAA (n = 49). HAIC was delivered via the proper hepatic artery. The BCAA group also received oral administration of BCAA. RESULTS: In the BCAA group, serum albumin increased significantly after HAIC, while there were no significant changes in serum total bilirubin, serum aminotransferases, prothrombin time, ascites, and hepatic encephalopathy. The C-P score decreased significantly after HAIC compared with before HAIC in C-P B patients, although there was no significant change in C-P A patients. Survival of the BCAA group was significantly longer than that of the HAIC group, with the median survival time being 426 versus 272 days for C-P B patients, although there was no significant difference for C-P A patients. CONCLUSIONS: Branched-chain amino acids might improve the survival and C-P score by increasing serum albumin in C-P B patients with aHCC receiving HAIC.

Changes of cytokines in patients with liver cirrhosis and advanced hepatocellular carcinoma treated by sorafenib.

PURPOSE: Recently, the oral multikinase inhibitor sorafenib has been used to treat advanced hepatocellular carcinoma (aHCC). Tumor necrosis factor (TNF) induces apoptosis of tumor cells by binding to TNF-related apoptosis-inducing ligand, while binding of the Fas ligand on cytotoxic T lymphocytes to the Fas receptor on hepatocytes also causes apoptosis. The aim of this study was to retrospectively evaluate changes of cytokines in patients with liver cirrhosis (LC) and aHCC receiving sorafenib therapy. METHODS: Fifty-seven adult Japanese LC patients received sorafenib for aHCC (200-800 mg/day for 4 weeks) between 2009 and 2012 at our hospital. Blood samples were collected in the early morning before and after treatment, and the serum levels of soluble TNF-alpha (sTNF-alpha), soluble TNF receptor (sTNF-R), soluble Fas ligand (sFas L), and soluble Fas (sFas) were evaluated. RESULTS: Ten patients were treated with sorafenib at 200 mg/day (200 mg group), 37 patients were given 400 mg/day (400 mg group), and 10 patients received 800 mg/day (800 mg group). The serum level of sTNF-alpha was significantly increased after treatment compared with before treatment in the 400 and 800 mg groups. The serum level of sTNF-R also showed a significant increase after treatment in the 400 mg group, although there was no significant difference of sTNF-R between before and after treatment in the 200 and 800 mg groups. sFas showed a significant decrease after treatment compared with before treatment in the 400 and 800 mg groups, although the serum level of sFas L never exceeded 0.15 ng/ml. CONCLUSIONS: 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.

Serum VEGF as a tumor marker in patients with HCV-related liver cirrhosis and hepatocellular carcinoma.

AIM: Vascular endothelial growth factor (VEGF) is a primary driving force for both physiological and pathological angiogenesis, and its overexpression has been found in hepatocellular carcinoma (HCC). The aim of this study was to retrospectively clarify the usefulness of serum VEGF levels as a tumor marker in patients with hepatitis C virus (HCV)-related liver cirrhosis (CLC) and HCC. MATERIALS AND METHODS: The patients with CLC were divided into three groups: 28 patients without HCC (CLC group), 11 patients with HCC (HCC group), and 48 patients with advanced HCC (aHCC group). The control group consisted of 37 patients with chronic HCV. RESULTS: When the relation of serum VEGF to liver function was assessed, there was no significant difference of VEGF levels between the control group and the CLC group. When serum VEGF levels were assessed in relation to the presence of HCC, the VEGF levels of the HCC group and aHCC group were found to be significantly higher than that of the control group, while there was no significant difference between the control group and the CLC group. For the detection of cancer, serum VEGF had the largest area under the curve (AUC) and the highest accuracy when we employed the cut-off value obtained by receiver operating characteristic (ROC) analysis using the Youden index. Evaluation of various tumor markers in the aHCC group showed that the serum levels of α-fetoprotein (AFP) were higher in patients with infiltrating tumors than in patients with multiple discrete nodules or confluent multinodular tumors, while there were no significant differences in the serum levels of VEGF, Lens culinaris agglutinin-reactive fraction of AFP (AFP-L3), and des-γ-carboxy prothrombin. There were no significant differences on the serum levels of all four markers between tumor stages, but serum VEGF was higher in patients with vascular invasion than in those without vascular invasion. CONCLUSION: The present findings suggest that the serum levels of VEGF might be a useful predictor of the presence of HCC in patients with CLC, while serum levels of AFP and VEGF can predict the tumor type and vascular invasion, respectively.

Visualization of segmental arterialization with arrival time parametric imaging using Sonazoid-enhanced ultrasonography in portal vein thrombosis: A case report.

A 55-year-old male was admitted in mid-April 2011 with a fever of >39°C and pain in the lower right abdomen. A medical examination revealed sepsis originating from colonic diverticulitis. Abdominal B-mode ultrasonography (US) performed on admission detected thrombi in the superior mesenteric vein and in the right branch of the hepatic portal vein. Arrival time parametric imaging (At-PI) using Sonazoid-enhanced US showed arterialization of the entire right lobe of the liver. The treatment for the sepsis and portal thrombi that had been started upon admission dissolved the thrombi by day 22, with the exception of one thrombus in the P8 branch of the portal vein. At-PI performed on the same day confirmed arterialization in segment 8, but portal vein dominance was restored elsewhere. When the blood inflow from the hepatic portal vein was reduced, the hepatic arterial blood flow was increased to compensate for the reduction in the total blood supply. The At-PI functions used in the Sonazoid-enhanced US were simple yet effective in visualizing the changes in the hepatic hemodynamics caused by the portal thrombus.

Arrival time parametric imaging using Sonazoid-enhanced ultrasonography is useful for the detection of spoke-wheel patterns of focal nodular hyperplasia smaller than 3 cm.

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.