Hidenari Nagai

Background/Aim: It has been reported that type 2 helper T-cell (Th2) cytokines down-regulate antitumor immunity, while Th1 cytokines up-regulate it. We previously reported that hepatocarcinogenesis was associated with Th2 dominance in patients with hepatitis C virus (HCV)-related liver cirrhosis (LC), but we did not determine whether Th2 dominance induced carcinogenesis or carcinogenesis led to Th2 dominance. The aim of the study was to clarify whether Th2 dominance induces carcinogenesis or vice versa in patients with HCV-related liver diseases. Patients and Methods: The study population was 82 adult Japanese patients who had chronic inflammation due to HCV infection diagnosed by pathological examination of liver biopsy specimens, including 21 patients with early hepatocellular carcinoma (eHCC) and HCV-related LC. All patients were admitted to our hospital between 2008 and 2014. eHCC was treated by radiofrequency ablation (RFA). The non-HCC patients were divided into four subgroups based on the fibrosis score of Desment (stage F1-4). Blood samples were collected just before starting RFA and after 4 weeks of RFA. Flow cytometry was used to assess the percentages of IFNγ⁺ and IL4⁻ (Th1) cells and IFNγ⁻ and IL4⁺ (Th2) cells in CD4⁺ T-cells of peripheral blood before the start of each RFA session. Results: There were 21 patients with fibrosis stage 1, 21 with stage 2, 18 with stage 3, 22 with stage 4, and 21 patients with eHCC. Before RFA, Th1 cells were significantly more frequent in the F4 and eHCC groups than in the F1 group, although there was no significant difference between the HCC and F1 groups after RFA. Both before and after RFA, Th2 cells were significantly more frequent in the HCC group than in the F1 group. Conclusion: Th2 dominance was not altered by elimination of eHCC after RFA therapy. Therefore, Th2 dominance might induce carcinogenesis in patients with HCV-related LC rather than carcinogenesis leading to Th2 dominance.

Purpose: We have previously reported that continuous hepatic arterial infusion chemotherapy (HAIC) might be more effective for advanced hepatocellular carcinoma (aHCC) in patients with liver cirrhosis (LC) related to HCV infection (C-LC) or alcohol abuse (A-LC) than in patients who had LC related to HBV infection (B-LC). The aim of the present study was to retrospectively assess the efficacy of lamivudine therapy for B-LC patients with aHCC undergoing HAIC. Methods: Seventeen adult Japanese B-LC patients with aHCC were treated by HAIC with or without lamivudine (100 mg/day) between 2002 and 2008 at our hospital. Their tumors were inoperable according to computed tomography findings. HAIC (LV at 12 mg/hr, CDDP at 10 mg/hr, and 5-FU at 250 mg/22 hr) was given via the proper hepatic artery every 5 days for 4 weeks using a catheter connected to a subcutaneously implanted drug delivery system. Results: Nine of the 17 patients received lamivudine at a dose of 100 mg/day together with HAIC (LAM group), while 8 patients did not receive lamivudine and only had HAIC (non-LAM group). The response rate was 12.5 in the non-LAM group and 0.0% in the LAM group. However, the survival of the LAM group was better than that of the non-LAM group, although there was no significant difference between them. The median survival time of the LAM and non-LAM groups was 310 and 157 days, respectively. HBV-DNA levels were significantly lower after chemotherapy compared with that before chemotherapy in the LAM group. In the non-LAM group, the percentage of Th2 cells before HAIC and after HAIC was significantly higher than in the control group. However, the percentage of Th2 cells in the LAM group after HAIC was not different from that in the control group, although it was significantly higher in the LAM group than in the control group before chemotherapy. Conclusions: These results indicate that lamivudine therapy may prolong the survival of B-LC patients receiving HAIC for aHCC by reducing HBV-DNA level and inhibiting the increase of Th2 cells in host immunity.

Purpose: We have previously reported that hepatic arterial infusion chemotherapy (HAIC) prolongs the survival of patients with advanced hepatocellular carcinoma (aHCC). However, 5- fluorouracil (5-FU) has been found to exacerbate liver damage in patients with liver cirrhosis (LC). We also previously reported that HAIC might cause occult hepatotoxicity and induces fibrosis without elevation of aminotransferases. The aim of this study was to clarify the effect of glutathione (GSH) on the hepatotoxicity of HAIC in LC patients with aHCC. Methods: Forty-one adult Japanese patients with LC and aHCC underwent HAIC between 2004 and 2009 at our hospital, and achieved multiple partial responses or had stable disease. The patients were divided into two groups, which were a non-GSH group receiving HAIC alone (n = 21) and a GSH group treated with HAIC plus GSH (n = 20). HAIC was delivered via the proper hepatic artery every 5 days for 4 weeks. GSH (100 mg) was given by intravenous injection on each morning of HAIC. Results: The Child-Pugh (C-P) class was A for 12 patients from the non-GSH group and 9 patients from the GSH group, while it was B for 9 and 11 patients, respectively. In class A and B patients from the non-GSH group, the C-P score showed a significant increase after chemotherapy compared with before chemotherapy. In contrast, there was no significant change the C-P score after chemotherapy in the GSH group. There were also no significant changes in the serum markers of liver fibrosis after chemotherapy in the GSH group, although a significant increase was noted in the non-GSH group. Conclusions: In LC patients with aHCC receiving HAIC, GSH might inhibit hepatotoxicity related to occult fibrosis occurring elevation of aminotransferases.

Vascular endothelial growth factor (VEGF) is a primary driving force for both physiological and pathological angiogenesis and over-expression of VEGF has been detected in hepatocellular carcinoma (HCC). The aim of the present study was to clarify the usefulness of VEGF for monitoring the response to intra-arterial chemotherapy in patients with HCC. Seventy-three patients with liver cirrhosis (LC) and advanced HCC (aHCC) received hepatic arterial infusion chemotherapy (HAIC: leucovorin (LV) at 12 mg/h, cisplatin (CDDP) at 10 mg/h and 5-fluorouracil (5-FU) at 250 mg/22 h) via the proper hepatic artery every 5 days for 4 weeks using a catheter connected to a subcutaneous drug delivery system. i) Serum VEGF levels were higher in patients with progressive disease than those in patients with a partial response or stable disease. ii) VEGF levels were higher in patients with alcoholic LC than those in patients with hepatitis C-related or hepatitis B-related LC. iii) VEGF levels were higher in stage IVB patients than those in patients with stage III or IVA disease. iv) VEGF levels were significantly higher in patients with giant or confluent multinodular tumors than those in patients with multiple discrete nodules. v) Serum VEGF levels were higher in patients with vascular invasion than in patients without vascular invasion. Monitoring the serum VEGF level is useful for predicting the response of aHCC to HAIC, as well as for predicting metastasis, tumor type and vascular invasion.

Patients with advanced hepatocellular carcinoma (aHCC) and portal vein tumor thrombus (PVTT) still have a very poor prognosis, even though the oral multikinase inhibitor sorafenib has revolutionized treatment of aHCC in patients with liver cirrhosis (LC). Standardization of multimodal therapy for aHCC with PVTT has not yet been achieved. This retrospective study was performed to clarify the usefulness of combined treatment with sorafenib and hepatic arterial infusion chemotherapy (HAIC) for patients with LC, aHCC and PVTT. Twenty adult Japanese patients with LC underwent HAIC (HAIC group) between 2002 and 2009, while 18 patients received HAIC after treatment with sorafenib between 2009 and 2014 (SF-HAIC group). Among patients with Child-Pugh class A disease, the median survival time of the SF-HAIC group (315 days) was significantly longer than that of the HAIC group (197 days), while there was no significant difference between the two groups (234 and 228 days) among patients with Child-Pugh class B disease. HAIC led to a partial response (PR) in 16.7% of patients with class A disease and 21.4% of patients with class B disease. With SF-HAIC, PR was obtained in 63.8% and 42.9% of patients respectively, although the PR rate was only 9.1% and 0.0%, respectively, after treatment with sorafenib alone for four weeks. When multimodal therapy is employed for patients with LC in Child-Pugh class A disease with aHCC and PVTT, performing HAIC after four weeks of sorafenib treatment might improve both the tumor response and patient survival.

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). 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. 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. 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.

This prospective non-randomized controlled trial aimed to compare the efficacy of sorafenib vs hepatic arterial infusion chemotherapy (HAIC) for advanced hepatocellular carcinoma. Forty-seven patients treated with sorafenib (sorafenib group) and 77 patients treated with HAIC (HAIC group) were investigated retrospectively using propensity score matching (PSM) to minimize selection bias. The cumulative survival rate was investigated before and after PSM in each of the sorafenib and HAIC groups. The cumulative survival rate was compared between the sorafenib and HAIC groups, and among the TNM stage by the Liver Cancer Study Group of Japan (LCSGJ TNM stage). No significant difference was noted in overall survival (OS) between the sorafenib and HAIC groups regardless of before or after PSM. On comparison of the cumulative survival rate between the groups by the same LCSGJ TNM stage, significant prolongation of OS was noted in stage IVB only in the sorafenib group (p = 0.032) after PSM. It may be better to actively introduce sorafenib for stage IVB, i.e., patients with extrahepatic metastasis.

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). Forty-three adult Japanese LC patients who had aHCC received CIAC. Blood samples were collected before and after CIAC. 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. 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.

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.

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. 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. 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. 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.