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Introduction: Atezolizumab plus bevacizumab (AteBev) combination treatment is widely used as first-line systemic therapy for unresectable hepatocellular carcinoma (uHCC). We aimed to clarify therapeutic issues regarding serum cytokines and the immune reaction in patients with uHCC treated with AteBev. Methods: We analyzed preserved serum from a previous prospective study on adult Japanese patients with chronic liver disease and uHCC who received AteBev treatment at our hospital. In that study, AteBev was administered intravenously every 3 weeks, and blood samples were collected before and after 3 weeks' treatment. Dynamic computed tomography was performed after 6 weeks of treatment to assess response. Results: In the prospective study, 21 of the 59 patients showed partial response (PR) and 19 patients showed stable disease, but 19 patients showed progressive disease (PD). We found that serum levels of tumor necrosis factor-alpha, interleukin (IL)-6, and soluble IL-2 receptor (IL-2R) increased significantly in the PR group, but only soluble IL-2R increased significantly in the PD group. Regulatory T cells decreased significantly in the PD group, but there was no significant change in Th1 or Th2 cells from before to after treatment in any group. As regards soluble MHC-class I, pre-treatment levels were significantly lower in the PD group than in the PR group, and serum levels increased significantly with treatment in the PD group. Conclusion: These findings reveal a need to further improve T-cell priming and to further make T cells recognize tumor antigens in uHCC. [ABSTRACT FROM AUTHOR]

Introduction: Previously, we reported that the tyrosine kinase inhibitor (TKI) sorafenib decreases serum levels of carnitine and reduces skeletal muscle volume. Moreover, others reported that TKIs might lead to cardiomyopathy or heart failure. Therefore, this study aimed to evaluate the effects of lenvatinib (LEN) on skeletal muscle volume and cardiac function in patients with hepatocellular carcinoma (HCC). Methods: This retrospective study included 58 adult Japanese patients with chronic liver diseases and HCC treated with LEN. Blood samples were collected before and after 4 weeks of treatment, and serum carnitine fraction and myostatin levels were measured. Before and after 4–6 weeks of treatment, the skeletal muscle index (SMI) was evaluated from computed tomography images and cardiac function was assessed by ultrasound cardiography. Results: After treatment, SMI, serum levels of total carnitine, and global longitudinal strain were significantly lower, but serum levels of myostatin were significantly higher. Left ventricular ejection fraction showed no significant change. Conclusion: In patients with HCC, LEN decreases serum levels of carnitine, skeletal muscle volume, and worsens cardiac function. [ABSTRACT FROM AUTHOR]

Introduction: Atezolizumab, an immune checkpoint inhibitor, plus bevacizumab, a monoclonal antibody that binds to vascular endothelial growth factor (VEGF), is an approved first-line systemic treatment for unresectable hepatocellular carcinoma (HCC). Immune checkpoint inhibitors are more effective in patients with HCC when administered with anti-VEGF drugs; however, these drugs affect host immunity. Lenvatinib is an anti-VEGF agent used to treat HCC; therefore, this study evaluated the effect of treatment of HCC with lenvatinib on host immunity in patients with chronic liver disease (CLD). Methods: We studied adult Japanese patients with CLD and unresectable HCC treated with lenvatinib at our hospital. Lenvatinib was administered for 4 weeks (8 mg/day for bodyweight <60 kg; 12 mg/day for bodyweight >60 kg). Blood samples were collected at baseline and at 4 weeks of treatment and examined for immune-related changes. Results: Forty-three patients were enrolled in this study. We found a significant increase in T helper (Th) 1 cells following 4 weeks of lenvatinib treatment, although there was no significant difference in Th2 cells and regulatory T cells. We also found a significant increase in serum levels of TNF-alpha, soluble TNF-alpha receptor I, and endothelial growth factor following 4 weeks of lenvatinib treatment. Furthermore, an increase in Th1 cells and serum levels of TNF-alpha was found in patients with partial response. Conclusion: Lenvatinib might induce Th1-dominant host immunity in patients with CLD and unresectable HCC treatment in patients who showed a partial response. These changes in host immunity may be a biomarker in HCC patients treated with lenvatinib. [ABSTRACT FROM AUTHOR]

Introduction: In atezolizumab plus bevacizumab (Atezo/Bev) combination treatment, both drugs act on the immune system. Previously, we reported that immunological changes after Atezo/Bev administration for unresectable hepatocellular carcinoma (uHCC) revealed significant alterations in interleukin (IL)-6, soluble IL-2 receptor, tumor necrosis factor-alpha, and programmed cell death-1 levels. Among these variable factors, serum levels of IL-6 can be easily measured on a commercial basis. Therefore, this study aimed to investigate the utility of serum IL-6 as a predictor of tumor response to Atezo/Bev treatment for uHCC. Method: The study included 44 patients with HCC treated with Atezo/Bev. Blood samples were collected before and 3 weeks after treatment, and tumor response was assessed using contrast-enhanced computed tomography 6 weeks after treatment. Results: Significant changes in serum IL-6 levels were observed in patients treated with Atezo/Bev as first-line therapy but not in those treated with it as second-line or later-line therapy. In patients treated with Atezo/Bev as first-line therapy, serum IL-6 levels increased significantly after treatment in patients with a complete or partial response but not in patients with stable or progressive disease. Furthermore, compared to other tumor markers such as alpha-fetoprotein, Lens culinaris agglutinin-reactive fraction of alpha-fetoprotein, and des-gamma-carboxyprothrombin, serum IL-6 levels exhibited the highest sensitivity in predicting tumor response during the treatment period. Conclusion: In patients with uHCC treated with Atezo/Bev, serum IL-6 levels could serve as a potential predictor of tumor response. Elevated levels after treatment may indicate a favorable tumor response and prognosis. [ABSTRACT FROM AUTHOR]

Background: 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., Aim: 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., Patients and Methods: 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)., Results: 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., Conclusion: 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., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Aim: 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., Patients and Methods: 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., Results: 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., Conclusion: 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., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)