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Purpose: To compare contrast-enhanced ultrasonography (CEUS) using Sonazoid with Gd-EOB-DTPA-enhanced MRI (EOB-MRI) in the diagnosis of liver metastases in patients with colorectal cancer., Methods: A total of 69 patients diagnosed with or suspected of having liver metastasis were enrolled. These hepatic lesions were diagnosed by histopathological examination after surgical resection or based on follow-up using various imaging modalities. The diagnostic accuracies of CEUS and EOB-MRI were compared., Results: One hundred thirty-three lesions were detected. Of these lesions, 109 were diagnosed as liver metastases. Of the 133 lesions, 90.2% were detected on CEUS, and 98.5% on EOB-MRI. One hundred nine lesions were diagnosed as liver metastasis. The areas under the receiver operating characteristic curve for diagnosis were 0.906 and 0.851 on CEUS and EOB-MRI, respectively (p = 0.41). Sensitivity, specificity, positive predictive value (PPV), negative predictive value, and overall accuracy were 90.8%, 84.5%, 97.1%, 67.1%, and 90.2%, respectively, for CEUS, and 95.4%, 70.8%, 93.7%, 77.3%, and 91%, respectively, for EOB-MRI., Conclusions: CEUS has a higher specificity and PPV for the diagnosis of liver metastasis than EOB-MRI. © 2016 Wiley Periodicals, Inc. J Clin Ultrasound 45:138-144, 2017., (© 2016 The Authors Journal of Clinical Ultrasound Published by Wiley Periodicals, Inc.)

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., (Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

We examined plasma biomarkers as predictive factors for advanced hepatocellular carcinoma(ad-HCC)patients treated with sorafenib. We analyzed a-fetoprotein(AFP), AFP-L3, des-g-carboxy prothrombin(DCP), neutrophil-to-lymphocyte ratio(NLR), platelet-to-lymphocyte ratio(PLR), and vascular endothelial growth factor(VEGF)before sorafenib therapy, and changes in AFP-L3, NLR, PLR, and VEGF 1 month after sorafenib therapy in 16 patients. High AFP-L3(hazard ratio: 1.058, 95%CI: 1.019-1.098, p=0.003)and high NLR(hazard ratio: 1.475, 95%CI: 1.045-2.082, p=0.027)were significantly associated with poor prognosis in ad-HCC patients treated with sorafenib. There were no significant differences in changes in AFP-L3, NLR, PLR, and VEGF 1 month after sorafenib therapy. We suggest that AFP-L3 and NLR levels before sorafenib therapy in patients with ad-HCC are an important predictive factor for the therapeutic effect of sorafenib and patient survival.

We aimed to determine the usefulness of arrival time parametric imaging (AtPI) using contrast-enhanced ultrasonography (CEUS)with Sonazoid in the evaluation of early response to sorafenib for hepatocellular carcinoma (HCC). Thirteen ad- vanced HCC patients with low a / -fetoprotein (AFP) level (≤35 ng/mL) who received sorafenib for at least 4 weeks were enrolled in this study. CEUS was performed before and after treatment (2 weeks), and the images of the target lesion in the arterial phase were analyzed by AtPI. In the color mapping images obtained by AtPI, the mean arrival time of the contrast agent in the target lesion from the starting point (mean time: MT) was calculated. In each patient, differences between MT before and MT 2 weeks after treatment were compared. MT (+) and MT(-) groups were designated as such if the difference was 0 or greater(blood flow velocity of the lesion was reduced)and less than 0 sec(blood flow velocity of the lesion was increased), respectively. The overall survival was evaluated between the 2 groups. In the MT (+) group (7 patients) and MT (-) group (6 patients), the median survival times were 307 and 208 days, respectively, which was statistically significant. We suggest AtPI is useful for evaluating early response to sorafenib in advanced HCC patients with low AFP level.

Aim: To compare therapeutic outcomes and adverse events in initial solitary hepatocellular carcinoma (HCC) treated with radiofrequency ablation (RFA) and CyberKnife(®)., Methods: Seventy three consecutive patients with initial solitary HCC treated with RFA (38 patients; RFA group) and CyberKnife(®) (35 patients; CK group) were enrolled in this study. Background factors were compared between the two groups. Local and intrahepatic distant recurrence control, and cumulative survival rates were compared between the two groups. These were determined using the Kaplan-Meier method, and the significance of differences was analyzed by log-rank test. The presence of more grade 3 on CTCAE ver. 4.0 early and late adverse events was investigated., Results: In background factors, age was significantly higher (P = 0.005) and the tumor diameter was significantly larger (P = 0.001) in the CK group. The 1-year local recurrence control rates were 97.4% and 97.1% in the RFA and CK groups, respectively (P = 0.71); the 1-year intrahepatic distant recurrence control rates were 85.6% and 86.1%, respectively (P = 0.91); and the 1-year cumulative survival rates were 100% and 95.2%, respectively (P = 0.075), showing no significant difference in any rate between the two groups. There were no late adverse event in the RFA group, but 11.4% in the CK group had late adverse events. In the CK group, the Child-Pugh score at 12 mo after treatment was significantly higher than that in the RFA group (P = 0.003) and significantly higher than the score before treatment (P = 0.034)., Conclusion: The occurrence of adverse events is a concern, but CyberKnife(®) treatment is likely to become an important option for local treatment of early HCC.

We compared the benefits of sorafenib with that of hepatic arterial infusion chemotherapy (HAIC) for advanced hepatocellular carcinoma (ad-HCC) refractory to transcatheter arterial chemoembolization (TACE). We evaluated the patient characteristics, the median survival time (MST), and the prognostic factors in 17 patients in the sorafenib group and in 26 patients in the HAIC group. No significant difference was observed in the patient characteristics between the groups. The MST in the sorafenib group and HAIC group was 483 days and 284 days, respectively. A significantly longer survival time was noted in the sorafenib group (p=0.033). The prognostic factors were sorafenib therapy in all 43 patients(hazard ratio: 3.32 [95% CI: 1.36-8.10], p=0.008) and the longer treatment period of sorafenib in the sorafenib group(hazard ratio: 0.99 [95% CI: 0.984- 0.999], p=0.009). When compared with HAIC, sorafenib showed favorable treatment results in patients with ad-HCC refractory to TACE.

A 66-year-old man with postsigmoidectomy status for colon cancer received laparoscopic partial hepatectomy due to a hepatic mass with employing titanium clips were for a vascular clamp. Histological examination showed liver metastasis from sigmoid colon cancer. Twenty-nine months after the partial hepatectomy, a mass developed on the stump at the hepatic resection. Laparoscopic left lateral segmentectomy was conducted under suspicion of cancer recurrence and an automatic titanium stapling device was used. The macroscopically cut surface of the liver showed a grey-white solid nodule measuring 23 x 20 mm and involving metal clips. The nodule was consistent with granuloma microscopically. Twenty-three months after the segmentectomy, a mass reappeared on the hepatic radial margin and an open left lateral hepatic lobectomy was performed because of its growth tendency. Histopathological examination revealed granuloma similar to the previous instance. Since these nodules formed a granulomatous lesion surrounding metal staples/clips and evidence of caseous necrosis was lacking, granuloma due to surgical staples/clips was suspected. Sporadic case reports of postoperative pulmonary granuloma at the staple line have been published previously, but there are no articles detailing a case involving hepatic granuloma. We present our case as the first report of postoperative staple-line hepatic granuloma.

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.)

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.

Background/aims: This prospective non-randomized controlled trial aimed to compare the efficacy of sorafenib vs hepatic arterial infusion chemotherapy (HAIC) for advanced hepatocellular carcinoma., Methodology: 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)., Results: 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., Conclusions: It may be better to actively introduce sorafenib for stage IVB, i.e., patients with extrahepatic metastasis.

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.

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.

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.

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.

Aim: To determine the usefulness of arrival time parametric imaging (AtPI) using contrast-enhanced ultrasonography (CEUS) with Sonazoid in evaluating early response to sorafenib for hepatocellular carcinoma (HCC)., Methods: Fourteen advanced HCC patients who received sorafenib 400/800 mg/d for at least 4 wk and were followed up by CEUS were enrolled in this study. CEUS was performed before treatment and 2 and 4 wk after treatment, and images of the target lesion in the arterial phase were recorded for each patient. The images were analyzed by AtPI. Color mapping (CM) images obtained by AtPI were compared before and after the treatment. In these CM images, the mean arrival time of the contrast agent in the region of interest from the starting point [mean time (MT)] was calculated. In each patient, differences between MT before and MT 2 and 4 wk after the treatment were compared with responses evaluated 4-8 wk after the treatment by dynamic computed tomography (CT), and statistical analysis was performed. Modified response evaluation criteria in solid tumors was used for the response evaluation., Results: In CM images both 2 and 4 wk after the treatment, delays in the arrival time of the contrast agent were noted in 8 of the 14 patients. In the other 6 patients, no color changes were observed in the tumor, or red and/or yellow increase, suggesting a decrease in blood flow velocity between images 2 and 4 wk after the treatment and those before the treatment. Dynamic CT could be performed 4-8 wk after the treatment in 13 of the 14 patients. Median differences in the MT were 1.13 s and 1.015 s, 2 and 4 wk after the treatment, respectively, in the 8 patients who showed stable disease (SD)/partial response (PR) on dynamic CT. Median differences in the MT were -0.39 s and -0.95 s, 2 and 4 wk after the treatment, respectively, in the 5 patients who showed progressive disease (PD). Differences in the median MT between SD/PR and PD groups were significant 2 and 4 wk after the treatment with P = 0.019 and P = 0.028, respectively., Conclusion: AtPI by CEUS using Sonazoid is suggested to be useful for evaluating early responses to sorafenib.

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.

A 60-year-old man with liver cirrhosis caused by hepatitis C, who was receiving warfarin anticoagulation following acute myocardial infarction, was diagnosed with advanced hepatocellular carcinoma and multiple lung metastases, and began treatment with sorafenib 200 mg daily. From the treatment's start to 14 and 63 days later, sorafenib was increased to 400 mg and 600 mg, respectively. After increasing the quantity to 600 mg, he had an increase in PT-INR values and experienced a lower-extremity hemorrhage. For the patient with liver cirrhosis, who is receiving warfarin, PT-INR values might be elevated during the early period of sorafenib treatment dosage as for the increase in quantity. Therefore, when increasing dosage, a frequent measurement of PT-INR and a careful follow-up for PT-INR is necessary.

Background/aims: Comparison of Parametric Imaging (PI) using Sonazoid-enhanced ultrasonography (US) and microflow imaging (MFI) to determine the possibility of hepatic hemangioma diagnosis using PI., Methodology: Twenty-two hepatic hemangioma nodules (mean±SD diameter: 31.6±19.1mm) undergoing Sonazoid-enhanced US between February 2008 and March 2009. After Sonazoid-enhanced US, COMMUNE ultrasonographic image analysis software was used for analysis of tumor imaging dynamics in the vascular phase using PI and MFI. In PI, 0s was set as the time contrast agent reached the tumor. Imaging within the tumor after 0s was color-coded according to time, and the images were displayed in color. In MFI, 0s was set as the time contrast agent reached the tumor. The path of microbubbles as it flowed through blood vessels was superimposed on the original B-mode images. Three trained physicians used these methods to analyze tumor imaging dynamics., Results: All physicians concluded all cases were hepatic hemangioma regardless of method used. However, compared to MFI, PI allowed determination of more detailed blood flow dynamics in high-flow hepatic hemangioma, where blood flow speed was faster than in normal hepatic hemangioma., Conclusions: It is possible to diagnose hepatic hemangioma using PI using sonazoid-enhanced US.

Purpose: We have previously shown that continuous intra-arterial combination chemotherapy (IACC) might be more effective for advanced hepatocellular carcinoma (aHCC) in patients with HCV-related liver cirrhosis (C-LC) or alcoholic liver cirrhosis (A-LC) than in patients with HBV-related LC (B-LC). However, it is still unknown whether IACC actually improves the prognosis of aHCC patients with liver cirrhosis (LC), because it is difficult to perform a randomized controlled trial for patients with a poor prognosis. The aim of this study was to retrospectively assess the influence of IACC on the prognosis of aHCC., Methods: Fifty-eight adult Japanese patients who had aHCC and LC underwent repeated trans-arterial chemoembolization (TACE) without IACC between 1990 and 1997 at our hospital (group T), while 43 patients with aHCC and LC received IACC between 2000 and 2008 after undergoing several TACE sessions (group R). The Japan Integrated Staging score (JIS score) of each patient was ≥ 3 at the time of presentation, except for patients with tumor thrombi involving the first or subsequent portal vein branches or those with tumor invasion of the inferior vena cava. The same IACC regimen was repeated for as long as possible in group R., Results: In group T, 13 patients had B-LC, 37 patients had C-LC, and 8 patients had A-LC, while the respective numbers were 14, 21, and 8 in group R. The median survival time (MST) was 248 days for patients with C-LC in group T and 708 days for those in group R, while it was 253 days for patients with A-LC in group T and 593 days for those in group R. There were significant differences of survival between the two groups. However, MST was 369 days for patients with B-LC in group T and 782 days for those in group R, without a significant difference. In group R, a complete or partial response was achieved after 4 weeks of chemotherapy in 14.3% of patients with B-LC versus 42.9% of patients with C-LC and 37.5% of patients with A-LC., Conclusions: In LC patients with a JIS score > 3 at diagnosis, multimodal therapy with IACC after TACE prolongs the MST of C-LC or A-LC patients compared with TACE alone, although it does not improve the MST of patients with B-LC.

Purpose: We have previously reported that 24-h intra-arterial combination chemotherapy (IACC) prolongs the survival of patients with advanced hepatocellular carcinoma (aHCC). However, it has also been reported that 5-fluorouracil (5-FU) exacerbates liver damage in patients with liver cirrhosis (LC). The aim of this study was to clarify the hepatotoxicity of IACC in LC patients with aHCC., Methods: Twenty-one adult Japanese patients (20 men and 1 woman) with aHCC and LC underwent IACC between 2004 and 2007 at our hospital. These patients showed multiple partial responses or stable disease, except for five patients who showed no response and three patients with tumors more than 30 mm in diameter. All patients had inoperable disease on the basis of computed tomography (CT) findings. IACC (leucovorin at 12 mg/h, cisplatin at 10 mg/h, and 5-FU at 250 mg/22 h) was delivered via the proper hepatic artery every 5 days for 4 weeks., Results: Twelve patients were in Child-Pugh class A (group A), and nine were in class B (group B). The Child-Pugh score was significantly increased after chemotherapy compared with before chemotherapy in both groups. Serum albumin was significantly decreased after chemotherapy, and the number of patients with ascites also increased after chemotherapy. Serum type IV collagen and N-terminal propeptide of type III procollagen were significantly increased after chemotherapy, although there was no significant change in serum aminotransferases., Conclusions: IACC might cause hepatotoxicity that induces fibrosis without releasing aminotransferases.

We encountered a patient who developed marked renal impairment and hyperuricemia in a short period after sorafenib administration, which suggested tumor lysis syndrome (TLS). A 79-year-old woman with hepatitis C-related liver cirrhosis was found to have intermediate hepatocellular carcinoma (HCC) according to Barcelona Clinic Cancer staging classification. Pre-treatment laboratory tests showed mild renal impairment. On the 10th day of sorafenib intake, the creatinine and uric acid levels rose to 2.99 and 16.1 mg/dl, respectively, and arterial blood gas analysis showed respiratory compensated metabolic acidosis, which suggested grade I clinical TLS according to the diagnostic criteria of TLS as defined by Cairo-Bishop. TLS is a group of metabolic abnormalities that arise from the rapid breakdown of many tumor cells upon the initiation of malignant tumor chemotherapy, resulting in the release of intracellular metabolites that exceed the ability of the kidney to excrete them. TLS occurs more rarely in solid tumors, including HCC, than in hematologic malignancies. Sorafenib is administered to patients with renal impairment at recommended doses. However, the drug may cause TLS or severe renal impairment in advanced HCC patients with preexisting mild renal impairment, necessitating reduced-dose therapy and careful follow-up after the start of therapy to facilitate early diagnosis and treatment. This is a very rare complication developed in a short period treated with sorafenib as a single-agent for an advanced HCC.

Purpose: To evaluate the effectiveness of contrast-enhanced ultrasonography (CEUS) using Sonazoid for the diagnosis of the local recurrence after treatment for hepatocellular carcinoma (HCC) by comparing it with dynamic CT., Methods: Seventy-one patients with 87 HCC lesions (mean +/- SD; 19.5 +/- 9.6 mm) underwent CEUS using Sonazoid and dynamic CT after radiofrequency ablation (n = 55), transcatheter arterial chemoembolization (n = 22), or radiofrequency ablation combined with transcatheter arterial chemoembolization (n = 10). Two hepatologists (observer 1; 10 years of experience, and 2; 20 years of experience) reviewed the CEUS and dynamic CT images independently and evaluated presence or absence of the local recurrence. Diagnostic performance for the local recurrence was assessed using receiver operating characteristic curve analysis., Results: The Az value for dynamic CT was significantly lower in observer 1 than 2 (p < 0.05). The sensitivity of CEUS was 79% in observer 1 and 83.9% in observer 2, and that of dynamic CT was 83.9% and 90.3%, respectively. The specificity of CEUS was 96%, and that of dynamic CT was 92%, in both observers., Conclusion: This study suggests that CEUS using Sonazoid is less affected by the observer's experience and is more accurate in the diagnosis of local recurrence after treatment for HCC than dynamic CT.

Background/aims: The incidence of local recurrence of hypervascular hepatocellular carcinoma (HCC) (15 mm or less) was compared retrospectively between a group treated with radiofrequency ablation (RFA) using cool-tip (Radionics, USA) 10-mm electrodes and a group treated with percutaneous ethanol injection (PEI)., Methodology: There were 23 patients who were treated for a total of 25 tumors during a 3-year period at our hospital. Ten of the tumors (11.1 +/- 2.7mm) were treated with RFA using cool-tip 10-mm electrodes and 15 tumors (10.6 +/- 2.7 mm) were treated with PEI. After treatment, progression was evaluated in enhanced CT scans every 3-6 months to confirm presence or absence of local recurrence., Results: The number of recurrences, mean observation period, and mean recurrence period in the RFA group were 2 (20%), 6.6 months, and 6 months. The number of recurrences, mean observation period, and mean recurrence period in the PEI group were 2 (13.3%), 19.1 months, and 18 months. The period between treatment and recurrence tended to be longer in the PEI group than in the RFA group to be significant p < 0.05., Conclusions: The results suggest that PEI treatment is more effective in local treatment of hypervascular HCC with tumor diameters of 15 mm or less.

Background/aims: Whether a cool-tip 10mm electrode is useful for radiofrequency ablation (RFA) of hepatocellular carcinoma (HCC) has not been established. Accordingly, the present study goal was to determine this electrode is indicated for RFA of HCC., Methodology: This study was conducted with 30 HCC patients who were treated with a cool-tip 10-mm electrode over a period of about 3 years. Ten had hypervascular HCC nodules and 20 had hypovascular HCC nodules; mean tumor diameter was 10.5 +/- 1.8mm. Patients underwent follow-up CT scans every 3 to 6 months to detect local progression., Results: Of the 30 lesions, 4 (13.3%) showed local progression. Enhanced CT imaging of the four cases with local progression revealed that two had hypervascular HCC. The remaining two cases had hypovascular HCC., Conclusions: The present study results suggest that, RFA with a cool-tip 10-mm electrode is indicated in cases of hypovascular HCC nodules if the lesion diameter is no more than 10mm. In addition, in order to avoid skin burns, only lesions at a depth of at least 16mm below the liver surface are suitable for this treatment. Because of its lesser invasiveness, the cool-tip 10-mm electrode appears to be more useful than other, more powerful, devices in patients with hepatic carcinoma.

Background/aims: Rapid aggressive tumor progression of hepatocellular carcinoma is one of the major complications after radiofrequency ablation. We statistically analyzed hepatocellular carcinoma patients with rapid aggressive tumor progression after radiofrequency ablation regarding patient characteristics, computed tomography findings, radiofrequency ablation methods, and the course of clinical and imaging changes and outcomes., Methodology: We defined the tumor not detected by previous CT and US rapidly increased more than double in compared with the ablated area as rapid aggressive tumor progression. Ten hundred seventy three lesions of 538 patients underwent ultrasound-guided radiofrequency ablation in our hospital between April 1999 and March 2008. Of these patients, the risk factors for rapid aggressive tumor progression of 7 with 7 lesions were analyzed., Results: The rate of rapid aggressive tumor progression was 0.65%. Subcapsular lesions, a pretreatment Protein Induced by Vitamin K Absence-II level > or = 40mAU/ml, and initial treatment for hepatocellular carcinoma were significantly identified as risk factors., Conclusions: There is possibility that portal vein invasion by hepatocellular carcinoma is an important factor involved in rapid aggressive tumor progression after radiofrequency ablation from the results of this study. In our opinion, these hepatocellular carcinomas need to be sufficiently ablated.

Purpose: It is known that tumors develop mechanisms to escape from the immune system and to inhibit antitumor responses. The aim of this study was to retrospectively assess changes of host immunity in relation to efficacy in liver cirrhosis (LC) patients with advanced hepatocellular carcinoma (aHCC) treated by combined intra-arterial chemotherapy., Methods: Thirty-seven adult Japanese LC patients with aHCC were treated by intra-arterial combination chemotherapy. The control group was composed of 19 adult Japanese patients with chronic hepatitis C diagnosed by pathological examination of liver biopsy specimens. All control patients were stage 1 according to the fibrosis score of Desment., Results: Ten of the 37 patients (group PR) showed a partial response and 17 of the 37 patients (group SD) showed stable disease, but 10 of the 37 patients (group PD) showed no response. There were no significant differences in the percentage of Th1 cells between any of the groups either before or after chemotherapy. The percentage of Th2 cells was significantly higher in group PD before and after chemotherapy than in the control group (P < 0.05 by Tukey's test). Although there was no significant difference, the percentage of Th2 cells was higher in group SD than in group PR., Conclusions: The percentage of Th2 cells increased in LC patients with aHCC as the efficacy of intra-arterial combination chemotherapy decreased. These results indicated that intra-arterial chemotherapy might be not useful for patients with aHCC, because it induces Th2 dominant host immunity.

Purpose: We have previously reported that intra-arterial chemotherapy prolongs the survival of patients with advanced HCC (aHCC); however, whether the response to intra-arterial chemotherapy depends on the etiology of underlying liver cirrhosis (LC) is still unknown., Aim: The aim of this study was to assess any influences of the etiology of LC on the response to combined intra-arterial chemotherapy for aHCC., Methods: A total of 53 adult Japanese LC patients (46 men and 7 women) with aHCC were treated with combined intra-arterial chemotherapy between 2002 and 2007 at our hospital. All of the patients had a Japan Integrated Staging (JIS) score of 3 or 4. Their tumors were inoperable according to computed tomography findings. Combined intra-arterial chemotherapy was administered via the proper hepatic artery every 5 days for 4 weeks and the chemotherapy regimen was continued for as long as possible., Results: There were 15 patients with HBV infection (B-LC group), 29 patients with HCV infection (C-LC group), and nine patients with alcoholic cirrhosis (A-LC group). The percentage of patients with a complete or partial response after 4 weeks of chemotherapy was 0% in the B-LC group versus 31.0% in the C-LC group and 44.4% in the A-LC group. The survival of the A-LC and C-LC groups was significantly longer than that of the B-LC group with the median survival time being 688, 368, and 211 days, respectively., Conclusions: Combined intra-arterial chemotherapy might be more effective for aHCC in patients with A-LC or C-LC than in patients with B-LC.

The majority of primary liver cancer is hepatocellular carcinoma (HCC). HCC has increased in many countries, particularly where hepatitis C virus infection is more common than hepatitis B virus infection. Several non-surgical treatment options, including transcatheter arterial embolization, percutaneous ethanol injection, microwave coagulation, and radiofrequency ablation have been developed and are widely used for unresectable HCC. However, these modalities are not indicated for patients with multifocal disease, invasion or thrombosis of major blood vessels, and poor liver function. The majority of patients with advanced hepatocellular carcinoma (aHCC) do not survive for longer than 6 months from the time of diagnosis. Combined intra-arterial chemotherapy is one of the few remaining options for patients with aHCC. Continuous local arterial infusion of 5-fluorouracil (5-FU) and cisplatin (CDDP) via an infuser pump and implanted reservoir has been shown to prolong the survival of patients with aHCC. When LC patients with aHCC undergo chemotherapy, we should consider the influence of both tumor factors and host immunity. This review focuses on therapeutic strategy of patients with aHCC by using combined intra-arterial chemotherapy and the influence of host immunity on the response to such chemotherapy based on our results. The present article shows some recent patents related to the field.

Purpose: It has been reported that Th2 cytokines down-regulate antitumor immunity, while activation of type 1 T cells promotes antitumor immunity. However, the immunological features of liver cirrhosis (LC) patients with advanced hepatocellular carcinoma (aHCC) treated by intra-arterial chemotherapy are still unclear. The aim of this study was to assess the influence of intra-arterial combination chemotherapy on the Th1/Th2 balance in LC patients with aHCC., Methods: Twenty-one adult Japanese LC patients with aHCC were treated by intra-arterial combination chemotherapy. The control group was composed of 20 adult Japanese patients with chronic hepatitis C diagnosed from examination of liver biopsy specimens. All control patients were over 55 years old and were stage 1 according to the fibrosis score of Desment., Results: Thirteen of the 21 aHCC patients (group R) showed an objective response, but the other 8 patients (group N) showed no response. There were no significant differences of Th1 cells between group R and group N either before or after chemotherapy. Although there was no significant difference from group R, group N had a significantly higher percentage of Th2 cells than the control group both before and after chemotherapy (p < 0.05 by Tukey's test)., Conclusions: These results indicate that the Th1/Th2 balance might be a useful indicator of the effect of intra-arterial combination chemotherapy in LC patients with aHCC. Inhibition of an increase of Th2 cells might be important for the efficacy of intra-arterial chemotherapy in such patients.

Introduction: It has been reported that Th2 cytokines down-regulate antitumor immunity, while activation of type 1 T cell responses promotes antitumor immunity. However, detailed information on the immunological background of patients with HCC is still unknown. The objectives of this study were to evaluate the Th1/Th2 balance and to investigate the relation between carcinogenesis and host immunity in patients with chronic hepatitis C, HCV-related liver cirrhosis (LC), or HCC., Patients/methods: The study population was 117 patients who had chronic inflammation due to HCV infection diagnosed from pathological examination of liver biopsy specimens, including 32 patients who had HCV-related LC with HCC. Apart from the patients with HCC, they were divided into the four subgroups based on the fibrosis score of Desment (stages 1-4). Blood samples were collected in the early morning before treatment. Flow cytometry was used to assess cytoplasmic IFN-gamma and IL-4 expression by peripheral blood CD4+ T cells, and the percentage of IFN-gamma+ and IL4- T cells (Th1) or IFN-gamma- and IL4+ T cells (Th2) was calculated before the start of each therapy., Results: There were 20 patients in F1, 25 patients in F2, 19 patients in F3, 21 patients in F4, and 32 patients with HCC. In the F4 and HCC groups, Th1 cells tended to increase depending on the extent of fibrosis, although there were no significant differences between these groups and the other groups. In the HCC group, Th2 cells showed a significantly higher percentage than in the F1 or F3 groups., Conclusions: These results suggest that Th1 dominance is lost due to an increase of Th2 cells in HCC patients and that carcinogenesis might occur in patients with chronic HCV infection and increased level of Th2 cells.

Introduction: Tumor necrosis factor (TNF) induces cancer cell-specific apoptosis by binding to a TNF-related apoptosis-inducing ligand. Binding of the Fas ligand on cytotoxic T lymphocytes to the Fas receptor on hepatocytes is also known to induce apoptosis. The aim of this study was to clarify changes of cytokines in patients with liver cirrhosis (LC) and advanced hepatocellular carcinoma (aHCC) receiving intra-arterial combination chemotherapy., Methods: Twenty-one adult Japanese LC patients with aHCC received intra-arterial combination chemotherapy. The serum levels of TNF-alpha, soluble TNF receptor-I (sTNFr-I), soluble Fas ligand (sFas L), and soluble Fas (sFas) were evaluated., Results: Thirteen of the 21 patients (group R) showed an objective response, while the other eight patients (group N) showed no response. The serum level of TNF-alpha was lower after chemotherapy than before chemotherapy in group N, but there was no difference of serum sTNFr-I levels between before and after chemotherapy and there were also no differences between the two groups. The serum sFas levels were higher after chemotherapy than before chemotherapy in group N, while there was no difference among groups., Conclusions: These results indicate that a high serum TNF-alpha level and a low serum sFas level might be important for successful combined arterial chemotherapy in LC patients with aHCC.

Aim: To evaluate the time dependence of intra-arterial 5-fluorouracil (5-FU) therapy for advanced hepatocellular carcinoma (aHCC)., Methods: Thirty-seven adult Japanese patients who had aHCC and liver cirrhosis were treated with combined intra-arterial 5-FU, cisplatin (CDDP), and leucovorin (LV). The Japan Integrated Staging score (JIS score) of each patient was 3 or more. The patients were divided into two groups, after which the 15 patients in group S were treated with 6-h infusion chemotherapy (LV at 12 mg/h, CDDP at 10 mg/h, and 5-FU at 250 mg/m2 per 4 h) and the 22 patients in group L were treated with 24-h infusion chemotherapy (LV at 12 mg/h, CDDP at 10 mg/h, and 5-FU at 250 mg/ m2 per 22 h). Continuous infusion chemotherapy was performed via the proper hepatic artery every 5 d for 4 wk using an implanted drug reservoir., Results: The percentages of patients with a partial response after 4 wk of chemotherapy were 6.7% in group S and 31.8% in group L. The survival of group L was significantly better than that of group S, with the median survival time being 496 d in group L and 226 d in group S (P < 0.05)., Conclusion: Continuous 24-h intra-arterial infusion is more effective for aHCC and can markedly prolong survival time as compared to 6-h infusion.

A 68-year-old Japanese woman was admitted to our hospital in September 1995, because of a mass detected by ultrasonography during a follow-up examination for chronic hepatitis B. Hepatocellular carcinoma (HCC) in the right liver lobe was diagnosed based on imaging studies and elevated alpha-fetoprotein (AFP). Percutaneous ethanol injection therapy (PEIT) was performed. PEIT was repeated in November 1998, because the tumor had enlarged and serum AFP was re-elevated. Follow-up ultrasonography (US) demonstrated low echoic mass in the left liver lobe in August 1999; serum AFP was normal, but serum carbohydrate antigen 19-9 (CA19-9) was elevated to 420 U/ml. In October 1999, radiofrequency interstitial tissue ablation (RITA) was performed after tumor biopsy. Pathological findings revealed adenocarcinoma and pathological diagnosis was made as intrahepatic cholangiocellular carcinoma (ICC). Three weeks later, her serum CA19-9 was remarkably decreased (180 U/ml). The patient has been well for 5 months. Her latest AFP and CA19-9 in the serum were 2 ng/ml and 89 U/ml, respectively. The incidence of double cancer in the liver is rare. This is also the first case report to discuss ICC treated with RITA.