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Left-side portal hypertension (LSPH) is caused by isolated obstruction of the splenic vein and is associated with esophagogastric varices that extend from the lower esophagus to the greater curvature of the gastric body. Here, we report on a 74-year-old man with a pancreatic neuroendocrine neoplasm (NEN) in the pancreatic tail with multiple liver metastases. We decided that partial splenic embolization (PSE) was the best course of treatment to prevent rupture of the gastric varices, which were classified as markedly enlarged, nodular, or tumor-shaped and showed erosion of the mucosa. After PSE, the patient had no major complications and was discharged. At 3 and 6 months after the procedure, esophagogastroduodenoscopy and enhanced computerized tomography showed that the gastric varices had improved. This case demonstrates the usefulness of PSE for LSPH in patients with unresected pancreatic NEN.

Hepatic venous pressure gradient (HVPG) and the model for end-stage liver disease (MELD) score were previously reported as prognostic factors for outcome in patients with liver cirrhosis (LC), and recently, the presence of sarcopenia was reported to be an indicator of worse prognosis in these patients.This retrospective study aimed to clarify the importance of sarcopenia as a prognostic factor in patients with LC.The MELD-Na score, HVPG, and skeletal muscle index (SMI) were measured in 202 patients between January 2013 and August 2020. We performed linear regression analysis between HVPG and SMI and calculated suitable cutoff values of HVPG for predicting presarcopenia and of HVPG, ΔSMI (i.e. the decrease in SMI per year, for predicting survival). Overall survival rates with the HVPG and ΔSMI cutoff values were compared by Kaplan-Meier estimates and log-rank tests. Prognostic factors for survival were analyzed by Cox regression univariate and multivariate analyses.In total, 71% (143/202) of patients presented with presarcopenia. Linear regression showed a significantly negative correlation between HVPG and SMI. Survival was significantly worse in the group with presarcopenia than in the group without. Survival was worse also in the group with an HVPG value ≥ 15 and ΔSMI ≥ -2.4. Cox regression multivariate analyses showed that MELD-Na score, HVPG, HVPG ≥ 15, ΔSMI, and ΔSMI ≥ -2.4 were independent prognostic factors.Skeletal muscle volume, especially ΔSMI, has a prognostic value equivalent to that of the MELD-Na score and HVPG.

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). 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.

Background/aim Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of cancers. Sorafenib, an oral multi-target TKI, improves the median overall survival time in patients with hepatocellular carcinoma (HCC). It also inhibits the absorption of carnitine by down-regulating the human organic cationic transporter OCTN2 located largely in the small intestinal mucosa and skeletal muscle. The aim of the study was to determine, by assessing carnitine metabolism, whether sarcopenia is induced in patients with HCC who are receiving sorafenib. Patients and methods This retrospective study included 110 adult Japanese patients with liver cirrhosis and HCC who received sorafenib. Sorafenib was administered at a dose of 200-800 mg/day for 4 weeks. Blood samples were collected before and after treatment, and serum carnitine fraction and myostatin levels were measured. Cross-sectional areas (cm2) of the skeletal muscles at the third lumbar vertebra level were determined by manually outlining computed tomography images before and after treatment. The cross-sectional areas were normalized for height [skeletal muscle index (SMI), cm2/m2]. Results Patients were allocated to two groups according to Child-Pugh (CP) class; 81 had CP-A liver function, and 29 had CP-B. SMI after treatment was significantly lower than that before treatment in both groups. Serum levels of total carnitine and free carnitine after treatment were significantly lower than those before treatment in both groups. There were no differences in serum levels of myostatin before and after treatment in either group. Conclusion Sorafenib might decrease serum levels of carnitine by inhibiting carnitine absorption. Decreasing of serum levels of carnitine might lead to presarcopenia.

Objective Sorafenib have been shown to be effective in the treatment of advanced HCC and has been standard therapy since its release in Japan in 2009 (Llovet et al., 2008; Cheng et al., 2009). However, due to a low response rate, more aggressive combination treatment has been utilized as a multimodal strategy. The present study aimed to determine the efficacy of sorafenib alone and in combination with transarterial chemoembolization (TACE) for the treatment of advanced HCC. Methods All patients with unresectable advanced HCC who were prescribed sorafenib at Kanto Rosai Hospital were included in the study. Five-year overall survival (OS) rates were estimated for patients treated with sorafenib alone or in combination with TACE. Multivariate and univariate regression analyses were performed to identify factors affecting OS. Analysis using propensity score matching and inverse-probability weights were also performed. Results A total of 46 patients were treated with sorafenib up to June 2018. The total sorafenib dose administered was higher in the TACE combination group (70900 mg vs. 24000 mg vs. with sorafenib alone), although the relative dose intensity was lower (11.7% vs. 17.6%, respectively). The 5-year survival prognosis estimated using the Kaplan-Meier method was longer in patients treated with sorafenib in combination with TACE versus sorafenib alone (36.3% vs. 7.7%). Combination with TACE was the only factor associated with improved OS in both univariate and multivariate analysis. Among cases matched by propensity scores the hazard rate for combination with TACE was 0.067 (95% CI 0.091-1.128). Conclusion With an array of therapeutic options currently available, it is important to determine the efficacy of different multimodal strategies, such as sorafenib combined TACE, for patients with unresectable HCC.

It is known that the microbubbles of Sonazoid are accumulated in the liver parenchyma due to the phagocytosis of Kupffer cells in the sinusoid. Because this phagocytic function decreases due to the progression of fibrosis in chronic liver disease, the deterioration of the liver function may be quantified by measuring the concentration of the accumulated Sonazoid microbubbles. In this article, a new method to quantify the concentration of microbubbles accumulated in attenuating media is proposed. This method utilizes the contrast-enhanced imaging with high mechanical index, measures the depth of the bubble destruction for each frame and analyze the shape of the destruction curve to estimate the concentration of the bubbles. A phantom experiment was performed with various concentrations of the contrast agent Sonazoid solution as well as various attenuation coefficients of the viscous media. Because of the theoretical model proposed, the estimated attenuation indexes, related to the concentration of Sonazoid microbubbles, were independent of the background attenuation of the propagating medium. The result suggest it has a potential to quantify Sonazoid concentration in the liver parenchyma more precisely against different liver attenuation conditions.

Aim Current approaches for hepatic steatosis assess only a small point within the liver and might cause inaccuracy for longitudinal observation. We aimed to establish a reliable non-invasive method for whole hepatic lipid content evaluation. Methods A total of 52 patients with hepatic steatosis underwent liver biopsy. Hepatic lipid content was assessed by Dixon in-phase/out-of-phase magnetic resonance imaging and proton magnetic resonance spectroscopy. Using multi-slice and multi-point magnetic resonance imaging, we calculated the lipid intensity of every voxel throughout the liver and showed the color-mapped lipid distributions. This new analysis could also quantify the whole hepatic lipid and whole liver volumes absolutely. The diagnostic performance of hepatic lipid content between the new analysis and proton magnetic resonance spectroscopy methods was compared by receiver operating characteristic curve analysis referring to the steatosis scores of the liver biopsy. Results Areas under the receiver operating characteristic for the diagnosis of steatosis scores ≥1, ≥2, and ≥3 using magnetic resonance imaging and proton magnetic resonance spectroscopy were 0.86 (95% confidence interval [CI] 0.70-1.00) and 0.98 (95% CI 0.93-1.00), 0.94 (95% CI 0.87-1.00) and 0.93 (95% CI 0.86-1.00), and 0.95 (95% CI 0.89-1.00) and 0.97 (95% CI 0.93-1.00), respectively, showing comparable diagnostic accuracies. However, color mapping showed some inconsistencies between the methods. Conclusions We described a non-invasive and repeatable evaluation method of whole hepatic lipid accumulation with absolute quantification and color mapping. Hepatic steatosis was accurately evaluated regardless of heterogeneous lipid accumulation. The whole hepatic lean volume, reflecting the hepatic parenchymal condition, can also be determined by this method.

Background: To investigate arrival-time parametric imaging (At-PI) in contrast-enhanced ultrasonography (CEUS) for diagnosing fibrosis in primary biliary cholangitis (PBC). Methods: Participants were 48 patients (male/female: 8/40; mean age, 60 ± 13 years) with PBC diagnosed by liver biopsy who underwent CEUS during 2009-2019. Of these, 27 (male/female: 4/23; mean age, 61 ± 13 years) who also underwent shear wave elastography (SWE) were further analyzed. SonazoidTM was intravenously injected and CEUS performed. Contrast dynamics of hepatic segment V and the right kidney were recorded. At-PI were generated from the recorded video clips. Contrast arrival time Results: ROR significantly differed between F0 and F2-F3 and between F1 and F2-3. Using ROR to diagnose ³F1 (³F2), area under the receiver operating characteristic curve (AUROC) was 0.77 (0.92) (cutoff, 36.7% [47.1%]; sensitivity, 0.75 [0.92]; specificity, 0.82 [0.81]). Vs significantly differed between F0 and F1, F0 and F2-3, and HA0 and HA1. For diagnosing ³F1 (³F2), Vs had AUROC of 0.84 (0.80) (cutoff, 1.23 m/s [1.40 m/s]; sensitivity, 0.75 [0.60]; specificity, 0.82 [0.86]).Conclusions: At-PI was useful for diagnosing fibrosis, especially F2 or worse, in PBC, suggesting that At-PI can correctly diagnose fibrosis regardless of hepatic inflammation.

Background: The number of patients with nonalcoholic fatty liver disease has been steadily increasing, and around 10%-20% of these patients are classified as having nonalcoholic steatohepatitis (NASH). The first step to identifying patients with NASH is assessing for hepatic steatosis, which is commonly done noninvasively by ultrasound examination. However, conventional methods are not always effective at lower levels of steatosis. Thus, we sought to determine the utility of a new method using the ultrasound-guided attenuation parameter (UGAP) for quantifying hepatic steatosis in NASH.Methods: Subjects were 36 patients with NASH (20 men, 16 women; mean age 56 [37 to 73] years) who underwent liver biopsy and ultrasonography using a GE LOGIQ E9 system and C1-6 probe at our hospital between 2017 and 2020. B-Mode imaging of segment V in the liver was acquired and echo attenuation was assessed using UGAP. Steatosis score (S0: Results: Steatosis score was S0 in 4 patients, S1 in 16, S2 in 10, and S3 in 6. AC by steatosis score was 0.54 ± 0.06, 0.63 ± 0.05, 0.74 ± 0.05, and 0.79 ± 0.05 dB/cm/MHz for S0, S1, S2, and S3, respectively. AC by UGAP differed significantly between S0 and S2 (p < 0.05), S0 and S3 (p < 0.05), S1 and S2 (p < 0.01), and S1 and S3 (p < 0.01), demonstrating a significant increase with steatosis score. Receiver operating characteristic analysis showed good diagnostic performance of UGAP for patients with steatosis score ≥1, ≥2, and ≥3 (AUROC = 0.95, 0.96, and 0.93, respectively). Liver fat content (%) from liver specimens and AC (r = 0.83, p < 0.01) showed a significant positive correlation.Conclusions: UGAP is useful for quantifying hepatic steatosis in patients with NASH.

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

Arrival time parametric imaging (At-PI) in contrast-enhanced ultrasonography is useful for assessing liver fibrosis in chronic hepatitis C (CHC) infection. The study aimed to elucidate the effect of hepatic inflammation on At-PI efficiency. Subjects were 159 CHC patients who underwent contrast-enhanced ultrasonography immediately before liver biopsy. Ultrasound contrast agent was injected, and contrast dynamics of the S5 to S6 region of the liver and right kidney were recorded for 40 seconds. The At-PI of liver parenchyma blood flow was generated using saved video clips. Hepatic blood flow during the first 5 seconds after starting contrast injection was displayed in red and that after another 5 seconds was displayed in yellow. The ratio of red (ROR) in At-PI images of the entire liver was measured with ImageJ. Ratio of red values of livers with different activity grades (0–3) were compared for each fibrosis (F) stage as determined by biopsy. Correlations of ROR with alanine aminotransferase (ALT) levels were analyzed using a linear regression line from the distribution map. Comparison of ROR for different activity grades in each F stage revealed no significant differences. Correlation coefficient R (P value) for ALT and ROR was R = −0.0094 (P = 0.43) at F0 to F1, R = −0.186 (P = 0.21) at F2, R = −0.233 (P = 0.27) at F3, and R = 0.041 (P = 0.89) at F4, with no significant correlation between ALT and ROR in any F stage. Hepatic inflammation in CHC infection does not affect At-PI diagnostic accuracy.

Nonalcoholic fatty liver disease (NAFLD) plays a crucial role in type 2 diabetes and hepatocellular carcinoma. The major underlying pathogenesis is hepatic insulin resistance. The aim of the present study was to characterize patients with NAFLD with paradoxically normal hepatic insulin sensitivity relative to patients with NAFLD with hepatic insulin resistance. We recruited 26 patients with NAFLD and divided them into three groups ranked by the level of hepatic insulin sensitivity (HIS; high-HIS, mid-HIS, low-HIS), as assessed by the hyperinsulinemic-euglycemic clamp studies using stable isotope. Hepatic insulin sensitivity of the high-HIS group was identical to that of the non-NAFLD lean control (clamped percent suppression of endogenous glucose production, 91.1% ± 5.2% versus 91.0% ± 8.5%, respectively) and was significantly higher than that of the low-HIS group (66.6% ± 7.5%; P < 0.01). Adiposity (subcutaneous, visceral, intrahepatic, and muscular lipid content), hepatic histopathology, and expression levels of various genes by using liver biopsies, muscle, and adipose tissue insulin sensitivity, plasma metabolites by metabolomics analysis, putative biomarkers, and lifestyles were assessed and compared between the high-HIS and low-HIS groups. Among these, adipose tissue insulin sensitivity assessed by clamped percent suppression of free fatty acid, serum high molecular weight adiponectin, and plasma tricarboxylic acid cycle metabolites, such as citric acid and cis-aconitic acid, were significantly higher in the high-HIS group compared to the low-HIS group. In contrast, there were no differences in adiposity, including intrahepatic lipid content assessed by proton magnetic resonance spectroscopy (28.3% ± 16.1% versus 20.4% ± 9.9%, respectively), hepatic histopathology, other putative biomarkers, and lifestyles. Conclusion: High levels of adipose tissue insulin sensitivity, serum high molecular weight adiponectin, and plasma tricarboxylic acid cycle metabolites are unique characteristics that define patients with hepatic insulin-sensitive NAFLD regardless of intrahepatic lipid content. (Hepatology Communications 2017;1:634-647).

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.

Aim We previously reported that sorafenib induces Th1 [interferon-γ (IFNγ)-positive interleukin 4 (IL4)-negative] dominance which prevents tumor cells from escaping the host immune system in patients with liver cirrhosis (LC) and advanced hepatocellular carcinoma (aHCC). However, in that study we did not assess the influence of sorafenib on host immunity according to the etiology of LC. Therefore, this study was retrospectively performed to evaluate the impact of sorafenib therapy for aHCC on host immunity in patients stratified according to the etiology of LC: Patients and Methods: A total of 116 adult Japanese patients with LC and aHCC received sorafenib therapy at our hospital. Blood samples were collected before and after treatment for 4 weeks. Results Twenty-two patients had hepatitis B virus (HBV)-related LC, 62 patients had hepatitis C virus (HCV)-related LC, 22 patients had alcoholic LC, and 10 patients had LC without these causative factors. In patients receiving sorafenib at a dose of 400 mg/day, patients in Child-Pugh class A, and patients with stage IVA aHCC, Th2 (IFNγ-negative/IL4-positive) cells decreased significantly after treatment, although there was no significant impact on the tumor response. In addition, Th2 cells decreased significantly in patients with HCV-related LC after treatment, while there were no significant changes in the other groups. Conclusion Sorafenib might prevent tumor cells from escaping the host immune system in patients with aHCC and HCV-related LC, although it does not seem to do so in those with LC of other etiologies.

Purpose. Restoration of the balance between T lymphocyte subsets and between Th1/Th2 cytokines together with improvement of antitumor immunity has been reported after hepatosplenectomy in patients with liver cirrhosis (LC) and hepatocellular carcinoma (HCC). However, the detailed effects of partial splenic embolization (PSE) on host immunity are unknown. Accordingly, this study evaluated host immunity in patients with cirrhosis receiving PSE for thrombocytopenia.Methods. Twenty-three adult Japanese patients with cirrhosis and thrombocytopenia underwent PSE using straight coils at our hospital between 2010 and 2015. Blood samples were collected before PSE and 4 weeks after PSE.Results. The platelet counts were significantly higher 4 weeks after PSE compared with before PSE. The white blood cell count (neutrophils, lymphocytes, and monocytes) also increased significantly after PSE. Furthermore, Th1 cells and Th2 cells showed a significant increase at 4 weeks after PSE compared with before PSE, although there was no significant change of Treg cells. Moreover, serum levels of TNF-alpha, soluble TNF receptor I, and soluble Fas were significantly increased after PSE. There was no significant change of the Child-Pugh score.Conclusions. In patients with cirrhosis and thrombocytopenia, PSE not only promoted the recovery of leukopenia and thrombocytopenia but also induced activation of host immunity.

Sonazoid is a commonly used contrast agent for characterizing liver tumors in ultrasonography (US). We performed flash imaging in the post-vascular phase of contrast-enhanced US (CEUS) to investigate associations between collapse of Sonazoid microbubbles (MB) and progression of liver disease. This study enrolled 409 patients (205 men, 204 women) with hepatitis C virus-related liver disease (CLD) between 2007 and 2017 (mean age 60 ± 14 y; range 20-90 y). In the post-vascular phase, 10 min after administering Sonazoid, flash imaging was performed to burst MB in the liver parenchyma; the range of bubble destruction was measured from the surface of the liver. The range of bubble destruction, stage of fibrosis, shear wave velocity (Vs), serologic markers and fibrosis-4 (FIB4) index were analyzed in 259 patients who underwent liver biopsy. Fibrosis stage was F0-1 in 108 patients, F2 in 73, F3 in 38 and F4 in 40. In 150 patients with cirrhosis, diagnosis was made based on imaging findings. The range of bubble destruction was 42.0 ± 10.4 mm in F0-1 patients, 42.9 ± 13.2 mm in F2, 51.5 ± 15.9 mm in F3 and 55.4 ± 17.3 mm in F4 and was significantly increased according to progression of fibrosis staging. The range of bubble destruction was positively correlated with Vs (r = 0.34; p0.01), total bilirubin (r = 0.25; p0.01) and FIB4 index (r = 0.38; p0.01). In contrast, the range of bubble destruction was negatively correlated with serum levels of albumin (r = -0.34; p0.01), platelet count (r = -0.35; p0.01) and prothrombin time (r = -0.36; p0.01). The results indicated that flash imaging in the post-vascular phase of CEUS was a non-invasive assessment and could predict disease progression in patients with CLD.

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

The number of amino acid (AA) mutations in the interferon sensitivity determining region (ISDR) of NS5A is reported to affect the response to interferon (IFN) therapy in patients with chronic hepatitis C (CHC). The aim of this study was to clarify whether host immunity is influenced by the number of AA mutations in the ISDR. Subjects included 44 patients with CHC infected with genotype 1b and high viral load. The number of AA mutations in the ISDR was retrospectively determined using stored serum samples taken immediately before starting therapy. All patients received IFN-alpha 2b or pegylated-IFN (PEG-IFN)-alpha 2b and ribavirin. When serum hepatitis C virus-ribonucleic acid (HCV-RNA) was negative at 4 or 12 weeks after starting therapy, the patient was defined as having rapid viral response (RVR) or early viral response (EVR), respectively. CD4+ T cell (Th1 or Th2) in peripheral blood (PB) before and until day 56 of treatment was analyzed. Rates of RVR and EVR were 0 (0/21) and 14% (3/21), respectively, in patients with one or fewer AA mutations in the ISDR (ISDR0-1), and 30 (7/23), and 74% (17/23), respectively, with two or more AA mutations in the ISDR (ISDR > 2). Although the percentage of PB Th1 cells did not differ between the two groups during the study period, the percentage of PB Th2 cells was significantly lower in the ISDR0-1 group than in the ISDR > 2 group at baseline and on days 3, 7, 14, and 28 of treatment. The number of AA mutations in the ISDR influenced PB Th2 cells before and until day 28, and was associated with higher RVR and EVR rates.

A 47-year-old man was referred to our hospital due to a splenic artery aneurysm. The course of the disease was monitored by ultrasound every 6 months. At each examination, the tumor was found to have increased in size by several millimeters, but the sonographer decided that the increase was within the range of error. After 4 years, the tumor showed a rapid increase in size. With a diagnosis of threatened rupture, the patient's life was saved by surgical intervention. In this case, the observations were only compared to the findings from the previous examination, and the slight increase in tumor size was considered within the range of error. It is important to compare the findings not only with those from the previous examination but also with earlier results.

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. 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. 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. IACC might cause hepatotoxicity that induces fibrosis without releasing aminotransferases.

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.

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.

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.

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.

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.

The effect of reduced glutathione (GSH) depletion by acetaminophen (APAP), diethylmaleate (DEM), or phorone on the mode of cell death and susceptibility to tumor necrosis factor (TNF)-induced cell death was studied in cultured mouse hepatocytes. Dose-dependent necrosis was the exclusive mode of cell death with APAP alone, but the addition of TNF-alpha induced a switch to about half apoptosis without changing total loss of viability. This effect was seen at 1 and 5 mmol/L but was inhibited at 10 and 20 mmol/L APAP. The switch to apoptosis was associated with increased caspase activities, release of cytochrome c, and DNA laddering and was inhibited by caspase inhibitors. DEM and phorone also induced dose-dependent necrosis. Treatment with TNF-alpha under these conditions lead to incremental cell death in the form of apoptosis at 0.25 and 0.5 mmol/L DEM and 0.1 and 0.2 mmol/L phorone. At 1.0 and 2.0 mmol/L DEM and 0.5 mmol/L phorone, 90% to 100% necrosis was observed with resistance to TNF-alpha effects. The apoptosis with TNF-alpha plus DEM was confirmed by DNA laddering and inhibition by caspase inhibitors. However, in the presence of caspase inhibitors, the increment in cell death induced by TNF-alpha persisted as an increase in necrosis. A combination of antioxidants, vitamin E, and butylated hydroxytoluene (BHT) markedly inhibited necrosis induced by APAP or DEM alone, but the sensitization to TNF-alpha-induced apoptosis was unaffected. GSH monoethylester (GSH-EE) protected against necrosis and apoptosis. In conclusion, depletion of GSH by APAP, DEM, or phorone causes oxidative stress-induced necrosis and sensitizes to an oxidative stress independent TNF-alpha-induced apoptosis.

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.

症例は40歳男性, ウイスキー1日1/2本×20年の常習大酒家. 全身倦怠感を主訴に受診. 血液検査と腹部超音波 (US) 検査にて, 肝障害と肝内腫瘤を指摘された. 入院時の腹部USで, 左葉外側区領域の辺縁明瞭な直径25mmの高エコー腫瘤像と, 両葉に細かい撒布性の高エコー小結節を認め, CTスキャンでは同病変は低吸収域として描出された. 肝動脈撮影では腫瘍濃染像や腫瘍血管などの異常所見は得られなかった. 左葉外側区領域の腫瘤に対しUS下肝腫瘤狙撃生検を行い, 単結節腫瘤型の限局性肝脂肪化と診断した. また両葉にわたる細かい撒布性の小結節も限局性肝脂肪化と考えた. 禁酒にて経過観察したところ, 約1カ月後には左葉外側区領域の単結節腫瘤は縮小し, 両葉にわたる細かい撒布性の小結節はほぼ消失した. 以上から, 単結節腫瘤型および小結節撒布型の2種類の限局性肝脂肪化を合併したアルコール性肝硬変の1例と考えられた.

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.

インターフェロン療法 (IFN) 無効のC型慢性活動性肝炎 (CAH) の多くにウルソデオキシコール酸 (UDCA) の投与が奏効するが, 無効例も存在する. 今回, UDCAの有効性を予測できるか否か有効例と無効例の臨床背景を検討した. 対象はIFNの無効であったCAH 27例で, 全例にUDCA 600mg/日を投与. 血清GPTが正常上限の2倍未満に維持されたものを有効とすると, 27例中14例 (52%) が有効, 13例 (48%) が無効であった. 両群のIFN前の肝組織像, ウイルス量, IFN投与量と種類, IFN開始前, 終了時およびUDCA開始時の血清GPT, γGTP, 総胆汁酸 (FTBA) に有意な差はなかった. しかし, UDCA投与平均12.6 (3～28) カ月後の血清胆汁酸分画上, UDCA, コール酸, ケノデオキシコール酸, 胆汁酸総量に占める総タウリン抱合型胆汁酸の割合は無効例で有効例に比し有意 (p

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.

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.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.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.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.

This case report concerns a 40-year-old male who had previously been treated for an esophageal varix rupture, at the age of 30 years. The medical examination at that time revealed occlusion of the inferior vena cava in the proximity of the liver, leading to the diagnosis of the patient with Budd-Chiari syndrome. The progress of the patient was therefore monitored in an outpatient clinic. The patient had no history of drinking or smoking, but had suffered an epileptic seizure in 2004. The patient's family history revealed nothing of note. In February 2012, color Doppler ultrasonography (US) revealed a change in the blood flow in the right portal vein branch, from hepatopetal to hepatofugal, during deep inspiration. Arrival time parametric imaging (At-PI), using Sonazoid-enhanced US, was subsequently performed to examine the deep respiration-induced changes observed in the hepatic parenchymal perfusion. US images captured during deep inspiration demonstrated hepatic parenchymal perfusion predominantly in red, indicating that the major blood supply was the hepatic artery. During deep expiration, the portal venous blood flow remained hepatopetal, and hepatic parenchymal perfusion was displayed predominantly in yellow, indicating that the portal vein was the major source of the blood flow. The original diagnostic imaging results were reproduced one month subsequently by an identical procedure. At-PI enabled an investigation into the changes that were induced in the hepatic parenchymal perfusion by a compensatory mechanism involving the hepatic artery. These changes occurred in response to a reduction in the portal venous blood flow, as is observed in the arterialization of hepatic blood flow that is correlated with the progression of chronic hepatitis C. It has been established that the peribiliary capillary plexus is important in the regulation of hepatic arterial blood flow. However, this case demonstrated that the peribiliary capillary plexus also regulates acute changes in portal venous blood flow, in addition to the chronic reduction in blood flow that is observed in patients with chronic hepatitis C.