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Introduction: We evaluated the efficacy and safety of lenvatinib-transcatheter arterial chemoembolization (LEN-TACE) sequential therapy for patients (n = 88) with intermediate-stage hepatocellular carcinoma (HCC). Methods: Eighty-eight patients who obtained tumor control by LEN treatment were analyzed; 30 received LEN followed by TACE (LEN-TACE sequential therapy), and 58 received LEN monotherapy. Propensity score matching was performed, and the outcomes of 19 patients in the LEN-TACE group and 19 patients in the LEN-alone group were compared. Objective response rate (ORR), progression-free survival (PFS), overall survival (OS), incidence of adverse events (AEs), and change in albumin-bilirubin (ALBI) score were evaluated. Results: After matching, baseline characteristics were similar between the groups. The ORR was 63.2% with LEN-TACE group and 63.2% with the LEN-alone group. Multivariate analysis showed that addition of TACE during LEN treatment (hazard ratio [HR] 0.264, 95% confidence interval [CI] 0.087–0.802, p = 0.019) and Child-Pugh score 5 (HR 0.223, 95% CI 0.070–0.704, p = 0.011) were the significant factors for PFS. Median PFS was 11.6 months with LEN-TACE and 10.1 months with LEN-alone. The survival rate of the LEN-TACE group was significantly higher than that of the LEN-alone group (median survival time; not reached vs. 16.9 months, p = 0.007). The incidence of common LEN-associated AEs was similar between groups. Although elevated aspartate aminotransferase/alanine aminotransferase and fever were more frequent with LEN-TACE group, these events were manageable. Conclusion: For patients with intermediate-stage HCC, LEN-TACE sequential therapy may provide a deep response and favorable prognosis.

Simple Summary With the recent increase in the number of drug therapy options for unresectable hepatocellular carcinoma (u-HCC), the key issue has become how to prolong overall survival (OS). The aim was to evaluate the association between radiological response and OS in patients treated with lenvatinib as a first-line systemic treatment for u-HCC. Radiological response using both Response Evaluation Criteria in Solid Tumors (RECIST) and modified Response Evaluation Criteria in Solid Tumors (mRECIST) is a predictor of OS and achieving an objective response at the first evaluation is an independent prognostic factor for OS. In addition, if an objective response is obtained at the initial evaluation, continuation of treatment appears desirable because prolonged OS can be expected; but, if stable disease is obtained at the initial evaluation, one should determine whether to continue or switch to the next treatment, with careful consideration of factors related to the tumor and hepatic reserve at the initial evaluation. Abstract The association between radiological response and overall survival (OS) was retrospectively evaluated in patients treated with lenvatinib as a first-line systemic treatment for unresectable hepatocellular carcinoma. A total of 182 patients with Child–Pugh class A liver function and an Eastern Cooperative Oncology Group performance status of zero or one were enrolled. Radiological evaluation was performed using Response Evaluation Criteria in Solid Tumors (RECIST) and modified Response Evaluation Criteria in Solid Tumors (mRECIST). Initial radiological evaluation confirmed significant stratification of OS by efficacy judgment with both RECIST and mRECIST, and that initial radiological response was an independent prognostic factor for OS on multivariate analysis. Furthermore, in patients with stable disease (SD) at initial evaluation, macrovascular invasion at the initial evaluation on RECIST and modified albumin–bilirubin grade at initial evaluation on mRECIST were independent predictors of OS on multivariate analysis. In conclusion, if objective response is obtained at the initial evaluation, continuation of treatment appears desirable because prolonged OS can be expected; but, if SD is obtained at the initial evaluation, one should determine whether to continue or switch to the next treatment, with careful consideration of factors related to the tumor and hepatic reserve at the initial evaluation.

Transarterial chemoembolization (TACE) has been the standard treatment for intermediate-stage, unresectable hepatocellular carcinoma (u-HCC). However, with recent advances in systemic therapy and the emergence of the concept of TACE-refractory or -unsuitable, the effectiveness of systemic therapy, as well as TACE, has been demonstrated for patients judged to be TACE-refractory or -unsuitable. In this study, the efficacy of lenvatinib and its combination with TACE after lenvatinib was investigated in 140 patients with intermediate-stage u-HCC treated with lenvatinib mainly because of being judged to be TACE-refractory or -unsuitable. Median overall survival (OS) and progression-free survival (PFS) were 24.4 and 9.0 months, respectively, indicating a good response rate. In multivariate analysis, modified albumin–bilirubin (mALBI) grade and up to seven criteria were identified as independent factors for OS, and mALBI grade and tumor morphology were identified as independent factors for PFS. While 95% of all patients were TACE-refractory or -unsuitable, the further prognosis was prolonged by the combination with TACE after lenvatinib initiation. These findings suggest that systemic therapy should be considered for intermediate-stage u-HCC, even in patients judged to be TACE-refractory or -unsuitable. The use of TACE after the start of systemic therapy may further improve prognosis.

[BACKGROUND & AIMS] Primary biliary cholangitis (PBC) is a chronic liver disease in which autoimmune destruction of the small intra-hepatic bile ducts eventually leads to cirrhosis. Many patients have inadequate response to licensed medications, motivating the search for novel therapies. Previous genome-wide association studies (GWAS) and meta-analyses (GWMA) of PBC have identified numerous risk loci for this condition, providing insight into its aetiology. We undertook the largest GWMA of PBC to date, aiming to identify additional risk loci and prioritise candidate genes for in silico drug efficacy screening. [METHODS] We combined new and existing genotype data for 10, 516 cases and 20, 772 controls from five European and two East Asian cohorts. [RESULTS] We identified 56 genome-wide significant loci (20 novel) including 46 in European, 13 in Asian, and 41 in combined cohorts; and a 57th genome-wide significant locus (also novel) in conditional analysis of the European cohorts. Candidate genes at newly identified loci include FCRL3, INAVA, PRDM1, IRF7, CCR6, CD226, and IL12RB1, each having key roles in immunity. Pathway analysis reiterated the likely importance of pattern recognition receptor and TNF signalling, Jak-STAT signalling, and differentiation of TH1 and TH17 cells in the pathogenesis of this disease. Drug efficacy screening identified several medications predicted to be therapeutic in PBC, some well-established in the treatment of other autoimmune disorders. [CONCLUSIONS] This study has identified additional risk loci for PBC, provided a hierarchy of agents that could be trialled in this condition, and emphasised the value of genetic and genomic approaches to drug discovery in complex disorders. [Lay summary] Primary biliary cholangitis (PBC) is a chronic liver disease that eventually leads to cirrhosis. In this study, we analysed genetic information from 10, 516 people with PBC and 20, 772 healthy individuals recruited in Canada, China, Italy, Japan, UK, or USA. We identified several genetic regions associated with PBC. Each of these regions contains several genes. For each region, we used diverse sources of evidence to help us choose the gene most likely to be involved in causing PBC. We used these ‘candidate genes’ to help us identify medications that are currently used for treatment of other conditions, which might also be useful for treatment of PBC., 原発性胆汁性胆管炎のゲノムワイド関連解析 --国際メタ解析による新規疾患感受性遺伝子と治療薬候補の同定--. 京都大学プレスリリース. 2021-06-28.

Introduction: This study compared clinical outcomes of 2nd- and 3rd-line regorafenib in patients with unresectable hepatocellular carcinoma. Methods: In this retrospective cohort study, 48 patients were treated with regorafenib for unresectable hepatocellular carcinoma. Thirty-five and 13 patients were initiated on 2nd- and 3rd-line therapy, respectively. We assessed the responses to and safety of the therapy. Results: There were no statistically significant differences in clinical characteristics at the start of 2nd- or 3rd-line regorafenib therapy. The overall response rate of 2nd- and 3rd-line regorafenib was 20 and 8%, respectively. The disease control rate was 57 and 54%, respectively. Median overall survival (mOS) from the start of 2nd-line regorafenib was 17.5 months. mOS from the start of 3rd-line regorafenib was not obtained. Median progression-free survival of 2nd- and 3rd-line regorafenib was 4.9 and 2.3 months, respectively. mOS from 1st-line therapy with tyrosine kinase inhibitor plus sorafenib-regorafenib-lenvatinib was 29.5 months; that with lenvatinib-sorafenib-regorafenib was not obtained. Patients on 3rd-line therapy tended to have better Child-Pugh scores and tumor factors at the start of 1st-line therapy than other patients. Conclusion: Patients on 2nd- and 3rd-line regorafenib showed favorable responses. Good Child-Pugh scores and tumor factors may be associated with a better response rate and OS.

Background: Although a strong antitumor effect of lenvatinib (LEN) has been noted for patients with unresectable hepatocellular carcinoma (HCC), there are still no reports on the prognosis for patients with disease progression after first-line LEN therapy. Methods: Patients (n = 141) with unresectable HCC, Child-Pugh class A liver function, and an Eastern Cooperative Oncology Group performance status (ECOG-PS) of 0 or 1 who were treated with LEN from March 2018 to December 2019 were enrolled. Results: One hundred and five patients were treated with LEN as first-line therapy, 53 of whom had progressive disease (PD) at the radiological evaluation. Among the 53 patients with PD, there were 27 candidates for second-line therapy, who had Child-Pugh class A liver function and an ECOG-PS of 0 or 1 at progression. After progression on first-line LEN, 28 patients were treated with a molecular targeted agent (MTA) as second-line therapy (sorafenib: n = 26; ramucirumab: n = 2). Multivariate analysis identified modified albumin-bilirubin grade 1 or 2a at LEN initiation (odds ratio 5.18, 95% confidence interval [CI] 1.465–18.31, p = 0.011) as a significant and independent factor for candidates. The median post-progression survival after PD on first-line LEN was 8.3 months. Cox hazard multivariate analysis showed that a low alpha-fetoprotein level (p = 0.003), a relative tumor volume p = 0.03), and switching to MTAs as second-line treatment after LEN (HR 0.299, 95% CI 0.12–0.746, p = 0.01) were significant prognostic factors. Conclusion: Among patients with PD on first-line LEN, good liver function at introduction of LEN was an important and favorable factor related to eligibility for second-line therapy. In addition, post-progression treatment with MTAs could improve the prognosis for patients who had been treated with first-line LEN.

Autoimmune hepatitis (AIH) is an uncommon chronic autoimmune liver disease. Several studies reported the association of polymorphisms between CD28, CTLA4 and ICOS gene cluster in 2q33.2 with autoimmune or inflammatory diseases. The previous genome-wide association study on type 1 AIH in a European population has reported a risk G allele of a single nucleotide polymorphism (SNP), rs4325730, in this region. Here, we conducted an association study of this SNP with type 1 AIH in a Japanese population, as a replication study.An association study of rs4325730 was conducted in 343 Japanese AIH patients and 315 controls.We found that rs4325730 is associated with AIH (P=0.0173, odds ratio (OR) 1.30, 95% confidence interval (CI) 1.05-1.62, under the allele model for G allele, P=0.0070, OR 1.62, 95% CI 1.14-2.31, under the dominant model for G allele). This SNP was strongly associated with definite AIH (P=0.0134, OR 1.36, 95% CI 1.07-1.74; under allele model for G, P=0.0035, OR 1.85, 95% CI 1.22-2.81, under dominant model for G).This is the first replication association study of rs4325730 upstream of ICOS with AIH in the Japanese population and rs4325730G is a risk allele.

Article, Scientific reports.9 :102(2019)

Autoimmune hepatitis (AIH) is an autoimmune liver disease that is characterized by a progressive destruction of the liver parenchyma and the development of liver fibrosis. We aimed to examine the relationship between circulating cytokines/chemokines and the Mac-2 binding protein glycosylation isomer (M2BPGi) levels in Japanese patients with autoimmune hepatitis (AIH). We investigated the relationship between circulating cytokines/chemokines and M2BPGi levels in Japanese patients with AIH. Seventy-seven patients with well-documented AIH were enrolled in the National Hospital Organization (NHO)-AIH-liver-network database. We measured the serum levels of 20 cytokines in 31 selected AIH patients before and after steroid treatment using multisuspension cytokine array. Eleven cytokines and soluble adhesion molecules were increased in untreated AIH patients compared with treated AIH patients. Among these cytokines and soluble adhesion molecules, soluble intercellular adhesion molecule-1 (sICAM-1) and interferon-γ-inducible protein 10 (IP-10) were most downregulated by steroid therapy in AIH patients. We measured serum sICAM-1 and IP-10 by ELISA and found the levels were significantly higher in AIH patients (n = 77) compared with chronic viral hepatitis C patients (n = 32). Furthermore, there was a positive correlation between sICAM-1 or IP-10 and alanine aminotransferase, total bilirubin, and circulating M2BPGi levels. M2BPGi levels were increased in AIH patients with high stages of liver fibrosis. Additionally, M2BPGi levels were correlated with the histological grade of inflammation in AIH. Circulating M2BPGi levels were significantly reduced by steroid treatment in AIH patients. sICAM-1 and IP-10 are useful markers to assess immune-mediated hepatitis activity in AIH and they correlate with circulating M2BPGi. Serum M2BPGi levels increased in untreated AIH patients with active hepatitis and were decreased by steroid therapy. M2BPGi reflects autoimmune-mediated hepatic inflammation as well as liver fibrosis.

Several studies reported that autoimmune diseases share a number of susceptibility genes. Of these genes, a SNP rs7708392 in TNIP1 was reported to be associated with systemic lupus erythematosus (SLE). Autoimmune hepatitis (AIH), a rare chronic progressive liver disease, shares some clinical features with SLE. Therefore, we investigated whether the SNP is associated with Japanese AIH. An association study of rs7708392 was conducted in 343 Japanese AIH patients and 828 controls. We found that rs7708392 is associated with AIH (P = 0.0236, odds ratio (OR) 1.26, 95% confidence interval (CI): 1.03–1.54), under the allele model for C allele. Significant differences of clinical characteristics of the AIH patients with or without G allele of rs7708392 were not detected. Of interest, the association was stronger in AIH without HLA-DRB1*04:05 allele (P = 0.0063, Q = 0.0127, OR 1.48, 95% CI: 1.12–1.96), though the association was not detected in AIH with DRB1*04:05. The C allele of rs7708392 was associated with AIH, especially AIH without DRB1*04:05, an already established risk factor.

Objectives Sorafenib is the standard treatment for advanced hepatocellular carcinoma (HCC) with distant metastasis, unresectable HCC, and those refractory to transcatheter arterial chemoembolization (TACE) or with macroscopic vascular invasion (MVI). The application of sorafenib has been approved by the Japanese Government-sponsored Medicare for unresectable HCC. In this retrospective cohort study we aimed to compare various aspects of HAIC with sorafenib in the treatment of Child–Pugh A patients with advanced HCC who were otherwise free of extrahepatic metastasis. Methods Altogether 177 patients with advanced HCC at Child–Pugh class A who were free of extrahepatic metastasis were retrospectively enrolled. The patients were divided into the HAIC group (n = 136) and the sorafenib group (n = 41), and were followed up until their death or withdrawal of therapy. Responses to treatment and overall survival were determined and compared between the two groups. Results The proportion of patients with complete response, partial response, stable disease and progressive disease were 5.9%, 25.0%, 40.4% and 21.3% in the HAIC and 2.4%, 2.4%, 43.9% and 41.5% in the sorafenib group, respectively. The response rate was higher in the HAIC group than in the sorafenib group (30.9% vs 4.8%). The median survival time was 10 months in both HAIC and sorafenib groups. In patients with macroscopic vascular invasion (MVI) by the case-control method, the response rate was higher in the HAIC group than in the sorafenib group. Overall survival was longer in the HAIC group than in the sorafenib group (14 months vs 7 months, P = 0.005). Multivariate analysis identified MVI (hazard ratio 2.4, P = 0.018) as an independent prognostic factor of survival in the sorafenib group. Conclusions Response rate to HAIC was higher than that to sorafenib monotherapy. Prognosis was favorable in HAIC responders despite MVI. HAIC might be a potential treatment option for advanced HCC without extrahepatic metastasis.

Objective To determine the efficacy of radiofrequency ablation (RFA) for initial recurrence of small hepatocellular carcinoma (HCC; ≤3 nodules, each nodule ≤3cm in diameter) after curative treatment and identify prognostic factors affecting therapeutic outcome, we compared clinical and outcome factors between patients with primary HCC and those with initial recurrent HCC who underwent RFA. Methods In this retrospective cohort study, 211 HCC patients who underwent RFA were enrolled and comprised two groups: primary group ( n =139) and initial recurrent group ( n =72). We compared local tumor progression, overall survival (OS), disease-free survival (DFS), and RFA safety between the groups. Results Median follow-up was 53 months. Local tumor progression rate was 5.8% in the primary group and 4.2% in the recurrent group. OS rates at 5 years and 10 years were 63.2% and 25.5% in the primary group and 54.5% and 33.4% in the recurrent group, respectively. Corresponding DFS rates were 30.7% and 14.6% and 19.2% and 11.0%. DFS was significantly shorter in the recurrent group (hazard ratio [HR]=1.81; 95% confidence interval [CI], 1.27–2.57; P =0.001). In the recurrent group, time from primary HCC development to recurrence was a determinant of OS (≤2 years; HR=3.42; 95% CI, 1.52–7.72; P =0.003). Conclusion Although local tumor control and OS were similar between the groups, the recurrent group had shorter DFS than the primary group. Time from primary HCC development to recurrence was a prognostic factor for recurrence of HCC.

Aim A genome-wide association study revealed that the single nucleotide polymorphism (SNP) rs738409 in the patatin-like phospholipase 3 gene (PNPLA3) was strongly associated with non-alcoholic fatty liver disease (NAFLD). Recent pilot studies investigated the effects of dipeptidyl peptidase-4 inhibitors on liver function and glucose metabolism in NAFLD with type 2 diabetes mellitus (DM). We herein evaluated the efficacy of alogliptin in NAFLD patients with type 2 DM as well as the relationship between genotypes at rs738409 in PNPLA3 and treatment efficacy. Methods Forty-one biopsy-proven NAFLD patients with type 2 DM treated with 25 mg/day alogliptin were retrospectively enrolled. SNP rs738409 in PNPLA3 was present in all patients. Clinical data were measured before and after the treatment. Results Average hemoglobin A1c (HbA1c) levels mostly remained unchanged. Moreover, significant changes were not noted in the levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) during the follow-up period. A positive correlation was observed between improvements in HbA1c (ΔHbA1c) levels and changes in AST (ΔAST) and ALT (ΔALT) levels (r = 0.325 and 0.439, respectively). Patients with the risk allele (G-allele) showed more positive correlation between ΔHbA1c and changes in transaminase. Furthermore, improvements in the levels of total cholesterol, triglycerides and hyaluronic acid were significantly greater in G-allele patients in the weight loss group. Conclusion The treatment of NAFLD with type 2 DM with alogliptin contributed to the amelioration of NAFLD. Our results suggested that differences in the PNPLA3 risk allele affected the therapeutic effects of this treatment.

Background and Aim To assess the early response and outcome of hepatic arterial infusion chemotherapy (HAIC) in patients with advanced hepatocellular carcinoma (HCC). Methods One hundred sixty-five HCC patients treated with HAIC were reviewed retrospectively. The early response to one course of HAIC treatment was evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST) and changes in α-fetoprotein (AFP) and des-γ-carboxy prothrombin (DCP). Results The median survival time (MST) for all patients was 9.5 months. The early imaging response by RECIST was assessed as partial response (PR), stable disease (SD), and progressive disease (PD) in 32 (19.3%), 86 (52.1%), and 47 (28.4%) patients, respectively. Survival correlated with early imaging response (MST in PR, 20.6; SD, 11.4; PD, 5.0 months; P 1 and DCP ratio of ≤ 1 or > 1 (worst MST, 6.5 months in patients with AFP ratio of > 1 and DCP ratio of > 1). Among patients with SD early imaging response, patients with AFP ratio of > 1 and DCP ratio of > 1 had significantly poorer survival than others (MST 7.4 vs 12.6 months, P = 0.014). The decrease in AFP and DCP in the early stage treatment with HAIC were identified as significant and independent factors associated with survival of not only all patients, but also patients with SD early imaging response. Conclusion The use of the combination of RECIST and tumor marker ratio could be useful for assessment of the early response to HAIC and prognosis of patients with advanced HCC.

Background and Aim Portal hypertensive enteropathy (PHE) is acknowledged as a source of bleeding, and predicting its presence has become more important. We assessed PHE using capsule endoscopy (CE) and investigated factors that may predict its presence, including portosystemic shunts (PSs). Methods We analyzed data from 134 consecutive patients with liver cirrhosis, from February 2009 to September 2013. All patients had undergone dynamic computed tomography and esophagogastroduodenoscopy before CE examination. The frequencies and types of PHE lesions, and the relationships between the presence of PHE and patients' clinical characteristics were evaluated. The distribution of the lesions was also determined. Results PHE was found in 91 (68%), erythema in 70 (52%), erosions in 25 (19%), angioectasia in 24 (18%), villous edema in 18 (13%), and varices in 10 (7%) patients. Most lesions were located in the jejunum. The clinical characteristics associated with the presence of PHE were a Child-Pugh grade of B or C (P = 0.0058), and the presence of PSs (P

A 50-year-old male patient was admitted to the hospital for persistent high fever and back pain. He was diagnosed with hepatocellular carcinoma (HCC), bone marrow metastasis and disseminated intravascular coagulation (DIC). Despite the diagnosis and treatment, the general condition deteriorated rapidly and he died of cerebral hemorrhage associated with generalized bleeding tendency. Autopsy showed multiple HCC in the liver and systemic metastasis including bone marrow. The case describes a rare complication of HCC with disseminated carcinomatosis of the bone marrow (DCBM) complicated with DIC, with rapid deterioration and death. This is the first case of DCBM from HCC. Physicians need to be aware of DCBM in patients with HCC.

Aim To assess the efficacy and safety of the anticoagulant drug, danaparoid sodium, in the treatment of portal vein thrombosis (PVT) in patients with liver cirrhosis. Methods A consecutive 26 cirrhotic patients with PVT were enrolled in this retrospective cohort study. The etiologies of cirrhosis were hepatitis B virus-related, hepatitis C virus-related, alcoholic and cryptogenic in five, 14, three and four patients, respectively. Child–Pugh grade A, B and C was noted in 13, eight and five patients, respectively. Patients were treated with 2 weeks' administration of danaparoid sodium followed by the evaluation of PVT reduction and adverse events. Results All patients experienced reduction of PVT through the treatment. The median volume of PVT before and after treatment was 2.40 cm3 (range, 0.18–16.63) and 0.37 cm3 (range, 0–5.74), respectively. The median reduction rate of PVT volume was 77.3% (range, 18–100%). According to the reduction rate, complete reduction (CR), partial reduction (PR, ≥50%) and stable disease (SD

Aim To evaluate the response, survival and safety on 3-D conformal radiotherapy (3D-CRT) for major portal vein tumor thrombosis (PVTT) combined with hepatic arterial infusion chemotherapy (HAIC) for advanced hepatocellular carcinoma (HCC). Methods In this retrospective study, 83 advanced HCC patients treated with HAIC who met the following criteria were enrolled: (i) PVTT of the main trunk or first branch of the portal vein; (ii) no extrahepatic metastasis; (iii) Child–Pugh score of 5–7; (iv) performance status of 0 or 1; and (v) no history of sorafenib treatment. The response, overall survival (OS), time to treatment failure (TTF), post-progression survival (PPS) and safety were compared between HAIC combined with 3D-CRT for PVTT (RT group, n = 41) and HAIC alone (non-RT group, n = 42). Results The objective response of PVTT was significantly higher in the RT group (56.1%) than in the non-RT group (33.3%), while that of intrahepatic tumor and OS were not significantly different between groups. Median OS, TTF and PPS were significantly longer in the RT group than in the non-RT group (8.6 and 5.0 months, 5.0 and 2.7 months, and 5.3 and 1.5 months, respectively) among intrahepatic tumor non-responders to HAIC, whereas those were not significantly different between groups among intrahepatic tumor responders to HAIC. By multivariate analysis, the combination of 3D-CRT with HAIC was an independent contributing factor for OS (hazard ratio, 3.2; 95% confidence interval, 1.692–6.021; P

Aim The predictive value of the recently identified interferon-λ (IFNL)4 polymorphism on the outcome of telaprevir (TVR), pegylated interferon (PEG IFN) plus ribavirin (RBV) combination therapy for chronic hepatitis C is unknown. Methods We assessed predictive factors for sustained virological response (SVR) for TVR, PEG IFN plus RBV combination therapy in 283 genotype 1 chronic hepatitis C patients. IFNL4 polymorphism ss469415590 was analyzed by Invader assay. Results SVR rates for patients with IFNL4 TT/TT genotype were significantly higher than for those with the IFNL4 TT/ΔG or ΔG/ΔG genotypes (93% and 59%, respectively, P

Aim The purpose of this study was to assess the clinical outcome and identify prognostic factors following treatment of patients with advanced hepatocellular carcinoma (HCC) and extrahepatic metastasis with sorafenib. Methods Sixty-one HCC patients with extrahepatic metastasis who were treated with sorafenib were enrolled in this retrospective cohort study. Results The median survival time (MST) of all patients was 11 months. The median time to radiological progression was 4.2 months. The response rates (complete response [CR] + partial response [PR]) by Response Evaluation Criteria in Solid Tumors (RECIST) and modified RECIST were 3.0% and 8.0%, respectively, while the disease control rates (CR + PR + stable disease) were 49% and 49%, respectively. Multivariate analysis identified T factor (intrahepatic tumor stage, T 0–2), response to disease control and des-γ-carboxy prothrombin (

Background and Aim To assess the short- and long-term outcome of patients with gastric varices (GV) after balloon-occluded retrograde transvenous obliteration (B-RTO) by comparing bleeding cases with prophylactic cases. Methods Consecutive 100 patients with GV treated by B-RTO were enrolled in this retrospective cohort study. We compared the technical success, complications, and survival rates between bleeding and prophylactic cases. Results Of 100 patients, 61 patients were bleeding cases and 39 patients were prophylactic cases. Technical success was achieved in 95% of bleeding case and in 100% of prophylactic case, with no significant difference between these groups (overall technical success rate, 97%). The survival rates at 5 and 10 years were 50% and 22% in bleeding case, and 49% and 36% in prophylactic case, respectively. There was also no significant difference (P = 0.420). By multivariate analysis, survival rates correlated significantly with liver function (hazard ratio 2.371, 95% CI 1.457–3.860, P = 0.001) and hepatocellular carcinoma development (HR 4.782, 95% CI 2.331–9.810, P

Aim The diagnosis of non-alcoholic fatty liver disease (NAFLD) is based on the histological findings. Further, there may be interobserver differences. Liver to spleen (L/S) ratio on computed tomography (CT) is employed to detect or even quantify the fat content of the liver. The objective of this study was to accurately diagnose fatty liver by evaluating the relationship between L/S ratio and histological findings. Methods Sixty-seven biopsy-proven NAFLD patients were enrolled. L/S ratio on CT was calculated. The area of steatosis in liver specimens was measured by BIOREVO BZ-9000 microscope, and the percentage of steatosis was calculated using Dynamic cell count BZ-H1C software. Results Steatotic grade assessed by pathologist was significantly correlated with the percentage of steatosis and L/S ratio. Factors associated with steatosis were L/S ratio, aspartate aminotransferase and Homeostasis Model of Assessment – Insulin Resistance as determined by multivariate analysis. L/S ratios were: S0, 1.16 ± 0.20 (mean ± standard deviation); S1, 0.88 ± 0.28; S2, 0.76 ± 0.20; and S3, 0.40 ± 0.18, respectively. The optimal cut-off value of L/S ratio to exclude steatosis was 1.1, and the area under the receiver–operator curve for the diagnosis of steatosis was 0.886. Conclusion Our study suggests that while 0% of steatosis showed 1.296 L/S ratio, the cut-off value of L/S ratio would be 1.1 at least to exclude clinically important liver steatosis.

Background and Aim Effectiveness of capsule endoscopy (CE) for screening the small bowel in patients with portal hypertension (PHT) has been reported. However, few reports discuss CE detection of specific esophagogastric lesions related to PHT. Thus, we assessed whether CE is useful for detecting such lesions. Methods One hundred nineteen consecutive patients with PHT comprised the study group. All had undergone esophagogastroduodenoscopy (EGD) prior to CE. The diagnostic yield of CE for esophageal varices (EVs), gastric varices (GVs), and portal hypertensive gastropathy (PHG) was evaluated. In addition, diagnostic yield in relation to form, location of the varices, grade, and extent of PHG was evaluated. Results EVs were found by EGD in 71 patients. The overall diagnostic yield of CE for EVs was 72% (51/71). The diagnostic yield was significantly greater for F2/F3 EVs than for F1 EVs (87% vs 61%, P = 0.03). The diagnostic yield was significantly greater for Lm/Ls EVs than for Li EVs (85% vs 55%, P = 0.01). The diagnostic yield was significantly greater for locus superior/locus medialis EVs than for locus inferior EVs (85% vs 55%, P = 0.01). GVs were found by EGD in 29 patients. Only one case was detected by CE. PHG was found by EGD in 35 patients. The diagnostic yield of CE for PHG was 69% (24/35). There was no difference in diagnostic yield between cases of severe and mild PHG (82% vs 63%, P = 0.44). Diagnostic yield of CE for PHG in the gastric body was significantly greater than that in the fundus (100% vs 48%, P = 0.0009). Conclusion CE is reliable for diagnosis of F2/F3 and/or Lm/Ls EVs and of PHG in the gastric body.

Older patients with chronic hepatitis C have a lower virological response to interferon (IFN) treatment compared to younger patients. The efficacy of telaprevir (TVR) and PEG-IFN plus ribavirin combination therapy and the predictive value of recently identified IFN lambda (IFNL) 4 polymorphisms on the outcome of therapy for older patients have not been addressed.We assessed predictive factors for sustained virological response (SVR) to triple therapy in 226 younger (≤65 years) and 87 older (65 years) Japanese patients with chronic genotype 1 hepatitis C. IFNL4 polymorphism ss469415590 was analyzed by Invader assay.The SVR rate for older patients was slightly lower than for younger patients (69 vs. 82%, P = 0.043). In the older group, the SVR rate for patients with the IFNL4 TT/TT genotype was significantly higher than patients with TT/ΔG or ΔG/ΔG genotypes (81.8 and 42.9%, P = 0.003). In multivariate regression analysis, rapid virological response (OR 36.601, P = 0.002) and IFNL4 TT/TT genotype (OR 19.502, P = 0.009) were identified as significant independent predictors for SVR in older patients. Treatment-related decreases in hemoglobin and increases in serum creatinine were higher in older patients than younger patients. Reduction of initial TVR dose to 1,500 mg per day alleviated these adverse events without compromising SVR rate in older patients.Analysis of IFNL4 polymorphisms is a valuable predictor in older patients receiving TVR triple therapy. 1,500 mg per day is a suitable initial TVR dose for older Japanese patients.

Background and Aim It has been reported about poor prognosis in patients with advanced hepatocellular carcinoma (HCC) refractory to hepatic arterial infusion chemotherapy (HAIC). We assessed the survival benefits of sorafenib therapy for advanced HCC in HAIC refractory patients. Methods The study subjects were 191 patients with advanced HCC who had been treated with HAIC. Sorafenib was used in 27 patients who finally failed to respond to HAIC (HAIC/sorafenib group). Clinical outcome was compared between HAIC/sorafenib and HAIC alone groups. Results There were no significant differences in clinical characteristics and response rate of HAIC between the two groups (response rate: 25.9%, HAIC/sorafenib group; 30.4%, HAIC alone group). The median survival time (MST) for all patients was 11.0 months. The survival rate was significantly higher in the HAIC/sorafenib group than HAIC alone group (MST 22.2 vs 8.7 months, P = 0.017). From administration sorafenib, the disease control rate was 51.8% with MST of 10.4 months. Among HAIC non-responders, the survival rate was significantly higher in the HAIC/sorafenib group than HAIC alone group. Multivariate analysis identified additional therapy with sorafenib as significant and independent determinant of overall survival in all patients and HAIC non-responders. Conclusion Additional therapy with sorafenib could probably improve the prognosis of HAIC refractory patients.

Aim To evaluate the clinical outcomes of percutaneous transvenous embolization (PTE) for portosystemic shunt (PSS) associated with encephalopathy Methods Fourteen patients with portosystemic encephalopathy (PSE) were enrolled in this retrospective cohort study. We evaluated technical success, clinical success, complication and outcomes. Results In cases in which PSS was one of main causes of PSE, three also had splenorenal shunts, four gastrorenal shunts, four superior mesenteric vein systemic shunts, one inferior mesenteric vein systemic shunt and two main trunk of portal vein inferior vena cava shunts. We used only ethanolamine oleate (EO) in five; EO and coils in five; EO, coils and n-butyl 2-cyanoacrylate (NBCA) in two; and coils and NBCA in two patients as embolic materials. The rate of primary and secondary technical success was 93% (13/14 patients) and 100%, respectively. No major complications were encountered related to PTE. Follow-up period was a median of 27 months (range, 12–79). All patients had sustained disappearance of PSE. PSE recurred in one patient because of another PSS development. Thus, clinical success was achieved in 93% (13/14 patients). The ammonia levels 1 year after PTE were significantly improved compared with pre-PTE (median, 102 vs 41 μmol/L) and maintained lower levels 2 and 3 years later. Child–Pugh scores did not change significantly. Esophageal varices were aggravated in 29% (4/14 patients). Five patients died, but no death of hepatic failure related to PTE was encountered. Conclusion PTE could be one of the useful treatment options for PSE.

Aim Acoustic radiation force impulse (ARFI) technology, involving the shear wave velocity (SWV) with virtual touch tissue quantification (VTTQ), are currently available for the assessment of liver fibrosis, while there is no index derived from the combination of SWV and blood tests. The aim of this study was to develop a new index for assessment of liver fibrosis. Methods The subjects were 176 consecutive patients with hepatitis C (training set [n = 120] and validation set [n = 56]) who underwent liver biopsy in our institution. Results In the training set, SWV, international normalized ratio (INR) and alanine aminotransferase (ALT) correlated independently and significantly with fibrosis. According to this, we developed the VIA index = −1.282 + 0.965 × SWV + 1.785 INR + 0.00185 ALT. The areas under the receiver–operator curve (AUROC) of the VIA index were 0.838 for the diagnosis of significant fibrosis (≥F2), 0.904 for the severe fibrosis (≥F3) and 0.958 for the cirrhosis (F4) in the training set. While in the validation set, AUROC of the VIA index were 0.917 for F2 or higher, 0.906 for F3 or higher and 1.000 for F4, respectively. AUROC of the VIA index was improved compared to SWV alone, equivalent for VIA for the diagnosis of F2 or higher, and superior to that of FIB-4 index and aspartate aminotransferase-to-platelet ratio index for the diagnosis of F3 or higher and F4. Conclusion The VIA index is potentially more useful for assessment of liver fibrosis than SWV alone, and easily and accurately measures liver fibrosis stage.

Aim Steatosis is a common histological feature of chronic liver disease, especially alcoholic and non-alcoholic fatty liver disease, as well as chronic hepatitis C. A recent study showed that evaluating the controlled attenuation parameter (CAP) with transient elastography was an efficient way of non-invasively determining the severity of hepatic steatosis. The objective of this study was to prospectively evaluate the utility of CAP for diagnosing steatosis in patients with chronic liver disease. Methods One hundred and fifty-five consecutive patients with suspected chronic liver disease underwent steatosis diagnosis using CAP, blood sample analyses, computed tomography for assessing the liver/spleen ratio and liver biopsy. Steatosis was graded according to the percentage of fat-containing hepatocytes: S0, less than 5%; S1, 5–33%; S2, 34–66%; and S3: more than 66%. Results The CAP was significantly correlated with steatosis grade, and there were significant differences between the CAP value of the S0 patients and those of the patients with other grades of steatosis. S0 and S1–3 hepatic steatosis were considered to represent mild and significant steatosis, respectively. The CAP values of the patients with mild and significant steatosis were significantly different (P

AbstactBackground and Aims To compare the tumor control and safety of stereotactic body radiation therapy (SBRT) combined with transcatheter arterial chemoembolization (TACE) for small, solitary, and hypervascular hepatocellular carcinoma (HCC) with TACE alone. Methods Three hundred and sixty-five HCC patients who had solitary, ≤ 3 cm, and hypervascular nodule were treated with TACE. Among them, 30 patients followed by SBRT (SBRT group) and 38 patients without additional therapy and previous HCC treatment (control group) were enrolled in this retrospective cohort study. Local tumor progression, complication, and disease-free survival were compared between these groups. Results There was no difference in clinical background between these groups. Complete response to therapy was noted in 29 (96.3%) patients of the SBRT group, and in only one (3.3%) patient of the TACE group (P

Background Although capsule endoscopy is available as a minimally invasive imaging technique that contributes significantly to the detection of small bowel lesions, there are only a very few published descriptions of small bowel abnormalities in patients with portal hypertension. Aims The aim of this study was to characterize the occurrence of small bowel lesions by means of capsule endoscopy in patients with portal hypertension, particularly those with compensated liver cirrhosis and associated anemia. Methods Sixty consecutive patients who met our criteria underwent capsule endoscopy. The frequency, type, and distribution of small bowel lesions were determined, and clinical factors associated with the lesions were examined. Results Small bowel abnormalities were found in 40 patients (67 %), including erythema (n = 32, 53 %), erosion (n = 10, 17 %), angioectasia (n = 9, 15 %), varices (n = 4, 7 %), and villous edema (n = 4, 7 %). Most lesions were located in the proximal or middle small bowel. Factors associated with the lesions were Child–Pugh class B (vs. class A, P = 0.0023), ascites (vs. no ascites, P = 0.0085), and portal hypertensive gastropathy (vs. no portal hypertensive gastropathy, P = 0.0434). Conclusions We found capsule endoscopy to be a useful diagnostic modality for detecting clinically significant small bowel lesions in patients with compensated liver cirrhosis. Based on our results, we suggest that this procedure should be especially considered for patients with Child–Pugh class B disease, ascites, and/or portal hypertensive gastropathy if they show evidence of gastrointestinal blood loss and/or iron-deficiency anemia.

Background and Aim We compared the treatment response, survival, and safety to hepatic arterial infusion chemotherapy (HAIC) in patients with advanced hepatocellular carcinoma (HCC) according to Child–Pugh (CP) score. Methods The study subjects were 249 patients with advanced HCC and CP class A and B who had been treated with HAIC. Patients were grouped according to CP score (5/6, 7 and 8/9) and their tumor response, tolerance, and survival were assessed. Results The median survival time (MST) was 8.2, 9.7, 6.3, and 3.9 months for the whole group, patients with CP 5/6, 7 and 8/9, respectively (P

Aim: In this study, we evaluated the clinical characteristics of hepatocellular carcinoma (HCC) because the etiology of HCC has been changing recently. Methods: Consecutive 1374 HCC patients at our institution from 1995 to 2009 were enrolled and clinical characteristics were investigated. Results: Seventeen percent and 67% of HCC were related to hepatitis B virus (HBV-HCC) and hepatitis C virus (HCV-HCC), respectively. Fifteen percent of that was negative for hepatitis B surface antigen (HBsAg) and antibody to hepatitis C virus (HCVAb) (NBNC-HCC). HCV-HCC tended to decrease and NBNC-HCC tended to increase in recent years. Patients with NBNC-HCC and HCV-HCC were significantly older than those with HBV-HCC. The complication rates of diabetes mellitus (DM), heavy alcohol consumption, hypertension, and hyperlipidemia in NBNC-HCC were significantly higher than those in other groups. Furthermore, the platelet counts and body mass index in NBNC-HCC were significantly higher than those of other groups. Among 209 NBNC-HCC patients, 58 patients underwent hepatic resection in which 29%, 36%, and 35% of those were based on non-alcoholic steatohepatitis (NASH), heavy alcohol consumption, and unknown etiology, respectively. DM was prevalent especially in NASH and heavy alcohol consumption. Cirrhosis was detected in 65%, 81%, and 15% in NASH-HCC, heavy alcohol consumption-HCC, and unknown etiology, respectively. Conclusions: NBNC-HCC has gradually been increasing in recent years. The present study elucidated that the presence of NASH and metabolic syndrome were important risk factors for NBNC-HCC and suggests that these patients should receive surveillance for HCC development.

Sorafenib is the standard treatment for advanced hepatocellular carcinoma (HCC) with distant metastasis, unresectable HCC, and those refractory to transcatheter arterial chemoembolization (TACE) or with macroscopic vascular invasion (MVI). The application of sorafenib has been approved by the Japanese Government-sponsored Medicare for unresectable HCC. In this retrospective cohort study we aimed to compare various aspects of HAIC with sorafenib in the treatment of Child-Pugh A patients with advanced HCC who were otherwise free of extrahepatic metastasis.Altogether 177 patients with advanced HCC at Child-Pugh class A who were free of extrahepatic metastasis were retrospectively enrolled. The patients were divided into the HAIC group (n = 136) and the sorafenib group (n = 41), and were followed up until their death or withdrawal of therapy. Responses to treatment and overall survival were determined and compared between the two groups.The proportion of patients with complete response, partial response, stable disease and progressive disease were 5.9%, 25.0%, 40.4% and 21.3% in the HAIC and 2.4%, 2.4%, 43.9% and 41.5% in the sorafenib group, respectively. The response rate was higher in the HAIC group than in the sorafenib group (30.9% vs 4.8%). The median survival time was 10 months in both HAIC and sorafenib groups. In patients with macroscopic vascular invasion (MVI) by the case-control method, the response rate was higher in the HAIC group than in the sorafenib group. Overall survival was longer in the HAIC group than in the sorafenib group (14 months vs 7 months, P = 0.005). Multivariate analysis identified MVI (hazard ratio 2.4, P = 0.018) as an independent prognostic factor of survival in the sorafenib group.Response rate to HAIC was higher than that to sorafenib monotherapy. Prognosis was favorable in HAIC responders despite MVI. HAIC might be a potential treatment option for advanced HCC without extrahepatic metastasis.

A genome-wide association study revealed that the single nucleotide polymorphism (SNP) rs738409 in the patatin-like phospholipase 3 gene (PNPLA3) was strongly associated with non-alcoholic fatty liver disease (NAFLD). Recent pilot studies investigated the effects of dipeptidyl peptidase-4 inhibitors on liver function and glucose metabolism in NAFLD with type 2 diabetes mellitus (DM). We herein evaluated the efficacy of alogliptin in NAFLD patients with type 2 DM as well as the relationship between genotypes at rs738409 in PNPLA3 and treatment efficacy.Forty-one biopsy-proven NAFLD patients with type 2 DM treated with 25 mg/day alogliptin were retrospectively enrolled. SNP rs738409 in PNPLA3 was present in all patients. Clinical data were measured before and after the treatment.Average hemoglobin A1c (HbA1c) levels mostly remained unchanged. Moreover, significant changes were not noted in the levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) during the follow-up period. A positive correlation was observed between improvements in HbA1c (ΔHbA1c) levels and changes in AST (ΔAST) and ALT (ΔALT) levels (r = 0.325 and 0.439, respectively). Patients with the risk allele (G-allele) showed more positive correlation between ΔHbA1c and changes in transaminase. Furthermore, improvements in the levels of total cholesterol, triglycerides and hyaluronic acid were significantly greater in G-allele patients in the weight loss group.The treatment of NAFLD with type 2 DM with alogliptin contributed to the amelioration of NAFLD. Our results suggested that differences in the PNPLA3 risk allele affected the therapeutic effects of this treatment.

Objective Autoimmune hepatitis (AIH) is a chronic progressive liver disease. AIH is composed predominantly of type 1 in Japanese populations. The genetic and environmental factors are associated with the pathogenesis of AIH. HLA-DRB1*03:01 and *04:01 are associated with type 1 AIH in European and *04:05 in Japanese populations. Here, we conducted an HLA association study in order to find HLA alleles or haplotypes predisposing or protective for Japanese AIH. Methods HLA-DRB1 and DQB1 genotyping of 360 type 1 AIH patients and 1026 healthy controls was performed. Results The predisposing association of DRB1*04:01 (P = 0.0006, corrected P [Pc] = 0.0193, odds ratio [OR] 2.97, 95% confidence interval [CI] 1.62–5.43), DRB1*04:05 (P = 1.89×10−21, Pc = 5.86×10−20, OR 3.41, 95% CI 2.65–4.38), and DQB1*04:01 (P = 4.66×10−18, Pc = 6.99×10−17, OR 3.89, 95% CI 2.84–5.33) and the protective association of DRB1*13:02 (P = 0.0003, Pc = 0.0080, OR 0.48, 95% CI 0.32–0.72) with Japanese type 1 AIH were observed. An association of the DR4/DR8 heterozygous genotype with Japanese AIH was identified for the first time (P = 3.12×10−9, OR 3.52, 95% CI 2.34–5.29). Susceptible diplotypes were DRB1*04:05-DQB1*04:01/DRB1*08:02-DQB1*03:02 (P = 0.0004, OR 24.77, 95% CI 1.45–424.31) and DRB1*04:05-DQB1*04:01/DRB1*08:03-DQB1*06:01 (P = 1.18×10−6, OR 10.64, 95% CI 3.19–35.46). Serum levels of Immunoglobulin G and Immunoglobulin M, International Autoimmune Hepatitis Group score, positive rate of anti-smooth muscle antibodies, and the rate of definite AIH were higher in AIH patients with DRB1*04:05 than without. Conclusions The important roles of specific combinations of DRB1 and DQB1 alleles or haplotypes in the pathogenesis of type 1 AIH were suggested. The association of DR4/DR8 heterozygous genotype suggested the pathologic importance of trans-complementing DQα-β heterodimer molecules encoded by DQA1 allele of one haplotype and the DQB1 allele of the other haplotype, as it was proposed in the HLA association studies of Type 1 diabetes.

Non-simple nodules in hepatocellular carcinoma (HCC) correlate with poor prognosis. Therefore, we examined the diagnostic ability of gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging (EOB-MRI) and contrast-enhanced ultrasound (CEUS) for diagnosing the macroscopic classification of small HCCs. A total of 85 surgically resected nodules (≤30 mm) were analyzed. HCCs were pathologically classified as simple nodular (SN) and non-SN. By evaluating hepatobiliary phase (HBP) of EOB-MRI and Kupffer phase of CEUS, the diagnostic abilities of both modalities to correctly distinguish between SN and non-SN were compared. Forty-six nodules were diagnosed as SN and the remaining 39 nodules as non-SN. The area under the ROC curve (AUROCs, 95 % confidence interval) for the diagnosis of non-SN were EOB-MRI, 0.786 (0.682–0.890): CEUS, 0.784 (0.679–0.889), in combination, 0.876 (0.792–0.959). The sensitivity, specificity, and accuracy were 64.1 %, 95.7 %, and 81.2 % in EOB-MRI, 56.4 %, 97.8 %, and 78.8 % in CEUS, and 84.6 %, 95.7 %, and 90.6 % in combination, respectively. High diagnostic ability was obtained when diagnosed in both modalities combined. The sensitivity was especially statistically significant compared to CEUS. Combined diagnosis by EOB-MRI and CEUS can provide high-quality imaging assessment for determining non-SN in small HCCs. • Non-SN has a higher frequency of MVI and intrahepatic metastasis than SN. • Macroscopic classification is useful to choose the treatment strategy for small HCCs. • Diagnostic ability for macroscopic findings of EOB-MRI and CEUS were statistically equal. • The diagnosis of macroscopic findings by individual modality has limitations. • Combined diagnosis of EOB-MRI and CEUS provides high diagnostic ability.

To assess the early response and outcome of hepatic arterial infusion chemotherapy (HAIC) in patients with advanced hepatocellular carcinoma (HCC).One hundred sixty-five HCC patients treated with HAIC were reviewed retrospectively. The early response to one course of HAIC treatment was evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST) and changes in α-fetoprotein (AFP) and des-γ-carboxy prothrombin (DCP).The median survival time (MST) for all patients was 9.5 months. The early imaging response by RECIST was assessed as partial response (PR), stable disease (SD), and progressive disease (PD) in 32 (19.3%), 86 (52.1%), and 47 (28.4%) patients, respectively. Survival correlated with early imaging response (MST in PR, 20.6; SD, 11.4; PD, 5.0 months; P 0.0001). The MST was also significantly different in patients with AFP ratio of ≤ 1 or 1 and DCP ratio of ≤ 1 or 1 (worst MST, 6.5 months in patients with AFP ratio of 1 and DCP ratio of 1). Among patients with SD early imaging response, patients with AFP ratio of 1 and DCP ratio of 1 had significantly poorer survival than others (MST 7.4 vs. 12.6 months, P = 0.014). The decrease in AFP and DCP in the early stage treatment with HAIC were identified as significant and independent factors associated with survival of not only all patients, but also patients with SD early imaging response.The use of the combination of RECIST and tumor marker ratio could be useful for assessment of the early response to HAIC and prognosis of patients with advanced HCC.

Dipeptidyl peptidase-4 inhibitor is useful for the treatment of type 2 diabetes mellitus (DM). However, effects on liver function and glucose metabolism in nonalcoholic fatty liver disease (NAFLD) have not been established. The objective of this study was to evaluate the efficacy and safety of sitagliptin in NAFLD patients with type 2 DM.Forty-four patients with biopsy-proven NAFLD with type 2 DM were evaluated. Patients were administered sitagliptin (50 mg/day) for 12 months.Hemoglobin A1c (HbA1c) decreased by 0.7% after treatment (P0.001). While HbA1c levels decreased by 0.4% in the low HbA1c (7.5%) group, those decreased by 1.2% in the high HbAlc (or = 7.5%) group. Liver transaminases did not change significantly during the treatment. Improvement of HbA1c (deltaHbA1c) and that of aspartate aminotransferase (deltaAST), alanine aminotransferase (deltaALT) was positively correlated (r = 0.425, and 0.455, respectively), especially in the high HbA1c (or = 7.5%) group before treatment (r = 0.568, and 0.501, respectively).Sitagliptin for the treatment of NAFLD with type2 DM was safe and showed similar antidiabetic effects as reported for type 2 DM, suggesting that tight glycemic control would contribute to the improvement of NAFLD based from the findings of correlation between the changes of HbA1c and transaminases.

We retrospectively evaluated the local tumor control and safety of transcatheter arterial chemoembolization (TACE) followed by stereotactic body radiation therapy (SBRT) for small hepatocellular carcinoma (HCC) in this pilot study.Twenty-eight patients not for the indication of hepatectomy or ablation procedures were enrolled in this study. Eligible criteria was as followed: i) less than 3 hypervascular HCC nodules, each up to 30 mm in diameter; ii) not suitable for the hepatic resection or ablative therapy; iii) Child-Turcotte-Pugh (CTP) scoreor = 7. SBRT was performed within 1-2 months after TACE. Treatment efficacy was evaluated, according to the Response Evaluation Criteria in Cancer of the Liver (RECICL).The median local tumor control time was not reached. The 1-year cumulative local tumor control rate was 96.3%. The median disease-free survival time was 18 months. The 1- year cumulative overall survival rate was 92.6%. One patient (3.6%) died due to intrahepatic ectopic multiple recurrence and systemic metastasis and one (3.6%) due to cerebral hemorrhage. No patients experienced severe acute hematologic or physical toxicity or radiation induced liver damage.Our study demonstrated SBRT combined with TACE is a safe and effective modality of the locoregional therapy for small primary HCC.

We previously reported our data on telaprevir (TVR) used in combination with pegylated-interferon and ribavirin (PEG-IFN/RBV) for the treatment of recurrent hepatitis C virus (HCV) genotype 1 infection after liver transplantation (LT). TVR substantially increases the blood levels of immunosuppressive agents such as cyclosporine and tacrolimus for drug-drug interactions. On the other hand, the effect of simeprevir (SMV) on the blood levels of these immunosuppressive agents is unclear. We report 2 patients who achieved viral responses with little effect on the blood levels of cyclosporine and tacrolimus using SMV plus PEG-IFN/RBV treatment. The first was a 71-year-old woman with HCV-related liver cirrhosis and hepatocellular carcinoma who failed to respond to PEG-IFN/RBV after living donor LT. She was treated with 40 mg/d of cyclosporine, and received SMV plus PEG-IFN/RBV treatment. The second was a 65-year-old man with HCV-related liver cirrhosis who failed to respond to PEG-IFN/RBV after living donor LT. He was treated with 3 mg/d of tacrolimus, and received SMV plus PEG-IFN/RBV treatment. Serum HCV RNA became undetectable using TaqMan polymerase chain reaction (PCR) test after 4 weeks of treatment in both patients, and no remarkable fluctuation in blood concentration was observed either in cyclosporine or tacrolimus during the 12 weeks of SMV treatment. Completion of 12-week SMV triple therapy was followed by PEG-IFNα2b plus RBV, and both patients achieved sustained virological response 12 weeks after the end of treatment. SMV plus PEG-IFNRBV treatment showed a remarkable viral response with little effect on blood levels of immunosuppressive agents for recurrent HCV genotype 1 infection after LT.

Portal hypertensive enteropathy (PHE) is acknowledged as a source of bleeding, and predicting its presence has become more important. We assessed PHE using capsule endoscopy (CE) and investigated factors that may predict its presence, including portosystemic shunts (PSs).We analyzed data from 134 consecutive patients with liver cirrhosis, from February 2009 to September 2013. All patients had undergone dynamic computed tomography and esophagogastroduodenoscopy before CE examination. The frequencies and types of PHE lesions, and the relationships between the presence of PHE and patients' clinical characteristics were evaluated. The distribution of the lesions was also determined.PHE was found in 91 (68%), erythema in 70 (52%), erosions in 25 (19%), angioectasia in 24 (18%), villous edema in 18 (13%), and varices in 10 (7%) patients. Most lesions were located in the jejunum. The clinical characteristics associated with the presence of PHE were a Child-Pugh grade of B or C (P = 0.0058), and the presence of PSs (P 0.0001), ascites (P = 0.0017), portal thrombosis (P = 0.016), esophageal varices (P = 0.0017), and portal hypertensive gastropathy (P = 0.0029). The presence of PSs was an independent predictor of PHE (odds ratio [OR]: 3.15; 95% confidence interval [CI]: 1.27-7.95). Among the shunt types, left gastric vein (OR: 5.31; 95% CI: 1.97-17.0) and splenorenal shunts (OR: 4.26; 95% CI: 1.29-19.4) were independent predictors of PHE.PSs, especially left gastric vein and splenorenal shunts, appear to reliably predict the presence of PHE.

To assess the efficacy and safety of the anticoagulant drug, danaparoid sodium, in the treatment of portal vein thrombosis (PVT) in patients with liver cirrhosis.A consecutive 26 cirrhotic patients with PVT were enrolled in this retrospective cohort study. The etiologies of cirrhosis were hepatitis B virus-related, hepatitis C virus-related, alcoholic and cryptogenic in five, 14, three and four patients, respectively. Child-Pugh grade A, B and C was noted in 13, eight and five patients, respectively. Patients were treated with 2 weeks' administration of danaparoid sodium followed by the evaluation of PVT reduction and adverse events.All patients experienced reduction of PVT through the treatment. The median volume of PVT before and after treatment was 2.40 cm(3) (range, 0.18-16.63) and 0.37 cm(3) (range, 0-5.74), respectively. The median reduction rate of PVT volume was 77.3% (range, 18-100%). According to the reduction rate, complete reduction (CR), partial reduction (PR, ≥50%) and stable disease (SD,50%) were observed in four (15%), 16 (62%) and six patients (23%), respectively. The median volume of PVT before treatment was significantly different between CR + PR and SD (2.09 vs 4.35 cm(3) , P = 0.045). No severe adverse events such as bleeding symptoms (e.g. gastrointestinal bleeding and cerebral hemorrhage) and thrombocytopenia were encountered.Danaparoid sodium for the treatment of PVT in patients with liver cirrhosis was safe and effective. Therefore, anticoagulation therapy with danaparoid sodium could have potential as one of the treatment options in PVT accompanied by cirrhosis.

A 50-year-old male patient was admitted to the hospital for persistent high fever and back pain. He was diagnosed with hepatocellular carcinoma (HCC), bone marrow metastasis and disseminated intravascular coagulation (DIC). Despite the diagnosis and treatment, the general condition deteriorated rapidly and he died of cerebral hemorrhage associated with generalized bleeding tendency. Autopsy showed multiple HCC in the liver and systemic metastasis including bone marrow. The case describes a rare complication of HCC with disseminated carcinomatosis of the bone marrow (DCBM) complicated with DIC, with rapid deterioration and death. This is the first case of DCBM from HCC. Physicians need to be aware of DCBM in patients with HCC.

The diagnosis of non-alcoholic fatty liver disease (NAFLD) is based on the histological findings. Further, there may be interobserver differences. Liver to spleen (L/S) ratio on computed tomography (CT) is employed to detect or even quantify the fat content of the liver. The objective of this study was to accurately diagnose fatty liver by evaluating the relationship between L/S ratio and histological findings.Sixty-seven biopsy-proven NAFLD patients were enrolled. L/S ratio on CT was calculated. The area of steatosis in liver specimens was measured by BIOREVO BZ-9000 microscope, and the percentage of steatosis was calculated using Dynamic cell count BZ-H1C software.Steatotic grade assessed by pathologist was significantly correlated with the percentage of steatosis and L/S ratio. Factors associated with steatosis were L/S ratio, aspartate aminotransferase and Homeostasis Model of Assessment - Insulin Resistance as determined by multivariate analysis. L/S ratios were: S0, 1.16 ± 0.20 (mean ± standard deviation); S1, 0.88 ± 0.28; S2, 0.76 ± 0.20; and S3, 0.40 ± 0.18, respectively. The optimal cut-off value of L/S ratio to exclude steatosis was 1.1, and the area under the receiver-operator curve for the diagnosis of steatosis was 0.886.Our study suggests that while 0% of steatosis showed 1.296 L/S ratio, the cut-off value of L/S ratio would be 1.1 at least to exclude clinically important liver steatosis.

To assess the short- and long-term outcome of patients with gastric varices (GV) after balloon-occluded retrograde transvenous obliteration (B-RTO) by comparing bleeding cases with prophylactic cases.Consecutive 100 patients with GV treated by B-RTO were enrolled in this retrospective cohort study. We compared the technical success, complications, and survival rates between bleeding and prophylactic cases.Of 100 patients, 61 patients were bleeding cases and 39 patients were prophylactic cases. Technical success was achieved in 95% of bleeding case and in 100% of prophylactic case, with no significant difference between these groups (overall technical success rate, 97%). The survival rates at 5 and 10 years were 50% and 22% in bleeding case, and 49% and 36% in prophylactic case, respectively. There was also no significant difference (P = 0.420). By multivariate analysis, survival rates correlated significantly with liver function (hazard ratio 2.371, 95% CI 1.457-3.860, P = 0.001) and hepatocellular carcinoma development (HR 4.782, 95% CI 2.331-9.810, P 0.001). The aggravating rates of esophageal varices (EV) were 21%, 50%, and 54% at 12, 60, and 120 months after B-RTO. By multivariate analysis, aggravating rates significantly correlated with EV existing before B-RTO (HR 18.114, 95% CI 2.463-133.219, P = 0.004).B-RTO for GV could provide the high rate of complete obliteration and favorable long-term prognosis even in bleeding cases as well as prophylactic cases. Management of EV after B-RTO, especially in coexisting case of GV and EV, would be warranted.

The purpose of this study was to assess the clinical outcome and identify prognostic factors following treatment of patients with advanced hepatocellular carcinoma (HCC) and extrahepatic metastasis with sorafenib.Sixty-one HCC patients with extrahepatic metastasis who were treated with sorafenib were enrolled in this retrospective cohort study.The median survival time (MST) of all patients was 11 months. The median time to radiological progression was 4.2 months. The response rates (complete response [CR] + partial response [PR]) by Response Evaluation Criteria in Solid Tumors (RECIST) and modified RECIST were 3.0% and 8.0%, respectively, while the disease control rates (CR + PR + stable disease) were 49% and 49%, respectively. Multivariate analysis identified T factor (intrahepatic tumor stage, T 0-2), response to disease control and des-γ-carboxy prothrombin (2600 mAU/mL) as significant and independent determinants of survival. Intrahepatic tumor stage before treatment allows stratification of prognosis of patients treated with sorafenib. Four T0 patients remained alive. The MST of patients with T1 (n = 6), T2 (n = 10), T3 (n = 23) and T4 (n = 18) of intrahepatic tumor stage was 20, 23, 7 and 5 months, respectively. Among the progressive disease group, patients with T0-2 intrahepatic tumor stage had better prognosis than patients with T3-4.In HCC patients with extrahepatic metastasis who are treated with sorafenib, intrahepatic tumor stage was a significant and independent prognostic factor.