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AIM Lenvatinib is an oral, multitargeted, tyrosine kinase inhibitor, which suppress tumor angiogenesis and tumor progression. It was non-inferior to sorafenib in overall survival in untreated advanced hepatocellular carcinoma (HCC). Sorafenib had a beneficial effect on portocollateral circulation with portal hypertension in translating and clinical studies. However, the hemodynamic effects of lenvatinib appear to be different from those of sorafenib because the efficacy of lenvatinib for vascular endothelial growth factor receptors and fibroblast growth factor receptors is different from that of sorafenib. This study was prospectively performed to evaluate the portal hemodynamic effect of lenvatinib in patients with advanced HCC using duplex Doppler ultrasonography. METHODS In total, 28 Child-Pugh class A or B patients with advanced HCC received lenvatinib depending on body weight daily for 2 weeks. Primary outcomes were changes in the hemodynamics of the portal venous system using duplex Doppler ultrasonography before and after the 2-week administration of lenvatinib. RESULTS The portal venous flow velocity (cm/s) significantly reduced (27 ± 12.1 vs. 22.6 ± 8.0, P = 0.019), while portal venous area (cm2 ) did not change after the 2-week administration (0.80 ± 0.36 vs. 0.82 ± 0.27, P = 0.665). Therefore, the congestion index (portal venous area/portal venous flow velocity), which reflects the pathophysiological hemodynamics of the portal venous system significantly worsened (0.037 ± 0.025 vs. 0.043 ± 0.024, P = 0.045). CONCLUSIONS Considering that this was a short-term study, because lenvatinib could be an agent that aggravates portal hypertension, it will be necessary to verify its clinical effects for portal hypertension in future studies.

The diverse treatments available for portal hypertension require specialized knowledge of hemodynamics and include endoscopic treatments, interventional radiology (IVR), and surgery. The Japan Society for Portal Hypertension has developed the skill qualification system (SQS) for portal hypertension and began examination in 2014. Here, the status and validity of the judgment of the SQS examination were evaluated.From 2014 to 2020, 79 applicants were evaluated by the SQS for portal hypertension. Each unedited video submitted as a candidate procedure was evaluated by two judges, and a grade of greater than 70% for the scoring items assessed by the judges was required to pass the examination. Inter-rater agreement of success/failure between the two judges was investigated by the ACThe results of two judges differed for 11 of the 79 videos (13.9%), and five applicants (6.3%) ultimately failed the examination. The percentages of total points received by the applicants with endoscopic treatments, IVR, and surgery were 87.3%, 79.4%, and 80.8%, respectively. There were significant differences in the percentages between endoscopic treatments and IVR (The SQS for portal hypertension of the Japan Society for Portal Hypertension showed high reliability for video assessments by the judges. This system may contribute to the spread and further development of safe and effective treatments for portal hypertension in Japan.

AIM Esophageal variceal ligation (EVL) is usually carried out to decrease the risk of hemorrhage. Several complications have been reported with the procedure, including bleeding from ligation-induced esophageal ulcers or heartburn. However, there is scant evidence for gastroesophageal reflux caused by EVL. The aim of this study was to assess 24-h pH monitoring in the esophagogastric junction before and after EVL and the bleeding rate for 18 months. METHODS We undertook this single-center prospective trial in Kitasato University Hospital (Sagamihara, Japan). We included patients with cirrhosis who were Child-Pugh classification A or B, without uncontrollable hepatocellular carcinoma, and had F2 or larger esophageal varices, and/or were red color sign (RC) positive. The study period was from July 2012 through September 2017 for 32 patients enrolled in this study and followed up until March 2019. RESULTS Baseline characteristics were: median Child-Pugh score, 6; and mean age, 64.3 years. Before and after EVL, the median 24-h under pH 4 holding time percentages of all patients were 0.6% (range, 0-5.6%) and 0.95% (range, 0-50.6%), respectively, without a significant difference (P = 0.107). We could not find any G3 or G4 adverse events during this study, and 75% of the patients who had already suffered from moderate gastroesophageal reflux became worse after EVL (P = 0.18) and required antacid therapies. There were no patients with hemorrhage from esophageal varices. CONCLUSIONS Esophageal variceal ligation for esophageal varices did not significantly change gastroesophageal reflux. Therefore, acid suppressive therapy might be unnecessary for patients who do not suffer from gastroesophageal reflux after EVL.

Aim To investigate the current status of portal vein thrombosis (PVT) in Japan, the Clinical Research Committee of the Japan Society of Portal Hypertension conducted a questionnaire survey. Methods A questionnaire survey of 539 cases of PVT over the previous 10 years was conducted at institutions affiliated with the Board of Trustees of the Japan Society of Portal Hypertension. Results The most frequent underlying etiology of PVT was liver cirrhosis (LC) in 75.3%. Other causes included inflammatory diseases of the hepatobiliary system and the pancreas, malignant tumors, and hematologic diseases. The most frequent site was the main trunk of the portal vein (MPV) in 70.5%, and complete obstruction of the main trunk of the PV was present in 11.5%. Among the medications for PVT, danaparoid was administered to 45.8%, warfarin to 26.2%, heparin to 17.3%, and anti-thrombin III (AT-III) to 16.9%. Observation of the course was practiced in 22.4%. Factors contributing to therapeutic efficacy were implementation of various medications, thrombi localized to either the right or left portal vein (PV) only, non-complete obstruction of the MPV and liver function of Child-Pugh class A. A survival analysis showed that the prognosis was favorable with PVT disappearance regardless of treatments. Conclusion The questionnaire survey showed the current status of PVT in Japan. Any medication should be administered to a patient with PVT when PVT is recognized. It is necessary to compile a large amount of information and reach a consensus on safe and highly effective management of PVT.

The liver has an immune tolerance against gut-derived products from the portal vein (PV). A disruption of the gut-liver axis leads to liver injury and fibrosis. The spleen is connected to the PV and regulates immune functions. However, possible splenic effects on liver fibrosis development are unclear. Lipocalin-2 (Lcn2) is an antimicrobial protein that regulates macrophage activation. To clarify the role of the spleen in liver fibrosis development, we induced liver fibrosis in mice after splenectomy, and investigated liver fibrosis development. Liver fibrosis resulted in significantly increased splenic Lcn2 levels, but all other measured cytokine levels were unchanged. Splenectomized mice showed enhanced liver fibrosis and inflammation accompanied by significantly decreased Lcn2 levels in PV. Lipopolysaccharide-stimulated primary Kupffer cells, resident liver macrophages, which were treated with recombinant Lcn2 (rLcn2) produced less tumor necrosis factor-α and Ccl2 and the activation of hepatic stellate cells, the effector cells for collagen production in the liver, was suppressed by co-culture with rLcn2-treated Kupffer cells. In addition, the involvement of gut-derived products in splenectomized mice was evaluated by gut sterilization. Interestingly, gut sterilization blocked the effect of splenectomy on liver fibrosis development. In conclusion, spleen deficiency accelerated liver fibrosis development and decreased PV Lcn2 levels. The mechanism of splenic protection against liver fibrosis development may involve the splenic Lcn2, triggered by gut-derived products that enter the liver through the PV, regulates Kupffer cells activated by the gut-liver axis. Thus, the splenic Lcn2 may have an important role in regulating the immune tolerance of the liver in liver fibrosis development.

Aim To examine whether superparamagnetic iron oxide (SPIO)-enhanced magnetic resonance imaging (MRI) can be used to assess the malignant potential of hepatic hypovascular nodules showing hypointensity during the hepatobiliary phase (HBP) on gadoxetic acid (Gd–EOB–DTPA)-enhanced MRI. Methods The study included 42 patients with chronic liver disease who had small hypovascular nodules (5–15 mm) showing hypointensity during the HBP on Gd–EOB–DTPA-enhanced MRI. The SPIO-enhanced T2-weighted MRI analyzed whether the signal intensity of each nodule was high. Nodules were prospectively followed up until hypervascularization by periodic Gd–EOB–DTPA-enhanced MRI. Initial MRI findings and clinical variables were used to analyze predictive factors for hypervascularization. Results We analyzed 77 nodules, of which 19 (25%) showed hypervascularization during the observation period. The cumulative rates for hypervascularization were 11% and 22% at 1 and 2 years, respectively. Hyperintensity was observed in 12 nodules (16%) on SPIO-enhanced T2-weighted MRI; among these, 7 (58%) showed hypervascularization, whereas 12 (18%) of the remaining 65 nodules without hyperintensity showed hypervascularization (P = 0.007). A Cox model revealed that independent predictors of hypervascularization included hyperintense nodules on SPIO-enhanced MRI (P

Idiopathic portal hypertension (IPH), causing aberrant portal hemodynamics, is a disease with an as yet unidentified cause and no treatment has been established so far. The Japanese research group on IPH in Japan was set up in 1975 by the Ministry of Health, Labour and Welfare, furthermore extra-hepatic portal obstruction (EHO) and Budd-Chiari syndrome (BCS) have been added to the research subjects and further work has continued. The aims of the research group are to accurately evaluate the current status of the three diseases in Japan, elucidate the disease aetiology and pathogenesis, and develop new treatments. Due to the long-term efforts of the Japanese research group, aberrant portal hemodynamics has been investigated to date in a variety of aspects, from epidemiological and pathological studies to molecular biology analysis. As a result, it has been shown that there are abnormal genes in the liver, specific for IPH. In addition, pathological findings of BCS were internationally compared and the difference in findings between Japan and Western countries has been clarified. Furthermore, it was found that complication rates of hepatocellular carcinoma (HCC) in BCS were higher in Japan. Based on the research, "Diagnosis and treatment of aberrant portal hemodynamics (2001)", including diagnostic criteria for aberrant portal hemodynamics, was published in 2001. In 2013, it was revised to "Diagnosis and treatment guidelines for aberrant portal hemodynamics (2013)" after the incorporation of diagnosis and treatment in accordance with its current status. This article is protected by copyright. All rights reserved.

Aim The indocyanine green (ICG) finger-piece method (FPM), which allows measurement of the ICG concentration by mounting a light sensor onto a finger, is used to assess liver function. We compared the ICG FPM with the conventional ICG blood sampling method (BSM) in patients with liver disorders. Methods Ninety consecutive patients simultaneously underwent the ICG BSM and ICG FPM. After ICG administration, blood samples were collected at 5, 10, and 15 min for the ICG BSM. The ICG concentration was measured through the finger piece by an ICG clearance meter. Results Seventy-one patients (78.9%) had Child–Pugh class A liver disease, and 19 (21.1%) had class B or C. The FPM-measured ICG plasma disappearance rate (PDR) was positively correlated with the BSM-measured values (r = 0.886, P

The treatment of portal vein thrombosis is performed based on a symptomatic acute clot or an asymptomatic chronic clot and further depends on whether the underlying disease is cirrhosis or not. In all cirrhotic cases, attention should be paid to hemorrhagic complications. In particular, it is necessary to perform appropriate prophylactic endoscopic injection sclerotherapy/endoscopic variceal ligation in complicated case of esophagogastric varices. In recent years the use of antithrombin-III (AT-III) preparations and danaparoid sodium have increased in place of heparin, urokinase, and warfarin for the treatment of portal vein thrombosis. Based on the fact that antithrombotic action (fibrinolysis) has been reported even with AT-III alone, and that AT-III doesn’t affect the bleeding tendency, it is safe and effective to use it for portal vein thrombosis with esophagogastric varices. And danaparoid sodium has higher anti-factor Xa activity than heparin. In addition, the usefulness of danaparoid with less risk of bleeding has also been reported.

Portal vein thrombosis is considered to develop from portal venous vascular wall disorder, abnormal portal venous flow, and abnormalities of the blood coagulation system as the thrombogenic origins. Portal vein thrombosis can easily occur in patients with hepatic cirrhosis due to three additional factors. The first factor is the hyperpermeability of the gastrointestinal mucous membrane. Cirrhosis creates an environment susceptible to bacterial translocation, and loads to the flow of lipopolysaccharide into a portal vein, resulting in sinusoid wall injury. The second factor is clot formation promoted by portal venous congestion (sluggish blood flow) due to portal hypertension. The third factor is a decrease of antithrombin-III synthesis in liver cirrhosis. Among the underlying diseases of 539 cases of portal vein thrombosis in Japan in 2014, there were 434 cases (80.5%) of portal hypertension, whose breakdown consisted of 406 cases (75.3%) of liver cirrhosis, 25 cases of idiopathic portal hypertension, 8 cases of extrahepatic obstruction, and 7 cases of others, while 105 cases (19.5%) were not associated with portal hypertension. Secondary portal vein thrombus accounted for 69 (12.8%) of the total, if it is defined as that developed within 30 days after an operation or interventional radiology.

Simeprevir is a substrate for organic anion-transporting polypeptides (OATPs) that transport bilirubin. Hyperbilirubinemia is an adverse event reported during treatment of chronic hepatitis C patients with simeprevir plus pegylated interferon and ribavirin. Because gadoxetic acid is also a substrate of OATPs, pretreatment gadoxetic acid-enhanced magnetic resonance imaging (MRI) may predict hyperbilirubinemia during treatment. This prospective study therefore evaluated 11 consecutive patients with chronic hepatitis C who underwent gadoxetic acid-enhanced MRI prior to treatment with simeprevir plus pegylated interferon and ribavirin for 12 weeks, followed by pegylated interferon and ribavirin for an additional 12 weeks. Their contrast enhancement index (CEI), an index of liver parenchymal enhancement during the hepatobiliary phase, was assessed before treatment. Plasma trough concentrations (Ctrough ) of simeprevir were determined 7 days after its administration, and serum bilirubin concentrations were measured throughout the course of treatment. Six patients (55%) developed hyperbilirubinemia (≥1.6 mg/dL) during treatment. Ctrough was significantly higher in patients with than without hyperbilirubinemia (P = .009), with a strong inverse relationship between CEI and Ctrough (r = -0.911, P < .001). CEI was significantly lower in patients with than without hyperbilirubinemia (P = .009), but there were no significant differences between the 2 groups in pretreatment serum albumin concentrations and FIB-4 index, an index of liver fibrosis. Hepatic enhancement with gadoxetic acid was related to Ctrough of simeprevir. Gadoxetic acid-enhanced magnetic resonance imaging may predict the development of hyperbilirubinemia during treatment of hepatitis C patients with simeprevir plus pegylated interferon and ribavirin.

Background Fatigue is a common adverse event during lenvatinib treatment in patients with hepatocellular carcinoma. One mechanism contributing to development of fatigue might involve abnormal adenosine triphosphate synthesis that is caused by carnitine deficiency. To address this possibility, we examined the relationship between carnitine levels and fatigue during lenvatinib treatment. Methods This prospective study evaluated 20 patients with hepatocellular carcinoma who underwent lenvatinib treatment. Both blood and urine samples were collected from the patients before starting lenvatinib therapy (day 0), and on days 3, 7, 14, and 28 thereafter. Plasma and urine concentrations of free and acyl carnitine (AC) were assessed at each time point. The changes in daily fatigue were evaluated using the Brief Fatigue Inventory (BFI). Results Plasma levels of free carnitine (FC) at days 3 and 7 were significantly higher compared with baseline (p = 0.005, p = 0.005, respectively). The urine FC level at day 3 was significantly higher compared with baseline (p = 0.030) and that of day 7 tended to be higher compared with baseline (p = 0.057). The plasma AC concentration at days 14 and 28 was significantly higher compared with that of baseline (p = 0.002, p = 0.005, respectively). The plasma AC-to-FC (AC/FC) ratio on days 14 and 28 was significantly higher compared with baseline (p = 0.001, p = 0.003, respectively). There were significant correlations between the plasma AC/FC ratio and the change in the BFI score at days 14 and 28 (r = 0.461, p = 0.041; r = 0.770, p = 0.002, respectively). Conclusions Longitudinal assessments of carnitine and fatigue in patients with hepatocellular carcinoma suggest that lenvatinib affects the carnitine system in patients undergoing lenvatinib therapy and that carnitine insufficiency increases fatigue. The occurrence of carnitine insufficiency may be a common cause of fatigue during the treatment.

Aim Transcatheter arterial chemoembolization (TACE) has been recognized as a treatment option for patients with intermediate hepatocellular carcinoma (HCC). This randomized, controlled study compared the local control efficacy of TACE with miriplatin (platinum monohydrate) or with epirubicin. Methods The study group consisted of 200 Japanese patients with unresectable HCC treated at the Kitasato University East Hospital (Sagamihara, Japan) between July 2010 and June 2013. The primary end-point of the study was time to tumor progression (TTP). Results We analyzed 198 patients (99 in the miriplatin group and 99 in the epirubicin group) treated with TACE. The median TTP in the epirubicin group was 5.9 months (95% confidence interval [CI], 4.8–7.0) and 7.6 months (95% CI, 5.8–9.4) in the miriplatin group. There was a significant difference between the two groups (P = 0.021; risk ratio, 1.488; 95% CI: 1.061–2.086). In the epirubicin group, 53 patients (53%) had complete response, 24 patients (24%) had partial response, 12 patients (12%) had stable disease, and 10 patients (10%) had progressive disease. In the miriplatin group, 38 patients (38%) had complete response, 41 patients (41%) had partial response, 2 patients (2%) had stable disease, and 18 patients (18%) had progressive disease. There was no significant difference in the response rate (P = 0.862). Overall incidences of adverse events and adverse drug reactions did not differ significantly between the two groups. Conclusion Miriplatin proved more effective than epirubicin in TACE for unresectable HCC. The trial described in this work has been registered under the trial number: UMIN000004790.

To investigate the current status of portal vein thrombosis (PVT) in Japan, the Clinical Research Committee of the Japan Society of Portal Hypertension undertook a questionnaire survey.A questionnaire survey of 539 cases of PVT over the previous 10 years was carried out at institutions affiliated with the Board of Trustees of the Japan Society of Portal Hypertension.The most frequent underlying etiology of PVT was liver cirrhosis in 75.3% of patients. Other causes included inflammatory diseases of the hepatobiliary system and the pancreas, malignant tumors, and hematologic diseases. The most frequent site was the main trunk of the portal vein (MPV) in 70.5%, and complete obstruction of the MPV was present in 11.5%. Among the medications for PVT, danaparoid was given to 45.8%, warfarin to 26.2%, heparin to 17.3%, and anti-thrombin III to 16.9%. Observation of the course was practiced in 22.4%. Factors contributing to therapeutic efficacy were implementation of various medications, thrombi localized to either the right or left portal vein only, non-complete obstruction of the MPV and Child-Pugh class A liver function. A survival analysis showed that the prognosis was favorable with PVT disappearance regardless of treatment.The questionnaire survey showed the current status of PVT in Japan. Any appropriate medication should be given to a patient with PVT when PVT is recognized. It is necessary to compile a large amount of information and reach a consensus on safe and highly effective management of PVT.

Aim Portal vein thrombosis (PVT) is one of the most critical disorders in liver disease patients. These patients have the imbalance of coagulation and coagulation inhibition resulting from decreased levels of coagulation inhibitory factors, such as protein C, protein S, and antithrombin III (AT-III). We designed this randomized, double-blind, placebo-controlled trial comparing the safety and efficacy of AT-III for PVT in liver disease patients with those who received no treatment. Methods Eligible patients were diagnosed with the association of thrombus, without tumor thrombus, and thrombus in more than 50% of the cross-sectional lumen of the portal vein. Patients with 70% or less serum level of AT-III were included. The study drug was given up to three times in a 5-day consecutive infusion interval if the thrombus decreased in size. Efficacy was evaluated by contrast enhanced computed tomography using a five-grade scale (complete response, partial response, slight response, no response, and progression). From October 2014 through to March 2016, 36 patients were randomly assigned to the AT-III group and 37 patients to the placebo group. Results The proportion of patients with complete response or partial response of PVT was significantly higher in the AT-III group (55.6%; 20/36 patients; 95% confidence interval, 38.1–72.1) than in the placebo group (19.4%; 7/36 patients, 95% confidence interval, 8.2–36.0) (P = 0.003). The overall incidence of adverse events and adverse drug reactions did not differ significantly between the two groups. Conclusion Antithrombin III is one of the essential therapies for patients with PVT in cases with lower concentration levels of AT-III.

A 65-year-old man was referred to our department due to repeated episodes of cholangitis in the past five years. Endoscopic retrograde cholangiopancreatography was performed, and a stricture of the lower bile duct was detected. At a later date, an irregular mucosa of the bile duct was confirmed using nasal endoscopy. Based on the biopsy results, the patient was diagnosed with bile duct cancer and subsequently underwent surgery. Postoperative histopathology did not show lymph node metastasis, and the condition was determined to be early-stage bile duct cancer. In the present case, it was presumed that the cancer had developed due to chronic cholangitis. Therefore, in patients with repeated episodes of cholangitis, attention should be focused on the possible and concomitant development of cancer.

Aim To compare the pharmacokinetics of radiofrequency (RF) ablation with chemolipiodolization using cisplatin (CDDP) powder and miriplatin (MPT) in a porcine liver. Methods Twelve pigs were divided equally into four groups. After each CDDP powder-lipiodol suspension (n = 6; groups A and B) or MPT-lipiodol suspension (n = 6; groups C and D) was injected into the lateral left artery, one RF ablation was performed at the lateral left lobe of each pig. Six pigs (groups A and C) were killed on the same day as treatment, whereas the other pigs (groups B and D) were killed 7 days after the treatment. The platinum concentrations in venous blood were assayed at 15, 60 and 120 min, and 7 days after treatment. The platinum concentrations in the ablated area and the surrounding liver were also examined. Results Plasma platinum concentrations of the CDDP group peaked at 15 min, and then gradually diminished over time (μg units), while plasma platinum levels in the MPT group gradually increased over time (ng units). Liver tissue platinum concentrations of the CDDP group were significantly lower in non-ablative areas than in ablated areas at days 0 and 7, while liver concentrations of the MPT group were significantly higher in non-ablative areas than in ablated areas at day 7. Conclusion MPT may be a suitable chemotherapeutic agent to stagnate platinum in the surrounding liver.

Background and Aim To examine the efficacy and outcomes of radiotherapy (RT) in patients who have hepatocellular carcinoma with invasion to intrahepatic large vessels (IHLVs). Methods Sixty-seven patients who had advanced hepatocellular carcinoma with invasion to IHLVs received three-dimensional conformal RT. IHLV invasion was associated with portal venous tumor thrombosis in 40 patients, tumor thrombosis involving the hepatic vein in 17, and both findings in 10. A daily radiation dose of 1.8–2 Gy was administered using 6 or 10 MV X-rays to deliver a total dose of 30–56 Gy. Results The overall objective response rate (complete response plus partial response) was 45% (n = 30). The median survival time was 13.7 months in the responder group and 5.9 months in the nonresponder group. An objective response was observed in 28 (56%) of 50 patients with Child-Pugh (C-P) class A and in 2 (12%) of 17 patients with C-P class B. Hepatic function of C-P class A was an independent factor for both RT responder and overall survival on Cox regression analysis (hazard ratio = 9.5, 95% confidence interval = 1.97–46.2, P = 0.005; and hazard ratio = 0.39, 95% confidence interval = 0.2–0.77, P = 0.007, respectively). Conclusion RT is an effective treatment option without serious adverse events. RT should be considered for the patients with better hepatic function who have invasion to IHLVs.

In order to attain better ablation and more effective management of hepatocellular carcinoma (HCC), new approaches and devices in radiofrequency ablation (RFA) therapy were presented and discussed in a workshop at the 50th Annual Meeting of the Liver Cancer Study Group of Japan. A novel bipolar RFA apparatus was introduced in Japan in January 2013. Hundreds of subjects with HCC were treated with multipolar RFA with varied devices and plans. Among these, no-touch ablation was one of the most useful procedures in the treatment of HCC with the apparatus. In RFA therapy, a few assisting devices and techniques were applied for convenience and improvement of the thermal ablation procedure. Contrast-enhanced ultrasonography and three-dimensional fusion imaging technique using volume data of CT or MRI could improve exact targeting and shorten the treatment time for RFA procedures under ultrasonographic guidance. A more complicated method using a workstation was also reported as being helpful in planning the ablated shape and volume in multineedle RFA. The effective use of sedatives and antianalgesics as well as a novel microwave apparatus with a cooled-tip electrode was also discussed.

Purpose To evaluate 90-day outcomes after balloon-occluded retrograde transvenous obliteration (BRTO) with ethanolamine oleate (EO) in patients with gastric varices (GVs). Materials and Methods An 8-site prospective single-arm clinical trial was conducted. Patients who had endoscopically confirmed GVs with a gastrorenal shunt were eligible for the study. Overnight BRTO was performed, and efficacy was evaluated by endoscopy and contrast-enhanced computed tomography (CT). Results Forty-five patients (26 men and 19 women; mean age, 67.8 y) were enrolled. The complete regression rate of GVs based on endoscopic images on day 90 was 79.5% (35 of 44 patients; 95% confidence interval, 64.7%–90.2%). The rate of complete thrombosis of GVs based on contrast-enhanced CT on day 90 was 93.0% (40 of 43 patients; 95% confidence interval, 80.9%–98.5%). One patient experienced 2 events of bleeding from GVs, which was different from the GVs treated with BRTO. Appearance of new esophageal varices (EVs) or worsening of existing EVs occurred in 16 of 45 patients (35.6%). Forty-four of 45 patients (97.8%) experienced adverse events (AEs) related to EO, which included fever in 24 (53.3%), hematuria in 23 (51.1%), hemolysis in 16 (35.6%), back pain in 16 (35.6%), and abdominal pain in 10 (22.2%). One case of moderate to severe ascites (2.3%) was observed on day 90. One case of sepsis was the only serious AE observed in relation to EO. Conclusions The present study demonstrates that BRTO with EO for the treatment of GVs is a clinically effective procedure with many mild to moderate AEs.

The indocyanine green (ICG) finger-piece method (FPM), which allows measurement of the ICG concentration by mounting a light sensor onto a finger, is used to assess liver function. We compared the ICG FPM with the conventional ICG blood sampling method (BSM) in patients with liver disorders.Ninety consecutive patients simultaneously underwent the ICG BSM and ICG FPM. After ICG administration, blood samples were collected at 5, 10, and 15 min for the ICG BSM. The ICG concentration was measured through the finger piece by an ICG clearance meter.Seventy-one patients (78.9%) had Child-Pugh class A liver disease, and 19 (21.1%) had class B or C. The FPM-measured ICG plasma disappearance rate was positively correlated with the BSM-measured values (r = 0.886, P 0.001). Bland-Altman analysis showed good agreement between the two methods (mean difference, 0.012 ± 0.018). The FPM-measured ICG plasma disappearance rate was positively correlated with the BSM-measured values both in patients with Child-Pugh class A liver disease (r = 0.821, P 0.001) and class B or C liver disease (r = 0.859, P 0.001).The ICG FPM may be an alternative to the ICG BSM for liver function assessment.

To determine the value of early alterations of the tumor markers α-fetoprotein (AFP) and des-γ-carboxy prothrombin (DCP) for predicting the outcomes of patients with advanced hepatocellular carcinoma (HCC) who receive sorafenib.Tumor response, overall survival (OS), and progression-free survival (PFS) were retrospectively analyzed in 59 patients with advanced HCC. Serum AFP and DCP were examined for early elevation within 4 weeks after the initiation of sorafenib. An increase in AFP was defined as AFP of more than 20%, and an increase in DCP was defined as more than two-fold higher level than the baseline. The relationship of the clinical characteristics, laboratory data at baseline, and early elevations of AFP and DCP with disease progression was analyzed.The median OS and PFS were 11 and 3.3 months, respectively. The rate of progressive disease (PD) was 54%, and an early increase in AFP was significantly related to PD (P=0.006) and was a significant independent predictor of both poorer OS and PFS (P0.001, hazard ratio, 4.14; 95% confidence interval, 1.946-8.811; and P=0.001, hazard ratio, 2.852; 95% confidence interval, 1.524-5.337, respectively). There was no association between early increase in DCP and clinical outcomes.Early increase in AFP predicted PD and poorer survival and may thus be a useful biomarker in patients with advanced HCC who receive sorafenib.

Treatment with terlipressin and albumin has been reported recently to be effective in improving renal function in the treatment of cirrhotic patients with hepatorenal syndrome (HRS). The aim of this prospective, multicenter study was to investigate the efficacy and safety of treatment with terlipressin and albumin in Japanese cirrhotic patients with type 1 HRS.Eight cirrhotic patients with type 1 HRS were included in the study. Terlipressin (2.8 ± 0.4 mg/day) and albumin (25.7 ± 2.8 g/day) were given simultaneously for 6.3 ± 4.2 days.Urine volume was significantly increased (p0.05) at the end of treatment compared with baseline. Serum creatinine levels were significantly decreased from 2.84 ± 0.45 to 1.08 ± 0.33 mg/dl (-61.9 ± 9.9%, p0.05) after terlipressin and albumin administration. Creatinine clearance was significantly increased (p0.05) after treatment. Plasma renin activity and norepinephrine were significantly decreased (p0.05) after therapy. Six of the 8 patients (75%) showed a complete response (reduction of serum creatinine to 1.5 mg/dl or less). The cumulative probabilities of survival at 4 and 12 weeks were 63 and 13%, respectively. Complication of congestive heart failure possibly related to this regimen was seen in 1 patient, but ischemic adverse events were not observed during the treatment.Treatment with terlipressin and albumin improves renal function in cirrhotic patients with type 1 HRS. However, the survival of cirrhotic patients with type 1 HRS remains poor, although it may be improved by this specific therapy.

Aim: The aim of this study was to evaluate the feasibility of gadolinium ethoxybenzyl diethylene triamine pentaacetic acid (Gd-EOB-DTPA) in magnetic resonance imaging (MRI) to assess the ablative margin of radiofrequency (RF) ablation to hepatocellular carcinoma (HCC). Methods: RF ablation was performed in the livers of six pigs after the i.v. administration of Gd-EOB-DTPA 20 min before ablation. Three pigs were killed 2 h after administration (group A), and the other pigs were killed 7 days after ablation (group B). Thereafter, correlation between pathological findings and MRI was investigated. Moreover, the Gd concentrations were examined in ablated and non-ablated regions. An initial clinical evaluation was conducted for 28 HCC nodules. Percutaneous RF ablation was performed 20 min after administration, and T1-weighted images were taken 2, 24 and 72 h post-treatment. Results: On T1-weighted images of the porcine liver, the RF ablated lesions showed hyperintense regions with hypointense rims, which histopathologically corresponded to sinusoidal congestion. The Gd concentrations in ablated regions in group A were significantly higher than those in non-ablated regions, while the concentrations in both regions in group B fell to nearly undetectable levels. In 27 of the 28 HCC nodules, the treated area consisted of a hypointense region, indicative of the tumor, and a surrounding hyperintense rim 2 h after ablation. Subsequently, a thin hypointense region was observed in the outermost layer 24 and 72 h after ablation. Conclusion: Administration of Gd-EOB-DTPA in conjunction with RF ablation of HCC may be feasible for the assessment of an accurate ablative margin.

Aim: We prospectively evaluated the reliability and validity of splenic volume with 3-D ultrasound measurement and clarified its clinical usefulness. Methods: Thirty healthy volunteers and 30 patients with cirrhosis were included in this study. All 3-D ultrasound examinations of splenic volumes were performed twice by two experienced sonographers with transabdominal ultrasound using virtual organ computer-aided analysis (VOCAL). Reliability was confirmed among all subjects by evaluating within-observer repeatability and between-observer reproducibility using intraclass correlation coefficients (ICC) and Bland–Altman plots. Overall between-instrument agreement of the measurements and computed tomography (CT) volumetry among cirrhotic patients were performed to determine validity. Results: For all 240 examinations, 3-D ultrasound visualization and measurement of the spleen volume was possible. Mean spleen volume was 104.0 mL for the volunteers and 283.5 mL for the cirrhotic patients. The repeatability was high, with ICC (95% confidence interval) of 0.996 (0.993–0.997) for observer A and 0.997 (0.994–0.998) for observer B. Moreover, the interobserver ICC was 0.996, indicating high reproducibility. Despite the difference in volume between the volunteers and cirrhotic patients, sensitivity analyses indicated consistent results for both groups. Regarding the validity of the 3-D ultrasound measurement, it also showed moderate to high agreement with CT volumetry, with mean ICC of 0.922 and 0.924 for observers A and B, respectively. The reliability and validity results from the Bland–Altman plots were similar to those from the ICC, with limits of agreement consistently narrow from a clinically practical view. Conclusion: 3-D ultrasound measurements using VOCAL are valid and reliable in spleen volume examinations.

Aim: The Clinical Research Committee of the Japan Society for Portal Hypertension has conducted a nationwide questionnaire survey to clarify the current status of ectopic varices in Japan. Methods: A total of 173 cases of ectopic varices were collected. Results: Duodenal varices were found in 57 cases, and most of them were located in the descending to transverse parts. There were 11 cases of small intestinal varices and 6 cases of colonic varices, whereas 77 patients had rectal varices, accounting for the greatest proportion (44.5%). Other sites of varices were the biliary tract, anastomotic sites, the stoma, and the diaphragm. Liver cirrhosis was the most frequent diseases (80.3%) underlying ectopic varices. It was noted that patients with rectal varices frequently had a history of esophageal varices (94.8%) and received endoscopic treatment (87.0%). The treatments for ectopic varices were as an emergency in 46.5%, elective in 35.4% and prophylactic in 18.2%. In emergency cases, endoscopic therapy was most frequent (67.4%), followed by interventional radiology (IVR; 15.2%), and endoscopy-IVR combination (6.5%). Elective treatment was performed by endoscopy in 34.3%, IVR in 28.6%, combined endoscopy-IVR in 5.7%, and surgical operation in 25.7%. The prophylactic treatment was endoscopic in 50.0%, IVR in 33.3%, combined treatments in 11.1%, and prophylactic surgery in none. The change of ectopic varices after treatment was disappearance in 54.9%, remnant in 35.4% and recurrence in 9.7%. The rate of disappearance was significantly lower in rectal varices (40.8%) than in duodenal varices (73.4%). The patient outcome did not differ among the various sites of the lesion. Conslusions: Current status of ectopic varices in Japan has been clarified by a nationwide questionnaire survey. The authors expect that the pathophysiology of ectopic varices will be further elucidated, and that improved diagnostic modalities and treatment methods are established in the future.

General rules for recording endoscopic findings of esophageal varices were initially proposed in 1980 and revised in 1991. These rules have widely been used in Japan and other countries. Recently, portal hypertensive gastropathy has been recognized as a distinct histological and functional entity. Endoscopic ultrasonography can clearly depict vascular structures around the esophageal wall in patients with portal hypertension. Owing to progress in medicine, we have updated and slightly modified the former rules. The revised rules are simpler and more straightforward than the former rules and include newly recognized findings of portal hypertensive gastropathy and a new classification for endoscopic ultrasonographic findings.

A 73-year-old woman had sudden dystrophy and amnesia in our hospital. Her serum ammonia level was high. Marked collateral vessels from the splenic vein to the left renal vein around the spleen were seen on a computed tomography (CT) scan with contrast enhancement. An abdominal angiogram showed that the direction of the splenic vein was hepatofugal on superior mesenteric arterial portography, with a marked splenorenal shunt on splenic arterial portography. Hepatic encephalopathy due to a marked extrahepatic portal-systemic shunt was diagnosed. Transjugular retrograde obliteration (TJO) was attempted, but the catheter and guide wire could not selectively approach the splenorenal shunt because of many outflow routes. We punctured the vessels from the left side of the back under ultrasonographic guidance. We injected microcoils and ethanolamine oleate to completely obliterate the shunt. Marked collateral vessels showed no venous flow on a CT scan after treatment. The serum ammonia level was in the normal range. There has been no recanalization of the shunt vessels for 4 years after treatment. Hepatic encephalopathy has not recurred, and no other collateral vessels have developed. To our knowledge, this is the first report to document the use of a percutaneous transretroperitoneal direct approach to occlude a major shunt in a patient with extrahepatic portal-systemic encephalopathy.

Background. The pathogenesis of frequent intrahepatic recurrence of hepatocellular carcinoma (HCC) after surgical resection or local ablation therapy remains uncertain. Risks and patterns of intrahepatic distant recurrence (IDR) of a single, primary HCC lesion after radiofrequency (RF) ablation were examined. Methods. Ninety patients with a single primary HCC lesion of less than 3 cm who had complete RF ablation were enrolled in the study. Risk factors for IDR and the patterns of IDR after RF ablation were analyzed. Results. The median follow-up was 37.4 months. IDR was observed in 44 (48.9%) patients. The cumulative rate of IDR was 10.4%, 52.5%, and 77.0% at 1, 3, and 5 years, respectively. Univariate analysis revealed that a pretreatment serum α-fetoprotein (AFP) level of ≥50 ng/ml (P = 0.0324), a des-γ-carboxy prothrombin (DCP) level of ≥40 mAu/ml (P = 0.006), an ablative margin of

OBJECTIVE. To identify the determinants of tumor progression, we examined the ablation zones and patterns of local progression of small single primary hepatocellular carcinomas after radiofrequency ablation. MATERIALS AND METHODS. Eighty-five patients with single primary hepatocellular carcinoma less than 3 cm in diameter underwent complete tumor ablation. Clinical and biochemical features, tumor characteristics, tumor location within 5 mm from intrahepatic vessels, needle biopsy before treatment, and presence of ablative margin of 5 mm or more were statistically analyzed as determinants of local tumor progression. The Kaplan-Meier method and a Cox model were used for the analyses. Patterns of local tumor progression were examined by image analysis. RESULTS. During a median observation period of 30.3 months, 14 (16.5%) of the 85 patients had local tumor progression. The results of the log-rank test showed that the presence of vessels contiguous with the tumor (p = 0.0292) and the absence of an ablative margin of at least 5 mm (p = 0.019) significantly correlated with local tumor progression. Cox regression analysis showed that the absence of an ablative margin of at least 5 mm was an independent factor (p = 0.04). The most common pattern of local tumor progression was a single viable outgrowth from the side of the ablated area when the ablative margin was less than 5 mm. Multiple viable outgrowths were observed in one case despite the presence of an ablative margin greater than 5 mm. CONCLUSION. An ablation zone with an ablative margin of 5 mm or greater was the most important factor for local control of hepatocellular carcinoma.

Nodular regenerative hyperplasia of the liver (NRH) is known to be a rare condition in patients with connective tissue diseases (CTD). In this report, we document three patients with CTD who had both NRH and pulmonary hypertension (PH). All three patients developed PH during their course and thereafter developed NRH. The clinical course of these patients suggests that circulatory disturbance caused by PH might be a trigger for NRH.

We examined whether sustained alleviation of inflammation as monitored by serum alanine aminotransferase (ALT) levels was associated with longer survival in hepatectomized hepatocellular carcinoma (HCC) patients with hepatitis C virus-associated liver cirrhosis (HCV-LC). Thirty-four hepatectomized patients with HCV-LC and HCC as a single nodule, and for whom more than 5 years had elapsed after the hepatectomy, were studied. They had no histologic evidence of portal or hepatic vein invasion. They were subdivided into two groups according to their serum ALT levels in the 2 years after hepatectomy: the low ALT group comprised 13 patients whose serum ALT levels showed a sustained low level below 80 IU, and the high ALT group comprised 21 patients whose serum ALT levels showed several peaks or plateaus above 80 IU. The patients had been followed-up prospectively with frequent ultrasonography and magnetic resonance imaging or computed tomography for recurrence for > 5 years. The survival period, non-recurrence interval and number of recurrences were observed. Recurrences were treated with transcatheter chemoembolization in all cases. The cumulative survival rate in the low ALT group was significantly better than that in the high ALT group (P < 0.05). The 5-year survival in the low ALT group was as high as 92.3% (12 of 13) compared with 33.3% (7 of 21) in the high ALT group (P < 0.05). The cumulative non-recurrence rate in the low ALT group was also significantly better than that in the high ALT group (P < 0.01). The survival period correlated well with the interval until the first recurrence (r = 0.545, P = 0.006). There was a tendency for the number of recurrences in the low ALT group (1.5 +/- 0.4, mean +/- SE) to be fewer than that in the high ALT group (2.2 +/- 0.4), although this was not significant. Sustained alleviation of inflammation, as indicated by low ALT levels, provides a survival advantage mainly due to the longer non-recurrence interval, and possibly because of fewer recurrences, in hepatectomized HCC patients with HCV-LC.

Background This study investigated the survival benefits of sorafenib vs. radiotherapy (RT) in patients with unresectable hepatocellular carcinoma (HCC) and portal vein tumor thrombosis (PVTT) in the main trunk or the first branch. Methods Ninety-seven patients were retrospectively reviewed. Forty patients were enrolled by the Kanagawa Liver Study Group and received sorafenib, and 57 consecutive patients received RT in our hospital. Overall survival was compared between the two groups with PVTT by propensity score (PS) analysis. Factors associated with survival were evaluated by multivariate analysis. Results The median treatment period with sorafenib was 45 days, while the median total radiation dose was 50 Gy. The Child-Pugh class and the level of invasion into hepatic large vessels were significantly more advanced in the RT group than in the sorafenib group. Median survival did not differ significantly between the sorafenib group (4.3 months) and the RT group (5.9 months; P = 0.115). After PS matching (n = 28 per group), better survival was noted in the RT group than in the sorafenib group (median survival, 10.9 vs. 4.8 months; P = 0.025). A Cox model showed that des-γ-carboxy prothrombin

Aim: This study aimed to investigate whether genetic polymorphisms of the organic anion transporting polypeptides influence hepatic enhancement in gadoxetic acid-enhanced MRI. Patients & methods: We analyzed the genotypes of SLCO1B1 388A>G, SLCO1B1 521T>C, SLCO1B3 334T>G and NR1H4 -1G>T and calculated the mean quantitative liver–spleen contrast ratio, as an index of liver parenchymal enhancement, in 226 patients with liver disease. Results: Multiple linear regression analysis using the mean quantitative liver–spleen contrast ratio as the dependent variable revealed that not only Child–Pugh score, but also SLCO1B1*1b haplotype (β = 0.12; p = 0.04), were significant predictors of liver parenchymal enhancement. In addition, SLCO1B3 334T>G (β = -0.18; p = 0.03) was a significant predictor when the data were analyzed in a subgroup of 117 patients, excluding the carriers of NR1H4 -1G>T, who reportedly exhibit reduced transcriptional activity of SLCO1B3. Conclusion: These genetic variants, as well as hepatic function, may contribute to individual differences in hepatic enhancement with gadoxetic acid. Original submitted 4 March 2013; Revision submitted 10 July 2013

We investigated whether or not a high serum alanine aminotransferase (ALT) level is associated with a more rapid recurrence of hepatocellular carcinoma (HCC) in hepatectomized patients with hepatitis C virus (HCV)-associated liver cirrhosis (LC) (HCV-LC) and HCC. Thirty-three hepatectomized patients with HCV-LC and HCC of a single nodule who had no histologic evidence of portal or hepatic vein invasion and who had been followed up for more than 3 years were included in the study. They were subdivided into two groups according to their serum ALT levels, ALT being a well-known marker of inflammatory necrosis in the liver. Seventeen patients whose serum ALT levels showed several peaks or plateaus above 80 international units (IU) were designated as the high ALT group, and 16 patients whose serum ALT levels showed a sustained low level below 80 IU until the first recurrence were designated as the low ALT group, and the interval between hepatectomy and the first recurrence was observed. In the high ALT group, HCC recurred within 3 years in 70.6% of the patients. In contrast, it recurred in only 18.8% of the low ALT group within the same period (p < 0.05). There was a significant difference (p = 0.0201) between the two groups in the cumulative nonrecurrence rate. The mean interval in recurrent patients between hepatectomy and the first recurrence in the high ALT group (23.6 ± 2.8 months; mean ± SE) was significantly (p < 0.02) shorter than that in the low ALT group (49.3 ± 9.7 months). The expected interval between hepatectomy and recurrence was as short as 2.8 ± 0.5 years (mean ± SE) in the high ALT group, compared with 5.8 ± 0.7 years in the low ALT group (p < 0.05). These results showed that the recurrence of HCC was accelerated in the high ALT group, suggesting that suppression of the rise in ALT level after hepatectomy by treatment with anti-inflammatory drugs may prolong the interval until recurrence by about 2 years in hepatectomized patients with HCC and HCV-LC.