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The association between thrombolytic therapy and the outcome in patients with portal vein thrombosis (PVT) remains controversial. This study aimed to evaluate the outcome in patients with PVT who received antithrombin III-based therapy.This study was a retrospective, multicenter study to investigate the liver-related events and the survival rates in 240 patients with PVT who received the therapy.The patients comprised 151 men and 89 women, with a median age of 69 years. The rate of favorable response, defined as maximum area of PVT changed to ≤75%, was 67.5% (162/240). The cumulative rates of liver-related events at 1, 2, and 3 years were 38.2%, 53.9%, and 68.5%, respectively. The multivariate analysis showed that viable hepatocellular carcinoma, absence of maintenance therapy, non-responder, and PVT progression were significantly associated with liver-related events. The PVT progression was observed in 23.3% (56/240). The multivariate analysis identified older age, absence of maintenance therapy, and non-responder as independent factors associated with PVT progression. The multivariate analysis revealed that younger age, no hepatocellular carcinoma, presence of maintenance therapy, and lower Model for End-stage Liver Disease-Sodium score significantly contributed to 3-year survival. Of the 240 patients, 13 (8.9%) prematurely discontinued treatment due to any adverse events.This study suggests that maintenance therapy, favorable response, and absence of PVT progression may suppress or control liver-related events in antithrombin III-based therapy for patients with PVT. Specifically, maintenance therapy could suppress not only liver-related events, but also PVT progression and improve the prognosis.

There are various types of pancreatic neoplasms, and their prognosis and treatment methods are different. Therefore, accurate diagnosis is important to determine the best treatment strategy. Transabdominal ultrasonography is frequently used as a screening examination for diagnostic imaging of pancreatic neoplasms. In this review, we have focused on the characteristics of ultrasonic findings for relatively rare pancreatic neoplasms.

Background The clinical characteristics of IgG4-related sclerosing cholangitis (IgG4-SC) especially without autoimmune pancreatitis (AIP) have not been investigated in a large cohort. Aims To clarify the clinical characteristics of IgG4-SC and IgG4-SC without AIP. Methods We retrospectively reviewed imaging, serology, other organ involvement (OOI) and histology of 872 patients with IgG4-SC who participated in a Japanese nationwide survey in 2019, and compared these items between IgG4-SC with and without AIP. Results AIP was present in 83.7% (730/872) of IgG4-SC. In IgG4-SC, bile duct wall thickening was observed on ultrasound (528/650; 81.2%), computed tomography (375/525; 71.4%) and magnetic resonance imaging or cholangiopancreatography (290/440; 65.9%). An elevated serum IgG4 level (≥ 135 mg/dL) was found in 88.0% (322/366). IgG4-related OOI other than AIP was observed in 25.2% (211/836). The proportion of females was significantly higher in IgG4-SC without AIP (28.9% vs. 20.1%; p = 0.025). Hilar stricture was the most common cholangiographic type in IgG4-SC without AIP (39/107; 36.4%).There were no significant differences between IgG4-SC with and without AIP in the rates of bile duct wall thickening, elevated serum IgG4 level, or IgG4-related OOI. Conclusions The clinical characteristics of IgG4-SC was similar between IgG4-SC with and without AIP in a large cohort.

Background and Aim This study investigated the efficacy of transcatheter arterial infusion (TAI) chemotherapy with cisplatin combined with transcatheter arterial chemoembolization (TACE). The goal was to prevent intrahepatic distant recurrence (IDR) of hepatocellular carcinoma (HCC), compared with TACE alone, in patients with unresectable HCC. Methods We conducted a historical cohort study, which involved 68 unresectable HCC patients. The study was performed on 44 and 24 consecutive patients who underwent TAI using cisplatin combined with TACE using epirubicin and TACE using epirubicin alone, respectively. We performed a propensity score analysis to identify the independent risk factors associated with IDR, and constructed propensity score‐adjusted survival curves. Results After propensity score‐adjusting, the adjusted cumulative IDR rates at 1 and 3 years were 76.8 and 76.8% in TACE alone group, and 21.3 and 73.1% in TACE with TAI group, respectively. TACE alone group had a significantly higher IDR rate in comparison with TACE with TAI group (P = 0.0073). Combined with TAI was associated with preventing IDR after propensity score‐adjusting (hazard ratio [HR] 0.40, 95% confidence intervals [CI] 0.17–0.91, P = 0.028). Combined with TAI (HR 0.26, 95% CI 0.10–0.68, P = 0.0056) and Stage ≥III (HR 2.98, 95% CI 1.25–7.12, P = 0.014) were independent IDR predictors after adjusting for significant risk factors with propensity score. Conclusions We demonstrated that cisplatin TAI accompanied with TACE decreased IDR compared with TACE alone. Our findings suggest that cisplatin TAI might contribute to a longer progression‐free period in unresectable HCC patients treated with TACE., Transcatheter arterial infusion (TAI) chemotherapy with cisplatin in combination with transcatheter arterial chemoembolization (TACE) decreases intrahepatic distant recurrence of unresectable hepatocellular carcinoma (HCC). These findings suggest that cisplatin TAI might contribute to a longer progression‐free period in unresectable HCC patients treated with TACE.

Background Measurement of the tricuspid regurgitation pressure gradient (TRPG) by echocardiography is recommended as the most objective examination for the detection of portopulmonary hypertension (PoPH). This prospective study aimed to identify factors associated with a high TRPG in patients with cirrhosis and develop a screening method for identifying patients most likely to benefit from investigation with echocardiography.Results Four hundreds and eighty-six patients with cirrhosis underwent Doppler echocardiography, and were analyzed in the present study. Of the 486 patients, 51 (10.5%) had TRPG ≥35 mmHg. The median BNP was 39.5 (range, 3.3–712.0) pg/mL. Ninety-one (18.7%) patients reported shortness of breath. Multivariate analysis identified female, shortness of breath, and BNP ≥49 pg/mL as independent factors for TRPG ≥35 mmHg. The risk score for predicting TRPG ≥35 mmHg was calculated: risk score = −3.230 + 0.622 × gender (female: 1, male: 0) + 1.403 × shortness of breath (presence: 1, absence: 0) + 0.726 × BNP (≥ 49pg/mL: 1, −8).Conclusions We clarified the characteristics of patients with suspected PoPH, and developed a scoring model for identifying patients at high risk of PoPH, which may have utility in selecting patients with cirrhosis that may benefit from echocardiography.

Background Endoscopic papillectomy of duodenal papillary tumors (PT) is indicated for adenomas or well-differentiated adenocarcinomas that do not involve the sphincter of Oddi. However, there is currently no reliable pre-operative method to diagnose the infiltration in the sphincter of Oddi.’ Insulin-like growth factor 2 mRNA protein 3 (IMP3) staining is reportedly associated with advanced disease stage and clinical outcomes in many carcinomas. The aim of this retrospective study was to investigate the ability of diagnosing sphincter of Oddi involvement in PT and predicting the prognoses using IMP3 immunohistochemistry. Methods Twenty-five resected specimens from patients with PT and 24 biopsy specimens from the same patients excluding one were immunostained for IMP3. The percentage of positive cells in the tumor was evaluated and compared with the final pathological diagnosis and prognosis. Results The final pathological diagnoses were adenoma in 5 patients and adenocarcinoma in 20 patients (no sphincter of Oddi involvement in 5 and involvement in 15). The ability to diagnose sphincter of Oddi involvement based on the percentage of IMP3-positive cells in resected specimens and tissue biopsies was the area under the curve 0.8 and 0.78, respectively, of the receiver operating characteristic curve, and the accuracies were 80.0% and 75.0% (cutoff value: 10%), respectively. Moreover, patients with an IMP3-positive cell rate of ≥ 10% had a significantly worse prognosis (log-rank test P = 0.01). Conclusion IMP3 immunostaining of resected and biopsy specimens from PT patients enables the diagnosis of sphincter of Oddi involvement objectively and is also effective in predicting the prognosis.

(1) Background: This study aimed to investigate clinical outcomes for cabozantinib in clinical practice in patients with advanced hepatocellular carcinoma (HCC) previously treated with atezolizumab plus bevacizumab (Atz/Bev), with a focus on whether patients met criteria of Child–Pugh Class A and Eastern Cooperative Oncology Group performance status (ECOG-PS) score 0/1 at baseline. (2) Methods: Eleven patients (57.9%) met the criteria of both Child–Pugh class A and ECOG-PS score 0/1 (CP-A+PS-0/1 group) and eight patients (42.1%) did not (Non-CP-A+PS-0/1 group); efficacy and safety were retrospectively evaluated. (3) Results: Disease control rate was significantly higher in the CP-A+PS-0/1 group (81.1%) than in the non-CP-A+PS-0/1 group (12.5%). Median progression-free survival, overall survival and duration of cabozantinib treatment were significantly longer in the CP-A+PS-0/1 group (3.9 months, 13.4 months, and 8.3 months, respectively) than in the Non-CP-A+PS-0/1 group (1.2 months, 1.7 months, and 0.8 months, respectively). Median daily dose of cabozantinib was significantly higher in the CP-A+PS-0/1 group (22.9 mg/day) than in the non-CP-A+PS-0/1 group (16.9 mg/day). (4) Conclusions: Cabozantinib in patients previously treated with Atz/Bev has potential therapeutic efficacy and safety if patients have good liver function (Child–Pugh A) and are in good general condition (ECOG-PS 0/1).

Background: Rifaximin is commonly used for hepatic encephalopathy (HE). However, the effects of long-term treatment for Japanese people are limited. Therefore, this study aimed to investigate the effects and safety of long-term treatment with rifaximin on HE. Methods: A total of 215 patients with cirrhosis administered with rifaximin developed overt or covert HE, which was diagnosed by an attending physician for >12 months. Laboratory data were extracted at pretreatment and 3, 6, and 12 months after rifaximin administration. The long-term effect of rifaximin was evaluated, and the incidence of overt HE during 12 months and adverse events was extracted. Results: Ammonia levels were significantly improved after 3 months of rifaximin administration and were continued until 12 months. There were no serious adverse events after rifaximin administration. The number of overt HE incidents was 9, 14, and 27 patients within 3, 6, and 12 months, respectively. Liver enzymes, renal function, and electrolytes did not change after rifaximin administration. Prothrombin activity is a significant risk factor for the occurrence of overt HE. The serum albumin, prothrombin activity, and albumin–bilirubin (ALBI) scores were statistically improved after 3 and 6 months of rifaximin administration. Moreover, the same results were obtained in patients with Child–Pugh C. Conclusions: The long-term rifaximin treatment was effective and safe for patients with HE, including Child–Pugh C.

ObjectiveThis trial compared the efficacy and safety of transarterial chemoembolisation (TACE) plus sorafenib with TACE alone using a newly established TACE-specific endpoint and pre-treatment of sorafenib before initial TACE.DesignPatients with unresectable hepatocellular carcinoma (HCC) were randomised to TACE plus sorafenib (n=80) or TACE alone (n=76). Patients in the combination group received sorafenib 400 mg once daily for 2–3 weeks before TACE, followed by 800 mg once daily during on-demand conventional TACE sessions until time to untreatable (unTACEable) progression (TTUP), defined as untreatable tumour progression, transient deterioration to Child-Pugh C or appearance of vascular invasion/extrahepatic spread. Co-primary endpoints were progression-free survival (PFS), which is not a conventional one but defined as TTUP, or time to any cause of death plus overall survival (OS). Multiplicity was adjusted by gatekeeping hierarchical testing.ResultsMedian PFS was significantly longer in the TACE plus sorafenib than in the TACE alone group (25.2 vs 13.5 months; p=0.006). OS was not analysed because only 73.6% of OS events were reached. Median TTUP (26.7 vs 20.6 months; p=0.02) was also significantly longer in the TACE plus sorafenib group. OS at 1 year and 2 years in TACE plus sorafenib group and TACE alone group were 96.2% and 82.7% and 77.2% and 64.6%, respectively. There were no unexpected toxicities.ConclusionTACE plus sorafenib significantly improved PFS over TACE alone in patients with unresectable HCC. Adverse events were consistent with those of previous TACE combination trials.Trial registration numberNCT01217034.

Objective The present study aimed to elucidate the effect of switching from branched-chain amino acid granules to branched-chain amino acid-enriched nutrient in patients with cirrhosis with hypoalbuminemia. Methods Twenty-six patients with cirrhosis with hypoalbuminemia despite treatment with branched-chain amino acid granules containing 12 g of branched-chain amino acid were enrolled in the prospective study. The branched-chain amino acid-enriched nutrient and control groups were composed of 16 and 10 patients, respectively. The patients in branched-chain amino acid-enriched nutrient group switched to branched-chain amino acid-enriched nutrient mixture containing 12.2 g of branched-chain amino acid and 410 kcal with a half of it consumed as a late evening snack, and the patients in the control group continued branched-chain amino acid granules. Laboratory data related to nutrition parameter were assessed at baseline, 3 months after baseline, and at 6 months after baseline. Results Two patients were withdrawn; hence, nine and 15 patients in the branched-chain amino acid granules and branched-chain amino acid-enriched nutrient groups, respectively, were subjected to full analysis. Serum albumin levels and total lymphocyte counts in both groups did not change in the study period. The branched-chain amino acid-to-tyrosine ratio in the branched-chain amino acid-enriched nutrient group significantly increased from baseline to 6 months after baseline (P = 0.030), whereas that in the control group did not increase. Conclusion Switching from branched-chain amino acid granules to branched-chain amino acid-enriched nutrients improves branched-chain amino acid-to-tyrosine ratio in patients with cirrhosis with hypoalbuminemia.

The present study evaluated the efficacy and safety of ramucirumab (RAM) in clinical practice as post-treatment, following atezolizumab plus bevacizumab (Atz/Bev) for advanced hepatocellular carcinoma (HCC) with alpha-fetoprotein (AFP) levels of ≥400 ng/ml.Of the 77 patients treated with Atz/Bev at our institution, 13 patients for whom RAM was introduced as post-treatment following Atz/Bev were enrolled in this retrospective study. There were 9 patients (69.2%) with Child-Pugh A and 11 patients (84.6%) for whom RAM was initiated as 3The objective response rate by Response Evaluation Criteria in Solid Tumours at 6 weeks was 15.4%, and the disease control rate was 69.2%. The median time to progression was 3.0 months; AFP level decreased at 2 weeks in 11 patients (84.6%) and at 6 weeks in seven patients (53.8%). The most common adverse events (AEs) within 6 weeks were ascites, peripheral oedema, and proteinuria, while grade 3 AEs occurred in six patients (46.2%). Albumin-bilirubin scores at both 4 and 6 weeks were significantly worse than those at baseline.In HCC patients with AFP levels of ≥400 ng/mL, RAM after Atz/Bev is expected to be an effective treatment option. Careful attention should be paid to the development of AEs and deterioration of liver function, especially when RAM is used as 3

Pancreatic neuroendocrine neoplasms (PNENs) are relatively rare with a reported incidence of 1-2/100,000 and generally thought to originate from the precursor of the neuroendocrine cells including the islet and the pancreatic duct cells. About 65% of PNENs are non-functional. While insulinomas and gastrinomas are the most common functional PNENs, ACTH-producing PNENs are extremely rare. We herein present an extremely rare case of a patient with Cushing's syndrome caused by PNEN. A 46-year-old woman with edema in bilateral lower extremities and moon face was admitted with a suspicious pancreatic tumor. Enhanced computed tomography and endoscopic ultrasonography revealed a pancreatic tumor. The final diagnosis of ACTH-producing PNEN with Cushing's syndrome was based on clinical and biochemical test results and endocrinological studies. The symptoms associated Cushing's syndrome improved after pancreaticoduodenectomy for PNEN.

Gallbladder (GB) diseases represent various lesions including gallstones, cholesterol polyps, adenomyomatosis, and GB carcinoma. This review aims to summarize the role of endoscopic ultrasound (EUS) in the diagnosis of GB lesions. EUS provides high-resolution images that can improve the diagnosis of GB polypoid lesions, GB wall thickness, and GB carcinoma staging. Contrast-enhancing agents may be useful for the differential diagnosis of GB lesions, but the evidence of their effectiveness is still limited. Thus, further studies are required in this area to establish its usefulness. EUS combined with fine-needle aspiration has played an increasing role in providing a histological diagnosis of GB tumors in addition to GB wall thickness.

Introduction: The aim of this study was to investigate the early changes in alpha-fetoprotein (AFP) and des-γ-carboxy prothrombin (DCP) levels in patients with advanced hepatocellular carcinoma (HCC) treated with atezolizumab plus bevacizumab and to evaluate the relationship between changes in these tumor markers and treatment efficacy. Methods: Of 58 consecutive patients who started atezolizumab plus bevacizumab at our institution, 50 patients with information on antitumor response obtained at 6 weeks after therapy were enrolled in this study and their treatment outcomes were retrospectively evaluated. Results: According to the Response Evaluation Criteria in Solid Tumors at 6 weeks, the objective response (OR) rate was 22.0% and the disease control (DC) rate was 78.0%. In patients who achieved OR at 6 weeks, median AFP and DCP ratios at weeks 1, 2, 3, and 6 were significantly lower than those in patients who did not achieve OR. AFP ratios in patients who did not achieve DC at 6 weeks (Non-6W-DC group) were significantly higher than in those who achieved DC at week 6 (6W-DC group). Median overall survival in the Non-6W-DC group was significantly shorter than in the 6W-DC group (156 days vs. not reached, p = 0.0008). An AFP ratio of 1.4 or higher at 3 weeks had a specificity of 88.0% and a sensitivity of 88.9% for predicting Non-6W-DC. Median progression-free survival was significantly shorter in patients with an AFP ratio of 1.4 or higher at 3 weeks than in those with an AFP ratio of p = 0.0003). Conclusion: Early changes in AFP might be useful for predicting the antitumor efficacy of atezolizumab plus bevacizumab in patients with advanced HCC. An AFP ratio of 1.4 or higher at 3 weeks might be an early predictor of refractoriness to atezolizumab plus bevacizumab therapy.

Pancreatic cystic lesions (PCLs) are incidental findings that are being increasingly identified because of recent advancements in abdominal imaging technologies. PCLs include different entities, with each of them having a peculiar biological behavior, and they range from benign to premalignant or malignant neoplasms. Therefore, accurate diagnosis is important to determine the best treatment strategy. As transabdominal ultrasonography (US) is noninvasive, inexpensive, and widely available, it is considered to be the most appropriate imaging modality for the initial evaluation of abdominal diseases, including PCLs, and for follow-up assessment. We present a review of the possibilities and limits of US in the diagnosis of PCLs, the technical development of US, and the ultrasonographic characteristics of PCLs.

Background/Aim: The aim of this study was to investigate the outcomes of atezolizumab plus bevacizumab in patients with advanced hepatocellular carcinoma (HCC), including those with disease refractory to lenvatinib, in clinical practice. Patients and Methods: Of 34 patients treated with atezolizumab plus bevacizumab, a total of 23, including 16 with lenvatinib failure, were enrolled in this retrospective study. The adverse events, changes in liver function and antitumor responses at 6 weeks after starting therapy were evaluated. Results: The incidence of grade 3 adverse events was low, at 13.0%. Albumin–bilirubin scores did not worsen at 3 and 6 weeks compared to baseline. The objective response rate and disease control rate at 6 weeks were 17.4% and 78.3% according to Response Evaluation Criteria in Solid Tumors (RECIST), and 30.4% and 78.3% according to modified RECIST, respectively. Conclusion: Our results suggest that atezolizumab plus bevacizumab might have potential therapeutic safety and efficacy in patients with advanced HCC, including those with disease refractory to lenvatinib. Further studies are needed to confirm the outcomes of atezolizumab plus bevacizumab after lenvatinib failure.

Type 2 diabetes (T2D) is associated with diabetic nephropathy as well as nonalcoholic steatohepatitis (NASH), which can be called “diabetic hepatopathy or diabetic liver disease”. NASH, a severe form of nonalcoholic fatty disease (NAFLD), can sometimes progress to cirrhosis, hepatocellular carcinoma and hepatic failure. T2D patients are at higher risk for liver-related mortality compared with the nondiabetic population. NAFLD is closely associated with chronic kidney disease (CKD) or diabetic nephropathy according to cross-sectional and longitudinal studies. Simultaneous kidney liver transplantation (SKLT) is dramatically increasing in the United States, because NASH-related cirrhosis often complicates end-stage renal disease. Growing evidence suggests that NAFLD and CKD share common pathogenetic mechanisms and potential therapeutic targets. Glucagon-like peptide 1 (GLP-1) receptor agonists and sodium–glucose cotransporter 2 (SGLT2) inhibitors are expected to ameliorate NASH and diabetic nephropathy/CKD. There are no approved therapies for NASH, but a variety of drug pipelines are now under development. Several agents of them can also ameliorate diabetic nephropathy/CKD, including peroxisome proliferator-activated receptors agonists, apoptosis signaling kinase 1 inhibitor, nuclear factor-erythroid-2-related factor 2 activator, C-C chemokine receptor types 2/5 antagonist and nonsteroidal mineral corticoid receptor antagonist. This review focuses on common drug pipelines in the treatment of diabetic nephropathy and hepatopathy.

Background and aim The image-based diagnosis of pancreatic diseases can be difficult and requires pathological evaluation. Probe-based confocal laser endomicroscopy (pCLE) enables real-time observation of the microscopic tissue pattern of lesion and may be a useful assistance for the diagnosis. This study aimed to evaluate the feasibility and utility of pCLE for the diagnosis of pancreatic diseases. Methods Thirty patients who underwent endoscopic retrograde cholangiopancreatography with pCLE for the evaluation of indeterminate pancreatic diseases from June 2015 to October 2018 were included in this study. The pCLE findings were interpreted according to the Miami Classification. Results Among a total of 30 patients, 12, 10, 4, and 4 patients received the definitive diagnoses of pancreatic ductal adenocarcinoma (PDAC), main duct intrapapillary mucinous neoplasm, autoimmune pancreatitis, and chronic pancreatitis, respectively. The diagnostic accuracy of pCLE for PDAC and pancreatitis (96.7% and 93.3%, respectively) was higher than that of cytology (76.7% and 63.3%, respectively) (P = 0.0227 and 0.0048, respectively). The sensitivity of pCLE for PDAC was significantly higher (91.7%) than that of cytology (41.7%) (P = 0.0094). Moreover, the specificity of pCLE for pancreatitis was significantly higher than that of cytology (90.9% vs 50%; P = 0.0029). However, the diagnostic accuracies of pCLE and cytology for main duct intrapapillary mucinous neoplasm did not differ significantly (96.7% and 86.7%, respectively). Conclusions Probe-based confocal laser endomicroscopy may be effective for the diagnosis of pancreatic diseases as adjunct modality. It requires technical learning and further evaluation of its usefulness.

270 Background: To date many trials have been conducted to compare the efficacy and toxicity between TACE plus molecular targeted agents and TACE alone; all of them failed to show its clinical benefit in terms of progression free survival (PFS) or OS. In TACTICS trial (NCT01217034) TACE plus sorafenib significantly improved PFS over TACE alone in patients with unresectable HCC. ( Gut 2020;69:1374-1376). Here we will report a final OS analysis from TACTICS trial with predefined mature OS events. Methods: Patients with unresectable HCC were randomized to TACE plus sorafenib (n=80) or TACE alone (n=76). Patients in the combination group received sorafenib 400 mg once daily for 2–3 weeks before TACE, followed by 800 mg twice daily during on-demand conventional TACE sessions until time to untreatable (unTACEable) progression (TTUP), defined as untreatable tumor progression, transient deterioration to Child-Pugh C or appearance of vascular invasion/extrahepatic spread. Co-primary endpoints were progression-free survival (PFS), which is defined as TTUP, or time to any cause of death and OS. Multiplicity was adjusted by gatekeeping hierarchical testing. Results: At the cut-off date of July 31, 2020, 131 OS events were observed. Median OS was 36.2 mo with TACE plus sorafenib vs 30.8 mo with TACE alone (HR, 0.861 [95%CI, 0.607, 1.223]; P=0.40). ΔOS was 5.4 mo. Updated PFS was 22.8 mo with TACE plus sorafenib vs 13.5 mo with TACE alone (HR, 0.661[95%CI, 0.466, 0.938]; P=0.02). Post-trial treatments with active procedures/agents were observed in 47 (58.8%) in TACE plus sorafenib and in 58 (76.3%) with TACE alone. Anticancer procedures in TACE alone group include resection/ablation in 14, transarterial therapy in 53 and radiation in 7. Anticancer medications in TACE alone include targeted agents in 40 (29 sorafenib, 5 regorafenib, 3 lenvatinib, 3 ramucirumab), other systemic chemotherapy in 5 and immunotherapy in 5. Safety was consistent with the primary analysis, with no new signals identified. Conclusion: In TACTICS, TACE plus sorafenib did not show OS benefit as compared with TACE alone although significantly better PFS was consistently observed. OS in TACE plus sorafenib in TACTICS trial showed the longest OS (36.2 mo) with the longest ΔOS (5.4 mo) as compared with the previous 5 TACE combination trials. The major reason for negative OS result was speculated that many post-trial active treatments were performed in control arm (76.3%), which implies that OS endpoint in TACE combination trial may not be feasible anymore in current era of sequential therapy with many active locoregional and systemic treatments. Clinical trial information: NCT01217034.

Aim Genome-wide association studies have revealed that single nucleotide polymorphism (SNP) of human leukocyte antigen (HLA)-DQ is associated with the clearance of hepatitis B surface antigen (HBsAg) in acute hepatitis B virus (HBV) infection. We examined the effects of the SNPs on the development of hepatocellular carcinoma (HCC) and markers of HBV in chronic HBV infection. Methods The SNPs of HLA-DQ (rs2856718 and rs7453920) were determined in 299 patients with chronic HBV infection. Results In 224 HBV envelope antigen (HBeAg)-negative patients, those with rs2856718 genotype AG + GG had significantly lower hepatitis B core-related antigen levels (p = 0.0184), less frequent treatment with nucleotide/nucleoside analogs (NAs) (p = 0.0433), and less frequent HCC development (p = 0.0256) than those with genotype AA. Multivariate analysis selected age (p = 0.0460), platelet (p = 0.0481), γ-GTP (p = 0.0030) and NAs treatment (p = 0.0003) as factors independently associated with HCC development. HBeAg-negative patients with rs7453920 genotype GG had significantly lower HBsAg levels (p

Aim Pegylated interferon (PegIFN) therapies for hepatitis C virus (HCV) infection often induce a depressive state. This study aimed to identify the risk factors for and clinical characteristics of PegIFN-induced depressive state. Methods Sixty-nine subjects with HCV who received PegIFN therapy were enrolled. Before beginning therapy, all subjects were evaluated using the Neuroticism–Extraversion–Openness Five-Factor Inventory and the List of Threatening Events Questionnaire. Beck Depression Inventory (BDI) scores were also evaluated at baseline, 2–4 weeks after initiating therapy, and every 4 weeks thereafter. Results During the study, 18 subjects (24.3%) developed a depressive state (BDI ≥ 10). A bimodal peak of onset was observed during the early (2–8 weeks) and late (after 20 weeks) therapy phases. Moreover, we observed that baseline BDI scores (odds ratio [OR] = 1.40, P = 0.0104) and neuroticism (OR = 1.14, P = 0.0275) were significant risk factors for developing a depressive state. To determine the specific characteristics of this condition, we compared the BDI subscales between the ‘PegIFN-induced’ and ‘general’ depressive state reported previously. We found that the score at ‘somatic symptoms’ was higher in the ‘PegIFN-induced’ group. Conclusion Our results indicate the following: (i) PegIFN-induced depressive state most frequently develops during the first 8 weeks of therapy; (ii) baseline BDI and neuroticism scores are risk factors for PegIFN-induced depressive state; and (iii) the core symptoms of PegIFN-induced depressive state are different from those of ‘general’ depression.

Background and study aims Biliary metallic stents are used to drain unresectable malignant distal biliary obstructions. This study aimed to evaluate the efficacy of a novel 12-mm-diameter covered, self-expandable end bare metal stent (12-mm CSEEMS). Patients and methods We evaluated 99 patients with unresectable malignant distal biliary obstructions treated with covered biliary metallic stents. Of the 99 patients, 33 underwent 12-mm CSEEMS placement between June 2015 and April 2017 (12-mm-CSEEMS group) and 66 underwent 10-mm fully-covered self-expandable metal stent (FCSEMS) placement between January 2010 and July 2015 (10-mm-FCSEMS group). The overall survival (OS), the recurrent biliary obstruction (RBO), cause of RBO, time to RBO (TRBO) and adverse events in 12-mm-CSEEMS group and 10-mm-FCSEMS group were evaluated retrospectively. Results The OS tended to be longer in the 12-mm-CSEEMS group (log rank, P = 0.081) and TRBO was significantly longer in the 12-mm-CSEEMS group (log rank, P = 0.001) than in the 10-mm-FCSEMS group. Both univariate (HR, 0.449; 95 % CI, 0.27967 – 0.72215; P = 0.001) and multivariate (HR, 0.458; 95 % CI, 0.28395 – 0.73744; P = 0.001) Cox hazard analysis found that risk of RBO was significantly lower in 12-mm CSEEMS than in 10-mm FCSEMS. There were no significant differences between the 12-mm-CSEEMS group and 10-mm-FCSEMS group regarding the cause of RBO and adverse events. Conclusions The 12-mm CSEEMS showed a low risk of RBO compared with 10-mm FCSEMS and was considered to be effective and safe for draining unresectable malignant distal biliary obstruction.

The aim was to assess the relationship between muscle mass depletion and chronic hepatitis C virus (HCV) infection.We retrospectively evaluated abdominal computed tomography data for 611 patients. The participants included 302 patients with HCV infection and 309 patients with gallstones (as a control). The skeletal muscle mass at the level of the third lumber vertebra (L3) was measured from the computed tomography images and normalized for height to calculate the L3 skeletal muscle index (L3-SMI, cm/m). Statistical analysis was carried out separately for each sex, given that L3-SMI differs significantly between men and women.L3-SMI showed no significant difference between chronic hepatitis patients and gallstone patients in either sex. L3-SMI was significantly lower in male cirrhotic patients than in those with chronic hepatitis (P0.001). The Child-Pugh score was correlated negatively with L3-SMI in male patients with HCV-related cirrhosis (ρ=0.200, P=0.031). In addition, the BMI in both sexes was associated with L3-SMI in the gallstone and chronic hepatitis group, in the chronic hepatitis and liver cirrhosis group, and in the liver cirrhosis group.Skeletal muscle mass is not affected by chronic HCV infection in patients without cirrhosis and decreases in accordance with liver disease progression in male patients with chronic HCV infection.

Objective To elucidate the mechanism of an increase in the albumin levels by daclatasvir (DCV)/asunaprevir (ASV) therapy, we assessed the factors associated with an increase in the albumin levels. Methods We retrospectively analyzed 125 patients with chronic hepatitis C virus (HCV) infection, treated with DCV/ASV from November 2014 to January 2016. Results Albumin levels significantly increased from 4.0 ± 0.4 g/dL at baseline to 4.2 ± 0.4 g/dL at 24 weeks after the end of treatment (EOT) (P < 0.0001) in 108 patients with SVR. Patients with SVR were divided into three groups according to their baseline albumin levels: group A, ≥ 4 g/dL; group B, 3.6–3.9 g/dL; and group C, ≤ 3.5 g/dL. The increase in albumin levels from baseline to at 24 weeks after EOT was significantly larger in group C (0.5 ± 0.5 g/dL, P < 0.0001) and group B (0.2 ± 0.4 g/dL, P = 0.0059) than in group A (0.0 ± 0.3 g/dL). Multivariate analysis showed that aspartate transaminase (AST) levels was the only factor associated with ≥ 0.3 g/dL increase in albumin levels in groups B and C (P = 0.0305). An increase in albumin levels was significantly correlated with a decrease in AST levels (r = 0.4729, P = 0.0119). Conclusion DCV/ASV therapy resulted in an increase in albumin levels in SVR patients, which was significantly correlated with a decrease in AST levels. It is probable that the reduction of inflammation, but not by reduction of fibrosis, mainly caused an increase in albumin levels.

Non-alcoholic fatty liver disease (NAFLD) is one of the major causes of liver disease worldwide. To detect early stages of NAFLD and start treatment or to monitor the changes in trials of new drugs, non-invasive diagnostic methods are needed, such as biochemical markers or liver stiffness measurement (LSM). LSM with transient elastography (TE) and acoustic radiation force impulse (ARFI) has been shown to be useful in NAFLD, although the cut-off values have varied among reports. Magnetic resonance elastography and real-time tissue elastography also can be useful for the diagnosis of NAFLD, although the number of studies is limited. Fibrosis is absent in 8-40% of patients with non-alcoholic steatohepatitis (NASH), making it difficult to diagnose NASH by LSM because LSM is usually associated with fibrotic stage. The presence of inflammation or hepatocyte ballooning may affect LSM and aid the diagnosis of NASH without fibrosis. However, obesity significantly increases the failure of LSM and its interference is more conspicuous in TE than in ARFI. The newly implemented XL probe of TE has overcome the difficulty to some degree. Nonetheless, the effects of obesity, hepatocyte ballooning, steatosis and inflammation on LSM values have not yet been adequately investigated, although they are likely to affect LSM values. Further studies are needed to establish the clinical utility of LSM in NAFLD.

Genome-wide association studies have revealed that single nucleotide polymorphism (SNP) of human leukocyte antigen (HLA)-DQ is associated with the clearance of hepatitis B surface antigen (HBsAg) in acute hepatitis B virus (HBV) infection. We examined the effects of SNPs on the development of hepatocellular carcinoma (HCC) and markers of HBV in chronic HBV infection.The SNPs of HLA-DQ (rs2856718 and rs7453920) were determined in 299 patients with chronic HBV infection.In 224 hepatitis B e antigen (HBeAg)-negative patients, those with rs2856718 genotype AG + GG had significantly lower hepatitis B core-related antigen levels (P = 0.0184), less frequent treatment with nucleotide/nucleoside analogs (NAs) (P = 0.0433), and less frequent HCC development (P = 0.0256) than those with genotype AA. Multivariate analysis selected age (P = 0.0460), platelet count (P = 0.0481), γ-glutamyl transpeptidase (P = 0.0030), and nucleotide/nucleoside analog treatment (P = 0.0003) as factors independently associated with HCC development. HBeAg-negative patients with rs7453920 genotype GG had significantly lower HBsAg levels (P 0.0001), a higher prevalence of HBV genotype C (P = 0.0063), and a lower prevalence of the wild-type basal core promoter region (P = 0.0045) than those with genotype AA + AG. Multivariate analysis selected age (P 0.0001), platelet count (P = 0.0021), HBV DNA levels (P = 0.0314), wild type of precore region (P = 0.0015), and rs7453920 (P 0.0001) as factors independently associated with HBsAg levels.This study revealed an association between rs2856718 and HCC development and an association between rs7453920 and HBsAg levels.

Pegylated interferon (PegIFN) therapies for hepatitis C virus (HCV) infection often induce a depressive state. This study aimed to identify the risk factors for and clinical characteristics of PegIFN-induced depressive state.Sixty-nine subjects with HCV who received PegIFN therapy were enrolled. Before beginning therapy, all subjects were evaluated using the Neuroticism-Extraversion-Openness Five-Factor Inventory and the List of Threatening Events Questionnaire. Beck Depression Inventory (BDI) scores were also evaluated at baseline, 2-4 weeks after initiating therapy, and every 4 weeks thereafter.During the study, 18 subjects (24.3%) developed a depressive state (BDI ≥ 10). A bimodal peak of onset was observed during the early (2-8 weeks) and late (after 20 weeks) therapy phases. Moreover, we observed that baseline BDI scores (odds ratio [OR] = 1.40, P = 0.0104) and neuroticism (OR = 1.14, P = 0.0275) were significant risk factors for developing a depressive state. To determine the specific characteristics of this condition, we compared the BDI subscales between the 'PegIFN-induced' and 'general' depressive state reported previously. We found that the score at 'somatic symptoms' was higher in the 'PegIFN-induced' group.Our results indicate the following: (i) PegIFN-induced depressive state most frequently develops during the first 8 weeks of therapy; (ii) baseline BDI and neuroticism scores are risk factors for PegIFN-induced depressive state; and (iii) the core symptoms of PegIFN-induced depressive state are different from those of 'general' depression.

Liver stiffness (LS) has been reported to correlate with fibrosis stage (F). The correlation between LS and fibrosis stage and the reduction of LS by antiviral therapy were examined in patients with hepatitis B infection.LS was measured by FibroScan in 212 patients infected with hepatitis B virus. Liver biopsies were done in 51 patients. Changes of LS were assessed in 29 patients treated with nucleotide or nucleoside analogs and 52 patients without antiviral therapy.LS was significantly correlated with fibrosis stage (ρ = 0.686, P0.0001). The optimal cut-off values of LS were 7.1 kPa for F ≥ 2, 10.7 kPa for F ≥ 3, and 16.0 kPa for F4. LS was significantly reduced by antiviral therapy, from 12.9 (range 6.2-17.9) kPa to 6.6 (4.4-10.3) kPa measured at an interval of 512 (range 366-728) days (P0.0001). Eleven of 19 (58%) patients with baseline fibrosis stages of F3-4 deduced from LS had 2-point or greater reductions of deduced stage at the last LS measurement. The change ratio of hyaluronic acid (P = 0.0390) was associated with a 2-point or greater reduction of deduced fibrosis stage. Without antiviral therapy, LS tended to increase, increasing from 6.1 (range 3.9-8.5) kPa to 6.3 (range 4.4-9.7) kPa at an interval of 422 (range 358-709) days (P = 0.0682).LS was significantly correlated with fibrosis stage in patients with chronic hepatitis B. The reduction of LS by antiviral therapy was significantly correlated with the reduction of hyaluronic acid. Thus, we conclude that LS can be useful to assess the progression and regression of liver fibrosis stage noninvasively.

Aim: Transient elastography is a non-invasive tool to measure liver stiffness (LS), which has been reported to correlate with stage of liver fibrosis. Extrahepatic cholestasis was reported to cause elevated LS, which is considered to be attributed to the increased hydrostatic pressure in the liver. In the present study, the correlation of LS with laboratory data was investigated in extrahepatic cholestasis. The change of LS after biliary drainage was also assessed. Methods: LS was measured in 29 patients with extrahepatic cholestasis due to carcinomas in 12 and non-neoplastic diseases of biliary tract or pancreas in 17. Results: In 15 patients, LS was 11.4 kPa or higher which suggested liver cirrhosis in chronic infection of hepatitis C virus. LS significantly correlated positively with serum bilirubin levels (r = 0.726, P

Aim: To assess the regression of liver fibrosis after interferon (IFN) treatment in patients with chronic hepatitis C, liver stiffness (LS) was measured repeatedly and the factors associated with reduction of LS were assessed. Methods: LS was measured by transient elastography before treatment, at end of treatment (EOT), and 1 year and 2 years after EOT in 145 patients with chronic hepatitis C treated by IFN with or without ribavirin. Results: In the patients with sustained virological response (SVR) (n = 93) and relapsers (n = 28), LS significantly decreased at EOT (median, 5.4 [interquartile range, 4.0–8.6] kilopascals [kPa], P

症例は29歳男性．小児期より光線過敏があった．父方の祖父，弟にも光線過敏を認める．2001年11月肝障害のため他院に入院し，プロトポルフィリン症（EPP）と診断され，肝生検では軽度線維化と色素沈着をみとめた．2005年8月腹痛，食欲不振，黄疸，肝障害のため同院に再入院した．肝生検では広範な線維化，多数の色素沈着をみとめた．2006年11月腹痛，食欲不振，便秘，微熱，黄疸のため当院に第1回目の入院をした．赤血球プロトポルフィリン13776 μg/dl ，ALT 287 IU/L，総ビリルビン5.1 mg/dl であった．2007年5月に同様の症状にて第2回目の入院をした．2008年8月に同様の症状にて第3回目の入院をし，肝不全が進行し11月死亡した．EPPは稀な遺伝性疾患であり，肝不全にて死亡する患者は多くない．しかし重症の肝障害の治療法としては肝移植しかなく，適切な時期に肝移植を考慮すべきと思われる．