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Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) and Helicobacter pylori infection are major causes of gastric mucosal lesions. In Japan, histamine-2 receptor antagonists are frequently prescribed, but the literature regarding their efficacy is limited. In this study, we compare the effects of famotidine and rebamipide on NSAID-associated gastric mucosal lesions using upper gastrointestinal endoscopy.Methods: This study examined 112 patients taking NSAIDs for either gastric hemorrhage or erosion. Before treatment, the patients were assessed by endoscopy. Using blind randomization, patients were divided into two groups: group F (famotidine, 20 mg/day) and group R (rebamipide, 300 mg/day). Efficacy was examined 4 weeks later using endoscopy.Results: After treatment, the Lanza score decreased significantly in group F (P < 0.001) but not in group R (P = 0.478). The change in the Lanza score in group F was significantly greater (P = 0.002) than that in group R.Conclusions: Famotidine was superior to rebamipide in treating NSAID-associated mucosal lesions. [ABSTRACT FROM AUTHOR]

Abstract Introduction Budd-Chiari syndrome is a very rare pathological entity that ultimately leads to liver failure. Several therapeutic modalities, including percutaneous transluminal angioplasty, have been attempted to save the life of patients with Budd-Chiari syndrome. Few reports have described a salvage living donor liver transplantation performed after percutaneous transluminal angioplasty in a patient with acute Budd-Chiari syndrome. Case presentation A 26-year-old Japanese man developed severe progressive manifestations, such as massive ascites and hematemesis due to rupture of esophageal varices. After making several investigations, we diagnosed the case as Budd-Chiari syndrome. We first performed percutaneous transluminal angioplasty to dilate a short-segment stenosis of his inferior vena cava. The first percutaneous transluminal angioplasty greatly improved the clinical manifestations. However, after a year, re-stenosis was detected, and a second percutaneous transluminal angioplasty failed to open the severe stricture of his inferior vena cava. Since our patient had manifestations of acute liver failure, we decided to perform salvage living donor liver transplantation from his brother. The transplantation was successfully performed and all clinical manifestations were remarkably alleviated. Conclusion In cases of recurrent Budd-Chiari syndrome, the blocked hepatic venous outflow is not always relieved, even with invasive therapies. We have to take into account the possibility of adopting alternative salvage therapies if the first therapeutic modalities fail. When invasive therapy such as percutaneous transluminal angioplasty fails, liver transplantation should be considered as an alternative option.

Background: Methotrexate-associated lymphoproliferative disorder (MTX-LPD) is a rare but critical complication that develops in patients treated with MTX. Although MTX-LPD has been recently reported, the incidence of follicular lymphoma in the intestine is very low., Case Presentation: A 73-year-old woman who had been receiving MTX for over 10 years visited our hospital complaining of postprandial abdominal pain and nausea. Upper and lower digestive tract endoscopies did not show any abnormal findings. A patency capsule was stagnated at the proximal part of the ileum with a mild dilation on the oral side. An oral balloon endoscopy revealed shallow ulcerative lesions in the jejunum. She was diagnosed with MTX-LPD based on histopathological findings. The symptoms did not improve with the discontinuation of MTX, and the patient required partial resection of the small intestine. The test result for Epstein-Barr virus-encoded small RNA was negative. She was diagnosed with follicular lymphoma based on the histology findings of a surgical specimen. Postoperative positron emission tomography-computed tomography and bone marrow aspiration did not show any findings of lymphoma. On follow-up, no recurrence was noted four years after the surgery., Conclusions: Herein, we report the first case of follicular lymphoma that occurred in the small intestine, negative for Epstein-Barr virus-encoded small RNA. If intestinal symptoms occur during MTX administration, it is important to directly observe by endoscopy and perform histological examination.

Aim: The aim of the present study is to investigate the effect of long-term zinc supplementation, which is important for the activation of various enzymes that contribute to antioxidant and antifibrotic activities, on the improvement of serum fibrotic markers in patients with autoimmune hepatitis (AIH)., Methods: A total of 38 patients with AIH under regular treatment at our hospital who provided their consent for being treated with polaprezinc (75 mg twice daily) were included and classified into 2 groups: the patients with zinc elevation ( n = 27) and the patients without zinc elevation ( n = 11). Serum biomarker of fibrosis, protein expression levels of matrix metalloproteinases (MMPs), and their inhibitors (TIMPs) were evaluated., Results: A significant difference was found between the variability of serum procollagen type Ⅲ and collagen type Ⅳ-7S between the 2 groups before and after zinc administration for more than 24 months ( p = 0.043 and p = 0.049). In the patients with zinc elevation, no significant changes were found in collagenase (MMP-1 and MMP-13) before and after zinc administration, whereas a significant increase in the expression of gelatinase (MMP-2 and MMP-9) was found after administration ( p = 0.021 and p = 0.005). As for the relative ratio of MMPs to TIMPs, only MMP-9 to TIMP-1 showed a significant increase ( p = 0.004)., Conclusions: Long-term treatment with polaprezinc has been demonstrated to safely improve serum fibrosis indices through increases in MMP-2/-9 and MMP-9/TIMP-1 and is expected to be well combined with direct antifibrotic therapies such as molecularly targeted agents.

Background/aims: Endoscopic resection (ER) for superficial non-ampullary duodenal epithelial tumors (SNADETs) is challenging. Conventional endoscopic mucosal resection (CEMR) is also problematic due to the anatomical features of the duodenum. We compared the safety and efficacy of underwater endoscopic mucosal resection (UEMR) with those of CEMR through a retrospective analysis., Methods: Altogether, 44 consecutive patients with 46 SNADETs underwent ER (18 CEMR cases and 28 UEMR cases) between January 2016 and October 2019. We investigated the proportions of en bloc resection, R0 resection, complications, resection time, and total procedure time and compared the outcomes of patients from the CEMR group with those of patients from the UEMR group., Results: The median tumor size was 8.0 mm (range, 2.0-20.0 mm). The UEMR group showed a higher proportion of en bloc resection (96.4% vs. 72.2%, p<0.05) and significantly lower median resection time and total procedure time (4 min vs. 9.5 min, p<0.05 and 13 min vs. 19 min, p<0.05; respectively) than the CEMR group. No complications were observed. However, two patients treated with piecemeal resection in the CEMR group had residual tumors., Conclusion: UEMR is a feasible therapeutic option for SNADETs. It can be recommended as a standard treatment.

Aim: Although some relationships between gut microbiota and liver diseases have been reported, it remains uncertain whether changes in gut microbiota owing to differences in race, food and living environment have similar effects. Response to ursodeoxycholic acid (UDCA) may predict the long-term prognosis of patients with primary biliary cholangitis (PBC); however, little is known about the significance of the gut microbiome in patients with PBC. We elucidated the relationships among clinical profiles, biochemical response to UDCA and gut microbiome composition in patients with PBC., Methods: Fecal samples from 76 patients with PBC treated at our hospital were collected; patients whose UDCA intake period was <1 year were excluded. The microbiome structures of patients were determined using 16S ribosomal RNA gene sequencing and were statistically compared with those of healthy subjects. The structures of patients in the UDCA responder (n = 43) and non-responder (n = 30) groups were compared according to the Nara criteria (reduction rate of gamma-glutamyl transpeptidase, ≥69%, after 1 year)., Results: Compared with healthy subjects, bacterial diversity was lower in patients with PBC, with a decreased abundance of the order Clostridiales and increased abundance of Lactobacillales. The UDCA non-responder group had a significantly lower population of the genus Faecalibacterium, known as butyrate-producing beneficial bacteria (P < 0.05), although no significant differences in gender, body mass index, medicated drugs or other serological data were indicated between these two groups., Conclusions: Gut dysbiosis with loss of beneficial Clostridiales commensals was observed in patients with PBC. Decrease in Faecalibacterium abundance might predict the long-term prognosis of patients with PBC., (© 2020 The Japan Society of Hepatology.)

We herein report a 52-year-old man with multiple hypoechoic lesions in the body and tail of the pancreas detected during a screening ultrasound. Computed tomography (CT) showed no lesions other than those in the pancreas and peripheral lymph nodes. Contrast-enhanced CT identified hypovascular tumors in the pancreas. Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) demonstrated partial fibrosis and noncaseating granulomas with Langhans giant cells. To our knowledge, this is the first report of isolated pancreatic sarcoidosis diagnosed by EUS-FNA. Although pancreatic sarcoidosis is very rare, clinicians should be aware of this possibility in patients presenting with multiple hypovascular pancreatic tumors.

Background and Aim: We previously reported the comparable efficacy of bi-monthly hepatic arterial infusion chemotherapy (B-HAIC) to that of sorafenib chemotherapy for the treatment of advanced hepatocellular carcinoma (aHCC) in patients with compensated cirrhosis. In this study, we demonstrate the efficacy of B-HAIC in patients with decompensated cirrhosis., Methods: Forty-five patients with aHCC refractory to transcatheter arterial chemo-embolization (TACE) were treated with B-HAIC and were divided into two groups according to hepatic functional reserve (Child-Pugh grade). Overall survival period, treatment response, and adverse events in each group were analyzed., Results: Efficacy and disease control rates in the Child-Pugh B group (n=24; 21% and 71%, respectively) were not significantly impaired compared the Child-Pugh A group (n=21; 38% and 67%, respectively). Median survival time and survival rate at 12 months in the Child-Pugh B group were 422 days and 58.3%, respectively, whereas those in the ChildPugh A group were 567 days and 70.8%, respectively. Importantly, the hepatic functional reserve of patients did not worsen in either group during the treatment period. Furthermore, the occurrence rate of adverse events leading to discontinuation of anti-tumor treatment was not significantly increased in the Child-Pugh B group., Conclusion: Given the preservation of hepatic functional reserve afforded by B-HAIC chemotherapy in patients with decompensated cirrhosis, B-HAIC might be an acceptable alternative strategy for aHCC patients who do not respond to TACE.

Aim: To identify laboratory predictors of histological progression (HP) of primary biliary cholangitis (PBC)., Methods: Sequential biopsies were carried out on 35 (11.4%) of 308 patients with PBC treated with ursodeoxycholic acid (UDCA). Patients were divided into high γ-glutamyl transpeptidase (GGT) (n = 18) and low GGT (n = 17) groups, based on the median value of GGT at baseline. Patients were then categorized as showing HP (progressive group, PG) or lacking HP (non-progressive group, NPG) according to the Scheuer and Nakanuma classifications, with the latter grading liver fibrosis (fibrosis score) and bile duct loss (BDL score)., Results: According to the Scheuer definition, 12 patients had HP and 23 did not. According to the Nakanuma definition, 8 and 27 patients were in the PG and NPG groups, respectively. The fibrosis and BDL scores progressed in 13 and 8 patients, respectively, whereas 22 and 25 patients did not show HP, respectively. Fisher's exact probability test analysis revealed that the rate of HP using the Nakanuma fibrosis score was significantly higher in the high GGT group compared to the low GGT group (P < 0.05). However, no significant correlation was found between the HP of PBC and the biochemical response to UDCA therapy. Both univariate and multivariate logistic regression analyses indicated that the serum GGT level at baseline is an independent risk factor for an increased Nakanuma fibrosis score., Conclusions: The level of serum GGT at baseline is significantly associated with liver fibrosis progression in PBC, and therefore could help to predict the HP of PBC., (© 2019 The Japan Society of Hepatology.)

Rationale: Mucinous cystic neoplasms (MCNs) are pancreatic mucin-producing cystic lesions with a distinctive ovarian-type stroma. The diagnosis is generally easy in typical cases; however, differential diagnosis is difficult in others such as in the case we report herein., Patient Concerns: A 27-year-old woman with sudden onset of epigastric pain was referred to our hospital for suspected acute pancreatitis. Contrast-enhanced computed tomography revealed a 25-mm cystic lesion in the pancreas and a low density area with delayed enhancement at the right upper side of the cystic lesion., Diagnoses: During its clinical course, the cystic lesion underwent various morphological changes. Eventually, it presented typical findings of MCNs, and could be accurately diagnosed., Interventions: Laparoscopic distal pancreatectomy was performed on the patient by preserving the spleen., Outcomes: The patient revealed no symptoms till 1 year after the operation., Lessons: This case of MCN with intriguing short-term morphological changes was associated with recurrent pancreatitis. A combination of imaging modalities is essential for accurate diagnosis of MCNs, and follow-up with serial imaging might be useful for certain unusual lesions.

Objectives: The diagnostic yield of endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) cytology widely varies depending on the treatment method used. Liquid-based cytology (LBC) has gained popularity in the gynecological field because of its efficacy in collection of target cells and simplicity in the manipulation of specimens. Since the introduction of EUS-FNA at our institution, we have used LBC for the diagnosis of pancreatic mass lesions. This study aims to investigate the diagnostic efficacy of EUS-FNA with LBC in patients with pancreatic mass lesions during the learning curve for EUS-FNA., Methods: In this study, we retrospectively enrolled 222 patients with pancreatic mass lesions who were diagnosed using EUS-FNA with LBC between 2011 and 2016. The diagnostic yields for EUS-FNA with LBC for pancreatic mass lesions were evaluated., Results: The diagnostic sensitivity, specificity, and accuracy for malignancy were found to be 93.9%, 95.1%, and 94.1%, respectively., Conclusions: This study suggests that EUS-FNA with LBC for specimens provides good diagnostic efficacy in patients with pancreatic mass lesions even during the learning curve for EUS-FNA.

Background: Gastric cancer has a wide spectrum of clinical features, imaging manifestations, and pathology. Punctate calcifications in gastric cancer are infrequent but are usually found in mucinous adenocarcinoma. However, there have only been a few autopsy case reports describing the correlation between the radiology and pathology findings of calcified mucinous adenocarcinoma of the stomach. We present an autopsy case of mucinous gastric adenocarcinoma with iris metastases as the initial symptom., Case Presentation: A 74-year-old Japanese woman presented with blurred vision. Her treating ophthalmologist diagnosed acute iritis with secondary glaucoma. The histopathological and immunohistochemical features of a trabeculectomy specimen favored metastatic carcinoma, most likely of gastrointestinal tract origin. Esophagogastroduodenoscopy revealed multiple irregularly shaped ulcerative lesions, multiple erosions, and thickened folds in the corpus of her stomach. Histologic examination of a gastric tissue specimen obtained by endoscopic biopsy revealed poorly differentiated carcinoma with signet ring cell features. Computed tomography revealed a tumor with multiple punctate calcifications in the thickened gastric wall with diffuse low attenuation and multiple lymph node metastases, including the para-aortic lymph nodes, and peritoneal dissemination. She was diagnosed with stage IV gastric cancer (T4N3M1) and underwent seven cycles of 5-weekly TS-1, a novel oral fluoropyrimidine derivative, plus cisplatin therapy. Serial follow-up computed tomography revealed successive increases in the gastric wall calcifications. Her disease stabilized, but she died of aspiration pneumonia 8 months after the first visit. Autopsy tissue specimens had miliary, punctate calcifications present in abundant extracellular mucin pools in the submucosa, corresponding to the thickened low-attenuating middle layer on computed tomography. The final diagnosis was mucinous gastric adenocarcinoma because mucinous adenocarcinoma is diagnosed when more than half of the tumor area contains extracellular mucin pools., Conclusions: We report the pathology and computed tomography imaging characteristics of a case of calcified mucinous adenocarcinoma of the stomach metastatic to the iris, including findings at autopsy. Metastatic carcinomas in the iris originating in the stomach are exceedingly rare. Multiple punctate calcifications were present in pools of extracellular mucin, a diagnostic clue for mucinous adenocarcinoma. Possible mechanisms underlying scattered punctuate calcifications in gastric mucinous adenocarcinoma warrant further investigation.

Aim: Intestinal endotoxin is important for the progression of non-alcoholic steatohepatitis (NASH). Circulating endotoxin levels are elevated in most animal models of diet-induced non-alcoholic fatty liver disease (NAFLD) and NASH. Furthermore, plasma endotoxin levels are significantly higher in NAFLD patients, which is associated with small intestinal bacterial overgrowth and increased intestinal permeability. By improving the gut microbiota environment and restoring gut-barrier functions, probiotics are effective for NASH treatment in animal models. It is also widely known that hepatic fibrosis and suppression of activated hepatic stellate cells (Ac-HSCs) can be attenuated using an angiotensin-II type 1 receptor blocker (ARB). We thus evaluated the effect of combination probiotics and ARB treatment on liver fibrosis using a rat model of NASH., Methods: Fisher 344 rats were fed a choline-deficient/L-amino acid-defined (CDAA) diet for 8 weeks to generate the NASH model. Animals were divided into ARB, probiotics, and ARB plus probiotics groups. Therapeutic efficacy was assessed by evaluating liver fibrosis, the lipopolysaccharide Toll-like receptor (TLR)4 regulatory cascade, and intestinal barrier function., Results: Both probiotics and ARB inhibited liver fibrosis, with concomitant HSC activation and suppression of liver-specific transforming growth factor-β and TLR4 expression. Probiotics reduced intestinal permeability by rescuing zonula occludens-1 disruption induced by the CDAA diet. Angiotensin-II type 1 receptor blocker was found to directly suppress Ac-HSCs., Conclusions: Probiotics and ARB are effective in suppressing liver fibrosis through different mechanisms. Currently both drugs are in clinical use; therefore, the combination of probiotics and ARB is a promising new therapy for NASH., (© 2018 The Japan Society of Hepatology.)

Background/aims: L-carnitine not only alleviates hyperammonemia and reduces muscle cramps in patients with liver cirrhosis, but also improves anemia in patients with chronic hepatitis and renal dysfunction. This study prospectively evaluated the preventative efficacy of L-carnitine supplementation against hemolytic anemia during antiviral treatment using ribavirin in patients with hepatitis C virus (HCV)-related chronic liver disease., Methods: A total of 41 patients with chronic hepatitis were consecutively enrolled in this study. Group A (n=22) received sofosbuvir plus ribavirin for 3 months, whereas group B (n=19) was treated with sofosbuvir, ribavirin, and L-carnitine. Hemoglobin concentration changes, the effects of antiviral treatment, and the health status of patients were analyzed using short form-8 questionnaires., Results: A significantly smaller decrease in hemoglobin concentration was observed in group B compared to group A at every time point. Moreover, the prescribed dose intensity of ribavirin in group B was higher than that of group A, resulting in a higher ratio of sustained virological response (SVR) 24 in group B compared with group A. The physical function of patients in group B was also significantly improved compared to group A at the end of antiviral treatment., Conclusion: L-carnitine supplementation alleviates ribavirin-induced hemolytic anemia in patients with HCV and helps relieve the physical burden of treatment with ribavirin-containing regimens. These advantages significantly increase the likelihood of achieving SVR.

Aim: Proton pump inhibitors (PPIs) are frequently prescribed in patients with cirrhosis, but this therapy entails potential complications. We aimed to investigate the influence of PPI use on intestinal permeability in patients with cirrhosis., Methods: We recruited 228 patients with cirrhosis and divided them into four groups. Group (Gp)1 comprised patients receiving a PPI with concurrent neomycin (NEO) (PPI-NEO group, n = 14 [6.1%]), Gp2 and Gp3 comprised those receiving either PPI or NEO (PPI group, n = 91 [39.9%]; and NEO group, n = 11 [4.4%]), and Gp4 comprised those receiving neither of these medications (control group; n = 112 [49.1%]). We assessed the intestinal permeability by measuring endotoxin activity (EA) using a luminol chemiluminescence method., Results: Endotoxin activity levels were significantly higher in patients with Child B cirrhosis than in those with Child A cirrhosis, but we found no significant differences in EA levels between patients with Child C cirrhosis and those with either Child A or B cirrhosis. We observed no significant differences in EA levels among groups 1-4. Patients without antibiotic exposure (n = 203), comprising 91 patients on PPI therapy (Gp2) and 112 no-PPI-therapy controls (Gp4), were subdivided according to Child-Pugh (CP) classification. We found no significant differences in EA levels between Gp2 and Gp4 in either CP class., Conclusion: Our results suggest that PPI usage does not have a significant impact on serum levels of gut-derived endotoxins, which are already elevated because of the increased intestinal permeability in patients with cirrhosis., (© 2018 The Japan Society of Hepatology.)

Depression is a major reason for interferon (IFN) therapy cessation. IFN-free direct-acting antiviral (DAA) therapy for depression is not well-documented. Thus, four different IFN-free regimens were assessed in genotype-1 hepatitis C virus (HCV) patients with depression. Overall, 287 HCV genotype-1 patients who received combination therapies with IFN-free DAAs of daclatasvir/asunaprevir (DCV/ASV) (n=84), sofosbuvir/ledipasvir (SOF/LDV) (n=95), ombitasvir/paritaprevir/ritonavir (OBV/PTV/r) (n=74), and elbasvir/grazoprevir (EBR/GZR) (n=34) were included. Treatment-induced depression as a complication of HCV therapy in IFN-free DAA regimens was assessed. The severity of depression was evaluated using the Beck Depression Inventory-II (BDI-II) questionnaire. It was demonstrated that all four DAA regimens achieved similar high efficacy in Japanese patients with HCV genotype-1 infection. Moreover, in seven patients with depression who received the 24-week DCV/ASV treatment regimen, the BDI-II scores significantly increased at week 4 as compared with pretreatment values; furthermore, they decreased below baseline at week 12 despite the rapid decline of serum HCV levels after the initiation of DCV/ASV therapy. The BDI-II scores gradually decreased during therapy in the remaining 77 DCV/ASV-treated patients without depression. The BDI-II scores showed a significant decrease from baseline to the end of treatment with 12-week regimens, including SOF/LDV and EBR/GZR. The 12-week DAA regimen of SOF/LDV and EBR/GZR can be safely used with high efficacy in patients with genotype-1 HCV infection, including those with depression.

Background: Even though the Barcelona Clinic Liver Cancer (BCLC) staging system is widely accepted, controversies on the management of hepatocellular carcinoma (HCC) still exist. We evaluated the efficacy of an approach with repeated hepatic arterial infusion chemotherapy (HAIC) given at eight-week intervals for the treatment of advanced HCC., Methods: Of the 66 compensated cirrhotic patients with advanced HCC refractory to transcatheter arterial chemo-embolization (TACE) enrolled in our study, 21 were treated by bi-monthly hepatic arterial infusion chemotherapy (B-HAIC) and the rest by sorafenib. The overall survival periods, curative responses, and adverse events in each group were retrospectively analyzed., Results: The efficacy rate was significantly higher in the B-HAIC group (38%, 11%, P<0.05). The median survival time and the survival rate at 12 months in the B-HAIC group were 567 days and 70.8%, and those in the sorafenib group were 366 days and 47.6%, respectively. Thus, our data suggests that the B-HAIC treatment is not inferior to sorafenib for the treatment of advanced HCC in compensated cirrhotic patients. Furthermore, the occurrence of serious adverse events leading to discontinuation of treatment was less frequent in the B-HAIC group., Conclusions: Given the hepatic function reserve preservation afforded by the B-HAIC treatment in our experience, we suggest that B-HAIC should be considered an alternative strategy for advanced HCC patients who do not respond to TACE., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Background: We present the first description of en bloc endoscopic submucosal dissection (ESD) for total circumferential Barrett's adenocarcinoma, predominantly of the long-segment Barrett's esophagus (LSBE), with a 2-year follow-up and management strategies for esophageal stricture prevention., Case Presentation: A 59-year-old man was diagnosed with LSBE and Barrett's adenocarcinoma by esophagogastroduodenoscopy (EGD). A 55-mm-long circumferential tumor was completely resected by ESD. Histopathology revealed a well-differentiated adenocarcinoma within the LSBE superficial muscularis mucosa. For post-ESD stricture prevention, the patient underwent an endoscopic triamcinolone injection administration, oral prednisolone administration, and preemptive endoscopic balloon dilatation. Two years later, there is no evidence of esophageal stricture or recurrence., Conclusions: ESD appears to be a safe, effective option for total circumferential Barrett's adenocarcinoma in LSBE.

A 75-year-old female patient with liver cirrhosis and hepatitis C was treated with direct-acting antivirals (DAA) (Sofosbuvir+Ledipasvir). The hepatitis C virus (HCV) -RNA level decreased to negative 4 weeks after the start of the treatment. Six weeks later, she developed ascites and showed declining hepatic spare ability. Accordingly, DAA treatment was stopped. She was started on furosemide 20mg/day and spironolactone 50mg/day. After 7 days, she started taking tolvaptan 7.5mg/day because furosemide and spironolactone proved to be ineffective. This new regimen resolved the ascites. The HCV-RNA level remained negative, although DAA was not restarted. Finally, she achieved a sustained virological response (SVR). The hepatic spare ability at the time of SVR recovered than that at the time of DAA treatment.

A 59-year-old man had been admitted to our hospital because of general malaise and abdominal fullness caused by massive ascites. He was diagnosed with alcoholic liver cirrhosis. Following the removal of ascites, he was referred to our department because of hematochezia. Emergent colonoscopy revealed the rupture of ascending colonic varices. Endoscopic variceal sclerotherapy using topical skin adhesive (75% Histoacryl) was performed to treat the colonic varices, which proved to be an effective treatment. Enhanced computerized tomography performed 5 days after the treatment of ascending colonic varices showed complete obstruction of the ileocolic varices without complication. It is important to consider the possibility of ectopic varices when a patient with liver cirrhosis reports bloody stool.

Hepatocellular carcinoma (HCC) with isolated right atrial metastasis is extremely rare; most cases are considered inoperable. We herein report the case of a 74-year-old man with HCC with isolated right atrial metastases without hepatic vein invasion; the right atrial lesion was resected because of the risk of heart failure and sudden death. Postoperatively, he underwent transcatheter arterial chemoembolization and radiofrequency ablation for intrahepatic HCC. He recovered completely, with a long-term survival of 36 months. This is the first report of an HCC patient with isolated right atrial metastases without hepatic vein invasion. Tumorectomy for solitary atrial metastasis is effective for HCC patients.

Hepatocellular carcinoma (HCC) is prone to recurrence following curative treatment. The purpose of the present study was to identify the predisposing factors of HCC recurrence following complete remission achieved by transarterial chemoembolization (TACE). A retrospective cohort study of 70 consecutive patients with HCC who underwent TACE as the initial treatment was conducted. The patients were divided into two groups according to their 1-year disease-free survival (DFS) status; the early recurrence group (ER group; n=32), with HCC recurring within 1 year of initial TACE; and the non-early recurrence group (NER group; n=38), who did not experience recurrence within 1 year. The parameters identified as significantly associated with DFS time on univariate analysis were aspartate aminotransferase (AST), alanine aminotransferase and α-fetoprotein levels, as well as the tumor number (P=0.003, P=0.027, P=0.002 and P=0.005, respectively). Multivariate analysis revealed that AST levels and tumor number were significantly associated with a shorter DFS period (P=0.009 and P=0.038, respectively). The Mantel-Haenszel test revealed a significant trend of decreasing DFS with increasing tumor number. Among the patients with HCC in the ER group, locoregional recurrence occurred more frequently in those who received TACE alone compared with those treated with TACE combined with radiofrequency ablation treatment. In summary, multinodularity of HCC is the most potent predictive factor for the recurrence of HCC within 1 year of initial TACE.

Excessive alcohol consumption is the most common cause of liver disease in the world. Chronic alcohol abuse leads to liver damage, liver inflammation, fibrosis and hepatocellular carcinoma. Inflammatory cytokines, such as tumor necrosis factor-α and interferon-γ, induce liver injury, which leads to the develo-pment of alcoholic liver disease (ALD). Hepatoprotective cytokines, such as interleukin (IL)-6 and IL-10, are also associated with ALD. IL-6 improves ALD via the activation of STAT3 and the subsequent induction of a variety of hepatoprotective genes in hepatocytes. Alcohol consumption promotes liver inflammation by incre-asing the translocation of gut-derived endotoxins to the portal circulation and by activating Kupffer cells through the lipopolysaccharide/Toll-like receptor 4 pathways. Oxidative stress and microflora products are also associated with ALD. Hepatic stellate cells play an important role in angiogenesis and liver fibrosis. Anti-angiogenic therapy has been found to be effective in the prevention of fibrosis. This suggests that blocking angiogenesis could be a promising therapeutic option for patients with advanced fibrosis. This review discusses the main pathways associated with liver inflammation and liver fibrosis as well as new therapeutic strategies.

Aims: The efficacy of the vasopressin V2 receptor antagonist tolvaptan for difficult-to-treat cirrhotic ascites has recently been reported. However, its effect is variable among patients. This study aimed to clarify the predictive factors for obtaining a good response to tolvaptan in patients with difficult-to-treat ascites., Methods: Data were collected from 50 patients with liver cirrhosis having ascites (hepatitis B, n = 1; hepatitis C, n = 22; alcoholism, n = 11; and others, n = 16) after treatment with tolvaptan (3.75-7.5 mg/day) in addition to conventional diuretics. A follow-up assessment was carried out after 7-day tolvaptan treatment for all patients., Results: After an uneventful 7-day tolvaptan treatment, 18 patients (36.0%) lost more than 2 kg of their body weight (responders). Twenty-six patients (52.0%) showed an increase in urine volume (>300 mL) on day 2. Tolvaptan was also effective for patients with pleural effusion, portal vein thrombosis, and hepatocellular carcinoma. Basal blood urea nitrogen (BUN) levels, plasma renin activity, and aldosterone levels were significantly higher in the poor responders (<2 kg weight loss), who were considered to be in the relative vascular underfilling state, than in the responders. Basal BUN was extracted as a predictive factor of responsiveness by multivariate logistic regression analysis., Conclusions: Tolvaptan is useful and safe for the treatment of cirrhotic ascites. This report showed that BUN will predict the response of tolvaptan even when measured before tolvaptan treatment., (© 2016 The Japan Society of Hepatology.)

Background: Inadequate response to ursodeoxycholic acid (UDCA) is associated with unfavorable outcomes in patients with primary biliary cholangitis (PBC). We aimed to identify surrogate markers for predicting long-term prognosis and biochemical response to UDCA in patients with PBC., Patients and Methods: In this single-center, retrospective study, 99 patients with PBC were classified into responders (n=53) and nonresponders (n=46) based on reductions in the γ-glutamyl transpeptidase levels at 1 year after initiating UDCA therapy (Nara criteria). We assessed whether the criteria for patentability by different countries are useful in predicting the prognosis of PBC. The accuracy of Scheuer and Nakanuma staging systems in predicting prognosis and treatment response was compared., Results: Nara definition had comparable utility to the Paris-II definition for selecting patients in whom UDCA monotherapy can be safely continued. Patients at Scheuer stage 1 had a significantly better prognosis than those at Scheuer stages 3 or 4 (P<0.05 and 0.0001, respectively). Patients at Nakanuma stage 4 had decreased survival compared with those at stage 1 (P<0.05). The proportion of responders to nonresponders was significantly higher in stages 1-3 PBC than in stage 4 PBC, according to both staging systems (P<0.05 for both). All patients with Scheuer stage 4 PBC were nonresponders, whereas only 28.6% (2/7) of those with Nakanuma stage 4 PBC were responders., Conclusion: The Scheuer staging system had greater utility in predicting long-term prognosis and UDCA response than the Nakanuma staging system.

Heyde syndrome describes the triad of aortic stenosis, acquired coagulopathy, and anemia due to bleeding from intestinal angiodysplasia. An 87-year-old man with iron deficiency anemia due to melena was admitted to our hospital. On examination, a systolic murmur was heard and echocardiography confirmed the presence of aortic stenosis. Esophagogastroduodenoscopy and colonoscopy were unremarkable. Capsule endoscopy and double balloon endoscopy revealed angiodysplasia throughout the small intestine. Laboratory investigations were significant for reduced plasma levels of high molecular weight von Willebrand factor multimers. On the basis of these findings, the patient was diagnosed with Heyde syndrome. The patient required frequent blood transfusions because of the intestinal bleeding, and underwent bioprosthetic aortic valve replacement. Twenty months after the operation, the gastrointestinal bleeding resolved and the patient no longer required blood transfusions. This is the first case report to describe an improvement in bleeding from angiodysplasia, one year after aortic valve replacement. It demonstrates the effective treatment of Heyde syndrome with aortic valve replacement, and highlights the importance of considering this differential diagnosis when evaluating patients presenting with repeated episodes of gastrointestinal bleeding and a concurrent systolic murmur.

Aim: To clarify whether Agtr1a methylation is involved in the development of nonalcoholic steatohepatitis (NASH)-related liver fibrosis in adult rats., Methods: A choline-deficient amino acid (CDAA) diet model was employed for methylation analysis of NASH-related liver fibrosis. Agtr1a methylation levels were measured in the livers of CDAA- and control choline-sufficient amino acid (CSAA)-fed rats for 8 and 12 wk using quantitative methylation-specific PCR. Hepatic stellate cells (HSCs) were isolated by collagenase digestion of the liver, followed by centrifugation of the crude cell suspension through a density gradient. Agtr1a methylation and its gene expression were also analyzed during the activation of HSCs., Results: The mean levels of Agtr1a methylation in the livers of CDAA-fed rats (11.5% and 18.6% at 8 and 12 wk, respectively) tended to be higher ( P = 0.06 and 0.09, respectively) than those in the livers of CSAA-fed rats (2.1% and 5.3% at 8 and 12 wk, respectively). Agtr1a was not methylated at all in quiescent HSCs, but was clearly methylated in activated HSCs (13.8%, P < 0.01). Interestingly, although Agtr1a was hypermethylated, the Agtr1a mRNA level increased up to 2.2-fold ( P < 0.05) in activated HSCs compared with that in quiescent HSCs, suggesting that Agtr1a methylation did not silence its expression but instead had the potential to upregulate its expression. These findings indicate that Agtr1a methylation and its upregulation of gene expression are associated with the development of NASH-related liver fibrosis., Conclusion: This is the first study to show that DNA methylation is potentially involved in the regulation of a renin-angiotensin system-related gene expression during liver fibrosis., Competing Interests: Conflict-of-interest statement: The authors declare that they have no conflicts of interest.

A 41-year-old man presented with abdominal fullness in late August 2012. Abdominal CT showed ileus caused by stenosis of the ileum and an enlargement of the ileocecal lymph nodes. Colonoscopy showed a steep elevated protruding tumor in the cecum, with multiple ulcerative lesions on top. A pathological analysis of the lesions confirmed chronic inflammatory infiltration and epithelioid granuloma. The findings of a tuberculin skin test and QuantiFERON-TB-Gold test were positive. As a result, we treated the patient for tuberculosis of the cecum. After 4 months of treatment, colonoscopy confirmed the disappearance of the tumor. In conclusion, intestinal tuberculosis should be considered in the differential diagnosis when protruding lesions appear in the cecum.

Gastric adenocarcinoma of fundic gland type [chief cell predominant type; (GA-FD-CCP)] is a rare gastric cancer variant arising from non-atrophic mucosa without Helicobacter pylori infection in the upper third portion of the stomach. GA-FD-CCP originates deep in the mucosal layer; hence, endoscopic lesion detection is often difficult at an early stage because of a minimal change in the mucosal surface. Here we present a 66-year-old man with an early stage of GA-FD-CCP showing characteristic endoscopic features. Esophagogastroduodenoscopy demonstrated a flat, slightly reddish area with black pigment dispersion and irregular micro-surface structure at the gastric fornix. The tumor was resected by endoscopic submucosal dissection and was pathologically diagnosed as GA-FD-CCP. Prussian blue staining revealed that the black pigment was a hemosiderin deposition. We reported a rare case of successfully treated GA-FD-CCP with black pigmentation that aided in early lesion detection., (© Acta Gastro-Enterologica Belgica.)

Background: Endoscopic submucosal dissection (ESD) has been developed for early gastric cancer (EGC). Helicobacter pylori eradication therapy has been reported to have a preventive effect against metachronous recurrence of EGC after ESD. However, the efficacy and safety of eradication therapy on ESD-induced ulcer healing are not clear. In a randomized control study, we compared the standard therapy (8-week proton pump inhibitor) and eradication therapy combined with subsequent treatment with 7-week rebamipide for healing ESD-induced ulcers., Methods: A multicenter, randomized, open-label study was conducted. In group A, patients received 20 mg of omeprazole for 56 days. In group B, patients received 40 mg of omeprazole, 1,500 mg of amoxicillin, and 800 mg of clarithromycin for 7 days, and then 300 mg of rebamipide for 49 days. The primary end point was to evaluate the scarring ratio., Results: The scarring rate in group A was significantly higher than that in group B [85.0 % (34/40) vs. 56.8 % (21/37), P = 0.011]. The scarring rate of ulcers with an area ≥565.5 mm(2) in group A was significantly higher than that in group B [78.9 % (15/19) vs. 37.5 % (6/16), P = 0.018]. There was no significant difference between the groups in the scarring rate of smaller ulcers. No serious adverse events were observed in any of the patients in either group., Conclusion: H. pylori eradication therapy and 7-week rebamipide monotherapy were not superior to PPI monotherapy, but this combination therapy for smaller sized ulcers was an optimal therapeutic option for healing. Serious adverse events were not observed in either group.

Nodular regenerative hyperplasia (NRH) is associated with autoimmune and hematologic diseases and may lead to portal hypertension. We herein report a case of NRH diagnosed based on a liver biopsy. A 63-year-old woman developed esophageal varices and splenomegaly. She had undergone surgery for transverse colon cancer 24 years earlier and received systemic chemotherapy (FOLFOX4 including oxaliplatin) to treat lymph node metastasis 21 years after the operation. The present liver biopsy confirmed NRH, and, after two years, she received endoscopic injection sclerotherapy. Oxaliplatin was suspected to be the causative agent of NRH in this case. Therefore, physicians must consider the possibility of NRH in patients who receive chemotherapy.

Objective: The aim of this study was to investigate the synergistic inhibitory effects of gemcitabine and losartan, angiotensin II type 1 (AT1) receptor blockers, on an orthotopic rat pancreatic cancer model., Methods: The rat orthotopic pancreatic cancer model was prepared using DSL-6A/C cells, a rat ductal pancreatic adenocarcinoma cell line. The rats were treated with gemcitabine alone (100 mg/kg per week), losartan alone (100 mg/kg per day), or gemcitabine plus losartan., Results: Survival was significantly improved by treatment with gemcitabine (89.6 ± 21.8 days) or losartan (76.9 ± 18.7 days) alone compared with that in the control group (59.6 ± 13.4 days; P < 0.05). Treatment with gemcitabine plus losartan further prolonged the survival time to 102.6 ± 16.5 days compared with that in the control group (P < 0.0001). Gemcitabine or losartan significantly and dose-dependently reduced the proliferation of DSL-6A/C cells in vitro. Both drugs inhibited pancreatic vascular endothelial growth factor expression compared with that in the control group (P < 0.05)., Conclusions: The results of this study indicate that combined treatment with gemcitabine and losartan significantly improved the survival of rats with orthotopic pancreatic cancer by inhibiting vascular endothelial growth factor synthesis and suppressing cancer cell proliferation via AT1 receptor blockade. Thus, an AT1 receptor blocker in combination with gemcitabine might improve the clinical outcomes of patients with advanced pancreatic cancer.

Background: The most common postoperative complication after distal pancreatectomy (DP) is still postoperative pancreatic fistula (POPF), which is closely associated with other major complications and remains an unsolved problem., Methods: This retrospective study included 47 consecutive patients who underwent a distal pancreatectomy with (DP-PG group, n = 21) or without (DP group, n = 26) duct-to-mucosa pancreaticogastrostomy from June 2010 to May 2012. Clinical data including POPF-related complications (POPF, fluid collection, intra-abdominal abscess, bleeding and delayed gastric emptying) as a primary endpoint were compared between the two groups., Results: The frequencies of POPF-related complications as well as overall POPF and complications in the DP-PG group were lower than in the DP group (P = 0.037, P < 0.001, respectively). The 30 days morbidity after hospital discharge in the DP-PG group was less than in the DP group (P = 0.014). In both groups median hospital stay was similar. Although additional time needed for pancreaticogastrostomy was 35 (20-55) min, there was no difference in operative times. Patients in the DP group had a higher medical cost for hospitalization than the DP-PG group (P = 0.048)., Conclusion: Pancreaticogastrostomy as an additional procedure following distal pancreatectomy was associated with a reduced rate of POPF-related complications that resulted in relatively lower medical cost for hospitalization., (© 2013 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

A 77-year-old man with jaundice and a pancreatic head tumor was referred to our hospital in August 2006. The initial laboratory tests, computed tomography (CT) scan, magnetic resonance imaging (MRI), and endoscopic retrograde cholangiopancreatography suggested IgG4-related cholangitis and autoimmune pancreatitis. Oral prednisolone (PSL) was then administered. This treatment reduced the size of the pancreatic parenchyma, and the lower common bile duct (CBD) returned to its normal size. Thus, the oral PSL was gradually tapered to a maintenance dose. In February 2010, a CT scan and MRI showed segmental wall thickening and stenosis of the middle CBD, the progression of which led to extrahepatic obstructive jaundice. We suspected the emergence of a cholangiocarcinoma rather than the exacerbation of the IgG4-related sclerosing cholangitis because the stricture of the CBD was short and localized. Then, a percutaneous transhepatic biliary drainage was performed. The biopsy specimens obtained via the percutaneous transhepatic tract indicated an abnormal glandular formation, suggesting the presence of a moderate, well-differencated adenocarcinoma. The gross examination, microscopic examination and immunohistochemical analysis of the pancreaticoduodenectomy specimen suggested that a cholangiocarcinoma developed from the IgG4-related sclerosing cholangitis.

Branched-chain amino acids (BCAAs) reportedly inhibit the incidence of hepatocellular carcinoma (HCC) in patients with liver cirrhosis and obesity that is frequently associated with insulin resistance (IR). We previously reported that BCAAs exert a chemopreventive effect against HCC under IR conditions in rats. The aim of the present study was to examine the effect of BCAAs on the cumulative recurrence of HCC under IR conditions in the clinical practice. BCAA granules (Livact®, 12 g/day) were administered for 60 months following the local curative therapy for HCC, and several indices were determined. Treatment with BCAAs markedly inhibited the cumulative recurrence of HCC in patients with a high IR index [homeostasis model assessment (HOMA)-IR >2.5], but not in patients with HOMA-IR of ≤2.5. BCAA also improved the HOMA-IR, and the inhibitory effect was observed regardless of the serum albumin (Alb) levels. Similarly, BCAA treatment revealed a marked suppressive effect in patients with high fasting insulin [immune reactive insulin (IRI)>15 U/ml], but not with IRI of ≤15. BCAA treatment did not result in differences in HCC recurrence in patients with high and low glucose levels [fasting blood sugar (FBS)>110 and ≤110, respectively]. Furthermore, serum levels of the soluble form of vascular endothelial growth factor receptor 2 (sVEGFR2) were significantly inhibited along with these clinical effects. Our findings indicate that the inhibitory effect of BCAAs was achieved, at least partly, by coordinated effects of anti-angiogenesis and IR improvement. Since BCAAs are widely and safely used in clinical practice to treat patients with chronic liver diseases, BCAAs may represent a new strategy for secondary chemoprevention for HCC patients with IR. Moreover, our findings suggest that sVEGFR2 may be a useful clinical predictive marker for BCAA treatment under IR conditions.

Background: To investigate the behavior of activated pancreatic stellate cells (PSCs), which express alpha-smooth muscle actin (α-SMA), and pancreatic cancer cells in vivo, we examined the expression of α-SMA-positive myofibroblast-like cells in pancreatic cancer tissue after treatment with gemcitabine (GEM) using a Lewis orthotopic rat pancreatic cancer model., Methods: The effect of GEM on DSL-6A/C1 cell proliferation was determined by cell counting method. The orthotopic pancreatic cancer animals were prepared with DSL-6A/C cells, and treated with GEM (100 mg/kg/weekly, for 3 weeks). At the end of treatment, α-SMA expression, fibrosis, transforming growth factor (TGF)-β1 and vascular endothelial growth factor (VEGF) were evaluated by histopathological and Western blot analyses., Results: DSL-6A/C1 cell proliferation was significantly reduced by co-culturing with GEM in vitro. Survival time of pancreatic cancer animals (59.6 ± 13.4 days) was significantly improved by treatment with GEM (89.6 ± 21.8 days; p = 0.0005). Alpha-SMA expression in pancreatic cancer tissue was significantly reduced after treatment with GEM (p = 0.03), however, there was no significant difference in Sirius-red expression. Expression of VEGF was significantly reduced by GEM treatment, but the expression of TGF-β1 was not inhibited., Conclusion: GEM may suppress not only the tumor cell proliferation but also suppress PSCs activation through VEGF reduction.