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Background: Although faecal DNA testing of Fusobacterium nucleatum ( Fn) is expected to be useful for colorectal neoplasia detection, there is no standardized quantification method of Fn. We performed this study to establish a possible standardized method. Methods: In this study, 322 participants including 71 subjects without colorectal neoplasia (control group), 31 patients with non-advanced colorectal adenoma, 93 patients with advanced colorectal adenoma, and 127 patients with colorectal cancer were enrolled. Faecal Fn were quantified by droplet digital PCR (ddPCR) using two PCR primer-probe sets reported previously that are tentatively named Fn1 and Fn2. Fn1 has been used in ddPCR by us and Fn2 has been widely used in quantitative real-time PCR. Results: The Fn copy number using Fn1 was five times higher than that using Fn2, with a linear relationship shown between them. Receiver operating characteristic curve analysis showed the area under the curve (AUC) to be almost the same between Fn1 and Fn2 in discriminating between the control group and the colorectal cancer group (AUC = 0.81 and 0.81, respectively), and between the control/non-advanced colorectal adenoma group and the advanced colorectal adenoma/colorectal cancer group (AUC = 0.74 and 0.74, respectively). Conclusions: As the diagnostic performance was quite similar between Fn1 and Fn2, ddPCR-based Fn testing using Fn1 and Fn2 could be a possible standardized method for a colorectal neoplasia screening test, considering that Fn levels quantified by Fn1 are about five times higher than those by Fn2.

The best palliation for double obstruction (duodenal obstruction with biliary obstruction) remains unclear. We aimed to compare outcomes of duodenal stenting (DuS) with gastrojejunostomy (GJ) and identify factors associated with survival time and time to recurrent biliary obstruction (TRBO).Patients who underwent DuS or GJ combined with biliary stenting for double obstruction due to unresectable malignancy were retrospectively enrolled.In total, 111 patients were included; 84 underwent DuS, and 27 underwent GJ. The weighted survival time of the DuS group was significantly shorter than that of the GJ group (86 days vs 134 days, P 0.01). Although the weighted TRBO was not significantly different between the two groups, when limited to patients with distal duodenal obstruction, the weighted TRBO was significantly longer in the DuS group than in the GJ group (207 days vs. 32 days, P 0.01). GJ for distal duodenal obstruction was identified as the factor with the highest hazard ratio and was associated with a shorter TRBO (hazard ratio 8.5, P 0.01).Regarding survival time, GJ should be considered the primary treatment for patients with double obstruction. However, for patients with distal duodenal obstruction, DuS should be considered because GJ may be a risk factor for a shorter TRBO.

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.

Objective CT enterography/enteroclysis (CTE) is listed in the clinical practice guidelines as a method for diagnosing small bowel bleeding, as is capsule endoscopy (CE), but there are no real-world data yet available on CTE in Japan. This study aimed to investigate the diagnostic ability of CTE and long-term prognosis after CTE in Japan. Patients We conducted a retrospective cohort study of patients suspected of having small bowel bleeding who underwent both CTE and CE within 30 days between April 2008 and March 2019. The number of patients free from rebleeding for up to 24 months was thus determined. Results Seventy-one patients were extracted from the database. The 43 patients (60.6%) with a definite and suspicious source of bleeding in the small bowel were detected by CTE. When the 31 patients with a definite source of bleeding in the small bowel were analyzed, the sensitivity of CTE was 19/31 (61.3%) and that of CE was 24/31 (77.4%), thus indicating no significant difference (p=0.332). However, the sensitivity when CTE and CE were used in combination was 30/31 (96.8%), which was significantly higher than that of CE alone (p=0.0412). No rebleeding was observed in the CTE and CE negative group (p=0.0965). Conclusion The combined use of CTE and CE increased the detection rate of small bowel bleeding. Therefore, in patients with suspected tumor/polyp lesions, not only CE, but also CTE should be performed. This study provides the first real-world data on the diagnostic accuracy of CTE for small bowel bleeding in Japan.

The first edition of the clinical practice guidelines for liver cirrhosis was published in 2010, and the second edition was published in 2015 by the Japanese Society of Gastroenterology (JSGE). The revised third edition was recently published in 2020. This version has become a joint guideline by the JSGE and the Japan Society of Hepatology (JSH). In addition to the clinical questions (CQs), background questions (BQs) are new items for basic clinical knowledge, and future research questions (FRQs) are newly added clinically important items. Concerning the clinical treatment of liver cirrhosis, new findings have been reported over the past 5 years since the second edition. In this revision, we decided to match the international standards as much as possible by referring to the latest international guidelines. Newly developed agents for various complications have also made great progress. In comparison with the latest global guidelines, such as the European Association for the Study of the Liver (EASL) and American Association for the Study of Liver Diseases (AASLD), we are introducing data based on the evidence for clinical practice in Japan. The flowchart for nutrition therapy was reviewed to be useful for daily medical care by referring to overseas guidelines. We also explain several clinically important items that have recently received focus and were not mentioned in the last editions. This digest version describes the issues related to the management of liver cirrhosis and several complications in clinical practice. The content begins with a diagnostic algorithm, the revised flowchart for nutritional therapy, and refracted ascites, which are of great importance to patients with cirrhosis. In addition to the updated antiviral therapy for hepatitis B and C liver cirrhosis, the latest treatments for non-viral cirrhosis, such as alcoholic steatohepatitis/non-alcoholic steatohepatitis (ASH/NASH) and autoimmune-related cirrhosis, are also described. It also covers the latest evidence regarding the diagnosis and treatment of liver cirrhosis complications, namely gastrointestinal bleeding, ascites, hepatorenal syndrome and acute kidney injury, hepatic encephalopathy, portal thrombus, sarcopenia, muscle cramp, thrombocytopenia, pruritus, hepatopulmonary syndrome, portopulmonary hypertension, and vitamin D deficiency, including BQ, CQ and FRQ. Finally, this guideline covers prognosis prediction and liver transplantation, especially focusing on several new findings since the last version. Since this revision is a joint guideline by both societies, the same content is published simultaneously in the official English journal of JSGE and JSH.

Portopulmonary hypertension (PoPH) is a subcategory of pulmonary arterial hypertension (PAH) associated with portal hypertension (PH). Certain drugs, including dasatinib, a tyrosine kinase inhibitor (TKI) for chronic myelogenous leukemia, have been identified as risk factors for the development of PAH.(1) However, although TKIs, such as lenvatinib, have been widely used for the treatment of HCC, no reports have demonstrated the association of TKIs for HCC with PAH.

Objective This study primarily aimed to investigate the short-term effects of partial splenic embolization (PSE) on the Child-Pugh score and identify predictive factors for changes in the score caused by PSE. The secondary aim was to analyze changes in various parameters at one month postoperatively using these identified factors. Methods Between September 2007 and December 2019, 118 patients with cirrhosis and hypersplenism underwent PSE at our hospital. Testing was conducted preoperatively and at one month after PSE. Results Overall, the Child-Pugh score was not significantly changed postoperatively. The Child-Pugh score before PSE was identified as the strongest independent predictor of ameliorated and deteriorated Child-Pugh scores after PSE. Higher pretreatment Child-Pugh scores were correlated with higher posttreatment amelioration rates of the score. A significant decrease in the portal vein diameter and a significant increase in the common hepatic artery diameter were evident at the same level postoperatively in 64 patients with Child-Pugh class A (group A) and in 54 patients with Child-Pugh class B or C (group B/C) preoperatively. According to Murray's Law, PSE resulted in decreased portal venous flow and increased hepatic arterial flow, suggesting a hepatic arterial buffer response (HABR) induced by the procedure. Despite equivalent splenic infarction rates and similar posttreatment changes in hepatic hemodynamics, PSE significantly increased the Child-Pugh score of group A; however, the procedure significantly decreased the score of group B/C. Conclusion Considering original portal venous-hepatic arterial hemodynamics, PSE is expected to produce HABR-mediated hepatic functional improvements in cirrhosis patients with Child-Pugh class B/C.

In recent years, research has been conducted to develop new medical treatments by simulating environments existing in space, such as zero-gravity. In this study, we evaluated the cell proliferation and gene expression of activated primary human hepatic stellate cells (HHSteCs) under simulated microgravity (SMG). Under SMG, cell proliferation was slower than in 1 G, and the evaluation of gene expression changes on day 1 of SMG by serial analysis of gene expression revealed the presence of Sirtuin, EIF2 signaling, hippo signaling, and epithelial adherence junction signaling. Moreover, reactive oxygen species were upregulated under SMG, and when N-acetyl-cystein was added, no difference in proliferation between SMG and 1 G was observed, suggesting that the oxidative stress generated by mitochondrial dysfunction caused a decrease in proliferation. Upstream regulators such as smad3, NFkB, and FN were activated, and cell-permeable inhibitors such as Ly294002 and U0126 were inhibited. Immunohistochemistry performed to evaluate cytoskeletal changes showed that more β-actin was localized in the cortical layer under SMG.

The average error rate in liver cirrhosis classification on B-mode ultrasound images using the traditional pattern recognition approach is still too high. In order to improve the liver cirrhosis classification performance, image correction methods and a convolution neural network (CNN) approach are focused on. The impact of image correction methods on region of interest (ROI) images that are input into the CNN for the purpose of classifying liver cirrhosis based on data from B-mode ultrasound images is investigated. In this paper, image correction methods based on tone curves are developed. The experimental results show positive benefits from the image correction methods by improving the image quality of ROI images. By enhancing the image contrast of ROI images, the image quality improves and thus the generalization ability of the CNN also improves.

Background Iron is required for cellular metabolism, and rapidly proliferating cancer cells require more of this essential nutrient. Therefore, iron regulation may well represent a new avenue for cancer therapy. We have reported, through in vitro and in vivo research involving pancreatic cancer cell lines, that the internal-use, next-generation iron chelator deferasirox (DFX) exhibits concentration-dependent tumour-suppressive effects, among other effects. After performing a microarray analysis on the tumour grafts used in that research, we found that DFX may be able to suppress the cellular movement pathways of pancreatic cancer cells. In this study, we conducted in vitro analyses to evaluate the effects of DFX on the invasive and migratory abilities of pancreatic cancer cells. Methods We used pancreatic cancer cell lines (BxPC-3, Panc-1, and HPAF II) to examine the efficacy of DFX in preventing invasion in vitro, evaluated using scratch assays and Boyden chamber assays. In an effort to understand the mechanism of action whereby DFX suppresses tumour invasion and migration, we performed G-LISA to examine the activation of Cdc42 and Rac1 which are known for their involvement in cellular movement pathways. Results In our scratch assays, we observed that DFX-treated cells had significantly reduced invasive ability compared with that of control cells. Similarly, in our Boyden chamber assays, we observed that DFX-treated cells had significantly reduced migratory ability. After analysis of the Rho family of proteins, we observed a significant reduction in the activation of Cdc42 and Rac1 in DFX-treated cells. Conclusions: DFX can suppress the motility of cancer cells by reducing Cdc42 and Rac1 activation. Pancreatic cancers often have metastatic lesions, which means that use of DFX will suppress not only tumour proliferation but also tumour invasion, and we expect that this will lead to improved prognoses.

BackgroundThis large-scale post-marketing surveillance study (START study) evaluated the effectiveness and safety of tolvaptan in Japanese liver cirrhosis patients with hepatic edema in real-world clinical settings. Here, we present the final analysis outcomes.MethodsA prospective, multicenter, non-interventional study involving patients who received tolvaptan for the treatment of liver cirrhosis with hepatic edema with an insufficient response to conventional diuretics. The observation period was up to 6 months. Effectiveness evaluation included changes in body weight and clinical symptoms. Safety analysis included evaluation of adverse drug reactions (ADRs).ResultsCase reports of 1111 patients were collected. Of these, 1109 were included in the safety analysis and 1098 in the effectiveness analysis. The mean age was 69.4 ± 11.5 years and 695 (62.7%) patients were male. After tolvaptan treatment, a decrease in body weight from baseline was − 2.6 ± 2.7 kg on day 7 and − 3.8 ± 4.1 kg on day 14. Moreover, clinical symptoms significantly improved over the 14-day treatment. Frequently reported ADRs were thirst (6.6%), hepatic encephalopathy (2.3%), dehydration (1.5%), and hypernatremia (1.2%). A serum sodium level of ≥ 150 mEq/L was reported in five patients (0.5%). Multivariate analyses showed that the baseline blood urea nitrogen (BUN) level (cut-off value: 22.4 mg/dL) was the predictive factor for tolvaptan treatment response.ConclusionsThe results suggest that tolvaptan was effective and well-tolerated in liver cirrhosis patients with hepatic edema. In the real-world clinical setting, tolvaptan provides a useful option for the treatment of hepatic edema.

Background Second-generation cryoballoon (2G-CB) ablation is highly effective for achieving pulmonary vein isolation (PVI) with a promising clinical outcome. However, the ideal freezing strategy for preventing gastroesophageal excessive transmural injury (ETI) remains under debate. This study aimed to clarify the correlation between gastroesophageal ETI and a bonus-freeze protocol after PVI using 2G-CBs. Method This study included 100 patients who underwent PVI using 2G-CB followed by an endoscopic examination. The freeze-cycle duration was set at 180 s. In the first 33 patients a 120 s bonus-freeze was applied after successful PVI (bonus group), while in the following 67 the bonus freeze was omitted (non-bonus group). Early freezing interruption was performed when the esophageal temperature reached 25 °C. Gastroesophageal ETI was defined as any injury that resulted from the PVI, including esophageal damage or periesophageal nerve injury. Results Gastroesophageal ETIs were observed in 9 (27.3%) and 6 (9.0%) patients and were all asymptomatic, esophageal damage in 3 and 0, and periesophageal nerve injury in the remaining 6 and 6 in the bonus group and non-bonus group, respectively (p = 0.033). In the multivariate analysis, the bonus freeze protocol (odds ratio 3.527; 95% confidence interval 1.110–11.208; p = 0.033) was the sole independent predictor of gastroesophageal ETI. During a one-year follow-up 26 of 33 bonus group patients (78.8%) and 52 of 67 (77.6%) non-bonus group patients remained in stable sinus rhythm without any differences between the groups. Conclusions In the patients with a bonus-freeze protocol using the 2G-CB, gastroesophageal ETIs were detected more often than in those with the non-bonus freeze protocol. In contrast, freedom from atrial fibrillation after the 2G-CB based PVI was comparable when applying either a bonus or non-bonus freeze protocol.

Patient: Male, 72 Final Diagnosis: Decompensated liver cirrhosis Symptoms: Disturbance of consciousness Medication: — Clinical Procedure: PSE • BRTO • HCV treatment Specialty: Radiology Objective: Unusual clinical course Background: The appearance of direct acting antivirals (DAAs) has produced a major paradigm shift in hepatitis C virus (HCV) infection treatment, and virus elimination has become possible in most patients. Improvement of the model for end-stage liver disease (MELD) score by elimination of HCV has been reported, but for decompensated liver cirrhosis, it is also important to overcome various complications before antiviral treatment. Case Report: A 72-year-old male, who had been treated for HCV-related liver cirrhosis was referred to our hospital for treatment of refractory hepatic encephalopathy. At that time, his Child-Pugh score was 10 and class was C. On contrast-enhanced computed tomography (CT), a splenorenal shunt, splenomegaly, and splenic artery aneurysm were noted. The disease was also complicated by cytopenia associated with hypersplenism, and embolization of the splenic artery aneurysm and partial splenic embolization (PSE) were concomitantly performed. One month after the PSE, balloon occluded retrograde transvenous obliteration (BRTO) for refractory hepatic encephalopathy was performed. Hepatic functional reserve improved compared with that at the first examination, and SOF/LDV therapy was initiated. Fortunately, no adverse effect occurred during treatment, and sustained virologic response (SVR) was achieved. Hepatic functional reserve further improved thereafter. At the time of this report, a Child-Pugh A status was being maintained without administration of a branched chain amino acid preparation, drugs for hyperammonemia, or diuretics. Conclusions: We encountered a patient with decompensated liver cirrhosis accompanied by complications of hypersplenism, hepatic encephalopathy, and splenic artery aneurysm. These complications were overcome by treatment with PSE and BRTO, which led to DAAs treatment and a marked improvement of hepatic function.

The significance of the 2018 Japanese diagnostic criteria for acute-on-chronic liver failure (ACLF) has not yet been evaluated. A nationwide survey was performed for patients with ACLF occurring between 2017 and 2019. Cirrhotic patients with a Child–Pugh score of 5–9 were diagnosed as having ACLF when liver failure (serum bilirubin level of ≥ 5.0 mg/dL and a prothrombin time international normalization rate [INR] of ≥ 1.5) occurred within 28 days after an acute insult. Patients who fulfilled either criterion (total serum bilirubin or INR) and/or those with indeterminate Child–Pugh scores at baseline were also enrolled. Among the 501 enrolled patients, 183 patients (37%) were diagnosed as having ACLF. The etiologies of the cirrhosis and acute insults were alcohol intake/abuse in 114 (62%) and 75 (41%) patients, respectively. Sixty-eight patients (37%) were also diagnosed as having severe alcoholic hepatitis. The survival rate without liver transplantation was 48% among the ACLF patients and 71% in the remaining patients (P

Background We previously reported that the incidence of hepatocellular carcinoma (HCC) with non-viral etiologies increased rapidly between 1991 and 2010 in Japan. Methods To update this investigation, we enrolled patients who were initially diagnosed as having non-B, non-C HCC at participating hospitals between 2011 and 2015. In addition to the patient characteristics investigated in the previous report, we also investigated the duration of alcohol consumption. The overall survival rate was analyzed using the Kaplan–Meier method, and the hazard function against the body mass index (BMI) was plotted using cubic splines. Results A total of 2087 patients were enrolled. The proportion of patients with non-viral etiologies has continued to increase from 10.0% in 1991 to 32.5% in 2015. Patients were also older (median ages, 70–73 years) and more obese (median BMIs, 23.9–24.2 kg/m2), and the proportions of patients with diabetes mellitus (46.1% to 51.6%), hypertension (42.7% to 58.6%), dyslipidemia (14.6% to 22.9%), and fatty liver (24.0% to 28.8%) had all increased significantly. There was a significant inverse relationship between the duration and the amount of daily alcohol consumption. The improvement in the overall survival was relatively small, with a decreased proportion of patients under surveillance (41.3% to 31.6%). A hazard function plot showed a curve similar to that in our previous report, with a lowest hazard of ~ 26 kg/m2. Conclusions The proportion of HCC patients with non-viral etiologies continues to increase in Japan. Lifetime total amount of alcohol consumption may be a risk factor. Electronic supplementary material The online version of this article (10.1007/s00535-018-1532-5) contains supplementary material, which is available to authorized users.

We report a case of methotrexate (MTX) delaying the healing of an endoscopic submucosal dissection (ESD)-induced gastric ulcer. The patient, who had been taking MTX for rheumatoid arthritis, underwent ESD for early gastric carcinoma. Despite taking vonoprazan after ESD, abdominal pain and anorexia continued, and the gastric ulcer did not heal after the ESD. After discontinuing MTX, the patient's symptoms improved and the ulcer healed. Patients taking MTX require careful follow-up after ESD, considering that ulcers can be difficult to heal. Discontinuation of MTX should be considered if delayed healing of an ulcer is observed.

Aim To evaluate the cost-effectiveness of therapeutic strategies initiated at different stages of liver fibrosis using three direct-acting antivirals (DAAs), sofosbuvir-ledipasvir (SL), glecaprevir-pibrentasvir (GP), and elbasvir plus grazoprevir (E/G), for Japanese patients with chronic hepatitis C (CHC) genotype 1. Methods We created an analytical decision model reflecting the progression of liver fibrosis stages to evaluate the cost-effectiveness of alternative therapeutic strategies applied at different fibrosis stages. We compared six treatment strategies: treating all patients regardless of fibrosis stage (TA), treating individual patients with one of four treatments starting at four respective stages of liver fibrosis progression (F1S: withholding treatment at stage F0 and starting treatment from stage F1 or higher, and three successive options, F2S, F3S, and F4S), and administering no antiviral treatment (NoRx). We adopted a lifetime horizon and Japanese health insurance payers’ perspective. Results The base case analysis showed that the incremental quality-adjusted life years (QALY) gain of TA by SL, GP, and E/G compared with the strategies of starting treatments for patients with the advanced fibrosis stage, F2S, varied from 0.32 to 0.33, and the incremental cost-effectiveness ratios (ICERs) were US$24,320, US$18,160 and US$17,410 per QALY, respectively. On the cost-effectiveness acceptability curve, TA was most likely to be cost-effective, with the three DAAs at the willingness to pay thresholds of US$50,000. Conclusions Our results suggested that administration of DAA treatment for all Japanese patients with genotype 1 CHC regardless of their liver fibrosis stage would be cost-effective under ordinary conditions.

Characteristics of the chronotypes of patients with gastrointestinal disease are unknown. We evaluated chronotypes of patients with upper gastrointestinal diseases with the Munich ChronoType Questionnaire (MCTQ). A total of 2027 subjects from 29 institutions in Japan who had undergone esophagogastroduodenoscopy were asked to answer the MCTQ. The subjects' chronotypes were divided into three groups (early, intermediate, and late chronotype) using the sleep-corrected mid-point of sleep on free days (MSF

Chronic liver diseases, including hepatocellular carcinoma (HCC), lead to an imbalance in energy metabolism. The non-protein respiratory quotient (npRQ), which estimates energy malnutrition, can be evaluated using an indirect calorimeter; however, npRQ measurement is limited in routine work. This study aimed to investigate the relationship between the albumin-bilirubin (ALBI) score and npRQ in patients with HCC.We conducted a retrospective cohort study in 109 patients with HCC who underwent indirect calorimetry and then compared the npRQ with various clinical parameters, including liver function and tumor factors.The median npRQ was 0.82. A significant negative correlation was found between the npRQ and the ALBI score (r = -0.35, p 0.001). The median npRQ in modified ALBI (mALBI) grades 1, 2a, 2b, and 3 were 0.84, 0.86, 0.81, and 0.79, respectively (grade 2a vs. 2b, p = 0.002). Factors associated with npRQ0.85, which is reported to be the best cutoff value for energy malnutrition, were analyzed. On multivariate analysis, the ALBI score (cutoff value, -2.18) was the only significant independent factor (odds ratio, 7.65; p 0.001). The proportion of HCC patients with npRQ0.85 significantly increased among patients with an ALBI score ≥-2.18 (45/51, 88.2%) compared with those with an ALBI score-2.18 (29/58, 50%) (p 0.001).The ALBI score might be a useful predictor for energy malnutrition in patients with HCC. In addition, most HCC patients with mALBI grade 2b or 3 can be considered to have energy malnutrition.

Hepatic stellate cells (HSCs) play a vital role in liver fibrosis, and a greater understanding of their regulation is required. Recent studies have focused on relationships between extracellular matrix (ECM) stiffness and gene expression or cellular metabolism, but none have provided a detailed metabolic analysis of HSC changes in spheroid cultures. Accordingly, in the present study, we created an HSC spheroid culture and analyzed changes in gene expression and metabolism. Expression of &alpha, smooth muscle actin (&alpha, SMA) decreased in the spheroids, suppressing proliferation. Gene expression analysis revealed the cell cycle, sirtuin signaling, mitochondrial dysfunction, and the Hippo pathway to be canonical pathways, believed to result from decreased proliferative ability or mitochondrial suppression. In the Hippo pathway, nuclear translocation of the yes-associated protein (YAP) was decreased in the spheroid, which was associated with the stiffness of the ECM. Metabolome analysis showed glucose metabolism changes in the spheroid, including glutathione pathway upregulation and increased lipid synthesis. Addition of the glycolytic product phosphoenolpyruvate (PEP) led to increased spheroid size, with increased expression of proteins such as &alpha, SMA and S6 ribosomal protein (RPS6) phosphorylation, which was attributed to decreased suppression of translation. The results of our study contribute to the understanding of metabolic changes in HSCs and the progression of hepatic fibrosis.

The efficacy of endoscopic ultrasound-guided hepaticogastrostomy (EUS-HGS) using a dedicated plastic stent has been reported.[1 2][1] We therefore describe a technical pitfall during EUS-HGS using the plastic stent. A 52-year-old man was admitted to our hospital with jaundice. He had undergone

A questionnaire survey was conducted regarding the prognosis for pancreatic cancer at 8 major hospitals in Yamaguchi Prefecture. A total of 552 patients with pancreatic cancer who underwent radical surgery between 1997 and 2016 were identified. Five of them survived for more than 10 years. Among the 5 patients, none was treated with neoadjuvant chemotherapy: 4 underwent PD and 1 underwent DP-CAR. Two of them were treated with adjuvant chemotherapy. No complications occurred during their postoperative courses. All of them had no recurrence and survived. Here, we reported the longterm postoperative survival of patients with pancreatic cancer with literature review.

Patient: Female, 67-year-old Final Diagnosis: Portal-systemic liver failure Symptoms: None (second opinion) Medication: None Clinical Procedure: Balloon-occluded retrograde transvenous obliteration (BRTO) Specialty: Radiology Objective: Unusual or unexpected effect of treatment Background: This is a case report validating our previous studies showing clinical benefit of balloon-occluded retrograde transvenous obliteration (BRTO) in improving hepatic function and outcomes in patients with a low liver stiffness (LS) and with procedural indication of encephalopathy. Here, we present the case of a woman in her late 60s suffering from hepatitis C virus-related decompensated liver cirrhosis with refractory encephalopathy. Case Report: The patient presented with a Child-Pugh score of 11, Model for End-Stage Liver Disease-Sodium (MELD-Na) score of 16, and LS of 21.5 kPa. BRTO was expected to improve both the intractable encephalopathy and hepatic function and prolong her vital prognosis. Portosystemic shunt (PSS) occlusion induced drastic changes in the portal-splenic vein hemodynamics, resulting in dramatically improved Child-Pugh and MELD-Na scores. This status was maintained for 1 year postoperatively. However, her LS increased 1 month postoperatively and declined steadily thereafter. The postoperative levels of hepatic fibrosis markers, including Mac-2 binding protein glycosylation isomer, decreased markedly. No ascites, pleural effusion, esophagogastric varices, or relapse of encephalopathy were observed during a 1-year postoperative follow-up period. Conclusions: Liver failure caused mainly by the advanced development of PSSs (as in our case), rather than hepatic parenchymal cell dysfunction, is considered reversible and controllable via PSS occlusion. We herein propose a novel concept, “portal-systemic liver failure,” to describe liver failure with a non-stiff liver and giant PSSs, as in the present case. In patients with “portal-systemic liver failure,” BRTO could potentially improve the prognosis in association with improved hepatic reserve and fibrosis.

We have performed a genome-wide association study (GWAS) including 473 Japanese HBV (hepatitis B virus)-positive HCC (hepatocellular carcinoma) patients and 516 HBV carriers including chronic hepatitis and asymptomatic carrier individuals to identify new host genetic factors associated with HBV-derived HCC in Japanese and other East Asian populations. We identified 65 SNPs with P values −4 located within the HLA class I region and three SNPs were genotyped in three independent population-based replication sets. Meta-analysis confirmed the association of the three SNPs (rs2523961: OR = 1.73, P = 7.50 × 10−12; rs1110446: OR = 1.79, P = 1.66 × 10−13; and rs3094137: OR = 1.73, P = 7.09 × 10−9). We then performed two-field HLA genotype imputation for six HLA loci using genotyping data to investigate the association between HLA alleles and HCC. HLA allele association testing revealed that HLA-A * 33:03 (OR = 1.97, P = 4.58 × 10−4) was significantly associated with disease progression to HCC. Conditioning analysis of each of the three SNPs on the HLA class I region abolished the association of HLA-A*33:03 with disease progression to HCC. However, conditioning the HLA allele could not eliminate the association of the three SNPs, suggesting that additional genetic factors may exist in the HLA class I region.

Mesenchymal stem cells (MSCs) are commonly used in regenerative medicine, but their therapeutic effects vary depending on the culture environment. Hypoxic culturing can be used to maintain stem cells in an undifferentiated state, but is expensive and difficult to perform. The aim of this study was to determine the effectiveness of desferrioxamine (DFO), a hypoxia-mimetic reagent, as an alternative to hypoxic culturing by analyzing metabolic changes in MSCs under hypoxic conditions compared with changes induced by DFO. Low concentrations of DFO reduced mitochondrial activity and apoptosis. Therefore, low concentrations of DFO may be useful for MSC preconditioning. Metabolome analysis showed that both hypoxic treatment and DFO administration exhibited similar metabolite patterns except purine, pyrimidine, and tricarboxylic acid cycle (TCA) cycle related metabolites. Therefore, the use of DFO at low concentrations is a potential substitute for hypoxic culturing. These findings may form the foundation for the development of future regenerative therapies using MSCs.

Purpose The utility of chromoendoscopy for early gastric cancer (GC) was determined by machine learning using data of color differences. Methods Eighteen histopathologically confirmed early GC lesions were examined. We prepared images from white light endoscopy (WL), indigo carmine (Indigo), and acetic acid-indigo carmine chromoendoscopy (AIM). A border between cancerous and non-cancerous areas on endoscopic images was established from post-treatment pathological findings, and 2000 pixels with equivalent luminance values were randomly extracted from each image of cancerous and non-cancerous areas. Each pixel was represented as a three-dimensional vector with RGB values and defined as a sample. We evaluated the Mahalanobis distance using RGB values, indicative of color differences between cancerous and non-cancerous areas. We then conducted diagnosis test using a support vector machine (SVM) for each image. SVM was trained using the 100 training samples per class and determined which area each of 1900 test samples per class came from. Results The means of the Mahalanobis distances for WL, Indigo, and AIM were 1.52, 1.32, and 2.53, respectively and there were no significant differences in the three modalities. Diagnosability per endoscopy technique was assessed using the F1 measure. The means of F1 measures for WL, Indigo, and AIM were 0.636, 0.618, and 0.687, respectively. AIM images were better than WL and Indigo images for the diagnosis of GC. Conclusion Objective assessment by SVM found AIM to be suitable for diagnosis of early GC based on color differences.

Background Sorafenib (SFN) is an anti-angiogenic chemotherapeutic that prolongs survival of patients with hepatocellular carcinoma (HCC); its side effects, including vascular damages such as hand-foot syndrome (HFS), are a major cause of therapy discontinuation. We previously reported that maintenance of peripheral blood flow by intake of dried bonito broth (DBB) significantly prevented HFS and prolonged the administration period. The amino acids contained in DBB probably contribute to its effects, but the mechanism has not been clarified. We hypothesized that histidine, the largest component among the amino acids contained in DBB, has effects on SFN-induced vascular damage, and evaluated this possibility using a novel medaka fish model. Methods The fli::GFP transgenic medaka fish model has a fluorescently visible systemic vasculature. We fed the fish with SFN with and without histidine to compare blood flow and vascular structure among the differently fed models. The vascular cross-sectional area of each fish was measured to determine vascular diameter changes. Results Our results demonstrated that SFN-fed medaka developed a narrower vascular diameter. In addition, this narrowing was counteracted by addition of histidine to the medaka diet. We observed no positive effect of histidine on regeneration of cut vessels or on cell growth of endothelial cells and HCC cell lines. Conclusion We proved the efficacy of the medaka model to assess vascular changes after administration of specific chemicals. And our results suggest that SFN causes vascular damage by narrowing peripheral vessel diameter, and that histidine effectively counteracts these changes to maintain blood flow.

A nationwide survey was performed to clarify the recent status of acute liver failure (ALF) and late-onset hepatic failure (LOHF) in Japan. Two-step surveys for patients with ALF and LOHF meeting the Japanese diagnostic criteria were performed annually in 782 hospitals. The clinical features of the patients were then compared to those reported in previous surveys. In total, 1554 and 49 patients with ALF and LOHF, respectively, who were seen between 2010 and 2015 were enrolled. The subjects were classified into 1280 patients with hepatitis (642 non-comatose and 638 comatose) and 323 patients without hepatitis (190 non-comatose and 133 comatose). Compared with patients seen between 1998 and 2009, an older patient age and a higher percentage of underlying extrahepatic disease were observed. Although hepatitis virus infection was the most frequent etiology, the percentage of patients with this etiology had decreased, compared with previous cohorts, while the percentages of patients with drug-induced liver injuries, autoimmune hepatitis, and an indeterminate etiology had increased. Liver transplantation was performed in 170 patients (10.6%), whereas artificial liver support with plasmapheresis and/or hemodiafiltration were performed for most of the comatose patients. The outcomes of comatose patients were unfavorable, similar to previous surveys, especially the outcomes of hepatitis B virus carriers, including those with de novo hepatitis B (survival rate of 5.4% without liver transplantation). Although the clinical features, including the etiologies, of patients with ALF and LOHF have changed, the outcomes of patients have not improved in recent years.

The purpose of this study was to evaluate predictors of reduction in ammonia levels by occlusion of portosystemic shunts (PSS) in patients with cirrhosis.Forty-eight patients with cirrhosis (21 women, 27 men; mean age, 67.8 years) with PSS underwent balloon-occluded retrograde transvenous obliteration (BRTO) at one institution between February 2008 and June 2014. The causes of cirrhosis were hepatitis B in one case, hepatitis C in 20 cases, alcohol in 15 cases, nonalcoholic steatohepatitis in eight cases, and other conditions in four cases. The Child-Pugh classes were A in 24 cases, B in 23 cases, and C in one case. The indication for BRTO was gastric varices in 40 cases and hepatic encephalopathy in eight cases. Testing was conducted before and 1 month after the procedure. Statistical analyses were performed to identify predictors of a clinically significant decline in ammonia levels after BRTO.Occlusion of PSS resulted in a clinically significant decrease in ammonia levels accompanied by increased portal venous flow and improved Child-Pugh score. Univariate analyses showed that a reduction in ammonia levels due to BRTO was significantly related to lower plasma glucose levels, higher RBC counts, and higher hemoglobin concentration before the treatment. Furthermore, multivariate logistic regression identified preoperative plasma glucose level as the strongest independent predictor of a significant ammonia reduction in response to BRTO. In addition, although BRTO resulted in significantly declined ammonia levels in patients with normal glucose tolerance before the procedure, ammonia levels were not significantly decreased after shunt occlusion in patients with diabetes mellitus or impaired glucose tolerance before BRTO, according to 75-g oral glucose tolerance test results.Preoperative plasma glucose level is a useful predictor of clinically significant ammonia reduction resulting from occlusion of PSS in patients with cirrhosis. Even if PSS are present, control of blood ammonia levels by BRTO alone may be difficult in patients with glucose intolerance.

Epstein–Barr virus-associated gastric carcinoma (EBVaGC) can develop in gastric mucosa affected by Helicobacter pylori (H. pylori)-induced atrophic gastritis. However, it is unclear whether EBVaGC can develop in gastric mucosa after successful eradication of H. pylori. We report 3 cases of EBVaGC discovered more than 5 years after successful eradication of H. pylori. All 3 cases are men with a history of smoking. The periods from successful eradication to development of EBVaGC were 18, 8, and 9 years, respectively. Their tumors were mainly depressed lesions located in the gastric corpus. Two patients had intramucosal cancer and the other had advanced gastric cancer. Mucosal atrophy was present in the background gastric mucosa of all of three, and the anti-H. pylori antibody titer in each patient had fallen to

Helicobacter pylori can infect the gastric mucosa and cause chronic inflammation, resulting in various diseases, including gastric cancer. Eradication of H. pylori in all infected subjects is recommended; however, the number of H. pylori strains with antibiotic resistance has increased, and the eradication rate has decreased. Vonoprazan, a potassium-competitive acid blocker, produces a stronger acid-inhibitory effect than proton pump inhibitors (PPIs). The H. pylori eradication rate with vonoprazan was found to be higher than that with PPIs. The H. pylori eradication rate with vonoprazan-based triple therapy (vonoprazan, amoxicillin, and clarithromycin) was approximately 90% and had an incidence of adverse events similar to that of PPIs. We review the current situation of H. pylori eradication in Japan, the first country in which vonoprazan was made available.

A questionnaire survey was conducted on the administration of secondary chemotherapy for unresectable or recurrent gastric cancer by 43 doctors involved in gastric cancer treatment in the Yamaguchi prefecture. Seventy-one percent of doctors replied that the secondary chemotherapy transfer rate was more than 60%, and 29% of doctors replied that the secondary chemotherapy transfer rate was less than 60%. The reasons why patients could not be transferred to secondary chemotherapy included inferior performance status, poor general condition, and elderly age, among others. Weekly paclitaxel plus ramucirumab therapy was used as the major regimen of secondary chemotherapy by 95% of doctors. In addition, 93% of doctors indicated that weekly nab-paclitaxel would be an option for gastric cancer secondary chemotherapy. Secondary chemotherapy for gastric cancer in the Yamaguchi prefecture has a standard regimen selection according to guidelines.

Liver cirrhosis is the end stage of chronic liver disease, and the only radical treatment for decompensated liver cirrhosis is still liver transplantation. Development of effective regenerative therapy for liver cirrhosis is an urgent task. Before human clinical trials can be considered, the safety and efficacy of any planned protocol must be confirmed in medium-to-large animals. Therefore, we have developed a novel canine liver fibrosis model for proof of concept (POC) studies.

An 81-year-old woman was brought to our hospital with septic shock due to severe acute cholangitis. Her blood pressure was 61/39 mm Hg, and her SpO2 was 99% with 6 L/min oxygen administration. CT showed common bile duct stones and abscess formation in the liver bed. We decided to perform urgent

Postoperative biliary strictures are usually complications of cholecystectomy. Endoscopic plastic stent prosthesis is generally undertaken for treating benign biliary strictures. Recently, fully covered metal stents have been shown to be effective for treating benign distal biliary strictures. We present the case of a 53-year-old woman with liver injury in which imaging studies showed a common hepatic duct stricture. Endoscopic retrograde cholangiopancreatography also confirmed the presence of a common hepatic duct stricture. Temporally fully covered metal stents with dilated diameters of 6 mm were placed in a side-by-side fashion in the left and right hepatic ducts, respectively. We removed the stents 2 months after their placement. Subsequent cholangiography revealed an improvement in the biliary strictures. Although we were apprehensive about the fully covered metal stents obstructing the biliary side branches, we noted that careful placement of the bilateral metal stents did not cause any complications. Side-by-side deployment of bilateral endoscopic fully covered metal stents can be one of the safe and effective therapies for postoperative biliary stricture.

Background and study aims: Light-emitting diodes (LEDs) are used widely for their high luminous efficiency and durability. We developed a novel prototype high definition endoscope with white LEDs and evaluated the image quality it produced against a commercial endoscope with conventional light source. Patients and methods: The specifications of both colonoscopes were identical, except for the LED light source at the tip of the prototype. We examined 20 patients with rectal or sigmoid colon lesions and the image quality was evaluated in 40 images (one image from the LED colonoscope and one from the conventional colonoscope for each lesion) by three endoscopists. We additionally evaluated the 17 videos recorded with the LED colonoscope that were available. Image quality, mucosal and vascular color, and luminous distribution and intensity were scored on a 5-point scale. Results: The mean score for vascular color given by one evaluator was significantly higher using the LED colonoscope than using the conventional colonoscope. The mean scores for mucosal color and luminous intensity from another evaluator were significantly lower with the LED colonoscope than with the conventional colonoscope. There were no significant differences in the luminous distribution scores for any of the evaluators. The image quality of the videos was evaluated as being similar with both colonoscopes. Conclusions: Image quality from the LED and conventional colonoscopes were similar, although the luminous intensity of the LEDs is inferior to that of the conventional light source at the present time.

The Japanese Society of Gastroenterology revised the evidence-based clinical practice guidelines for liver cirrhosis in 2015. Eighty-three clinical questions were selected, and a literature search was performed for the clinical questions with use of the MEDLINE, Cochrane, and Igaku Chuo Zasshi databases for the period between 1983 and June 2012. Manual searching of the latest important literature was added until August 2015. The guidelines were developed with use of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. This digest version in English introduces selected clinical questions and statements related to the management of liver cirrhosis and its complications. Branched-chain amino acids relieve hypoalbuminemia and hepatic encephalopathy and improve quality of life. Nucleoside analogues and peginterferon plus ribavirin combination therapy improve the prognosis of patients with hepatitis B virus related liver cirrhosis and hepatitis C related compensated liver cirrhosis, respectively, although the latter therapy may be replaced by direct-acting antivirals. For liver cirrhosis caused by primary biliary cirrhosis and active autoimmune hepatitis, urosodeoxycholic acid and steroid are recommended, respectively. The most adequate modalities for the management of variceal bleeding are the endoscopic injection sclerotherapy for esophageal varices and the balloon-occluded retrograde transvenous obliteration following endoscopic obturation with cyanoacrylate for gastric varices. Beta-blockers are useful for primary prophylaxis of esophageal variceal bleeding. The V2 receptor antagonist tolvaptan is a useful add-on therapy in careful diuretic therapy for ascites. Albumin infusion is useful for the prevention of paracentesis-induced circulatory disturbance and renal failure. In addition to disaccharides, the nonabsorbable antibiotic rifaximin is useful for the management of encephalopathy. Anticoagulation therapy is proposed for patients with acute-onset or progressive portal vein thrombosis.

Advancements in antiviral drugs have enabled control of viral hepatitis; yet, many patients with liver cirrhosis (LC) are awaiting liver transplants. Liver transplantation yields dramatic therapeutic effects, but problems such as shortage of donors, surgical invasiveness, immunological rejection and costs, limit the number of transplantations. Advances in liver regeneration therapy through cell transplantation as a non-invasive treatment for cirrhosis will supplement these restrictions to the number of liver transplants. Clinical trials for LC have included hematopoietic stem cell mobilization by administration of granulocyte colony-stimulating factor, infusion of autologous bone marrow cells, and administration of autologous mesenchymal stem cells derived from bone marrow or umbilical cord. Several recently reported randomized controlled studies have shown the effectiveness of these approaches. However, to promote implementation of new liver regeneration therapies, it is important to develop a system whereby cell therapies with ensured safety can be approved quickly.

Background/Aims: Distinguishing pancreatic ductal carcinoma (DC) from other pancreatic masses remains challenging. This study aims at evaluating the efficacy of contrast-enhanced harmonic endoscopic ultrasonography (CEH-EUS) in the diagnosis of DC. Patients and Methods: Forty-nine patients with solid pancreatic mass lesions underwent CEH-EUS. EUS (B-mode) was used to evaluate the inner echoes, distributions, and borders of the masses. The vascular patterns of the masses were evaluated with CEH-EUS at 30–50 s (early phase) and 70–90 s (late phase) after the administration of Sonazoid®. Results: The final diagnoses included DCs (37), mass-forming pancreatitis (6), endocrine neoplasms (3), a solid pseudopapillary neoplasm (1), a metastatic carcinoma (1), and an acinar cell carcinoma (1). The sensitivity, specificity, and accuracy of the diagnoses of DC in hypoechoic masses using EUS (B-mode) were 89.2%, 16.7%, and 71.4%, respectively. The sensitivity, specificity, and accuracy for the diagnosis of DC in hypovascular masses using CEH-EUS were 73.0%, 91.7%, and 77.6% in the early phase and 83.8%, 91.7%, and 85.7% in the late phase, respectively. Conclusions: CEH-EUS for the diagnosis of DC is superior to EUS. CEH-EUS in the late phase was particularly efficacious in the diagnosis of DC.

Introduction We have reported previously that fecal DNA testing of TWIST1 methylation in combination with the fecal immunochemical test for hemoglobin (FIT) (combination test) is useful for colorectal neoplasia screening. In this study, using larger sample sizes, we studied the clinical performance of the combination test for the detection of colorectal neoplasia and, especially, advanced colorectal adenoma. Methods We performed a prospective study in which FIT, fecal DNA testing of TWIST1 methylation, and colonoscopy were performed on 372 patients with colorectal neoplasia and 71 subjects without colorectal neoplasia. We assessed the individual clinical performance of each of FIT and fecal DNA testing of TWIST1 methylation and of the combination test for the detection of colorectal neoplasia including advanced adenoma based on morphologic subtypes. Results The FIT alone had a sensitivity of 7.5% (3/40) for nonadvanced adenoma, 32.3% (41/127) for advanced adenoma, and 93.7% (192/205) for colorectal cancer and a specificity of 87.3% (62/71). The combination test had a sensitivity of 35.0% (14/40) for nonadvanced adenoma, 68.5% (87/127) for advanced adenoma, and 95.6% (196/205) for colorectal cancer and a specificity of 80.3% (57/71). For morphological subtypes of advanced adenoma, the sensitivity of FIT was only 28.2% (20/71) for polypoid type and 16.1% (5/31) for nonpolypoid type, whereas the combination test increased the sensitivities to 64.8% (46/71) and 71.0% (22/31), respectively. Discussion The combination of the fecal DNA test with FIT seemed to be useful to detect colorectal neoplasia and, especially, advanced adenoma of the nonpolypoid type.