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AIM This study aimed to demonstrate the feasibility of identifying candidates of portopulmonary hypertension (PoPH) from general portal hypertension patients based on chest computed tomography (CT) results. METHODS One hundred and thirty patients with portal hypertension who had undergone interventional radiology therapies at our hospital between August 2011 and July 2021 were included, and preoperative clinical data were collected. Suspicious PoPH was defined as main pulmonary artery diameter (mPA-D) ≥ 29 mm or the ratio of mPA-D to ascending aorta diameter (mPA-D/aAo-D) ≥ 1.0, and probable PoPH as mPA-D ≥ 33 mm based on the chest CT. Prevalence of suspicious and probable PoPH was evaluated, and the differences in clinical characteristics of each population were compared. RESULTS Overall, 29 (22.3%) and 5 (3.8%) patients were categorized as suspicious and probable PoPH, respectively. Univariate analyses revealed that female sex, higher shortest diameter of inferior vena cava, presence of portosystemic shunts ≥ 5 mm, and lower blood urea nitrogen levels were significantly associated with suspicious PoPH (P < 0.05). Multivariate analysis identified all four factors as significantly independent determinants of suspicious PoPH (P < 0.05). In addition, among the population of suspicious PoPH, there were significant differences in seven parameters, including total bilirubin levels and spleen volume between patients with and without probable PoPH (P < 0.05). However, no significant independent indicators of probable PoPH were found. CONCLUSIONS CT-based measurements of mPA-D and mPA-D/aAo-D have the potential to screen patients with suspicious PoPH in clinical practice focused on portal hypertension. This article is protected by copyright. All rights reserved.

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.

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 Japanese 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.

Background and Aim In Japan, corticosteroids have been commonly used as a part of multidisciplinary therapy for patients with acute liver failure and late‐onset hepatic failure. However, there is controversy regarding the development of infections and other complications. In this study, the influence of corticosteroids on patient outcomes after liver transplantation was investigated. Methods This study included 167 patients with acute liver failure and late‐onset hepatic failure who underwent liver transplantation between 2010 and 2015. The effects of pretransplant corticosteroid therapy on patient outcomes were evaluated using a database constructed by the subcommittee for fulminant hepatitis in the Intractable Hepato‐Biliary Diseases Study Group of Japan. Results The subacute type and the median total bilirubin levels were higher in those receiving corticosteroids than in those not receiving corticosteroids. Although infections tended to be higher in patients receiving corticosteroids, pretransplant corticosteroid administration did not affect the survival rates. The duration from corticosteroid initiation to liver transplantation was longer in patients who developed infections. The survival rates, however, did not differ between patients with and without infections. Conclusions Corticosteroids were administered to patients with poor prognoses. Otherwise, the overall outcome in those administered corticosteroids was not significantly different from that in those administered without corticosteroids. Although infectious complications tended to occur, they were generally controllable and nonfatal. Pretransplant corticosteroid therapy may be permissible, with regarding for infections and performed within the minimum duration., Corticosteroids are commonly used for acute liver failure in Japan. However, there is controversy regarding the development of complications. We analyzed the influence of corticosteroids on patient outcomes after liver transplantation. Although, infections tended to occur in patients receiving corticosteroids, pretransplant corticosteroid didn't affect the survival rates. The duration from corticosteroid initiation to liver transplantation was longer in patients with infections. Pretransplant corticosteroid may be a permissible treatment with caution for infections and within the minimum duration.

Objective Persistent hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are major causative factors of hepatic cirrhosis and hepatocellular carcinoma. However, the development of antiviral treatment has enabled their suppression. Therefore, the early detection and treatment of these infections are important. The objective of this study was to assess the level of awareness among healthcare professionals about hepatitis virus infection and electronic medical records alert system. Methods We surveyed healthcare professionals from 10 institutions with electronic medical records alert systems. All participants attended a lecture about the reactivation risk due to HBV infections, the most recent antiviral treatment for HCV infections, and the electronic medical records alert system. They participated in a questionnaire-based survey about their awareness of these infections, current status of intra-hospital referral, need for intra-hospital referrals before and after the lecture, and reasons for non-referral of patients to specialists. Results Responses were received from 1,281 healthcare professionals. Physicians and pharmacists had a high level of awareness about HBV and HCV. Among physicians, the level of awareness of those in the surgical field and other fields was significantly lower than that of the professionals in the internal medicine field. The awareness of the need to refer patients to hepatologists increased from 84.7-85.4% before to 93.0% after the lecture. The most frequent reasons for not referring patients previously were "I had no knowledge and/or interest" (28.1% of responses) and "All I did was explain the results orally" (24.2%). Conclusion More widespread education of healthcare personnel is important to increase the number of individuals receiving appropriate treatment from specialist physicians.

Organisms living in temperate regions are sensitive to seasonal variations in the environment; they are known to accumulate energy as fat in their livers during the winter when days are shorter, temperatures are lower, and food is scarce. However, the effect of variations in photoperiod alone on hepatic lipid metabolism has not been well studied. Therefore, in this study, we analyzed lipid metabolism in the liver of medaka, Oryzias latipes, while varying the length of days at constant temperature. Larger amounts of fatty acids accumulated in the liver after 14 days under short‐day conditions than under long‐day conditions. Metabolome analysis showed no accumulation of long‐chain unsaturated fatty acids, but showed a significant accumulation of long‐chain saturated fatty acids. Short‐day conditions induced a reduction in the levels of succinate, fumarate, and malate in the tricarboxylic acid cycle, decreased expression of PPARα, and decreased accumulation of acylcarnitine, which suggested inhibition of lipolysis. In addition, transparent medaka fed on a high‐fat diet under short‐day conditions exhibited greater amounts of fat accumulation and developed fatty liver. The findings of our study will be useful for creating a medaka hepatic steatosis model for future studies of hepatic steatosis‐related diseases., In this study, we analyzed lipid metabolism in the liver of medaka, Oryzias latipes, while varying the length of days at constant temperature. Larger amounts of fatty acids accumulated in the liver after 14 days under short‐day conditions than under long‐day conditions. The findings of our study will be useful for creating a medaka hepatic steatosis model for future studies of hepatic steatosis‐related diseases.

Background: Although serum carbohydrate antigen 19-9 (CA19-9) is widely used as a useful biomarker of pancreatic cancer for monitoring the response to therapy, it is not recommended for screening of early pancreatic cancer because of its limited sensitivity for small tumors. Thus, it is critical to discover novel serum biomarkers to complement CA19-9 in order to improve sensitivity. Although methylated runt-related transcription factor 3 (RUNX3) is a biomarker of pancreatic cancer, its detection by conventional bisulfite-based methylation assays from a small serum sample amount is very difficult. Therefore, we developed a new methylation assay, the combined restriction digital PCR (CORD) assay, that enables counting of even one copy of a methylated gene in a small DNA sample amount without DNA bisulfite treatment. Objectives: We evaluated the sensitivity and specificity of serum DNA testing of methylated RUNX3 by the CORD assay in combination with and without CA19-9 for the detection of pancreatic cancer in 55 patients with pancreatic cancer, 12 patients with benign pancreatic disease, and 80 healthy individuals. Results: The CORD assay of methylated RUNX3 had a sensitivity of 50.9% (28/55) and specificity of 93.5% (86/92). Combination of the CORD assay of methylated RUNX3 and CA19-9 resulted in a sensitivity of 85.5% (47/55) and specificity of 93.5% (86/92) for all stages of pancreatic cancer and a sensitivity of 77.8% (7/9) for stage I pancreatic cancer. Conclusions: ombination of the CORD assay and CA19-9 may provide an alternative screening strategy for detecting early-stage pancreatic cancer.

Liver transplantation is the only radical treatment for decompensated cirrhosis, but its use is limited owing to a shortage of donors; hence, there is an urgent need for new treatments. Previously, we developed a liver-regeneration therapy using autologous bone marrow-derived mesenchymal stem cells (BMSCs), which is under clinical investigation. Cell-cell interactions between BMSCs and macrophages (Mφs) participate in the improvement of liver function and alleviation of liver fibrosis, although the associated mechanisms have not been elucidated. Therefore, in this study, we investigated phenotypic changes in Mφs caused by interactions with BMSCs, as well as the underlying mechanisms. Co-culturing lipopolysaccharide (LPS)-stimulated murine bone marrow-derived Mφs (BMDMs) with BMSCs substantially upregulated matrix metalloproteinase 9 (

The incidence of nonalcoholic steatohepatitis-related liver cirrhosis is increasing. We used a steatohepatitis murine model fed a choline-deficient, l-amino acid-defined (CDAA) diet with a single injection of carbon tetrachloride (CCl4) to evaluate the efficacy of trans-portal hepatic infusion of bone marrow-derived mesenchymal stem cells (BMSCs) for liver fibrosis, liver steatosis, and oxidative stress. Mice were fed a CDAA diet and injected with a single intraperitoneal dose of CCl4 (0.5 ml/kg) after 4 weeks of CDAA diet. After 12 weeks of CDAA diet, 1 × 106 luciferase-positive syngeneic BMSCs (Luc-BMSCs) were infused into the animal spleen. An in vivo imaging system was used to confirm Luc-BMSC accumulation in the liver via the portal vein, and at 4 weeks after infusion, we compared liver fibrosis, liver steatosis, and oxidative stress. After the BMSC-infusion, serum albumin and serum total bilirubin were significantly improved. Liver fibrosis assessed by Sirius red staining, α-smooth muscle actin protein, and collagen 1A1 mRNA expression was significantly suppressed. Furthermore, liver steatosis area was significantly lower, the 8-hydroxy-2'-deoxyguanosine-positive cells were significantly fewer, and superoxide dismutase 2 protein expression of the liver was significantly increased. In conclusion, our data confirmed the efficacy of trans-portal hepatic infusion of BMSCs in a steatohepatitis murine model.

Aim To describe a case of hepatitis C virus-related decompensated cirrhosis with portal-systemic liver failure and refractory encephalopathy that was successfully managed with a combination of interventional radiology and pharmacotherapy to improve hepatic function including hyperammonemia and to control portal-splenic venous hemodynamics with hepatic venous pressure gradient (HVPG) monitoring. Case presentation A man in his late 50s presented with a Child-Pugh score of 13, Model for End-Stage Liver Disease-sodium (MELD-Na) score of 19, and blood ammonia level of 185 μg/dL. He underwent balloon-occluded retrograde transvenous obliteration (BRTO) followed by partial splenic embolization (PSE) and non-selective beta-blocker (NSBB) administration. BRTO induced drastic changes in the portal-splenic venous hemodynamics, resulting in dramatically improved hepatic function and reduced hyperammonemia. However, the procedure resulted in increased HVPG from 13.6 mmHg at baseline to 23.5 mmHg at 1-month post-BRTO, accompanied by ascites retention and portal hypertensive gastropathy (PHG) development. Thereafter, PSE was performed, followed by NSBB administration, to control the elevated portal venous pressure following BRTO. Postoperatively, the patient's ascites and PHG improved after splenic artery embolization, which eventually disappeared after the additional administration of NSBBs at 1 month later. The HVPG finally decreased to 16.9 mmHg, and Child-Pugh score, MELD-Na score, and blood ammonia level improved to 7, 11, and 22 μg/dL, respectively, after all therapies. Conclusion BRTO significantly improved the symptoms of portal-systemic liver failure with refractory encephalopathy. PSE and NSBB administration could contribute to additional amelioration of hepatic function and successful management of complications induced by portal hemodynamic changes following BRTO.

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.

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.

Liquid biopsies are not used in practice for hepatocellular carcinoma (HCC). Epi proColon is the first commercial blood‐based test for colorectal cancer screening based on methylated DNA testing of the septin 9 gene (SEPT9). However, Epi proColon has some disadvantages, including the requirement of a large amount of blood and lack of quantitative performance. Therefore, we previously developed a novel liquid biopsy test that can quantitatively detect even a single copy of methylated SEPT9 in a small amount of DNA. In the current study, we evaluated the application potential of this assay for diagnosing HCC. Study subjects included 80 healthy volunteers, 45 patients with chronic liver disease (CLD) without HCC, and 136 patients with HCC (stage 0, 12; stage A, 50; stage B, 31; stage C, 41; and stage D, 2), according to the Barcelona Clinic Liver Cancer staging system. For the assay, DNA was treated with methylation‐sensitive restriction enzymes in two steps, followed by multiplex droplet digital polymerase chain reaction. The median copy number of methylated SEPT9 was 0.0, 2.0, and 6.4 in the healthy control, CLD, and HCC groups, respectively, with significant differences among the groups (HCC vs. healthy control, P

Introduction: Radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC) is considered a safe and minimally invasive procedure. We previously reported that the mortality and complication rates for RFA were 0.038% (5/13,283 patients) and 3.54% (579 complications/16,346 procedures), respectively, from 1999 to 2010 (previous period). In this study, we investigated the clinical criteria for RFA and the mortality and complication rates from 2011 to 2015 (recent period). Methods: Data were collected from 25 centers by using a questionnaire developed by the Chugoku-Shikoku Society for Local Ablation Therapy of HCC. The criteria for RFA, RFA modification, use of image-guidance modalities, mortality, and complications during the previous and recent periods were compared. Results: We evaluated 11,298 procedures for 9,411 patients, including those that involved new devices (bipolar RFA and internally adjustable electrode system). The criterion of hepatic function for RFA increased from a Child-Pugh score ≤8 during the previous period to ≤9 during the recent period. The criteria regarding the tumor location and other risk factors have been expanded recently because of the increased use of several modifications of the RFA procedure and image-guidance modalities. The mortality rate was 0.064% (6/9,411 patients), and the complication rate was 2.92% (330 complications/11,298 procedures). There was no difference in mortality rates between the 2 periods (p = 0.38), but the complication rates was significantly lower during the recent period (p = 0.038). Discussion and Conclusions: Our findings confirmed that RFA, including the use of new devices, is a low-risk procedure for HCC, despite the expansion of the criteria for RFA during the recent period.

Mesenchymal stem cells, which have the potential to be used in regenerative medicine, require improvements in quality for patient use. To maintain stemness of cultured bone marrow-derived mesenchymal stem cells, we focused on the bone marrow microenvironment, generated a conditioned medium of whole bone marrow cells (BMC-CM), and assessed its effects on bone marrow-derived mesenchymal stem cells. BMC-CM suppressed morphological deterioration and proliferative decline in cultured bone marrow-derived mesenchymal stem cells, suppressed mitochondrial oxidative phosphorylation activity, a stemness indicator, and upregulated suppressors of oxidative phosphorylation such as hypoxia-inducible factor-1 alpha, Sirtuin 3, 4, and 5. Furthermore, BMC-CM upregulated TNF-stimulated gene 6 and ameliorated the therapeutic effects of cells on liver injury in carbon tetrachloride-administered rats. Since the elimination of 20-220-nm particles attenuated the effects of BMC-CM, we further analyzed exosomal microRNAs produced by whole bone marrow cells. Among the 49 microRNAs observed to be upregulated during the preparation of BMC-CM, several were identified that were associated with suppression of oxidative phosphorylation, upregulation of TNF-stimulated gene 6, and the pathogenesis of liver diseases. Thus, bone marrow-derived humoral factors including exosomal microRNAs may help to improve the therapeutic quality of bone marrow-derived mesenchymal stem cells for liver regenerative therapy.

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.

Daily salt intake can be estimated by measuring sodium and creatinine concentrations in spot urine. Excessive salt intake is risk factor for gastric cancer. We examined the correlation between estimated salt intake from spot urine and risk of gastric cancer. This study included gastric cancer patients who underwent treatment at our hospital and patients in whom esophagogastroduodenoscopy was performed but gastric cancer was not observed. The history of H. pylori infection was known in these patients. Spot urine was collected, and daily salt intake was estimated from urine sodium and urine creatinine. Mean estimated salt intake was significantly higher in 120 gastric cancer patients (9.18 g/day) than in 80 non-gastric cancer patients (8.22 g/day). Multivariate analysis revealed estimated salt intake and H. pylori infection to be independent risk factors for gastric cancer. Among H. pylori-infected patients, salt intake was significantly higher in gastric cancer patients (9.25 g/day) than in non-gastric cancer patients (8.01 g/day). In conclusion, salt intake estimated from spot urine was high in patients with gastric cancer, especially in H. pylori infected patients. Spot urine is a simple examination and it may be applied as a new risk assessment of gastric cancer.

Among lifestyle-related diseases, fatty liver is the most common liver disease. To date, mammalian models have been used to develop methods for inhibiting fatty liver progression, however, new, more efficient models are expected. This study investigated the creation of a new model to produce fatty liver more efficiently than the high-fat diet medaka model that has been used to date. We compared the GAN (Gubra-Amylin nonalcoholic steatohepatitis) diet, which has been used in recent years to induce fatty liver in mice, and the high-fat diet (HFD). Following administration of the diets for three months, enlarged livers and pronounced fat accumulation was noted. The GAN group had large fat vacuoles and lesions, including ballooning, compared to the HFD group. The GAN group had a higher incidence of lesions. When fenofibrate was administered to the fatty liver model created via GAN administration and liver steatosis was assessed, a reduction in liver fat deposition was observed, and this model was shown to be useful in drug evaluations involving fatty liver. The medaka fatty liver model administered with GAN will be useful in future fatty liver research.

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

Few studies exist on the relationship between post-progression survival (PPS) and skeletal muscle volume in hepatocellular carcinoma (HCC) patients receiving sorafenib. This study aimed to analyze the effects of muscle volume on clinical outcomes. We retrospectively enrolled 356 HCC patients. Various clinical parameters, including skeletal muscle index, were analyzed as predictors of overall survival (OS), progression-free survival (PFS), and PPS. Patients with high muscle volume showed longer survival or PPS than those with low muscle volume (median survival time: 12.8 vs. 9.5 months, p = 0.005, median PPS: 8.2 vs. 6.3 months, p = 0.015), however, no differences in PFS were found. Multivariate analysis indicated that muscle volume was an independent predictor of PPS and OS. Skeletal muscle volume was a PPS predictor in HCC patients receiving sorafenib. Therefore, survival can be prolonged by the upregulation of skeletal muscle volume, especially in HCC patients with skeletal muscle depletion.

Objectives Liver transplantation remains the only curative therapy for decompensated liver cirrhosis. However, it has several limitations, and not all patients can receive liver transplants. Therefore, liver regenerative therapy without liver transplantation is considered necessary. In this study, we attempted minimally invasive liver regenerative therapy by peripheral vein infusion of bone marrow-derived mesenchymal stem cells (BMSCs) cultured from a small amount of autologous bone marrow fluid and evaluated the effects of BMSCs on hepatocarcinogenesis in a mouse model. Methods C57BL/6 male mice were injected intraperitoneally with N-nitrosodiethylamine once at 2 weeks of age, followed by carbon tetrachloride twice a week from 6 weeks of age onwards, to create a mouse model of highly oncogenic liver cirrhosis. From 10 weeks of age, mouse isogenic green fluorescent protein–positive BMSCs (1.0 × 106/body weight) were infused once every 2 weeks, for a total of 5 times, and the effects of frequent BMSC infusion on hepatocarcinogenesis were evaluated. Results In the histologic evaluation, no significant differences were observed between the controls and BMSC-administered mice in terms of incidence rate, number, or average size of foci and tumors. However, significant suppression of fibrosis and liver injury was confirmed in the group that received BMSC infusions. Discussion Considering that BMSC infusion did not promote carcinogenesis, even in the state of highly oncogenic liver cirrhosis, autologous BMSC infusion might be a safe and effective therapy for human decompensated liver cirrhosis.

Differences in the culturing conditions of mesenchymal stem cells used in regenerative medicine may affect their differentiation ability, genome instability, and therapeutic effects. In particular, bone marrow-derived mesenchymal stem cells cultured under hypoxia are known to proliferate while maintaining an undifferentiated state and the use of deferoxamine, a hypoxia mimetic reagent, has proven to be a suitable strategy to maintain the cells under hypoxic metabolic state. Here, the deferoxamine effects were investigated in mesenchymal stem cells to gain insights into the mechanisms regulating stem cell survival. A 12-h deferoxamine treatment reduced proliferation, oxygen consumption, mitochondrial activity, and ATP production. Microarray analysis revealed that deferoxamine enhanced the transcription of genes involved in glycolysis and the HIF1α pathway. Among the earliest changes, transcriptional variations were observed in HIF1α, NUPR1, and EGLN, in line with previous reports showing that short deferoxamine treatments induce substantial changes in mesenchymal stem cells glycolysis pathway. NUPR1, which is induced by stress and involved in autophagy-mediated survival, was upregulated by deferoxamine in a concentration-dependent manner. Consistently, NUPR1 knockdown was found to reduce cell proliferation and increase the proapoptotic effect of staurosporine, suggesting that deferoxamine-induced NUPR1 promotes mesenchymal stem cell survival and cytoprotective autophagy. Our findings may substantially contribute to improve the effectiveness of mesenchymal stem cell-based regenerative medicine.

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.