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Introduction: Globally, the number of patients with primary biliary cholangitis (PBC) is increasing. Growing evidence suggests that oxidative stress plays a significant role in the pathogenesis of chronic liver disease regardless of its etiology. Hesperidin, a natural antioxidative substance derived from citrus peel, has been shown to have an anti-inflammatory effect in a rat arthritis model and may be a potential substance to attenuate intrahepatic inflammation in patients with PBC. In this study, the potential of glucosyl hesperidin as a therapeutic agent for PBC will be investigated through antioxidative stress mechanisms., Methods: Patients with PBC who are 20 years or older will be eligible to participate. Patients will be assigned to 1 of 2 groups and given either 500 or 1000 mg of glucosyl hesperidin per day. The primary endpoint is the ratio of changes in serum gamma-glutamyl transferase levels before and after 24 weeks of glucosyl hesperidin administration. The secondary endpoints are serum hepatobiliary enzyme levels (alkaline phosphatase, transaminase, and total bilirubin levels) and the protein expression levels of nuclear factor erythroid 2-related factor 2 and its target molecule 8, 16, and 24 weeks after administration compared to before administration., Discussion: The prospective clinical interventional study was designed to assess the supportive effect of glucosyl hesperidin on hepatic function in patients with PBC receiving basic ursodeoxycholic acid treatment., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Delayed hemobilia, a rare but potentially fatal complication of endoscopic metallic stenting for malignant biliary obstruction, requires prompt identification of the source of bleeding and subsequent embolization. However, hemobilia is characteristically intermittent, and computed tomography (CT) often fails to show pseudoaneurysms or extravasations. In particular, because the posterior superior pancreaticoduodenal artery (PSPDA) runs alongside the common bile duct for its whole length, it is readily obscured by metallic artifacts in that duct, such as stents, making identification of the source of bleeding by CT difficult. We have encountered three patients with delayed hemobilia from the PSPDA following endoscopic biliary stenting for malignant biliary obstruction in whom no extravasation or pseudoaneurysms were detected by contrast-enhanced CT during bleeding. However, when we identified that the PSPDA had a smaller diameter than in previous CTs in all three cases, we suspected that the PSPDA was the source of the bleeding. No extravasation or pseudoaneurysms were detected with celiac arteriography or superior mesenteric arteriography; however, extravasation and pseudoaneurysms were detected by direct PSPDA angiography. Hemostasis was achieved through embolization. Detecting a large decrease in the diameter of the PSPDA on contrast-enhanced CT during biliary bleeding may help to identify the source of that bleeding., (© 2022. The Author(s), under exclusive licence to American Society of Emergency Radiology (ASER).)

There are many types of ovarian tumors, and these different types often form cystic masses with a similar appearance, which can make their differentiation difficult. However, with the exclusion of rare ovarian tumors, the number of ovarian tumors encountered in daily practice is somewhat fixed. It goes without saying that magnetic resonance imaging (MRI) is useful for differentiating ovarian tumors. In this review, we summarize the differential diagnoses for each of the five types of MRI findings commonly encountered in daily practice. First, unilocular cystic masses without mural nodules/solid components include benign lesions such as serous cystadenoma, functional cysts, surface epithelial inclusion cysts, paratubal cysts, and endometriosis. Second, multilocular cystic ovarian lesions include mucinous tumors and ovarian metastases. It should be noted that mucinous tumors may be diagnosed as borderline or carcinoma, even if no solid component is observed. Third, cystic lesions with mural nodules that are unrelated to endometriosis include serous borderline tumor and serous carcinoma. Cystic lesions with solid components are more likely to be malignant, but some may be diagnosed as benign. Fourth, ovarian tumors deriving from endometriosis include seromucinous borderline tumors, endometrioid carcinoma, and clear cell carcinoma. These tumors sometimes need to be differentiated from serous tumors. Finally, cystic lesions with lipid contents include teratoma-related tumors. In mature cystic teratoma, mural nodules (called "Rokitansky protuberance" or "dermoid nipple") are sometimes seen, but they do not suggest malignancy. Some of these lesions can be diagnosed accurately by considering their characteristic imaging findings, their changes over time, MRI findings other than those of the primary lesion, and information from other modalities such as tumor markers. To ensure the optimal treatment for ovarian tumors, it is important to estimate the histological type as well as to diagnose whether a lesion is benign or malignant., (© 2022. The Author(s).)

Background/aim: The current study evaluated the efficacy and toxicity of atezolizumab plus bevacizumab in patients with advanced-stage hepatocellular carcinoma in a real-world setting., Patients and Methods: This retrospective study enrolled 23 patients. The primary endpoint was progression-free survival (PFS). Antitumor responses 6 weeks after initiation of atezolizumab plus bevacizumab were assessed using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 and the modified RECIST (mRECIST). The Common Terminology Criteria for Adverse Events version 5.0 was used to evaluate the severity of adverse events. Relative changes in hepatic function and nutritional status were investigated., Results: The median PFS was 119 days. The objective response rate (ORR) and disease control rate (DCR) at 6 weeks based on RECIST were 21.7% and 60.9%, respectively. The ORR and DCR based on mRECIST were 26.1% and 69.6%, respectively. The group with hepatitis B/C-related HCC had a higher ORR based on mRECIST than the non-hepatitis B and C-related group. Patients with Barcelona Clinic Liver Cancer (BCLC) stage A and B disease had a higher DCR based on RECIST than those with BCLC stage C disease. The incidence rates of any grade and grade ≥3 adverse events were 65.2% and 21.7%, respectively. The albumin-bilirubin and Child-Pugh scores, neutrophil-to-lymphocyte ratio and skeletal muscle index did not significantly worsen within 6 weeks after treatment initiation., Conclusion: Atezolizumab plus bevacizumab is effective and safe and can help achieve complete remission in patients with advanced-stage hepatocellular carcinoma in a real-world setting. Nevertheless, large-scale studies must be conducted to validate its outcomes in this patient group., (Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Objectives: Serial pancreatic juice aspiration cytological examination (SPACE) via endoscopic retrograde cholangiopancreatography is a useful diagnostic method for early-stage pancreatic cancer, such as carcinoma in situ that are difficult to diagnose by endoscopic ultrasound-guided fine needle aspiration (EUS-FNA). However, the diagnostic accuracy of SPACE is low, which is attributed to problems regarding specimen treatment. Hence, we evaluated the diagnostic efficacy of liquid-based cytology (LBC) in pancreatic juice cytology for pancreatic cancer., Methods: We retrospectively analyzed 24 patients with suspected pancreatic cancer that was difficult to diagnose by endoscopic ultrasound-guided fine needle aspiration who underwent SPACE using LBC between April 2017 and April 2021., Results: The most common reason for performing SPACE was localized stenosis of the main pancreatic duct without a mass. Eleven patients were diagnosed with malignancy after surgical resection, nine of whom had pancreatic ductal adenocarcinoma. Ten patients were diagnosed as benign after a follow-up of more than 1 year. The nine cases of malignancy were diagnosed before surgical resection by SPACE using LBC, with a sensitivity of 81.8% and specificity of 100%. The overall diagnostic accuracy was 91.7%. A total of 152 LBC examinations were performed via SPACE, with an adequate sample collection rate of 88.9%. No adverse events, including acute pancreatitis, occurred after endoscopic retrograde cholangiopancreatography., Conclusion: SPACE with LBC offers good diagnostic efficacy in patients with pancreatic cancer that is difficult to diagnose by endoscopic ultrasound-guided fine needle aspiration., Competing Interests: The authors declare that they have no conflict of interest., (© 2022 The Authors. DEN Open published by John Wiley & Sons Australia, Ltd on behalf of Japan Gastroenterological Endoscopy Society.)

Background: Dysbiosis of gut microbiota promotes colitis in ulcerative colitis (UC). Enterococcus faecium is an important constituent of dysbiotic microbiota. However, the mechanisms underlying E. faecium-induced colitis remain unclear., Methods: Overall, 23 E. faecium strains isolated from human feces and 3 commercial strains were inoculated into Il10 -/- mice. Mouse colons were histologically evaluated and analyzed using real-time PCR analysis of cytokines. Genes in 26 E. faecium strains were identified by whole-genome shotgun sequencing of genomic DNA. The production of reactive oxygen species (ROS) from each strain was measured. An antioxidant, lipoic acid, was orally administered to the colitis mouse model., Results: Inoculation of E. faecium derived from patients with UC resulted in colitis in Il10 -/- mice. The genotypes of 26 strains were characterized by identifying 1893 known genes; clustering all the strains based on the genotypes showed two major groups-inflammatory and probiotic clusters. Additionally, linear discriminant analysis clarified that lipoic acid metabolism was a significantly abundant pathway in the probiotic cluster compared to the inflammatory cluster. Further, the production of ROS was greater in inflammatory than in probiotic strains. Administration of lipoic acid in E. faecium-inoculated mice ameliorated colitis., Conclusions: Enterococcus faecium strains in the inflammatory cluster promoted colitis with higher production of ROS than the strains in the probiotic cluster., (© 2022. Japanese Society of Gastroenterology.)

Background: Although gut-derived lipopolysaccharide (LPS) affects the progression of non-alcoholic steatohepatitis (NASH) pathogenesis, few studies have focused on this relationship to develop treatments for NASH., Aims: To explore the effects of combination with rifaximin and lubiprostone on NASH liver fibrosis through the modulation of gut barrier function., Methods: To induce steatohepatitis, F344 rats were fed a choline-deficient l-amino acid-defined (CDAA) diet for 12 weeks and received oral administration of rifaximin and/or lubiprostone. Histological, molecular, and fecal microbial analyses were performed. Barrier function in Caco-2 cells were assessed by in vitro assays., Results: Combination rifaximin/lubiprostone treatment significantly suppressed macrophage expansion, proinflammatory responses, and liver fibrosis in CDAA-fed rats by blocking hepatic translocation of LPS and activation of toll-like receptor 4 signaling. Rifaximin and lubiprostone improved intestinal permeability via restoring tight junction proteins (TJPs) with the intestinal activation of pregnane X receptor and chloride channel-2, respectively. Moreover, this combination increased the abundance of Bacteroides, Lactobacillus, and Faecalibacterium as well as decreased that of Veillonella resulting in an increase of fecal short-chain fatty acids and a decrease of intestinal sialidase activity. Both agents also directly suppressed the LPS-induced barrier dysfunction and depletion of TJPs in Caco-2 cells., Conclusion: The combination of rifaximin and lubiprostone may provide a novel strategy for treating NASH-related fibrosis., (Copyright © 2022. Published by Elsevier Ltd.)

Background/aim: To identify predictors of severe adverse events (≥grade 3) in patients with advanced hepatocellular carcinoma treated with lenvatinib., Patients and Methods: Of 41 patients, 25 and 16 were stratified into the severe and non-severe adverse events groups, respectively. Of these, 19 formed a lactulose-mannitol test subgroup, which was divided into severe adverse events (n=11) and non-severe adverse events (n=8) groups. Severe adverse events were assessed by liver disease etiology and modified albumin-bilirubin grade. Intestinal permeability by lactulose-mannitol test and serum soluble CD163, soluble mannose receptor, and zonulin levels., Results: Severe adverse event incidence rates were higher in patients with advanced hepatocellular carcinoma related to alcoholic liver disease and nonalcoholic fatty-liver disease than in those with advanced hepatocellular carcinoma of other etiologies (p=0.014). The rates were higher for modified albumin-bilirubin grades 2a and 2b compared to modified albumin-bilirubin grade 1 (p=0.0104). Zonulin levels were higher in the severe adverse event group (p=0.0331) and were independently associated with severe adverse events (odds ratio=140, 95% confidence interval=1.66-11800; p=0.029). Patients with high zonulin levels (≥0.518 ng/ml) experienced more severe adverse events than those with low levels (<0.518 ng/ml) (p=0.0137). In the lactulose-mannitol test subgroup, the urine lactulose:mannitol ratio was higher in the severe vs. non-severe adverse event group (p=0.0164). Moreover, it was higher in patients with alcoholic liver disease and nonalcoholic fatty-liver disease-related advanced hepatocellular carcinoma compared to those with other advanced hepatocellular carcinoma etiologies (p=0.0108)., Conclusion: Serum zonulin levels predict severe adverse events in patients with advanced hepatocellular carcinoma treated with lenvatinib., (Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

The prognosis of highly advanced unresectable hepatocellular carcinoma (HCC) with a portal vein tumor thrombus (PVTT) is poor. There are currently no reports of long-term survival for up to 5 years in patients with advanced HCC who were treated with sorafenib. We describe a patient with Vp4 HCC who was treated with a sorafenib-based multidisciplinary treatment and experienced long-term survival, which may be the longest survival to date. A man in his late 60 s presented with general fatigue. Eight years previously, he received interferon monotherapy for chronic hepatitis C for 48 weeks and achieved a sustained virological response. He was diagnosed with a PVTT (Vp4) with diffuse-type HCC in the S6 lobe of the liver. He received hepatic arterial infusion of chemotherapy using 5-fluorouracil and cisplatin. Because of the occurrence of adverse effects, he was placed on sorafenib treatment. The treatment was effective and the HCC reduced. However, after 3 years of treatment, a 2-cm HCC was observed in the S5 lobe, and the patient underwent laparoscopic partial hepatectomy. After the operation, he continued to receive sorafenib, with no obvious recurrence, and survived for over 108 months after the first treatment. There are currently no reported cases of long-term progression-free survival by sorafenib for five years in patients of Vp4 HCC. In conclusion, we report a case of longest survival of a patient with Vp4 HCC treated with sorafenib-based multidisciplinary treatment., (© 2022. Japanese Society of Gastroenterology.)

Purpose: IgG4-related disease (IgG4-RD) is a chronic fibrotic inflammatory and an immune-mediated disease characterized by high serum IgG4 concentration and IgG4-bearing plasma cell infiltration in affected organs. IgG4-related periaortitis/periarteritis is a recently identified disease entity in IgG4-RD that affects the cardiovascular system, and its pathogenesis and characteristics remain unclear. The inflammatory cytokine IL-1β is involved in a variety of cellular activities including inflammation, fibrosis, and angiogenesis. The present study compared the levels of the inflammatory cytokine IL-1β and two soluble IL-1 receptors, IL-1R1 and IL-1R2, between IgG4-RD patients with and without IgG4-related periaortitis/periarteritis., Methods: The patients with IgG4-related periaortitis/periarteritis (n ​= ​38), those without (n ​= ​66) and healthy (n ​= ​33) were recruited to measure cytokines of IL-1β and soluble receptors (sIL-1R1 and sIL-1R2) in sera by ELISA assay., Results: Serum IgG4 was significantly higher in patients with periaortitis/periarteritis compared to non-periaortitis/periarteritis (p ​= ​0.0074), while serum IL-1β was significantly lower in patients with periaortitis/periarteritis (p ​= ​0.00037). The three groups did not show significant difference in sIL1-R1, while sIL-1R2 in the periaortitis/periarteritis and healthy group was higher than in the group without periaortitis/periarteritis (p ​= ​0.00001)., Conclusions: The characteristic changes in IL-1β, sIL-1R1, and sIL-1R2 levels in IgG4-RD patients with and without IgG4-related periaortitis/periarteritis may indicate an active phase of the inflammatory process in these diseases., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2022 Medical University of Bialystok. Published by Elsevier B.V. All rights reserved.)

Primary biliary cholangitis (PBC) has a wide variation in clinical presentation and course. There is no significant correlation between these symptoms and the disease stage, although patients with more advanced stages generally have more symptoms. It is important to develop biomarkers in order to identify patients with an increased risk of complications and end-stage liver disease. This study investigated surrogate markers for risk estimation of PBC-related complications, including a study population of 77 patients with PBC who underwent liver biopsy and were measured for serum levels of macrophage activation markers, soluble CD163 (sCD163), soluble mannose receptor (sMR), and zonulin. Patients with PBC were divided into symptomatic (Group S, n = 20) and asymptomatic (Group A, n = 57) groups. The correlations of histological stages based on both Scheuer and Nakanuma classifications with the three serum markers were investigated. The Nakanuma classification involves grading for liver fibrosis and bile duct loss. The three biomarkers were assessed for their diagnostic ability to identify patients with PBC having high risk of developing complications. The predictive factors of these complications were examined as well. Group S had significantly higher serum sMR (p = 0.011) and sCD163 (p = 0.048) levels versus Group A. A composite index of sMR and sCD163 measurements had significantly better prediction performance than sCD163 alone (p = 0.012), although not when compared to sMR alone (p = 0.129). Serum sMR was an independent factor for developing complications on both univariate (Odds ratio (OR) = 30.20, 95% confidence interval (95% CI): 3.410−267.0, p = 0.00220), and multivariate (OR = 33.70, 95% CI: 3.6600−311.0, p = 0.0019) analyses. Patients with PBC having sMR of ≥56.6 had a higher incidence of clinical complications versus those with a sMR of <56.6. Serum sMR predicts the development of complications in patients with PBC. sMR plus sCD163 showed better predictive power than either marker alone, although the addition of sCD163 did not improve the predictive power of sMR. Future prospective studies are required in order to validate the findings of the present study.

The gut‑liver‑muscle axis is associated with the development of sarcopenia in liver cirrhosis. The present study aimed to illustrate the combined effects of rifaximin and L‑carnitine on skeletal muscle atrophy in cirrhotic rats with steatohepatitis. For this purpose, a total of 344 Fischer rats were fed a choline‑deficient L‑amino acid‑defined (CDAA) diet with the daily oral administration of rifaximin (100 mg/kg) and/or L‑carnitine (200 mg/kg), and measurements of psoas muscle mass index and forelimb grip strength were performed. After feeding for 12 weeks, blood samples, and liver, ileum and gastrocnemius muscle tissues were harvested. The effects of L‑carnitine on rat myocytes were assessed using in vitro assays. Treatment with rifaximin attenuated hyperammonemia and liver fibrosis in the CDAA‑fed rats. Moreover, it improved intestinal permeability with the restoration of tight junction proteins and suppressed the lipopolysaccharide (LPS)‑mediated hepatic macrophage activation and pro‑inflammatory response. In addition, rifaximin prevented skeletal muscle mass atrophy and weakness by decreasing intramuscular myostatin and pro‑inflammatory cytokine levels. Moreover, rifaximin synergistically enhanced the L‑carnitine‑mediated improvement of skeletal muscle wasting by promoting the production of insulin‑like growth factor‑1 and mitochondrial biogenesis, resulting in the inhibition of the ubiquitin‑proteasome system (UPS). The in vitro assays revealed that L‑carnitine directly attenuated the impairment of mitochondrial biogenesis, thereby inhibiting the UPS in rat myocytes that were stimulated with LPS or tumor necrosis factor‑α. On the whole, the present study demonstrates that the combination of rifaximin with L‑carnitine may provide a clinical benefit for liver cirrhosis‑related sarcopenia.

Background: Ascites commonly complicates cirrhosis and is refractory to the vasopressin-2 antagonist tolvaptan and fluid restriction in approximately 60% of patients. We aimed to identify risk factors associated with adverse events following cell-free and concentrated ascites reinfusion therapy (CART) in patients with cirrhosis and ascites., Patients and Methods: We evaluated the efficacy and tolerability to the CART system in 18 patients with decompensated liver cirrhosis and ascites. We determined serum endotoxin activity using endotoxin activity (EA) assays and serum and ascitic fluid concentrations of interleukin 6 (IL6) and tumor necrosis factor-α (TNFα) before and after the CART procedures., Results: Body weight and waist circumference significantly decreased after CART (both p<0.001). Body temperature (BT) increased significantly at an average rate of 1.1°C during CART (p<0.001). The change in BT was correlated with EA and not interleukin IL6 or TNFα. The rise in BT was positively correlated with serum EA levels at baseline. The increase in BT was significantly higher in the group with high EA (≥0.37) than in the low EAA group (<0.37) (p=0.02). TNFα and serum IL6 levels in ascites were significantly increased during CART (both p<0.001). However, no significant differences in the EA, serum TNFα or IL6 levels were found in ascitic fluid before and after the CART procedures., Conclusion: Although this discovery warrants further study, EA assay can indicate an increase in BT during effective CART in patients with cirrhosis and ascites., (Copyright © 2022, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aims: Covered self-expandable metallic stents (CMSs) are widely used for malignant distal biliary obstructions (MDBOs) caused by pancreatic carcinoma. This study compared the efficacy and safety of the laser-cut-type and braided-type CMSs., Methods: To palliate MDBOs caused by pancreatic carcinoma, the laser-cut-type CMSs was used from April 2014 to March 2017, and the braided-type CMSs was used from April 2017 to March 2019. The tested self-expandable metallic stents were equipped with different anti-migration systems., Results: In total, 47 patients received CMSs for MDBOs (24 laser-cut type, 23 braided-type). The time to recurrent biliary obstruction (TRBO) was significantly longer in the braided-type CMSs (p=0.0008), and the median time to stent dysfunction or patient death was 141 and 265 days in the laser-cut-type CMSs and braided-type CMSs, respectively (p=0.0023). Stent migration was the major cause of stent dysfunction in both groups, which occurred in 37.5% of the laser-cut-type CMSs and 13.0% of the braidedtype CMSs. There were no differences in the survival duration between the groups., Conclusion: The TRBO was significantly longer for the braided-type CMSs with an anti-migration system than for the laser-cuttype. Stent migration tended to be less frequent with the braided-type CMSs than with the laser-cut-type CMSs.

Introduction: Clostridioides difficile (C. difficile) produces three kinds of toxins: toxin A (enterotoxin), toxin B (cytotoxin), and C. difficile transferase (CDT), a binary toxin. Some strains show positivity only for toxin B. These strains reportedly possess a gene for toxin A, tcdA. However, toxin A production is inhibited due to a mutated stop codon and/or deletion within the tcdA gene. Here for the first case in Japan, we describe toxin genomes and proteins of a strain possessing only toxin B and lacking a complete tcdA gene, along with clinical manifestations., Methods: C. difficile was isolated from the bloody stool of a 60-year-old female patient treated with meropenem. Although a rapid detection kit of toxins (C. DIFF QUIK CHEK COMPLETE®, TechLab, Blacksburg, VA, USA) showed positivity, Western blotting detected no toxins. Therefore, we explored the strain's toxin genes and their sequences to determine whether the strain possessed a toxin., Results: Polymerase chain reaction did not identify toxin genes. Whole-genome sequencing analysis showed that a gene for toxin A, tcdA, was completely deleted in the strain. Moreover, 701 mutations and some deletions/insertions were identified on the tcdB gene., Conclusions: We isolated a rare strain of C. difficile producing only toxin B and lacking a complete tcdA gene herein Japan. The possibility of a false negative needs to be considered with a genetic method for a diagnose of C. difficile infection., (Copyright © 2022 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: IgG4-related disease (IgG4-RD) is an immune-mediated disorder characterized by high serum IgG4 concentration and IgG4-bearing plasma cell infiltration in affected organs. IgG4-related periaortitis/periarteritis is a recently identified disease entity in IgG4-RD that affects the cardiovascular system. Since the genetic factors related to disease onset are unclear, we examined the genetic associations with IgG4-related periaortitis/periarteritis susceptibility., Methods: A small scale of genome-wide association analysis identified that interleukin 1 receptor type 1 (IL1R1) gene variants were correlated with the development of IgG4-related periaortitis/periarteritis in 75 patients with IgG4-RD. Accordingly, 8 single nucleotide polymorphisms (SNPs) in the IL1R1 gene were selected and genotyped in 124 patients with IgG4-RD (43 with periaortitis/periarteritis and 81 without periaortitis/periarteritis) and 344 healthy subjects., Results: The minor allele frequencies of 6 SNPs (rs2287049, rs3917273, rs2160227, rs951192, rs3917318, rs7582198) were significantly increased in IgG4-related periaortitis/periarteritis patients compared with those without periaortitis/periarteritis (corrected P < 0.05). In addition, the frequency of the AGAAA haplotype, comprised of 5 SNPs (rs3917273, rs2160227, rs951192, rs3917318, rs7582198), was significantly higher in patients with periaortitis/periarteritis (OR = 2.41, 95% CI:1.42-4.10)., Conclusion: Our findings indicated that IL1R1 genetic polymorphisms contributed to IgG4-related periaortitis/periarteritis and the possibility of certain genetic factors influencing the risk of specific IgG4-RD manifestations., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Aim: Acute-on-chronic liver failure (ACLF) is associated with a high risk of short-term mortality after progression to multiple organ failure. A disintegrin-like and metalloproteinase with thrombospondin type-1 motifs 13 (ADAMTS13) is a metalloproteinase that specifically cleaves multimeric von Willebrand factor (VWF). An imbalance between ADAMTS13 enzyme and VWF substrate is associated with liver cirrhosis progression that induces ACLF. This study examined the relationship between ADAMTS13 and VWF and ACLF development to determine whether ADAMTS13 and VWF are useful predictive biomarkers for ACLF development and prognosis of patients with liver cirrhosis., Methods: The study enrolled 67 patients with Child-Pugh class A and B liver cirrhosis. ADAMTS13 activity (ADAMTS13:AC) and VWF antigen (VWF:Ag) were measured using enzyme-linked immunosorbent assays. The ratio of VWF:Ag to ADAMTS13:AC (VWF:Ag/ADAMTS13:AC) was used to divide patients into two groups according to the classification and regression tree based on Gray model survival analysis., Results: Compared with patients with Child-Pugh class A liver cirrhosis, class B patients had a higher VWF:Ag/ADAMTS13:AC and a higher risk of ACLF development. Cumulative incidence of ACLF was significantly higher in patients with high (>7.9) versus low (≤7.9) VWF:Ag/ADAMTS13:AC (hazard ratio [HR], 6.50; 95% CI, 2.31-18.29; p < 0.001). Cumulative survival was significantly lower in cirrhotic patients with high versus low VWF:Ag/ADAMTS13:AC (HR 5.11; 95% CI, 1.85-14.14; p = 0.002)., Conclusions: For patients with liver cirrhosis, VWF:Ag/ADAMTS13:AC is associated with functional liver reserve and predicts the development of ACLF and the prognosis., (© 2021 Japan Society of Hepatology.)

In response to the latest knowledge and the amendment of the Japanese diagnostic criteria for autoimmune pancreatitis (AIP) in 2018, the Japanese consensus guidelines for managing AIP in 2013 were required to be revised. Three committees [the professional committee for developing clinical questions (CQs) and statements by Japanese specialists; the expert panelist committee for rating statements by the modified Delphi method; and the evaluating committee of moderators] were organized. Twenty specialists in AIP extracted the specific clinical statements from a total of 5218 articles (1963-2019) from a search in PubMed and the Cochrane Library. The professional committee made 14, 9, 5, and 11 CQs and statements for the current concept and diagnosis, extra-pancreatic lesions, differential diagnosis, and treatment, respectively. The expert panelists regarded the statements as valid after a two-round modified Delphi approach with individually rating these clinical statements, in which a clinical statement receiving a median score greater than 7 on a 9-point scale from the panel was regarded as valid. After evaluation by the moderators, the amendment of the Japanese consensus guidelines for AIP has been proposed in 2020., (© 2022. The Author(s).)

Objective: Nonalcoholic steatohepatitis (NASH) is difficult to diagnose in patients with no symptoms. We aimed to investigate the combined effect of farnesoid X receptor (FXR) agonist, obeticholic acid (OCA), and angiotensin II type 1 receptor blocker (ARB: losartan) on an ongoing hepatic fibrosis in a NASH rat model., Methods: Fischer 344 rats were fed with choline-deficient L-amino-acid-defined (CDAA) diet for 16 weeks. After 8-week administration of CDAA diet, OCA, losartan, or a combination of these drugs was administered at a dose of 30 mg/kg/day for 8 weeks by oral gavage. The in vivo and in vitro effects of OCA + losartan and liver fibrosis progression, lipopolysaccharide (LPS), Toll-like receptor 4 (TLR4) regulatory cascade, and gut barrier function were evaluated., Results: OCA + losartan alleviated hepatic fibrosis progression by suppressing α-SMA expression. It inhibited the proliferation of activated hepatic stellate cell (Ac-HSC) and mRNA expression of hepatic transforming growth factor-β1 (TGF-β1), TLR4, and tissue inhibitor of metalloproteinase-1 (TIMP-1) and decreased the hydroxyproline levels. OCA increased the hepatic matrix metalloproteinase-2 (MMP-2) mRNA expression. OCA decreased the mRNA expression of hepatic LPS-binding protein and intestinal permeability by ameliorating the disruption of CDAA diet-induced zonula occludens-1. Losartan directly inhibited the proliferation of Ac-HSC. The in vitro suppressive effects of OCA + losartan on the mRNA expressions of TGF-β1 and α1(I)-procollagen, TLR4, and TIMP-1 in Ac-HSCs were almost in parallel., Conclusions: OCA + losartan suppressed the ongoing hepatic fibrosis by attenuating gut barrier dysfunction and suppressing Ac-HSC proliferation. Combined therapy may be a promising novel approach for NASH with fibrosis., (© 2021. Indian Society of Gastroenterology.)

ADAMTS13 specifically cleaves the multimeric von Willebrand factor (VWF), and an imbalance between ADAMTS13 activity (ADAMTS13:AC) and VWF antigen (VWF:Ag) levels is associated with the severity of liver cirrhosis (LC). However, the reason for this imbalance in patients with LC is unknown. This study investigated the relationship among ADAMTS13:AC, VWF:Ag, and endotoxin (Et) levels in patients with LC. ADAMTS13:AC and VWF:Ag levels were determined using ELISA, whereas Et levels were estimated using a chromogenic substrate assay. The levels of ADAMTS13 inhibitor (ADAMTS13:INH) were evaluated by measuring the extent that heat-inactivated patient's plasma reduces the ADAMTS13:AC of the control. The status (degraded, normal, or unusually large [UL]) of the VWF multimer (VWFM) was determined through vertical agarose gel electrophoresis. ADAMTS13:AC, VWF:Ag, and Et levels decreased, increased, and increased, respectively, with the severity of LC. Patients with cirrhosis with high Et levels had lower and higher ADAMTS13:AC and VWF:Ag levels, respectively, than those with low Et levels. Patients with cirrhosis with detectable ADAMTS13:INH had higher Et levels than those with undetectable ADAMTS13:INH. Patients whose VWFM was either normal or UL had higher Et levels than those with degraded VWFM. In conclusion, ADAMTS13, VWF, and Et may be interrelated and associated with the severity of LC via hypercoagulability.

Background/aim: Sarcopenia increases the mortality in patients with cirrhosis. Approximately 60% of zinc is accumulated in skeletal muscle. We aimed to determine the role of subclinical zinc deficiency on sarcopenia development in patients with cirrhosis., Patients and Methods: We enrolled 151 patients with cirrhosis and divided them into the group with normal serum zinc levels (Group N: 80-130 μg/dl; n=38) and group with subclinical zinc deficiency (Group D: <80 μg/dl; n=113). The risk factors for sarcopenia were then investigated., Results: Group D had more sarcopenia cases than Group N (31.0% vs. 13.2%). In group D, HGS exhibited a weakly positive but significant correlation with serum zinc levels (R=0.287, p=0.00212), serum zinc levels negatively correlated with both ammonia and myostatin levels (R=-0.254, p=0.0078; R=-0.33, p<0.01), and low zinc levels were independently associated with sarcopenia development., Conclusion: Patients with cirrhosis showing subclinical zinc deficiency have a significantly higher risk of developing sarcopenia., Competing Interests: The Authors declare no conflicts of interest., (Copyright 2022, International Institute of Anticancer Research.)

Clostridium botulinum produces botulinum neurotoxin complexes that cause botulism. Previous studies elucidated the molecular pathogenesis of botulinum neurotoxin complexes; however, it currently remains unclear whether other components of the bacterium affect host cells. Recent studies provided insights into the role of bacterial membrane vesicles (MVs) produced by some bacterial species in host immunity and pathology. We herein examined and compared the cellular effects of MVs isolated from four strains of C. botulinum with those of closely related Clostridium sporogenes and two strains of the symbiont Clostridium scindens . MVs derived from all strains induced inflammatory cytokine expression in intestinal epithelial and macrophage cell lines. Cytokine expression was dependent on myeloid differentiation primary response (MyD) 88 and TIR-domain-containing adapter-inducing interferon-β (TRIF), essential adaptors for toll-like receptors (TLRs), and TLR1/2/4. The inhibition of actin polymerization impeded the uptake of MVs in RAW264.7 cells, however, did not reduce the induction of cytokine expression. On the other hand, the inhibition of dynamin or phosphatidylinositol-3 kinase (PI3K) suppressed the induction of cytokine expression by MVs, suggesting the importance of these factors downstream of TLR signaling. MVs also induced expression of Reg3 family antimicrobial peptides via MyD88/TRIF signaling in primary cultured mouse small intestinal epithelial cells (IECs). The present results indicate that MVs from C. botulinum and related clostridial species induce host innate immune responses., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kobayashi, Abe, Akagi, Kitamura, Shiraishi, Yamaguchi, Yutani, Amatsu, Matsumura, Nomura, Ozaki, Obana and Fujinaga.)

Introduction: Gut microbiota alterations cause inflammation in patients with ulcerative colitis (UC). Fecal microbiota transplantation (FMT) enables manipulating the microbiota's composition, but the mechanisms underlying colonization of the posttransplantation microbiota are poorly understood., Methods: In this open-label, nonrandomized study, the FMT efficacy and changes in the gut microbiota were evaluated in 8 UC patients with mild-to-moderately active endoscopic colonic lesions. Compositional changes in the fecal and mucosal microbiotas between donors and recipients were examined via 16S rRNA-based sequencing. To investigate the effects of oral corticosteroids on microbiota colonization, FMT was performed in germ-free prednisolone (PSL)-administered mice to examine the factors determining colonization., Results: Four UC patients achieved clinical remission (CR) after FMT, and 3 also achieved endoscopic remission. The fecal microbiotas of the CR patients changed similar to those of the donors after FMT. The mucin-coding gene, MUC2, was less expressed in the colons of the PSL-dependent patients than in the PSL-free patients. In the mice, PSL treatment decreased the fecal mucin production and altered the posttransplantation fecal microbiota composition. Adding either exogenous mucin or the mucin secretagogue, rebamipide, partially alleviated the PSL-induced dysbiosis of the gut microbiota. Administering rebamipide with FMT from healthy donors relieved inflammation in mice with Enterococcus faecium-induced colitis., Conclusion: Colonic mucin controlled the gut microbiota composition, and oral corticosteroid treatment modified the gut microbiota partly by reducing the colonic mucin., (© 2022 S. Karger AG, Basel.)

Objective: To optimize the scan protocol for high temporal resolution magnetic resonance (MR) imaging of the liver under single breath-holding, using compressed sensing (CS) and parallel imaging (PI) techniques in a 1.5 T MR system., Methods: 31 healthy volunteers who underwent fat-suppressed gradient-echo T 1 weighted imaging using a 1.5 T MR system were included. Image quality was evaluated on altering various imaging parameters in CS and PI so that the scan time was adjusted to 10 and 6 s within a single breath-holding. Normalized standard deviation (nSD = SD/mean value) and signal-to-noise ratio (SNR = mean value/SD) of liver signal intensity were measured. Visual scores for the outline of the liver and inferior right hepatic vein (IRHV) were evaluated using a 4-point scale and compared with that of the reference standard (20 s scan without CS)., Results: The nSD and SNR were not significantly different when the 10 s scan with CS factor 2.0 and the 6 s scan with CS factor 2.0 and 2.5 were compared to the 20 s scan. Overall visual score (mean score of the outline of the liver and IRHV) was significantly better ( p < 0.05) with the 10 s scan with CS factor 2.0 compared to the other scan protocols., Conclusion: The 10 s scan with CS factor 2.0 should be recommended for high temporal resolution MR imaging of the liver using CS and PI in a 1.5 T MR system., Advances in Knowledge: This study conducts a novel MR imaging of the liver using CS and PI in a 1.5 T MR system., (© 2021 The Authors. Published by the British Institute of Radiology.)

Equol is a metabolite of daidzein, a major soybean isoflavone with estrogenic and antioxidant activities. As the production of equol depends on the presence of certain members of the intestinal microflora, not all individuals can produce equol. We examined the relationship between NASH histological features and equol production. In an animal model, obese OLETF rats were intraperitoneally injected with a porcine serum to augment liver fibrogenesis. Equol-rich soy product, SE5-OH was orally administered during the experimental period. Treatment with SE5-OH markedly attenuated the development of liver fibrosis and expression of alpha-smooth muscle actin. In clinical research, 38 NAFLD patients (13 men and 25 women) were included. The degree of fibrosis and ballooning in equol-nonproducers was significantly higher than in equol-producers in women. The percentage of nonproducers with NAFLD activity score (NAS) ≥ 5 was significantly higher than that of producers. None of the histological features were significantly different between nonproducers and producers in men. Decision tree analysis identified predictors for NAS ≥ 5 in women. The status of equol production was the strongest predictor, followed by fasting glucose. Since equol can be noninvasively detected in urine, it can be applied as a screening tool for the progression of NASH in women.

Purpose: This study aimed to evaluate the safety and efficacy of preoperative arterial embolization of organized hematoma of the maxillary sinus., Material and Methods: Seven patients who were pathologically diagnosed with an organized hematoma of the maxillary sinus and who underwent endoscopic sinus surgery following preoperative arterial embolization for the same from July 2013 to April 2020 at our hospital were included. A literature review of the PubMed database was performed to identify 13 cases on organized hematomas of the maxillary sinuses. The embolization and nonembolization groups comprised patients who underwent preoperative embolization (n = 10, seven from this study and three from literature) and those who did not undergo preoperative embolization (n = 10, from literature), respectively. Outcomes of embolization including embolization-related complications and postoperative bleeding were assessed, and volumes of intraoperative blood loss and duration of surgery were compared between the groups., Results: No preoperative embolization-related complications were observed in our cases. The volume of surgical blood loss in the seven cases varied from 0 to 100 mL with a median of 30 mL, and the duration of surgery ranged from 45 to 166 minutes with a median of 112 minutes. The volume of blood loss was significantly lower for the embolization group than that for the nonembolization group ( p = 0.0031). There was no statistically significant difference regarding duration of surgery between the groups ( p > 0.10)., Conclusions: Preoperative embolization of an organized hematoma of the maxillary sinus is a safe and effective method that helps prevent serious intraoperative hemorrhage., Competing Interests: None, (© 2021 Japanese Society of Interventional Radiology.)

Mortality and recurrence rates of hepatocellular carcinoma (HCC) are high. Recent studies show that for patients with HCC beyond up-to-seven criteria, treatment with molecular-targeted agents (MTAs) is recommended because the treatment efficiency of transcatheter arterial chemoembolization (TACE) is poor; further, TACE increases decline in liver function. However, the relationship between TACE and liver function decline in patients with HCC within up-to-seven criteria has not been clarified. Hence, we aimed to investigate this relationship. This retrospective observational study included 189 HCC tumors within up-to-seven criteria in 114 Child-Pugh class A patients. Twenty-four (12.7%) tumors were changed from Child-Pugh class A to B after TACE, and 116 (61.4%) tumors exhibited recurrence within 6 months after TACE. Prothrombin time (PT) and albumin-bilirubin (ALBI) score before TACE were significantly associated with liver dysfunction from Child-Pugh class A to B. The combination of PT and ALBI score before TACE had high predictive ability for liver dysfunction from Child-Pugh class A to B after TACE (specificity = 100%, sensitivity = 91.7%). The combined use of pre-TACE PT and ALBI score has a high predictive ability for liver dysfunction after TACE for Child-Pugh class A patients with HCC within up-to-seven criteria.

Objectives: This study aimed to evaluate and compare the outcomes of palliative endoscopic biliary stenting (EBS) and complete stone removal among elderly patients with choledocholithiasis using propensity score matching., Methods: From April 2012 to October 2017, 161 patients aged 75 years and older with choledocholithiasis underwent endoscopic retrograde cholangiopancreatography at our institution. Among them, 136 (84.5%) had complete stone removal, and 25 (15.5%) underwent palliative EBS without further intervention until symptom occurrence. The median age of the EBS group was significantly higher than that of the complete stone removal group. The proportion of patients with dementia, cerebral infarction, preserved gallbladder with gallstones, and surgically altered anatomy was higher in the EBS group than in the complete stone removal group. Propensity score matching was used to adjust for different factors. In total, 50 matched patients (n = 25 in each group) were analyzed., Results: The median duration of cholangitis-free periods was significantly shorter in the EBS group (596 days) than in the complete stone removal group. About half of patients in the EBS group required retreatment and rehospitalization for cholangitis during the observation period. Cholangitis was mainly caused by stent migration. There was no significant difference in terms of mortality rate and procedure-related adverse events between the two groups. Death was commonly attributed to underlying diseases. However, one patient in the EBS group died due to severe cholangitis., Conclusions: Palliative EBS should be indicated only to patients with choledocholithiasis who have a poor prognosis., (© 2021. The Author(s).)

Clostridium botulinum causes infant and adult intestinal botulism by colonizing in the intestine and producing botulinum neurotoxin (BoNT). Antimicrobial agents are not currently used for treatment due to the potential facilitation of BoNT production and bacterial cell lysis, which releases toxins into the intestinal lumen. In this study, we analyzed effects of four antibiotics on the viability of and BoNT production by four C. botulinum group I strains. Our results indicate that metronidazole rapidly reduced their viability without enhancing BoNT production. Antibiotics with these properties may promote elimination of C. botulinum from the intestines while maintaining low levels of BoNT., (© 2021 The Societies and John Wiley & Sons Australia, Ltd.)

Gut dysbiosis is observed in chronic hepatobiliary diseases and is frequently associated with liver carcinogenesis; however, the extent and specific mechanisms triggered by alterations in the microbiota mediating tumorigenesis in these patients remain unclear. Here we show that Enterococcus faecalis is abundant in the microbiota of patients with hepatitis C virus-related chronic liver disease. Xenotransplantation of gut microbiota from these patients increased the number of spontaneous liver tumors in mice and enhanced susceptibility to liver carcinogens. Hepatic colonization by gelE-positive E. faecalis increased liver expression of proliferative genes in a TLR4-Myd88-dependent manner, leading to liver tumorigenesis. Moreover, decreased fecal deoxycholic acid levels were associated with colonization by E. faecalis. Overall, these data identify E. faecalis as a key promoter of liver carcinogenesis., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Abstract: The presence of bridging fibrosis predicts survival of primary biliary cholangitis (PBC). This study aimed to compare serum parameters for the estimation of liver fibrosis and prediction of clinical outcomes in PBC.Out of 392 patients with PBC, 102 who underwent liver biopsy and in whom fibrosis indices, platelet count, hyaluronic acid, type IV collagen 7 second domain, procollagen type III amino-terminal peptide, tissue inhibitor of metalloproteinases 1, Mac-2 binding protein glycosylation isomer, N-terminal type III collagen propeptide levels; fibrosis index based on 4 factors, aspartate aminotransferase-to-platelet ratio index, and enhanced liver fibrosis (ELF) score were determined, were included. The correlation of histological stages based on both Scheuer and Nakanuma classifications with fibrosis indices was investigated. The Nakanuma system comprises grading for liver fibrosis and bile duct loss. Diagnostic performances of 10 fibrosis indices were evaluated to identify patients with poor prognosis. Moreover, correlations of those with PBC clinical manifestation and survival were also investigated.Enhances liver fibrosis (ELF) score had the highest correlation coefficient for liver fibrosis evaluated according to either the Scheuer or Nakanuma classification among 10 serum fibrosis indices. It also had the highest diagnostic performance in estimating Scheuer stage III and Nakanuma fibrosis score 2, both of which represent portal-bridging fibrosis. Patients with an ELF score of ≥10.0 had shorter survival and presented more frequently clinical complications than those with an ELF score of <10.0.ELF score determines the severity of liver fibrosis and predicts the occurrence of complications and survival in patients with PBC., Competing Interests: The authors have no conflicts of interests to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Abstract: We aimed to prospectively identify the risk factors of sarcopenia in patients with cirrhosis.Patients (n = 193) included in a discovery cohort (January 2011 and December 2014) were categorized into alcoholic (A1; n = 55) and non-alcoholic cirrhosis (NA; n = 138) groups, and those (n = 235) in a validation cohort (January 2015 to December 2019) were categorized into alcoholic (n = 92), non-alcoholic steatohepatitis-related (n = 27), and hepatitis C virus-related cirrhosis groups (n = 116). Skeletal muscle mass index (SMI) was determined using computed tomography (SMI-CT) and bioelectrical impedance analysis (SMI-BIA). Endotoxin activity (EA) was measured with an EA assay.SMI-CT correlated with grip strength in all the groups but significantly correlated with SMI-BIA of the men in group A1 (R = 0.64, P < .0001) and both sexes in group NA (male: R = 0.44, P = .0001; female: R = 0.35, P = .003). SMI-CT inversely correlated with the EA levels of the men in group A1 (R = -0.67, P < .0001) and myostatin levels in group NA (R = -0.53, P < .0001). Lower extremity SMI had a strong negative correlation with the EA levels of the men in group A1 (R = -0.58, P < .001), whereas upper extremity SMI showed an inverse trend with EA levels (R = -0.28, P = .08). SMI-CT also inversely correlated with the EA levels in groups A2 (R = -0.52, P = .003) and N (R = -0.67, P < .0001) and myostatin levels in group C (R = -0.65, P < .0001). Moreover, SMI-CT correlated with nutritional factors, including cholinesterase (R = 0.50, P = .005), zinc (R = 0.45, P = .01), branched amino acid-to-tyrosine ratio (R = 0.39, P = .02), and triglyceride (R = 0.33, P = .03) in group N.Sarcopenia risk factors differ among cirrhosis etiologies. Alcohol-induced, intestine-mediated peripheral endotoxemia could participate in sarcopenia development in patients with alcoholic cirrhosis., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

PurposeWe aimed to evaluate the extent of collagenase clostridium histolyticum (CCH) diffusion in Dupuytren's contracture (DC) for tissues outside of the contracture cord using Magnetic Resonance Imaging (MRI) immediately after CCH injection. Methods: 10 male patients aged 57-79 with DC of the metacarpophalangeal (MCP) joints were examined. Extension deficits were 10-60°(mean, 34.3) and 0-60°(mean, 26.6) in the MCP and proximal interphalangeal (PIP) joints, respectively. CCH injection was performed according to the standard method. MRI was performed within 15 min of CCH injection. Results: In all 10 cases, the extended area of high-intensity signal change outside of the cord was observed on short-T1 inversion recovery images (STIRs). Continuity from the insertion site was observed in the area of signal change involving the flexor tendon and neurovascular bundle. The signal change area spanned distally and proximally beyond the injection level. The signal change area expanded along the tendon sheath but no signal changes were observed inside the flexor tendon, suggesting the tendon sheath serves as a protective barrier from the CCH solution. After 1 week of injection, the mean decrease in contracture was 32.5°(94.7%) for the MCP joint and 19.8°(74.4%) for the PIP joint. In nine out of 10 cases, the extension deficit was within five degrees of full extension in the affected finger. There was no neurovascular injury or tendon rupture at 3 months of observation. Conclusions: MRI indicated the possible leakage of the drug outside of the cord during the early phase after administration, suggesting that CCH could persistently affect healthy tissues until CCH inactivates its enzyme process.

Purpose: This study aimed to examine MRI features and staging of neuroendocrine carcinoma (NEC) of the endometrium and evaluate survival., Methods: Clinical data, pathological, and preoperative pelvic MRI findings in 22 patients with histologically surgery-proven endometrial NEC were retrospectively reviewed. Tumors were pure NEC (n = 10) or mixed histotype (n = 12), with 13 large and nine small cell type., Results: International Federation of Gynecology and Obstetrics (FIGO) staging was I, II, III, and IV in 6, 2, 12, and 2 patients, respectively. In 13 (76.4%) of 17 patients with pathological deep myometrial invasion, MRI showed abnormal diffusely infiltrative high T 2 signal intensity throughout the myometrium with loss of normal uterine architecture. All tumors had restricted diffusion (apparent diffusion coefficient map low signal intensity, diffusion weighted imaging high signal intensity). Accuracy of T staging by MRI for all cases was 81.8%, with reference to pathology staging, while patient-based sensitivity, specificity, and accuracy for detecting metastatic pelvic lymph nodes was 60.0%, 100%, and 77.8%, respectively. Two intrapelvic peritoneal dissemination cases were detected by MRI. During follow-up (mean 30.4, range 3.3-138.4 months), 16 patients (72.7%) experienced recurrence and 12 (54.5%) died of disease. Two-year disease-free and overall survival rates for FIGO I, II, III, and IV were 66.7% and 83.3%, 50% and 100%, 10% and 33.3%, and 0% and 0%, respectively., Conclusion: Abnormal diffusely infiltrative high T 2 signal intensity throughout the myometrium with normal uterine architecture loss and obvious restricted diffusion throughout the tumor are suggestive features of endometrial NEC. Pelvic MRI is reliable for intrapelvic staging of affected patients.

Ovarian primary mucinous tumours (OPMTs) show an adenoma-borderline-carcinoma sequence with gastrointestinal metaplasia. Gastric gland mucin-specific O -glycans are unique with an α1,4-linked N -acetylglucosamine (αGlcNAc) residue attached to mucin 6 (MUC6). Although αGlcNAc is expected to be expressed in OPMTs, the relationship between αGlcNAc expression and OPMT progression remains unknown. Here, we analysed 104 areas of benign mucinous tumours (benign), 55 areas of borderline mucinous tumours (borderline), and 18 areas of malignant mucinous tumours (malignant) to investigate the expression patterns of αGlcNAc, mucin 2 (MUC2), mucin 5AC (MUC5AC), and MUC6 during the progression of OPMT from benign to malignant. MUC5AC expression was observed in all areas. The frequencies of MUC6- and αGlcNAc-positive areas were decreased with tumour progression. In particular, the decrease in αGlcNAc-positive areas was remarkable. Furthermore, αGlcNAc expression was lower than MUC6 expression at all grades (benign, p < 0.0001; borderline, p = 0.0014; malignant, p = 0.0039). Conversely, there was no difference in the expression frequency or level of MUC2 among the three grades. These results suggest that decreased expression of αGlcNAc relative to MUC6 occurs early in tumour development and marks the initiation of OPMT progression., Competing Interests: VThe authors have no conflict of interest., (2021 The Japan Society of Histochemistry and Cytochemistry.)

Background: This study aimed to compare the diagnostic performance of carbohydrate-deficient transferrin (CDT) and gamma-glutamyltranspeptidase (γ-GTP) to assess the single and combined benefits of these biological markers for the detection of chronic excessive alcohol consumption in patients with alcoholic cirrhosis. Methods: Biological markers were determined in blood samples from patients with alcoholic cirrhosis (drinking group, n = 35; nondrinking group, n = 81). The prediction accuracy of %CDT alone, γ-GTP alone, and their combination for the detection of excessive alcohol consumption was determined in patients with alcoholic cirrhosis. Results: Serum total bilirubin, alanine aminotransferase, aspartate aminotransferase, γ-GTP, and alkaline phosphatase levels and %CDT were significantly higher and serum albumin levels were significantly lower in the drinking group than in the nondrinking group. The combination of %CDT and γ-GTP compared with %CDT or γ-GTP alone showed a higher prediction accuracy. The combination of %CDT and γ-GTP exhibited a higher specificity than γ-GTP alone. However, in terms of sensitivity, no significant difference was found between single or combined markers. Conclusions: The combination of %CDT and γ-GTP is considered a useful biomarker of chronic excessive alcohol consumption in patients with alcoholic cirrhosis.

Recent studies have suggested that an alteration in the gut microbiota and their products, particularly endotoxins derived from Gram-negative bacteria, may play a major role in the pathogenesis of liver diseases. Gut dysbiosis caused by a high-fat diet and alcohol consumption induces increased intestinal permeability, which means higher translocation of bacteria and their products and components, including endotoxins, the so-called "leaky gut". Clinical studies have found that plasma endotoxin levels are elevated in patients with chronic liver diseases, including alcoholic liver disease and nonalcoholic liver disease. A decrease in commensal nonpathogenic bacteria including Ruminococaceae and Lactobacillus and an overgrowth of pathogenic bacteria such as Bacteroidaceae and Enterobacteriaceae are observed in cirrhotic patients. The decreased diversity of the gut microbiota in cirrhotic patients before liver transplantation is also related to a higher incidence of post-transplant infections and cognitive impairment. The exposure to endotoxins activates macrophages via Toll-like receptor 4 (TLR4), leading to a greater production of proinflammatory cytokines and chemokines including tumor necrosis factor-alpha, interleukin (IL)-6, and IL-8, which play key roles in the progression of liver diseases. TLR4 is a major receptor activated by the binding of endotoxins in macrophages, and its downstream signal induces proinflammatory cytokines. The expression of TLR4 is also observed in nonimmune cells in the liver, such as hepatic stellate cells, which play a crucial role in the progression of liver fibrosis that develops into hepatocarcinogenesis, suggesting the importance of the interaction between endotoxemia and TLR4 signaling as a target for preventing liver disease progression. In this review, we summarize the findings for the role of gut-derived endotoxemia underlying the progression of liver pathogenesis.

Purpose: To evaluate various imaging features on magnetic resonance imaging (MRI) and tumor markers and their utility to assess various grades of ovarian primary mucinous tumors (OPMTs): benign, borderline, or malignant., Methods: Ninety-five pathologically diagnosed OPMTs [53 benign, 24 borderline malignant (BM), and 18 malignant] were selected in this retrospective study. MRI features of the ovarian mass, namely the maximum diameter, honeycomb loculi, solid components (SC), stained-glass pattern, and signal intensity of the cyst on T1- (T1WI) and T2-weighted imaging (T2WI) with/without fat suppression, and preoperative STMs, namely carcinoembryonic antigen (CEA), carbohydrate antigen (CA) 19-9, and CA125, were compared between the three tumor grades using univariate analysis. We also analyzed the findings to estimate the pathological diagnosis using classification tree (CT) analysis., Results: Maximum diameter, honeycomb loculi, SC, stained-glass pattern, signal intensity of the cyst [hyperintensity on both T1WI and T2WI (T1-hyper/T2-hyper), and hyperintense on T1WI and hypointense on T2WI (T1-hyper/T2-hypo)], and CEA and CA 19-9 concentrations were significantly different between the three tumor grades (p < 0.05). The concordance rate with the pathological diagnosis was the highest with diagnosis by the CT comprising T1-hyper/T2-hypo, CEA, and CA 19-9 and by the CT comprising T1-hyper/T2-hypo, CEA, and SC., Conclusion: Four types of findings were important for OPMT grading. Lesions negative for both T1-hyper/T2-hypo and CEA suggest benign; lesions positive for T1-hyper/T2-hypo and negative for CA 19-9 or SC suggest BM; and lesions negative for T1-hyper/T2-hypo and positive for CEA, or positive for both T1-hyper/T2-hypo and CA 19-9 or SC suggest malignancy.

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

Purpose: To compare the quality of images obtained by T1-weighted hepatobiliary MR cholangiography using Gd-EOB-DTPA with 1-mm isovoxel acquisition and compressed sensing (T1-MRC CS ) or parallel imaging (T1-MRC PI ) for assessment of biliary tree anatomy., Method: We prospectively reviewed T1-MRC CS , T1-MRC PI , and respiratory-triggered 3D T2-weighted MR cholangiography (T2-MRC) images in 58 patients. Two radiologists independently assessed the three sets of images and scored the biliary tree visualization and overall image quality in all cases using a 5-point Likert scale. The resulting scores were compared among T1-MRC CS , T1-MRC PI , and T2-MRC images using a Friedman test followed by a Scheffe test. The inter-reader agreement in scoring was assessed using κ statistics., Results: The image quality scores for the gallbladder on both T1-MRC CS and T1-MRC PI were significantly lower than those on T2-MRC (p < 0.01) for both readers. Meanwhile, the image quality scores for the right and left hepatic ducts and the anterior and posterior branches of the right hepatic duct on both T1-MRC CS and T1-MRC PI were significantly higher than those on T2-MRC (p < 0.05) for both readers. For Reader 2, the overall image quality scores on T1-MRC CS and T1-MRC PI were both significantly higher than those on T2-MRC (p < 0.05). There were no significant differences between the image quality scores on T1-MRC CS and T1-MRC PI for visualization of each bile duct (p < 0.05)., Conclusions: There may be no significant difference in quality between T1-MRC CS images and T1-MRC PI images for assessment of biliary tree anatomy, and both types of images may be better than T2-MRC images, although clinical indication is limited compared with T2-MRC., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: A peritumoral hypointense rim (PTHR) is sometimes observed around hepatocellular carcinoma (HCC) on T2*-weighted images (T2*WIs). We aimed to investigate the association between the PTHR and histopathologic findings on T2*WIs., Methods: We assessed the presence of a PTHR on T2*WIs in 39 pathologically proven HCCs from April 2012 to December 2013. Prussian blue staining was performed, and iron deposition was evaluated by semiquantitative and quantitative methods. Optical density was used in the quantitative methods. The associations between a PTHR on T2*WI and histopathologic peritumoral or background liver iron deposition were analyzed., Results: A PTHR on T2*WI was observed in 23 of 39 (59%) HCCs. There was no significant difference in the histopathologic fibrous capsule findings (P = 0.394). In the semiquantitative methods, both peritumoral and background liver iron deposition grade were significantly higher in HCCs with a PTHR compared with HCCs without a PTHR (P < 0.001). The mean optical density in HCCs with a PTHR was significantly higher compared with HCCs without a PTHR, in the quantitative peritumoral (42,244.1 ± 20,854.9 vs. 18,739.1 ± 12,258.7, respectively; P < 0.001) and background liver iron deposition analyses (35,554.7 ± 19,854.8 vs. 17,292.4 ± 11,605.8, respectively; P < 0.001). Tumor size (P = 0.005), etiology (P = 0.001), and degree of fibrosis (P = 0.042) were significantly associated with the presence of a PTHR., Conclusions: A PTHR in HCCs on T2*WIs was strongly associated with peritumoral iron deposition in the iron-deposited background liver but not with the fibrous capsule.

Aim: To evaluate the usefulness of the 'cosmos pattern' (CP) on magnetic resonance (MR) images for differentiating between gastric-type mucin-positive lesions (GMPL) and gastric-type mucin-negative lesions (GMNL)., Methods: This study included 131 patients with clinical suspicion of lobular endocervical glandular hyperplasia (LEGH) who underwent pelvic MR imaging and a Pap smear and/or latex agglutination assay. Differences in MR findings, such as cyst and solid component patterns, cervical location and T1-weighted image (T1WI) signal intensity, were compared between GMPL and GMNL. The diagnostic performances of the findings were assessed., Results: The frequencies of CP (63.1%), upper part (UP) lesions (72.3%) and hypointense area compared with the cervical stroma on T1WI (61.3%) were significantly greater in GMPL than in GMNL (P < 0.05). The sensitivity, specificity, positive predictive value, negative predictive value and odds ratio of the CP for diagnosis of GMPL were 63.1%, 87.9%, 83.7%, 70.7% and 12.4, respectively. In GMNL, a 'macrocystic pattern' was observed in 65.2% of patients; an isointense or hyperintense area on T1WI was observed in 86.4% of patients. The sensitivity was highest (90.8%) when one or more of the following were observed: CP, UP lesion, or hypointense area on T1WI. The specificity was highest (95.5%) when the CP was observed as a hypointense area on T1WI., Conclusion: The CP is a highly specific finding for diagnosis of GMPL. If the CP is observed as a hypointense area compared with the cervical stroma on T1WI, GMPL (i.e., LEGH or gastric-type mucinous carcinoma) should be strongly suspected., (© 2020 Japan Society of Obstetrics and Gynecology.)

Patients with liver cirrhosis frequently experience non-specific symptoms and report severe reductions in their quality of life (QOL). The underlying mechanisms of the disease are multifactorial that may be specific to the disease or directly related to the liver. The major concern of liver cirrhosis with ascites, however, is the decreased QOL. Therefore, in the present study, the Ascites Symptom Inventory-7 (ASI-7) questionnaire was applied to subjectively evaluate the symptoms in patients with cirrhotic ascites following tolvaptan administration. In total, 69 patients with liver cirrhosis with ascites hospitalized to Nara Medical University were evaluated after being treated with tolvaptan (3.75-7.5 mg/day) and conventional diuretics between December 2013 and April 2018. A follow-up assessment was conducted 7 days after tolvaptan treatment, whilst ASI-7 was used on days 1 and 8 of the study. After an uneventful 7-day tolvaptan treatment regimens, 49 patients (71.0%) lost >1.5 kg of their body weight, who were referred to as responders, with the change in the ASI-7 score being found to correlate with the body weight change. By contrast, changes in urine volume did not correlate with those in the ASI-7 score. The responders experienced a greater reduction in the ASI-7 score after 7 days compared with those in the non-responders (P<0.01). ASI-7 scores were also found to correlate with body weight after tolvaptan administration. In conclusion, ASI-7 accurately reflected changes in body weight but not urine volume and results of the study highlighted the value of ASI-7 in the evaluation of ascitic volume and effectiveness of tolvaptan in cirrhotic ascites. The present clinical trial was registered onto the UMIN-Clinical Trial Registry on 1st March 2014 (registration no. UMIN000013095)., (Copyright © 2020, Spandidos Publications.)

Primary biliary cholangitis (PBC) is currently diagnosed at an early stage; therefore, the number of patients with PBC without symptoms at the time of diagnosis is increasing. However, up to 30% of patients with PBC exhibit the suboptimal response to ursodeoxycholic acid (UDCA) and are at high risk of end-stage liver disease. Obeticholic acid is an approved second-line therapy for patients with PBC that are refractory to UDCA. Novel surrogate endpoints are required to identify individuals eligible for second-line therapies. An inadequate biochemical response to UDCA is a useful predictor of poor outcomes in patients with PBC. In addition to UDCA effects on biochemical parameters, histological outcomes could be considered as candidate surrogate endpoints. Alterations in liver histology are used as surrogate endpoints in clinical studies. However, current staging systems are insufficient to determine PBC disease severity and progression because of the pathological heterogeneity of the disease. Histological features at baseline and biochemical response to UDCA treatment can affect the disease course of PBC. Therefore, novel surrogate endpoints must be represented by parameters characterized by histological outcomes and treatment responses in PBC. In this review, we discuss the existing histological parameters and newly created factors to identify patients with PBC who are at a high risk of developing end-stage liver disease and, consequently, the potential need for additional treatments., (© 2021 The Japan Society of Hepatology.)

Background: Prediction of HAIC treatment response is important for improving the prognosis in patients with hepatocellular carcinoma (HCC). The progression of HCC is related to hypercoagulability and angiogenesis. It is known that ADAMTS13 and von Willebrand factor (VWF) are related to hypercoagulability. In addition, previous study reported that the association between ADAMTS13 and VWF, and angiogenesis via vascular endothelial growth factor (VEGF). Recently, ADAMTS13 and VWF have been associated with the prognosis in patients with various kinds of cancer undergoing chemotherapy., Aim: To investigate whether ADAMTS13 and VWF become useful biomarkers of treatment response in HCC patients before the initiation of HAIC treatment., Methods: Seventy-two patients were enrolled in this study. ADAMTS13 activity (ADAMTS13:AC), VWF antigen (VWF:Ag) and VEGF levels were determined via enzyme-linked immunosorbent assay. Univariable and multivariable analyses were performed to determine the predictive factors of treatment response in patients with HCC undergoing HAIC treatment., Results: ADAMTS13:AC levels in HCC patients with stable disease (SD) + partial response (PR) of HAIC treatment were significantly higher than those with progressive disease (PD) ( P < 0.05). In contrast, VWF:Ag/ADAMTS13:AC ratio and VEGF levels in HCC patients with SD + PR were significantly lower than those with PD (both P < 0.05). Patients with high VWF:Ag/ADAMTS13:AC ratio (> 2.7) had higher VEGF levels than those with low ratio (≤ 2.7). Multivariable analysis revealed that VWF:Ag/ADAMTS13:AC ratio was a predictive factor of HAIC treatment response., Conclusion: VWF:Ag/ADAMTS13:AC ratio may become a useful biomarker of treatment response in HCC patients before the initiation of HAIC treatment., Competing Interests: Conflict-of-interest statement: The authors declare that they have no conflicts of interest., (©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.)

A potential restriction of the Baveno VI consensus, which helps to avoid unnecessary endoscopies, is the limited availability of FibroScan. We aimed to identify serum fibrosis indices that might aid in ruling out the presence of high-risk varices in cirrhotic patients. This retrospective study included 541 consecutive patients with cirrhosis who underwent endoscopy and had data available for nine serum fibrosis indices, including platelet count, hyaluronic acid, 7S fragment of type 4 collagen, procollagen type III N-terminal peptide, tissue inhibitor of metalloproteinases 1, Mac-2 binding protein glycosylation isomer, fibrosis index based on four factors (FIB-4), aspartate transaminase/platelet ratio index and enhanced liver fibrosis score. Optimal index cutoffs for predicting high-risk varices were calculated in an estimation cohort ( n = 127) and evaluated in a validation cohort ( n = 351). The diagnostic performance of the indices was assessed by receiver operating characteristic curve analysis. In the estimation cohort, a FIB-4 cutoff of 2.78 provided the greatest diagnostic accuracy in predicting both all-grade and high-risk varices. FIB-4 had a negative predictive value of 1.00 for high-risk varices in both cohorts, and 21.3% (27/127) and 14.8% (52/351) of the estimation and validation cohorts, respectively, avoided esophagogastroduodenoscopy; no high-risk varices were missed in either cohort. FIB-4 correctly identifies the absence of high-risk varices in patients with cirrhosis. Therefore, those with a FIB-4 of ≥2.78 should undergo esophagogastroduodenoscopy, and FIB-4 determination should be recommended every 6-12 months concurrently with the other blood tests until the index value reaches 2.78 in those with a FIB-4 of <2.78., Competing Interests: The authors declare no conflicts of interest.

Objectives: To investigate neuroendocrine carcinoma (NEC) of the uterine cervix cases for MRI features and staging, as well as pathological correlations and survival., Results: FIGO was I in 42, II in 14, III in 1, and IV in 5 patients. T2-weighted MRI showed homogeneous slightly high signal intensity and obvious restricted diffusion (ADC map, low intensity; DWI, high intensity) throughout the tumor in most cases, and mild enhancement in two-thirds. In 50 patients who underwent a radical hysterectomy and lymphadenectomy without neoadjuvant chemotherapy (NAC), intrapelvic T staging by MRI overall accuracy was 88.0% with reference to pathology staging, while patient-based sensitivity, specificity, and accuracy for metastatic pelvic lymph node detection was 38.5%, 100%, and 83.3%, respectively. During a mean follow-up period of 45.6 months (range 4.3-151.0 months), 28 patients (45.2%) experienced recurrence and 24 (38.7%) died. Three-year progression-free and overall survival rates for FIGO I, II, III, and IV were 64.3% and 80.9%, 50% and 64.3%, 0% and 0%, and 0% and 0%, respectively., Materials and Methods: Sixty-two patients with histologically surgery-proven uterine cervical NEC were enrolled. Twelve received NAC. Clinical data, pathological findings, and pretreatment pelvic MRI findings were retrospectively reviewed. Thirty-two tumors were pure NEC and 30 mixed with other histotypes. The NECs were small cell type (41), large cell type (18), or a mixture of both (3)., Conclusions: Homogeneous lesion texture with obvious restricted diffusion throughout the tumor are features suggestive of cervical NEC. Our findings show that MRI is reliable for T staging of cervical NEC., Competing Interests: CONFLICTS OF INTEREST The authors declare that they have no conflicts of interest., (Copyright: © 2020 Kitajima et al.)

Aims: Thrombocytopenia is a common complication among patients with chronic liver disease (CLD). Lusutrombopag, an oral thrombopoietin receptor agonist, is used to reduce the risk of hemorrhage in patients with thrombocytopenia who are undergoing invasive procedures. Platelet transfusion was the standard treatment for thrombocytopenia; however, multiple platelet transfusions lead to the production of antiplatelet antibody. The effect of giving lusutrombopag three times or more has not been previously reported. In this study, we investigated the effect of lusutrombopag readministration in patients with thrombocytopenia., Methods: This study included 14 patients (total, 24 readministrations) who received lusutrombopag two times or more. Changes in platelet counts were evaluated. Treatment response was defined as an increased platelet count of ≥20 000/μL after lusutrombopag treatment., Results: Lusutrombopag was given twice in nine patients, three times in three patients, five times in one patient, and six times in one patient. An elevated platelet count of <20 000/μL was noted in only one of the 24 readministrations. There were no postoperative hemorrhagic complications, and no patient had an increased platelet count of >200 000/μL. One patient had a portal venous mural thrombus; however, he was asymptomatic, and the thrombus resolved after anticoagulant treatment, without recurrence. The comparison between the first, second, and third or more treatments showed there was no significant difference in platelet increase., Conclusion: Repeated treatment of lusutrombopag is effective for CLD patients with thrombocytopenia. Moreover, three or more treatments with lusutrombopag showed equal effect compared with one and two treatments with the medication., (© 2020 The Japan Society of Hepatology.)