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Background/Aims: This study aimed to evaluate the safety and efficacy of continuous propofol infusion for anesthesia during endoscopic ultrasonography (EUS). Methods: A total of 427 consecutive patients who underwent EUS between May 2018 and February 2019 were enrolled in this study. The patients were divided into two propofol infusion groups: continuous (n=207) and intermittent (n=220). The following parameters were compared: (1) propofol dose, (2) respiratory and circulatory depression, (3) body movement requiring discontinuation of the examination, (4) awakening score, and (5) patient satisfaction. Results: The median total maintenance dose of propofol was significantly higher in the continuous group than in the intermittent group (160.0 mg vs. 130.0 mg, respectively); however, the reduction in SpO2 was significantly lower in the continuous group (2.9% vs. 13.2%). Body movements occurred less frequently in the continuous group than in the intermittent group (40.1% vs. 49.5%, respectively). The rate of complete awakening was significantly higher in the continuous group than in the intermittent group. Finally, there was a significant difference in the percentage of patients who answered "absolutely yes" when asked about receiving EUS again: 52.7% in the continuous group vs. 34.3% in the intermittent group. Conclusions: Continuous infusion resulted in stable sedation and reduced propofol-associated risks. [ABSTRACT FROM AUTHOR]

Background: Detection of a common channel outside the duodenal wall is important in diagnosing pancreaticobiliary maljunction (PBM). The present study evaluated the utility of contrast-enhanced harmonic endoscopic ultrasonography (CH-EUS) in diagnosing PBM. Methods: This single-center retrospective study enrolled 45 patients who were diagnosed with PBM or high confluence of pancreatobiliary ducts (HCPBD) between January 2007 and December 2021. The diagnostic sensitivities of contrast-enhanced computed tomography (CE-CT), magnetic resonance imaging (MRI), and CH-EUS for diagnosing PBM were analyzed. Imaging findings were evaluated by two reviewers blinded to the clinicopathological results. Results: Based on diagnostic criteria, 33 patients were diagnosed with PBM and 12 with HCPBD. Compared with the patients with HCPBD, those with PBM had significantly longer common channel (12.5 mm vs. 8.1 mm, P = 0.018) and common bile duct (13.0 mm vs. 8.6 mm, P = 0.049) lengths. The κ-coefficients for differentiating PBM and HCPBD were 0.871 between CE-CT and MRI, 0.330 between CE-CT and CH-EUS, and 0.611 between MRI and CH-EUS. The diagnostic sensitivity of CH-EUS (95.2%) was higher than that of CE-CT (83.3%) and MRI (82.8%), although the differences were not statistically significant. Conclusion: CH-EUS may be useful for the diagnosis of PBM. [ABSTRACT FROM AUTHOR]

Background: This prospective cohort study evaluated the feasibility of using endoscopic ultrasound-guided fine-needle biopsy (EUS-FNB) samples for comprehensive mutational analysis of cancer-related genes using microtissues. Methods: Fifty patients with suspected pancreatic cancer presenting consecutively at the Kindai University Hospital between January 2018 and January 2019 were enrolled. Cancerous tissues from EUS-FNB were obtained from each tumor and subjected to histological examination and mutational analysis. The primary endpoint was the collection rate of EUS-FNB specimens suitable for comprehensive cancer panels using deep sequencing. Clinical history and genetic variations between the disease control and progressive disease groups of patients on chemotherapy were evaluated as secondary endpoints. Results: The collection rate of EUS-FNB specimens suitable for comprehensive cancer panels using deep sequencing was 93.6%. The cancer panel was sequenced for 25 patients with pancreatic cancer treated initially with systemic chemotherapy. Mutation in p53 and Smad4 were positively and negatively associated, respectively, with disease control at the initial evaluation. The median time to progression in 15 patients with p53 and without Smad4 mutations was 182.0 days; whereas, it was 92.5 days in other 10 patients; this difference was significant (p = 0.020). Conclusions: Tissue samples from EUS-FNB were suitable for mutational analysis. Pancreatic cancers with p53 and without Smad4 mutations responded better to chemotherapy and had a better prognosis than those others. [ABSTRACT FROM AUTHOR]

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor expressed in hematopoietic and non-hematopoietic cells. Activation of the AhR by xenobiotics, microbial metabolites, and natural substances induces immunoregulatory responses. Autoimmune pancreatitis (AIP) is a chronic fibroinflammatory disorder of the pancreas driven by autoimmunity. Although AhR activation generally suppresses pathogenic autoimmune responses, the roles played by the AhR in AIP have been poorly defined. In this study, we examined how AhR activation affected the development of experimental AIP caused by the activation of plasmacytoid dendritic cells producing IFN-α and IL-33. Experimental AIP was induced in MRL/MpJ mice by repeated injections of polyinosinic-polycytidylic acid. Activation of the AhR by indole-3-pyruvic acid and indigo naturalis, which were supplemented in the diet, inhibited the development of experimental AIP, and these effects were independent of the activation of plasmacytoid dendritic cells producing IFN-α and IL-33. Interaction of indole-3-pyruvic acid and indigo naturalis with AhRs robustly augmented the production of IL-22 by pancreatic islet α cells. The blockade of IL-22 signaling pathways completely canceled the beneficial effects of AhR ligands on experimental AIP. Serum IL-22 concentrations were elevated in patients with type 1 AIP after the induction of remission with prednisolone. These data suggest that AhR activation suppresses chronic fibroinflammatory reactions that characterize AIP via IL-22 produced by pancreatic islet α cells. Indigo naturalis and dietary tryptophan rich in broccoli activate aryl hydrocarbon receptor (AhR). AhR activation inhibits the development of experimental autoimmune pancreatitis through IL-22 produced by pancreatic islet alpha cells. [ABSTRACT FROM AUTHOR]

Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is useful for the diagnosis of pancreatic masses. According to three meta-analyses, the sensitivity, specificity, and accuracy of EUS-FNA are 84–92%, 96–98%, and 86–91%, respectively. However, the occurrence of false-negative and false-positive results indicates that the diagnostic performance of EUS-FNA needs to be improved. Contrast-enhanced harmonic endoscopic ultrasonography (CH-EUS) is used for the characterization of pancreatic masses and can be applied to improve the performance of EUS-FNA. When CH-EUS is used to evaluate intratumor blood flow, an avascular area inside the pancreatic mass that is considered to be fibrosis is often detected. This area can be avoided by performing EUS-FNA under CH-EUS guidance. In this review, we summarize the data on contrast-enhanced harmonic endoscopic ultrasound-guided fine-needle aspiration (CH-EUS-FNA), which suggest that its benefit is still a matter of debate. Of eight studies analyzed, only one showed that CH-EUS improved the sensitivity of EUS-FNA. The future challenge is to determine under what circumstances CH-EUS-FNA is useful. [ABSTRACT FROM AUTHOR]

Objectives: This study evaluated the efficacy of endoscopic ultrasound-guided celiac plexus neurolysis (EUS-CPN) in combination with EUS-guided celiac ganglia neurolysis (EUS-CGN) for pancreatic cancer-associated pain. Methods: This multicenter prospective trial was registered in the University Hospital Medical Information Network (UMIN000031228). Fifty-one consecutive patients with pancreatic cancer-associated pain who presented at one of five Japanese referral centers between February 2018 and March 2021 were enrolled. EUS-CGN was added in cases of visible celiac ganglia. The primary endpoint was effectiveness, defined as a decrease in the numerical rating scale (NRS) by ≥ 3 points. NRS data were prospectively acquired at 1 week after the procedure to evaluate its effectiveness and the extent of pain relief. Results: The technical success rates of EUS-CPN and EUS-CGN were 100% and 80.4%, respectively. The overall efficacy rate was 82.4% [90% confidence interval (CI) 71.2–90.5, P < 0.0001]. The complete pain relief rate was 27.4%. The adverse events rate was 15.7%. The average pain relief period was 72 days. The efficacy rate was higher in the EUS-CPN plus EUS-CGN group than in the EUS-CPN alone group. EUS-CPN plus EUS-CGN was superior to EUS-CPN alone for achieving complete pain relief (P = 0.045). EUS-CGN did not improve the average length of the pain relief period. Conclusions: EUS-CPN combined with EUS-CGN is safe, feasible, and effective for pain relief in patients with pancreatic cancer. The patients who received additional EUS-CGN had a better short-term response. Clinical trial number: UMIN000031228. [ABSTRACT FROM AUTHOR]

Background and Aim: Contrast‐enhanced harmonic endoscopic ultrasonography (CH‐EUS) is useful for the diagnosis of lesions inside and outside the digestive tract. This study evaluated the value of artificial intelligence (AI) in the diagnosis of gastric submucosal tumors by CH‐EUS. Methods: This retrospective study included 53 patients with gastrointestinal stromal tumors (GISTs) and leiomyomas, all of whom underwent CH‐EUS between June 2015 and February 2020. A novel technology, SiamMask, was used to track and trim the lesions in CH‐EUS videos. CH‐EUS was evaluated by AI using deep learning involving a residual neural network and leave‐one‐out cross‐validation. The diagnostic accuracy of AI in discriminating between GISTs and leiomyomas was assessed and compared with that of blind reading by two expert endosonographers. Results: Of the 53 patients, 42 had GISTs and 11 had leiomyomas. Mean tumor size was 26.4 mm. The consistency rate of the segment range of the tumor image extracted by SiamMask and marked by the endosonographer was 96% with a Dice coefficient. The sensitivity, specificity, and accuracy of AI in diagnosing GIST were 90.5%, 90.9%, and 90.6%, respectively, whereas those of blind reading were 90.5%, 81.8%, and 88.7%, respectively (P = 0.683). The κ coefficient between the two reviewers was 0.713. Conclusions: The diagnostic ability of CH‐EUS results evaluated by AI to distinguish between GISTs and leiomyomas was comparable with that of blind reading by expert endosonographers. [ABSTRACT FROM AUTHOR]

Background: The value of contrast-enhanced harmonic endoscopic ultrasonography (CH-EUS) for T-staging in patients with extrahepatic bile duct cancer was evaluated. Methods: This single-center, retrospective study included consecutive patients with extrahepatic bile duct cancer who underwent surgical resection after preoperative EUS, CH-EUS, and contrast-enhanced CT (CE-CT) examinations between June 2014 and August 2017. The capacity of these modalities for T-staging of extrahepatic bile duct cancer was evaluated by assessing invasion beyond the biliary wall into the surrounding tissue, gallbladder, liver, pancreas, duodenum, portal vein system (portal vein and/or superior mesenteric vein), inferior vena cava, and hepatic arteries (proper hepatic artery, right. and/or left. hepatic artery). Blind reading of EUS, CH-EUS, and CE-CT images was performed by two expert reviewers each. Results: 38 patients were eligible for analysis, of which eight had perihilar bile duct cancer and 30 had distal bile duct cancer. Postoperative T-staging was T1 in 6, T2 in 16, and T3 in 16 cases. CH-EUS was superior to CE-CT for diagnosing invasion beyond the biliary wall into surrounding tissue (92.1% vs. 45.9%, P = 0.0002); the ability to detect invasion to other organs did not differ significantly between the two modalities. The accuracy of CH-EUS for T-staging of tumors was better than that of CE-CT (73.7% vs. 39.5%, P = 0.0059). CH-EUS tended to have a better accuracy than EUS for the diagnosis of invasion beyond the biliary wall into the surrounding tissue (92.1% vs. 78.9%, P = 0.074) and T-staging (73.7% vs. 60.5%, P = 0.074). Conclusion: CH-EUS is useful for T-staging of extra hepatic bile duct cancer, especially in terms of invasion beyond the biliary wall into the surrounding tissue. [ABSTRACT FROM AUTHOR]

Background and Aims: Pancreatic neuroendocrine neoplasms (PanNENs), including Grade 1 (G1) or G2 tumors, can have a poor prognosis. This study investigated the value of contrast‐enhanced harmonic endoscopic ultrasonography (CH‐EUS) for predicting the prognosis of PanNENs. Methods: This single‐center, retrospective study included 47 consecutive patients who underwent CH‐EUS and were diagnosed with PanNEN by surgical resection or EUS‐guided fine needle aspiration between December 2011 and February 2016. Patients were divided into aggressive and non‐aggressive groups according to the degree of clinical malignancy. CH‐EUS was assessed regarding its capacity for diagnosing aggressive PanNEN, the correspondence between contrast patterns and pathological features, and its ability to predict the prognosis of PanNEN. Results: There were 19 cases of aggressive PanNEN and 28 cases of non‐aggressive PanNEN. The aggressive group included three G1, four G2, three G3 tumors, three mixed neuroendocrine non‐neuroendocrine neoplasms, and six neuroendocrine carcinomas. CH‐EUS was superior to contrast‐enhanced computed tomography for the diagnosis of aggressive PanNEN (P < 0.001): hypo‐enhancement on CH‐EUS was an indicator of aggressive PanNEN, with sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of 94.7%, 100%, 100%, 96.6%, and 97.9%, respectively. Among G1/G2 PanNENs, cases with hypo‐enhancement on CH‐EUS had a poorer prognosis than those with hyper/iso‐enhancement (P = 0.0009). Assessment of 36 resected specimens showed that hypo‐enhancement on CH‐EUS was associated with smaller and fewer vessels and greater degree of fibrosis. Conclusion: Contrast‐enhanced harmonic endoscopic ultrasonography may be useful for predicting the prognosis of PanNENs. [ABSTRACT FROM AUTHOR]

Autoimmune pancreatitis (AIP) is a pancreatic manifestation of a newly proposed disease entity, IgG4-related disease (IgG4-RD), characterized by enhanced IgG4 antibody responses and involvement of multiple organs. We have previously reported that innate immune activation contributes to the development of AIP and IgG4-RD, as these diseases are characterized by the production of IFN-α and IL-33 by plasmacytoid dendritic cells (pDCs) that mediate chronic fibroinflammatory responses. In this study, we investigated the roles played by innate immunity against intestinal microflora in experimental AIP induced in MRL/MpJ mice by repeated administrations of 100 µg of polyinosinic-polycytidylic acid [poly (I:C)]. Bowel sterilization with a broad spectrum of antibiotics inhibited pancreatic accumulation of pDCs producing IFN-α and IL-33, and thereby suppressed the development of AIP. Mice treated with 10 µg of poly (I:C) developed severe AIP equivalent to that induced by 100 µg of poly (I:C) upon co-housing with mice treated with 100 µg of poly (I:C). Fecal microbiota transplantation (FMT) from donor mice treated with 100 µg of poly (I:C) led to the development of severe AIP in the recipient mice upon injection with 10 µg of poly (I:C). Induction of severe AIP in mice with 10 µg of poly (I:C) was associated with pancreatic accumulation of pDCs producing IFN-α and IL-33 in the co-housing and FMT experiments. These data collectively suggest that innate immune responses against intestinal microflora are involved in the development of experimental AIP, and that intestinal dysbiosis increases sensitivity to experimental AIP via activation of pDCs. [ABSTRACT FROM AUTHOR]

Endoscopic methods are increasingly used in the diagnosis of cystic lesions of the pancreas. The two major endoscopic approaches are endoscopic ultrasonography (EUS) and transpapillary diagnosis. EUS‐guided fine‐needle aspiration cytology and EUS‐guided fine needle‐based confocal laser endomicroscopy have been used in the differential diagnosis of mucinous and non‐mucinous pancreatic cysts. EUS is the most sensitive modality for detecting mural nodules (MN) in intraductal papillary mucinous neoplasms (IPMN). Contrast‐enhanced harmonic EUS (CH‐EUS), as an add‐on to EUS, is useful for identifying and characterizing MN. Recent studies show that CH‐EUS has a sensitivity of 60–100% and a specificity of 75–92.9% for diagnosing malignant cysts. Intraductal ultrasonography and peroral pancreatoscopy are especially useful for detecting MN and IPMN. A recent meta‐analysis showed that cytological assessment of pancreatic juice using a transpapillary approach had a pooled sensitivity, specificity, and accuracy of 35.1%, 97.2%, and 92.9%, respectively, for diagnosing malignant IPMN. Further studies are warranted to determine the indications for each of these novel techniques in assessing cystic lesions of the pancreas. [ABSTRACT FROM AUTHOR]

Background and Aim: This study evaluated the utility of endoscopic ultrasonography (EUS) combined with contrast‐enhanced harmonic EUS (CH‐EUS) for surveillance of the remnant pancreas after surgery for intraductal papillary mucinous neoplasm (IPMN). Methods: This was a single‐center, retrospective, descriptive study. A total of 134 consecutive patients who underwent surgical resection for IPMN between April 2009 and March 2015 were evaluated. Rates of recurrence and development of IPMN‐concomitant pancreatic ductal adenocarcinoma (PDAC) during follow up were assessed. Clinical findings of patients with recurrence or development of PDAC were also evaluated. Results: Of 134 resected IPMN 56 (41.8%) and 78 (58.2%) were classified as benign and malignant, respectively. Patients were followed up for a median of 29 months, 33 (24.6%) by both contrast‐enhanced computed tomography (CE‐CT) and EUS, and 101 (75.4%) by computed tomography (CT) alone. Thirteen patients (9.7%) showed tumor recurrence, five with intra‐pancreatic recurrence and eight with extra‐pancreatic metastases. An enhancing mural nodule within the dilated main pancreatic duct was successfully detected by EUS in one patient, but not by CE‐CT. Two patients developed IPMN‐concomitant PDAC during follow up. EUS combined with CH‐EUS successfully detected small IPMN‐concomitant PDAC in two patients, whereas these lesions were not detected by CT. CH‐EUS was useful for better visualization of the margins of IPMN‐concomitant PDAC in one of these two patients. Conclusion: Endoscopic ultrasonography combined with CH‐EUS may improve follow up of patients with resected IPMN. [ABSTRACT FROM AUTHOR]

Background and Aim Differential diagnosis of localized gallbladder lesions is challenging. The aim of the present study was to evaluate the utility of contrast-enhanced harmonic endoscopic ultrasonography ( CH- EUS) for diagnosis of localized gallbladder lesions. Methods One hundred and twenty-five patients with localized gallbladder lesions were evaluated by CH- EUS between March 2007 and February 2014. This was a single-center retrospective study. Utilities of fundamental B-mode EUS ( FB- EUS) and CH- EUS in the differentiation of gallbladder lesions and sludge plug were initially compared. Thereafter, these two examinations were compared with respect to their accuracy in the diagnosis of malignant lesions. Five reviewers blinded to the clinicopathological results evaluated microcirculation patterns in the vascular and perfusion images. Results In the differentiation between gallbladder lesions and sludge plug, FB- EUS had a sensitivity, specificity, and accuracy of 82%, 100%, and 95%, respectively, whereas CH- EUS had a sensitivity, specificity, and accuracy of 100%, 99%, and 99%, respectively. FB- EUS-based diagnosis of carcinomas based on tumor size and/or shape had a sensitivity, specificity, and accuracy of 61-87%, 71-88%, and 74-86%, respectively. Additional information regarding irregular vessel patterns in the vascular image and/or heterogeneous enhancement in the perfusion image on CH- EUS increased the sensitivity, specificity, and accuracy for the diagnosis of carcinomas to 90%, 98%, and 96%, respectively. There was a significant difference between FB- EUS and CH- EUS in terms of carcinoma diagnosis. Conclusion CH- EUS was useful for the evaluation of localized gallbladder lesions. [ABSTRACT FROM AUTHOR]

Background and Aims: Risk factors for pancreatic ductal adenocarcinoma (PDAC) include diabetes mellitus, chronic pancreatitis, obesity, a family history of pancreatic cancer, and a history of smoking or alcohol consumption. The aim of this study was to evaluate the association between risk factors for PDAC and malignant intraductal papillary mucinous neoplasm (IPMN). Methods: The study included 134 consecutive patients with IPMN who underwent surgical resection at Kindai University Hospital between April 2009 and March 2015. Data on the presence or absence of mural nodules (MNs) and risk factors for PDAC were evaluated. Multivariable logistic regression analysis was performed with malignant IPMN as the outcome variable and MNs and risk factors for PDAC as explanatory variables. Results: The odds ratio of malignant IPMN to MNs was 3.88 (95% confidence interval [CI] 1.53-9.84; p = 0.004), whereas that of malignant IPMN to smoking history was 1.66 (95% CI 0.74-3.71; p = 0.22). When the presence of MNs was considered as a predictive factor for malignancy, the sensitivity and specificity were 88.5 and 32.1%, respectively, whereas when the presence of both smoking history and MNs was considered, the specificity improved to 73.2%, with a decrease in sensitivity to 42.3%. Conclusions: The presence of both a smoking history and MNs was a valuable predictive factor for malignant IPMN with high specificity. A smoking history should be considered before surgical resection in addition to the presence of MNs. [ABSTRACT FROM AUTHOR]

Background and Aim The study aims to evaluate contrast-enhanced harmonic endoscopic ultrasonography (CH-EUS) for the differential diagnosis of submucosal tumors (SMT) of the upper gastrointestinal tract. Methods Between June 2008 and May 2015, 157 consecutive patients with submucosal lesions of the upper gastrointestinal tract were evaluated by CH-EUS. This was a single-center retrospective analysis of prospectively collected data in a registry. The data from 73 patients who later underwent surgical resection were analyzed in this study. Surgical specimens served as the final diagnoses. The two CH-EUS variables of blood flow (hyper-enhancement vs hypo-enhancement) and homogeneity of enhancement pattern were evaluated. Results The final diagnoses were 58 gastrointestinal stromal tumors (GISTs) and 15 benign SMTs (two lipomas, five leiomyomas, five schwannomas, two glomus tumors, and one ectopic pancreas). On CH-EUS, 49 of 58 (84.5%) GISTs presented with hyper-enhancement, whereas 4 of 15 (26.7%) benign SMTs showed hyper-enhancement; 21 of 58 (36.2%) GISTs showed inhomogeneous contrast enhancement, while only 2 of 15 (13.3%) benign SMTs demonstrated inhomogeneous contrast enhancement. If hyper-enhancement was considered to indicate GISTs, the sensitivity, specificity, and accuracy were 84.5%, 73.3%, and 82.2%, respectively. If inhomogeneous enhancement was considered to indicate GISTs, the sensitivity, specificity, and accuracy were 36.2%, 86.7%, and 46.6%, respectively. In lesions of less than 2 cm, hyper-enhancement was a more sensitive indicator of GISTs than inhomogeneous enhancement. Conclusions Hyper-enhancement and inhomogeneous enhancement were found to be a characteristic of GISTs. CH-EUS was useful for discrimination of benign SMTs from GISTs. [ABSTRACT FROM AUTHOR]

Tumor size correlates with malignancy in nonfunctioning pancreatic endocrine tumor. Therefore, malignancy of PanNENs can be determined by combination with conventional pathological examinations, semi-quantitative assessment of intratumor fibrosis and vascularity, and CH-EUS. Prognostic value of tumor architecture, tumor-associated vascular characteristics, and expression of angiogenic molecules in pancreatic endocrine tumor. [Extracted from the article]

The article presents a case study of a 64-year-old woman with ampullary cancer who developed obstructive pancreatitis before pancreatoduodenectomy and hence Endoscopic ultrasound-guided pancreatic duct drainage EUS-PD was carried out to resolve it. It includes Abdominal computed tomography (CT) showing dilation of the main pancreatic duct, puncturing of pancreatic duct with a 19-gauge needle and deployment of the plastic stent.

Endoscopic ultrasound-guided pancreatic drainage (EUSPD) was performed in a patient with unresectable pancreatic cancer who developed pancreatitis. In this case, EUS-PD was useful as salvage therapy for pancreatitis as the transpapillary approach was difficult. [ABSTRACT FROM AUTHOR]

In cases of malignant obstructive cholangitis with surgically altered gastrointestinal anatomy, if the intra-hepatic bile duct is not expanded, both percutaneous transhepatic biliary drainage (PTBD) and endoscopic ultrasound (EUS)-guided biliary drainage are difficult to perform.[[1]] In such case, percutaneous transhepatic gallbladder drainage (PTGBD) become a good indication. We report a successful case of conversion from PTGBD to EUS-guided hepaticogastrostomy (EUS-HGS) with intentional expansion of the intra-hepatic bile duct by contrast injection through the PTGBD route.[[3]] The continuous contrast medium injection form PTGBD route, the gallbladder and intra-hepatic bile duct were expanded. [Extracted from the article]

Objectives: Texture and color enhancement imaging (TXI) reportedly improves the identification of the papilla of Vater for selective biliary cannulation compared with white light imaging (WLI). This multicenter study evaluated the efficacy of short‐type single‐balloon enteroscopy (SBE)‐assisted biliary cannulation using a new‐generation image‐enhanced endoscopy processing system equipped with TXI in patients who underwent Roux‐en‐Y gastrectomy. Methods: Patients with Roux‐en‐Y gastrectomy with a native papilla, and underwent short SBE‐assisted biliary cannulation during endoscopic retrograde cholangiopancreatography‐related procedures between January 2019 and April 2023 were retrospectively reviewed. Outcomes of biliary cannulation using TXI and WLI were compared. The primary outcome was time to successful biliary cannulation. Results: Thirty‐three patients underwent biliary cannulation with TXI and 98 underwent WLI. The biliary cannulation success rates and median time to successful biliary cannulation with TXI and WLI were 93.9% (95% confidence interval [CI] 79.8–99.3%) and 83.7% (95% CI 74.8–90.4%), respectively (P = 0.14), and 10 min (interquartile range [IQR] 2.5–23.5) and 18 min (IQR 9.75–24), respectively (P = 0.04). Biliary cannulation with TXI required a shorter cannulation time than that required with WLI. Adverse event rates with TXI and WLI did not differ significantly (P = 0.58). Multivariate linear regression analysis showed that the use of TXI and short length of oral protrusion were associated with a shorter successful biliary cannulation time. Conclusion: Short SBE‐assisted biliary cannulation was effective and safe on TXI in patients who underwent Roux‐en‐Y gastrectomy, and achieved shorter successful biliary cannulation time. [ABSTRACT FROM AUTHOR]

The Asian Federation of Societies for Ultrasound in Medicine and Biology aimed to provide information on techniques and indications for contrast-enhanced harmonic endoscopic ultrasound (CH-EUS), and to create statements including the level of recommendation. These statements are based on current scientific evidence reviewed by a Consensus Panel of 15 internationally renowned experts. The reliability of clinical questions was measured by agreement rates after voting. Six statements were made on techniques, including suitable contrast agents for CH-EUS, differences between contrast agents, setting of mechanical index, dual imaging and duration and phases for observation. Thirteen statements were made on indications, including pancreatic solid masses, pancreatic cancer staging, pancreatic cystic lesions and mural nodules, detection of subtle pancreatic lesions, gallbladder sludge and polyps, hepatic lesions, lymph nodes, subepithelial lesions, visceral vascular diseases, guidance of fine needle aspiration and evaluation for local therapy. These international expert consensus guidelines will assist endosonographers in conducting CH-EUS according to evidence-based information. [ABSTRACT FROM AUTHOR]

Purpose: To examine whether MRCP using a combination of compressed sensing and sensitivity encoding with navigator-triggered and breath-hold techniques (NT C-SENSE and BH C-SENSE, respectively) have comparable image quality to that of navigator-triggered MRCP using only sensitivity encoding (NT SENSE) at 1.5-T. Methods: Fifty-one participants were enrolled in this prospective study between July and October 2018 and underwent the three 3D MRCP sequences each. The acquisition time and relative duct-to-periductal contrast ratios (RC values) of each bile duct segment were obtained. Visualization of the bile and main pancreatic ducts, background suppression, artifacts, and overall image quality were scored on 5-point scales. Mean and median differences in RC values and qualitative scores of NT C-SENSE and BH C-SENSE relative to NT SENSE were calculated with 95% confidence intervals (CIs). Results: Acquisition time of NT SENSE, NT C-SENSE, and BH C-SENSE were 348, 143 (mean for both), and 18 s (for all participants), respectively. The RC value of each bile duct segment was inferior, but the lower limits of the 95% CIs of the mean differences were ≥ − 0.10, for both NT C-SENSE and BH C-SENSE. The visualization score of the intrahepatic duct in BH C-SENSE was inferior to that in NT SENSE (lower 95% CI limit, − 1.5). In both NT C-SENSE and BH C-SENSE, the 95% CIs of the median differences in the other qualitative scores were from − 1.0 to 0.0. Conclusion: NT C-SENSE and BH C-SENSE have comparable image quality to NT SENSE at 1.5-T. [ABSTRACT FROM AUTHOR]

The authors reflect on the paucity of data on the comparison of endoscopic ultrasonography (EUS)-guided gallbladder drainage and percutaneous drainage. They mention that it is probably that EUS-guided gallbladder is unlikely to dislodge, offers for better quality of life and not related to skin infections. They state that much more has to be done, even though technological innovations improved procedural success rates and reduced complications related to EUS-guided drainage procedures.

Background: Balloon enteroscopy-assisted endoscopic retrograde cholangiopancreatography (BE-ERCP) has been reported to be effective for patients with surgically altered gastrointestinal anatomy. However, selective biliary cannulation remains difficult in BE-ERCP. We examined the usefulness of a modified double-guidewire technique using an uneven double lumen cannula (the uneven method) for BE-ERCP in patients with surgically altered gastrointestinal anatomy.Methods: To clarify the usefulness of the uneven method for selective biliary cannulation in BE-ERCP in comparison to the pancreatic guidewire (PGW) method, 40 patients with surgically altered gastrointestinal anatomy who underwent BE-ERCP with successful placement of a guidewire in the pancreatic duct were evaluated. The uneven method was used in 18 cases (uneven group) and the PGW method was used in the remaining 22 cases (PGW group).Results: The technical success rate of biliary cannulation was higher in the uneven group than in the PGW group (83.3 vs. 59.0%; P = 0.165). In addition, the time to biliary cannulation were significantly shorter in the uneven group than in the PGW group (6 vs. 18 min; P = 0.004; respectively). In the PGW group, post-ERCP pancreatitis (PEP) occurred in 3 of 22 cases (13.6%). No adverse events, including PEP, occurred in the uneven group.Conclusions: The uneven method may be a useful option of selective biliary cannulation in BE-ERCP for the patients with surgically altered gastrointestinal anatomy. [ABSTRACT FROM AUTHOR]

Previous studies have shown that inhibition of receptor-interacting serine/threonine kinase (RICK) (also known as RIP2) results in amelioration of experimental colitis. This role has largely been attributed to nucleotide-binding oligomerization domain 2 (NOD2) signaling since the latter is considered a major inducer of RICK activation. In this study, we explored the molecular mechanisms accounting for RICK-mediated inhibition of inflammatory bowel disease (IBD). In an initial series of studies focused on trinitrobenzene sulfonic acid (TNBS)-colitis and dextran sodium sulfate (DSS)-colitis we showed that down-regulation of intestinal RICK expression in NOD2-intact mice by intra-rectal administration of a plasmid expressing RICK-specific siRNA was accompanied by down-regulation of pro-inflammatory cytokine responses in the colon and protection of the mice from experimental colitis. Somewhat surprisingly, intra-rectal administration of RICK-siRNA also inhibited TNBS-colitis and DSS-colitis in NOD2-deficient and in NOD1/NOD2-double deficient mice. In complementary studies of humans with IBD we found that expression of RICK, cellular inhibitor of apoptosis protein 2 (cIAP2) and downstream signaling partners were markedly increased in inflamed tissue of IBD compared to controls without marked elevations of NOD1 or NOD2 expression. In addition, the increase in RICK expression correlated with disease activity and pro-inflammatory cytokine responses. These studies thus suggest that NOD1- or NOD2-independenent activation of RICK plays a major role in both murine experimental colitis and human IBD. [ABSTRACT FROM AUTHOR]

The combination of second-generation ultrasound contrast agents and an endoscopic ultrasonography ( EUS) system with a broad-band transducer has allowed contrast-enhanced harmonic imaging in the field of EUS. In contrast-enhanced harmonic EUS ( CH-EUS), diffuse homogeneous enhancement is obtained in normal parenchyma of the pancreas. The bile duct and pancreatic duct are depicted as non-enhanced ductal structures with strong contrast in comparison to the surrounding parenchyma. CH-EUS identifies pancreatic adenocarcinomas as solid lesions exhibiting hypo-enhancement with a sensitivity and specificity of 88-96% and 88-94%, respectively. In particular, 80-100% of false-negative cases in endoscopic ultrasound-guided fine-needle aspiration ( EUS-FNA) are correctly classified by CH-EUS, suggesting CH-EUS complements EUS-FNA. Moreover, CH-EUS improves depiction of some subtle lesions in conventional EUS, thus facilitating EUS-FNA. For quantitative perfusion analysis, a time-intensity curve ( TIC) for the region of interest can be generated during CH-EUS. The maximum intensity gain and the echo intensity reduction rate from the peak at 1 min obtained by TIC can be used for differentiation of pancreatic adenocarcinoma from other tumors. CH-EUS is also useful for differentiation of invasive intraductal papillary mucinous neoplasms ( IPMN) from non-invasive IPMN, identification of malignant lesions in the gallbladder, and T- and N-staging of pancreatobiliary tumors. [ABSTRACT FROM AUTHOR]

Autoimmune pancreatitis (AIP) is a pancreatic manifestation of a recently defined disease form known as IgG4-related disease (AIP/IgG4-RD). AIP/IgG4-RD is characterized by elevated systemic IgG4 antibody concentrations and lesional tissues infiltrated by IgG4-expressing plasmacytes. In addition, recent studies have revealed that, in common with other autoimmune diseases, such as systemic lupus erythematosus (SLE) and psoriasis, AIP/IgG4-RD is associated with increased type I IFN (IFN-I) production by plasmacytoid dendritic cells (pDCs). However, unlike SLE, AIP/IgG4-RD is characterized by elevated IFN-I-dependent IL-33 production, the latter emerging as an important contributor to inflammation and fibrotic responses characterizing this disease. On this basis, we propose that blockade of the IFN-I/IL-33 axis might constitute a successful approach to treating this unique type of autoimmunity. Highlights AIP is a pancreatic manifestation of systemic AIP/IgG4-RD, a newly established disease entity in humans. AIP/IgG4-RD is characterized by enhanced IgG4 antibody responses, multiple organ involvement, and storiform fibrosis. IFN-I and pDCs have pathogenic roles in AIP/IgG4-RD as in SLE and psoriasis. In mice, IFN-I-dependent IL-33 production by pDCs mediates fibrosis as well as inflammation in AIP. IFN-I-dependent IL-33 production might have a pathogenic role in other diseases exhibiting both autoimmunity and fibrosis. The IFN-I/IL-33 axis in pDCs represents a new putative therapeutic target of AIP/IgG4-RD, although further studies in humans are warranted. [ABSTRACT FROM AUTHOR]

Translocation of gut bacteria into the pancreas promotes the development of severe acute pancreatitis (SAP). Recent clinical studies have also highlighted the association between fungal infections and SAP. The sensing of gut bacteria by pattern recognition receptors promotes the development of SAP via the production of proinflammatory cytokines; however, the mechanism by which gut fungi mediate SAP remains largely unknown. Leucine-rich repeat kinase 2 (LRRK2) is a multifunctional protein that regulates innate immunity against fungi via Dectin-1 activation. Here, we investigated the role of LRRK2 in SAP development and observed that administration of LRRK2 inhibitors attenuated SAP development. The degree of SAP was greater in Lrrk2 transgenic (Tg) mice than in control mice and was accompanied by an increased production of nuclear factor-kappaB-dependent proinflammatory cytokines. Ablation of the fungal mycobiome by anti-fungal drugs inhibited SAP development in Lrrk2 Tg mice, whereas the degree of SAP was comparable in Lrrk2 Tg mice with or without gut sterilization by a broad range of antibiotics. Pancreatic mononuclear cells from Lrrk2 Tg mice produced large amounts of IL-6 and TNF-α upon stimulation with Dectin-1 ligands, and inhibition of the Dectin-1 pathway by a spleen tyrosine kinase inhibitor protected Lrrk2 Tg mice from SAP. These data indicate that LRRK2 activation is involved in the development of SAP through proinflammatory cytokine responses upon fungal exposure. Leucine-rich repeat kinase 2 (Lrrk2) transgenic mice were sensitive to cerulein-induced severe acute pancreatitis. Myeloid cells and dendritic cells overexpressing LRRK2 produce large amounts of proinflammatory cytokines upon sensing of fungal cell wall components. [ABSTRACT FROM AUTHOR]

The most common symptom in patients with advanced pancreatic cancer is abdominal pain. This has traditionally been treated with nonsteroidal anti-inflammatory drugs and opioid analgesics. However, these treatments result in inadequate pain control or drug-related adverse effects in some patients. An alternative pain-relief modality is celiac plexus neurolysis, in which the celiac plexus is chemically ablated. This procedure was performed percutaneously or intraoperatively until 1996, when endoscopic ultrasound (EUS)-guided celiac plexus neurolysis was first described. In this transgastric anterior approach, a neurolytic agent is injected around the celiac trunk under EUS guidance. The procedure gained popularity as a minimally invasive approach and is currently widely used to treat pancreatic cancer-associated pain. We focus on two relatively new techniques of EUS-guided neurolysis: EUS-guided celiac ganglia neurolysis and EUS-guided broad plexus neurolysis, which have been developed to improve efficacy. Although the techniques are safe and effective in general, some serious adverse events including ischemic and infectious complications have been reported as the procedure has gained widespread popularity. We summarize reported clinical outcomes of EUS-guided neurolysis in pancreatic cancer (from the PubMed and Embase databases) with a goal of providing information useful in developing strategies for pancreatic cancer-associated pain alleviation. [ABSTRACT FROM AUTHOR]

Objectives: Clinical Practice Guidelines for Pancreatic Cancer was first published in 2006 by the Japan Pancreas Society, and revised in 2009, 2013, 2016, and 2019. In July 2022, Clinical Practice Guidelines for Pancreatic Cancer was newly revised in Japanese. Methods: For this revision, we developed an entirely new guideline according to the Minds Manual for Guideline Development 2020, which includes the concepts of GRADE—Grading Recommendations Assessment, Development, and Evaluation, to enable a better understanding of the current guidelines. Patients and the public were actively involved in both the development and implementation of the guideline. Results: The guideline includes algorithms for diagnosis, treatment, chemotherapy, and precision medicine of pancreatic cancer, and addresses 7 subjects: diagnosis, surgical therapy, adjuvant therapy, radiation therapy, chemotherapy, stent therapy, and supportive & palliative medical care. It includes 73 clinical questions and 112 statements. The statements correspond to the clinical questions, evidence levels, recommendation strengths, and agreement rates. Conclusions: This guideline represents the most standard clinical and practical management guideline available until date in Japan. This is the English synopsis of the Clinical Practice Guidelines for Pancreatic Cancer 2022 in Japanese, and is an attempt to disseminate the Japanese guideline worldwide to introduce the Japanese approach to the clinical management of pancreatic cancer. [ABSTRACT FROM AUTHOR]

Mutations in nucleotide-binding oligomerization domain 2 (NOD2) are associated with Crohn's disease (CD). Although NOD2 activation contributes to the maintenance of intestinal homeostasis through the negative regulation of pro-inflammatory cytokine responses mediated by Toll-like receptors (TLRs), the effects of NOD2 activation on interferon (IFN)-α responses induced by TLR9 have been poorly defined. To explore the cross-talk between NOD2 and TLR9, human monocytes or dendritic cells (DCs) were stimulated with NOD2 and/or TLR9 ligands to measure IFN-α production. The severity of dextran sodium sulfate (DSS)-induced colitis was compared in mice treated with NOD2 and/or TLR9 ligands. Expression of IFN-α and IFN-stimulated genes (ISGs) was examined in the colonic mucosa of patients with inflammatory bowel disease (IBD). NOD2 activation reduced TLR9-induced IFN-α production by monocytes and DCs in a deubiquitinating enzyme A (DUBA)-dependent manner. Activation of DUBA induced by the co-stimulation of TLR9 and NOD2 inhibited Lys63-linked polyubiquitination of TRAF3 and suppressed TLR9-mediated IFN-α production. NOD2 activation in hematopoietic cells protected mice from TLR9-induced exacerbation of DSS-induced colitis by down-regulating IFN-α responses and up-regulating DUBA expression. Colonic mucosa of patients with active and remitted IBD phases was characterized by the enhanced and reduced expression of ISGs, respectively. Expression levels of IFN-α and IL-6 positively correlated in the active colonic mucosa of patients with ulcerative colitis and CD, whereas DUBA expression inversely correlated with that of IFN-α in patients with CD. Collectively, these data suggest that DUBA-dependent negative effect of NOD2 on TLR9-mediated IFN-α responses contributes to the maintenance of intestinal homeostasis. [ABSTRACT FROM AUTHOR]

S-1 has shown promising efficacy with a mild toxicity profile in patients with advanced biliary tract cancer. The aim of this study was to evaluate whether adjuvant S-1 improved overall survival compared with observation for resected biliary tract cancer. This open-label, multicentre, randomised phase 3 trial was conducted in 38 Japanese hospitals. Patients aged 20–80 years who had histologically confirmed extrahepatic cholangiocarcinoma, gallbladder carcinoma, ampullary carcinoma, or intrahepatic cholangiocarcinoma in a resected specimen and had undergone no local residual tumour resection or microscopic residual tumour resection were randomly assigned (1:1) to undergo observation or to receive S-1 (ie, 40 mg, 50 mg, or 60 mg according to body surface area, orally administered twice daily for 4 weeks, followed by 2 weeks of rest for four cycles). Randomisation was performed by the minimisation method, using institution, primary tumour site, and lymph node metastasis as adjustment factors. The primary endpoint was overall survival and was assessed for all randomly assigned patients on an intention-to-treat basis. Safety was assessed in all eligible patients. For the S-1 group, all patients who began the protocol treatment were eligible for a safety assessment. This trial is registered with the University hospital Medical Information Network Clinical Trials Registry (UMIN000011688). Between Sept 9, 2013, and June 22, 2018, 440 patients were enrolled (observation group n=222 and S-1 group n=218). The data cutoff date was June 23, 2021. Median duration of follow-up was 45·4 months. In the primary analysis, the 3-year overall survival was 67·6% (95% CI 61·0–73·3%) in the observation group compared with 77·1% (70·9–82·1%) in the S-1 group (adjusted hazard ratio [HR] 0·69, 95% CI 0·51–0·94; one-sided p=0·0080). The 3-year relapse-free survival was 50·9% (95% CI 44·1–57·2%) in the observation group compared with 62·4% (55·6–68·4%) in the S-1 group (HR 0·80, 95% CI 0·61–1·04; two-sided p=0·088). The main grade 3–4 adverse events in the S-1 group were decreased neutrophil count (29 [14%]) and biliary tract infection (15 [7%]). Although long-term clinical benefit would be needed for a definitive conclusion, a significant improvement in survival suggested adjuvant S-1 could be considered a standard of care for resected biliary tract cancer in Asian patients. The National Cancer Center Research and the Ministry of Health, Labour, and Welfare of Japan. [ABSTRACT FROM AUTHOR]

Autoimmune pancreatitis (AIP) is an autoimmune disorder of the pancreas characterized by enhanced IgG4 antibody responses and multiple organ involvement. AIP is a pancreatic manifestation of the systemic IgG4-related disease (IgG4-RD). Although AIP and IgG4-RD predominantly occur in middle-aged and elderly men, the roles of eating habits and lifestyle in the pathogenesis of these conditions are poorly understood. In this study, we examined whether a high-fat diet (HFD), preferred by middle-aged and elderly men, increases sensitivity to experimental AIP. We modeled AIP in MRL/MpJ mice by repeated injections of polyinosinic:polycytidylic acid. HFD exacerbated AIP development and promoted pancreatic accumulation of interferon (IFN)-α-producing plasmacytoid dendritic cells (pDCs). However, HFD did not increase the severity of autoimmune sialadenitis, another disorder associated with AIP and IgG4-RD. Neutralization of type I IFN signaling pathways prevented the development of severe AIP induced by HFD. In contrast, leaky gut was less likely to be associated with the HFD-induced exacerbation of AIP, as was evidenced by the lack of significant alterations in the jejunal or ileal expression of tight junction proteins. These data suggest that HFD exacerbates experimental AIP through the activation of pDCs producing IFN-α. • High-fat diet exacerbates experimental autoimmune pancreatitis (AIP). • Type I IFNs exacerbate AIP induced by high-fat diet. • Impaired function of tight junction proteins is not associated with AIP exacerbation. [ABSTRACT FROM AUTHOR]

Autoimmune pancreatitis (AIP) and IgG4-related disease (IgG4-RD) are new disease entities characterized by enhanced IgG4 antibody responses and involvement of multiple organs, including the pancreas and salivary glands. Although the immunopathogenesis of AIP and IgG4-RD is poorly understood, we previously reported that intestinal dysbiosis mediates experimental AIP through the activation of IFN-α- and IL-33-producing plasmacytoid dendritic cells (pDCs). Because intestinal dysbiosis is linked to intestinal barrier dysfunction, we explored whether the latter affects the development of AIP and autoimmune sialadenitis in MRL/MpJ mice treated with repeated injections of polyinosinic–polycytidylic acid [poly (I:C)]. Epithelial barrier disruption was induced by the administration of dextran sodium sulfate (DSS) in the drinking water. Mice co-treated with poly (I:C) and DSS, but not those treated with either agent alone, developed severe AIP, but not autoimmune sialadenitis, which was accompanied by the increased accumulation of IFN-α- and IL-33-producing pDCs. Sequencing of 16S ribosomal RNA revealed that Staphylococcus sciuri translocation from the gut to the pancreas was preferentially observed in mice with severe AIP co-treated with DSS and poly (I:C). The degree of experimental AIP, but not of autoimmune sialadenitis, was greater in germ-free mice mono-colonized with S. sciuri and treated with poly (I:C) than in germ-free mice treated with poly (I:C) alone, which was accompanied by the increased accumulation of IFN-α- and IL-33-producing pDCs. Taken together, these data suggest that intestinal barrier dysfunction exacerbates AIP through the activation of pDCs and translocation of S. sciuri into the pancreas. [ABSTRACT FROM AUTHOR]

[Display omitted] Enhanced IgG4 antibody (Ab) response is a prominent feature of type 1 autoimmune pancreatitis (AIP). Innate immune responses associated with IgG4 Ab production are poorly defined. We have previously reported that peripheral blood mononuclear cells (PBMCs) isolated from patients with type 1 AIP produce large amounts of IgG4 Abs upon stimulation with bacterial cell wall components. In addition, we showed that activation of plasmacytoid dendritic cells producing interferon (IFN)-α, interleukin (IL)-33, and B cell-activating factor (BAFF) upon sensing intestinal bacteria mediates the development of experimental AIP. In this study, we attempted to clarify the role of innate immunity against fungi in inducing enhanced IgG4 Ab responses in type 1 AIP. PBMCs isolated from healthy controls and patients with type 1 AIP were stimulated with a broad range of bacterial and fungal cell wall components. The concentrations of IgG1, IgG4, and cytokines were measured using enzyme-linked immunosorbent assays. Cell wall components derived from bacteria and fungi induced IgG1 and IgG4 Ab production in patients with type 1 AIP. Various types of microbe-associated molecular pattern motifs enhanced IgG4 Ab production in patients with type 1 AIP compared with the limited motifs in healthy controls. The enhanced IgG1 and IgG4 Ab production that followed in response to bacterial and fungal cell wall components was parallel to that of IFN-α, IFN-γ, IL-10, IL-33, and BAFF. In conclusion, cell wall components derived from fungi as well as bacteria promote IgG4 Ab responses in patients with type 1 AIP. [ABSTRACT FROM AUTHOR]

OBJECTIVES:Endoscopic ultrasonography (EUS)-guided celiac plexus neurolysis (EUS-CPN) is safe and effective but not beneficial for some patients with extended abdominal cancer. We compared the effectiveness of standard EUS-CPN and EUS-guided broad plexus neurolysis (EUS-BPN) that extends over the superior mesenteric artery (SMA) using a 25-gauge needle.METHODS:Consecutive patients referred to our quaternary EUS centers were eligible for inclusion. To evaluate the neurolytic spread, contrast was mixed with the neurolytic agent and post-procedure computed tomography scanning was performed. The regions containing the celiac, superior, and inferior mesenteric arteries were divided on the frontal plane into six areas: upper right and left, middle right and left, and lower right and left. The number of contrast-bearing areas after EUS-CPN and EUS-BPN were related to the degree of pain relief achieved.RESULTS:A total of 67 patients with advanced abdominal cancer were included (34 EUS-CPN and 33 EUS-BPN). The qualitative variables of the two groups did not differ significantly. The EUS-BPN group had more patients with six contrast-bearing areas (42%) than the EUS-CPN group (0%). These patients had significantly better short-term and long-lasting pain relief than patients with less than five contrast-bearing areas. EUS-BPN patients exhibited significantly greater reductions in days 7 and 30 visual analog pain scale scores than EUS-CPN patients.CONCLUSIONS:Our preliminary data suggested that EUS-BPN using a 25-gauge needle provides patients with advanced abdominal cancer with better pain relief than standard EUS-CPN, and without incurring serious complications. Moreover, it seems that broad neurolysis over the SMA may provide superior analgesia. [ABSTRACT FROM AUTHOR]

Fluoroscopy forms an essential part of endoscopic ultrasound-guided hepaticogastrostomy (EUS-HGS) and hepaticogastrostomy with antegrade stenting (EUS-HGAS). To date, no study has assessed and compared radiation exposure between EUS-HGS and EUS-HGAS. This study aimed to compare the radiation exposure parameters between EUS-HGS and EUS-HGAS. This retrospective single-center cohort study included consecutive patients who underwent EUS-HGS or EUS-HGAS from October 2017 to March 2019. The air kerma (AK: mGy), kerma–area product (KAP: Gycm2), fluoroscopy time (FT: min), and procedure time (PT: min) were assessed and compared between the two procedures. Altogether, 45 and 24 patients underwent EUS-HGS and EUS-HGAS, respectively. The median AK, KAP, FT, and PT were higher in the EUS-HGAS group than in the EUS-HGS group. A comparison revealed no difference in the technical success rate, complications rate, adverse event occurrence rate, and re-intervention rate between both procedures. This is the first report in which radiation exposure was used as a comparative parameter between EUS-HGS and EUS-HGAS. This study revealed that radiation exposure is significantly higher in EUS-HGAS than in EUS-HGS. Increased awareness on radiation exposure is warranted among gastroenterologists so that they choose the procedure with lower radiation exposure in cases where both procedures are indicated. [ABSTRACT FROM AUTHOR]

Objectives: The transpapillary drainage by endoscopic retrograde cholangiopancreatography (ERCP‐D) cannot be performed without fluoroscopy, and there are many situations in which fluoroscopy is required even in endoscopic ultrasound‐guided drainage (EUS‐D). Previous studies have compared the efficacy, but not the radiation exposure of EUS‐D and ERCP‐D. While radiation exposure in ERCP‐D has been previously evaluated, there is a paucity of information regarding radiation doses in EUS‐D. This study aimed to assess radiation exposure in EUS‐D compared with that in ERCP‐D. Methods: This retrospective single‐center cohort study included consecutive patients who underwent EUS‐D and ERCP‐D between October 2017 and March 2019. The air kerma (AK, mGy), kerma‐area product (KAP, Gycm2), fluoroscopy time (FT, min), and procedure time (PT, min) were assessed. The invasive probability weighting method was used to qualify the comparisons. Results: We enrolled 372 and 105 patients who underwent ERCP‐D and EUS‐D, respectively. The mean AK, KAP, and FT in the EUS‐D group were higher by 53%, 28%, and 27%, respectively, than those in the ERCP‐D group, whereas PT was shorter by approximately 11% (AK, 135.0 vs. 88.4; KAP, 28.1 vs. 21.9; FT, 20.4 vs. 16.0; PT, 38.7 vs. 43.5). The sub‐analysis limited to biliary drainage cases showed the same trend (AK, 128.3 vs. 90.9; KAP, 27.0 vs. 22.2; FT, 16.4 vs. 16.1; PT, 32.5 vs. 44.4). Conclusions: This is the first study to assess radiation exposure in EUS‐D compared with that in ERCP‐D. Radiation exposure was significantly higher in EUS‐D than in ERCP‐D, despite the shorter procedure time. [ABSTRACT FROM AUTHOR]

Cellular inhibitors of apoptosis proteins 1 (cIAP1) and 2 (cIAP2) are involved in signaling pathways mediated by Toll-like receptors (TLRs) and tumor necrosis factor (TNF)-α. Excessive activation of TLRs and TNF-α underlies the immunopathogenesis of Crohn's disease (CD) and ulcerative colitis (UC). However, the roles played by cIAP1 and cIAP2 in the development of CD and UC remain poorly understood. In this study, we attempted to clarify the molecular link between cIAP1/cIAP2 and colonic inflammation. Human monocyte-derived dendritic cells (DCs) treated with siRNAs specific for cIAP1 or cIAP2 exhibited reduced pro-inflammatory cytokine responses upon stimulation with TLR ligands. Expression of cIAP1 and cIAP2 in human DCs was suppressed in the presence of interferon regulatory factor 4 (IRF4). This effect was associated with inhibition of cIAP1 and cIAP2 polyubiquitination. To verify these in vitro findings, we created mice overexpressing IRF4 in DCs and showed that these mice were resistant to trinitrobenzene sulfonic acid-induced colitis as compared with wild-type mice; these effects were accompanied by reduced expression levels of cIAP1 and cIAP2. Pro-inflammatory cytokine production by mesenteric lymph node cells upon stimulation with TLR ligands was reduced in mice with DC-specific IRF4 overexpression as compared with that in wild-type mice. Finally, in clinical samples of the colonic mucosa from patients with CD, there was a negative relationship between the percentage of IRF4+ DCs and percentages of cIAP1+ or cIAP2+ lamina propria mononuclear cells. These data suggest that the colitogenic roles of cIAP1 and cIAP2 are negatively regulated by IRF4. Expression of cIAP1 and cIAP2 is inversely correlated with activation of IRF4 in Crohn's disease. Expression of pro-inflammatory cytokines is inversely correlated with activation of IRF4 in Crohn's disease. [ABSTRACT FROM AUTHOR]

Nucleotide-binding oligomerization domain 2 (NOD2) is an intracellular receptor for muramyl dipeptide derived from the intestinal microbiota. Loss-of-function mutations in Nod2 are associated with the development of Crohn's disease, suggesting that NOD2 signaling plays critical roles in the maintenance of intestinal immune homeostasis. Although NOD2 activation prevents the development of short-term experimental colitis, it remains unknown whether the sensitivity to long-term experimental colitis is influenced by NOD2. In this study, we explored the roles played by NOD2 in the development of long-term adoptive transfer colitis. Unexpectedly, we found that Rag1 −/− Nod2 −/− mice were more resistant to adoptive transfer colitis than Rag1 −/− mice and had reduced proinflammatory cytokine responses and enhanced accumulation of regulatory T cells (Tregs) expressing forkhead box P3 in the colonic mucosa. Prevention of colitis in Rag1 −/− Nod2 −/− mice was mediated by TGF-β1 because neutralization of TGF-β1 resulted in the development of more severe colitis due to reduced accumulation of Tregs. Such paradoxical Treg responses in the absence of NOD2 could explain why Nod2 mutations in humans are not sufficient to cause Crohn's disease. • Rag1 −/− Nod2 −/− mice are more resistant to adoptive transfer colitis than Rag1 −/− mice. • Rag1 −/− Nod2 −/− mice have more regulatory T cells in the colonic mucosa. • TGF-β1 mediates the protection of the mucosa from colitis in Rag1 −/− Nod2 −/− mice. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICIs) targeting programmed cell death 1 (PD-1) and cytotoxic T-lymphocyte antigen-4 (CTLA-4) are widely used to treat advanced metastatic cancers. Neutralisation of PD-1 or CTLA-4 by ICIs results in immune-related adverse events (irAEs). The clinicopathological features of twelve patients with hepatic irAEs were evaluated and compared to those of ten patients with autoimmune hepatitis (AIH) or graft-versus-host disease (GVHD). No significant difference was seen in serum levels of transaminases, whereas serum levels of IgG and anti-nuclear antibody were higher in patients with AIH than in those with GVHD or hepatic irAEs. Inflammation was limited to the liver lobes in patients with GVHD or hepatic irAEs, whereas patients with AIH exhibited both portal and lobular inflammation. Immunohistochemical analyses revealed a predominant infiltration of CD8+ T cells and defective accumulation of regulatory T cells (Tregs) expressing forkhead box p3 (FOXP3) in the lobular areas of patients with hepatic irAEs and GVHD. In contrast, periportal lesions of patients with AIH were characterised by an infiltration of CD4+ T cells, CD8+ T cells, CD20+ B cells, and FOXP3+ Tregs. Overall, the activation of CD8+ T cells in the absence of activation of Tregs potentially underlies the immunopathogenesis of hepatic irAEs. [ABSTRACT FROM AUTHOR]

Polymorphisms in the autophagy-related protein 16 like 1 (ATG16L1) and nucleotide-binding oligomerization domain 2 (NOD2) genes are associated with Crohn's disease (CD). Impaired interaction between ATG16L1 and NOD2 underlies CD immunopathogenesis. Although activation of the receptor-interacting serine–threonine kinase (RICK, also known as RIP2), a downstream signaling molecule for NOD2 and multiple toll-like receptors (TLRs), plays a pathogenic role in the development of inflammatory bowel disease, the molecular interaction between ATG16L1 and RICK/RIP2 remains poorly understood. In this study, we examined the physical interaction between ATG16L1 and RICK/RIP2 in human embryonic kidney 293 cells and human monocyte-derived dendritic cells (DCs) expressing excessive and endogenous levels of these proteins, respectively. We established that ATG16L1 binds to RICK/RIP2 kinase domain and negatively regulates TLR2-mediated nuclear factor-kappa B (NF-κB) activation and pro-inflammatory cytokine responses by inhibiting the interaction between TLR2 and RICK/RIP2. Binding of ATG16L1 to RICK/RIP2 suppressed NF-κB activation by down-regulating RICK/RIP2 polyubiquitination. Notably, the percentage of colonic DCs expressing ATG16L1 inversely correlated with IL-6 and TNF-α expression levels in the colon of CD patients. These data suggest that the interaction between ATG16L1 and RICK/RIP2 maintains intestinal homeostasis via the down-regulation of TLR-mediated pro-inflammatory cytokine responses. [ABSTRACT FROM AUTHOR]

Background: Excessive type I IFN (IFN-I) production by plasmacytoid dendritic cells (pDCs) promotes autoimmunity. Recently, we reported that a prominent feature of both experimental autoimmune pancreatitis (AIP) and human type 1 AIP is pDC activation followed by enhanced production of IFN-I and IL-33. However, the roles played by interferon regulatory factor 7 (IRF7), a critical transcription factor for IFN-I production in pDCs, in these disorders have not been clarified.Methods: Whole and nuclear extracts were isolated from pancreatic mononuclear cells (PMNCs) from MRL/MpJ mice exhibiting AIP. Expression of phospho-IRF7 and nuclear translocation of IRF7 was examined in these extracts by immunoblotting. Pancreatic expression of IRF7 was assessed by immunofluorescence analysis in experimental AIP. Nuclear translocation of IRF7 upon exposure to neutrophil extracellular traps (NETs) was assessed in peripheral blood pDCs from type 1 AIP patients. Pancreatic IRF7 expression was examined in surgically operated specimens from type 1 AIP patients.Results: IRF7 activation was induced in pancreatic pDCs in experimental AIP. siRNA-mediated knockdown of IRF7 expression prevented AIP development, which was accompanied by a marked reduction in both pancreatic accumulation of pDCs and production of IFN-α and IL-33. Notably, in peripheral blood pDCs isolated from patients with type 1 AIP, nuclear translocation of IRF7 was enhanced as compared with the translocation in pDCs from healthy controls. Furthermore, IRF7-expressing pDCs were detected in the pancreas of patients with type 1 AIP.Conclusions: These findings suggest that the IRF7-IFN-I-IL-33 axis activated in pDCs drives pathogenic innate immune responses associated with type 1 AIP. [ABSTRACT FROM AUTHOR]

Background: Although Gankyrin is overexpressed in many malignancies, the role of Gankyrin for tumorigenesis and chemoresistance remains to be elucidated in sporadic colorectal cancer (CRC). Aims: We investigate whether Gankyrin affects Adenomatous polyposis coli (Apc) inactivation-induced tumorigenesis and therapeutic response to anti-angiogenic agents. Methods: Epithelial cell-specific APC and/or Gankyrin-deficient mice were used. The patients with metastatic CRC (n = 53) who were enrolled in this study underwent resection of primary cancer followed by systemic chemotherapy containing bevacizumab. We determined whether gene expression in CRC tissues before chemotherapy is associated with radiological responses. Results: Deletion of Gankyrin in epithelial cell reduced the expression of c-Myc, a critical mediator of the APC signaling pathway, and interleukin-6. Gankyrin deficiency decreased the expression of Bmi1, a downstream molecule of c-Myc, and the activity of V-Akt murine thymoma viral oncogene homolog and extracellular signal-regulated protein kinase, leading to reduced Apc inactivation-induced tumorigenesis. Of 53 patients, 38 (72%) had increased Gankyrin expression in tumor cells. The enhanced Gankyrin expression in tumor cells was associated with unfavorable progression-free survival (log-rank test p = 0.026). Conclusion: Gankyrin in epithelial cell contributes to the development of sporadic CRC and the expression could serve as a biomarker to predict therapeutic response in patients with metastatic CRC. [ABSTRACT FROM AUTHOR]

Pancreatic intraepithelial neoplasia (PanIN) is a microscopic papillary noninvasive lesion arising from the pancreatic ductal epithelium. However, the natural history and time to progression of high-grade PanIN remain unclear. Herein, we report 2 cases of high-grade PanIN without morphological changes of the main pancreatic duct (MPD) over relatively long periods. In the first case, a 63-year-old man was identified with MPD dilation. Magnetic resonance cholangiopancreatography showed localized stenosis in the pancreatic body with distal MPD dilation. Endoscopic retrograde pancreatography (ERP) was attempted because of possible highgrade PanIN but was unsuccessful. At 15-month follow-up, there was no change in the form of the MPD in various images. However, ERP was re-performed because of possible high-grade PanIN, and cytology showed adenocarcinoma. Postoperative pathology indicated diffuse lesions corresponding to high-grade PanINs in the MPD stenosis and surrounding branches. Final diagnosis was high-grade PanIN. In the second case, a 77-year-old man was identified with MPD dilation. Magnetic resonance cholangiography showed localized stenosis in the MPD of the pancreatic head with distal MPD dilation. He was diagnosed with MPD stenosis caused by chronic pancreatitis, and further examination was not recommended. At 25 months, the patient was referred to our hospital because of a mild change in MPD dilation. ERP showed localized irregular stenosis in the MPD, and cytology showed suspected adenocarcinoma. Postoperative pathology indicated a localized lesion with high-grade PanIN in the branch duct around the MPD stenosis. Final diagnosis was high-grade PanIN. In conclusion, we report 2 cases of highgrade PanIN without morphological changes of the MPD over relatively long periods. Even if a definite diagnosis is not obtained at initial examination, a strict follow-up observational study should be performed. Re-examination, including ERP, should also be considered in cases with risk factors of pancreatic cancer, even if there is no change in MPD form. [ABSTRACT FROM AUTHOR]

Introduction: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disorder characterized by multiple fibrotic strictures of the bile duct. More than 40% of deaths in PSC patients are related to malignant tumors, including cholangiocarcinoma. Primary hepatic adenosquamous carcinoma (ASC) is a rare subtype of cholangiocarcinoma containing adenocarcinoma (AC) and squamous cell carcinoma (SCC) components, with a poorer prognosis than other cholangiocarcinomas. We report the first case of a hepatic ASC in a patient with PSC. Case Report: A 28-year-old man was referred for diagnosis and treatment of a liver abscess suspected by contrast-enhanced computed tomography (CECT). He had a history of ulcerative colitis and PSC. Abdominal CE-CT revealed a 60-mm-diameter ring-shaped mass with central necrosis in the left lobe. Magnetic resonance imaging demonstrated a poorly circumscribed low-signal-intensity mass in T1-weighted imaging and a high-signalintensity mass with a scattered low-signal-intensity area in T2-weighted imaging. Abdominal ultrasonography showed a hypoechoic component with a diffuse hyperechoic area in the tumor. Ultrasound-guided biopsy and histological examination showed tumor cells with both squamous and glandular differentiation. Left lobectomy was performed. Microscopic examination revealed 2 components, including moderately differentiated AC and well-differentiated SCC. The final diagnosis was hepatic ASC. Conclusion: This is the first reported case of hepatic ASC in a patient with PSC. Patients with PSC should be recognized as being at a risk of not only general cholangiocarcinoma, hepatocellular carcinoma, and metastatic liver tumor, but also ASC. [ABSTRACT FROM AUTHOR]

Background: Endoscopic ultrasound (EUS)-guided biliary drainage (BD) is a well-recognized alternative BD method after unsuccessful endoscopic transpapillary drainage. EUSguided hepaticogastrostomy (HGS) with antegrade stenting (AGS) was recently applied to the treatment of malignant obstructive jaundice. Objective: To assess the efficacy and safety of HGS combined with AGS for treatment of malignant biliary stricture-induced obstructive jaundice. Design: Retrospective cohort study. Setting: Single academic tertiary care center. Patients: From January 2006 to December 2014, endoscopic retrograde cholangiopancreatography was attempted in patients with obstructive jaundice; it was successful in 641 patients and impossible in 154 patients (postsurgically altered anatomy or duodenal stenosis, n = 101; difficult cannulation, n = 53). In total, 145 patients underwent EUS-guided BD; HGS and HGS with AGS were attempted in 42 patients (Group A, January 2006-August 2011) and 37 patients (Group B, September 2011-December 2014), respectively. Interventions: Under EUS and fluoroscopy guidance, HGS and HGS with AGS were performed via needle puncture, guidewire insertion, puncture-hole dilation, and stent placement. Main Outcome Measurements: Groups A and B were compared in terms of technical success, functional success, adverse event rates, re-intervention rates, patient survival time, and time to stent dysfunction or patient death. The two groups were also compared in a subgroup analysis of only 28 patients who underwent chemotherapy. Results: The technical success rate was significantly higher in Group A than B (97.6 vs. 83.8%, p = 0.03). The functional success rate was comparable between the two groups (90.2 vs. 90.3%), although the rate of adverse events was significantly higher in Group A than B (26.1 vs. 10.8%, p = 0.03). The re-intervention rate tended to be higher in Group A than B (16.7 vs. 8.1%, p = 0.25). Groups A and B did not differ significantly in terms of median overall patient survival (75 vs. 61 days, p = 0.70) or median time to stent dysfunction or patient death (68 vs. 63 days, p = 0.08). Among patients who underwent chemotherapy, there was no difference in overall patient survival time between the two groups (121 vs. 157 days, p = 0.08), although time to stent dysfunction or patient death was significantly shorter in Group A than B (71 vs. 95 days, p = 0.02). Conclusion: Although the technical success rate of HGS with AGS was lower than that of HGS, HGS with AGS was superior to HGS in terms of adverse event rate and stent patency in patients receiving chemotherapy. [ABSTRACT FROM AUTHOR]

Endoscopic ultrasound-guided fine-needle aspiration (EUSFNA) has been widely used for diagnosis of both inflammatory and tumor lesions located in and adjacent to the gastrointestinal tract. EUS-FNA has been considered to be a safe technique with few complications, as shown in recent review articles in which EUS-FNA-related morbidity and mortality rates were reported to be <1%. It should be noted, however, that needle tract seeding, although uncommon, can occur after diagnostic EUS-FNA and that this complication affects the prognosis of patients. Although an accurate value for the frequency of needle tract seeding caused by EUS-FNA has not been reported, the numbers of case reports on needle tract seeding have been rapidly increasing, especially in Japan. These case reports regarding EUS-FNA-related needle tract seeding prompted us to reevaluate the safety of EUSFNA because this complication may have a significant influence on patients' prognoses. In this review, we summarize the clinical features and outcomes of needle tract seeding after EUS on the basis of the previously reported cases and provide useful information to prevent and reduce this serious complication. [ABSTRACT FROM AUTHOR]

Repeated pancreatic juice cytology via endoscopic nasopancreatic drainage (ENPD) has a high diagnostic yield and might be useful for the diagnosis of early-stage pancreatic cancer. A 67-year-old man presented with a pancreatic cyst occasionally detectable in the body of the pancreas by ultrasonography (US). No obvious pancreatic tumor was detected by US, computed tomography (CT), magnetic resonance cholangiopancreatography, and endoscopic ultrasound (EUS) (although the latter did reveal a weak, low echoic area). Endoscopic retrograde pancreatography showed irregular narrowing of the main pancreatic duct (MPD) at the pancreatic body. Pancreatic juice cytology was also performed, but did not give evidence of a malignancy. Therefore, the patient was followed up. CT and EUS performed after 3 months showed the same findings as did endoscopic retrograde pancreatography; however, the results of repeated pancreatic juice cytology performed via ENPD tube revealed a suspected malignancy on 2 of 6 occasions. Therefore, we performed a central pancreatectomy. Histopathological examination of a resected specimen revealed carcinoma in situ in the narrow MPD at the body of the pancreas. In the current case, repeated pancreatic juice cytology via ENPD was effective. A weak low echoic area around the MPD stricture on EUS might be related to the inflammatory change accompanying carcinoma in situ of the pancreas. [ABSTRACT FROM AUTHOR]