BACKGROUND/OBJECTIVES: Acute pancreatitis (AP) may obscure small pancreatic cancers (PCs) on computed tomography during the acute phase. Surveillance with magnetic resonance cholangiopancreatography (MRCP) and endoscopic ultrasonography (EUS) may enhance early detection and improve patient outcomes. This study evaluated the impact of early MRCP/EUS surveillance on PC outcomes in AP patients and identified high-risk subgroups for early screening. METHODS: We retrospectively analyzed 1562 AP patients treated between 2010 and 2021, categorizing them into early surveillance (MRCP/EUS within three months of AP onset; n = 760) and nonearly surveillance groups (n = 802). Key outcomes included time to PC diagnosis, surgical resection rate, tumor stage, and overall survival. Multivariate analysis was performed to identify risk factors for concealed PC in AP patients. RESULTS: Among 27 PC cases analyzed, the early surveillance group achieved significantly earlier diagnosis, higher surgical resection rates, increased detection of early-stage PC, and improved overall survival compared with the nonearly surveillance group. Multivariate analysis revealed that subthreshold main pancreatic duct (MPD) dilation (≥2.5 mm) and moderately severe AP were significant predictors of PC. CONCLUSIONS: Early MRCP/EUS surveillance in AP patients facilitates timely detection of occult PC and enhances patient prognosis. These findings support prioritizing early surveillance for AP patients with subthreshold MPD dilation and moderately severe disease. Further large-scale studies are warranted to validate these strategies in clinical practice.

Type 1 autoimmune pancreatitis (AIP) and systemic lupus erythematosus (SLE) are caused by type I IFNs secreted by plasmacytoid dendritic cells (pDCs). Our understanding of the immune consequences before and after pDC activation in SLE is expanding, whereas knowledge on those in AIP are insufficient. In this article, we summarize the similarities and dissimilarities in pDC activation between AIP and SLE. In SLE, neutrophil extracellular traps containing self-DNA, anti-microbial peptides, and endogenous alarmins form anti-DNA antibody complexes, promoting type I IFN production by pDCs. Type I IFNs produced by pDCs function as initiators rather than effectors in SLE, as evidenced by the fact that these cytokines induce the maturation of conventional DCs (cDCs) leading to the expansion of autoreactive T cells and B cells. Notably, type I IFNs produced by pDCs were observed at the maturation phase but not at the induction phase in experimental AIP. Mechanistically, cDCs producing type I IFNs, C-X-C motif chemokine ligand 9 (CXCL9), and CXCL10 are initiator cells of AIP, and C-X-C chemokine receptor 3 (CXCR3)⁺T helper type 1(Th1) cells migrate to the pancreas in response to CXCL9 and CXCL10. CXCR3⁺Th1 cells produce C-C chemokine ligand 25 (CCL25) to attract C-C chemokine receptor 9 (CCR9)⁺pDCs to the pancreas. Pancreatic pDCs producing type I IFNs, CXCL9, CXCL10, and CXCR3⁺Th1 cells producing CCL25 form a positive feedback loop in which the sensing of intestinal dysbiosis induces large amounts of type I IFNs by pDCs.

BACKGROUND: S-1, an oral fluoropyrimidine derivative, is standard adjuvant therapy for resected biliary tract cancer (BTC), based on the results of the JCOG1202, a phase III trial evaluating the survival benefit with adjuvant S-1 following curative resection for BTC compared to surgery alone. This multicenter ancillary study of the JCOG1202 aimed to evaluate the prognostic impact of the 5-fluorouracil (5-FU) metabolic pathway genes including thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD). METHODS: The 5-FU metabolic pathway genes were measured in tumor cells from formalin-fixed paraffin-embedded resected specimens from 183 patients (surgery alone: n = 94; adjuvant S-1: n = 89). We randomly divided them into training (n = 96) and validation sets (n = 87) for evaluating the interaction between gene levels and RFS benefits in the treatment arm. RESULTS: RFS benefits of adjuvant S-1 were observed in the low DPD (HR = 0.440 and 0.748, respectively in the training and validation sets) and the low TP groups (HR = 0.709 and 0.602, respectively). Clinicopathological characteristics were well balanced between low and high DPD populations. More advanced stage tumors were observed in high TP populations as compared to those in low TP populations (p = .0332). CONCLUSION: The results suggest the RFS benefit of adjuvant S-1 in resected BTC patients with low DPD and low TP gene expressions.

BACKGROUND: The natural history of branch-duct intraductal papillary mucinous cystic neoplasms (BD-IPMNs) in the pancreas remains unclear. This study aimed to answer this clinical question by focusing on the development of concomitant pancreatic ductal adenocarcinomas (cPDAC). METHODS: The Japan Pancreas Society conducted a prospective multicenter surveillance study of BD-IPMN every six months for five years. The primary endpoints were progression of BD-IPMN, progression to high-grade dysplasia/invasive carcinoma (HGD/IC), and cPDAC. Factors predicting the progression of BD-IPMN to HGD/IC and development of cPDAC were also assessed as secondary endpoints. RESULTS: Among the 2104 non-operated patients, 348 (16.5 %) showed progression of primary BD-IPMN. Cumulative incidences of BD-IPMN with HGD/IC and cPDAC during the 5.17-year surveillance period were 1.90 % and 2.11 %, respectively, and standard incidence ratios of BD-IPMN with HGD/IC and cPDAC were 5.28 and 5.73, respectively. Of 38 cPDACs diagnosed during surveillance, 25 (65.8 %) were resectable. The significant predictive characteristics of BD-IPMN for progression to HGD/IC were larger cyst size (p = 0.03), larger main pancreatic duct size (p < 0.01), and mural nodules (p = 0.02). Significant predictive characteristics for the development of cPDAC were male sex (p = 0.03) and older age (p = 0.02), while the size of IPMN was not significant. CONCLUSION: Careful attention should be given to "dual carcinogenesis" during BD-IPMN surveillance, indicating the progression of BD-IPMN to HGD/IC and development of cPDAC distinct from BD-IPMN, although the establishment of risk factors that predict cPDAC development remains a challenge (UMIN000007349).

INTRODUCTION: Major hepatectomy (MH) may produce the impaired liver function and affect the feasibility of adjuvant chemotherapy in terms of early period after the surgery, but there have not been detailed investigations. JCOG1202 (UMIN000011688) is a randomized phase III trial demonstrating the superiority of adjuvant S-1 chemotherapy for biliary tract cancer (BTC). The aim of this study is to examine the influence of MH for BTC on adjuvant S-1. MATERIALS AND METHODS: Of the total 424 patients, 207 received S-1 (S-1 arm) while the remaining 217 were not. We compared MH with non-major hepatectomy (NMH) for BTC. RESULTS: In the S-1 arm, 42 had undergone MH, and 165 had undergone NMH. MH had similar pretreatment features to NMH, including the proportion of biliary reconstruction, to NMH, except for a lower platelet count (17.7 vs. 23.4 × 104/mm3, p < 0.0001) and lower serum albumin level (3.5 vs. 3.8 g/dL, p < 0.0001). The treatment completion proportion tended to be lower for MH than for NMH (59.5 % vs. 75.8 %; risk ratio, 0.786 [95 % confidence interval, 0.603-1.023], p = 0.0733), and the median dose intensity was lower as well (88.7 % vs. 99.6 %, p = 0.0358). The major reasons for discontinuation were biliary tract infections and gastrointestinal disorders after MH. The frequency of grade 3-4 biliary tract infection was 19.0 % in MH vs. 4.2 % in NMH. CONCLUSION: The treatment completion proportion and dose intensity were lower in MH than in NMH. Caution should be exercised against biliary tract infections and gastrointestinal disorders during adjuvant S-1 after MH for BTC.

BACKGROUND/OBJECTIVES: The association between autoimmune pancreatitis (AIP) and pancreatic cancer (PC) remains controversial. This study aimed to clarify the long-term prognosis and risk of malignancies in AIP patients in Japan. METHODS: We conducted a multicenter retrospective cohort study on 1364 patients with type 1 AIP from 20 institutions in Japan. We calculated the standardized incidence ratio (SIR) for malignancies compared to that in the general population. We analyzed factors associated with overall survival, pancreatic exocrine insufficiency, diabetes mellitus, and osteoporosis. RESULTS: The SIR for all malignancies was increased (1.21 [95 % confidence interval: 1.05-1.41]) in patients with AIP. Among all malignancies, the SIR was highest for PC (3.22 [1.99-5.13]) and increased within 2 years and after 5 years of AIP diagnosis. Steroid use for ≥6 months and ≥50 months increased the risk of subsequent development of diabetes mellitus and osteoporosis, respectively. Age ≥65 years at AIP diagnosis (hazard ratio [HR] = 3.73) and the development of malignancies (HR = 2.63), including PC (HR = 7.81), were associated with a poor prognosis, whereas maintenance steroid therapy was associated with a better prognosis (HR = 0.35) in the multivariate analysis. Maintenance steroid therapy was associated with a better prognosis even after propensity score matching for age and sex. CONCLUSIONS: Patients with AIP are at increased risk of developing malignancy, especially PC. PC is a critical prognostic factor for patients with AIP. Although maintenance steroid therapy negatively impacts diabetes mellitus and osteoporosis, it is associated with decreased cancer risk and improved overall survival.

BACKGROUND: We compared the results of preoperative pancreatic juice cytology (PJC) and final pathological diagnosis after resection in patients who underwent resection of intraductal papillary mucinous neoplasm (IPMN) of the pancreas to determine whether preoperative PJC can help determine therapeutic strategies. METHODS: Of 1130 patients who underwent surgical resection IPMN at 11 Japanese tertiary institutions, the study included 852 patients who underwent preoperative PJC guided by endoscopic retrograde cholangiopancreatography (ERCP). RESULTS: The accuracy of preoperative PJC for differentiation between cancerous and noncancerous lesions were 55% for IPMN overall; 59% for the branch duct type; 49% for the main pancreatic duct type; 53% for the mixed type, respectively. On classifying IPMN according to the diameters of the mural nodule (MN) and main pancreatic duct (MPD), the corresponding values for diagnostic performance were 40% for type 1 (MN ≥5 mm and MPD ≥ 10 mm); 46% for type 2 (MN ≥5 mm and MPD < 10 mm); 61% for type 3 (MN < 5 mm and MPD ≥ 10 mm); 72% for type 4 (MN < 5 mm and MPD < 10 mm), respectively. CONCLUSIONS: PJC in IPMN is not a recommended examination because of its low overall sensitivity and no significant difference in diagnostic performance by type, location, or subclassification. Although the sensitivity is low, the positive predictive value is high, so we suggest that pancreatic juice cytology be performed only in cases where the patient is not sure about surgery.

Abstract 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.

Abstract Background and Aim A multicenter, open‐label randomized Phase II trial was conducted to determine whether low‐dose gemcitabine plus nab‐paclitaxel (GnP) could improve tolerability and show equivalent efficacy to the standard‐dose GnP for elderly patients with metastatic pancreatic cancer. Methods Consecutive patients aged ≥65 years with metastatic pancreatic cancer who presented at one of four Japanese referral centers between November 2016 and January 2021 were enrolled. The 60 patients were randomly assigned to low‐ or standard‐dose groups with a 1:1 ratio. Patients in the low‐dose GnP group received gemcitabine at a dose of 250 mg/m² and nab‐paclitaxel at 125 mg/m². Results Low‐dose GnP significantly decreased the rate of cases requiring dose reduction (16.7% vs 63.3%). The response rate (36.7% vs 33.3%) and progression‐free survival (7.3 vs 8 months) were comparable between the low‐ and standard‐dose groups as determined by independent review. The difference in the median overall survival between the two groups was not significant (7.9 vs 12 months). The proportion of patients with hematologic and non‐hematologic treatment‐related adverse events was comparable between the two groups. Conclusion Low‐dose GnP had an equivalent efficacy to conventional therapy; however, it did not reduce adverse events.

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.

BACKGROUND/OBJECTIVES: The detection of malignancy is a major concern in the management of intraductal papillary mucinous neoplasm (IPMN). The height of the mural nodule (MN), estimated using endoscopic ultrasound (EUS) and computed tomography (CT), has been considered crucial for predicting malignant IPMN. Currently, whether surveillance using CT or EUS alone is sufficient for detecting MNs remains unclear. This study aimed to compare the ability of CT and EUS to detect MNs in IPMN. METHODS: This multicenter, retrospective observational study was conducted in 11 Japanese tertiary institutions. Patients who underwent surgical resection of IPMN with MN after CT and EUS examinations were eligible to participate. The MN detection rates between CT and EUS were examined. RESULTS: Two-hundred-and-forty patients who underwent preoperative EUS and CT had pathologically confirmed MNs. The MN detection rates of EUS and CT were 83% and 53%, respectively (p < 0.001). Additionally, the MN detection rate of EUS was significantly higher than that of CT regardless of morphological type (76% vs. 47% in branch-duct-type IPMN; 90% vs. 54% in mixed IPMN; 98% vs. 56% in main-duct-type IPMN; p < 0.001). Further, pathologically confirmed MNs ≥5 mm were more frequently observed on EUS than on CT (95% vs. 76%, p < 0.001). CONCLUSIONS: EUS was superior to CT for the detection of MN in IPMN. EUS surveillance is essential for the detection of MNs.

Abstract 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.

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.

BACKGROUND: 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. METHODS: 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). FINDINGS: 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%]). INTERPRETATION: 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. FUNDING: The National Cancer Center Research and the Ministry of Health, Labour, and Welfare of Japan.

AIM: We compared the efficacy of modified 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (mFOLFIRINOX) with that of gemcitabine plus nab-paclitaxel (GnP) for locally advanced pancreatic cancer (LAPC). METHODS: Patients with untreated LAPC were randomly assigned (1:1) to receive mFOLFIRINOX or GnP. One-year overall survival (OS) was the primary endpoint. The major secondary end-points included progression-free survival (PFS), response rate (RR), carbohydrate antigen 19-9 (CA19-9) response, and adverse events. The sample size was 124 patients to select a more effective regimen with a minimum probability of 0.85 and to examine the null hypothesis of the 1-year OS <53%. RESULTS: Of the 126 patients enrolled from 29 institutions, 125 were deemed eligible. The 1-year OS was 77.4% (95% CI, 64.9-86.0) and 82.5% (95% CI, 70.7-89.9) in the mFOLFIRINOX and GnP arms, respectively. The median PFS was 11.2 (95% CI, 9.9-15.9) and 9.4 months (95% CI, 7.4-12.8) in the mFOLFIRINOX and GnP arms, respectively. The RR and CA19-9 response rate were 30.9% (95% CI, 19.1-44.8) and 57.1% (95% CI, 41.0-72.3) and 42.1% (95% CI 29.1-55.9) and 85.0% (95% CI, 70.2-94.3) in the mFOLFIRINOX and GnP arms, respectively. Grade 3-4 diarrhoea and anorexia were predominant in the mFOLFIRINOX arm. CONCLUSION: GnP was considered the candidate for a subsequent phase III trial because of its better RR, CA19-9 response, and mild gastrointestinal toxicities. Both regimens displayed higher efficacy in the 1-year survival than in the historical data of gemcitabine monotherapy.

Hepatocytes and liver-resident antigen-presenting cells are exposed to microbe-associated molecular patterns (MAMPs) and microbial metabolites, which reach the liver from the gut via the portal vein. MAMPs induce innate immune responses via the activation of pattern recognition receptors (PRRs), such as toll-like receptors (TLRs), nucleotide-binding oligomerization domain 1 (NOD1), and NOD2. Such proinflammatory cytokine responses mediated by PRRs likely contribute to the development of chronic liver diseases and hepatocellular carcinoma (HCC), as shown by the fact that activation of TLRs and subsequent production of IL-6 and TNF-α is required for the generation of chronic fibroinflammatory responses and hepatocarcinogenesis. Similar to TLRs, NOD1 and NOD2 recognize MAMPs derived from the intestinal bacteria. The association between the activation of NOD1/NOD2 and chronic liver diseases is poorly understood. Given that NOD1 and NOD2 can regulate proinflammatory cytokine responses mediated by TLRs both positively and negatively, it is likely that sensing of MAMPs by NOD1 and NOD2 affects the development of chronic liver diseases, including HCC. Indeed, recent studies have highlighted the importance of NOD1 and NOD2 activation in chronic liver disorders. Here, we summarize the roles of NOD1 and NOD2 in hepatocarcinogenesis and liver injury.

Abstract 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 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.

Acute pancreatitis is a common emergent disorder, a significant population of which develops the life-threatening condition, called severe acute pancreatitis (SAP). It is generally accepted that bacterial infection is associated with the development and persistence of SAP. In addition to bacterial infection, recent clinical studies disclosed a high incidence of fungal infection in patients with SAP. Moreover, SAP patients with fungal infection exhibit a higher mortality rate than those without infection. Although these clinical studies support pathogenic roles played by fungal infection in SAP, beneficial effects of prophylactic anti-fungal therapy on SAP have not been proved. Here we summarize recent clinical findings as to the relationship between fungal infection and the development of SAP. In addition, we discuss molecular mechanisms accounting for the development of SAP in the presence of fungal infection.

Background Pancreatic neuroendocrine carcinoma (PanNEC) is a rare disease entity with rapid progression and poor prognosis. Here, we report a PanNEC case with unique morphological features mimicking intraductal papillary mucinous carcinoma. Case presentation A 69-year-old Japanese man was referred to our hospital for further evaluation of weight loss and deterioration of diabetes mellitus. Contrast-enhanced computed tomography showed a solid and cystic mass with hypo-enhancement at the tail of the pancreas. The main pancreatic duct (MPD) was diffusely dilated without obstruction, accompanied by marked parenchymal atrophy. Multiple peritoneal and omental nodules were observed, suggesting tumor dissemination. Endoscopic retrograde cholangiopancreatography revealed that the mass correlated with the dilated MPD. During pancreatography, a large amount of mucus was extruded from the pancreatic orifice of the ampulla. Based on these imaging findings, intraductal papillary mucinous carcinoma was suspected. Per-oral pancreatoscopy (POPS)-guided tumor biopsies were conducted for the lesion's solid components. Histopathological examination of the biopsied material confirmed small-cell-type PanNEC with a Ki-67 labeling index of 90%. Due to his condition's rapid decline, the patient was given the best supportive care and died 28 days after diagnosis. Conclusion Although rare, PanNEC, which correlates with the MPD and is accompanied by marked dilation of the MPD, does exist as one phenotype. In such cases, POPS-guided biopsy could be a useful diagnostic modality.

Background/Aims: Bispectral index (BIS) monitors process and display electroencephalographic data and are used to assess the depth of anesthesia. This study retrospectively evaluated the usefulness of BIS monitoring during endoscopic ultrasonography (EUS). Methods: This study included 725 consecutive patients who underwent EUS under sedation with propofol. BIS monitoring was used in 364 patients and was not used in 361. The following parameters were evaluated: (1) median dose of propofol; (2) respiratory and circulatory depression; (3) occurrence of body movements; (4) awakening score >8 at the time; and (5) awakening score 2 hours after leaving the endoscopy room. Results: The BIS group received a significantly lower median dose of propofol than the non-BIS group (159.2 mg vs. 167.5 mg; p=0.015) in all age groups. For patients aged ≥75 years, the reduction in heart rate was significantly lower in the BIS group than in the non-BIS group (1.2% vs. 9.1%; p=0.023). Moreover, the occurrence of body movements was markedly lower in the BIS group than in the non-BIS group (8.5% vs. 39.4%; p<0.001). Conclusions: During EUS examination, BIS monitoring is useful for maintaining a constant depth of anesthesia, especially in patients 75 years of age or older.

Background: The value of contrast-enhanced harmonic EUS (CH-EUS) for diagnosis of portal vein invasion in patients with pancreatic cancer was evaluated. Patients and Methods: This single-center, retrospective study included consecutive patients with pancreatic cancer who underwent both surgical resection after preoperative EUS, CH-EUS, and contrast-enhanced computed tomography (CE-CT) examinations between April 2015 and August 2017. CH-EUS evaluation was performed during the late phase. Portal vein invasion on EUS and CH-EUS was defined as no continuity in the line of the vessel wall. Definition of portal vein invasion on CE-CT was based on the Loyer's criteria. The accuracy of three modalities for diagnosis of invasion into the portal vein was compared using the McNemar's test. Results: Eighty-eight patients (mean age: 71.0 years, ratio of male to female: 48:40) were eligible. Postoperative pathological results were as follows: seven cases of portal vein invasion; 81 cases without. Diagnostic accuracy of EUS, CH-EUS, and CE-CT for diagnosing invasion into the portal vein was 72.7%, 93.2%, and 81.8%, respectively. The differences between CH-EUS and CE-CT (P = 0.0094) and CH-EUS and EUS (P = 0.0022) were significant. EUS and CE-CT were comparable. Conclusion: CH-EUS is useful for diagnosis of portal vein invasion by pancreatic cancer.

Efficient protection against coronavirus disease 2019 (COVID-19) has been achieved by immunization with mRNA-based vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, efficient immune responses against this novel virus by vaccination are accompanied by a wide variety of side effects. Indeed, flares or new-onset of autoimmune disorders have been reported soon after the COVID-19 vaccination. Although pro-inflammatory cytokine responses play pathogenic roles in the development of autoimmunity, cytokines charactering COVID-19 vaccination-related autoimmune responses have been poorly understood. Given that mRNA derived from COVID-19 vaccine is a potent inducer for pro-inflammatory cytokine responses, these cytokines might mediate autoimmune responses after COVID-19 vaccination. Here we report a case with new-onset rheumatoid arthritis (RA) following COVID-19 vaccination. Serum concentrations not only of arthrogenic cytokines, interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), but also of type I interferon (IFN) were elevated at the active phase in this case. Induction of remission by methotrexate and tocilizumab was accompanied by a marked reduction in serum concentrations of type I IFN, IL-6, and TNF-α. These results suggest that production of type I IFN, IL-6, and TNF-α induced by COVID-19 vaccination might be involved in this case with new-onset RA.

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.

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.

In the FUGA-BT trial (JCOG1113), gemcitabine plus S-1 (GS) showed non-inferiority to gemcitabine plus cisplatin (GC) in overall survival (OS) with good tolerance for patients with advanced biliary tract cancer (BTC). We performed a subgroup analysis focused on the elderly cohort of this trial. All 354 enrolled patients in JCOG1113 were classify into two groups; < 75 (non-elderly) and ≥ 75 years (elderly) group. We investigated the influence of age on the safety analysis, including the incidence of chemotherapeutic adverse events and the efficacy analysis, including OS. There were no remarkable differences in OS between the elderly (n = 60) and the non-elderly groups (n = 294). In the elderly group, median OS was 12.7 and 17.7 months for those who received GC (n = 20) and GS (n = 40), respectively. The prevalence of all-grade adverse events was similar between the elderly and the non-elderly groups. However, among the elderly group, Grade ≥ 3 hematological adverse events were more frequently observed in the GC arm than in the GS arm. The clinical outcomes of combination chemotherapy in elderly patients with advanced BTC were comparable to non-elderly patients. GS may be the more favorable treatment for elderly patients with advanced BTC.

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.

Cellular inhibitor 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-αunderlies 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.

BACKGROUND: Pancreatic cancer (PC) exhibits extremely rapid growth; however, it remains largely unknown whether the early stages of PC also exhibit rapid growth speed equivalent to advanced PC. This study aimed to investigate the natural history of early PCs through retrospectively assessing pre-diagnostic images. METHODS: We examined the data of nine patients, including three patients with carcinoma in situ (CIS), who had undergone magnetic resonance cholangiopancreatography (MRCP) to detect solitary main pancreatic duct (MPD) stenosis >1 year before definitive PC diagnosis. We retrospectively analyzed the time to diagnosis and first-time tumor detection from the estimated time point of first-time MPD stenosis detection without tumor lesion. RESULTS: The median tumor size at diagnosis and the first-time tumor detection size were 14 and 7.5 mm, respectively. The median time to diagnosis and first-time tumor detection were 26 and 49 months, respectively. CONCLUSIONS: No studies have investigated the PC history, especially that of early PCs, including CIS, based on the initial detection of MPD stenosis using MRCP. Assessment of a small number of patients showed that the time to progression can take several years in the early PC stages. Understanding this natural history is very important in the clinical setting.

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.

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.

Due to the tendency of gastric linitis plastica (GLP) to cause extensive submucosal infiltration, a superficial endoscopic biopsy sometimes yields no evidence of malignancy, hindering definite diagnosis. The present study was a single-center retrospective analysis of 54 consecutive patients diagnosed with GLP between 2016 and 2020 to evaluate EUS-guided fine-needle aspiration (EUS-FNA) biopsy outcomes in patients with negative endoscopic biopsy findings. A pathological GLP diagnosis was achieved by endoscopic biopsy in 40 patients (74.1%). EUS-FNA biopsy with a 22-gauge needle was performed in 13 of the remaining 14 patients, and GLP diagnosis was confirmed in 10 patients, with a median of three needle passes. The remaining four patients were laparoscopically diagnosed with GLP. The diagnostic ability of EUS-FNA biopsy for GLP was 76.9%, and EUS-FNA biopsy contributed to GLP diagnosis in 18.5% (10/54) of all cases. None of the 13 patients exhibited EUS-FNA biopsy-related adverse events. Univariable and multivariable analyses revealed an absence of superficial ulcerations as a predictor of false-negative endoscopic biopsy findings in patients with GLP. These results suggest EUS-FNA biopsy as a minimally invasive and safe alternative diagnostic modality for GLP in cases where conventional endoscopic biopsy fails to verify malignancy, although prospective studies with larger cohorts are warranted to confirm these findings.

BACKGROUND: Granulomatosis with polyangiitis (GPA) is characterized by granulomatous inflammation, vasculitis, and elevated levels of serum proteinase 3 (PR3)-anti-neutrophil cytoplasmic antibody (PR3-ANCA). OBJECTIVE: We tried to characterize immune cells accumulated into the lung lesions of a GPA patient exhibiting spontaneous regression. METHODS: Transbronchial lung biopsy (TBLB) samples were subjected to immunohistochemical analyses. RESULTS: Multiple lung nodules were detected by CT. TBLB showed granulomatous inflammation and small vessel vasculitis. This case was diagnosed as GPA based on pathological findings and elevation of PR-3 ANCA levels. Spontaneous disappearance of multiple lung nodules was observed in CT. CD3+ T cells and CD20+ B cells accumulated in the inflammatory lesions surrounding the vessels whereas granulomatous inflammation was mainly comprised of CD3+ T cells and CD68+ macrophages, but not B cells or myeloperoxidase+ neutrophils. CONCLUSIONS: We characterized immune cell compositions of the lung lesions of a patient with GPA exhibiting spontaneous regression.

Unsuccessful stent replacement in transpapillary biliary drainage with plastic stents (PSs) has a significant impact on patient prognosis; thus, a safe and reliable replacement method is required. We aimed to compare the snare-over-the-guidewire (SOG) method, wherein the PS lumen is used as an access route to the biliary tract and the PS is removed with a snare inserted via the inserted guidewire, with the conventional side-of-stent (SOS) method, wherein the biliary approach is performed from the side of the PS. This retrospective single-center study included 244 consecutive patients who underwent biliary PS replacement between January 2018 and July 2020. The procedural success rates were compared between the two methods. A predictive analysis of unsuccessful PS replacement was also performed. The procedural success rate in the SOG group was significantly higher than that in the SOS group (p = 0.026). In the proximal biliary stenosis lesion, the same trend was observed (p = 0.025). Multivariate analysis also showed that the SOS method (p = 0.0038), the presence of proximal biliary stenosis (p < 0.0001), and parapapillary diverticulum (p = 0.0007) were predictors of unsuccessful PS replacement. The SOG method may be useful for biliary PS replacement, especially in cases of proximal hilar bile duct stenosis.

JCOG1113 is a randomized phase III trial in patients with advanced biliary tract cancers (BTCs) (UMIN000001685), and gemcitabine plus S-1 (GS) was not inferior to gemcitabine plus cisplatin (GC). However, poor renal function often results in high toxicity of S-1. Therefore, we examined whether GS can be recommended for patients with low creatinine clearance (CCr). Renal function was classified by CCr as calculated by the Cockcroft-Gault formula: high CCr (CCr ≥ 80 ml/min) and low CCr (80 > CCr ≥ 50 ml/min). Of 354 patients, 87 patients on GC and 91 on GS were included in the low CCr group, while there were 88 patients on GC and 88 patients on GS in the high CCr group. The HR of overall survival for GS compared with GC was 0.687 (95% CI 0.504-0.937) in the low CCr group. Although the total number of incidences of all Grade 3-4 non-haematological adverse reactions was higher (36.0% vs. 11.8%, p = 0.0002), the number of patients who discontinued treatment was not different (14.1% vs. 16.9%, p = 0.679) for GS compared with GC in the low CCr group. This study suggests that GS should be selected for the treatment of advanced BTC patients with reduced renal function.

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.

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.

Solitary organ autoimmune disorders, formerly known as autoimmune pancreatitis (AIP), autoimmune sialadenitis, and autoimmune sclerosing cholangitis, are now considered organ-specific manifestations of systemic immunoglobulin G4-related disease (IgG4-RD). AIP and IgG4-RD are characterized by elevated serum concentration of IgG4 antibody (Ab), accumulation of IgG4-expressing plasmacytes in the affected organs, and involvement of multiple organs. It is well established that enhanced IgG4 Ab responses are a hallmark of AIP and IgG4-RD for diagnosis and monitoring disease activity. However, a significant fraction of patients with AIP and IgG4-RD who develop chronic fibroinflammatory responses have normal serum concentrations of this IgG subtype. In addition, disease flare-up is sometimes seen even in the presence of normalized serum concentrations of IgG4 Ab after successful induction of remission by prednisolone. Therefore, it is necessary to identify new biomarkers based on the understanding of the pathophysiology of AIP and IgG4-RD. Recently, we found that activation of plasmacytoid dendritic cells producing both interferon-α (IFN-α) and interleukin-33 (IL-33) mediate murine AIP and human IgG4-RD. More importantly, we provided evidence that serum concentrations of IFN-α and IL-33 could be useful biomarkers for the diagnosis and monitoring of AIP and IgG4-RD activity after induction of remission in these autoimmune disorders. In this Frontier article, we have summarized and discussed biomarkers of AIP and IgG4-RD, including Igs, autoAbs, and cytokines to provide useful information not only for clinicians but also for researchers.

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.

This study aimed to investigate whether the incorporation of contrast-enhanced harmonic endoscopic ultrasound (CH-EUS) into the international consensus guidelines (ICG) for the management of intraductal papillary mucinous neoplasm (IPMN) could improve its malignancy diagnostic value. In this single-center retrospective study, 109 patients diagnosed with IPMN who underwent preoperative CH-EUS between March 2010 and December 2018 were enrolled. We analyzed each malignancy diagnostic value (sensitivity (Se), specificity (Sp), positive predictive value (PPV), and negative predictive value (NPV)) by replacing fundamental B-mode EUS with CH-EUS as the recommended test for patients with worrisome features (WF) (the CH-EUS incorporation ICG) and comparing the results to those obtained using the 2017 ICG. The malignancy diagnostic values as per the 2017 ICG were 78.9%, 42.3%, 60.0%, and 64.7% for Se, Sp, PPV, and NPV, respectively. The CH-EUS incorporation ICG plan improved the malignancy diagnostic values (Se 78.9%/Sp, 53.8%/PPV, 65.2%/NPV 70.0%). CH-EUS may be useful in determining the appropriate treatment strategies for IPMN.

BACKGROUND: Despite the high incidence of spondyloarthritis (SpA) as an extra-intestinal manifestation of Crohn's disease (CD), the immunopathogenesis of CD-associated SpA remains largely unknown. OBJECTIVE: We tried to explore molecular mechanisms accounting for the development of CD-associated SpA in a patient successfully treated with infliximab. METHODS: Peripheral blood mononuclear cells (PBMCs) before infliximab treatment were stimulated with Toll-like receptor (TLR) ligands to measure pro-inflammatory cytokine responses. Endoscopic biopsy samples before and after infliximab treatment were subjected to quantitative polymerase chain reaction. RESULTS: PBMCs from this CD-associated SpA patient exhibited higher production of pro-inflammatory cytokines upon stimulation with TLR ligands than PBMCs from healthy controls. Induction of remission by infliximab was associated with the downregulation of pro-inflammatory cytokine responses in the small intestinal mucosa, which is continually exposed to TLR ligands. CONCLUSIONS: Excessive pro-inflammatory cytokine responses to TLR ligands might underlie the immunopathogenesis of CD-associated SpA.

BACKGROUND: Type 1 autoimmune pancreatitis (AIP) is a pancreatic manifestation of IgG4-related disease (IgG4-RD). Although AIP and IgG4-RD are characterized by multiple organ involvement including salivary glands, lung, and kidney, co-occurrence of chronic rhinosinusitis (CRS) and AIP/IgG4-RD has been poorly defined. OBJECTIVE: We explored molecular mechanism accounting for the co-occurrence of CRS and AIP/IgG4-RD. METHODS: Serum concentrations of IFN-α and IL-33 were measured by enzyme-linked immune-sorbent assay. RESULTS: We encountered a patient with concurrent type 1 AIP/IgG4-RD and CRS. Induction of remission by prednisolone (PSL) for type 1 AIP/IgG4-RD led to a marked improvement of CRS. Serum cytokine analysis after PSL treatment revealed a marked reduction in serum concentrations of IFN-α and IL-33, both of which are candidate pathogenic cytokines for AIP/IgG4-RD. CONCLUSIONS: Given that IL-33 is shared as one of pathogenic cytokines by type 1 AIP/IgG4-RD and CRS, enhanced IL33 responses may cause concurrent type 1 AIP/IgG4-RD and CRS.

Background and Objectives: Differential diagnosis to estimate the malignant potential of gastric submucosal tumor (g-SMT) is important for decision-making. This study evaluated the use of a 20G needle with a core trap for EUS-guided fine-needle biopsy (EUS-FNB) for g-SMT. Methods: This multicentric prospective trial was registered in the University Hospital Medical Information Network (UMIN000021410). Consecutive patients with g-SMT who presented at one of the nine Japanese Referral Centers between June 2017 and November 2018 were enrolled. All patients underwent EUS-FNB using a 20G needle with a core trap. Samples obtained with the first-needle pass were used for central pathological review. EUS-FNB was evaluated in terms of (i) technical success rate, (ii) adequacy for histological evaluation, (iii) rate of complications, (iv) accuracy for histological diagnosis of gastrointestinal stromal tumor (GIST), and (v) concordance between GIST mitotic index determined by EUS-FNB and after tumor resection. Results: The study included 52 patients. The technical success rate of EUS-FNB was 100%. The adequacy rate for histological evaluation was 90.4% (P < 0.001). There were no complications related to EUS-FNB. Of the 38/52 patients who underwent surgical resection, 36 were finally diagnosed with GIST. The sensitivity, specificity, and accuracy of EUS-FNB for the histological diagnosis of g-SMT were 80.6%, 100%, and 81.6%, respectively. The concordance rate between the mitotic index on EUS-FNB and that after analysis of the resected tumor was 89.7%. Conclusions: EUS-FNB using a 20G needle with a core trap is feasible, providing histological samples of sufficient quality for diagnosing g-SMT.

Eosinophilic gastroenteritis (EGE) is a chronic allergic disorder characterized by infiltration of eosinophils in the gastrointestinal (GI) tract and hypereosinophilia. Although T helper type 2 (Th2) responses play pathogenic roles in EGE, roles of innate immunity cytokines including IL-6 and TNF-α have been poorly defined. Here, we describe a case of EGE exhibiting accumulation of eosinophils in the upper GI mucosa and hypereosinophilia. Induction of remission by prednisolone reduced expression levels not only of Th2 cytokines but also of IL-6 and TNF-α in the GI mucosa. Moreover, induction of remission was accompanied by a marked reduction in serum levels of chemokine C-C motif ligand 17 (CCL17, TARC), IL-6 and TNF-α, implicating that both Th2 and innate immune responses were involved in the development of EGE in this case. Collectively, this case suggests possible involvement of IL-6 and TNF-α in the development of EGE.

IL-33 is a pleiotropic cytokine that promotes inflammation and fibrosis. IL-33 is produced by a broad range of cells, including antigen-presenting cells (APCs), epithelial cells, and fibroblasts. IL-33 produced by the innate immune cells has been shown to activate pro-inflammatory T helper type 1 (Th1) and T helper type 2 (Th2) responses. The intestinal barrier and tolerogenic immune responses against commensal microbiota contribute to the maintenance of gut immune homeostasis. Breakdown of tolerogenic responses against commensal microbiota as a result of intestinal barrier dysfunction underlies the immunopathogenesis of inflammatory bowel diseases (IBD) and pancreatitis. Recent studies have provided evidence that IL-33 is an innate immune cytokine that bridges adaptive Th1 and Th2 responses associated with IBD and pancreatitis. In this Mini Review, we discuss the pathogenic roles played by IL-33 in the development of IBD and pancreatitis and consider the potential of this cytokine to be a new therapeutic target.

Autoimmune pancreatitis (AIP) is a chronic fibro-inflammatory disorder of the pancreas. Recent clinicopathological analysis revealed that most cases of AIP are pancreatic manifestations of systemic IgG4-related disease (IgG4-RD), a newly established disease characterized by enhanced IgG4 antibody responses and the involvement of multiple organs. Although the immuno-pathogenesis of AIP and IgG4-RD has been poorly defined, we recently showed that activation of plasmacytoid dendritic cells (pDCs) with the ability to produce large amounts of IFN-α and IL-33 mediates chronic fibro-inflammatory responses in experimental and human AIP. Moreover, M2 macrophages producing a large amount of IL-33 play pathogenic roles in the development of human IgG4-RD. Interestingly, recent studies including ours provide evidence that compositional alterations of gut microbiota are associated with the development of human AIP and IgG4-RD. In addition, intestinal dysbiosis plays pathological roles in the development of chronic pancreatic inflammation as dysbiosis mediates the activation of pDCs producing IFN-α and IL-33, thereby causing experimental AIP. In this Mini Review, we focus on compositional alterations of gut microbiota in AIP and IgG4-RD to clarify the mechanisms by which intestinal dysbiosis contributes to the development of these disorders.

Inflammatory bowel diseases (IBDs) are becoming more frequent worldwide. A significant fraction of patients with IBD are refractory to various types of therapeutic biologics and small molecules. Therefore, identification of novel therapeutic targets in IBD is required. Receptor-interacting serine/threonine kinase 2 (RIPK2), also known as receptor-interacting protein 2 (RIP2), is a downstream signaling molecule for nucleotide-binding oligomerization domain 1 (NOD1), NOD2, and Toll-like receptors (TLRs). RIPK2 is expressed in antigen-presenting cells, such as dendritic cells and macrophages. Recognition of microbe-associated molecular patterns by NOD1, NOD2, and TLRs leads to the interaction between RIPK2 and these innate immune receptors, followed by the release of pro-inflammatory cytokines such as TNF-α, IL-6, and IL-12/23p40 through the activation of nuclear factor kappa B and mitogen-activated protein kinases. Thus, activation of RIPK2 plays a critical role in host defense against microbial infections. Recent experimental and clinical studies have provided evidence that activation of RIPK2 is involved in the development of autoimmune diseases, especially IBDs. In addition, the colonic mucosa of patients with IBD exhibits enhanced expression of RIPK2 and associated signaling molecules. Furthermore, the blockage of RIPK2 activation ameliorates the development of experimental murine colitis. Thus, activation of RIPK2 underlies IBD immunopathogenesis. In this review, we attempt to clarify the roles played by RIPK2 in the development of IBD by focusing on its associated signaling pathways. We also discuss the possibility of using RIPK2 as a new therapeutic target in IBD.

Behçet's disease (BD) is a rare inflammatory condition characterized by oral and genital ulcers, skin lesions, as well as ophthalmological, neurological, and gastrointestinal manifestations. BD involving the gastrointestinal tract is known as intestinal BD. The mucosa of the gastrointestinal tract of patients with intestinal BD exhibits enhanced levels of proinflammatory cytokines, such as IL-1β, IL-6, and TNF-α. These proinflammatory cytokines play pathogenic roles in the development of BD, as evidenced by the fact that biologics targeting these cytokines effectively induce BD remission. It should be noted, however, that the molecular mechanisms by which the blockade of these cytokines suppresses chronic inflammatory responses in BD are poorly understood. Herein, we report a case of intestinal BD resistant to prednisolone that was successfully treated with infliximab (IFX). The induction of remission by IFX was accompanied by a marked elevation of IL-6 and forkhead box P3 (FOXP3) at mRNA level. This case suggests that induction of remission by IFX is mediated not only by the suppression of TNF-α-mediated signaling pathways, but also by the promotion of IL-6 expression and accumulation of regulatory T cells expressing FOXP3.

Double expressor lymphoma (DEL), defined as overexpression of BCL2 and MYC, is an aggressive subtype of diffuse large B cell lymphoma (DLBCL). Here we report a case of a 64-year-old female diagnosed with abdominal DEL transformed from jejunum follicular lymphoma (FL). 18F-fluorodeoxyglucose (FDG)-positron emission tomography showed diffuse accumulation of FDG into the peritoneum and small bowel wall. Double balloon-assisted enteroscopy revealed whitish submucosal tumors in the proximal jejunum. Aggregation of atypical lymphocytes positive for CD20, CD79a, and BCL2 was seen in the jejunal biopsy samples. These atypical lymphocytes were monoclonal since cell surface expression of Ig light chains was limited to κ chain by flow-cytometry. Thus, immunohistochemical and flowcytometric analyses data were consistent with FL of the jejunum. Neoplastic lymphocytes obtained from ascites were positive for CD10, CD20, CD79a, BCL2, and BCL6. Fluorescence in situ hybridization (FISH) showed formation of BCL2/IgH fusion gene and extra copies of MYC, the former of which is a characteristic chromosomal abnormality of FL. These genetic alterations and protein expression profiles of ascitic fluid cells were consistent with those of DEL transformed from FL. Given that a significant population of patients with indolent FL of the gastrointestinal tract developed into aggressive DLBCL, it is likely that primary FL of the jejunum transformed into the abdominal aggressive DEL in this case. This case is unique in that concurrent occurrence of FL and DEL was confirmed by immunohistochemical and FISH analyses and that abdominal DEL transformed from jejunal FL was highly suspected.

Collagenous colitis (CC), a prototypical microscopic colitis, is a chronic inflammatory disorder of the colon. The diagnosis of CC depends on the pathological examination. The colonic mucosa of patients with CC is characterized by the presence of a substantially thickened collagen band (>10μm) under the surface epithelium. In addition, intraepithelial and lamina propria lymphocytes are markedly increased in patients with CC. However, the roles played by the lymphocytes accumulating in the colonic mucosa of patients with CC are poorly defined. Recent studies indicate that T cells infiltrating the colonic mucosa of patients with CC are mainly represented by CD4+ T cells, CD8+ T cells, and forkhead box P3 (FOXP3)+ regulatory T cells (Tregs). Given that activation of CD4+/CD8+ T cells and FOXP3+ Tregs usually mediates pro-inflammatory and anti-inflammatory responses, respectively, alterations in the colonic numbers of these adaptive T cells might be related to the resolution of colitis in patients with CC. We determined alterations in the composition of colonic T cells by extensive immunohistochemical (IHC) analyses in a case of CC successfully treated with budesonide and metronidazole. Colonic lamina propria immune cells mainly comprised CD3+ T cells, CD4+ T cells, CD8+ T cells, CD68+ macrophages, and FOXP3+ Tregs, but not CD20+ B cells or myeloperoxidase (MPO)+ granulocytes in the active phase. During remission, the numbers of CD3+ T cells, CD4+ T cells, CD8+ T cells, and CD68+ macrophages did not change significantly in the colonic lamina propria, whereas FOXP3+ Tregs were markedly decreased, suggesting that induction of remission was achieved in a Treg-independent manner. Thus, our study indicates that accumulation of FOXP3+ Tregs in the colonic mucosa of patients with CC might be a counter-regulatory mechanism reflecting persistent inflammation and that induction of remission might be achieved without activation of Tregs.

Although plasmacytoid dendritic cells (pDCs) able to produce large amounts of type 1 interferons (IFN-I) play beneficial roles in host defense against viral infections, excessive activation of pDCs, followed by robust production of IFN-I, causes autoimmune disorders including systemic lupus erythematosus (SLE) and psoriasis. Autoimmune pancreatitis (AIP), which is recognized as a pancreatic manifestation of systemic immunoglobulin G4-related disease (IgG4-RD), is a chronic fibroinflammatory disorder driven by autoimmunity. IgG4-RD is a multi-organ autoimmune disorder characterized by elevated serum concentrations of IgG4 antibody and infiltration of IgG4-expressing plasmacytes in the affected organs. Although the immunopathogenesis of IgG4-RD and AIP has been poorly elucidated, recently, we found that activation of pDCs mediates the development of murine experimental AIP and human AIP/IgG4-RD via the production of IFN-I and interleukin-33 (IL-33). Depletion of pDCs or neutralization of signaling pathways mediated by IFN-I and IL-33 efficiently inhibited the development of experimental AIP. Furthermore, enhanced expression of IFN-I and IL-33 was observed in the pancreas and serum of human AIP/IgG4-RD. Thus, AIP and IgG4-RD share their immunopathogenesis with SLE and psoriasis because in all these conditions, IFN-I production by pDCs contributes to the pathogenesis. Because the enhanced production of IFN-I and IL-33 by pDCs promotes chronic inflammation and fibrosis characteristic for AIP and IgG4-RD, neutralization of IFN-I and IL-33 could be a new therapeutic option for these disorders. In this Mini Review, we discuss the pathogenic roles played by the pDC-IFN-I-IL-33 axis and the development of a new treatment targeting this axis in AIP and IgG4-RD.

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.

OBJECTIVES: Preoperative grading of pancreatic neuroendocrine tumors (PanNET) is challenging. The aim of this study was to prospectively evaluate the use of a 25-gauge needle with a core trap for diagnosis and grading of PanNET. METHODS: This multicenter prospective trial was registered with the University Hospital Medical Information Network (UMIN000021409). Consecutive patients with suspected PanNET between June 2016 and November 2017 were enrolled. All patients underwent endoscopic ultrasound-guided fine needle biopsy (EUS-FNB) using a 25-gauge needle with a core trap. Samples obtained after the first needle pass were used for central pathological review. EUS-FNB was evaluated in terms of (i) technical success rate, (ii) adequacy for histological evaluation, (iii) complication rate during the procedure, and (iv) concordance between PanNET grading on EUS-FNB and that after analysis of the resected tumor. RESULTS: Fifty-two patients were enrolled. Of the 36/52 patients who underwent surgical resection, 31 were finally diagnosed with PanNET and were eligible for analysis. The technical success rate of EUS-FNB was 100%. The rate of adequacy for histological evaluation was 90.3%. There were no complications related to EUS-FNB. The concordance rate between PanNET grading on EUS-FNB and that after analysis of the resected tumor was 82.6% (95% confidence interval = 61.22-95.05, P = 0.579). CONCLUSIONS: EUS-FNB using a 25-gauge needle with a core trap is feasible, providing histological samples are of sufficient quality for diagnosis and grading of PanNET.

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.

IgG4-related disease (IgG4-RD) is a multi-organ autoimmune disease characterized by elevated serum IgG4 concentration. Although serum IgG4 concentration is widely used as a biomarker for IgG4-RD and type 1 autoimmune pancreatitis (AIP), a pancreatic manifestation of IgG4-RD, a significant number of patients have normal serum IgG4 levels, even in the active phase of the disease. Recently, we reported that the development of experimental AIP and human type 1 AIP is associated with increased expression of IFN-α and IL-33 in the pancreas. In this study, we assessed the utility of serum IFN-α and IL-33 levels as biomarkers for type 1 AIP and IgG4-RD. Serum IFN-α and IL-33 concentrations in patients who met the diagnostic criteria for definite type 1 AIP and/or IgG4-RD were significantly higher than in those with chronic pancreatitis or in healthy controls. Strong correlations between serum IFN-α, IL-33, and IgG4 concentrations were observed. Diagnostic performance of serum IFN-α and IL-33 concentrations as markers of type 1 AIP and/or IgG4-RD was comparable to that of serum IgG4 concentration, as calculated by the receiver operating characteristic curve analysis. Induction of remission by prednisolone treatment markedly decreased the serum concentration of these cytokines. We conclude that serum IFN-α and IL-33 concentrations can be useful as biomarkers for type 1 AIP and IgG4-RD.

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 (HEK293) 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 proinflammatory cytokine responses by inhibiting the interaction between TLR2 and RICK/RIP2. Binding of ATG16L1 to RICK/RIP2 suppressed NF-κB activation by downregulating 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 downregulation of TLR-mediated proinflammatory cytokine responses.

Nephroptosis is a benign disorder defined as a significant descent of the affected kidney as the patient moves from supine to erect. Patients with nephroptosis sometimes manifest symptoms including abdominal pain, back pain, nausea and hematuria, while the majority of those are asymptomatic. Downward migration of the affected kidney induced by a postural change from the supine to the upright position underlies the pathophysiology of nephroptosis. The diagnosis of nephroptosis is difficult since routine imaging examinations are conducted in the supine position alone. Here, we report a case presenting recurrent abdominal pain due to unknown causes. This patient was successfully diagnosed as nephroptosis by ultrasonography and drip infusion pyelography, both of which were performed in both supine and upright positions. This case report strongly suggests that we need to take into consideration a possibility of nephroptosis when we encounter with patients complaining abdominal and/or back pain due to unknown causes.

Although patients with anorexia nervosa (AN) present with various gastrointestinal disorders, little has been understood regarding the incidence and pathophysiology of gastrointestinal ulcers related to AN. A 20-year-old woman with a past history of AN was hospitalized for further examination of dysphagia and chest pain. Her nutritional status was very poor as evidenced by very low body mass index. Esophagogastroduodenoscopy detected longitudinal and geographical ulcers in the entire circumference of the cervical and upper esophagus. Enhanced expression of autophagy-related proteins, LC3B and p62, was seen in the esophageal epithelium surrounding the active ulcers. Expression of these autophagy markers disappeared from the esophageal epithelium soon after the nutritional rehabilitation. Given the fact that starvation and malnutrition are potent inducers for autophagy, these findings suggest that autophagy might be involved in the development of gastrointestinal ulcers in patients with AN.

BACKGROUND: This study aimed to evaluate and identify the specific CT findings by focusing on abnormalities in the main pancreatic duct (MPD) and pancreatic parenchyma in patients with small pancreatic cancer (PC) including carcinoma in situ (CIS). METHODS: Nine CT findings indicating abnormalities of MPD and pancreatic parenchyma were selected as candidate findings for the presence of small PC ≤ 10 mm. The proportions of patients positive for each finding were compared between small PC and benign MPD stenosis groups. Interobserver agreement between two independent image reviewers was evaluated using kappa statistics. RESULTS: The final analysis included 24 patients with small PC (including 11 CIS patients) and 28 patients with benign MPD stenosis. The proportion of patients exhibiting partial pancreatic parenchymal atrophy (PPA) corresponding to the distribution of MPD stenosis (45.8% vs. 7.1%, p < 0.01), upstream PPA arising from the site of MPD stenosis (33.3% vs. 3.6%, p = 0.01), and MPD abrupt stenosis (45.8% vs. 14.3%, p = 0.03) was significantly higher in the small PC group than in the benign MPD stenosis group. CONCLUSIONS: The presence of partial PPA, upstream PPA, and MPD abrupt stenosis on a CT image was highly suggestive of the presence of small PCs including CIS.

The first edition of the guidelines for the use of ultrasound contrast agents was published in 2004, dealing with liver applications. The second edition of the guidelines in 2008 reflected changes in the available contrast agents and updated the guidelines for the liver, as well as implementing some nonliver applications. The third edition of the contrast-enhanced ultrasound (CEUS) guidelines was the joint World Federation for Ultrasound in Medicine and Biology-European Federation of Societies for Ultrasound in Medicine and Biology (WFUMB-EFSUMB) venture in conjunction with other regional US societies such as Asian Federation of Societies for Ultrasound in Medicine and Biology, resulting in a simultaneous duplicate on liver CEUS in the official journals of both WFUMB and EFSUMB in 2013. However, no guidelines were described mainly for Sonazoid due to limited clinical experience only in Japan and Korea. The new proposed consensus statements and recommendations provide general advice on the use of Sonazoid and are intended to create standard protocols for the use and administration of Sonazoid in hepatic and pancreatobiliary applications in Asian patients and to improve patient management.

BACKGROUND AND AIMS: Kupffer-phase imaging visualized by perfluorobutane (Sonazoid) distribution into normal liver tissues upon phagocytosis by Kupffer cells potentially aids in improving detection of liver metastasis compared with fundamental B-mode EUS (FB-EUS). However, the diagnostic performance of Kupffer-phase imaging in contrast-enhanced harmonic EUS (CH-EUS) remains unclear. Hence, this study aimed to evaluate the usefulness of CH-EUS-based Kupffer-phase imaging for diagnosing liver metastasis from pancreatic cancer. METHODS: We retrospectively analyzed consecutive patients with pancreatic cancer who underwent contrast-enhanced CT (CE-CT) and FB-EUS, followed by CH-EUS, from 2011 to 2017. The diagnostic ability of CH-EUS against that of CE-CT and FB-EUS for metastasis in the left liver lobe was compared. Subsequently, the influences of CH-EUS on the determination of clinical stage and patient management for pancreatic cancer were assessed. RESULTS: We enrolled 426 patients with pancreatic cancer. Metastasis in the left liver lobe was present in 27.2% of patients. The diagnostic accuracy of CE-CT, FB-EUS, and CH-EUS was 90.6%, 93.4%, and 98.4%, respectively. The sensitivity and diagnostic accuracy of CH-EUS for metastasis in the left liver lobe were significantly higher than those of FB-EUS or CE-CT. The sensitivity of CH-EUS for detecting small liver metastasis (<10 mm) was considerably higher than that of CE-CT or FB-EUS (P < .001). In 2.1% of patients, only CH-EUS could detect a single distant metastasis of the left liver lobe, thereby upgrading the tumor staging and altering the clinical management. CONCLUSIONS: CH-EUS-based Kupffer-phase imaging increased the detectability of metastasis in the left liver lobe. This technique could be a reliable pretreatment imaging modality for clinical decision-making in patients with pancreatic cancer.

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.

BACKGROUND: Although several techniques for endoscopic ultrasound-guided biliary drainage (EUS-BD) are available at present, an optimal treatment algorithm of EUS-BD has not yet been established. AIM: To evaluate the clinical utility of treatment method conversion during single endoscopic sessions for difficult cases in initially planned EUS-BD. METHODS: This was a single-center retrospective analysis using a prospectively accumulated database. Patients with biliary obstruction undergoing EUS-BD between May 2008 and April 2016 were included. The primary outcome was to evaluate the improvement in EUS-BD success rates by converting the treatment methods during a single endoscopic session. Secondary outcomes were clarification of the factors leading to the conversion from the initial EUS-BD and the assessment of efficacy and safety of the conversion as judged by technical success, clinical success, and adverse events (AEs). RESULTS: A total of 208 patients underwent EUS-BD during the study period. For 18.8% (39/208) of the patients, the treatment methods were converted to another EUS-BD technique from the initial plan. Biliary obstruction was caused by pancreatobiliary malignancies, other malignant lesions, biliary stones, and other benign lesions in 22, 11, 4, and 2 patients, respectively. The reasons for the difficulty with the initial EUS-BD were classified into the following 3 procedures: Target puncture (n = 13), guidewire manipulation (n = 18), and puncture tract dilation (n = 8). Technical success was achieved in 97.4% (38/39) of the cases and clinical success was achieved in 89.5% of patients (34/38). AEs occurred in 10.3% of patients, including bile leakage (n = 2), bleeding (n = 1), and cholecystitis (n = 1). The puncture target and drainage technique were altered in subsequent EUS-BD procedures in 25 and 14 patients, respectively. The final technical success rate with 95%CI for all 208 cases was 97.1% (95%CI: 93.8%-98.9%), while that of the initially planned EUS-BD was 78.8% (95%CI: 72.6%-84.2%). CONCLUSION: Among multi-step procedures in EUS-BD, guidewire manipulation appeared to be the most technically challenging. When initially planned EUS-BD is technically difficult, treatment method conversion in a single endoscopic session may result in successful EUS-BD without leading to severe AEs.

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.

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.

BACKGROUND: Gemcitabine plus cisplatin (GC) is the standard treatment of advanced biliary tract cancer (BTC); however, it causes nausea, vomiting, and anorexia, and requires hydration. Gemcitabine plus S-1 (GS) reportedly has equal to, or better, efficacy and an acceptable toxicity profile. We aimed to confirm the non-inferiority of GS to GC for patients with advanced/recurrent BTC in terms of overall survival (OS). PATIENTS AND METHODS: We undertook a phase III randomized trial in 33 institutions in Japan. Eligibility criteria included chemotherapy-naïve patients with recurrent or unresectable BTC, an Eastern Cooperative Oncology Group Performance Status of 0 - 1, and adequate organ function. The calculated sample size was 350 with a one-sided α of 5%, a power of 80%, and non-inferiority margin hazard ratio (HR) of 1.155. The primary end point was OS, while the secondary end points included progression-free survival (PFS), response rate (RR), adverse events (AEs), and clinically significant AEs defined as grade ≥2 fatigue, anorexia, nausea, vomiting, oral mucositis, or diarrhea. RESULTS: Between May 2013 and March 2016, 354 patients were enrolled. GS was found to be non-inferior to GC [median OS: 13.4 months with GC and 15.1 months with GS, HR, 0.945; 90% confidence interval (CI), 0.78-1.15; P = 0.046 for non-inferiority]. The median PFS was 5.8 months with GC and 6.8 months with GS (HR 0.86; 95% CI 0.70-1.07). The RR was 32.4% with GC and 29.8% with GS. Both treatments were generally well-tolerated. Clinically significant AEs were observed in 35.1% of patients in the GC arm and 29.9% in the GS arm. CONCLUSIONS: GS, which does not require hydration, should be considered a new, convenient standard of care option for patients with advanced/recurrent BTC. CLINICAL TRIAL NUMBER: This trial has been registered with the UMIN Clinical Trials Registry (http://www.umin.ac.jp/ctr/index.htm), number UMIN000010667.

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.

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.

BACKGROUND AND AIMS: Contrast-enhanced harmonic endoscopic ultrasonography (CH-EUS) is used for the diagnosis of pancreatic cancer (PC). Here, we examined the usefulness of CH-EUS for evaluating therapeutic responses in PC. METHODS: The study included 23 patients with PC who received chemotherapy. Patients underwent contrast-enhanced computed tomography (CE-CT) and CH-EUS before chemotherapy and at the time of evaluation of the therapeutic response. Patients with a ≧50% reduction in serum carbohydrate antigen 19-9 levels after chemotherapy were defined as "super responders". The incidence of an avascular area in the tumor on CH-EUS after chemotherapy was compared between "super responders" and non-super responders. RESULTS: Nine patients were included in the "super responders" group.Tumor reduction rates did not differ significantly between CE-CT and CH-EUS in the "super responders". The appearance of an avascular area was detected in 7 of 9 super responders (77.8%) and in 4 of 14 non-super responders (28.6%), and the difference was significant (P = 0.036). The mean survival time of patients with an avascular area after chemotherapy was longer than that of without an avascular area. CONCLUSIONS: Detection of avascular areas by CH-EUS after chemotherapy may predict long-term survival of patients with PC.

Klebsiella oxytoca (K. oxytoca) is a causative organism for hemorrhagic antibiotic-associated colitis. K. oxytoca infection is a typical example of microbial substitution diseases caused by exposure to antibiotics prior to the onset of diarrhea. Here, we repot a case with ileitis associated with K. oxytoca infection in the absence of preceding antibiotic treatment. Interestingly, abdominal computed tomography revealed wall thickening of the ileum and hepatic portal venous gas (HPVG). K. oxytoca was isolated from the stool. This very elderly patient had been treated with azathioprine for long-standing history of ulcerative colitis. Immuno-compromised state of this patient was considered to allow overgrowth of K. oxytoca in the small bowel to cause not only ileitis but also HPVG.

Objective Although modified FOLFIRINOX (mFOLFIRINOX, mFFX) is widely used for patients with advanced pancreatic ductal adenocarcinoma (PDAC), maintenance of the standard dose intensity is often difficult due to the high incidence of neutropenic events. Pegylated granulocyte colony-stimulating factor (G-CSF) (Peg G) is a long-lasting G-CSF agent that is applicable for prophylaxis against neutropenic complications. The aim of this study was to assess the clinical safety and efficacy of mFFX combined with secondary prophylaxis using Peg G in advanced PDAC patients. Methods Advanced PDAC patients who had received more than two cycles of mFFX were analyzed. The clinical safety and efficacy were compared between patients in the Peg G group and those in the non-Peg G group in a retrospective manner. Results Among 45 patients treated with mFFX, 28 exhibited grade 3-4 neutropenia or febrile neutropenia. Among these 28 patients, 4 who received only 1 or 2 mFFX cycles were excluded from this study. Finally, 11 patients in the Peg G group and 13 in the non-Peg G group were enrolled. The combination therapy with Peg G and mFFX markedly prolonged the progression-free survival compared with the non-Peg G group, and its effects were associated with a reduced incidence of neutropenic events as well as lower rates of dosage reduction, delayed chemotherapy due to neutropenic events and altered blood cell counts after chemotherapy. Conclusion The scheduled administration of secondary prophylactic Peg G prolonged the progression-free survival in patients treated with mFFX. The combination therapy of Peg G and mFFX may be recommended in patients who exhibit grade 3-4 neutropenic events after prior mFFX cycles.

Autoimmune diseases including inflammatory bowel disease (IBD) occur in association with myelodysplastic syndrome (MDS). MDS-associated IBD frequently demonstrates a complicated course. We herein report the first case with MDS-associated IBD that was successfully treated with ustekinumab (UST), an anti-interleukin (IL) 12/23p40 monoclonal antibody. A 63-year-old man with a 7-year history of MDS was referred for examination of diarrhea, abdominal pain and fever. A blood examination revealed a marked elevation of C-reactive protein. Colonoscopy showed multiple ulcers in the terminal ileum. He was resistant to anti-tumor necrosis factor (TNF)-α antibody and azacitidine. Subsequently, UST treatment reduced colonic IL-17 and IL-6 expression and the patient currently maintains a state of remission.

Autoimmune pancreatitis (AIP) is now considered a pancreatic manifestation of a newly proposed disease condition, IgG4-related disease (IgG4-RD). IgG4-RD is characterized by enhanced IgG4 antibody responses and multiple organ involvements. Recent epidemiological studies have addressed the incidence of cancer in patients with AIP and/or IgG4-RD. Surprisingly, a significant number of AIP patients were detected with cancer at or within one year of the diagnosis of AIP. Furthermore, around 50% of all cancers detected in AIP patients comprised mainly 3 types (gastric, lung, and prostate cancer). Thus, AIP appears to be associated with cancer of other organs rather than the pancreas itself, which suggests that AIP is not a pre-cancerous condition of the pancreas. Moreover, the simultaneous occurrence of cancer and AIP in many patients has led to the establishment of an attractive concept that AIP might sometimes arise from co-existing cancers as a paraneoplastic syndrome.

Immunotherapy targeting programmed cell death-1 (PD-1) signaling is becoming the standard of care for advanced gastric cancer. We herein report a patient with gastric adenocarcinoma with peritoneal dissemination who was treated with nab-paclitaxel and ramucirumab following nivolumab and developed sclerosing cholangitis. Endoscopic retrograde cholangiography showed irregular narrowing and widening of the entire intrahepatic biliary system. Intriguingly, the patient receiving second-line chemotherapy with nab-paclitaxel plus ramucirumab prior to being administered nivolumab, however, he had experienced progressive disease. Thereafter, the administration of fourth-line chemotherapy with nab-paclitaxel and ramucirumab following nivolumab resulted in a clinical response. Nivolumab may enhance the efficacy of the subsequent chemotherapy regimens but also induce sclerosing cholangitis.

IgG4-related disease (IgG4-RD) is a newly defined multi-organ disease proposed by Japanese physicians. IgG4-RD is characterized by elevated serum levels of IgG4 and massive infiltration of IgG4-expressing plasma cells in the affected organs. Recent studies have shown that abnormal adaptive immune responses mediated by T helper type 2 cells, regulatory T cells, follicular helper T cells, cytotoxic CD4+ T cells, and plasmablasts are involved in IgG4-RD immunopathogenesis. In addition to adaptive immune responses, innate immune responses play pathogenic roles in IgG4-RD. Plasmacytoid dendritic cells (pDCs), M2 macrophages, and basophils are activated to produce various kinds of cytokines in IgG4-RD. Recent studies highlight the importance of type I IFN and IL-33 produced by pDCs in IgG4-RD immunopathogenesis.

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.

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.

Neurilemmomas are benign tumors arising from the sheaths of peripheral nerves. They appear rarely in the abdominal cavity. We herein report an 80-year-old man with a multilocular cystic neurilemmoma mimicking a liver lesion. Preoperative images showed a lesion in the porta hepatis. Although a preoperative diagnosis was difficult, surgery was undertaken because of the possibility of malignancy. Histologically, the tumor consisted of spindle-shaped cells with positivity for S-100 protein. The final diagnosis was a neurilemmoma. Porta hepatic neurilemmomas are rare. When we encounter a multilocular cystic lesion of the liver, neurilemmoma should be considered in the differential diagnosis.

Although hyperparathyroidism has been reported to cause acute pancreatitis, little is known about the mechanism involved. This study describes the case of an 86-year-old woman with acute pancreatitis and consciousness disturbance caused by hyperparathyroidism and hypercalcemia, respectively. The consciousness disturbance caused by severe hypercalcemia probably masked the typical symptoms associated with pancreatitis because she did not report abdominal pain during the clinical course.

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.

Hepatocellular carcinoma (HCC) causes one of the most frequent cancer-related deaths; an HCC subset shows rapid progression that affects survival. We clarify molecular features of aggressive HCC, and establish a molecular scoring system that predicts metastasis after curative treatment. In total, 125 HCCs were examined for TP53, CTNNB1, and TERT promoter mutation, methylation of 8 tumor suppressor genes, and 3 repetitive DNA sequences to estimate promoter hypermethylation and global hypomethylation. A fractional allelic loss (FAL) was calculated to represent chromosomal instability through microsatellite analysis. Molecular subclasses were determined using corresponding and hierarchical clustering analyses. Next, twenty-five HCC patients who underwent liver transplantation were analyzed for associations between molecular characteristics and metastatic recurrence; survival analyses were validated using a publicly available dataset of 376 HCC cases from the Cancer Genome Atlas (TCGA). An HCC subtype characterized by TP53 mutation, high FAL, and global hypomethylation was associated with aggressive tumor characteristics, like vascular invasion; CTNNB1 mutation was a feature of the less-progressive phenotype. A number of molecular risk factors, including TP53 mutation, high FAL, significant global hypomethylation, and absence of CTNNB1 mutation, were noted to predict shorter recurrence-free survival in patients who underwent liver transplantation (p = 0.0090 by log-rank test). These findings were validated in a cohort of resected HCC cases from TCGA (p = 0.0076). We concluded that molecular risks determined by common genetic and epigenetic alterations could predict metastatic recurrence after curative treatments, and could be a marker for considering systemic therapy for HCC patients.

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.

Nucleotide-binding oligomerization domain 1 (NOD1) is an intracellular innate immune sensor for small molecules derived from bacterial cell components. NOD1 activation by its ligands leads to robust production of pro-inflammatory cytokines and chemokines by innate immune cells, thereby mediating mucosal host defense systems against microbes. Chronic gastric infection due to Helicobacter pylori (H. pylori) causes various upper gastrointestinal diseases, including atrophic gastritis, peptic ulcers, and gastric cancer. It is now generally accepted that detection of H. pylori by NOD1 expressed in gastric epithelial cells plays an indispensable role in mucosal host defense systems against this organism. Recent studies have revealed the molecular mechanism by which NOD1 activation caused by H. pylori infection is involved in the development of chronic gastritis and gastric cancer. In this review, we have discussed and summarized how sensing of H. pylori by NOD1 mediates the prevention of chronic gastritis and gastric cancer.

Myelodysplastic syndrome [MDS] is a clonal disorder of bone marrow [BM] cells, caused by acquired chromosomal abnormalities and gene mutations. Pro-inflammatory antigen-presenting cells [APCs] originating from BM cells bearing chromosomal abnormalities and gene mutations can cause immune-mediated disorders including inflammatory bowel disease [IBD]. Here, we report the first case with MDS-associated IBD that was successfully treated with the DNA methyltransferase inhibitor, azacitidine [AZA]. A 75-year-old man with a 5-year history of MDS was admitted for examination of diarrhoea and high fever. Blood examination revealed pancytopenia and a marked elevation of C-reactive protein. Colonoscopy revealed multiple round ulcers from the terminal ileum to the sigmoid colon. Pathological examination of the endoscopic biopsy specimens showed destruction of crypt architecture and infiltration of CD3+ T cells and CD68+ macrophages. Surprisingly, administration of AZA, which has been approved for the treatment of high-risk MDS, improved the symptoms, and the multiple round ulcers disappeared. AZA treatment markedly decreased the expressions of tumour necrosis factor-α, interleukin-12 (IL-12)/23p40 and IL-17 in colonic biopsy samples, as assessed by quantitative reverse transcription polymerase chain reaction. In contrast, AZA treatment did not change the expression of forkhead box P3, a master regulator of regulatory T cells. These data suggest that AZA treatment led to complete remission in MDS-associated IBD through suppression of pro-inflammatory cytokine responses.

Autoimmune pancreatitis (AIP) is a chronic fibro-inflammatory disorder of the pancreas. However, extensive clinico-pathological analyses have revealed that AIP is, in reality, a pancreatic manifestation of a newly described systemic disease known as IgG4-related disease (IgG4-RD). IgG4-RD is characterized by enhanced local and systemic IgG4 antibody (Ab) responses as well as inflammation involving multiple organs, including the pancreas, bile ducts, and salivary glands. Although mice lack the IgG4 Ab subtype, autoimmune-prone MRL/Mp mice treated with repeated injection with polyinosinic-polycytidylic acid (poly (I:C)) provide an experimental model of AIP. These mice exhibit massive destruction of pancreatic architecture associated with pancreatic immune cell infiltration and fibrosis. Moreover, this experimental AIP may be accompanied by involvement of multiple organs as well as elevation of serum levels of autoAbs, resembling humans with IgG4-RD. Thus, elucidation of the molecular mechanisms accounting for the development of experimental AIP can potentially provide new insights into the immuno-pathogenesis of human IgG4-related AIP. © 2018 by John Wiley & Sons, Inc.

Cap polyposis is a rare gastrointestinal disease characterized by multiple inflammatory polyps located between the distal colon and the rectum. Despite the lack of clarity regarding its pathogenesis, mucosal prolapse, chronic inflammatory responses, and Helicobacter pylori infection are considered key contributors to the development of this disease entity. Although it is now generally accepted that dysbiosis of gut microbiota is associated with intestinal and extra-intestinal diseases, alterations of intestinal microbiota have been poorly defined in cap polyposis. Here, we report a patient with H. pylori-negative cap polyposis who was successfully treated with antibiotics and exhibited dramatic alterations in intestinal microbiota composition after antibiotic treatment. The patient was treated with oral administration of ampicillin and metronidazole and showed regression of cap polyposis 6 months after antibiotic treatment. Fecal microbiota analysis using the next-generation sequencing technology revealed a significant alteration in the intestinal microbiota composition following antibiotic treatment-a marked reduction of Blautia, Dorea, and Sutterella was observed concomitant with a marked increase in Fusobacterium. These data suggest that cap polyposis may originate from dysbiosis and that microbiome-targeted therapy may be useful in this disorder.

We report a case of successful transluminal drainage of walled-off necrosis (WON) under contrast-enhanced harmonic endoscopic ultrasonography (CH-EUS) guidance. Recently, EUS-guided transluminal drainage (EUS-TD) of WON has been increasingly used as a minimally invasive treatment option with reportedly high technical and clinical success rates; however, B-mode EUS occasionally fails to depict the target lesion and its margins, particularly in cases where the target shows a heterogeneous echogenicity. In our case, EUS-TD was attempted for infected WON, but visualization using B-mode EUS imaging was poor. Thus, CH-EUS was performed to enhance the contrast between the targeted WON and its surrounding tissues. Immediately after injecting a sonographic contrast agent, WON and its margins were clearly identified as an avascular area and were punctured under CH-EUS guidance. CH-EUS enables the assessment of the microvasculature and hemodynamics of the target lesion in real time. It may also provide valuable information and could be a useful modality for EUS-TD to clearly visualize target lesions and their margins and to decisively puncture them, even when they could not be identified using B-mode EUS.

We present a case ofa 67-year-old woman with Stage IV pancreatic head cancer with invasion to the superior mesenteric vein and artery, and distant lymph node metastases. The patient received S-1 mono-chemotherapy. After 2 courses of chemotherapy, the tumor marker was decreased to the normal levels, and the tumor size was dramatically reduced with undetectable lymph node metastases on CT. As the disease status was maintained following chemotherapy, the patient underwent subtotal stomach preserving pancreaticoduodenectomy, 8 months after initiation of the chemotherapy. Histopathologically, no cancer cells were found in the main tumor and dissected lymph nodes. Final diagnosis was made with pathological complete response. The patient was alive without recurrence for 10 months after surgery.

OBJECTIVES: This study evaluated whether quantitative perfusion analysis with contrast-enhanced harmonic (CH) endoscopic ultrasonography (EUS) characterizes pancreatic tumors, and compared the hemodynamic parameters used to diagnose pancreatic carcinoma. METHODS: CH-EUS data from pancreatic tumors of 76 patients were retrospectively analyzed. Time-intensity curves (TIC) were generated to depict changes in signal intensity over time, and 6 parameters were assessed: baseline intensity, peak intensity, time to peak, intensity gain, intensity at 60 s (I60), and reduction rate. These parameters were compared between pancreatic carcinomas (n = 41), inflammatory pseudotumors (n = 14), pancreatic neuroendocrine tumors (n = 14), and other tumors (n = 7). All 6 TIC parameters and subjective analysis for diagnosing pancreatic carcinoma were compared. RESULTS: Values of peak intensity and I60 were significantly lower and time to peak was significantly longer in the groups with pancreatic carcinomas than in the other 3 tumor groups (p < 0.05). Reduction rate was significantly higher in pancreatic carcinomas than in pancreatic neuroendocrine tumors (p < 0.05). Areas under the receiver-operating characteristic curves for the diagnosis of pancreatic carcinoma using subjective analysis, baseline intensity, peak intensity, intensity gain, I60, time to peak, and reduction rate, were 0.817, 0.664, 0.810, 0.751, 0.845, 0.777, and 0.725, respectively. I60 was the most accurate parameter for differentiating pancreatic carcinomas from the other groups, giving values of sensitivity/specificity of 92.7/68.6% when optimal cutoffs were chosen. CONCLUSIONS: In pancreatic carcinomas, TIC patterns were markedly different from the other tumor types, with I60 being the most accurate diagnostic parameter. Quantitative perfusion analysis is useful for differentiating pancreatic carcinomas from other pancreatic tumors.

BACKGROUND: Endoscopic ultrasound (EUS)-guided biliary drainage (BD) is a well-recognized alternative BD method after unsuccessful endoscopic transpapillary drainage. EUS-guided 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.

Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) 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 EUS-FNA 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.

BACKGROUND: Colonoscopic removal of adenomatous polyps or early cancer prevents death from colorectal cancer. Endoscopic submucosal dissection (ESD), which enables endoscopists to perform en bloc resection of flat or depressed colorectal tumors >20 mm, has recently been introduced and become a standard procedure in Japan. Although postoperative bleeding (POB) is a major complication associated with ESD, risk factors for POB have not been fully identified. METHODS: A total of 451 patients (509 lesions) who underwent colorectal ESD were retrospectively analyzed to identify clinical parameters associated with POB. RESULTS: POB occurred in 14 patients, and 7 of them had received antithrombotic therapy before ESD. Uni- and multivariate analyses revealed that antithrombotic therapy and rectal tumor location were strongly associated with POB following colorectal ESD. The incidence of POB was higher in patients on heparin bridge therapy (HBT) for the replacement of antithrombotic therapy than in patients with no HBT. Four of 7 patients (57.1%) on antithrombotic therapy experienced POB from the rectal lesions. CONCLUSION: Antithrombotic therapy and rectal lesions result in a higher POB incidence after colorectal ESD.

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 (CE-CT). 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-signal-intensity 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.

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 high-grade 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 high-grade 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.

INTRODUCTION: Endoscopic submucosal dissection (ESD) has been widely used in the resection of superficial esophageal cancers. Since its use has been extended to cases involving large esophageal tumors occupying nearly the whole or the whole circumference of the lumen, the occurrence of esophageal stricture has increased. Although endoscopic injection of triamcinolone (TA) is widely used for the prevention of postoperative stricture, a significant number of patients still develop stricture after TA injection therapy. METHODS: We performed a retrospective study to identify the clinical parameters that predispose post-ESD patients to esophageal stricture after TA injection therapy. RESULTS: A total of 207 patients who were diagnosed with superficial esophageal cancer and subsequently underwent ESD were enrolled in this study. Among these patients, 53 patients and 57 lesions bearing mucosal defects covering greater than two-thirds of the esophageal circumference after ESD were treated with TA injection therapy. The rate of esophageal stricture was found to be highest in cases involving mucosal defects that covered more than seven-eighths of the circumference. CONCLUSION: Endoscopic TA injection is not sufficient for preventing esophageal stricture in patients bearing mucosal defects covering more than seven-eighths of the esophageal circumference after ESD.

Endoscopic ultrasound-guided pancreatic drainage (EUS-PD) 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.

The prophylactic closure of mucosal defects after endoscopic resection is known to prevent postoperative bleeding in colorectal lesions. However, closure of large mucosal defects is difficult with conventional clips only, and several closure techniques have been previously described; use of an Endoloop, 8-ring loop, or loop clip and a small incision around the mucosal defect. Given that the prophylactic closure requires much cost and time, the application should be limited to high-risk cases. Medication of antithrombotics or antiplatelet agents would be one of the reasonable indications for prophylactic closure of mucosal defects after endoscopic resection of colorectal tumors.

INTRODUCTION: Clarithromycin (CAM)-based triple therapy comprising proton pump inhibitors and amoxicillin is administered as first-line eradication treatment against Helicobacter pylori infection. However, the eradication rate achieved with CAM-based triple therapy has decreased to <80% owing to the emergence of CAM-resistant strains. This prospective randomized study aimed to compare the efficacy of CAM-based and metronidazole (MNZ)-based triple therapy in terms of H. pylori eradication. METHODS: H. pylori-positive patients were treated with CAM-based triple therapy comprising esomeprazole and amoxicillin (EAC group) or with MNZ-based triple therapy comprising esomeprazole and amoxicillin (EAM group). RESULTS: H. pylori eradication rates achieved in the intention-to-treat (ITT) and per protocol (PP) analyses were 70.6 and 72.7%, respectively, in the EAC group. Eradication rates obtained via ITT and PP analyses were 91.7 and 94.3%, respectively, in the EAM group. In the EAC group, eradication rates were significantly lower in patients harboring CAM-resistant strains than in those harboring CAM-sensitive strains. In contrast, eradication rates were comparable between patients harboring CAM-resistant strains and those harboring CAM-sensitive strains in the EAM group. CONCLUSION: MNZ-based triple therapy consisting of esomeprazole and amoxicillin is superior to CAM-based triple therapy containing esomeprazole and amoxicillin as first-line eradication treatment against H. pylori.

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.

BACKGROUND: Although the stem cell marker Bmi1 is overexpressed in many malignancies, its role in inflammation-associated cancer is unclear. Colitis-associated cancer (CAC) is caused by chronic intestinal inflammation and often results from refractory inflammatory bowel disease (IBD). METHODS: To assess the involvement of Bmi1 in the development of CAC, we analyzed the gene expression of colon tissues collected from 111 patients with IBD and CAC. RESULTS: In the colonic mucosa of patients with ulcerative colitis, the expression of Bmi1 correlated significantly with the expression of inflammatory cytokines such as IL-6, IL-17, IL-23, and tumor necrosis factor α (TNF-α). In the colonic mucosa of patients with Crohn's disease, the expression of Bmi1 correlated significantly with the expression of TNF-α and IL-23. The expression of Bmi1 was enhanced in the colonic mucosae of refractory IBD, suggesting that Bmi1 expression might be related to increased cancer risk. In addition, patients with high Bmi1 expression showed significantly lower response rates upon subsequent anti-TNF-α therapy as compared to patients with low Bmi1 expression. In human CAC specimens, the expression of Bmi1 was upregulated in nontumor tissues as well as tumors. CONCLUSIONS: Bmi1 expression is related to a refractory clinical course of IBD and upregulated in refractory IBD and CAC. Measurement of Bmi1 expression is a promising approach for the advanced treatment and personalized management of IBD patients.

Pancreatic tumors are highly diverse, as they can be solid or cystic, and benign or malignant. Since their imaging features overlap considerably, it is often difficult to characterize these tumors. In addition, small pancreatic tumors, especially those less than 2 cm in diameter, are difficult to detect and diagnose. For characterizing pancreatic tumors and detecting small pancreatic tumors, endoscopic ultrasonography (EUS) is the most sensitive of the imaging procedures currently available. This technique also provides good results in terms of the preoperative staging of pancreatic tumors. EUS-guided fine needle aspiration (EUS-FNA) has also proved to be a safe and useful method for tissue sampling of pancreatic tumors. Despite these advantages, however, it is still difficult to differentiate between benign and malignant, solid or cystic pancreatic tumors, malignant neoplasms, and chronic pancreatitis using EUS, even when EUS-FNA is performed. Recently, contrast-enhanced EUS with Doppler mode (CE-EUS) employing ultrasound contrast agents, which indicate vascularization in pancreatic lesions, has been found to be useful in the differential diagnosis of pancreatic tumors, especially small pancreatic tumors. However, Doppler ultrasonography with contrast-enhancement has several limitations, including blooming artifacts, poor spatial resolution, and low sensitivity to slow flow. Consequently, an echoendoscope was developed recently that has a broad-band transducer and an imaging mode that was designed specifically for contrast-enhanced harmonic EUS (CEH-EUS) with a second-generation ultrasound contrast agent. The CEH-EUS technique is expected to improve the differential diagnosis of pancreatic disease in the future. This review describes the EUS appearances of common solid and cystic pancreatic masses, the diagnostic accuracy of EUS-FNA, and the relative efficacies and advantages of CE-EUS and CEH-EUS along with their relative advantages and their complementary roles in clinical practice.

芳香族炭化水素受容体(AhR)は、リガンドで活性化される転写因子で、造血系細胞および非造血系細胞に発現している。本研究では、IFN-αとIL-33を産生する形質細胞様樹状細胞（pDC）の活性化によって引き起こされる実験的自己免疫性膵炎(AIP)の発症をAhR活性化が抑制するかどうかを検討することを試みた。インドール-3-ピルビン酸（IPA）およびインジゴ・ナチュラリス（IN）のAhR活性化は、実験的AIPの発症を抑制することが示された。また、膵島α細胞によるIL-22の産生促進が認められた。さらに、プレドニゾロンにより寛解が得られた後のAIP患者において血清IL-22濃度の上昇がみられた。

Aryl hydrocarbon receptor (AhR)は腸内細菌由来代謝産物や環境因子 (ダイオキシン・タバコの煙など) を認識する転写 因子であり、免疫システムの恒常性の維持に重要な役割を果たしている。「腸内細菌叢の変化に伴う細菌由来代謝産物のProfile変化」がAhRの活性化を介して、自己免疫性膵炎の発症を制御するという仮説を検証した結果、AhRリガンドである2, 3, 7, 8-Tetrachlorodibenzodioxin (TCDD)の投与あるいはIndole-3-pyruvic acid (IPA)の給餌により、自己免疫性膵炎の発症は抑制されることを見出した。

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