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BACKGROUND: Endoscopic ultrasound (EUS)-guided transluminal drainage has become a first-line treatment modality for symptomatic pancreatic pseudocysts. Despite the increasing popularity of lumen-apposing metal stents (LAMSs), plastic stents may resolve non-necrotic fluid collections effectively with lower costs and no LAMS-specific adverse events. To date, there has been a paucity of data on the appropriate stent type in this setting. This trial aims to assess the non-inferiority of plastic stents to a LAMS for the initial EUS-guided drainage of pseudocysts. METHODS: The WONDER-02 trial is a multicentre, open-label, non-inferiority, randomised controlled trial, which will enrol pancreatic pseudocyst patients requiring EUS-guided treatment in 26 centres in Japan. This trial plans to enrol 80 patients who will be randomised at a 1:1 ratio to receive either plastic stents or a LAMS (40 patients per arm). In the plastic stent group, EUS-guided drainage will be performed using two 7-Fr double pigtail stents. In the LAMS group, the treatment will be performed in the same way except for LAMS use. The step-up treatment will be performed via endoscopic and/or percutaneous procedures at the trial investigator's discretion. The primary endpoint is clinical success, which is defined as a decrease in a pseudocyst size to ≤ 2 cm and an improvement in inflammatory indicators (i.e. body temperature, white blood cell count, and serum C-reactive protein). Secondary endpoints include technical success, adverse events including mortality, pseudocyst recurrence, and medical costs. DISCUSSION: The WONDER-02 trial will investigate the efficacy and safety of plastic stents compared to a LAMS in EUS-guided treatment of symptomatic pancreatic pseudocysts with a particular focus on the non-inferior efficacy of plastic stents. The findings will help establish a new treatment algorithm for this population. TRIAL REGISTRATION: ClinicalTrials.gov NCT06133023 registered on 9 November 2023. UMIN000052647 registered on 30 October 2023. jRCT1032230444 registered on 7 November 2023.

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BACKGROUND: Patients with isolated IgG4-related sclerosing cholangitis (IgG4-SC) often undergo unnecessary resection. The aim of this study was to validate the revised Japanese diagnostic criteria for isolated IgG-4-SC and to improve awareness about this condition in the population. METHODS: This was a Japanese retrospective multicenter study. We focused on the data and diagnostic yield obtained using the Japanese diagnostic criteria published initially in 2012 and revised later in 2020 for the diagnosis of isolated IgG4-SC. RESULTS: Patients with isolated IgG4-SC could be classified into two groups based on the primary location of the lesion: the hilar type (n = 40) and the extrahepatic type (n = 13). In total, 10 patients with the hilar type had undergone unnecessary resection. The revised 2020 criteria are useful for the diagnosis of extrahepatic lesions, which are not included in the 2012 criteria. The need for a steroid trial was reduced from 37.7% when the diagnosis was based on the 2012 criteria to 7.6% when the diagnosis was based on the revised 2020 criteria. The diagnostic specificity also improved from 58.5% for the 2012 criteria to 88.7% for the revised 2020 criteria. CONCLUSION: Our validation of the 2020 criteria for the diagnosis of IgG4-SC could contribute to avoiding unnecessary resection in patients with isolated IgG4-SC, which can be classified into the hilar and extrahepatic types. The 2020 criteria can enhance the diagnosis rate of isolated IgG4-SC and uncover this tough-to-diagnose entity based on inclusion of the imaging findings and decrease the dependence on a steroid trial.

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OBJECTIVES: Unresectable ampullary cancer (AC) is a rare disease entity. The risk factors for recurrent biliary obstruction (RBO) following endoscopic biliary stenting (EBS) for unresectable AC remain unknown. In this study we aimed to evaluate the cumulative RBO rate and to identify risk factors for RBO following palliative EBS in patients with unresectable AC. METHODS: This multicenter retrospective observational study enrolled consecutive patients with unresectable AC who had undergone palliative EBS between April 2011 and December 2021. The cumulative rate of and risk factors for RBO following palliative EBS were evaluated via multivariate analysis. RESULTS: The study analysis comprised 107 patients with a median age of 84 years (interquartile range 79-88 years). Plastic stents (PSs) and self-expandable metal stents (SEMSs) were placed in 53 and 54 patients, respectively. Functional success was accomplished in 104 (97.2%) patients. Of these, RBO occurred in 62 (59.6%) patients, with obstruction and complete/partial migration occurring in 47 and 15 patients, respectively. The median time to RBO was 190 days. Multivariate analysis showed that PS was associated with a higher rate of RBO compared to SEMS (hazard ratio [HR] 2.48; P < 0.01) and that the presence of common bile duct stones/sludge immediately after EBS was an independent risk factor for RBO (HR 1.99; P = 0.04). CONCLUSIONS: The use of SEMS compared to PS during EBS reduced the time to RBO in patients with unresectable AC. Common bile duct stones/sludge immediately after EBS was a risk factor for RBO.

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BACKGROUND: Endoscopic retrograde cholangiography (ERC)-related procedures, usually performed before biliary tract cancer (BTC) surgery, are associated with increased risk for various complications, which can cause sarcopenia. No study has previously elucidated the relationship between preoperative ERC-related procedures and sarcopenia/skeletal muscle mass loss. METHODS: Patients with BTC who underwent radical surgical resection following ERC-related procedures were included. Skeletal muscle mass was evaluated using the psoas muscle mass index (PMI), which was determined using computed tomography images, and the change in PMI before the initial pre-ERC and surgery (ΔPMI) was calculated. Risk factors for advanced skeletal muscle mass loss, defined as a large ΔPMI, were evaluated. RESULTS: The study cohort included 90 patients with a median age of 72 (interquartile range, 65-75) years. The median PMI pre-ERC and surgery was 4.40 and 4.15 cm2/m2, respectively (p < .01). The median ΔPMI was -6.2% (interquartile range, -10.9% to 0.5%). By multivariate analysis, post-ERC pancreatitis and cholangitis before surgery were independent predictive factors for large PMI loss (odds ratio, 4.57 and 3.18, respectively; p = .03 and p = .02, respectively). CONCLUSIONS: Skeletal muscle mass decreases preoperatively in most patients with BTC undergoing ERC. Post-ERC pancreatitis and cholangitis before surgery were independent risk factors for large skeletal muscle mass loss.

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Post-ERCP pancreatitis (PEP) is an acute pancreatitis caused by endoscopic-retrograde-cholangiopancreatography (ERCP). About 10% of patients develop PEP after ERCP. Here we show that gamma-glutamyltransferase 1 (GGT1)-SNP rs5751901 is an eQTL in pancreatic cells associated with PEP and a positive regulator of the IL-6 amplifier. More PEP patients had the GGT1 SNP rs5751901 risk allele (C) than that of non-PEP patients at Hokkaido University Hospital. Additionally, GGT1 expression and IL-6 amplifier activation were increased in PEP pancreas samples with the risk allele. A mechanistic analysis showed that IL-6-mediated STAT3 nuclear translocation and STAT3 phosphorylation were suppressed in GGT1-deficient cells. Furthermore, GGT1 directly associated with gp130, the signal-transducer of IL-6. Importantly, GGT1-deficiency suppressed inflammation development in a STAT3/NF-κB-dependent disease model. Thus, the risk allele of GGT1-SNP rs5751901 is involved in the pathogenesis of PEP via IL-6 amplifier activation. Therefore, the GGT1-STAT3 axis in pancreas may be a prognosis marker and therapeutic target for PEP.

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BACKGROUND AND AIMS: We compared ERCP using a balloon-assisted endoscope (BE-ERCP) with EUS-guided antegrade treatment (EUS-AG) for removal of common bile duct (CBD) stones in patients with Roux-en-Y (R-Y) gastrectomy. METHODS: Consecutive patients who had previous R-Y gastrectomy undergoing BE-ERCP or EUS-AG for CBD stones in 16 centers were retrospectively analyzed. RESULTS: BE-ERCP and EUS-AG were performed in 588 and 59 patients, respectively. Baseline characteristics were similar, except for CBD diameter and angle. The technical success rate was 83.7% versus 83.1% (P = .956), complete stone removal rate was 78.1% versus 67.8% (P = .102), and early adverse event rate was 10.2% versus 18.6% (P = .076) in BE-ERCP and EUS-AG, respectively. The mean number of endoscopic sessions was smaller in BE-ERCP (1.5 ± .8 vs 1.9 ± 1.0 sessions, P = .01), whereas the median total treatment time was longer (90 vs 61.5 minutes, P = .001). Among patients with biliary access, the complete stone removal rate was significantly higher in BE-ERCP (93.3% vs 81.6%, P = .009). Negative predictive factors were CBD diameter ≥15 mm (odds ratio [OR], .41) and an angle of CBD <90 degrees (OR, .39) in BE-ERCP and a stone size ≥10 mm (OR, .07) and an angle of CBD <90 degrees (OR, .07) in EUS-AG. The 1-year recurrence rate was 8.3% in both groups. CONCLUSIONS: Effectiveness and safety of BE-ERCP and EUS-AG were comparable in CBD stone removal for patients after R-Y gastrectomy, but complete stone removal after technical success was superior in BE-ERCP.

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BACKGROUND AND AIM: The utility of a passive bending colonoscope (PBCS) in ERCP for patients with surgically altered anatomy has not been established. This study compared the outcome of PBCS-ERCP and balloon-assisted enteroscope (BAE)-ERCP. METHODS: This multicenter observational study included 343 patients with surgically altered anatomy who underwent ERCP. Among these, 110 underwent PBCS-ERCP and 233 underwent BAE-ERCP. Propensity score matching was applied, and a final cohort of 210 (105 in each group) with well-balanced backgrounds was analyzed. The primary outcome was the success rate of reaching anastomosis or ampulla of Vater. Secondary endpoints included the cannulation success rate, completion rate, procedure time (to reach, cannulate, complete), and adverse events. RESULTS: The success rate for reaching the target was 91.4% (96/105) with PBCS and 90.5% (95/105) with BAE (odds ratio [95% CI] 1.12, [0.44-2.89], P = 0.809). The mean time required to reach the target was significantly shorter in PBCS: 10.04 min (SD, 9.62) with PBCS versus 18.77 min (SD, 13.21) with BAE (P < 0.001). There were no differences in the success of cannulation or procedure completion, although the required times for cannulation and procedure completion were significantly shorter in PBCS. The incidence of adverse events was significantly higher in BAE (19.0%) than in PBCS (4.8%; P < 0.001). CONCLUSIONS: In patients with surgically altered anatomy, PBCS-ERCP showed promising results with shorter time to reach, cannulate, and a lower incidence of adverse events compared with BAE-ERCP. The success rate of reaching was favorable through PBCS compared with BAE. CLINICAL TRIAL REGISTRATION: UMIN000045546.

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BACKGROUND: Pancreatic tail cancer (Pt-PC) is generally considered resectable when metastasis is absent, but doubts persist in clinical practice due to the variability in local tumor extent. We conducted a multicenter retrospective study to comprehensively identify prognostic factors associated with Pt-PC after resection. METHODS: We enrolled 100 patients that underwent distal pancreatectomy. The optimal combination of factors influencing relapse-free survival (RFS) was determined using the maximum likelihood method (MLM) and corrected Akaike and Bayesian information criteria (AICc and BIC). Prognostic elements were then validated to predict oncological outcomes. RESULTS: Therapeutic interventions included neoadjuvant treatment in 16 patients and concomitant visceral resection (CVR) in 37 patients; 89 patients achieved R0. Median RFS and OS after surgery were 23.1 and 37.1 months, respectively. AICc/BIC were minimized in the model with ASA-PS (≥2), CA19-9 (≥112 U/mL at baseline, non-normalized postoperatively), need for CVR, 6 pathological items (tumor diameter ≥19.5 mm, histology G1, invasion of the anterior pancreatic border, splenic vein invasion, splenic artery invasion, lymph node metastasis), and completed adjuvant treatment (cAT) for RFS. Regarding the predictive value of these 11 factors, area under the curve was 0.842 for 5-year RFS. Multivariate analysis of these 11 factors showed that predictors of RFS include CVR (hazard ratio, 2.13; 95 % confidence interval, 1.08-4.19; p = 0.028) and cAT (0.38, 0.19-0.76; p = 0.006). CONCLUSIONS: The MLM identified certain Pt-PC cases warranting consideration beyond resectable during clinical management. Particular attention should be paid to conditions requiring CVR, even though immortal time bias remains unresolved with adjuvant treatment.

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The poor prognosis of malignant biliary diseases is partially caused by their difficult early diagnosis. Therefore, many patients are only diagnosed at advanced stages. This study aimed to improve diagnosis by clarifying the differences in the duodenal juice metabolomes of benign and malignant biliary diseases. From October 2021 to January 2023, duodenal juice was obtained from 67 patients with suspected biliary diseases who required endoscopic ultrasonography and endoscopic retrograde cholangiography for diagnosis/treatment. The samples metabolomes were analyzed via nuclear magnet resonance spectroscopy using an 800-MHz spectrometer. Metabolomes of malignant and benign diseases were then compared, and multivariate analysis was performed to determine the relevant factors for malignancy/benignancy. For benignancy, no significant predictors were observed. For malignancy, acetone was a significant predictor, with higher concentrations in the malignant group than in the benign group. Regarding the receiver operating characteristic curve analysis for biliary tract carcinoma diagnosis, the predictive value of acetone in duodenal juice was comparable with serum CA19-9 levels (area under the curve: 0.7330 vs. 0.691, p = 0.697). In conclusion, duodenal juice metabolomics is a feasible method that is available for differential diagnosis in the biliary disease field.

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To overcome the poor prognosis of cholangiocarcinoma (CCA), highly targeted therapies, such as antibody-drug conjugates (ADCs), photodynamic therapy (PDT) with/without systemic chemotherapy, and experimental photoimmunotherapy (PIT), have been developed. Three preclinical trials have investigated the use of ADCs targeting specific antigens, namely HER2, MUC1, and glypican-1 (GPC1), for CCA. Trastuzumab emtansine demonstrated higher antiproliferative activity in CCA cells expressing higher levels of HER2. Similarly, "staphylococcal enterotoxin A-MUC1 antibody" and "anti-GPC1 antibody-monomethyl auristatin F" conjugates showed anticancer activity. PDT is effective in areas where appropriate photosensitizers and light coexist. Its mechanism involves photosensitizer excitation and subsequent reactive oxygen species production in cancer cells upon irradiation. Hematoporphyrin derivatives, temoporfin, phthalocyanine-4, talaporfin, and chlorine e6 derivatives have mainly been used clinically and preclinically in bile duct cancer. Currently, new forms of photosensitizers with nanotechnology and novel irradiation catheters are being developed. PIT is the most novel anti-cancer therapy developed in 2011 that selectively kills targeted cancer cells using a unique photosensitizer called "IR700" conjugated with an antibody specific for cancer cells. PIT is currently in the early stages of development for identifying appropriate CCA cell targets and irradiation devices. Future human and artificial intelligence collaboration has potential for overcoming challenges related to identifying universal CCA cell targets. This could pave the way for highly targeted therapies for CCA, such as ADC, PDT, and PIT.

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BACKGROUND: With the increasing popularity of endoscopic ultrasound (EUS)-guided transmural interventions, walled-off necrosis (WON) of the pancreas is increasingly managed via non-surgical endoscopic interventions. However, there has been an ongoing debate over the appropriate treatment strategy following the initial EUS-guided drainage. Direct endoscopic necrosectomy (DEN) removes intracavity necrotic tissue, potentially facilitating early resolution of the WON, but may associate with a high rate of adverse events. Given the increasing safety of DEN, we hypothesised that immediate DEN following EUS-guided drainage of WON might shorten the time to WON resolution compared to the drainage-oriented step-up approach. METHODS: The WONDER-01 trial is a multicentre, open-label, superiority, randomised controlled trial, which will enrol WON patients aged ≥ 18 years requiring EUS-guided treatment in 23 centres in Japan. This trial plans to enrol 70 patients who will be randomised at a 1:1 ratio to receive either the immediate DEN or drainage-oriented step-up approach (35 patients per arm). In the immediate DEN group, DEN will be initiated during (or within 72 h of) the EUS-guided drainage session. In the step-up approach group, drainage-based step-up treatment with on-demand DEN will be considered after 72-96 h observation. The primary endpoint is time to clinical success, which is defined as a decrease in a WON size to ≤ 3 cm and an improvement of inflammatory markers (i.e. body temperature, white blood cell count, and C-reactive protein). Secondary endpoints include technical success, adverse events including mortality, and recurrence of the WON. DISCUSSION: The WONDER-01 trial will investigate the efficacy and safety of immediate DEN compared to the step-up approach for WON patients receiving EUS-guided treatment. The findings will help us to establish new treatment standards for patients with symptomatic WON. TRIAL REGISTRATION: ClinicalTrials.gov NCT05451901, registered on 11 July 2022. UMIN000048310, registered on 7 July 2022. jRCT1032220055, registered on 1 May 2022.

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ABSTRACT: The shear wave dispersion (SWD) slope has become available in the clinical practice and is related to tissue viscosity. However, clinical evaluation using SWD was not yet performed for obstructive jaundice. We aimed to evaluate the change of SWD values between before and after biliary drainage in patients with obstructive jaundice. This prospective observational cohort study evaluated 20 patients with obstructive jaundice who underwent biliary drainage. The SWD and liver elasticity values were measured before versus after biliary drainage, comparing between days -5 and 0 (day 0), days 1 and 3 (day 2), and days 6 and 8 (day 7). The mean ± SD values of SWD measured at day 0, day 2, and day 7 were 15.3 ± 2.7, 14.2 ± 3.3, and 13.3 ± 2.4 m/s/kHz, respectively. Dispersion slope values were decreased significantly from day 0 to day 2, from day 2 to day 7, and from day 0 to day 7 ( P < 0.05). Liver elasticity levels and serum hepatobiliary enzymes were additionally decreased significantly over time after biliary drainage. The correlations between SWD and liver elasticity values were strong ( r = 0.91, P < 0.01). In conclusion, t he SWD values decreased significantly over time after biliary drainage concomitant with liver elasticity.

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BACKGROUND AND AIMS: The efficacy of the suprapapillary placement of inside plastic stents (iPSs) for unresectable malignant hilar biliary obstructions (MHOs) is unknown compared with that of uncovered inside metal stents (iMSs). This randomized controlled trial was designed to evaluate the outcomes of endoscopic placement of these stents for unresectable MHOs. METHODS: This open-label, randomized study was conducted at 12 Japanese institutions. The enrolled patients with unresectable MHOs were allocated to iPS and iMS groups. The primary outcome was defined as the time to recurrent biliary obstruction in patients for whom the intervention was both technically and clinically successful. RESULTS: Among 87 enrollments, 38 patients in the iPS group and 46 patients in the iMS group were analyzed. Technical success rates were 100% (38 of 38) and 96.6% (44 of 46), respectively (P = 1.00). After transferring 1 unsuccessful iMS-group patient to the iPS group (since iPSs were deployed), the clinical success rates were 90.0% (35 of 39) for the iPS group and 88.9% (40 of 45) for the iMS group from a per-protocol analysis (P = 1.00). Among the patients with clinical success, the median times to recurrent biliary obstruction were 250 (95% confidence interval, 85-415) and 361 (95% confidence interval, 107-615) days (log-rank test, P = .34). No differences were detected in rates of adverse events. CONCLUSIONS: This Phase II randomized trial did not show any statistically significant difference in stent patency between suprapapillary plastic versus metal stents. Considering the potential advantages of plastic stents for malignant hilar obstruction, these findings suggest that suprapapillary plastic stents could be a viable alternative to metal stents for this condition.

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BACKGROUND AND AIM: Recently, dispersion imaging by shear wave elastography has been developed to visualize a tissue viscosity-related factor by measuring the dispersion slope. However, clinical significance of dispersion imaging in the field of pancreatic cancer is unknown. This study aimed to investigate the clinical significance of dispersion imaging in the treatment and diagnosis of pancreatic cancer. METHODS: We measured shear wave dispersion slope (SWD) (m/s/kHz) and shear wave elasticity (SWE) (kPa) in patients with pancreatic ductal adenocarcinoma (PDA). The primary endpoint was the relationship between the changes in SWD and SWE values before and after chemotherapy and the response to chemotherapy. Secondary endpoints included SWD and SWE values in relation to differences between PDA and non-PDA sites and histopathological scores of stroma, inflammation, fibrosis, and necrosis in endoscopic ultrasound-guided fine-needle aspiration specimens. RESULTS: Fifty-six patients were included, 30 of whom underwent chemotherapy. There was no relationship between the changes of SWD and SWE values and chemotherapy responses. In 56 patients, the median SWD value was 12.20 m/s/kHz (interquartile range [IQR]: 10.88-13.61) at PDA sites and 13.57 m/s/kHz (IQR: 12.28-16.20) at non-PDA sites (P = 0.005). The median SWE value was 8.18 kPa (IQR: 7.00-9.74) at PDA sites and 6.14 kPa (IQR: 5.40-6.77) at non-PDA sites (P < 0.001). Histopathological evaluation revealed that inflammation scores were correlated with SWD values (rs  = 0.42, P < 0.001). CONCLUSIONS: Dispersion imaging in pancreatic cancer would be useful for diagnosis and assessing inflammation.

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Poor prognosis of pancreaticobiliary malignancies is attributed to intrinsic biological aggressiveness and the lack of reliable methods for early diagnosis. This study aimed to evaluate the feasibility and availability of pancreatic juice- and bile-derived cell-free DNA (cfDNA) for diagnosing pancreaticobiliary strictures. From October 2020 to February 2022, pancreatic juice or bile was obtained from 50 patients with pancreaticobiliary strictures during endoscopic retrograde cholangiopancreatography. cfDNAs extracted from the samples were analyzed using next-generation sequencing and a cancer gene panel. The obtained cfDNAs, genetic data and clinical information were analyzed for diagnosis. cfDNA concentrations in pancreatic juice were higher in the intraductal papillary mucinous neoplasm group than in the other groups, whereas those in bile were similar in all groups. In pancreatic juice, the sensitivity, specificity and positive and negative predictive values of cfDNA analyses were 33%, 100%, 100% and 71.4%, respectively, whereas those of cytological analyses were 0%, 100%, 0% and 62.5%, respectively. In bile, those of cell-free DNA analyses were 53%, 75%, 89.5% and 28.6%, respectively, whereas those of cytological analyses were 19%, 100%, 100% and 16%, respectively. In conclusion, pancreatic juice- and bile-derived cfDNA is a novel liquid biopsy tool that can diagnose pancreaticobiliary strictures.

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OBJECTIVES: Most previous studies have analyzed bacteria in tumors using resected pancreatic cancer (PC) tissues, because it is difficult to obtain tissue samples from unresectable advanced PC. We aimed to determine whether minimal tissue obtained by endoscopic ultrasound-guided fine-needle aspiration is useful for microbiome analysis. METHODS: Thirty PC and matched duodenal and stomach tissues (N = 90) were prospectively collected from 30 patients who underwent endoscopic ultrasound-guided fine-needle aspiration. Bacterial DNA was extracted, and 16S rRNA sequencing was performed. The primary outcome was the success rate of bacterial detection in tumors. Bacterial diversity and structure were investigated. RESULTS: The bacterial detection rates were 80%, 100%, and 97% in PC, gastric, and duodenal samples, respectively. Pancreatic cancer tissues showed a lower α-diversity and a significantly different microbial structure than stomach and duodenal tissues. Proteobacteria were more abundant, whereas Firmicutes, Bacteroidetes, and Fusobacteria were less abundant in PC tissues than in stomach and duodenal tissues. Acinetobacter was more abundant in PC tissues than in stomach and duodenal tissues, and Delftia was more frequently detected in resectable PC. CONCLUSIONS: Endoscopic ultrasound-guided fine-needle aspiration samples were valuable for PC microbiome analysis, revealing that the bacterial composition of PC is different from that of the stomach and duodenum.

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