Human Gut Microbiota and Its Metabolites Impact Immune Responses in COVID-19 and Its Complications.

BACKGROUND & AIMS: We investigate interrelationships between gut microbes, metabolites, and cytokines that characterize COVID-19 and its complications, and we validate the results with follow-up, the Japanese 4D (Disease, Drug, Diet, Daily Life) microbiome cohort, and non-Japanese data sets. METHODS: We performed shotgun metagenomic sequencing and metabolomics on stools and cytokine measurements on plasma from 112 hospitalized patients with SARS-CoV-2 infection and 112 non-COVID-19 control individuals matched by important confounders. RESULTS: Multiple correlations were found between COVID-19-related microbes (eg, oral microbes and short-chain fatty acid producers) and gut metabolites (eg, branched-chain and aromatic amino acids, short-chain fatty acids, carbohydrates, neurotransmitters, and vitamin B6). Both were also linked to inflammatory cytokine dynamics (eg, interferon γ, interferon λ3, interleukin 6, CXCL-9, and CXCL-10). Such interrelationships were detected highly in severe disease and pneumonia; moderately in the high D-dimer level, kidney dysfunction, and liver dysfunction groups; but rarely in the diarrhea group. We confirmed concordances of altered metabolites (eg, branched-chain amino acids, spermidine, putrescine, and vitamin B6) in COVID-19 with their corresponding microbial functional genes. Results in microbial and metabolomic alterations with severe disease from the cross-sectional data set were partly concordant with those from the follow-up data set. Microbial signatures for COVID-19 were distinct from diabetes, inflammatory bowel disease, and proton-pump inhibitors but overlapping for rheumatoid arthritis. Random forest classifier models using microbiomes can highly predict COVID-19 and severe disease. The microbial signatures for COVID-19 showed moderate concordance between Hong Kong and Japan. CONCLUSIONS: Multiomics analysis revealed multiple gut microbe-metabolite-cytokine interrelationships in COVID-19 and COVID-19related complications but few in gastrointestinal complications, suggesting microbiota-mediated immune responses distinct between the organ sites. Our results underscore the existence of a gut-lung axis in COVID-19.

Long-term outcomes after EUS-guided antegrade intervention for benign bilioenteric anastomotic stricture.

BACKGROUND AND AIMS: Bilioenteric anastomotic stricture (BES) is a well-known adverse event after bilioenterostomy. Recently, EUS-guided antegrade intervention (EUS-AI) has been developed for cases that are difficult to treat by balloon enteroscopy-assisted ERCP. However, no data are available on the long-term outcomes after EUS-AI. The main goal of the present study was to clarify the long-term outcomes of EUS-AI in such patients. METHODS: Between November 2013 and November 2021, 34 patients who were followed for more than 1 year after EUS-AI for BES were identified. The primary endpoint was the rate of stricture resolution. Secondary endpoints were factors associated with stricture resolution, rate of BES recurrence, rate of conversion to surgery, and rate of hepatic fibrosis progression during follow-up. RESULTS: The median follow-up period was 56.7 months. Stricture resolution was achieved in 17 of 34 patients (50%). A multivariate analysis confirmed that the presence of bile duct stones (odds ratio, 9.473; 95% confidence interval, 1.66-53.98; P = .01) was significantly associated with stricture resolution. The stricture recurrence rate was 33%, and the median time from stent removal to recurrence was 31.2 months. Four patients underwent surgery because of recurrent cholangitis. During the median follow-up period of 56.7 months, 25% progressed to hepatic fibrosis based on the Fibrosis-4 index grade. Interestingly, patients without cholangitis during follow-up did not show progression of hepatic fibrosis. CONCLUSIONS: EUS-AI has achieved acceptable long-term clinical outcomes. EUS-AI can be a viable alternative treatment of choice before surgical treatment in patients who are difficult to treat by conventional approaches.

ERCP using balloon-assisted endoscopes versus EUS-guided treatment for common bile duct stones in Roux-en-Y gastrectomy.

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.

Risk of map-like redness development after eradication therapy for Helicobacter pylori infection.

BACKGROUND: Map-like redness is a newly identified endoscopic risk factor for gastric cancer in patients who received Helicobacter pylori eradication therapy. However, the incidence rate of map-like redness in patients who received eradication, and the risk factors for the development of map-like redness remain unclear. We hence aimed to investigate the incidence rate of map-like redness at 1-year post H. pylori eradication, and evaluated its associations with map-like redness and gastric cancer in relation with gastric condition. MATERIALS AND METHODS: Endoscopic severity of gastritis and map-like redness were retrospectively evaluated according to the Kyoto Classification of Gastritis in patients who had undergone endoscopy before and after H. pylori eradication therapy. RESULTS: The incidence rate of map-like redness for all 328 patients at a mean of 1.2 ± 0.6 years after eradication was 25.3% (95% confidence interval [CI]: 20.7%-30.4%). Patients who developed map-like redness were older, had more severe atrophy and intestinal metaplasia, a higher total score of the Kyoto Classification of Gastritis both before and after eradication, and a higher rate of gastric cancer history than patients who did not have map-like redness. On multivariate analysis, risk of map-like redness was increased in patients with intestinal metaplasia (odds ratio [OR]: 2.794, 95% CI: 1.155-6.757) and taking acid inhibitors (OR: 1.948, 95% CI: 1.070-3.547). Characteristics of H. pylori-positive patients with gastric cancer history were patients who were older (OR: 1.033, 95% CI: 1.001-1.066), taking acid inhibitors (OR: 4.456, 95% CI: 2.340-8.484), and with occurrence of map-like redness after eradication therapy (OR: 2.432, 95% CI: 1.264-4.679). CONCLUSIONS: Map-like redness is observed in one fourth of patients at 1-year post eradication. Patients who developed map-like redness were found to have severe intestinal metaplasia and taking acid inhibitors, and hence such patients require increased attention at surveillance endoscopy.

TOKYO criteria 2024 for the assessment of clinical outcomes of endoscopic biliary drainage.

The consensus-based TOKYO criteria were proposed as a standardized reporting system for endoscopic transpapillary biliary drainage. The primary objective was to address issues arising from the inconsistent reporting of stent outcomes across studies, which has complicated the comparability and interpretation of study results. However, the original TOKYO criteria were not readily applicable to recent modalities of endoscopic biliary drainage such as biliary drainage based on endoscopic ultrasound or device-assisted endoscopy. There are increasing opportunities for managing hilar biliary obstruction and benign biliary strictures through endoscopic drainage. Biliary ablation has been introduced to manage benign and malignant biliary strictures. In addition, the prolonged survival times of cancer patients have increased the importance of evaluating overall outcomes during the period requiring endoscopic biliary drainage rather than solely focusing on the patency of the initial stent. Recognizing these unmet needs, a committee has been established within the Japan Gastroenterological Endoscopy Society to revise the TOKYO criteria for current clinical practice. The revised criteria propose not only common reporting items for endoscopic biliary drainage overall, but also items specific to various conditions and interventions. The term "stent-demanding time" has been defined to encompass the entire duration of endoscopic biliary drainage, during which the overall stent-related outcomes are evaluated. The revised TOKYO criteria 2024 are expected to facilitate the design and reporting of clinical studies, providing a goal-oriented approach to the evaluation of endoscopic biliary drainage.

Investigation of the relationship between colonoscopy insertion difficulty factors and endoscope shape using an endoscopic position detection unit.

In this study, we investigated the relationship between the cecal intubation time (CIT) and the form and method used for passing through the sigmoid/descending colon junction (SDJ) and the hepatic flexure using an endoscopic position detection unit (UPD), with reference to various factors [age, sex, body mass index (BMI), history of abdominal and pelvic surgery, and diverticulum]. A total of 152 patients underwent colonoscopy with UPD. The mean age was 66.9 ±â€…12.4 years, and the male to female ratio was 3.6:1. The average CIT time was 14.3 ±â€…8.2 min. Age, number of experienced endoscopies, history of abdominal and pelvic surgery, BMI, and diverticulum were associated with prolonged CIT; SDJ passage pattern was straight: 8.6 ±â€…5.0, alpha loop: 11.8 ±â€…5.6, puzzle ring-like loop: 20.2 ±â€…5.0, reverse alpha loop: 22.4 ±â€…9.7, and other loop: 24.7 ±â€…10.5. The hepatic flexure passing method was in the following order: right rotation maneuver: 12.6 ±â€…6.6, push maneuver: 15.1 ±â€…5.9, and right rotation with positional change maneuver: 20.5 ±â€…7.2. In conclusion, colonoscopy with UPD revealed an association between CIT and SDJ passage pattern and hepatic flexure passing method.

Population-level Metagenomics Uncovers Distinct Effects of Multiple Medications on the Human Gut Microbiome.

BACKGROUND & AIMS: Medication is a major determinant of human gut microbiome structure, and its overuse increases the risks of morbidity and mortality. However, effects of certain commonly prescribed drugs and multiple medications on the gut microbiome are still underinvestigated. METHODS: We performed shotgun metagenomic analysis of fecal samples from 4198 individuals in the Japanese 4D (Disease, Drug, Diet, Daily life) microbiome project. A total of 759 drugs were profiled, and other metadata, such as anthropometrics, lifestyles, diets, physical activities, and diseases, were prospectively collected. Second fecal samples were collected from 243 individuals to assess the effects of drug initiation and discontinuation on the microbiome. RESULTS: We found that numerous drugs across different treatment categories influence the microbiome; more than 70% of the drugs we profiled had not been examined before. Individuals exposed to multiple drugs, polypharmacy, showed distinct gut microbiome structures harboring significantly more abundant upper gastrointestinal species and several nosocomial pathobionts due to additive drug effects. Polypharmacy was also associated with microbial functions, including the reduction of short-chain fatty acid metabolism and increased bacterial stress responses. Even nonantibiotic drugs were significantly correlated with an increased antimicrobial resistance potential through polypharmacy. Notably, a 2-time points dataset revealed the alteration and recovery of the microbiome in response to drug initiation and cessation, corroborating the observed drug-microbe associations in the cross-sectional cohort. CONCLUSION: Our large-scale metagenomics unravels extensive and disruptive impacts of individual and multiple drug exposures on the human gut microbiome, providing a drug-microbe catalog as a basis for a deeper understanding of the role of the microbiome in drug efficacy and toxicity.

Metagenomic Identification of Microbial Signatures Predicting Pancreatic Cancer From a Multinational Study.

BACKGROUND & AIMS: To identify gut and oral metagenomic signatures that accurately predict pancreatic ductal carcinoma (PDAC) and to validate these signatures in independent cohorts. METHODS: We conducted a multinational study and performed shotgun metagenomic analysis of fecal and salivary samples collected from patients with treatment-naïve PDAC and non-PDAC controls in Japan, Spain, and Germany. Taxonomic and functional profiles of the microbiomes were characterized, and metagenomic classifiers to predict PDAC were constructed and validated in external datasets. RESULTS: Comparative metagenomics revealed dysbiosis of both the gut and oral microbiomes and identified 30 gut and 18 oral species significantly associated with PDAC in the Japanese cohort. These microbial signatures achieved high area under the curve values of 0.78 to 0.82. The prediction model trained on the Japanese gut microbiome also had high predictive ability in Spanish and German cohorts, with respective area under the curve values of 0.74 and 0.83, validating its high confidence and versatility for PDAC prediction. Significant enrichments of Streptococcus and Veillonella spp and a depletion of Faecalibacterium prausnitzii were common gut signatures for PDAC in all the 3 cohorts. Prospective follow-up data revealed that patients with certain gut and oral microbial species were at higher risk of PDAC-related mortality. Finally, 58 bacteriophages that could infect microbial species consistently enriched in patients with PDAC across the 3 countries were identified. CONCLUSIONS: Metagenomics targeting the gut and oral microbiomes can provide a powerful source of biomarkers for identifying individuals with PDAC and their prognoses. The identification of shared gut microbial signatures for PDAC in Asian and European cohorts indicates the presence of robust and global gut microbial biomarkers.

A comparative study between computed tomography and endoscopic ultrasound in the detection of a mural nodule in intraductal papillary mucinous neoplasm -Multicenter observational study in Japan.

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.

The usefulness of a newly developed full-core biopsy needle in liver biopsy.

AIM: To evaluate the usefulness and safety of a newly developed full-core biopsy needle. METHODS: We selected 149 patients who underwent percutaneous liver biopsy at our institution from February 2019 to April 2021. We excluded 35 patients with hepatic fibrosis stage F3 or higher, which made it histopathologically difficult to measure the number of complete portal triads. The patients were divided into two groups as follows: 62 cases with the 18-G conventional automated needle (TruCore needle: T needle), and 52 cases with the 18-G full-core needle (CorVocet needle: C needle). We measured the number of complete portal triads in the liver tissue specimens, and the sum of the length and width of the collected tissues. Moreover, we compared the number of session counts, fragmentations, and complications. RESULTS: The sum of the length and the width was 12.8 mm (11.2-14.3) and 15.9 mm (13.1-17.3; p < 0.001), and 0.68 mm (0.63-0.74) and 0.82 mm (0.78-0.90; p < 0.001) for the T needle and C needle, respectively. The number of complete portal triads and fragmentation was six (3-8) and 10 (6-13; p < 0.001), and one (1-10) and one (1-3; p < 0.001), for the T needle and C needle, respectively. There was one session count (1-2) in both groups; however, there were significantly higher cases of two sessions with the T needle than that with the C needle (p = 0.018). There were no serious adverse events. CONCLUSIONS: Compared with the conventional needles, the newly developed full-core needles enabled the acquisition of a larger amount of tissue sample in liver biopsy.

Tumor steatosis and glutamine synthetase expression in patients with advanced hepatocellular carcinoma receiving atezolizumab plus bevacizumab therapy.

AIM: The anti-programmed death-ligand 1 antibody atezolizumab and vascular endothelial growth factor-neutralizing antibody bevacizumab in combination (Atezo + Bev) have become the first-line therapy in advanced hepatocellular carcinoma (HCC). Distinct types of tumor immune microenvironment (TIME) and their associations with specific molecular subclasses and driver gene mutations have been identified in HCC; however, these insights are mainly based on surgically resected early-stage tumors. The current study aimed to reveal the biology and TIME of advanced HCC and their significance in predicting clinical outcomes of Atezo + Bev therapy. METHODS: Thirty-three patients with advanced HCC who were scheduled for treatment with Atezo + Bev therapy were included in this study. Pretreatment tumor biopsy, pre- and posttreatment diffusion-weighted magnetic resonance imaging (MRI) with nine b values (0-1500 s/mm2 ), and other clinicopathologic factors were analyzed. RESULTS: Compared with resectable HCC, advanced HCC was characterized by higher proliferative activity, a higher frequency of Wnt/ß-catenin-activated HCC, and lower lymphocytic infiltration. Prognostically, two metabolism-related factors, histopathologically determined tumor steatosis and/or glutamine synthetase (GS) expression, and MRI-determined tumor steatosis, were the most significant prognostic indicators for progression-free survival (PFS) and overall survival after Atezo + Bev therapy. Furthermore, changes in the pre- and posttreatment true diffusion coefficients on MRI, which might reflect changes in TIME after treatment, were significantly associated with better PFS. CONCLUSIONS: The biology and TIME of HCC were strikingly different in advanced HCC compared with those of surgically resected HCC. Two metabolism-related factors, pathologically determined tumor steatosis and/or GS expression, and MRI-determined tumor steatosis, were found to be the most significant prognostic indicators for Atezo + Bev therapy in advanced HCC.

Underwater endoscopic submucosal dissection for colorectal tumors decreases the incidence of post-electrocoagulation syndrome.

BACKGROUND AND AIMS: Underwater endoscopic submucosal dissection (U-ESD) is a recently developed procedure that has the potential to prevent post-ESD coagulation syndrome (PECS) owing to its heat-sink effect. We aimed to clarify whether U-ESD decreases the incidence of PECS compared with conventional ESD (C-ESD). METHODS: A total of 205 patients who underwent colorectal ESD (C-ESD: 125; U-ESD: 80) were analyzed. Propensity score matching analysis was performed to adjust for patient backgrounds. Ten C-ESD and two U-ESD patients with muscle damage or perforation during ESD were excluded when comparing PECS. The primary outcome was to compare the incidence of PECS between the U-ESD and C-ESD groups (54 matched pairs). Secondary outcomes were to compare procedural outcomes between the C-ESD and U-ESD groups (62 matched pairs). RESULTS: Among the 78 patients who underwent U-ESD, PECS occurred in only one patient (1.3%). Adjusted comparisons between the U-ESD and C-ESD groups demonstrated a significantly lower incidence of PECS in the U-ESD group (0% vs 11.1%; P = 0.027). Median dissection speed was significantly faster in the U-ESD than in the C-ESD group (10.9 mm2 /min vs 6.9 mm2 /min; P < 0.001). En bloc and complete resection rates were 100% in the U-ESD group. Although perforation and delayed bleeding occurred in one patient each (1.6%) as adverse events in the U-ESD group, there were no differences compared with the C-ESD group. CONCLUSIONS: Our study demonstrates that U-ESD effectively decreases the incidence of PECS and is a faster and safer method for colorectal ESD.

Targeted Metabolomic Profiling of Plasma Samples in Gastric Cancer by Liquid Chromatography-Mass Spectrometry.

INTRODUCTION: As the high mortality rate of gastric cancer (GC) is due to delayed diagnosis, early detection is vital for improved patient outcomes. Metabolic deregulation plays an important role in GC. Although various metabolite-level biomarkers for early detection have been assessed, there is still no unified early detection method. We conducted a plasma metabolome study to assess metabolites that may distinguish GC samples from non-GC samples. METHODS: Blood samples were collected from 72 GC patients and 29 control participants (non-GC group) at the Tokyo Medical University Hospital between March 2020 and November 2020. Hydrophilic metabolites were identified and quantified using liquid chromatography-time-of-flight mass spectrometry. Differences in metabolite concentrations between the GC and non-GC groups were evaluated using the Mann-Whitney test. The discrimination ability of each metabolite was evaluated by the area under the receiver operating characteristic curve. A radial basis function (RBF) kernel-based support vector machine (SVM) model was developed to assess the discrimination ability of multiple metabolites. The selection of variables used for the SVM utilized a step-wise regression method. RESULTS: Of the 96 quantified metabolites, 8 were significantly different between the GC and non-GC groups. Of these, N1-acetylspermine, succinate, and histidine were used in the RBF-SVM model to discriminate GC samples from non-GC samples. The area under the curve (AUC) of the RBF-SVM model was higher (0.915; 95% CI: 0.865-0.965, p < 0.0001), indicating good performance of the RBF-SVM model. The application of this RBF-SVM to the validation dataset resulted from the AUC of the RBF-SVM model was (0.885; 95% CI: 0.797-0.973, p < 0.0001), indicating the good performance of the RBF-SVM model. The sensitivity of the RBF-SVM model was better (69.0%) than those of the common tumor markers carcinoembryonic antigen (CEA) (10.5%) and carbohydrate antigen 19-9 (CA19-9) (2.86%). The RBF-SVM showed a low correlation with CEA and CA19-9, indicating its independence. CONCLUSION: We analyzed plasma metabolomics, and a combination of the quantified metabolites showed high sensitivity for the detection of GC. The independence of the RBF-SVM from tumor markers suggested that their complementary use would be helpful for GC screening.

Urgent and emergency endoscopic retrograde cholangiopancreatography for gallstone-induced acute cholangitis and pancreatitis.

Urgent or emergency endoscopic retrograde cholangiopancreatography (ERCP) is indicated for gallstone-induced acute cholangitis and pancreatitis. The technique and optimal timing of ERCP depend on the disease state, its severity, anatomy, patient background, and the institutional situation. Endoscopic transpapillary biliary drainage within 24 h is recommended for moderate to severe acute cholangitis. The clinical outcomes of biliary drainage with nasobiliary drainage tube placement and plastic stent placement are comparable, and the choice is made on a case-by-case basis considering the advantages and disadvantages of each. The addition of endoscopic sphincterotomy (EST) is basically not necessary when performing drainage alone, but single-session stone removal following EST is acceptable in mild to moderate cholangitis cases without antithrombotic therapy or coagulopathy. For gallstone pancreatitis, early ERCP/EST are recommended in cases with impacted gallstones in the papilla. In some cases of gallstone pancreatitis, a gallstone impacted in the papilla has already spontaneously passed into the duodenum, and early ERCP/EST lacks efficacy in such cases, with unfavorable findings of cholangitis or cholestasis. If it is difficult to diagnose the presence of gallstones impacted in the papilla on imaging, endoscopic ultrasonography can be useful in determining the indication for ERCP.

Endoscopic ultrasound-guided balloon-occluded gastrojejunostomy bypass, duodenal stent or laparoscopic gastrojejunostomy for unresectable malignant gastric outlet obstruction.

OBJECTIVES: Malignant gastric outlet obstruction (GOO) can be relieved by either laparoscopic gastrojejunostomy (LGJ), endoscopic stenting (SEMS) or endoscopic ultrasound-guided gastrojejunostomy (endoscopic ultrasound-guided balloon-occluded gastrojejunostomy bypass; EPASS). This study aimed to compare the outcomes of the three treatment methods. METHODS: This was a retrospective study of patients who suffered from malignant GOO between January 2012 to November 2020 that received either EPASS, LGJ or SEMS. The outcomes included the technical and clinical success, 30-day adverse events and mortality, pre and post stenting GOO scores (GOOSs), stent patency and causes of stent dysfunction. RESULTS: One hundred and fourteen patients were included (30 EPASS, 35 LGJ, 49 SEMS). The technical success of EPASS, LGJ and SEMS were 93.3%, 100%, 100% (P = 0.058) and clinical success rates were 93.3%, 80%, 87.8% (P = 0.276), respectively. Procedural time was longest for the LGJ group (P < 0.001). The EPASS group had the shortest hospital stay (EPASS 1.5 [1-17], LGJ 7 [2-44], SEMS 5 [2-46] days, P < 0.001). EPASS group also had the lowest rates of recurrent obstruction (EPASS 3.3%, LGJ 17.1%, SEMS 36.7%, P = 0.002) and re-intervention (EPASS 3.3%, LGJ 17.1%, SEMS 26.5%, P = 0.031). The 1-month GOOS was highest in the EPASS group (EPASS 3 [1-3], LGJ 3 [0-3], SEMS 2 [0-3], P = 0.028). CONCLUSION: Endoscopic ultrasound-guided gastrojejunostomy was associated with better clinical outcomes then the other two procedures. The procedure may be the best option provided that the expertise is available.

Postprocedure serum amylase or lipase levels predict postendoscopic retrograde cholangiopancreatography pancreatitis: Meta-analysis of diagnostic test accuracy studies and utility assessment.

OBJECTIVES: We aimed to clarify the clinical utility of measuring serum pancreatic enzymes after endoscopic retrograde cholangiopancreatography (ERCP) for the purpose of predicting post-ERCP pancreatitis (PEP) by a meta-analysis of diagnostic test accuracy studies. METHODS: Studies on the prediction accuracy of PEP by serum amylase or lipase measured at 2, 3, and 4 h after ERCP were collected. A literature search was performed in PubMed and the Cochrane Library database for studies published between January 1980 and March 2023. The quality of individual studies was evaluated using the Quality Assessment of Diagnostic Accuracy Studies-2. Data were analyzed using Meta-DiSc 2.0 software. RESULTS: We searched the databases and identified 20 observational studies (12,313 participants). PEPs were defined according to criteria by Cotton or modified Cotton, revised Atlanta criteria, or the Japanese criteria. Meta-analysis of eight studies (4389 participants) showed a pooled sensitivity of 71.1% (95% confidence interval [CI] 56.1-82.5) and pooled specificity of 91.2% (95% CI 85.9-94.6) for the serum amylase cut-off value at 3 times the upper limit of normal (ULN). Another meta-analysis of five studies (1970 participants) showed a pooled sensitivity of 85.8% (95% CI 61.9-95.7) and pooled specificity of 85.3% (95% CI 81.9-88.1) for the serum lipase cut-off value at 3 times ULN. CONCLUSION: Despite a high risk of bias due to various reference standards, this updated meta-analysis and the utility assessment by a decision tree showed the utility of serum amylase or lipase levels more than 3 times ULN measured 2-4 h after ERCP for predicting PEP.

Factors associated with long-term efficacy of lubiprostone for chronic constipation.

The prevalence of chronic constipation in Japan is increasing, and is presently almost 1 in 5 people. Because constipation is common, especially in older patients, to avoid adverse events and polypharmacy, simple treatments at low doses are generally desired. Although the chloride channel activator lubiprostone is candidate drug that may solve these problems, factors associated with the long-term efficacy of lubiprostone monotherapy for chronic constipation in treatment-naive patients remain unclear. We here retrospectively investigated the clinical characteristics and factors of patients who achieved long-term constipation improvement with lubiprostone monotherapy. Seventy-four patients with chronic constipation treated with lubiprostone monotherapy (24 or 48 µg/day) from January 2017 to August 2018 were reviewed. Patient characteristics and clinical time-courses were compared between those who sustained improvement for 6 months, and those who became refractory to treatment. In 54 patients (76.1%), constipation improved by lubiprostone administration for 6 months. On multivariate analysis, a significant clinical factor associated with sustained improvement was a starting lubiprostone dose of 24 µg/day (odds ratio: 5.791; 95% confidence interval: 1.032-32.498; p = 0.046). A starting lubiprostone dose of 24 µg/day has efficacy to improve chronic constipation and to prevent adverse events of nausea and diarrhea in Japanese patients.

Circulating cancer-associated extracellular vesicles as early detection and recurrence biomarkers for pancreatic cancer.

Early detection of pancreatic ductal adenocarcinoma (PDAC) is essential for improving patient survival rates, and noninvasive biomarkers are urgently required to identify patients who are eligible for curative surgery. Here, we examined extracellular vesicles (EVs) from the serum of PDAC patients to determine their ability to detect early-stage disease. EV-associated proteins purified by ultracentrifugation and affinity columns underwent proteomic analysis to identify novel PDAC markers G protein-coupled receptor class C group 5 member C (GPRC5C) and epidermal growth factor receptor pathway substrate 8 (EPS8). To verify the potency of GPRC5C- or EPS8-positive EVs as PDAC biomarkers, we analyzed EVs from PDAC patient blood samples using ultracentrifugation in two different cohorts (a total of 54 PDAC patients, 32 healthy donors, and 22 pancreatitis patients) by immunoblotting. The combination of EV-associated GPRC5C and EPS8 had high accuracy, with area under the curve values of 0.922 and 0.946 for distinguishing early-stage PDAC patients from healthy controls in the two cohorts, respectively, and could detect PDAC patients who were negative for CA19-9. Moreover, we analyzed 30 samples taken at three time points from 10 PDAC patients who underwent surgery: before surgery, after surgery, and recurrence as an early-stage model. These proteins were detected in EVs derived from preoperative and recurrence samples. These results indicated that GPRC5C- or EPS8-positive EVs were biomarkers that have the potential to detect stage I early pancreatic cancer and small recurrent tumors detected by computed tomography.

Risk of Pancreatitis Following Biliary Stenting With/Without Endoscopic Sphincterotomy: A Randomized Controlled Trial.

BACKGROUND & AIMS: The efficacy of endoscopic sphincterotomy (ES) before endoscopic transpapillary biliary drainage in preventing post-endoscopic retrograde cholangiopancreatography pancreatitis (PEP) has not been established. The aim of this study was to evaluate the effect of performing ES before biliary stent/tube placement on the occurrence of PEP. METHODS: Three hundred seventy patients with biliary stricture requiring endoscopic biliary stenting were enrolled and randomly allocated to the ES group (n = 185) or non-ES group (n = 185). All participants were followed up for 30 days after the procedure. The data and occurrence of adverse events were prospectively collected. The primary outcome measure of this study was the incidence of PEP within 2 days of initial transpapillary biliary drainage. Secondary outcome measures were the incidence of other adverse events related to biliary stent/tube placement. RESULTS: PEP occurred in 36 patients (20.6%) in the non-ES group and in 7 patients (3.9%) in the ES group (P < .001). The difference in the incidence of PEP between the 2 groups in the per-protocol population was 16.7% (95% confidence interval, 10.1%-23.3%), which was not within the noninferiority margin of 6%. Except for bleeding, the incidences of other adverse events were not significantly different between the groups. CONCLUSION: ES before endoscopic biliary stenting could have the preventive effect on the occurrence of PEP in patients with biliary stricture. University Hospital Medical Information Network Number, UMIN000025727.University Hospital Medical Information Network Clinical Trial Registry URL: https://www.umin.ac.jp/ctr/index.htm.

Endoscopic Ultrasound-guided Fine-needle Biopsy With or Without Rapid On-site Evaluation for Diagnosis of Solid Pancreatic Lesions: A Randomized Controlled Non-Inferiority Trial.

BACKGROUND AND AIMS: The benefit of rapid on-site evaluation (ROSE) on the diagnostic accuracy of endoscopic ultrasound-guided fine-needle biopsy (EUS-FNB) has never been evaluated in a randomized study. This trial aimed to test the hypothesis that in solid pancreatic lesions (SPLs), diagnostic accuracy of EUS-FNB without ROSE was not inferior to that of EUS-FNB with ROSE. METHODS: A noninferiority study (noninferiority margin, 5%) was conducted at 14 centers in 8 countries. Patients with SPLs requiring tissue sampling were randomly assigned (1:1) to undergo EUS-FNB with or without ROSE using new-generation FNB needles. The touch-imprint cytology technique was used to perform ROSE. The primary endpoint was diagnostic accuracy, and secondary endpoints were safety, tissue core procurement, specimen quality, and sampling procedural time. RESULTS: Eight hundred patients were randomized over an 18-month period, and 771 were analyzed (385 with ROSE and 386 without). Comparable diagnostic accuracies were obtained in both arms (96.4% with ROSE and 97.4% without ROSE, P = .396). Noninferiority of EUS-FNB without ROSE was confirmed with an absolute risk difference of 1.0% (1-sided 90% confidence interval, -1.1% to 3.1%; noninferiority P < .001). Safety and sample quality of histologic specimens were similar in both groups. A significantly higher tissue core rate was obtained by EUS-FNB without ROSE (70.7% vs. 78.0%, P = .021), with a significantly shorter mean sampling procedural time (17.9 ± 8.8 vs 11.7 ± 6.0 minutes, P < .0001). CONCLUSIONS: EUS-FNB demonstrated high diagnostic accuracy in evaluating SPLs independently on execution of ROSE. When new-generation FNB needles are used, ROSE should not be routinely recommended. (ClinicalTrial.gov number NCT03322592.).