Adverse events of self-expandable metal stent placement for malignant distal biliary obstruction: a large multicenter study.

BACKGROUND AND AIMS: Endoscopic placement of self-expandable metal stents (SEMSs) for malignant distal biliary obstruction (MDBO) may be accompanied by several types of adverse events. The present study analyzed the adverse events occurring after SEMS placement for MDBO. METHODS: The present study retrospectively investigated the incidence and types of adverse events in patients who underwent SEMS placement for MDBO between April 2018 and March 2021 at 26 hospitals. Risk factors for acute pancreatitis, cholecystitis, and recurrent biliary obstruction (RBO) were evaluated by univariate and multivariate analyses. RESULTS: Of the 1425 patients implanted with SEMSs for MDBO, 228 (16.0%) and 393 (27.6%) experienced early adverse events and RBO, respectively. Pancreatic duct without tumor involvement (P = .023), intact papilla (P = .025), and SEMS placement across the papilla (P = .037) were independent risk factors for acute pancreatitis. Tumor involvement in the orifice of the cystic duct was an independent risk factor for cholecystitis (P < .001). Use of fully and partially covered SEMSs was an independent risk factor for food impaction and/or sludge. Use of fully covered SEMSs was an independent risk factor for stent migration. Use of uncovered SEMSs and laser-cut SEMSs was an independent risk factor for tumor ingrowth. CONCLUSIONS: Pancreatic duct without tumor involvement, intact papilla, and SEMS placement across the papilla were independent risk factors for acute pancreatitis, and tumor involvement in the orifice of the cystic duct was an independent risk factor for cholecystitis. The risk factors for food impaction and/or sludge, stent migration, and tumor ingrowth differed among types of SEMSs.

Low-power pure-cut hot snare polypectomy for colorectal polyps 10-14 mm in size: a multicenter retrospective study.

BACKGROUND AND AIM: Hot snare excision using electrocautery is widely used for large colorectal polyps (>10 mm); however, adverse events occur due to deep thermal injury. Colorectal polyps measuring 10-14 mm rarely include invasive cancer. Therefore, less invasive therapeutic options for this size category are demanding. We have developed hot snare polypectomy with low-power pure-cut current (LPPC HSP), which is expected to contribute to less deep thermal damage and lower risk of adverse events. This study aimed to evaluate the efficacy and safety of LPPC HSP for 10-14 mm colorectal polyps, compared with conventional endoscopic mucosal resection (EMR). METHODS: In this multicenter, retrospective, observational study, clinical outcomes of EMR and LPPC HSP for 10-14 mm nonpedunculated colorectal polyps between January 2021 and March 2022 were compared using propensity score matching. RESULTS: We identified 203 EMR and 208 LPPC HSP cases. After propensity score matching, the baseline characteristics between the groups were comparable, with 120 pairs. The en bloc and R0 resection rates were not significantly different between EMR and LPPC HSP groups (95.8% vs 97.5%, P = 0.72; 90.0% vs 91.7%, P = 0.82). The rates of delayed bleeding and perforation did not differ between the groups. CONCLUSIONS: Compared with conventional EMR, LPPC HSP showed a similar resection ability without an increase in adverse events. These results suggest that LPPC HSP is a safe and effective treatment for 10-14 mm nonpedunculated colorectal polyps.

Altered gut microbiota in patients with small intestinal bacterial overgrowth.

BACKGROUND AND AIM: Small intestinal bacterial overgrowth (SIBO) is diagnosed by using quantitative culture of duodenal aspirates and/or a hydrogen breath test. However, few studies have analyzed bacterial microbiota in Japanese patients with SIBO. METHODS: Twenty-four patients with any abdominal symptoms and suspected SIBO were enrolled. Quantitative culture of duodenal aspirates and a glucose hydrogen breath test were performed on the same day. SIBO was diagnosed based on a bacterial count ≥ 103  CFU/mL or a rise in the hydrogen breath level of ≥ 20 ppm. The composition of the duodenal microbiota was analyzed by 16S rRNA gene sequencing. RESULTS: Small intestinal bacterial overgrowth was diagnosed in 17 of the 24 patients (71%). The positive rates for the hydrogen breath test and quantitative culture of duodenal aspirates were 50% and 62%, respectively. Patients with SIBO showed significantly reduced α-diversity compared with non-SIBO patients, and analysis of ß-diversity revealed significantly different distributions between SIBO and non-SIBO patients. In addition, the intestinal microbiome in SIBO patients was characterized by increased relative abundance of Streptococcus and decreased relative abundance of Bacteroides compared with non-SIBO patients. CONCLUSIONS: Duodenal dysbiosis was identified in patients with SIBO and may play a role in the pathophysiology of SIBO.

Gastrojejunostomy versus endoscopic duodenal stent placement for gastric outlet obstruction in patients with unresectable pancreatic cancer: a propensity score-matched analysis.

BACKGROUND: Treatments for patients with gastric outlet obstruction (GOO) due to unresectable pancreatic cancers (URPC) include gastrojejunostomy (GJJ) and endoscopic duodenal stent placement (EDSP). This study compared the efficacy and safety of GJJ and EDSP in patients with GOO due to URPC. METHODS: This study retrospectively evaluated consecutive patients with GOO due to URPC who underwent GJJ or EDSP between April 2016 and March 2020. The efficacy and safety of GJJ and EDSP were compared with propensity score analysis. Subgroup analyses of overall survival (OS) were compared after propensity matching. RESULTS: Data were obtained from 54 patients who underwent GJJ and from 73 who underwent EDSP at five tertiary care hospitals. After propensity matching, OS was significantly longer in patients who underwent GJJ than EDSP (110 vs. 63 days, respectively; p = 0.019). Evaluation of long-term adverse events showed that the frequency of cholangitis and obstructive jaundice was significantly lower in the matched GJJ than in the matched EDSP group (p = 0.012). Subgroup analyses showed that OS in patients with good performance status (PS; p = 0.041), biliary obstruction (p = 0.007), and duodenal obstruction near the papilla (p = 0.027), and those receiving chemotherapy (p = 0.010), was significantly longer in the matched GJJ group than in matched EDSP group. CONCLUSION: GJJ provides longer OS than EDSP for patients with GOO caused by URPC, especially for patients with good PS, biliary obstruction, and duodenal obstruction near the papilla, and those receiving chemotherapy.

Clinical Outcomes of Inside Stents and Conventional Plastic Stents as Bridge-to-Surgery Options for Malignant Hilar Biliary Obstruction.

BACKGROUND: The appropriate method of preoperative endoscopic biliary drainage (EBD) for cholangiocarcinoma with hilar biliary obstruction remains controversial. The inside-stent technique is a method of placing plastic stents entirely inside the bile duct. Several studies of patients with unresectable stage have reported longer stent patency compared with conventional endoscopic biliary stenting (EBS). Inside-stent techniques have been introduced as a bridge-to-surgery option and as an alternative to conventional EBS. AIMS: We aimed to evaluate the clinical outcomes of inside stent use and conventional EBS. METHODS: During this retrospective multicenter study, we reviewed consecutive patients with cholangiocarcinoma who underwent radical surgery after conventional EBS or inside-stent insertion. Adverse event (AE) rates after EBD and post-surgical AEs were compared. A multivariable analysis was performed to identify factors affecting cholangitis after EBD. RESULTS: Conventional EBS and inside-stent procedures were performed for 56 and 73 patients, respectively. Patient backgrounds were similar between groups, except for percutaneous transhepatic portal vein embolization. The waiting time before surgery was similar between groups (28.5 days vs. 30 days). There were no significant differences in the cholangitis rate (21.4% vs. 26.0%; P = 0.68) and all AEs (25.0% vs. 30.1%; P = 0.56) between groups. The post-surgical AE rate was similar between the groups. The multivariable analysis found that preprocedural cholangitis was a risk factor for cholangitis after EBD (odds ratio: 5.67; 95% confidence interval: 1.61-19.9). CONCLUSIONS: The outcomes of inside-stent techniques and conventional EBS for the management of preoperative EBD are comparable for patients with cholangiocarcinoma.

Single-Nucleotide Polymorphisms, c.415C > T (Arg139Cys) and c.416G > A (Arg139His), in the NUDT15 Gene Are Associated with Thiopurine-Induced Leukopenia.

While nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) gene polymorphism Arg139Cys (rs116855232) is known to be a risk factor for thiopurine-induced severe leukopenia, association with the NUDT15 gene polymorphism Arg139His (rs147390019) has not yet been clarified. In addition, the accuracy of TaqMan PCR to assess these two polymorphisms has not been investigated. In this study, we evaluated TaqMan PCR for detection of the NUDT15 single-nucleotide polymorphisms (SNPs) and examined the clinical impact of Arg139His on thiopurine-induced leukopenia. First, we demonstrated that a TaqMan PCR assay successfully detected the Arg139His polymorphism of NUDT15 in clinical samples. Next, the NUDT15 gene polymorphisms (Arg139Cys and Arg139His) were separately analyzed by TaqMan Real-Time PCR in 189 patients from August 2018 to July 2019. The incidences of leukopenia within 2 years were 16.2, 57.9, and 100% for arginine (Arg)/Arg, Arg/cysteine (Cys), and Arg/histidine (His), respectively. The leukopenia was significantly increased in Arg/Cys and Arg/His compared with Arg/Arg. This retrospective clinical study indicated that, in addition to Arg139Cys, Arg139His may be clinically associated with a high risk of leukopenia. Pharmacogenomics will help in selecting drugs and determining the individualized dosage of thiopurine drugs.

Endoscopic nasobiliary drainage versus endoscopic biliary stenting for preoperative biliary drainage in patients with malignant hilar biliary obstruction: Propensity score-matched multicenter comparative study.

OBJECTIVES: For preoperative biliary drainage (PBD) of malignant hilar biliary obstruction (MHBO), current guidelines recommend endoscopic nasobiliary drainage (ENBD) due to the higher risk of cholangitis after endoscopic biliary stenting (EBS) during the waiting period before surgery. However, few studies have supported this finding. Therefore, we aimed to compare the outcomes of preoperative ENBD and EBS in patients with MHBO. METHODS: Patients with MHBO who underwent laparotomy for radical surgery after ENBD or EBS were included from retrospectively collected data from 13 centers (January 2014 to December 2018). We performed a 1:1 propensity score matching between the ENBD and EBS groups. These patients were compared for the following: cholangitis and all adverse events (AEs) after endoscopic biliary drainage (EBD) until surgery, time to cholangitis development after EBD, postsurgical AEs, and in-hospital death after surgery. RESULTS: Of the 414 patients identified, 355 were analyzed in this study (226 for ENBD and 129 for EBS). The matched cohort included 63 patients from each group. The proportion of cholangitis after EBD was similar between the two groups (20.6% vs. 25.4%, P = 0.67), and no significant difference was observed in the time to cholangitis development. The proportions of surgical site infections, bile leaks, and in-hospital mortality rates were similar between the groups. CONCLUSION: For PBD of MHBO, the proportion of AEs, including cholangitis, after EBD until surgery was similar when either ENBD or EBS was used.

Comparison of 22-gauge standard and Franseen needles in EUS-guided tissue acquisition for diagnosing solid pancreatic lesions: a multicenter randomized controlled trial.

BACKGROUND AND AIMS: This large multicenter randomized controlled trial compared the diagnostic yields of 22-gauge standard and 22-gauge Franseen needles for EUS-guided tissue acquisition (EUS-TA) of solid pancreatic lesions. METHODS: Consecutive patients with solid pancreatic lesions were prospectively randomized to EUS-TA using standard or Franseen needles. Samples obtained with the first needle pass and with second and subsequent passes were evaluated separately. The primary endpoint was the rate of accuracy for diagnosis of malignancy. Other endpoints were technical success rate, sample cellularity, adverse events, diagnostic accuracy in patient subgroups, and the diagnostic accuracy and numbers of second and subsequent needle passes. RESULTS: Of 523 patients undergoing EUS-TA, 260 were randomized to using standard 22-gauge needles and 263 to 22-gauge Franseen needles. The technical success rate in each group was 99.6%, with similar adverse event rates in the standard (1.5%) and Franseen (.8%) needle groups. First-pass EUS-TA using the Franseen needle resulted in significantly greater diagnostic accuracy (84.0% vs 71.2%, P < .001) and sensitivity (82.4% vs 66.7%, P < .001) than first-pass EUS-TA using a standard needle and also resulted in superior diagnostic accuracy in patients requiring immunostaining. Second and subsequent EUS-TA using Franseen needles showed significantly greater accuracy (94.7% vs 90.0%, P = .049) and sensitivity (94.0% vs 88.6%, P = .047) and required fewer needle passes (1.81 vs 2.03, P = .008) than using standard needles. CONCLUSIONS: EUS-TA with the Franseen needle is superior to EUS-TA with a standard needle with respect to diagnostic accuracy per pass, particularly in patients who require immunostaining, and number of passes when using macroscopic on-site evaluation. (Clinical trial registration numbers: UMIN000030634 and jRCTs052180062.).

Ustekinumab trough levels predicting laboratory and endoscopic remission in patients with Crohn's disease.

BACKGROUNDS: Optimal concentration of ustekinumab (UST) predicting endoscopic remission has not been fully investigated in Crohn's disease (CD). We aimed to identify the optimal UST trough levels predicting clinical, laboratory and endoscopic remission in CD patients. METHODS: Twenty-eight patients with CD were enrolled and investigated (27 patients by enteroscopy and 1 by colonoscopy). The endoscopic activity was assessed using the scoring system that applied the Rutgeerts score to observed intestine. Serum UST trough levels and anti-UST antibodies (AUAs) levels were determined by in-house immunoassays. RESULTS: Endoscopic activity was negatively correlated with serum UST trough levels (Spearman's rank correlation coefficient (ρ) = - 0.66, P = 0.0001) and serum albumin levels (ρ = - 0.60, P = 0.0007). The endoscopic activity was positively and significantly correlated with CRP (ρ = 0.59, P = 0.0009) and ESR (ρ = 0.44, P = 0.033). There was no significant association between the endoscopic score and AUA levels and/or Crohn's disease activity index (CDAI). Serum UST trough levels and albumin levels were significantly higher in the endoscopic remission group (scores of 0 and 1) than in the non-endoscopic remission group (UST trough, mean 3.3 vs. 1.8 µg/mL). No significant difference was observed in AUAs between the endoscopic remission and non-remission groups. Receiver operation curve (ROC) analysis revealed that the optimal cutoff value of UST trough levels predicting normal CRP and serum albumin levels was 1.7 µg/mL for each, and the optimal cutoff value predicting endoscopic remission was 2.0 µg/mL (AUC: 0.80, 95% CI 0.64-0.96). CONCLUSION: Achievement of endoscopic remission requires higher UST trough levels than required for normalization of CRP and serum albumin levels.

Effect of ice water injection toward the duodenal papilla for preventing post-ERCP pancreatitis: study protocol for a multicenter, single-blinded, randomized controlled trial (EUTOPIA study).

BACKGROUND: Endoscopic retrograde cholangiopancreatography (ERCP) is an essential procedure in the diagnosis and treatment of biliopancreatic diseases. The most common adverse event of ERCP is post-ERCP pancreatitis (PEP), which can sometimes be severe. Our previous study suggested that injecting ice water at the end of ERCP suppressed PEP, and we decided to investigate this effect in a multicenter randomized controlled trial. METHODS: This study is being conducted at eight hospitals in Japan starting in April 2022. Patients undergoing ERCP will be randomized to ice water group and control group. In the ice water group, 250 ml of ice water is injected toward the papilla at the end of ERCP. The next morning, a physical examination and blood tests are performed to evaluate for the development of pancreatitis. The goal is to have 440 cases in each group. DISCUSSION: The main cause of PEP is thought to be papilla edema. Cooling the papilla, as everyone naturally does at the time of a burn, is expected to prevent its inflammation and edema. Various methods to suppress PEP have been reported, but so far none of them are reliable. The method we have devised is very simple, easy, and safe. We hope that our study will change the world's ERCP common practice. TRIAL REGISTRATION: UMIN000047528. Registered 20 April 2022, https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000053209.

Low immunogenicity of vedolizumab determined by a simple drug-tolerant assay in patients with ulcerative colitis.

Vedolizumab is a humanized monoclonal antibody against the α4ß7 integrin and is approved for treatment of inflammatory bowel diseases. In this study, we evaluated the immunogenicity of vedolizumab using a simple drug-tolerant assay developed in our laboratory. Serum vedolizumab trough levels and anti-vedolizumab antibody (AVA) levels were measured using new immunoassays in 37 patients with ulcerative colitis (UC) under vedolizumab maintenance therapy. The median vedolizumab trough level at week 30 was 16.0 µg/ml (interquartile range, 7.3-24.4). The vedolizumab trough level of the patients with clinical remission (partial Mayo score ≤1) was significantly higher than that of clinically active patients (16.7 µg/ml vs 6.8). The cut-off value of vedolizumab level predicting clinical remission at week 30 was 7.34 µg/ml. The median AVA level of patients under vedolizumab maintenance therapy was similar to that of healthy controls (n = 20) (0.032 µg/ml-c vs 0.022). One of 37 patients (2.7%) was judged to be AVA positive. There was no significant difference in serum AVA and vedolizumab trough levels between biologics-naïve (n = 19) and biologics-switched (prior anti-TNFα-exposed) patients (n = 18). In conclusion, the simple drug-tolerant assay developed in our laboratory demonstrated low immuno-genicity of vedolizumab. Prior use of anti-TNFα drugs did not affect the immunogenicity of vedolizumab.

The anti-inflammatory and protective role of interleukin-38 in inflammatory bowel disease.

Interleukin (IL)-38 exerts an anti-inflammatory function by binding to several cytokine receptors, including the IL-36 receptor. In this study, we evaluated IL-38 expression in the inflamed mucosa of patients with inflammatory bowel disease (IBD) and investigated its functions. IL-38 mRNA expression in endoscopic biopsy samples was evaluated using quantitative PCR. IL-38 protein expression was analyzed using immunohistochemical technique. Dextran sulfate sodium-induced colitis was induced in C57BL/6 background IL-38KO mice. The IL-38 mRNA and protein expression were enhanced in the active mucosa of ulcerative colitis, but not in Crohn's disease. The ratio of IL-36γ to IL-38 mRNA expression was significantly elevated in the active mucosa of UC patients. Immunofluorescence staining revealed that B cells are the major cellular source of IL-38 in the colonic mucosa. IL-38 dose-dependently suppressed the IL-36γ-induced mRNA expression of CXC chemokines (CXCL1, CXCL2, and CXCL8) in HT-29 and T84 cells. IL-38 inhibited the IL-36γ-induced activation of nuclear-factor kappa B (NF-κB) and mitogen-activated protein kinases in HT-29 cells. DSS-colitis was significantly exacerbated in IL-38KO mice compared to wild type mice. In conclusion, IL-38 may play an anti-inflammatory and protective role in the pathophysiology of IBD, in particular ulcerative colitis, through the suppression of IL-36-induced inflammatory responses.

[A case of obstructive jaundice due to the movement of pancreatic calculi].

A 44-year-old man with a history of chronic alcoholic pancreatitis and Crohn's disease presented with abdominal pain. Computed tomography revealed pancreatic calculi in the head of the pancreas and a dilated pancreatic duct. The patient was diagnosed with an acute exacerbation of chronic pancreatitis due to the impact of pancreatic calculi on the main pancreatic duct. During the clinical course, the movement of pancreatic calculi to the major papilla was confirmed, leading to obstructive jaundice. Endoscopic treatment with sphincterotomy of the pancreatic duct was successful. Herein, we report the case of an unusual clinical course involving obstructive jaundice caused by the movement of pancreatic calculi.

Utility and safety of a new uneven double-lumen sphincterotome in cases of difficult biliary cannulation.

BACKGROUND: We investigated the utility and safety of a new uneven double-lumen sphincterotome in biliary cannulation in comparison with the conventional pancreatic guidewire (PGW) method. METHODS: We retrospectively evaluated 119 patients who required PGW placement because of difficult biliary cannulation. Endoscopic retrograde cholangiopancreatography (ERCP) was performed using a conventional ERCP catheter or a new uneven double-lumen sphincterotome. The success rate of bile duct cannulation, the operation time of bile duct cannulation, and the incidence of post-ERCP pancreatitis (PEP) were evaluated. RESULTS: Forty-four patients were treated with a new double-lumen sphincterotome (the new sphincterotome group) and 75 patients underwent conventional PGW placement (the conventional group). The success rate of bile duct cannulation was 39/44 (88.6%) in the new sphincterotome group and 63/75 (84.0%) in the conventional group (not significant). The total biliary cannulation time (from the reach to the papilla to the finish of biliary cannulation) was 16.0 (6.5-78) min in the new sphincterotome group and 26.0 (5-80) min in the conventional group (P < 0.01). The time from PGW placement to bile duct cannulation was 3.5 (0.3-57) min in the magictome group and 12.0 (1-65) min in the conventional group (P < 0.01). Hyperamylasemia was observed in 13/44 (29.5%) and 17/75 (22.7%), respectively (not significant). Five of 44 (11.3%) of the new sphincterotome group and 14/75 (18.7%) of the conventional group were diagnosed with PEP (not significant). CONCLUSION: A new double-lumen sphincterotome allows selective bile duct cannulation to be performed in a shorter time than the conventional PGW method.

Vonoprazan vs lansoprazole for the treatment of artificial gastric ulcer after endoscopic submucosal dissection: a prospective randomized comparative study.

Vonoprazan is a potent inhibitor of gastric acid secretion and may have better response than proton pump inhibitors (PPIs) in the treatment of endoscopic submucosal dissection induced artificial ulcers. However, reported outcomes remain controversial. In this study, we conducted a prospective, randomized comparative trial to evaluate healing effects of vonoprazan and lansoprazole on endoscopic submucosal dissection (ESD)-induced ulcers. We enrolled 216 patients who underwent endoscopic submucosal dissection for early gastric neoplasms. They were randomly divided into vonoprazan (20 mg/day) and lansoprazole (30 mg/day) groups. The primary endpoint was the reduction rate of ulcer and complete healing (scar) ratio of ESD-induced ulcers at 4 and 8 weeks. Finally, 101 patients of the vonoprazan group and 95 patients of the lansoprazole group were included in the analysis. There were no significant differences in the reduction rate between the vonoprazan and lansoprazole groups at either timepoint (4 weeks, 94.0 vs 93.4%; 8 weeks, 99.8 vs 99.9%, respectively). The complete healing ratio at 4 and 8 weeks did not differ significantly between the vonoprazan and lansoprazole groups (4 weeks, 11.9 vs 12.6%; 8 weeks, 87.1 vs 86.3%, respectively). In the anti-H. pylori-antibody negative or positive patients, there were no significant differences in the reduction rate and complete healing ratio between the vonoprazan and lansoprazole groups. Regardless of treatment choice, the overall complete healing ratio at 8 weeks was significantly higher in the anti-H. pylori-antibody negative patients than the positive patients (p = 0.006). The healing effects of vonoprazan on ESD-induced ulcers were comparative to those of lansoprazole.

Targeted deletion of Atg5 in intestinal epithelial cells promotes dextran sodium sulfate-induced colitis.

Autophagy-associated genes have been identified as susceptible loci for inflammatory bowel disease. We investigated the role of a core autophagy factor, Atg5, in the development of dextran sodium sulfate (DSS)-induced colitis. Intestinal epithelial cell (IEC)-specific Atg5 gene deficient mice (Atg5 ΔIEC mice) were generated by cross of Atg5-floxed mice (Atg5 fl/fl ) with transgenic mice expressing Cre-recombinase driven by the villin promotor. Mice were given three cycles of 1.5% DSS in drinking water for 5 days and regular water for 14 days over a 60-day period. The dysfunction of autophagy characterized by a marked accumulation of p62 protein, a substrate for autophagy degradation, was detected in epithelial cells in the non-inflamed and inflamed mucosa of inflammatory bowel disease patients. DSS-colitis was exacerbated in Atg5 ΔIEC mice compared to control Atg5 fl/fl mice. Phosphorylation of inositol-requiring transmembrane kinase/endonuclease1α (IRE1α), a sensor for endoplasmic reticulum stress, and c-Jun N-terminal kinase, a downstream target of IRE1α, were significantly enhanced in IECs in DSS-treated Atg5 ΔIEC mice. Accumulation of phosphorylated IRE1α was enhanced by the treatment with chloroquine, an autophagy inhibitor. Apoptotic IECs were more abundant in DSS-treated Atg5 ΔIEC mice. These findings suggest that Atg5 suppresses endoplasmic reticulum stress-induced apoptosis of IECs via the degradation of excess p-IRE1α.

Mucosa-associated gut microbiome in Japanese patients with functional constipation.

The number of patients with chronic constipation is increasing in Japan. We investigated the gut mucosa-associated microbiome in Japanese patients with functional constipation. Diagnosis was made according to the Rome IV criteria. Mucosal samples were obtained by gentle brushing of mucosa surfaces. The gut microbiome was analyzed using 16S rRNA gene sequencing. There were no significant differences in bacteria α-diversity such as richness and evenness. The PCoA indicated significant structural differences between the constipation group and healthy controls (p = 0.017 for unweighted and p = 0.027 for weighted). The abundance of the phylum Bacteroidetes was significantly higher in the constipation group. The abundance of the genera Streptococcus, Fusobacterium, Comamonas, and Alistipes was significantly higher in the constipation group. The abundance of the genera Acinetobacter, Oscillospilla, Mucispirillum, Propinibacterium, and Anaerotruncus was significantly lower in the constipation group. In the constipation group, the proportion of genes responsible for sulfur metabolism, selenocompound metabolism, sulfur relay system was significantly higher and the proportion of d-arginine and d-ornithine metabolism and flavonoid biosynthesis was significantly lower. In conclusion, we identified differences of the mucosa-associated microbiome between Japanese patients with functional constipation and healthy controls. The mucosa-associated microbiome of functional constipation was characterized by higher levels of Bacteroidetes (Alistipes).

Clinical relevance of innovative immunoassays for serum ustekinumab and anti-ustekinumab antibody levels in Crohn's disease.

BACKGROUND AND AIM: Ustekinumab is a human monoclonal antibody to the p40 subunit of human IL-12/IL-23. The purpose of this report is to verify the newly developed immunoassays for serum ustekinumab and anti-ustekinumab antibody (AUA) concentrations and assess their clinical utility. METHODS: Serum ustekinumab trough levels and AUA levels were measured using new immunoassays in 38 patients with Crohn's disease under ustekinumab maintenance injection. RESULTS: Mean ustekinumab trough levels were 2.54 ± 2.1 µg/mL, and 3 of 38 patients (7.9%) were positive for AUAs. There was no association between ustekinumab trough levels and AUA levels. The optimal trough level of ustekinumab to maintain negative C-reactive protein levels (≤ 0.3 mg/dL) was 1.67 µg/mL determined by receiver operating characteristic curve analysis. Ustekinumab trough level negatively but significantly correlated with C-reactive protein, erythrocyte sedimentation rate, and Crohn's disease activity index and positively and significantly correlated with serum albumin levels. Ustekinumab trough levels were significantly higher in biologics-naïve patients than in biologics-experienced patients, although there was no difference in AUA levels. CONCLUSIONS: We developed new assays for serum ustekinumab trough and AUA levels. These assays might provide new insights into therapeutic drug monitoring-based management of Crohn's disease patients under ustekinumab therapy.

[Prediction of pancreatitis following endoscopic retrograde cholangiopancreatography].

OBJECTIVE: The aim of this study was to determine if the difference in serum amylase levels prior to, and two hours following, an endoscopic retrograde cholangiopancreatography (ERCP), or the ratio of the two-hour post-ERCP amylase level to the pre-ERCP amylase level was a better predictor of post-ERCP pancreatitis (PEP). METHODS: This was a retrospective, single-center study of consecutive patients, who underwent ERCP between April 2015 and August 2018. Serum amylase was measured before and two hours following ERCP. We compared the difference and the ratio of the two levels in predicting PEP using a receiver operating characteristic (ROC) curve analysis. RESULTS: A total of 1029 patients underwent ERCP, with PEP occurring in 118 (11.5%). Multivariate analysis revealed that an elevated two-hour post-ERCP serum amylase level was a significant predictor of PEP. ROC analysis of the difference and the ratio of the two levels found good performance for both parameters, with an area under the curve (AUC) of 0.861 (95% confidence interval [CI], 0.823-0.900) and 0.847 (95% CI, 0.809-0.886), respectively. The difference between the values was a significantly more effective predictor of PEP, based on the AUC analysis (P = 0.011). CONCLUSION: The difference between pre and two-hour post-ERCP amylase levels is a better predictor of PEP than the ratio of the two.

pH-Dependent 5-Aminosalicylates Releasing Preparations Do Not Affect Thiopurine Metabolism.

BACKGROUND/AIMS: Thiopurines are key drugs in maintenance therapy for treating inflammatory bowel disease (IBD). Time-dependent 5-aminosalicylates (5-ASA) releasing preparations (time-dependent 5-ASA) increase 6-thioguanine nucleotide (6-TGN), an active metabolite of thiopurines. However, the effects of pH-dependent 5-ASA releasing preparations (pH-dependent 5-ASA) on thiopurine metabolism were not reported. METHODS: We conducted a retrospective study of 134 IBD patients who received thiopurine treatment. The 6-methylmercaptopurine (6-MMP)/6-TGN values after taking the same dose of thiopurine preparations for at least 28 days were included. RESULTS: There was a significant decrease in the 6-MMP/6-TGN ratio in time-dependent 5-ASA compared with group without 5-ASA preparations and the pH-dependent 5-ASA group (p = 0.008 and < 0.001 respectively). Spearman's rank correlation coefficient indicated a negative relationship between the daily oral dose of time-dependent 5-ASA and the 6-MMP/6-TGN ratio (r = -0.362, p = 0.003). Multivariate logistic regression analysis was performed in the groups with 6-MMP/6-TGN ratios of 1 or more and less than 1. The use of time-dependent 5-ASA and concomitant allopurinol negatively affected the independent 6-MMP/6-TGN ratio (p = 0.006 and 0.007 respectively). CONCLUSION: Our study revealed that time-dependent but not pH-dependent 5-ASA decreases the 6-MMP/6-TGN ratio. We also confirmed that concomitant allopurinol results in a low 6-MMP/6TGN ratio.