High incidence of lung cancer death after curative endoscopic submucosal dissection for superficial esophageal squamous cell carcinoma.

BACKGROUND AND AIM: Following treatment of superficial esophageal squamous cell carcinoma (ESCC), surveillance for a second primary malignancy (SPM) is necessary. However, detailed evidence regarding the timing and prognosis of SPMs is insufficient. We aimed to clarify the details of SPMs and their effects on patient outcomes. METHODS: This retrospective, multicenter study involved 11 hospitals. Patients with superficial ESCC curatively resected using endoscopic submucosal dissection between May 2005 and December 2012, were included in this study. RESULTS: The 5-year survival rate of 187 patients was 92.6% during a median follow-up duration of 96.8 months. Thirty-one patients died, 14 of whom died of SPMs. Compared to patients with SPMs detectable by esophagogastroduodenoscopy (EGD), patients with SPMs detectable only by modalities other than EGD had a significantly higher mortality rate (p < 0.001). Patients with second primary lung cancer (LC) had a high mortality rate (56.3%). Univariate and multivariate analyses showed that multiple Lugol-voiding lesions (LVLs) tended to be associated with SPMs (p = 0.077, hazard ratio [HR] 4.43, 95% confidence interval [CI]: 0.91-6.50), and metachronous ESCC was an independent risk factor for the incidence of second primary LC (p = 0.037, HR 3.51, 95% CI: 1.08-11.41). CONCLUSIONS: SPMs that cannot be detected by EGD, such as LC, must be considered after the curative resection of ESCC. We suggest strict screening by both EGD and computed tomography for patients with multiple LVLs or metachronous ESCC to detect SPMs in their early stages.

A machine learning model for predicting the lymph node metastasis of early gastric cancer not meeting the endoscopic curability criteria.

BACKGROUND: We developed a machine learning (ML) model to predict the risk of lymph node metastasis (LNM) in patients with early gastric cancer (EGC) who did not meet the existing Japanese endoscopic curability criteria and compared its performance with that of the most common clinical risk scoring system, the eCura system. METHODS: We used data from 4,042 consecutive patients with EGC from 21 institutions who underwent endoscopic submucosal dissection (ESD) and/or surgery between 2010 and 2021. All resected EGCs were histologically confirmed not to satisfy the current Japanese endoscopic curability criteria. Of all patients, 3,506 constituted the training cohort to develop the neural network-based ML model, and 536 constituted the validation cohort. The performance of our ML model, as measured by the area under the receiver operating characteristic curve (AUC), was compared with that of the eCura system in the validation cohort. RESULTS: LNM rates were 14% (503/3,506) and 7% (39/536) in the training and validation cohorts, respectively. The ML model identified patients with LNM with an AUC of 0.83 (95% confidence interval, 0.76-0.89) in the validation cohort, while the eCura system identified patients with LNM with an AUC of 0.77 (95% confidence interval, 0.70-0.85) (P = 0.006, DeLong's test). CONCLUSIONS: Our ML model performed better than the eCura system for predicting LNM risk in patients with EGC who did not meet the existing Japanese endoscopic curability criteria. We developed a neural network-based machine learning model that predicts the risk of lymph node metastasis in patients with early gastric cancer who did not meet the endoscopic curability criteria.

A novel artificial intelligence-based endoscopic ultrasonography diagnostic system for diagnosing the invasion depth of early gastric cancer.

BACKGROUND: We developed an artificial intelligence (AI)-based endoscopic ultrasonography (EUS) system for diagnosing the invasion depth of early gastric cancer (EGC), and we evaluated the performance of this system. METHODS: A total of 8280 EUS images from 559 EGC cases were collected from 11 institutions. Within this dataset, 3451 images (285 cases) from one institution were used as a development dataset. The AI model consisted of segmentation and classification steps, followed by the CycleGAN method to bridge differences in EUS images captured by different equipment. AI model performance was evaluated using an internal validation dataset collected from the same institution as the development dataset (1726 images, 135 cases). External validation was conducted using images collected from the other 10 institutions (3103 images, 139 cases). RESULTS: The area under the curve (AUC) of the AI model in the internal validation dataset was 0.870 (95% CI: 0.796-0.944). Regarding diagnostic performance, the accuracy/sensitivity/specificity values of the AI model, experts (n = 6), and nonexperts (n = 8) were 82.2/63.4/90.4%, 81.9/66.3/88.7%, and 68.3/60.9/71.5%, respectively. The AUC of the AI model in the external validation dataset was 0.815 (95% CI: 0.743-0.886). The accuracy/sensitivity/specificity values of the AI model (74.1/73.1/75.0%) and the real-time diagnoses of experts (75.5/79.1/72.2%) in the external validation dataset were comparable. CONCLUSIONS: Our AI model demonstrated a diagnostic performance equivalent to that of experts.

Real-world NUDT15 genotyping and thiopurine treatment optimization in inflammatory bowel disease: a multicenter study.

BACKGROUND: This study evaluated the effectiveness of NUDT15 codon 139 genotyping in optimizing thiopurine treatment for inflammatory bowel disease (IBD) in Japan, using real-world data, and aimed to establish genotype-based treatment strategies. METHODS: A retrospective analysis of 4628 IBD patients who underwent NUDT15 codon 139 genotyping was conducted. This study assessed the purpose of the genotyping test and subsequent prescriptions following the obtained results. Outcomes were compared between the Genotyping group (thiopurine with genotyping test) and Non-genotyping group (thiopurine without genotyping test). Risk factors for adverse events (AEs) were analyzed by genotype and prior genotyping status. RESULTS: Genotyping test for medical purposes showed no significant difference in thiopurine induction rates between Arg/Arg and Arg/Cys genotypes, but nine Arg/Cys patients opted out of thiopurine treatment. In the Genotyping group, Arg/Arg patients received higher initial doses than the Non-genotyping group, while Arg/Cys patients received lower ones (median 25 mg/day). Fewer AEs occurred in the Genotyping group because of their lower incidence in Arg/Cys cases. Starting with < 25 mg/day of AZA reduced AEs in Arg/Cys patients, while Arg/Arg patients had better retention rates when maintaining ≥ 75 mg AZA. Nausea and liver injury correlated with thiopurine formulation but not dosage. pH-dependent mesalamine reduced leukopenia risk in mesalamine users. CONCLUSIONS: NUDT15 codon 139 genotyping effectively reduces thiopurine-induced AEs and improves treatment retention rates in IBD patients after genotype-based dose adjustments. This study provides data-driven treatment strategies based on genotype and identifies risk factors for specific AEs, contributing to a refined thiopurine treatment approach.

Recent steroid use and the relapse risk in ulcerative colitis patients with endoscopic healing.

BACKGROUND: Endoscopic healing (EH) is a therapeutic target in ulcerative colitis (UC). However, even patients who have achieved EH relapse frequently. AIMS: To investigate the association between recent steroid use and relapse risk in UC patients with EH. METHODS: This multi-centre cohort study included 1212 UC patients with confirmed EH (Mayo endoscopic subscore ≤1). We excluded patients with current systemic steroid use or history of advanced therapy. We divided patients into a recent steroid group (last systemic steroid use within 1 year; n = 59) and a non-recent or steroid-naïve group (n = 1153). We followed the patients for 2 years to evaluate relapse, defined as induction of systemic steroids or advanced therapy. We used logistic regression to estimate the odds ratio (OR) of relapse. RESULTS: Relapse occurred in 28.8% of the recent steroid group and 5.6% of the non-recent/steroid-naïve group (multi-variable-adjusted OR 5.53 [95% CI 2.85-10.7]). The risk of relapse decreased with time since the last steroid use: 28.8% for less than 1 year after steroid therapy, 22.9% for 1 year, 16.0% for 2 years and 7.9% beyond 3 years, approaching 4.0% in steroid-naïve patients. (ptrend <0.001). CONCLUSIONS: Even for patients with UC who achieved EH, the risk of relapse remains high following recent steroid therapy. Physicians need to consider the duration since last steroid use to stratify the relapse risk in UC patients with EH.

The apelin­apelin receptor signaling pathway in fibroblasts is involved in tumor growth via p53 expression of cancer cells.

Cancer­associated fibroblasts (CAFs) are pivotal in tumor progression. TP53­deficiency in cancer cells is associated with robust stromal activation. The apelin­apelin receptor (APJ) system has been implicated in suppressing fibroblast­to­myofibroblast transition in non­neoplastic organ fibrosis. The present study aimed to elucidate the oncogenic role of the apelin­APJ system in tumor fibroblasts. APJ expression and the effect of APJ suppression in fibroblasts were investigated for p53 status in cancer cells using human cell lines (TP53­wild colon cancer, HCT116, and Caco­2; TP53­mutant colon cancer, SW480, and DLD­1; and colon fibroblasts, CCD­18Co), resected human tissue samples of colorectal cancers, and immune­deficient nude mouse xenograft models. The role of exosomes collected by ultracentrifugation were also analyzed as mediators of p53 expression in cancer cells and APJ expression in fibroblasts. APJ expression in fibroblasts co­cultured with p53­suppressed colon cancer cells (HCT116sh p53 cells) was significantly lower than in control colon cancer cells (HCT116sh control cells). APJ­suppressed fibroblasts treated with an antagonist or small interfering RNA showed myofibroblast­like properties, including increased proliferation and migratory abilities, via accelerated phosphorylation of Sma­ and Mad­related protein 2/3 (Smad2/3). In addition, xenografts of HCT116 cells with APJ­suppressed fibroblasts showed accelerated tumor growth. By contrast, apelin suppressed the upregulation of phosphorylated Smad2/3 in fibroblasts. MicroRNA 5703 enriched in exosomes derived from HCT116sh p53 cells inhibited APJ expression, and inhibition of miR­5703 diminished APJ suppression in fibroblasts caused by cancer cells. APJ suppression from a specific microRNA in cancer cell­derived exosomes induced CAF­like properties in fibroblasts. Thus, the APJ system in fibroblasts in the tumor microenvironment may be a promising therapeutic target.

Carbon dioxide insufflation reduces the relapse of ulcerative colitis after colonoscopy: A randomized controlled trial.

BACKGROUND AND AIM: Colonoscopy is necessary for diagnosing and surveilling patients with ulcerative colitis, though it may cause disease flares. Colonoscopy with carbon dioxide (CO2) insufflation decreases abdominal discomfort; however, its effect on exacerbation incidence in ulcerative colitis remains unclear. Therefore, this study aimed to evaluate the colonoscopy effects using CO2 insufflation in patients with ulcerative colitis. METHODS: Overall, 96 remissive patients with ulcerative colitis (partial Mayo score ≤ 2) who underwent total colonoscopy between March 2015 and December 2019 at Osaka University Hospital were enrolled and blindly randomized to the CO2 (n = 45) and air (n = 51) insufflation group (UMIN-CTR, number: UMIN000018801). The post-procedural abdominal discomfort and the clinical relapse (partial Mayo score ≥ 3) rate within 8 weeks were evaluated. RESULTS: Baseline backgrounds did not differ between the groups. The mean abdominal fullness and pain scores were significantly lower in the CO2 group than in the Air group immediately (p = 0.0003, p = 0.0003) and 30 min (p < 0.0001, p < 0.0001) after colonoscopy. While the overall clinical relapse rate remained unchanged between the groups, the clinical relapse rate at 8 weeks after colonoscopy was significantly lower in the CO2 group than in the Air group in patients not in complete remission (Mayo endoscopic subscore ≥ 1, p = 0.049; or partial Mayo score ≥ 1, p = 0.022). CONCLUSIONS: CO2 insufflation can reduce abdominal discomfort in remissive patients with ulcerative colitis and decrease clinical relapse at 8 weeks after colonoscopy for those not in complete remission.

Seasonal variations in gut microbiota and disease course in patients with inflammatory bowel disease.

BACKGROUND AND AIM: Environmental factors are associated with onset and course of inflammatory bowel disease (IBD). Our previous study by about 1,100 IBD patients revealed half of the patients experienced seasonal exacerbation of disease. We investigated the seasonality of fecal microbiota composition of IBD patients. METHODS: Fecal samples were consecutively collected in each season from IBD outpatients and healthy controls between November 2015 and April 2019. Participants who were treated with full elemental diet or antibiotics within 6 months or had ostomates were excluded. Bacterial profiles were analyzed by 16S rRNA sequencing, and the changes between the diseases and seasons were compared. RESULTS: A total of 188 fecal samples were analyzed from 47 participants comprising 19 Crohn's disease (CD) patients, 20 ulcerative colitis (UC) patients, and 8 healthy controls (HC). In CD patients, the phylum Actinobacteria and TM7 were both significantly more abundant in autumn than in spring and winter, but not in UC patients and HC. Moreover, the genera Actinomyces, a member of Actinobacteria, and c_TM7-3;o_;f_;g_ (TM7-3), that of TM7, were significantly more abundant in autumn than in spring, and the abundance of Actinomyces was significantly correlated with that of TM7-3 throughout the year in CD patients, but not in UC patients and HC. CD patients with high abundance of TM7-3 in the autumn required significantly fewer therapeutic intervention than those without seasonal fluctuation. CONCLUSIONS: Oral commensals Actinomyces and its symbiont TM7-3 were correlatively fluctuated in the feces of CD patients by season, which could affect the disease course.

Lysophosphatidylserines derived from microbiota in Crohn's disease elicit pathological Th1 response.

Microbiota alteration and IFN-γ-producing CD4+ T cell overactivation are implicated in Crohn's disease (CD) pathogenesis. However, it remains unclear how dysbiosis enhances Th1 responses, leading to intestinal inflammation. Here, we identified key metabolites derived from dysbiotic microbiota that induce enhanced Th1 responses and exaggerate colitis in mouse models. Patients with CD showed elevated lysophosphatidylserine (LysoPS) concentration in their feces, accompanied by a higher relative abundance of microbiota possessing a gene encoding the phospholipid-hydrolyzing enzyme phospholipase A. LysoPS induced metabolic reprogramming, thereby eliciting aberrant effector responses in both human and mouse IFN-γ-producing CD4+ T cells. Administration of LysoPS into two mouse colitis models promoted large intestinal inflammation. LysoPS-induced aggravation of colitis was impaired in mice lacking P2ry10 and P2ry10b, and their CD4+ T cells were hyporesponsive to LysoPS. Thus, our findings elaborate on the mechanism by which metabolites elevated in patients with CD harboring dysbiotic microbiota promote Th1-mediated intestinal pathology.

Exacerbation of non-steroidal anti-inflammatory drug-induced enteropathy in C-C chemokine receptor type 7-deficient mice.

BACKGROUND AND AIM: Non-steroidal anti-inflammatory drugs (NSAIDs) induce intestinal enteropathy and the pathophysiology is related to immune-mediated mechanisms. We aimed to investigate the role of C-C chemokine receptor type 7 (CCR7) which regulates immune cell migration in NSAID-induced enteropathy. METHODS: Injury of the small intestine was evaluated 24 h after the subcutaneous injection of indomethacin in CCR7-deficient (Ccr7-/- ) and wild-type (WT) mice. The cellular profile and cytokine production in intestinal cells were analyzed. Indomethacin-induced enteropathy was evaluated in mice adoptively transferred with CD103+ dendritic cells (DCs) from Ccr7-/- or WT mice. RESULTS: Indomethacin induced more severe intestinal injury in Ccr7-/- mice than in WT mice. The major inflammatory cytokines were not increased and the proportion of regulatory T cells following indomethacin injection was not decreased in Ccr7-/- mice compared with WT mice. The expression of interleukin (IL)-22 binding protein (IL-22BP), which inhibits IL-22 activity, was significantly higher in CD103+ DCs from Ccr7-/- mice than those from WT mice. Mice adoptively transferred with CD103+ DCs isolated from Ccr7-/- mice exhibited more severe intestinal injury following indomethacin injection compared with those adoptively transferred with CD103+ DCs of WT mice. Ccr7-/- mice injected with indomethacin showed a significant reduction in regenerating islet-derived 1 (Reg1) mRNA expression, which is regulated by IL-22, in intestinal epithelial cells. CONCLUSIONS: C-C chemokine receptor type 7 deficiency exacerbated NSAID-induced enteropathy in association with an altered phenotype of CD103+ DCs that produces IL-22BP. CCR7 contributes to protect the small intestine from NSAID-induced mucosal injury.

Elderly onset age is associated with low efficacy of first anti-tumor necrosis factor treatment in patients with inflammatory bowel disease.

The outcomes of patients with elderly onset (EO) inflammatory bowel disease (IBD) treated with anti-tumor necrosis factor (TNF) remains uncertain. The present study evaluated the efficacy and safety of anti-TNF treatment for bio-naïve EO-IBD. Elderly patients were defined as those 60 years and older, and further divided into those with EO (Elderly-EO) and those with non-elderly onset (Elderly-NEO). A total of 432 bio-naïve patients were enrolled in this multicenter observational study, comprising 55 with Elderly-EO (12.7%), 25 with Elderly-NEO (5.8%), and 352 under age 60 (Non-elderly, 81.5%). After 52 weeks of anti-TNF treatment, clinical and steroid-free remission rates were significantly lower in Elderly-EO than in Non-elderly (37.7% and 60.8%; P = 0.001, and 35.9% and 57.8%; P = 0.003, respectively), and comparable between Elderly-NEO and Non-elderly. Multivariate analysis revealed that elderly onset was a significant factor for both clinical remission (OR, 0.49, 95% CI 0.25-0.96) and steroid-free remission (OR, 0.51, 95% CI 0.26-0.99) after 52 weeks of anti-TNF treatment. The rate of cumulative severe adverse events was significantly higher in Elderly-EO than in Non-elderly (P = 0.007), and comparable between Elderly-NEO and Non-elderly. In conclusion, anti-TNF treatment for bio-naïve EO-IBD may be less effective and raise safety concerns.

Vascular endothelial growth factor-A is an Immunohistochemical biomarker for the efficacy of bevacizumab-containing chemotherapy for duodenal and jejunal adenocarcinoma.

BACKGROUND: The efficacy and safety of bevacizumab-containing chemotherapy for patients with metastatic duodenal and jejunal adenocarcinoma (mDJA) are unclear. The present study aimed to evaluate the efficacy of bevacizumab and to explore immunohistochemical markers that can predict the efficacy of bevacizumab for patients with mDJA. METHODS: This multicentre study included patients with histologically confirmed small bowel adenocarcinoma who received palliative chemotherapy from 2008 to 2017 at 15 hospitals. Immunostaining was performed for vascular endothelial growth factor-A (VEGF-A), TP53, Ki67, ß-catenin, CD10, MUC2, MUC5AC, MUC6, and mismatch repair proteins. RESULTS: A total of 74 patients were enrolled, including 65 patients with mDJA and 9 with metastatic ileal adenocarcinoma. Patients with mDJA who received platinum-based chemotherapy with bevacizumab as first-line treatment tended to have a longer progression-free survival and overall survival than those treated without bevacizumab (P = 0.075 and 0.077, respectively). Multivariate analysis extracted high VEGF-A expression as a factor prolonging progression-free survival (hazard ratio: 0.52, 95% confidence interval: 0.30-0.91). In mDJA patients with high VEGF-A expression, those who received platinum-based chemotherapy with bevacizumab as a first-line treatment had significantly longer progression-free survival and tended to have longer overall survival than those treated without bevacizumab (P = 0.025 and P = 0.056, respectively), whereas no differences were observed in mDJA patients with low VEGF-A expression. CONCLUSION: Immunohistochemical expression of VEGF-A is a potentially useful biomarker for predicting the efficacy of bevacizumab-containing chemotherapy for patients with mDJA.

Use of a convolutional neural network for classifying microvessels of superficial esophageal squamous cell carcinomas.

BACKGROUND AND AIM: The morphological diagnosis of microvessels on the surface of superficial esophageal squamous cell carcinomas using magnifying endoscopy with narrow-band imaging is widely used in clinical practice. Nevertheless, inconsistency, even among experts, remains a problem. We constructed a convolutional neural network-based computer-aided diagnosis system to classify the microvessels of superficial esophageal squamous cell carcinomas and evaluated its diagnostic performance. METHODS: In this retrospective study, a cropped magnifying endoscopy with narrow-band images from superficial esophageal squamous cell carcinoma lesions was used as the dataset. All images were assessed by three experts, and classified into three classes, Type B1, B2, and B3, based on the Japan Esophagus Society classification. The dataset was divided into training and validation datasets. A convolutional neural network model (ResNeXt-101) was trained and tuned with the training dataset. To evaluate diagnostic accuracy, the validation dataset was assessed by the computer-aided diagnosis system and eight endoscopists. RESULTS: In total, 1777 and 747 cropped images (total, 393 lesions) were included in the training and validation datasets, respectively. The diagnosis system took 20.3 s to evaluate the 747 images in the validation dataset. The microvessel classification accuracy of the computer-aided diagnosis system was 84.2%, which was higher than the average of the eight endoscopists (77.8%, P < 0.001). The area under the receiver operating characteristic curves for diagnosing Type B1, B2, and B3 vessels were 0.969, 0.948, and 0.973, respectively. CONCLUSIONS: The computer-aided diagnosis system showed remarkable performance in the classification of microvessels on superficial esophageal squamous cell carcinomas.

Concomitant use of an immunomodulator with ustekinumab as an induction therapy for Crohn's disease: A systematic review and meta-analysis.

BACKGROUND AND AIM: Ustekinumab (UST), a fully humanized monoclonal antibody against the p40 subunit of interleukin-12/23, is effective for the treatment of Crohn's disease (CD). The benefit of concomitant use of an immunomodulator (IM) with UST, however, is unclear. This study aimed to provide a systematic review and meta-analysis comparing the efficacy and safety of concomitant use of an IM with UST as an induction therapy for CD patients. METHODS: A systematic literature search was performed using PubMed/MEDLINE, the Cochrane Library, and the Japana Centra Revuo Medicina from inception to October 31, 2019. The main outcome measure was achievement of clinical efficacy (remission, response, and clinical benefit) at 6-12 weeks. The quality of the included studies was assessed using the risk of bias in non-randomized studies of interventions (ROBINS-I) tools. The fixed-effects model was used to calculate the pooled odds ratios. RESULTS: From 189 yielded articles, six including a total of 1507 patients were considered in this meta-analysis. Concomitant use of an IM with UST was significantly effective than UST monotherapy as an induction therapy (pooled odds ratio in the fixed-effects model: 1.35, 95% confidence interval [1.06-1.71], P = 0.015). The heterogeneity among studies was low (I2  = 2.6%). No statistical comparisons of the occurrence of adverse events between UST monotherapy and concomitant use of an IM with UST were performed. CONCLUSION: The efficacy of concomitant use of an IM with UST as an induction therapy for CD was significantly superior to that of monotherapy with UST.

Oligosaccharide-dependent anti-inflammatory role of galectin-1 for macrophages in ulcerative colitis.

BACKGROUND AND AIM: Galectin-1 plays a protective role against colitis by binding with polylactosamine structures on macrophages in ß-1,4-galactosyltransferase I-deficient mice, but the precise function of galectin-1 remains unknown. In the present study, we investigated the anti-inflammatory role of galectin-1 on macrophages to ameliorate ulcerative colitis in both animal model and human tissue samples. METHODS: The expression of galectin-1 in colonic tissues of ulcerative colitis patients was evaluated by immunohistochemistry. Cytokine production of mouse bone marrow-derived macrophages (BMDMs) cultured with galectin-1 was investigated. Galectin-1 binding capacity and polylactosamine expression in macrophages stimulated with lipopolysaccharides were evaluated by flow cytometry. BMDMs cultured with galectin-1 were transferred into Recombination activating gene (Rag) 2-/- mice, and the severity of the dextran sodium sulfate-induced colitis model was investigated. Furthermore, RNA sequencing was performed to characterize macrophages treated with galectin-1. RESULTS: In ulcerative colitis patients, tissue expression of galectin-1was decreased in inflamed mucosa compared with non-inflamed mucosa. Galectin-1 induced interleukin-10 production in BMDMs, and the interleukin-10 production was abrogated by lactose, which inhibits the interaction of oligosaccharide-galectin binding. Dextran sodium sulfate colitis was significantly ameliorated in Rag2-/- mice undergoing galectin-1-treated BMDM transfer compared with those undergoing vehicle-treated BMDM transfer. RNA sequencing revealed that treatment with galectin-1 increased the expression of CCAAT/enhancer binding protein ß and CD163, but decreased the expression of CD80 on BMDMs. CONCLUSION: Galectin-1, whose expression is decreased in the inflamed mucosa of ulcerative colitis patients, can ameliorate murine colitis by conferring oligosaccharide-dependent anti-inflammatory properties to macrophages.

Novel mass spectrometry-based comprehensive lipidomic analysis of plasma from patients with inflammatory bowel disease.

BACKGROUND AND AIM: Lipids play important roles in inflammation and may be involved in the pathophysiology of inflammatory bowel disease (IBD). Here, we evaluated the characteristics of the plasma lipid profile in patients with IBD. METHODS: Plasma samples were collected from 20 patients with Crohn's disease (CD), 20 patients with ulcerative colitis (UC), and 10 healthy volunteers (HVs) after overnight fasting. The subjects were men between 20 and 49 years of age with no history of hyperlipidemia. A total of 698 molecular species in 22 lipid classes were analyzed by ultra-performance liquid chromatography-electrospray ionization-tandem mass spectrometry. RESULTS: Lipid classes of lysophosphatidic acid, lysophosphatidylserine (LPS), phosphatidylserine (PS), and shingosine-1-phosphate (S1P) were significantly increased in UC patients compared with the HV. The LPS, PS, and S1P levels were significantly increased, while those of lysophosphatidylinositol and phosphatidylcholine were significantly decreased in CD patients compared with HV. Among PS species, the levels of PSacyl (PSa) 40:3, PSa 38:3, and PSa 42:4 were significantly higher in CD patients, both active and remissive stage, than in HV. The LPS 18:0 level was significantly higher in CD and UC patients compared with HV. PSa 40:3 and PSa 38:3 levels positively correlated with the Crohn's Disease Activity Index, erythrocyte sedimentation rate, and platelet count and negatively correlated with hemoglobin, hematocrit, and albumin levels in CD patients. CONCLUSION: The lipid profile in IBD patients exhibits significant alterations, and PS levels are associated with clinical disease activity in CD patients.

Tissue Drug Concentrations of Anti-tumor Necrosis Factor Agents Are Associated with the Long-term Outcome of Patients with Crohn's Disease.

BACKGROUND: Many reports indicate that a high-serum trough level of anti-tumor necrosis factor (TNF) agents is required for sustained remission in patients with Crohn's disease The pharmacokinetics of anti-TNF agents in inflamed intestinal tissue, however, is not well investigated. We investigated the association between the tissue concentration of anti-TNF agents and long-term disease outcome. METHODS: This was a prospective single-center study that enrolled 25 patients with Crohn's disease who were administered infliximab or adalimumab. All participants underwent endoscopy 2 weeks after administration of the anti-TNF agents, and biopsy samples were obtained from both inflamed and noninflamed intestinal tissue. Tissue concentrations of anti-TNF agents were evaluated and the correlation with serum trough levels was compared. The relation between the tissue drug concentration and clinical course over 24 months was also investigated. RESULTS: Concentrations of anti-TNF agents were significantly higher in inflamed tissue than in noninflamed tissue. Patients with high-serum trough concentrations of anti-TNF agents had significantly higher drug levels in the noninflamed tissue than those with low-serum trough concentrations, but no difference in the levels was detected in the inflamed tissue. Patients with high-drug levels in the noninflamed tissue had a significantly higher sustained response rate than patients with low-drug levels. CONCLUSIONS: Concentrations of anti-TNF agents in the noninflamed tissue can reflect sustained remission and may be a useful biomarker for monitoring therapeutic intensity in patients with Crohn's disease treated with anti-TNF agents (see Video Abstract, Supplemental Digital Content 1, http://links.lww.com/IBD/B623).

25 mg versus 50†mg dose of rectal diclofenac for prevention of post-ERCP pancreatitis in Japanese patients: a retrospective study.

OBJECTIVES: The aim of the present study was to assess the appropriate administration dose of non-steroidal anti-inflammation drugs to prevent pancreatitis after endoscopic retrograde cholangiopancreatography (ERCP). Importantly, the 100 mg dose of diclofenac recommended in Western countries has not been permitted in Japan. DESIGN: A retrospective study. SETTINGS: A single centre in Japan. PARTICIPANTS: This study enrolled patients who underwent ERCP at the Department of Gastroenterology, Osaka Saiseikai Senri Hospital, from April 2011 through June 2013, and who received either a 25 or a 50 mg dose of rectal diclofenac after ERCP. PRIMARY OUTCOME MEASURE: The occurrence of post-ERCP pancreatitis (PEP). A multivariate regression model was used to assess the effect of the 50 mg dose (the 50 mg group) of rectal diclofenac and to compare it to the occurrence of PEP referring to the 25 mg group. RESULTS: A total of 155 eligible patients received either 25 mg (84 patients) or 50 mg (71 patients) doses of rectal diclofenac after ERCP to prevent PEP. The proportion of PEP was significantly lower in the 50 mg group than in the 25 mg group (15.5% (11/71) vs 33.3% (28/84), p=0.018). In a multivariate analysis, the occurrence of PEP was significantly lower in the 50 mg group than in the 25 mg group even after adjusting potential confounding factors (adjusted OR=0.27, 95% CI 0.11 to 0.70). CONCLUSIONS: From this observation, the occurrence of PEP was significantly lower among ERCP patients with the 50 mg dose of rectal diclofenac than among those with the 25 mg dose.