Deep learning-based screening tool for rotator cuff tears on shoulder radiography.

BACKGROUND: Early diagnosis of rotator cuff tears is essential for appropriate and timely treatment. Although radiography is the most used technique in clinical practice, it is difficult to accurately rule out rotator cuff tears as an initial imaging diagnostic modality. Deep learning-based artificial intelligence has recently been applied in medicine, especially diagnostic imaging. This study aimed to develop a deep learning algorithm as a screening tool for rotator cuff tears based on radiography. METHODS: We used 2803 shoulder radiographs of the true anteroposterior view to develop the deep learning algorithm. Radiographs were labeled 0 and 1 as intact or low-grade partial-thickness rotator cuff tears and high-grade partial or full-thickness rotator cuff tears, respectively. The diagnosis of rotator cuff tears was determined based on arthroscopic findings. The diagnostic performance of the deep learning algorithm was assessed by calculating the area under the curve (AUC), sensitivity, negative predictive value (NPV), and negative likelihood ratio (LR-) of test datasets with a cutoff value of expected high sensitivity determination based on validation datasets. Furthermore, the diagnostic performance for each rotator cuff tear size was evaluated. RESULTS: The AUC, sensitivity, NPV, and LR- with expected high sensitivity determination were 0.82, 84/92 (91.3%), 102/110 (92.7%), and 0.16, respectively. The sensitivity, NPV, and LR- for full-thickness rotator cuff tears were 69/73 (94.5%), 102/106 (96.2%), and 0.10, respectively, while the diagnostic performance for partial-thickness rotator cuff tears was low at 15/19 (78.9%), NPV of 102/106 (96.2%) and LR- of 0.39. CONCLUSIONS: Our algorithm had a high diagnostic performance for full-thickness rotator cuff tears. The deep learning algorithm based on shoulder radiography helps screen rotator cuff tears by setting an appropriate cutoff value. LEVEL OF EVIDENCE: Level III: Diagnostic Study.

Deep Learning-Based Time-to-Death Prediction Model for COVID-19 Patients Using Clinical Data and Chest Radiographs.

Accurate estimation of mortality and time to death at admission for COVID-19 patients is important and several deep learning models have been created for this task. However, there are currently no prognostic models which use end-to-end deep learning to predict time to event for admitted COVID-19 patients using chest radiographs and clinical data. We retrospectively implemented a new artificial intelligence model combining DeepSurv (a multiple-perceptron implementation of the Cox proportional hazards model) and a convolutional neural network (CNN) using 1356 COVID-19 inpatients. For comparison, we also prepared DeepSurv only with clinical data, DeepSurv only with images (CNNSurv), and Cox proportional hazards models. Clinical data and chest radiographs at admission were used to estimate patient outcome (death or discharge) and duration to the outcome. The Harrel's concordance index (c-index) of the DeepSurv with CNN model was 0.82 (0.75-0.88) and this was significantly higher than the DeepSurv only with clinical data model (c-index = 0.77 (0.69-0.84), p = 0.011), CNNSurv (c-index = 0.70 (0.63-0.79), p = 0.001), and the Cox proportional hazards model (c-index = 0.71 (0.63-0.79), p = 0.001). These results suggest that the time-to-event prognosis model became more accurate when chest radiographs and clinical data were used together.

Evaluation of long-term survival in patients with severe comorbidities after endoscopic submucosal dissection for esophageal squamous cell carcinoma.

BACKGROUND: Endoscopic submucosal dissection (ESD) is becoming widely popular as a less invasive treatment option for superficial esophageal squamous cell carcinoma. However, data on long-term survival after esophageal ESD in patients with severe comorbidities are limited. This study aimed to evaluate long-term survival after ESD in such patients. METHODS: Altogether, 584 consecutive patients underwent esophageal ESD at our institution from May 2004 to September 2016. Based on the American Society of Anesthesiologists Physical Status (ASA-PS) classification system, patients were grouped according to severe (ASA-PS ≥ 3) or non-severe comorbidities (ASA-PS 1/2). The overall survival (OS), disease-specific survival (DSS), and risk factors for mortality were compared between the groups using a propensity score matching analysis. RESULTS: In a matched cohort of 69 pairs, the 5-year OS rate was poorer in ASA-PS 3 patients than in ASA-PS 1/2 patients (63.9% vs. 92.5%, P < 0.01), while the 5-year DSS rate was similar between the groups (100% vs. 100%). The mortality rate was significantly higher in ASA-PS 3 patients than in ASA-PS 1/2 patients (hazard ratio 3.47; 95% confidence interval 1.79-6.74; P < 0.01). Death due to exacerbation of comorbidities was significantly more frequent in ASA-PS 3 patients than in ASA-PS 1/2 patients (42.4% vs. 8.3%, P < 0.04). CONCLUSION: Because of the exacerbation of comorbidities, patients with severe comorbidities had poorer long-term outcomes after esophageal ESD than those with non-severe comorbidities. Further studies will be necessary to evaluate esophageal ESD in patients with severe comorbidities.

Predictive factors for difficult endoscopic submucosal dissection for esophageal neoplasia including failure of en bloc resection or perforation.

BACKGROUND: Endoscopic submucosal dissection (ESD) is accepted as the standard treatment for early-stage esophageal neoplasia. However, esophageal perforation may occur, leading to mediastinitis and pneumothorax, which occasionally require emergency surgery. Moreover, failure of en bloc resection causes local recurrence. However, studies on the predictors of such difficulties during ESD are limited. Hence, we evaluated the predictors associated with the difficulty of ESD for esophageal neoplasia including failure of en bloc resection or perforation. METHODS: Data of 549 consecutive patients who were treated with ESD between May 2004 and March 2016 at a single institution were retrospectively studied. Exclusion criteria were the presence of metachronous esophageal neoplasia or missing data. The primary outcome was determining the predictors associated with the difficulty of ESD for esophageal neoplasia including failure of en bloc resection or perforation. RESULTS: Altogether, 543 patients with 736 lesions were evaluated. Failure of en bloc resection occurred in 6 patients (1.1%) with 6 lesions, and perforation occurred in 11 patients (2.0%) with 11 lesions (1.5%). Multivariate logistic regression analysis showed that large lesion diameter (odds ratio [OR] 1.49; 95% confidence interval [CI] 1.21-1.84; p < 0.001) and previous chemoradiotherapy (OR 5.24; 95% CI 1.52-18.06; p = 0.009) were independent predictive factors. CONCLUSIONS: Larger lesions and previous chemoradiotherapy for esophageal cancer increased the risk for failure of en bloc resection or perforation in patients who underwent esophageal ESD.

Positive correlation between pancreatic volume and post-endoscopic retrograde cholangiopancreatography pancreatitis.

BACKGROUND AND AIM: Post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) remains the most common and serious adverse event associated with ERCP. Risk factors for PEP have been described in various reports. However, risk factors have not been quantified to date. The aim of this study was to investigate the risk factors for PEP by quantification of pancreatic volume using pre-ERCP images. METHODS: Overall, 800 patients were recruited from April 2012 to February 2015 for this study. There were 168 patients who satisfied the inclusion criteria. Measurement of pancreatic volume was achieved using the volume analyzer SYNAPSE VINCENT in all cases and was used to evaluate the risk factors for PEP. RESULTS: According to the criteria established by the consensus guidelines (Cotton classification), 17 patients (10.1%) were classified as having mild disease, 4 (2.4%) as having moderate disease, and 5 (3.0%) as having severe disease. Multivariate model analysis showed that a large pancreatic volume was a significant risk factor for PEP (odds ratio [OR] 1.10, 95% confidence interval [CI] 1.06-1.13; P < 0.001). In addition, the association between the pancreatic volume and the severity of PEP was positively correlated (the effect of volume [per 1 mL]; OR 1.09, 95% CI 1.07-1.12; P < 0.001, the effect of volume [per 10 mL]; OR 2.27, 95% CI 1.72-3.00; P < 0.001). A larger pancreatic volume was significantly associated with a higher incidence of PEP. CONCLUSIONS: A large pancreatic volume was identified as a risk factor for PEP. The results of this study suggest that pre-ERCP images might be useful for predicting PEP.

Impact of preoperative biopsy sampling on severe submucosal fibrosis on endoscopic submucosal dissection for colorectal laterally spreading tumors: a propensity score analysis.

BACKGROUND AND AIMS: It is believed that preoperative biopsy sampling for superficial-type colorectal tumors should be avoided because submucosal fibrosis caused by biopsy sampling makes EMR impossible. However, few studies have reported the influence of biopsy sampling on colorectal endoscopic submucosal dissection (ESD). This study aimed to examine the effect of biopsy sampling on submucosal fibrosis and treatment outcomes of ESD for laterally spreading tumors (LSTs). METHODS: Between April 2005 and September 2015, 441 consecutive patients underwent colorectal ESD in Osaka City University Hospital. Using propensity score matching and inverse probability of treatment weighting (IPTW), we retrospectively evaluated risk factors for severe submucosal fibrosis and treatment outcomes for patients with LSTs, with or without preoperative biopsy sampling. RESULTS: A total of 428 LSTs resected using ESD were enrolled. After matching, there were 136 matched pairs of lesions that did or did not undergo biopsy sampling. Preoperative biopsy sampling increased severe fibrosis compared with that in the non-biopsy sampling group (20.6% vs 11.0%; P = .03) and was significantly associated with severe fibrosis after matching (odds ratio [OR], 2.09; 95% confidence interval [CI], 1.07-4.10; P = .03). After adjustment with IPTW, biopsy sampling also increased the risk of severe fibrosis (OR, 2.33; 95% CI, 1.17-4.63; P = .02). However, no significant differences were observed between the 2 groups in treatment outcomes. CONCLUSIONS: Preoperative biopsy sampling for colorectal LSTs might cause severe submucosal fibrosis but has no adverse influence on clinical outcomes of ESD.

Long-term outcome of endoscopic submucosal dissection for early gastric cancer in patients with severe comorbidities: a comparative propensity score analysis.

BACKGROUND: Recently, endoscopic submucosal dissection (ESD) for early gastric cancer (EGC) has been performed on patients with severe comorbidities because it is less invasive, although little is known regarding long-term outcomes. This study aimed to assess the long-term outcomes of ESD for patients with severe and non-severe comorbidities. METHODS: We enrolled 1081 patients who underwent ESD for EGC between February 2004 and June 2013. Based on the American Society of Anesthesiologists Physical Status (ASA-PS) classification, we defined patients with severe and non-severe comorbidities as ASA-PS 3 and 1/2, respectively. We retrospectively compared the overall survival, risk factors for mortality, and adverse events between these two groups using propensity score matching and inverse probability of treatment weighting. RESULTS: A total of 488 patients met the eligibility criteria. After matching, the ASA-PS 3 group showed a significantly shorter survival than the ASA-PS 1/2 group (5-year overall survival rate, 79.1 vs. 87.7%; p < 0.01). In addition, only the ASA-PS 3 group had a significant risk factor for mortality using both the Cox analysis [hazard ratio (HR), 2.56; 95% confidence interval (CI) 1.18-5.52; p = 0.02] and the IPTW method (HR, 3.14; 95% CI 1.91-5.14; p < 0.01). There was no significant difference in adverse events after matching between the two groups (p = 0.21). CONCLUSIONS: The long-term outcome of gastric ESD for patients with severe comorbidities was worse than for those with non-severe comorbidities. Further studies will be necessary to determine if ESD is truly warranted in these patients.

Heparin-bridging therapy is associated with post-colorectal polypectomy bleeding in patients whose oral anticoagulation therapy is interrupted.

OBJECTIVES: The American and Japanese Societies for Gastrointestinal Endoscopy Guidelines recommend heparin-bridging therapy for patients whose oral anticoagulants are interrupted for endoscopic procedures. However, little is known about the potential association between heparin-bridging therapy and post-polypectomy bleeding (PPB). The aim was to investigate the incidence of PPB associated with heparin-bridging therapy administered to patients whose anticoagulants were interrupted. MATERIALS AND METHODS: This was a retrospective observational study using inverse propensity analysis. Between 2013 and 2015, 1004 patients with 2863 lesions were included. The primary outcomes were the rates of PPB and thromboembolism associated with heparin-bridging therapy. The risk factors associated with PPB were identified using multivariate logistic regression analysis involving probability of treatment weighting (IPTW). RESULTS: The patients were categorized into a heparin-bridging therapy group (78 patients with 255 lesions) or a control group (926 patients with 2608 lesions). The PPB rate in the heparin-bridging therapy group (10.2%, 8/78) was significantly higher than in the control group (1.1%, 11/926) (p <.01). Thromboembolism occurred in one patient in the control group. The multivariate analysis revealed that heparin-bridging therapy was an independent risk factor associated with PPB (odds ratio [OR], 8.21; 95% confidence interval [95% CI], 2.32-29.10; p <.01). IPTW showed heparin-bridging therapy increased PPB (OR, 7.68; 95% CI, 1.83-32.28; p <.01). CONCLUSIONS: Heparin-bridging therapy administered to patients whose oral anticoagulants were interrupted was associated with an increased PPB risk.

Efficacy of a concomitant elemental diet to reduce the loss of response to adalimumab in patients with intractable Crohn's disease.

BACKGROUND AND AIM: Secondary loss of response to adalimumab (ADA-LOR) commonly occurs in patients with Crohn's disease (CD) treated with adalimumab (ADA). We evaluated the efficacy of concomitant elemental diet (ED) therapy to reduce ADA-LOR in adult CD patients. METHODS: Patients were divided into either an ED (≥900 kcal/day) or a non-ED group (<900 kcal/day). Cumulative non-ADA-LOR rates were compared between groups. The effects of ED intake to reduce ADA-LOR were also assessed in antitumor necrosis factor-alpha (TNF-α)-naïve and infliximab (IFX)-intolerant or refractory CD patients. Serum ADA and TNF-α levels were measured. RESULTS: We enrolled 117 CD patients into the ED (n = 25) or non-ED (n = 92) groups. Although the cumulative non-ADA-LOR rate was higher in the ED group than in the non-ED group, ED intake was not an independent reducing factor for ADA-LOR (adjusted hazard ratio = 0.725; 95% confidence interval: 0.448-1.180; P = 0.196) in all patients. ED intake was significantly more effective in reducing ADA-LOR in IFX-intolerant or refractory patients than in anti-TNF-α-naïve patients in a dose-related manner (P for interaction <0.20). Serum ADA levels did not differ between the groups. Serum TNF-α levels were significantly lower in the ED group than in the non-ED group at week 28 (P = 0.044) and week 52 (P = 0.043). CONCLUSIONS: Concomitant ED therapy reduced ADA-LOR in IFX-intolerant or refractory patients in a dose-related manner. Reductions in the TNF-α levels by concomitant ED intake may contribute to reduce ADA-LOR in CD patients.

Endoscopic Submucosal Dissection for Adenocarcinomas of the Esophagogastric Junction.

BACKGROUND: Adenocarcinoma of the esophagogastric junction (EGJ) is uncommon in Eastern countries, including Japan, but it is believed that the incidence of EGJ adenocarcinoma will increase in Asia in the future due to the decreasing incidence of Helicobacter pylori infection. Endoscopic submucosal dissection (ESD) is a minimally invasive and curative treatment that allows precise pathological assessment. SUMMARY: Magnifying endoscopy with narrow-band imaging may be useful for differential diagnoses and for delineating the cancer margin of EGJ adenocarcinoma, but subsquamous carcinoma extension, which is the invasion of EGJ adenocarcinoma beneath the normal esophageal squamous epithelium, makes it difficult to detect cancer margins of the oral side in ESD for EGJ adenocarcinoma. Since subsquamous carcinoma extension was reported to be less than 1 cm in most cases, the oral safety margin that is placed 1 cm from the squamocolumnar junction is useful for negative cancerous horizontal margin. A multicenter retrospective study of esophageal adenocarcinoma including EGJ adenocarcinoma showed that mucosal and submucosal cancer within 500 µm from the muscularis mucosa without lymphovascular involvement, a poorly differentiated component, and lesion size over 3 cm were not associated with metastasis. Several retrospective studies about ESD for EGJ adenocarcinoma have suggested feasible short-term and long-term outcomes using curative criteria based on gastric cancer guidelines. Key Messages: ESD would be a good first-line treatment for superficial EGJ adenocarcinoma, including Barrett's adenocarcinoma. Additional information about the incidence of metastasis would help confirm the indication of ESD for EGJ adenocarcinoma.

Clinical Utility of Capsule Endoscopy and Double-Balloon Enteroscopy in the Management of Obscure Gastrointestinal Bleeding.

BACKGROUND: Obscure gastrointestinal bleeding (OGIB) is a common but embarrassing problem for gastroenterologists. Most bleeding lesions associated with OGIB are present in the small intestine and sometimes cannot be identified due to the difficulty associated with physical accessibility. Capsule endoscopy (CE) and double-balloon enteroscopy (DBE) have enabled in the process of diagnosing and have evolved to become approaches to treating OGIB. SUMMARY: CE is a minimally invasive procedure and has a high diagnostic yield in patients with OGIB. DBE offers additional advantage of biopsy collection for pathological diagnosis and therapeutic intervention, but it should be noted that it sometimes causes severe adverse events such as acute pancreatitis, intestinal bleeding, and intestinal perforation. CE should be performed early in the workup course of OGIB. Positive CE findings enhance the diagnostic yield of subsequent DBE, and the effective therapeutic intervention improves the clinical outcomes of OGIB patients. On the contrary, there are no clear guidelines for further investigation of patients with negative CE findings at the present. Although patients in stable general condition may only require follow-up, repeated CE is useful to detect positive findings in patients with evidence of sustained bleeding and progressing anemia. We have revealed that repeated CE has higher positive finding rate than DBE in OGIB patients with negative CE findings in a preliminary study. Key Messages: CE and DBE have complementary roles in the management of OGIB, and the precise timing and proper sequence may be important for the approach to treating OGIB.

Prediction of esophageal stricture in patients given locoregional triamcinolone injections immediately after endoscopic submucosal dissection.

BACKGROUND AND AIM: Esophageal endoscopic submucosal dissection (ESD) to resect widespread lesions has increased the incidence of strictures, and some patients develop strictures despite receiving prophylactic locoregional triamcinolone injections. The present study evaluated the predictive factors for esophageal stricture formation in patients given prophylactic triamcinolone injections after ESD. METHODS: This was a retrospective observational study. Of 552 consecutive patients who underwent ESD, those who received prophylactic triamcinolone injections immediately after ESD were enrolled. Primary outcome was predictive factors for esophageal stricture formation in patients given prophylactic triamcinolone injections. RESULTS: We evaluated 101 en bloc resections involving 144 lesions in 96 patients. Strictures occurred following 17 (16.8%) resections. Wider circumferential mucosal defect (odds ratio [OR] 2.42, 95% confidence interval [CI]: 1.01-5.80; P = 0.048) was an independent predictive factor for stricture development. Cut-off value associated with stricture formation was five-sixths of the circumferential mucosal defect. Propensity analysis determined that frequency of esophageal strictures increased in patients with circumferential mucosal defects of more than five-sixths compared with those less than five-sixths (OR = 5.70, 95% CI: 1.61-20.18; P = 0.007). CONCLUSION: Resections involving circumferential mucosal defects of more than five-sixths increased the likelihood of stricture formation in patients given prophylactic locoregional triamcinolone injections after esophageal ESD.

Long-term prognosis of expanded-indication differentiated-type early gastric cancer treated with endoscopic submucosal dissection or surgery using propensity score analysis.

BACKGROUND AND AIMS: Although endoscopic submucosal dissection (ESD) for expanded-indication lesions of differentiated-type early gastric cancer (EGC) has been widely accepted, no prospective randomized study has been conducted on this subject. This study aimed to evaluate the long-term outcomes of ESD and surgery for expanded-indication lesions of differentiated-type EGC. METHODS: Between 1997 and 2012, 1500 consecutive patients with EGC were treated in Osaka City University Hospital. Using propensity score matching and inverse probability of treatment weighting (IPTW), we retrospectively evaluated the long-term outcomes, risk factors for mortality, and adverse events for patients with expanded-indication lesions of differentiated-type EGC who underwent ESD or surgical treatments. RESULTS: A total of 308 patients with expanded-indication lesions of differentiated-type EGC confirmed by pathologic examination after ESD or surgery met the eligibility criteria. After matching, the 5-year overall survival rate was higher in the ESD group than in the surgery group (97.1% vs 85.8%; P = .01). We also found that surgery was significantly associated with mortality using both the IPTW method (hazard ratio [HR], 10.89; 95% confidence interval [CI], 1.37-86.6; P < .01), and Cox analysis (HR, 8.60; 95% CI, 1.11-66.52; P = .04) after matching. Significantly fewer adverse events were associated with ESD than with surgery (6.8% vs 28.4%; P < .01). No cause-specific mortality was observed in either group. CONCLUSIONS: Our results indicate that ESD might be an alternative treatment modality for expanded-indication lesions of differentiated-type EGC.

Clinical factors associated with positive capsule endoscopy findings in patients with obscure gastrointestinal bleeding: a single-center study.

BACKGROUND: Capsule endoscopy (CE) is a useful tool for patients with obscure gastrointestinal bleeding (OGIB), but positive finding rate differs among trials, which may be attributable to the difference in patients' background. OBJECTIVES: To evaluate the predictive factors associated with positive findings on CE. METHODS: Consecutive patients with OGIB who underwent CE between March 2004 and May 2015 at a single university hospital were enrolled. Patients' clinical factors and CE data were reviewed retrospectively, and we evaluated the relationship between clinical factors and positive findings by univariate and multivariate logistic regression analyses. RESULTS: Five hundred and seventy-eight patients were included in the analysis. Positive CE findings were obtained in 284 patients (49.1%). In multivariate analysis, low hemoglobin level (odds ratio (OR), 1.142 per 1 g/dL decrease; p < .001), Charlson comorbidity index (CCI) score (OR, 1.170 per 1 point increase; p = .002), and non-steroidal anti-inflammatory drug (NSAID) use (OR, 1.640; p = .044) were associated with an increased prevalence of positive findings. As for components of CCI, malignant tumor (OR, 1.839; p = .017) was associated with the positive findings. CONCLUSIONS: OGIB patient with a low-hemoglobin level, complex and severe comorbidities, and NSAID use should receive CE.

A comparison between capsule endoscopy and double balloon enteroscopy using propensity score-matching analysis in patients with previous obscure gastrointestinal bleeding.

BACKGROUND: Recently, diagnosis of obscure gastrointestinal bleeding (OGIB) has improved greatly due to introduction of capsule endoscopy (CE) and double balloon enteroscopy (DBE). However, the efficacy of CE over DBE in patients with previous OGIB remains unclear. This study aimed to compare, in terms of diagnostic yield, the efficacy of DBE with that of CE in patients with previous OGIB. PATIENTS AND METHODS: We enrolled 223 consecutive patients with previous OGIB who were treated between May 2007 and March 2012. We retrospectively evaluated the respective diagnostic yields of CE and DBE in patients with previous OGIB using propensity score-matching analysis. We compared the diagnostic yield of CE with that of DBE. RESULTS: The diagnostic yields were 41.9% in DBE group and 11.6% in CE group, respectively (p < .01). On logistic regression analysis, DBE was significantly superior to CE after matching (Odds ratio [OR], 4.25; 95% confidence interval [CI], 1.43-12.6; p < .01), even after adjustment for propensity score (OR, 5.65; 95% CI, 1.56?20.5; p < .01). CONCLUSIONS: Our results indicate that DBE might be more useful and perhaps safer than CE in achieving a positive diagnosis in patients with previous OGIB.

Microbiota Plays a Key Role in Non-Steroidal Anti-Inflammatory Drug-Induced Small Intestinal Damage.

BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) damage the small intestine by causing multiple erosions and ulcers. However, to date, no established therapies and prophylactic agents are available to treat such damages. We reviewed the role of intestinal microbiota in NSAID-induced intestinal damage and identified potential therapeutic candidates. SUMMARY: The composition of the intestinal microbiota is an important factor in the pathophysiology of NSAID-induced small intestinal damage. Once mucosal barrier function is disrupted due to NSAID-induced prostaglandin deficiency and mitochondrial malfunction, lipopolysaccharide from luminal gram-negative bacteria and high mobility group box 1 from the injured epithelial cells activate toll-like receptor 4-signaling pathway and nucleotide-binding oligomerization domain-like receptor family, pyrin domain-containing 3 inflammasome; this leads to the release of proinflammatory cytokines such as tumor necrosis factor-α and interleukin-1ß. Proton pump inhibitors (PPIs) are often used for the prevention of NSAID-induced injuries to the upper gastrointestinal tract. However, several studies indicate that PPIs may induce dysbiosis, which may exacerbate the NSAID-induced small intestinal damage. Our recent research suggests that probiotics and rebamipide could be used to prevent NSAID-induced small intestinal damage by regulating the intestinal microbiota. Key Messages: Intestinal microbiota plays a key role in NSAID-induced small intestinal damage, and modulating the composition of the intestinal microbiota could be a new therapeutic strategy for treating this damage.

Tumor necrosis factor α decreases glucagon-like peptide-2 expression by up-regulating G-protein-coupled receptor 120 in Crohn disease.

Glucagon-like peptide (GLP)-2, secreted by L cells in the small intestine, has anti-inflammatory effects in the gastrointestinal tract. A GLP-2 analogue has been an effective treatment for Crohn disease (CD). G-protein-coupled receptor (GPR) 40 and GPR120 are probably involved in GLP-2 production, the mechanisms of which remain unclear. In our experiments, normal ileal mucosa expressed GPR40, but rarely expressed GPR120. However, both GPRs were overexpressed in the L cells of the inflamed ileal mucosa of CD patients. Mucosal inflammation induced the overexpression of GPR40, GPR120, and several inflammatory cytokines, with correlations between ileal concentrations of tumor necrosis factor (TNF)-α and GPR expression levels; however, inflammation did not induce the expression of proglucagon, a precursor of GLP-2 in CD patients. In rat L cells and GLUTag cells, TNF-α treatment increased GPR120 mRNA expression without affecting GPR40 mRNA expression. Dual agonists of GPR40 and GPR120, GW9508 and linoleic acid, respectively, increased GLP-2 production from L cells, but these agonists decreased it in the presence of TNF-α. The GPR40 antagonist, GW1100, inhibited the GW9508-induced increase in GLP-2 production, and silencing GPR120 resulted in further elevation of GLP-2 production. Thus, GPR120-dependent signaling inhibited the stimulatory effects of GPR40 on GLP-2 expression, and TNF-α treatment decreased GLP-2 expression by up-regulating GPR120 expression in L cells.

Reduction of prostaglandin transporter predicts poor prognosis associated with angiogenesis in gastric adenocarcinoma.

BACKGROUND AND AIM: Prostaglandin (PG) E2 promotes gastrointestinal carcinogenesis and tumor progression. The total amount of biologically active PGE2 in tissues is determined by a balance of PG biosynthesis and degradation pathways, which involve the PG transporter (PGT). We investigated PGT in gastric adenocarcinoma by determining its expression pattern and examining associations of PGT with prognosis and tumor angiogenesis. METHODS: PGT expression was determined by immunohistochemistry in advanced gastric adenocarcinoma specimens obtained from 96 patients who underwent surgical resection. Correlations between PGT expression level and clinicopathological factors were statistically analyzed. Angiogenesis in the tumor tissue was evaluated by counting the number of microvessels. The role of PGT in mRNA and protein expression of vascular endothelial growth factor (VEGF) was examined in gastric cancer cells stimulated by PGE2 . RESULTS: Based on multivariate and Kaplan-Meier analyses, negativity for PGT expression was an independent poor prognostic factor. There were more microvessels in PGT-negative tumors than in PGT-positive tumors. Transfection of AGS and MKN7 gastric cancer cells with PGT-specific siRNA led to increased VEGF mRNA and protein expression accompanied by increased PGE2 in the culture media. CONCLUSIONS: PGT expression is an independent predictor of poor survival and is associated with tumor angiogenesis in gastric adenocarcinoma.

Prediction of Poor Response to Modified Neuroleptanalgesia with Midazolam for Endoscopic Submucosal Dissection for Esophageal Squamous Cell Carcinoma.

BACKGROUND/AIMS: Modified neuroleptanalgesia (m-NLA) with midazolam is often used for sedation and analgesia during endoscopic submucosal dissection (ESD) for gastrointestinal neoplasia. However, interruption due to poor response to midazolam is often experienced during ESD for esophageal squamous cell carcinoma (ESCC) because most patients with ESCC have a history of heavy alcohol intake. We examined the incidence and risk factors for poor response to m-NLA with midazolam and pethidine hydrochloride. METHODS: This retrospective cross-sectional study was conducted at a single institution. Between April 2007 and July 2013, 151 patients with superficial ESCC who underwent ESD under sedation using m-NLA with midazolam and pethidine hydrochloride were enrolled. Poor response to sedation was defined as the use of a second drug when Ramsay Sedation Score 1-2. RESULTS: Poor response to sedation occurred in 66.2% patients. Most cases of poor response were controlled by using additional flunitrazepam. Multivariate logistic regression analysis showed that cumulative alcohol intake and major specimen size were independent risk factors for poor response to sedation (OR 3.63, 95% CI 1.20-10.99, and OR 3.23, 95% CI 1.26-8.25). CONCLUSION: Our study indicated that cumulative alcohol intake and major specimen size were associated with poor response to m-NLA with midazolam and pethidine hydrochloride.

Concentration of Glial Cell Line-Derived Neurotrophic Factor Positively Correlates with Symptoms in Functional Dyspepsia.

BACKGROUND: In patients with functional dyspepsia (FD), mild duodenal inflammation correlates with increased mucosal permeability. Enteric glial cells can produce glial cell line-derived neurotrophic factor (GDNF) to repair disrupted epithelial barrier function. AIMS: We examined the role of duodenal GDNF in FD pathophysiology and its association with dyspeptic symptoms. METHODS: Duodenal biopsies taken from FD patients and control subjects were used for analysis. GDNF protein expression and localization were examined. Cellular infiltration of eosinophils and mast cells was measured. We also examined the intercellular space between the adjacent epithelial cells at the apical junction complex using transmission electron microscopy. RESULTS: In FD patients, expression of GDNF protein was significantly increased compared with controls, 107.3 (95.3-136.7) versus 49.3 (38.0-72.6) pg/mg protein (median (interquartile range), p = 0.006), respectively. GDNF was localized in enteric glial cells, eosinophils, and epithelial cells. The number of eosinophils was significantly greater in FD patients than in controls, 1039 (923-1181) versus 553 (479-598) cells/mm2 (p = 0.021), respectively. The intercellular space was dilated at the adherent junction in FD patients compared to control patients, 32.4 (29.8-34.8) versus 22.0 (19.9-26.1) nm (p = 0.002), respectively. Intercellular distance positively correlated with the frequency of postprandial fullness and early satiation (p = 0.001, r = 0.837 and p = 0.009, r = 0.693, respectively). Expression of GDNF correlated with epigastric burning (p = 0.041, r = 0.552). CONCLUSIONS: Increased expression of duodenal GDNF might be involved in FD pathophysiology and symptom perception.