Esophageal submucosal hematoma during transnasal endoscopy: A rare case report.

Esophageal submucosal hematoma is a rare, often incidental complication of therapeutic endoscopic procedures marked by disrupted blood vessels beneath the esophageal mucosa, forming a hematoma. We report the unique case of a severely thin and alcoholic 38-year-old woman with a history of reflux esophagitis who developed an esophageal submucosal hematoma during an unsedated transnasal endoscopy for health check-up. During the procedure, the patient experienced strong vomiting reflexes and vomited blood, leading to the initial suspicion of either Mallory-Weiss syndrome or epistaxis. However, subsequent sedated endoscopy revealed an esophageal submucosal tumor-like lesion and a mucosal laceration with blood clots, prompting a dual diagnosis of esophageal submucosal hematoma and Mallory-Weiss syndrome. The bleeding was not severe enough to require hemostatic intervention. The patient opted for conservative treatment with vonoprazan, which resulted in the improvement and healing of the hematoma within 28 days. This is the first report of an esophageal submucosal hematoma during transnasal endoscopy and emphasizes the importance of including an esophageal submucosal hematoma and Mallory-Weiss syndrome in the differential diagnosis of hematemesis encountered in similar scenarios. Factors such as severe thinness, daily alcohol consumption, and reflux esophagitis may have possibly contributed to the development of the esophageal submucosal hematoma in this patient.

Chronological improvement of survival in patients with advanced gastric cancer over 15 years.

Background: Recent trials have reported a median overall survival (OS) of 11-17 months in patients with advanced gastric cancer (AGC). However, it is unclear how recently approved drugs contribute to patient prognosis. Objectives: We aimed to evaluate the characteristics and survival in patients with AGC over the past 15 years. Design: Retrospective study. Methods: We evaluated data of 1355 patients with AGC who received first-line chemotherapy between January 2005 and March 2019 at a single institution. We compared the characteristics and survival rates across four periods: January 2005-December 2007 (period A), January 2008-February 2011 (period B), March 2011-May 2015 (period C), and June 2015-March 2019 (period D). The median follow-up duration was 13.1 months, with 312, 333, 393, and 317 patients in periods A, B, C, and D, respectively. Results: There were no significant differences in patient characteristics between the four periods, except for the proportion of patients who underwent prior gastrectomy and human epidermal growth factor receptor 2 (HER2) testing. Patients in period D had significantly longer OS than those in period A [median: 15.7 versus 12.4 months; adjusted hazard ratio (aHR): 0.79; p = 0.02]. The mean OS in patients with liver metastasis (LM) in period D was remarkably longer than that in patients in period A (median: 19.3 versus 12.4 months; aHR: 0.61; p < 0.01), while that in patients with peritoneal metastasis showed limited improvement. Conclusion: Clinical strategy changes, including gastrectomy, HER2 testing, and approval of new drugs, may be associated with improved OS in patients with AGC. In the last 4 years, a remarkable improvement has been observed in patients with LM.

Differential Efficacy of Targeted Monoclonal Antibodies in Left-Sided Colon and Rectal Metastatic Cancers.

BACKGROUND: The recommended first-line chemotherapy for RAS/BRAF wild-type metastatic colorectal cancer (mCRC) is bevacizumab (BEV)-containing therapy for right-sided colon cancer (R) and antiepidermal growth factor receptor antibody (anti-EGFR)-containing therapy for left-sided colon cancer (L) or rectal cancer (RE). However, anatomical or biological heterogeneity reportedly exists between L and RE. Therefore, we aimed to compare the efficacies of anti-EGFR and BEV therapies for L and RE, respectively. METHODS: We retrospectively reviewed 265 patients with KRAS (RAS)/BRAF wild-type mCRC treated with fluoropyrimidine-based doublet chemotherapy plus anti-EGFR or BEV as the first-line treatment at a single institution. They were divided into 3 groups: R, L, and RE. Overall survival (OS), progression-free survival (PFS), objective response rate, and conversion surgery rate were analyzed. RESULTS: Forty-five patients had R (anti-EGFR/BEV: 6/39), 137 patients had L (45/92), and 83 patients had RE (25/58). In patients with R, both median (m) PFS and OS were superior with BEV therapy (mPFS, anti-EGFR vs. BEV: 8.7 vs. 13.0 months, hazard ratio [HR]: 3.90, P = .01; mOS, 17.1 vs. 33.9 months, HR: 1.54, P = .38). In patients with L, better mPFS and comparable mOS with anti-EGFR therapy were observed (mPFS, 20.0 vs. 13.4 months, HR: 0.68, P = .08; mOS, 44.8 vs. 36.0 months, HR: 0.87, P = .53), whereas, in patients with RE, comparable mPFS and worse mOS with anti-EGFR therapy were observed (mPFS, 17.2 vs. 17.8 months, HR: 1.08, P = .81; mOS, 29.1 vs. 42.2 months, HR: 1.53, P = .17). CONCLUSIONS: Efficacies of anti-EGFR and BEV therapies may differ between patients with L and RE.

Clinical outcomes of patients diagnosed with cancer of unknown primary or malignancy of undefined primary origin who were referred to a regional cancer center.

BACKGROUND: A regional cancer hospital has been identified to be crucial in the management of malignancies of undefined primary origin (MUO) and cancer of unknown primary (CUP). This hospital primarily consists of oncologists with expertise in CUP, pathologists, and interventional radiologists. Early consultation or referral of MUO and CUP to a cancer hospital is deemed important. METHODS: This study retrospectively collected and analyzed the clinical, pathological, and outcome data of all patients (n = 407) referred to the Aichi Cancer Center Hospital (ACCH) in Japan over an 8-year period. RESULTS: In total, 30% of patients were referred for a second opinion. Among 285 patients, 13% had non-neoplastic disease or confirmed primary site and 76% had confirmed CUP (cCUP), with 29% of cCUP being identified as favorable risk. In 155 patients with unfavorable-risk CUP, 73% had primary sites predicted by immunohistochemistry (IHC) and distribution of metastatic sites, whereas 66% of them received site-specific therapies based on the predicted primary sites. The median overall survival (OS) was found to be poor in patients with MUO (1 month) and provisional CUP (6 months). In addition, the median OS of 206 patients with cCUP treated at the ACCH was 16 months (favorable risk, 27 months; unfavorable risk, 12 months). No significant difference was noted in OS between patients with non-predictable and predictable primary-sites (13 vs 12 months, p = 0.411). CONCLUSION: The outcome of patients with unfavorable-risk CUP remains to be poor. Site-specific therapy based on IHC is not recommended for all patients with unfavorable-risk CUP.

Short bevacizumab infusion as an effective and safe treatment for colorectal cancer.

Bevacizumab is a humanized monoclonal antibody that contains <10% murine protein. To prevent infusion-related hypersensitivity reactions (HSRs), the initial bevacizumab infusion is delivered for 90 min, the second for 60 min and subsequent doses for 30 min. Several previous studies have shown that short bevacizumab infusions are safe and do not result in severe HSRs in patients with colorectal, lung, ovarian and brain cancer. However, the efficacy of short bevacizumab infusions for colorectal cancer management remains unclear. Therefore, to investigate this issue, a prospective multicenter study was conducted using 23 patients enrolled between June 2017 and March 2019. The initial infusion of bevacizumab was for 30 min followed by a second infusion rate of 0.5 mg/kg/min (5 mg/kg over 10 min and 7.5 mg/kg over 15 min. The primary endpoint was progression-free survival (PFS). The overall response and disease control rates were 57 and 87%, respectively. The median PFS time was 306 days (interquartile range, 204-743 days). No HSRs were noted. Adverse events associated with bevacizumab included grade 4 small intestinal perforation and grade 3 stroke in 1 patient each. These results suggest that a short bevacizumab infusion regime comprising an initial infusion for 30 min followed by a second infusion at 0.5 mg/kg/min is safe and efficacious for the management of colorectal cancer.

Clinical and microbiological features of obstructive cholangitis with bloodstream infection caused by Pandoraea apista identified by MALDI-TOF mass spectrometry and ribosomal RNA sequencing in a cancer patient.

BACKGROUND: Pandoraea species are multidrug-resistant glucose-nonfermenting gram-negative bacilli that are usually isolated from patients with cystic fibrosis (CF) and from water and soil. Reports of diseases, including bloodstream infections, caused by Pandoraea spp. in non-CF patients are rare, and the clinical and microbiological characteristics are unclear. The identification of Pandorea spp. is limited by conventional microbiological methods and may be misidentified as other species owing to overlapping biochemical profiles. Here, we report the first case of obstructive cholangitis with bacteremia caused by Pandoraea apista in a patient with advanced colorectal cancer. A 61-year-old man with advanced colorectal cancer who underwent right nephrectomy for renal cell carcinoma 4 years earlier with well-controlled diabetes mellitus was admitted to our hospital with fever for 2 days. The last chemotherapy (regorafenib) was administered approximately 3 weeks ago, and an endoscopic ultrasound-guided hepaticogastrostomy was performed 2 weeks ago under hospitalization for obstructive jaundice. Two days prior, he presented with fever with chills. He was treated with piperacillin-tazobactam for obstructive cholangitis and showed improvement but subsequently presented with exacerbation. Bacterial isolates from the blood and bile samples were identified as P. apista using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) and 16S ribosomal RNA sequencing. Based on the susceptibility results of the isolates, he was successfully treated with oral trimethoprim-sulfamethoxazole 160 mg/800 mg/day for 14 days for P. apista infection. CONCLUSIONS: Pandoraea species are often misidentified. Therefore, multiple approaches should be used to identify them, and decisions regarding antimicrobial treatment should be based on actual in vitro susceptibility. Only seven cases of Pandoraea spp. bloodstream infections have been reported, and we report the first case of cholangitis with bacteremia.

Gastrointestinal IgG4 Deposition Is a New Histopathological Feature of Eosinophilic Gastroenteritis.

BACKGROUND: The pathogenesis of eosinophilic esophagitis involves immunoglobulin G4 (IgG4) deposition. However, the relationship between IgG4 and eosinophilic gastroenteritis (EGE) is unclear. AIMS: To investigate gastrointestinal deposition of IgG4 in EGE. METHODS: Biopsies of the esophagus, stomach, and small intestine were evaluated in patients with and without EGE. Immunohistochemical staining for IgG4 was performed, and the proportions of the stained areas were compared. Sera from patients with EGE were assayed for food-specific IgG4, including egg white, wheat, rice, soy, and cow milk. RESULTS: Seventeen patients were included in this study (EGE group, n = 10; control group, n = 7). Compared with the control group, the proportion of IgG4-stained area in the EGE group was approximately threefold higher (40.2% [32.3-49.5]) vs. 12.1% [4.0-21.9], p = 0.014) in the esophagus, fivefold higher in the stomach (17.3% [11.1-26.2] vs. 3.7% [1.5-5.2], p = 0.014), and sixfold higher in the small intestine (28.0% [15.0-33.2] vs. 4.5% [2.6-9.8], p = 0.019). There was no significant association between the proportion of IgG4-stained area and the number of infiltrating eosinophils. Serum egg white-specific IgG4 levels were correlated with the proportion of IgG4-stained areas in the small intestine (R = 0.7, p = 0.035). CONCLUSIONS: IgG4 accumulated within the gastrointestinal mucosa in EGE. The positive correlation between serum egg white-specific IgG4 levels and the proportion of IgG4-stained areas in the small intestine suggests a role for IgG4 in the disease pathophysiology.

Impact of the COVID-19 Pandemic on Patients with Gastrointestinal Cancer Undergoing Active Cancer Treatment in an Ambulatory Therapy Center: The Patients' Perspective.

BACKGROUND: The mortality risk increases greatly in patients with cancer if they are infected with severe acute respiratory syndrome coronavirus 2. The new American Society of Clinical Oncology (ASCO) and the European Society of Medical Oncology (ESMO) guidelines for the COVID-19 pandemic suggested modifications to the standards of care to reduce harm from treatment. However, it is unclear whether these changes suit the wishes of patients. METHODS: We conducted a survey of patients with gastrointestinal cancer who were undergoing active chemotherapy in our ambulatory therapy center between 17 August and 11 September 2020. The survey comprised 18 questions on five topics: patient characteristics, lifestyle changes, disturbance in their psychological health, thoughts on the cancer treatment, and infection control in the hospital. RESULTS: Among the 63 patients who received the questionnaire, 61 participated in the study. The COVID-19 pandemic has led to changes in their lifestyles and substantially impacted their psychological wellbeing. The incidence of anxiety and insomnia has considerably increased during the pandemic. However, female patients and patients aged 70 years or older reported no notable differences. There was no significant difference in the responses to the questions regarding thoughts on the cancer treatment. CONCLUSION: Our study revealed that the COVID-19 pandemic has substantially impacted patients' lifestyles and psychological wellbeing. However, most patients preferred to continue their usual treatment without any change to their treatment plan. It is important to involve the patient in the decision-making process when formulating treatment goals.

A case of nivolumab-induced cervical lymphadenopathy in a patient with gastric cancer.

Nivolumab is a monoclonal antibody targeting programmed cell death-1 (PD-1) that has been recently shown to exhibit clinical efficacy in patients with gastric cancer. However, various degrees of immune-related adverse events (irAEs) have been reported. We report the case of a 71-year-old male patient diagnosed with gastric cancer with peritoneal metastases. He was treated with nivolumab as third-line chemotherapy. On the 10th day after completing seven cycles of nivolumab treatment, he urgently visited the hospital because of mild left cervical lymphadenopathy. We suspected it to be due to inflammation and initiated treatment with levofloxacin hydrate. However, 3 days later, he was admitted to the emergency room due to exacerbation of his lymphadenopathy. A diagnosis of nivolumab-induced lymphadenopathy was made as the antibiotics were ineffective, and the patient was administered prednisolone (PSL) 20 mg. One day after admission, the pain and swelling of the lymph node greatly lessened, and the following day, the pain gradually disappeared; thereafter, the PSL dose was tapered and nivolumab treatment was resumed. The patient again developed cervical lymphadenopathy approximately 4-5 days after nivolumab was reintroduced, which disappeared 1 week later. During each episode of lymphadenopathy, he received a dose of 20 mg of PSL for 4 days, which would be eventually tapered to 10 mg without antibiotics and NSAIDs. After 2 months, cervical lymphadenopathy completely disappeared while 10 mg of PSL was continued, which was also eventually tapered off. To our knowledge, this is the first case report of nivolumab-induced lymphadenopathy in a patient with gastric cancer. This case suggested that we should keep in mind that various irAEs may occur during treatment with immune checkpoint inhibitors. It is necessary to ensure the absence of infection and metastasis before treatment and to promptly administer systemic corticosteroids to address them.

Classification of patients with esophageal eosinophilia by patterns of sensitization revealed by a diagnostic assay for multiple allergen-specific IgEs.

BACKGROUND: Eosinophilic esophagitis (EoE) is considered to be an immunoglobulin E (IgE)-mediated allergic disorder. Our goal was to examine IgE-mediated allergic sensitization patterns in patients with esophageal eosinophilia (EE). METHODS: We enrolled subjects with EE who underwent evaluation with a diagnostic panel to document multiple allergen-specific IgEs. Statistically significant groups were identified by cluster analysis. We also defined allergens based on their characteristics including outdoor, indoor, plant, and animal allergens. RESULTS: We classified patients with EE into 3 distinct groups, including cluster 1 (n = 62) who were minimally sensitized to most allergens except pollen and house dust, cluster 2 (n = 30) who were hypersensitized to outdoor and plant allergens, and cluster 3 (n = 15) who were hypersensitized to most allergens, most notably to indoor and animal allergens. Dysphagia reported among those in clusters 1, 2, and 3 at 35.5%, 46.7%, and 73.3%, respectively, (p = 0.028) and EoE endoscopic reference scores (EREFS) at 3.0, 6.0, and 8.0, respectively, (p < 0.001) differed significantly between the 3 clusters. Those in cluster 3 had a significantly higher prevalence of dysphagia (35.5% vs. 73.3%, p = 0.030), and higher EREFS with respect to rings (0.3 vs. 0.9, p = 0.003) and strictures (0.0 vs. 0.13, p = 0.011) compared to those in cluster 1. CONCLUSIONS: IgE-mediated allergic sensitization patterns are associated with clinical features of patients with EE. Use of a diagnostic panel that detects multiple allergen-specific IgEs can help to explain the heterogeneous phenotype of this patient cohort.

Role of nucleotide binding oligomerization domain-like receptor protein 3 inflammasome in stress-induced gastric injury.

BACKGROUND AND AIM: The inflammasomes promote pro-caspase-1 cleavage, leading to processing of pro-interleukin (IL)-1ß into its mature form. We investigated the role of the IL-1ß and nucleotide binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome in gastric injury in mice receiving water-immersion restraint stress (WIRS), focusing on the cyclooxygenase (COX)-2/prostaglandin (PG) E2 axis. METHODS: To induce gastric injury, the mice were placed in a restraint cage and immersed in the water bath to the level of the xiphoid process. Protein levels of mature caspase-1 and IL-1ß were assessed by western blotting. RESULTS: Water-immersion restraint stress induced gastric injury with increase in IL-1ß expression by activation of NLRP3 inflammasome. Exogenous IL-1ß attenuated the injury, whereas anti-IL-1ß neutralizing antibody and IL-1ß receptor antibody aggravated it. NLRP3-/- and caspase-1-/- mice enhanced the injury with reducing of mature IL-1ß, and this aggravation was reduced by exogenous IL-1ß supplementation. Toll-like receptor 4-/- mice were hyporesponsive to WIRS in terms of mature IL-1ß production. Rabeprazole attenuated the injury with preventing inflammasome activation. WIRS injured the stomach with promotion of COX-2 mRNA and PGE2 production, and exogenous IL-1ß enhanced these molecules, while IL-1ß immunoneutralization exerted opposite effect. PGE2 supplementation abolished the hypersensitivity in NLRP3-/- and caspase-1-/- mice through negative regulation of inflammatory cytokines. CONCLUSION: These results suggest that NLRP3 inflammasome-derived IL-1ß plays a protective role in stress-induced gastric injury via activation of the COX-2/PGE2 axis. Toll-like receptor 4 signaling and gastric acid may be involved in NLRP3 inflammasome activation.

NOD-Like Receptor Family Pyrin Domain-Containing 3 Inflammasome Activation Exacerbates 5-Fluorouracil-Induced Small Intestinal Mucositis via Interleukin-1ß Activation.

BACKGROUND AND AIM: 5-Fluorouracil (5-FU) is an anticancer agent that induces intestinal mucositis, which causes diarrhea and dehydration. The NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is responsible for inflammatory response activation via caspase-1 cleavage and subsequent interleukin-1ß (IL-1ß) and IL-18 activation and secretion. The objective of this study was to determine the role of the NLRP3 inflammasome in 5-FU-induced small intestinal mucositis. METHODS: Small intestinal mucositis was induced in wild-type, NLRP3-/-, and caspase-1-/- mice by intraperitoneal injection of 5-FU. Some mice received intraperitoneal injection of a caspase-1 inhibitor, recombinant IL-1ß or IL-18, or neutralizing antibody against IL-1ß. RESULTS: Mice treated with 5-FU developed small intestinal mucositis with diarrhea and body weight loss, characterized by a decrease in villus height and the villus height-to-crypt depth ratio. These histological changes peaked on day 3 and were accompanied by an increase in mRNA expression of NLRP3 and IL-1ß and protein expression of cleaved caspase-1 and mature IL-1ß. Mature IL-18 protein expression was not affected by 5-FU administration. NLRP3-/- mice exhibited less severe 5-FU-induced mucositis, and this phenotype was mimicked by genetic depletion or pharmacological inhibition of caspase-1. Small intestinal mucositis was aggravated by exogenous IL-1ß and neutralized by IL-1ß antibody treatment. Administration of exogenous IL-18 or anti-IL-18 antibody did not affect any parameters associated with mucositis. NLRP3, cleaved caspase-1, and IL-1ß were expressed by inflammatory cells (mainly macrophages) in the lamina propria and damaged epithelial cells. CONCLUSIONS: NLRP3 inflammasome activation may exacerbate 5-FU-induced small intestinal mucositis via IL-1ß maturation.

Utility of Kyoto Classification of Gastritis in subjects with a high-negative titer of anti-Helicobacter pylori antibody during a medical check-up.

Subjects with a high-negative titer (3-9.9 U/ml) of serum anti-Helicobacter pylori (H. pylori) antibody represent a heterogeneous group of currently H. pylori-infected, H. pylori-uninfected, and previously H. pylori-infected cases. We investigated the characteristics of subjects with a high-negative titer during a medical check-up and the utility of H. pylori infection score, the sum of scores of endoscopic findings based on the Kyoto Classification of Gastritis, for diagnosing H. pylori infection. Subjects with 13C-urea breath test-positive or H. pylori stool antigen test-positive were diagnosed as currently H. pylori-infected. Although around half of subjects with a high-negative titer were after eradication therapy (48.6%), currently H. pylori-infected were considerably confirmed (11.7%). H. pylori infection score showed a high value of area under the receiver operating characteristic curve [0.92; 95% confidence interval (CI), 0.84-1.00] with the most suitable cut-off value of 1.0 (sensitivity: 0.92; specificity: 0.90). Multivariate logistic regression analysis revealed that H. pylori infection score was an independent factor associated with increased prevalence of H. pylori infection (odds ratio, 9.53; 95% CI, 2.64-34.40; p<0.001). Currently H. pylori-infected subjects were considerably included among the subjects with a high-negative titer, and the Kyoto Classification of Gastritis was useful to predict current H. pylori infection.

A Rare Case of Clival Metastasis in a Patient with Gastric Cancer.

We report a rare case of clival metastasis from gastric cancer. A 73-year-old man with advanced gastric cancer treated with nivolumab as a third-line chemotherapy experienced headache, tongue deviation, and difficulties in speaking clearly. We suspected stroke or brain metastasis, but brain contrast-enhanced magnetic resonance imaging demonstrated a clival mass, diagnosed as clival metastasis from gastric cancer. The tumor could not be identified by plain computed tomography and plain magnetic resonance imaging alone. He received palliative radiotherapy (30 Gy/10 fr); his symptoms improved gradually. Although metastasis from gastric cancer to other organs is common, bone metastases are rare.

Gastric acid inhibitor aggravates indomethacin-induced small intestinal injury via reducing Lactobacillus johnsonii.

Proton pump inhibitors (PPIs) alter the composition of the intestinal microbiome, exacerbating indomethacin (IND)-induced small intestinal damage. Vonoprazan fumarate inhibits gastric acid secretion using a different mechanism from PPIs. We investigated the effects of both drugs on the intestinal microbiome and IND-induced small intestinal damage. We sought to clarify whether PPI-induced dysbiosis and worsening of the damage were due to a specific drug class effect of PPIs. Rabeprazole administration increased operational taxonomic unit numbers in the small intestines of C57BL/6 J mice, whereas the difference was not significant in the vonoprazan-treated group but exhibited a trend. Permutational multivariate analysis of variance of the unweighted UniFrac distances showed significant differences between vehicle- and vonoprazan- or rabeprazole-treated groups. L. johnsonii was the predominant microbial species, and the population ratio decreased after vonoprazan and rabeprazole administration. The vonoprazan- and rabeprazole-treated groups showed increased IND-induced damage. This high sensitivity to IND-induced damage was evaluated by transplantation with contents from the small intestine of mice treated with either vonoprazan or rabeprazole. Supplementation of L. johnsonii orally in mice treated with rabeprazole and vonoprazan prevented the increase in IND-induced small intestinal damage. In conclusion, both rabeprazole and vonoprazan aggravated NSAID-induced small intestinal injury by reducing the population of L. johnsonii in the small intestine via suppressing gastric acid secretion.

[A case of pancreatic neuroendocrine tumor with ring-like enhancement].

An 82-year-old female underwent contrast computed tomography (CT) that revealed multiple ring-like enhanced masses in the pancreatic tail. Additionally, the inside of the masses showed enhancement on contrast endoscopic ultrasound (EUS). She was diagnosed with a pancreatic neuroendocrine tumor on histopathological examination after EUS-guided fine-needle aspiration, and distal pancreatectomy and splenectomy were performed. In the resected specimen, toward the tumor center, tumor cells with lipid droplets and fibrosis were remarkably observed. These rare histopathological features well reflected the image findings of contrast CT and contrast EUS.

Involvement of gliadin, a component of wheat gluten, in increased intestinal permeability leading to non-steroidal anti-inflammatory drug-induced small-intestinal damage.

Gliadin, a component of wheat gluten known to be an important factor in the etiology of celiac disease, is related to several other diseases through its enhancing effect on intestinal paracellular permeability. We investigated the significance of gliadin in non-steroidal anti-inflammatory drug (NSAID)-induced small-intestinal damage in mice. 7-week-old C57BL/6 male mice were divided into the following groups: standard diet group, in which mice were fed with wheat-containing standard rodent diet (CE-2); gluten-free diet group, in which mice were fed with gluten-free diet (AIN-76A); and gliadin-administered group, in which mice fed with gluten-free diet were administered with gliadin (~250 mg/kg BW). Each group was subdivided into negative, healthy control group and NSAID-treated group. To some mice fed with gluten-free diet and administered with gliadin, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor was administered for clarification of the significance of EGFR in NSAID-induced small intestinal damage and intestinal permeability. In mice fed with a gluten-free diet, indomethacin or diclofenac induced very mild mucosal damage in the small intestine compared with that in mice fed with a wheat-containing standard diet. Gliadin exacerbated the NSAID-induced small-intestinal damage in mice fed with a gluten-free diet. With the administration of indomethacin, MPO activity, a marker of neutrophil infiltration into the mucosa and mRNA expression level of tumor necrosis factor α and interleukin-1ß in the small intestine were higher in the gliadin-administered mice. Gliadin increased the intestinal paracellular permeability without indomethacin administration (4.3-fold) and further increased the permeability after indomethacin administration (2.1-fold). Gliadin induced phosphorylation of epidermal growth factor receptor (EGFR) in small-intestinal tissues, and erlotinib (an EGFR tyrosine kinase inhibitor) attenuated the indomethacin-induced intestinal damage and permeability exacerbated by gliadin, accompanied by inhibition of EGFR phosphorylation. These results suggest that gliadin plays an important role in the induction and exacerbation of NSAID-induced small-intestinal damage, and that increase in intestinal permeability via the EGFR signalling pathway is involved in its mechanism.