Tsuyoshi Mishiro

Specific locations of linear furrows in patients with esophageal eosinophilia

Linear furrows are the most frequently found endoscopic abnormality in patients with esophageal eosinophilia (EE); however, the precise endoscopic features remain to be fully elucidated. Here, we aimed to clarify the endoscopic features of EE, essential for the diagnosis of eosinophilic esophagitis (EoE), by focusing on the specific locations of linear furrows in a Japanese population.

Diagnosis and treatment of eosinophilic esophagitis in Japan

Patients in Japan affected by eosinophilic esophagitis (EoE), considered to be a dietary allergen related chronic esophageal disease, are slowly increasing. For diagnosis, careful assessments of atopic diathesis and symptoms, an endoscopic examination focusing on EoE characteristic findings, and histopathological examination of appropriate biopsy samples are important. When clinicopathological examination results suggest EoE, proton pump inhibitor (PPI) administration should be attempted to determine the response (PPI-responsive esophageal eosinophilia, PPI-REE). For PPI-refractory cases, oral topical glucocorticoid administration is the first therapeutic option, followed by systemic glucocorticoids as necessary. Evidence-based guidelines are currently under development in Japan for standardizing diagnosis and treatment.

Crosstalk between TLR5 and Notch1 signaling in epithelial cells during intestinal inflammation.

During intestinal inflammation, a variety of signaling events are activated to perform several cell functions. Although the distinct roles of these pathways have been elucidated, the effects of their crosstalk activities remain to be clarified. We evaluated the crosstalk between two evolutionary conserved cell signaling systems, toll-like-receptor (TLR) 5 and Notch1, in intestinal epithelial cells during inflammation. Significant induction of the expression of Notch1 and Jagged1 was observed in the distal part of the colon, together with abundant localization of Notch1 intracellular domain (N1ICD) in the surface epithelium of inflamed colonic mucosa. By targeting intestinal epithelial cells, it was shown that recombination-signal-binding-protein-Jκ (RBP-Jκ)-mediated Notch functions are dependent on a flagellin-TLR5-mediated pathway. Conversely, using a γ-secretase inhibitor, we demonstrated that Notch synergistically increases TLR5‑mediated NF-κB activation. In addition, the effects of Notch on the NF-κB target gene interleukin-6 (IL-6) expression were revealed by evaluating the RBP-Jκ responsive element in the IL-6 promoter in vitro. Modulation of TLR5 and Notch crosstalk by transient blocking of Notch during the acute phase of colitis was beneficial for ameliorating colonic inflammation as well as disease status. In conclusion, the results suggest the effectiveness of Notch-targeted drug strategy for the treatment of intestinal inflammation.

Esophageal triamcinolone acetonide–filling method: a novel procedure to prevent stenosis after extensive esophageal endoscopic submucosal dissection (with videos)

BACKGROUND AND AIMS Endoscopic submucosal dissection (ESD) for extensive esophageal carcinomas may cause severe stenosis requiring endoscopic balloon dilations (EBDs). A standard prevention method has not been established. We propose the esophageal triamcinolone acetonide (TA)-filling method as a novel local steroid administration procedure. METHODS We enrolled 22 consecutive patients with early esophageal cancer who were treated using either subcircumferential or circumferential ESD (15 and 7 procedures, respectively) in this case series. Esophageal TA filling was performed on the day after ESD and 1 week later and was performed again if mild stenosis was found on follow-up. EBD with TA filling was performed only for severe stenosis that prevented endoscope passage. The primary endpoint was the incidence of severe stenosis. Secondary endpoints were the total number of EBDs and additional TA filling, dysphagia score, time to stenosis and to complete re-epithelialization, and any adverse events. RESULTS The incidence of severe stenosis was 4.5% (1/22; confidence interval, .1%-22.8%), and EBD was performed 2 times in 1 patient. Mild stenosis was found in 9 patients. Additional TA filling was performed in 45.5% of patients (10/22; median, 5 times; range, 1-13). The dysphagia score deteriorated to 1 to 2 in 31.8% (7/22) but showed a final score of 0 after complete re-epithelialization in 90.9% (20/22). The median time to stenosis was 3 weeks (range, 3-4) and that to complete re-epithelialization was 7 weeks (range, 4-36). No severe adverse events occurred. CONCLUSIONS The esophageal TA-filling method is highly effective for preventing severe stenosis after extensive esophageal ESD.

Poor inter-observer agreement on the endoscopic diagnosis of eosinophilic esophagitis among Japanese endoscopists

BackgroundA variety of endoscopic findings are considered useful for the diagnosis of eosinophilic esophagitis (EoE). However, the diagnostic consistency among Japanese endoscopists for those findings has not been fully examined. The aim of this study was to investigate the inter- and intra-observer agreement for endoscopic findings suggesting EoE.MethodsForty endoscopists, including 20 with board certification from the Japan Gastroenterological Endoscopy Society (JGES), participated in this study. Initially, they examined 50 randomized white-light endoscopic images from 30 patients with EoE and 20 without EoE. Four weeks later, the same 50 endoscopic images were re-examined in a different random order. Inter- and intra-observer agreement was calculated using kappa statistics for multiple observers.ResultsThe kappa coefficient of reliability [95% confidence interval (CI)] for all 40 endoscopists for diagnosis of EoE was 0.34 (0.33–0.35), indicating poor level of inter-observer agreement, while intra-observer agreement showed a moderate value of 0.52 (0.47–0.57). Among 4 possible endoscopic findings (linear furrows, concentric rings, edema, white exudates) for EoE, acceptable levels (kappa value >0.4) of inter- and intra-observer agreement were seen only for linear furrows. When the JGES board-certified and non-certified endoscopists were compared for successful diagnosis of EoE, the value was significantly higher for the board-certified group. However, the level of inter-observer agreement remained poor level.ConclusionWe concluded that inter-observer agreement on the endoscopic diagnosis of EoE among Japanese endoscopists did not reach a clinically acceptable level.

Mucosal breaks show same circumferential distribution in majority of patients with recurrent reflux esophagitis

Background and study aims Esophageal mucosal breaks in patients with reflux esophagitis (RE) have a unique circumferential distribution. However, the specific location of mucosal breaks during recurrence of RE remains unclear. We investigated the circumferential distribution of mucosal breaks in patients with recurrent RE and compared their location to that noted at the initial diagnosis. Patients and methods We retrospectively enrolled patients with recurrent RE with Los Angeles (LA) grade A-C who were treated at our University Hospital between July 1996 and June 2014. The circumferential distribution of esophageal mucosal breaks was evaluated at the time of the initial diagnosis and again at the time of recurrence. Information regarding clinical parameters, including proton pump inhibitor administration, presence of hiatal hernia, and mucosal atrophy, was also reviewed. Results A total of 114 patients with recurrent RE were examined during the study period, with a mean duration to recurrence after initial diagnosis of 39.4 months. The majority (72.8 %) had the same LA grade at recurrence. In addition, recurrent mucosal breaks in 96 (84.2 %) patients were observed to have occurred in the same circumferential location as at the initial diagnosis, while those in 18 (15.8 %) were observed in a different location. When recurrent lesions had a different location, the LA grade also tended to be different (P = 0.02). Conclusions We found that most patients with recurrent RE developed lesions in the same circumferential location as noted for the initial lesions. Those in different locations at recurrence were associated with a change in LA grade.

Oral microbiome alterations of healthy volunteers with proton pump inhibitor: Influence of PPI on oral microbiota

Acid suppressive agents including proton pump inhibitors (PPIs) are used as first‐line treatment for various acid‐related gastrointestinal disorders. Although known to profoundly reduce gastric acid production, their influence on inhibition of acid secretion as part of the function of the gastrointestinal tract microbiome remains to be elucidated. The aim of the present study was to examine the effects of PPI usage on oral and gut microbiota in healthy volunteers.

Recent progress in the research of Eosinophilic GastroIntestinal Diseases (EGIDs)

Eosinophilic esophagitis (EoE) and eosinophilic gastroenteritis (EGE), which are included in eosinophilic gastrointestinal disorders (EGIDs), are allergic gastrointestinal diseases mainly caused by food allergens, which features dense infiltration of eosinophiles in the gastrointestinal mucosa. A possible mechanism of these diseases are Th2 type allergic reactions, including IL-5, IL-13, and IL-15, thymic stromal protein (TSLP), and eotaxin 3, which are considered to have important roles. The number of patients with EoE is rapidly increasing in both Western and Asian countries. In Japan, a research group of the Ministry of Health, Labor and Welfare has announced recommendations for the diagnosis and management of EoE and EGE in 2015. For a diagnosis of EoE, endoscopic abnormalities and histological confirmation of dense eosinophile infiltration in the esophageal epithelial layer are important, in addition to identifying dysphagia symptoms. As for eosinophilic gastroenteritis, blood test findings are more useful and the role of an endoscopic examination is reduced. Glucocorticoid administration is standard treatment for these diseases, while proton pump inhibitors are frequently effective for EoE. As for EoE, on the one hand, a variety of studies have been performed and new findings collected. On the other hand, information concerning EGE is limited and additional evidence is needed to establish effective treatment options.

Ankylosaurus back sign: novel endoscopic finding in esophageal eosinophilia patients indicating proton pump inhibitor response

Background and study aims  Characteristic endoscopic findings, such as linear furrows, rings, and whitish exudates, indicate the presence of esophageal eosinophilia (EE), though no specific findings are known to distinguish eosinophilic esophagitis (EoE) from proton pump inhibitor-responsive esophageal eosinophilia (PPI-REE). Here, we present a novel endoscopic finding in some EE patients possessing a linear longitudinal arrangement of whitish nodules with the appearance of the back of an Ankylosaurus dinosaur, termed Ankylosaurus back sign (ABS), and evaluations of its significance in affected patients. Patients and methods  Fifty-five patients diagnosed with EE (≥ 15 eosinophils/high power field) who were treated at our hospital and shown to evaluate a PPI response were enrolled. Endoscopic findings at baseline and clinical parameters were retrospectively reviewed. Furthermore, the clinicopathological features of patients with ABS, as well as the relationship between its presence and PPI response were evaluated. Results  Fifty-five patients (47 males, 8 females) with EE (17 with EoE, 38 with PPI-REE) were evaluated, of whom 50 (90.9 %) had linear furrows, the most frequently found feature, while ABS was found in 9 (16.4 %). Inter-observer agreement was substantial for ABS (κ 0.77). Interestingly, all patients with ABS had PPI-REE. Our findings revealed that the presence of ABS was closely associated with reflux esophagitis (RE) in patients with PPI-REE. Conclusions  Although ABS was less frequent than typical endoscopic findings such as linear furrows in EE, this novel finding was closely associated with PPI-REE accompanied with RE. The clinical implications of ABS in patients with EE should be investigated further.

Is Asymptomatic Esophageal Eosinophilia the Same Disease Entity as Eosinophilic Esophagitis

Eosinophilic esophagitis (EoE) is an allergic inflammatory disorder that is characterized clinically by symptoms related to esophageal dysfunction and histologically by eosinophil-predominant inflammation.1,2 Its prevalence has been increasing rapidly in both Western and Asian countries. In Japan, most of the cases of esophageal eosinophilia (EE) are found in an upper endoscopy examination for gastric cancer screening performed during a comprehensive health check-up.3,4 Indeed, we frequently encounter patients with asymptomatic EE showing typical endoscopic findings, such as linear furrows, as well as histologic findings compatible with EoE. However, the current clinical guidelines for EoE diagnosis include symptoms related to esophageal dysfunction, thus patients without symptoms do not fulfill the diagnostic criteria.1,2 The clinical characteristics remain to be fully elucidated,5 thus we aimed to clarify clinical features of asymptomatic EE as compared with those of EoE.