Evaluation of the circumferential location of mild reflux esophagitis (Grade A and B) in the lower esophagus.

Background and Aim: Discrepancies have been reported in the circumferential locations of mild mucosal breaks. We investigated their locations using a new method. Methods: This is a retrospective study. Eighty patients (Grade A/B: 53/27) with mild mucosal breaks in the lower esophagus were examined. Since the 3 o'clock position corresponded to the right wall of the lower esophagus using our method with sufficient accuracy, the circumferential locations of mucosal breaks were identified as times on a clock face, which were changed to circular data to calculate the mean direction. The circumferential distribution of mucosal breaks was evaluated in the single lesion group (single group) and multiple lesion group (multiple group). Results: Forty-eight of 80 patients had 1 mucosal break, while 32 had ≥2 mucosal breaks. Circumferential locations markedly differed between the single and multiple groups. In the single group, mucosal breaks were exclusively distributed between 2 and 7 o'clock, with 50% in the 3 o'clock direction (right wall). In the multiple group, 81 mucosal breaks were distributed circumferentially, not uniformly; however, at least 1 lesion was located between 2 and 7 o'clock in 91% of subjects. Therefore, a factor for the development of mucosal breaks from the right to posterior wall was present in both groups. Conclusion: In the single group, mucosal breaks were localized from the right to posterior wall, mainly in the right wall. In the multiple group, mucosal breaks were located circumferentially, but often between the right lateral and posterior wall. These two distributions significantly differed.Clinical trial registration: This is a retrospective study, so it was not registered.

Definition of Mucosal Breaks in the Era of Magnifying Endoscopy with Narrow-Band Imaging.

Background: Gastroesophageal reflux disease is diagnosed endoscopically based on the presence of mucosal breaks. However, mucosal breaks can be judged differently depending on the endoscopist, even in the same image. We investigated how narrow-band imaging (NBI) and magnified endoscopy affect the judgment of mucosal breaks. Methods: A total of 43 consecutive patients were enrolled who had suspected mucosal breaks on white-light images (WLI) and underwent nonmagnified NBI (N-NBI) and magnified NBI (M-NBI) by a single endoscopist. From WLI, N-NBI, and M-NBI, 129 image files were created. Eight endoscopists reviewed the image files and judged the presence of mucosal breaks. Results: The 8 endoscopists determined mucosal breaks were present in 79.4 ± 9.5% (67.4%-93.0%) on WLI, and 76.7 ± 12.7% (53.5%-90.7%) on N-NBI. However, the percentage of mucosal breaks on M-NBI was significantly lower at 48.8 ± 17.0% (18.6%-65.1%) (p < 0.05). Intraclass correlation between observers was 0.864 (95% CI 0.793-0.918) for WLI and 0.863 (95% CI 0.791-0.917) for N-NBI but was lower for M-NBI at 0.758 (95% CI 0.631-0.854). Conclusion: Rates of detection and agreement for mucosal breaks on WLI and N-NBI were high among endoscopists. However, these rates were lower on M-NBI.

Efficacy of Vonoprazan for Refractory Reflux Esophagitis after Esophagectomy.

BACKGROUND: Refractory reflux esophagitis (RRE), unresponsive to conventional proton-pump inhibitors (PPIs), is a complication in esophagectomy with gastric pull-up. Vonoprazan (VPZ), a novel potassium-competitive acid blocker, has been available in Japan since 2015. Here, we investigated the efficacy of VPZ on PPI-resistant RRE after esophagectomy with gastric pull-up. METHODS: This was a single-center retrospective study. We used the revised Los Angeles (r-LA) classification based on the Los Angeles classification and the modified Los Angeles classification to evaluate abnormal forms of mucosal breaks such as lateral spreading consistently. Patients who underwent esophagectomy with gastric pull-up and had RRE grade B-D as per the r-LA classification, despite using standard-dose PPIs or double dose of rabeprazole, were included. Sixteen patients who switched to VPZ (20 mg/day) and 14 patients who continued PPIs were assigned to the VPZ and PPI groups, respectively. Endoscopic observations were reviewed by 3 endoscopists using the r-LA classification to ensure consistent diagnosis, while the treatment arm and patient information were blinded to evaluators. We defined mucosal breaks that improved by at least one grade after treatment as improved mucosa and recovery to grade M or N as mucosal healing. RESULTS: The percentage of patients with improved mucosa in the VPZ and PPI groups was 81.3 and 14.3%, respectively (p < 0.001). The rate of mucosal healing was 68.8 and 7.1%, respectively (p = 0.001). CONCLUSION: VPZ significantly improved PPI-resistant RRE after esophagectomy with gastric pull-up.

Defining the Position of the Right Wall of the Esophageal Hiatus to Identify the Circumferential Distribution of Small Lesions of the Lower Esophagus.

BACKGROUND: The reliability of methods for identifying the circumferential position of small lower esophageal lesions is unknown. We prospectively investigated a new method that presents lesion positions as times on a clock face. METHODS: Eighty-seven patients were consecutively examined by endoscopy. After observing the esophagus, an endoscope was inserted into the stomach and fixed, and the greater curvature folds at the upper gastric corpus were set as horizontal on the endoscope monitor display. The scope was retrogressed into the lower esophagus. At this point, the right wall at the hiatus is at the 3 o'clock position (R-line). The scope was then retrogressed from the gastric angle to the cardia along the center of the lesser curvature in the retroflexed view to obtain the LC-line (the center of the lesser curvature at the cardia). The LC-line in the esophageal hiatus in the frontal view was then identified, and the angle between the R- and LC-lines (R-LC) was measured. RESULTS: After excluding 7 patients with hernias >2 cm and 3 with esophageal stenosis, data from 77 patients were analyzed. The R-LC angle ranged from -38° to +35°. The mean R-LC angle was -0.3°± 15.9°, and its 95% confidence interval was [-4.0°, 3.3°] within [-15°, + 15°]. When indicating lesion locations as times on a clock face, there was an error of ±30 min (±15°); therefore, R- and LC-lines were shown to be identical on an equivalence test. CONCLUSIONS: This new method allows the circumferential position of small lower esophageal lesions to be reliably represented as a clock face.

Columnar epithelium morphology after esophagectomy: clinical insight into the development of Barrett's esophagus.

BACKGROUND: The presence of Barrett's mucosa in the esophageal remnant is a result of post-esophagectomy anastomotic site exposure to gastric acid and is regarded as a human model of Barrett's esophagus onset. Here, we attempted to clarify the relationship between duodenogastric reflux and formation of columnar epithelium by following the changes over time after esophagectomy. METHODS: A total of 96 patients underwent esophagectomy due to superficial cancer from April 2000 to March 2018 were included in this study. Cases were divided into two groups according to the reconstruction technique after esophagectomy as either the gastric pull-up (Ga) group and ileocolonic interposition (Ic) group. Previously obtained endoscopic pictures of the cases were reviewed retrospectively and chronologically. RESULTS: There were 24 cases of columnar epithelium in the Ga group (42%) and 1 in the Ic group (2.6%) (P < 0.01) with 32 reflux cases (56%) in the Ga group and 1 (2.6%) in the Ic group (P < 0.01). Reflux precedes the development of columnar epithelium in both the Ga- and Ic groups. Multivariate analysis revealed surgical technique (odds ratio 10.6, 95% CI 1.2-97.5, P = 0.037) and reflux (odds ratio 4.5, 95% CI 1.3-15.6, P = 0.0017) as risk factors. CONCLUSIONS: The development of columnar epithelium was preceded by reflux comprising principally gastric acid and was strongly associated with a strong inflammatory state.

Efficacy of Vonoprazan for Proton Pump Inhibitor-Resistant Reflux Esophagitis.

BACKGROUND: Vonoprazan (VPZ) is a novel potassium-competitive acid blocker that may be clinically beneficial for proton pump inhibitor (PPI)-resistant reflux esophagitis (RE). The aim of this study was to investigate the efficacies of VPZ therapy at 20 mg for 4 weeks in patients with PPI-resistant RE and VPZ maintenance therapy at 10 mg for 8 weeks in patients who have been successfully treated. METHODS: Subjects comprised 24 patients with PPI-resistant RE (Los Angeles classification grade A/B/C/D: 3/7/11/3). After confirming PPI-resistant RE by endoscopy, 20 mg VPZ was administered. Endoscopy was performed 4 weeks after the initiation of VPZ. Symptoms were evaluated using the frequency scale for the symptoms of gastroesophageal reflux disease (FSSG). Maintenance therapy with 10 mg VPZ was performed and endoscopy was conducted after 8 weeks. RESULTS: In 21 (87.5%) out of 24 patients, esophageal mucosal breaks were successfully treated by 20 mg VPZ. The median FSSG score was significantly lower on days 1-7, 14, and 28 after the initiation of VPZ than before its administration. Maintenance therapy with 10 mg VPZ prevented the relapse of esophageal mucosal breaks in 16 (76.2%) out of 21 patients. CONCLUSION: VPZ was effective for most patients with PPI-resistant RE.

Pathogenesis of Double-Dose Proton Pump Inhibitor-Resistant Non-Erosive Reflux Disease, and Mechanism of Reflux Symptoms and Gastric Acid Secretion-Suppressive Effect in the Presence or Absence of Helicobacter pylori Infection.

BACKGROUND: Various mechanisms have been suggested to be responsible for contributing to the occurrence of proton pump inhibitor (PPI)-resistant non-erosive reflux disease (NERD). The aims of this study were to clarify the pathogenesis of PPI-resistant NERD. METHODS: Fifty-three patients with NERD, who had persistent reflux symptoms despite taking double-dose PPI, were included in this study. After excluding eosinophilic esophagitis (EoE) and primary esophageal motility disorder, esophageal impedance-pH monitoring was carried out. In symptom index (SI)-positive patients, the mechanism of SI positivity and the percent time with intragastric pH >4 were investigated according to the presence or absence of Helicobacter pylori infection. RESULTS: One of the 53 patients had EoE, and 4 had primary esophageal motility disorder. Twenty-three and 2 patients were SI-positive for liquid and gas-only reflux respectively. Of 17 SI-positive, H. pylori-negative patients, 5 were SI-positive for acid reflux, whereas all of the H. pylori-positive patients were SI-positive for non-acid reflux. The percent time with intragastric pH >4 was significantly lower in the H. pylori-negative patients than in the H. pylori-positive patients. CONCLUSIONS: The pathogenesis of double-dose PPI-resistant NERD was identified in 57%. In some of H. pylori-negative patients, acid-related symptoms were observed. However, in H. pylori-positive patients, these symptoms were excluded by taking double-dose PPI.

Evidence-based clinical practice guidelines for gastroesophageal reflux disease 2015.

As an increase in gastroesophageal reflux disease (GERD) has been reported in Japan, and public interest in GERD has been increasing, the Japanese Society of Gastroenterology published the Evidence-based Clinical Practice Guidelines for GERD (1st edition) in 2009. Six years have passed since its publication, and there have been a large number of reports in Japan concerning the epidemiology, pathophysiology, treatment, and Barrett's esophagus during this period. By incorporating the contents of these reports, the guidelines were completely revised, and a new edition was published in October 2015. The revised edition consists of eight items: epidemiology, pathophysiology, diagnosis, internal treatment, surgical treatment, esophagitis after surgery of the upper gastrointestinal tract, extraesophageal symptoms, and Barrett's esophagus. This paper summarizes these guidelines, particularly the parts related to the treatment for GERD. In the present revision, aggressive proton pump inhibitor (PPI) maintenance therapy is recommended for severe erosive GERD, and on-demand therapy or continuous maintenance therapy is recommended for mild erosive GERD or PPI-responsive non-erosive GERD. Moreover, PPI-resistant GERD (insufficient symptomatic improvement and/or esophageal mucosal break persisting despite the administration of PPI at a standard dose for 8 weeks) is defined, and a standard-dose PPI twice a day, change in PPI, change in the PPI timing of dosing, addition of a prokinetic drug, addition of rikkunshito (traditional Japanese herbal medicine), and addition of histamine H2-receptor antagonist are recommended for its treatment. If no improvement is observed even after these treatments, pathophysiological evaluation with esophageal impedance-pH monitoring or esophageal manometry at an expert facility for diseases of the esophagus is recommended.

Endoscopic classification of reflux esophagitis.

It is important to accurately classify the severity of reflux esophagitis, because the clinical response to treatment is dependent on the severity of erosive lesions. In Japan we had used Savary-Miller classification for endoscopic grading. In this classification stage I to III encompass mucosal erosions of increasing extent, while stage IV includes all complications, which make it difficult to follow the evolution of the esophagitis and its response to treatment. A new endoscopic classification was proposed at the World Congress of Gastroenterology in Los Angeles in 1994. A mucosal break was emphasized which was defined as an area of slough or erythema with a sharp demarcation between it and the adjacent mucosa. Mucosal breaks are classified into 4 grades from A to D according to their extension. The complica- tions are not included in this grading system. Japanese study revealed that only 20 % of patients with heartburn had grade Aio D. This means that LA classification is insufficient at least in Japan. We have proposed,the modified LA classification including grade M and N, adding the original classification. Grade M pre- sents minimal change esophagitis and an undemarcated erythema after treatment of the muco- sal break using H2 blocker or PPI, whilst grade N represents no findings of esophagitis. Now this modified LA classification is widely used in Japan.

Histopathological diagnosis of adenocarcinoma in Barrett's esophagus.

The present review describes the histological markers of Barrett's esophagus (BE) that make it possible to distinguish between Barrett's carcinoma (BC) and gastric carcinoma. With regard to high-grade dysplasia, the indications for endoscopic resection (ER) or major surgery for management of BC cannot be decided on the basis of biopsy histology, and the choice between them should be made according to BC invasion depth. Therefore, we recommend that the term 'well-differentiated tubular adenocarcinoma' be used rather than 'high-grade dysplasia' (intraepithelial neoplasia). High-grade dysplasia is regarded as BC in Japan and other countries such as Germany. Such lesions should not be treated by endoscopic ablation but by ER, because components of invasive carcinoma are frequently present in the mucosa and submucosa, and knowledge obtained from ER samples is needed for additional therapy. Further studies on the relationship between the incidence of nodal metastasis and mucosal depth in mucosal BC are needed to decide the indications for ER. Suchstudies should involve subserial microscopic examination of slices 2-3 mm thick. To resolve the issue of regression of high-grade dysplasia, international experts in gastroenterological pathology need to conduct histopathological reviews of the first and last samples taken from such cases, as there are large differences between North American, European, and Japanese pathologists in the criteria used for histological diagnosis of dysplasia and adenocarcinoma without clear invasion, and both interobserver and intraobserver variations have been reported. Future studies will need to focus on which carcinomas are curable by ER.

Digestive disease management in Japan: a report on the 6th diagnostic pathology summer fest in 2012.

The 6th Diagnostic Pathology Summer Fest, held in Tokyo on August 25-26, 2012, opened its gates for everyone in the medical profession. Basic pathology training can contribute to the improvement of algorithms for diagnosis and treatment. The 6th Summer Fest with the theme 'Pathology and Clinical Treatment of Gastrointestinal Diseases' was held at the Ito International Research Center, The University of Tokyo. On August 25, 'Treatment of Early Gastrointestinal Cancer and New Guidelines' was discussed in the first session, followed by 'Biopsy Diagnosis of Digestive Tract: Key Points of Pathological Diagnosis for Inflammation and Their Clinical Significance' in the second session. On August 26, cases were discussed in the third session, and issues on pathological diagnosis and classification of neuroendorcrine tumor in the fourth session. The summaries of speeches and discussions are introduced along with the statements of each speaker. This meeting was not a formal evidence-based consensus conference, and 20 experts gave talks on their areas of specialty. Discussion was focused on how the management strategy should be standardized on the algorithm of patient care.

Apurinic/apyrimidinic endonuclease-1 (APE-1) is overexpressed via the activation of NF-κB-p65 in MCP-1-positive esophageal squamous cell carcinoma tissue.

Apurinic/apyrimidinic endonuclease-1 (APE-1), a key enzyme responsible for DNA base excision repair (BER), has been linked to cancer chemoradiosensitivity. The phosphorylation of p65 plays a role in the activation of this pathway. In this study, we investigated APE-1 expression and its interaction with p65 in esophageal squamous cell carcinoma (ESCC) tissue. The expression of APE-1, p65, p65 nuclear localization sequence (p65-NLS), and monocyte chemoattractant protein-1 (MCP-1) was assessed by immunohistochemical analysis in 67 human ESCC tissue samples. Real-time PCR and western blotting were also performed. p65 siRNA was evaluated to determine the role of p65 in the regulation of APE-1 expression. We found nuclear localization of APE-1 in 89.6% (60/67) of ESCC tissue samples. We also observed the colocalization of p65-NLS and APE-1 in esophageal cancer tissue. In KYSE220 cells, pretreatment of MG-132 significantly abrogated upregulation of p65 and APE-1 levels induced by MCP-1, and treatment with 10 and 20 nM p65 siRNA significantly inhibited APE-1 mRNA expression. siRNA for p65 treatment significantly increased the apoptotic index in 5-FU-treated KYSE220 cells. We conclude that APE-1 is overexpressed and mainly localized in the nuclear compartment of cancer cells, and partly regulated by p65 in the NF-κB pathway in ESCC tissue.

Palisade vessels as a new histologic marker of esophageal origin in ER specimens from columnar-lined esophagus.

It is difficult for surgical pathologists to determine the origin of tissues in samples taken from the columnar-lined esophagus (CLE) or stomach by biopsy or endoscopic resection (ER) on the basis of histologic examination alone. We examined histopathologically a single section (5 to 22 mm in size; mean, 12 mm) from each of 66 cases of CLE (36 short segments, 30 long segments) from German patients with reference to 3 histologic markers of esophageal origin: esophageal glands proper and/or ducts, squamous islands, and double muscularis mucosae, all of which had been reported previously, and palisade vessels as a new histologic parameter as well. Palisade vessels were defined histologically as veins >100 µm in size in and above the original muscularis mucosae. Esophageal glands proper and/or ducts, squamous islands, and double muscularis mucosae were seen in 33%, 18%, and 71% of the specimens, respectively. Palisade longitudinal vessels were observed in 78% and 63% of specimens of short-segment and long-segment CLE, respectively. Palisade vessels were never seen in ER specimens from the stomach or in the middle esophagus and stomach among control autopsy specimens. At least 1 of these 4 markers was seen in 88% of the sections. Therefore, ER specimens were confirmed to originate from CLE in 88% of single histologic sections of CLE on the basis of histologic examination alone.

The effects of nizatidine on transient lower esophageal sphincter relaxations (TLESRs) and acid reflux in healthy subjects.

BACKGROUND: A study in Japan has found that nizatidine (NIZ) is more effective than other histamine H2 receptor agonists (H2RAs) in treating reflux esophagitis (RE), although the NIZ group included a greater number of patients with severe RE. As there was no difference in the level of acid suppression among H2RAs, it is possible that NIZ has other effects on esophageal acid exposure (EAE) besides acid suppression. In this study, the effect of NIZ on transient lower esophageal sphincter relaxations (TLESRs) and acid reflux was evaluated in healthy subjects. METHODS: In 10 healthy subjects, while in a sitting position, esophageal motility and a pH study were measured for 3 hours after a meal on 2 separate days at least 2 weeks apart. Participants received an oral dose of 150 mg of NIZ, 60 min before the meal on one day and a placebo on the other. Both studies were preceded by a week of treatment with either NIZ (150 mg, bid) or a placebo and the order of treatment was randomized. RESULTS: Basal LES pressure in the NIZ group (14.1 mmHg, median) was significantly greater than that of the placebo group (8.5 mmHg). The rate of TLESRs in the NIZ group (22.0/3 h) for the postprandial 3-hour period was significantly less than that of the placebo group (16.5/3 h) and the rate of acid reflux during TLESRs (24.7%) and the EAE (0.2%) in the NIZ group for the postprandial 3-hour period was also significantly less than that of the placebo group (74.4% and 2.8%, respectively). CONCLUSION: NIZ significantly reduces acid reflux by inhibiting both the rate of TLESRs and acid reflux during TLESRs.

Characteristics of symptomatic reflux episodes in patients with non-erosive reflux disease who have a positive symptom index on proton pump inhibitor therapy.

BACKGROUND AND AIM: The reason that some reflux episodes evoke symptoms is poorly understood, therefore the aim of this study is to assess the determinants of reflux perception in patients with non-erosive reflux disease (NERD) on proton pump inhibitor (PPI) therapy. METHODS: Ten NERD patients with persistent symptoms, despite double-dose PPI therapy, were included in this study. All patients had a positive symptom index (SI), which was determined by ambulatory 24-hour combined impedance-pH monitoring. Reflux episodes were identified and classified as acid, weakly acidic or weakly alkaline reflux and were considered symptomatic if patients recorded a symptom within 5 min after a reflux episode. RESULTS: A total of 954 liquid reflux episodes were detected, including 135 (14.2%) acid, 782 (82.0%) weakly acidic, and 37 (3.9%) weakly alkaline. Overall, 59 (6.2%) reflux episodes were symptomatic and the majority (88.1%) of symptomatic reflux episodes were weakly acidic reflux. When reflux episodes were confined to the distal esophagus, there were very few reflux symptoms. Proximal reflux is significantly more likely to be associated with reflux symptoms, irrespective of the acidity of the refluxate or the duration of proximal reflux episodes. CONCLUSIONS: In NERD patients who have a positive SI on double-dose PPI therapy, the high proximal extent of refluxate is a major factor associated with reflux perception.

Predictors of a better outcome of pneumatic dilatation in patients with primary achalasia.

OBJECTIVE: Pneumatic dilatation (PD) has been widely used in the treatment of primary achalasia. The aim of this study was to evaluate the effectiveness of PD and its predictive factors in Japanese patients with primary achalasia. METHODS: Fifty-five consecutive patients were treated using PD (Rigiflex balloon dilator). Diagnosis was established through radiographic and/or esophageal manometry. All patients underwent a pre-designed clinical evaluation prior to and 6 months after PD treatment. We defined success of PD as 6 months or more of clinical remission, with a total score (0-4) or=1 and the score for each item 40-year age group was 85.7%, while the <40-year age group achieved a rate of only 38.5%. Multivariate logistic regression analysis also demonstrated that older age was the only independent factor associated with the success of PD. There was no perforation related to PD. CONCLUSIONS: PD is a safe and effective treatment for achalasia, particularly in older patients who experience a better outcome than younger patients.

Eosinophilic esophagitis: a case report with a review of the literature.

Eosinophilic esophagitis (EE) is an allergic inflammatory condition of the esophagus and is characterized by dense eosinophilic infiltration of the esophagus. There has been a dramatic increase in the diagnosis of EE in Western countries in recent years; however, in Japan, there are very few reports of EE. We present a rare case of EE in a 70-year-old Japanese woman, who had dysphasia for 2 years, but which worsened over a 6-month period. Laboratory examinations showed peripheral eosinophilia (1279/µl). Significant thickening of the esophageal wall was observed on computed tomography scan and many circular rings appeared when an esophagogastroduodenoscopy was carried out. From these circular rings, EE was suspected and a biopsy was then taken from the esophagus. As the histologic findings from the esophageal biopsy showed that >25 eosinophils existed per high-power field, the patient was diagnosed with EE. Oral corticosteroid (prednisolone 30 mg/day) therapy was administered and after 3 days of treatment her symptoms almost disappeared. EE needs to be considered as a differential diagnosis if patients with non-erosive reflux disease have dysphagia but do not respond to high-dose proton pump inhibitor therapy.