Yoshio Hoshihara

Differences in the Definitions Used for Esophageal and Gastric Diseases in Different Countries Endoscopic Definition of the Esophagogastric Junction, the Precursor of Barrett's Adenocarcinoma, the Definition of Barrett's Esophagus, and Histologic Criteria for Mucosal Adenocarcinoma or High-Grade Dysplasia

Background: Definitions and opinions in the field of gastroenterology vary widely in different countries. Methods: Here we discuss four such important differences: the definition of the esophagogastric junction (EGJ), the possible precursor of Barrett’s adenocarcinoma, the definition of Barrett’s esophagus (BE), and the histologic criteria for mucosal adenocarcinoma. In addition, we consider which definitions and opinions might be valid and practical. Results: There are two different endoscopic definitions of the EGJ. Our research on German subjects has indicated that many small Barrett’s adenocarcinomas may arise not in the intestinal-type but in the cardiac-type mucosa. If an area of columnar-lined esophagus (CLE) is only partially involved by intestinal metaplasia, then the latter cannot always be demonstrated in biopsy specimens. Therefore, we do not think that a definition of BE as CLE with histologic intestinal metaplasia is practical. Data from the literature have shown that many cases of high-grade dysplasia (HGD) progress to carcinoma within a very short time, and in most such cases the carcinoma has been underdiagnosed in biopsy specimens as HGD. Conclusion: With regard to the definitions and opinions, an exchange of views between gastroenterologists in North America, Europe, and Japan would be desirable.

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.

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 &mgr;m 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.

What are longitudinal vessels? Endoscopic observation and clinical significance of longitudinal vessels in the lower esophagus

We have reviewed articles on the longitudinal vessels observed in the lower esophagus. In our previous study, we observed longitudinal (palisading) vessels through the mucosal epithelium in 884 (98%) of 905 consecutive endoscopic examinations of the lower esophagus, whereas in 20 examinations (2%) they could not be observed because of inflammation. The lengths of the longitudinal vessels were within the range of 2 to 3 cm in 90% of investigations. “Indentation” (notch or narrowing) compatible with the esophageal hiatus was observed in the transitional zone between the tubal esophagus and saccular stomach by both radiographic (as an indentation) and endoscopic (as a narrowing; we used the term indentation in this article) examinations. In cases without hiatal hernia, the indentation coincided with the esophagogastric junction (EGJ). We examined endoscopically the relationships among the locations of the indentation, squamocolumnar junction, and the longitudinal vessels. In no patients did we observe longitudinal vessels through the gastric mucosa beyond the indentation. Therefore, observation of longitudinal vessels through the mucosal epithelium was an indicator that the mucosa was located within the esophagus. However, in 21% of the 884 observations, columnar-lined mucosa was seen continuously from the gastric mucosa proximally beyond the indentation, and longitudinal vessels were observed through this columnar-lined mucosa. Because the longitudinal vessels were peculiar to the esophageal mucosa, we could assume that this columnar-lined mucosa was located within the esophagus and was Barretts mucosa, although very short. Therefore, Barretts mucosa can be precisely diagnosed endoscopically by using the longitudinal vessels as diagnostic markers. The Japan Esophageal Society has authorized the endoscopic definition that the lower ends of the longitudinal vessels mark the limit of the EGJ.

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.

Peptic ulcer recurrence during maintenance therapy with H2-receptor antagonist following first-line therapy with proton pump inhibitor

Abstract: We investigated the peptic ulcer recurrence rates during maintenance therapy with H2-receptor antagonists (H2RAs) following first-line therapy with a proton pump inhibitor (PPI). Patients with gastric ulcer (GU) or duodenal ulcer (DU) were enrolled in this study; 583 eligible patients (GU, 325; DU, 258) were administered lansoprazole (30 mg/day for 8 weeks for GU, and the same dosage for 6 weeks for DU) as first-line therapy, and a half dose of H2RA as maintenance therapy for 12 months. Endoscopic photographs were taken before administration and after 8 (GU) and 6 (DU) weeks of lansoprazole administration. Ulcer stage was evaluated using the classification of Sakita and Miwa. Endoscopic examinations were performed 6 months or 12 months after the start of maintenance therapy or when a recurrence was suspected because of the appearance of subjective symptoms. The healing rates for GU and DU patients after completion of lansoprazole therapy were 79% in both groups, while the S2-stage healing rates were 18% and 31%, respectively. At 1 year after the start of maintenance therapy, the recurrence rates were 25% for GU and 39% for DU patients. In DU patients, the recurrence rates from S1-stage and S2-stage were 49% and 20%, respectively (P = 0.004), but no significant difference was found between these rates in GU patients. The recurrence rates in H. pylori-positive patients before lansoprazole administration were 27% for GU and 43% for DU patients. We concluded that the maintenance therapy with a half-dose of H2RA following PPI therapy was insufficient to prevent recurrences of GU and DU.

Histopathological diagnosis of adenocarcinoma in Barrett's esophagus.

The present review describes the histological markers of Barretts esophagus (BE) that make it possible to distinguish between Barretts 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.

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.

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.

Interobserver agreement on endoscopic diagnosis of low-grade reflux esophagitis, including minimal changes

BackgroundIn Japan, the majority of patients with gastroesophageal reflux disease have low-grade reflux esophagitis (RE), including minimal changes, and the modified Los Angeles (LA) classification is widely used. However, there have been few evaluations of interobserver agreement with this classification. This study was performed to elucidate the level of interobserver agreement for diagnosis low-grade RE, including minimal changes, and to identify any clinical factors that influenced the results.MethodsA total of 114 endoscopists from university hospitals, community hospitals, and private practice participated. They assessed the grade of esophagitis in 8 patients by viewing endoscopic images. The images were projected onto a screen, and all of the endoscopists reviewed images together. The diagnosis was selected from the following five categories: grade M, grade A, short-segment columnar-lined esophagus, diagnosis difficult due to poor image quality, and others. After discussiing the endoscopic diagnosis, the images were projected in a random order and the endoscopists viewed them again. Kappa coefficients of reliability were calculated before and after the discussion, and we also evaluated factors influencing the results.ResultsThe kappa values obtained before and after discussion were 0.41 and 0.70, respectively. We found three factors that influenced interobserver agreement: specialty, years of experience with endoscopic examination, and mean esophageal observation time per endoscopic examination.ConclusionsThe modified LA classification is reliable for diagnosing low-grade RE (including minimal changes) in Japan, although several factors can influence interobserver agreement.