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.

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.

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.

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.

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.

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.

Acid and non-acid reflux in Japanese patients with non-erosive reflux disease with persistent reflux symptoms, despite taking a double-dose of proton pump inhibitor: a study using combined pH-impedance monitoring.

BACKGROUND: Combined multi-channel intra-luminal impedance and pH (Mll-pH) monitoring can detect gastro-esophageal reflux and identify acid and non-acid reflux (NAR) events. It can be used for patients with persistent symptoms who are having proton pump inhibitor (PPI) therapy. The aim of this study is to determine the frequency of acid reflux and NAR and to establish their relationship with persistent reflux symptoms in Japanese patients with non-erosive reflux disease (NERD) who are on a double-dose of PPI therapy. METHODS: Thirteen patients with NERD, with persistent reflux symptoms, despite taking PPI at least twice daily, were included in this study. Twenty-four-hour combined Mll-pH monitoring was carried out on all patients and reflux episodes were detected by impedance channels, located at 3, 5, 7, 9, 15 and 17 cm above the lower esophageal sphincter (LES) and classified into acid reflux and NAR, based on pH data from 5 cm above the LES. A positive symptom index (SI) was declared, if at least half of the symptoms were preceded by reflux episodes within 5 min. RESULTS: A total of 916 liquid reflux episodes were detected, and a total of 171 symptoms were recorded. Eight (4.7%) of 171 symptoms were related to acid reflux, and 68 (39.8%) were related to NAR. Seven (53.8%) patients had a positive SI and in these seven patients, a total of 79 symptoms were recorded. 5 (6.3%) of the 79 symptoms were related to acid reflux and 44 (55.7%) were related to NAR. CONCLUSIONS: Persistent reflux symptoms, in SI-positive patients with NERD on double-dose PPI therapy, are more likely to be associated with primarily non-acid reflux.

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.

Mechanisms of excessive esophageal acid exposure in patients with reflux esophagitis.

The pathophysiology of excessive esophageal acid exposure, including the way refluxed acid extends towards the proximal esophagus, in patients with reflux esophagitis (RE), is not yet clear. For 3 h after a meal, concurrent esophageal manometry and pH monitoring was carried out on 14 patients with severe RE, 15 patients with mild RE, and 15 healthy subjects. At 2 cm above the proximal margin of the lower esophageal sphincter (LES) there was no difference between the three groups in the total number of acid-reflux episodes, the rate of transient LES relaxations (TLESRs), or the rate of acid reflux during TLESRs. The rate of acid reflux at 7 cm above the proximal margin of the LES, during TLESRs, in patients with severe RE (50.9%, median) was, however, significantly higher than in patients with mild RE (35.7%) and healthy subjects (15.4%). In addition, the rate of acid reflux during TLESRs in patients with mild RE was significantly higher than in healthy subjects. Both the amplitude and the success rate of primary peristalsis in patients with severe RE were significantly lower than those of healthy subjects and patients with mild RE but there was no difference between healthy subjects and patients with mild RE. The cause of excessive acid exposure in patients with RE is the difference in the way refluxed acid extends towards the proximal esophagus and acid bolus clearance, not the number of acid-reflux episodes.

[A case of gastric cancer presenting with obstructive jaundice and responding to biweekly CPT-11 and CDDP combination administration].

A 74-year-old man was suffering from Borrmann type 2 advanced gastric cancer with abdominal lymph node metastases and multiple lung metastases. He started to undergo outpatient treatment with oral administration of TS-1. But pyloric stenosis was found after 6 courses of TS-1 chemotherapy, so he underwent palliative distal gastrectomy. TS-1 chemotherapy was continued afterwards, however obstructive jaundice was found. So combination chemotherapy of CPT-11 60 mg/m(2)and CDDP 30 mg/m(2)biweekly was selected as a second-line therapy after PTCD. As no side effects were found, he could be treated on an outpatient basis by CPT-11 60 mg/body and CDDP 30 mg/body biweekly. Four months has passed since the palliative operation, and the PTCD tube was successfully removed. The abdominal lymph nodes had decreased in size and the patient has maintained good QOL. Thus, combination CPT-11 and CDDP therapy could well be a new candidate for a second-line chemotherapy in outpatients.

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.