Kiichi Satoh

Guidelines for the Management of Helicobacter pylori Infection in Japan: 2009 Revised Edition

Background:  Over the past few years, the profile of Helicobacter pylori infection has changed in Japan. In particular, the relationship between H. pylori and gastric cancer has been demonstrated more clearly. Accordingly, the committee of the Japanese Society for Helicobacter Research has revised the guidelines for diagnosis and treatment of H. pylori infection in Japan.

Success rate of curative endoscopic mucosal resection with circumferential mucosal incision assisted by submucosal injection of sodium hyaluronate

BACKGROUND Circumferential mucosal incision around a lesion is effective for reliable endoscopic mucosal resection. However, mucosal incision with a needle knife is difficult, even with submucosal injection of normal saline solution. To make needle-knife incision easier and safer, sodium hyaluronate has been used rather than normal saline solution. The aim of this study was to evaluate the clinical outcome of endoscopic mucosal resection with circumferential mucosal incision assisted by submucosal injection of sodium hyaluronate. METHODS For 70 gastric lesions treated by submucosal injection of sodium hyaluronate, the size of the lesion and the resection specimen, the en bloc resection rate, complications, and local recurrence during follow-up were assessed. RESULTS The mean size of the lesions and resection specimens were, respectively, 19.9 mm and 30.0 mm. The en bloc resection rates were 89% (42/47) for lesions up to 20 mm in diameter and 48% (11/23) for those greater than 20 mm (1-20 mm vs. >20 mm, p = 0.0004). Three patients underwent surgery because of invasive cancer in the EMR specimen. During follow-up (median 14 months, range 3-38 months), 2 recurrent lesions were found. No major complication occurred. CONCLUSIONS Submucosal injection of sodium hyaluronate is a reliable method with a high success rate for en bloc resection of lesions up to 20 mm in diameter. Mucosal incision with a needle knife can be performed safely with submucosal injection of sodium hyaluronate.

Aberrant expression of CDX2 in Barrett's epithelium and inflammatory esophageal mucosa

Background: There have been no detailed reports directly comparing the expression of CDX1 with that of CDX2 in the inflammatory esophageal mucosa and Barretts epithelium. The present study was designed to examine the expression of CDX 1/2 in inflammatory esophageal mucosa with or without Barretts epithelium. Methods: The expression of CDX1/2 genes was analyzed using the reverse transcriptase-polymerase chain reaction (RT-PCR) in 34 human esophageal biopsy specimens, and CDX2 expression was also evaluated immunohistochemically, using anti-human CDX2 monoclonal antibody. The biopsy specimens for RNA extraction were taken endoscopically from esophageal mucosa with mucosal break due to gastroesophageal reflux disease (GERD), Barretts epithelium, and normal epithelium. The expressions of mucin markers (MUC2) and intestine-specific genes (sucrase-isomal-tase, human defensin-5, alkaline phosphatase) were also comparatively analyzed. Results: CDX1/2 expression was not found in the normal esophageal mucosa. The prevalence of CDX1/2 mRNA expression was significantly higher in the mucosa with Barretts epithelium than in the mucosa without Barretts epithelium. It is noteworthy, however, that the CDX2 mRNA expression was initiated at the stage of esophagitis, when neither CDX1 nor intestine-specific genes had emerged yet. In contrast to CDX2, CDX1 was expressed only in Barretts epithelium. Immunohistochemical study demonstrated strong and extensive nuclear immunoreactivity for CDX2 in Barretts epithelium. Furthermore, fine granular cytoplasmic staining was also observed in the cytoplasm in Barretts epithelium, as well as in inflammatory esophageal mucosa. Conclusions: We report here, for the first time, that CDX2 is expressed in patients with Barretts epithelium and inflammatory esophageal mucosa. These findings imply that the expression of CDX2 may be an early event leading to the development of Barretts esophagus.

Development of Gastric Carcinoma from Intestinal Metaplasia in Cdx2-transgenic Mice

In the progression of chronic gastritis, gastric mucosal cells deviate from the normal pathway of gastric differentiation to an intestinal phenotype. Many epidemiologic studies have found an association between the formation of intestinal metaplasia and the development of gastric carcinoma. However, there is no direct evidence that shows intestinal metaplasia is a precursor lesion of gastric carcinoma, to date. We periodically examined the intestinal metaplastic mucosa of Cdx2-transgenic mice we have previously generated. Gastric polyps developed from intestinal metaplastic mucosa in all stomachs of Cdx2-transgenic mice examined. These gastric polyps consisted of intestinal-type adenocarcinoma that invaded the submucosa and muscularis propria and occasionally spread into the subserosa. p53 and APC gene mutations were recognized in the adenocarcinomas. The participation of APC and p53 gene mutations in gastric carcinogenesis from the intestinal metaplasia was verified by the Cdx2-transgenic mice, carrying ApcMin mutation or p53 deficiency, that developed gastric polyps much earlier than Cdx2 alone. We successfully showed that long-term intestinal metaplasia induces invasive gastric carcinoma. These results indicate that intestinal metaplasia itself plays a significant role in the genesis and progression of gastric carcinoma.

Expression of homeobox gene CDX2 precedes that of CDX1 during the progression of intestinal metaplasia

Background. The CDX1 and CDX2 genes are intestinal transcription factors that may be involved in the regulation of proliferation and differentiation of intestinal epithelial cells. There have been no detailed reports directly comparing the expression of CDX1 with that of CDX2 in chronic gastritis and intestinal metaplasia. Accordingly, we examined the expression of CDX1/2 and its association with the expression of other intestinal metaplasia-associated genes during the development of intestinal metaplasia. Methods. The expression of CDX1/2 genes was analyzed, using the reverse transcriptase-polymerase chain reaction, in 44 human gastric tissue samples obtained endoscopically. The expressions of mucin markers (MUC2, MUC5AC), intestine-specific genes (sucrase-isomaltase, human defensin-5, alkaline phosphatase), a gene marker for fundic gland area (H+/K +ATPase β subunit), and a gene for entire gastric glands (pepsinogen C) were also comparatively analyzed. Results. There was no expression of CDX1/2 in gastric mucosa not infected by Helicobacter pylori. The prevalence of CDX1 mRNA expression was significantly higher in mucosa with intestinal metaplasia than in mucosa without intestinal metaplasia. It is noteworthy that CDX2 was expressed in the antral and fundic mucosa in the absence of the expression of CDX1 and gene markers for intes-tinal metaplasia. Conclusions. The expression of CDX2 precedes those of CDX1, sucrase-isomaltase, other intestine-specific genes (human defensin-5, alkaline phosphatase), and MUC2 during the progression of intestinal metaplasia. These findings imply that the expression of CDX2 may trigger the initiation and development of intestinal metaplasia.

A Multicenter, Double‐Blind Study on Triple Therapy with Lansoprazole, Amoxicillin and Clarithromycin for Eradication of Helicobacter pylori in Japanese Peptic Ulcer Patients

Two triple therapies with lansoprazole (LPZ)/amoxicillin (AMPC)/clarithromycin (CAM) for eradication of Helicobacter pylori were studied in multicenter, double‐blind fashion to evaluate the eradication rate of H. pylori and safety of eradiation treatment in Japanese patients with H. pylori‐positive active gastric ulcers or duodenal ulcers.

Cdx1 induced intestinal metaplasia in the transgenic mouse stomach: comparative study with Cdx2 transgenic mice

Background and aims: Gastric intestinal metaplasia, which is mainly induced by Helicobacter pylori infection, is thought to be a precancerous lesion of gastric adenocarcinoma. Intestinal metaplastic mucosa expresses intestine specific homeobox genes, Cdx1 and Cdx2, in the human gastric mucosa. We and others have reported that ectopic expression of Cdx2 in the gastric epithelium generates intestinal metaplasia in the transgenic mouse model. Methods: To clarify the differences in the roles of Cdx1 and Cdx2 in intestinal metaplasia, we generated transgenic mice expressing Cdx1 in the gastric mucosa and compared Cdx1 induced gastric mucosal morphological changes with Cdx2 induced intestinal metaplasia. Results: The gastric mucosa in Cdx1 transgenic mice was completely replaced by intestinal metaplastic mucosa, consisting of all four intestinal epithelial cell types: absorptive enterocytes, goblet, enteroendocrine, and Paneth cells. Paneth cells, which were not recognised in Cdx2 transgenic mice, were in the upper portion of the intestinal metaplastic mucosa. Pseudopyloric gland metaplasia, which was induced in Cdx2 transgenic mice, was not recognised in Cdx1 transgenic mice. Proliferating cell nuclear antigen (PCNA) positive cells were diffusely scattered in Cdx1 induced intestinal metaplastic mucosa while PCNA positive cells in Cdx2 induced intestinal metaplastic mucosa were in the base of the metaplastic mucosa. Intestinal metaplastic mucosa of Cdx1 transgenic mouse stomach was significantly thicker than that of wild-type or Cdx2 transgenic mouse stomach. Conclusions: We have confirmed that Cdx1 induced gastric intestinal metaplasia but that it differed from Cdx2 induced intestinal metaplasia in differentiation, structure, and proliferation.

Aberrant Expression of CDX2 in the Gastric Mucosa With and Without Intestinal Metaplasia: Effect of Eradication of Helicobacter pylori

Background. The intestine‐specific transcription factor CDX2 plays an important role in differentiation and maintenance of intestinal epithelial cells. Development and progression of intestinal metaplasia (IM) in the stomach is closely associated with Helicobacter pylori‐gastritis. We investigated expression of CDX2 protein in the gastric mucosa with and without IM before and after eradication of H. pylori.

Guidelines in the Management of Helicobacter pylori Infection in Japan

In preparation of the approval of Helicobacter pylori therapy by the Japanese national health system, the board of directors of the Japanese Society for Helicobacter Research decided to prepare guidelines on the diagnosis and treatment of H. pylori infection for physicians in routine medical practice.

Assessment of Atrophic Gastritis Using the OLGA System

Background:  An international group of gastroenterologists and pathologists (Operative Link for Gastritis Assessment (OLGA)) proposed the staging system of atrophy. The aim of this study was to assess the severity of atrophic gastritis using the OLGA system.