Noniatrogenic Meningitis Caused by Streptococcus salivarius Associated with Early Esophageal Cancer and Early Gastric Cancer.

Streptococcus salivarius is part of the normal oral cavity and gastrointestinal tract microflora and an unusual cause of acute bacterial meningitis. We herein report an 81-year-old man with S. salivarius meningitis, which led to a diagnosis of early esophageal cancer and early gastric cancer. S. salivarius infection may occur through the gastrointestinal mucosa when it is disrupted in association with early gastrointestinal cancer. To our knowledge, this is the first report describing S. salivarius meningitis associated with multiple early gastrointestinal cancers in the absence of other sources of infection.

Diagnosis of histological gastritis based on the Kyoto classification of gastritis in Japanese subjects - including evaluation of aging and sex difference of histological gastritis.

OBJECTIVES: The Kyoto classification of gastritis was established for diagnosing Helicobacter pylori (H. pylori) infection via endoscopic findings. We investigated the role of the Kyoto classification of gastritis in the diagnosis of H. pylori infection and histological gastritis in Japanese individuals. Moreover, the histological findings of gastritis in H. pylori infection were examined based on age and sex differences. METHODS: We selected 561 patients aged 20-79 years who underwent gastroduodenal endoscopy at our hospital between 2010 and 2018. Endoscopic biopsy specimens from the antrum and corpus were used to investigate H. pylori infection and histology. Endoscopic findings were based on the Kyoto classification of gastritis, and histological findings were based on the updated Sydney System. RESULTS: Endoscopic findings based on the Kyoto classification of gastritis (H. pylori positive, 303 patients; H. pylori negative, 258 patients, based on endoscopic findings) had 98.7% sensitivity and 98.4% specificity for histological gastritis. In addition, endoscopic findings in the three age groups (20-39, 40-59, and 60-79 years) had high sensitivity and specificity. Atrophy and intestinal metaplasia were found only in the H. pylori-positive group and progressed with age. Histological inflammation of pyloric mucosa in the younger age group of H. pylori-positive patients was significantly higher than that in the elderly group. Significant inflammation was observed in young women. CONCLUSIONS: The Kyoto classification of gastritis can not only diagnose H. pylori infection but also detect histological gastritis. Histological gastritis has varying characteristics of inflammation, atrophy, and intestinal metaplasia, depending on age and sex.

Associations between lifestyle behaviour changes and the optimal well-being of middle-aged Japanese individuals.

BACKGROUND: Psychological well-being has been associated with reduced mortality rates in both healthy and diseased populations. However, there is considerably less evidence on the effect of lifestyle behaviours on positive health outcomes such as well-being. This study examines the association between lifestyle behaviours and optimal well-being. METHODS: From a total of 4324 Japanese individuals who participated in an annual health check-up in 2017, this study recruited 2295 participants (mean age: 49.3 ± 8.4 years; female: 54.3%) without a history of cerebrovascular, cardiovascular, or chronic renal disease and not on medication for hypertension, diabetes, or dyslipidaemia. The World Health Organization-Five Well-Being Index (WHO-5) scores were compared to self-reported scores on each of the following items: dietary habits, physical activity, smoking, alcohol consumption, and sleep quality. Logistic regression analysis was used to examine the association between optimal well-being (the top quartile of WHO-5 scores) and individual lifestyle behaviours. The association between change in dietary habits and physical activity from 2016 to 2017 and optimal well-being was also investigated. RESULTS: Good dietary habits and regular physical activity were associated with higher raw WHO-5 scores and were positively associated with optimal well-being after adjusting for age, sex, body mass index (BMI), and sleep quality. Raw WHO-5 scores were significantly higher in those who maintained good dietary and physical activity behaviours than in those who did not. Furthermore, maintaining regular physical activity for two years was positively associated with optimal well-being, after adjusting for age, sex, BMI, and sleep quality. CONCLUSION: These results demonstrate that not only currently practising good dietary and physical activity behaviours but also maintaining such behaviours over time is associated with optimal well-being. Maintaining good lifestyle behaviours, particularly regarding physical activity, could potentially improve people's well-being.

Inflammatory Cell Numbers in the Stomach of Japanese Subjects with Endoscopically Normal Mucosa without Helicobacter pylori Infection.

INTRODUCTION: Since inflammatory cells, such as lymphocytes and plasma cells, normally inhabit the stomach, the border between normal and mild inflammation is difficult to visually determine using the updated Sydney system scale of gastritis. Additionally, eosinophils in the gastric mucosa must be counted to diagnose eosinophilic gastritis. We aimed to determine the normal number of inflammatory cells in patients with endoscopically normal mucosa and without Helicobacter pylori infections. METHODS: We assessed patients aged 20-79 years, who had undergone upper gastrointestinal endoscopy at Kawasaki Medical School Hospital between January 2010 and December 2014. Inflammatory cells were counted in 1,000 µm2 fields of pyloric and fundic gland mucosal biopsy specimens. We finally included 325 (male, n = 141; female, n = 184; average age = 49.3 years) patients without inflammation who had H. pylori-negative endoscopic results and negative histological findings interpreted based on the updated Sydney System and the Kyoto classification of gastritis. RESULTS: The average numbers of nucleated cells were 83.3 ± 14.2 and 65.4 ± 12.6/mm2 in the pyloric and fundic gland mucosae, respectively. Inflammatory cells were significantly more abundant in the pyloric mucosa than in the fundic gland mucosa (p < 0.05). Age and sex distribution did not significantly differ. Eosinophils were absent or scanty in the gastric mucosae of both glands in all patients. CONCLUSION: We determined the absolute values of inflammatory cells, including eosinophils, in normal mucosae of pyloric and fundic glands. These findings could be important in defining gastric mucosal inflammation, including eosinophilic gastritis diagnosis.

Overexpression of CD55 from Barrett's esophagus is associated with esophageal adenocarcinoma risk.

BACKGROUND AND AIM: Although several molecular biomarkers for esophageal adenocarcinoma (EAC) have been shown to be useful disease indicators, none has been established as a reliable indicator for risk of EAC or have progressed to routine use. The aim was to identify biomarkers of high risk for EAC in patients with Barrett's esophagus (BE). METHODS: Following endoscopic observation by magnified endoscopy with narrow band imaging (ME-NBI), brushing was followed by obtaining biopsy samples from columnar-lined esophagus (CLE) and from EAC lesions of EAC patients, and from age- and sex-matched non-EAC controls with BE. Total RNA was extracted for microarray analysis using Affymetrix GeneChip Human Genome U133 plus 2.0 Array. Real-time-PCR analysis of identified candidate genes was used to confirm the results. RESULTS: Overall, 9 EAC patients and 50 patients with BE were studied. Seventy-nine candidate genes were identified by microarray analysis based on a proportional hazards model (P < 0.005). Six genes exhibited significantly differential expressions in both BE and cancer lesions of the EAC group compared to BE of the controls. In the brushing samples, median CD55 relative expression levels in cancer lesions were highest and decreased in BE of EAC group and BE of the controls, in that order (P < 0.001). CONCLUSION: Over expression of CD55 in brushing samples taken from BE may be associated with the risk of EAC.

A novel APC mosaicism in a patient with familial adenomatous polyposis.

Using next-generation sequencing (NGS) to analyze a patient with sporadic familial adenomatous polyposis in whom no APC mutations were found by Sanger sequencing, we identified a novel APC mosaicism at a spliced donor site (c.834+2 T>C) in his leukocytes, normal colonic mucosa and adenoma. The detection of APC mosaicism using NGS can be useful in providing appropriate genetic counseling and surveillance of at risk family members as well as the proband.

Safety of gastrointestinal endoscopic biopsy in patients taking antithrombotics.

BACKGROUND AND AIM: Current Japanese gastrointestinal (GI) endoscopic guidelines permit endoscopic biopsy without cessation of antiplatelet agents and warfarin in patients with a therapeutic range of prothrombin time-international normalized ratio (PT-INR) levels, although the evidence levels are low. We evaluated the safety of endoscopic biopsy in patients currently taking antithrombotics. METHODS: Consecutive patients receiving antithrombotics who underwent GI endoscopy from August 2012 to August 2013 were enrolled. Adverse events and endoscopic hemostasis after biopsy were evaluated. PT-INR level was measured in patients taking warfarin the day before endoscopy. RESULTS: Among 7939 patients undergoing endoscopy, 1034 patients (13.0%, 706 men and 328 women, average age 72.8 years) were receiving antithrombotics. Antithrombotics included aspirin (44.8%), warfarin (34.7%), thienopyridine (16.1%), cilostazol (10.3%), dabigatran (4.8%) etc. PT-INR levels in patients taking warfarin were >3.0 in 13 patients (4.3%), between 2.5 and 3.0 in 18 patients (6.0%), <2.5 in 269 patients (89.7%). Two hundred and six patients received endoscopic biopsy while taking aspirin (51.2%), warfarin (22.8%), and thienopyridine (13.6%). Endoscopic hemostasis was required in three patients after endoscopic biopsy (spraying thrombin in two patients, spraying thrombin and clipping in one patient). There were no major complications. The incidence of endoscopic hemostasis after biopsy in patients without antithrombotic cessation was not significantly different than in the controls not taking antithrombotics (1.5% vs 0.98%, P = 0.51). CONCLUSION: Endoscopic biopsy did not increase the bleeding risk despite not stopping antithrombotics prior to biopsy even among patients taking warfarin whose PT-INR was within the therapeutic range.

[European guideline for the management of precancerous conditions in the stomach and it's application to Japan].

Atrophic gastritis, intestinal metaplasia, and Helicobacter pylori (H. pylori) infection are commonly recognized as the risk factor of gastric cancer. In Japan mass screening by the X-ray examination or endoscopy has been performed for a long time in general population or in work place because of the high death rate and high incidence of gastric cancer. Periodic endoscopy has been recommended for the subjects with atrophic gastritis and/or intestinal metaplasia to detect gastric cancer in early stage. On the other hand, there was no guideline to manage premalignant conditions such as atrophic gastritis, intestinal metaplasia, and dysplasia in foreign countries. Recently the guideline for the management of precancerous conditions and lesions in the stomach (MAPS) has been published by the combined efforts of the European Society of Gastrointestinal Endoscopy, European Helicobacter Study Group, European Society of Pathology, and the Sociedade Portuguesa de Endoscopia Digestiva. In this article the main statements have been discussed on comparing the understandings as the premalignant conditions in Japan.

Usefulness of endoscopic brushing and magnified endoscopy with narrow band imaging (ME-NBI) to detect intestinal phenotype in columnar-lined esophagus.

BACKGROUND: Barrett's esophagus with specialized intestinal metaplasia (SIM), which is at high risk of progressing to esophageal adenocarcinoma, has been identified by obtaining biopsy specimens randomly. Magnified endoscopy with narrow band imaging (ME-NBI) is reported to be useful for detecting SIM or the intestinal phenotype. We aimed to evaluate the usefulness of endoscopic brushing followed by ME-NBI for the detection of the intestinal phenotype. METHODS: Biopsy and brushing samples were taken following endoscopic observation by ME-NBI. Total RNA was extracted from the whole sample and microdissected samples, and quantitative reverse transcription-polymerase chain reaction (PCR) analysis of SHH, CDX2, and mucin mRNA expression was performed. RESULTS: Fifty patients (32 men, 18 women, average age 67.3 years) with metaplastic columnar epithelium of the lower esophagus were studied. MUC2 (85 vs. 65 %) and CDX2 (95 vs. 75 %) were detected more frequently in the brushing samples than in the biopsy samples. MUC2 expression levels were significantly higher in the brushing samples than those in the biopsy samples. CDX2 and MUC2 expression levels in the brushing samples were significantly higher in the mucosa with tubular/villous pattern observed by ME-NBI than the levels in mucosae with other patterns. CONCLUSIONS: Endoscopic brushing in mucosa of columnar epithelium with a tubular/villous pattern visualized by ME-NBI is useful to detect the intestinal phenotype.

Relationship between gastroesophageal junction adenocarcinoma and Helicobacter pylori infection in Japan.

BACKGROUND/AIMS: The relationship between gastroesophageal junction adenocarcinoma (GEJA) and Helicobacter pylori infection is not well defined; thus, we retrospectively investigated this relationship. METHODS: We examined 852 cases (646 men) of gastric cancer. GEJA was defined as type II according to the classification system of Siewert and Stein. We compared the prevalence of H. pylori infection and corporal gastritis in GEJA patients with distal gastric cancer. RESULTS: GEJA was observed in 80 (including 6 cases of Barrett's esophageal cancer) of the 852 cases of gastric cancer examined (9.4%). The rate of H. pylori infection was significantly lower in patients with GEJA than in patients with distal gastric cancer (73.8 vs. 94.1%, p < 0.05). The prevalence of corporal gastritis was also significantly lower in patients with GEJA than in patients with distal gastric cancer (80.7 vs. 94.6%, p < 0.05). Concurrent H. pylori infection and corporal gastritis were not observed in patients with Barrett's esophageal cancer. CONCLUSION: Our study demonstrated that GEJA has 2 etiologic types; one of these types is associated with H. pylori infection and resembles distal gastric cancer, and the other one is not associated with H. pylori infection or Barrett's esophageal cancer.

Analysis of small-bowel capsule endoscopy reading by using Quickview mode: training assistants for reading may produce a high diagnostic yield and save time for physicians.

GOAL: The aim was to investigate the clinical utility of RAPID Access 6.5 Quickview software and to evaluate whether preview of the capsule endoscopy video by a trained nurse could detect significant lesions accurately compared with endoscopists. BACKGROUND: As reading capsule endoscopy is time consuming, one possible cost-effective strategy could be the use of trained nonphysicians or newly available software to preread and identify potentially important capsule images. STUDY: The 100 capsule images of a variety of significant lesions from 87 patients were investigated. The minimum percentages for settings of sensitivity that could pick up the selected images and the detection rate for significant lesions by a well-trained nurse, two endoscopists with limited experience in reading, and one well-trained physician were examined. RESULTS: The frequency of the selected lesions picked up by Quickview mode using percentages for sensitivity settings of 5%, 15%, 25%, and 35% were 61%, 74%, 93%, and 98%, respectively. The percentages for sensitivity significantly correlated (r=0.78, P<0.001) with the reading time. The detection rate by the nurse or the well-trained physician was significantly higher than that by the physician with limited capsule experience (87% and 84.1% vs. 62.7%; P<0.01). The clinical use of Quickview at 25% did not significantly improve the detection rate. CONCLUSIONS: Quickview mode can reduce reading time but has an unacceptably miss rate for potentially important lesions. Use of a trained nonphysician assistant can reduce physician's time and improve diagnostic yield.

Eradication of H. pylori did not improve abnormal sonic hedgehog expression in the high risk group for gastric cancer.

BACKGROUND: Sonic hedgehog (SHH) acts as a proliferation factor in both the normal mucosa and in malignant lesions. Helicobacter pylori-associated atrophic gastritis is characterized by loss of SHH. AIM: The purpose of this study was to investigate the effects of H. pylori eradication on SHH mRNA and methylation levels in the patients at high risk for gastric cancer comparing to those in the controls. METHODS: Gastric corpus biopsies taken from 20 patients with endoscopic resection for early gastric cancer and 14 sex- and age-matched controls before and 1 year after eradication were examined for SHH and downstream regulators mRNA expression using whole biopsy specimens and microdissected gastric glands. Methylation of SHH promoter was evaluated using quantitative methylation-specific PCR. RESULTS: SHH mRNA levels eradication were significantly lower (2.75 × 10(-2) vs. 7.37 × 10(-2), P = 0.004) in the cancer group than in the controls. PTCH and BMP4 mRNA levels as well as MUC5AC were significantly increased only in the control group and were significantly higher in the controls than those in the cancer group after eradication. After eradication, SHH methylation levels in the non-metaplastic glands were significantly higher (86.4% vs. 22.2%, P < 0.001) in the cancer group than in the controls. CONCLUSIONS: H. pylori eradication can enhance SHH and its downstream regulators expression diminishing SHH methylation and reverse gastric phenotype, but not in the patients with high risk for gastric cancer.

Renin-angiotensin system associated with risk of upper GI mucosal injury induced by low dose aspirin: renin angiotensin system genes' polymorphism.

BACKGROUND: We have previously shown that co-treatment of angiotensin type 1 receptor (AT1R) blocker (ARB) or angiotensin converting enzyme (ACE) inhibitor seem to reduce peptic ulcer among patients taking low dose aspirin. It is reported that a series of renin-angiotensin system (RAS) gene polymorphisms significantly influence the rate of the gene transcription. AIM: The aim of this study was to examine the genotypes of RAS genes related to the risk of peptic ulcer and ulcer bleeding among patients taking low dose aspirin. METHODS: Patients taking 100 mg of aspirin who were planning to undergo endoscopy for surveillance or who had history of recent upper GI ulcer bleeding were included. ACE (Ins/Del), angiotensinogen (AGT; G-217A, A-20C, A-6G, T174 M, M235T), and AT1R (T-713G, C-521T, A1166C) genotypes were determined by PCR or PCR-RFLP. RESULTS: Four hundred twenty-five patients were enrolled including 68 patients with peptic ulcer and 20 patients with ulcer bleeding. Co-treatment of ARB was significantly associated with peptic ulcer and ulcer bleeding. AGT-20 CC (adjusted OR 4.94, 95% CI 1.21-20.2) was significantly associated with ulcer bleeding. The CC genotype of AT1R-521 was significantly associated with peptic ulcer only in the subgroup taking neither ACE inhibitor nor ARB. CONCLUSIONS: Co-treatment of ARB reduces peptic ulcer and bleeding among patients taking low dose aspirin. RAS may play an important role in the development of upper GI mucosal injury induced by low dose aspirin.

Expression of Sonic hedgehog (SHH) and CDX2 in the columnar epithelium of the lower oesophagus.

BACKGROUND: Decreases in Sonic hedgehog (SHH) and CDX2 expression are associated with atrophy and intestinal metaplasia in the gastric mucosa. The pathogenesis of development of Barrett's oesophagus is still unclear. OBJECTIVE: To examine the gene expression of CDX2 and SHH and their signalling pathways in the columnar epithelium and the association with endoscopic appearance, gastric pH or bile acids. SUBJECTS/METHODS: Sixty-three patients with metaplastic columnar epithelium of the lower oesophagus were studied. Whole biopsy specimens and microdissected tissues were examined for messenger RNA. RESULTS: BMP4 expression was significantly higher in patients with tubular mucosal patterns of columnar epithelium visualised by Narrow Band Imaging with magnification. The expression of SHH was significantly lower and that of CDX2 was higher in the goblet columnar epithelium than in non-goblet columnar epithelium. CDX2 expression was significantly higher in the patients with hypoacidity than in the others. BMP4 and PTCH1 expression was significantly higher in the group with higher concentrations of deoxycholic acid than in the group with lower concentrations. CONCLUSIONS: SHH might be the initial factor inducing columnar metaplasia, and subsequent or simultaneous BMP4 stimuli might induce the CDX2 expression that causes goblet-cell metaplasia.

Aspirin-induced peptic ulcer and genetic polymorphisms.

There are a few studies of the association between genetic polymorphisms and the risks of acetylsalicylic acid (aspirin)-induced ulcer or its complications. Two single nucleotide polymorphisms (SNP) of cyclooxygenase-1 (COX-1), A-842G and C50T, exhibited increased sensitivity to aspirin and had lower prostaglandin synthesis capacity, lacking statistical significance in the association with bleeding peptic ulcer. A recent Japanese study indicated that the number of COX-1-1676T alleles was a significant risk factor for peptic ulcer in users of non-steroidal anti-inflammatory drugs (NSAIDs). There are some genetic polymorphisms for aspirin resistance, such as platelet membrane glycoproteins, thromboxane A2 (TXA2) receptor, platelet activating factor acetylhydrolase and coagulation factor XIII; however, data on the frequency of gastrointestinal (GI) events in these variants are lacking. Carrying the CYP2C9 variants is reported a significantly increased risk of non-aspirin NSAID-related GI bleeding. The polymorphisms of interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) have been associated with development of peptic ulcer or gastric cancer. In a recent investigation, carriage of the IL-1beta-511 T allele was significantly associated with peptic ulcer among low-dose aspirin users. Hypoacidity in corpus gastritis related to polymorphisms of pro-inflammatory cytokines seems to reduce NSAIDs or aspirin-related injury. Data on which polymorphisms are significant risk factors for GI events in aspirin users are still lacking and further large-scale clinical studies are required.

[Gastritis].

Eradication of Helicobacter pylori (H. pylori) has suggested not only the decrease in the incidence of peptic ulcer diseases and gastric cancer, and but also the improvement of dyspeptic symptoms. Dyspepsia is a common condition in the world, and dyspepsia-related medical cost is high due to consultations, investigations, and drug consumption. Although the role of H. pylori in functional dyspepsia is still unknown, recent studies including meta-analysis have indicated that H. pylori eradication improves dyspeptic symptoms. In addition, the reduction of medical cost by H. pylori eradication has been discussed in the more recent studies.

The preventive factors for aspirin-induced peptic ulcer: aspirin ulcer and corpus atrophy.

PURPOSE: Interleukin-1beta (IL-1beta) polymorphisms are associated with peptic ulcer and atrophic gastritis. This study aimed to examine effects of corpus atrophy and the genotypes of genes related to peptic ulcer, including IL-1beta, on risk of aspirin ulcer. METHODS: 232 patients taking 100 mg of aspirin for cardiovascular diseases, of whom 40 had peptic ulcer, were enrolled. IL1beta, interleukin-1 receptor antagonist (IL-1RN), tumor necrosis factor (TNF)-alpha, cyclooxygenase (COX)-1, cytochrome p450 2C9 (CYP2C9), UDP-glucuronosyltransferase (UGT1A6) genotypes were determined, and serum pepsinogen levels were measured. RESULTS: The polymorphisms of IL-1beta-511/-31 were significantly associated with peptic ulcer, but other genotypes were not. Serum pepsinogen I and II levels and I/II ratio were significantly higher in the ulcer group than in the non-ulcer group. Taking PPI [adjusted odds ratio (OR), 0.09; 95% confidence interval (CI), 0.02-0.39], pepsinogen I of less than 50 ng/ml (OR, 0.24; 95% CI, 0.10-0.56) and IL-1beta-511 T carrier (OR, 0.42; 95% CI, 0.18-0.93) were significantly associated with peptic ulcer. CONCLUSIONS: Hypoacidity related to corpus atrophy as well as taking PPI seems to be preventively associated with development of peptic ulcer among low dose aspirin users.

Upper gastrointestinal ulcer in Japanese patients taking low-dose aspirin.

BACKGROUND: There are few studies on the association of the risks of upper gastrointestinal (GI) ulcer induced by aspirin combined with other medicines. We investigated the association between peptic ulcer and clinical parameters, including Helicobacter pylori infection and combinations of medicines. METHODS: Patients taking 100 mg aspirin for cardiovascular diseases who were planning to undergo endoscopy were enrolled. Serum H. pylori IgG antibody was measured. RESULTS: A total of 305 patients were enrolled, and 38 patients (12.4%) had ulcer lesions. Sex, smoking, drinking, body mass index, endoscopic findings for gastric atrophy (open type), or presence of H. pylori were not significantly associated with ulcer lesions. Cotreatment with anticoagulants [ticlopidine, 34.2% vs. 21.3%; adjusted odds ratio (OR), 3.1; 95% confidence interval (CI), 1.4-7.1; ticlopidine plus warfarin, 13.2% vs. 3.7%; adjusted OR, 4.4; 95% CI, 1.3-15], proton pump inhibitor (PPI 5.3% vs. 34.8%; adjusted OR, 0.10; 95% CI, 0.02-0.43), and antihypertensive medicine were significantly associated with peptic ulcer. Among antihypertensive medicines, AT1 receptor blocker and angiotensin-converting enzyme (ACE) inhibitor tended to be associated with upper GI ulcer. CONCLUSIONS: PPI was superior to H2-receptor antagonist for prevention of peptic ulcer, and cotreatment with AT1 receptor blocker or ACE inhibitor seemed to reduce peptic ulcer among patients taking low-dose aspirin.

Sonic hedgehog and CDX2 expression in the stomach.

Sonic hedgehog (Shh) is an essential regulator of patterning processes throughout development, and CDX proteins act as the master regulators for intestinal development and differentiation. Shh and CDX2 seem to be interdependently linked with cellular differentiation through different signal cascades. We have recently shown that the loss of Shh and aberrant expression of CDX2 in Helicobacter pylori (H. pylori)-associated atrophic gastritis can be modified by H. pylori eradication prior to incomplete intestinal metaplasia. On the other hand, abnormal signaling of the hedgehog pathway has been reported in gastric cancer, especially diffuse-type cancer and advanced gastric cancer, and Shh acts as a proliferation factor in both the normal mucosa and malignant lesions. CDX2 expressed in the early stage of gastric carcinogenesis is associated with the intestinal phenotypic region and thus with a better outcome. However, it remains unclear how Shh and CDX2 are involved with intestinal transformation and further carcinogenesis.