Landscape of driver mutations and their clinical effects on Down syndrome-related myeloid neoplasms.

ABSTRACT: Transient abnormal myelopoiesis (TAM) is a common complication in newborns with Down syndrome (DS). It commonly progresses to myeloid leukemia (ML-DS) after spontaneous regression. In contrast to the favorable prognosis of primary ML-DS, patients with refractory/relapsed ML-DS have poor outcomes. However, the molecular basis for refractoriness and relapse and the full spectrum of driver mutations in ML-DS remain largely unknown. We conducted a genomic profiling study of 143 TAM, 204 ML-DS, and 34 non-DS acute megakaryoblastic leukemia cases, including 39 ML-DS cases analyzed by exome sequencing. Sixteen novel mutational targets were identified in ML-DS samples. Of these, inactivations of IRX1 (16.2%) and ZBTB7A (13.2%) were commonly implicated in the upregulation of the MYC pathway and were potential targets for ML-DS treatment with bromodomain-containing protein 4 inhibitors. Partial tandem duplications of RUNX1 on chromosome 21 were also found, specifically in ML-DS samples (13.7%), presenting its essential role in DS leukemia progression. Finally, in 177 patients with ML-DS treated following the same ML-DS protocol (the Japanese Pediatric Leukemia and Lymphoma Study Group acute myeloid leukemia -D05/D11), CDKN2A, TP53, ZBTB7A, and JAK2 alterations were associated with a poor prognosis. Patients with CDKN2A deletions (n = 7) or TP53 mutations (n = 4) had substantially lower 3-year event-free survival (28.6% vs 90.5%; P < .001; 25.0% vs 89.5%; P < .001) than those without these mutations. These findings considerably change the mutational landscape of ML-DS, provide new insights into the mechanisms of progression from TAM to ML-DS, and help identify new therapeutic targets and strategies for ML-DS.

A gain-of-function mutation in microRNA 142 is sufficient to cause the development of T-cell leukemia in mice.

MicroRNAs (miRNAs) play a crucial role in regulating gene expression. MicroRNA expression levels fluctuate, and point mutations and methylation occur in cancer cells; however, to date, there have been no reports of carcinogenic point mutations in miRNAs. MicroRNA 142 (miR-142) is frequently mutated in patients with follicular lymphoma, diffuse large B-cell lymphoma, chronic lymphocytic leukemia (CLL), and acute myeloid leukemia/myelodysplastic syndrome (AML/MDS). To understand the role of miR-142 mutation in blood cancers, the CRISPR-Cas9 system was utilized to successfully generate miR-142-55A>G mutant knock-in (Ki) mice, simulating the most frequent mutation in patients with miR-142 mutated AML/MDS. Bone marrow cells from miR-142 mutant heterozygous Ki mice were transplanted, and we found that the miR-142 mutant/wild-type cells were sufficient for the development of CD8+ T-cell leukemia in mice post-transplantation. RNA-sequencing analysis in hematopoietic stem/progenitor cells and CD8+ T-cells revealed that miR-142-Ki/+ cells had increased expression of the mTORC1 activator, a potential target of wild-type miR-142-3p. Notably, the expression of genes involved in apoptosis, differentiation, and the inhibition of the Akt-mTOR pathway was suppressed in miR-142-55A>G heterozygous cells, indicating that these genes are repressed by the mutant miR-142-3p. Thus, in addition to the loss of function due to the halving of wild-type miR-142-3p alleles, mutated miR-142-3p gained the function to suppress the expression of distinct target genes, sufficient to cause leukemogenesis in mice.

Changes in Eating Attitudes and Risk for Developing Disordered Eating Behaviors in College Students with Subthreshold Eating Disorders: A Cohort Study.

INTRODUCTION: The number of young adults with eating disorders or subthreshold eating disorders has increased recently. Although disordered eating behaviors persist once they appear, there have been relatively few studies on factors that might cause disordered eating behaviors. The purpose of this study was to investigate how the eating attitudes of young adults change over time and the risk factors that increase disordered eating behaviors. METHODS: A total of 1,141 college students, 639 males and 502 females, participated. We investigated changes in eating attitudes (using EAT-26 and BITE), depressive symptoms (using BDI-II), and stress coping (using CISS, which has three subscales) between 2 time points: at college entrance and in the fourth year of college. We divided the students into three groups (clinical, subthreshold, and healthy) based on EAT-26 scores and compared their BDI-II and CISS scores. Next, we identified students who developed disordered eating behaviors, both clinical and subthreshold, during their time at college (exacerbated students) and compared depressive symptoms and stress coping styles between exacerbated students and healthy students (unchanged students). RESULTS: The students in the subthreshold group (both males and females) scored significantly higher on the BDI-II and emotion-oriented coping (CISS-E) than the students in the healthy group at college entrance. Additionally, the exacerbated students (both males and females) scored significantly higher on the CISS-E in the fourth year than unchanged students. The female exacerbated students scored significantly higher on the BDI-II than female unchanged students at both time points. CONCLUSIONS: Our results show that depressive symptoms and nonadaptive stress coping are associated with an increased risk of disordered eating behaviors. This study suggests that early intervention may be necessary for both the clinical and subthreshold groups. The key to early intervention may be to manage not only eating behaviors but also depressive symptoms and stress coping.

Potential of Helicobacter pylori-uninfected signet ring cell carcinoma to invade the submucosal layer.

BACKGROUND AND AIM: The typical histology of Helicobacter pylori-uninfected gastric cancer is signet ring cell carcinoma (SRCC) localized in the mucosal layer, but the potential of these SRCCs to invade the submucosal layer is unclear. This study aimed to investigate the clinicopathological characteristics of SRCC in H. pylori-uninfected patient and its prevalence in diffuse-type gastric cancer (DGC) within Japan. METHODS: We enrolled consecutive pure DGC patients diagnosed with the disease either localized in the mucosal layer or with submucosal invasion. H. pylori infection was investigated, and the patients were divided into three groups according to histological types: pure SRCC, SRCC with poorly differentiated adenocarcinoma (PDA), and pure PDA. RESULTS: Of the 345 pure DGC patients, 132 (38%), 127 (37%), and 86 (25%) had pure SRCC, SRCC with PDA, and pure PDA histologies, respectively. The prevalence of H. pylori infection and the SM ratio were significantly lower in the pure SRCC group than other groups (P < 0.01). Twenty-two (6.4%) patients, including two with submucosal invasion, were negative for H. pylori and had mucosal SRCC component in the cancer lesions. Of the 259 SRCC cases (pure SRCC or SRCC + PDA), H. pylori-uninfected cases had different clinicopathological characteristics compared with H. pylori-positive cases. Particularly, the ratio of patients with submucosal invasive SRCC was significantly lower in the H. pylori-uninfected gastric cancer group than in those with H. pylori infection. CONCLUSION: Helicobacter pylori-uninfected gastric cancer is not rare among pure DGC patients in Japan. SRCC in patients without H. pylori infection is less likely to be invasive.

Optimal Criteria and Diagnostic Ability of Serum Pepsinogen Values for Helicobacter pylori Infection.

BACKGROUND: Practical criteria for the use of serum pepsinogen (PG) values in diagnosing Helicobacter pylori infection have not yet been determined. METHODS: The results of gastric endoscopies, H. pylori infection tests, and PG values were retrospectively reviewed. Subjects were assigned to groups, including never-infected (with neither infection nor gastric mucosal atrophy), infected (with atrophy or findings indicating infection in endoscopy and positive infection tests except for antibody tests), and ex-infected (with gastric mucosal atrophy and negative infection tests, except for antibody tests). The optimal criteria with combined use of the PG II concentrations and the PG I/PG II ratio were investigated separately for PG measurements obtained with the chemiluminescent magnetic particle immunoassay (CLIA) and latex agglutination (LA) methods, such that the specificity was greater than 70% and the sensitivity was no less than 95% among the never-infected and infected subjects. Similar analyses were performed by combining the data from ex-infected and infected subjects. RESULTS: For the CLIA (LA) method, the optimal criterion among 349 (397) never-infected and 748 (863) infected subjects was a PG II value of at least 10 (12) ng/mL or a PG I/PG II ratio no more than 5.0 (4.0), which produced 96.3% (95.1%) sensitivity and 82.8% (72.8%) specificity. When 172 (236) ex-infected subjects were included, the optimal criterion was the same, and the sensitivity was 89.1% (86.9%). CONCLUSIONS: The above criteria may be practical for clinical use, and PG tests using these criteria might prevent unnecessary endoscopic examinations for never-infected subjects.

Clinical Significance of Reddish Depressed Lesions Observed in the Gastric Mucosa after Helicobacter pylori Eradication.

BACKGROUND AND AIM: Reddish depressed lesions (RDLs) frequently observed in patients following Helicobacter pylori eradication are indistinguishable from gastric cancer. We examined the clinical and histological feature of RDLs and its relevant endoscopic diagnosis including magnifying narrow-band imaging (M-NBI). METHODS: We enrolled 301 consecutive patients with H. pylori eradication who underwent endoscopy using white light imaging (WLI). We examined the prevalence and host factors contributing to the presence of RDLs. Next, we used M-NBI in 90 patients (104 RDLs), and compared the diagnostic efficacy between M-NBI and WLI groups using propensity-score matching analysis. RESULTS: In 301 patients after eradication, 117 (39%) showed RDLs. Male, open-type atrophy, and gastric cancer history were risk factors for RDLs. A gastric biopsy was needed in 83 (71%) during WLI observation and only 2 were diagnosed with adenocarcinoma. In M-NBI group, a biopsy was performed in 21 (20%), and 9 were diagnosed with adenocarcinoma. A biopsy was required in fewer patients, and the positive predictive value of a biopsy was statistically higher in M-NBI than in the WLI group (p < 0.01). CONCLUSIONS: RDLs are frequently observed in high-risk patients for gastric cancer after eradication. M-NBI demonstrated significantly superior diagnostic efficacy with respect to RDL.

Diagnostic performance of Japan NBI Expert Team classification for differentiation among noninvasive, superficially invasive, and deeply invasive colorectal neoplasia.

BACKGROUNDS AND AIMS: The Japan NBI Expert Team (JNET) classification is the first universal narrow-band imaging magnifying endoscopic classification of colorectal tumors. Considering each type in this classification, the diagnostic ability of Type 2B is the weakest. Generally, clinical behavior is believed to be different in each gross type of colorectal tumor. We evaluated the differences in the diagnostic performance of JNET classification for each gross type (polypoid and superficial) and examined whether the diagnostic performance of Type 2B could be improved by subtyping. METHODS: We analyzed 2933 consecutive cases of colorectal lesions, including 136 hyperplastic polyps/sessile serrated polyps, 1926 low-grade dysplasias (LGDs), 571 high-grade dysplasias (HGDs), and 300 submucosal (SM) carcinomas. We classified lesions as polypoid and superficial type and compared the diagnostic performance of the classification system in each type. Additionally, we subtyped Type 2B into 2B-low and 2B-high based on the level of irregularity in surface and vessel patterns, and we evaluated the relationship between the subtypes and histology, as analyzed separately for polypoid and superficial types. We also estimated interobserver and intraobserver variability. RESULTS: The diagnostic performance of JNET classification did not differ significantly between polypoid and superficial lesions. Ninety-nine percent of Type 2B-low lesions were LGDs, HGDs, or superficial submucosal invasive (SM-s) carcinomas. In contrast, 60% of Type 2B-high lesions were deep submucosal invasive (SM-d) carcinomas. The results were not different between each gross type. Interobserver and intraobserver agreements for Type 2B subtyping were good, with kappa values of .743 and .786, respectively. CONCLUSIONS: Type 2B subtyping may be useful for identifying lesions that are appropriate for endoscopic resection. JNET classification and Type 2B sub classification are useful criteria, regardless of gross type.

Clinical impact and characteristics of the narrow-band imaging magnifying endoscopic classification of colorectal tumors proposed by the Japan NBI Expert Team.

BACKGROUND AND AIMS: The Japan NBI Expert Team (JNET) was established in 2011 and has proposed a universal narrow-band imaging (NBI) magnifying endoscopic classification of colorectal tumors. The aim of this study was to evaluate the clinical usefulness of the JNET classification for colorectal lesions. METHODS: We analyzed 2933 colorectal lesions, which were diagnosed by NBI magnifying observation before endoscopic treatment or surgery. The colorectal lesions consisted of 136 hyperplastic polyps/sessile serrated polyps (HPs/SSPs), 1926 low-grade dysplasia (LGD), 571 high-grade dysplasia (HGD), 87 superficial submucosal invasive (SM-s) carcinomas, and 213 deep submucosal invasive (SM-d) carcinomas. We evaluated the relationship between the JNET classification and the histologic findings of these lesions. RESULTS: The sensitivity, specificity, positive and negative predictive values, and accuracy of Type 1 lesions for the diagnosis of HP/SSP were, respectively, 87.5%, 99.9%, 97.5%, 99.4%, and 99.3%; of Type 2A lesions for the diagnosis of LGD were 74.3%, 92.7%, 98.3%, 38.7%, and 77.1%; of Type 2B lesions for the diagnosis of HGD/SM-s carcinoma were 61.9%, 82.8%, 50.9%, 88.2%, and 78.1%; for Type 3 lesions for the diagnosis of SM-d carcinoma were 55.4%, 99.8%, 95.2%, 96.6%, and 96.6%, respectively. CONCLUSIONS: Types 1, 2A, and 3 of the JNET classification were very reliable indicators for HP/SSP, LGD, and SM-d carcinoma, respectively. However, the specificity and positive predictive value of Type 2B were relatively lower than those of others. Therefore, an additional examination such as pit pattern diagnosis using chromoagents is necessary for accurate diagnosis of Type 2B lesions.

Endoscopic findings of the gastric mucosa during long-term use of proton pump inhibitor - a multicenter study.

BACKGROUND AND AIM: It is clinically important to diagnose drug-induced gastric lesions correctly. Recently, the use of proton pump inhibitors (PPI) has increased worldwide. The histological features induced by PPI have been reported; however, few reports have described endoscopic findings induced by PPI. Therefore, we aimed to clarify the characteristic endoscopic features in PPI users and associated pathogenic factors. METHODS: We prospectively registered 1007 consecutive participants (70 PPI users and 937 nonusers) who underwent endoscopic examination for cancer screening in three hospitals/clinics. Clinical data and endoscopic findings were recorded in the registration forms. We compared the endoscopic features between the two groups and evaluated contributing factors via univariate and multivariate analyses. RESULTS: Multiple white elevated lesions (MWEL) and cobblestone-like mucosa (CLM) were more commonly observed in PPI users compared with nonusers (p < .01). Foveolar hyperplastic polyps were also frequently observed in PPI users but were not statistically significantly different (p = .06). MWEL and CLM were more frequently observed in older patients than in younger patients. MWEL was more frequently observed in female patients than in male patients; however, CLM was predominantly observed in male patients. CONCLUSION: MWEL and CLM are characteristic endoscopic features in PPI users. A gender-associated difference was noted in terms of the frequency of these lesions.

Characteristics of gastric cancer in negative test of serum anti-Helicobacter pylori antibody and pepsinogen test: a multicenter study.

BACKGROUND AND AIM: The serological risk prediction system combines the pepsinogen test and anti-Helicobacter pylori (H. pylori) antibody determination. In this system, chronic atrophic gastritis (CAG) is diagnosed using the pepsinogen test. Patients who are H. pylori negative and pepsinogen negative are classified into group A, are assumed to be H. pylori uninfected, and are at an extremely low risk for gastric cancer. However, gastric cancers are detected in this group. The aim of this study is to clarify the clinicopathological status of group A patients with gastric cancer. METHODS: A total of 109 gastric cancer patients classified as group A were enrolled in a multicenter study. Group A patients were divided into two subgroups: group AN (H. pylori uninfected) and group AP (H. pylori infected). They were compared to 183 H. pylori-infected gastric cancer patients who were not in group A. RESULTS: Of the 109 patients, only 7 were classified as group AN; the other 102 were classified as group AP. The clinicopathological features of group AP included older age, predominantly differentiated type cancer, endoscopically visualized CAG, and pepsinogen (PG) I/II ratio lower than that of group AN. In group AN, the depressed type was dominant, and the PG I/II ratio was higher than in those gastric cancer patients who were infected with H. pylori. CONCLUSION: Patients in group AP had CAG, and their gastric cancers were similar to those of H. pylori-eradicated patients. Concerning the recent ABC classification system, advanced decision criteria should be proposed to decrease the false-negative evaluation of gastric cancer risk.

Serological Evaluation of Gastric Cancer Risk Based on Pepsinogen and Helicobacter pylori Antibody: Relationship to Endoscopic Findings.

BACKGROUNDS AND AIMS: The serological risk-prediction system combined the pepsinogen (PG) test, and anti-Helicobacter pylori antibody is available for evaluation of gastric cancer risk. In this system, chronic atrophic gastritis (CAG) or H. pylori infection is diagnosed. Subjects with H. pylori negative and PG test negative (group A) are supposed to be those who have never been infected with H. pylori and are at extremely low risk for gastric cancer. However, a certain proportion of patients with CAG has been identified as the extremely low-risk group (group A). Here we examined endoscopic atrophy and investigated its relationship with the ABC classification system. METHODS: We examined 540 patients. All patients underwent an endoscopic examination for evaluating corpus atrophy. Fasting sera were collected and serum PGs and anti-H. pylori antibody (Hp-Ab) titer (E-plate Eiken) were evaluated. RESULTS: Of the 540 patients, 306 were classified into group A. However, 136 of them showed signs of endoscopic atrophy (group A with CAG). Group A with CAG frequently comprised the elderly. A new titer cut-off (<3 U/mL) of the Hp-Ab improved the discrimination of group A with CAG by 8%. CONCLUSION: The prevalence of group A with CAG patients is a critical problem, especially in elderly subjects.

Time Trends in Helicobacter pylori Infection and Atrophic Gastritis Over 40 Years in Japan.

BACKGROUND: Helicobacter pylori infection produces progressive mucosal damage that may eventually result in gastric cancer. We studied the changes that occurred in the presence and severity of atrophic gastritis and the prevalence of H. pylori infection that occurred coincident with improvements in economic and hygienic conditions in Japan since World War II. MATERIALS AND METHODS: The prevalence of H. pylori infection and histologic grades of gastric damage were retrospectively evaluated using gastric biopsy specimens obtained over a 40-year period. Gastric atrophy and intestinal metaplasia were scored using the updated Sydney classification system. RESULTS: The prevalence of H. pylori and severity of atrophy were examined in 1381 patients including 289 patients examined in the 1970s (158 men; mean age, 44.9 years), 787 in the 1990s (430 men; 44.2 years), and 305 in the 2010s (163 men; 53.2 years). Overall, the prevalence of H. pylori infection decreased significantly from 74.7% (1970s) to 53% (1990s) and 35.1% (2010s) (p < .01). The prevalence of atrophy in the antrum and corpus was significantly lower in the 2010s (33, 19%, respectively) compared to those evaluated in either the 1970s (98, 82%) (p < .001) or 1990s (80, 67%) (p < .001). The severity of atrophy and intestinal metaplasia also declined remarkably among those with H. pylori infection. CONCLUSIONS: There has been a progressive and rapid decline in the prevalence of H. pylori infection as well a fall in the rate of progression of gastric atrophy among H. pylori-infected Japanese coincident with the westernization and improvements in economic and hygienic conditions in Japan since World War II.

A computer system to be used with laser-based endoscopy for quantitative diagnosis of early gastric cancer.

GOALS: To evaluate the usefulness of a newly devised computer system for use with laser-based endoscopy in differentiating between early gastric cancer, reddened lesions, and surrounding tissue. BACKGROUND: Narrow-band imaging based on laser light illumination has come into recent use. We devised a support vector machine (SVM)-based analysis system to be used with the newly devised endoscopy system to quantitatively identify gastric cancer on images obtained by magnifying endoscopy with blue-laser imaging (BLI). We evaluated the usefulness of the computer system in combination with the new endoscopy system. STUDY: We evaluated the system as applied to 100 consecutive early gastric cancers in 95 patients examined by BLI magnification at Hiroshima University Hospital. We produced a set of images from the 100 early gastric cancers; 40 flat or slightly depressed, small, reddened lesions; and surrounding tissues, and we attempted to identify gastric cancer, reddened lesions, and surrounding tissue quantitatively. RESULTS: The average SVM output value was 0.846 ± 0.220 for cancerous lesions, 0.381 ± 0.349 for reddened lesions, and 0.219 ± 0.277 for surrounding tissue, with the SVM output value for cancerous lesions being significantly greater than that for reddened lesions or surrounding tissue. The average SVM output value for differentiated-type cancer was 0.840 ± 0.207 and for undifferentiated-type cancer was 0.865 ± 0.259. CONCLUSIONS: Although further development is needed, we conclude that our computer-based analysis system used with BLI will identify gastric cancers quantitatively.

Diagnosis of Helicobacter pylori-induced gastritis by serum pepsinogen levels.

BACKGROUND AND AIM: Gastric cancer develops due to atrophic gastritis induced by Helicobacter pylori (H. pylori) infection. Serum levels of pepsinogen (PG) are known to be excellent markers for evaluating the degree of atrophic gastritis. We investigated whether chronic gastritis could be diagnosed by evaluating serum PG levels. METHODS: A total of 4483 patients (average age, 49.7 years; 2879 men) were included in this study. Fasting serum samples were collected and anti-H. pylori antibody and PG levels were evaluated. We evaluated the endoscopic atrophy grade or histological extent of gastritis, and calculated the diagnostic capability of this serum marker. RESULTS: A total of 4483 patients, were diagnosed as being positive (4160) or negative (323) for H. pylori-induced gastritis. In patients with H. pylori-induced gastritis, the PG II levels were higher and the PG I/II ratios were lower than among those without H. pylori gastritis. A cut-off values of (i) PG I/II ≤ 5; (ii) PG II ≥ 10 or PG I/II ≤ 5; (iii) PG II ≥ 12 or PG I/II ≤ 4.5 showed high sensitivity and accuracy (over 90%) for diagnosing H. pylori-induced gastritis. Moreover, in a mass screening of healthy subjects, a cut-off value of PG I/II ≤ 4.5 might be better for diagnosing the presence of gastritis because of a sensitivity and specificity > 80%. CONCLUSIONS: The presence of H. pylori-induced gastritis can be evaluated using serum PG levels.

Predictors of incomplete resection and perforation associated with endoscopic submucosal dissection for colorectal tumors.

BACKGROUND AND OBJECTIVE: Colorectal endoscopic submucosal dissection (ESD) is technically challenging. Our aim was to identify predictors of incomplete resection and perforation in colorectal ESD. DESIGN: Retrospective study. SETTING: Academic Japanese endoscopy unit. PATIENTS AND MAIN OUTCOME MEASUREMENTS: A total of 267 consecutive cases of colorectal tumors treated by ESD from May 2010 to February 2013 were analyzed. Predictors of incomplete resection and perforation, including lesion size, growth type, pathological diagnosis, use of hemostatic forceps, degree of fibrosis, history of biopsy, history of local endoscopic treatment, and endoscopic operability. RESULTS: The incomplete resection rate was 4.1%. The perforation rate was 5.6%. Univariate analysis identified severe fibrosis (P = .032), submucosal (SM) deep (>1000 µm) invasion (P = .033) and poor endoscopic operability (P = .030) as predictors of incomplete resection, and severe fibrosis (P = .038), postendoscopic treatment (P = .016), and poor endoscopic operability (P = .012) as predictors of perforation. Multivariate analysis identified poor endoscopic operability and SM deep invasion as independent predictors of incomplete resection, and poor endoscopic operability and severe fibrosis as independent predictors of perforation. There was no adjustment of P values for multiple testing. LIMITATION: A single-center study by a single colonoscopist. All statistical results should be taken as descriptive only. CONCLUSIONS: Poor endoscopic operability and SM deep invasion were significant independent predictors of incomplete resections. Poor endoscopic operability and severe fibrosis were significant independent predictors of perforation. These features may provide helpful information when planning colorectal ESD.

Advanced method for evaluation of gastric cancer risk by serum markers: determination of true low-risk subjects for gastric neoplasm.

BACKGROUND: Patients with negative anti-Helicobacter pylori antibody titer and high pepsinogen (PG) level (group A) are regarded as having a low risk for gastric cancer. However, gastric cancer cases are occasionally observed in this group. We aimed to elucidate the clinical features of gastric neoplasm in group A patients and reviewed advanced methods for mass screening. MATERIALS AND METHODS: A total of 271 gastric epithelial neoplasm patients were enrolled. We classified them according to the H. pylori-PG system and determined the number of patients in each group. After excluding true H. pylori-negative cases from group A (group A'), we examined the differences between group A' and group non-A. RESULTS: Group A included 30 (11%) patients, and only three of these were true negative for H. pylori. All patients in group A' (n = 27) exhibited endoscopic atrophy in the gastric corpus. Serologically, these patients showed low gastrin, low PG II and high PG I/II ratio, indicative of post-eradication. Histologically, 24 (89%) of these had little inflammation, and 26 (96%) were negative for H. pylori by immunohistochemistry. No difference was observed in the incidence of metachronous gastric tumors between group A' and group non-A. The discriminant function using gastrin and PGs could distinguish these 27 patients from true H. pylori-negative controls with 85% sensitivity and 84% specificity. CONCLUSIONS: Group A included a certain number of patients with atrophic gastritis who were potentially at risk of gastric neoplasm development. Although evaluation of corpus atrophy is necessary for the identification of these patients, the discriminant function may be useful.

Characteristic epithelium with low-grade atypia appears on the surface of gastric cancer after successful Helicobacter pylori eradication therapy.

BACKGROUND: The incidence of gastric cancer after successful Helicobacter pylori eradication has been increasing. We previously reported that epithelium with low-grade atypia (ELA) appeared on the surface of gastric cancer after H. pylori eradication. Here, we investigate the clinical and biological characteristics of such ELA. METHODS: We studied 27 cases of gastric cancer detected after successful H. pylori eradication therapy. We examined the prevalence of ELA among these cases and its significance for endoscopic discovery after H. pylori eradication. We additionally investigated the mucus, p53 and Ki67 expressions in ELA. RESULTS: Epithelium with low-grade atypia that continuous with the gastric tumor was detected in 22 of 27 cases (81%), a significantly greater percentage than that for controls (p < 0.01). We found that gastric-type mucin was frequently expressed in this epithelium. Neither p53- nor Ki67-positive cells were found in ELA, irrespective of their expression in tumor tissue. The presence of ELA was positively correlated with the clinical interval between H. pylori eradication and gastric cancer detection. CONCLUSIONS: Epithelium with low-grade atypia on gastric cancer tissue, which may develop from gastric cancer cells, is frequently present after successful eradication therapy. This phenomenon could influence the practice of endoscopic diagnosis of gastric cancers.

Quantitative identification of mucosal gastric cancer under magnifying endoscopy with flexible spectral imaging color enhancement.

BACKGROUND AND AIM: Magnifying endoscopy with flexible spectral imaging color enhancement (FICE) is clinically useful in diagnosing gastric cancer and determining treatment options; however, there is a learning curve. Accurate FICE-based diagnosis requires training and experience. In addition, objectivity is necessary. Thus, a software program that can identify gastric cancer quantitatively was developed. METHODS: A bag-of-features framework with densely sampled scale-invariant feature transform descriptors to magnifying endoscopy images of 46 mucosal gastric cancers was applied. Computer-based findings were compared with histologic findings. The probability of gastric cancer was calculated by means of logistic regression, and sensitivity and specificity of the system were determined. RESULTS: The average probability was 0.78 ± 0.25 for the images of cancer and 0.31 ± 0.25 for the images of noncancer tissue, with a significant difference between the two groups. An optimal cut-off point of 0.59 was determined on the basis of the receiver operating characteristic curves. The computer-aided diagnosis system yielded a detection accuracy of 85.9% (79/92), sensitivity for a diagnosis of cancer of 84.8% (39/46), and specificity of 87.0% (40/46). CONCLUSION: Further development of this system will allow for quantitative evaluation of mucosal gastric cancers on magnifying gastrointestinal endoscopy images obtained with FICE.

High expression of gastrin receptor protein in injured mucosa of Helicobacter pylori-positive gastritis.

BACKGROUND AND AIM: Gastrin is a growth factor for the gastric epithelial cells. However, it is unknown how gastric receptor (GR) expression is regulated in the gastric mucosa. We studied GR expression using a newly raised antibody and investigated the relationship between GR expression and gastritis. METHODS: Gastric receptor expression in 63 human gastric mucosa was studied. Helicobacter pylori infection and histological gastritis status were evaluated in gastric biopsy samples. In gastric ulcer cases, additional biopsy specimens were taken from injured mucosa. Fasting sera were collected and serum gastrin level evaluated. MKN-28 cells were cultured at various pH conditions, and the change in GR expression was determined. RESULTS: Gastric receptor expression was detected in the foveolar epithelium of the gastric mucosa, and its expression was stronger in patients infected with H. pylori. In particular, higher expression was detected in regenerating injured mucosa. There was no association between gastritis score/serum gastrin level and GR expression in H. pylori-positive cases. In MKN-28 cells, GR protein expression was lower in neutral conditions than in acidic or alkaline conditions. CONCLUSION: Gastric mucosal injury with H. pylori infection destroys the pH barrier on the foveolar epithelium and may induce GR expression through pH changes.

Recent advances in in situ Notch signaling measurement.

Notch signaling is necessary for the development of many organ systems, including the nervous system, biliary system, and visual and auditory sensory systems. This signaling pathway is composed of DSL ligands and Notch receptors. Upon the interaction of those components between neighboring cells, the intracellular domain of the Notch receptor is cleaved from the cell membrane to act as a transcription factor. To date, many mechanistic insights, including lateral inhibition and lateral induction, have been proposed from observation of patterning morphogenesis and expression profiles of Notch signaling-associated molecules. The lack of a direct measurement method for Notch signaling, however, has impeded the examination of those mechanistic insights. In this mini-review, recent advances in the direct measurement of Notch signaling are introduced with a focus on the application of genetic modification of Notch receptors with the components of the Cre/loxP system and Gal4/UAS system. The combination of such conventional genetic techniques is opening a new era in Notch signaling biology by direct visualization of Notch "signaling" in addition to Notch signaling-associated molecules.