Atrophic Border Research Articles

Endoscopic Diagnosis and Therapy for Epstein-Barr Virus-Associated Gastric Cancer.

Epstein-Barr-virus-associated gastric cancer (EBVaGC) represents almost 7% of all GC and is a distinct subtype of GC with extreme DNA hypermethylation. EBVaGC is a tumor-infiltrating lymphocyte-rich tumor with little lymph-node metastasis in its early stage and with a relatively favorable prognosis in its advanced stage. Using upper gastrointestinal endoscopy, we recognize EBVaGC as a mainly depressed type with SMT-like protrusion in the upper part of the stomach near the gastric mucosal atrophic border or remnant stomach. The EBVaGC recognition rate of 21.4% with the endoscopic motif is not high, and further progress in endoscopic diagnosis of EBVaGC is needed. As less invasive endoscopic therapy, the extension of the criteria of endoscopic submucosal dissection (ESD) for early EBVaGC with little lymph-node metastasis should be discussed. Endoscopic diagnosis of EBVaGC may be relevant for the selection of patients who could benefit from endoscopic treatment or chemotherapy.

Identifying the gastric atrophic border according to Kimura-Takemoto classification by using high-definition endoscopes and a new virtual chromoendoscopy modality

Identifying the gastric atrophic border according to Kimura-Takemoto classification by using high-definition endoscopes and a new virtual chromoendoscopy modality

Linked Color Imaging for Stomach.

Image-enhanced endoscopy (IEE) plays an important role in the detection and further examination of gastritis and early gastric cancer (EGC). Linked color imaging (LCI) is also useful for detecting and evaluating gastritis, gastric intestinal metaplasia as a pre-cancerous lesion, and EGC. LCI provides a clear excellent endoscopic view of the atrophic border and the demarcation line under various conditions of gastritis. We could recognize gastritis as the lesions of the diffuse redness to purple color area with LCI. On the other hand, EGCs are recognized as the lesions of the orange-red, orange, or orange-white color area in the lesion of the purple color area, which is the surround atrophic mucosa with LCI. With further prospective randomized studies, we will be able to evaluate the diagnosis ability for EGC by IEE, and it will be necessary to evaluate the role of WLI/IEE and the additional effects of the diagnostic ability by adding IEE to WLI in future.

Clinicopathological features of Epstein-Barr virus-associated superficial early stage gastric cancer treated with endoscopic submucosal dissection.

Epstein-Barr virus (EBV) is known to be involved in gastric carcinogenesis. EBV-associated early gastric carcinoma (EBVEGC) has a lower incidence of lymph node involvement and could be an expanded indication for endoscopic submucosal dissection (ESD) treatment. To clarify the prevalence and clinicopathological features of EBVEGC. This study reviewed 618 lesions in 519 patients treated with ESD between 2014 and 2016. Tissue microarray sections were subjected to in situ hybridization staining for EBV-encoded small RNA transcripts (EBER). Lesions positive for EBER were compared with control lesions and were retrospectively analyzed. 12 (1.9%) of the 618 lesions were EBVEGC. EBVEGCs were more frequently located near the atrophic border than control lesions in the middle or upper stomach and were reddish. EBVEGC invasion was deeper and more often histologically undifferentiated. On narrow-band imaging magnifying endoscopy, the EBVEGC group significantly more often showed an endoscopic lace pattern, defined as an absent or obscure microsurface pattern and a microvascular pattern of a tiny, dense, and irregular subepithelial capillary network. The rate of curative resection was significantly lower in the EBVEGC group. Only 1.9% of the ESD specimens were EBV-positive. Endoscopic features could raise clinical suspicion of EBV infection.

Identifying the gastric atrophic border according to Kimura-Takemoto classification by using high-definition endoscopes and a new virtual chromoendoscopy modality

Identifying the gastric atrophic border according to Kimura-Takemoto classification by using high-definition endoscopes and a new virtual chromoendoscopy modality

Linked color imaging effectively detects the endoscopic atrophic border in transnasal endoscopy.

In oral endoscopy, linked color imaging (LCI) detects atrophic border and gastric mucosal diseases better than white light imaging (WLI), but its usefulness in transnasal endoscopy has not been fully investigated. Here, we retrospectively compared WLI and LCI using the L*a*b* color space in images from 57 patients aged ≥20 years who had undergone transnasal endoscopy as part of a health check-up from May 2016 to January 2017. We measured color differences at the atrophic/non-atrophic and fundic/pyloric mucosal borders. Gastritis severity scored using the Kyoto classification of gastritis was similar between the two techniques. However, in patients with current and with past Helicobacter pylori infection, color difference at the atrophic border was greater with LCI (21.58 ± 6.97 and 27.34 ± 10.32, respectively) than with WLI [14.42 ± 5.95 (p = 0.004) and 17.9 ± 8.48 (p<0.001)]; in those never infected with Helicobacter pylori, color difference at the fundic/pyloric mucosal border was greater with LCI than with WLI (p<0.001). Because of its enhancement of atrophic border detection, we recommend linked color imaging as the method of choice for transnasal endoscopy in health check-ups, particularly for identifying people at high risk of gastric cancer.

Improved Visibility of Early Gastric Cancer after Successful Helicobacter pylori Eradication with Image-Enhanced Endoscopy: A Multi-Institutional Study Using Video Clips.

The visibility and diagnostic accuracy of early gastric cancer (EGC) after Helicobacter pylori (HP) eradication have been reported to improve using image-enhanced endoscopy (IEE) compared with white light imaging (WLI). The present study clarified the appropriate IEE for the detection and diagnosis of EGC in clinical settings. This prospective and cross-sectional study evaluated the visibility of EGC and endoscopic findings of gastric mucosa after successful HP eradication (n = 31) using videos with WLI and IEE. Three endoscopists evaluated high-definition videos in a randomized order. The mean visibility scores (MVSs) on linked color imaging (LCI) for atrophic border, intestinal metaplasia, map-like redness, and EGC were the highest among each modality (3.87 ± 0.34, 3.82 ± 0.49, 3.87 ± 0.50, and 3.35 ± 0.92, respectively). The MVSs with blue laser imaging (BLI) were highest for magnifying view of the demarcation line (DL), microsurface pattern (MSP), and microvascular pattern (MVP) for EGC (3.77 ± 0.49, 3.94 ± 0.25, and 3.92 ± 0.34, respectively). LCI had the highest visibility among findings of gastric mucosa and EGC after HP eradication, and BLI had the highest visibility of MVP, MSP, and DL in magnifying observation. These results suggest that LCI observation in the entire stomach and further magnifying BLI are the best methods for detecting and diagnosing EGCs after HP eradication, respectively.

Endoskopik Atrofik Gastrit Görünümünün Histopatolojik Karşılığının Değerlendirilmesi: Sistematik İnceleme

Objective: Atrophic gastritis (AG), which is defined as the loss of gastric glands, can be precancerous. The objective of this study is examination of histopathological correlation of our patients with AG, considered according to endoscopic findings and determination of the other concomitant pathological findings. Material and Methods: Biopsy was performed in the atrophic areas and/or different areas on a total of 201 patients during gastroscopic evaluation due to the pre-diagnosis of AG between 2013 and 2014 in our clinic. Their pathological evaluation was performed and the cases of these patients were examined retrospectively. Endoscopic diagnosis of AG was made based on observation of the gastric mucosa as pale compared to the normal gastric mucosa and the separation of this area from the normal gastric mucosa, which can be defined as an endoscopic atrophic border with the prominence of submucosal thin vascular structures. Diagnosis of AG was pathologically defined as loss of glands. Results: The average age of the total 201 patients, who were 133 (67%) women and 68 (33%) men, was 69 years. Endoscopic and histological AG correlation in the whole group was 63 (31%). Considering the gastric localisation of the cases with confirmed diagnosis of AG in histopathological examination; it was determined that 89% affect the proximal, 9% the distal and 2% the distal and proximal together. Intestinal metaplasia (IM) was accompanied in 68% of cases with chronic active gastritis (21%) and neuroendocrine cell hyperplasia (NEHD) (14%). Chronic active gastritis was detected in 32% and IM 17% in cases without histopathological AG. While Helicobacter pylori positivity was 6% in those with histopathologically AG, it was 24% in those without AG (p=0.003). When evaluated in terms of accompanying pathological findings, NEHD, IM and lymphoid follicle hyperplasia were found with a higher rate in patients with histopathologically AG, and found statistically significant. Conclusion: Pathological examination must be performed if AG is suspected in endoscopy. While IM and NECH were more commonly concomitantly observed in patients with AG in pathological examination, the rate of H. Pylori was lower compared to the patients who did not have AG.

Endoscopic Characteristics of Rugal Hyperplasia and Related Acid Condition in Helicobacter pylori-Infected Stomach

Background/AimsRugal hyperplastic gastritis (RHG) is associated with Lauren’s diffuse-type gastric cancer (GC) and the accompanying active inflammation is linked to gastric hypoacidity. We tried to establish the steps for identifying high-risk GC patients. MethodsWe included 196 patients with confirmed Helicobacter pylori infection by rapid urease test during screening endoscopy for health check-up from January 2016 to September 2016; all patients underwent blood tests for pepsinogen I and II and fasting serum gastrin. We compared RHG findings with various other endoscopic mucosal images. We also evaluated the relationships between RHG and other mucosal aspects for a given acid status based on serological markers. ResultsHypoacid and ultra-low-acid (67%) statuses were dominant, with only 18% hyperacid patients. RHG with high acid was related to a less atrophic body type (p=0.001), and RHG with ultra-low acid was associated with body xanthoma (p=0.029) and increased serum gastrin level (p=0.038). However, RHG’s influence on gastric acidity was only seen in closed-type endoscopic atrophic border (EAB), not in open type (p=0.001). ConclusionsThe majority of RHG patients had hypoacid status. RHG frequency showed no difference between closed and opentype EAB, but gastric acidity was influenced by RHG only in closed-type EAB.

Endoscopic grading of gastric atrophy on risk assessment of gastric neoplasia: A systematic review and meta-analysis.

Endoscopic examination of gastric atrophy has been developed to determine the extent of atrophy by identifying the atrophic border of gastric mucosa, but its value in predicting the risk of developing gastric neoplasms is not quantified. Thus, this systematic review and meta-analysis aim to assess the incidence risk of gastric neoplasms on the basis of endoscopic grading of gastric atrophy. Two authors independently searched the electronic databases (PubMed, Embase, and the Cochrane Library) from inception through December 31, 2019, without language restriction. The effect size on study outcomes is calculated using random-effects model and presented as risk ratio (RR) with 95% confidence interval (CI). Heterogeneity, publication bias, and quality of included studies were also assessed. Fourteen retrospective studies are identified to perform systematic review and meta-analysis, 11 were cohort studies, and three were cross-sectional research. The pooled RR for developing gastric neoplasms is 3.89 (95% CI 2.92-5.17) among general patients with severe endoscopic atrophy. For patients who underwent endoscopic resection for early gastric neoplasms, nearly two times increased risk of synchronous or metachronous neoplasms is pooled (RR=1.96, 95% CI 1.39-2.75). In terms of the type of endoscopic atrophy, patients with open-type endoscopic atrophy have a higher risk of gastric cancer development (RR 8.02; 95% CI 2.39-26.88) than those with close type. [Correction added on 22 December 2020, after first online publication: '(RR = 7.27; 95% CI 1.64-32.33)' has been corrected to '(RR 8.02; 95% CI 2.39-26.88)'] CONCLUSIONS: Grading endoscopic atrophy according to the Kimura-Takemoto classification can assess the risk of gastric neoplasia development. Patients with severe or open-type endoscopic gastric atrophy at baseline should undergo rigorous surveillance to early detect premalignant lesions and cancer.

Linked Color Imaging and the Kyoto Classification of Gastritis: Evaluation of Visibility and Inter-Rater Reliability

Background/Aims: To compare white light imaging (WLI) with linked color imaging (LCI) and blue LASER imaging (BLI) in endoscopic findings of Helicobacter pylori presently infected, previously infected, and uninfected gastric mucosae for visibility and inter-rater reliability. Methods: WLI, LCI and BLI bright mode (BLI-bright) were used to obtain 1,092 endoscopic images from 261 patients according to the Kyoto Classification of Gastritis. Images were evaluated retrospectively by 10 experts and 10 trainee endoscopists and included diffuse redness, spotty redness, map-like redness, patchy redness, red streaks, intestinal metaplasia, and an atrophic border (52 cases for each finding, respectively). Physicians assessed visibility as follows: 5 (improved), 4 (somewhat improved), 3 (equivalent), 2 (somewhat decreased), and 1 (decreased). Visibility was assessed from totaled scores. The inter-rater reliability (intraclass correlation coefficient) was also evaluated. Results: Compared with WLI, all endoscopists reported improved visibility with LCI: 55.8% for diffuse redness; LCI: 38.5% for spotty redness; LCI: 57.7% for map-like redness; LCI: 40.4% for patchy redness; LCI: 53.8% for red streaks; LCI: 42.3% and BLI-bright: 80.8% for intestinal metaplasia; LCI: 46.2% for an atrophic border. For all endoscopists, the inter-rater reliabilities of LCI compared to WLI were 0.73–0.87. Conclusion: The visibility of each endoscopic finding was improved by LCI while that of intestinal metaplasia was improved by BLI-bright.

Visual Function at the Atrophic Border in Choroideremia Assessed with Adaptive Optics Microperimetry

Recent advances in retinal imaging allow visualization of structural abnormalities in retinal disease at the cellular level. This study used adaptive optics (AO) microperimetry to assess visual sensitivity with high spatial precision and to examine how function varies across 2 phenotypic features observed in choroideremia: atrophic lesion borders and outer retinal tubulations (ORTs). Cross-sectional study. Twelve choroideremia patients. A custom AO scanning light ophthalmoscope (AOSLO) equipped with both confocal and nonconfocalsplit-detection imaging methods was used to image the photoreceptor inner and outer segment mosaics. For AO microperimetry, circular 550-nm stimuli were presented through the AOSLO system; stimuli were either 9.6 or 38.3 arcmin2 (approximately 60 or 15 times smaller than a Goldman III stimulus). Test locations were identified in structural images and stimuli were targeted to these locations using real-time retinal tracking combined with measurements of transverse chromatic aberration. Psychophysical detection thresholds were measured at the atrophic border in 12 patients. Additionally, visual sensitivity was probed along ORTs in 4patients. Visual sensitivity thresholds measured with AO microperimetry at retinal locations corresponding to structural phenotypes observed on AOSLO retinal images. In choroideremia, sharp borders between intact central islands of the photoreceptor mosaic and complete atrophy of the outer retina and retinal pigment epithelium were observed in both split-detection and confocal structural images. Adaptive optics microperimetry at locations spanning these borders showed a commensurately sharp decrease in function, with readily measurable visual sensitivity on one side and dense scotoma on the other. These functional transitions often occurred over a distance smaller than the diameter of the Goldman III stimulus. Thresholds measured along ORTs showed dense scotoma over the tubule in all 4 participants, despite the visibility of remnant cone inner segments on the AO images. Choroideremia patients exhibited sharp functional transitions that collocated with structural transitions from intact to severely degenerated retina. We found no evidence of visual sensitivity over ORTs. Measuring cone function with high resolution offered insight into disease mechanisms and may enable precise assessment of whether experimental therapies, such as gene therapy, provide a functional benefit.

Clinical features of Helicobacter pylori antibody-positive junior high school students in Nagano Prefecture, Japan.

Previously, we conducted an epidemiological study screening for Helicobacter pylori antibody positivity among Japanese junior high school students. In this study, we updated the epidemiological data and assessed the clinical features of Hpylori antibody-positive junior high school students. We assessed Hpylori antibody-positive subjects who were identified between 2012 and 2015 at four junior high schools in Nagano Prefecture, Japan. Hpylori infection was confirmed by urea breath test (UBT) or endoscopic examination. Endoscopy was performed after obtaining consent from the subject and their guardians. Eradication therapy consisted of triple therapy with proton pump inhibitor (PPI), amoxicillin (AMPC), and clarithromycin (CAM) or metronidazole (MNZ) for seven days. Eradication of Hpylori was confirmed by UBT. We reviewed subjects' characteristics, endoscopic findings, histological findings, eradication regimes, outcomes, and adverse effects. The overall prevalence of Hpylori antibody positivity was 3.2% (42/1298). We assessed thirteen Hpylori antibody-positive subjects. Eight subjects had a family history of Hpylori infection. Six subjects had abdominal pain, and two subjects had iron deficiency anemia (IDA). Twelve subjects underwent endoscopy; one subject had duodenal ulcer, eleven subjects had antral nodular gastritis, and six subjects showed grade 2 closed type atrophic border according to the Kimura-Takemoto classification. All subjects received eradication therapy; CAM was used in five subjects with CAM susceptibility as well as in three subjects with unknown information on CAM susceptibility, and MNZ was used in five subjects with CAM resistance. Eradication was successful in twelve subjects (one unconfirmed). There were three mild adverse effects (abdominal pain or diarrhea). Helicobacter pylori test for junior high school students represents an opportunity to diagnose the peptic ulcer, iron deficiency anemia, and gastric atrophy.

Blue laser imaging-bright improves the real-time detection rate of early gastric cancer: a randomized controlled study

Blue laser imaging-bright (BLI-bright) has shown promise as a more useful tool for detection of early gastric cancer (EGC) than white-light imaging (WLI). However, the diagnostic performance of BLI-bright in the detection of EGC has not been investigated. We aimed to compare real-time detection rates of WLI with that of BLI-bright for EGC. This was a prospective, randomized, controlled study in 2 Japanese academic centers. We investigated 629 patients undergoing follow-up endoscopy for atrophic gastritis with intestinal metaplasia or surveillance after endoscopic resection of EGC. Patients were randomly assigned to receive primary WLI followed by BLI-bright or primary BLI-bright followed by WLI. The real-time detection rates of EGC were compared between primary WLI and primary BLI-bright. There were 298 patients in each group. The real-time detection rate of EGC with primary BLI-bright was significantly greater than that with primary WLI (93.1% vs 50.0%; P= .001). Primary BLI-bright had a significantly greater ability to detect EGCs in patients with a history of endoscopic resection for EGC, no Helicobacter pylori infection in the stomach after eradication therapy, lesions with an open-type atrophic border, lesions in the lower third of the stomach, depressed-type lesions, small lesions measuring<10mm and 10 to 20mm in diameter, reddish lesions, well-differentiated adenocarcinomas, and lesions with a depth of invasion of T1a. BLI-bright has a higher real-time detection rate for EGC than WLI. BLI-bright should be performed during surveillance endoscopy in patients at high risk for EGC. (Clinical trial registration number: UMIN000011324.).

Objective Endoscopic Analysis with Linked Color Imaging regarding Gastric Mucosal Atrophy: A Pilot Study.

Objectives We aimed to determine whether linked color imaging (LCI), a new image-enhanced endoscopy that enhances subtle differences in mucosal colors, can distinguish the border of endoscopic mucosal atrophy. Methods This study included 30 patients with atrophic gastritis. In endoscopy, we continuously took images in the same composition with both LCI and white light imaging (WLI). In each image, the color values of atrophic and nonatrophic mucosae were quantified using the International Commission on Illumination 1976 (L∗, a∗, b∗) color space. Color differences at the atrophic border, defined as Euclidean distances of color values between the atrophic and nonatrophic mucosae, were compared between WLI and LCI for the overall cohort and separately for patients with Helicobacter pylori infection status. Results We found that the color difference became significantly higher with LCI than with WLI in the overall samples of 90 points in 30 patients. LCI was 14.79 ± 6.68, and WLI was 11.06 ± 5.44 (P < 0.00001). LCI was also more effective in both of the Helicobacter pylori-infected group (P = 0.00003) and the Helicobacter pylori-eradicated group (P = 0.00002). Conclusions LCI allows clear endoscopic visualization of the atrophic border under various conditions of gastritis, regardless of Helicobacter pylori infection status.

A Possible Link between Gastric Mucosal Atrophy and Gastric Cancer after Helicobacter pylori Eradication.

BackgroundThe effect of H. pylori eradication in gastric cancer prevention can be attributed to the improvement of atrophic gastritis, which is a known risk of gastric cancer. However, gastric cancer has also been diagnosed after long-term H. pylori eradication. This study aimed to clarify the association between gastric atrophy and gastric cancer after H. pylori eradication, including its clinicopathological features.MethodsA total of 55 consecutive patients with 64 early gastric cancers (EGCs) diagnosed after H. pylori eradication were enrolled. The degree of endoscopic atrophy and the histological degrees of mononuclear cell infiltration, atrophy, and metaplasia in the corpus and adjacent mucosa of the EGCs were determined and scored.ResultsThe majority of EGCs (63/64) were located within the endoscopically assessed atrophic mucosa or along the atrophic border. The adjacent mucosa of the EGCs presented significantly higher degrees of all histological parameters than in the corpus (mononuclear cell infiltration, 0.86+/-0.09 vs. 0.51+/-0.11, P = 0.016; atrophy, 1.77+/-0.13 vs. 0.65+/-0.14, P<0.0001; metaplasia, 1.68+/-0.13 vs. 0.48+/-0.1, P<0.0001). The degree of endoscopic atrophy improved in the patients with longer post-H. pylori eradication periods; however, this trend was not observed for the histological parameters, and high degrees of atrophy and metaplasia were observed in the adjacent mucosa of the EGCs compared with the corpus during all periods (all P<0.05). The histological degrees of atrophy and metaplasia in the adjacent mucosa were particularly higher in the patients who underwent eradication due to gastric ulcers.ConclusionsSevere gastric atrophy remained in the adjacent mucosa of the EGCs after H. pylori eradication, which may be linked to gastric carcinogenesis.

Useful condition of chromoendoscopy with indigo carmine and acetic acid for identifying a demarcation line prior to endoscopic submucosal dissection for early gastric cancer.

BackgroundIdentifying a precise demarcation line (DL) is indispensable for pathological complete en bloc endoscopic submucosal dissection (ESD) for early gastric cancer (EGC). We evaluated the useful condition of chromoendoscopy with indigo carmine and acetic acid for marking dots around lesions before ESD for EGC.MethodsWe examined 98 consecutive patients with 109 intramucosal EGCs (mean diameter, 17.8 ± 12.4 mm; main histologic type, 96 intestinal and 13 diffuse) resected by en bloc ESD after chromoendoscopy with indigo carmine and acetic acid between December 2012 and February 2014. The DL was identified by this technique just before ESD (mean chromoendoscopy observation time, 71.6 s); subsequently, marking dots were placed around the EGC. EGCs were classified into two groups: useful for identifying the DL or useless. Clinicopathological characteristics and clinical outcomes were evaluated in each group.ResultsForty-two of the 109 cases (38.5 %) were determined useful for chromoendoscopy with indigo carmine and acetic acid. Multivariate analysis with logistic regression showed that macroscopic type (protruded or flat elevated-type) and atrophic border (the oral side of tumor) were independently associated with the usefulness of chromoendoscopy using indigo carmine and acetic acid for identifying the DL of EGCs (P < 0.05). The histologically positive horizontal margin after ESD was 0 % (0/42) in useful cases, and 7.5 % (5/67) in useless cases.ConclusionsBefore ESD, chromoendoscopy with indigo carmine and acetic acid can be used for creating precise markings in protruded or flat elevated-type EGC or at the atrophic border on the oral side of EGCs.

Association of extensive delayed overmethylation influenced by advanced atrophy with risk for gastric cancer.

13 Background: Helicobacter pylori (HP) infection facilitates overmethylation of CpG-island genes, which can be delayed by advanced mucosal atrophy. Delayed overmethylation results in unstable cell phenotypes responsible for gastric cancer. To delineate cancer risk period, the overmethylation period from HP infection to severe atrophy was traced in the gastric cancer and dysplasia. Methods: A pair of normal-appearing mucosal specimens was obtained from the antrum and body of 110 HP-positive and 95 HP-negative controls, 99 cancer patients, and 118 dysplasia patients. Gastric mucosal atrophy was assessed using the endoscopic atrophic border score. Eight CpG-island genes adjacent to Alu (CDH1, ARRDC4, PPARG, TRAPPC2L) and LTR retroelements (MMP2, CDKN2A, RUNX2, RUNX3) and the TFF3 gene lacking CpG island were chosen. The methylation-variable sites in gene-control regions were analyzed using radioisotope-labeling methylation-specific PCR. Results: The antrum-specific TFF3 gene on the antrum tended to be overmethylated earlier than Alu-type CpG-island genes on the body in the HP-positive controls with mild mucosal atrophy (mean age; 50 years vs. 52 years). In moderate atrophic cases, the antrum-site TFF3 overmethylation was delayed four years compared with the whole cases (58 years vs. 54 years) and the Alu-type overmethylation on the body was early detected (49 years). Gastric cancer patients with moderate atrophy induced a late overmethylation on both the antrum and body site (56 and 58 years) and increased LTR-type slow overmethylation (OD, 5.3; 95% CI, 2.0-14.1). Dysplasia patients (65 years) older than gastric cancer sustained an early Alu-type overmethylation on the body site. Conclusions: Moderate atrophy of the gastric mucosa can delay overmethylation of CpG-island genes, which leads to unstable cancer period and subsequent stable dysplasia period.

Slow Overmethylation of Housekeeping Genes in the Body Mucosa Is Associated with the Risk for Gastric Cancer

Helicobacter pylori infection increases age-related diverse overmethylation in gene-control regions, which increases the risk of gastric cancer. The H. pylori-associated overmethylation changes subsequently disappear when gastric atrophy and cancer develop. To identify cancer-risk epigenotypes, we traced dynamic methylation changes in the background mucosa of the stomach depending on the extent of gastric atrophy. Paired biopsy specimens were obtained from the noncancerous antrum and body mucosa of 102 patients with cancer and 114 H. pylori-positive and 112 H. pylori-negative controls. The grade of gastric atrophy was evaluated using the endoscopic atrophic border score. The methylation-variable sites at the CpG-island margins and near the transcriptional start sites lacking CpG islands were semiquantitatively analyzed by radioisotope-labeling methylation-specific PCR. We selected eight housekeeping genes adjacent to Alu (CDH1, ARRDC4, PPARG, and TRAPPC2L) or LTR retroelements (MMP2, CDKN2A, RUNX2, and RUNX3) and eight stomach-specific genes (TFF2, PGC, ATP4B, TFF1, TFF3, GHRL, PGA, and ATP4A). Analysis of age-related methylation in the H. pylori-positive controls revealed slow overmethylation in the body and in the LTR-adjacent genes. A high-frequency overmethylation defined based on the slowly overmethylated genes was frequently observed in the body of patients with gastric cancer with open-type atrophy (OR, 12.7; 95% confidence interval, 3.2-49.8). The rapidly changing methylation of Alu-adjacent genes was barely increased in the antrum of patients with gastric cancer. Among diverse methylation changes associated with H. pylori infection, an increase in slowly changing methylation could serve as a cancer-risk marker.

Metachronous gastric cancer after successful Helicobacter pylori eradication.

The high incidence of gastric cancer in Japan initially resulted in establishment of a country-wide gastric cancer screening program to detect early and treatable cancers. In 2013 countrywide Helicobacter pylori (H. pylori) eradication was approved coupled with endoscopy to assess for the presence of chronic gastritis. Current data support the notion that cure of the infection in those with non-atrophic gastritis will prevent development of gastric cancer. However, while progression to more severe damage is halted in those who have already developed, atrophic gastritis/gastric atrophy remain at risk for subsequent development of gastric cancer. That risk is directly related to the extent and severity of atrophic gastritis. Methods to stratify cancer risk include those based on endoscopic assessment of the atrophic border, histologic grading, and non-invasive methods based on serologic testing of pepsinogen levels. Continued surveillance is required because those with atrophic gastritis/gastric atrophy retain considerable gastric cancer risk even after H. pylori eradication. Those who have already experienced a resectable early gastric cancer are among those at highest risk as metachronous lesions are frequent even after H. pylori eradication. We review the role of H. pylori and effect of H. pylori eradication indicating the incidence and the predictive factors on development of metachronous cancer after endoscopic therapy of early gastric cancer. Studies to refine risk markers to stratify for risk, surveillance methods, intervals, and duration after successful H. pylori eradication, and whether adjuvant therapy would change risk are needed.