Severe induction of aberrant DNA methylation by nodular gastritis in adults.

BACKGROUND: Nodular gastritis (NG) is characterized by marked antral lymphoid follicle formation, and is a strong risk factor for diffuse-type gastric cancer in adults. However, it is unknown whether aberrant DNA methylation, which is induced by atrophic gastritis (AG) and is a risk for gastric cancer, is induced by NG. Here, we analyzed methylation induction by NG. METHODS: Gastric mucosal samples were obtained from non-cancerous antral tissues of 16 NG and 20 AG patients with gastric cancer and 5 NG and 6 AG patients without, all age- and gender-matched. Genome-wide methylation analysis and expression analysis were conducted by a BeadChip array and RNA-sequencing, respectively. RESULTS: Clustering analysis of non-cancerous antral tissues of NG and AG patients with gastric cancer was conducted using methylation levels of 585 promoter CpG islands (CGIs) of methylation-resistant genes, and a large fraction of NG samples formed a cluster with strong methylation induction. Promoter CGIs of CDH1 and DAPK1 tumor-suppressor genes were more methylated in NG than in AG. Notably, methylation levels of these genes were also higher in the antrum of NG patients without cancer. Genes related to lymphoid follicle formation, such as CXCL13/CXCR5 and CXCL12/CXCR4, had higher expression in NG, and genes involved in DNA demethylation TET2 and IDH1, had only half the expression in NG. CONCLUSIONS: Severe aberrant methylation, involving multiple tumor-suppressor genes, was induced in the gastric antrum and body of patients with NG, in accordance with their high gastric cancer risk.

Clinical meaning of sarcopenia in patients undergoing endoscopic treatment.

With increasing global life expectancy, the significance of geriatric assessment parameters has increased. Sarcopenia is a crucial assessment parameter and is defined as the age-related loss of muscle mass and strength. Sarcopenia is widely acknowledged as a risk factor for postoperative complications in diverse advanced malignancies and has a detrimental effect on the long-term prognosis. While most studies have primarily concentrated on the correlation between sarcopenia and advanced cancer, more recent investigations have focused on the relationship between sarcopenia and early-stage cancer. Endoscopic submucosal dissection (ESD), which is less invasive than surgical intervention, is extensively employed in the management of early-stage cancer, although it is associated with complications such as bleeding and perforation. In recent years, several reports have revealed the adverse consequences of sarcopenia in patients with early-stage cancer undergoing ESD. This literature review briefly summarizes the recent studies on the association between sarcopenia and ESD.

Verification of the increase in concomitant dysplasia and cancer with the size of sessile serrated lesions.

Background and study aims This study aimed to evaluate the relationship between sessile serrated lesion (SSL) size and the comorbidity rate of SSL with dysplasia (SSLD) and cancer in SSL (SSL-cancer). Patients and methods This retrospective, single-center analysis identified SSL cases that underwent endoscopic resection between January 2015 and December 2022. The prevalence of SSL, SSLD, and SSL-cancer and their annual trends were assessed. The tumor diameter was stratified as 0 to 5 mm, 6 to 9 mm, 10 to 19 mm, and ≥ 20 mm in size. Furthermore, the frequency of SSL-D/SSL-cancer was determined in each group. Results The prevalence of SSL was 2.9% (1328/45799). This prevalence was 1.8% (112/6192) in 2015 and 4.2% (230/5500) in 2022, indicating an increasing trend over time. A total of 1825 lesions were assessed: 1751 (96.0%), 55 (3.0%), 14 (0.8%), and 5 (0.3%) of lesions were SSL, SSL with low-grade dysplasia, SSL with high-grade dysplasia and SSL-cancer, respectively. Stratifying the SSLs by size: 0 to 5 mm, 5 to 9 mm, 10 to 19 mm, and ≥ 20 mm, SSLD and SSL-cancer rates were 2.3% (10/429), 2.4% (16/674), 5.3% (31/584), and 11.8% (16/136), respectively. SSLD and SSL-cancer were observed in 2.4% (26/1103) of small SSLs < 10 mm. Conclusions In cases of SSL, the rate of SSLD and SSL-cancer increased as the lesion diameter increased. A certain rate of SSLD and SSL-cancer was observed even in small SSLs less than 5mm.

Feasibility of colorectal endoscopic submucosal dissection in elderly patients: the impact of sarcopenia.

INTRODUCTION: Colorectal cancer (CRC) is a public health concern associated with high incidence rates. Sarcopenia is a known risk factor for postoperative complications, although an association between increased complications after colorectal endoscopic submucosal dissection (ESD) and sarcopenia remains undocumented. Herein, we aimed to explore the feasibility of colorectal ESD in patients with sarcopenia. METHODS: This retrospective study included 499 patients (69 with and 430 without sarcopenia). We evaluated the short- and long-term outcomes of colorectal ESD. RESULTS: There were no significant differences between the two groups regarding en bloc, R0, or curative resection rates. However, poor bowel preparation was significantly more common in the sarcopenia group. Moreover, patients with sarcopenia exhibited a significant increase in complications (37.7% vs. 10.5%). Multivariate analysis revealed that sarcopenia (odds ratio [OR] 3.78, 95% confidence interval [Cl] 1.85-7.73, p < 0.001), anticoagulation therapy (OR 3.59, 95% Cl 1.86-6.92, p < 0.001), procedure time (OR 1.28, 95% Cl 1.11-1.47, p < 0.001), and resection size (OR 1.25, 95% Cl 1.03-1.52, p = 0.02) were significantly correlated with Common Terminology Criteria for Adverse Events (CTCAE) ≥ grade 2. The correlation between sarcopenia and CTCAE ≥ grade 2 was maintained after matching, resulting in more extended hospital stays in patients with sarcopenia. However, we detected no association between sarcopenia and overall survival and ESD-related death. CONCLUSION: Sarcopenia is a risk factor for complications in colorectal ESD, suggesting that colorectal ESD could be performed for patients with sarcopenia, although much caution should be taken.

Marked intestinal trans-differentiation by autoimmune gastritis along with ectopic pancreatic and pulmonary trans-differentiation.

BACKGROUND: Autoimmune gastritis (AIG) is a prevalent chronic inflammatory disease with oncogenic potential that causes destruction of parietal cells and severe mucosal atrophy. We aimed to explore the distinctive gene expression profiles, activated signaling pathways, and their underlying mechanisms. METHODS: A comprehensive gene expression analysis was conducted using biopsy specimens from AIG, Helicobacter pylori-associated gastritis (HPG), and non-inflammatory normal stomachs. Gastric cancer cell lines were cultured under acidic (pH 6.5) conditions to evaluate changes in gene expression. RESULTS: Gastric mucosa with AIG had a unique gene expression profile compared with that with HPG and normal mucosa, such as extensively low expression of ATP4A and high expression of GAST and PAPPA2, which are involved in neuroendocrine tumorigenesis. Additionally, the mucosa with AIG and HPG showed the downregulation of stomach-specific genes and upregulation of small intestine-specific genes; however, intestinal trans-differentiation was much more prominent in AIG samples, likely in a CDX-dependent manner. Furthermore, AIG induced ectopic expression of pancreatic digestion-related genes, PNLIP, CEL, CTRB1, and CTRC; and a master regulator gene of the lung, NKX2-1/TTF1 with alveolar fluid secretion-related genes, SFTPB and SFTPC. Mechanistically, acidic conditions led to the downregulation of master regulator and stemness control genes of small intestine, suggesting that increased environmental pH may cause abnormal intestinal differentiation in the stomach. CONCLUSIONS: AIG induces diverse trans-differentiation in the gastric mucosa, characterized by the transactivation of genes specific to the small intestine, pancreas, and lung. Increased environmental pH owing to AIG may cause abnormal differentiation of the gastric mucosa.

Precancerous nature of intestinal metaplasia with increased chance of conversion and accelerated DNA methylation.

OBJECTIVE: The presence of intestinal metaplasia (IM) is a risk factor for gastric cancer. However, it is still controversial whether IM itself is precancerous or paracancerous. Here, we aimed to explore the precancerous nature of IM by analysing epigenetic alterations. DESIGN: Genome-wide DNA methylation analysis was conducted by EPIC BeadArray using IM crypts isolated by Alcian blue staining. Chromatin immunoprecipitation sequencing for H3K27ac and single-cell assay for transposase-accessible chromatin by sequencing were conducted using IM mucosa. NOS2 was induced using Tet-on gene expression system in normal cells. RESULTS: IM crypts had a methylation profile unique from non-IM crypts, showing extensive DNA hypermethylation in promoter CpG islands, including those of tumour-suppressor genes. Also, the IM-specific methylation profile, namely epigenetic footprint, was present in a fraction of gastric cancers with a higher frequency than expected, and suggested to be associated with good overall survival. IM organoids had remarkably high NOS2 expression, and NOS2 induction in normal cells led to accelerated induction of aberrant DNA methylation, namely epigenetic instability, by increasing DNA methyltransferase activity. IM mucosa showed dynamic enhancer reprogramming, including the regions involved in higher NOS2 expression. NOS2 had open chromatin in IM cells but not in gastric cells, and IM cells had frequent closed chromatin of tumour-suppressor genes, indicating their methylation-silencing. NOS2 expression in IM-derived organoids was upregulated by interleukin-17A, a cytokine secreted by extracellular bacterial infection. CONCLUSIONS: IM cells were considered to have a precancerous nature potentially with an increased chance of converting into cancer cells, and an accelerated DNA methylation induction due to abnormal NOS2 expression.

Reduced DEFA5 Expression and STAT3 Activation Underlie the Submucosal Invasion of Early Gastric Cancers.

INTRODUCTION: Submucosal invasion is a core hallmark of early gastric cancer (EGC) with poor prognosis. However, the molecular mechanism of the progression from intramucosal gastric cancer (IMGC) to early submucosal-invasive gastric cancer (SMGC) is not fully understood. The objective of this study was to identify genes and pathways involved in the submucosal invasion in EGC using comprehensive gene expression analysis. METHODS: Gene expression profiling was performed for eight cases of IMGC and eight cases of early SMGC with submucosal invasion ≥500 µm. To validate the findings of gene expression analysis and to examine the gene expression pattern in tissues, immunohistochemical (IHC) staining was performed for 50 cases of IMGC and SMGC each. RESULTS: Gene expression analysis demonstrated that the expression levels of small intestine-specific genes were significantly decreased in SMGC. Among them, defensin alpha 5 (DEFA5) was the most downregulated gene in SMGC, which was further validated in SMGC tissues by IHC staining. Gene set enrichment analysis showed a strong association between SMGC, the JAK-STAT signaling pathway, and the upregulation of STAT3-activating cytokines. The expression of phosphorylated STAT3 was significant in the nucleus of tumor cells in SMGC tissues but not in areas expressing DEFA5. CONCLUSION: The results of this study strongly suggest that the downregulation of DEFA5 and the activation of STAT3 play a significant role in the submucosal invasion of EGC.

Gut microbial carbohydrate metabolism contributes to insulin resistance.

Insulin resistance is the primary pathophysiology underlying metabolic syndrome and type 2 diabetes1,2. Previous metagenomic studies have described the characteristics of gut microbiota and their roles in metabolizing major nutrients in insulin resistance3-9. In particular, carbohydrate metabolism of commensals has been proposed to contribute up to 10% of the host's overall energy extraction10, thereby playing a role in the pathogenesis of obesity and prediabetes3,4,6. Nevertheless, the underlying mechanism remains unclear. Here we investigate this relationship using a comprehensive multi-omics strategy in humans. We combine unbiased faecal metabolomics with metagenomics, host metabolomics and transcriptomics data to profile the involvement of the microbiome in insulin resistance. These data reveal that faecal carbohydrates, particularly host-accessible monosaccharides, are increased in individuals with insulin resistance and are associated with microbial carbohydrate metabolisms and host inflammatory cytokines. We identify gut bacteria associated with insulin resistance and insulin sensitivity that show a distinct pattern of carbohydrate metabolism, and demonstrate that insulin-sensitivity-associated bacteria ameliorate host phenotypes of insulin resistance in a mouse model. Our study, which provides a comprehensive view of the host-microorganism relationships in insulin resistance, reveals the impact of carbohydrate metabolism by microbiota, suggesting a potential therapeutic target for ameliorating insulin resistance.

Performing the ABC Method Twice for Gastric Cancer Risk Stratification: A Retrospective Study Based on Data from a Large-Scale Screening Facility.

The ABC method is a classification method used for stratifying the risk of gastric cancer. However, whether the ABC method should be performed only once or multiple times throughout an individual's lifetime remains unclear. Therefore, this study aimed to analyze whether performing ABC screening twice in a lifetime is useful. We retrospectively analyzed the data of individuals who participated in health checkups in 2010 and 2015. We collected data on patient characteristics, pepsinogen levels, anti-Helicobacter pylori antibody titers, and the presence of gastric cancer. Overall, 7129 participants without a history of H. pylori eradication were included in this study. The participants' average age in 2010 was 48.4 ± 8.3 years, and 58.1% were male. In addition, 11 and 20 cases of new H. pylori infection (0.15%) and spontaneous eradication (0.28%), respectively, were recorded. No significant difference was found in the incidence of gastric cancer between participants who underwent the ABC method once and those who underwent it twice (Group A: 0.16% vs. 0.16%; Group B: 0.47% vs. 0.39%; and Group C + D: 1.97% vs. 1.82%). Therefore, performing the ABC method twice, 5 years apart, does not significantly improve gastric cancer risk stratification.

Transcriptome analysis reveals the essential role of NK2 homeobox 1/thyroid transcription factor 1 (NKX2-1/TTF-1) in gastric adenocarcinoma of fundic-gland type.

BACKGROUND: Gastric adenocarcinoma of fundic-gland type (GA-FG) is a gastric malignancy with little relation to Helicobacter pylori. Clinical characteristics of GA-FG have been established, but molecular mechanisms leading to tumorigenesis have not yet been elucidated. METHODS: We subjected three GA-FG tumors-normal mucosa pairs to microarray analysis. Network analysis was performed for the top 30 up-regulated gene transcripts, followed by immunohistochemical staining to confirm the gene expression analysis results. AGS and NUGC4 cells were transfected with the gene-encoding NK2 homeobox 1/thyroid transcription factor 1 (NKX2-1/TTF-1) to evaluate transcriptional changes in its target genes. RESULTS: Comprehensive gene expression analysis identified 1410 up-regulated and 1395 down-regulated gene probes with ≥ two-fold difference in expression. Among the top 30 up-regulated genes in GA-FG, we identified transcription factor NKX2-1/TTF-1, a master regulator of lung/thyroid differentiation, together with surfactant protein B (SFTPB), SFTPC, and secretoglobin family 3A member 2(SCGB3A2), which are regulated by NKX2-1/TTF-1. Immunohistochemical analysis of 16 GA-FG specimens demonstrated significantly higher NKX2-1/TTF-1 and SFTPB levels, as compared to that in adjacent normal mucosa (P < 0.05), while SCGB3A2 levels did not differ (P = 0.341). Transduction of NKX2-1/TTF-1 into AGS and NUGC4 cells induced transactivation of SFTPB and SFTPC, indicating that NKX2-1/TTF-1 can function as normally in gastric cells as it can in the lung cells. CONCLUSIONS: Our first transcriptome analysis of GA-FG indicates significant expression of NKX2-1/TTF1 in GA-FG. Immunohistochemistry and cell biology show ectopic expression and normal transactivation ability of NKX2-1/TTF-1, suggesting that it plays an essential role in GA-FG development.

Cytomorphology and Gene Expression Signatures of Anchorage-independent Aggregations of Oral Cancer Cells.

BACKGROUND/AIM: Cancer cells with high anchorage independence can survive and proliferate in the absence of adhesion to the extracellular matrix. Under anchorage-independent conditions, cancer cells adhere to each other and form aggregates to overcome various stresses. In this study, we investigated the cytomorphology and gene expression signatures of oral cancer cell aggregates. MATERIALS AND METHODS: Two oral cancer-derived cell lines, SAS and HSC-3 cells, were cultured in a low-attachment plate and their cytomorphologies were observed. The transcriptome between attached and detached SAS cells was examined using gene expression microarrays. Subsequently, gene enrichment analysis and Ingenuity Pathway Analysis were performed. Gene expression changes under attached, detached, and re-attached conditions were measured via RT-qPCR. RESULTS: While SAS cells formed multiple round-shaped aggregates, HSC-3 cells, which had lower anchorage independence, did not form aggregates efficiently. Each SAS cell in the aggregate was linked by desmosomes and tight junctions. Comparative transcriptomic analysis revealed 1,698 differentially expressed genes (DEGs) between attached and detached SAS cells. The DEGs were associated with various functions and processes, including cell adhesion. Moreover, under the detached condition, the expression of some epithelial genes (DSC3, DSP, CLDN1 and OCLN) were up-regulated. The changes in both cytomorphology and epithelial gene expression under the detached condition overall returned to their original ones when cells re-attached. CONCLUSION: The results suggest specific cytomorphological and gene expression changes in oral cancer cell aggregates. Our findings provide insights into the mechanisms underlying anchorage-independent oral cancer cell aggregation and reveal previously unknown potential diagnostic and therapeutic molecules.

Fibrosis-4 index efficiently predicts chronic hepatitis and liver cirrhosis development based on a large-scale data of general population in Japan.

A non-invasive method to evaluate the fibrosis stage and the risk stratification of non-alcoholic fatty liver disease (NAFLD) is required. A total of 416,066 generally healthy subjects who underwent health check-ups between 1990 and 2019 were investigated. Fatty liver prevalence greatly increased from the 1990s (21.9%) to the 2000s (37.1%) but showed no considerable change between 2001-2010 (39.2%) and 2011-2019 (35.5%). During the 30 years, the rate of high FIB-4 index (≥2.67) and mean body mass index (BMI) did not markedly change. Fatty liver was significantly associated with BMI, but not with alcohol intake or FIB-4 index. Cox regression analyses for development of chronic hepatitis or liver cirrhosis identified that the risk of developing chronic hepatitis and liver cirrhosis was higher in subjects without fatty liver than in those with it (hazard ratio [HR]=0.09; 95% confidence interval [CI], 0.03-0.22, p <0.001 and HR=0.04; 95% CI, 0.01-0.26, p =0.001, respectively), and much larger in subjects with a high FIB-4 index (≥ 2.67) than in those without it (HR=78.6; 95% CI, 29.0-213.1, p <0.001 and HR=5950.7; 95% CI,761.7-46,491.4, p <0.001, respectively). Adjusted survival curves for Cox proportional hazards regression further reinforced these results. In conclusion, the FIB-4 index is a useful indicator of chronic hepatitis and liver cirrhosis development in the general population.

Gender-specific factors contributing to visceral obesity including the sleep-obesity relationship: a large-scale cross-sectional study from East Asia.

Our study aimed to evaluate the relationship between visceral obesity and its associated factors, especially sleep duration in East Asia. We conducted univariate and multivariate analyses using the data of 2538 participants (mean age 56.4 ± 10.8 years) who underwent medical checkups and computed tomography of the abdomen to calculate the visceral fat area from 2008 to 2020. We additionally performed logistic regression analyses using each sleep-duration group (< 5, 5-6, 6-7, 7-8, and ≥ 8 h) and their respective propensity scores as covariates. According to the criteria of visceral obesity(a visceral fat area ≥ 100 cm2), 1147 of 1918 men (59.8%) and 131 of 620 women (21.1%) had visceral obesity. In multivariate analyses, visceral obesity was significantly associated with age, body mass index and triglyceride in both genders, high-density lipoproteins, uric acid levels, and daily alcohol consumption in men; and glycated hemoglobin (HbA1c) in women. In both multivariate and propensity score matching analyses, sleep duration of > 8 h and visceral obestiy showed a positive association in men but a negative association in women with statistical significance. In conclusion, our large-scale cross-sectional study in East Asia identified various gender-specific factors associated with visceral obesity including the long sleep duration.

The impact of sarcopenia on short- and long-term outcomes of endoscopic submucosal dissection for early gastric cancer.

BACKGROUND: Sarcopenia prevalence has increased in proportion to the aging population in Japan. We aimed to investigate the association between sarcopenia and clinical outcomes and the prognostic factors of endoscopic submucosal dissection (ESD) for early gastric cancer (EGC). METHODS: This retrospective study involved patients aged ≥ 65 years who had undergone gastric ESD for EGC at our institution between January 2009 and December 2019. Patients were divided into two groups, namely, a sarcopenia group (109 patients) and a non-sarcopenia group (658 patients), based on the skeletal muscle index and intramuscular adipose tissue content (IMAC). Clinicopathological features, ESD-related adverse events, and outcomes were then compared. RESULTS: In the sarcopenia group, the mean age was higher, whereas performance and nutritional statuses were lower. There were no between-group differences in terms of treatment outcomes. Multivariate analyses (odds ratio [95% confidence interval (CI)]) indicated that a geriatric nutritional risk index score (GNRI) < 92 (2.12 [1.09-4.11], p = 0.03), anticoagulant therapy (1.76 [1.13-2.76], p = 0.01), tumor size ≥ 30 mm (2.09 [1.23-3.55], p = 0.01), and sarcopenia (1.90 [1.05-3.45], p = 0.03) were significantly associated with ESD-related adverse events. High Charlson comorbidity index, low prognostic nutritional index, low GNRI, and high IMAC were significantly associated with poor overall survival (OS). OS was significantly shorter in the sarcopenia group even after matching. CONCLUSIONS: Patients with sarcopenia had significantly more adverse events and shorter OS; therefore, evaluation of a patient's general condition, including sarcopenia, before ESD is important.

Analysis of Barrett's Esophagus and Its Risk Factors: A Cross-Sectional Study of 10,122 Subjects at a Japanese Health Examination Center.

INTRODUCTION: Helicobacter pylori eradication is expected to significantly change the prevalence of Barrett's esophagus (BE). However, few reports on this relationship exist. We analyzed the risk factors of BE using the current consensus on length of BE considering H. pylori infection status. METHODS: We analyzed 10,122 individuals (5,962 men; mean age = 52.9 ± 9.9 years) who had undergone esophagogastroduodenoscopy as part of a medical checkup. Correlations among factors including H. pylori infectious status, endoscopic findings, and BE ≥1 cm were analyzed. RESULTS: Prevalence of BE, long-segment BE, and esophageal adenocarcinoma was 22.5%, 0.014%, and 0%, respectively. Logistic regression analysis showed that the risk factors for BE were hiatal hernia (odds ratio [OR]: 2.89 [2.59-3.24]), female sex (OR: 0.52 [0.46-0.59]), social drinking (OR:0.77 [0.68-0.87]), H. pylori eradication therapy (OR: 1.34 [1.19-1.51]), proton pump inhibitor (PPI) use (OR: 1.52 [1.18-1.96]), bile reflux (OR: 1.18 [1.04-1.33]), age ≥50 years (OR: 1.13 [1.02-1.26]), and nonsteroidal anti-inflammatory drug (NSAID) use (OR: 1.29 [1.02-1.62]). Although reflux esophagitis (RE) was more common in H. pylori-negative patients (17.2%) than in those after H. pylori eradication therapy (11.8%, p < 0.00001), the latter was correlated with BE, disputing RE as a strong risk factor for BE. Therefore, we conducted a subgroup analysis; most of the risk factors except for PPI use (p = 0.75), H2-receptor antagonist use (p = 0.078), and atrophic gastritis absence (p = 0.72) were positively correlated with BE after H. pylori eradication therapy compared with H. pylori-negative status. CONCLUSIONS: H. pylori eradication, bile reflux, PPI use, and NSAID use were risk factors for BE along with hiatal hernia, male sex, and older age.

Endoscopic Treatment of Superficial Gastric Cancer: Present Status and Future.

Although the mortality rates of gastric cancer (GC) are gradually declining, gastric cancer is still the fourth leading cause of cancer-related death worldwide. This may be due to the high rate of patients who are diagnosed with GC at advanced stages. However, in countries such as Japan with endoscopic screening systems, more than half of GCs are discovered at an early stage, enabling endoscopic resection (ER). Especially after the introduction of endoscopic submucosal dissection (ESD) in Japan around 2000, a high en bloc resection rate allowing pathological assessment of margin and depth has become possible. While ER is a diagnostic method of treatment and may not always be curative, it is widely accepted as standard treatment because it is less invasive than surgery and can provide an accurate diagnosis for deciding whether additional surgery is necessary. The curability of ER is currently assessed by the completeness of primary tumor removal and the possibility of lymph node metastasis. This review introduces methods, indications, and curability criteria for ER of EGC. Despite recent advances, several problems remain unsolved. This review will also outline the latest evidence concerning future issues.

Trends in proton pump inhibitor use, reflux esophagitis, and various upper gastrointestinal symptoms from 2010 to 2019 in Japan.

The increasing usage of proton pump inhibitors (PPIs) has been reported worldwide, but information on PPI use in East Asia is inadequate. This study aimed to examine the trends in PPI use in Japan, along with the changes in histamine H2 receptor antagonist (H2RA) use, disease rate of reflux esophagitis, and the prevalence of upper gastrointestinal symptoms. We analyzed 217,712 healthy subjects (127,607 men and 90,105 women; 51.4 ± 9.7 years old) participating in the health check program from 2010 to 2019. Various upper gastrointestinal symptoms were evaluated using the frequency scale for the symptoms of gastroesophageal reflux disease (FSSG) questionnaire. Reflux esophagitis was diagnosed by esophageal erosion using the Los Angeles classification grades A, B, C, and D. From 2010 to 2019, the percentage of PPI users increased markedly from approximately 1.8% to 5.3%, whereas that of H2RA users decreased gradually from approximately 2.5% to 1.9%. The use of all classical types of PPIs (omeprazole, lansoprazole, rabeprazole, and esomerazole) and a new type of PPI, a potassium-competitive acid blocker (vonoprazan), greatly increased during the 10 years. An upward trend in the prevalence of reflux esophagitis was observed from 2010 to 2015, but not from 2016 to 2019, indicating that the monotonic rising prevalence of reflux disease stopped in the middle of the 2010s in Japan. In contrast, various upper gastrointestinal symptoms significantly improved between 2010 and 2019. All 12 FSSG symptoms of PPI users were significantly worse than those of non-PPI users, suggesting that PPIs still cannot completely control upper gastrointestinal symptoms. In conclusion, this study revealed a significant increase in PPI use and a slight decrease in H2RA use from 2010 to 2019. Despite a plateau in the prevalence of reflux esophagitis and considerable improvement in various upper gastrointestinal symptoms, PPI use has continued to increase in Japan.

Transcriptome of sessile serrated adenoma/polyps is associated with MSI-high colorectal cancer and decreased expression of CDX2.

The objective of this study was to elucidate the molecular background of sessile serrated adenoma/polyp (SSA/P) endoscopically resected with comprehensive gene expression analysis. Gene expression profiling was performed for 10 tumor-normal pairs of SSA/P. Cluster analysis, gene set enrichment analysis (GSEA), and consensus molecular subtype (CMS) classification of colorectal cancer (CRC) were applied to our transcriptome analysis. Unsupervised cluster analysis showed that the gene expression profile of SSA/Ps is different from that of adjacent normal epithelial cells, even in the very early stage of tumorigenesis. According to the CMS classification, our microarray data indicated that SSA/Ps were classified as CMS1. GSEA demonstrated a strong association between SSA/P and microsatellite instability-high (MSI-H) CRC (p < 10-5 ). Transcriptome analysis of five MSI-related genes (MSH2, MSH6, MLH1, PMS1, and PMS2) and five CRC-related genes (BRAF, KRAS, APC, TP53, and CDX2) showed that CDX2 expression was most severely decreased in SSA/P. Immunohistochemical staining confirmed that CDX2 protein was reduced compared with the surrounding mucosa. Direct sequencing of the BRAF gene showed that the BRAF V600E mutation was detected in only nine of 36 cases. In a mouse model, BRAF, APC, or CDX2 deficiency indicated that the gene expression pattern with loss of CDX2 is more similar to our SSA/Ps compared with those induced by BRAF or APC mutation. Transcriptome analysis of SSA/Ps showed characteristic gene expression with a strong resemblance to MSI-H CRC. Downregulation of CDX2 expression is an essential molecular mechanism involved in the initial stage of SSA/P tumorigenesis. (UMIN000027365).

Magnifying endoscopy with narrow-band imaging is useful in differentiating gastric cancer from matched adenoma in white light imaging.

This study assessed the effect of magnifying endoscopy with narrow-band imaging (M-NBI) on the endoscopic differential diagnosis between intramucosal gastric carcinomas and adenomas with matched characteristics. Associations between magnified endoscopic findings and pathological high-grade cellular and architectural atypia were also investigated. In total, the records of 50 adenomas and 50 intramucosal well-differentiated adenocarcinomas matched by tumor size (≥ 20 mm or < 20 mm), shape (depression or non-depression), and color (red or non-red) were extracted. Fourteen endoscopists diagnosed adenoma or cancer in the 100 cases with conventional white light imaging (C-WLI), then did the same with C-WLI + M-NBI.The cancer diagnostic sensitivity, specificity, and accuracy were assessed. The sensitivity of C-WLI + M-NBI for cancer diagnosis was 79.9% compared to 71.6% with C-WLI (p < 0.001). There were no significant differences in specificity (40.1% vs. 36.3%, p = 0.296) and accuracy (55.9% vs. 58.1%, p = 0.163). High-grade cytological or architectural atypia was diagnosed more often with irregular microvascular pattern (IMVP) or microsurface pattern (IMSP), respectively, than the low-grade forms. In conclusion, IMVP and IMSP correlate with high-grade cytological and architectural atypia. M-NBI is useful in differentiating intramucosal carcinoma from adenoma and can reduce underdiagnosis of cancer.