Atrophic gastritis (AG) is characterized by atrophy of gastric glands-in particular, oxyntic glands-in the setting of chronic inflammation; it is often autoimmune. The diagnosis is confirmed by immunohistochemistry (IHC) for gastrin (to confirm biopsy site), and pathologists often use IHC for neuroendocrine markers to evaluate for enterochromaffin-like cell hyperplasia (ECL-H). The utility of neuroendocrine staining is unclear, and we undertook this study to determine whether ECL pattern provided any additional information in cases of Helicobacter-negative AG.

We reviewed clinicopathologic findings in 184 cases from 184 patients with histologic AG and no evidence of Helicobacter infection. Using neuroendocrine IHC markers, cases were divided into 3 groups: Group 1 showed complete ECL-H (both qualitative and quantitative criteria met), group 2 showed focal ECL-H (qualitative but not quantitative criteria met), and group 3 showed no ECL-H (neither criteria met).

Group 1 patients were more likely to have positive autoantibody serologies (73%, P = .0007 vs group 2) and higher mean gastrin levels (700 pg/mL, P = .017 vs group 3), and only these patients developed gastric neuroendocrine tumors. Group 2 patients were more likely to take proton pump inhibitors (64%, P = .0002 vs group 1). Group 3 patients were more likely to be male (70%, P = .008 vs group 1) and to have microcytic anemia (44%, P = .022 vs group 2) and less likely to have intestinal metaplasia (50%, P = .044 vs group 1).

Stratification based on degree of ECL-H is not necessary for diagnosis of AG but does lead to statistically significant clinical and pathologic differences among groups.

Little is known about trends in cancer among the older segments of the population, even less for South America.

To describe time trends in mortality of the most frequent causes of cancer death among the population aged 70 and over.

Using the World Health Organization´s Cancer Mortality Database, we studied trends in mortality from lung, colorectal, stomach, liver, prostate, breast, and cervical cancer from 1985 onwards. Joinpoint analyses allow discerning changes in average annual percent change (i.e., slope AAPC) of these trends over time.

The region has a 2-3-fold variation in absolute age-specific cancer mortality rates, with the lowest rates in Argentina and Paraguay and the highest in Chile, Uruguay, and Venezuela. In most countries except for Brazil and Paraguay (both sexes), Peru (females and males 80 +), and Venezuela (males), overall cancer mortality rates were declining in the studied age range, with some fluctuations during the period. The most common causes by sex vary throughout the continent and by age group, but overall, increasing trends were observed for colorectal and breast cancer. In all countries, time trends show reductions in mortality from stomach cancer (AAPC up to -4.77 %) and in some countries (Argentina, Chile, Colombia, and Ecuador AAPC between -0.04 % and -4.37 %) for cervical cancer. In the other countries, cervical cancer mortality remained stable. Lung cancer declined in all countries in males (AAPC between -0.39 % and -2.24 %) except Brazil, Paraguay and the eldest males in Venezuela but among females, increases were observed in most countries (AAPC between +0.47 % and +4.05 %).

Cancer-specific mortality rates vary considerably between countries in South America and the high cancer mortality rates in the oldest segments of the population. Effective primary prevention strategies, vaccination implementation, early detection, effective treatment programs, and better access to healthcare overall can positively impact the trends.

KMT2C and KMT2D ( KMT2C/D ) are frequently mutated in gastric adenocarcinoma, yet their function in cancer initiation remains poorly understood. In this study, based on the observation that loss-of-function mutations of KMT2C and KMT2D are enriched and co-occur in gastric adenocarcinoma, we developed genetically engineered mouse models to selectively knock out Kmt2c and Kmt2d in gastric epithelial cells with Tmprss2-CreER T2 . Through histological staining and single-cell RNA sequencing, we observed that Kmt2c/d loss led to nuclear dysplasia and expansion of cells with mixed gastric lineage markers. When combined with Pten deletion, Kmt2c/d loss drove rapid development of muscle-invasive gastric adenocarcinoma as early as 3 weeks post Cre-mediated gene deletion. The adenocarcinoma exhibited decreased expression of gastric lineage markers and increased expression of intestinal differentiation markers, phenocopying human gastric adenocarcinoma. Kmt2c/d knockout reduced protein synthesis but upregulated transcription of ribosomal proteins, rendering sensitivity to mTORC1 inhibitors. Additionally, Kmt2c/d knockout increased MHC-I molecule expression and enhanced antigen presentation. Combination of mTROC1 inhibition and anti-PD1 immunotherapy significantly suppressed tumor growth in immune-competent mice. Together, these findings reveal the role of Kmt2c / d loss in gastric cancer initiation and suggest the potential therapeutic strategies for KMT2C/D -deficient gastric cancer.

Immunotherapy for gastrointestinal cancers has elicited considerable amount of attention as a viable therapeutic option for several cancer types. Gut microbiome as a whole plays a critical role in shaping immune responses and influencing cancer progression. Recent evidence suggests that Helicobacter pylori (H. pylori), may influence immunotherapy efficacy by modulating the tumor microenvironment. Infection with H. pylori is common as it affects approximately 50% of the global population and remains the leading risk factor for gastric cancer. Interestingly, recent clinical and preclinical data has associated H. pylori with colorectal cancer carcinogenesis. Gut microbiome appears to be a modulator of the relationship between the immune system, gastrointestinal cancer development and existing therapies. Infection with H. pylori may affect immunotherapy results in both gastroesophageal and colorectal cancer; favorable results were noticed in H. pylori positive patients with gastric cancer, while in colorectal cancer patients the pathogen seemed to impede immunotherapy's action. This article aims to review current data on the role of H. pylori in triggering gastric inflammation and cancer, as well as its potential involvement in colorectal cancer development. Additionally, it seeks to highlight the impact of H. pylori infection on the response to immunotherapy in gastrointestinal cancers.

The risk of gastric cancer among immigrants from countries where Helicobacter pylori is endemic greatly exceeds those born in the United States. Among patients in the Los Angeles safety-net health system, the risk of advanced and fatal gastric cancer is higher in Hispanic versus non-Hispanic patients. There is an urgent need to define whether this reflects concomitant illnesses, such as metabolic disease, occupational exposures, or differential access to H. pylori eradication and endoscopic gastric cancer screening programs. See related article by Klingbeil et al., p. 75.

Gastric metaplasia may arise as a consequence of chronic inflammation and is associated with an increased risk of gastric cancer development. Although Helicobacter pylori (Hp) infection and autoimmune gastritis (AIG) both induce gastric metaplasia, possible distinctions in resulting metaplastic cells and their respective cancer risks requires further investigation.

Using both mouse models and human participants, we scrutinized the metaplasia originating from Hp infection and AIG. Gastric pathology and metaplasia were examined through histopathologic assessment. Molecular features of metaplastic cells were defined using single-cell transcriptomics in murine models of Hp infection and AIG, as well as in human biopsy specimens from patients with Hp infection and AIG. Expression of a newly defined cancer-related metaplastic biomarker was confirmed through immunofluorescence.

Metaplasia in Hp infection and AIG displayed comparable histopathologic and transcriptional features. Diverse metaplastic subtypes were identified across both disease settings, with subtle differences in the prevalence of certain subtypes between inflammatory contexts. Notably, Hp infection did not drive a unique metaplastic cell phenotype. One metaplastic subtype, which resembled incomplete intestinal metaplasia and shared transcriptional features with gastric cancer, was identified in both diseases. This cancer-like metaplastic subtype was characterized by expression of the cancer-associated biomarker ANPEP/CD13.

Both Hp infection and AIG trigger a diverse array of metaplastic cell types. Identification of a cancer-related metaplastic cell uniquely expressing ANPEP/CD13, present in both Hp- and AIG-induced gastritis, indicates the carcinogenic capacity of both diseases. This discovery can guide early detection and risk stratification for patients with chronic gastritis.

The 5-year survival rate of patients with advanced gastric cancer remains extremely low (< 15%), whereas the 5-year survival rate of patients with early gastric cancer (EGC) is > 90%. Consequently, strengthening the screening of patients with EGC and precancerous lesions (PCLs) is essential.

To identify the value of serum pepsinogen ratio (PGR) screening for EGC and PCLs in the Shengli Oilfield Central Hospital.

We first selected 385 patients with gastric lesions in the Youcheng area, determining benign lesions, PCLs, and EGC in 135, 123, and 127 cases, respectively, based on endoscopy and case diagnosis. The positive rates of pepsinogen I, pepsinogen II and Helicobacter pylori (H. pylori) in the three groups were detected, and the PGR was calculated. Subsequently, we plotted receiver operating characteristic curves to analyze the screening value of PGR and H. pylori-positive rates for PCLs and EGC.

PGR expression demonstrated a decreasing trend in patients with benign lesions, PCLs, and EGC successively according to the detection results, whereas the H. pylori-positive rate was notably increased in patients with PCLs and EGC compared to those with benign lesions. The area under the curves (AUCs) of PGR, H. pylori, and their combination in differentiating patients with benign lesions from those with PCLs were 0.611, 0.582, and 0.689, respectively; PGR, H. pylori, and their combination had an AUC of 0.618, 0.502, and 0.618 in distinguishing PCL patients from EGC patients, respectively; the AUCs of PGR, H. pylori, and their combination in discriminating patients with benign lesions from those with EGC were 0.708, 0.581, and 0.750, respectively.

PGR has great screening potential for patients with EGC and PCLs in the Youcheng area, and the screening efficiency is further improved by combining the H. pylori-positive rate.

Gastric intestinal metaplasia (GIM) represents a precancerous stage characterized by morphological and pathophysiological changes in the gastric mucosa, where gastric epithelial cells transform into a phenotype resembling that of intestinal cells. Previous studies have demonstrated that the intragastric administration of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) induces both gastric carcinoma and intestinal metaplasia in mice. Here, we show that MNNG induces GIM in three-dimensional (3D) mouse organoids. Our histological analyses reveal that MNNG-induced gastric organoids undergo classical morphological alterations, exhibiting a distinct up-regulation of CDX2 and MUC2, along with a down-regulation of ATP4B and MUC6. Importantly, metaplastic cells observed in MNNG-treated organoids originate from MIST1+ cells, indicating their gastric chief cell lineage. Functional analyses show that activation of the RAS signaling pathway drives MNNG-induced metaplasia in 3D organoids, mirroring the characteristics observed in human GIM. Consequently, modeling intestinal metaplasia using 3D organoids offers valuable insights into the molecular mechanisms and spatiotemporal dynamics of the gastric epithelial lineage during the development of intestinal metaplasia within the gastric mucosa. We conclude that the MNNG-induced metaplasia model utilizing 3D organoids provides a robust platform for developing preventive and therapeutic strategies to mitigate the risk of gastric cancer before precancerous lesions occur.

The immune landscape associated with different subtypes of intestinal metaplasia (IM) and early gastric cancer (EGC) remains unclear. This study aimed to investigate the immune landscape of complete intestinal metaplasia (CIM), incomplete intestinal metaplasia (IIM), and EGC, as well as the underlying mechanisms of EGC progression.

Gastric biopsy samples were collected from five patients with CIM, six patients with IIM, and four patients with EGC, followed by single-cell RNA sequencing. Multiplex immunohistochemical staining was employed to validate the samples from the aforementioned patients. To elucidate the potential mechanisms involved, in vitro coculture experiments were conducted using FOLR2+/FOLR2- macrophages and CD8+ T cells. Flow cytometry was utilized to investigate the biological functions of FOLR2+ macrophages in the progression of EGC.

Five subpopulations of macrophages were identified in CIM, IIM and EGC samples. FOLR2+ macrophages possess antitumor immune potential, and the proportion of FOLR2+ macrophage gradually decreased from the CIM stage to the IIM and EGC stages. FOLR2+ macrophages were significantly positively correlated with CD8+ T cells and activated the cytotoxicity of CD8+ T cells via antigen cross-presentation. Additionally, during the progression of EGC, epithelial cells progressively upregulated APP expression, thus inducing necroptosis of FOLR2+ macrophages via the APP‒TNFRSF21 axis.

Our work provides an understanding of the potential mechanisms underlying the malignant transformation of IM mediated by FOLR2+ macrophages.

Biomarkers associated with the progression from gastric intestinal metaplasia (GIM) to gastric adenocarcinoma (GA), i.e., GA-related GIM, could provide valuable insights into identifying patients with increased risk for GA. The aim of this study was to utilize multi-bioinformatics to reveal potential biomarkers for the GA-related GIM and predict potential drug repurposing for GA prevention in patients. The multi-bioinformatics included gene expression matrix (GEM) by microarray gene expression (MGE), ScType (a fully automated and ultra-fast cell-type identification based solely on a given scRNA-seq data), Ingenuity Pathway Analysis, PageRank centrality, GO and MSigDB enrichments, Cytoscape, Human Protein Atlas and molecular docking analysis in combination with immunohistochemistry. To identify GA-related GIM, paired surgical biopsies were collected from 16 GIM-GA patients who underwent gastrectomy, yielding 64 samples (4 biopsies per stomach x 16 patients) for MGE. Co-analysis was performed by including scRNAseq and immunohistochemistry datasets of endoscopic biopsies of 37 patients. The results of the present study showed potential biomarkers for GA-related GIM, including GEM of individual patients, individual genes (such as RBP2 and CD44), signaling pathways, network of molecules, and network of signaling pathways with key topological nodes. Accordingly, potential treatment targets with repurposed drugs were identified including epidermal growth factor receptor, proto-oncogene tyrosine-protein kinase Src, paxillin, transcription factor Jun, breast cancer type 1 susceptibility protein, cellular tumor antigen p53, mouse double minute 2, and CD44.

As a biologically essential transition metal, copper is widely involved in various enzymatic reactions and crucial biological processes in the body. It plays an increasingly important role in maintaining normal cellular metabolism and supporting the growth and development of the human body. As a trace element, copper maintains the dynamic balance of its concentration in body fluids through active homeostatic mechanisms. Both excess and deficiency of copper ions can impair cell function, ultimately leading to cell damage and death. Cuproptosis is a novel form of cell death where copper ions cause cell death by directly binding to the lipoylated components of the citric acid cycle (CAC) in mitochondrial respiration and interfering with the levels of iron-sulfur cluster (Fe-S cluster) proteins, ultimately causing protein toxic stress. Its primary characteristics are Cu2+ concentration dependence and high expression in mitochondrial respiratory cells. Recent research has revealed that, compared to other forms of programmed cell death such as apoptosis, necrosis, and autophagy, cuproptosis has unique morphological and biochemical features. Cuproptosis is associated with the occurrence and development of various diseases, including cancer, neurodegenerative diseases, and cardiovascular diseases. This article focuses on a review of the relevance of cuproptosis in gastric cancer (GC).

Recent advances in spatial transcriptomics (ST) techniques provide valuable insights into cellular interactions within the tumor microenvironment (TME). However, most analytical tools lack consideration of histological features and rely on matched single-cell RNA sequencing data, limiting their effectiveness in TME studies. To address this, we introduce the Morphology-Enhanced Spatial Transcriptome Analysis Integrator (METI), an end-to-end framework that maps cancer cells and TME components, stratifies cell types and states, and analyzes cell co-localization. By integrating spatial transcriptomics, cell morphology, and curated gene signatures, METI enhances our understanding of the molecular landscape and cellular interactions within the tissue. We evaluate the performance of METI on ST data generated from various tumor tissues, including gastric, lung, and bladder cancers, as well as premalignant tissues. We also conduct a quantitative comparison of METI with existing clustering and cell deconvolution tools, demonstrating METI's robust and consistent performance.

Helicobacter pylori is the most common cause of infection-associated cancer worldwide. We aimed to evaluate the impact of H. pylori infection and treatment on colorectal cancer (CRC) incidence and mortality.

US Veterans who completed H. pylori testing between 1999 and 2018.

We conducted a retrospective cohort analysis among adults within the Veterans Health Administration who completed testing for H. pylori. The primary exposures were (1) H. pylori test result (positive/negative) and (2) H. pylori treatment (untreated/treated) among H. pylori-positive individuals. The primary outcomes were CRC incidence and mortality. Follow-up started at the first H. pylori testing and continued until the earliest of incident or fatal CRC, non-CRC death, or December 31, 2019.

Among 812,736 individuals tested for H. pylori, 205,178 (25.2%) tested positive. Being H. pylori-positive versus H. pylori-negative was associated with higher CRC incidence and mortality. H. pylori treatment versus no treatment was associated with lower CRC incidence and mortality (absolute risk reduction 0.23%-0.35%) through 15-year follow-up. Being H. pylori-positive versus H. pylori-negative was associated with an 18% (adjusted hazard ratio [adjusted HR], 1.18 [95% CI, 1.12 to 1.24]) and 12% (adjusted HR, 1.12 [95% CI, 1.03 to 1.21]) higher incident and fatal CRC risk, respectively. Individuals with untreated versus treated H. pylori infection had 23% (adjusted HR, 1.23 [95% CI, 1.13 to 1.34]) and 40% (adjusted HR, 1.40 [95% CI, 1.24 to 1.58]) higher incident and fatal CRC risk, respectively. The results were more pronounced in the analysis restricted to individuals with nonserologic testing.

H. pylori positivity may be associated with small but statistically significant higher CRC incidence and mortality; untreated individuals, especially those with confirmed active infection, appear to be most at risk.

Gastric cancer is the fifth most common cancer and the fourth cause of global cancer mortality. The identification of new biomarkers and drug targets is crucial to allow the better prognosis and treatment of patients. The mitotic spindle positioning (MISP) protein has the function of correcting mitotic spindle positioning and centrosome clustering and has been implicated in the cytokinesis and migration of cancer cells. The goal of this work was to evaluate the expression and clinical relevance of MISP in gastric cancer. MISP expression was evaluated by immunohistochemistry in a single hospital series (n = 286) of gastric adenocarcinomas and compared with normal gastric mucosa and intestinal metaplasia, a preneoplastic lesion. MISP was detected on the membrane in 83% of the cases, being overexpressed in gastric cancer compared to normal gastric mucosa (n = 10). Its expression was negatively associated with diffuse and poorly cohesive types. On the other hand, it was strongly expressed in intestinal metaplasia where it was associated with MUC2 and CDX2 expression. Furthermore, when we silenced MISP in vitro, a significant decrease in the viability of gastric carcinoma cells was observed. In conclusion, MISP is overexpressed in gastric cancer, being associated with an intestinal phenotype in gastric carcinogenesis and having a role in cellular proliferation.

We consider the newly developed multinomial mixed-link models for a high-risk intestinal metaplasia (IM) study with DNA methylation data. Different from the traditional multinomial logistic models commonly used for categorical responses, the mixed-link models allow us to select the most appropriate link function for each category. We show that the selected multinomial mixed-link model (Model 1) using the total number of stem cell divisions (TNSC) based on DNA methylation data outperforms the traditional logistic models in terms of cross-entropy loss from ten-fold cross-validations with significant p-values 8.12×10-4 and 6.94×10-5. Based on our selected model, the significance of TNSC's effect in predicting the risk of IM is justified with a p-value less than 10-6. We also select the most appropriate mixed-link models (Models 2 and 3) when an additional covariate, the status of gastric atrophy, is available. When the status is negative, mild, or moderate, we recommend Model 2; otherwise, we prefer Model 3. Both Models 2 and 3 can predict the risk of IM significantly better than Model 1, which justifies that the status of gastric atrophy is informative in predicting the risk of IM.

Helicobacter pylori is a Gram-negative pathogen that colonizes the stomach, induces inflammation, and drives pathological changes in the stomach tissue, including gastric cancer. As the principal cytokine produced by Th17 cells, IL-17 mediates protective immunity against pathogens by inducing the activation and mobilization of neutrophils. Whereas IL-17A is largely produced by lymphocytes, the IL-17 receptor is expressed in epithelial cells, fibroblasts, and hematopoietic cells. Loss of the IL-17RA in mice results in impaired antimicrobial responses to extracellular bacteria. In the context of H. pylori infection, this is compounded by extensive inflammation in Il17ra-/- mice. In this study, Foxa3creIl17rafl/fl (Il17raΔGI-Epi) and Il17rafl/fl (control) mice were used to test the hypothesis that IL-17RA signaling, specifically in epithelial cells, protects against severe inflammation after H. pylori infection. The data indicate that Il17raΔGI-Epi mice develop increased inflammation compared with controls. Despite reduced Pigr expression, levels of IgA increased in the gastric wash, suggesting significant increase in Ag-specific activation of the T follicular helper/B cell axis. Gene expression analysis of stomach tissues indicate that both acute and chronic responses are significantly increased in Il17raΔGI-Epi mice compared with controls. These data suggest that a deficiency of IL-17RA in epithelial cells is sufficient to drive chronic inflammation and hyperactivation of the Th17/T follicular helper/B cell axis but is not required for recruitment of polymorphonuclear neutrophils. Furthermore, the data suggest that fibroblasts can produce chemokines in response to IL-17 and may contribute to H. pylori-induced inflammation through this pathway.

Most gastric cancers arise in the setting of chronic inflammation which alters gland organization, such that acid-pumping parietal cells are lost, and remaining cells undergo metaplastic change in differentiation patterns. From a basic science perspective, recent progress has been made in understanding how atrophy and initial pyloric metaplasia occur. However, pathologists and cancer biologists have long been focused on the development of intestinal metaplasia patterns in this setting. Arguably, much less progress has been made in understanding the mechanisms that lead to the intestinalization seen in chronic atrophic gastritis and pyloric metaplasia. One plausible explanation for this disparity lies in the notable absence of reliable and reproducible small animal models within the field, which would facilitate the investigation of the mechanisms underlying the development of gastric intestinal metaplasia (GIM). This review offers an in-depth exploration of the current state of research in GIM, shedding light on its pivotal role in tumorigenesis. We delve into the histological subtypes of GIM and explore their respective associations with tumor formation. We present the current repertoire of biomarkers utilized to delineate the origins and progression of GIM and provide a comprehensive survey of the available, albeit limited, mouse lines employed for modeling GIM and engage in a discussion regarding potential cell lineages that serve as the origins of GIM. Finally, we expound upon the myriad signaling pathways recognized for their activity in GIM and posit on their potential overlap and interactions that contribute to the ultimate manifestation of the disease phenotype. Through our exhaustive review of the progression from gastric disease to GIM, we aim to establish the groundwork for future research endeavors dedicated to elucidating the etiology of GIM and developing strategies for its prevention and treatment, considering its potential precancerous nature.

Mucosal gastric atrophy and intestinal metaplasia (IM) increase the risk for the development of gastric cancer (GC) as they represent a field for development of dysplasia and intestinal-type gastric adenocarcinoma.

We have investigated the expression of two dysplasia markers, CEACAM5 and TROP2, in human antral IM and gastric tumors to assess their potential as molecular markers.

In the normal antral mucosa, weak CEACAM5 and TROP2 expression was only observed in the foveolar epithelium, while inflamed antrum exhibited increased expression of both markers. Complete IM exhibited weak CEACAM5 expression at the apical surface, but no basolateral TROP2 expression. On the other hand, incomplete IM demonstrated high levels of both CEACAM5 and TROP2 expression. Notably, incomplete IM with dysplastic morphology (dysplastic incomplete IM) exhibited higher levels of CEACAM5 and TROP2 expression compared to incomplete IM without dysplastic features (simple incomplete IM). In addition, dysplastic incomplete IM showed diminished SOX2 and elevated CDX2 expression compared to simple incomplete IM. CEACAM5 and TROP2 positivity in incomplete IM was similar to that of gastric adenomas and GC. Significant association was found between CEACAM5 and TROP2 positivity and histology of GC.

These findings support the concept that incomplete IM is more likely associated with GC development. Overall, our study provides evidence of the heterogeneity of gastric IM and the distinct expression profiles of CEACAM5 and TROP2 in dysplastic incomplete IM. Our findings support the potential use of CEACAM5 and TROP2 as molecular markers for identifying individuals with a higher risk of GC development in the context of incomplete IM.

At the end of the last century, a far-sighted 'working party' held in Sydney, Australia addressed the clinicopathological issues related to gastric inflammatory diseases. A few years later, an international conference held in Houston, Texas, USA critically updated the seminal Sydney classification. In line with these initiatives, Kyoto Global Consensus Report, flanked by the Maastricht-Florence conferences, added new clinical evidence to the gastritis clinicopathological puzzle.The most relevant topics related to the gastric inflammatory diseases have been addressed by the Real-world Gastritis Initiative (RE.GA.IN.), from disease definitions to the clinical diagnosis and prognosis. This paper reports the conclusions of the RE.GA.IN. consensus process, which culminated in Venice in November 2022 after more than 8 months of intense global scientific deliberations. A forum of gastritis scholars from five continents participated in the multidisciplinary RE.GA.IN. consensus. After lively debates on the most controversial aspects of the gastritis spectrum, the RE.GA.IN. Faculty amalgamated complementary knowledge to distil patient-centred, evidence-based statements to assist health professionals in their real-world clinical practice. The sections of this report focus on: the epidemiology of gastritis; Helicobacter pylori as dominant aetiology of environmental gastritis and as the most important determinant of the gastric oncogenetic field; the evolving knowledge on gastric autoimmunity; the clinicopathological relevance of gastric microbiota; the new diagnostic horizons of endoscopy; and the clinical priority of histologically reporting gastritis in terms of staging. The ultimate goal of RE.GA.IN. was and remains the promotion of further improvement in the clinical management of patients with gastritis.

Gastric cancer is one of the leading causes of cancer deaths worldwide, with chronic gastritis representing the main predisposing factor initiating the cascade of events leading to metaplasia and eventually progressing to cancer. A widely accepted classification distinguishes between autoimmune and environmental atrophic gastritis, mediated, respectively, by T cells promoting the destruction of the oxyntic mucosa, and chronic H. pylori infection, which has also been identified as the major risk factor for gastric cancer. The original dogma posits Th1 immunity as a main causal factor for developing gastritis and metaplasia. Recently, however, it has become evident that Th2 immune responses play a major role in the events causing chronic inflammation leading to tumorigenesis, and in this context, many different cell types and cytokines are involved. In particular, the activity of cytokines, such as IL-33 and IL-13, and cell types, such as mast cells, M2 macrophages and eosinophils, are intertwined in the process, promoting chronic gastritis-dependent and more diffuse metaplasia. Herein, we provide an overview of the critical events driving the pathology of this disease, focusing on the most recent findings regarding the importance of Th2 immunity in gastritis and gastric metaplasia.

Helicobacter pylori infection is the predominant risk factor for the development of gastric cancer. Risk is enhanced by specific H. pylori virulence factors, diet, and the inflammatory response. Chronic activation of T helper (Th) 1 and Th17 pathways contributes to prolonged inflammation; yet, higher expression of IL-17 receptor (IL-17RA) is a favorable prognostic marker for survival after gastric cancer diagnosis. The protective impact of IL-17RA signaling is not understood. To investigate if IL-17RA signaling protects during H. pylori-induced carcinogenesis, the transgenic InsGAStg/tg mouse, which is prone to H. pylori-induced gastric cancer, was utilized. InsGAStg/tg mice and InsGAStg/tgIl17ra-/- mice were infected with a cag type 4 secretion system (T4SS) positive H. pylori strain for up to 6 months. Six weeks post-infection, IL-17RA deficiency led to increased bacterial burden, increased gastritis, and development of lymphoid follicles. Increased inflammation was associated with heightened cellular proliferation and earlier loss of parietal and chief cells in InsGAStg/tgIl17ra-/- mice. Gastric cancers developed more frequently by 3- and 6-months post-infection in H. pylori-infected InsGAStg/tgIl17ra-/- mice compared to InsGAStg/tg mice. Chronic inflammation was exacerbated with IL-17RA deficiency, characterized by elevated Th1/Th17 cytokines, increased B cell infiltration, and enhanced IgA production, despite reduced expression of the polymeric immunoglobulin receptor. Further, paragastric lymph nodes of InsGAStg/tgIl17ra-/- mice were enlarged relative to controls and displayed altered gene expression profiles. Increased inflammation was accompanied by a significant increase in Cybb expression, which encodes NADPH oxidase 2, suggesting that increased oxidative damage may occur in the absence of IL-17RA. Further, there is increased phosphorylation of histone 2AX in IL-17RA deficient mice, indicating that the DNA damage response is highly activated. These data suggest that IL-17RA signaling activates a protective pathway to prevent excessive inflammation which otherwise can lead to increased oxidative stress, DNA damage, and drive gastric carcinogenesis after H. pylori infection.

Introduction. The OLGA system has been proved to be useful in Asia and Europe as a risk marker of gastric cancer. However, its usefulness in high-risk populations in Colombia is still unknown. Objective. To assess potential associations between the OLGA staging system and an increased risk of gastric cancer and dysplasia in a high-risk Colombian population and to establish diagnostic capacity of the scale to assess the risk. Materials and methods. We carried out a multicenter study including patients with cancer and dysplasia (cases) and patients with atrophy and intestinal metaplasia (controls). A total of 506 patients were recruited from three centers in an area with a high risk population in Colombia. The endoscopic and histopathologic studies were evaluated according to the Sydney system and the OLGA staging system proposed by Rugge. The effect of each variable on the disease (gastric cancer and dysplasia) was evaluated using bivariate and multivariate models. Statistical significance was set considering a p value inferior to 0.05. Results. Advanced stages of the OLGA system (III-IV) were associated with a higher risk of dysplasia and gastric cancer (adjusted OR = 8.71; CI95% = 5.09-14.9; p=0.001), sensitivity=54.9%, specificity=89.3% and positive likelihood ratio=5.17. Conclusions. The OLGA staging system is a risk marker for gastric cancer and dysplasia in the studied population. We recommend its implementation to improve the timely diagnosis and follow-up of patients with the highest cancer risk.

Gastric intestinal metaplasia (GIM), which denotes conversion of gastric mucosa into an intestinal phenotype, can occur in all regions of the stomach, including cardiac, fundic, and pyloric mucosa. Since the earliest description of GIM, its association with gastric cancer of the differentiated (intestinal) type has been a well-recognized concern. Many epidemiologic studies have confirmed GIM to be significantly associated with subsequent gastric cancer development. Helicobacter pylori, the principal etiologic factor for gastric cancer, plays the most important role in predisposing to GIM. Although the role of GIM in the stepwise progression model of gastric carcinogenesis (the so-called "Correa cascade") has come into question recently, we review the scientific evidence that strongly supports this long-standing model and propose a new progression model that builds on the Correa cascade. Eradication of H pylori is the most important method for preventing gastric cancer globally, but the effect of eradication on established GIM, is limited, if any. Endoscopic surveillance for GIM may, therefore, be necessary, especially when there is extensive corpus GIM. Recent advances in image-enhanced endoscopy with integrated artificial intelligence have facilitated the identification of GIM and neoplastic lesions, which will impact preventive strategies in the near future.

Gastric cancer in the United States has a low survival rate mainly because of the late stage of diagnosis. Furthermore, there are no well-established guidelines concerning screening and surveillance even for higher risk patients such as those with nondysplastic noncardia gastrointestinal metaplasia (GIM), and thus they are not routinely performed. This study was designed to provide new evidence-based data that can be used to support the implementation of biennial surveillance guidelines in individuals with nondysplastic noncardia GIM. This practice can help detect early malignant lesions, thereby decreasing morbidity and mortality. We evaluated the cost-effectiveness of surveillance endoscopies for noncardia gastric cancer in populations with two different pathological diagnoses: mixed GIM and incomplete GIM (iGIM).

Markov state transition models were developed using a cohort simulation of 1000 hypothetical patients. Analysis was conducted for both mixed and iGIM. Quality-adjusted life-years and transition probabilities were derived from the published medical literature. Costs associated with endoscopy, cancer care, and surgery were based on Medicare reimbursement. A willingness-to-pay threshold of $100,000 per quality-adjusted life-year was used to determine cost-effectiveness.

Our study determined that it is significantly cost-effective to perform biennial endoscopy surveillance in patients who have been incidentally found to have noncardia mixed GIM, with a cost savings of $5783.84 per person, and in those with iGIM, with a cost savings of $8093.08 per person.

Biennial endoscopy surveillance should be considered in all individuals found to have mixed or incomplete noncardia GIM on endoscopy. Furthermore, screening specifically for iGIM after differentiating between the two groups can lead to further cost savings. As such, we recommend that pathologists routinely differentiate between the two and recommend robust routine surveillance of iGIM.

The incidence of metachronous gastric cancer (MGC) after endoscopic treatment for early gastric cancer (EGC) is high, but a method of risk assessment for MGC based on endoscopic findings has not been established. In this study, we focused on endoscopic intestinal metaplasia (IM) and investigated the risk for MGC after endoscopic submucosal dissection (ESD) for EGC.

This retrospective observational study involved patients who underwent curative ESD for EGC from April 2015 to January 2021. We assessed endoscopic IM using the pretreatment endoscopic examination images. The severity of endoscopic IM was classified into four levels: 0 (none), 1 (mild), 2 (moderate), and 3 (severe). Four different gastric areas were evaluated. We divided the patients into a low-score group and a high-score group, and compared the cumulative incidence of MGC.

In total, 156 patients who met the inclusion criteria were followed up for at least 12 months after ESD, and MGC developed in 14 patients during a mean period oof 41.5 months. The endoscopic IM scores in the lesser curvature of the antrum, lesser curvature of the corpus, and greater curvature of the corpus were higher in patients with MGC than in those without MGC. In the corpus, the 5-year cumulative incidence of MGC was significantly higher in the high-score group than in the low-score group (29.8% vs 10.0%, P = 0.004).

The severity of endoscopic corpus IM was associated with MGC. Thus, patients with severe corpus IM at the time of ESD require careful examination and intensive follow-up.

Clarithromycin resistance of Helicobacter pylori (H. pylori) represents a major challenge in eradication therapy. In this study, we assessed if non-invasive stool tests can be used to verify successful H. pylori eradication and determine clarithromycin resistance.

In this prospective study, patients undergoing urea breath testing (UBT) for confirmation of H. pylori eradication were asked to collect the stool as both a dry fecal sample and fecal immunochemical test (FIT). Stool H. pylori antigen testing (SAT) was performed on these samples and assessed for its accuracy in eradication verification. Type and duration of antibiotic treatment were retrospectively collected from patient records and compared with clarithromycin resistance determined by PCR of stool samples.

H. pylori eradication information was available for a total of 145 patients (42.7% male, median age: 51.2). Successful eradication was achieved in 68.1% of patients. SAT on FIT samples had similar accuracy for eradication assessment compared to dry fecal samples, 72.1% [95% CI 61.4-81.2] versus 72.2% [95% CI 60.9-81.7]. Clarithromycin resistance rate was 13.4%.

H. pylori antigen testing on FIT stool samples to verify H. pylori eradication is feasible and has similar accuracy as H. pylori antigen testing on dry stool samples. Dry stool, but not FIT, was suitable for non-invasive identification of H. pylori clarithromycin resistance by rt-PCR personalizing antibiotic treatment strategies without the need for invasive diagnostics is desirable, as the cure rate of first-line empirical H. pylori treatment remains low.

The high incidence of gastric cancer in many nations and poor overall survival rates has remained a serious global health concern. Chemoresistance in gastric cancer is a significant issue that hinders the efficacy of available treatment options. In gastric cancer, non-coding RNAs like microRNAs, long non-coding RNAs, and circular RNAs have become effective regulators of chemoresistance. These non-coding RNAs can influence several mechanisms, including drug efflux transporters, drug metabolism, and detoxification, cancer stem cells and the epithelial-mesenchymal transition, autophagy and apoptosis, and the tumor microenvironment. In this article review, we summarize the key roles non-coding RNAs play in the chemoresistance of gastric cancer and consider how they might be used in clinical settings as markers for diagnosis and prognosis, as well as potential targets and treatment plans. We also emphasize the need for additional study and collaborations in this area and highlight the difficulties and opportunities in non-coding RNA research for gastric cancer chemoresistance. This review offers crucial insights into the intricate relationship between non-coding RNAs and chemoresistance in gastric cancer, with implications for precision oncology and personalized medicine.

Helicobacter pylori (HP) is a gram-negative and spiral-shaped bacterium colonizing the human stomach and has been recognized as the risk factor of gastritis, peptic ulcer disease, and gastric cancer (GC). Moreover, it was recently identified as a class I carcinogen, which affects the occurrence and progression of GC via inducing various oncogenic pathways. Therefore, identifying the HP-related key genes is crucial for understanding the oncogenic mechanisms and improving the outcomes of GC patients. We retrieved the list of HP-related gene sets from the Molecular Signatures Database. Based on the HP-related genes, unsupervised non-negative matrix factorization (NMF) clustering method was conducted to stratify TCGA-STAD, GSE15459, GSE84433 samples into two clusters with distinct clinical outcomes and immune infiltration characterization. Subsequently, two machine learning (ML) strategies, including support vector machine-recursive feature elimination (SVM-RFE) and random forest (RF), were employed to determine twelve hub HP-related genes. Beyond that, receiver operating characteristic and Kaplan-Meier curves further confirmed the diagnostic value and prognostic significance of hub genes. Finally, expression of HP-related hub genes was tested by qRT-PCR array and immunohistochemical images. Additionally, functional pathway enrichment analysis indicated that these hub genes were implicated in the genesis and progression of GC by activating or inhibiting the classical cancer-associated pathways, such as epithelial-mesenchymal transition, cell cycle, apoptosis, RAS/MAPK, etc. In the present study, we constructed a novel HP-related tumor classification in different datasets, and screened out twelve hub genes via performing the ML algorithms, which may contribute to the molecular diagnosis and personalized therapy of GC.

Gastric intestinal metaplasia (GIM) is defined as the replacement of the normal gastric epithelium by intestinal-type epithelium. GIM is considered a preneoplastic lesion for gastric adenocarcinoma in adults and is found in 25% of Helicobacter pylori ( H pylori ) exposed adults. However, the significance of GIM in pediatric gastric biopsies is still unknown.

We conducted a retrospective study of children with GIM on gastric biopsies at Boston Children's Hospital between January 2013 and July 2019. Demographic, clinical, endoscopic, and histologic data were collected and compared to age and sex-matched cohort without GIM. Gastric biopsies were reviewed by the study pathologist. GIM was classified as complete/incomplete based on Paneth cell presence or absence and limited/extensive based on its distribution in the antrum or both antrum and corpus.

Of 38 patients with GIM, 18 were male (47%), mean age of detection was 12.5 ± 5.05 years (range, 1-18 years). The most common histologic was chronic gastritis (47%). Complete GIM was present in 50% (19/38) and limited GIM was present in 92% (22/24). H pylori was positive in 2 patients. Two patients had persistent GIM on repeat esophagogastroduodenoscopy (2/12). No dysplasia or carcinoma was identified. Proton-pump inhibitor use and chronic gastritis were more common in GIM patients compared to control ( P = 0.02).

Most children with GIM had low-risk histologic subtype (complete/limited) for gastric cancer; GIM was rarely associated with H pylori gastritis in our cohort. Larger multicenter studies are needed to better understand outcomes and risk factors in children with GIM.

Sleeve gastrectomy (SG) is a widely used surgical method in the treatment of obesity. This study aimed to reveal the histopathological changes in SG materials and to investigate the prevalence of clinically important lesions requiring follow-up.

Three hundred five patients' data who underwent SG were analyzed. Cases were divided into three groups as normal, chronic inactive gastritis (CIG), and chronic active gastritis (CAG). Age, gender, and body mass index (BMI) of the three groups and the differences in the gastritis parameters of CIG and CAG groups were compared.

Thirty-three patients (10.8%) were in the normal group, 145 (47.5%) were in the CIG group, and 127 (41.6%) were in the CAG group. Preoperative endoscopic examination was performed in all cases, but Helicobacter pylori (HP) treatment was not applied. HP were detected in 39.3%, atrophy in 3.9%, intestinal metaplasia (IM) in 4.9%, and lymphoid follicle (LF) in 30% of the cases. Inflammation, atrophy, IM, LF, and HP were significantly higher in the CAG group. The proton pump inhibitor (PPI)-related changes were seen in 20 cases and it was more frequent in the CIG group. Intramucosal signet ring cell carcinoma was detected in 1 case. Endocrine cell hyperplasia and dysplasia were present in 7 cases with CAG. Multiple grade 1 neuroendocrine tumors were detected in just 1 case.

In our SG specimens, HP and clinically important lesions were significantly higher in the CAG group. Pathological examination should be carefully done as the lesions detected in SG specimens can change patient management.

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.

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.

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.

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.

After being ingested and entering the human stomach, Helicobacter pylori (H. pylori) adopts several effective strategies to adhere to and colonize the gastric mucosa and move to different regions of the stomach to obtain more nutrients and escape from the harsher environments of the stomach, leading to acute infection and chronic gastritis, which is the basis of malignant gastric tumors. The endoscopic manifestations and pathological features of H. pylori infection are diverse and vary with the duration of infection. In this review, we describe the endoscopic manifestations of each stage of H. pylori gastritis and then reveal the potential mechanisms of bacterial intragastric colonization and migration from the perspective of endoscopists to provide direction for future research on the effective therapy and management of H. pylori infection.

The epithelial lining of the stomach undergoes rapid turnover to preserve its structural and functional integrity, a process driven by long-lived stem cells residing in the antral and corpus glands. Several subpopulations of gastric stem cells have been identified and their phenotypic and functional diversities linked to spatiotemporal specification of stem cells niches. Here, we review the biological features of gastric stem cells at various locations of the stomach under homeostatic conditions, as demonstrated by reporter mice, lineage tracing, and single cell sequencing. We also review the role of gastric stem cells in epithelial regeneration in response to injury. Moreover, we discuss emerging evidence demonstrating that accumulation of oncogenic drivers or alteration of stemness signaling pathways in gastric stem cells promotes gastric cancer. Given a fundamental role of the microenvironment, this review highlights the role reprogramming of niche components and signaling pathways under pathological conditions in dictating stem cell fate. Several outstanding issues are raised, such as the relevance of stem cell heterogeneity and plasticity, and epigenetic regulatory mechanisms, to Helicobacter pylori infection-initiated metaplasia-carcinogenesis cascades. With the development of spatiotemporal genomics, transcriptomics, and proteomics, as well as multiplexed screening and tracing approaches, we anticipate that more precise definition and characterization of gastric stem cells, and the crosstalk with their niche will be delineated in the near future. Rational exploitation and proper translation of these findings may bring forward novel modalities for epithelial rejuvenation and cancer therapeutics.

To study the levels of carcinoembryonic antigen (CEA), carbohydrate antigen (CA) 199, CA724, CA242, pepsinogen (PG) I, PGII, gastrin-17 (G-17), the PGI/PGII ratio (PGR), as well as the expression of p27 and Ki67, in patients suffering from early gastric cancer and intraepithelial neoplasia and to provide new markers for the diagnosis of early gastric cancer and precancerous lesions.

A retrospective study where the blood serum concentration of CEA, CA199, CA724, CA242, PGI, PGII, G-17 and PGR were tested and also the protein expression of p27 and Ki67 was detected in patients tissues by immunohistochemistry in the Gastrointestinal Endoscopy Center of the Affiliated Hospital of Xuzhou Medical University, Xuzhou, China, from March 2018 to March 2021.

Carbohydrate antigen 242 and CA199 levels in tumor tissue significantly differed among the groups. Pepsinogen I levels decreased with increasing disease severity, G-17 levels increased with the aggravation of severity, and p27 expression decreased with the severity.

The combination of serum gastric function markers (PGI and G-17) and p27 digestive tumor indices can serve as markers for the diagnosis of early gastric cancer and intraepithelial neoplasia.

Gastric atrophy (GA) and gastric intestinal metaplasia (GIM) are precursor conditions to gastric adenocarcinoma (GAC) and should be monitored endoscopically in selected individuals. However, little is known about adherence to recommendations in clinical practice in low-risk countries.

The aim of this study was to evaluate endoscopic recognition and adequacy of surveillance for GA and GIM in countries with low GAC prevalence.

We retrospectively analysed patients diagnosed with GIM or GA in three centers in The Netherlands and UK between 2012 and 2019. Cases with GIM and/or GA diagnosis at index endoscopy were retrieved through systematic search of pathology databases using 'gastric' and 'intestinal metaplasia' or 'atrophy' keywords. Endoscopy reports were analysed to ascertain accuracy of endoscopic diagnoses. Adequacy of surveillance was assessed following histological diagnosis at the index endoscopy based on ESGE guidelines published in 2012.

We included 396 patients with a median follow-up of 57.2 months. Mean age was 66 years and the rates of antrum-predominant versus extensive GIM were comparable (37% vs 38%). Endoscopic recognition rates were 48.5% for GA and 16.3% for GIM. Surveillance was adequately carried out in 215 of 396 patients (54.3%).

In countries with a low incidence of GAC, the rate of endoscopic recognition of gastric pre-cancerous lesions and adherence to surveillance recommendation are low. Substantial improvement is required in endoscopic training and awareness of guidelines recommendation in order to optimise detection and management of pre-malignant gastric conditions.

Diverse acute and chronic injuries induce damage responses in the gastrointestinal (GI) system, and numerous cell types in the gastrointestinal tract demonstrate remarkable resilience, adaptability, and regenerative capacity in response to stress. Metaplasias, such as columnar and secretory cell metaplasia, are well-known adaptations that these cells make, the majority of which are epidemiologically associated with an elevated cancer risk. On a number of fronts, it is now being investigated how cells respond to injury at the tissue level, where diverse cell types that differ in proliferation capacity and differentiation state cooperate and compete with one another to participate in regeneration. In addition, the cascades or series of molecular responses that cells show are just beginning to be understood. Notably, the ribosome, a ribonucleoprotein complex that is essential for translation on the endoplasmic reticulum (ER) and in the cytoplasm, is recognized as the central organelle during this process. The highly regulated management of ribosomes as key translational machinery, and their platform, rough endoplasmic reticulum, are not only essential for maintaining differentiated cell identity, but also for achieving successful cell regeneration after injury. This review will cover in depth how ribosomes, the endoplasmic reticulum, and translation are regulated and managed in response to injury (e.g., paligenosis), as well as why this is essential for the proper adaptation of a cell to stress. For this, we will first discuss how multiple gastrointestinal organs respond to stress through metaplasia. Next, we will cover how ribosomes are generated, maintained, and degraded, in addition to the factors that govern translation. Finally, we will investigate how ribosomes and translation machinery are dynamically regulated in response to injury. Our increased understanding of this overlooked cell fate decision mechanism will facilitate the discovery of novel therapeutic targets for gastrointestinal tract tumors, focusing on ribosomes and translation machinery.