Precursor Of Gastric Cancer Research Articles

The diagnostic value of serum trefoil factor 3 and pepsinogen combination in chronic atrophic gastritis: a retrospective study based on a gastric cancer screening cohort in the community population

Background Chronic atrophic gastritis (CAG) is an important precursor of gastric cancer(GC), and there is currently a lack of reliable non-invasive diagnostic markers. This study aims to find a biomarker for non-invasive screening of CAG in the community. Methods A total of 540 individuals were enrolled (test set = 385, validation set = 155). ROC curve analysis was used to evaluate the diagnostic significance of serum Trefoil Factor 3 (TFF3) alone or in combination with pepsinogen (PG) for CAG in the test and validation set. Furthermore, the diagnostic value of TFF3 and PG in different Helicobacter pylori (H. pylori) infection states was studied. Results When compared with chronic superficial gastritis (CSG), the expression level of serum TFF3 in the CAG was higher (27 ng/ml vs 19.61, P < 0.001). ROC curve analysis found that the sensitivity, specificity, and area under the curve (AUC) of CAG diagnosis using serum TFF3 alone at the optimal cut-off value of 26.55 ng/ml were 0.529, 0.87, and 0.739, respectively. When TFF3 was combined with The Ratio of PGI to PGII (PGR), the AUC and specificity reached 0.755 and 0.825, respectively. TFF3 individual or combined with PGR had good predictive value, especially in the H. Pylori negative patients. Conclusion TFF3 combined with PGR can effectively predict CAG, especially in patients with H. pylori negative.

Gastric Carcinogenesis and Potential Role of the Transient Receptor Potential Vanilloid 1 (TRPV1) Receptor: An Observational Histopathological Study.

The potential role of the transient receptor potential Vanilloid 1 (TRPV1) non-selective cation channel in gastric carcinogenesis remains unclear. The main objective of this study was to evaluate TRPV1 expression in gastric cancer (GC) and precursor lesions compared with controls. Patient inclusion was based on a retrospective review of pathology records. Patients were subdivided into five groups: Helicobacter pylori (H. pylori)-associated gastritis with gastric intestinal metaplasia (GIM) (n = 12), chronic atrophic gastritis (CAG) with GIM (n = 13), H. pylori-associated gastritis without GIM (n = 19), GC (n = 6) and controls (n = 5). TRPV1 expression was determined with immunohistochemistry and was significantly higher in patients with H. pylori-associated gastritis compared with controls (p = 0.002). TRPV1 expression was even higher in the presence of GIM compared with patients without GIM and controls (p < 0.001). There was a complete loss of TRPV1 expression in patients with GC. TRPV1 expression seems to contribute to gastric-mucosal inflammation and precursors of GC, which significantly increases in cancer precursor lesions but is completely lost in GC. These findings suggest TRPV1 expression to be a potential marker for precancerous conditions and a target for individualized treatment. Longitudinal studies are necessary to further address the role of TRPV1 in gastric carcinogenesis.

Abstract 6099: Identification of intrinsic precursors of Barrett's and gastric intestinal metaplasia

Abstract The origin of Barrett's esophagus (BE) and gastric intestinal metaplasia (GIM), obligate precursors of esophageal adenocarcinoma (EAC) and intestinal gastric cancer (iGC), has intrigued investigators for decades and would likely guide preemptive strategies. From endoscopic biopsies of clinically confirmed BE and GIM, we have cloned stem cells committed to intestinal metaplasia in vitro. Remarkably, the gene expression profiles of BE and GIM stem cells are highly related down to broad arrays of transcription factors compared with stem cells of the normal gastric mucosa. Using cell surface markers in common between BE and GIM stem cells, we have identified clusters of cells at the squamocolumnar junction and the distal stomach in mice and have used Fluorescence-activated cell sorting (FACS) to clone these cells from both sites. These murine clones can be differentiated in air-liquid interface cultures, and both are committed to intestinal metaplasia marked by goblet cells and Alcian blue staining. To ask whether similar cells exist in humans, we generated stem cell libraries from endoscopic biopsies taken from the gastroesophageal junction (GEJ) and the antrum-body junction (ABJ) in patients without BE or GIM. FACS sorting of these stem cell libraries using the same cell surface markers common to BE and GIM stem cells and the murine precursors, we have identified stem cells from the GEJ and ABJ that show similar gene expression profiles and share a commitment to intestinal metaplasia upon in vitro differentiation. Using identical transformation protocols involving retrovirally transduced protooncogenes, we find that these transformed intrinsic cells give rise to tumors with expression profiles similar to EAC and iGC in TCGA datasets, whereas transformed gastric mucosal stem cells yield tumors marked by signet ring cells typical of diffuse gastric cancer. Lastly, we find that drugs we have developed that target the stem cells of BE and GIM also eliminate the putative precursor cells of BE and GIM, suggesting the potential of therapeutics that might eliminate the emergence of intestinal metaplasia and the cancers derived from them. Citation Format: Wa Xian, Frank McKeon, Yusuke Yamamoto, Melika Khorrami, Melina Khorrami, Zaal Mory, Jeremy Siegelman, Amber Su, Raul Caballero Montes, Ashley Hoffman, Jaffer Ajani, Christopher Crum, William Bachovchin, Shan Wang, Matthew Vincent, Crystal Nguyen. Identification of intrinsic precursors of Barrett's and gastric intestinal metaplasia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6099.

Abstract 1140: A spatially mapped gene expression signature for intestinal stem-like cells identifies high-risk precursors of gastric cancer

Abstract Gastric intestinal metaplasia (GIM) is a precursor lesion for the intestinal subtype of gastric cancer (GC). A risk stratification tool is the Operative Link on GIM (OLGIM), a system that relies on histopathologic annotation of gastric biopsies. Advanced OLGIM (stages III and IV) have the highest risk of progression to GC. Molecular biomarkers for advanced OLGIM are lacking. We explored transcriptomics biomarkers for advanced OLGIM to aid risk assessment efforts among GC precursors.We used clinical and genomic data from four cohorts: 1) GAPS, a cohort of OLGIM-staged patients (N=303); 2) a subset of confirmed intestinal-type GC from The Cancer Genome Atlas (TCGA, N=198); 3) a compilation of scRNA-seq data (N=40), and 4) a spatial transcriptomics cohort (N=5) with annotated H&amp;E-stained histopathology slides from GC or OLGIM-staged patients.We separated the GAPS bulk RNAseq gene expression dataset into independent discovery (N=88) and validation (N=215) sets. Through a combination of differential expression analysis and co-expression analysis, we identified a discrete set of 100 significantly upregulated genes characterizing advanced OLGIM that were confirmed in the validation set. Importantly, these genes were overexpressed both in the corpus and antrum of the stomach. We leveraged spatial transcriptomics assays to refine this signature to genes overexpressed specifically in GIM foci. We interrogated the TCGA dataset and confirmed these genes to be also expressed in gastric tumors. The final high-risk signature included 26 genes. Single-cell RNAseq analysis revealed these genes to be expressed by aberrant intestinal-like lineages. Further, reference-mapping identified cells resembling mature enterocytes and goblet cells that expressed 16 of these genes, whereas 10 genes from the high-risk signature pinpoint immature intestinal stem-like cells at varying stages of differentiation (duodenum stem cells, duodenum differentiating stem cells, and duodenum transit amplifying cells). Finally, we confirmed expression of 12 of these genes by single-molecule fluorescence in situ hybridization (smFISH), that distinguish differentiated from stem-like lineages in metaplasia and are absent in normal gastric glands in intact tissue sections from GC precursors.Our study identified as signature of 26 genes that are: i) characteristically over-expressed in advanced OLGIM stages, ii) localize specifically to metaplasia, iii) are expressed in gastric tumors, and iv) distinguish differentiated from stem-like cells in GIM. These results provide transcriptomics biomarkers that indicate the establishment and expansion of intestinal stem-like cells in advanced OLGIM, with profound translational implications, as these cells may harbor and expand mutations that predispose advanced OLGIM patients to GC. Citation Format: Ignacio A. Wichmann, Robert J. Huang, Andrew Su, Anuja Sathe, Miranda V. Shum, Susan M. Grimes, Rithika Meka, Alison Almeda, Xiangqi Bai, Jeanne Shen, Quan Nguyen, Manuel Amieva, Joo Ha Hwang, Hanlee P. Ji. A spatially mapped gene expression signature for intestinal stem-like cells identifies high-risk precursors of gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1140.

Protocolo de evaluación de las lesiones premalignas gástricas

Gastric carcinogenesis is associated with Helicobacter pylori(H. pylori) infection and occurs through histologic gastric cancer precursor lesions (GCPL). This protocol will discuss intestinal gastric cancer. It does not cover prevention of diffuse and cardia gastric cancer, neuroendocrine tumors, or hereditary syndromes. The most significant factors that cause an increased risk of gastric cancer are family history of the disease and the presence of GCPL. The two strategies evaluated to reduce the incidence and/or mortality of gastric cancer are eradication of H. pylori and monitoring and/or endoscopic treatments.

Genome-wide DNA methylation and transcriptomic patterns of precancerous gastric cardia lesions.

Intestinal metaplasia (IM) and intraepithelial neoplasia (IEN) are considered precursors of gastric cardia cancer (GCC). Here, we investigated the histopathologic and molecular profiles of precancerous gastric cardia lesions (PGCLs) and biomarkers for risk stratification of gastric cardia IM. We conducted a hospital-based evaluation (n = 4578) for PGCL profiles in high-incidence and non-high-incidence regions for GCC in China. We next performed 850K methylation arrays (n = 42) and RNA-seq (n = 44) in tissues with PGCLs. We then examined the protein expression of candidate biomarker using immunohistochemistry. Of the 4578 participants, 791 were diagnosed with PGCLs (600 IM, 62 IM with IEN, and 129 IEN). We found that individuals from high-incidence regions (26.7%) were more likely to develop PGCLs than those from non-high-incidence areas (13.5%). DNA methylation and gene expression alterations, indicated by differentially methylated probes (DMPs) and differentially expressed genes (DEGs), exhibited a progressive increase from type I IM (DMP = 210, DEG = 24), type II IM (DMP = 3402, DEG = 129), to type III IM (DMP = 3735, DEG = 328), peaking in IEN (DMP = 47 373, DEG = 2278). Three DEGs with aberrant promoter methylation were identified, shared exclusively by type III IM and IEN. Of these DEGs, we found that OLFM4 expression appears in IMs and increases remarkably in IENs (P < .001). We highlight that type III IM and IEN share similar epigenetic and transcriptional features in gastric cardia and propose biomarkers with potential utility in risk prediction.

Immunohistochemical Expression of CDX2 as Early Biomarkers for Gastric Intestinal Metaplasia among Sudanese Patients with Chronic Gastritis

Background: Chronic gastric infection with Helicobacter pylori can cause intestinal metaplasia, a pathologic change that is frequently a precursor of gastric cancer; CDX2 has an essential role in the development and maintenance of intestinal differentiation in the gut and ectopic sites such as intestinal metaplasia of the stomach. Objective: This study aimed to investigate caudal-type home box (CDX2) Immuno expression as an early indicator for gastric intestinal metaplasia among Sudanese patients with chronic gastritis. Materials and methods: This is a descriptive retrospective cross-sectional study conducted at Atbara Medical Complex and El-MakNimr University Hospital at River Nile State in the period from 2019 to 2022. 140 archival paraffin tissue blocks were collected from patients diagnosed with chronic gastritis, immunohistochemistry was used to detect (CDX2 expression as an early indicator for gastric intestinal metaplasia. Results: From 140 samples, 80 were females (57.1 %) and 60 were males (42.9%), the patient's ages ranged from (12 to 97) with a mean age of (53.27) years, and age was categorized into three groups, less than 40 (27) (19.3%), 40- 60 (64) (45.7%), more than 60 (49) (35.0%). The prevalence of gastric intestinal metaplasia was (17.9%, while no statistically significant correlation of gastric intestinal metaplasia with gender and age as the P.value was (0.308 and 0.256) respectively. Conclusion: The development of gastric intestinal metaplasia as a premalignant condition of gastric carcinoma is important to detect this change at an early point to prevent and control gastric cancer.

Schlafen4+-MDSC in Helicobacter-induced gastric metaplasia reveals role for GTPases.

MDSCs express SCHLAFEN 4 (SLFN4) in Helicobacter-infected stomachs coincident with spasmolytic polypeptide-expressing metaplasia (SPEM), a precursor of gastric cancer. We aimed to characterize SLFN4+ cell identity and the role of Slfn4 in these cells. Single-cell RNA sequencing was performed on immune cells sorted from PBMCs and stomachs prepared from uninfected and 6-month H. felis-infected mice. Knockdown of Slfn4 by siRNA or PDE5/6 inhibition by sildenafil were performed in vitro. Intracellular ATP/GTP levels and GTPase activity of immunoprecipitated Slfn4 complexes were measured using the GTPase-Glo assay kit. The intracellular level of ROS was quantified by the DCF-DA fluorescent staining, and apoptosis was determined by cleaved Caspase-3 and Annexin V expression. Gli1CreERT2 x Slfn4 fl/fl mice were generated and infected with H. felis. Sildenafil was administered twice over 2 weeks by gavaging H. felis infected mice ~4 months after inoculation once SPEM had developed. Slfn4 was highly induced in both monocytic and granulocytic MDSCs from infected stomachs. Both Slfn4 +-MDSC populations exhibited strong transcriptional signatures for type-I interferon responsive GTPases and exhibited T cell suppressor function. SLFN4-containing protein complexes immunoprecipitated from myeloid cell cultures treated with IFNa exhibited GTPase activity. Knocking down Slfn4 or PDE5/6 inhibition with sildenafil blocked IFNa induction of GTP, SLFN4 and NOS2. Moreover, IFNa induction of Slfn +-MDSC function was inhibited by inducing their reactive oxygen species (ROS) production and apoptosis through protein kinase G activation. Accordingly, in vivo disruption of Slfn4 in Gli1CreERT2 x Slfn4 fl/fl mice or pharmacologic inhibition by sildenafil after Helicobacter infection also suppressed SLFN4 and NOS2, reversed T cell suppression and mitigated SPEM development. Taken together, SLFN4 regulates the activity of the GTPase pathway in MDSCs and precludes these cells from succumbing to the massive ROS generation when they acquire MDSC function.

P-191 Helicobacter pylori ancestors associated to gastric microbiota dysbiosis in Colombian patients with gastric cancer precursor lesions

P-191 Helicobacter pylori ancestors associated to gastric microbiota dysbiosis in Colombian patients with gastric cancer precursor lesions

Serum Pepsinogen as a Biomarker for Gastric Cancer in the United States: A Nested Case-Control Study Using the PLCO Cancer Screening Trial Data.

Gastric cancer lacks specific symptoms, resulting in diagnosis at later stages and high mortality. Serum pepsinogen is a biomarker for atrophic gastritis, a gastric cancer precursor, and may be useful to detect persons at increased risk of gastric cancer. The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial was conducted in the United States between 1993 and 2001. ELISA-based pepsinogen tests were conducted on prediagnostic serum samples of 105 PLCO participants who developed gastric cancer and 209 age, sex, and race-matched controls. Pepsinogen positive (PG+) was defined as pepsinogen I ≤ 70 μg/L and pepsinogen I/II ratio ≤3.0. Results of conditional logistic regression models, and sensitivity and specificity, of PG+ for gastric cancer are reported. Gastric cancer cases were more likely to be PG+ (31.4% vs. 5.5%, P < 0.001) at baseline than controls. Compared to PG-, PG+ was associated with an 8.5-fold increased risk for gastric cancer [95% confidence interval (CI) = 3.8-19.4]. This risk remained significant after adjusting for Helicobacter pylori, family history of gastric cancer, education, smoking, and BMI (aOR, 10.6; 95% CI, 4.3-26.2). In subgroup analysis, PG+ individuals were 11-fold more like to develop non-cardia gastric cancer (OR, 11.1; 95% CI, 4.3-28.8); conversely, they were not significantly more likely to develop cardia gastric cancer (OR, 2.0; 95% CI = 0.3-14.2). PG+ status yielded low sensitivity but high specificity for both noncardia (44.3%; 93.6%) and cardia gastric cancer (5.7%; 97.2%). Prediagnostic serum pepsinogen levels from a large, prospective cohort study were associated with risk of gastric cancer, particularly noncardia gastric cancer. PG status may identify individuals at higher risk of noncardia gastric cancer for targeted screening or interventions. See related commentary by Zhou and Huang, p. 1257.

Application of a novel scoring system for gastric cancer opportunistic screening in hospital visits

BackgroundA novel scoring system and screening procedure for gastric cancer (GC) screening was proposed based on the national conditions of China, which state that endoscopy professionals and facilities are relatively limited compared with the large Chinese population.MethodsA novel scoring system for gastric cancer screening was used to retrospectively analyse the patients who met the screening procedure from April 2017 to December 2019 in our hospital. We divided all of the patients into three groups: low-risk group (0–11 scores), medium-risk group (12–16 scores), and high-risk group (17–23 scores). Statistical analysis was performed on the detection rate of gastric cancer and precursors of gastric cancer among these three groups.ResultsA total of 6701 patients were enrolled in this study, including 4,352(64.95%) in the low-risk group, 1,948 patients (29.07%) in the medium-risk group, and 401 patients (5.98%) in the high-risk group. The total detection rate of gastric cancer was 2.84% (190/6,701), with a 0.94% rate (41/4,352) in the low-risk group, a 5.18% rate (101/1,948) in the medium-risk group, and a 11.97% rate (48/401) in the high-risk group. There were statistically significant differences in the detection rate of gastric cancer among these three groups (all P < 0.05). The detection rate of early gastric cancer was 46.31% (88/190) among all of the detected gastric cancers in this study. In addition, the detection rates of differentiated gastric cancer and precursors of gastric cancer in the medium-risk group and high-risk group were significantly higher than those in the low-risk group. In addition, the area under the curve (AUC) of the receiver operating characteristic curve (ROC) of the novel scoring system in differentiating GC was 0.79.ConclusionThe screening strategy based on the novel scoring system can significantly improve the efficiency of gastric cancer opportunistic screening in hospital visits. Gastroscopy should be strongly recommended for patients in the medium-risk group and high-risk group, and detailed gastroscopy should be adopted as early as possible to improve the detection rate of early gastric cancer.

Prevalence of gastric cancer precursor lesions in patients of a secondary care center in a state in south of Brazil

Background: Atrophy of the gastric mucosa and intestinal metaplasia is considered malignant precursor lesions of gastric cancer, which is considered the fifth most common neoplasm in the world and the third cause of death from cancer. The main risk factor is the infection by Helicobacter pylori (H. pylori), which increases up to six times the risk of gastric cancer, through gastritis, atrophy, and hypochlorhydria, consequences of the infection. Other risk factors are also worth noting, like smoking and a family history of gastric cancer. Objective: To investigate the prevalence of malignant precursor lesions and their associated factors in patients who underwent upper gastrointestinal endoscopy. Methods: A descriptive, observational study was performed based on an analysis of endoscopic gastric biopsies performed in two affiliated private laboratories to the Unified Health System (Sistema Único de Saúde [SUS]) in a city in Paraná state. Patients were assessed for age, sex, active or recent smoking, family history of gastric cancer, and previous treatment for H. pylori. The samples were evaluated for the presence of glandular atrophy, intestinal metaplasia, dysplasia, and H. pylori infection. Results: A total of 1,549 medical records and patient reports were evaluated and 945 were eligible, the average age was 52.2 (±14.3) years old and most patients (73.3%) were female. The prevalence of H. pylori infection was 47.5% (n= 449) and the highest percentage was between 30-39 years (58.7%). Among H. pylori-positive (+) patients who had developed intestinal metaplasia, there is more risk of having incomplete than complete metaplasia (OR: 4.34; 1.1–17.1; 95%CI). Patients who smoke are more increase the risk to developed glandular atrophy (OR: 1.91; 1.09-3.33; 95%CI) and intestinal metaplasia (OR: 1.93; 0.72-5.11; 95%CI). Conclusion: The study reinforces risk factors such as smoking and H. pylori infection as precursors for developing pre-neoplastic lesions in a population in southern Brazil, highlighting the importance of smoking cessation and prevention of H. pylori infection and the treatment of infected patients.

Epstein-Barr Virus is Associated with Gastric Cancer Precursor: Atrophic Gastritis.

Background: About 10% of gastric cancer (GC) has been described to be Epstein-Barr virus (EBV) positive. Previous researches have described the association between EBV and GC. However, the association of EBV with atrophic gastritis (AG) is underrecognized. Our study aimed to investigate the relationship between EBV and AG and assess the influence of EBV on gastric function.Methods: A total of 468 pathologically-confirmed chronic gastritis patients underwent circulating EBV DNA test, include 271 non-atrophic gastritis (NAG) and 197 AG patients.Results: In this study, H. pylori infection rate was 33.3%, EBV infection rate was 40%, and co-infection rate was 15%. The EBV DNA-positive was significantly associated with AG (P=0.031, OR= 1.509, 95% CI 1.037-2.194), especially in H. pylori-negative subjects (P=0.044, OR=1.619, 95% CI 1.012-2.589). EBV DNA-positive patients had a lower pepsinogen I (PG I) / pepsinogen II (PG II) ratio (PGR) than EBV DNA-negative patients (P=0.0026), especially in the AG subgroup (P=0.0062). There was no significant association between EBV and H. pylori co-infection with increased risk of AG (P>0.05).Conclusion: EBV infection significantly increased the risk of AG, especially in H. pylori-negative patients. The circulating EBV DNA had a potential in predicting the risk of atrophic gastritis.

Essential role of ALKBH5-mediated RNA demethylation modification in bile acid-induced gastric intestinal metaplasia

Bile acid reflux and subsequent caudal-related homeobox 2 (CDX2) activation contribute to gastric intestinal metaplasia (IM), a precursor of gastric cancer; however, the mechanism underlying this phenomenon is unclear. Here, we demonstrate that alkylation repair homolog protein 5 (ALKBH5), a major RNA N6-adenosine demethylase, is required for bile acid-induced gastric IM. Mechanistically, we revealed the N6-methyladenosine (m6A) modification profile in gastric IM for the first time and identified ZNF333 as a novel m6A target of ALKBH5. ALKBH5 was shown to demethylate ZNF333 mRNA, leading to enhanced ZNF333 expression by abolishing m6A-YTHDF2-dependent mRNA degradation. In addition, ALKBH5 activated CDX2 and downstream intestinal markers by targeting the ZNF333/CYLD axis and activating NF-κB signaling. Reciprocally, p65, the key transcription factor of the canonical NF-κB pathway, enhanced the transcription activity of ALKBH5 in the nucleus, thus forming a positive feedforward circuit. Furthermore, ALKBH5 levels were positively correlated with ZNF333 and CDX2 levels in IM tissues, indicating significant clinical relevance. Collectively, our findings suggest that an m6A modification-associated positive feedforward loop between ALKBH5 and NF-κB signaling is involved in generating the IM phenotype of gastric epithelial cells. Targeting the ALKBH5/ZNF333/CYLD/CDX2 axis may be a useful therapeutic strategy for gastric IM in patients with bile regurgitation.

Rescue Therapy with Furazolidone in Patients with at Least Five Eradication Treatment Failures and Multi-Resistant H. pylori infection.

Helicobacter pylori infection may persist after multiple eradication treatments. The aim of this study was to evaluate the efficacy and safety of a furazolidone-based rescue regimen in hyper-refractory patients. A unicentre, prospective study was designed. Patients in whom five or more treatments had consecutively failed were included. All patients had previously received bismuth and key antibiotics, such as amoxicillin, clarithromycin, metronidazole, levofloxacin, tetracycline, and rifabutin, and had positive H. pylori culture, demonstrating resistance to clarithromycin, metronidazole, and levofloxacin. A quadruple regimen with furazolidone (200 mg), amoxicillin (1 g), bismuth (240 mg), and esomeprazole (40 mg) was prescribed twice a day for 14 days. Eradication was confirmed by the stool antigen test. Compliance was determined through questioning, and adverse effects using a questionnaire. Eight patients (mean age 56 years, 63% men, 38% peptic ulcer disease, 12% gastric cancer precursor lesions, and 50% functional dyspepsia) were included. Per-protocol and intention-to-treat eradication rates were 63%. Compliance was 100%. Adverse effects were reported in two (25%) patients, and all were mild. Even after five or more previous H. pylori eradication failures, and a multi-resistant infection, rescue treatment with furazolidone may be effective in approximately two-thirds of the cases, constituting a valid strategy after multiple previous eradication failures with key antibiotics such as clarithromycin, metronidazole, tetracycline, levofloxacin, and rifabutin.

Quality in diagnostic upper gastrointestinal endoscopy for the detection and surveillance of gastric cancer precursor lesions: Position paper of AEG, SEED and SEAP

This position paper, sponsored by the Asociación Española de Gastroenterología [Spanish Association of Gastroenterology], the Sociedad Española de Endoscopia Digestiva [Spanish Gastrointestinal Endoscopy Society] y the Sociedad Española de Anatomía Patológica [Spanish Anatomical Pathology Society], aims to establish recommendations for performing an high quality upper gastrointestinal endoscopy for the screening of Gastric Cancer Precursor Lesions (GCPL) in low-incidence populations, such as the Spanish population. To establish the quality of the evidence and the levels of recommendation, we used the methodology based on the GRADE system (Grading of Recommendations Assessment, Development and Evaluation). We obtained a consensus among experts using a Delphi method. The document evaluates different measures to improve the quality of upper gastrointestinal endoscopy in this setting and makes recommendations on how to evaluate and treat the identified lesions. We recommend that upper gastrointestinal endoscopy for surveillance of GCPL should be performed by endoscopists with adequate training, administering oral premedication and use of sedation. To improve the identification of GCPL, we recommend the use of high definition endoscopes and conventional or digital chromoendoscopy and, for biopsies, NBI should be used to target the most suspicious areas of intestinal metaplasia. Regarding the evaluation of visible lesions, the risk of submucosal invasion should be evaluated with magnifying endoscopes and endoscopic ultrasound should be reserved for those with suspected deep invasion. In lesions amenable to endoscopic resection, submucosal endoscopic dissection is considered the technique of choice. Este documento de posicionamiento, auspiciado por la Asociación Española de Gastroenterología, la Sociedad Española de Endoscopia Digestiva y la Sociedad Española de Anatomía Patológica tiene como objetivo establecer recomendaciones para realizar una endoscopia digestiva (EDA) de calidad en la detección y vigilancia de lesiones precursoras de cáncer gástrico (LPCG) en poblaciones con incidencia baja, como la española. Para establecer la calidad de la evidencia y los niveles de recomendación se ha utilizado la metodología basada en el sistema GRADE ( Grading of Recommendations Assessment, Development and Evaluation) . Se obtuvo el consenso entre expertos mediante un método Delphi. El documento evalúa diferentes medidas para mejorar la calidad de la EDA en este contexto y hace recomendaciones de cómo evaluar y tratar las lesiones identificadas. Se recomienda que la EDA de vigilancia de LPCG sea realizada por endoscopistas con capacitación adecuada, administrando premedicación oral y uso de sedación. Para mejorar la identificación de LPCG se recomienda el uso de endoscopios de alta definición y cromoendoscopia convencional o digital y, para las biopsias, debe utilizarse el NBI para dirigirlas a las áreas más sospechosas de metaplasia intestinal. En cuanto a la evaluación de las lesiones visibles, el riesgo de invasión de la submucosa debe evaluarse con endoscopios de magnificación y reservar la ecoendoscopia para aquellas con sospecha de invasión profunda. En las lesiones susceptibles de resección endoscópica, la disección endoscópica submucosa se considera la técnica de elección.

Gastric cancer screening in low incidence populations: Position statement of AEG, SEED and SEAP

This positioning document, sponsored by the Asociacion Espanola de Gastroenterologia, the Sociedad Espanola de Endoscopia Digestiva and the Sociedad Espanola de Anatomia Patologica, aims to establish recommendations for the screening of gastric cancer (GC) in low incidence populations, such as the Spanish. To establish the quality of the evidence and the levels of recommendation, we used the methodology based on the GRADE system (Grading of Recommendations Assessment, Development and Evaluation). We obtained a consensus among experts using a Delphi method. The document evaluates screening in the general population, individuals with relatives with GC and subjects with GC precursor lesions (GCPL). The goal of the interventions should be to reduce GC related mortality. We recommend the use of the OLGIM classification and determine the intestinal metaplasia (IM) subtype in the evaluation of GCPL. We do not recommend to establish endoscopic mass screening for GC or Helicobacter pylori. However, the document strongly recommends to treat H.pylori if the infection is detected, and the investigation and treatment in individuals with a family history of GC or with GCPL. Instead, we recommend against the use of serological tests to detect GCPL. Endoscopic screening is suggested only in individuals that meet familial GC criteria. As for individuals with GCPL, endoscopic surveillance is only suggested in extensive IM associated with additional risk factors (incomplete IM and/or a family history of GC), after resection of dysplastic lesions or in patients with dysplasia without visible lesion after a high quality gastroscopy with chromoendoscopy.

High frequency of gastric cancer precursor lesions in patients with gastric xanthelasma: a prospective case-control study.

An association of gastric cancer and precursor lesions with gastric xanthelasma has frequently been reported. However, the incidence of both gastric xanthelasma and gastric cancer precursor lesions increases with age. The aim of this study was to evaluate the frequency and characteristics of atrophic gastritis, intestinal metaplasia and dysplasia in patients with gastric xanthelasma compared to controls. Cases with gastric xanthelasma endoscopically and histopathologically were included in this prospective study. The patients included in the study were compared with age- and sex-matched controls in terms of the frequency and characteristics of atrophic gastritis, intestinal metaplasia, dysplasia and cancer. In a series of 1892 upper endoscopies, 108 patients (5.7%) were found to have gastric xanthelasma. The average age of the patients was 61.41 ± 11.43 years. Among the patients, 58 (53.7%) were male. The frequencies of atrophic gastritis, intestinal metaplasia, dysplasia and gastric cancer in the xanthelasma group (n = 108) were 31.5, 68.5, 3.7 and 2.8%, respectively. The frequencies of atrophic gastritis, intestinal metaplasia, dysplasia and gastric cancer in the control group (n = 183) were 11.5, 31.7, 0.5 and 0.5%, respectively. Compared to the control group, the frequency of these cancer precursor lesions and the prevalence of advanced stage based on operative link on gastritis intestinal metaplasia assessment were found to be higher in the xanthelasma group (P < 0.05). Gastric xanthelasma is associated with an increased frequency of gastric precancerous lesions and should be considered an important marker.

Diffuse MIST1 expression and decreased α1,4-linked N-acetylglucosamine (αGlcNAc) glycosylation on MUC6 are distinct hallmarks for gastric neoplasms showing oxyntic gland differentiation.

Gastric neoplasms showing oxyntic gland differentiation (GAOGs) constitute a gastric neoplasm subtype that shows low atypia, thus similar to non-neoplastic gastric oxyntic glands. Therefore, their diagnosis in biopsy specimens is difficult. GAOGs were first described in 2007, and introduced in the latest World Health Organization classification book as gastric adenocarcinoma of the fundic gland type (GA-FG) and oxyntic gland adenoma. Previously, we assessed α1,4-linked N-acetylglucosamine (αGlcNAc) residues attached to the MUC6 scaffold in gastric neoplasms, and observed decreased αGlcNAc glycosylation in both differentiated-type gastric cancer and high-grade pyloric gland adenoma (PGA), a gastric cancer precursor. GA-FG and PGA often harbour the same mutations. However, the αGlcNAc status in GAOGs remained unknown. To elucidate αGlcNAc expression in GAOGs, we performed the study. We assessed the expression of αGlcNAc; the mucin markers MUC6, MUC5AC, and MUC2; the gastric gland cell markers MIST1, pepsinogen 1 (PG1), H/K-ATPase and chromogranin-A (CGA); and the proliferation marker Ki67 in 13 GAOG lesions. All 13 (100%) were MUC6-positive, whereas 10 (76.2%) were αGlcNAc-negative. Moreover, all 13 (100%) were MIST1- and PG1-positive, three (23.1%) were MUC5AC-positive, four (30.8%) were H/K-ATPase-positive, and one (7.7%) was CGA-positive. GAOGs frequently lost αGlcNAc residues on MUC6, but expressed the gastric gland progenitor marker MIST1 and aberrantly expressed various types of gastric gland cell lineage marker, suggestive of immature differentiation to gastric gland cells. Thus, diffuse MIST1 positivity and decreased αGlcNAc glycosylation on MUC6-positive cells could serve as important biomarkers for the histopathological diagnosis of GAOG.

Gastric Corpus Mucosal Hyperplasia and Neuroendocrine Cell Hyperplasia, but not Spasmolytic Polypeptide-Expressing Metaplasia, Is Prevented by a Gastrin Receptor Antagonist in H+/K+ATPase Beta Subunit Knockout Mice.

Proton pump inhibitor use is associated with an increased risk of gastric cancer, which may be mediated by hypergastrinemia. Spasmolytic polypeptide-expression metaplasia (SPEM) has been proposed as a precursor of gastric cancer. We have examined the effects of the gastrin receptor antagonist netazepide (NTZ) or vehicle on the gastric corpus mucosa of H+/K+ATPase beta subunit knockout (KO) and wild-type (WT) mice. The gastric corpus was evaluated by histopathology, immunohistochemistry (IHC), in situ hybridization (ISH) and whole-genome gene expression analysis, focusing on markers of SPEM and neuroendocrine (NE) cells. KO mice had pronounced hypertrophy, intra- and submucosal cysts and extensive expression of SPEM and NE cell markers in the gastric corpus, but not in the antrum. Numerous SPEM-related genes were upregulated in KO mice compared to WT mice. NTZ reduced hypertrophia, cysts, inflammation and NE hyperplasia. However, NTZ neither affected expression of SPEM markers nor of SPEM-related genes. In conclusion, NTZ prevented mucosal hypertrophy, cyst formation and NE cell hyperplasia but did not affect SPEM. The presence of SPEM seems unrelated to the changes caused by hypergastrinemia in this animal model.