Gastric Metaplasia Research Articles

Immune-enhancing effects of endogenous glucocorticoids on gastric macrophages contribute to the development of gastric inflammation and metaplasia.

Immune-enhancing effects of endogenous glucocorticoids on gastric macrophages contribute to the development of gastric inflammation and metaplasia.

Altering Trends in Pathological Spectrum of Cholecystectomy Specimen: Time to be More Vigilant

Abstract Background: Gall bladder cancer is a rare, most common and aggressive malignancy of the biliary tree, accounting for 80%–90% of biliary tract cancers. Gallstones are one of the major causes of the development of cholecystitis and long-term malignancy in developing countries. Cholecystectomy specimens have a great value in documenting various entities with clinical significance. Early detection is the most important step in improving the prognosis of gall bladder carcinoma (GBC) screening. Aim: Clinico- pathological spectrum of cholecystectomy specimen and Incidence of malignancy and its precursor lesion with gallstones. Patient and Methods: We conducted a retrospective analysis of all gall bladder specimens (cholecystectomy, laparoscopic, open or radical) from the period of January 2019–January 2022, including demographic data of the patients such as age and sex. Additional findings, such as the presence of gallstones, cholesterolosis, gastric or intestinal metaplasia, dysplasia and histopathological type of GBC, were documented. Results: A total of 1221 gall bladder specimens were received, with a higher female preponderance and a female-to-male ratio of 2.6:1. The mean age of presentation was 45 years. The most common histopathological diagnosis made was chronic cholecystitis (97%), and malignant cases accounted for 3% of the total cases. Conclusions: The high propensity of GBC with non-cholelithiasis cases, more than half of cases with metaplasia and increased incidence of adenosquamous carcinoma indicate a high burden of tumours, alerting the clinician as well as the pathologist.

Ciliated foregut cysts involving the hepatopancreaticobiliary system: a clinicopathological evaluation with focus on atypical features

AimsForegut cystic malformations are rare developmental abnormalities, which may involve the hepatopancreaticobiliary tract (HPBT). These cysts are composed of inner ciliated epithelium; subepithelial connective tissue layer; smooth muscle layer; and...

Abstract C059: Regulatory Elements of Pancreas Development License the Initiation of Pancreatic Ductal Adenocarcinoma

Abstract Mutations in DNA are a known cause of cancer. However, they become oncogenic only under specific cellular conditions and within certain tissue contexts. Tissue injury often leads to the aberrant activation of developmental pathways, eroding markers of cellular differentiation and giving rise to transient cellular states. These states resemble developmental progenitors, characterized by higher transcriptional plasticity. Oncogenes, particularly KRAS, co-opt cellular plasticity by acting on tissue-specific enhancers, preventing the resolution of acinar plasticity and maintaining the pancreas in a pro-inflammatory phase that progresses to cancer1,2. However, the specific role of tissue-specific enhancers in pancreas regeneration and cancer initiation remains unexplored, and strategies to target these regenerative processes are yet to be developed. Our laboratory investigates non-mutational mechanisms of cancer, with a special interest in the intersection of developmental biology and cancer, aiming to elucidate the processes of cellular plasticity and cancer initiation. Recent studies have shown that acinar cells possess remarkable cellular plasticity, giving rise to a diverse population of cellular states in pancreas regeneration and cancer contexts3-5. We have discovered that the transcription factor Sox4 is necessary for the specification of tuft cells and gastric metaplasia found in chronic pancreatitis and in pancreatic intraepithelial lesions (PanINs). Moreover, we have shown that cellular plasticity has a non-cell autonomous protective effect; losing Sox4 and cellular heterogeneity in PanINs results in a fibrotic and immunosuppressive tumor microenvironment and disease progression. Our results demonstrated that targeting cellular plasticity accelerates or prevents cancer initiation through autonomous and non-autonomous cellular processes6. In this study, we leverage a comprehensive resource of ncRNAs transcribed from enhancer elements of pancreas development, together with their inferred target genes and correlations with clinical outcomes. We focused on an ncRNA associated with the risk of pancreatic cancer. To study its function, we developed two novel mouse strains for tissue-specific deletion, enabling precise manipulation and study of its role in the pancreas and other tissues. Our phenotypic analysis demonstrates that the ncRNA is activated following tissue injury and is essential for developing PanINs. Moreover, we show that it regulates cell-cell communication after tissue injury. This mechanism operates independently of cellular plasticity but significantly creates a pro-inflammatory environment that favors cancer development. Our results demonstrate that enhancer elements are actionable targets to regulate cell fate decisions in regeneration and cancer. Additionally, KRAS-induced cancer initiation depends on developmental regulatory elements, opening the window to develop prophylactic interventions to delay tumor onset. Citation Format: Luis Arnes. Regulatory Elements of Pancreas Development License the Initiation of Pancreatic Ductal Adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr C059.

Metabolic reprogramming by mutant GNAS creates an actionable dependency in intraductal papillary mucinous neoplasms of the pancreas

BackgroundOncogenic ‘hotspot’ mutations of KRAS and GNAS are two major driver alterations in intraductal papillary mucinous neoplasms (IPMNs), which are bona fide precursors to pancreatic ductal adenocarcinoma. We previously reported...

361. PHOTODYNAMIC THERAPY IN THE TREATMENT OF ESOPHAGEAL MUCOSAL METAPLASIA IN CHILDREN

Abstract Background The urgency of the problem of gastroesophageal reflux disease (GERD) in pediatrics is due to the high prevalence of this pathology in children. The problem of GERD in childhood has become especially important, when a direct correlation between the duration of esophagitis and the development of Barrett's esophagus (BE) and, later, esophageal adenocarcinoma has been revealed. Photodynamic therapy (PDT) is used as one of the elements of complex treatment after antireflux surgeries for direct impact on metaplastic mucosa and restoration of normal esophageal lumen. Due to the increased detection of esophageal malignancies in adult patients, we aimed to investigate this method in the treatment of Barrett's esophagus in children. Methods There were 3 patients diagnosed with esophageal mucosal metaplasia in the thoracic surgery department. Intestinal esophageal metaplasia was detected and histologically confirmed in 1 patient, in 2 patients - gastric metaplasia of cardiac type. All patients were female. The average age of the patients was 15 years. Children underwent multiple sessions of balloon dilatation of esophageal stenosis with temporary positive effect. Taking into account persistent restenosis, presence of metaplasia areas we applied PDT. Intravenous injection of photosensitizer (PS) of chlorine series for 30 minutes was carried out 5 hours before the beginning of PDT. For PDT we used a laser unit with a wavelength of 662 nm, power of 1 W with exposure of 25-30 minutes (at the rate of 300 J/cm2), optical power meter, video gastroscope, spectroanalyzer. Results To achieve the result: complete destruction of metaplasia sites and recanalization of the esophageal lumen, 1 patient with intestinal metaplasia needed 3 sessions, 2 patients with gastric metaplasia of cardiac type - 4 sessions of PDT. In children with gastric metaplasia, an "initiation" method was developed and applied at first PDT session to induce inflammation in the esophageal mucosa. During PDT macroscopic changes of mucosa in the metaplasia area were registered: ischemia, edema and hyperemia, hemorrhagic manifestations, "parchment" mucosa. We were also focused on the amount of PS in tissues according to the graphic images of the spectroanalyzer. During control examinations we noted healing of the metaplasia zone with subsequent regeneration of the epithelium, which was confirmed histologically, and preservation of the normal esophageal lumen. Conclusion Thus, there is a possibility of effective use of photodynamic therapy for esophageal mucosal metaplasia in children and adolescents. Taking into account the minimally invasive technique, comparative cheapness of photosensitizers, equipment for generation of laser radiation, registration of photosensitizer concentration in tissues, it is possible to create the basis for conducting studies in the treatment of this pathology in children. The method of photodynamic therapy in Barrett's esophagus demonstrates high efficiency in its eradication. Increasing the number of observations will allow to make more meaningful conclusions in the future. Eradication of Barrett's esophagus in children meets the requirements of cancer vigilance.

Helicobacter Pylori and Metaplastic Changes in Chronic Cholecystitis: A Correlation Study

Abstract Introduction: Various types of metaplastic changes, such as gastric metaplasia (foveolar type or antral type) and intestinal metaplasia, are observed in chronic cholecystitis but not in normal mucosa. Helicobacter species can be detected in the bile and gallbladder tissue of patients with benign gallbladder disease. Objective: The present study aimed to observe the correlation between chronic cholecystitis and the presence of Helicobacter pylori as well as the different types of metaplastic changes in gallbladder mucosa. Materials and Methods: This descriptive, observational study was conducted at the Departments of Pathology and Surgery at a tertiary care medical college and hospital from April 2021 to March 2022, using a cross-sectional design. All confirmed cases of chronic cholecystitis, with or without cholelithiasis, were included in the study. Results: Intestinal metaplasia was the most common type of metaplastic change in the gallbladder epithelium in chronic cholecystitis in this region. PAS and Alcian Blue positivity were significantly higher in cases with metaplasia compared to those without metaplasia. H. pylori was detected in 3 cases (1.55%) of chronic cholecystitis in this study population. Conclusion: Mucin histochemistry may help identify early metaplastic changes in gallbladder epithelium. The use of a combination of methods for the detection of H. pylori in gallbladder tissue may increase the detection of positive cases.

An Update on Eradication of Helicobacter Pylori in Iran: A Review.

Helicobacter pylori, the most prevalent infection in the world, has great importance due to being related to peptic ulcer disease, gastric metaplasia, dysplasia, and even gastric adenocarcinoma or mucosa-associated lymphoid tissue (MALT) lymphoma. The standard H. pylori eradication regimen is based on antibiotic susceptibility testing. If susceptibility testing is not available, a standard treatment regimen will be recommended based on records of H. pylori resistance rates to antibiotics in a region or locally proven highly effective regimens (equal to or higher than 90% eradication rate). The aim of this review was to define suitable recommendations for local treatment in different cities of Iran. This review article consists of randomized controlled trials related to H. pylori eradication in Iran. Data including the kind of therapy, number of patients and per-protocol H. pylori eradication rates were recorded in data gathering forms. Data search was conducted in PubMed and Google Scholar databases from 2018 to December 2023. According to our review of Iranian articles regarding first-line H. pylori eradication regimens, these treatment protocols could be recommended: Bismuth-clarithromycin quadruple therapy in Ardabil, bismuth-clarithromycin quadruple therapy with probiotics in Birjand, standard triple therapy in Ilam, bismuth quadruple therapy or bismuth triple therapy or concomitant regimen in Sari, sequential therapy in Tehran and bismuth quadruple therapy in Yazd. These regimes can be extended to other regions that have a similar situation. According to the reports of Iranian researchers, a quinolone-containing regimen (levofloxacin preferred) is recommended for second-line eradication therapy. Various H. pylori eradication regimens can be used as first-line therapy; however, choices for second-line therapy are limited. We recommend the quinolone-containing regimens as the preferred second-line therapy.

The role of gastric mucins and mucin-related glycans in gastric cancers.

Gastric mucins serve as a protective barrier on the stomach's surface, protecting from external stimuli including gastric acid and gut microbiota. Their composition typically changes in response to the metaplastic sequence triggered by Helicobacter pylori infection. This alteration in gastric mucins is also observed in cases of gastric cancer, although the precise connection between mucin expressions and gastric carcinogenesis remains uncertain. This review first introduces the relationship between mucin expressions and gastric metaplasia or cancer observed in humans and mice. Additionally, we discuss potential pathogenic mechanisms of how aberrant mucins and their glycans affect gastric carcinogenesis. Finally, we summarize challenges to target tumor-specific glycans by utilizing lectin-drug conjugates that can bind to specific glycans. Understanding the correlation and mechanism between these mucin expressions and gastric carcinogenesis could pave the way for new strategies in gastric cancer treatment.

A Rare Case of Signet Ring Cell Carcinoma Arising on Duodenal Brunner’s Gland Hyperplasia Successfully Treated Via Endoscopic Resection

Signet-ring cell carcinoma (SRCC) is a rare tumor that most commonly occurs in the stomach. Duodenal SRCCs are extremely uncommon and account for approximately 1% of duodenal adenocarcinomas. Although Brunner’s gland hyperplasia (BGH) is a benign duodenal condition, studies have reported several cases of adenocarcinoma originating in an area of BGH. We report a rare case of early-stage SRCC originating in an area of BGH that was successfully treated using endoscopic mucosal resection. Based on the mucin phenotype observed in this case, it is reasonable to conclude that SRCC originated from gastric metaplasia in the area of BGH. Although BGH is a benign condition, careful evaluation is warranted for early detection of combined neoplasms.

Modifying the gastric tumor microenvironment with tadalafil: A transcriptomic analysis of immune signatures from underserved patients of southern Arizona.

e16104 Background: Gastric adenocarcinoma (GAC) is the fifth most common cancer worldwide with significant morbidity and mortality. Recently, southern Arizona has seen a concerning surge in incidence of GAC due to ineffective H. pylori screening and treatment. Moreover, peri-operative chemotherapy treatment in stage IB-III GAC represents an area of unmet need for new targets. Our center serves a catchment area that is 40% Hispanic and sees a high volume of GAC patients, making this our research focus. Our preclinical work in Helicobacter infected mice showed a subset of myeloid derived suppressor cells (MDSCs) expressing Schlafen4 (SLFN4) concurrently with gastric metaplasia, a GAC precursor. SLFN4+ MDSCs exhibit robust transcriptional signatures associated with type I interferon(IFN-I) inducible genes, coupled with T cell suppressor function. Pharmacological inhibition via phosphodiesterase (PDE) 5,6 inhibitor sildenafil resulted in the suppression of SLFN4, reversal of T cell suppression, and mitigation of metaplasia. This is the first clinical study aimed to characterize SLFN12L, the human ortholog of mouse SLFN4, and to analyze the neoplastic and immune signatures in GAC before and after PDE5 inhibition with tadalafil. Methods: Using single-cell RNA sequencing, we examined tissues from GAC patients enrolled in a "Window of Opportunity" study (NCT05709574). The patients receive tadalafil (20mg) for 14 days, followed by combined tadalafil and FLOT (5-fluorouracil, leucovorin, oxaliplatin, and docetaxel) for 8 weeks. Gastric tissue and blood samples were collected i) before treatment, ii) after 14 days of tadalafil, and iii) after 8 weeks of combined treatment. We have enrolled 3 Hispanic patients to date with ongoing enrollment. Results: Tumors exhibited responses as per radiologic and pathologic criteria. In contrast to SLFN4, primarily expressed in myeloid cells, SLFN12L was found in most CD14+T lymphocytes and natural killer cells. A prominently activated and expanded myeloid population expressing SLFN12L was identified in the gastric mucosa of GAC patients. These cells exhibited transcriptional signatures associated with IFN-I signaling and immunosuppressive activities, diminishing after tadalafil treatment. Within GAC tissue, a notable increase in exhausted T cells and regulatory T cells was observed, decreasing after tadalafil. Post-tadalafil testing showed tissue PDE5/6 inhibition and higher plasma cGMP. Effector T cells exhibited an upward trend following tadalafil, suggesting a reduction in tumor immunosuppression. Conclusions: Preliminary data of this ongoing study show that tadalafil treatment combined with FLOT, has the potential to decrease SLFN12L+ MDSC, to attenuate their immunosuppression, and potentially inhibit tumor progression. The trial is active and further analysis will be presented in due course.

Lower IFN-γ expression causes more severe gastric inflammation in BALB/c infected by Bali 03 Helicobacter pylori isolate that provided by low iron diet

Background: Helicobacter pylori (H. pylori) infection is associated with various gastrointestinal diseases including gastritis, peptic ulcers, gastric carcinoma, and gastric mucosa-associated lymphoid-tissue lymphoma (MALT) lymphoma. Several studies have shown that H. pylori plays a role in iron deficiency that is refractory to iron administration. This study aims to analyze whether the lower IFN-γ expression causes more severe gastric inflammation in BALB/c infected by Bali 03 H. pylori isolate that is provided by a low iron diet. Methods: This research was an experimental study by inoculating the bacterial isolate H. pylori Bali 03 in two groups of BALB/c mice. The treatment group was given a low iron diet at a dose of <3 mg/kgBW of mice, while the control group was given a normal dose of iron diet at a dose of 40 mg/kgBW of mice. The cellular immune response of the two groups of BALB/c mice was measured by comparing the expression of IFN-γ, granzyme B, IFN-γ/IL-10 ratio to the degree of gastric inflammation. Results: The results of the research were that the H. pylori Bali 03 isolate caused inflammation in 36 (100%) gastric of the mice. The degree of gastric inflammation of mice was more severe in the treatment group than in the control group, within 6 weeks precancerous lesions occurred, namely gastric gland atrophy and metaplasia in the treatment group, 1 (2.7%). There is a significant difference between the control group and the treatment group (p=0.019). There was a significant difference in IFN-γ expression between the treatment group and the control group (p=0.034). Conclusion: Iron deficiency affects the degree of gastric inflammation through IFN-γ expression in BALB/c infected with H. pylori isolate Bali 03. Iron deficiency worsens the degree of gastric inflammation in BALB/c mice infected with H. pylori isolate Bali 03.

Heterogeneity of Monocarboxylate Transporter Function in Gastrointestinal Epithelium

Short-chain fatty acids and ketone bodies are important energy fuels of GI epithelial cells. Slc16a family encodes proton-coupled monocarboxylate transporters (MCTs) that mediate cellular metabolism of those energy fuels. Increasing evidence demonstrates that adenocarcinomas with overexpression of MCTs are better able to maintain microenvironmental pH and high energy metabolism to grow. However, the precise distribution and function of each MCT subtype in normal epithelial or precancerous cell lineages are mostly unknown. We investigated cell type-specific expressions of MCT subtypes MCT1, MCT2, and MCT4 by immunofluorescence in normal and gastric metaplasia model mice. As total MCT knockout leads to early lethality, we generated inducible, intestine-targeted knockout mouse models for MCT1 and MCT4, respectively. In normal GI tissues, MCT1 was strongly expressed on basolateral membranes of gastric surface cells and enterocytes, with intense staining of proliferating cells and enteroendocrine cells. No staining was observed in Brunner’s glands or Paneth cells. The low affnity subtype, MCT4 expression was localized to the first corpus glands and tuft cells in the stomach, suggesting that these cells may monitor the luminal chemical environment. Intestinal MCT4 was localized on basolateral membranes of mature enterocytes and tuft cells. In contrast, MCT2, which has the highest affnity for lactate, was localized reciprocally to MCT1. Strong MCT2 staining was identified on the basolateral membrane of secretory cells, including gastric parietal and chief cells, Brunner’s glands, and Paneth cells. The distinct MCT2 expression suggests that those secretory cells possess different energy metabolism and MCT2 may contribute to their intracellular pH homeostasis. In gastric metaplasia tissues of Mist1-Kras(G12D) mice, MCT1+ metaplastic cells were increased, and Ki67+ cells were more dependent on MCT1 than normal tissues. MCT2 expression in chief cells was disappeared during metaplasia development. MCT1ΔIEC mice lost MCT1 expression on day 8 after tamoxifen injection and decreased transcriptions of other subtypes, Mct4, Mct7, and Mct10 in intestinal mucosa. MCT1ΔIEC jejunum showed significant increase in crypt length, indicating that MCT1 loss disrupted proliferative cell function. Contrary, MCT4ΔIEC mice had no change in crypt length or Mct1 expression, but increased Mct7, and Mct10. These observations indicate that different cell types require a different MCT subtype. The increase in MCT1-dependency in proliferative metaplastic glands is consistent with the predicted effect of MCT1 inhibitors for cancer treatment. Alterations in MCT subtype expression might be a marker for early diagnosis of metaplastic cells. R37 CA244970 and R01 CA272687 to EC, VDDRC P30-058404 and VICC GI SPORE P50-CA236733 to IK. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Is there any difference between Eastern and Western clinical practice guidelines in management of gastric cancer?

Gastric cancer (GC) has been known as one of the most common causes of cancer mortality both in Western and Eastern countries. However, there might be differences between how it is managed in different countries. Thus, we aimed to investigate these differences. The most well-known clinical guidelines in field of GC management including Korean GC Association (KGCA), Japanese GC Association (JGCA), National Comprehensive Cancer Network (NCCN), European Society for Medical Oncology (ESMO), British Society of Gastroenterology (BSG), and National Institute for health and Care Excellence (NICE) have been reviewed. The contents of these guidelines were categorized under eight headings including (1) genetic predisposition, (2) prevention, (3) management of gastric polyp, atrophy, dysplasia and metaplasia, (4) diagnosis, (5) pathology and molecular biology, (6) treatment, (7) supportive and palliative care, and (8) follow up. Difference in each section was discussed. Considering KGCA and JGCA as Eastern and NCCN, ESMO, BSG, and NICE as Western guidelines, it is revealed that both sets of guidelines share common practices such as prioritizing comprehensive diagnostic evaluations, personalizing treatment plans, and palliative care. However, main differences can be seen in treatment regimens, the adoption of newer therapies like immunotherapy, and the utilization of emerging techniques such as HIPEC. These differences reflect the diverse clinical landscapes, research focuses, and healthcare systems within these regions.

Comparison of gastric inflammation and metaplasia induced by Helicobacter pylori or Helicobacter felis colonization in mice.

Mouse infection models with Helicobacter species are widely used to study Helicobacter pathogenesis and gastric cancer initiation. However, Helicobacter pylori is not a natural mouse pathogen, and mouse-adapted H. pylori strains are poorly immunogenic. In contrast, Helicobacter felis is a natural mouse pathogen that induces robust gastric inflammation and is often used in mice to investigate gastric cancer initiation. Although both bacterial strains are widely used, their disease pathogenesis in mice differs dramatically. However, few studies have directly compared the pathogenesis of these bacterial species in mice, and the contrasting features of these two models are not clearly defined. This study directly compares the gastric inflammation, atrophy, and metaplasia development triggered by the widely used PMSS1 H. pylori and CS1 H. felis strains in mice. It serves as a useful resource for researchers to select the experimental model best suited for their studies.

Understanding the malignant potential of gastric metaplasia of the oesophagus and its relevance to Barrett’s oesophagus surveillance: individual-level data analysis

ObjectiveWhether gastric metaplasia (GM) of the oesophagus should be considered as Barrett’s oesophagus (BO) is controversial. Given concern intestinal metaplasia (IM) may be missed due to sampling, the UK guidelines...

Abstract 4776: The role of angiogenesis in gastric tumorigenesis

Abstract Introduction: Gastric or stomach cancer remains one of the most lethal malignancies, with an estimated 1,089,103 new cases and 768,793 deaths worldwide in 2020. In the United States, it is estimated that there were 26,500 new cases and 11,130 deaths from stomach cancer in 2023. Unfortunately, despite improved treatment in recent years, ~65% of gastric cancer patients present with aggressive metastatic disease, and they die within one year of diagnosis. Therefore, the identification of newer and effective therapies to target the precancerous stages of the disease promises possibilities for the prevention of gastric cancer in patients harboring these lesions. Gastric metaplasia and dysplasia are precancerous lesions that often progress to gastric cancer. Since anti-VEGF-A anti-angiogenic agents have shown efficacy in advanced gastric cancer patients, we hypothesized that VEGF-A-mediated angiogenesis has a functional role in the pathogenesis of gastric metaplasia and dysplasia. Experimental Procedures: The Initial experiments were undertaken in human gastric metaplasia and dysplasia tissues and murine gastric metaplasia and dysplasia tissues collected from a well-established Helicobacter felis (H. felis) induced murine model of gastric tumorigenesis simulating human patients to detect angiogenesis (CD31/MVD) and identify angiogenic pathways using GeoMx DSP Spatial Proteomics and NanoString nCounter assay. Thereafter, further experiments were undertaken in the H. felis-induced murine model of gastric metaplasia and dysplasia, simulating human patients using VEGF-A hypo mice to determine the role of VEGF-A-induced angiogenesis in the progression of these lesions. Results and Conclusion: Although our results indicated angiogenesis and VEGF-A expression in both human and mouse gastric metaplasia and dysplasia, inhibition in the progression of the precancerous gastric lesions was observed in only 40% of the VEGF-A hypo mice, thereby suggesting that VEGF-A induced angiogenesis might not be the major angiogenic pathway in these precancerous lesions in every patient. A similar phenomenon is also seen in some gastric cancer patients. Citation Format: Venu Akkanapally, SUJIT BASU. The role of angiogenesis in gastric tumorigenesis [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 4776.

Does Portal Hypertension Increase the Risk of Helicobacter pylori Infection and Pre-Malignant Gastric Lesions?

Background and Aims: The presence of portal hypertension in cirrhotic patients is a major prognostic factor associated with the development of severe complications and increased mortality. The gold standard for diagnosing portal hypertension is the hepatic venous pressure gradient. More recently, spleen stiffness has emerged as a new and non-invasive diagnostic tool, and has already been included in the last Baveno VII guidelines. The exact prevalence of Helicobacter pylori infection, pre-malignant lesions and their relation to portal hypertension have never been described. The aim of our study was to evaluate the relationship between the presence of portal hypertension assessed via liver and spleen elastography and Helicobacter pylori infection and pre-malignant gastric lesions. Methods: An observational study was conducted, including consecutive patients admitted from December 2020 to December 2022. All patients underwent upper endoscopy and were also subjected to liver and spleen elastography (using the new probe of 100 Hz) by the same blinded operator in a tertiary center. Results: We included 155 cirrhotic patients, with a mean age of 64.1 years (±8.8), and 81.3% were male. The most common etiology was alcoholic liver disease (72.9%). The median value of liver stiffness measurement was 24.4 kPa [3.1-75.0], and the spleen stiffness measurement was 49.1 kPa [12.8-100.0]. Akin to endoscopic findings, 50.3% presented esophageal varices, 5.2% gastric atrophy, 11.6% gastric metaplasia, and 32.9% portal hypertension gastropathy. Regarding histologic findings, we found that 34.8% presented H. pylori infection, 35.5% gastric atrophy (OLGA 1-58.2%) and 38.7% gastric metaplasia (OLGIM 1-63.3%). Liver stiffness and spleen stiffness measurements were associated with the presence of portal hypertensive gastropathy (p < 0.01), but not with H. pylori infection or pre-malignant gastric lesions. Conclusions: Although present in almost one third of cirrhotic patients, H. pylori infection and pre-malignant gastric lesions are not associated with liver stiffness and spleen stiffness measurements. On the other hand, we found an association between liver stiffness and spleen stiffness measurements and portal hypertensive gastropathy.

Helicobacter pylori vacA affects the expression of COX-2 in the duodenal mucosa of patients with duodenitis.

Duodenitis refers to inflammation that occurs in the duodenum. Helicobacter pylori (Hp) is a known risk factor for duodenitis. This paper attempted to analyze the correlation between Hp virulence genotypes and the initiation and development of duodenal bulbar inflammation (DBI) to lay the foundation for the management of duodenitis induced by Hp infection. Total RNA was extracted from duodenal samples of 156 Hp-positive patients [70 with DBI and 86 with duodenal bulbar ulcer (DBU)] and 80 Hp-free DBI patients, followed by RT-qPCR detection of COX-2 mRNA expression and the presence of virulence factors. The cagA positive (62.2%), vacAs1 (21.79%), vacAm2 (23.72%), vacAs1m2 (19.87%) and iceA1 (55.80%) genotypes were dominant in 156 Hp-positive samples. Statistical difference was observed in vacAs and vacA mixtures between DBI and DBU patients. Gastric metaplasia had an association with vacA allelotypes, and its occurrence had strong correlations with vacAs1 and vacAs1m2 genotypes. The vacAs1 and vacAs1m2 genotypes were correlated with gastric metaplasia occurrence (all p<0.05). There were significant correlations between vacAs and vacA mixtures with cagA genotypes, and between iceA genotypes with vacA mixtures (all p<0.05). COX-2 was strongly expressed in Hp-infected duodenal mucosa and showed correlations with vacA genotype. COX-2 was differentially expressed in vacAs1- and vacAs2-positive patients. COX-2 was more highly upregulated in vacAs1m1- and vacAs1m2-positive patients than vacAs2m2-positive patients. Overall, Hp virulence genotype vacA was correlated with DBI and DBU initiation and development.

The Importance of Th2 Immune Responses in Mediating the Progression of Gastritis-Associated Metaplasia to Gastric Cancer

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.