Gastric Metaplasia Research Articles

Histological assessment of gastric pseudopyloric metaplasia: Intra- and inter-observer consistency

BackgroundThe histological spectrum of oxyntic mucosal atrophy (a major determinant of gastric cancer risk) includes pseudopyloric metaplasia (PPM), which histological assessment has been regarded as unreliable. PPM consistently expresses Trefoil-Factor 2 (TFF2), which is histochemically detecteble (TFF2-IHC). AimsIntra- and inter-observer consistency in assessing PPM was examined using both hematoxylin & eosin (H&E) and TFF2-IHC. Materials and methodsSeventy-four oxyntic biopsy samples obtained from autoimmune gastritis were considered. Two serial histological sections obtained from the paraffin-embedded tissue-samples were stained with H&E and TFF2-IHC. Three pathologists (Alpha, Beta, Gamma) independently scored PPM by both staining and the Intra- and inter-observer consistency (H&E versus TFF2-IHC) was calculated using k-statistics and/or Spearman's coefficient. ResultsBased on H&E-stain versus TFF2-IHC, intra-observer consistency in PPM assessement was ranked as consistently “good” (k-values: Alpha=0.79; Beta=0.78; Gamma=0.75). Based on H&E, the overall PPM inter-observer consistency among the 3 observers was ranked as “good” (k=0.77) (the inter-observer consistency for pairs of observers was as follows: Alpha versus Beta k=0.88; Alpha versus Gamma k=0.87; Beta versus Gamma k=0.80). Based on TFF2-IHC, the overall PPM inter-observer agreement was ranked as “excellent” (k=0.91) (the inter-observer consistency for pairs of observers was as follows: Alpha versus Beta k=1; Alpha versus Gamma k=0.91; Beta versus Gamma k=0.91). ConclusionRelying on either H&E staining or TFF2-IHC, pathologists assess PPM consistently.

Gastroesophageal reflux disease in pediatric esophageal atresia: Assessment of clinical symptoms and pH-impedance data.

BACKGROUNDEsophageal atresia (EA) is the most common congenital anomaly of the gastrointestinal tract. Gastroesophageal reflux disease (GERD) is a frequent and lifelong problem in these patients. GERD can be asymptomatic and the incidence of esophageal gastric and intestinal metaplasia (Barrett’s esophagus) is increased in adults with EA compared with the general population. Timely and accurate diagnosis of GERD is important to reduce long-term problems and this may be achieved by pH-impedance testing.AIMTo assess symptoms and pH-impedance data in children after EA, in order to identify their specific features of GERD.METHODSThis study was conducted from November 2017 to February 2020 and involved 37 children who had undergone EA via open surgical repair (51.35% boys, 48.65% girls; age range: 1-14 years, median: 4.99 years). GERD diagnosis was made based on multichannel intraluminal impedance/pH study and two groups were established: EA without GERD, n = 17; EA with GERD, n = 20. A control group was established with 66 children with proven GERD (68.18% boys, 31.82% girls; median age: 7.21 years), composed of a nonerosive reflux disease (referred to as NERD) group (n = 41) and a reflux esophagitis group (n = 25). Upper gastrointestinal endoscopy with a mucosal esophageal biopsy was performed on all patients.RESULTSThe most frequently observed symptom in EA patients with GERD and without GERD was cough (70% and 76.5% respectively). The number of patients with positive symptom association probability in the EA groups was significantly larger in the EA without GERD group (P = 0.03). In the control reflux esophagitis group, prevalence of gastrointestinal symptoms was significantly higher than in the NERD group (P = 0.017). For both EA groups, there was strong correlation with index of proximal events (IPE) and total proximal events (EA with GERD: 0.96, P < 0.001; EA without GERD: 0.97, P < 0.001) but level of IPE was significantly lower than in GERD patients without any surgical treatment (P < 0.001). Data on distal mean nocturnal baseline impedance were significantly different between the EA with GERD group (P < 0.001) and the two control groups but not between EA without GERD and the two control groups.CONCLUSIONMean nocturnal baseline impedance may have diagnostic value for GERD in EA children after open surgical repair. IPE might be an additional parameter of pH-impedance monitoring.

Single-Cell Transcriptional Analyses Identify Lineage-Specific Epithelial Responses to Inflammation and Metaplastic Development in the Gastric Corpus

Chronic atrophic gastritis can lead to gastric metaplasia and increase risk of gastric adenocarcinoma. Metaplasia is a precancerous lesion associated with an increased risk for carcinogenesis, but the mechanism(s) by which inflammation induces metaplasia are poorly understood. We investigated transcriptional programs in mucous neck cells and chief cells as they progress to metaplasia mice with chronic gastritis. We analyzed previously generated single-cell RNA-sequencing (scRNA-seq) data of gastric corpus epithelium to define transcriptomes of individual epithelial cells from healthy BALB/c mice (controls) and TxA23 mice, which have chronically inflamed stomachs with metaplasia. Chronic gastritis was induced in B6 mice by Helicobacter pylori infection. Gastric tissues from mice and human patients were analyzed by immunofluorescence to verify findings at the protein level. Pseudotime trajectory analysis of scRNA-seq data was used to predict differentiation of normal gastric epithelium to metaplastic epithelium in chronically inflamed stomachs. Analyses of gastric epithelial transcriptomes revealed that gastrokine 3 (Gkn3) mRNA is a specific marker of mouse gastric corpus metaplasia (spasmolytic polypeptide expressing metaplasia, SPEM). Gkn3 mRNA was undetectable in healthy gastric corpus; its expression in chronically inflamed stomachs (from TxA23 mice and mice with Helicobacter pylori infection) identified more metaplastic cells throughout the corpus than previously recognized. Staining of healthy and diseased human gastric tissue samples paralleled these results. Although mucous neck cells and chief cells from healthy stomachs each had distinct transcriptomes, in chronically inflamed stomachs, these cells had distinct transcription patterns that converged upon a pre-metaplastic pattern, which lacked the metaplasia-associated transcripts. Finally, pseudotime trajectory analysis confirmed the convergence of mucous neck cells and chief cells into a pre-metaplastic phenotype that ultimately progressed to metaplasia. In analyses of tissues from chronically inflamed stomachs of mice and humans, we expanded the definition of gastric metaplasia to include Gkn3 mRNA and GKN3-positive cells in the corpus, allowing a more accurate assessment of SPEM. Under conditions of chronic inflammation, chief cells and mucous neck cells are plastic and converge into a pre-metaplastic cell type that progresses to metaplasia.

The Association between Metaplasia and Gastric Malignancy with Helicobater pylori Infection

Background: Helicobacter pylori (H. pylori) infection is the main cause of peptic ulcer disease, gastric mucosa metaplasia, and gastric malignancy. The hypothesis of this study is whether there’s an association between metaplasia and gastric malignancy with H. pylori infection.Method: We conducted a retrospective study on 1.127 dyspepsia subjects who performed endoscopy between 2001 to 2011 at a hospital in North Jakarta. Data is obtained based on endoscopy and histopathology data. Investigation of H. pylori in this study using histopathology examination.Results: Of the 1.127 dyspepsia subjects who performed endoscopy and biopsy, there were 130 (11,54%) H. pylori-positive subjects. Gender proportion was composed of 55,37% men and 44,63% women, with median age was 47 years. On the histopathology examination, we obtained 45 metaplasia subjects with median age of 45 years and 7 malignancy subjects with median age of 64 years. Metaplasia was found in 33 of 997 (3,31%) H. pylori-negative subjects and 12 of 130 (9.23%) H. pylori-positive subjects. All gastric malignancy subjects had H. pylori-negative results.Conclusion: There was an association between metaplasia and H. pylori infection, but no association between gastric malignancy and H. pylori infection.

256-OR: Using Human Induced Pluripotent Stem Cell Derived Organoids to Identify New Pathologies in Patients with Pdx1 Mutations

Pancreas and gastrointestinal (GI) tract development is guided by several transcription factors, including pancreatic and duodenal homeobox gene-1 (PDX1). While it is well known that PDX1is essential for pancreatic development and beta cell function, its role in GI development and function is not fully understood. We identified a patient with a homozygous point mutation in PDX1 causing total loss of PDX1 protein resulting in pancreatic agenesis. We differentiated induced pluripotent stem cells from the patient into human antral gastric (HAGO) and intestinal (HIO) organoids as a novel diagnostic approach to identify new GI pathologies. Immunofluorescence staining revealed that portions of the PDX1-null HAGOs lost the gastric marker claudin18 and increased intestinal villin1 expression, signifying that regions of the antrum are converting to an intestinal phenotype. Similarly, PDX1-null HIOs lost the intestinal marker cadherin17 and increased claudin18, indicating that regions of the intestine are undergoing gastric metaplasia. Examination of functional markers revealed an increase in acid producing parietal cells, complete lack of gastrin producing endocrine cells in HAGOs, and an increase in gastric surface mucin in HIOs. These in vitro results were further validated using endoscopy biopsies from two patients with PDX1 mutations, which showed a similar disruption in gastric and intestinal identity. CRISPR/Cas9-mediated correction of the PDX1 mutation reversed the observed PDX1-null metaplasic phenotypes in HAGOs and HIOs and also allowed for the successful generation of pancreatic tissue indicating unambiguously that the PDX1 mutation is responsible for these pathologies. Based on these findings, these PDX1-null patients will have additional screening to monitor the progression of metaplasia into gastric and intestinal cancer. This study further demonstrates the utility of organoids in improving patient diagnoses and treatment. Disclosure M. Krishnamurthy: None. T.R. Broda: None. D.O. Kechele: None. X. Zhang: None. J.J. Palermo: None. M.H. Collins: None. I.H. Thomas: None. A. Heider: None. A. Dauber: None. J. Wells: None. Funding American Diabetes Association (1-19-PDF-036 to M.K.)

McCune Albright Syndrome: Gastrointestinal Polyps and Platelet Dysfunction over 12 Years

Background and Objective: Gastrointestinal (GI) polyps with unknown malignant potential and a platelet storage pool deficiency that increases the risk of severe intraoperative and other types of bleeding have been identified in McCune-Albright syndrome (MAS). The natural course of these disorders has not been well characterized. The aim of this study was to report the follow-up of GI polyps and platelet dysfunction (PD) in a cohort of 28 patients with MAS. Methods: Twenty-eight patients with MAS (15 females) were included. Endoscopic screening for GI polyps was undertaken in 14 subjects and 19 were tested for PD. Results: Six subjects (5 males) were diagnosed with GI polyps at a median age of 23 (range 15–43) years, and were monitored for a median period of 8 (range 4.5–11.5) years. At endoscopic follow-up, the 4 patients with hamartomatous polyps at first endoscopy had either normal findings (n = 2), or duodenal gastric metaplasia (n = 2). Two patients with caecal polyps were identified. Of 8 subjects with a platelet storage pool deficiency, 5 required transfusions during surgery, and subsequent platelet cover in 2 markedly reduced intraoperative blood loss. Conclusions: New polyps with uncertain malignant potential are diagnosed after long term follow-up in MAS. Platelet cover reduces the need for red blood cell transfusion during orthopaedic surgery and may be useful to reduce non-operative bleeding events. We recommend regular upper and lower endoscopy and screening for PD in all MAS patients.

Influence of &lt;i&gt;Helicobacter pylori&lt;/i&gt; on cytokine regulation in chronic atrophic gastritis

At present, the level of Helicobacter pylori infection is determined by geographic area, gender and age of the examined individuals, and can reach up to 95% of the total population. Environmental adaptation of H. pylori is exhibited in its ability to adhere to the gastric mucosal epithelium and modulated expression of its own virulent factors. Current concepts implicate that H. pylori can survive inside epithelial cells, evading host immune response. Cytokines are produced by immune cells and act to regulate its major stages. A cytokine cascade launched after Helicobacter pylori infection triggers immune reactions, progression of chronic inflammatory and destructive processes in the gastric mucosa. The role of cytokines in precancerous diseases of the stomach is ambiguous because, on the one hand, they activate immune response aimed at eliminating the pathogen, whereas on the other hand, they do contribute to the disease progression. The aim of our study was to examine profile of some cytokines and features of cytokine regulation in H. pylori-infected middle-aged males with chronic gastritis (CG) as well as chronic atrophic gastritis (CAG). In patients with CG with H. pylori, CAG and CAG with H. pylori, an increase in the cytokine IL-2 was observed that might contribute to augmented damaging effect of cytotoxic lymphocytes, as well as implementation of antitumor effect. CAG with H. pylori was featured with IL-8 hyperproduction, which resulted in increased absolute numbers of band neutrophils in peripheral blood and their decreased phagocytic activity evidencing about altered host defense mechanisms. There was increased amount of IFNy involved in recognition of malignantly transformed cells and upregulated expression of the major histocompatibility complex molecules on antigen-presenting cells. In patients with CG with H. pylori and CAG with H. pylori, production of IL-4 was increased, which might serve as a contributing factor to the chronicity of H. pylori-associated diseases. Overproduction of type 1 and type 2 cytokines indicates about activated Th1 and Th2 type immune reactions in H. pylori-associat-ed CG. A potent pro-inflammatory cytokine cascade triggers inflammatory changes in gastric mucosa with developing neutrophil infiltration and lymphocyte activation. Damage and death of epithelial cells upon inflammation form erosive and ulcerative defects, or changes manifested as gastric mucosal atrophy, metaplasia and neoplasia. The data obtained may be used as additional diagnostic criteria in early diagnostics of precancerous stomach diseases.

Endometrial Gastric-type Carcinoma: An Aggressive and Morphologically Heterogenous New Histotype Arising From Gastric Metaplasia of the Endometrium.

Travaglino, Antonio MD*; Raffone, Antonio MD†; Gencarelli, Annarita MD*; Mollo, Antonio MD, PhD†; Zullo, Fulvio MD, PhD†; Insabato, Luigi MD, PhD* Author Information

GPR30-Expressing Gastric Chief Cells Do Not Dedifferentiate But Are Eliminated via PDK-Dependent Cell Competition During Development of Metaplasia

Gastric chief cells, a mature cell type that secretes digestive enzymes, have been proposed to be the origin of metaplasia and cancer through dedifferentiation or transdifferentiation. However, studies supporting this claim have had technical limitations, including issues with the specificity of chief cell markers and the toxicity of drugs used. We therefore sought to identify genes expressed specifically in chief cells and establish a model to trace these cells. We performed transcriptome analysis of Mist1-CreERT-traced cells, with or without chief cell depletion. Gpr30-rtTA mice were generated and crossed to TetO-Cre mice, and lineage tracing was performed after crosses to R26-TdTomato mice. Additional lineage tracing experiments were performed using Mist1-CreERT, Kitl-CreERT, Tff1-Cre, and Tff2-Cre mice crossed to reporter mice. Mice were given high-dose tamoxifen or DMP-777 or were infected with Helicobacter pylori to induce gastric metaplasia. We studied mice that expressed mutant forms of Ras in gastric cells, using TetO-KrasG12D, LSL-KrasG12D, and LSL-HrasG12V mice. We analyzed stomach tissues from GPR30-knockout mice. Mice were given dichloroacetate to inhibit pyruvate dehydrogenase kinase (PDK)-dependent cell competition. We identified GPR30, the G-protein-coupled form of the estrogen receptor, as a cell-specific marker of chief cells in gastric epithelium of mice. Gpr30-rtTA mice crossed to TetO-Cre;R26-TdTomato mice had specific expression of GPR30 in chief cells, with no expression noted in isthmus stem cells or lineage tracing of glands. Expression of mutant Kras in GPR30+ chief cells did not lead to the development of metaplasia or dysplasia but, instead, led to a reduction in labeled numbers of chief cells and a compensatory expansion of neck lineage, which was derived from upper Kitl+ clones. Administration of high-dose tamoxifen, DMP-777, or H pylori decreased the number of labeled chief cells. Chief cells were eliminated from epithelia via GPR30- and PDK-dependent cell competition after metaplastic stimuli, whereas loss of GRP30 or inhibition of PDK activity preserved chief cellnumbers and attenuated neck lineage cell expansion. In tracing studies of mice, we found that most chief cells are lost during metaplasia and therefore are unlikely to contribute to gastric carcinogenesis. Expansion of cells that coexpress neck and chief lineage markers, known as spasmolytic polypeptide-expressing metaplasia, does not occur via dedifferentiation from chief cells but, rather, through a compensatory response from neck progenitors to replace the eliminated chief cells.

Interleukin 27 Protects From Gastric Atrophy and Metaplasia During Chronic Autoimmune Gastritis.

Background & AimsThe association between chronic inflammation and gastric carcinogenesis is well established, but it is not clear how immune cells and cytokines regulate this process. We investigated the role of interleukin 27 (IL27) in the development of gastric atrophy, hyperplasia, and metaplasia (preneoplastic lesions associated with inflammation-induced gastric cancer) in mice with autoimmune gastritis.MethodsWe performed studies with TxA23 mice (control mice), which express a T-cell receptor against the H+/K+ adenosine triphosphatase α chain and develop autoimmune gastritis, and TxA23xEbi3-/- mice, which develop gastritis but do not express IL27. In some experiments, mice were given high-dose tamoxifen to induce parietal cell atrophy and spasmolytic polypeptide-expressing metaplasia (SPEM). Recombinant IL27 was administered to mice with mini osmotic pumps. Stomachs were collected and analyzed by histopathology and immunofluorescence; we used flow cytometry to measure IL27 and identify immune cells that secrete IL27 in the gastric mucosa. Single-cell RNA sequencing was performed on immune cells that infiltrated stomach tissues.ResultsWe identified IL27-secreting macrophages and dendritic cell in the corpus of mice with chronic gastritis (TxA23 mice). Mice deficient in IL27 developed more severe gastritis, atrophy, and SPEM than control mice. Administration of recombinant IL27 significantly reduced the severity of inflammation, atrophy, and SPEM in mice with gastritis. Single-cell RNA sequencing showed that IL27 acted almost exclusively on stomach-infiltrating CD4+ T cells to suppress expression of inflammatory genes.ConclusionsIn studies of mice with autoimmune gastritis, we found that IL27 is an inhibitor of gastritis and SPEM, suppressing CD4+ T-cell–mediated inflammation in the gastric mucosa.

Muc5ac null mice are predisposed to spontaneous gastric antro-pyloric hyperplasia and adenomas coupled with attenuated H.pylori-induced corpus mucous metaplasia

Gastric cancer (GC) is the third leading cause of cancer-related deaths worldwide and is strongly associated with chronic Helicobacter pylori (Hp) infection. The ability of Hp to closely adhere to the gastric surface protective mucous layer containing mucins (MUC in humans and Muc in animals), primarily Muc5ac, is integral in the stepwise pathogenesis from gastritis to cancer. To probe the role of Muc5ac in Hp-induced gastric pathology, Muc5ac−/− and Muc5ac+/+ (WT) mice were experimentally infected with Hp Sydney strain (SS1). At 16 weeks and 32 weeks post infection (wpi), groups of mice were euthanized and evaluated for the following: gastric histopathological parameters, immunohistochemical expression of mucins (Muc5ac, Muc1, Muc2), Trefoil factor family proteins (Tff1 and Tff2), Griffonia (Bandeiraea) simplicifolia lectin II (GSL II) (mucous metaplasia marker) and Clusterin (Spasmolytic Polypeptide Expressing Metaplasia (SPEM) marker), Hp colonization density by qPCR and gastric cytokine mRNA levels. Our results demonstrate that Muc5ac−/− mice developed spontaneous antro-pyloric proliferation, adenomas and in one case with neuroendocrine differentiation; these findings were independent of Hp infection along with strong expression levels of Tff1, Tff2 and Muc1. Hp-infected Muc5ac−/− mice had significantly lowered gastric corpus mucous metaplasia at 16 wpi and 32 wpi (P = 0.0057 and P = 0.0016, respectively), with a slight reduction in overall gastric corpus pathology. GSII-positive mucous neck cells were decreased in Hp-infected Muc5ac−/− mice compared to WT mice and clusterin positivity was noted within metaplastic glands in both genotypes following Hp infection. Additionally, Hp colonization densities were significantly higher in Muc5ac−/− mice compared to WT at 16 wpi in both sexes (P = 0.05) along with a significant reduction in gastric Tnfα (16 wpi—males and females, P = 0.017 and P = 0.036, respectively and 32 wpi—males only, P = 0.025) and Il-17a (16 wpi—males) (P = 0.025). Taken together, our findings suggest a protective role for MUC5AC/Muc5ac in maintaining gastric antral equilibrium and inhibiting Hp colonization and associated inflammatory pathology.

Non-invasive laboratory markers assessing efficacy of Helicobacter pylori eradication therapy

Effective eradication of Helicobacter pylori infection is an important means to reduce the risk of precancerous changes in the gastric mucosa and prevention of gastric cancer. A search for non-invasive diagnostic tools for Helicobacter pylori infection, evaluation of the effectiveness of eradication remains of high importance.The aim of the study was to assess an informative value of detecting pepsinogen I and II as well as serum antibodies to Helicobacter pylori while assessing an efficacy of treated chronic Helicobacter gastritis and identifying preneoplastic changes in the stomach mucosa. There enrolled 113 male patients with chronic gastritis aged 41 to 76, average age- (56.7±0.7) years. Examination of patients was carried out at admission to the clinic, as well as at 2 and 12 months after administering a standard eradication therapy. It was found that Helicobacter pylori infection was detected in 101 (89.4%) patients. Groups of patients with effective eradication therapy were noted. A time-dependent level of antibodies to Helicobacter pylori, as well as measured concentration of pepsinogen I and II after the onset of eradication treatment were determined. Which were analyzed in connection with the results of histology examination of gastric mucosa biopsy specimens and expression of oncoproteins Ki-67, Bcl-2, c-erbB-2, p16 in the gastric mucosa depending on efficacy of eradication therapy. It is shown that effective eradication therapy was characterized by significantly decreased serum level of IgG antibodies to Helicobacter pylori 2 months after the onset of treatment. Moreover, a significantly decreased pepsinogen II and serum IgG antibodies to Helicobacter pylori during eradication therapy were accompanied by a significant decrease in Ki-67 expression in the gastric epithelium. Decreased concentration of pepsinogen II within the first year after Helicobacter pylori eradication therapy was due to a greater decrease in activity of inflammatory changes in the gastric mucosa than to dynamic changes in gastric atrophy and metaplasia. An inverse relation between the serum level of pepsinogen I and atrophy as well as intestinal metaplasia within the gastric mucosa were found.

2587 Never Too Old for Meckel's: A Unique Presentation of an Uncommon Source of Gastrointestinal Bleeding in Adults

INTRODUCTION: Meckel's diverticulum is a common gastrointestinal congenital malformation, affecting approximately 2% of the population. Related complications such as bleeding commonly occurs in the pediatric age group; although, in adults it is often missed. We present a case of recurrent obscure-overt gastrointestinal (GI) bleeding secondary to a Meckel's diverticulum which remained elusive after multiple diagnostic studies. CASE DESCRIPTION/METHODS: 30-year-old male with history of recurrent GI bleeding, presents to the outpatient GI clinic for further evaluation after being admitted to the intensive care unit (ICU) 3 weeks prior with massive hematochezia requiring several blood transfusions for a drop-in hemoglobin from 14 gm/dL to &lt;7 gm/dL. The patient had undergone endoscopy, colonoscopy, and video capsule endoscopy (VCE) three years prior for similar symptoms without an identifiable source. A nuclear tagged red blood cell scan was performed showing bleeding in the proximal colon. CT angiography following showed contrast extravasation in the distal jejunum and ileum which was treated with gel foam. The patient had no further episodes of hematochezia and was discharged. After the clinic visit, the patient underwent a Meckel's scan which did not show ectopic gastric mucosa but revealed colonic bleeding proximal to the hepatic flexure. Ileocolonoscopy was normal. Subsequent VCE showed abnormal mucosa in the distal small bowel. He finally underwent a retrograde balloon enteroscopy which revealed a distal small bowel diverticulum with a single adjacent, nonbleeding ulcer (Figure 1). Biopsies of the ulcer showed gastric foveolar metaplasia. Based on the findings, he was referred for a small bowel resection which revealed a jejunal Meckel's diverticulum with gastric oxyntic heterotopia on histology (Figures 2 and 3). DISCUSSION: This case highlights the potential morbidity and possible mortality of Meckel's diverticulum as a source of lower GI bleeding. Recent studies have recommended against prophylactic surgical resection in the absence of certain risk factors including age less than 40, male gender, and macroscopic mucosal alteration. Given this patient's significant hematochezia, transfusion requirements, and gross peri-diverticular ulceration, we opted for small bowel resection. Meckel's diverticulum should always be included in the differential for occult or overt GI bleeding, especially in young patients when no other sources of bleeding are readily identifiable.

3101 Barrett's Esophagus With Metastatic Neuroendocrine Tumor

INTRODUCTION: Neuroendocrine tumors are a rare group of cancers that can occur in many different organs. Due to their rarity and variable presentation, they are not well understood. In contrast, Barrett's esophagus is a well-known condition frequently associated with the development of esophageal adenocarcinoma. A review of literature has shown only 8 cases demonstrating an association between neuroendocrine tumors and Barrett's esophagus. CASE DESCRIPTION/METHODS: A 73-year-old male presented to the hospital status post fall due to altered mental status. Relevant past medical history included GERD, Barrett's esophagus, and gastric adenocarcinoma which was treated with surgery and chemoradiation 6 years prior. Imaging of the head revealed metastatic lesions. Further investigation with a CT chest, abdomen, and pelvis showed metastatic lesions in the bilateral lung lobes and the left trochanter. Biopsies of the esophagus and stomach on esophagogastroduodenoscopy (EGD) showed Barrett's esophagus with no presence of gastric metaplasia. A biopsy of the trochanter was also performed. Pathology results were positive for synaptophysin, chromogranin, CK7, and CK20, at both sites of biopsy for the esophagus and trochanter. Ultimately, the patient was placed on hospice. DISCUSSION: Neuroendocrine carcinomas of the esophagus are rare, accounting for 0.4-5.9% of all esophageal carcinomas. The rarity of neuroendocrine tumors and their ability to manifest in many different organs often makes diagnosis difficult. As with this patient, the origin of metastatic disease was initially unclear due to the multiple sites involved. Synaptophysin and chromogranin are specific to neuroendocrine tumors which were found in both the esophagus and trochanter. CK7 and CK20 are markers usually found in gastrointestinal mucosa, suggesting that the esophagus was the primary site of cancer. Furthermore, biopsies of the esophagus and stomach were positive for Barrett's esophagus and negative for metaplasia of the stomach, indicating that these metastatic lesions were not from a recurrence of the patient's prior gastric cancer. Further research is needed to determine if these findings are coincidental or if there is a true association between Barrett's esophagus and neuroendocrine tumors.

Autoimmune gastritis: problems of diagnosis and therapy

Chronic gastritis (CG) is one of the most widespread internal diseases, which affects up to 20 % of the adult population. The modern CG paradigm considers disease as a launchpad for the formation of stomach cancer, as well as erosive and ulcerative lesions, including those induced by anti-inflammatory drugs’ intake. The widespread symptoms of gastric dyspepsia often lead to the CG overdiagnosis, while verification of the diagnosis should be based on clinical endoscopic and pathomorphological criteria. In recent years, a large body of scientific data has been presented on the role of different types of microorganisms, including H. Pylori bacteria, of the duodenogastric reflux, medications’ intake in the CG development and progression. However, the autoimmune form of this disease is poorly understood. It is well known that autoimmune gastritis (AIG) is the most important factor in the development of pernicious anemia, and hypochlorhydria leads to iron deficiency anemia. At the same time, the role of AIG in the formation of gastric atrophy and metaplasia is not well understood. A question of gastro-carcinogenic potential of AIG remains open. Diagnosis of AIG requires the determination of not only clinical endoscopic, histopathological parameters, but also a comprehensive analysis of serological data. From the standpoint of modern classifications: Kyoto consensus and the OLGA/OLGIM CG system, it is of interest to correlate between serological and pathological markers in patients with AIG. The treatment of AIG is not specific and does not fundamentally differ from the treatment of other forms of CG. However, given the pathogenetic features of AIG, the development of methods for the correction of immunopathological processes that characterize this disease is promising. AIG treatment is aimed of the infection eradication, restoration of the motor-evacuation function of the gastroduodenal zone, neutralizing the damaging effects of bile acids, but gastroprotection is a strategic direction in the treatment of the disease. In particular, the use of drugs based on bismuth salts promotes restoration of the structural and functional state of the gastric mucosa, inhibits the progression of AIG, as well as promotes regression of atrophy and intestinal metaplasia.

Prevalence of barrett's esophagus, its relationship with chronic Helicobacter pylori-associated gastritis, atrophy and metaplasia of gastric mucosa

The aim - to identify the frequency of Helicobacter pylori infection, atrophic and metaplastic changes in the gastric mucosa in patients with Barrett's esophagus.&#x0D; Materials and methods. A retrospective study of 7392 cases of complex esophagogastroscopy with a biopsy of the epithelium of the mucous membrane of the esophagus and stomach, followed by a morphological study, was conducted on the basis of the Medical Centre “Oberig” clinic for the period 2010-2018. Statistical data was performed using the MedStat package. To assess the prevalence of changes in the esophagus and stomach, a 95% confidence interval was calculated using the Fisher angular transformation method. The probability of differences between group averages and relative values ​​was determined using the method of parametric statistics by calculating the t-Student criterion. The difference between the average values ​​was considered significant at p &lt;0.05. To compare the frequencies in different groups, the Pearson chi-square test was used.&#x0D; Results. Endoscopically cylindrical columnar metaplasia of the esophagus epithelium was detected in 2994 patients (40.5% CI 39.4% -41.6% at a significance level of p = 0.05). In a histological examination, esophageal epithelial metaplasia was confirmed in 2910 patients (39.4% CI 38.3%-40.5%). 876 cases of gastric-type esophagus epithelial metaplasia were diagnosed (30.1%, CI 28.4-31.5%); 2034 cases of intestinal type metaplasia (69.9%, CI 68.2-71.6%). Histological examination of biopsy samples of the gastric mucosa in 5640 (76.3%, CI 75.3-77.3%) patients revealed atrophy of the gastric mucosa. In 2532 cases (34.3%, CI 33.2-35.3%), complete and incomplete intestinal metaplasia of the gastric epithelium was diagnosed. In 4524 (61.2%, CI 60.1-62.3%) patients, Helicobacter pylori was detected. In the presence of H. pylori, gastric esophageal epithelial metaplasia was detected in 510 of 3558 (14.3%, CI 13.2-15.5%, p = 0.05), intestinal metaplasia of the esophagus epithelium - in 966 of 4014 (24.1% CI 22.8 -25.4%, p = 0.05).&#x0D; Conclusion. Esophageal epithelial metaplasia is a common pathology, accounting for 39.4% among patients who underwent esophagogastroscopy. The presence of a strong connection between intestinal metaplasia of the epithelium of the esophagus and atrophy of the gastric mucosa with intestinal metaplasia of the epithelium of the stomach was found. Esophageal epithelial metaplasia is significantly less common with Helicobacter pylori gastritis, therefore the presence of H. pylori has a protective effect on the occurrence of esophageal epithelial metaplasia.

Downregulation of Notch Signaling in Kras-Induced Gastric Metaplasia

Activating mutations and amplification of Kras and, more frequently, signatures for Kras activation are noted in stomach cancer. Expression of mutant KrasG12D in the mouse gastric mucosa has been shown to induce hyperplasia and metaplasia. However, the mechanisms by which Kras activation leads to gastric metaplasia are not fully understood. Here we report that KrasLSL-G12D/+;Pdx1-cre, a mouse model known for pancreatic cancer, also mediates KrasG12D expression in the stomach, causing gastric hyperplasia and metaplasia prior to the pathologic changes in the pancreas. These mice exhibit ectopic cell proliferation at the base of gastric glands, whereas wild-type mice contain proliferating cells primarily at the isthmus/neck of the gastric glands. Notch signaling is decreased in the KrasLSL-G12D/+;Pdx1-cre gastric mucosa, as shown by lower levels of cleaved Notch intracellular domains and downregulation of Notch downstream target genes. Expression of a Notch ligand Jagged1 is downregulated at the base of the mutant gland, accompanied by loss of chief cell marker Mist1. We demonstrate that exogenous Jagged1 or overexpression of Notch intracellular domain stimulates Mist1 expression in gastric cancer cell lines, suggesting positive regulation of Mist1 by Notch signaling. Finally, deletion of Jagged1 or Notch3 in KrasLSL-G12D/+;Pdx1-cre mice promoted development of squamous cell carcinoma in the forestomach, albeit short of invasive adenocarcinoma in the glandular stomach. Taken together, these results reveal downregulation of Notch signaling and Mist1 expression during the initiation of Kras-driven gastric tumorigenesis and suggest a tumor-suppressive role for Notch in this context.

Prevalence of Helicobacter pylori infection rate in heterotopic gastric mucosa in histological analysis of duodenal specimens from patients with duodenal ulcer.

Heterotopic gastric mucosa in the duodenal bulb is a rare congenital disorder with varied clinical presentations. The mechanism of formation of a duodenal ulcer is failure of balance of the attack factor and the defense factor, which is the same as the mechanism of formation of a gastric ulcer. However, the true etiology of the duodenal ulcer remains unknown. Gastric mucosa can secrete gastric juice which injures itself, but the duodenal mucosa does not contain cells secreting a digestive enzyme. We assume that duodenal ulcers are caused by the presence of heterotopic gastric mucosa that can secrete gastric acid. This study was designed to assess the prevalence and associations of heterotopic gastric mucosa in duodenal ulcers. The present study included 137 patients who underwent biopsy or resection of duodenal ulcer. We detected gastric foveolar metaplasia due to inflammation from a heterotopic gastric mucosa using immunohistochemical staining. Heterotopic gastric mucosa consists of foveolar epithelium (MUC5AC-positive) and fundic gland (H⁺K⁺ ATPase-positive parietal cells, pepsinogen I-positive chief cells and MUC6-positive mucous neck cells), whereas gastric metaplasia is composed of foveolar epithelium without fundic glands. These specimens were stained with toluidine blue for detection of Helicobacter pylori infection. Among the 137 patients with duodenal ulcer, 76 cases (55%) had heterotopic gastric mucosa in the obtained specimens, and Helicobacter pylori was found in 45 cases (59%,45/76) among those with heterotopic gastric mucosa. Our results suggest that heterotopic gastric mucosa was strongly associated with concurrent duodenal ulcer.

DOZ047.31: Screening and surveillance in adults after esophageal atresia repair: yield of follow-up endoscopies

Abstract Aim of the Study Because of the high prevalence of Barrett's esophagus (BE) and esophageal carcinoma, it is internationally recommended to perform routine endoscopies in adult esophageal atresia (EA) patients. This study aimed to evaluate the yield of follow-up after the first screening endoscopy. Methods Prospective cohort study in a tertiary referral center since November 2011 was considered. All patients with EA ≥ 17 years old were invited to participate in the screenings and surveillance program. All patients underwent upper endoscopies with random biopsies of the distal esophagus at the level of the gastroesophageal junction and standard four-quadrant biopsies in case of BE. From the age of 25 years old chromoendoscopy with Lugol's staining was performed for detection of superficial squamous cell carcinoma. Depending on their age and the histologic results patients were recommended follow-up endoscopy every 3–5 years. Ethical approval had been obtained. Results In February 2019, 190 patients (58% male, 83% type C, median age at time of first endoscopy 25.5) (range: 16.8–68.6 years) participated in the screenings and surveillance program. Forty-six patients underwent at least one follow-up endoscopy after median 4.7 (range: 1.0–5.9) years. Most recent surveillance endoscopy revealed a normal esophagus in 62%, esophagitis in 10%, and columnar-lined esophagus in 26% of the patients. Histology revealed inflammatory changes within normal limits in 49%, esophagitis in 22%, gastric metaplasia in 18%, and intestinal metaplasia without dysplasia in 6%. In 8 patients (6 males, median age: 25.9 (range: 22.5–34.4)) columnar-lined mucosa was a new finding at the second endoscopy, after median 5.0 (range: 3.6–5.9) years. In two of them histology revealed intestinal metaplasia without dysplasia. Conclusions In line with previous studies, we found a 4-times increased prevalence (6.3%) of BE in adults with EA. Follow-up endoscopies detected two new cases of BE. Future studies are needed to identify patients at risk and personalize screening and surveillance regimes.

330-LB: Using Human Induced Pluripotent Stem Cell-Derived Organoids to Identify New Pathologies in Patients with PDX1 Mutations

Pancreas and gastrointestinal (GI) tract development is guided by several transcription factors, including Pancreatic and duodenal homeobox gene-1 (PDX1). While it is well known that PDX1 is essential for pancreas development, its role in GI development and function in humans has not been investigated. We have identified two patients with a homozygous point mutation in PDX1 (c.188delC(p.P63fs)), causing total loss of protein function. These patients have additional GI complications however endoscopy and histological analysis of gastric and ?intestinal biopsies did not? reveal any pathologies. We used patient derived GI organoids from induced pluripotent stem cells (iPSCs) as a novel diagnostic approach and identified a myriad of undiagnosed GI pathologies. Analyses of human antral gastric organoids (HAGO) using immunofluorescence staining demonstrated a loss of gastric marker? claudin18 (CLDN18) and increased intestinal villin expression in PDX1-null? organoids, signifying that regions of the antrum are converting to an intestinal?phenotype. Similarly, human intestinal organoids (HIO) demonstrated a loss of intestinal marker ?Cadherin17 and an increase in gastric marker? CLDN18, indicating that regions of the intestine are undergoing gastric metaplasia. We also observed an increase in parietal cells in HAGOs, a lack of gastrin hormone in HAGO, and an increase in mucin production in HIOs. Based on this data we re-analyzed antral and duodenal biopsies of both patients and confirmed gastric and intestinal metaplasia increased parietal cells, decreased gastrin and increased mucin production. Because of our findings, these patients will have additional screening to monitor for development of gastric and intestinal cancer. This clearly demonstrates the utility of organoids in improving patient diagnoses and developing new clinical treatment plans. Disclosure M. Krishnamurthy: None. T.R. Broda: None. X. Zhang: None. J.J. Palermo: None. I.H. Thomas: None. A. Heider: None. D.B. Steien: None. A. Dauber: Consultant; Self; Novo Nordisk Inc. Research Support; Self; Novo Nordisk Inc. J. Wells: None. Funding American Diabetes Association (1-19-PDF-036 to M.K.)