Acinar Metaplasia Research Articles

Optimization of the selection of the volume of surgical intervention in cases of pronounced morphological and structural changes of the parenchyma in patients with a high risk of developing pancreatic cancer

Chronic pancreatitis is a common recurrent pathology of the pancreas. The long course of the inflammatory process, accompanied by chronicity, is often attributed to the causes that lead to the development of pancreatic cancer. The aim of the work is to study the morphological changes of the pancreas in rats and the level of matrix metalloproteinases and tissue inhibitor of metalloproteinases in patients with complicated forms of chronic pancreatitis and a high risk of developing pancreatic cancer in order to optimize the selection of the volume of surgical intervention. A histological study of the pancreas of rats with chronic pancreatitis and chronic pancreatitis on the background of diabetes was carried out. 27 patients operated on during 2020-2022 were examined. In 15 of them, we were unable to clearly and convincingly differentiate of chronic pancreatitis from pancreatic cancer, since quite often the clinical symptoms and diagnostic picture of these diseases are similar. In the remaining 12 patients it was confirmed with all the inherent clinical signs of chronic pancreatitis and ductal hypertension. Matrix metalloproteinases (MMP-1, -2, -3, -8, -9, -10) and tissue inhibitor of metalloproteinases were studied. The obtained results were processed statistically. Morphological changes of the pancreas in rats correspond to high and moderate ductal dysplasia of the PanIN 2 and PanIN 3 class, which are direct predictors of pancreatic adenocarcinoma. In 22 patients moderate and severe exocrine insufficiency was observed, confirmed by a significant decrease in fecal elastase. An intraoperative biopsy of the changed tissue of the pancreas was performed. Among the 15 operated patients of the main group, 9 were diagnosed with diabetes mellitus and changes in MMTs and a peptide pool inherent in malignant tissue. Intraoperatively, after performing a punch biopsy, acinar metaplasia was detected in 3 patients, tissue changes characteristic of PanIN2-PanIN3 in 4 patients, and pancreatic cancer in the head area was confirmed in 3 patients. Changes in the protein profile of the plasma, clinical manifestations, as well as characteristic changes in the pancreas tissue, gave us grounds for performing extended resection interventions. Studying the morphological structure of the pancreas, using as many methods as possible for differential diagnosis between chronic pancreatitis and pancreatic cancer, as well as a comprehensive approach to the patient will allow for the most correct and effective intervention.

Pancreatic acinar metaplasia at the gastroesophageal junction is associated with protective effect against intestinal metaplasia in patients with gastroesophageal reflux disease

Anecdotal evidence suggests that pancreatic acinar metaplasia (PAM) and intestinal metaplasia (IM) overlap infrequently at the gastroesophageal junction/distal esophagus (GEJ/DE). The goal of this study was to evaluate the significance of PAM at GEJ/DE in relation to IM in patients with gastroesophageal reflux disease (GERD). Group 1 comprised 230 consecutive patients with GEJ/DE biopsies (80.6% with GERD symptoms). Group 2 comprised 151 patients with established GERD and GEJ/DE biopsies taken before Nissen fundoplication. Group 3 comprised 540 consecutive patients used for a follow-up study of PAM. PAM was present in 15.7%-15.9% and IM in 24.8%-31.1% of patients in groups 1 and 2, respectively. PAM-IM overlap was present in 2.2%-3.3%, respectively. Patients with PAM were, on average, 6-12 years younger than patients with IM, and were predominantly female (72.2%-75%), in contrast to patients with IM (47.3%-32%). In the unadjusted logistic regression model, patients with PAM were 69%-65% less likely to also have IM, as compared to patients without PAM. In the fully adjusted model, patients with PAM were 35%-61% less likely to also have IM, although the P-value was not significant. Follow-up analysis of patients with PAM from group 3 (n=28) demonstrated the prevalence of IM and PAM in subsequent biopsies at 7.1% and 60.7%, respectively. No cases showed PAM-IM overlap on follow-up. The data suggests that PAM at the GEJ/DE is associated with protective effect against IM and thus could be useful as a marker of decreased susceptibility to IM.

NFATc1 Is a Central Mediator of EGFR-Induced ARID1A Chromatin Dissociation During Acinar Cell Reprogramming

Loss of AT-rich interactive domain-containing protein 1A (ARID1A) fosters acinar-to-ductal metaplasia (ADM) and pancreatic carcinogenesis by down-regulating transcription programs controlling acinar cell identity. However, how ARID1A reacts to metaplasia-triggering environmental cues remains elusive. Here, we aimed to elucidate the role of ARID1A in controlling ductal pancreatic gene signatures and deciphering hierarchical signaling cues determining ARID1A-dependent chromatin regulation during acinar cell reprogramming. Acinar cell explants with differential ARID1A status were subjected to genome-wide expression analyses. The impact of epidermal growth factor receptor (EGFR) signaling, NFATc1 activity, and ARID1A status on acinar reprogramming processes were characterized by exvivo ADM assays and transgenic mouse models. EGFR-dependent ARID1A chromatin binding was studied by chromatin immunoprecipitation sequencing analysis and cellular fractionation. EGFR signaling interferes with ARID1A-dependent transcription by inducing genome-wide ARID1A displacement, thereby phenocopying ARID1A loss-of-function mutations and inducing a shift toward ADM permissive ductal transcription programs. Moreover, we show that EGFR signaling is required to push ARID1A-deficient acinar cells toward a metaplastic phenotype. Mechanistically, we identified the transcription factor nuclear factor of activated T cells 1 (NFATc1) as the central regulatory hub mediating both EGFR signaling-induced genomic ARID1A displacement and the induction of ADM-promoting gene signatures in the absence of ARID1A. Consequently, pharmacologic inhibition of NFATc1 or its depletion in transgenic mice not only preserves genome-wide ARID1A occupancy, but also attenuates acinar metaplasia led by ARID1A loss. Our data describe an intimate relationship between environmental signaling and chromatin remodeling in orchestrating cell fate decisions in the pancreas, and illustrate how ARID1A loss influences transcriptional regulation in acinar cell reprogramming.

Abstract 5821: Enhanced tumorigenesis in a novel miR-216a knockout/KPC mouse model of pancreatic cancer

Abstract Pancreatic ductal adenocarcinoma (PDAC) originates from both ductal and acinar cells of the pancreas. The highly abundant and acinar cell-enriched miR-216a is reduced during in vitro acinar ductal metaplasia (ADM), throughout PanIN progression, during the development of pancreatitis in mice and humans, and during development of mouse and human PDAC. To investigate the contribution of miR-216a in the development of PDAC, we generated a miR-216a germline knockout mouse (216aKO) via CRISPR genetic editing of a minimal and precise deletion of the miR-216a precursor sequence without affecting the host gene. We crossed this 216aKO mouse to the LSL-KrasG12D; LSL-Trp53Flox/+; Pdx1Cre/+ (KPC) mice to produce a transgenic mouse with an activating Kras mutation, p53 deletion, and knockout of miR-216a (referred to here as miR216aKPC). miR216aKPC displayed an increase in tumor progression compared to KPC and had reduced survival - median 15 weeks miR216aKPC vs. 25 weeks for KPC. miR216aKPC produced lung metastasis by 12 weeks of age which were not present in the lungs of similarly aged KPC mice. Transfection of miR-216a mimetic oligo into cell lines derived from KPC or 216aKPC mice did not reduce viability or alter cellular morphology, suggesting that a potential tumor suppressive role of miR-216a functions during the early stages of PDAC development. A three dimensional ADM assay using acinar cells derived from both mouse and human pancreata will be applied to investigate the contributions of miR-216a on the development of ADM and cell polarity. To discover miR-216a target genes that are responsible for the increased tumorigenesis, cell lines derived from miR216aKPC will be transfected with miR-216a mimetic or scrambled control oligo followed by RNA sequencing. Our results thus far suggest a tumor suppressive role for miR-216a in the early development of PDAC and future studies will investigate molecular and cellular mechanisms driving acinar cell-induced PDAC. Citation Format: Andrew A. Brock, Katherine Powell, Thomas D. Schmittgen, Lorenzo F. Sempere. Enhanced tumorigenesis in a novel miR-216a knockout/KPC mouse model of pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5821.

Abstract 816: Cyclin c suppresses pancreatic intraepithelial neoplasm progression and neuroendocrine neoplasm development in a murine Kras model

Abstract Cyclin c is a component of the Cdk8 kinase module that plays both a positive and negative role in transcription. In addition, cellular damage induces cyclin c re-localization to the mitochondria where it stimulates fission and recruits Bax in preparation for apoptotic initiation. Previous studies revealed that cyclin c suppresses thyroid hyperplasia in a Pten knockout mouse model. In the present study, a role for cyclin c in suppressing pancreatic cancer progression was investigated in the Pdx1-Cre LSL-KrasG12D murine pancreatic cancer model. Within eight weeks, a 6-8 fold increase in the appearance of pancreatic intraepithelial neoplasia (PanIN) and acinar ductal metaplasia (ADM) lesions was observed in the KrasG12D+Ccnc-/- animals compared to KrasG12D alone. Surprisingly, high-grade neuroendocrine neoplasms (NEN) were also observed. These aggressive NEN showed mixed morphology with areas of acinar-like differentiation. High grade NEN exhibited pronounced proliferative index (Ki67), high EZH2 expression, and elevated Notch1, suggesting a connection between aberrant Notch signaling and NEN formation. Our previous studies identified a positive role for cyclin c in autophagy gene transcription. Similarly, cell lines derived from a KrasG12D+Ccnc-/- pancreas exhibited a reduction in autophagy compared to KrasG12D+Ccnc+/+ cells. Autophagic deficiency induces pancreatic cell stress and is associated with apoptosis. Consistent with this model, high caspase 3 expression was observed in early KrasG12D+Ccnc-/- NEN but not in KrasG12D+Ccnc+/+ tissues. Taken together, these results demonstrate a role for cyclin c in suppressing both progression of early PanIN and the development of high-grade NEN and suggest a model that cyclin c loss suppresses autophagy and increases apoptosis. Acknowledgements: Support was provided by NCI CCSG grant CA06927 for the FCCC Histopathology and Cell Culture Facilities, the PA Department of Health CURE fund (KSC), the Boye Foundation (RS), and the New Jersey Health Foundation (RS). Citation Format: Kathy Q. Cai, Sara E. Hanley, Andres Klein-Szanto, Kerry S. Campbell, Randy Strich. Cyclin c suppresses pancreatic intraepithelial neoplasm progression and neuroendocrine neoplasm development in a murine Kras model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 816.

Clinicopathological characteristics of pancreatic acinar cell metaplasia associated with Helicobacter pylori infection

BackgroundPancreatic acinar cell metaplasia (PACM) has been rarely reported in the gastric mucosa. In the present study, we aimed to elucidate the clinical and pathological characteristics of PACM associated with Helicobacter pylori (H. pylori).Method5930 patients who underwent five- or two-point gastric biopsy according to the updated Sydney system (USS) by upper gastrointestinal endoscopy were enrolled. The patients were categorized into current H. pylori infection (CHI), post-H. pylori eradication (PHE), and non-H. pylori infection (NHI) groups according to the H. pylori infection status, and the frequency and location of PACM were compared. Additionally, a case–control study was performed to compare the USS scores between patients with CHI and PACM and those with CHI but not PACM.ResultThe frequencies of PACM were 0.49% (10/2039), 0.75% (25/3332), and 0% (0/559) in the CHI, PHE, and NHI groups, respectively. PACM was found in the greater curvature of the antrum in 33 of the 35 patients with PACM. Among the patients with CHI, the inflammation scores in the greater curvature of the antrum and the greater curvature of the corpus were lower in patients with PACM than in those without PACM.ConclusionAlthough rarely reported in the gastric mucosa, PACM was closely related to H. pylori infection, especially in the antrum, and was associated with relatively mild inflammation.

Activated Pancreatic Stellate Cells Promote Acinar Duct Metaplasia by Disrupting Mitochondrial Respiration and Releasing Reactive Oxygen Species

Background: Chronic Pancreatitis (CP) is a long-term risk factor for pancreatic ductal adenocarcinoma (PDAC), and both diseases share a common etiology. The activation of Pancreatic stellate cells (PaSCs) caused by inflammation of the chronic pancreas plays a pivotal role in the pathology of pancreatic fibrosis and the malignant phenotype of PDAC. However, the central role of activated PaSCs in Acinar-to-Ductal Metaplasia (ADM) remains unknown. Objective: In the present study, we investigated the link between pancreatic fibrosis and ADM and the possible underlying mechanism. Methods: A caerulein-treated mouse CP model was established, and Masson trichrome histochemical stain and Transmission Electron Microscope (TEM) were used to observe stromal fibrosis and cell ultrastructure, respectively. The expression of amylase and cytokeratin 19 (CK19), mitochondria respiration, and reactive oxygen species (ROS) were detected in vitro in the co-culture model of primary pancreatic acinar cells and PaSCs. Results: The activation of PaSCs and pancreatic fibrosis were accompanied by ADM in pancreatic parenchyma in caerulein-treated mice, which was verified by the co-cultivation experiment in vitro. Furthermore, we showed that activated PaSCs promote ADM by disrupting mitochondrial respiration and releasing ROS. The expression of inflammation-and ADM-related genes, including S100A8, S100A9, and CK19, was observed to be up-regulated in pancreatic acinar cells in the presence of activated PaSCs. The expression of S100A9 and CK19 proteins was also up-regulated in acinar cells co-cultured with activated PaSCs. Conclusion: The manipulation of mitochondrial respiration and ROS release is a promising preventive and/or therapeutic strategy for PDAC, and S100A9 is expected to be a therapeutic target to block the ADM process induced by the activation of PaSCs.

S3707 Pancreatic Acinar Metaplasia at the Gastroesophageal Junction in a Patient With Chronic Reflux

Introduction: Pancreatic acinar metaplasia (PAM) is defined as pancreatic glandular tissue forming acini outside of the pancreas. Recent studies have shown a possible association between chronic use of proton pump inhibitors (PPIs) and nonsteroidal anti-inflammatory drugs (NSAIDs). Here, we present a case of PAM in a patient with chronic reflux on PPIs without a history of NSAID use. Case Description/Methods: A 41-year-old female with a longstanding history of gastroesophageal reflux disease (GERD) presented to clinic for evaluation of chronic reflux. The patient reported having symptoms of reflux for over 20 years. Over this time, she trialed multiple medications such as PPIs and antacids, but denied the use of NSAIDs. She also underwent multiple esophagogastroduodenoscopies (EGDs) for evaluation of her reflux, the last being 5 years ago, which showed mild gastric erythema but was otherwise unremarkable. Due to persistent symptoms despite medical management, she was scheduled for repeat EGD. EGD showed salmon-colored mucosa and gastric erythema. Pathology from esophagus biopsies revealed junctional mucosa with focal pancreatic acinar metaplasia (PAM). The patient was transitioned to Dexlansoprazole for symptomatic management and was scheduled for repeat EGD in 1 year for surveillance of PAM. Discussion: Pancreatic acinar metaplasia (PAM) is a term used to describe pancreatic glandular tissue organized in nests found outside of the pancreas. It is most commonly found in the gastric antrum, but can be found elsewhere in the gastrointestinal tract such as at the gastroesophageal junction (GEJ). While endoscopic findings of PAM differ, one study showed that the most commonly found appearance is salmon-colored mucosa. PAM is diagnosed histologically by pancreatic acinar-like cells that have a prominent cytoplasm with eosinophilic apical areas and basophilic basal areas. The exact pathogenesis of PAM is unknown; studies have shown that PAM may be associated with chronic NSAID or PPI use. While our patient used PPIs for years, she denies a history of NSAID usage. Another study by Schneider et al. showed that there was no association between PAM and reflux or gastritis, suggesting that PAM be have a congenital component. Further research is needed to determine the etiology of PAM. It can be found in patients with Barrett’s esophagus and may be associated with Helicobacter pylori. Therefore, it is important that these patients undergo routine surveillance.

Abstract LB200: A transcriptionally distinct subpopulation of healthy acinar cells exhibit features of pancreatic progenitors and pancreatic ductal adeno carcinoma

Abstract The stochasticity of transcription leads to phenotypic variation within a clonal population. This means that within a healthy tissue, a fraction of cells could assume an “edge” transcriptional state that is primed for a transition toward malignancy. We find such an edge transcriptional state amongst acinar cells in a publicly available PDAC single-cell RNA-seq dataset. These acinar edge cells (AE) cells have transcriptomes that are highly diverged from a typical normal acinar cell, and show transcriptional similarities to pancreatic ductal adenocarcinoma (PDAC). The AE state can be found in several single-cell datasets from healthy human pancreatic tissue. The AE state is not mutationally-driven as AE cells in healthy tissues do not possess any known oncogenic driver mutations, nor are they clonally derived. The transition from a non-edge acinar to an AE state recapitulates key aspects of pancreatic biology; genes associated with this transition are enriched for known markers of acinar de-differentiation and acinar-ductal metaplasia. Further, the AE state represents a partial reversion to a SOX9+PTF1A+ multi-potent embryonic pancreatic progenitor state, likely through the activation of KLF5, HES1 and RBPJ targets. Remarkably, the promoters of genes upregulated in the AE state are significantly hypomethylated in PDAC relative to normal pancreas, while the genes up-regulated in the AE state are up-regulated in PDAC samples in the Cancer Genome Atlas (TCGA) database. It is thus likely that transcriptomic changes in the edge state are fixed epigenetically during tumor initiation and progression. A gene signature derived from the AE cells shows strong association with survival among PDAC patients. Remarkably, we also find that the fraction of AE cells in the healthy pancreas increases with age, which points to a strong non-genetic and transcriptomic component to the known increase in PDAC risk with age. We also observed edge-like transcriptomic heterogeneity among alveolar, ciliated and club cells in the human lung, and amongst hepatocytes in liver tissues. This suggests that, across tissues, gene expression heterogeneity can lead to sub-populations of healthy cells across tissues existing in pre-malignant states. Citation Format: Vishaka Gopalan, Arashdeep Singh, Farid Rashidi, Li Wang, Eytan Ruppin, Efsun Arda, Sridhar Hannenhalli. A transcriptionally distinct subpopulation of healthy acinar cells exhibit features of pancreatic progenitors and pancreatic ductal adeno carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB200.

Peroxiredoxin-I Sustains Inflammation During Pancreatitis.

Peroxiredoxin-I Sustains Inflammation During Pancreatitis.

Abstract PO-092: Development of an organoid assay for studying racial disparity in pancreatic acinar ductal metaplasia

Abstract Blacks have higher rates of incidence and mortality of pancreatic cancer compared to Whites and non-White Hispanics. In an effort to identify a biological basis for this disparity, we propose examining the early events in the development of pancreatic cancer. The process by which pancreatic acini transdifferentiate into ductal epithelial cells (i.e. acinar ductal metaplasia or ADM) is one of the earliest events in the development of pancreatic ductal adenocarcinoma. We adapted the classic in vitro ADM assay, by which primary mouse pancreatic acini undergo ADM once plated onto the extracellular matrix matrigel, to an assay to culture and transdifferentiate human pancreatic organoids. We have received normal, human pancreatic acini from pancreatic islet transplantation centers from Black (n=8), White (n=19) and Hispanic (n=16) donors. The gender distribution was 29 males and 14 females. The acinar cells were cultured on matrigel and allowed to undergo ADM over a 5 to 6 day period. The number of ductal epithelial cells were microscopically counted and the rate of transdifferentiation was determined by kinetic modeling of the data. We have successfully cultured and transdifferentiated 40 of 43 human pancreatic acinar cells. Data from our study suggests that females undergo ADM at a faster rate than males and among the different races, the rate of acinar transdifferentiation decreases in the following order Blacks > Whites > non-White Hispanics. In summary, we demonstrate that women and Blacks have the highest rate of pancreatic transdifferentiation. Future studies include sequencing of the RNA isolated from the tissues to identify molecular drivers of acinar transdifferentiation and their impact on health disparities of pancreatic cancer. Citation Format: Alyssa Gosling, Jinmai Jiang, Corey M. Perkins, Yingwei Yao, Thomas D. Schmittgen. Development of an organoid assay for studying racial disparity in pancreatic acinar ductal metaplasia [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr PO-092.

Single-cell transcriptomes of pancreatic preinvasive lesions and cancer reveal acinar metaplastic cells\u2019 heterogeneity

Acinar metaplasia is an initial step in a series of events that can lead to pancreatic cancer. Here we perform single-cell RNA-sequencing of mouse pancreas during the progression from preinvasive stages to tumor formation. Using a reporter gene, we identify metaplastic cells that originated from acinar cells and express two transcription factors, Onecut2 and Foxq1. Further analyses of metaplastic acinar cell heterogeneity define six acinar metaplastic cell types and states, including stomach-specific cell types. Localization of metaplastic cell types and mixture of different metaplastic cell types in the same pre-malignant lesion is shown. Finally, single-cell transcriptome analyses of tumor-associated stromal, immune, endothelial and fibroblast cells identify signals that may support tumor development, as well as the recruitment and education of immune cells. Our findings are consistent with the early, premalignant formation of an immunosuppressive environment mediated by interactions between acinar metaplastic cells and other cells in the microenvironment.

Clinicopathological features of autoimmune gastritis

Objective: To study the clinicopathological characteristics and pathologic diagnosis of autoimmune gastritis. Methods: Fourteen biopsies of autoimmune gastritis were collected from January 2018 to March 2019 at Guangdong Provincial People's Hospital. Their clinical data, histological features and immunohistochemical (IHC) results were analyzed, with review of relevant literature. Results: All 14 patients' ages ranged from 41 to 79 years (mean 55 years). There were 12 females and 2 males. All patients had non-specific symptoms, but they all had positive serum anti-parietal cell antibody and/or anti-intrinsic factor antibody. Seven patients had variable degree of anemia. Two patients had concomitant H. pylori infection. Two patients presented with multiple protruding polyps in corpus/fundus, 0.2 to 0.9 cm in diameter, or multiple large lobulated and broad based polyps (0.8 to 3.5 cm in diameters). The former cases were diagnosed as type 1 neuroendocrine tumors, the latter were multiple hyperplastic polyps. Microscopically, autoimmune gastritis showed typical morphology, characterized by diffuse corpus-restricted atrophic gastritis with variable proportions of intestinal metaplasia, or pseudopyloric metaplasia, pancreatic, acinar metaplasia, foveolar hyperplasia and hyperplasia of the endocrine-like cells (ECL cells). Hyperplasia of ECL cells often needed IHC staining to confirm. CgA/Syn IHC stain highlighted linear and micronodular ECL cell hyperplasia. In the absence of concurrent or past H. pylori infection, the antrum was usually normal. Gastrin IHC stain showed hyperplasia of gastrin-producing cells (G cells) in the antrum. Two cases were in the early phase, six were in florid phase, and six were end phase. Conclusions: Most patients of autoimmune gastritis have non-specific symptoms or are asymptomatic and show various endoscopic findings. There are three histologic phases of autoimmune gastritis. Recognition of this entity would be beneficial for pathologists to avoid misdiagnosis. Pathologists can make preferred diagnosis of autoimmune gastritis depending on the histologic clues and prompt appropriate and timely management for the patients.

Abstract D112: Development of an organoid assay for studying racial disparity in pancreatic acinar ductal metaplasia

Abstract Blacks have a higher rate of incidence and mortality of pancreatic cancer compared to whites. In an effort to identify a biological basis for this disparity, we propose examining the early events in the development of pancreatic cancer. The process by which pancreatic acini transdifferentiate into ductal epithelial cells (i.e. acinar ductal metaplasia or ADM) is one of the earliest events in the development of pancreatic ductal adenocarcinoma. We adapted the classic in vitro ADM assay, by which primary mouse pancreatic acini undergo ADM once plated onto the extracellular matrix matrigel, to an assay to culture and transdifferentiate human pancreatic organoids. Human pancreatic acini was received from black (n=5), white (n=3) and Hispanic (n=6) donors from pancreatic islet transplantation centers. The gender distribution was 8 males and 6 females. The acinar cells were cultured on matrigel and allowed to undergo ADM over a 5 to 6 day period. The number of ductal epithelial cells were microscopically counted and the rate of transdifferentiation was determined. Using this technique, we successfully cultured and transdifferentiated 14 of 14 human pancreatic acinar cells. Preliminary data from our study suggests that females undergo ADM at a greater rate than males. Data on race was inconclusive due to the low number of samples. In summary, we have developed an assay to culture and study pancreatic ADM using human specimens. Future studies using increased sample size will investigate if racial disparity exists for pancreatic ADM. Citation Format: Julie Bray, Sihem Ait-Oudhia, Martha Campbell-Thompson, Thomas D Schmittgen. Development of an organoid assay for studying racial disparity in pancreatic acinar ductal metaplasia [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr D112.

1840 Salivary Gland Choristoma: A Rare Finding at Gastroesophageal Junction

INTRODUCTION: Choristoma is tumor-like outgrowth of heterotopic and mature tissue located at anatomically unusual sites. Heterotopic salivary gland tissue (HSGT) has been most commonly described in head and neck region but can rarely involve gastrointestinal (GI) tract with a few cases reported in the literature. CASE DESCRIPTION/METHODS: An 87-year-old female with past medical history of gastroesophageal reflux disease (GERD), hypertension, and chronic kidney disease was admitted for an acute DVT. Due to worsening anemia, she underwent an upper endoscopy that showed a small nodularity at the GE junction (Figure 1a), a large hiatal hernia, and reflux esophagitis in the lower one-third of the esophagus (Figure 1b). Biopsy of the nodule demonstrated an esophagogastric junction-type mucosa with mild to moderate chronic inflammation, mild acute inflammation and focal glandular tissue consistent with heterotopic salivary gland tissue (Figure 1c, d). No intestinal metaplasia or dysplasia were noted. DISCUSSION: Salivary gland choristoma at the gastroesophageal junction (GEJ) is an extremely rare entity, with only one case reported in the English literature. Additionally, two other cases of HSGT at GEJ not in the form of choristoma were described in the same report. All of the cases had a medical history of GERD. One of the HSGT cases had reflux esophagitis while the other had Barret’s esophagus with high-grade dysplasia. Similarly, our patient had a history of GERD with reflux esophagitis. She was diagnosed incidentally, through an EGD-guided biopsy of the nodule to exclude malignancy. It is well-known that intestinal columnar metaplasia at the GEJ can occur secondary to chronic acid exposure and inflammation in the setting of GERD. The origin of these intestinal glandular cells remains unknown. Furthermore, pancreatic acinar metaplasia at the GEJ is a relatively common finding, but the causative relationship between GERD and pancreatic acinar metaplasia is obscure. Salivary gland choristoma of the GEJ could be a metaplastic change in the setting chronic inflammation as a result of reflux esophagitis. However, the biological and clinical significance of this finding is yet to be investigated.

Pancreatic Acinar Metaplasia in Distal Esophageal Biopsies Is Associated With Chronic Nonsteroidal Anti-inflammatory Drug Use.

The cause of pancreatic acinar metaplasia (PAM) at the distal esophagus/esophagogastric junction is still controversial. Whereas some authors believe it is congenital, others believe it is acquired because of inflammation of the gastric cardia, and more recently it was proposed to be due to chronic proton pump inhibitor use based on a study in rats. To determine whether there is correlation between chronic proton pump inhibitor use and PAM in humans. We also investigated the correlation between several clinical and pathologic factors and PAM. Four hundred forty-four consecutive biopsies from the distal esophagus/esophagogastric junction were reviewed for the presence of PAM, which was then correlated with several clinical and pathologic findings. Pancreatic acinar metaplasia was found in 71 patients (16%). Pancreatic acinar metaplasia was significantly associated with patient age younger than 51 years ( P < .001), chronic carditis ( P = .01), and chronic proton pump inhibitor use ( P = .008). Surprisingly, we also found significant association between PAM and chronic nonsteroidal anti-inflammatory drug use ( P < .001). These associations, including that with chronic nonsteroidal anti-inflammatory drug use, remained significant in multivariate analysis. Our findings confirm the previous reports of significant association between PAM and chronic carditis and the findings from animal studies of association with chronic proton pump inhibitor use. The strong association with chronic nonsteroidal anti-inflammatory drug use has not been previously reported and warrants further studies.

The Significance of Pancreatic Acinar Metaplasia at the Lower Esophagus

The Significance of Pancreatic Acinar Metaplasia at the Lower Esophagus

Oncogenic KRas-induced Increase in Fluid-phase Endocytosis is Dependent on N-WASP and is Required for the Formation of Pancreatic Preneoplastic Lesions

Fluid-phase endocytosis is a homeostatic process with an unknown role in tumor initiation. The driver mutation in pancreatic ductal adenocarcinoma (PDAC) is constitutively active KRasG12D, which induces neoplastic transformation of acinar cells through acinar-to-ductal metaplasia (ADM). We have previously shown that KRasG12D-induced ADM is dependent on RAC1 and EGF receptor (EGFR) by a not fully clarified mechanism. Using three-dimensional mouse and human acinar tissue cultures and genetically engineered mouse models, we provide evidence that (i) KRasG12D leads to EGFR-dependent sustained fluid-phase endocytosis (FPE) during acinar metaplasia; (ii) variations in plasma membrane tension increase FPE and lead to ADM in vitro independently of EGFR; and (iii) that RAC1 regulates ADM formation partially through actin-dependent regulation of FPE. In addition, mice with a pancreas-specific deletion of the Neural-Wiskott–Aldrich syndrome protein (N-WASP), a regulator of F-actin, have reduced FPE and impaired ADM emphasizing the in vivo relevance of our findings. This work defines a new role of FPE as a tumor initiating mechanism.

Transcriptional Maintenance of Pancreatic Acinar Identity, Differentiation, and Homeostasis by PTF1A

Maintenance of cell type identity is crucial for health, yet little is known of the regulation that sustains the long-term stability of differentiated phenotypes. To investigate the roles that key transcriptional regulators play in adult differentiated cells, we examined the effects of depletion of the developmental master regulator PTF1A on the specialized phenotype of the adult pancreatic acinar cell in vivo Transcriptome sequencing and chromatin immunoprecipitation sequencing results showed that PTF1A maintains the expression of genes for all cellular processes dedicated to the production of the secretory digestive enzymes, a highly attuned surveillance of unfolded proteins, and a heightened unfolded protein response (UPR). Control by PTF1A is direct on target genes and indirect through a ten-member transcription factor network. Depletion of PTF1A causes an imbalance that overwhelms the UPR, induces cellular injury, and provokes acinar metaplasia. Compromised cellular identity occurs by derepression of characteristic stomach genes, some of which are also associated with pancreatic ductal cells. The loss of acinar cell homeostasis, differentiation, and identity is directly relevant to the pathologies of pancreatitis and pancreatic adenocarcinoma.

Adenomyomatosis of the gallbladder in childhood: A systematic review of the literature and an additional case report.

To investigate the diagnostic and therapeutic assessment in children with adenomyomatosis of the gallbladder (AMG). AMG is a degenerative disease characterized by a proliferation of the mucosal epithelium which deeply invaginates and extends into the thickened muscular layer of the gallbladder, causing intramural diverticula. Although AMG is found in up to 5% of cholecystectomy specimens in adult populations, this condition in childhood is extremely uncommon. Authors provide a detailed systematic review of the pediatric literature according to PRISMA guidelines, focusing on diagnostic and therapeutic assessment. An additional case of AMG is also presented. Five studies were finally enclosed, encompassing 5 children with AMG. Analysis was extended to our additional 11-year-old patient, who presented diffuse AMG and pancreatic acinar metaplasia of the gallbladder mucosa and was successfully managed with laparoscopic cholecystectomy. Mean age at presentation was 7.2 years. Unspecific abdominal pain was the commonest symptom. Abdominal ultrasound was performed on all patients, with a diagnostic accuracy of 100%. Five patients underwent cholecystectomy, and at follow-up were asymptomatic. In the remaining patient, completely asymptomatic at diagnosis, a conservative approach with monthly monitoring via ultrasonography was undertaken. Considering the remote but possible degeneration leading to cancer and the feasibility of laparoscopic cholecystectomy even in small children, evidence suggests that elective laparoscopic cholecystectomy represent the treatment of choice. Pre-operative evaluation of the extrahepatic biliary tree anatomy with cholangio-MRI is strongly recommended.