Pancreatic Acinar Tissue Research Articles

Exocrine pancreatic insufficiency in dogs and cats.

Exocrine pancreatic insufficiency (EPI) is a malabsorptive syndrome caused by insufficient secretion of digestive enzymes from pancreatic acini. The most common causes of EPI in dogs and cats are pancreatic acinar atrophy and chronic pancreatitis. EPI is diagnosed by measurement of species-specific immunoassays for serum trypsin-like immunoreactivity, the concentration of which directly reflects the mass of functioning pancreatic acinar tissue. EPI is treated by pancreatic enzyme replacement therapy, nutritional management (low-residue diets with moderate fat content), and supplementation of cobalamin. Some dogs and cats have persistent clinical signs despite these treatments. Growing evidence suggests that these clinical signs may be due to enteric microbiota dysbiosis or the presence of concurrent diseases such as chronic enteropathies. Management of these abnormalities may improve outcome in dogs and cats with EPI. The long-term prognosis for dogs and cats with EPI is generally good if high-quality medical therapy is provided. Future studies are needed to further understand the causes of persistent dysbiosis in animals with EPI following initiation of pancreatic enzyme replacement therapy and assess the efficacy of treatments to ameliorate these abnormalities.

Association Between Preoperative Pancreatic Exocrine Function and Pathological Evaluation With Postoperative Pancreatic Fistulas Following Pancreaticoduodenectomy.

Postoperative pancreatic fistula (POPF) may cause severe complications. In this study, risk factors for postoperative pancreatic fluid leakage after pancreaticoduodenectomy (PD) were investigated, with a particular focus on preoperative pancreatic exocrine function and pathological evaluations of the resected pancreas. A total of 67 patients underwent the N-benzoyl-L-tyrosyl-para-aminobenzoic acid (BT-PABA) test and PD in our department between June 2003 and March 2018. The endpoint was the development of POPF. Patients' clinical characteristics, preoperative test results, surgery-related parameters, and pathological evaluations of the resected samples were investigated. Preoperative pancreatic exocrine function was evaluated by the BT-PABA test, and the proportion of residual acinar tissue and the fibrosis rate of the resected pancreatic tissue were assessed. 17 (25.4%) patients with Grade B and C POPF were compared with 50 patients without POPF. On univariate analysis, pancreatic carcinoma (p=0.028), BT-PABA test results higher than 66.3% (p=0.030), and main pancreatic duct (MPD) diameter lower than 5.0 mm (p=0.006) were identified as risk factors for postoperative pancreatic fluid leakage. On multivariate analysis, pancreatic carcinoma (p=0.008), BT-PABA test results higher than 66.3% (p=0.036), MPD diameter lower than 5.0mm (p=0.029) were significant risk factors. BT-PABA test results have a moderate correlation with both the proportion of pancreatic acinar tissue (r=0.421, p=0.028) and the pancreatic fibrosis rate (r=-0.443, p=0.021). The preoperative BT-PABA test results higher than 66.3% were an independent risk factor for POPF. This suggests that the development of POPF may be attenuated by diminished exocrine function with poor pancreatic fluid flow and the progression of fibrosis.

Evaluating the Potential for ABO-incompatible Islet Transplantation: Expression of ABH Antigens on Human Pancreata, Isolated Islets, and Embryonic Stem Cell-derived Islets.

ABO-incompatible transplantation has improved accessibility of kidney, heart, and liver transplantation. Pancreatic islet transplantation continues to be ABO-matched, yet ABH antigen expression within isolated human islets or novel human embryonic stem cell (hESC)-derived islets remain uncharacterized. We evaluated ABH glycans within human pancreata, isolated islets, hESC-derived pancreatic progenitors, and the ensuing in vivo mature islets following kidney subcapsular transplantation in rats. Analyses include fluorescence immunohistochemistry and single-cell analysis using flow cytometry. Within the pancreas, endocrine and ductal cells do not express ABH antigens. Conversely, pancreatic acinar tissues strongly express these antigens. Acinar tissues are present in a substantial portion of cells within islet preparations obtained for clinical transplantation. The hESC-derived pancreatic progenitors and their ensuing in vivo-matured islet-like clusters do not express ABH antigens. Clinical pancreatic islet transplantation should remain ABO-matched because of contaminant acinar tissue within islet preparations that express ABH glycans. Alternatively, hESC-derived pancreatic progenitors and the resulting in vivo-matured hESC-derived islets do not express ABH antigens. These findings introduce the potential for ABO-incompatible cell replacement treatment and offer evidence to support scalability of hESC-derived cell therapies in type 1 diabetes.

Identification and Validation of Potentially Clinically Relevant CpG Regions within the Class 2 Tumor Suppressor Gene SFRP1 in Pancreatic Cancer.

In pancreatic cancer treatment, tumor stage-dependent chemotherapies are used to prolong overall survival. By measuring DNA promoter hypermethylation in the plasma of patients with stage IV pancreatic cancer, it was recently shown that promoter DNA methylation of the tumor suppressor gene SFRP1 has a high value for predicting failure of drug treatment with gemcitabine. In this study, we therefore aimed to identify as precisely as possible the region in the SFRP1 promoter that is frequently hypermethylated in pancreatic cancer tissue. First, we used the TCGA data set to define CpG-rich regions flanking the SFRP1 transcription start site that were significantly more methylated in pancreatic cancer compared to normal pancreatic acinar tissue. A core CpG island was identified that exhibited abundant tumor DNA methylation and anti-correlation of SFRP1 mRNA expression. To validate our in silico results, we performed bisulfide conversion followed by DNA pyrosequencing of 28 matched formalin-fixed, paraffin-embedded (FFPE) pancreatic cancer cases and six pancreatic cancer cell lines. A defined block of seven CpG sites within the core CpG island was identified, which confirmed our in silico results by showing significantly higher SFRP1 methylation in pancreatic cancer specimens than in normal pancreatic tissue. By selecting this core CpG island, we were able to determine a median overall survival benefit for the low SFRP1 methylation group compared to the high SFRP1 methylation group (702 versus 517 days, p = 0.01) in the TCGA pancreatic cancer cohort. We propose a compact pyrosequencing assay that can be used in the future to further investigate the prognostic value of SFRP1 promoter hypermethylation in predicting pancreatic cancer chemoresistance. Therefore, instead of DNA analysis from blood (liquid biopsy), DNA easily extractable from cancer tissue blocks (FFPE material) could be used.

Pediatric pancreatic lesions: a clinicopathological analysis of 42 cases

Objective: To investigate the clinicopathological characteristics of pancreatic lesions in children. Methods: The clinicopathological data of pancreatic lesions in children were analyzed including 42 cases of pancreatic tumors diagnosed from January 2000 to May 2021 in Guangzhou Women's and Children's Medical Center, Guangzhou, China. Histological and immunohistochemical assessments were performed. Related literature was reviewed. Results: The 42 pediatric patients with pancreatic lesions aged 1 day to 12 years (mean, 4.25 years). There were 23 males and 19 females. Clinical presentations included abdominal masses, abdominal pain, vomiting and persistent hypoglycemia after birth. Ultrasound and computerized tomography examination showed space-occupying pancreatic lesions in 31 cases, but no detectable pancreatic lesions in 11 cases. Histologically, among the 42 cases, 22 cases (52.4%) were neoplastic, including 18 cases of epithelial origin. Nine cases of pancreatoblastoma showed that the epithelial tumor cells were arranged in a trabecular pattern, with squamous nests. Six cases of solid-pseudopapillary tumors revealed hemorrhagic and necrotic cysts and monomorphic epithelioid cells arranged in solid sheets, nests or pseudopapillae. Two cases of neuroendocrine tumors showed tumor cells arranged in cords or nests; one case had a mitotic count of about 3/10 high power field, and a Ki-67 index of about 5%, which was consistent with G2 neuroendocrine tumor; the other case showed tumor cells with cytological atypia, brisk mitoses, about 25/10 HPF and a Ki-67 index of about 80%, consistent with small-cell type neuroendocrine carcinoma. The case of acinar cell carcinoma showed high cellularity, tumor cells in solid, cord-like or acinar-like arrangement with little stroma, and monotonous tumor cells with single distinct nucleolus. There were 4 cases of mesenchymal tumors, including 3 cases of Kaposi's hemangioendothelioma and 1 case of inflammatory myofibroblastic tumor. Among the 20 cases (47.6%) of non-neoplastic lesions, there were 11 cases of hyperinsulinism with ATP-sensitive potassium channel abnormality (HAPCA). Severn cases of diffuse type HAPCA in which the islets scattered between the pancreatic acinar tissue, enlarged, and prominent nuclei. Three cases of focal type HAPCA showed pancreatic islet hyperplasia in the form of nested nodules (0.6-1.5 cm). One case of atypical type HAPCA had extensive islet hyperplasia in pancreatic tissue, and scattered proliferation of nest-like nodules was noted. There were also 7 cases of pseudocyst and 2 cases of congenital cyst. Immunohistochemically, pancreatoblastomas were diffusely positive for CKpan, CK8/18, and β-catenin (nuclear staining of squamous nests only). Solid-pseudopapillary tumors expressed CD10, cyclin D1, CD99, vimentin, CD56, and β-catenin (nuclear staining). Neuroendocrine tumors were positive for CK, Syn, NSE, CgA, CD56, and β-catenin (membranous staining). The acinar cell carcinoma was positive for CK8/18, trypsin, and β-catenin (membranous staining). Conclusions: Pancreatic lesions in children have a wide range of histopathological types. HAPCA is the most common lesion of newborns. Pediatric pancreatic tumors are rare and mostly malignant. It is important to recognize them and make correct pathological diagnoses.

1467-P: Chemical Profiles of Acinar Tissue and Pancreatic Islets from Healthy and T2D-Affected Pancreata

Both the endocrine and exocrine pancreas demonstrate morphological and chemical changes associated with T2D development. Despite significant progress, chemical profiles of the islets and acinar tissue following disease progression are not well characterized. In this work we investigated isolated populations of pancreatic islets (n=18) and acinar tissues (n=7) collected from healthy and T2D affected pancreata using several mass spectrometry (MS) approaches. Samples are provided by the ADI IsletCore and the Network for Pancreatic Organ Donors with Diabetes (nPOD) . Both peptide and metabolite profiles were determined and compared via chemical profiling with matrix-assisted laser desorption/ionization Fourier-transform ion cyclotron resonance MS. Not surprisingly, the peptide profiles from T2D islets demonstrated lower signal intensities compared to healthy islets (ROC analysis, AUC=0.9) . Somatostatin, pancreatic icosapeptide, and insulin-related signals are most decreased. Preliminary data for acinar tissues indicate lower peptide levels in samples collected from T2D-affected (n=2) vs. healthy (n=5) pancreata. Several unique peptides are detected specifically in acinar tissue obtained from T2D-affected pancreata. Liquid chromatography-MS reveals a complex endogenous peptide complement of acinar tissue. Analysis of extracellular media for both islet types demonstrated similar differences (AUC=0.7) indicating higher levels of observed peptides in preparations from healthy islets, perhaps suggesting that peptides are released from the islets during shipment. Integrity of received islets was verified using dithizone staining prior to measurement. In contrast, almost no peptide markers of acinar tissue are found in corresponding extracellular media. Our results enhance knowledge on biochemical signature of T2D in the pancreas. Disclosure S.Rubakhin: None. E.V.Romanova: None. J.V.Sweedler: None. Funding American Diabetes Association (1-18-VSN-19)

Suppression of mutant Kirsten-RAS (KRASG12D)-driven pancreatic carcinogenesis by dual-specificity MAP kinase phosphatases 5 and 6

The cytoplasmic phosphatase DUSP6 and its nuclear counterpart DUSP5 are negative regulators of RAS/ERK signalling. Here we use deletion of either Dusp5 or Dusp6 to explore the roles of these phosphatases in a murine model of KRASG12D-driven pancreatic cancer. By 56-days, loss of either DUSP5 or DUSP6 causes a significant increase in KRASG12D-driven pancreatic hyperplasia. This is accompanied by increased pancreatic acinar to ductal metaplasia (ADM) and the development of pre-neoplastic pancreatic intraepithelial neoplasia (PanINs). In contrast, by 100-days, pancreatic hyperplasia is reversed with significant atrophy of pancreatic tissue and weight loss observed in animals lacking either DUSP5 or DUSP6. On further ageing, Dusp6−/− mice display accelerated development of metastatic pancreatic ductal adenocarcinoma (PDAC), while in Dusp5−/− animals, although PDAC development is increased this process is attenuated by atrophy of pancreatic acinar tissue and severe weight loss in some animals before cancer could progress. Our data suggest that despite a common target in the ERK MAP kinase, DUSP5 and DUSP6 play partially non-redundant roles in suppressing oncogenic KRASG12D signalling, thus retarding both tumour initiation and progression. Our data suggest that loss of either DUSP5 or DUSP6, as observed in certain human tumours, including the pancreas, could promote carcinogenesis.

Safety of Irreversible Electroporation Ablation of the Pancreas.

To evaluate the safety of irreversible electroporation (IRE) on swine pancreatic tissue including its effects on peripancreatic vessels, bile ducts, and bowel. Eighteen Yorkshire pigs underwent IRE ablation of the pancreas successfully and without clinical complications. Contrast-enhanced computed tomography angiography and laboratory studies before the IRE ablation with follow-up computed tomography angiography, laboratory testing, and pathological examination up to 4 weeks postablation were performed. In a subset of cases, anatomic peripancreatic vessel narrowing was seen by 1 week postablation, persisting at 4 weeks postablation, without apparent functional impairment of blood flow. Laboratory studies revealed elevated amylase and lipase at 24 hours post-IRE, suggestive of acute pancreatitis, which normalized by 4 weeks post-IRE. There was extensive pancreatic tissue damage 24 hours after IRE with infiltration of immune cells, which was gradually replaced by fibrotic tissue. Ductal regeneration without loss of pancreatic acinar tissue and glandular function was observed at 1 and 4 weeks postablation. In our study, we demonstrated and confirmed the safety and minimal complications of IRE ablation in the pancreas and its surrounding vital structures. These results show the potential of IRE as an alternative treatment modality in patients with pancreatic cancer, especially those with locally advanced disease.

Histological and transcriptional characterization of the pancreatic acinar tissue in type 1 diabetes

IntroductionDespite a reduced function and volume of the exocrine pancreas in type 1 diabetes, the acinar cells remain understudied in type 1 diabetes research. The hypothesis of this study is...

Large pancreatic myoepithelial hamartoma associated with familial insulin dependent diabetes mellitus

Presenter: Jeffrey Ord BS | Duke University Medical Center Background: Pancreatic myoepithelial hamartoma (PMEH) is a rare, benign solid and cystic lesion of the pancreas which can appear as a solid mass or solid-cystic lesion. Patients with pancreatic hamartomas may present with vague abdominal pain, pancreatitis, biliary obstruction or may be entirely asymptomatic. Histologic features of PMEH include small to medium-sized ductal structures lined by columnar epithelium and disarranged acini surrounded by smooth muscles and varying amounts of fibrous stroma. While several reports of pancreatic hamartomas exist, there are only 3 confirmed cases of PMEH in the literature, all of which presented as discrete pancreatic head masses. Two of these cases were associated with a single family, all originated in Eastern Asia. Methods: The first case of an adult with a giant myoepithelial hamartoma extending throughout the pancreatic gland associated with familial diabetes is described. Results: A 46-year-old male was referred to Duke University Hospital with recurrent acute pancreatitis. CT showed a 10.3x9.3x6.7cm heterogeneous calcified pancreatic head solid-cystic mass (figure 1). Pertinent medical history includes insulin dependent diabetes mellitus (IDDM) diagnosed at age 30 and family history of endocrine and exocrine pancreatic disease in paternal lineage. Paternal grandmother similarly had early adult onset IDDM and chronic pancreatitis which required a pancreaticoduodenectomy, revealing a 3x4x2cm necrotic pancreatic pseudocyst with hamartomatous characteristics. Endoscopic ultrasound (EUS) showed a large heterogenous, calcified, mixed solid and cystic mass extending from the pancreatic head through the pancreatic body. Fine-needle aspiration (FNA) returned benign pancreatic acinar tissue and smooth muscle without evidence of malignancy. Surgery was performed due to recurrent bouts of pancreatitis requiring multiple hospitalizations. Total pancreatectomy was performed due to the diffuse nature of the cystic disease and preexisting IDDM. On gross examination, the pancreas was diffusely enlarged, particularly in the head with replacement of normal parenchyma by pale tan to white whorled solid tissue with multiple cystic spaces up to 1.3x1cm filled with viscous fluid and calculi (figure 2). Microscopic hematoxylin-eosin staining showed disorganized bundles of smooth muscle with numerous embedded small ducts and cysts, with scattered pancreatic exocrine lobules exhibiting chronic inflammation and pancreatic calculi (figure 3). Immunohistochemical stain for desmin and caldesmon was strongly positive in smooth muscle cells. The histopathologic diagnosis was consistent with myoepithelial hamartoma. Conclusion: There are three published cases of PMEH, all originating from Eastern Asia. This is the first case of PMEH reported in the western literature and the first case of diffuse PMEH with near total replacement of the entire pancreatic parenchyma. This case draws several similarities to one case series of PMEH in mother, son and daughter—including possible familial inheritance, recurrent episodes of acute pancreatitis, honeycombed/microcystic appearance on MRI. However, uniquely, this case includes a strong family history of heritable IDDM. Improved identification and management of rare conditions including PMEH will heavily depend on increasing awareness, reporting and genetic study of future cases.

Clinicо-morphological diagnostics and surgical treatment of paraduodenal pancreatitis

Paraduodenal pancreatitis (PDP) is a rare disease that develops as a result of chronic inflammation of the ectopically located pancreas in the duodenal wall. Aim. Present our own observations of paraduodenal pancreatitis as a rare pathological condition, its clinical and pathomorphological manifestations, methods of diagnosis and surgical treatment.Materials and methods. An analysis of clinical and instrumental studies and the results of surgical treatment was carried out in eight patients with PDP, who underwent pancreatoduodenal resection in the clinic of surgery and minimally invasive technologies of Zaporizhzhia State Medical Academy of Postgraduate Education of the Ministry of Health of Ukraine and in the multidisciplinary clinical hospital VITACENTER (Zaporizhzhia) in 2015–2019 (6 patients), gastric resection according to Billroth 2 (1 patient), one patient refused surgery. All patients were examined by laboratory methods and modern methods of radiation diagnostics, pathomorphological examination of the operating material was performed in the pathological department of the Zaporizhzhia Regional Pathological Bureau. Paraffin sections for histopathological examination were stained with hematoxylin and eosin and analyzed using Leica DM2000Led microscope (Germany) with Leica MC190HD camera.Results. Preoperative diagnosis of PDP was established in 7 (87.5 %) patients, in 1 case, before the operation, the diagnosis was made of cystic tumor of the head of the PO. A characteristic feature of PDP on computer tomography was the presence of a thickened fibrous plate between the head of the pancreas (RV) and the duodenum (DPC), more pronounced in the venous phase, and the presence of cystic formations in the paraduodenal zone. Endoscopic examination revealed deformity with stenosis or submucosal formation in the descending part of the duodenum. Endoscopic ultrasound examination revealed a thickening of the duodenum wall with the presence of cystic formations.In macroscopic examination of the removed pathology specimen, the walls of the duodenum were thickened, with cicatricial changes and cystic cavities. The main pathological sign of PDP was the presence of ectopic foci of pancreatic acinar tissue and clusters of abnormal pancreatic ducts of various sizes with periductal chronic inflammation found in 4 (57.2 %) cases in the fibrously changed thickened wall of the duodenum. In all cases, in the fields of fibrosis and chronic inflammation, cysts of various sizes were found: ductal cysts lined with ductal epithelium, and acinar cysts without epithelial lining with thickened connective tissue walls (encapsulated foci of enzymatically self-destroyed pancreatic tissue). In 5 (62.5 %) patients in the area of pancreatic ectopia microscopy Brunner’s gland hyperplasia was revealed. In 6 (75 %) patients, chronic inflammation and dense fibrosis in the region of the pancreato-duodenal sulcus was revealed, as well as chronic inflammation and peri-intralobular fibrosis of the pancreatic head adhesion to the duodenum. Complications after pancreatoduodenectomy were observed in 2 (28.5 %) patients in the form of gastrostasis (type B according to ISGPS) and pancreatic fistula (type B according to ISGPF). In the long-term period, there was an improvement in the condition of 2 patients with stabilization of weight and an improvement in the functional state according to the scales of the SF-36 and EORTIC questionnaires. In other patients, the follow-up period does not exceed 1 year. Conclusions. The optimal method of clinical diagnosis of paraduodenal pancreatitis is endoscopic ultrasound, and its pathomorphological confirmation is the presence of ectopic pancreatic tissue or cysts in the duodenal wall, chronic inflammation and fibrosis, Brunner's gland hyperplasia, chronic inflammation in the area of pancreato-duodenal inflammation and fibrosis in the pancreatic head adhesion. The most justified method of surgical treatment of paraduodenal pancreatitis is still pancreatoduodenectomy.

A Case Of Pancreatic Hamartoma Mimicking Malignancy: An Uncommon Pitfall

Abstract Casestudy Hamartomas are benign, disordered, tumor-like growth of cellular constituents resembling the tissue of its origin. Hamartomas are usually seen in lung, heart, kidney and spleen. Pancreatic hamartomas (PH) are extremely rare, accounting for <1% of all hamartomas. PH occurs at any age (median: 50 years) without gender predilection. PH presents as single or multiple, solid and/or cystic mass composed of exocrine tissues. Admixed neuroendocrine cells may be seen, but well-formed islets are unusual. PH stroma is typically positive for CD34 by immunohistochemistry. We present a case of a PH resected for the clinical suspicion of malignancy, with the final diagnosis established postoperatively. The case is that of a 74-year-old male with an incidental 2.3 x 1.7 x 1.1 cm hyperenhancing solid mass of the pancreatic uncinate process, found during anemia workup. The radiologic appearance was suspicious for a neuroendocrine tumor. Biopsy of the mass showed benign-appearing pancreatic ductal and acinar tissue. Given the clinical suspicion of malignancy, the patient elected to undergo a pancreaticoduodenectomy. Macroscopically the mass was well-circumscribed with solid, tan-white, firm cut surface. Microscopic examination revealed well- circumscribed proliferation of disorderly-arranged, well-differentiated, bland exocrine pancreatic tissue. Chromogranin, synaptophysin and CD56 immunostains did not highlight significant neuroendocrine component. Ki-67 proliferation index was low (1%). CD34 and CD117 immunostains were negative in the stroma. The findings were consistent with PH. Conclusion PH may mimic a malignant process of the pancreas. The preoperative diagnosis of PH is extremely challenging due to the lack of characteristic clinical and radiological features, therefore, the diagnosis of PH is often made on resection specimen. CD34 immunostain is not always helpful for the diagnosis as it may be negative in PH stroma. Although extremely rare, pancreatic hamartoma should be considered in the differential diagnosis of a pancreatic tumor.

Fatty acid ethyl ester (FAEE) associated acute pancreatitis: An ex-vivo study using human pancreatic acini

Background & aimFatty acid ethyl esters (FAEEs), are produced by non-oxidative alcohol metabolism and can cause acinar cell damage and subsequent acute pancreatitis in rodent models. Even though experimental studies have elucidated the FAEE mediated early intra-acinar events, these mechanisms have not been well studied in humans. In the present study, we evaluate the early intra-acinar events and inflammatory response in human pancreatic acinar tissues and cells in an ex-vivo model. MethodsExperiments were conducted using normal human pancreatic tissues exposed to FAEE. Subcellular fractionation was performed on tissue homogenates and trypsin and cathepsin B activities were estimated in these fractions. Acinar cell injury was evaluated by histology and immunohistochemistry. Cytokine release from exposed acinar cells was evaluated by performing Immuno-fluorescence. Serum was collected from patients with AP within the first 72 h of symptom onset for cytokine estimation using FACS. ResultsWe observed significant trypsin activation and acinar cell injury in FAEE treated tissue. Cathepsin B was redistributed from lysosomal to zymogen compartment at 30 min of FAEE exposure. IHC results indicated the presence of apoptosis in pancreatic tissue at 1 & 2hrs of FAEE exposure. We also observed a time dependent increase in secretion of cytokines IL-6, IL-8, TNF-α from FAEE treated acinar tissue. There was also a significant elevation in plasma cytokines in patents with alcohol associated AP within 72 h of symptom onset. ConclusionOur data suggest that alcohol metabolites can cause acute acinar cell damage and subsequent cytokine release which could eventually culminant in SIRS.

83-OR: Pancreatic Exocrine to Endocrine Cell Cross Talk Mediates Endoplasmic Reticulum Stress and Beta-Cell Dysfunction in MODY8

MODY8 (maturity onset diabetes of the young, type 8) is a dominantly inherited monogenic form of diabetes. This disease is associated with frameshift mutations in the carboxyl ester lipase (CEL) gene expressed by pancreatic acinar tissue. Patients with the mutation develop childhood-onset exocrine pancreas dysfunction followed by diabetes during adulthood. However, it is unclear how CEL mutations cause diabetes in MODY8 patients. In this study, we investigated the potential crosstalk between exocrine acinar cells and endocrine beta cells in vitro. Co-culture of beta cells (EndoC-bH1 beta cells) with donor cells (HEK293 embryonic kidney cells or 266-6 acinar cells) overexpressing mutant or wild type CEL gene in an in vitro transwell system demonstrated transfer of mutant protein from donor cells to beta cells. While both the wild type and mutant CEL proteins were observed to be taken up by the beta cells there was a significantly higher amount of the mutant (11.4±2.3% cells) compared to the wild type protein (1.8±0.7% cells) (n=3, p<0.01 mutant vs. wild type). The mutant protein formed intracellular aggregates represented as punctuate structures within the cytoplasm of beta cells. Culturing beta cells in mutant donor cell-conditioned media for 12 days activated the unfolded protein response, and increased endoplasmic reticulum stress by promoting the gene expression of BiP, spliced XBP1, and caused beta cell secretory dysfunction (insulin stimulation index 16.7 mM/3.3 mM: 1.3±0.1 (mutant) vs. 2.1±0.3 fold (wild type), n=8, p=0.05). Our data indicate a unique crosstalk between pancreatic acinar and beta cells, which adversely affects the latter by increasing ER stress and impairing insulin secretion. This study provides one possible explanation of how a mutant gene expressed specifically in acinar cells causes endocrine cell dysfunction and diabetes in MODY8 patients. Disclosure S. Kahraman: None. D. Diegisser: None. B.B. Johansson: None. A. Molven: None. R. Kulkarni: None. Funding National Institutes of Health (R01DK67536)

Development of pancreatic acini in embryos of the grass snake Natrix natrix (Lepidosauria, Serpentes).

This study report about the differentiation of pancreatic acinar tissue in grass snake, Natrix natrix, embryos using light microscopy, transmission electron microscopy, and immuno-gold labeling. Differentiation of acinar cells in the embryonic pancreas of the grass snake is similar to that of other amniotes. Pancreatic acini occurred for the first time at Stage VIII, which is the midpoint of embryonic development. Two pattern of acinar cell differentiation were observed. The first involved formation of zymogen granules followed by cell migration from ducts. In the second, one zymogen granule was formed at the end of acinar cell differentiation. During embryonic development in the pancreatic acini of N. natrix, five types of zymogen granules were established, which correlated with the degree of their maturation and condensation. Within differentiating acini of the studied species, three types of cells were present: acinar, centroacinar, and endocrine cells. The origin of acinar cells as well as centroacinar cells in the pancreas of the studied species was the pancreatic ducts, which is similar as in other vertebrates. In the differentiating pancreatic acini of N. natrix, intermediate cells were not present. It may be related to the lack of transdifferentiation activity of acinar cells in the studied species. Amylase activity of exocrine pancreas was detected only at the end of embryonic development, which may be related to animal feeding after hatching from external sources that are rich in carbohydrates and presence of digestive enzymes in the egg yolk. Mitotic division of acinar cells was the main mechanism of expansion of acinar tissue during pancreas differentiation in the grass snake embryos.

3096 Esophageal Pancreatic Acinar Ectopia—Premalignant or Benign: A Case Report and Brief Literature Review

INTRODUCTION: Esophageal Pancreatic Acinar Ectopia (EPAE) is a rare incidental endoscopy finding with reported prevalence ranging from 16% to 24% in asymptomatic patients and 3% in patients with Barrette Esophagitis, EPAE has been found in patients as young as 1 day old to incidental autopsy finding. We present a brief literature review and a case of EPAE in distal esophagus with severe dysphagia associated with active inflammation and focal metaplasia. CASE DESCRIPTION/METHODS: A 59 year old male with medical history of Degenerative Joint Disease (DJD), HTN, GERD, and chronic constipation presented to GI clinic with complaint of insidiously worsening dysphagia to solid food of 4 months duration. He also endorsed 30-pound weight loss and denied any other associated symptoms. He has significant family history of colon cancer. He is a current smoker with 10 pack years. His medications include Hydrochlorothiazide, Amlodipine, Lisinopril, Atorvastatin and Nexium. Physical exam revealed no significant findings in all systems, including gastrointestinal. Most recent labs including hematology and chemistry were within normal limits. An endoscopy was performed which revealed slightly irregular gastroesophageal (GE) junction, 5 × 3 cm pink rubbery mass at the GE junction which was biopsied, and an irregular gastric mucosa with biopsy obtained. The biopsy obtained from the GE junction revealed intestinal metaplasia and pancreatic acinar type tissue with no dysplasia while the biopsy from the stomach revealed numerous h-pylori, intestinal metaplasia with active chronic gastritis. At follow up appointment 2 weeks after the endoscopy, patient reported complete resolution of dysphagia and improvement in constipation. DISCUSSION: A review of the literature showed that Esophageal Pancreatic Acinar Ectopia (EPAE) is often an incidental finding, with prevalence in up to 24 percent of all adults and no associated symptoms in most. It has however been associated with symptoms like epigastric pain, hemoptysis, odynophagia, dysphagia, and pathologies like esophageal atresia, anaplastic carcinoma, pancreatitis, IPMN, and squamous cell carcinoma. EPAE has been documented in neonates making congenital etiology most plausible. Our case bolsters the knowledge that dysphagia, which is the most common presenting symptom in EPAE, is likely due to mass effect and our literature review revealed that most pathologies known to pancreatic tissue are possible in EPAE.

2932 Histological Diagnosis of Pancreatic Serous Cystadenomas Using a 22G Core Biopsy Needle: A Case Series

INTRODUCTION: Pancreatic Serous Cystadenoma or Pancreatic Cystic Serous Neoplasm (SCN) are a type of benign pancreatic tumor that account for 1-2% of all pancreatic masses. They are most often benign, with very rare malignant potential. SCN's will often have a cystic or honeycomb appearance on CT scan. In the past, the mainstay of diagnosing SCN has been via endoscopy ultrasound (EUS) with fine needle aspiration (FNA) to assess fluid for CEA levels and also for cytological analysis. However fluid can be difficult to obtain and often there is not enough cellularity for cytology. In this case series of 7 patients we performed fine needle biopsy (FNB) of the cell walls of pancreatic cysts as a technique for histological review. METHODS: We retrospectively reviewed medical records of patients who underwent EUS for FNA for fluid sampling of pancreatic cysts but due to microcystic nature a decision was made to proceed with FNB to obtain tissue for histology. FNB was done using 22 G FNB needle with slow stylet pull technique. The tissue was placed in formalin for histological analysis by an expert GI pathologist. RESULTS: A total of seven patients were evaluated. The mean age was 75 years old and 5 of the patients were female. All patients had one cyst that was sampled. The location of the cyst was on the head in 1 of the patients and body or tail of the other 6 patients. The mean cyst size was 31.1 mm (range 14-40 mm). There were no post procedure complications. All seven samples were adequate for histological analysis. Six out of the seven biopsy samples were consistent with serous cystadenomas. One samples showed benign pancreatic acinar tissue and stroma without malignancy. CONCLUSION: Management of pancreatic SCNs can be challenging as no follow up is recommended if the diagnosis is confirmed but lots of times a definite diagnosis cannot be made based on endosonographic and CT/MRI findings. These patients can be potentially subject to repeat imaging for surveillance. Here we show that pursuing FNB instead of FNA for microcystic lesions can yield enough tissue for histological diagnosis of SCNs and can alter management and avoid further imaging.

NMR-based metabolic profiling of urine, serum, fecal, and pancreatic tissue samples from the Ptf1a-Cre; LSL-KrasG12D transgenic mouse model of pancreatic cancer.

Pancreatic cancer is the third leading cause of cancer deaths in the United States with more than 53,000 expected to be diagnosed with the disease in 2018. The median survival time after diagnosis is four to six months. The poor survival statistics are due in part to the fact that pancreatic cancer is typically asymptomatic until it reaches advanced stages of the disease. Although surgical resection provides the best chance of survival, pancreatic cancer is rarely detected when surgery is still possible due, in part, to lack of effective biomarkers for early detection. The goal of the research reported here was to determine if it was possible to identify metabolic biomarkers for detection of pre-cancerous pancreatic intraepithelial neoplasia (PanIN) that precede pancreatic adenocarcinoma. The transgenic Ptf1a-Cre; LSL-KrasG12D mouse strain was used as a model of pancreatic cancer progression. Nuclear magnetic resonance (NMR) spectroscopy was employed to compare metabolic profiles of urine, sera, fecal extracts, and pancreatic tissue extracts collected from control and study mice aged 5, 11, and 15 months, including 47 mice with tumors. We were able to identify the following potential biomarkers: decreased 3-indoxylsulfate, benzoate and citrate in urine, decreased glucose, choline, and lactate in blood, and decreased phenylalanine and benzoate and increased acetoin in fecal extracts. Potential biomarkers were validated by p-values, PLS-DA VIP scores, and accuracies based on area under ROC curve analyses. Essentially, all of the metabolic profiling changes could be explained as being associated with the consequences of bicarbonate wasting caused by a complete substitution of the normal pancreatic acinar tissue by tissue entirely composed of PanIN. Given the nature of the mouse model used here, our results indicate that it may be possible to use NMR-based metabolic profiling to identify biomarkers for detection of precancerous PanIN that immediately precede pancreatic cancer.

Phenylalanine regulates initiation of digestive enzyme mRNA translation in pancreatic acinar cells and tissue segments in dairy calves.

As new nutritional strategies for ruminant are designed to change production efficiency by improving the supply of rumen protect protein, lipid, and even starch, the digestive system must fit to utilize these increased nutrient supplies, especially the pancreas. The objective of this study was to investigate the effects of phenylalanine (Phe) on digestive enzymes synthesis or secretion and cellular signaling in pancreatic acinar (PA) cells of dairy calves. The PA cells isolated from fresh pancreas of dairy calves, and cultured in completed RIPA 1640 medium with no fetal serum but 0, 0.15 and 0.45 mM Phe at 37°C in CO2 incubator for 120 min. The pancreatic tissue segments (PTS) was cut approximately 2 × 2 mm from the fresh pancreas, and incubated in oxygenated Krebs-Ringer bicarbonate (KRB) buffer containing 0 or 0.35 mM Phe at 39°C for 180 min, and the samples were collected every 60 min after incubation. In PA cells, Phe increased (P < 0.05) the α-amylase secretion and mRNA expression, the phosphorylation of ribosomal protein S6 kinase 1 (S6K1) and eukaryotic initiation factor 4E binding protein 1 (4EBP1). In PTS, the Phe increased (P < 0.05) α-amylase and trypsin synthesis, secretion and mRNA expression, as well as the phosphorylation of S6K1 and 4EBP1. Conclusively, these results suggested that Phe regulates the synthesis or secretion of α-amylase, trypsin and lipase through mRNA translation initiation factors – S6K1 and 4EBP1.

Transient Impairment of Islet Architectural Development in Pancreas-Specific Bmpr1a-Deleted Prenatal Mice Involves Reduced Expression of E-Cadherin.

Bone morphogenetic protein (BMP) signaling plays critical roles on the development of a large array of embryonic organs and promotes the in vitro formation of pancreatic cystoid colonies containing insulin-producing cells. However, this signaling and its underlying mechanism on in vivo development of prenatal pancreas have not been clearly understood. To address these questions, we analyzed, with a variety of techniques, the prenatal mouse pancreas after Pdx1 (the pancreas and duodenum homeobox factor 1 gene)-driving deletion of the BMP receptor type 1a gene (Bmpr1a). In this study, we report that the Pdx1-driving deletion of Bmpr1a transiently disrupted only the assembly of architectural structure of prenatal islets. The differentiation of endocrine lineage cells and the development of pancreatic acinar tissue were comparable between Bmpr1a-deleted fetuses and -undeleted Controls throughout the period examined. Molecular studies revealed that among many proteins surveyed, the key cell-cell interaction molecule E-cadherin (E-cad) only was expressed significantly less at both messenger RNA (mRNA) and protein levels in Bmpr1a-deleted than Control fetal endocrine cells. We thus conclude that BMP signaling transiently regulates the expression of E-cad and the establishment of prenatal islet architecture.