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Pancreatic adenocarcinoma patients with localised chronic severe pancreatitis show an increased number of single beta cells, without alterations in fractional insulin area.

ABSTRACT: AIMS/HYPOTHESIS:Recent histological analysis of pancreases obtained from patients with long-standing type 1 diabetes identified chronic islet inflammation and limited evidence suggestive of beta cell replication. Studies in rodent models also suggest that beta cell replication can be induced by certain inflammatory cytokines and by gastrin. We therefore tested the hypothesis that beta cell replication is observed in non-autoimmune human pancreatic disorders in which localised inflammation or elevated gastrin levels are present. METHODS:Resected operative pancreatic specimens were obtained from patients diagnosed with primary adenocarcinoma (with or without chronic severe pancreatitis) or gastrinoma. Additional pancreatic tissue was obtained from autopsy control patients. Immunohistochemistry was used to assess fractional insulin area, beta cell number and replication rate and differentiation factors relevant to beta cell development. RESULTS:Fractional insulin area was similar among groups. Patients with pancreatic adenocarcinoma and localised chronic severe pancreatitis displayed significant increases in the number of single beta cells, as well as increased beta cell replication rate and levels of neurogenic differentiation 1 in islets. Patients with gastrinoma demonstrated significant increases in the number of single beta cells, but the beta cell replication rate and islet differentiation factor levels were similar to those in the control group. CONCLUSIONS/INTERPRETATION:These findings indicate that chronic severe pancreatic inflammation can be associated with significant effects on beta cell number or replication rate, depending on the distribution of the cells. This information may prove useful for attempts seeking to design therapies aimed at inducing beta cell replication as a means of reversing diabetes.

SUBMITTER: Campbell-Thompson M

PROVIDER: S-EPMC7321839 | biostudies-literature | 2009 Feb

REPOSITORIES: biostudies-literature

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Pancreatic adenocarcinoma patients with localised chronic severe pancreatitis show an increased number of single beta cells, without alterations in fractional insulin area.

Campbell-Thompson M M Dixon L R LR Wasserfall C C Monroe M M McGuigan J M JM Schatz D D Crawford J M JM Atkinson M A MA

Diabetologia 20081111 2

<h4>Aims/hypothesis</h4>Recent histological analysis of pancreases obtained from patients with long-standing type 1 diabetes identified chronic islet inflammation and limited evidence suggestive of beta cell replication. Studies in rodent models also suggest that beta cell replication can be induced by certain inflammatory cytokines and by gastrin. We therefore tested the hypothesis that beta cell replication is observed in non-autoimmune human pancreatic disorders in which localised inflammatio ...[more]

PMID: 19002428

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Project description:ObjectivesMetabolomics-based diagnosis or prediction of risk may improve patient outcomes and improve understanding of the pathogenesis of acute pancreatitis (AP). Endoscopic retrograde cholangiopancreatography (ERCP) is a risk factor for developing AP. This pilot study examined metabolomes of patients before and after ERCP, hypothesizing that metabolomics could differentiate between patients who did and did not develop post-ERCP pancreatitis, and that biomarkers associated with development of AP could be identified.MethodsPatients at high risk for developing post-ERCP pancreatitis were prospectively enrolled at the University of Minnesota from October 2012 to February 2014. Urine and serum samples were collected before ERCP, 2 h after ERCP, and daily thereafter if patients were admitted to the hospital with AP. Pancreatitis severity was calculated with Bedside Index for Severity in Acute Pancreatitis (BISAP) and Modified Glasgow scores. Patients who developed AP (n=9) were matched to patients who did not develop AP (n=18) by age and gender. Urine and serum metabolites were profiled with nuclear magnetic resonance spectroscopy. Partial least squares discriminant analysis (PLS-DA) was performed to detect changes in metabolic profiles associated with development of pancreatitis. Metabolic networks were constructed to probe functional relationships among metabolites.ResultsOf the 113 enrolled patients, 9 developed mild AP according to BISAP and modified Glasglow scores. PLS-DA showed common differences between pre- and post-ERCP metabolic profiles in urine and serum regardless of AP status, characterized by increases in serum and urine ketones and serum glucose. Pre-ERCP lipase levels were somewhat elevated in those who went on to develop AP, though this did not reach statistical significance. Metabolic networks differed between patients with AP and those without after ERCP; however, metabolomics did not identify specific prognostic or diagnostic markers of ERCP-induced AP. Aspartate and asparagine were identified as well-connected hubs in post-ERCP serum networks of cases and were correlated with aspartate transaminase (AST) and white blood cell count levels. These features were not evident in controls. Serum aspartate was elevated in AP patients relative to those without AP after ERCP (P=0.03).ConclusionsIn this pilot study, ERCP was found to induce global changes in urine and serum metabolomes indicative of alterations in pancreatic function and insulin resistance. This should be taken into consideration in future research on this topic. Post-ERCP serum metabolic networks indicate functional differences surrounding aspartate metabolism between patients with AP and those without. Further study must be done in larger patient populations to test elevated lipase as a prognostic biomarker associated with risk of developing AP and to examine active metabolic mechanisms at work.

Project description:Background: Lung adenocarcinoma (LUAD) possesses a poor prognosis with a low 5-year survival rate even for stages I-III resected patients, it is thus critical to understand the determinants that affect the survival and discover new potentially prognostic biomarkers. Somatic copy number alterations (CNAs) are major source of genomic variations driving tumor evolution, CNAs screening may identify prognostic biomarkers. Methods: Oncoscan MIP array was used to analyze the patterns of CNAs on formalin fixed paraffin embedded(FFPE) tumor specimens from 163 consecutive stage I-III resected LUAD patients, 145 out of which received platinum-based adjuvant chemotherapy. Results: Of the 163 patients, 91(55.8%) were recurred within 3 years after surgery. The most common aberrations in our cohort were 1q, 5p, 5q, 7p, 8q, 14p, 16p, 17q, 20q for copy number gains and 8p, 9p, 13p, 16q, 18q for losses. The GISTIC2 analysis produced 45 amplification peaks and 40 deletion peaks, involving some reported genes TERT, EGFR, MYC, CCND1, CDK4, MDM2, ERBB2, NKX2-1, CCNE1, and CDKN2A, most of which were consistent with TCGA database. The amplifications of 12p12.1 (CMAS, GOLT1B, YS2, LDHB, RECQL, ETNK1, IAPP, PYROXD1, KRAS) and KDM5A were correlated with worse prognosis in our cohort, this result was further validated in 506 LUAD patients from TCGA. In addition, 163 patients could be well-classified into five groups, and the clinical outcomes were significantly different based on threshold copy number at reoccurring alteration peaks. Among the 145 patients who received adjuvant chemotherapy, focal amplification of ERBB2 and deletion of 4q34.3 were found to be specific in relapsed patients, this result was validated in an independent group of Imielinski et al., demonstrating these two CNAs may contribute to resected LUAD recurrence after adjuvant chemotherapy. Conclusion: This study suggests that CNAs profiling may be a potential prognostic classifier in resected LAUD patients. Amplifications of 12p12.1 and KDM5A might be prognostic biomarkers for LUAD, and amplification of ERBB2 and deletion of 4q34.3 predicted early relapse after adjuvant chemotherapy. These novel findings may provide implication for better implementation of precision therapy for lung cancer patients.

Dataset Information

Pancreatic adenocarcinoma patients with localised chronic severe pancreatitis show an increased number of single beta cells, without alterations in fractional insulin area.

Publications

Pancreatic adenocarcinoma patients with localised chronic severe pancreatitis show an increased number of single beta cells, without alterations in fractional insulin area.

Similar Datasets

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