Pancreatic Juice

BackgroundPancreatic intraepithelial neoplasias (PanINs) are precursors of malignant pancreatic cancer, an ideal stage for early cancer detection. We applied quantitative proteomics to identify aberrantly elevated proteins in pancreatic juice samples derived from patients with PanIN3.ResultsTwenty proteins were found elevated in all three PanIN juices by at least two-fold. Among these proteins, anterior gradient-2 (AGR2) was found to be 2-10 fold elevated in PanIN3 juice samples analyzed by quantitative proteomics. An ELISA assay was developed to evaluate AGR2 levels in 51 pancreatic juice samples and 23 serum samples from patients with pancreatic cancer, pre-malignant lesions (including PanIN3, PanIN2, Intraductal Papillary Mucinous Neoplasms (IPMNs)) and benign disease controls (including chronic pancreatitis). AGR2 levels in the pancreatic juice samples were found significantly elevated in patients with pre-malignant conditions (PanINs and IPMNs) as well as pancreatic cancer compared to control samples (p ConclusionsThese results suggest that elevation of AGR2 levels in pancreatic juice occurs in early pancreatic cancer progression and could be further investigated as a potential candidate juice biomarker for early detection of pancreatic cancer.

BackgroundPancreatic fistula (PF) is a common complication after pancreatic surgery. It is unclear how microbes in PF fluid affect outcomes and which microbes are present after pancreatoduodenectomy (PD) and distal pancreatectomy (DP). The aim of this study was to compare the microbiological spectrum of PF fluid after PD versus DP, and its association with postoperative complications.MethodsBacterial strains and antibiotic resistance rates of bacterial swabs obtained from the PF fluid of patients who underwent DP or PD were analysed. Cultured bacteria were classified as Enterobacterales and as 'other intestinal and non-intestinal microorganisms' based on whether they are typically part of the normal human intestinal flora.ResultsA total of 847 patients had a pancreatic resection (PD 600; DP 247) between July 2007 and December 2016. Clinically relevant PF was detected in 131 patients (15·5 per cent). Bacterial swabs were obtained from 108 patients (DP 47; PD 61), of which 19 (17·6 per cent) were sterile. Enterobacterales were detected in 74 per cent of PF fluid swabs after PD, and in 34 per cent after DP. Infected, polymicrobial or multidrug-resistant PF fluid was more common after PD (rates of 95, 50 and 48 per cent respectively) than after DP (66, 26 and 6 per cent respectively). Patients with higher grade complications (Clavien-Dindo grade IV-V) or grade C PF had more Enterobacterales and multidrug-resistant Enterobacterales in the PF fluid after DP.ConclusionEnterobacterales and multidrug-resistant bacteria are detected frequently after PD and DP, and are associated with more severe complications and PF in patients undergoing DP.

Intraductal papillary mucinous neoplasm (IPMN) of pancreas has a high risk to develop into invasive cancer or co-occur with malignant lesion. Therefore, it is important to assess its malignant risk by less-invasive approach. Pancreatic juice cell-free DNA (PJD) would be an ideal material in this purpose, but genetic biomarkers for predicting malignant risk from PJD are not yet established. We here performed deep exome sequencing analysis of PJD from 39 IPMN patients with or without malignant lesion. Somatic alterations and copy number alterations (CNAs) detected in PJD were compared with the histologic grade of IPMN to evaluate their potential as a malignancy marker. Somatic mutations of KRAS, GNAS, TP53, and RNF43 were commonly detected in PJD of IPMNs, but no association with the histologic grades of IPMN was found. Instead, mutation burden was positively correlated with the histologic grade (r = 0.427, P = 0.015). We also observed frequent copy number deletions in 17p13 (TP53) and amplifications in 7q21 and 8q24 (MYC) in PJDs. The amplifications in 7q21 and 8q24 were positively correlated with the histologic grade and most prevalent in the cases of invasive carcinoma (P = 0.002 and 7/11; P = 0.011 and 6/11, respectively). We concluded that mutation burden and CNAs detected in PJD may have potential to assess the malignant progression risk of IPMNs.

Pancreatic exocrine secretion is regulated by the physicochemical properties and nutrient composition of gastric and intestinal chyme. The present study examined integrative feedback mechanisms involved in the physiological control of pancreatic secretion, with particular emphasis on interactions between pancreatic juice, bile, and gut-derived regulatory and metabolic signals. A chronic porcine model enabling selective withdrawal and controlled reintroduction of pancreatic juice and bile into defined intestinal segments was employed. Duodenal and ileal exposure to pancreatic juice suppressed pancreatic enzyme secretion, while intraduodenal administration of pancreatin elicited a biphasic inhibitory response. Interruption of bile flow to the duodenum resulted in increased pancreatic protein output and was associated with reduced circulating cholecystokinin concentrations. In contrast, intraduodenal infusion of bile acids attenuated pancreatic exocrine secretion. Prolonged bile deprivation led to sustained pancreatic hypersecretion accompanied by a marked reduction in biliary leptin output. Collectively, these findings indicate that pancreatic exocrine secretion in pigs is regulated by multiple interacting feedback pathways operating along the gastrointestinal tract. The observed responses support functional contributions of protease-dependent luminal feedback, distal intestinal sensing, hormone-dependent regulation, and bile-associated metabolic modulation.