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This study investigates the degradation of six different types of absorbable surgical threads commonly used in clinical practice, focusing on their response to exposure to physiological fluids. The threads were subjected to hydrolytic and enzymatic degradation in physiological saline, bile, and pancreatic juice. Our findings demonstrate that bile and pancreatic juice, particularly when contaminated with bacterial strains such as Escherichia coli , Klebsiella spp., and Enterococcus faecalis , significantly accelerate the degradation process. Using Fourier-transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), and tensile strength testing, we observed distinct differences in the chemical structure and mechanical integrity of the sutures. Principal component analysis (PCA) of the FTIR spectra revealed that PDS threads exhibited the highest resistance to degradation, maintaining their mechanical properties for a longer duration compared with Monocryl and Vicryl. These results highlight the critical role of thread selection in gastrointestinal surgeries, where prolonged exposure to bile and pancreatic juice can compromise the suture integrity and lead to postoperative complications. The insights gained from this study will contribute to improving the selection and application of absorbable threads in clinical settings.

Background/objectives: Screening patients with intraductal papillary mucinous neoplasms (IPMN) has the primary goal of identifying potentially curable noninvasive precursors. We aimed to evaluate the diagnostic impact of genetic and epigenetic biomarkers in the presence of noninvasive precursors., Methods: Mutated KRAS/GNAS and methylated SOX17/TBX15/BMP3/TFPI2 DNA were assessed by droplet digital PCR in a discovery cohort of 70 surgically aspirated cyst fluids, and diagnostic performances for differentiating high-grade dysplasia (HGD) from low-grade dysplasia (LGD) was evaluated. We then tested these markers using an independent test cohort consisting of 156 serially collected pancreatic juice samples from 30 patients with IPMN., Results: Mutated KRAS and GNAS are specific for IPMNs but are not helpful for the prediction of histological grades. Cyst fluids from IPMN with HGD showed higher methylation levels of SOX17 (median, 0.141 vs. 0.021; P = 0.086) and TBX15 (median, 0.030 vs. 0.003; P = 0.028) than those with LGD. The combination of all tested markers yielded a diagnostic performance with sensitivity of 69.6%, and specificity of 90.0%. Among the 30 pancreatic juice samples exhibiting the highest abundance of KRAS/GNAS mutations in each patient in the test cohort, patients with histologically proven HGD due to pancreatic resection had a significantly higher prevalence (100% vs. 31%, P = 0.018) and abundance (P = 0.037) of methylated TBX15 than those without cytohistological diagnosis undergoing surveillance., Conclusions: A simultaneous and sequential combination of mutated and methylated DNA markers in pancreatic cyst fluid and juice sample markers can help detect noninvasive pancreatic precursor neoplasms., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2023 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Background and Aims: Pancreatic cancer has a dismal prognosis. So far, imaging has been proven incapable of establishing an early enough diagnosis. Thus, biomarkers are urgently needed for early detection and improved survival. Our aim was to evaluate the pooled diagnostic performance of DNA alterations in pancreatic juice., Methods: A systematic literature search was performed in EMBASE, MEDLINE Ovid, Cochrane CENTRAL and Web of Science for studies concerning the diagnostic performance of DNA alterations in pancreatic juice to differentiate patients with high-grade dysplasia or pancreatic cancer from controls. Study quality was assessed using QUADAS-2. The pooled prevalence, sensitivity, specificity and diagnostic odds ratio were calculated., Results: Studies mostly concerned cell-free DNA mutations (32 studies: 939 cases, 1678 controls) and methylation patterns (14 studies: 579 cases, 467 controls). KRAS, TP53, CDKN2A, GNAS and SMAD4 mutations were evaluated most. Of these, TP53 had the highest diagnostic performance with a pooled sensitivity of 42% (95% CI: 31-54%), specificity of 98% (95%-CI: 92%-100%) and diagnostic odds ratio of 36 (95% CI: 9-133). Of DNA methylation patterns, hypermethylation of CDKN2A, NPTX2 and ppENK were studied most. Hypermethylation of NPTX2 performed best with a sensitivity of 39-70% and specificity of 94-100% for distinguishing pancreatic cancer from controls., Conclusions: This meta-analysis shows that, in pancreatic juice, the presence of distinct DNA mutations (TP53, SMAD4 or CDKN2A) and NPTX2 hypermethylation have a high specificity (close to 100%) for the presence of high-grade dysplasia or pancreatic cancer. However, the sensitivity of these DNA alterations is poor to moderate, yet may increase if they are combined in a panel., Competing Interests: Declaration of competing interest I.J. Visser: No conflicts of interest. I.J.M Levink: No conflicts of interest. G.M Fuhler: No conflicts of interest. M.J. Bruno: Boston Scientific (Consultant, support for industry and investigator-initiated studies), Cook Medical (Consultant, support for industry and investigator-initiated studies), Pentax Medical (Consultant, support for investigator-initiated studies), Mylan (Support for investigator-initiated studies), ChiRoStim (Support for investigator-initiated studies). D.L Cahen: No conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: In intraductal papillary mucinous neoplasm, a mural nodule ≥5 mm is an important predictor of malignancy. Surgical indication is less clear in cases of intraductal papillary mucinous neoplasm without mural nodule ≥5 mm. This is a retrospective study evaluating predictors of high-grade dysplasia or invasive intraductal papillary mucinous carcinoma for intraductal papillary mucinous neoplasm without mural nodule ≥5 mm., Methods: Among consecutive patients who underwent surgery for intraductal papillary mucinous neoplasm between 1999 and 2018, 174 had intraductal papillary mucinous neoplasm with mural nodule ≥5 mm (mural nodule[+] ≥5 mm group). The remaining 155 patients had intraductal papillary mucinous neoplasm but did not have mural nodule ≥5 mm: 24 patients with mural nodule <5 mm (mural nodule[+] <5 mm group) and 131 patients without mural nodule (mural nodule[-] group). We investigated predictors of high-grade dysplasia or invasive intraductal papillary mucinous neoplasm in cases of intraductal papillary mucinous neoplasm without mural nodule ≥5 mm., Results: The frequency of high-grade dysplasia invasive intraductal papillary mucinous neoplasm was significantly higher in the mural nodule(+) ≥5 mm group (87.4%) than in the mural nodule(+) <5 mm group (37.5%, P < .001) and mural nodule(-) group (45.0%, P < .001). However, frequency was not significantly different between mural nodule(+) <5 mm and mural nodule(-) groups (P = .494). Multivariate analysis showed three independent predictors of high-grade dysplasia invasive intraductal papillary mucinous carcinoma in intraductal papillary mucinous neoplasm without mural nodule ≥5 mm: branch cyst ≥40 mm (P = .038, odds ratio 3.704; 95% confidence interval, 1.075-12.821), positive cytology of pancreatic juice (P = .039, odds ratio 16.792; 95% confidence interval, 1.152-244.744), and carcinoembryonic antigen in pancreatic juice ≥30 mg/mL (P < .001, odds ratio 14.925; 95% confidence interval, 4.525-50.0)., Conclusion: For cases of intraductal papillary mucinous neoplasm without mural nodule ≥5 mm, large cysts, positive cytology of the pancreatic juice, and high levels of carcinoembryonic antigen in pancreatic juice may be useful to determine surgical indication, although further studies are needed to confirm these results., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objectives: Endoscopic pancreatic function tests are used to diagnose pancreatic diseases and are a viable source for the discovery of biomarkers to better characterize pancreatic disorders. However, pancreatic fluid (PF) contains active enzymes that degrade biomolecules. Therefore, we tested how preservation methods and time to storage influence the integrity and quality of proteins and nucleic acids., Methods: We obtained PF from 9 subjects who underwent an endoscopic pancreatic function test. Samples were snap frozen at the time of collection; after 1, 2, and 4 hours on ice; or after storage overnight at 4°C with or without RNase or protease inhibitors (PIs). Electrophoresis and mass spectrometry analysis determined protein abundance and quality, whereas nucleic acid integrity values determined DNA and RNA degradation., Results: Protein degradation increased after 4 hours on ice and DNA degradation after 2 hours on ice. Adding PIs delayed degradation. RNA was significantly degraded under all conditions compared with the snap frozen samples. Isolated RNA from PF-derived exosomes exhibited similar poor quality as RNA isolated from matched PF samples., Conclusions: Adding PIs immediately after collecting PF and processing the fluid within 4 hours of collection maintains the protein and nucleic acid integrity for use in downstream molecular analyses., Competing Interests: Z.C.-M., P.A.H., G.B.L., and D.Y. received pilot funds from ChiRhoClin Research Institute, Inc. The rest of the authors declare no conflict of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Lycopene is one of the carotenoids often consumed by humans in their diet. Although lycopene exists mainly in the form of the all E-isomer in foods, the considerable quantity of its Z-isomers is found in the human plasma and liver. This observation suggested that the lycopene all-E-isomer was converted into Z-isomers in the human body. In this study, the Z-isomerization of the all-E-isomer was induced in vitro by the pancreatic juice and small intestinal homogenate of male rats under the conditions of 37 °C, pH = 7.5, nitrogen and darkness, as well as shaking. After 2 hours, the proportion of the all E-isomer decreased to 25% and Z-isomer amounts increased relatively. The converted products were identified as 5, 9, and 11 Z-isomers by electronic absorption spectroscopy and mass spectrometry (MS). The observations from this experiment suggested that the Z-isomerization site of the lycopene all E-isomer was located in the small intestinal wall of the rat.

Porcine pancreatic extracts (PPE), also named pancreatin, are commonly used as a global source of pancreatic enzymes for enzyme replacement therapy in patients with exocrine pancreatic insufficiency. They are considered as a good substitute of human pancreatic enzymes and they have become a material of choice for in vitro models of digestion. Nevertheless, while the global PPE contents in lipase, protease and amylase activities are well characterized, little is known about individual enzymes. Here we characterized the lipase, phospholipase, cholesterol esterase and galactolipase activities of PPE and compared them with those of porcine (PPJ) and human (HPJ) pancreatic juices. The phospholipase to lipase activity ratio was similar in PPJ and HPJ, but was 4-fold lower in PPE. The galactolipase and cholesterol esterase activities were found at lower levels in PPJ compared to HPJ, and they were further reduced in PPE. The enzymes known to display these activities in HPJ, pancreatic lipase-related protein 2 (PLRP2) and carboxylester hydrolase/bile salt-stimulated lipase (CEH/BSSL), were identified in PPJ using gel filtration experiments, SDS-PAGE and LC-MS/MS analysis. The galactolipase and cholesterol esterase activities of PPE indicated that PLRP2 and CEH/BSSL are still present at low levels in this enzyme preparation, but they were not detected by mass spectrometry. Besides differences between porcine and human enzymes, the lower levels of phospholipase, galactolipase and cholesterol esterase activities in PPE are probably due to some proteolysis occurring during the production process. In conclusion, PPE do not provide a full substitution of the lipolytic enzymes present in HPJ., (Copyright © 2019. Published by Elsevier B.V.)

Background: The present study aimed to determine the ability of diagnosing malignancy and predicting malignant transformation in patients with IPMN using carcinoembryonic antigen (CEA) level in the pancreatic juice., Methods: We enrolled patients with IPMN who underwent endoscopic retrograde pancreatography (ERP) between 2002 and 2018. We examined the ability of diagnosing malignancy in 63 patients who underwent surgery (surgical group). Furthermore, we examined the value of predicting malignant transformation in 52 patients who underwent follow-up for over 1 year after ERP (follow-up group)., Results: In the surgical group, the overall sensitivity and specificity of CEA level (≥ 97 ng/ml) in the pancreatic juice for diagnosing malignancy were 45% and 100%, respectively. The specificity was excellent for all IPMN types; however, the sensitivity was highest in main duct type, followed by mixed type and branch duct type. In the follow-up group, malignant transformation was observed in four patients (7.7%) during the follow-up, and the median time until malignant transformation was 58 months. High CEA level in the pancreatic juice demonstrated a statistically significant difference in multivariate analysis and was found to be an independent predictor of malignant transformation (hazard ratio 17; P = 0.02). The cumulative malignant transformation rate was significantly higher in the high CEA group than that in the low CEA group (5-year cumulative malignant transformation rates, 69% vs. 0%, P < 0.001)., Conclusions: Carcinoembryonic antigen level in the pancreatic juice is useful not only in diagnosing malignancy but also in predicting future malignant transformations in IPMN patients receiving follow-up.

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., (© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

A hereditary predisposition to pancreatic ductal adenocarcinoma (PDAC) is reported in approximately 5% of patients. Familial pancreatic cancer (FPC) accounts for the vast majority of hereditary PDAC cases. FPC defines families with two or more affected first-degree relatives with PDAC that do not fulfil the criteria of any other inherited tumor syndrome or families with PDAC in three or more relatives of any degree. The current progress report focuses on the knowledge of FPC with regard to molecular pathogenesis, clinical and molecular diagnosis, surveillance and novel treatment options reported in the last 5 years.

Euptox A, from Ageratina adenophora juice, is a toxin associated with the plant's resistance to infections, invasiveness and traditional use in cancer treatment. We used FTIR spectroscopy and protein profiling of cell lines to study the impact of euptox A on human cells, to clarify its mechanism of action in a top-down approach. Euptox A was extracted from the juice of A. adenophora. Its stability in the gastrointestinal tract was evaluated, as the compound/juice is generally taken orally. Cytotoxicity was determined in HeLa, Caco-2 and MCF7 cells, and the mechanism of action analyzed by protein and metabolite profiles using electrophoresis and FTIR spectroscopy. Euptox A resisted gastrointestinal digestion and was the most cytotoxic component of the extract for all cell lines tests. Euptox A-treated HeLa cells showed changes in protein profile, especially on 40S ribosomal protein S8 (RP), generally associated with cancer cells. FTIR profiles of treated cells diverged in the same metabolites as cells treated with cisplatin, both in metabolite directed analysis and in multivariate analysis (principal component analysis). In conclusion, euptox A in this top-down study showed a cellular impact that suggests a strong potential against cancer, acting on cancer targeted cellular characteristics., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Exosomes are nanovesicles that have been shown to mediate carcinogenesis in pancreatic ductal adenocarcinoma (PDAC). Given the direct communication of pancreatic duct fluid with the tumor and its relative accessibility, we aimed to determine the feasibility of isolating and characterizing exosomes from pancreatic duct fluid., Methods: Pancreatic duct fluid was collected from 26 patients with PDAC (n = 13), intraductal papillary mucinous neoplasm (IPMN) (n = 8) and other benign pancreatic diseases (n = 5) at resection. Exosomes were isolated by serial ultracentrifugation, proteins were identified by mass spectrometry, and their expression was evaluated by immunohistochemistry., Results: Exosomes were isolated from all specimens with a mean concentration of 5.9 ± 1 × 10 8  particles/mL and most frequent size of 138 ± 9 nm. Among the top 35 proteins that were significantly associated with PDAC, multiple carcinoembryonic antigen-related cell adhesion molecules (CEACAMs) and extracellular matrix (ECM) proteins were identified. Interestingly, CEACAM 1/5 expression by immunohistochemistry was seen only on tumor epithelia whereas tenascin C positivity was restricted to stroma, suggesting that both tumor and stromal cells contributed to exosomes., Conclusion: This is the first study showing that exosome isolation is feasible from pancreatic duct fluid, and that exosomal proteins may be utilized to diagnose patients with PDAC., (Copyright © 2017 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Objectives: The aim of this study is to compare gene expression profiles in RNA isolated from pancreatic ductal juice with the RNA expression profiles of the same genes from matched intra-operative tissue samples from pancreatic tumours., Methods: Intra-operative sampling of pancreatic juice and collection of matched tissue samples was undertaken in patients undergoing pancreatoduodenectomy for clinically suspected pancreatic cancer and a precursor lesion, main-duct intraductal papillary mucinous neoplasm. RNA was isolated and Poly A PCR was used to globally amplify the RNA. Real-time polymerase chain reaction (RT-PCR) was used to measure expression levels of 17 genes selected from microarray studies. Spearman's rank correlation test was used to examine the relationship of gene expression between pancreatic juice and tissue. The study was approved by Regional Ethics Committee., Results: Mesothelin (MSLN) showed significant correlation (p < 0.008) in expression levels between paired pancreatic juice and tissue samples in pancreas cancer. In intraductal papillary mucinous neoplasms (IPMN), Matrix Metalloproteinase 7 (MMP7), showed significant correlation (p < 0.01) in the expression levels between paired pancreatic juice and tissue samples., Conclusion: This study confirms that RNA analysis of paired pancreatic juice and tissue samples and establishment of cDNA using poly A PCR is technically feasible. Application of the technique to non-invasively obtained pancreatic juice during endoscopic assessment of tumours and the use of gene arrays of cancer indicator genes are the next steps in development of this technique., (Copyright © 2018 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Aims: The prognosis of patients with pancreatic cancer has remained virtually unchanged with a high mortality rate compared to other types of cancers. An earlier detection would provide a time window of opportunity for treatment and prevention of deaths. In the present study we investigated extracellular vesicle (EV)-associated potential biomarkers for pancreatic cancer by directly assessing EV size-based subpopulations in pancreatic juice samples of patients with chronic pancreatitis or pancreatic cancer. In addition, we also studied blood plasma and pancreatic cancer cell line-derived EVs., Methods: Comparative proteomic analysis was performed of 102 EV preparations from human pancreatic juices, blood, and pancreatic cancer cell lines Capan-1 and MIA PaCa-2. EV preparations were also characterized by electron microscopy, tunable resistive pulse sensing, and flow cytometry., Results: Here we describe the presence of EVs in human pancreatic juice samples. Pancreatic juice EV-associated proteins that we identified as possible candidate markers for pancreatic cancer included mucins, such as MUC1, MUC4, MUC5AC, MUC6 and MUC16, CFTR, and MDR1 proteins. These candidate biomarkers could also be detected by flow cytometry in EVs found in pancreatic juice and those secreted by pancreatic cancer cell lines., Conclusions: Together our data show that detection and characterization of EVs directly in pancreatic juice is feasible and may prove to be a valuable source of potential biomarkers of pancreatic cancer., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Four healthy Holstein heifers (235 ± 12 kg) fitted with duodenal and pancreatic cannulas were used to investigate infusion of isoleucine (Ile) on the pancreatic exocrine function in a 4 × 4 Latin square design. Three doses of Ile, 10, 20 and 30 g in 2500 ml water, respectively, were infused into the duodenum over a period of 12 h in Experiment (Exp) 1 and over 10 d in Exp 2. Hourly pancreatic juice and jugular blood were taken during the infusion period in Exp 1, and the blood samples were taken in 2-h intervals over the last 2 d in Exp 2. Compared with no Ile infusion, the Ile infusions in both experiments increased the concentration and secretion rate of the protein, activity of ɑ-amylase and trypsin and plasma cholecystokinin. The secretion rate of ɑ-amylase and the activity of trypsin linearly increased with the Ile doses. The pancreatic juice secretion linearly increased with Ile in Exp 2 but not in Exp 1. Isoleucine linearly increased plasma insulin in Exp 1, but not in Exp 2. No effects of Ile on pH of pancreatic juice, the activity of chymotrypsin and lipase and plasma glucose were found. In conclusion, duodenal Ile infusion could increase the pancreatic exocrine function of Holstein heifers, especially ɑ-amylase, and the increment appeared to be dose and time dependent.

The pancreas, the salivary glands and the dental enamel producing ameloblasts have marked developmental, structural and functional similarities. One of the most striking similarities is their bicarbonate-rich secretory product, serving acid neutralization. An important difference between them is that while pancreatic juice and saliva are delivered into a lumen where they can be collected and analyzed, ameloblasts produce locally precipitating hydroxyapatite which cannot be easily studied. Interestingly, the ion and protein secretion by the pancreas, the salivary glands, and maturation ameloblasts are all two-step processes, of course with significant differences too. As they all have to defend against acid exposure by producing extremely large quantities of bicarbonate, the failure of this function leads to deteriorating consequences. The aim of the present review is to describe and characterize the defense mechanisms of the pancreas, the salivary glands and enamel-producing ameloblasts against acid exposure and to compare their functional capabilities to do this by producing bicarbonate., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Context: Ruta genus (Rutaceae) is abundantly used and described in the most ancient systematic records of medical practice of the Mediterranean world. In Tunisia, this genus is represented by two medicinal and aromatic shrubs: Ruta chalepensis L. and Ruta montana L., Objective: This study investigates the antioxidant and acetylcholinesterase inhibition (AChE) activities before and after in vitro gastrointestinal metabolism of leaf decoction of R. chalepensis and R. montana., Materials and Methods: We study, in vitro, the effect of the gastrointestinal juices gastric (1.75 mL) or pancreatic (2.5 mL) juices, on the biological activity by the measurement of the antioxidant activity and AChE inhibition during 4 h of decoction extract obtained from the leaves of the two species of Ruta., Results: The results showed that the ability to inhibit the AChE enzyme was similar; being the greatest inhibitory activity exhibited by the ethanol extract (IC 50  =   12 ± 1.1 μg/mL) obtained from leaves of R. chalepensis., Conclusion: In conclusion, we showed that there was no appreciable degradation and that the activity was kept constant after gastric and pancreatic juice digestion.

Background and Aims: Direct pancreas juice testing of bicarbonate, lipase, or trypsin after stimulation by secretin or cholecystokinin is used to determine exocrine function, a surrogate for diagnosing chronic pancreatitis (CP). Endoscopic pancreas function tests (ePFTs), where a peak bicarbonate concentration (PBC) ≥80 mEq/L in pancreas juice is considered normal, are now used more frequently. In this ePFT, aspirates start 35 minutes after secretin administration because pancreas output peaks 30 minutes after secretagogue administration. The performance of ePFT in a cohort of patients with a presumptive diagnosis of CP referred to a pancreas clinic for consideration of an intervention including total pancreatectomy and islet autotransplantation was studied, compared with EUS, ERCP, histology, and consensus diagnosis. The effect of sedation, narcotic use, aspirate volume, body mass index, age, and proton pump inhibitors (PPIs) on test performance is reported., Methods: After a test dose, synthetic human secretin was administered intravenously, and 30 minutes later sedation was achieved with midazolam and fentanyl or propofol. A gastroscope was advanced to the major papilla where 4 continuous aspiration samples were performed at 5-minute intervals in sealed bottles. PBC ≥80 mEq/L was normal., Results: Eighty-one patients had ePFTs from August 2010 through October 2015. Twenty-seven patients (33%) were diagnosed with CP. Eighteen of the 27 patients with CP and 1 of the 54 patients without CP had an abnormal ePFT, producing a sensitivity of 66% (95% CI, 46.0-83.5), specificity 98% (95% CI, 90.1-99.9), positive predictive value 94.7% (95% CI, 74-99.9), and negative predictive value 85.5% (95% CI, 74.2-93.1). ERCP and PBC concordance was generally poor, but none of the patients without CP had major EUS changes, and only 3 patients with a PBC <80 mEq/L had a normal EUS. The PBC was affected by narcotics and PPI use., Conclusion: A 20-minute ePFT after secretin administration had a marginal sensitivity for diagnosis of CP. The diagnosis of CP should not rely on a single study and certainly not a PFT. The duodenal aspirate volume did not correlate with the PBC, which contrasts with current secretin-enhanced MRCP knowledge; therefore, further studies on this subject are warranted. Neither type of sedation, BMI, nor age affected test performance. Narcotics and PPIs may affect the PBC, so borderline results should be interpreted with caution in these groups., (Copyright © 2017 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)

The ability to capture cell-free DNA from the gastrointestinal tract, in a minimally invasive manner, could enhance our ability to diagnose gastrointestinal disease, or gain a better understanding of the spatial mapping of the intestinal microbiota. We, therefore, sought to identify a class of capture agents that could directly and efficiently sequester genetic material from intestinal fluids. As a particular case study, we examined the ability to capture DNA from pancreatic secretions, for potential application in enabling the sequestration of early, genetic biomarkers of pancreatic disease. We hypothesized that the cholestyramine series of strong cation exchange resins, which are FDA approved for the treatment of high cholesterol, may be capable of capturing DNA from pancreatic secretions. We identified a particular cholestyramine resin, DOWEX 1 × 2 100-200 mesh, which is able to efficiently capture and purify DNA from pancreatic fluid. Using only 200 μL of pancreatic secretions, we are able to recover 247 ± 182 ng of amplifiable human DNA, giving an estimated pancreatic fluid DNA content of 1.23 ± 0.91 ng/μL. To our knowledge, this is the first demonstration of a material that can effectively capture and purify DNA directly from untreated pancreatic fluids. Thus, our approach could hold high utility for the in vivo capture of DNA and disease biomarkers if incorporated into an appropriate sampling device. Biotechnol. Bioeng. 2017;114: 934-938. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Objective: The measurement of duodenal amylase by a colorimetric end-point assay has been the most used method for amylase activity analyses. The method is manual, time consuming and dependent on specialized equipment. In this study, we compare an automated kinetic spectrophotometric method for pancreatic amylase measurement in duodenal juice with a standardized colorimetric end-point assay., Methods: We used specimen of duodenal juice at random from a biobank obtained by short endoscopic secretin test in patients with suspected exocrine pancreatic failure of different reasons. Duodenal juice was tested for amylase activity with a conservative manual colorimetric endpoint assay (Phadebas Amylase test, Magle AB) and an automated enzymatic kinetic spectrophotometric method using standard reagents for pancreatic amylase activity for Cobas c111 (Roche Diagnostics)., Results: 52 samples for assay of amylase were analyzed in pairs. Correlation between measurements with the two methods was r = 0.99 (p < 0.001), linear regression 0.99 (p < 0.001)., Conclusion: Quantification of duodenal amylase activity with automated spectrophotometry has excellent correlation to measurements made by the manual method. This allows for standardized, center independent analyses of duodenal amylase for the assessment of acinar pancreatic function., (Copyright © 2017 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Purpose: To determine if T1-weighted MR signal of the pancreas can be used to detect early CP., Methods: A retrospective analysis was performed on 51 suspected CP patients, who had both secretin-enhanced magnetic resonance cholangiopancreatography (S-MRCP) and an intraductal secretin stimulation test (IDST). There were 29 patients in normal and 22 patients in the low bicarbonate group. Bicarbonate level, total pancreatic juice volume, and excretory flow rate were recorded during IDST. Signal intensity ratio of pancreas (SIR), fat signal fraction, pancreatograms findings, and grade of duodenal filling were recorded on S-MRCP by two blinded radiologists., Results: There was a significant difference in the signal intensity ratio of the pancreas to spleen (SIR p/s ) between the normal and low bicarbonate groups (p < 0.0001). A significant positive correlation was found between pancreatic fluid bicarbonate level and SIR p/s (p < 0.0001). SIR p/s of 1.2 yielded sensitivity of 77% and specificity of 83% for detection of pancreatic exocrine dysfunction (AUC: 0.89)., Conclusion: T1-weighted MR signal of the pancreas has a high sensitivity and specificity for the detection of parenchymal abnormalities related to exocrine dysfunction and can therefore be helpful in evaluation of suspected early CP.

Pancreatic secretions have an important role in the regulation of a normal nutritional state but can be altered owing to a variety of pathophysiological mechanisms in the context of exocrine pancreatic disease. The development of an endoscopic technique for collection of pancreatic fluid, termed endoscopic pancreatic function testing, has led to improved understanding of these alterations and is particularly helpful to characterize chronic pancreatitis. In addition, investigators have found endoscopically collected pancreatic fluid to be a valuable biofluid for the purposes of translational science. Techniques such as proteomic, cytokine, genetic mutation, DNA methylation, and microRNA analyses, among others, can be utilized to gain a better understanding of the molecular characteristics of chronic pancreatitis and other pancreatic diseases. Endoscopic collection of pancreatic fluid is safe and relatively straightforward, permitting opportunities for longitudinal analysis of these translational markers throughout the course of disease. This manuscript summarizes our current knowledge of pancreatic fluid, with an emphasis on proper techniques for sample collection and handling, its clinical utility, and preliminary observations in translational science.

Emerging molecular tools promise to extend the diagnostic reach of the endoscopist and open doors to population screening for gastrointestinal (GI) cancers. This review briefly addresses biological considerations in marker detection and types of markers, highlights examples of tools under development at each organ site, and appraises the possibility of universal GI cancer screening. The outlook is positive, but further technical refinement and rigorous clinical validation are needed before most of these new approaches are ready for clinical application., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: K-ras codon 12 mutation is one of the earliest genetic changes in the development of pancreatic cancer (PC) and accurate detection of K-ras mutations is gaining increasing attention in the field of molecular diagnosis., Methods: Original research articles which evaluated the diagnostic accuracy of K-ras mutation detection in PC were selected. Data were presented as forest plots and summary receiver operating characteristic curve analysis was used to summarize the overall test performance., Results: We assessed 16 studies from 15 published articles. The pooled sensitivity and specificity were 59% (95%CI: 54%-64%) and 87% (95%CI: 84%-89%), respectively. The pooled positive likelihood ratio and negative likelihood ratio were 4.13 (95%CI: 2.73-6.25) and 0.42 (95%CI: 0.32-0.56), respectively, and the pooled diagnostic odds ratio was 13.66 (95% CI: 7.25-25.74)., Conclusions: Our results indicate that the analysis of K-ras mutations in pancreatic juice has a considerable diagnostic value in PC. Further studies with rigorous design, large sample size, and multi-regional co-operation are needed., (Copyright © 2016 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Purpose: To determine the clinical, histopathologic and imaging features of pancreatic adenocarcinomas without secondary signs on dynamic CT., Materials and Methods: Seventy patients (mean age 70 years) with histologically proven pancreatic adenocarcinoma underwent preoperative contrast material-enhanced multiphasic multidetector CT before pancreatic resection. In each patient, clinical data including carbohydrate antigen 19-9, frequency of isoattenuating tumours, and presence of secondary signs and histopathologic findings such as tumour location, tumour stage, and microscopic infiltrative growth grade were evaluated., Results: Ten tumours (14%) were without secondary signs, and 60 (86%) were with secondary signs. Tumours without and with secondary signs were located in the uncinate process in 5 (50%) and 3 (5%), head in 3 (30%) and 29 (48%), body in 2 (20%) and 22 (37%), and tail in 0 (0%) and 6 (10%), respectively (p = .001). The frequency of isoattenuating pancreatic adenocarcinomas without secondary signs was significantly higher than those with secondary signs (p = 0.034). The tumour stage of pancreatic adenocarcinomas without secondary signs was earlier than that in tumours with secondary signs (p = 0.041)., Conclusions: Pancreatic adenocarcinomas without secondary signs is characterized by the presence of uncinate and isoattenuating tumours and earlier tumour stage compared to tumours with secondary signs., Key Points: Frequency of pancreatic adenocarcinomas without secondary signs on multiphasic CT is 14 . Pancreatic adenocarcinomas without secondary signs are common in the uncinate process. Pancreatic adenocarcinomas without secondary signs are common in isoattenuating tumours. Pancreatic adenocarcinomas without secondary signs are characterized by earlier-stage tumours.

Objectives: We have recently evaluated a short endoscopic secretin test for exocrine pancreatic function. Bicarbonate concentration in duodenal juice is an important parameter in this test. Measurement of bicarbonate by back titration as the gold standard method is time consuming, expensive and technically difficult, thus a simplified method is warranted. We aimed to evaluate an automated spectrophotometric method in samples spanning the effective range of bicarbonate concentrations in duodenal juice. We also evaluated if freezing of samples before analyses would affect its results., Methods: Patients routinely examined with short endoscopic secretin test suspected to have decreased pancreatic function of various reasons were included. Bicarbonate in duodenal juice was quantified by back titration and automatic spectrophotometry. Both fresh and thawed samples were analysed spectrophotometrically., Results: 177 samples from 71 patients were analysed. Correlation coefficient of all measurements was r = 0.98 (p < 0.001). Correlation coefficient of fresh versus frozen samples conducted with automatic spectrophotometry (n = 25): r = 0.96 (p < 0.001) CONCLUSIONS: The measurement of bicarbonate in fresh and thawed samples by automatic spectrophotometrical analysis correlates excellent with the back titration gold standard. This is a major simplification of direct pancreas function testing, and allows a wider distribution of bicarbonate testing in duodenal juice. Extreme values for Bicarbonate concentration achieved by the autoanalyser method have to be interpreted with caution., (Copyright © 2016 IAP and EPC. Published by Elsevier India Pvt Ltd. All rights reserved.)

Pancreatic cancer is usually diagnosed at an advanced stage and curative resection is feasible in only a small minority of patients at the time of diagnosis. Diagnosis at an early stage is unequivocally associated with better long-term survival. Several candidate molecular markers for early detection are currently under investigation in different phases of discovery and validation. Recent advances in the technology for whole genome, methylome, ribonucleome, and proteome interrogation has enabled rapid advancements in the field of biomarker discovery. In this review we discuss the current status of molecular markers for detection of pancreatic cancer in blood, pancreatic cyst fluid, pancreatic juice and stool and briefly highlight some promising preliminary results of new approaches that have the potential of advancing this field in the near future.

A simple and sensitive method based on the combination of derivatization and high-performance liquid chromatography with ultraviolet and fluorimetric detection was developed for the simultaneous determination of octreotide and gabexate mesylate metabolite in human pancreatic juice samples. Parameters of the derivatization procedure affecting extraction efficiency were optimized. The developed method was validated according to the International Conference on Harmonization guidelines. The calibration curves were linear over a range of 0.1-15 µg/mL for octreotide and 0.20-15 µg/mL for gabexate mesylate metabolite. Derivatized products of octreotide and gabexate mesylate metabolite were separated on a Luna C18 column (4.6 × 250 mm; 5 µm particle size) using a gradient with a run time of 36 min, without further purification. The limits of detection were 0.025 and 0.05, respectively, for octreotide and gabexate mesylate metabolite. This paper reports the validation of a quantitative high performance liquid chromatography-photodiode array-fluorescence (HPLC-PDA-FL) method for the simultaneous analysis of octreotide and gabexate mesylate metabolite in pancreatic juice by protein precipitation using zinc sulfate-methanol-acetonitrile containing the derivatizing reagent, 4-fluoro-7-nitro-[2,1,3]-benzoxadiazole (NBD-F). Derivatized products of octreotide and gabexate mesylate metabolite were separated on a Luna C18 column (4.6 × 250 mm; 5 µm particle size) using a gradient with a run time of 36 min, without further purification. The method was validated over the concentration ranges 0.1-15 and 0.2-15 µg/mL for octreotide and gabexate mesylate metabolite, respectively, in human pancreatic juice. Biphalin and methyl-p-hydroxybenzoate were used as the internal standards. This method was successfully utilized to support clinical studies in humans. The results from assay validations show that the method is selective, sensitive and robust. The limit of quantification of the method was 0.1 µg/mL for octreotide and 0.2 µg/mL for gabexate mesylate metabolite, and matrix matched standard curves showed a good linearity up to 15 µg/mL. In the entire analytical range the intra- and inter-day precision (RSD%) values were respectively ≤5.9% and ≤3.1% for octreotide and ≤2.0% and ≤3.9% for gabexate mesylate metabolite. For both analytes the intra- and inter-day accuracy (bias) values ranged respectively from -6.8 to -2.5% and from -4.6 to -5.7%. This method utilizes derivatization with NBD-F and provides adequate sensitivity for both drugs., (Copyright © 2014 John Wiley & Sons, Ltd.)

Background & Aims: Pancreatic imaging can identify neoplastic cysts but not microscopic neoplasms. Mutation analysis of pancreatic fluid after secretin stimulation might identify microscopic neoplasias in the pancreatic duct system. We determined the prevalence of mutations in KRAS and guanine nucleotide-binding protein α-stimulating genes in pancreatic juice from subjects undergoing endoscopic ultrasound for suspected pancreatic intraepithelial neoplasia, intraductal papillary mucinous neoplasms, or pancreatic adenocarcinoma., Methods: Secretin-stimulated juice samples were collected from the duodenum of 272 subjects enrolled in Cancer of the Pancreas Screening studies; 194 subjects were screened because of a family history of, or genetic predisposition to, pancreatic cancer, and 78 subjects were evaluated for pancreatic cancer (n = 30) or other disorders (controls: pancreatic cysts, pancreatitis, or normal pancreata, n = 48). Mutations were detected by digital high-resolution melt-curve analysis and pyrosequencing. The number of replicates containing a mutation determined the mutation score., Results: KRAS mutations were detected in pancreatic juice from larger percentages of subjects with pancreatic cancer (73%) or undergoing cancer screening (50%) than controls (19%) (P = .0005). A greater proportion of patients with pancreatic cancer had at least 1 KRAS mutation detected 3 or more times (47%) than screened subjects (21%) or controls (6%, P = .002). Among screened subjects, mutations in KRAS (but not guanine nucleotide-binding protein α-stimulating) were found in similar percentages of patients with or without pancreatic cysts. However, a greater proportion of patients older than age 50 years had KRAS mutations (54.6%) than younger patients (36.3%) (P = .032); the older subjects also had more mutations in KRAS (P = .02)., Conclusions: Mutations in KRAS are detected in pancreatic juice from the duodenum of 73% of patients with pancreatic cancer, and 50% of asymptomatic individuals with a high risk for pancreatic cancer. However, KRAS mutations were detected in pancreatic juice from 19% of controls. Mutations detected in individuals without pancreatic abnormalities, based on imaging analyses, likely arise from small pancreatic intraepithelial neoplasia lesions. ClinicalTrials.gov no: NCT00438906 and NCT00714701., (Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Objectives: Individuals from hereditary pancreatitis (HP) and familial pancreatic cancer (FPC) kindreds are at increased risk of developing pancreatic cancer. Premalignant molecular changes may be detected in pancreatic juice collected by endoscopic retrograde cholangiopancreatography (ERCP). The objective was to determine the risk of post-ERCP pancreatitis (PEP)., Methods: A prospective study (1999-2013) was undertaken of 80 ERCPs (24 in HP and 56 in FPC) from 60 individuals and the impact of PEP prophylaxis using a self-expelling pancreatic stent and 50 mg diclofenac per rectum from 2008., Results: There was no PEP in the HP cohort and 13 (23.2%) PEP from 56 procedures in the FPC cohort (P = 0.0077). Up to 2008 PEP had occurred in 7 (43.8%) of 16 procedures in FPC individuals versus none of 18 procedures in HP individuals (P = 0.0021). After the introduction of prophylaxis, the incidence of PEP fell to 6 (15.0%) of 40 procedures in FPC individuals (P = 0.0347).The odds ratio (95% confidence interval) was 0.23 (0.06-0.84) in favor of prophylaxis (0.035)., Conclusions: Individuals with HP are at minimal risk for PEP. Although the risk of PEP in individuals with FPC can be reduced by using prophylactic self-expelling stents and diclofenac, it remains too high for routine screening.

Pancreatic ductal adenocarcinoma is an aggressive malignancy with a 5-year survival rate of approximately 5%. The lack of established strategies for early detection contributes to this poor prognosis. Although several novel candidate biomarkers have been proposed for earlier diagnosis, none have been adopted into routine clinical use. In this review, the authors examine the challenges associated with finding new pancreatic cancer diagnostic biomarkers and explore why translation of biomarker research for patient benefit has thus far failed. The authors also review recent progress and highlight advances in the understanding of the biology of pancreatic cancer that may lead to improvements in biomarker detection and implementation.

Background and Aim: Pancreatic juice cytology (PJC) is considered optimal for differentially diagnosing pancreatic masses, but the accuracy of PJC ranges from 46.7% to 93.0%. The aim of this study was to evaluate the clinical impact of measuring the KL-6 concentration of pancreatic juice for diagnosing pancreatic masses., Methods: PJC and the KL-6 concentration measurements of pancreatic juice were performed for 70 consecutive patients with pancreatic masses (39 malignancies and 31 benign)., Results: The average KL-6 concentration of pancreatic juice was significantly higher for pancreatic ductal adenocarcinomas (PDACs) (167.7 ± 396.1 U/mL) and intraductal papillary mucinous carcinomas (IPMCs) (86.9 ± 21.1 U/mL) than for pancreatic inflammatory lesions (17.5 ± 15.7 U/mL, P = 0.034) and intraductal papillary mucinous neoplasms (14.4 ± 2.0 U/mL, P = 0.026), respectively. When the cut-off level of the KL-6 concentration of pancreatic juice was 16 U/mL, the sensitivity, specificity, and accuracy of the KL-6 concentration of pancreatic juice alone were 79.5%, 64.5%, and 72.9%, respectively. Adding the KL-6 concentration of pancreatic juice to PJC when making a diagnosis caused the values of sensitivity and accuracy of PJC to increase by 15.3% (P = 0.025) and 8.5% (P = 0.048), respectively., Conclusions: The KL-6 concentration of pancreatic juice may be as useful as PJC for diagnosing PDACs.

Ethnopharmacological Relevance: Decoctions of the leaves of Annona cherimola Mill. are traditionally used in Azores to treat hypercholesterolemia. Although they are sold and consumed by people in order to improve their health, these are products that cannot be sold with claims for health benefits as they have never been studied scientifically., Materials and Methods: The activities of decoctions from Annona cherimola leaves were analysed for the two therapeutic approaches currently used to reduce plasma cholesterol: inhibition of dietary cholesterol uptake and inhibition of HMG-CoA reductase activity. Furthermore, the composition of the decoction was elucidated by LC-MS and the permeability of the active components was analysed using Caco-2 cell monolayers as a model of the intestinal barrier (dietary cholesterol uptake)., Results: The chemical composition of the Annona cherimola leaves' extract revealed that rutin was its main component. The in vitro gastrointestinal digestion did not modify the chemical composition of the extract. This extract was able to originate a slight reduction in cholesterol absorption through Caco-2 cells lines and to reduce the HMG-CoA reductase activity in 50% when using 137.3 μg of the extract/mL. Rutin, when used in the same concentration as that found in the extract, was able to reduce cholesterol absorption through Caco-2 cells monolayer in approximately 47%. This flavonoid had an IC50 of 17.85 μM relatively to the HMG-CoA reductase activity., Conclusions: The traditional use of decoctions from the leaves of Annona cherimola may be justified, at least by the inhibition of HMG-CoA reductase activity., (© 2013 Elsevier Ireland Ltd. All rights reserved.)

Freeze-dried beads made of α-cyclodextrin and soybean oil were reported previously as an efficient system for the oral delivery of lipophilic drugs. In the present study, oven-drying was evaluated as another method for drying beads. Oven-drying was optimised and the properties of the resulting beads were assessed. The behavior of oven-dried beads and the release of indomethacin from these beads were evaluated in vitro in simulated gastrointestinal fluids and compared with those of freeze-dried beads. The stability of freeze-dried and oven-dried unloaded beads stored at 25°C for 12 months and at 40°C for 6 months in closed and open vials was also studied by different techniques. An oven-drying time of 6 hours at 25°C was chosen as optimal conditions. Oven-dried beads exhibited a sticky texture making them difficult to handle. They were harder, less fragile and smaller than the freeze-dried ones. The characteristics of oven-dried beads make them more resistant in vitro even in media containing bile salt. The rate of indomethacin release from oven-dried beads was much slower than that from the freeze-dried ones. Whatever the drying method, beads must be stored at room temperature protected from humidity. However, no products of oil degradation were detected with both kinds of beads. This work clearly emphasized that the drying method of the beads had a strong influence on their properties, behavior in simulated gastrointestinal fluids and drug release.

Hydralazine hydrochloride is an antihypertensive used alone or in combination with isosorbide nitrate for the treatment of congestive heart failure. Since control of blood pressure should be continuous, sustained release delivery of this drug is considered therapeutically beneficial. Core beads for oral administration of this drug were prepared by extrusion-spheronization. Using experimental design to define the coat that was applied, the core beads were coated using a fluid bed coater to different coat thickness with combinations of two commercially available products dissolved in a hydroalcoholic solvent. The coat is a film with a combination of ethylcellulose and hydroxypropylcellulose that can provide desirable release profiles. Visually spherical and rugged bead products were obtained. Two products were identified that exhibited essentially a zero order release profile following a 2-h lag time with release of greater than 70% of the drug over the next 10 h in simulated intestinal fluid.

Background: Pancreatic fistula (PF) remains the most serious complication after digestive surgery. It is difficult to prevent because of the inability to visualize the leakage of pancreatic juice during surgery or to evaluate the protease activity of leaked fluid, which is responsible for PF formation., Methods: The fluorescence intensities of a chymotrypsin probe (glutaryl-phenylalanine [corrected] hydroxymethyl rhodamine green with added trypsin) in pancreatic juice and in intestinal or abdominal fluids drained after pancreatic resection were evaluated. The chymotrypsin probe was sprayed on to filter papers that had been placed on the resected pancreatic stump in patients undergoing pancreaticoduodenectomy or central pancreatectomy. The ability of this technique to visualize the leakage of pancreatic juice and predict postoperative PF formation was assessed., Results: The fluorescence intensity of the chymotrypsin probe in 76 fluid samples correlated positively with amylase levels (r(s) = 0.678, P < 0.001). The fluorescence patterns of the pancreatic stump were classified grossly into the three types: duct (fluorescence signal visualized only on the stump of the main pancreatic duct, 16 patients), diffuse (ductal stump and surrounding pancreatic parenchyma, 7) and negative (no fluorescence signal, 7). Symptomatic PFs developed in 13 of 23 patients with duct- or diffuse-type fluorescence, but in none of the seven patients with negative-type fluorescence (P = 0.008)., Conclusion: The chymotrypsin probe enabled determination of the protease activity in drained pancreatic fluid samples and allowed real-time visualization of pancreatic juice leakage during surgery., (© 2013 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.)

Objectives: To examine the exocrine pancreatic function in carriers of the hepatocyte nuclear factor 1β gene (HNF1B) mutation by direct testing., Methods: Patients with HNF1B mutations and control subjects were assessed using rapid endoscopic secretin tests and secretin-stimulated magnetic resonance imaging. Seven patients and 25 controls underwent endoscopy, while eight patients and 20 controls had magnetic resonance imaging. Ductal function was assessed according to peak bicarbonate concentrations and acinar function was assessed according to peak digestive enzyme activities in secretin-stimulated duodenal juice. The association of pancreatic exocrine function and diabetes status with pancreatic gland volume was examined., Results: The mean increase in secretin-stimulated duodenal fluid was smaller in patients than controls (4.0 vs 6.4 ml/min; P = 0.003). We found lower ductal function in patients than controls (median peak bicarbonate concentration: 73 vs 116 mEq/L; P < 0.001) and lower acinar function (median peak lipase activity: 6.4 vs 33.5 kU/ml; P = 0.01; median peak elastase activity: 0.056 vs 0.130 U/ml; P = 0.01). Pancreatic fluid volume outputs correlated significantly with pancreatic gland volumes (r² = 0.71, P = 0.008) in patients. The total fluid output to pancreatic gland volume ratios were higher in patients than controls (4.5 vs 1.3 ml/cm³; P = 0.03), suggesting compensatory hypersecretion in the remaining gland., Conclusion: Carriers of the HNF1B mutation have lower exocrine pancreatic function involving both ductal and acinar cells. Compensatory hypersecretion suggests that the small pancreas of HNF1B mutation carriers is attributable to hypoplasia, not atrophy., (© 2013 The Authors. Diabetic Medicine © 2013 Diabetes UK.)

This study examined the penetration of meropenem into pancreatic juice in patients who had undergone hepato-biliary-pancreatic surgery. The patients received a 0.5-h infusion of 500 mg meropenem. The observed maximum concentration (mean ± standard deviation, n = 5) was 39.1 ± 11.2 μg/ml at 0.5 h in plasma and 2.12 ± 0.73 μg/ml at 1.10 ± 0.14 h in pancreatic juice. The pancreatic juice/plasma ratio was 0.06 ± 0.02. The area under the drug concentration-time curve was 73.0 ± 37.5 μg•h/ml in plasma and 4.24 ± 2.77 μg•h/ml in pancreatic juice. The pancreatic juice/plasma ratio was 0.06 ± 0.01. The mean drug-exposure times above 0.125 μg/ml and 0.25 μg/ml (the minimum inhibitory concentrations (MIC) for common pathogens) in pancreatic juice were 99.4% and 87.3%, respectively, for 500 mg meropenem 3 times daily. This commonly used regimen for pancreatitis achieved the drug-exposure time target (40% of the time above the MIC) at the action site, despite the low penetrability of meropenem.

Context: We have shown previously that trichloroacetic acid precipitation is an effective method of protein extraction from pancreatic fluid for downstream biomarker discovery, compared to other common extraction methods tested., Objective: We aim to assess the utility of ultracentrifugation as an alternative method of protein extraction from pancreatic fluid., Design: Proteins extracted from trichloroacetic acid- and ultracentrifugation-precipitated pancreatic fluid were identified using mass spectrometry techniques (in-gel tryptic digestion followed by liquid chromatography-tandem mass spectrometry; GeLC-MS/MS). Data were analyzed using Proteome Discoverer and Scaffold 3., Setting: This is a proteomic analysis experiment of endoscopically collected fluid in an academic center., Patients: The study population included adult patients referred to the Center for Pancreatic Disease at Brigham and Women's Hospital, Boston, MA, USA for the evaluation of abdominal pain and gastrointestinal symptoms., Interventions: Secretin-stimulated pancreatic fluid was collected as standard of care for the evaluation of abdominal pain and gastrointestinal symptoms., Main Outcome Measures: We compared proteins identified via standard trichloroacetic acid precipitation and this alternative ultracentrifugation strategy., Results: A subset of pancreatic fluid proteins was identified via the ultracentrifugation method. Of these proteins, similar numbers were obtained from fully tryptic or semi-tryptic database searching. Proteins identified in the ultracentrifugation-precipitated samples included previously identified biomarker candidates of chronic pancreatitis., Conclusions: This alternative ultracentrifugation strategy requires less time and fewer handling procedures than standard trichloroacetic acid precipitation, at the expense of higher sample volume. As such, this method is well suited for targeted assays (i.e., dot blotting or targeted mass spectrometry) if the protein of interest is among those readily identified by ultracentrifugation-promoted precipitation.

Objective: To compare pancreatic duct cell function in smokers (current and past) and never smokers by measurement of secretin-stimulated peak bicarbonate concentration ([HCO3-]) in endoscopic collected pancreatic fluid (PF)., Methods: This retrospective study was cross-sectional in design, recording demographic information (age, gender, etc.), smoking status (former, current, never), alcohol intake, clinical data (imaging, endoscopy), and laboratory results (peak PF [HCO3-]) from subjects evaluated for pancreatic disease at a tertiary pancreas center. Univariate and multivariate statistical analysis (SAS Version 9.2, Cary, NC, USA) was performed to assess the relationship between cigarette smoking and secretin-stimulated pancreatic fluid bicarbonate concentration., Results: A total of 131 subjects underwent pancreatic fluid collection (endoscopic pancreatic function test, ePFT) for bicarbonate analysis: 25.2% (33 out of 131) past smokers, 31.3% (41 out of 131) current smokers, and 43.5% (57 out of 131) were never smokers. Measures of Association: The mean peak PF [HCO3-] in never smokers (81.3 ± 18.5 mEq/L) was statistically higher (indicating better duct cell function) when compared to past smokers (66.8 ± 24.7 mEq/L, P=0.005) and current smokers (70.0 ± 20.2 mEq/L, P=0.005). However, the mean peak [HCO3-] in past smokers was not statistically different from that in current smokers (P=0.575), and therefore, the two smoking groups were combined to form a single "smokers cohort". When compared to the never smokers, the smokers cohort was older (P=0.037) and had a greater proportion of subjects with definite chronic pancreatitis imaging (P=0.010), alcohol consumption ≥20 g/day (P=0.012), and abnormal peak PF [HCO3-] (P<0.001). Risk-Based Estimates: Cigarette smoking (risk ratio, RR: 2.2, 95% CI: 1.3-3.5; P<0.001), diagnosis of definite chronic pancreatitis imaging (RR: 2.2, 95% CI: 1.6-3.2; P<0.001) and alcohol consumption ≥20 g/day (RR: 1.6, 95% CI: 1.1-2.4; P=0.033) were all associated with low mean peak PF [HCO3-] (indicating duct cell secretory dysfunction). Multivariate Analysis: Smoking (odds ratio, OR: 3.8, 95% CI: 1.6-9.1; P=0.003) and definite chronic pancreatitis imaging (OR: 5.7, 95% CI: 2.2-14.8; P<0.001) were determined to be independent predictors of low peak PF [HCO3-], controlling for age, gender, and alcohol intake. Furthermore there was no interaction between smoking status and alcohol intake in predicting duct cell dysfunction (P=0.571)., Conclusion: Measurement of pancreatic fluid bicarbonate in smokers reveals that cigarette smoking (past and current) is an independent risk factor for pancreatic duct cell secretory dysfunction (low PF [HCO3-]). Furthermore, the risk of duct cell dysfunction in subjects who smoked was approximately twice the risk (RR: 2.2) in never smokers. Further in depth, translational research approaches to pancreatic fluid analysis may help unravel mechanisms of cigarette smoking induced pancreatic duct cell injury.

There are many reviews of pancreatic acinar cell function and also of pancreatic duct function, but there is an almost total absence of synthetic reviews bringing the integrated functions of these two vitally and mutually interdependent cells together. This is what we have attempted to do in this chapter. In the first part, we review the normal integrated function of the acinar-ductal system, with particular emphasis on how regulation of one type of cell also influences the other cell type. In the second part, we review a range of pathological processes, particularly those involved in acute pancreatitis (AP), an often-fatal human disease in which the pancreas digests itself, in order to explore how malfunction of one of the cell types adversely affects the function of the other.

In experiments on dogs the exocrine secretion of pancreatic segment graft after its autotransplantation and of pancreatic stamps after proximal resection of the pancreas was investigated. More significant impairment of the exocrine secretion of the pancreas was revealed in animals after pancreatic graft autotransplantation in comparison with animals after the proximal resection of the pancreas. Maintenance of the adaptation of pancreatic exocrine secretion to the nutritional composition of the intestinal contents and "generalized inhibition" of pancreatic exocrine secretion caused by duodenal trypsin infusion was revealed in all groups.

The aim of this work was to investigate whether Ca-alginate biopolymer beads (CaABBs) can be used to reduce the bioavailability of radionuclides in the gastrointestinal tract of humans. The uptake of strontium, uranium and thorium from a simulated gastrointestinal system was studied by in vitro techniques using CaABBs. This agent was prepared from Na-alginate through cross-linking with divalent calcium ions according to the egg-box model. The effects of process variables such as pH of the gastrointestinal juice, incubation time and solid-to-solution ratio for the removal of radionuclides from the gastrointestinal juice were investigated. The results suggest that CaABBs are a potent material for reducing the bioavailability of radionuclides with a high uptake efficiency in the gastrointestinal tract.

Objectives: (1) To quantitate volume production during secretin stimulation testing in patients suspected of having chronic pancreatitis (CP); (2) to compare volume production to clinical criteria for the diagnosis of CP., Methods: A total of 224 patients referred for suspected CP were reviewed retrospectively for clinical information supporting the diagnosis of CP. The patients were divided into 2 groups: those with peak bicarbonate (PB) of less than 80 mEq/L and those with PB of 80 mEq/L or greater (ie, CP and no CP). For a separate comparison, the patients were also placed into similar 2 groups based on clinical criteria. The volume, total bicarbonate output, volume per kilogram, and PB of pancreatic juice after secretin stimulation in patients thought to have CP were compared to those thought not to have CP., Results: Volume was lower in the patients with PB of less than 80 mEq/L (206 ± 114 and 269 ± 106 mL) and lower in patients who met clinical criteria for CP (203 ± 109 and 271 ± 108 mL), P < 0.001 for both, but there was significant overlap (volume alone did not accurately discriminate CP from no CP)., Conclusions: During secretin stimulation testing, bicarbonate parameters likely are better predictors of CP than volume parameters. Changes in the production of the volume of pancreatic juice during secretin stimulation likely reflect relatively late changes in pancreatic function.

An aqueous suspension of almond oil bodies (about 10% lipids) was prepared and subjected to in vitro gastric (with pepsin) and intestinal (with bile salts and pancreatin) digestion, simulating fasting conditions. The physicochemical and structural changes of the almond oil body emulsion were examined. The almond oil body emulsion behaved similarly to a protein-stabilized emulsion, with flocculation of the oil bodies occurring under gastric conditions. Proteins, peptides, and phospholipids covered the surface of the oil bodies throughout gastric digestion. Under intestinal conditions, bile salts displaced the interfacial peptides and phospholipids, and disrupted the flocs. Gastric pepsinolysis of almond proteins was a prerequisite for their digestion in the duodenum. The oil body membrane had a negative impact on the efficiency of gastric digestion, and long chain fatty acids, the main lipolytic products, accumulated at the surface of the oil bodies and therefore limited the activity of pancreatic lipase.

There is a growing interest in the optimization of dietary emulsions for monitoring postprandial lipid metabolism in the frame of preventing metabolic diseases. Using various emulsions, we investigated in a systematic scheme the combination of (i) in vitro gastrointestinal lipolysis and (ii) absorption and metabolism of lipolysis media in Caco-2 cells. Four emulsions based on either milk fat olein (OL) or rapeseed oil (RA) as the dispersed phase and either lecithin (LE) or sodium caseinate (CA) as the emulsifier were tested. After a sequential incubation of these emulsions with gastric and pancreatic enzymes, lipolysis media were incubated with Caco-2 cells, after dilution (1 : 20) to maintain the barrier integrity. Both gastric and duodenal lipolysis levels were similar to values reported in vivo and the rates of lipolysis were higher with LE-stabilized emulsions than with CA-stabilized emulsions (P < 0.05). TAG secretion by Caco-2 cells was found to be higher using (i) duodenal vs. gastric media (P < 0.001) and (ii) emulsions stabilized with CA vs. LE (P < 0.01). Consistently, gene expression of both FABP2 and FATP4 induced by the duodenal media was (i) higher than that with gastric media (P < 0.001) and (ii) faster than that with model mixed micelles. Using gastric media, TAG secretion of Caco-2 cells after 12 h was higher with RA than with OL (P < 0.001). Moreover, the RA-CA emulsion increased the size of secreted lipoprotein particles (514 nm vs. 61 to 130 nm; P < 0.01). In conclusion, it was possible to observe distinct responses in the lipid metabolism of Caco-2 cells incubated with lipolysis media obtained from different dietary emulsions digested by gastrointestinal lipases in vitro.

Objective: Identification of predictors of malignancy for branch duct type intraductal papillary mucinous neoplasms (IPMN)., Background: Main duct type IPMN has been recommended for resection. However, the indications for resection of the branch duct type IPMN have been controversial., Methods: We retrospectively analyzed the clinicopathological factors of 134 patients undergoing resection for branch duct type IPMN, excluding main duct type IPMN, to identify predictors of the malignant behavior of this neoplasm. The cutoff values of tumor size, main pancreatic duct (MPD) size, mural nodule size, and carcinoembryonic antigen (CEA) level in the pancreatic juice obtained during preoperative endoscopic retrograde pancreatography (ERP) were analyzed using receiver-operator characteristic curves., Results: We found 7 significant predictors for malignancy in the branch duct type IPMN in a univariate analysis; jaundice, tumor occupying the pancreatic head, MPD size >5 mm, mural nodule size >5 mm, serum carbohydrate antigen (CA)19-9 level, positive cytology in the pancreatic juice, and CEA level in the pancreatic juice >30 ng/mL. In a multivariate analysis, a mural nodule size >5 mm and a CEA level in the pancreatic juice >30 ng/mL were independent factors associated with malignancy. The positive predictive value of a mural nodule size >5 mm and a CEA level in the pancreatic juice >30 ng/mL was 100%, and the negative predictive value was 96.3%., Conclusions: We identified 2 useful predictive factors for malignancy in branch duct type IPMN; a mural nodule size >5 mm and a CEA level in the pancreatic juice obtained by preoperative ERP >30 ng/mL.

Objectives: The aims of this study were to characterize the proteome of normal pancreatic juice, to analyze the effect of secretin on the normal proteome, and to compare these results with published data from patients with pancreatic cancer., Methods: Paired pancreatic fluid specimens (before and after intravenous secretin stimulation) were obtained during endoscopic pancreatography from 3 patients without significant pancreatic pathology. Proteins were identified and quantified by mass spectrometry-based protein quantification technology. The human RefSeq (NCBI) database was used to compare the data in samples from patients without pancreatic disease with published data from 3 patients with pancreatic cancer., Results: A total of 285 proteins were identified in normal pancreatic juice. Ninety had sufficient amino acid sequences identified to characterize the protein with a high level of confidence. All 90 proteins were present before and after secretin administration but with altered relative concentrations, usually by 1 to 2 folds, after stimulation. Comparison with 170 published pancreatic cancer proteins yielded an overlap of only 42 proteins., Conclusions: Normal pancreatic juice contains multiple proteins related to many biological processes. Secretin alters the concentration but not the spectrum of these proteins. The pancreatic juice proteome of patients without pancreatic disease and that of patients with pancreatic cancer differ markedly.