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Background: GPR18 is a recently deorphanized receptor which was reported to act with several endogenous cannabinoid ligands. Here, we aimed to describe the role of GPR18 in intestinal inflammation and inflammatory pain., Methods: The anti-inflammatory activity of selective GPR18 agonist, PSB-KK-1415, and antagonist, PSB-CB5, was characterized in semi-chronic and chronic mouse models of colitis induced by 2,4,6-trinitrobenzenesulfonic acid (TNBS). The extent of inflammation was evaluated based on the macroscopic and microscopic scores, quantification of myeloperoxidase (MPO) activity, and Western blot analyses of tumor necrosis factor-α (TNF-α) and interleukin-6 in colonic tissue. The expression of GPR18 in colonic samples from patients with Crohn's disease (CD) was quantified using real-time PCR. The anti-nociceptive potential of the agonist in intestinal inflammation was evaluated in the mouse model of inflammatory pain., Key Results: In semi-chronic colitis, PSB-KK-1415 reduced macroscopic score (1.79 ± 0.22 vs. 2.61 ± 0.48), expression of TNF-α (1.89 ± 0.36 vs. 2.83 ± 0.64), and microscopic score (5.00 ± 0.33 vs. 6.45 ± 0.40), all compared to mice with colitis. In chronic colitis, PSB-KK-1415 decreased macroscopic score (3.33 ± 1.26 vs. 4.00 ± 1.32) and MPO activity (32.23 ± 8.51 vs. 41.33 ± 11.64) compared to inflamed mice. In the mouse model of inflammatory pain, PSB-KK-1415 decreased the number of pain-induced behaviors in both, controls (32.60 ± 2.54 vs. 58.00 ± 6.24) and inflamed mice (60.83 ± 2.85 vs. 85.00 ± 5.77) compared to animals without treatment with PSB-KK-1415 (P < 0.005 for both). Lastly, we showed an increased expression of GPR18 in CD patients compared to healthy controls (3.77 ± 1.46 vs. 2.38 ± 0.66, p = 0.87)., Conclusions & Inferences: We showed that GPR18 is worth considering as a potential treatment target in intestinal inflammation and inflammatory pain., (© 2020 John Wiley & Sons Ltd.)

Background: The G-protein-coupled receptor Class C Group 6 Member A (GPRC6A) is activated by multiple ligands and is important for the regulation of calcium homeostasis. Extracellular calcium is capable to increase NLRP3 inflammasome activity of the innate immune system and deletion of this proinflammatory pathway mitigated pancreatitis severity in vivo. As such this pathway and the GPRC6A receptor is a reasonable candidate gene for pancreatitis. Here we investigated the prevalence of sequence variants in the GPRC6A locus in different pancreatitis aetiologies., Methods: We selected 6 tagging SNPs with the SNPinfo LD TAG SNP Selection tool and the functional relevant SNP rs6907580 for genotyping. Cohorts from Germany, further European countries and China with up to 1,124 patients and 1,999 controls were screened for single SNPs with melting curve analysis., Results: We identified an association of rs1606365(G) with alcoholic chronic pancreatitis in a German (odds ratio (OR) 0.76, 95% confidence interval (CI) 0.65-0.89, p = 8 × 10 -5 ) and a Chinese cohort (OR 0.78, 95% CI 0.64-0.96, p = 0.02). However, this association was not replicated in a combined cohort of European patients (OR 1.18, 95% CI 0.99-1.41, p = 0.07). Finally, no association was found with acute and non-alcoholic chronic pancreatitis., Conclusions: Our results support a potential role of calcium sensing receptors and inflammasome activation in alcoholic chronic pancreatitis development. As the functional consequence of the associated variant is unclear, further investigations might elucidate the relevant mechanisms., Competing Interests: Declaration of competing interest The authors report no conflicts of interest., (Copyright © 2020 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Background: Insulin-like growth factor 1 (IGF-1) and insulin-like growth factor-binding protein 2 (IGFBP-2) are proteins that belong to the IGF axis, which is involved in glucose and lipid metabolism and may as well promote carcinogenesis., Goals: The aim of this study was to evaluate the serum concentration levels of IGF-1 and IGFBP-2 in patients with newly diagnosed pancreatic adenocarcinoma (PDAC) to verify their possible role in the diagnosis of the disease., Study: The study included 69 patients with PDAC and 20 healthy controls. The concentrations of IGF-1 and IGFBP-2 were estimated by means of ELISA. The study protocol was approved by the Bioethics Committee at the Medical University of Lodz in Poland., Results: PDAC patients compared with controls have a significantly lower mean serum IGF-1 level (45.83±30.03 vs. 70.66±60.57 ng/mL; P<0.0001). In contrast, in PDAC patients, the mean IGFBP-2 level was significantly higher compared with the control group (225.06±86.37 vs. 51.92±29.40 ng/mL; P<0.0001). The results show that, at the 0.01 sensitivity level, the IGF-1/IGFBP-2 ratio <0.85 points indicates PDAC presence. At this level of sensitivity, the test has a specificity of 0.097 (α=0.01; β=0.097; IGF-1/IGFBP-2≤0.85)., Conclusions: Our results show that IGF-1 to IGFBP-2 ratio ≤0.85 may be a powerful PDAC indicator. Further studies in this area in a larger patient group are necessary to confirm our findings.

Acute pancreatitis (AP) is one of the most common diseases requiring hospitalization with increasing incidence. This pathology has variable severity and is associated with significant morbidity and mortality. Early diagnosis, including prognosis of clinical course of the disease is key in the initial clinical management. However, currently available prognostic markers have variable efficacy and the limited utility. Adipokines that are released from the peripancreatic adipose tissue during AP may represent the easy to use and practical AP prognostic markers. This review discusses the current state of knowledge concerning the clinical value of the adipokines in AP, such as adiponectin, ghrelin, interleukin 6, interleukin 8, interleukin 18, leptin, neutrophil gelatinase associated lipocalin, obestatin, resistin, visfatin. Among described adipokines, interleukin 6, neutrophil gelatinase associated lipocalin and resistin seem to be the most valuable as the diagnostic and prognostic markers in AP.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by progressive weight loss and nutritional deterioration. Several cytokines, such as activin A and myostatin, ligands of the transforming growth factor-β superfamily, have been shown to influence the pathogenesis of muscle wasting and tumor progression. The aim of our study was to assess the clinical significance of these cytokines in patients with different stages of PDAC. The study included 93 patients: 73 with newly diagnosed PDAC and 20 healthy volunteers as the control group. PDAC patients included 42 diagnosed with non-metastatic pancreatic cancer (stage I - III) and 31 patients with metastatic cancer (stage IV). The peripheral venous blood samples were collected from each patients at the time of cancer diagnosis and plasma concentrations of activin A and myostatin have been measured with an enzyme-linked immunoassay. Forty five patients (61.6%) presented weight loss > 5%, including 24 (57.1%) with stage I - II and 21 (67.7%) with metastatic PDAC (P > 0.05). Plasma levels of activing A were significantly higher in metastatic PDAC patients compared with stage I - III PDAC patients and control group (P < 0.01). The relationship between higher activin A levels and weight loss was also observed (P < 0.05). On the other hand, myostatin was not associated with weight loss in analysed group of patients. In conclusion, the current study demonstrates that high activin A plasma levels at the time of PDAC diagnosis is associated with unintentional weight loss and may be an useful biomarker for identifying patients with metastatic disease. However, further prospective studies are needed to fully explore the clinical significance of myostatin in pathogenesis of progressive weight loss in PDAC patients.

Introduction: Chronic pancreatitis (CP) may be caused by oxidative stress. An important source of reactive oxygen species (ROS) is the methylglyoxal-derived formation of advanced glycation endproducts (AGE). Methylglyoxal is detoxified by Glyoxalase I (GLO1). A reduction in GLO1 activity results in increased ROS. Single nucleotide polymorphisms (SNPs) of GLO1 have been linked to various inflammatory diseases. Here, we analyzed whether common GLO1 variants are associated with alcoholic (ACP) and non-alcoholic CP (NACP)., Methods: Using melting curve analysis, we genotyped a screening cohort of 223 ACP, 218 NACP patients, and 328 controls for 11 tagging SNPs defined by the SNPinfo LD TAG SNP Selection tool and the functionally relevant variant rs4746. For selected variants the cohorts were extended to up to 1,441 patient samples., Results: In the ACP cohort, comparison of genotypes for rs1937780 between patients and controls displayed an ambiguous result in the screening cohort (p = 0.08). However, in the extended cohort of 1,441 patients no statistically significant association was found for the comparison of genotypes (p = 0.11), nor in logistic regression analysis (p = 0.214, OR 1.072, 95% CI 0.961-1.196). In the NACP screening cohort SNPs rs937662, rs1699012, and rs4746 displayed an ambiguous result when patients were compared to controls in the recessive or dominant model (p = 0.08, 0.08, and 0.07, respectively). Again, these associations were not confirmed in the extended cohorts (rs937662, dominant model: p = 0.07, logistic regression: p = 0.07, OR 1.207, 95% CI 0.985-1.480) or in the replication cohorts for rs4746 (Germany, p = 0.42, OR 1.080, 95% CI 0.673-1.124; France, p = 0.19, OR 0.90, 95% CI 0.76-1.06; China, p = 0.24, OR 1.18, 95% CI 0.90-1.54) and rs1699012 (Germany, Munich; p = 0.279, OR 0.903, 95% CI 0.750-1.087)., Conclusions: Common GLO1 variants do not increase chronic pancreatitis risk., Competing Interests: The authors have declared that no competing interests exist.

Background and Aims: Molecular basis of abdominal pain in IBD is not fully characterized. Serotonin (5-HT) increases visceral pain severity and contributes to exacerbation of inflammation. Moreover, it is well established that decreased anandamide (AEA) signaling in the gut increases visceral pain severity. The aim of this study was to investigate the interplay between 5-HT and endocannabinoid signaling in colitis., Methods: We used 3% DSS in drinking water to induce colitis in mice. From day 3 5-HT was administered for 5 days and each day visceromotor response to colorectal distention (CRD) was measured. Expression of cannabinoid (CB) receptors as well as enzymes responsible of biosynthesis and degradation of endocannabinoids were investigated. Moreover, endocannabinoid levels were assessed by mass spectrometry. Additionally, we measured the expression of enzymes synthesizing 5-HT and AEA in the colon of IBD patients and healthy controls., Results: Chronic exposure to 5-HT increased visceromotor response to CRD and worsened colitis, which was associated with decrease of AEA via 5-HT 3 and 5-HT 4 receptors. Moreover, exposure to 5-HT led to the downregulation of CB1 receptors. Colonic levels of N-acyl-phosphatidylethanolamine-specific phospholipase D (NAPE-PLD), which is responsible for synthesis of AEA, significantly declined after chronic treatment with 5-HT and this effect was reversed by the 5-HT 3 and 5-HT 4 receptor antagonists. NAPE-PLD was also downregulated in the colon of UC patients., Conclusions: Our study shows a link between 5-HT and endocannabinoid signaling pathways in IBD. Thus, pharmacological blockade of 5-HT signaling or supplementation with endocannabinoids in the gut might be of benefit in severe cases of abdominal pain in IBD., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: Alcohol-related pancreatitis is associated with a disproportionately large number of hospitalisations among GI disorders. Despite its clinical importance, genetic susceptibility to alcoholic chronic pancreatitis (CP) is poorly characterised. To identify risk genes for alcoholic CP and to evaluate their relevance in non-alcoholic CP, we performed a genome-wide association study and functional characterisation of a new pancreatitis locus., Design: 1959 European alcoholic CP patients and population-based controls from the KORA, LIFE and INCIPE studies (n=4708) as well as chronic alcoholics from the GESGA consortium (n=1332) were screened with Illumina technology. For replication, three European cohorts comprising 1650 patients with non-alcoholic CP and 6695 controls originating from the same countries were used., Results: We replicated previously reported risk loci CLDN2-MORC4 , CTRC , PRSS1-PRSS2 and SPINK1 in alcoholic CP patients. We identified CTRB1-CTRB2 (chymotrypsin B1 and B2) as a new risk locus with lead single-nucleotide polymorphism (SNP) rs8055167 (OR 1.35, 95% CI 1.23 to 1.6). We found that a 16.6 kb inversion in the CTRB1-CTRB2 locus was in linkage disequilibrium with the CP-associated SNPs and was best tagged by rs8048956 . The association was replicated in three independent European non-alcoholic CP cohorts of 1650 patients and 6695 controls (OR 1.62, 95% CI 1.42 to 1.86). The inversion changes the expression ratio of the CTRB1 and CTRB2 isoforms and thereby affects protective trypsinogen degradation and ultimately pancreatitis risk., Conclusion: An inversion in the CTRB1-CTRB2 locus modifies risk for alcoholic and non-alcoholic CP indicating that common pathomechanisms are involved in these inflammatory disorders., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

New-onset diabetes mellitus (DM) is one of the first symptoms of pancreatic adenocarcinoma (PDAC). The frequency of endocrine disorders is estimated between 40% and 80% in patients with pancreatic cancer. DM is a risk factor for cancer development but it may also be a consequence of the tumor growth. Data confirming the existence of a relationship between long standing type 2 DM and an increased risk of PDAC comes from numerous clinical studies. Insulin resistance phenomenon and hyperinsulinemia may result in the increased proliferation of pancreatic islets which in turn may cause a predisposition to cancer development. In contrast, it is proved that new-onset DM among patients over 50 years old significantly increases the risk of PDAC recognition. Insulin-like growth factor 1 (IGF-1) and their complex proteins, IGF binding proteins, which comprise the IGF axis play a crucial role in carbohydrate metabolism disorders and, studies have shown that they may contribute to PDAC growth. Some studies confirm that IGF-1 is connected with early carcinogenesis in animals and humans. Assessing the levels of these proteins may thus be helpful in early recognition of PDAC in patients with recently detected endocrine disorders, especially pancreatic DM.

Background/objectives: Acute pancreatitis (AP) is one of the most common gastrointestinal disorders often requiring hospitalization. Frequent aetiologies are gallstones and alcohol abuse. In contrast to chronic pancreatitis (CP) few robust genetic associations have been described. Here we analysed whether common variants in the CLDN2-MORC4 and the PRSS1-PRSS2 locus that increase recurrent AP and CP risk associate with AP., Methods: We screened 1462 AP patients and 3999 controls with melting curve analysis for SNPs rs10273639 (PRSS1-PRSS2), rs7057398 (RIPPLY), and rs12688220 (MORC4). Calculations were performed for the overall group, aetiology, and gender sub-groups. To examine genotype-phenotype relationships we performed several meta-analyses., Results: Meta-analyses of all AP patients depicted significant (p-value < 0.05) associations for rs10273639 (odds ratio (OR) 0.88, 95% confidence interval (CI) 0.81-0.97, p-value 0.01), rs7057398 (OR 1.27, 95% CI 1.07-1.5, p-value 0.005), and rs12688220 (OR 1.32, 95% CI 1.12-1.56, p-value 0.001). For the different aetiology groups a significant association was shown for rs10273639 (OR 0.76, 95% CI 0.63-0.92, p-value 0.005), rs7057398 (OR 1.43, 95% CI 1.07-1.92, p-value 0.02), and rs12688220 (OR 1.44, 95% CI 1.07-1.93, p-value 0.02) in the alcoholic sub-group only., Conclusions: The association of CP risk variants with different AP aetiologies, which is strongest in the alcoholic AP group, might implicate common pathomechanisms most likely between alcoholic AP and CP., (Copyright © 2018 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Pancreatic ductal adenocarcinoma (PDAC) is a very aggressive tumor with a five-year survival of less than 6%. Chronic pancreatitis (CP), an inflammatory process in of the pancreas, is a strong risk factor for PDAC. Several genetic polymorphisms have been discovered as susceptibility loci for both CP and PDAC. Since CP and PDAC share a consistent number of epidemiologic risk factors, the aim of this study was to investigate whether specific CP risk loci also contribute to PDAC susceptibility. We selected five common SNPs (rs11988997, rs379742, rs10273639, rs2995271 and rs12688220) that were identified as susceptibility markers for CP and analyzed them in 2,914 PDAC cases, 356 CP cases and 5,596 controls retrospectively collected in the context of the international PANDoRA consortium. We found a weak association between the minor allele of the PRSS1-PRSS2-rs10273639 and an increased risk of developing PDAC (OR homozygous  = 1.19, 95% CI 1.02-1.38, p = 0.023). Additionally all the SNPs confirmed statistically significant associations with risk of developing CP, the strongest being PRSS1-PRSS2-rs10273639 (OR heterozygous  = 0.51, 95% CI 0.39-0.67, p = 1.10 × 10 -6 ) and MORC4-rs 12837024 (OR homozygous  = 2.07 (1.55-2.77, p trend  = 0.7 × 10 -11 ). Taken together, the results from our study do not support variants rs11988997, rs379742, rs10273639, rs2995271 and rs12688220 as strong predictors of PDAC risk, but further support the role of these SNPs in CP susceptibility. Our study suggests that CP and PDAC probably do not share genetic susceptibility, at least in terms of high frequency variants., (© 2017 UICC.)

Protease inhibition has become a possible new approach in inflammatory bowel disease (IBD) therapy. A serine exopeptidase, dipeptidyl peptidase IV (DPP IV), is responsible for the inactivation of incretin hormone, glucagon-like peptide 2 (GLP-2), a potent stimulator of intestinal epithelium regeneration and growth. Recently, we showed that the novel peptide analog of endomorphin-2, Tyr-Pro-D-ClPhe-Phe-NH 2 (EMDB-1) is a potent blocker of DPP IV and has an inhibitory effect on gastrointestinal (GI) smooth muscle contractility. The aim of this study was to characterize the anti-inflammatory effect and mechanism of action of EMDB-1 in the mouse GI tract. We used two models of experimental colitis (induced by TNBS and DSS). The anti-inflammatory effect of EMDB-1 was assessed by the determination of macroscopic score, ulcer score, colonic wall thickness, as well as myeloperoxidase activity. Additionally, we measured the expression of GLP-2, GLP2R, and DPP IV in the colon of control and colitic animals treated with the test compound. The expression of GLP-2 and GLP2R in the serum and colon of IBD patients and healthy control subjects has been assessed. We showed that EMDB-1 elevates the half-life of GLP-2 in vitro and attenuates acute, semichronic, and relapsing TNBS as well as DSS-induced colitis in mice after topical administration. The anti-inflammatory action of EMDB-1 is associated with changes in the level of colonic GLP-2 but not DPP IV expression. Our results validate DPP IV as a pharmacological target for the anti-IBD drugs, and its inhibitors based on natural substrates, such as EMDB-1, have the potential to become valuable anti-inflammatory therapeutic agents., (Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.)

Background and Aims: Pharmacological treatment and/or maintenance of remission in inflammatory bowel disease [IBD] is currently one of the biggest challenges in the field of gastroenterology. Here we aimed to assess the anti-inflammatory effect and the mechanism of action of sialorphin, the natural blocker of the endogenous opioid peptide-degrading enzymes neprilysin [NEP] and aminopeptidase N [APN], in mouse models of IBD and the changes in the expression of these enzymes in IBD patients., Methods: We used two models of experimental colitis in mice [2,4,6-trinitrobenzene sulphonic acid [TNBS]- and dextran sulphate sodium [DSS]-induced]. Macroscopic score, ulcer score, colonic wall thickness, and myeloperoxidase [MPO] activity were recorded. Additionally, we measured the expression of NEP and APN in the colon of IBD patients and healthy controls., Results: We showed that sialorphin attenuated acute, semichronic, and relapsing TNBS-induced colitis in mice after systemic administration, and its anti-inflammatory action is associated with mu and kappa opioid receptors., Conclusions: We show that indirect stimulation of opioid receptors by the blockade of NEP and APN is a promising pharmacological strategy for the treatment of IBD, and may become of greater importance than the use of classical opioid agonists., (Copyright © 2017 European Crohn's and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com)

Background/objectives: The elevation of insulin-like growth factor 1 (IGF-1) and adipokine retinol-binding protein 4 (RBP-4) is known to be associated with the risk of many cancers. The aim of this study was to evaluate the serum concentrations of IGF-1 and RBP-4 in patients with PDAC and chronic pancreatitis (CP)., Methods: The study included 43 patients with PDAC, 39 patients with CP and 10 controls. The concentrations of IGF-1 and RBP-4 were obtained using the ELISA method (Corgenix UK Ltd R&D Systems). The study protocol was approved by the Bioethics Committee at the Medical University of Lodz., Results: In PDAC patients the serum IGF-1 level was significantly higher than in patients with CP (107.79 ± 66.40 ng/ml vs 89.91 ± 74.06 ng/ml; P < 0.05). Patients with both CP and diabetes mellitus (DM) were noted to have a significantly lower level of IGF-1 compared with those who only had CP (51.33 ± 24.30 ng/ml vs 108.42 ± 82.39 ng/ml; P = 0.01). The same result was obtained for men with and without DM (58.05 ± 32.44 ng/ml vs 98.79 ± 79.47 ng/ml, P = 0.05). As regards the serum level of RBP-4, the PDAC and CP groups were not significantly different from each other., Conclusions: Diabetes accompanying PDAC does not influence the level of IGF-1 as opposed to diabetes in the course of CP. The IGF-1 level can be useful for early diagnosis of PDAC. High concentration of RBP-4 is not specific to pancreatic cancer, so it does not appear to be a useful biomarker for PDAC., (Copyright © 2017 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Expression of the solute carrier (SLC) transporter SLC22A3 gene is associated with overall survival of pancreatic cancer patients. This study tested whether genetic variability in SLC22A3 associates with pancreatic cancer risk and prognosis. Twenty four single nucleotide polymorphisms (SNPs) tagging the SLC22A3 gene sequence and regulatory elements were selected for analysis. Of these, 22 were successfully evaluated in the discovery phase while six significant or suggestive variants entered the validation phase, comprising a total study number of 1,518 cases and 3,908 controls. In the discovery phase, rs2504938, rs9364554, and rs2457571 SNPs were significantly associated with pancreatic cancer risk. Moreover, rs7758229 associated with the presence of distant metastases, while rs512077 and rs2504956 correlated with overall survival of patients. Although replicated, the association for rs9364554 did not pass multiple testing corrections in the validation phase. Contrary to the discovery stage, rs2504938 associated with survival in the validation cohort, which was more pronounced in stage IV patients. In conclusion, common variation in the SLC22A3 gene is unlikely to significantly contribute to pancreatic cancer risk. The rs2504938 SNP in SLC22A3 significantly associates with an unfavorable prognosis of pancreatic cancer patients. Further investigation of this SNP effect on the molecular and clinical phenotype is warranted.

Introduction: Barrett's esophagus (BE), which develops as a result of gastroesophageal reflux disease, is a preneoplastic condition for esophageal adenocarcinoma (EAC). A new hypothesis suggests that cancer is a disease of stem cells, however, their expression and pathways in BE - EAC sequence are not fully elucidated yet., Aims: We used a panel of putative cancer stem cells markers to identify stem cells in consecutive steps of BE-related cancer progression., Methods: Immunohistochemistry was performed on formalin-fixed, paraffin-embedded blocks from 58 patients with normal cardiac mucosa (n=5), BE (n=14), early EAC (pT1) from mucosal resection (n=17) and advanced EAC (pT1-T4) from postoperative specimens (n=22). Expression of the CD133, CD44, Musashi-1 and EpCAM was analyzed using respective monoclonal antibodies., Results: All markers showed a heterogeneous expression pattern, mainly at the base of the crypts of Barrett's epithelium and EAC, with positive stromal cells in metaplastic and dysplastic lesions. Immuno-expression of EpCAM, CD44 and CD133 in cardiac mucosa was significantly lower (mean immunoreactivity score (IRS)=1.2; 0.0; 0.4; respectively) compared to their expression in Barrett's metaplasia (mean IRS=4.3; 0.14; 0.7; respectively), in early adenocarcinoma (mean IRS=4.4; 0.29; 1.3; respectively) and in advanced adenocarcinoma (mean IRS=6.6; 0.7; 2.7; respectively) (p<0.05). On the contrary, Musashi-1 expression was higher in BE and early ADC compared to GM and advanced ADC (NS)., Conclusion: Our results suggest that the stem cells could be present in premalignant lesions. EpCAM, CD44 and CD133 expression could be candidate markers for BE progression, whereas Musashi-1 may be a marker of the small intestinal features of Barrett's mucosa., (Copyright © 2016 Elsevier GmbH. All rights reserved.)

Cancer stem cells (CSC) play an important role in pancreatic carcinogenesis and prognosis. The study aimed at examining the expression of CD24, CD44, and CD133 in human PDAC and CP in order to evaluate its clinicopathological correlations and the clinical significance. Surgical specimens from 23 patients with PDAC and 15 patients with chronic pancreatitis after pancreatic resection were stained with CD24, CD44, and CD133 antibodies. The intensity of staining was scored from 0 (negative) to 3 (strongly positive). Results . Mean CD24 staining score in PDAC was 1.38 ± 0.76 and was significantly higher than that in CP: 0.70 ± 0.53 ( p < 0.01); CD44 score in PDAC was 2.23 ± 0.42 and was significantly higher than that in CP: 1.87 ± 0.55 ( p < 0.05); CD133 score 0.93 ± 0.58 was not different from CP: 0.71 ± 0.43 ( p > 0.05). CD44 immunoreactivity was significantly higher ( p < 0.05) in pT1 and pT2 patients together as regards pT3: 2.45 ± 0.37 versus 2.06 ± 0.38 as well as in N0 patients compared to N1 patients: 2.5 ± 0.38 versus 2.04 ± 0.34. Conclusions . CD24 and CD44 are upregulated in human pancreatic cancer compared to chronic pancreatitis. CD44 immunoreactivity decreases with the tumor advancement and may represent the negative PDAC prognostic factor. Each CSC marker was differently related to PDAC advancement. CD133 may lack clinical significance in PDAC.

Pancreatic neuroendocrine tumors (PNETs) are heterogeneous neoplasms which represent only 2% of all pancreatic neoplasms by incidence, but 10% by prevalence. Genetic risk factors could have an important role in the disease aetiology, however only a small number of case control studies have been performed yet. To further our knowledge, we genotyped 13 SNPs belonging to the pleiotropic CDKN2A/B gene region in 320 PNET cases and 4436 controls, the largest study on the disease so far. We observed a statistically significant association between the homozygotes for the minor allele of the rs2518719 SNP and an increased risk of developing PNET (OR hom  = 2.08, 95% CI 1.05-4.11, p = 0.035). This SNP is in linkage disequilibrium with another polymorphic variant associated with increased risk of several cancer types. In silico analysis suggested that the SNP could alter the sequence recognized by the Neuron-Restrictive Silencer Factor (NRSF), whose deregulation has been associated with the development of several tumors. The mechanistic link between the allele and the disease has not been completely clarified yet but the epidemiologic evidences that link the DNA region to increased cancer risk are convincing. In conclusion, our results suggest rs2518719 as a pleiotropic CDKN2A variant associated with the risk of developing PNETs.

The CDKN2A (p16) gene plays a key role in pancreatic cancer etiology. It is one of the most commonly somatically mutated genes in pancreatic cancer, rare germline mutations have been found to be associated with increased risk of developing familiar pancreatic cancer and CDKN2A promoter hyper-methylation has been suggested to play a critical role both in pancreatic cancer onset and prognosis. In addition several unrelated SNPs in the 9p21.3 region, that includes the CDNK2A, CDNK2B and the CDNK2B-AS1 genes, are associated with the development of cancer in various organs. However, association between the common genetic variability in this region and pancreatic cancer risk is not clearly understood. We sought to fill this gap in a case-control study genotyping 13 single nucleotide polymorphisms (SNPs) in 2,857 pancreatic ductal adenocarcinoma (PDAC) patients and 6,111 controls in the context of the Pancreatic Disease Research (PANDoRA) consortium. We found that the A allele of the rs3217992 SNP was associated with an increased pancreatic cancer risk (ORhet=1.14, 95% CI 1.01-1.27, p=0.026, ORhom=1.30, 95% CI 1.12-1.51, p=0.00049). This pleiotropic variant is reported to be a mir-SNP that, by changing the binding site of one or more miRNAs, could influence the normal cell cycle progression and in turn increase PDAC risk. In conclusion, we observed a novel association in a pleiotropic region that has been found to be of key relevance in the susceptibility to various types of cancer and diabetes suggesting that the CDKN2A/B locus could represent a genetic link between diabetes and pancreatic cancer risk., Competing Interests: John P. Neoptolemos has the following conflicts of interest. Payment for Lectures: Amgen, Mylan Research Grants: Taiho Pharma (Japan); KAEL GemVax (Korea); AstraZeneca; Clovis Oncology and Ventana; Pharma Nord. Consultancy: Boehringer Ingelheim Pharma GmbH & Co. KG; Novartis Pharma AG; KAEL GemVax; Astellas. Educational Travel Grants: NUCANA. The other authors do not have any conflict of interest to declare.

Esophageal complications caused by gastroesophageal reflux disease (GERD) include reflux esophagitis and Barrett's esophagus (BE). BE is a premalignant condition with an increased risk of developing esophageal adenocarcinoma (EAC). The carcinogenic sequence may progress through several steps, from normal esophageal mucosa through BE to EAC. A recent advent of functional esophageal testing (particularly multichannel intraluminal impedance and pH monitoring) has helped to improve our knowledge about GERD pathophysiology, including its complications. Those findings (when properly confirmed) might help to predict BE neoplastic progression. Over the last few decades, the incidence of EAC has continued to rise in Western populations. However, only a minority of BE patients develop EAC, opening the debate regarding the cost-effectiveness of current screening/surveillance strategies. Thus, major efforts in clinical and research practice are focused on new methods for optimal risk assessment that can stratify BE patients at low or high risk of developing EAC, which should improve the cost effectiveness of screening/surveillance programs and consequently significantly affect health-care costs. Furthermore, the area of BE therapeutic management is rapidly evolving. Endoscopic eradication therapies have been shown to be effective, and new therapeutic options for BE and EAC have emerged. The aim of the present review article is to highlight the status of screening/surveillance programs and the current progress of BE therapy. Moreover, we discuss the recent introduction of novel esophageal pathophysiological exams that have improved the knowledge of the mechanisms linking GERD to BE.

Pancreatic cancer is the fourth leading cause of cancer death in the developed world. Both inherited high-penetrance mutations in BRCA2 (ref. 2), ATM, PALB2 (ref. 4), BRCA1 (ref. 5), STK11 (ref. 6), CDKN2A and mismatch-repair genes and low-penetrance loci are associated with increased risk. To identify new risk loci, we performed a genome-wide association study on 9,925 pancreatic cancer cases and 11,569 controls, including 4,164 newly genotyped cases and 3,792 controls in 9 studies from North America, Central Europe and Australia. We identified three newly associated regions: 17q25.1 (LINC00673, rs11655237, odds ratio (OR) = 1.26, 95% confidence interval (CI) = 1.19-1.34, P = 1.42 × 10(-14)), 7p13 (SUGCT, rs17688601, OR = 0.88, 95% CI = 0.84-0.92, P = 1.41 × 10(-8)) and 3q29 (TP63, rs9854771, OR = 0.89, 95% CI = 0.85-0.93, P = 2.35 × 10(-8)). We detected significant association at 2p13.3 (ETAA1, rs1486134, OR = 1.14, 95% CI = 1.09-1.19, P = 3.36 × 10(-9)), a region with previous suggestive evidence in Han Chinese. We replicated previously reported associations at 9q34.2 (ABO), 13q22.1 (KLF5), 5p15.33 (TERT and CLPTM1), 13q12.2 (PDX1), 1q32.1 (NR5A2), 7q32.3 (LINC-PINT), 16q23.1 (BCAR1) and 22q12.1 (ZNRF3). Our study identifies new loci associated with pancreatic cancer risk.

Background and Objective: Irritable Bowel Syndrome (IBS) has a substantial impact on health-related quality of life (HR-QoL) but high-quality data pre- and post-treatment using the IBS-Quality of Life (IBS-QOL) measure are limited. The objective of this study was to evaluate the changes from baseline of the IBS-QOL scores, symptom scores and health economic data in IBS patients, after 4 and 8 weeks of treatment with mebeverine hydrochloride or pinaverium bromide., Methods: This was a prospective observational cohort study in patients with IBS, diagnosed using the Rome III criteria in four countries (Poland, Egypt, Mexico and China)., Results: A total of 607 patients were enrolled. At baseline, the IBS-QOL total scores were 52.0 in Poland, 48.9 in Egypt, 51.9 in Mexico, 76.4 in China and 56.4 overall. Increases in IBS-QOL total score were statistically significant at Weeks 4 and 8 overall and in each country (overall: 11.8 at Week 4, 24.3 at Week 8; p < 0.001). Improvements were shown in all IBS-QOL subscales and scores. Symptoms and health economic outcomes were improved. Furthermore, the favourable safety profile of these treatments was confirmed in this study., Conclusions: This study demonstrated that IBS patients have a substantially reduced HR-QoL and that treatment with mebeverine hydrochloride or pinaverium bromide improved HR-QoL.

Background/aims: Esophageal adenocarcinoma (ADC) incidence has been increasing dramatically in the past 3 decades despite the surveillance programs in patients with Barrett’s esophagus (BE). Therefore, markers of early neoplastic progression are required to predict of cancer risk in BE patients. The aim of this study was to investigate the frequency of Her2/neu amplification in different stages during Barrett’s-related carcinogenesis., Methodology: Her2/neu amplification analysis in 39 patients with gastroesophageal reflux disease (GERD), in 34 with BE, in 11 with dysplasia and 13 with ADC were performed with PCR., Results: Her2/neu amplification was detected in 8% (3/39) GERD patients, 15% (5/34) with BE, 41% (7/17) with dysplasia and in 54% (7/13) with ADC. We observed an increasing trend in the frequency of Her2/neu alteration between BE-carcinogenesis stages (p=0.001). This finding was confirmed in the logistic regression analysis showing gradient in odds ratios between BE (2.07; 95% CI: 0.46-9.39), dysplasia (8.4; 95% CI: 1-83-38.53) and ADC (14.0; 95% CI: 2.81-69.69) compared to GERD; it was even higher after adjustment for age and gender., Conclusions: Her2/neu alterations may occur early and increasingly during Barrett’s malignant progression. We suggest that it may be useful to stratify the risk of adenocarcinoma in patients with Barrett’s esophagus.

Background: The aim of the study was to evaluate the concentration of proteolytic enzymes, MMP-2 and MMP-9, and their tissue inhibitors, TIMP-1 and TIMP-2, in the blood of patients with benign and malignant pancreatic tumors., Methods: MMP-2, MMP-9, TIMP-1, and TIMP-2 were evaluated in the patients with benign and malignant pancreatic tumors before surgery and in the 30-day follow-up. The study covered 134 patients aged 54 to 76 years, who were divided into groups by TNM staging., Results: Before the operation, the highest mean concentration of MMP-2 was found in patients with unresectable cancer, whereas the highest level of MMP-9 was in patients with resectable cancer. The highest level of TIMP-1 was noted in patients with inflammatory tumors. In 1 month following the operation, the highest level of MMP-2 was also in patients with unresectable cancer and the highest level of TIMP-2 in patients with inflammatory tumors., Conclusions: The evaluation of the level of the studied cytokines in the pancreatic tumor patients can be diagnostically significant in the differentiation of benign and malignant changes. The changes in the levels of the studied enzymes and their inhibitors can have a prognostic value in the clinical severity of pancreatic cancer.

Unlabelled: Esophageal adenocarcinoma incidence is rapidly increasing which may be due to the growing incidence of Barrett's esophagus (BE) and obesity. The mechanisms linking obesity and progression of Barrett's carcinogenesis is poorly understood. The aim of the study was to evaluate the expression of adipokines receptors in BE and in normal squamous epithelium in the same patients in correlation with obesity parameters., Methods: Expression of adiponectin receptors 1 and 2 protein (AdipoR1, AdipoR2) as well as leptin receptor protein (ObR) in biopsies from 27 BE and normal squamous epithelium (N) in the same patients as well as in obese and normal controls were assessed with Western-blot analysis. These correlations were confirmed with the quantitative RT-PCR (qRT-PCR). AdipoR1 and ObR protein levels were similar in BE mucosa and squamous epithelium in the same patients in Western-blot analysis (2303 vs. 2448 OB units; 106927 vs. 103390, respectively; p>0.05). RT-PCR analysis confirmed this observation for AdipoR1, R2 and ObR genes expression (0.11±0.08 vs. 0.19±0.24, p=0.78; 0.24±0.36 vs. 0.33±0.49, p=0.5375; 0.71±0.8 vs. 1.33±2.95, p=1.0; respectively). Using linear correlation analysis we found the positive correlation between AdipoR1 expression in Barrett's epithelium compared to squamous epithelium in the same patients (N) (r=0.5; p=0.008) and between ObR expression in BE and N (r=0.8; p<0.001). The AdipoR1 and ObR protein levels were significantly higher in BE patients compared to controls and obese controls (2303 vs. 895 vs. 1674 and OD units, p<0.05)., Conclusions: in opposite to the prior hypothesis adiponectin and leptin receptors activation in BE may be not caused by obesity.

Background: Histopathologic differentiation between the stages of Barrett's carcinogenesis is often challenging. Liver-intestine (LI)-cadherin, an intestine-specific marker, is involved in intestinal metaplasia development in gastric and colon cancers and could be of value in diagnosis and differentiation., Aims: To examine the expression of LI-cadherin in the sequence of Barrett's carcinogenesis and to evaluate its association with clinicopathological data., Methods: LI-cadherin expression was immunohistologically investigated, by use of anti-CDH17 antibody, in gastric mucosa (GM) biopsies taken from the cardia (n = 9), in Barrett's esophagus (BE) without intraepithelial neoplasia (without IEN) (n = 9) and BE with low-grade IEN (n = 11), and in esophageal adenocarcinoma (ADC) (n = 13)., Results: The immunoreactivity score was highest in adenocarcinoma (mean IRS = 4.0), and dropped gradually from BE with IEN and BE without IEN (mean IRS = 2.0) to cardia mucosa (IRS = 0). Similarly, the intensity of staining and the percentage of positive cells increased during the sequential stages of BE carcinogenesis. Comparative analysis showed that LI-cadherin expression was significantly different between cardiac epithelium and ADC. Also, percentage of positive cells in GM was significantly different from that in BE with IEN. LI-cadherin IRS was lower for tumors with poor differentiation than for moderately differentiated tumors, but the difference was not statistically significant., Conclusions: LI-cadherin is a sensitive marker of intestinal metaplasia and can be helpful for early histologic diagnosis of Barrett's esophagus; it is, however, not significantly different between BE with and without IEN, and cannot be used to distinguish between these.

The majority of pancreatic cysts are detected incidentally when abdominal imaging is performed during unrelated procedures. The aim of the present study was to assess the diagnostic utility and clinical value of carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA 19-9) and amylase analysis in pancreatic cyst fluid. The study included 52 patients with pancreatic cystic lesions, who underwent fine-needle aspiration biopsy to collect cystic fluid for cytological and biochemical analysis. Cysts were classified as benign (simple cysts, pseudocysts and serous cystadenomas) in 36 patients or premalignant/malignant (mucinous cyst-adenomas, intraductal papillary mucinous neoplasm and cystadenocarcinomas) in 16 patients. CEA and CA 19-9 were elevated in patients with malignant cysts (238±12.5 ng/ml and 222±31.5 U/ml, respectively) compared with benign lesions (34.5±3.7 ng/ml and 18.5±1.9 U/ml, respectively; P<0.001). Based on these results, the sensitivity and specificity of CEA were 91.8 and 63.9% and of CA 19-9 were 81.3 and 69.4%, respectively. Mean amylase levels in benign lesions (27825.7±91.9 U/l) were higher compared with malignant pancreatic cysts (8359.2±32.7 U/l; P<0.05). Cyst fluid analysis may prove a safe and useful adjunct for the differential diagnosis of pancreatic cystic lesions. In the present study, promising results for CEA and CA 19-9 have been demonstrated, however, the clinical value of these molecules must be confirmed.

Pancreatic cancer is the fourth leading cause of cancer deaths in the European Union and in the USA, but little is known about its genetic susceptibility. The PANcreatic Disease ReseArch (PANDoRA) consortium was established to unite the efforts of different research groups; its aim is to create a large bio-database to uncover new genetic factors for pancreatic cancer risk, response to treatment, and patient survival. So far 2220 cases of pancreatic adenocarcinoma, a smaller number of cases of endocrine pancreatic tumours (n=86), chronic pancreatitis (n=272) and 3847 healthy controls have been collected. As a collective effort of the consortium, SNPs associated with pancreatic adenocarcinoma risk from a genome-wide association study performed in Caucasians were replicated. The possibility that the same genetic polymorphisms may influence patient survival as well was also addressed. This collective effort is particularly important for pancreatic cancer because it is a relatively rare disease for which little is known about aetiopathogenesis and risk factors. The recruitment of additional collaborators and partner institutions is continuously on-going., (Copyright © 2012 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background/aims: Central obesity is a risk factor for GERD, Barrett's esophagus and esophageal adeno-carcinoma. Recent studies have suggested that adipocytokines are the possible link between adiposity and Barrett's carcinogenesis. To determine the adiponectin, resistin and leptin concentration as well as the central adiposity parameters in BE patients with and without intestinal metaplasia (IM) in comparison to GERD and healthy controls., Methodology: Total of 77 patients (30 patients with GERD, 26 BE with IM and 21 BE without IM) and 30 healthy controls were investigated for the central obesity parameters. Serum levels of adipocytokines were measured with ELISA., Results: The serum concentration of adiponectin was significantly lower in BE compared to those in GERD and to controls (p<0.001). Levels of leptin was slightly higher in BE than in GERD and controls (NS). Level of resistin was significantly higher in GERD compared to both control and BE patients (p<0.001). Waist circumference, WHR and WTR were significantly higher in BE patients compared to GERD (p<0.001) and to control group (p<0.001)., Conclusions: Features of central obesity rather than BMI are associated with BE development. Adipokines may be important at the early step of BE development, before the IM occurrence.