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Background: Genetic predisposition is crucial in the pathogenesis of early-onset chronic pancreatitis (CP). So far, several genetic alterations have been identified as risk factors, predominantly in genes encoding digestive enzymes. However, many early-onset CP cases have no identified underlying cause. Chymotrypsins are a family of serine proteases that can cleave trypsinogen and lead to its degradation. Because genetic alterations in the chymotrypsins CTRC, CTRB1, and CTRB2 are associated with CP, we genetically and functionally investigated chymotrypsin-like protease (CTRL) as a potential risk factor., Methods: We screened 1005 non-alcoholic CP patients and 1594 controls for CTRL variants by exome sequencing. We performed Western blots and activity assays to analyse secretion and proteolytic activity. We measured BiP mRNA expression to investigate the potential impact of identified alterations on endoplasmic reticulum (ER) stress., Results: We identified 13 heterozygous non-synonymous CTRL variants: five exclusively in patients and three only in controls. Functionality was unchanged in 6/13 variants. Four alterations showed normal secretion but reduced (p.G20S, p.G56S, p.G61S) or abolished (p.S208F) activity. Another three variants (p.C201Y, p.G215R and p.C220G) were not secreted and already showed reduced or no activity intracellularly. However, intracellular retention did not lead to ER stress., Conclusion: We identified several CTRL variants, some showing potent effects on protease function and secretion. We observed these effects in variants found in patients and controls, and CTRL loss-of-function variants were not significantly more common in patients than controls. Therefore, CTRL is unlikely to play a relevant role in the development of CP., Competing Interests: Declaration of competing interest The authors report no conflicts of interest., (Copyright © 2023 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Background: Patients with chronic pancreatitis (CP) have an increased risk of pancreatic cancer. We present the international consensus guidelines for surveillance of pancreatic cancer in CP., Methods: The international group evaluated 10 statements generated from evidence on 5 questions relating to pancreatic cancer in CP. The GRADE approach was used to evaluate the level of evidence available per statement. The working group voted on each statement for strength of agreement, using a nine-point Likert scale in order to calculate Cronbach's alpha reliability coefficient., Results: In the following domains there was strong consensus: (1) the risk of pancreatic cancer in affected individuals with hereditary pancreatitis due to inherited PRSS1 mutations is high enough to justify surveillance; (2) the risk of pancreatic cancer in patients with CP associated with SPINK1 p. N34S is not high enough to justify surveillance; (3) surveillance should be undertaken in pancreatic specialist centers; (4) surveillance should only be introduced after the age of 40 years and stopped when the patient would no longer be suitable for surgical intervention. All patients with CP should be advised to lead a healthy lifestyle aimed at avoiding risk factors for progression of CP and pancreatic cancer. There was only moderate or weak agreement on the best methods of screening and surveillance in other types of environmental, familial and genetic forms of CP., Conclusions: Patients with inherited PRSS1 mutations should undergo surveillance for pancreatic cancer, but the best methods for cancer detection need further investigation., Competing Interests: Declaration of competing interest JPN reports grants from NUCANA, Stiftung Deutsche Krebshilfe and Heidelberger Stiftung Chirurgie all outside of the submitted work; DCW is co-founder of Ariel Precision Medicine and may have equity., (Copyright © 2020 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Purpose of Review: To discuss how to recognise and manage high-risk individuals., Recent Findings: Publication of initial results of screening for pancreatic cancer from US centres. Several masses and premalignant lesions have been detected, but the detection of the first pancreatic cancer through an organised study of screening has yet to be published. There has been progress in risk stratification; the role of diabetes in predisposing for cancer has been characterised and molecular modalities have been published which could be used in conjunction with imaging in a screening programme. A mutation in the palladin gene was found to segregate with the disease in a family with a clear predisposition for pancreatic cancer, though this has yet to be found in other such kindreds., Summary: Significant challenges remain to be solved in screening for early pancreatic cancer. Risk stratification needs to be improved and high-risk patients included in research-based screening programmes. It will be impossible to confirm that screening can detect cancers early enough for curative treatment until the results of these prospective studies become available., ((c) 2009 S. Karger AG, Basel.)

Pancreatic cancer, like many other complex diseases, has genetic and environmental components to its etiology. It is likely that relatively common genetic variants with modest effects on pancreatic cancer risk play an important role in both familial and sporadic forms of the disease, either individually or in interaction with environmental factors. The relatively high frequency of such variants means that they could potentially explain a substantial portion of disease risk. Here we summarize the findings published to date from genetic association studies. In general, very few low-penetrance variants have been identified and those that have require replication in independent studies. Possible gene-environment interactions arising from these studies also require replication. More comprehensive approaches are needed to make progress, including global analyses of biologically sound pathways and genome-wide association studies. Large sample sizes are required to do this appropriately and multi-study consortia make this possible. A number of consortia of pre-existing studies have already been formed, and these will facilitate the identification of further low-penetrance variants and gene-environment interaction. However, these approaches do not substitute for the design of novel, sufficiently powered studies that apply uniform criteria to case selection, the acquisition of environmental exposure information, and to biological sample collection., ((c) 2009 S. Karger AG, Basel.)

Purpose: To describe the need for multinational registries of families at high risk of pancreatic cancer and the issues surrounding identification of such families., Results: A consensus position was published describing surveillance of individuals at high risk of pancreatic cancer. Hereditary pancreatitis patients, people with Peutz-Jeghers syndrome, individuals with CDKN2A or BRCA1/2 mutations with a family history of pancreatic cancer and kindred with multiple pancreatic cancers were considered suitable for research-based screening. Mutations responsible for familial predisposition are mostly unknown, although BRCA2 mutations have been identified in some families and a mutation in the palladin gene has been shown to segregate with pancreatic cancer in one kindred. Specific autosomal dominant inheritance of pancreatic cancer risk seems to involve anticipation; this finding aids identification of families and determination of individual risk. Diabetes mellitus is an early symptom of pancreatic cancer, but recent publications suggest that it may not be a significant predisposing factor; this remains controversial. However, in the context of hereditary pancreatitis, diabetes probably does predispose to pancreatic cancer as shown in a recent description of French families., Conclusion: Appropriate inclusion of patients within registries of high-risk families provides a framework for secondary screening and research on risk stratification and early tumorigenesis. and IAP., (Copyright 2008 S. Karger AG, Basel and IAP.)

Background: The aim of this study was to evaluate expression of the bcl-2 family of apoptosis regulating proteins in normal and diseased human pancreatic tissues., Method: Expression of bcl-2, bax, bcl-x, bak and p53 was determined in formalin-fixed paraffin wax-embedded archival specimens of normal pancreatic tissue (n = 7), chronic pancreatitis (n = 7), pancreatic ductal adenocarcinoma (n = 23) and ampullary cancer (n = 7) by immunohistochemistry using specific antibodies., Results: In normal pancreas and chronic pancreatitis tissues, bcl-2, bax and bcl-x were predominantly expressed in ductal epithelial cells while p53 was not detected. In pancreatic ductal adenocarcinoma and ampullary cancer, bcl-2 was not detected compared with expression seen in normal acini (p < 0.01), minor (p < 0.001) and major ducts (p < 0.01), bax expression was reduced with respect to minor ducts (p < 0.01) but no different from normal acini or major ducts. bak and bcl-x were more strongly expressed in malignant epithelia compared with acini and major ducts but reduced when compared with minor ducts (p < 0.01). Overexpression of p53 was identified in 11 (48%) of 23 pancreatic adenocarcinomas and 4 (57%) of 7 ampullary cancers. Differential survival of individual patients was predicted by the relative level of bcl-x expression but not bax or bak, such that strong expression of bcl-x was associated with a median postoperative survival of 171 days when compared with 912 days for diminished expression (p < 0.001) of bcl-x., Conclusion: Pancreatic and ampullary cancer are associated with absent bcl-2 expression. bax, bak and bcl-x expression was reduced compared with normal minor ducts whilst bak and bcl-x expression was increased when compared with major ducts. bcl-x expression correlates with survival following resection and may represent a potential prognosis marker.

The prevalence of pancreatic cancer in the general population is too low--even in high-prevalence areas such as Northern Europe and North America (8-12 per 10(5) population)--relative to the diagnostic accuracy of present detection methods to permit primary screening in the asymptomatic adult population. The recognition that the lifetime risk of developing pancreatic cancer for patients with hereditary pancreatitis (HP) is extremely high (20% by the age of 60 years and 40% by the age of 70 years) poses considerable challenges and opportunities for secondary screening in those patients without any clinical features of pancreatic cancer. Even for secondary screening, the detection of cancer at a biological stage that would be amenable to cure by surgery (total pancreatectomy) still requires diagnostic modalities with a very high sensitivity and specificity. Conventional radiological imaging methods such as endoluminal ultrasound and endoscopic retrograde pancreatography, which have proved to be valuable in the early detection of early neoplastic lesions in patients with familial pancreatic cancer, may well be applicable to patients with HP but only in those without gross morphological features of chronic pancreatitis (other than parenchymal atrophy). Unfortunately, most cases of HP also have associated gross features of chronic pancreatitis that are likely to seriously undermine the diagnostic value of these conventional imaging modalities. Pre-malignant molecular changes can be detected in the pancreatic juice of patients. Thus, the application of molecular screening in patients with HP is potentially the most powerful method of detection of early pancreatic cancer. Although mutant (mt) K-ras can be detected in the pancreatic juice of most patients with pancreatic cancer, it is also present in patients with non-inherited chronic pancreatitis who do not progress to pancreatic cancer (at least in the short to medium term), as well as increasingly in the older population without pancreatic disease. Nevertheless, the presence of mt-K-ras may identify a genuinely higher-risk group, enabling additional diagnostic imaging and molecular resources to be focussed on such a group. What is clear is that prospective multi-centre studies, such as that being pursued by the European Registry of Hereditary Pancreatitis and Familial Pancreatic Cancer (EUROPAC), are essential for the development of an effective secondary screening programme for these patients.