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Individuals carrying a germline CDKN2Apathogenic variant (PV) are at a high risk of developing pancreatic ductal adenocarcinoma. Risk stratification could allow tailored surveillance. To develop a Fine‐Gray prediction model for the risk of PDAC in carriers of a CDKN2APV. Data from two large Dutch pancreatic cancer surveillance programs were used. A limited set of predictor variables were selected bsased on previous literature and the clinical expertise of the study group. A total of 506 CDKN2APV carriers were included, among whom we showed a substantial lifetime risk of PDAC (23%). The model identifies having a first‐degree relative with PDAC (B= 0.7256) and a history of smoking (B= 0.4776) as significant risk factors. However, the model shows limited discrimination (c‐statistic 0.64) and calibration. Our study highlights the high lifetime risk of PDAC in carriers of a CDKN2APV. While identifying significant risk factors such as family history of PDAC and smoking, our prediction model shows limited precision, highlighting the need for additional factors such as biomarkers to improve its clinical utility for tailored surveillance of high‐risk individuals.

Pancreatic cancer (PC) is one of the most lethal cancer types. Despite advancements that have led to some modest improvements in survival rates over the past decade, PC still has a dismal prognosis. Patients diagnosed with early-stage disease have higher survival rates. Unfortunately, PC seldom manifests itself early, and symptoms prompting diagnostic investigations usually develop when the disease is already advanced. PC screening may lead to better patient outcomes through detection of asymptomatic early-stage cancers and precursor lesions. Population-based screening is deemed unfeasible because of the low incidence of PC. However, screening of individuals with an inherited lifetime risk of ≥5%-10% for developing PC may prove beneficial. In the context of high-risk individuals, screening is referred to as surveillance. Yet, critical aspects such as suitable candidates for surveillance, the ideal time to initiate and discontinue surveillance, as well as the most effective surveillance method, preferred surveillance modalities, and optimal surveillance interval remain unclear. Herein, we summarize the current state of knowledge regarding PC surveillance by reviewing current expert consensus statements and guidelines. In addition, we review the management of identified lesions, the yield in different cohorts, and future directions to improve the outcomes of individuals at high-risk of developing PC.

Surveillance of pancreatic cysts focuses on the detection of (mostly morphologic) features warranting surgery. European guidelines consider elevated CA19.9 as a relative indication for surgery. We aimed to evaluate the role of CA19.9 monitoring for early detection and management in a cyst surveillance population. The PACYFIC‐registry is a prospective collaboration that investigates the yield of pancreatic cyst surveillance performed at the discretion of the treating physician. We included participants for whom at least one serum CA19.9 value was determined by a minimum follow‐up of 12 months. Of 1865 PACYFIC participants, 685 met the inclusion criteria for this study (mean age 67 years, SD 10; 61% female). During a median follow‐up of 25 months (IQR 24, 1966 visits), 29 participants developed high‐grade dysplasia (HGD) or pancreatic cancer. At baseline, CA19.9 ranged from 1 to 591 kU/L (median 10 kU/L [IQR 14]), and was elevated (≥37 kU/L) in 64 participants (9%). During 191 of 1966 visits (10%), an elevated CA19.9 was detected, and these visits more often led to an intensified follow‐up (42%) than those without an elevated CA19.9 (27%; p< 0.001). An elevated CA19.9 was the sole reason for surgery in five participants with benign disease (10%). The baseline CA19.9 value was (as continuous or dichotomous variable at the 37 kU/L threshold) not independently associated with HGD or pancreatic cancer development, whilst a CA19.9 of ≥ 133 kU/L was (HR 3.8, 95% CI 1.1–13, p= 0.03). In this pancreatic cyst surveillance cohort, CA19.9 monitoring caused substantial harm by shortening surveillance intervals (and performance of unnecessary surgery). The current CA19.9 cutoff was not predictive of HGD and pancreatic cancer, whereas a higher cutoff may decrease false‐positive values. The role of CA19.9 monitoring should be critically appraised prior to implementation in surveillance programs and guidelines.

Identifying branch‐duct intraductal papillary mucinous neoplasms (BD‐IPMNs) at lowest risk of progression may allow for a reduced intensity of surveillance. We aimed to externally validate the previously developed Dutch‐American Risk stratification Tool (DART‐1; https://rtools.mayo.edu/DART/), which identifies cysts at low risk of developing worrisome features (WFs) or high‐risk stigmata (HRS). Three prospective cohorts of individuals under surveillance for BD‐IPMNs were combined, independent from the original development cohort. We assessed the performance (discrimination and calibration) of DART‐1, a multivariable Cox‐proportional logistic regression model with five predictors for the development of WFs or HRS. Of 832 individuals (mean age 77 years, SD 11.5) under surveillance for a median of 40 months (IQR 44), 163 (20%) developed WFs or HRS. DART‐1's discriminative ability (C‐statistic 0.68) was similar to that in the development cohort (0.64–0.72) and showed moderate calibration. DART‐1 adequately estimated the risk for patients in the middle risk quintile, and slightly underestimated it in the lowest quintiles. Their range of predicted versus observed 3‐year risk was 0%–0% versus 0%–3.7% for Q1; 0.3%–0.4% versus 3%–11% for Q2; and 2.6%–3% versus 2.4%–9.8% for Q3. The development of WFs or HRS was associated with pancreatic cancer (p< 0.001). Vice versa, in absence of WFs or HRS, the risk of malignancy was low (0.3%). The performance of DART‐1 to predict the development of WFs or HRS in BD‐IPMN was validated in an external international cohort, with a discriminative ability equal as in the development cohort. Risk estimations were most accurate for patients with BD‐IPMNs in the middle risk quintile and slightly underestimated in the lowest quintiles.

ObjectiveWe aimed to determine the long-term yield of pancreatic cancer surveillance in hereditary predisposed high-risk individuals.DesignFrom 2006 to 2019, we prospectively enrolled asymptomatic individuals with an estimated 10% or greater lifetime risk of pancreatic ductal adenocarcinoma (PDAC) after obligatory evaluation by a clinical geneticist and genetic testing, and subjected them to annual surveillance with both endoscopic ultrasonography (EUS) and MRI/cholangiopancreatography (MRI/MRCP) at each visit.Results366 individuals (201 mutation-negative familial pancreatic cancer (FPC) kindreds and 165 PDAC susceptibility gene mutation carriers; mean age 54 years, SD 9.9) were followed for 63 months on average (SD 43.2). Ten individuals developed PDAC, of which four presented with a symptomatic interval carcinoma and six underwent resection. The cumulative PDAC incidence was 9.3% in the mutation carriers and 0% in the FPC kindreds (p<0.001). Median PDAC survival was 18 months (range 1–32). Surgery was performed in 17 individuals (4.6%), whose pathology revealed 6 PDACs (3 T1N0M0), 7 low-grade precursor lesions, 2 neuroendocrine tumours <2 cm, 1 autoimmune pancreatitis and in 1 individual no abnormality. There was no surgery-related mortality. EUS detected more solid lesions than MRI/MRCP (100% vs 22%, p<0.001), but less cystic lesions (42% vs 83%, p<0.001).ConclusionThe diagnostic yield of PDAC was substantial in established high-risk mutation carriers, but non-existent in the mutation-negative proven FPC kindreds. Nevertheless, timely identification of resectable lesions proved challenging despite the concurrent use of two imaging modalities, with EUS outperforming MRI/MRCP. Overall, surveillance by imaging yields suboptimal results with a clear need for more sensitive diagnostic markers, including biomarkers.

BackgroundPathogenic variants in the CDKN2Agene are generally associated with the development of melanoma and pancreatic ductal adenocarcinoma (PDAC), but specific genotype-phenotype correlations might exist and the extent of PDAC risk is not well established for many variants.MethodsUsing the Dutch national familial melanoma database, we identified all families with a pathogenic CDKN2Avariant and investigated the occurrence of PDAC within these families. We also estimated the standardised incidence ratio and lifetime PDAC risk for carriers of a highly prevalent variant in these families.ResultsWe identified 172 families in which 649 individuals carried 15 different pathogenic variants. The most prevalent variant was the founder mutation c.225_243del (p16-Leiden, 484 proven carriers). Second most prevalent was c.67G>C (55 proven carriers). PDAC developed in 95 of 163 families (58%, including 373 of 629 proven carriers) harbouring a variant with an effect on the p16INK4a protein, whereas PDAC did not occur in the 9 families (20 proven carriers) with a variant affecting only p14ARF. In the c.67G>C families, PDAC occurred in 12 of the 251 (5%) persons at risk. The standardised incidence ratio was 19.1 (95% CI 8.3 to 33.6) and the cumulative PDAC incidence at age 75 years (lifetime risk) was 19% (95% CI 7.5% to 30.1%).ConclusionsOur results support the notion that pathogenic CDKN2Avariants affecting the p16INK4a protein, including c.67G>C, are associated with increased PDAC risk and carriers of such variants should be offered pancreatic cancer surveillance. There is no clinical evidence that impairment of only the p14ARF protein leads to an increased PDAC risk.

Background and aimThe International Cancer of the Pancreas Screening Consortium met in 2018 to update its consensus recommendations for the management of individuals with increased risk of pancreatic cancer based on family history or germline mutation status (high-risk individuals).MethodsA modified Delphi approach was employed to reach consensus among a multidisciplinary group of experts who voted on consensus statements. Consensus was considered reached if ≥75% agreed or disagreed.ResultsConsensus was reached on 55 statements. The main goals of surveillance (to identify high-grade dysplastic precursor lesions and T1N0M0 pancreatic cancer) remained unchanged. Experts agreed that for those with familial risk, surveillance should start no earlier than age 50 or 10 years earlier than the youngest relative with pancreatic cancer, but were split on whether to start at age 50 or 55. Germline ATMmutation carriers with one affected first-degree relative are now considered eligible for surveillance. Experts agreed that preferred surveillance tests are endoscopic ultrasound and MRI/magnetic retrograde cholangiopancreatography, but no consensus was reached on how to alternate these modalities. Annual surveillance is recommended in the absence of concerning lesions. Main areas of disagreement included if and how surveillance should be performed for hereditary pancreatitis, and the management of indeterminate lesions.ConclusionsPancreatic surveillance is recommended for selected high-risk individuals to detect early pancreatic cancer and its high-grade precursors, but should be performed in a research setting by multidisciplinary teams in centres with appropriate expertise. Until more evidence supporting these recommendations is available, the benefits, risks and costs of surveillance of pancreatic surveillance need additional evaluation.

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Despite its low incidence in the general population, pancreatic cancer is one of the leading causes of cancer-related mortality. Survival greatly depends on operability, but most patients present with unresectable disease. Therefore, there is great interest in the early detection of pancreatic cancer and its precursor lesions by surveillance. Worldwide, several programs have been initiated for individuals at high risk for pancreatic cancer. Their first results suggest that surveillance in high-risk individuals is feasible, but their effectiveness in decreasing mortality remains to be proven. This review will discuss which individuals are eligible for surveillance, which lesions are aimed to be detected, and which surveillance modalities are being used in current clinical practice. Furthermore, it addresses the management of abnormalities found during surveillance and topics for future research.

OBJECTIVES:Autoimmune pancreatitis (AIP) is a rare form of chronic pancreatitis, clinically mimicking pancreatic cancer. In 2009, a serological diagnostic test detecting antibodies against plasminogen-binding protein (PBP) of Helicobacter pylori was reported with outstanding test performances (NEJM 361:135). We aimed to validate these findings.METHODS:Between March 2007 and May 2011, sera were collected from consecutive patients presenting with type 1 AIP, pancreatic ductal adenocarcinoma (PDAC), chronic pancreatitis (CP), primary sclerosing cholangitis (PSC), and healthy controls (HC) with or without antibodies against H. pylori. Serum antibody binding to synthetic PBP peptide was quantified by enzyme-linked immunosorbent assay (ELISA), using standard curves of custom-made PBP rabbit polyclonal antibodies. A synthetic Flag peptide (DYKDDDK), to which no antibodies are found in human serum, was included as negative control.RESULTS:High sensitivity of PBP peptide recognition was demonstrated by selective binding of PBP peptide over Flag peptide by PBP-immunized rabbit serum. Competition assays with PBP peptide validated the selectivity for antibodies recognizing this antigen. A total of 114 patients were subsequently tested: 34 AIP, 29 PDAC, 17 CP, 16 PSC, and 18 HCs (9 positive and 9 negative for H. pylori). No significant differences in detection of antibodies against the PBP peptide were found between different the patient groups and healthy controls.CONCLUSIONS:Using a sensitive and selective ELISA-based assay, we did not find increased serum antibodies against PBP peptide in AIP patients. PBP serum antibodies are therefore not a useful diagnostic tool to diagnose AIP.

In cancer of the pancreatic head region, exocrine insufficiency is a well-known complication, leading to steatorrhea, weight loss, and malnutrition. Its presence is frequently overlooked, however, because the primary attention is focused on cancer treatment. To date, the risk of developing exocrine insufficiency is unspecified. Therefore, we assessed this function in patients with tumors of the pancreatic head, distal common bile duct, or ampulla of Vater.