Early detection of pancreatic cancer in high-risk individuals

Earlier detection of pancreatic cancer is necessary to improve its poor prognosis. Currently, screening of the general population is not feasible due to the relatively low lifetime risk. However, up to one in ten cases occur in individuals with a strong family history of germline mutation carriers, known as high-risk individuals (HRIs). For these HRIs, pancreatic cancer surveillance in expert centers is recommended. The first part of this thesis focuses on evaluating the effectiveness of pancreatic cancer surveillance in carriers of a germline CD2KNA/p16 mutation who have a very high lifetime risk of developing pancreatic cancer. The second part focuses on various aspects to improve pancreatic cancer surveillance programs, including the study of biomarkers, risk stratification, and assessment of psychosocial aspects. Finally, attention is given to the identification of individuals at increased risk from the general population. Immunovia, Nederlandse Vereniging voor Gastroenterologie, Chipsoft, Viatris, ABN Amro, TramedicoLUMC / Geneeskund

Identification of individuals at high-risk for pancreatic cancer using a digital patient-input tool combining family cancer history screening and new-onset diabetes

Capturing family history might be a valuable tool for identification of individuals at increased risk of pancreatic cancer, which would allow enrollment into pancreatic surveillance programs. In addition, weight loss and concurrent new-onset diabetes may be utilized as an early marker for pancreatic cancer. This study evaluates the yield of combining family history and the Enriching New-Onset Diabetes for Pancreatic Cancer (ENDPAC) model to identify individuals who could benefit from pancreatic surveillance. A novel questionnaire and digital input tool was created that combined questions on family cancer history and criteria of the ENDPAC model. Individuals meeting ENDPAC criteria were enrolled directly in the high-risk pancreatic clinic. Individuals who met the criteria for a significant family history of cancer were offered referral to a genetic counselor. The questionnaire was completed by 453 patients. Of those, 25.8% (117/453) had significant familial risk factors. Eighteen individuals (15.4%) completed genetic testing previously, of whom five had a pathogenic variant. Thirty-four (29.9%) out of 117 individuals with a strong family history – flagged by the questionnaire – underwent genetic testing. Four (11.8%) of these patients harbored a pathogenic variant. Additionally, through cascade family testing, two siblings were found to carry pathogenic variants. Four (0.9%) of the 453 patients matched ENDPAC criteria. Two were diagnosed with pancreatic cancer and the others were enrolled in the surveillance program. In conclusion, identification of high-risk individuals for pancreatic cancer can be achieved by combining family history screening and the ENDPAC model to facilitate referral to genetic counseling and high-risk clinics.Gastroenterology and Hepatolog

Pancreatic Cancer Surveillance in Carriers of a Germline CDKN2A Pathogenic Variant: Yield and Outcomes of a 20-Year Prospective Follow-Up

PURPOSE Pancreatic cancer surveillance in high-risk individuals may lead to detection of pancreatic ductal adenocarcinoma (PDAC) at an earlier stage and with improved survival. This study evaluated the yield and outcomes of 20 years of prospective surveillance in a large cohort of individuals with germline pathogenic variants (PVs) in CDKN2A. METHODS Prospectively collected data were analyzed from individuals participating in pancreatic cancer surveillance. Surveillance consisted of annual magnetic resonance imaging with magnetic resonance cholangiopancreatography and optional endoscopic ultrasound. RESULTS Three hundred forty-seven germline PV carriers participated in surveillance and were followed for a median of 5.6 (interquartile range 2.3-9.9) years. A total of 36 cases of PDAC were diagnosed in 31 (8.9%) patients at a median age of 60.4 (interquartile range 51.3-64.1) years. The cumulative incidence of primary PDAC was 20.7% by age 70 years. Five carriers (5 of 31; 16.1%) were diagnosed with a second primary PDAC. Thirty (83.3%) of 36 PDACs were considered resectable at the time of imaging. Twelve cases (12 of 36; 33.3%) presented with stage I disease. The median survival after diagnosis of primary PDAC was 26.8 months, and the 5-year survival rate was 32.4% (95% CI, 19.1 to 54.8). Individuals with primary PDAC who underwent resection (22 of 31; 71.0%) had an overall 5-year survival rate of 44.1% (95% CI, 27.2 to 71.3). Nine (2.6%; 9 of 347) individuals underwent surgery for a suspected malignant lesion, which proved to not be PDAC, and this included five lesions with low-grade dysplasia. CONCLUSION This long-term surveillance study demonstrates a high incidence of PDAC in carriers of a PV in CDKN2A. This provides evidence that surveillance in such a high-risk population leads to detection of early-stage PDAC with improved resectability and survival.Cellular mechanisms in basic and clinical gastroenterology and hepatolog

Surveillance for pancreatic cancer in high-risk individuals leads to improved outcomes: a propensity score-matched analysis

BACKGROUND & AIMS: Recent pancreatic cancer surveil-lance programs of high-risk individuals have reported improved outcomes. This study assessed to what extent outcomes of pancreatic ductal adenocarcinoma (PDAC) patients with a CDKN2A/p16 pathogenic variant diagnosed under surveillance are better as compared with patients with PDAC diagnosed outside surveillance.METHODS: In a pro-pensity score matched cohort using data from the Netherlands Cancer Registry, we compared resectability, stage, and survival between patients diagnosed under sur-veillance with non-surveillance patients with PDAC. Survival analyses were adjusted for potential effects of lead time.RESULTS: Between January 2000 and December 2020, 43,762 patients with PDAC were identified from the Netherlands Cancer Registry. Thirty-one patients with PDAC under surveillance were matched in a 1:5 ratio with 155 non surveillance patients based on age at diagnosis, sex, year diagnosis, and tumor location. Outside surveillance, 5.8% of the patients had stage I cancer, as compared with 38.7% of surveillance patients with PDAC (odds ratio [OR], 0.09; 95% confidence interval [CI], 0.04-0.19). In total, 18.7% of non surveillance patients vs 71.0% of surveillance patients un- derwent a surgical resection (OR, 10.62; 95% CI, 4.56-26.63). Patients in surveillance had a better prognosis, reflected by 5-year survival of 32.4% and a median overall survival of 26.8 months vs 4.3% 5-year survival and 5.2 months median overall survival in non-surveillance patients (hazard ratio, 0.31; 95% CI 0.19-0.50). For all adjusted lead times, survival remained significantly longer in surveillance patients than non-surveillance patients.CONCLUSION: Surveillance for PDAC in carriers of a CDKN2A/p16 pathogenic variant results in earlier detection, increased resectability, and improved survival as compared with non-surveillance patients with PDAC

Longitudinal changes of serum protein N-Glycan levels for earlier detection of pancreatic cancer in high-risk individuals

Background: Surveillance of individuals at risk of developing pancreatic ductal adenocarcinoma (PDAC) has the potential to improve survival, yet early detection based on solely imaging modalities is challenging. We aimed to identify changes in serum glycosylation levels over time to earlier detect PDAC in high-risk individuals.Methods: Individuals with a hereditary predisposition to develop PDAC were followed in two surveillance programs. Those, of which at least two consecutive serum samples were available, were included. Mass spectrometry analysis was performed to determine the total N-glycome for each consecutive sample. Potentially discriminating N-glycans were selected based on our previous cross-sectional analysis and relative abundances were calculated for each glycosylation feature.Results: 165 individuals ("FPC-cohort" N = 119; Leiden cohort N = 46) were included. In total, 97 (59%) individuals had a genetic predisposition (77 CDKN2A, 15 BRCA1/2, 5 STK11) and 68 (41%) a family history of PDAC without a known genetic predisposition (>10-fold increased risk of developing PDAC). From each individual, a median number of 3 serum samples (IQR 3) was collected. Ten individuals (6%) developed PDAC during 35 months of follow-up; nine (90%) of these patients carried a CDKN2A germline mutation. In PDAC cases, compared to all controls, glycosylation characteristics were increased (fucosylation, tri-and tetra-antennary structures, specific sialic linkage types), others decreased (complex-type diantennary and bisected glycans).The largest change over time was observed for tri-antennary fucosylated glycans, which were able to differentiate cases from controls with a specificity of 92%, sensitivity of 49% and accuracy of 90%.Conclusion: Serum N-glycan monitoring may support early detection in a pancreas surveillance program.(c) 2022 The Authors. Published by Elsevier B.V. on behalf of IAP and EPC. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).Cellular mechanisms in basic and clinical gastroenterology and hepatolog

Association Between Proton Pump Inhibitor Use and Risk of Progression of Chronic Kidney Disease

Clinical epidemiolog