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Background: The International Cancer of the Pancreas Screening Consortium recommended annual imaging for individuals at increased risk for developing a pancreatic ductal adenocarcinoma (PDAC) who did not have concerning pancreatic findings or a cyst <3 cm without worrisome features. We aimed to determine if 3-cm cyst size accurately predicted advanced precursor lesions in high-risk individuals undergoing surveillance., Methods: Imaging for high-risk individuals (HRIs) undergoing PDAC surveillance from 2007 to 2021 was reviewed and pancreatic abnormalities were recorded including dominant cyst size and number of cysts. Subjects were excluded if they had the following: (1) no follow-up imaging after baseline, (2) solid lesion at baseline, or (3) development of solid lesion without having cyst on prior imaging., Results: Five of the 77 HRIs found to have a cystic lesion on surveillance developed a PDAC: 3 with cystic lesion >1 cm as compared with only 2 of 67 HRIs with cystic lesions <1 cm (P < 0.05). None of these cysts developed worrisome findings and 4/5 PDACs did not arise from visualized cystic precursor lesion., Conclusions: Patients with a cyst ≥1 cm were at increased risk for developing PDAC compared with patients with cyst <1 cm. Pancreatic ductal adenocarcinoma usually did not arise from a recognized cystic lesion., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: Data from the International Cancer of the Pancreas Screening Consortium studies have demonstrated that screening for pancreatic ductal adenocarcinoma can be effective and that surveillance improves survival in high-risk individuals. Endoscopic ultrasound (EUS) and cross-sectional imaging are both used, although there is some suggestion that EUS is superior. Demonstration of the cost-effectiveness of screening is important to implement screening in high-risk groups., Methods: Results from centers with EUS-predominant screening were pooled to evaluate efficacy of index EUS in screening. A decision analysis model simulated the outcome of high-risk patients who undergo screening and evaluated the parameters that would make screening cost-effective at a US $100,000 per quality-adjusted life-year willingness to pay., Results: One-time index EUS has a sensitivity of 71.25% and specificity of 99.82% to detection to detect high-risk lesions. Screening with index EUS was cost-effective, particularly at lifetime pancreatic cancer probabilities of greater than 10.8%, or at lower probabilities if life expectancy after resection of a lesion that was at least 16 years, and if missed, lesion rates on index EUS are 5% or less., Conclusions: Pancreatic cancer screening can be cost-effective through index EUS, particularly for those individuals at high-lifetime risk of cancer., Competing Interests: S.K. received travel support from the Boston Scientific Corporation and Olympus. B.W.K, is a consultant of Exact Sciences and received travel support from Janssen. M.L.K. is a consultant of Boston Scientific, Olympus, and Pentax. Equity MAB: Dark Canyon Laboratories, VIRGO. The other authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: Presentation of pancreatic adenocarcinoma (PC) as acute pancreatitis (AP), association of chronic pancreatitis (CP) with PC, and role of inflammation in PC carcinogenesis are well recognized. We hypothesized that inflammatory changes associated with remote history of AP (≥2 years before PC diagnosis) would result in earlier age of PC diagnosis., Methods: We evaluated PC patients prospectively enrolled in the Pancreatic Adenocarcinoma Gene Environment Risk (PAGER) study at the University of Pittsburgh for history of pancreatitis and reviewed relevant medical records and imaging studies. Univariate and multivariable linear regression analyses evaluated the relationship between PC and remote history of AP., Results: Among 790 patients with histologically confirmed PC, 114 (14.4%) had a history of pancreatitis (AP within 2 years of PC diagnosis in 69 [8.7%], remote history of AP in 28 [3.5%], CP in 4 [0.5%], and unknown duration of pancreatitis in 13 [1.6%]). After controlling for age, sex, body mass index, smoking, alcohol history, and diabetic status at diagnosis, patients with a remote history of AP were diagnosed on average 4.7 years earlier with PC when compared with PC patients without history of AP (P < 0.035)., Conclusions: Remote history of AP may accelerate carcinogenesis in PC.

The National Cancer Institute and the National Institute for Diabetes and Digestive and Kidney Diseases initiated the Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer (CPDPC) in 2015 (the CPDPC's origin, structure, governance, and research objectives are described in another article in this journal). One of the key objectives of CPDPC is to assemble a cohort of 10,000 subjects 50 years or older with new-onset diabetes, called the NOD cohort. Using a define, enrich, and find early detection approach, the aims of the NOD study are to (a) estimate the 3-year probability of pancreatic ductal adenocarcinoma (PDAC) in NOD (define), (b) establish a biobank of clinically annotated biospecimens from presymptomatic PDAC and control new-onset type 2 diabetes mellitus subjects, (c) conduct phase 3 validation studies of promising biomarkers for identification of incident PDAC in NOD patients (enrich), and (d) provide a platform for development of a future interventional screening protocol for early detection of PDAC in patients with NOD that incorporates imaging studies and/or clinical algorithms (find). It is expected that 85 to 100 incidences of PDAC will be diagnosed during the study period in this cohort of 10,000 patients.

Pancreatic cancer requires many genetic mutations. Combinations of underlying germline variants and environmental factors may increase the risk of cancer and accelerate the oncogenic process. We systematically reviewed, annotated, and classified previously reported pancreatic cancer-associated germline variants in established risk genes. Variants were scored using multiple criteria and binned by evidence for pathogenicity, then annotated with published functional studies and associated biological systems/pathways. Twenty-two previously identified pancreatic cancer risk genes and 337 germline variants were identified from 97 informative studies that met our inclusion criteria. Fifteen of these genes contained 66 variants predicted to be pathogenic (APC, ATM, BRCA1, BRCA2, CDKN2A, CFTR, CHEK2, MLH1, MSH2, NBN, PALB2, PALLD, PRSS1, SPINK1, TP53). Pancreatic cancer risk genes were organized into key biological mechanisms that promote pancreatic oncogenesis within an oncogenic model. Development of precision medicine approaches requires updated variant information within the framework of an oncogenic progression model. Complex risk modeling may improve interpretation of early biomarkers and guide pathway-specific treatment for pancreatic cancer in the future. Precision medicine is within reach.

Objective: Secretin-stimulated pancreatic juice is collected from the duodenum and analyzed to identify biomarkers of pancreatic neoplasia, but the optimal duration of pancreatic juice collection is not known., Methods: We compared the yield of KRAS mutations detected in pancreatic juice samples aspirated from near the duodenal papilla at 1 to 5, 6 to 10, and 11 to 15 minutes after secretin infusion, and from the third part of the duodenum (at 15 minutes) from 45 patients undergoing endoscopic ultrasound pancreatic surveillance. KRAS mutation concentrations were measured by using droplet digital polymerase chain reaction., Results: Forty of 45 patients had KRAS mutations detected in their pancreatic juice, and most patients' juice samples had more than 1 KRAS mutation. Of 106 KRAS mutations detected in 171 pancreatic juice samples, 58 were detected in the 5-minute samples, 70 mutations were detected in the 10-minute samples, and 65 were detected in the 15-minute samples. Nine patients who did not have KRAS mutations detected in their 5-minute sample had mutations detected in samples collected at later time points. Ninety-percent of all pancreatic juice mutations detected in any sample were detected in the 5- or 10-minute samples., Conclusions: Collecting pancreatic juice for 10 minutes after secretin infusion increases the likelihood of detecting pancreatic juice mutations over shorter collections.

Objective: Historically, chronic pancreatitis (CP) was considered a disease of alcoholic males, but recent data suggest its etiology to be complex. To better understand CP in women, we compared data on women and men with CP in a large, prospectively ascertained multicenter US cohort., Methods: Patients with CP enrolled in the NAPS2 Continuation and Validation study were studied. Information on demographics, etiology, risk factors, phenotype, and treatment(s) used was obtained from detailed questionnaires completed by the patients and physicians., Results: Of 521 cases, 45% were women. Women were significantly (P < 0.05) less likely to have alcohol etiology (30% vs 58.5%) and more likely to have nonalcoholic etiologies (idiopathic, 32% vs 18%; obstructive, 12% vs 2.4%; genetic, 12.8% vs 7.3%). Demographics, pain experience, morphologic findings, exocrine and endocrine insufficiency, CP-related disability, and use of medical therapies were mostly similar in both sexes. Sphincterotomy (biliary, 33% vs 24%; pancreatic, 38% vs 28%; P < 0.05) was performed more frequently in women, whereas cyst/pseudocyst operations were more common in men (6.6 vs 2.6%, P = 0.02)., Conclusions: Most CP cases in women are from nonalcoholic etiologies. In contrast to many other chronic diseases, clinical phenotype of CP is determined by the disease and is independent of sex.

Objectives: In considering whether medications that increase insulin levels accelerate pancreatic adenocarcinoma (PC) development, we hypothesized that PC patients with diabetes mellitus (DM) who used exogenous insulin or insulin-stimulating medications should have an earlier age at diagnosis or present with more advanced disease., Methods: Patients enrolled in our PC registry from June 1, 2003, to May 31, 2012, were stratified according to treatment solely with insulin, insulin-stimulating medications, or insulin-independent medications. Age at PC diagnosis, PC stage, and years between DM and PC diagnoses were analyzed among the cohorts., Results: Of 122 DM patients (mean age, 67.4 ± 10.2 years), the mean ages at PC diagnosis within the insulin-only (n = 40), insulin-stimulating (n = 11), insulin-independent (n = 71), and non-DM (n = 321) cohorts were 68.7 ± 10.5, 69.6 ± 10.8, 66.3 ± 9.7, and 65.5 ± 10.5 years, respectively. No significant difference among the age at PC diagnosis was observed based on duration or type of DM treatment. There was no correlation between PC stage and increased insulin exposure., Conclusions: Anti-DM medications that increase exposure to insulin do not appear to accelerate PC development using outcomes of mean age at PC diagnosis, PC stage, or duration between DM and PC diagnoses.

Objective: Cholecystokinin (CCK) and gastrin stimulate growth of pancreatic cancer through the CCK-B receptor (CCK-BR). A splice variant of the CCK-BR that results from a single nucleotide polymorphism (SNP) has been identified. Because the splice variant receptor has an extended third intracellular loop, an area involved in cell signaling and growth, we hypothesized that this genetic variant could contribute to the poor prognosis and short survival of this malignancy., Methods: DNA from 931 patients with pancreatic cancer was evaluated for the SNP (C > A; rs1800843) in the CCK-BR gene. For statistical analysis, the Fisher exact test was used to compare the genotype and allele frequency between the cancer cohort and normal controls and the dependence of genotype on factors, such as stage of disease and age, was analyzed using Cox proportional hazards models., Results: Compared to the normal cohort, the frequency of the A-allele in pancreatic cancer subjects was increased (P = 0.01123; odds ratio, 2.283). Even after adjustment for stage of disease, survival of subjects with the minor allele was significantly shorter than those with the wild-genotype (hazard ratio, 1.83; P = 3.11 × 10(-11))., Conclusions: The CCK-BR SNP predicts survival and should be studied as a candidate genetic biomarker for those at risk of pancreatic cancer.

Objective: This study aims to describe the frequency of use and reported effectiveness of endoscopic and surgical therapies in patients with chronic pancreatitis treated at US referral centers., Methods: Five hundred fifteen patients were enrolled prospectively in the North American Pancreatitis Study 2, where patients and treating physicians reported previous therapeutic interventions and their perceived effectiveness. We evaluated the frequency and effectiveness of endoscopic (biliary or pancreatic sphincterotomy, biliary or pancreatic stent placement) and surgical (pancreatic cyst removal, pancreatic drainage procedure, pancreatic resection, surgical sphincterotomy) therapies., Results: Biliary and/or pancreatic sphincterotomy (42%) were the most common endoscopic procedure (biliary stent, 14%; pancreatic stent, 36%; P < 0.001). Endoscopic procedures were equally effective (biliary sphincterotomy, 40.0%; biliary stent, 40.8%; pancreatic stent, 47.0%; P = 0.34). On multivariable analysis, the presence of abdominal pain (odds ratio, 1.82; 95% confidence interval, 1.15-2.88) predicted endoscopy, whereas exocrine insufficiency (odds ratio, 0.63; 95% confidence interval, 0.42-0.94) deterred endoscopy. Surgical therapies were attempted equally (cyst removal, 7%; drainage procedure, 10%; resection procedure, 12%) except for surgical sphincteroplasty (4%; P < 0.001). Surgical sphincteroplasty was the least effective (46%; P < 0.001) versus cyst removal (76% drainage [71%] and resection [73%])., Conclusions: Although surgical therapies were performed less frequently than endoscopic therapies, they were more often reported to be effective.

Objective: Individuals with chronic pancreatitis are at increased risk for pancreatic cancer. We hypothesized that genetic variation in the γ-glutamyltransferase 1 (GGT1) gene, which was recently reported associated with pancreatic cancer risk in a genome-wide association study, is also associated with risk of chronic pancreatitis., Methods: Associations between common polymorphisms in GGT1 and chronic pancreatitis were evaluated using data and samples from the North American Pancreatitis Study 2. Patients (n = 496) and control subjects (n = 465) were genotyped for 4 single-nucleotide polymorphisms: rs4820599, rs2017869, rs8135987, and rs5751901. Odds ratios (ORs) and corresponding 95% confidence intervals (95% CI) for chronic pancreatitis risk were calculated using multiple logistic regression models. Interactions with cigarette smoking and alcohol use were explored., Results: Single-nucleotide polymorphisms rs8135987 and rs4820599 were both statistically significantly associated with risk of chronic pancreatitis; compared with common allele homozygotes, individuals with at least 1 minor allele were at increased risk (rs8135987: OR, 1.36; 95% CI, 1.03-1.80 [P(trend) = 0.01]; rs4820599: OR, 1.39; 95% CI, 1.04-1.84 [P(trend) = 0.0]; adjusted for age, sex, race, smoking status, and alcohol use). No significant interactions with cigarette smoking and alcohol use were observed., Conclusion: Our results suggest that common variation in the GGT1 gene may also affect risk of chronic pancreatitis.

Objectives: The objective of this study was to define the quality of life (QOL) in patients with chronic pancreatitis (CP)., Methods: We studied 443 well-phenotyped CP subjects and 611 control subjects prospectively enrolled from 20 US centers between 2000 and 2006 in the North American Pancreatitis Study 2. Responses to the SF-12 questionnaire were used to calculate the mental (MCS) and physical component summary scores (PCS) with norm-based scoring (normal ≥50). Quality of life in CP subjects was compared with control subjects after controlling for demographic factors, drinking history, smoking, and medical conditions. Quality of life in CP was also compared with known scores for several chronic conditions., Results: Both PCS (38 [SD, 11.5] vs 52 [SD, 9.4]) and MCS (44 [SD, 11.5] vs 51 [SD, 9.2]) were significantly lower in CP compared with control subjects (P < 0.001). On multivariable analyses, compared with control subjects, a profound decrease in physical QOL (PCS 12.02 points lower) and a clinically significant decrease in mental QOL (MCS 4.24 points lower) was seen due to CP. Quality of life in CP was similar to (heart, kidney, liver, lung disease) or worse than (nonskin cancers, diabetes mellitus, hypertension, rheumatoid arthritis) other chronic conditions., Conclusions: The impact of CP on QOL appears substantial. The QOL in CP subjects appears to be worse or similar to the QOL of many other chronic conditions.

Objectives: A risk association has been observed between non-O blood groups and pancreatic adenocarcinoma. Chronic pancreatitis also increases risk for pancreatic cancer, raising questions as to whether non-O blood groups are a risk for chronic pancreatitis and whether the pathophysiologic pathways are linked. Our goal was to determine whether ABO blood group may affect the risk of chronic pancreatitis., Methods: The study cohort included chronic pancreatitis patients (n = 499) and healthy controls (n = 631) from the North American Pancreatitis Study 2 study. Genotyping was performed using Sequenom assay of rs8176746 A/C and rs505922 C/T to classify participants into ABO blood groups., Results: O blood group was nonsignificantly more common among cases (44.7% vs 42.0%; P = 0.36), particularly among cases with alcohol-related chronic pancreatitis (49.3% vs 42%; P = 0.060). Alcoholic patients without coexisting high-risk PRSS1, CFTR, or SPINK1 variants had a significant overrepresentation of O blood type when compared with controls (odds ratio, 1.54; 95% confidence interval, 1.09-2.17; P = 0.01)., Conclusions: A, B, and AB blood groups were not associated with a greater likelihood of having chronic pancreatitis and may decrease the risk of chronic pancreatitis in individuals who are very heavy drinkers. These results suggest that the mechanism linking non-O blood type with pancreatic pathology is specific to carcinogenesis.

Objectives: Serum biomarkers for early diagnosis of pancreatic adenocarcinoma are not currently available. We recently observed elevated expression of CEACAM1 in pancreatic adenocarcinomas and sought to determine whether serum CEACAM1 levels were elevated in pancreatic cancer patients., Methods: CEACAM1 messenger RNA levels were measured in pancreatic tissue samples using quantitative reverse transcription-polymerase chain reaction. CEACAM1 was localized by immunohistochemistry in adenocarcinomas and in pancreatic intraductal neoplasia lesions. CEACAM1 serum levels were assessed by a double determinant enzyme-linked immunosorbent assay and compared with serum levels of CA19-9., Results: CEACAM1 had higher expression levels in pancreatic adenocarcinomas compared with noncancerous pancreas (P < 0.0001) and was localized to neoplastic cells (95% (45/47) of adenocarcinomas and 85% (17/20) of pancreatic intraductal neoplasia 3 lesions. CEACAM1 was expressed in the sera of 91% (74/81) of pancreatic cancer patients, 24% (15/61) of normal patients, and 66% (35/53) of patients with chronic pancreatitis, with a sensitivity and specificity superior to CA19-9. The combination of CEACAM1 and CA19-9 had significantly higher diagnostic accuracy than CA19-9., Conclusions: CEACAM1 is expressed in pancreatic adenocarcinoma, and serum levels of CEACAM1 serve as a useful indicator for the presence of pancreatic cancer. Additional validation studies on the use of serum CEACAM1 as a diagnostic marker in pancreatic cancer are warranted.

This review describes the recent advances in the molecular events involved in pancreatic cancer initiation, progression, and metastasis. Additionally, the importance of deregulated cellular signaling elements as potential targets for developing novel therapeutic strategies against incurable forms of pancreatic cancer is reported. The emphasis is on the critical functions gained by numerous growth factors and their receptors, such as epidermal growth factor receptor, hedgehog signaling, and proangiogenic agents such as vascular endothelial factor and interleukin-8 for the sustained growth, survival, and metastasis of pancreatic cancer cells. The molecular mechanisms associated with antitumoral properties and the clinical benefits of gemcitabine alone or in combination with other cytotoxic agents for the treatment of pancreatic cancer are discussed.