Risk perception and surveillance uptake in individuals at increased risk for pancreatic ductal adenocarcinoma.

BACKGROUND: Surveillance for pancreatic ductal adenocarcinoma (PDAC) is recommended for high-risk individuals with genetic variants in PDAC-associated genes and/or family history. Surveillance uptake and adherence may depend on the perception of PDAC risk and cancer worry. We aimed to determine PDAC risk perception in at-risk individuals and assess factors associated with PDAC surveillance uptake. METHODS: At-risk individuals identified from a prospective academic registry were sent a survey electronically. PDAC risk perception, cancer worry and surveillance uptake were surveyed. Factors associated with increased risk perception and surveillance were assessed. Five-year PDAC risk was calculated using the PancPRO risk assessment model, and correlation with subjective risk assessment was assessed. RESULTS: The overall survey response rate was 34% (279/816). The median perceived PDAC risk was twofold (IQR 1-4) above respondents' estimates of general population risk. Factors significantly associated with higher perceived PDAC risk included non-Hispanic white race, post-graduate education level, PDAC-affected first-degree relative, genetic variants and lack of personal cancer history. Cancer worry had a very weak correlation across PDAC risk estimates (r=0.16). No correlation between perceived PDAC risk and 5-year calculated PDAC risk was found. Older age, having a first-degree relative with PDAC, meeting with a medical provider about PDAC cancer risk and awareness of surveillance modalities were significant predictors of undergoing PDAC surveillance. CONCLUSIONS: Individuals at risk for PDAC do not report risk perception that correlates with calculated risk. This presents an opportunity for counselling of at-risk patients to individualise management and improve surveillance uptake for eligible individuals.

The benefit of pancreatic cancer surveillance in carriers of germline BRCA1/2 pathogenic variants.

BACKGROUND: Surveillance of high-risk individuals for pancreatic ductal adenocarcinoma (PDAC) is recommended. This study aimed to determine the prevalence and outcomes of PDAC and its precursor lesions in BRCA1/2 pathogenic variants (PVs) carriers undergoing pancreatic surveillance. METHODS: A retrospective multicenter cohort study of pancreatic surveillance outcomes in Israeli BRCA1/2 carriers preferably with a family history of PDAC. RESULTS: A total of 180 asymptomatic carriers participated in the screening programs, including 57 (31.7%) with BRCA1 PVs, 121 (67.2%) with BRCA2 PVs, and 12 (6.6%) with PVs in BRCA1/2 and other genes, for a median follow-up period of 4 years. Ninety-one individuals (50.5%) fulfilled the International Cancer of the Pancreas Screening (CAPS) criteria for surveillance whereas 116 (64.4%) fulfilled the American College of Gastroenterology (ACG) criteria. There were four cases of adenocarcinoma and four cases of grade 1-neuroendocrine tumor (G1-NET). All were BRCA2 carriers, and two had no family history of PDAC. Three cancer patients were at resectable stages (IA, IIA, IIB) whereas one had a stage IIIB tumor. Of the G1-NET cases, one had surgery and the others were only followed. Success rate for detection of confined pancreatic carcinoma was thus 1.6% (three of 180) in the whole cohort, 1.6% (two of 116) among individuals who fulfilled ACG criteria and 2.2% (two of 91) in those fulfilling CAPS criteria for surveillance. CONCLUSIONS: Despite the low detection rate of PDAC and its' high-risk neoplastic precursor lesions among BRCA1/2 carriers undergoing pancreatic surveillance, 75% of cancer cases were detected at a resectable stage.

Risk Factors for Progression in Patients Undergoing Surveillance for Pancreatic Cysts.

OBJECTIVE: To identify risk factors associated with the progression of pancreatic cysts in patients undergoing surveillance. BACKGROUND: Previous studies of intraductal papillary mucinous neoplasms (IPMNs) rely on surgical series to determine malignancy risk and have inconsistently identified characteristics associated with IPMN progression. METHODS: We conducted a retrospective review of 2197 patients presenting with imaging concerning for IPMN from 2010 to 2019 at a single institution. Cyst progression was defined as resection or pancreatic cancer development. RESULTS: The median follow-up time was 84 months from the presentation. The median age was 66 years, and 62% were female. Ten percent had a first-degree relative with pancreatic cancer, and 3.2% had a germline mutation or genetic syndrome associated with an increased risk of pancreatic ductal adenocarcinoma (PDAC). Cumulative incidence of progression was 17.8% and 20.0% at 12 and 60 months postpresentation, respectively. Surgical pathology for 417 resected cases showed noninvasive IPMN in 39% of cases and PDAC with or without associated IPMN in 20%. Only 18 patients developed PDAC after 6 months of surveillance (0.8%). On multivariable analysis, symptomatic disease [hazard ratio (HR)=1.58; 95% CI: 1.25-2.01], current smoker status (HR=1.58; 95% CI: 1.16-2.15), cyst size (HR=1.26; 95% CI: 1.20-1.33), main duct dilation (HR=3.17; 95% CI: 2.44-4.11), and solid components (HR=1.89; 95% CI: 1.34-2.66) were associated with progression. CONCLUSIONS: Worrisome features on imaging at presentation, current smoker status, and symptomatic presentation are associated with IPMN progression. Most patients progressed within the first year of presentation to Memorial Sloan Kettering Cancer Center (MSKCC). Further investigation is necessary to develop personalized cyst surveillance strategies.

Intraductal Papillary Mucinous Neoplasms in High-Risk Individuals: Incidence, Growth Rate, and Malignancy Risk.

BACKGROUND AND AIMS: In high-risk individuals (HRIs), we aimed to assess the cumulative incidence of intraductal papillary mucinous neoplasms (IPMNs) and compare IPMN growth, neoplastic progression rate, and the value of growth as predictor for neoplastic progression to these in sporadic IPMNs. METHODS: We performed annual surveillance of Dutch HRIs, involving carriers of germline pathogenic variants (PVs) and PV-negative familial pancreatic cancer kindreds. HRIs with IPMNs were compared with Italian individuals without familial risk under surveillance for sporadic IPMNs. RESULTS: A total of 457 HRIs were followed for 48 (range 2-172) months; the estimated cumulative IPMN incidence was 46% (95% confidence interval, 28%-64%). In comparison with 442 control individuals, IPMNs in HRIs were more likely to grow ≥2.5 mm/y (31% vs 7%; P < .001) and develop worrisome features (32% vs 19%; P = .010). PV carriers with IPMNs more often displayed neoplastic progression (n = 3 [11%] vs n = 6 [1%]; P = .011), while familial pancreatic cancer kindreds did not (n = 0 [0%]; P = 1.000). The malignancy risk in a PV carrier with an IPMN was 23% for growth rates ≥2.5 mm/y (n = 13), 30% for ≥5 mm/y (n = 10), and 60% for ≥10 mm/y (n = 5). CONCLUSIONS: The cumulative incidence of IPMNs in HRIs is higher than previously reported in the general population. Compared with sporadic IPMNs, they have an increased growth rate. PV carriers with IPMNs are suggested to be at a higher malignancy risk. Intensive follow-up should be considered for PV carriers with an IPMN growing ≥2.5 mm/y, and surgical resection for those growing ≥5 mm/y.

Medicaid Expansion Increases Access for Rural and Impoverished Patients with Pancreatic Ductal Adenocarcinoma in Southern States.

INTRODUCTION: Medicaid expansion (ME) impacted patients when assessed at a national level. However, of the 32 states in which Medicaid expansion occurred, only 3 were Southern states. Whether results apply to Southern states that share similar geopolitical perspectives remains elusive. We aimed to assess the impact of ME on pancreatic ductal adenocarcinoma (PDAC) treatment in eight Southern states in the USA. PATIENTS AND METHODS: We identified uninsured or Medicaid patients (age 40-64 years) diagnosed with PDAC between 2011 and 2018 in Southern states from the North American Association of Central Cancer Registries-Cancer in North America (NAACCR-CiNA) research dataset. Medicaid-expanded states (MES; Louisiana, Kentucky, and Arkansas) were compared with non-MES (NMES; Tennessee, Alabama, Mississippi, Texas, and Oklahoma) using multivariate logistic regression. P < 0.05 was considered statistically significant. RESULTS: Among 3036 patients, MES significantly increased odds of Medicaid insurance by 36%, and increased proportions of insured Black patients by 3.7%, rural patients by 3.8%, and impoverished patients by 18.4%. After adjusting for age, race, rural-urban status, poverty status, and summary stage, the odds of receiving radiation therapy decreased by 26% for each year of expansion in expanded states (P = 0.01). Last, ME did not result in a significant difference between MES and NMES in diagnosing early stage disease (P = 0.98) nor in receipt of chemotherapy or surgery (P = 0.23 and P = 0.63, respectively). CONCLUSIONS: ME in Southern states increased insurance access to traditionally underserved groups. Interestingly, ME decreased the odds of receiving radiation therapy yearly and had no significant impact on receipt of chemotherapy or surgery.

Transportome Malfunctions and the Hallmarks of Pancreatic Cancer.

Ion channels and transporters (ICT) play important roles in almost all basic cellular processes. During last decades, abundant evidences have been provided that ICT (e.g., Ca2+ and K+ channels) are notable for regulating physiological pancreatic duct cellular function and deregulation of ICT is closely associated with the widely accepted hallmarks of pancreatic ductal adenocarcinoma (PDAC) such as proliferation, apoptosis resistance, invasion, and metastasis. Hence this review focuses on the role of ICT malfunctions in context with the hallmarks of PDAC. After briefly introducing epidemiology and history of molecular oncology of PDAC and summarizing the recent studies on molecular classification systems, we focus then on the exocrine pancreas as a very active secretory gland which considerably impacts the changes in the ion transport system (the transportome) upon malignant transformation. We highlight multiplicity of ICT members (H+ transporters, Ca2+, K+, Na+ and Cl- channels) and their functional impact in PDAC. We also present some selective therapeutic options to interfere with transportome functions and thereby with key mechanisms of malignant progression. This will hopefully contribute to a better clinical outcome based on improved therapeutic strategies for this still extremely deadly disease.

Benefit of Extended Surveillance of Low-Risk Pancreatic Cysts After 5-Year Stability: A Systematic Review and Meta-Analysis.

BACKGROUND & AIMS: Low-risk branch duct intraductal papillary mucinous neoplasms (BD-IPMNs) lacking worrisome features (WF) and high-risk stigmata (HRS) warrant surveillance. However, their optimal duration, especially among cysts with initial 5 years of size stability, warrants further investigation. We systematically reviewed the surveillance of low-risk BD-IPMNs and investigated the incidence of WF/HRS and advanced neoplasia, high-grade dysplasia, and pancreatic cancer during the initial (<5 years) and extended surveillance period (>5-years). METHODS: A systematic search (CRD42020117120) identified studies investigating long-term IPMN surveillance outcomes of low-risk IPMN among the Cochrane Library, Embase, Google Scholar, Ovid Medline, PubMed, Scopus, and Web of Science, from inception until July 9, 2021. The outcomes included the incidence of WF/HRS and advanced neoplasia, disease-specific mortality, and surveillance-related harm (expressed as percentage per patient-years). The meta-analysis relied on time-to-event plots and used a random-effects model. RESULTS: Forty-one eligible studies underwent systematic review, and 18 studies were meta-analyzed. The pooled incidence of WF/HRS among low-risk BD-IPMNs during initial and extended surveillance was 2.2% (95% CI, 1.0%-3.7%) and 2.9% (95% CI, 1.0%-5.7%) patient-years, respectively, whereas the incidence of advanced neoplasia was 0.6% (95% CI, 0.2%-1.00%) and 1.0% (95% CI, 0.6%-1.5%) patient-years, respectively. The pooled incidence of disease-specific mortality during initial and extended surveillance was 0.3% (95% CI, 0.1%-0.6%) and 0.6% (95% CI, 0.0%-1.6%) patient-years, respectively. Among BD-IPMNs with initial size stability, extended surveillance had a WF/HRS and advanced neoplasia incidence of 1.9% (95% CI, 1.2%-2.8%) and 0.2% (95% CI, 0.1%-0.5%) patient-years, respectively. CONCLUSIONS: A lower incidence of advanced neoplasia during extended surveillance among low-risk, stable-sized BD-IPMNs was a key finding of this study. However, the survival benefit of surveillance among this population warrants further exploration through high-quality studies before recommending surveillance cessation with certainty.

Predicting Pancreatic Cancer in the UK Biobank Cohort Using Polygenic Risk Scores and Diabetes Mellitus.

BACKGROUND & AIMS: Diabetes mellitus (DM) is known to be associated with pancreatic ductal adenocarcinoma (PDAC), particularly new-onset DM (NODM). Others have developed polygenic risk scores (PRS) associated with PDAC risk. We aimed to compare the performance of these PRS in an independent cohort to determine if they can discriminate between NODM and long-standing DM patients with PDAC. METHODS: Cases (1042) and matched cancer-free controls (10,420) were drawn from the UK Biobank. Five PRS models were calculated using single nucleotide polymorphisms (SNPs) from previous studies (Nakatochi, Galeotti, Molina, Jia, and Rashkin) and a combination of these. Regression models were used to assess the association between PDAC and PRS adjusted for ancestry, smoking, DM, waist circumference, and family history of digestive cancer. Receiver operator characteristic curves and area under the curve metrics (AUC) were used to assess the performance of each PRS for classifying PDAC risk. RESULTS: The combined PRS model achieved the highest AUC (0.605), and significantly improved a clinical risk model in this cohort (AUC = 0.83; P = .0002). Individuals within the fifth quintile have a 2.74-fold increased risk of developing PDAC vs those in the first quintile (P < .001), and have a 3.05-fold increased risk of developing PDAC if they have DM vs those without DM (P < .001). The positive predictive value was 11.9% in participants without DM, 23.9% with long-standing DM, and 86.7% with NODM. CONCLUSIONS: The PDAC-related common genetic variants are more strongly associated with DM. This PRS has the potential for targeting individuals with NODM for PDAC secondary screening measures.

Clinical Outcomes of Intraductal Papillary Mucinous Neoplasms With Dilatation of the Main Pancreatic Duct.

BACKGROUND & AIMS: Dilatation of the main pancreatic duct (MPD) has been a surgical indication for intraductal papillary mucinous neoplasms (IPMNs). Few studies have investigated long-term outcomes of IPMNs with MPD dilatation. METHODS: Among 3610 patients diagnosed with pancreatic cysts between 1994 and 2021, we identified 2829 IPMN patients, including 282 patients with MPD ≥5 mm, and examined short-term (≤6 months) and long-term risks of pancreatic carcinoma. Utilizing competing risks proportional hazards models, we estimated subdistribution hazard ratios for incidence of pancreatic carcinoma with adjustment for potential confounders. RESULTS: In analyses of short-term outcomes of the 282 patients with MPD dilatation, 72 (26%) patients were diagnosed with pancreatic carcinoma based on surgical or nonsurgical exploration. During long-term follow-up of 168 patients, we documented 24 (14%) patients diagnosed with pancreatic carcinoma (18 with IPMN-derived carcinoma and 6 with concomitant ductal adenocarcinoma). The patients with the MPD = 5-9.9 mm had cumulative incidence rates of pancreatic carcinoma diagnosis of 8.1% (95% confidence interval [CI], 4.3%-13.5%) and 10.0% (95% CI, 5.5%-15.9%) at 2 and 5 years, respectively; and the patients with the MPD ≥10 mm had the corresponding rates of 16.0% (95% CI, 3.6-36.5%) and 33.3% (95% CI, 10.3%-58.8%). The multivariable subdistribution hazard ratios were 2.78 (95% CI, 1.57-4.90) and 7.00 (95% CI, 2.58-19.0) for the MPD = 5-9.9 mm and ≥10 mm (vs <5 mm), respectively. CONCLUSIONS: IPMNs with MPD dilatation at baseline were associated with higher prevalence and incidence of pancreatic carcinoma compared with IPMNs with no MPD dilatation.

Late-Stage Pancreatic Cancer Detected During High-Risk Individual Surveillance: A Systematic Review and Meta-Analysis.

BACKGROUND & AIMS: Identification and resection of successful targets, that is, T1 N0M0 pancreatic ductal adenocarcinoma (PDAC) and high-grade precursors during surveillance of high-risk individuals (HRIs) confers improved survival. Late-stage PDACs refer to T2-4 N0M0 and nodal or distant metastatic PDAC stages diagnosed during the follow-up phase of HRI surveillance. This study aimed to quantify late-stage PDACs during HRI surveillance and identify associated clinicoradiologic factors. METHODS: A systematic search (PROSPERO:CRD42018117189) from Cochrane Library, Embase, Google Scholar, Medline, PubMed, Scopus, and Web of Science was last performed on April 18, 2021. Only original HRI surveillance manuscripts that specified follow-up strategies were included, and studies with only baseline information were excluded. Cumulative incidences of advanced neoplasia: high-grade precursors and all PDACs, and surveillance-detected/interval late-stage PDACs were calculated through random-effects model. Incidence of late-stage PDACs underwent metaregression to identify association with HRI clinicoradiologic features. Publication bias was assessed through the funnel plot and Egger's regression line. RESULTS: Thirteen original surveillance studies included 2169 HRIs followed over 7302.72 patient-years. Cumulative incidence of advanced neoplasia and late-stage PDACs was 3.3 (95% confidence interval [CI]: 0.6-7.4) and 1.7 (95% CI: 0.2-4.0) per 1000 patient-years, respectively. Late-stage PDACs lacked significant association with surveillance imaging, baseline pancreatic morphology, study location, genetic background, gender, or age. Limited information on diagnostic error, symptoms, timing of presentation, lesion site, and surveillance adherence precluded formal meta-analysis. CONCLUSION: A sizeable proportion of late-stage PDACs were detected during follow-up. Their incidence lacked association with baseline clinicoradiologic features. Further causal investigation of stage-based outcomes is warranted for overall improvement in HRI surveillance.

Derivation and External Validation of Machine Learning-Based Model for Detection of Pancreatic Cancer.

INTRODUCTION: There is currently no widely accepted approach to screening for pancreatic cancer (PC). We aimed to develop and validate a risk prediction model for pancreatic ductal adenocarcinoma (PDAC), the most common form of PC, across 2 health systems using electronic health records. METHODS: This retrospective cohort study consisted of patients aged 50-84 years having at least 1 clinic-based visit over a 10-year study period at Kaiser Permanente Southern California (model training, internal validation) and the Veterans Affairs (VA, external testing). Random survival forests models were built to identify the most relevant predictors from >500 variables and to predict risk of PDAC within 18 months of cohort entry. RESULTS: The Kaiser Permanente Southern California cohort consisted of 1.8 million patients (mean age 61.6) with 1,792 PDAC cases. The 18-month incidence rate of PDAC was 0.77 (95% confidence interval 0.73-0.80)/1,000 person-years. The final main model contained age, abdominal pain, weight change, HbA1c, and alanine transaminase change (c-index: mean = 0.77, SD = 0.02; calibration test: P value 0.4, SD 0.3). The final early detection model comprised the same features as those selected by the main model except for abdominal pain (c-index: 0.77 and SD 0.4; calibration test: P value 0.3 and SD 0.3). The VA testing cohort consisted of 2.7 million patients (mean age 66.1) with an 18-month incidence rate of 1.27 (1.23-1.30)/1,000 person-years. The recalibrated main and early detection models based on VA testing data sets achieved a mean c-index of 0.71 (SD 0.002) and 0.68 (SD 0.003), respectively. DISCUSSION: Using widely available parameters in electronic health records, we developed and externally validated parsimonious machine learning-based models for detection of PC. These models may be suitable for real-time clinical application.

Acute Pancreatitis Recurrences Augment Long-Term Pancreatic Cancer Risk.

INTRODUCTION: In animal models, inflammation caused by experimental acute pancreatitis (AP) promotes pancreatic carcinogenesis that is preventable by suppressing inflammation. Recent studies noted higher long-term risk of pancreatic ductal adenocarcinoma (PDAC) after AP. In this study, we evaluated whether the long-term PDAC risk after AP was influenced by the etiology of AP, number of recurrences, and if it was because of progression to chronic pancreatitis (CP). METHODS: This retrospective study used nationwide Veterans Administration database spanning 1999-2015. A 2-year washout period was applied to exclude patients with preexisting AP and PDAC. PDAC risk was estimated in patients with AP without (AP group) and with underlying CP (APCP group) and those with CP alone (CP group) and compared with PDAC risk in patients in a control group, respectively, using cause-specific hazards model. RESULTS: The final cohort comprised 7,147,859 subjects (AP-35,550 and PDAC-16,475). The cumulative PDAC risk 3-10 years after AP was higher than in controls (0.61% vs 0.18%), adjusted hazard ratio (1.7 [1.4-2.0], P < 0.001). Adjusted hazard ratio was 1.5 in AP group, 2.4 in the CP group, and 3.3 in APCP group. PDAC risk increased with the number of AP episodes. Elevated PDAC risk after AP was not influenced by the etiology of AP (gallstones, smoking, or alcohol). DISCUSSION: There is a higher PDAC risk 3-10 years after AP irrespective of the etiology of AP, increases with the number of episodes of AP and is additive to higher PDAC risk because of CP.

The Landmark Series: Intraductal Papillary Mucinous Neoplasms of the Pancreas-From Prevalence to Early Cancer Detection.

Modern series report a prevalence of pancreatic cysts in the general population of up to 50% in prospective studies. Of these, about half will be pancreatic cystic neoplasms (PCNs) that have varying degrees of malignant potential. Intraductal papillary mucinous neoplasms (IPMNs) of the pancreas are the most common PCNs and are known predecessors of pancreatic adenocarcinoma. Critically, they are one of the only radiographically identifiable precursors of pancreatic cancer and thus provide an opportunity for early cancer detection and surgical resection with curative intent. The combination of high prevalence and potential for malignant degeneration underscore the relevance of discussing the best management of IPMNs and improving the existing standard of care. Landmark data on IPMN prevalence, guidelines, surveillance, biomarkers, and immune landscape are highlighted.

Machine learning versus regression for prediction of sporadic pancreatic cancer.

BACKGROUND/OBJECTIVES: There is currently no widely accepted approach to identify patients at increased risk for sporadic pancreatic cancer (PC). We aimed to compare the performance of two machine-learning models with a regression-based model in predicting pancreatic ductal adenocarcinoma (PDAC), the most common form of PC. METHODS: This retrospective cohort study consisted of patients 50-84 years of age enrolled in either Kaiser Permanente Southern California (KPSC, model training, internal validation) or the Veterans Affairs (VA, external testing) between 2008 and 2017. The performance of random survival forests (RSF) and eXtreme gradient boosting (XGB) models were compared to that of COX proportional hazards regression (COX). Heterogeneity of the three models were assessed. RESULTS: The KPSC and the VA cohorts consisted of 1.8 and 2.7 million patients with 1792 and 4582 incident PDAC cases within 18 months, respectively. Predictors selected into all three models included age, abdominal pain, weight change, and glycated hemoglobin (A1c). Additionally, RSF selected change in alanine transaminase (ALT), whereas the XGB and COX selected the rate of change in ALT. The COX model appeared to have lower AUC (KPSC: 0.737, 95% CI 0.710-0.764; VA: 0.706, 0.699-0.714), compared to those of RSF (KPSC: 0.767, 0.744-0.791; VA: 0.731, 0.724-0.739) and XGB (KPSC: 0.779, 0.755-0.802; VA: 0.742, 0.735-0.750). Among patients with top 5% predicted risk from all three models (N = 29,663), 117 developed PDAC, of which RSF, XGB and COX captured 84 (9 unique), 87 (4 unique), 87 (19 unique) cases, respectively. CONCLUSIONS: The three models complement each other, but each has unique contributions.

Risk of pancreatic cancer in people with new-onset diabetes: A Danish nationwide population-based cohort study.

BACKGROUND: New onset diabetes (NOD) in people 50 years or older may indicate underlying pancreatic ductal adenocarcinoma (PDAC). The cumulative incidence of PDAC among people with NOD remains uncertain on a population-based level. METHODS: This was a nationwide population-based retrospective cohort study based on the Danish national health registries. We investigated the 3-year cumulative incidence of PDAC in people 50 years or older with NOD. We further characterised people with pancreatic cancer-related diabetes (PCRD) in relation to demographic and clinical characteristics, including trajectories of routine biochemical parameters, using people with type 2 diabetes (T2D) as a comparator group. RESULTS: During a 21-year observation period, we identified 353,970 people with NOD. Among them, 2105 people were subsequently diagnosed with pancreatic cancer within 3 years (0.59%, 95% CI [0.57-0.62%]). People with PCRD were older than people with T2D at diabetes diagnosis (median age 70.9 vs. 66.0 years (P < 0.001) and had a higher burden of comorbidities (P = 0.007) and more prescriptions of medications used to treat cardiovascular diseases (all P < 0.001). Distinct trajectories of HbA1c and plasma triglycerides were observed in PCRD vs. T2D, with group differences observed for up to three years prior to NOD diagnosis for HbA1c and up to two years for plasma triglyceride levels. CONCLUSIONS: The 3-year cumulative incidence of PDAC is approximately 0.6% among people 50 years or older with NOD in a nationwide population-based setting. Compared to T2D, people with PCRD are characterised by distinct demographic and clinical profiles, including distinctive trajectories of plasma HbA1c and triglyceride levels.

The Evaluation of Gallstone Disease in the Year Before Pancreatic Cancer Diagnosis.

INTRODUCTION: Patients with pancreatic cancer can present with a variety of insidious abdominal symptoms, complicating initial diagnosis. Early symptoms of pancreatic cancer often mirror those associated with gallstone disease, which has been demonstrated to be a risk factor for this malignancy. This study aims to compare the incidence of gallstone disease in the year before diagnosis of pancreatic ductal adenocarcinoma (PDAC) as compared to the general population, and evaluate the association of gallstone disease with stage at diagnosis and surgical intervention. METHODS: Patients with PDAC were identified from SEER-Medicare (2008-2015). The incidence of gallstone disease (defined as cholelithiasis, cholecystitis and/or cholecystectomy) in the 1 year before cancer diagnosis was compared to the annual incidence in an age-matched, sex-matched, and race-matched noncancer Medicare cohort. RESULTS: Among 14,654 patients with PDAC, 4.4% had gallstone disease in the year before cancer diagnosis. Among the noncancer controls (n = 14,654), 1.9% had gallstone disease. Both cohorts had similar age, sex and race distributions. PDAC patients with gallstone disease were diagnosed at an earlier stage (stage 0/I-II, 45.8% versus 38.1%, P < 0.0001) and a higher proportion underwent resection (22.7% versus 17.4%, P = 0.0004) compared to patients without gallstone disease. CONCLUSIONS: In the year before PDAC diagnosis, patients present with gallstone disease more often than the general population. Improving follow-up care and differential diagnosis strategies may help combat the high mortality rate in PDAC by providing an opportunity for earlier stage of diagnosis and earlier intervention.

Patients with deleterious germline mutations: A heterogeneous population for pancreatic cancer screening?

BACKGROUND AND OBJECTIVES: Modest data exist on the benefits of screening and surveillance for pancreatic cancer (PC) in high-risk individuals. Intraductal papillary mucinous neoplasms (IPMN) are known precursors to PC. We hypothesized that patients with high-risk deleterious germline mutations have a higher prevalence of IPMN. METHODS: All patients undergoing prospective screening at a single institution from 2013 to 2019 were reviewed. RESULTS: Of 1166 patients screened, 358 (31%) possessed germline mutations and/or family history of PC (mutations n = 201/358, 56%, family history n = 226/358, 63%) (median follow-up 2.7 years). IPMN was found in 127 patients (35.5%). The prevalence of IPMN in mutation carriers (18%) was higher than in the general population (p < 0.01). Germline mutation was an independent predictor of IPMN (odds ratio [OR] = 3.2; p < 0.01), while family history was not (p = 0.22). IPMN prevalence was distributed unevenly between mutation types (67%-Peutz-Jeghers; 43%-HNPCC, 24%-BRCA2; 17%-ATM; 9%-BRCA1; 0%-CDKN2A and PALB2). CONCLUSION: In this series, 18% of mutation carriers harbored IPMN, higher than the general population. Germline mutation, but not a family history of PC, was independently associated with IPMN. This prevalence varied across mutation subtypes, suggesting not all mutation carriers develop precancerous lesions. Genetic testing for patients with a positive family history may improve screening modalities for this high-risk population.

Long-term surveillance of branch-duct intraductal papillary mucinous neoplasms without worrisome or high-risk features.

INTRODUCTION: Long-term data evaluating clinical outcomes in patients with branch-duct Intraductal papillary mucinous neoplasms (BD-IPMN) without high-risk stigmata (HRS) or worrisome features (WF) remain limited. METHODS: This observational cohort study included all patients diagnosed with BD-IPMN without HRS or WF between 2003 and 2019 who were enrolled in a prospective surveillance program. Time-to-progression analysis was performed using a cumulative incidence function plot and survival analysis was conducted using Kaplan-Meier. RESULTS: The median follow-up time for the 267 patient cohort was 44.5 months (interquartile range [IQR]: 24.1-72.2). Radiographic cyst growth was observed in 123 (46.1%) patients; 65 (24.3%) patients progressed to WF/HRS. Twenty-six (9.7%) patients were selected for resection during surveillance: 21 (80.8%) WF, 4 (15.4%) HRS; 1 (3.9%) transformed to mixed-duct. Of all the patients who underwent resection, 5 (19.2%) had adenocarcinoma, and 1 (3.8%) had carcinoma-in-situ. The probability of any radiographic progression was 21.3% (5-year) and 51.3% (10-year). For the entire cohort, there was 1.1% mortality secondary to pancreatic adenocarcinoma and 8.2% all-cause mortality. The 5-year overall survival rate was 91.5%, and at 10 years, 81.5%. CONCLUSION: Approximately one in four patients with nonworrisome BD-IPMN have progression to WF/HRS stigmata during surveillance. However, the risk of malignant transformation remains low. Surveillance strategy remains prudent in this patient population.

Incidence and Prevalence of Intraductal Papillary Mucinous Neoplasms in Individuals With BRCA1 and BRCA2 Pathogenic Variant.

BACKGROUND: The natural history of branch-duct intraductal papillary neoplasm (BD-IPMN) in BRCA1/2 patients is unknown. Our goal was to estimate the incidence and prevalence of BD-IPMN and other pancreatic lesions in BRCA1/2 patients and compare it to that for average-risk individuals. METHODS: We identified a cohort of BRCA1/2 patients followed at our institution between 1995 and 2020. Medical records and imaging results were reviewed to determine prevalence of pancreatic lesions. We then identified those who had undergone follow-up imaging and determined the incidence of new pancreatic lesions. We categorized pancreatic lesions as low, intermediate, or high-risk based on their malignant potential. RESULTS: During the study period, 359 eligible BRCA1/2 patients were identified. Average patient age was 56.8 years, 88.3% were women, and 51.5% had BRCA1 . The prevalence of low-risk pancreatic lesions was 14.4%, intermediate-risk 13.9%, and high-risk 3.3%. The prevalence of BD-IPMN was 13.6% with mean cyst size 7.7 mm (range: 2 to 34 mm). The prevalence of pancreatic cancer was 3.1%. Subsequent imaging was performed in 169 patents with mean follow-up interval of 5.3 years (range: 0 to 19.7 y). The incidence of BD-IPMN was 20.1%, with median cyst size 5.5 mm (range: 2 to 30 mm). The incidence of pancreatic cancer was 2.9%. BRCA2 patients were almost 4-times more likely to develop pancreatic cancer than BRCA1 patients, however, there was no difference in incidence or prevalence of BD-IPMN. CONCLUSIONS: Incidence and prevalence of BD-IPMNs in BRCA1/2 patients was similar to that reported for average-risk individuals. BRCA2 patients were more likely than BRCA1 patients to develop pancreatic cancer but had similar rates of BD-IPMN.

The association of new-onset diabetes with subsequent diagnosis of pancreatic cancer-novel use of a large administrative database.

BACKGROUND: Screening options for pancreatic ductal adenocarcinoma (PDAC) are limited. New-onset type 2 diabetes (NoD) is associated with subsequent diagnosis of PDAC in observational studies and may afford an opportunity for PDAC screening. We evaluated this association using a large administrative database. METHODS: Patients were identified using claims data from the OptumLabs® Data Warehouse. Adult patients with NoD diagnosis were matched 1:3 with patients without NoD using age, sex and chronic obstructive pulmonary disease (COPD) status. The event of PDAC diagnosis was compared between cohorts using the Kaplan-Meier method. Factors associated with PDAC diagnosis were evaluated with Cox's proportional hazards modeling. RESULTS: We identified 640 421 patients with NoD and included 1 921 263 controls. At 3 years, significantly more PDAC events were identified in the NoD group vs control group (579 vs 505; P < 0.001). When controlling for patient factors, NoD was significantly associated with elevated risk of PDAC (HR 3.474, 95% CI 3.082-3.920, P < 0.001). Other factors significantly associated with PDAC diagnosis were increasing age, increasing age among Black patients, and COPD diagnosis (P ≤ 0.05). CONCLUSIONS: NoD was independently associated with subsequent diagnosis of PDAC within 3 years. Future studies should evaluate the feasibility and benefit of PDAC screening in patients with NoD.