ABSTRACT
Genome-wide association studies (GWAS) are a powerful tool for detecting variants associated with complex traits and can help risk stratification and prevention strategies against pancreatic ductal adenocarcinoma (PDAC). However, the strict significance threshold commonly used makes it likely that many true risk loci are missed. Functional annotation of GWAS polymorphisms is a proven strategy to identify additional risk loci. We aimed to investigate single-nucleotide polymorphisms (SNP) in regulatory regions [transcription factor binding sites (TFBSs) and enhancers] that could change the expression profile of multiple genes they act upon and thereby modify PDAC risk. We analyzed a total of 12,636 PDAC cases and 43,443 controls from PanScan/PanC4 and the East Asian GWAS (discovery populations), and the PANDoRA consortium (replication population). We identified four associations that reached study-wide statistical significance in the overall meta-analysis: rs2472632(A) (enhancer variant, OR 1.10, 95%CI 1.06,1.13, p = 5.5 × 10-8), rs17358295(G) (enhancer variant, OR 1.16, 95%CI 1.10,1.22, p = 6.1 × 10-7), rs2232079(T) (TFBS variant, OR 0.88, 95%CI 0.83,0.93, p = 6.4 × 10-6) and rs10025845(A) (TFBS variant, OR 1.88, 95%CI 1.50,1.12, p = 1.32 × 10-5). The SNP with the most significant association, rs2472632, is located in an enhancer predicted to target the coiled-coil domain containing 34 oncogene. Our results provide new insights into genetic risk factors for PDAC by a focused analysis of polymorphisms in regulatory regions and demonstrating the usefulness of functional prioritization to identify loci associated with PDAC risk.
Subject(s)
Carcinoma, Pancreatic Ductal , Pancreatic Neoplasms , Humans , Genome-Wide Association Study , Genetic Predisposition to Disease , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/epidemiology , Pancreatic Neoplasms/pathology , Carcinoma, Pancreatic Ductal/genetics , Carcinoma, Pancreatic Ductal/pathology , Regulatory Sequences, Nucleic Acid , Polymorphism, Single Nucleotide/genetics , Transcription Factors/genetics , Transcription Factors/metabolism , Binding Sites/geneticsABSTRACT
Correlated regions of systemic interindividual variation (CoRSIV) represent a small proportion of the human genome showing DNA methylation patterns that are the same in all human tissues, are different among individuals, and are partially regulated by genetic variants in cis. In this study we aimed at investigating single-nucleotide polymorphisms (SNPs) within CoRSIVs and their involvement with pancreatic ductal adenocarcinoma (PDAC) risk. We analyzed 29,099 CoRSIV-SNPs and 133,615 CoRSIV-mQTLs in 14,394 cases and 247,022 controls of European and Asian descent. We observed that the A allele of the rs2976395 SNP was associated with increased PDAC risk in Europeans (p = 2.81 × 10-5). This SNP lies in the prostate stem cell antigen gene and is in perfect linkage disequilibrium with a variant (rs2294008) that has been reported to be associated with risk of many other cancer types. The A allele is associated with the DNA methylation level of the gene according to the PanCan-meQTL database and with overexpression according to QTLbase. The expression of the gene has been observed to be deregulated in many tumors of the gastrointestinal tract including pancreatic cancer; however, functional studies are needed to elucidate the function relevance of the association.
Subject(s)
Antigens, Neoplasm , Carcinoma, Pancreatic Ductal , DNA Methylation , GPI-Linked Proteins , Genetic Predisposition to Disease , Linkage Disequilibrium , Neoplasm Proteins , Pancreatic Neoplasms , Polymorphism, Single Nucleotide , Humans , Pancreatic Neoplasms/genetics , Carcinoma, Pancreatic Ductal/genetics , Male , GPI-Linked Proteins/genetics , Antigens, Neoplasm/genetics , Neoplasm Proteins/genetics , Case-Control Studies , White People/genetics , Female , Quantitative Trait Loci , Alleles , Asian People/genetics , Middle AgedABSTRACT
OBJECTIVE: To quantify the rate of low-yield surgery, defined as no high-grade dysplastic precursor lesions or T1N0M0 pancreatic cancer at pathology, during pancreatic cancer surveillance. BACKGROUND: Global efforts have been made in pancreatic cancer surveillance to anticipate the diagnosis of pancreatic cancer at an early stage and improve survival in high-risk individuals (HRIs) with a hereditary predisposition. The negative impact of pancreatic cancer surveillance when surgery is performed for low-grade dysplasia or a non-neoplastic condition is not well quantified. MATERIALS AND METHODS: A systematic search and prevalence meta-analysis was performed for studies reporting surgery with final diagnoses other than those defined by the Cancer of the Pancreas Screening (CAPS) goals from January 2000 to July 2023. The secondary outcome was the pooled proportion of final diagnoses matching the CAPS goals (PROSPERO: #CRD42022300408). RESULTS: Twenty-three articles with 5027 patients (median 109 patients/study, interquartile range 251) were included. The pooled prevalence of low-yield surgery was 2.1% (95% CI: 0.9-3.7, I2 : 83%). In the subgroup analysis, this prevalence was nonsignificantly higher in studies that only included familial pancreatic cancer subjects without known pathogenic variants, compared with those enrolling pathogenic variant carriers. No effect modifiers were found. Overall, the pooled prevalence of subjects under surveillance who had a pancreatic resection that contained target lesions was 0.8% (95% CI, 0.3-1.5, I2 : 24%]. The temporal analysis showed that the rate of low-yield surgeries decreased in the last decades and stabilized at around 1% (test for subgroup differences P <0.01). CONCLUSIONS: The risk of "low-yield" surgery during pancreatic cancer surveillance is relatively low but should be thoroughly discussed with individuals under surveillance.
Subject(s)
Pancreatic Neoplasms , Humans , Prevalence , Risk Factors , Pancreatic Neoplasms/diagnosis , Pancreatic Neoplasms/epidemiology , Pancreatic Neoplasms/surgery , Pancreas/pathology , Genetic Predisposition to DiseaseABSTRACT
BACKGROUND & AIMS: Several studies have compared primary endoscopic ultrasound (EUS)-guided biliary drainage to endoscopic retrograde cholangiopancreatography (ERCP) with insertion of metal stents in unresectable malignant distal biliary obstruction (MDBO) and the results were conflicting. The aim of the current study was to compare the outcomes of the procedures in a large-scale study. METHODS: This was a multicenter international randomized controlled study. Consecutive patients admitted for obstructive jaundice due to unresectable MDBO were recruited. Patients were randomly allocated to receive EUS-guided choledocho-duodenostomy (ECDS) or ERCP for drainage. The primary outcome was the 1-year stent patency rate. Other outcomes included technical success, clinical success, adverse events, time to stent dysfunction, reintervention rates, and overall survival. RESULTS: Between January 2017 and February 2021, 155 patients were recruited (ECDS 79, ERCP 76). There were no significant differences in 1-year stent patency rates (ECDS 91.1% vs ERCP 88.1%, P = .52). The ECDS group had significantly higher technical success (ECDS 96.2% vs ERCP 76.3%, P < .001), whereas clinical success was similar (ECDS 93.7% vs ERCP 90.8%, P = .559). The median (interquartile range) procedural time was significantly shorter in the ECDS group (ECDS 10 [5.75-18] vs ERCP 25 [14-40] minutes, P < .001). The rate of 30-day adverse events (P = 1) and 30-day mortality (P = .53) were similar. CONCLUSION: Both procedures could be options for primary biliary drainage in unresectable MDBO. ECDS was associated with higher technical success and shorter procedural time then ERCP. Primary ECDS may be preferred when difficult ERCPs are anticipated. This study was registered to Clinicaltrials.gov NCT03000855.
Subject(s)
Cholestasis , Neoplasms , Humans , Cholangiopancreatography, Endoscopic Retrograde/adverse effects , Cholangiopancreatography, Endoscopic Retrograde/methods , Cholestasis/diagnostic imaging , Cholestasis/etiology , Cholestasis/surgery , Duodenostomy , Common Bile Duct , Neoplasms/etiology , Endosonography/methods , Stents/adverse effects , Drainage/adverse effects , Drainage/methods , Ultrasonography, Interventional/methodsABSTRACT
INTRODUCTION: Pancreatic cancer (PC) surveillance of high-risk individuals (HRI) is becoming more common worldwide, aiming at anticipating PC diagnosis at a preclinical stage. In 2015, the Italian Registry of Families at Risk of Pancreatic Cancer was created. We aimed to assess the prevalence and incidence of pancreatic findings, oncological outcomes, and harms 7 years after the Italian Registry of Families at Risk of Pancreatic Cancer inception, focusing on individuals with at least a 3-year follow-up or developing events before. METHODS: HRI (subjects with a family history or mutation carriers with/without a family history were enrolled in 18 centers). They underwent annual magnetic resonance with cholangiopancreatography or endoscopic ultrasound (NCT04095195). RESULTS: During the study period (June 2015-September 2022), 679 individuals were enrolled. Of these, 524 (77.2%) underwent at least baseline imaging, and 156 (29.8%) with at least a 3-year follow-up or pancreatic malignancy/premalignancy-related events, and represented the study population. The median age was 51 (interquartile range 16) years. Familial PC cases accounted for 81.4% of HRI and individuals with pathogenic variant for 18.6%. Malignant (n = 8) and premalignant (1 PanIN3) lesions were found in 9 individuals. Five of these 8 cases occurred in pathogenic variant carriers, 4 in familial PC cases (2 tested negative at germline testing and 2 others were not tested). Three of the 8 PC were stage I. Five of the 8 PC were resectable, 3 Stage I, all advanced cases being prevalent. The 1-, 2-, and 3-year cumulative hazard of PC was 1.7%, 2.5%, and 3%, respectively. Median overall and disease-free survival of patients with resected PC were 18 and 12 months (95% CI not computable). Considering HRI who underwent baseline imaging, 6 pancreatic neuroendocrine neoplasms (1 resected) and 1 low-yield surgery (low-grade mixed-intraductal papillary mucinous neoplasm) were also reported. DISCUSSION: PC surveillance in a fully public health care system is feasible and safe, and leads to early PC or premalignant lesions diagnoses, mostly at baseline but also over time.
Subject(s)
Carcinoma, Pancreatic Ductal , Carcinoma , Pancreatic Neoplasms , Humans , Adolescent , Prospective Studies , Pancreatic Neoplasms/diagnostic imaging , Pancreatic Neoplasms/epidemiology , Pancreas/pathology , Magnetic Resonance Imaging , Carcinoma, Pancreatic Ductal/pathologyABSTRACT
BACKGROUND: Objectives: To investigate communication clarity and understanding at the time of pancreatic adenocarcinoma (PDAC) diagnosis and whether they can influence patient engagement and compliance. METHODS: Consecutive PDAC patients were enrolled at the time of diagnosis after obtaining informed consent in a single-center study. The patients completed a validated scale (PHE-s®), and the understanding rate was assessed using standardized tools. Patient compliance was evaluated, and the correlation between the PHE-s®, understanding, and compliance was calculated. RESULTS: Thirty patients were enrolled (15 female) with a mean age 64.4, 13 were metastatic. The mean visit time was 31 min, being longer if visiting doctor was an oncologist (p = 0.002). The engagement level was high in 70% of the patients, and all but one were compliant. The analysis of doctor-patient interactions showed a median of 121 conversational turns for doctors, 75 for patients, and 20 for caregivers (p < 0.0001), and the median percentage of speaking time was 77% for doctors, 13% for patients, and 2% for caregivers (p < 0.0001). Female caregivers spent more time speaking than did male caregivers (median 11.6% vs. 1.3%; p = 0.06). There were 290 instances of problematic understanding, most of which occurred during the taking of patients' personal medical history for doctors, while for patients and caregivers, these occurred mainly during the discussion of diagnosis/treatment (p < 0.0001). In a multivariable analysis, only origin from central or southern Italy was associated with high engagement (p = 0.0087). CONCLUSION: In this first attempt to measure clarity of communication and engagement in patients with PDAC, typical features of conversation and problematic understanding emerged, which deserves further investigation.
Subject(s)
Adenocarcinoma , Pancreatic Neoplasms , Humans , Male , Female , Communication , Patient Compliance , ItalyABSTRACT
BACKGROUND: Endoscopic ultrasound (EUS) is the most sensitive method for diagnosing chronic pancreatitis (CP) in its early stages, and Rosemont Classification (RC) is used for its evaluation. Data on the correlation between EUS features and pancreatic exocrine insufficiency (PEI) are limited. We investigated the correlation between the EUS findings and PEI. METHODS: This was a retrospective, monocentric cohort study involving patients prospectively enrolled from 2018 to 2022, with definite or probable CP according to the M-ANNHEIM criteria. All the patients underwent EUS and exocrine function investigations within 12 months of diagnosis. PEI was diagnosed using fecal elastase (FE) or when overt steatorrhea was reversed by pancreatic enzyme replacement therapy. Logistic regression analyses, rank correlation, ROC curve, and area under the curve (AUROC) were performed to evaluate the association between EUS features and PEI, and the accuracy of RC in predicting PEI. RESULTS: Among 128 patients examined (63.3 % male; mean age, 47 years), 69.5 % were diagnosed with PEI. In multivariate logistic regression among all the RC criteria, only lithiasis in the main pancreatic duct (MPD) was associated with increased risk of PEI (OR 2.92, 95 % CI 1.29-6.61; p = 0.01). Rank analysis showed a weak inverse correlation between RC and FE (Spearman's rho = -0.02; p = 0.03). The accuracy of RC was moderate (AUROC 0.62, p = 0.014). CONCLUSIONS: Among RC EUS features, lithiasis in the MPD is helpful for predicting the risk of PEI, while other findings are of limited utility in evaluating exocrine function.
ABSTRACT
INTRODUCTION: Only a small number of risk factors for pancreatic ductal adenocarcinoma (PDAC) has been established. Several studies identified a role of epigenetics and of deregulation of DNA methylation. DNA methylation is variable across a lifetime and in different tissues; nevertheless, its levels can be regulated by genetic variants like methylation quantitative trait loci (mQTLs), which can be used as a surrogate. MATERIALS AND METHODS: We scanned the whole genome for mQTLs and performed an association study in 14 705 PDAC cases and 246 921 controls. The methylation data were obtained from whole blood and pancreatic cancer tissue through online databases. We used the Pancreatic Cancer Cohort Consortium and the Pancreatic Cancer Case-Control Consortium genome-wide association study (GWAS) data as discovery phase and the Pancreatic Disease Research consortium, the FinnGen project and the Japan Pancreatic Cancer Research consortium GWAS as replication phase. RESULTS: The C allele of 15q26.1-rs12905855 showed an association with a decreased risk of PDAC (OR=0.90, 95% CI 0.87 to 0.94, p=4.93×10-8 in the overall meta-analysis), reaching genome-level statistical significance. 15q26.1-rs12905855 decreases the methylation of a 'C-phosphate-G' (CpG) site located in the promoter region of the RCCD1 antisense (RCCD1-AS1) gene which, when expressed, decreases the expression of the RCC1 domain-containing (RCCD1) gene (part of a histone demethylase complex). Thus, it is possible that the rs12905855 C-allele has a protective role in PDAC development through an increase of RCCD1 gene expression, made possible by the inactivity of RCCD1-AS1. CONCLUSION: We identified a novel PDAC risk locus which modulates cancer risk by controlling gene expression through DNA methylation.
Subject(s)
Carcinoma, Pancreatic Ductal , Pancreatic Neoplasms , Humans , Genome-Wide Association Study , Pancreatic Neoplasms/genetics , Carcinoma, Pancreatic Ductal/genetics , DNA Methylation/genetics , Pancreatic NeoplasmsABSTRACT
Choledocholithiasis is one of the most common indications for endoscopic retrograde cholangiopancreatography (ERCP) in daily practice. Although the majority of stones are small and can be easily removed in a single endoscopy session, approximately 10-15% of patients have complex biliary stones, requiring additional procedures for an optimum clinical outcome. A plethora of endoscopic methods is available for the removal of difficult biliary stones, including papillary large balloon dilation, mechanical lithotripsy, and electrohydraulic and laser lithotripsy. In-depth knowledge of these techniques and the emerging literature on them is required to yield the most optimal therapeutic effects. This narrative review aims to describe the definition of difficult bile duct stones based on certain characteristics and streamline their endoscopic retrieval using various modalities to achieve higher clearance rates.
Subject(s)
Choledocholithiasis , Gallstones , Humans , Treatment Outcome , Cholangiopancreatography, Endoscopic Retrograde/methods , Gallstones/surgery , Catheterization/methods , Choledocholithiasis/surgeryABSTRACT
Coding sequence variants comprise a small fraction of the germline genetic variability of the human genome. However, they often cause deleterious change in protein function and are therefore associated with pathogenic phenotypes. To identify novel pancreatic ductal adenocarcinoma (PDAC) risk loci, we carried out a complete scan of all common missense and synonymous SNPs and analysed them in a case-control study comprising four different populations, for a total of 14 538 PDAC cases and 190 657 controls. We observed a statistically significant association between 13q12.2-rs9581957-T and PDAC risk (Pâ =â 2.46â ×â 10-9), that is in linkage disequilibrium (LD) with a deleterious missense variant (rs9579139) of the URAD gene. Recent findings suggest that this gene is active in peroxisomes. Considering that peroxisomes have a key role as molecular scavengers, especially in eliminating reactive oxygen species, a malfunctioning URAD protein might expose the cell to a higher load of potentially DNA damaging molecules and therefore increase PDAC risk. The association was observed in individuals of European and Asian ethnicity. We also observed the association of the missense variant 15q24.1-rs2277598-T, that belongs to BBS4 gene, with increased PDAC risk (Pâ =â 1.53â ×â 10-6). rs2277598 is associated with body mass index and is in LD with diabetes susceptibility loci. In conclusion, we identified two missense variants associated with the risk of developing PDAC independently from the ethnicity highlighting the importance of conducting reanalysis of genome-wide association studies (GWASs) in light of functional data.
Subject(s)
Carcinoma, Pancreatic Ductal , Pancreatic Neoplasms , Humans , Case-Control Studies , Genome, Human , Genome-Wide Association Study , Genetic Predisposition to Disease , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/pathology , Carcinoma, Pancreatic Ductal/genetics , DNA , Polymorphism, Single Nucleotide/geneticsABSTRACT
Genes carrying high-penetrance germline mutations may also be associated with cancer susceptibility through common low-penetrance genetic variants. To increase the knowledge on genetic pancreatic ductal adenocarcinoma (PDAC) aetiology, the common genetic variability of PDAC familial genes was analysed in our study. We conducted a multiphase study analysing 7745 single nucleotide polymorphisms (SNPs) from 29 genes reported to harbour a high-penetrance PDAC-associated mutation in at least one published study. To assess the effect of the SNPs on PDAC risk, a total of 14 666 PDAC cases and 221 897 controls across five different studies were analysed. The T allele of the rs1412832 polymorphism, that is situated in the CDKN2B-AS1/ANRIL, showed a genome-wide significant association with increased risk of developing PDAC (OR = 1.11, 95% CI = 1.07-1.15, P = 5.25 × 10-9 ). CDKN2B-AS1/ANRIL is a long noncoding RNA, situated in 9p21.3, and regulates many target genes, among which CDKN2A (p16) that frequently shows deleterious somatic and germline mutations and deregulation in PDAC. Our results strongly support the role of the genetic variability of the 9p21.3 region in PDAC aetiopathogenesis and highlight the importance of secondary analysis as a tool for discovering new risk loci in complex human diseases.
Subject(s)
Carcinoma, Pancreatic Ductal , Pancreatic Neoplasms , RNA, Long Noncoding , Humans , Carcinoma, Pancreatic Ductal/genetics , Genetic Predisposition to Disease , Pancreatic Neoplasms/genetics , Polymorphism, Single Nucleotide , RNA, Long Noncoding/genetics , Pancreatic NeoplasmsABSTRACT
BACKGROUND & AIMS: The aims of this study were to: (1) assess the performance of the Pancreatitis Activity Scoring System (PASS) in a large intercontinental cohort of patients with acute pancreatitis (AP); and (2) investigate whether a modified PASS (mPASS) yields a similar predictive accuracy and produces distinct early trajectories between severity subgroups. METHODS: Data was prospectively collected through the Acute Pancreatitis Patient Registry to Examine Novel Therapies In Clinical Experience (APPRENTICE) consortium (2015-2018) involving 22 centers from 4 continents. AP severity was categorized per the revised Atlanta classification. PASS trajectories were compared between the three severity groups using the generalized estimating equations model. Four mPASS models were generated by modifying the morphine equivalent dose (MED), and their trajectories were compared. RESULTS: A total of 1393 subjects were enrolled (median age, 49 years; 51% males). The study cohort included 950 mild (68.2%), 315 (22.6%) moderately severe, and 128 (9.2%) severe AP. Mild cases had the lowest PASS at each study time point (all P < .001). A subset of patients with outlier admission PASS values was identified. In the outlier group, 70% of the PASS variation was attributed to the MED, and 66% of these patients were from the United States centers. Among the 4 modified models, the mPASS-1 (excluding MED from PASS) demonstrated high performance in predicting severe AP with an area under the receiver operating characteristic curve of 0.88 (vs area under the receiver operating characteristic of 0.83 in conventional PASS) and produced distinct trajectories with distinct slopes between severity subgroups (all P < .001). CONCLUSION: We propose a modified model by removing the MED component, which is easier to calculate, predicts accurately severe AP, and maintains significantly distinct early trajectories.
Subject(s)
Pancreatitis , Acute Disease , Cohort Studies , Female , Humans , Male , Middle Aged , Pancreatitis/diagnosis , ROC Curve , Severity of Illness IndexABSTRACT
BACKGROUND/OBJECTIVES: Within the last two decades, an increased incidence of acute pancreatitis (AP) has been reported in childhood, with some progressing to acute recurrent pancreatitis (ARP) or chronic pancreatitis (CP). Training future pancreatologists is critical to improve the care of children with pancreatic diseases. There are no studies to assess whether the pediatric gastroenterology (GI) fellowship curriculum prepares specialists to care for children with pancreatic diseases. METHODS: An electronic survey was distributed to all North American Pediatric Gastroenterology Fellows. The survey included 31 questions on pancreatology training including academic resources, research experience, clinical exposure, clinical confidence, and career plans. RESULTS: A total of 112 (25.8%) fellows responded from 41 (41/72, 56.9%) training centers in North America. Pancreas-specific didactic lectures were reported by 90.2% (n = 101); 49.5% (50/101) had at least quarterly or monthly lectures. Clinical confidence (Likert 4-5) was highest in managing and treating AP (94.6% and 93.8% respectively), relatively lower for ARP (84.8% and 71.4%) and lowest for CP (63.4% and 42.0%). Confidence in diagnosing both ARP and CP was associated with the variety of pancreatic diseases seen (p < 0.001) and total number of patients followed over a 6 month period (p = 0.04). Nine (8%) reported interest in specializing in pancreatology, 12 (10.7%) in pursuing research in the pancreatology. CONCLUSIONS: Trainee confidence is highest in managing AP, lowest in CP, and seems to be directly correlated with the variety of pancreatic diseases and number of patients followed. Continued commitment is necessary to foster training of the next generation of pediatric pancreatologists.
Subject(s)
Fellowships and Scholarships , Gastroenterology/education , Pediatrics/education , Child , Clinical Competence , Humans , North America , Pancreatic Diseases/diagnosis , Pancreatic Diseases/therapy , Surveys and QuestionnairesABSTRACT
BACKGROUND/OBJECTIVES: The relationship between pre-existing diabetes mellitus (DM) and acute pancreatitis (AP) severity has not been established. We assessed the impact of pre-existing DM on AP severity in an international, prospectively ascertained registry. METHODS: APPRENTICE registry prospectively enrolled 1543 AP patients from 22 centers across 4 continents (8 US, 6 Europe, 5 Latin America, 3 India) between 2015 and 2018, and collected detailed clinical information. Pre-existing DM was defined a diagnosis of DM prior to AP admission. The primary outcome was AP severity defined by the Revised Atlanta Classification (RAC). Secondary outcomes were development of systemic inflammatory response syndrome (SIRS) or intensive care unit (ICU) admission. RESULTS: Pre-existing DM was present in 270 (17.5%) AP patients, of whom 252 (93.3%) had type 2 DM. Patients with pre-existing DM were significantly (p < 0.05) older (55.8 ± 16 vs. 48.3 ± 18.7 years), more likely to be overweight (BMI 29.5 ± 7 vs. 27.2 ± 6.2), have hypertriglyceridemia as the etiology (15% vs. 2%) and prior AP (33 vs. 24%). Mild, moderate, and severe AP were noted in 66%, 23%, and 11% of patients, respectively. On multivariable analysis, pre-existing DM did not significantly impact AP severity assessed by the RAC (moderate-severe vs. mild AP, OR = 0.86, 95% CI 0.63-1.18; severe vs. mild-moderate AP, OR = 1.05, 95% CI, 0.67-1.63), development of SIRS, or the need for ICU admission. No interaction was noted between DM status and continent. CONCLUSION: About one in 5 patients with AP have pre-existing DM. Once confounding risk factors are considered, pre-existing DM per se is not a risk factor for severe AP.
Subject(s)
Diabetes Mellitus, Type 2/epidemiology , Pancreatitis/epidemiology , Acute Disease , Adult , Aged , Diabetes Mellitus, Type 2/complications , Female , Hospitalization , Humans , Male , Middle Aged , Pancreatitis/complications , Prevalence , Registries , Retrospective Studies , Severity of Illness Index , Systemic Inflammatory Response Syndrome/epidemiologyABSTRACT
INTRODUCTION: Telomere length (TL) is a potential indicator of cancer predisposition; however, the multitude of techniques used to measure it causes the results to be heterogeneous and, in some cases, controversial. In the last years, several studies adopted a strategy based on TL-associated genetic variants to generate a polygenic score, often referred as teloscore, used in lieu of direct TL measurement. For pancreatic neuroendocrine neoplasms (PanNEN), this strategy has not been attempted yet. METHODS: A teloscore was generated using 11 SNPs (NAF1-rs7675998, ZNF676-rs409627, TERC-rs10936599, CTC1-rs3027234, PXK-rs6772228, DHX35-rs6028466, OBFC1-rs9420907, ZNF208-rs8105767, ACYP2-rs11125529, TERT-rs2736100, and ZBTB46-rs755017), and 291 PanNEN cases and 1,686 controls collected by the PANcreatic Disease ReseArch (PANDoRA) consortium were genotyped to analyse the association of the teloscore and its individual SNPs with the risk of developing PanNEN. RESULTS: An association between genetically determined long telomeres and the risk of developing PanNEN (OR = 1.99, CI: 1.33-2.98, p = 0.0008) for highest versus median (third) quintile was observed. In addition, two novel SNPs associated with PanNEN risk were identified: ZNF676-rs409627 (ORC/C_vs_G/G = 2.27, CI: 1.58-3.27, p = 8.80 × 10-6) and TERT-rs2736100 (ORC/A_vs_C/C = 2.03, CI: 1.42-2.91, p = 1.06 × 10-4). CONCLUSION: In conclusion, this study provides for the first time a clear indication of the association between long genetically determined telomeres and increased risk of developing PanNEN.
Subject(s)
Neoplasms , Pancreatic Neoplasms , Humans , Genome-Wide Association Study , Case-Control Studies , Telomere/genetics , Polymorphism, Single Nucleotide/genetics , Pancreatic Neoplasms/genetics , Acid Anhydride Hydrolases/geneticsABSTRACT
BACKGROUND: Most cases of pancreatic ductal adenocarcinoma (PDAC) are asymptomatic in early stages, and the disease is typically diagnosed in advanced phases, resulting in very high mortality. Tools to identify individuals at high risk of developing PDAC would be useful to improve chances of early detection. OBJECTIVE: We generated a polygenic risk score (PRS) for PDAC risk prediction, combining the effect of known risk SNPs, and carried out an exploratory analysis of a multifactorial score. METHODS: We tested the associations of the individual known risk SNPs on up to 2851 PDAC cases and 4810 controls of European origin from the PANcreatic Disease ReseArch (PANDoRA) consortium. Thirty risk SNPs were included in a PRS, which was computed on the subset of subjects that had 100% call rate, consisting of 839 cases and 2040 controls in PANDoRA and 6420 cases and 4889 controls from the previously published Pancreatic Cancer Cohort Consortium I-III and Pancreatic Cancer Case-Control Consortium genome-wide association studies. Additional exploratory multifactorial scores were constructed by complementing the genetic score with smoking and diabetes. RESULTS: The scores were associated with increased PDAC risk and reached high statistical significance (OR=2.70, 95% CI 1.99 to 3.68, p=2.54×10-10 highest vs lowest quintile of the weighted PRS, and OR=14.37, 95% CI 5.57 to 37.09, p=3.64×10-8, highest vs lowest quintile of the weighted multifactorial score). CONCLUSION: We found a highly significant association between a PRS and PDAC risk, which explains more than individual SNPs and is a step forward in the direction of the construction of a tool for risk stratification in the population.
Subject(s)
Multifactorial Inheritance , ABO Blood-Group System/genetics , Alleles , Carcinoma, Pancreatic Ductal/diagnosis , Carcinoma, Pancreatic Ductal/genetics , Early Detection of Cancer , Female , Gene Frequency , Humans , Male , Pancreatic Neoplasms/genetics , Polymorphism, Single Nucleotide , Risk AssessmentABSTRACT
Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal cancers. Its poor prognosis is predominantly due to the fact that most patients remain asymptomatic until the disease reaches an advanced stage, alongside the lack of early markers and screening strategies. A better understanding of PDAC risk factors is essential for the identification of groups at high risk in the population. Genome-wide association studies (GWAS) have been a powerful tool for detecting genetic variants associated with complex traits, including pancreatic cancer. By exploiting functional and GWAS data, we investigated the associations between polymorphisms affecting gene function in the pancreas (expression quantitative trait loci, eQTLs) and PDAC risk. In a two-phase approach, we analysed 13 713 PDAC cases and 43 784 controls and identified a genome-wide significant association between the A allele of the rs2035875 polymorphism and increased PDAC risk (P = 7.14 × 10-10). This allele is known to be associated with increased expression in the pancreas of the keratin genes KRT8 and KRT18, whose increased levels have been reported to correlate with various tumour cell characteristics. Additionally, the A allele of the rs789744 variant was associated with decreased risk of developing PDAC (P = 3.56 × 10-6). This single nucleotide polymorphism is situated in the SRGAP1 gene and the A allele is associated with higher expression of the gene, which in turn inactivates the cyclin-dependent protein 42 (CDC42) gene expression, thus decreasing the risk of PDAC. In conclusion, we present here a functional-based novel PDAC risk locus and an additional strong candidate supported by significant associations and plausible biological mechanisms.
Subject(s)
Carcinoma, Pancreatic Ductal/genetics , Genetic Predisposition to Disease , Genome-Wide Association Study , Pancreatic Neoplasms/genetics , Quantitative Trait Loci , Aged , Alleles , Case-Control Studies , Female , GTPase-Activating Proteins/genetics , Humans , Male , Middle Aged , Polymorphism, Single NucleotideABSTRACT
Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second cancer-related cause of death by 2030. Identifying novel risk factors, including genetic risk loci, could be instrumental in risk stratification and implementation of prevention strategies. Long noncoding RNAs (lncRNAs) are involved in regulation of key biological processes, and the possible role of their genetic variability has been unexplored so far. Combining genome wide association studies and functional data, we investigated the genetic variability in all lncRNAs. We analyzed 9893 PDAC cases and 9969 controls and identified a genome-wide significant association between the rs7046076 SNP and risk of developing PDAC (P = 9.73 × 10-9 ). This SNP is located in the NONHSAG053086.2 (lnc-SMC2-1) gene and the risk allele is predicted to disrupt the binding of the lncRNA with the micro-RNA (miRNA) hsa-mir-1256 that regulates several genes involved in cell cycle, such as CDKN2B. The CDKN2B region is pleiotropic and its genetic variants have been associated with several human diseases, possibly though an imperfect interaction between lncRNA and miRNA. We present a novel PDAC risk locus, supported by a genome-wide statistical significance and a plausible biological mechanism.
Subject(s)
Carcinoma, Pancreatic Ductal/genetics , Cyclin-Dependent Kinase Inhibitor p15/genetics , MicroRNAs/genetics , Pancreatic Neoplasms/genetics , Polymorphism, Single Nucleotide , RNA, Long Noncoding/genetics , Aged , Case-Control Studies , Computational Biology/methods , Female , Genetic Predisposition to Disease , Genome-Wide Association Study , Humans , Male , Middle AgedABSTRACT
GOALS: The present survey from the Italian Society of Digestive Endoscopy (SIED-Società Italiana di Endoscopia Digestiva) was aimed at reporting infection control practice and outcomes at Digestive Endoscopy Units in a high-incidence area. BACKGROUND: Lombardy was the Italian region with the highest coronavirus disease-2019 (COVID-19) prevalence, at the end of March 2020 accounting for 20% of all worldwide deaths. Joint Gastro-Intestinal societies released recommendations for Endoscopy Units to reduce the risk of the contagion. However, there are few data from high-prevalence areas on adherence to these recommendations and on their efficacy. METHODS: A survey was designed by the Lombardy section of SIED to analyze (a) changes in activity and organization, (b) adherence to recommendations, (c) rate of health care professionals' (HCP) infection during the COVID-19 outbreak. RESULTS: In total, 35/61 invited centers (57.4%) participated; most modified activities were according to recommendations and had filtering face piece 2/filtering face piece 3 and water-repellent gowns available, but few had negative-pressure rooms or provided telephonic follow-up; 15% of HCPs called in sick and 6% had confirmed COVID-19. There was a trend (P=0.07) toward different confirmed COVID-19 rates among endoscopists (7.9%), nurses (6.6%), intermediate-care technicians (3.4%), and administrative personnel (2.2%). There was no correlation between the rate of sick HCPs and COVID-19 incidence in the provinces and personal protective equipment availability and use, whereas an inverse correlation with hospital volume was found. CONCLUSIONS: Adherence to recommendations was rather good, though a minority were able to follow all recommendations. Confirmed COVID-19 seemed higher among endoscopists and nurses, suggesting that activities in the endoscopy rooms are at considerable viral spread risk.
Subject(s)
COVID-19 , Endoscopy, Gastrointestinal , Humans , Infection Control , Italy/epidemiology , SARS-CoV-2ABSTRACT
BACKGROUND: Hypertriglyceridemia (HTG) is considered within the top 5 etiologies in acute pancreatitis (AP), but the association of serum triglyceride (TG) levels with the clinical course of AP remains controversial. OBJECTIVES: This study aims to examine the effect of TG levels on severity of AP. METHODS: Patients were enrolled prospectively through APPRENTICE. High TG levels were defined based on the Endocrine Society Clinical Practice Guidelines. HTG was categorized as mild (serum TG levels 150-199 mg/dL), moderate (200-999 mg/dL), severe (1,000-1,999 mg/dL), and very severe (≥2,000 mg/dL). Severity of AP was based on the revised Atlanta classification criteria. RESULTS: Early TG levels were measured in 764 subjects and found elevated in 342 (120 with mild; 176, moderate; and 46, severe/very severe HTG). Patients with increased TG levels were younger (age ≥60, 16.7 vs. 30.3%), more likely to be male (66.1 vs. 51.2%), with more frequent alcohol use (62.8 vs. 50.7%), and diabetes mellitus (30.2 vs. 12.3%; all p ≤ 0.005). Severe AP (24.9 vs. 10.0%), ICU admission (32.5 vs. 19.7%), and mortality (5.3 vs. 1.7%; all p ≤ 0.005) were more frequently seen in patients with elevated TG levels. Based on multivariable analysis, elevated TG levels were independently associated with severe AP (p < 0.05). CONCLUSION: This large multicenter study confirms that elevated TG levels are associated with severe disease regardless of AP etiology.