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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., (© 2024 UICC.)

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers with patients having unresectable or metastatic disease at diagnosis, with poor prognosis and very short survival. Given that genetic variation within autophagy-related genes influences autophagic flux and susceptibility to solid cancers, we decided to investigate whether 55,583 single nucleotide polymorphisms (SNPs) within 234 autophagy-related genes could influence the risk of developing PDAC in three large independent cohorts of European ancestry including 12,754 PDAC cases and 324,926 controls. The meta-analysis of these populations identified, for the first time, the association of the BID rs9604789 variant with an increased risk of developing the disease (OR Meta  = 1.31, p = 9.67 × 10 -6 ). We also confirmed the association of TP63 rs1515496 and TP63 rs35389543 variants with PDAC risk (OR = 0.89, p = 6.27 × 10 -8 and OR = 1.16, p = 2.74 × 10 -5 ). Although it is known that BID induces autophagy and TP63 promotes cell growth, cell motility and invasion, we also found that carriers of the TP63 rs1515496G allele had increased numbers of FOXP3+ Helios+ T regulatory cells and CD45RA+ T regulatory cells (p = 7.67 × 10 -4 and p = 1.56 × 10 -3 ), but also decreased levels of CD4+ T regulatory cells (p = 7.86 × 10 -4 ). These results were in agreement with research suggesting that the TP63 rs1515496 variant alters binding sites for FOXA1 and CTCF, which are transcription factors involved in modulating specific subsets of regulatory T cells. In conclusion, this study identifies BID as new susceptibility locus for PDAC and confirms previous studies suggesting that the TP63 gene is involved in the development of PDAC. This study also suggests new pathogenic mechanisms of the TP63 locus in PDAC., (© 2024 The Author(s). International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Pleiotropic variants (i.e., genetic polymorphisms influencing more than one phenotype) are often associated with cancer risk. A scan of pleiotropic variants was successfully conducted ten years ago in relation to pancreatic ductal adenocarcinoma susceptibility. However, in the last decade, genetic association studies performed on several human traits have greatly increased the number of known pleiotropic variants. Based on the hypothesis that variants already associated with a least one trait have a higher probability of association with other traits, 61,052 variants reported to be associated by at least one genome wide association study (GWAS) with at least one human trait were tested in the present study consisting of two phases (discovery and validation), comprising a total of 16,055 pancreatic ductal adenocarcinoma (PDAC) cases and 212,149 controls. The meta-analysis of the two phases showed two loci (10q21.1-rs4948550 (P=6.52×10-5) and 7q36.3-rs288762 (P=3.03×10-5) potentially associated with PDAC risk. 10q21.1-rs4948550 shows a high degree of pleiotropy and it is also associated with colorectal cancer risk while 7q36.3-rs288762 is situated 28,558 base pairs upstream of the Sonic Hedgehog (SHH) gene, which is involved in the cell differentiation process and PDAC etiopathogenesis. In conclusion, none of the single nucleotide polymorphisms (SNPs) showed a formally statistically significant association after correction for multiple testing. However, given their pleiotropic nature and association with various human traits including colorectal cancer, the two SNPs showing the best associations with PDAC risk merit further investigation through fine mapping and ad hoc functional studies., (© The Author(s) 2024. Published by Oxford University Press on behalf of the UK Environmental Mutagen Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

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., (Copyright © 2023 by The American College of Gastroenterology.)

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., (© 2024. The Author(s).)

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 (P = 2.46 × 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 (P = 1.53 × 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., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Pancreatic cystic lesions are often asymptomatic, incidentally detected and include a range of entities with varying degrees of concern for malignancy. Among these, intraductal papillary mucinous neoplasms (IPMN) are considered premalignant pancreatic lesions, with a broad pathological spectrum ranging from lesions without dysplasia, which can be managed conservatively, to malignant lesions that require surgical resection. The increasing use of CT and MRI has led to increased recognition of this entity incidentally, with branch-duct IPMN representing the most common subtype and the most challenging lesions in terms of patient management. The main imaging modality involved in diagnosis and surveillance of IPMN is MRI. Radiologists play an important role in the management of patients with IPMN, including lesion detection, characterization, follow-up and prognostication, allowing early MRI identification of features that are concerning for malignancy. The main aim of this pictorial review is to illustrate MRI features of IPMN and to discuss risk stratification scores based on different guidelines, with a main focus on branch-duct IPMN. The secondary aims include the presentation of common and uncommon imaging evolution of BD-IPMN as well as the discussion on current controversies on the appropriate management of IPMN., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors. Published by Elsevier Ltd.)

(1) Background: Patients with pancreatic Neuroendocrine Neoplasms (PanNENs) often have a long overall survival. We evaluated determinants of quality of life (QoL) after surgery for PanNENs. (2) Methods: Patients operated on for a PanNEN in our center (1990-2021) received three EORTC QoL questionnaires (QLQ-C30, QLQ-GI.NET21, QLQ-PAN26). Six domains were selected as outcome variables (global QoL, physical function -PF, social function -SF, disease-related worries -DRWs, pain, upper-gastrointestinal (GI) symptoms) and evaluated in relation to the clinical variables. Statistical analysis was performed using R software v 4.2.2. (3) Results: One hundred and four patients enrolled showed a good global QoL (median 83.3). Old age was a determinant of worse global QoL ( p 0.006) and worse PF ( p 0.003). Multiple comorbidities ( p 0.002) and old age ( p 0.034) were associated with pain, while male gender was related to better PF ( p 0.007) and less pain ( p 0.012). Patients who had undergone parenchyma-sparing surgery demonstrated better PF ( p 0.037), better SF ( p 0.012), and less upper-GI symptoms ( p 0.047). At multivariable analysis, age ( p 0.005) and type of surgery ( p 0.028) were confirmed as determinants of global QoL. (4) Conclusions: In patients operated on for a PanNEN, a good HRQoL is generally reported; notably, younger age and parenchyma-sparing surgery seem to positively affect HRQoL.

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., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Early-onset pancreatic cancer (EOPC) represents 5-10% of all pancreatic ductal adenocarcinoma (PDAC) cases, and the etiology of this form is poorly understood. It is not clear if established PDAC risk factors have the same relevance for younger patients. This study aims to identify genetic and non-genetic risk factors specific to EOPC., Methods: A genome-wide association study was performed, analysing 912 EOPC cases and 10 222 controls, divided into discovery and replication phases. Furthermore, the associations between a polygenic risk score (PRS), smoking, alcohol consumption, type 2 diabetes and PDAC risk were also assessed., Results: Six novel SNPs were associated with EOPC risk in the discovery phase, but not in the replication phase. The PRS, smoking, and diabetes affected EOPC risk. The OR comparing current smokers to never-smokers was 2.92 (95% CI 1.69-5.04, P = 1.44 × 10 -4 ). For diabetes, the corresponding OR was 14.95 (95% CI 3.41-65.50, P = 3.58 × 10 -4 )., Conclusion: In conclusion, we did not identify novel genetic variants associated specifically with EOPC, and we found that established PDAC risk variants do not have a strong age-dependent effect. Furthermore, we add to the evidence pointing to the role of smoking and diabetes in EOPC., Competing Interests: Conflict of interest M.F.B. has received research funding from Celgene and Lead Pharma and acted as a consultant to Servier. H.W.M.L. reports research funding and/or medication supply from Bristol-Myers Squibb, Bayer Schering Pharma, Celgene, Janssen-Cilag, Lilly, Nordic Pharma, Philips Healthcare, Roche, Merck Sharp and Dohme, Servier, Incyte; and consultant/advisory board member for Lilly, Nordic Pharma, Bristol-Myers Squibb, Dragonfly, Merck Sharp and Dohme, Servier, all outside the submitted work. The other authors do not have any conflict of interest to declare., (Copyright © 2023 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background: The genomes of present-day non-Africans are composed of 1-3% of Neandertal-derived DNA as a consequence of admixture events between Neandertals and anatomically modern humans about 50-60 thousand years ago. Neandertal-introgressed single nucleotide polymorphisms (aSNPs) have been associated with modern human disease-related traits, which are risk factors for pancreatic ductal adenocarcinoma (PDAC), such as obesity, type 2 diabetes, and inflammation. In this study, we aimed at investigating the role of aSNPs in PDAC in three Eurasian populations., Results: The high-coverage Vindija Neandertal genome was used to select aSNPs in non-African populations from 1000 Genomes project phase 3 data. Then, the association between aSNPs and PDAC risk was tested independently in Europeans and East Asians, using existing GWAS data on more than 200 000 individuals. We did not find any significant associations between aSNPs and PDAC in samples of European descent, whereas, in East Asians, we observed that the Chr10p12.1-rs117585753-T allele (MAF = 10%) increased the risk to develop PDAC (OR = 1.35, 95%CI 1.19-1.54, P = 3.59 × 10 -6 ), with a P-value close to a threshold that takes into account multiple testing., Conclusions: Our results show only a minimal contribution of Neandertal SNPs to PDAC risk., (© 2023. Sociedad de Biologia de Chile.)

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., (© 2022 UICC.)

Pancreatic cancer has an incidence that almost matches its mortality. Only a small number of risk factors and 33 susceptibility loci have been identified. so Moreover, the relative rarity of pancreatic cancer poses significant hurdles for research aimed at increasing our knowledge of the genetic mechanisms contributing to the disease. Additionally, the inability to adequately power research questions prevents small monocentric studies from being successful. Several consortia have been established to pursue a better understanding of the genetic architecture of pancreatic cancers. The Pancreatic disease research (PANDoRA) consortium is the largest in Europe. PANDoRA is spread across 12 European countries, Brazil and Japan, bringing together 29 basic and clinical research groups. In the last ten years, PANDoRA has contributed to the discovery of 25 susceptibility loci, a feat that will be instrumental in stratifying the population by risk and optimizing preventive strategies., Competing Interests: Declaration of Competing Interest MFB has received research funding from Celgene, Frame Therapeutics, and Lead Pharma, and has acted as a consultant to Servier., (Copyright © 2023. Published by Elsevier B.V.)

Background: Pancreatic neuroendocrine neoplasms (pNENs) are often detected as large primary lesions, even with distant metastases, and their prognosis may be difficult to predict., Methods: In this retrospective study, we retrieved data of patients treated for a large pNEN in our Surgical Unit (1979-2017) to evaluate the possible prognostic role of clinic-pathological features and surgery. Cox-proportional hazard regression models were used to find possible associations among some variables (clinical features, surgery, and histology) and survival at univariate and multivariate analyses., Results: Among 333 pNENs, we identified 64 patients (19%) with a lesion > 4 cm. Patients' median age was 61 years, median tumor size was 6.0 cm, and 35 (55%) patients had distant metastases at diagnosis. There were 50 (78%) nonfunctioning pNENs, and 31 tumors localized in the body/tail region of the pancreas. Overall, 36 patients underwent a standard pancreatic resection (with 13 associated liver resection/ablation). Regarding histology, 67% of pNENs were N1, and 34% were grade 2. After a median follow-up of 48 months (up to 33 years), 42 patients died of disease. Median survival after surgery was 79 months, and six patients experienced recurrence (median DFS 94 months). At multivariate analysis, distant metastases were associated with a worse outcome, while having undergone radical tumor resection was a protective factor., Conclusions: In our experience, about 20% of pNENs have a size > 4 cm, 78% are nonfunctioning, and 55% show distant metastases at diagnosis. Nevertheless, a long-term survival of more than five years may be achieved after surgery.

Background: Despite the important advances in research on neuroendocrine neoplasms of the gastro-entero-pancreatic tract, their precursor lesions are much less well known., Summary: This review analyzes the preneoplastic neuroendocrine lesions of the gastro-entero-pancreatic tract, by adopting a coherent anatomical benchmark. In particular, the settings in which neuroendocrine precursor lesions represent well-recognized pathophysiological and morphological entities (with eventual molecular correlates) have been distinguished from the ones in which the nature of preneoplastic changes is still obscure., Key Messages: The aim of the paper was to summarize what is known about precursor lesions of gastro-entero-pancreatic neuroendocrine tumors, with the goal of providing a useful tool for future research aimed at obtaining a fuller understanding of the underlying biology and early development of these diseases., (© 2022 S. Karger AG, Basel.)

The incidence of pancreatic ductal adenocarcinoma (PDAC) is different among males and females. This disparity cannot be fully explained by the difference in terms of exposure to known risk factors; therefore, the lower incidence in women could be attributed to sex-specific hormones. A two-phase association study was conducted in 12,387 female subjects (5436 PDAC cases and 6951 controls) to assess the effect on risk of developing PDAC of single nucleotide polymorphisms (SNPs) in 208 genes involved in oestrogen and pregnenolone biosynthesis and oestrogen-mediated signalling. In the discovery phase 14 polymorphisms showed a statistically significant association (P < 0.05). In the replication none of the findings were validated. In addition, a gene-based analysis was performed on the 208 selected genes. Four genes (NR5A2, MED1, NCOA2 and RUNX1) were associated with PDAC risk, but only NR5A2 showed an association (P = 4.08 × 10 -5 ) below the Bonferroni-corrected threshold of statistical significance. In conclusion, despite differences in incidence between males and females, our study did not identify an effect of common polymorphisms in the oestrogen and pregnenolone pathways in relation to PDAC susceptibility. However, we validated the previously reported association between NR5A2 gene variants and PDAC risk., (© 2022. The Author(s).)

Neuroendocrine neoplasms (NENs) of the major and minor ampulla are rare diseases with clinico-pathologic features distinct from non-ampullary-duodenal NENs. However, they have been often combined and the knowledge on prognostic factors specific to ampullary NENs (Amp-NENs) is limited. The aim of this study was to identify factors associated with metastatic potential and patient prognosis in Amp-NENs. We clinically and histologically investigated an international series of 119 Amp-NENs, comprising 93 ampullary neuroendocrine tumors (Amp-NETs) and 26 neuroendocrine carcinomas (Amp-NECs). Somatostatin-producing tubulo-acinar NET represented the predominant Amp-NET histologic subtype (58 cases, 62%, 12 associated with type 1 neurofibromatosis). Compared to Amp-NETs, Amp-NECs arose in significantly older patients and showed a larger tumor size, a more frequent small vessel invasion, a deeper level of invasion and a higher rate of distant metastasis, and, importantly, a tremendously worse disease-specific patient survival. In Amp-NETs, the WHO grade proved to be a strong predictor of disease-specific survival (hazard ratio: 12.61, p < 0.001 for G2 vs G1), as well as patient age at diagnosis > 60 years, small vessel invasion, pancreatic invasion, and distant metastasis at diagnosis. Although nodal metastatic disease was not associated with survival by itself, patients with > 3 metastatic lymph nodes showed a worse outcome in comparison with the remaining Amp-NET cases with lymphadenectomy. Tumor epicenter in the major ampulla, small vessel invasion, and tumor size > 16 mm were independent predictors of nodal metastases in Amp-NETs. In conclusion, we identified prognostic factors, which may eventually help guide treatment decisions in Amp-NENs., (© 2022. The Author(s).)

Background: Duodenal gastric metaplasia (DGM) is considered a precancerous lesion. No data are available regarding its possible role as a risk factor for duodenal neuroendocrine neoplasms (dNENs)., Aims: To assess the prevalence of DGM in a cohort of dNENs., Methods: Subgroup analysis of a retrospective study including dNEN patients who underwent surgical resection between 2000 and 2019 and were observed at eight Italian tertiary referral centers., Results: 109 dNEN patients were evaluated. Signs of DGM associated with the presence of dNEN were reported in 14 patients (12.8%). Among these patients, nine (64.4%) had a dNEN of the superior part of the duodenum, one (7.1%) a periampullary lesion, three (21.4%) a dNEN located in the second portion of the duodenum, with a different localization distribution compared to patients without DGM ( p = 0.0332). Ten were G1, three G2, and in one patient the Ki67 was not available. In the group with DGM, six patients (35.7%) were classified at stage I, five (28.6%) at stage II, three (21.4%) at stage III, and no one at stage IV. In the group without DGM, 20 patients (31%) were at stage I, 15 (15%) at stage II, 42 (44%) at stage III, and 19 (20%) at stage IV ( p = 0.0236). At the end of the study, three patients died because of disease progression., Conclusions: our findings might suggest that DGM could represent a feature associated with the occurrence of dNEN, especially for forms of the superior part of the duodenum, which should be kept in mind in the endoscopic follow up of patients with DGM. Interestingly, dNEN inside DGM showed a more favorable staging, with no patients in stage IV. The actual relationship and the clinical relevance of this possible association require further clarification.

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&#95;vs&#95;G/G = 2.27, CI: 1.58-3.27, p = 8.80 × 10-6) and TERT-rs2736100 (ORC/A&#95;vs&#95;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., (© 2022 S. Karger AG, Basel.)

Although 21 pancreatic cancer susceptibility loci have been identified in individuals of European ancestry through genome-wide association studies (GWASs), much of the heritability of pancreatic cancer risk remains unidentified. A recessive genetic model could be a powerful tool for identifying additional risk variants. To discover recessively inherited pancreatic cancer risk loci, we performed a re-analysis of the largest pancreatic cancer GWAS, the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4), including 8,769 cases and 7,055 controls of European ancestry. Six single nucleotide polymorphisms (SNPs) showed associations with pancreatic cancer risk according to a recessive model of inheritance. We replicated these variants in 3,212 cases and 3,470 controls collected from the PANcreatic Disease ReseArch (PANDoRA) consortium. The results of the meta-analyses confirmed that rs4626538 (7q32.2), rs7008921 (8p23.2) and rs147904962 (17q21.31) showed specific recessive effects (p<10 -5 ) compared with the additive effects (p>10 -3 ), although none of the six SNPs reached the conventional threshold for genome-wide significance (p < 5×10 -8 ). Additional bioinformatic analysis explored the functional annotations of the SNPs and indicated a possible relationship between rs36018702 and expression of the BCL2L11 and BUB1 genes, which are known to be involved in pancreatic biology. Our findings, while not conclusive, indicate the importance of considering non-additive genetic models when performing GWAS analysis. The SNPs associated with pancreatic cancer in this study could be used for further meta-analysis for recessive association of SNPs and pancreatic cancer risk and might be a useful addiction to improve the performance of polygenic risk scores., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Lu, Gentiluomo, Macauda, Gioffreda, Gazouli, Petrone, Kelemen, Ginocchi, Morelli, Papiris, Greenhalf, Izbicki, Kiudelis, Mohelníková-Duchoňová, Bueno-de-Mesquita, Vodicka, Brenner, Diener, Pezzilli, Ivanauskas, Salvia, Szentesi, Aoki, Németh, Sperti, Jamroziak, Chammas, Oliverius, Archibugi, Ermini, Novák, Kupcinskas, Strouhal, Souček, Cavestro, Milanetto, Vanella, Neoptolemos, Theodoropoulos, van Laarhoven, Mambrini, Moz, Kala, Loveček, Basso, Uzunoglu, Hackert, Testoni, Hlaváč, Andriulli, Lucchesi, Tavano, Carrara, Hegyi, Arcidiacono, Busch, Lawlor, Puzzono, Boggi, Guo, Małecka-Panas, Capurso, Landi, Talar-Wojnarowska, Strobel, Gao, Vashist, Campa and Canzian.)

Background: The mitochondrial metabolism has been associated with pancreatic ductal adenocarcinoma (PDAC) risk. Recent evidence also suggests the involvement of the genetic variability of the mitochondrial function in several traits involved in PDAC etiology. However, a systematic investigation of the genetic variability of mitochondrial genome (mtSNP) and of all the nuclear genes involved in its functioning (n-mtSNPs) has never been reported., Methods: We conducted a two-phase association study of mtSNPs and n-mtSNPs to assess their effect on PDAC risk. We analyzed 35,297 n-mtSNPs and 101 mtSNPs in up to 55,870 individuals (12,884 PDAC cases and 42,986 controls). In addition, we also conducted a gene-based analysis on 1,588 genes involved in mitochondrial metabolism using Multi-marker Analysis of GenoMic Annotation (MAGMA) software., Results: In the discovery phase, we identified 49 n-mtSNPs and no mtSNPs associated with PDAC risk ( P < 0.05). In the second phase, none of the findings were replicated. In the gene-level analysis, we observed that three genes ( TERT , SUGCT , and SURF1 ) involved in the mitochondrial metabolism showed an association below the Bonferroni-corrected threshold of statistical significance ( P = 0.05/1588 = 3.1 × 10 -5 )., Conclusions: Even though the mitochondrial metabolism might be involved in PDAC etiology, our results, obtained in a study with one of the largest sample sizes to date, show that neither n-mtSNPs nor mtSNPs are associated with PDAC risk., Impact: This large case-control study does not support a role of the genetic variability of the mitochondrial function in PDAC risk., (©2021 American Association for Cancer Research.)

Purpose: Pretreatment staging is the milestone for planning either surgical or endoscopic treatment in duodenal neuroendocrine neoplasms (dNENs). Herein, a series of surgically treated dNEN patients was evaluated to assess the concordance between the pre- and postsurgical staging., Methods: Retrospective analysis of patients with a histologically confirmed diagnosis of dNENs, who underwent surgical resection observed at eight Italian tertiary referral centers. The presurgical TNM stage, based on the radiological and functional imaging, was compared with the pathological TNM stage, after surgery., Results: From 2000 to 2019, 109 patients were included. Sixty-six patients had G1, 26 a G2, 7 a G3 dNEN (Ki-67 not available in 10 patients). In 46/109 patients (42%) there was disagreement between the pre- and postsurgical staging, being it understaged in 42 patients (38%), overstaged in 4 (3%). As regards understaging, in 25 patients (22.9%), metastatic loco-regional nodes (N) resulted undetected at both radiological and functional imaging. Understaging due to the presence of distal micrometastases (M) was observed in 2 cases (1.8%). Underestimation of tumor extent (T) was observed in 12 patients (11%); in three cases the tumor was understaged both in T and N extent., Conclusions: Conventional imaging has a poor detection rate for loco-regional nodes and micrometastases in the presurgical setting of the dNENs. These results represent important advice when local conservative approaches, such as endoscopy or local surgical excision are considered and it represents a strong recommendation to include endoscopic ultrasound in the preoperative tools for a more accurate local staging., (© 2021. Italian Society of Endocrinology (SIE).)

Genetic factors play an important role in the susceptibility to pancreatic cancer (PC). However, established loci explain a small proportion of genetic heritability for PC; therefore, more progress is needed to find the missing ones. We aimed at identifying single nucleotide polymorphisms (SNPs) affecting PC risk through effects on micro-RNA (miRNA) function. We searched in silico the genome for SNPs in miRNA seed sequences or 3 prime untranslated regions (3'UTRs) of miRNA target genes. Genome-wide association data of PC cases and controls from the Pancreatic Cancer Cohort (PanScan) Consortium and the Pancreatic Cancer Case-Control (PanC4) Consortium were re-analyzed for discovery, and genotyping data from two additional consortia (PanGenEU and PANDoRA) were used for replication, for a total of 14,062 cases and 11,261 controls. None of the SNPs reached genome-wide significance in the meta-analysis, but for three of them the associations were in the same direction in all the study populations and showed lower value of p in the meta-analyses than in the discovery phase. Specifically, rs7985480 was consistently associated with PC risk (OR = 1.12, 95% CI 1.07-1.17, p = 3.03 × 10 -6 in the meta-analysis). This SNP is in linkage disequilibrium (LD) with rs2274048, which modulates binding of various miRNAs to the 3'UTR of UCHL3 , a gene involved in PC progression. In conclusion, our results expand the knowledge of the genetic PC risk through miRNA-related SNPs and show the usefulness of functional prioritization to identify genetic polymorphisms associated with PC risk., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Lu, Corradi, Gentiluomo, López de Maturana, Theodoropoulos, Roth, Maiello, Morelli, Archibugi, Izbicki, Sarlós, Kiudelis, Oliverius, Aoki, Vashist, van Eijck, Gazouli, Talar-Wojnarowska, Mambrini, Pezzilli, Bueno-de-Mesquita, Hegyi, Souček, Neoptolemos, Di Franco, Sperti, Kauffmann, Hlaváč, Uzunoğlu, Ermini, Małecka-Panas, Lucchesi, Vanella, Dijk, Mohelníková-Duchoňová, Bambi, Petrone, Jamroziak, Guo, Kolarova, Capretti, Milanetto, Ginocchi, Loveček, Puzzono, van Laarhoven, Carrara, Ivanauskas, Papiris, Basso, Arcidiacono, Izbéki, Chammas, Vodicka, Hackert, Pasquali, Piredda, Costello-Goldring, Cavestro, Szentesi, Tavano, Włodarczyk, Brenner, Kreivenaite, Gao, Bunduc, Vermeulen, Schneider, Latiano, Gioffreda, Testoni, Kupcinskas, Lawlor, Capurso, Malats, Campa and Canzian.)

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., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Pancreatic solid pseudopapillary neoplasm (pSPN) is a rare exocrine neoplasm, which generally occurs in young women. This study analyses the clinical characteristics of pSPN in male patients through a systematic review of the literature, adding three new cases from our institution. We reviewed our experience in Pspns, and we performed a systematic review of pSPN of all articles published in English in PubMed and SCOPUS from 1980. Using the final included articles, we evaluated clinic-pathological features, surgical treatment and prognosis of male patients affected by pSPN. From the literature review and our cases, we collected 246 male patients with a proven pSPN. Mean age was 34.3 (range 4-78) years, with 26.2% patients younger than 18 years. Patients were asymptomatic in 35.9% of cases, despite a mean tumour size of 6.3 cm. In 63.7% of cases, the pSPN was located in the body-tail region. Distant metastases were reported at diagnosis in only 10 (4.1%) patients. A correct pre-operative diagnosis (including cytopathology) was provided in 53.6% of patients, with only 40 fine-needle aspiration/biopsy performed. Standard pancreatic resections represented 90.4% of surgical procedures. Beta-catenin and progesterone receptors were positive at immunostaining in 100% and 77.8% of cases, respectively. Fourteen (7.2%) patients relapsed after a mean disease-free survival of 43.1 months. After a mean follow-up of 47 (range 4-180) months, 89.5% of patients were alive and disease-free. Although rare, when dealing with a solid-cystic pancreatic mass, even in asymptomatic male patients, a pSPN should be considered as a possible diagnosis., (© 2020. The Author(s).)

Cystic lesions of the pancreas may range from benign to precursors of pancreatic cancer. Simple mucinous cyst (SMC) is larger than 1 cm, has a gastric-type flat mucinous lining, and minimal atypia without ovarian-type stroma. We report a new case of pancreatic SMC, coupling a systematic review of the English literature mainly focused on their clinic-pathological features. We reviewed 103 cases of SMC in adults (73 women), averaging 57 (range, 26-70) years. The SMCs were located in the body-tail region of the pancreas in 60 (58%) cases, presenting as single cystic lesions in 94% of cases; 43% of patients were asymptomatic. A preoperative fine-needle aspiration of the cyst fluid detected amylase and carcinoembryonic antigen positivity in 71% and 76% of cases, respectively. Patients underwent surgery mostly for suspected malignancy; in 83% of cases, a standard pancreatic resection was performed. Mean SMC size was 4.9 (range, 1.5-12.0) cm. Mucins MUC5AC and MUC6 resulted positive in 77% and 81% of cases performed, respectively, whereas MUC2 was negative in all but one patient. The SMC from our institution was characterized by a KRAS somatic mutation. The diagnosis of SMC should be considered when a solitary pancreatic cyst larger than 1 cm is detected in asymptomatic patients. To establish a correct diagnosis, an extensive histologic/immunohistochemical analysis is essential. The presence of a KRAS mutation highlights that SMC may represent another potential pancreatic cancer precursor., (© 2021. The Author(s).)

The knowledge of the molecular landscape of ileal neuroendocrine tumors (NETs) is affected by the lack of systematic studies investigating intra-tumoral heterogeneity. In this study, intra-tumoral heterogeneity was investigated in 27 primary ileal G1-NETs and their matched nodal and liver metastases in order to assess the tumor grading, the expression status of two somatostatin receptor isoforms (i.e. SSTR2A and SSTR5) and mTOR signaling dysregulation (ph-mTOR, ph-p70S6K, ph-4EBP1, PTEN and miR-21). Among the 27 G1 primary tumors, 4 shifted to G2 in the matched liver metastasis. Although mTOR activation was pretty consistent between primary and secondary malignancies, mTOR effectors (ph-p70S6K and ph-4EBP1) were overexpressed in matched liver metastases, whereas PTEN expression profile changed in only two cases. MiR-21 was significantly up-regulated in the metastatic setting. Although SSTRs expression was present in most of the primary tumors and matched metastasis, we found SSTR5 expression to be significantly increased in liver metastases. Notably, SSTRs expression was heterogeneous within the same lesions in most of the lesions. Overall, despite primary and metastatic ileal NETs show a similar molecular landscape, tumor grading and mTOR signaling pathway may diverge in the metastatic setting, thus affecting prognosis and treatment.

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., (© 2021 UICC.)

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., Competing Interests: Competing interests: MFB has received research funding from Celgene. HvL has acted as a consultant for Celgene, and Eli Lilly and Company, Nordic Pharma Group and Philips, and has received research grants from Amgen, Bayer Schering Pharma, Celgene, Eli Lilly and Company, GlaxoSmithKline Pharmaceuticals, MSD, Nordic Pharma Group, Philips and Roche Pharmaceuticals., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Although pancreatic ductal adenocarcinoma (PDAC) survival is poor, there are differences in patients' response to the treatments. Detection of predictive biomarkers explaining these differences is of the utmost importance. In a recent study two genetic markers (CD44-rs353630 and CHI3L2-rs684559) were reported to be associated with survival after PDAC resection. We attempted to replicate the associations in 1856 PDAC patients (685 resected with stage I/II) from the PANcreatic Disease ReseArch (PANDoRA) consortium. We also analysed the combined effect of the two genotypes in order to compare our results with what was previously reported. Additional stratified analyses considering TNM stage of the disease and whether the patients received surgery were also performed. We observed no statistically significant associations, except for the heterozygous carriers of CD44-rs353630, who were associated with worse OS (HR = 5.01; 95% CI 1.58-15.88; p = 0.006) among patients with stage I disease. This association is in the opposite direction of those reported previously, suggesting that data obtained in such small subgroups are hardly replicable and should be considered cautiously. The two polymorphisms combined did not show any statistically significant association. Our results suggest that the effect of CD44-rs353630 and CHI3L2-rs684559 cannot be generalized to all PDAC patients.

Early onset pancreatic cancer (EOPC) is a rare disease with a very high mortality rate. Almost nothing is known on the genetic susceptibility of EOPC, therefore, we performed a genome-wide association study (GWAS) to identify novel genetic variants specific for patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) at younger ages. In the first phase, conducted on 821 cases with age of onset ≤60 years, of whom 198 with age of onset ≤50, and 3227 controls from PanScan I-II, we observed four SNPs (rs7155613, rs2328991, rs4891017 and rs12610094) showing an association with EOPC risk (P < 1 × 10 -4 ). We replicated these SNPs in the PANcreatic Disease ReseArch (PANDoRA) consortium and used additional in silico data from PanScan III and PanC4. Among these four variants rs2328991 was significant in an independent set of 855 cases with age of onset ≤60 years, of whom 265 with age of onset ≤50, and 4142 controls from the PANDoRA consortium while in the in silico data, we observed no statistically significant association. However, the resulting meta-analysis supported the association (P = 1.15 × 10 -4 ). In conclusion, we propose a novel variant rs2328991 to be involved in EOPC risk. Even though it was not possible to find a mechanistic link between the variant and the function, the association is supported by a solid statistical significance obtained in the largest study on EOPC genetics present so far in the literature., (© 2020 UICC.)

Background: Pancreatic metastases from renal-cell carcinoma (RCC-PMs) are rare. Surgery may play a role in improving overall (OS) and disease-free survival (DFS)., Methods: Clinical-pathological features, surgery and follow-up data of patients with RCC-PMs operated on in three pancreatic surgical centers (2000-2019) were retrospectively evaluated., Results: Thirty-nine patients (21 male/18 female, averaging 65 years) were enrolled. RCC-PMs were metachronous in 36 patients (mean 94 months, up to 24 years after nephrectomy), multiple in 21 patients, and with a median size of 2.5 (range, 0.7-7.5) cm. All the patients underwent pancreatic surgery (33 standard resections, 6 limited resections). Fifteen patients had post-operative complications (morbidity 38.5%). The median DFS was 63 months, and 19 out of 36 patients showed a disease recurrence. The median OS was 134 months, and 13 out of 36 patients were alive with no evidence of disease. At univariate analysis, lymph node positivity (HR 5.1, 95% CI 1.5-18), multi-visceral resection (HR 3.4, 95% CI 1.1-10) and synchronous RCC-PMs (HR 13, 95% CI 3-55) were significantly associated with a short OS., Conclusion: Surgery may allow a DFS up to 17 years in more than one third of patients, even after limited resections. Splenectomy and lymph node dissection are not mandatory.

Objective: Pancreatic neuroendocrine neoplasms (pNENs) and gastrointestinal stromal tumors (GISTs) represent rare neoplasms. Nonsyndromic cases of pNENs associated with a synchronous GIST were evaluated, and a review of the literature was performed., Methods: We evaluated clinicopathologic features, postoperative outcome, and follow-up of patients operated on for nonsyndromic synchronous pNENs and GISTs in our unit (2003-2017)., Results: Five (3.2%) of 156 patients with a pNEN had an associated GIST (3 male/2 female; average age, 67 years). They were diagnosed with a pNEN preoperatively and underwent pancreatic surgery. In 4 patients, GISTs were detected intraoperatively. Histology showed 3 G1 and 2 G2 pNENs. All GISTs were low risk (median size, 0.9 cm). Two patients were alive without disease 108 and 132 months after surgery. In the literature, 7 cases were described. They had low-risk GISTs, with a gastric location in 6 cases (median size, 2.85 cm)., Conclusions: Sporadic pNENs coexisting with a GIST have been demonstrated in 12 cases. This association is considered fortuitous, and its true incidence may be underestimated. Surgery should be performed on the GIST during the pancreatic surgery. The prognosis strictly depends on the pancreatic NENs.

Background: Serotonin-secreting pancreatic neuroendocrine tumours (5-HT-secreting pNETs) are very rare, and characterised by high urinary 5-hydroxyindole-acetic acid (5-HIAA) levels (or high serum 5-HT levels)., Methods: Patients with 5-HT-secreting pancreatic neoplasms observed in our unit (1986-2015) were included. Diagnosis was based on urinary 5-HIAA or serum 5-HT levels., Results: Seven patients were enrolled (4 M/3 F), with a median age of 64 (range 38-69) years. Two patients had a carcinoid syndrome. Serum 5-HT was elevated in four patients. Urinary 5-HIAA levels were positive in six patients. The median tumour size was 4.0 (range 2.5-10) cm. All patients showed liver metastases at diagnosis. None underwent resective surgery; lymph node/liver biopsies were taken. Six lesions were well-differentiated tumours and one a poorly differentiated carcinoma (Ki67 range 3.4-70%). All but one patient received chemotherapy. Four patients received somatostatin analogues; three patients underwent ablation of liver metastases. One patient is alive with disease 117 months after observation. All the others died from disease progression after a follow-up within 158 months., Conclusions: Primary 5-HT-secreting pNETs are mostly metastatic to the liver; patients are not amenable to resective surgery. Despite high 5-HIAA urinary levels, few patients present with carcinoid syndrome. A five-year survival rate of 42.9% may be achieved with multimodal treatment., Competing Interests: The authors declare no conflict of interest.

Rare truncating BRCA2 K3326X (rs11571833) and pathogenic CHEK2 I157T (rs17879961) variants have previously been implicated in familial pancreatic ductal adenocarcinoma (PDAC), but not in sporadic cases. The effect of both mutations in important DNA repair genes on sporadic PDAC risk may shed light on the genetic architecture of this disease. Both mutations were genotyped in germline DNA from 2,935 sporadic PDAC cases and 5,626 control subjects within the PANcreatic Disease ReseArch (PANDoRA) consortium. Risk estimates were evaluated using multivariate unconditional logistic regression with adjustment for possible confounders such as sex, age and country of origin. Statistical analyses were two-sided with p values <0.05 considered significant. K3326X and I157T were associated with increased risk of developing sporadic PDAC (odds ratio (OR dom ) = 1.78, 95% confidence interval (CI) = 1.26-2.52, p = 1.19 × 10 -3 and OR dom = 1.74, 95% CI = 1.15-2.63, p = 8.57 × 10 -3 , respectively). Neither mutation was significantly associated with risk of developing early-onset PDAC. This retrospective study demonstrates novel risk estimates of K3326X and I157T in sporadic PDAC which suggest that upon validation and in combination with other established genetic and non-genetic risk factors, these mutations may be used to improve pancreatic cancer risk assessment in European populations. Identification of carriers of these risk alleles as high-risk groups may also facilitate screening or prevention strategies for such individuals, regardless of family history., (© 2019 UICC.)

Pancreatic ductal adenocarcinoma (PDAC) has an extremely poor prognosis, caused by various factors, such as the aggressiveness of the disease, the limited therapeutic options and the lack of early detection and risk markers. The ATP binding cassette subfamily C member 2 (ABCC2) protein plays a critical role in response to various drugs and is differentially expressed in gemcitabine sensitive and resistant cells. Moreover, single nucleotide polymorphisms (SNPs) in the gene have been associated with differential outcomes and prognosis in several tumour types. The aim of this study was to investigate the possible association between SNPs in the ABCC2 gene and overall survival (OS) in PDAC patients. We analysed 12 polymorphisms, including tagging-SNPs covering all the genetic variability of the ABCC2 gene and genotyped them in 1415 PDAC patients collected within the Pancreatic Disease ReseArch (PANDoRA) consortium. We tested the association between ABCC2 SNPs and PDAC OS using Cox proportional hazard models. We analysed PDAC patients dividing them by stage and observed that the minor alleles of three SNPs showed an association with worse OS [rs3740067: hazard ratio (HR) = 3.29, 95% confidence interval (CI) = 1.56-6.97, P = 0.002; rs3740073: HR = 3.11, 95% CI = 1.52-6.38, P = 0.002 and rs717620: HR = 2.90, 95% CI = 1.41-5.95, P = 0.004, respectively] in stage I patients. In patients with more advanced PDAC, we did not observe any statistically significant association. Our results suggest that rs3740067, rs3740073 and rs717620 could be promising prognostic markers in stage I PDAC patients., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Neuroendocrine tumors (NETs) of the minor papilla/ampulla (MIPA) are rare and poorly studied. Only individual case reports and no comprehensive analysis are available from the literature. We collected 16 MIPA NETs and investigated their clinicopathologic and immunohistochemical features, including markers such as somatostatin, pancreatic polypeptide, gastrin, serotonin, MUC1, cytokeratin 7, and somatostatin receptors type 2A and 5. The median age at diagnosis was 57.5 years, and the female-to-male ratio was 2.2:1. The median NET size was 1.45 cm, and most (94%) were low-grade (G1) tumors. Similarly to what was observed in the major ampulla, 3 histotypes were found: (i) ampullary-type somatostatin-producing tumors (ASTs, 10 cases), characterized by somatostatin expression in most tumor cells, focal-to-extensive tubulo-acinar structures, often with psammoma bodies, MUC1 reactivity, and no or rare membranous reactivity for somatostatin receptor type 2A; (ii) gangliocytic paragangliomas (3 cases), characterized by the coexistence of 3 tumor cell types: epithelioid, often reactive for pancreatic polypeptide, ganglion-like cells, and S100 reactive sustentacular/stromal cells; and (iii) ordinary nonfunctioning NETs (3 cases), resembling those more commonly observed in the extra-ampullary duodenum. Comparable histotypes could also be recognized among the 30 MIPA NETs from the literature. No NET-related patient death among MIPA cases was observed during a median follow-up of 38 months; however, MIPA ASTs showed lymph node metastases and invasion of the duodenal muscularis propria or beyond in 44% and 40% of cases, respectively. In conclusion, MIPA NETs closely resemble tumors arising in the major ampulla, with predominance of ASTs.

Background: Overall survival for patients with small intestinal neuroendocrine tumours (siNETs) is long, even with metastatic disease, making quality of life issues relevant. The impact of surgery on quality of life is not known. We investigated determinants of health-related quality of life in patients who had undergone surgery for a siNET., Methods: Patients operated for a siNET between 1998 and 2016 at Skåne University Hospital (Lund, Sweden), who were alive in February 2017, were sent two questionnaires constructed by the European Organisation for Research and Treatment of Cancer (EORTC QLQ-C30, EORTC QLQ-GINET21). Global quality of life, physical function, disease-related worries, diarrhoea and endocrine symptoms were evaluated with linear and logistic regression in relation to patient-, tumour- and treatment-related factors. Statistical analysis was performed using STATA 11 ® ., Results: One hundred patients (84%) completed the questionnaires. Women had worse global quality of life (p = 0.019), more disease-related worries (p < 0.001) and endocrine symptoms (p = 0.017) than men. Older age was associated with more disease-related worries (p = 0.007), but fewer endocrine symptoms (p = 0.034). Non-symptomatic tumour versus symptomatic tumour (p = 0.002), and treatment with somatostatin analogues versus no treatment (p = 0.040) were associated with less diarrhoea. Small versus large bowel resection was associated with better global quality of life (p = 0.036) and physical function (p = 0.035)., Conclusions: Male gender, younger age, treatment with somatostatin analogues, non-symptomatic tumour, and small intestinal surgery rather than large bowel surgery were associated with better quality of life.

Purpose: Ampullary neuroendocrine neoplasms (NENs) account for < 0.3% of gastrointestinal NENs. Surgical options include transduodenal ampullectomy/tumour excision or pancreaticoduodenectomy (PD). We report the experience of two high-volume pancreatic surgical centres of ampullary NENs., Methods: Clinical records of patients who underwent surgery for ampullary NENs (January 2007-November 2017) in the study centres were retrieved retrospectively. We evaluated clinical-pathological features, post-operative outcome and follow-up (FU)., Results: Eighteen patients (9 M/9 F, averaging 62 years) were enrolled. All but one were non-functioning NENs; four (22%) patients presented with jaundice. Seven (39%) of the patients underwent ampullectomy/excision (median tumour size 1.5 cm), and 11 (61%) patients underwent PD (median tumour size 2.4 cm). The median operation time of ampullectomy/excision was 221 min with operative blood loss of 75 ml (vs. 506 min and 425 ml in PD). The median hospital stay was 10 days in both groups. Overall surgical morbidity was 33%, due to four biochemical leaks, one pancreatic fistula and one abdominal haemorrhage. No reoperations were needed. The median tumour size was 1.8 (range 0.5-6.7) cm. All G2-G3 NENs were N1 (vs. 1/7 in G1 NENs). Three (17%) cases were mixed exocrine/G3 NECs. After a median FU of 45 (up to 124) months, recurrence occurred in four G3 NEC (31%) patients (median disease-free survival 14 months) after an R0 PD. Disease-related survival was 93, 77 and 66% at 1, 3 and 5 years, respectively., Conclusion: Ampullary NENs are mostly G1-G2 neoplasms. Lymph node metastases rarely occur in G1 NENs < 2 cm in size, which may be treated with ampullectomy/excision. Survival is 66% 5 years after surgery.

Background: Pancreatic neuroendocrine tumors (PNETs) are rare neoplasms for which very little is known about either environmental or genetic risk factors. Only a handful of association studies have been performed so far, suggesting a small number of risk loci. Methods: To replicate the best findings, we have selected 16 SNPs suggested in previous studies to be relevant in PNET etiogenesis. We genotyped the selected SNPs (rs16944, rs1052536, rs1059293, rs1136410, rs1143634, rs2069762, rs2236302, rs2387632, rs3212961, rs3734299, rs3803258, rs4962081, rs7234941, rs7243091, rs12957119, and rs1800629) in 344 PNET sporadic cases and 2,721 controls in the context of the PANcreatic Disease ReseArch (PANDoRA) consortium. Results: After correction for multiple testing, we did not observe any statistically significant association between the SNPs and PNET risk. We also used three online bioinformatic tools (HaploReg, RegulomeDB, and GTEx) to predict a possible functional role of the SNPs, but we did not observe any clear indication. Conclusions: None of the selected SNPs were convincingly associated with PNET risk in the PANDoRA consortium. Impact: We can exclude a major role of the selected polymorphisms in PNET etiology, and this highlights the need for replication of epidemiologic findings in independent populations, especially in rare diseases such as PNETs. Cancer Epidemiol Biomarkers Prev; 26(8); 1349-51. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Expression of the solute carrier (SLC) transporter SLC22A3 gene is associated with overall survival of pancreatic cancer patients. This study tested whether genetic variability in SLC22A3 associates with pancreatic cancer risk and prognosis. Twenty four single nucleotide polymorphisms (SNPs) tagging the SLC22A3 gene sequence and regulatory elements were selected for analysis. Of these, 22 were successfully evaluated in the discovery phase while six significant or suggestive variants entered the validation phase, comprising a total study number of 1,518 cases and 3,908 controls. In the discovery phase, rs2504938, rs9364554, and rs2457571 SNPs were significantly associated with pancreatic cancer risk. Moreover, rs7758229 associated with the presence of distant metastases, while rs512077 and rs2504956 correlated with overall survival of patients. Although replicated, the association for rs9364554 did not pass multiple testing corrections in the validation phase. Contrary to the discovery stage, rs2504938 associated with survival in the validation cohort, which was more pronounced in stage IV patients. In conclusion, common variation in the SLC22A3 gene is unlikely to significantly contribute to pancreatic cancer risk. The rs2504938 SNP in SLC22A3 significantly associates with an unfavorable prognosis of pancreatic cancer patients. Further investigation of this SNP effect on the molecular and clinical phenotype is warranted.