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.

• MeSH
• celogenomová asociační studie MeSH
• DNA MeSH
• duktální karcinom pankreatu * genetika   MeSH
• genetická predispozice k nemoci MeSH
• genom lidský MeSH
• jednonukleotidový polymorfismus genetika   MeSH
• lidé MeSH
• nádory slinivky břišní * genetika   patologie   MeSH
• studie případů a kontrol MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• DNA MeSH

BACKGROUND: This study aimed to validate the accuracy of the Preoperative Pancreatic Resection (PREPARE) risk score in pancreatic resection patients. PATIENTS AND METHODS: This prospective study included 216 patients who underwent pancreatic resection between January 2015 and December 2018. All patients in our cohort with weight loss or lack of appetite received dietary advice and preoperative oral nutritional supplementation (600 kcal/day). Demographic, clinicopathological, operative, and postoperative data were collected prospectively. The PREPARE score and the predicted risk of major complications were computed for each patient. Differences in major postoperative complications were analyzed using a multivariate Cox proportional hazards regression model. The predicted and observed risks of major complications were tested using the C-statistic. RESULTS: The study included 216 patients [117 men (54.2%)] with a median age of 65.0 (30.0-83.0) years. The majority of patients were classified as American Society of Anesthesiologists (ASA)' Physical Status score II (N = 164/216; 75.9%) and as "low risk" PREPARE score (N = 185/216; 85.6%) before the surgery. Only 4 (1.9%) patients were malnourished, with albumin levels of less than 3.5 g/dl. The most common type of pancreatic resection was a pylorus-preserving pancreaticoduodenectomy (N = 122/216; 56.5%). Major morbidity and 30-day mortality rates were 11.1% and 1.9%, respectively. The type of surgical procedure (hazard ratio [HR]: 3.849; 95% confidence interval [CI]: 1.208-12.264) and ASA score (HR: 3.089; 95% CI: 1.067-8.947) were significantly associated with the incidence of major postoperative complications in multivariate analysis. The receiver operating characteristic curve was 0.657 for incremental values and 0.559 for risk categories, indicating a weak predictive model. CONCLUSION: The results of the present study suggest that the PREPARE risk score has low accuracy in predicting the risk of major complications in patients with consistent preoperative nutritional support. This limits the use of PREPARE risk score in future preoperative clinical routines.

• Klíčová slova
• PREPARE, morbidity, nutritional support, pancreatic resection, prognostic risk score,
• Publikační typ
• časopisecké články MeSH

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.

• Klíčová slova
• Early onset, GWAS, Pancreatic cancer, Risk factor,
• MeSH
• celogenomová asociační studie MeSH
• diabetes mellitus 2. typu * epidemiologie   genetika   komplikace   MeSH
• duktální karcinom pankreatu * genetika   patologie   MeSH
• lidé MeSH
• nádory slinivky břišní * patologie   MeSH
• rizikové faktory MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

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.

• Klíčová slova
• Admixture, Association study, Eurasians, Introgression, Neandertal, Pancreatic cancer,
• MeSH
• diabetes mellitus 2. typu * MeSH
• duktální karcinom pankreatu * genetika   MeSH
• jednonukleotidový polymorfismus MeSH
• lidé MeSH
• nádory slinivky břišní * genetika   MeSH
• neandertálci * genetika   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Pancreatic cancer (PDAC) has a poor prognosis despite surgical removal and adjuvant therapy. Additionally, the effects of postoperative analgesia with morphine and piritramide on survival among PDAC patients are unknown, as are their interactions with opioid/cannabinoid receptor gene expressions in PDAC tissue. Cancer-specific survival data for 71 PDAC patients who underwent radical surgery followed by postoperative analgesia with morphine (n = 48) or piritramide (n = 23) were therefore analyzed in conjunction with opioid/cannabinoid receptor gene expressions in the patients' tumors. Receptor gene expressions were determined using the quantitative real-time polymerase chain reaction. Patients receiving morphine had significantly longer cancer-specific survival (CSS) than those receiving piritramide postoperative analgesia (median 22.4 vs. 15 months; p = 0.038). This finding was supported by multivariate modelling (p < 0.001). The morphine and piritramide groups had similar morphine equipotent doses, receptor expression, and baseline characteristics. The opioid/cannabinoid receptor gene expression was analyzed in a group of 130 pancreatic cancer patients. Of the studied receptors, high cannabinoid receptor 2 (CB2) and opioid growth factor receptor (OGFR) gene expressions have a positive influence on the length of overall survival (OS; p = 0.029, resp. p = 0.01). Conversely, high delta opioid receptor gene expression shortened OS (p = 0.043). Multivariate modelling indicated that high CB2 and OGFR expression improved OS (HR = 0.538, p = 0.011, resp. HR = 0.435, p = 0.001), while high OPRD receptor expression shortened OS (HR = 2.264, p = 0.002). Morphine analgesia, CB2, and OGFR cancer tissue gene expression thus improved CSS resp. OS after radical PDAC surgery, whereas delta opioid receptor expression shortened OS.

• Klíčová slova
• cancer recurrence, cannabinoid receptors, morphine, opioid receptors, pancreatic cancer, pancreatic surgery, patient survival, piritramide, postoperative analgesia,
• Publikační typ
• časopisecké články MeSH

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.

• Klíčová slova
• association study, genetic susceptibility, pancreatic ductal adenocarcinoma, single nucleotide polymorphisms,
• MeSH
• duktální karcinom pankreatu * genetika   MeSH
• genetická predispozice k nemoci MeSH
• jednonukleotidový polymorfismus MeSH
• lidé MeSH
• nádory slinivky břišní * genetika   MeSH
• RNA dlouhá nekódující * genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• CDKN2B antisense RNA, human MeSH Prohlížeč
• RNA dlouhá nekódující * MeSH

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.

• Klíčová slova
• Chronic pancreatitis, Consortium, Genetic epidemiology, Intraductal papillary mucinous neoplasms, Pancreatic cancer, Pancreatic ductal adenocarcinoma, Pancreatic neuroendocrine tumors,
• MeSH
• duktální karcinom pankreatu * MeSH
• jednonukleotidový polymorfismus MeSH
• lidé MeSH
• nádory slinivky břišní * etiologie   genetika   MeSH
• rizikové faktory MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

BACKGROUND: The painless form of chronic pancreatitis is one of the rarer forms of the disease. While 80% to 90% of all chronic pancreatitis cases have abdominal pain as their clinical symptom, a smaller proportion of persons with chronic pancreatitis do not report typical pain. This form of the disease is often associated with exocrine and endocrine pancreatic insufficiency and weight loss, but the absence of pain symptoms may initially lead to misdiagnosis. METHODS: In a cohort of 257 people with chronic pancreatitis, the painless form was diagnosed in 30 individuals (11.6%), with an average age of 56 years and a predominance of men (71.4%). Thirty-eight percent were non-smokers and 47.6% of patients smoked up to 10 cigarettes per day. Alcohol intake of less than 40 g per day was reported by 61.9% of subjects. A quarter were moderately overweight, with a mean BMI of 26.5. Newly diagnosed diabetes mellitus had 25.7% of the subjects. RESULTS: A frequent finding was the demonstration of morphological changes, with calcifications found in 85,7% and dilatation of the pancreatic duct greater than 6.0 mm in 66%. A surprising finding was the presence of metabolic syndrome in 42.8% and the most frequent finding was the demonstration of decreased external pancreatic secretion (90%). CONCLUSION: Painless chronic pancreatitis is usually treated conservatively. We demonstrate a subset of 28 patients with painless chronic pancreatitis treated surgically. Most frequent indications were benign stenosis of the intrapancreatic bile duct and stenosis of the pancreatic duct. Although approximately 1 in 10 people with chronic pancreatitis present with a painless form of it, so that the form of the disease is described as rare, this does not change the fact that management of these people is still not optimal.

• Klíčová slova
• diabetes mellitus, exocrine insufficiency, painless form of pancreatitis, pancreatic calcifications, pancreatic pain,
• MeSH
• bolest MeSH
• chronická nemoc MeSH
• chronická pankreatitida * komplikace   diagnóza   MeSH
• lidé středního věku MeSH
• lidé MeSH
• stenóza MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH

BACKGROUND AND AIMS: Lumen-apposing metal stents (LAMSs) have proven to be effective for drainage of pancreatic walled-off necrosis (WON), although associated adverse events (AEs) have been reported. Anchoring coaxial double-pigtail plastic stents (DPSs) within LAMSs have been proposed to prevent LAMS-related AEs but have not been assessed in prospective studies. We aimed to evaluate the utility of such measures with a randomized controlled trial. METHODS: We randomly assigned consecutive patients with WON indications for drainage to EUS-guided transluminal drainage using LAMSs with (group A) or without (group B) DPSs. All LAMSs were to be removed after 3 weeks had elapsed from the index procedure with a preceding CT to decide whether additional steps needed to be taken (eg, transluminal necrosectomy or placing transluminal plastic stents in patients with incomplete resolution of WON). The main outcomes were failure of the index method, defined as necessity of reintervention (endoscopic, percutaneous, or surgical) before LAMS removal because of LAMS-related AEs and/or clinical deterioration; AE rates; and mortality with the LAMS in place. Variables were evaluated using the Mann-Whitney U test, χ2 test, or Fisher exact test as appropriate. P < .05 was considered significant. RESULTS: Sixty-seven patients (37.3% women; mean age, 54 ± 14.4 years) underwent LAMS placement with (n = 34) or without (n = 33) DPS placement in 2 tertiary centers. Baseline characteristics including demographics, etiology, comorbidity, and clinical presentation (sterile vs infected necrosis) were comparable between both groups. The technical success rate in placing LAMSs and DPSs was 100%. The global rate of AEs was significantly lower in group A versus group B (20.7% vs 51.5%, respectively; P = .008). Stent occlusion was the most frequently observed AE (14.7% vs 36.3%, P = .042). Failure of the index method was lower in group A versus group B (29.4% vs 48.5%, respectively; P = .109); however, the difference did not achieve statistical significance. The same applied to the mortality rate with LAMSs in place (2.9% vs 12.1%, P = .197). CONCLUSIONS: The addition of a coaxial DPS within a LAMS was associated with a significantly lower global rate of AEs and stent occlusion rate in EUS-guided drainage of WON. (Clinical trial registration number: NCT03923686.).

• MeSH
• akutní nekrotizující pankreatitida * chirurgie   MeSH
• dospělí MeSH
• drenáž metody   MeSH
• endosonografie MeSH
• lidé středního věku MeSH
• lidé MeSH
• nekróza etiologie   MeSH
• plastické hmoty MeSH
• prospektivní studie MeSH
• retrospektivní studie MeSH
• senioři MeSH
• stenty * škodlivé účinky   MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• plastické hmoty MeSH

PURPOSE: Bile duct injury (BDI) remains the most serious complication following cholecystectomy. However, the actual incidence of BDI in the Czech Republic remains unknown. Hence, we aimed to identify the incidence of major BDI requiring operative reconstruction after elective cholecystectomy in our region despite the prevailing modern 4 K Ultra HD laparoscopy and Critical View of Safety (CVS) standards implemented in daily surgical practice among the Czech population. METHODS: In the absence of a specific registry for BDI, we analysed data from The Czech National Patient Register of Reimbursed Healthcare Services, where all procedures are mandatorily recorded. We investigated 76,345 patients who were enrolled for at least a year and underwent elective cholecystectomy during the period from 2018-2021. In this cohort, we examined the incidence of major BDI following the reconstruction of the biliary tract and other complications. RESULTS: A total of 76,345 elective cholecystectomies were performed during the study period, and 186 major BDIs were registered (0.24%). Most elective cholecystectomies were performed laparoscopically (84.7%), with the remaining open (15.3%). The incidence of BDI was higher in the open surgery group (150 BDI/11700 cases/1.28%) than in laparoscopic cholecystectomy (36 BDI/64645 cases/0.06%). Furthermore, the total hospital stays with BDI after reconstruction was 13.6 days. However, the majority of laparoscopic elective cholecystectomies (57,914, 89.6%) were safe and standard procedures with no complications. CONCLUSION: Our study corroborates the findings of previous nationwide studies. Therefore, though laparoscopic cholecystectomy is reliable, the risks of BDI cannot be eliminated.

• Klíčová slova
• Bile duct injury, Cholecystectomy, Critical view of safety, Postoperative complications,
• MeSH
• cholecystektomie laparoskopická * škodlivé účinky   MeSH
• cholecystektomie škodlivé účinky   MeSH
• iatrogenní nemoci epidemiologie   MeSH
• lidé MeSH
• poranění břicha * chirurgie   MeSH
• registrace MeSH
• žlučové cesty chirurgie   zranění   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Česká republika epidemiologie   MeSH