Polymorphisms in transcription factor binding sites and enhancer regions and pancreatic ductal adenocarcinoma risk.

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.

Potential association between PSCA rs2976395 functional variant and pancreatic cancer risk.

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.

Polymorphic variants involved in methylation regulation: a strategy to discover risk loci for pancreatic ductal adenocarcinoma.

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.

A scan of all coding region variants of the human genome, identifies 13q12.2-rs9579139 and 15q24.1-rs2277598 as novel risk loci for pancreatic ductal adenocarcinoma.

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.

Exploring the Neandertal legacy of pancreatic ductal adenocarcinoma risk in Eurasians.

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.

A new silver dressing, StopBac, used in the prevention of surgical site infections.

Ideal dressings of surgical wounds should provide moist, semi-permeable, and antiseptic environments for optimal wound healing. To maximise patient comfort, surgical dressings must be hypoallergenic, not restrict movement, and allow patients to manage their personal hygiene. From the aspect of health care personnel, dressings should enable visual monitoring of the wound without the need for removing them, thus reducing the number of dressing changes. The active antimicrobial effect of silver cations has been demonstrated by many studies. StopBac is a unique surgical dressing based on the sol-gel process. Silver cations are bound in a colloidal solution in an organic-inorganic hybrid organosilicate oligomer. This gel is deposited on a pad using spray atomisation. The result is a polymer nanolayer matrix with prolonged and controlled release of silver ions. This pad forms part of a waterproof hypoallergenic transparent adhesive bandage. The goal of this study was to prospectively evaluate the ability of StopBac to prevent surgical site infections (SSIs) in patients after abdominal surgery. The secondary goal was to compare costs and determine the properties of this new material. A total of 32 patients were included in the study. The patients were followed up until their surgical wounds healed completely. An SSI occurred only in one patient.

Associations between pancreatic expression quantitative traits and risk of pancreatic ductal adenocarcinoma.

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.

Genome-wide scan of long noncoding RNA single nucleotide polymorphisms and pancreatic cancer susceptibility.

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.

Serum transferrin as a biomarker of hepatocyte nuclear factor 4 alpha activity and hepatocyte function in liver diseases.

BACKGROUND: Serum transferrin levels represent an independent predictor of mortality in patients with liver failure. Hepatocyte nuclear factor 4 alpha (HNF4α) is a master regulator of hepatocyte functions. The aim of this study was to explore whether serum transferrin reflects HNF4α activity. METHODS: Factors regulating transferrin expression in alcoholic hepatitis (AH) were assessed via transcriptomic/methylomic analysis as well as chromatin immunoprecipitation coupled to DNA sequencing. The findings were corroborated in primary hepatocytes. Serum and liver samples from 40 patients with advanced liver disease of multiple etiologies were also studied. RESULTS: In patients with advanced liver disease, serum transferrin levels correlated with hepatic transferrin expression (r = 0.51, p = 0.01). Immunohistochemical and biochemical tests confirmed reduced HNF4α and transferrin protein levels in individuals with cirrhosis. In AH, hepatic gene-gene correlation analysis in liver transcriptome revealed an enrichment of HNF4α signature in transferrin-correlated transcriptome while transforming growth factor beta 1 (TGFß1), tumor necrosis factor α (TNFα), interleukin 1 beta (IL-1ß), and interleukin 6 (IL-6) negatively associated with transferrin signature. A key regulatory region in transferrin promoter was hypermethylated in patients with AH. In primary hepatocytes, treatment with TGFß1 or the HNF4α inhibitor BI6015 suppressed transferrin production, while exposure to TNFα, IL-1ß, and IL-6 had no effect. The correlation between hepatic HNF4A and transferrin mRNA levels was also seen in advanced liver disease. CONCLUSIONS: Serum transferrin levels constitute a prognostic and mechanistic biomarker. Consequently, they may serve as a surrogate of impaired hepatic HNF4α signaling and liver failure.

Genome-wide association study identifies an early onset pancreatic cancer risk locus.

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.

Variations of the celiac trunk investigated by multidetector computed tomography: Systematic review and meta-analysis with clinical correlations.

In recent years multidetector computed tomography (MDCT) has been used to investigate vascular anatomy for scientific and diagnostic purposes. These studies allow for much larger sample sizes than traditional cadaveric studies. The aim of this research was to perform a systematic review and meta-analysis on studies investigating the variations of the celiac trunk using MDCT. Major medical databases were used to find studies investigating celiac trunk anatomy using MDCT. Extracted information included demographic details, number of normal celiac trunks, and number of each variant celiac trunk. Using a random effects meta-analysis the pooled prevalence of each variation was calculated. A total of 36 studies from 14 countries and four continents were included in the meta-analysis. The total number of subjects included was 17,391. The total prevalence of variant celiac trunks was 10.85%. The different types of celiac trunk variations with their prevalences were: gastrosplenic trunk (3.46%), hepatosplenic trunk (3.88%), hepatogastric trunk (0.24%), absent celiac trunk (0.28%), celiacomesenteric trunk (0.46%), hepatosplenomesenteric trunk (0.26%), gastrosplenomesenteric trunk (0.07%), and celiacomesenteric anastomosis (0.09%). A total of 61 cases (0.19%) were either not described or not described adequately to be included in our classification. Major variations of the celiac trunk are not uncommon and should be anticipated before radiological and surgical interventions. Knowledge of celiac trunk anatomy is important in hepatopancreatobiliary surgery, transplantology, and interventional radiology.

Oncosurgery in older patients.

Population aging is one of the most significant health problems of the 21st century and has led to an increased need for surgery in elderly patients. Only chronological age should not be decisive when indicating patients for elective procedures. Other objective findings should be taken into account too. The complex geriatric examination is an optimized, detailed and accurately defined method, which leads to better postoperative outcomes in elderly patients. In everyday practice it is sufficient to evaluate the mental, physical and nutritional state of the patient. The goal of our study was to evaluate the perioperative morbidity and mortality of elderly patients undergoing hepatopancreatobiliary procedures. In our retrospective study we evaluated prospectively collected data of patients who underwent surgical procedures between 2015 and March 2019. In total 245 patients underwent pancreatic procedures and 156 underwent hepatic procedures. Morbidity and mortality were evaluated in the first 75 postoperative days and classified according the Clavien-Dindo classification. Our results show that when surgical procedures are correctly indicated in elderly patients, acceptable postoperative morbidity and mortality can be achieved. Since the year 2018 we have been actively using prerehabilitation in our center and it has led to improved postoperative outcomes in elderly and high-risk patients.

Pathology of cholangiocellular carcinoma.

Cholangiocellular carcinoma (CCC) is a malignant tumor harboring a poor prognosis, occurring in the liver, gallbladder and in extra- or intrahepatic biliary ducts. The article reviews the topic concerning CCC from the point of view of a surgical pathologist. The paper deals with classification of CCC into an intrahepatic/peripheral and hilar/extrahepatic subtype with different morphology, molecular features and prognosis; together with classical gross pathology, histopathology and natural history of CCC. Hilar and extrahepatic CCC share some biological characteristics with pancreatic ductal adenocarcinoma. The review comprises various types of precancerous lesions of biliary tract, summarizes updates in 8th edition of TNM classification and describes the routine issues concerning histopathological diagnostics of CCC, including immunohistochemistry and frozen section methods.

Molecular pathology of cholangiocellular carcinomas.

Cholangiocellular carcinoma is a relatively rare malignant tumor, originating from cholangiocytes, with poor prognosis and late diagnosis. It is a malignancy with a variable biological etiology, numerous genetic and epigenetic changes. Its incidence in the Czech Republic is about 1.4 per 100,000 people per year. For good prognosis and long-term survival, early diagnosis with surgical treatment is important. In these cases, a 5-year survival rate is about 20-40 %. In the early diagnosis imaging methods and histopathological verification play an essential role, whereas laboratory oncomarkers are not yet sufficiently accurate. The same applies for genetic markers. This leads to the search of new molecular targets and the high effort in the introduction of cytological and molecular-biological methods with high specificity and sensitivity into routine practice. Current early diagnosis is based on the use of efficient imaging methods. The use of genetic testing, and especially knowledge of the molecular basis of this disease, will be of a great benefit. The observation of the association between the genetic pathways, IDH1, RAS-MAPK etc., and genetic mutations of genes, such as TP53, KRAS, SMAD4, BRAF, IDH1/2, may be significant. From the molecular point of view, it is also interesting to monitor oncogenic potential in HBV/HCV infection.

The role of single-operator cholangioscopy (SpyGlass) in the intraoperative diagnosis of intraductal borders of cholangiocarcinoma proliferation - pilot study.

Cholangiocarcinoma is a relatively rare, highly fatal neoplasm originating from the biliary epithelium. Its only potentially curative treatment option is a radical surgical resection. The aim of our work was to evaluate the feasibility and the safety of intraoperative ERCP and direct cholangioscopy (SpyGlass) to assess the intraductal border of cholangiocarcinoma proliferation. The study ran from November 2015 to January 2018. The group included patients with histologically verified cholangiocarcinoma and, based on available examinations, the resectability of the tumor was assessed by a multidisciplinary team. In cases of indicated surgical resection we peroperatively performed ERCP with cholangioscopy SpyGlass and "diaphanoscopy" in all patients. The resectability was assessed on the basis of these examinations and the peroperative surgical findings. The resection procedure itself was performed only in 2 out of the total of 14 patients, as other patients were indicated for the implantation of metallic SEMS within the ERCP procedure in the operating room instead. To validate the cholangioscopic findings, we used our own criteria based on both the Monaco and other criteria. We divided the findings according to the presence or absence of ulceration, prominent polyposis, pathological vascularization (4 types), pressure defect with a coagulum in the presence of previous stent implantation, papillomatous changes or discolorations of the mucosa. Out of the total number of 14 patients only two patients were indicated for resection and in both cases R0 resection was achieved. The remaining patients were intraoperatively indicated for palliative implantation of SEMS based on the same unresectable finding during cholangioscopy and laparotomy. We demonstrated the technical feasibility and safety of direct peroperative cholangioscopy. Our results show that direct perioperative cholangioscopy is one of the methods which can contribute to a more accurate determination of tumor spread margins.

Surgery for cholangiocarcinoma.

Cholangiocarcinoma represents the second most common primary liver malignancy. Despite it comprises only 3 % of all gastrointestinal malignancies, its incidence has been increasing recently. Cholangiocarcinomas are hepatobiliary cancers with features of cholangiocyte differentiation and from clinical point of view they are classified anatomically as intrahepatic or extrahepatic form. The only curative treatment with aim of long term and disease-free survival is surgery - liver resection or liver transplantation. Current progress in perioperative treatment and increased surgical skills has changed old treatment algorithms and widen number of patients suitable for curative treatment. On the other hand, surgical intervention is connected with not negligible morbidity and mortality. A rigorous knowledge of the disease extent and all prognostic factors is main condition for proper treatment decision.

The current role of radiotherapy and systemic therapy in the multidisciplinary treatment of cholangiocarcinoma.

Cholangiocarcinoma is a cancer with very poor prognosis. The only potentially curative approach is surgical resection of tumor. However, the rate of local and distant recurrence after radical surgery is still high. Benefit of adjuvant therapy is not clearly defined, nevertheless patients at high risk of recurrence are indicated to chemotherapy or chemoradiotherapy. Locally advanced, unresectable disease can also be treated with chemotherapy alone, or with her combination with radiotherapy. Required radiation doses are relatively high, therefore it is necessary to use highly conformal radiation therapy. Treatment of metastatic disease is currently based on systemic therapy, combination of gemcitabine and cisplatin as standard of care. Benefit of targeted molecular therapy is not clear at present, but ongoing research in genetic profiling of tumor may help to improve current clinical practice. Patients with cholangiocarcinoma have to be discussed during multidisciplinary team meetings.

Crohn's Disease and Intestinal Transplantation.

BACKGROUND: Most patients with Crohn's disease (CD) require one or more operations during their lifetime. Repeated resections and surgical complications may result in short gut in a subset of patients, typically those with extensive small bowel disease or a penetrating CD phenotype. The effects of short bowel syndrome (SBS) can range in seriousness from mild to life-threatening advanced intestinal failure. Worldwide, CD is the second leading indication for intestinal transplantation (ITx) in SBS, but the overall incidence of ITx is quite low. Key Messages: Currently, total parenteral nutrition (TPN) is the preferred treatment option for patients with SBS because of its superior survival outcome. However, TPN can fail from loss of venous access due to catheter-associated thromboses, recurrent catheter-related blood stream infections, or intestinal-failure-associated liver dysfunction. Three types of transplantations are available for CD patients - small bowel alone, liver plus small bowel and multivisceral, which includes other intra-abdominal organs. An abdominal wall transplant is required in case of abdominal wall defects or lack of free intra-abdominal space. The current 5-year survival rate of 54% following ITx of the isolated small bowel appears worse than that associated with TPN. However, outcomes are substantially improving because of surgical and technical advances and progress in medical therapy. On the other hand, ITx carries the risk of both complications (e.g., rejection, infections, and post transplant lymphoproliferative disorders) and adverse events associated with immunosuppression. CD recurrence has been reported in a few patients, but this primarily histologic recurrence might not be of great clinical importance. CONCLUSIONS: ITx has become a well-established treatment for those who fail on TPN and who have life-threatening complications. Fortunately, it concerns only a small proportion of CD patients, but it does offer reasonable survival and quality of life. Primary management of patients with small bowel failure should be provided by a center experienced in medical intestinal rehabilitation, nutrition, and transplantation of other solid organs.

[Intestinal transplantation in Czech Republic]. / Transplantace tenkého streva v Ceské republice.

Intestinal transplantation represents a suitable treatment for patients with intestinal failure who then develop life-threatening complications of total parenteral nutrition and for some patients with complex abdominal disorders not suitable for conventional treatment. METHODS: prior to launch of the clinical program, preparation started in 2006 initially with extensive experimentation carried out on pigs. The clinical phase involved a specialized, multidisciplinary team who examined 23 patients being considered for transplantation. Seven patients were put on a waiting list and one female, due to the improvement of her medical status, was unlisted. The first ever intestinal transplantation was done in 2014. RESULTS: three out of six transplanted patients are alive with 380 days of actual survival; median 131 days (63-763). Two patients are on a full oral diet and nutritionally independent with an excellent quality of life. One female is nutritionally independent but with the need for partial supplemental parenteral rehydration due to the stomal output. CONCLUSION: intestinal transplantation is a suitable treatment for highly selected patients with intestinal failure who meet specific listing criteria.

Association of genetic polymorphisms with survival of pancreatic ductal adenocarcinoma patients.

Germline genetic variability might contribute, at least partially, to the survival of pancreatic ductal adenocarcinoma (PDAC) patients. Two recently performed genome-wide association studies (GWAS) on PDAC overall survival (OS) suggested (P < 10(-5)) the association between 30 genomic regions and PDAC OS. With the aim to highlight the true associations within these regions, we analyzed 44 single-nucleotide polymorphisms (SNPs) in the 30 candidate regions in 1722 PDAC patients within the PANcreatic Disease ReseArch (PANDoRA) consortium. We observed statistically significant associations for five of the selected regions. One association in the CTNNA2 gene on chromosome 2p12 [rs1567532, hazard ratio (HR) = 1.75, 95% confidence interval (CI) 1.19-2.58, P = 0.005 for homozygotes for the minor allele] and one in the last intron of the RUNX2 gene on chromosome 6p21 (rs12209785, HR = 0.88, 95% CI 0.80-0.98, P = 0.014 for heterozygotes) are of particular relevance. These loci do not coincide with those that showed the strongest associations in the previous GWAS. In silico analysis strongly suggested a possible mechanistic link between these two SNPs and pancreatic cancer survival. Functional studies are warranted to confirm the link between these genes (or other genes mapping in those regions) and PDAC prognosis in order to understand whether these variants may have the potential to impact treatment decisions and design of clinical trials.