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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 Although evidence suggests frequent gastrointestinal (GI) involvement during coronavirus disease 2019 (COVID-19), endoscopic findings are scarcely reported. Aims We aimed at registering endoscopic abnormalities and potentially associated risk factors among patients with COVID-19. Methods All consecutive patients with COVID-19 undergoing endoscopy in 16 institutions from high-prevalence regions were enrolled. Mann-Whitney U, χ 2 or Fisher's exact test were used to compare patients with major abnormalities to those with negative procedures, and multivariate logistic regression to identify independent predictors. Results Between February and May 2020, during the first pandemic outbreak with severely restricted endoscopy activity, 114 endoscopies on 106 patients with COVID-19 were performed in 16 institutions (men=70.8%, median age=68 (58-74); 33% admitted in intensive care unit; 44.4% reporting GI symptoms). 66.7% endoscopies were urgent, mainly for overt GI bleeding. 52 (45.6%) patients had major abnormalities, whereas 13 bled from previous conditions. The most prevalent upper GI abnormalities were ulcers (25.3%), erosive/ulcerative gastro-duodenopathy (16.1%) and petechial/haemorrhagic gastropathy (9.2%). Among lower GI endoscopies, 33.3% showed an ischaemic-like colitis. Receiver operating curve analysis identified D-dimers >1850 ng/mL as predicting major abnormalities. Only D-dimers >1850 ng/mL (OR=12.12 (1.69-86.87)) and presence of GI symptoms (OR=6.17 (1.13-33.67)) were independently associated with major abnormalities at multivariate analysis. Conclusion In this highly selected cohort of hospitalised patients with COVID-19 requiring endoscopy, almost half showed acute mucosal injuries and more than one-third of lower GI endoscopies had features of ischaemic colitis. Among the hospitalisation-related and patient-related variables evaluated in this study, D-dimers above 1850 ng/mL was the most useful at predicting major mucosal abnormalities at endoscopy. Trial registration number ClinicalTrial.gov (ID: NCT04318366). ©

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. © 2021, The Author(s).

Telomere deregulation is a hallmark of cancer. Telomere length measured in lymphocytes (LTL) has been shown to be a risk marker for several cancers. For pancreatic ductal adenocarcinoma (PDAC) consensus is lacking whether risk is associated with long or short telomeres. Mendelian randomization approaches have shown that a score built from SNPs associated with LTL could be used as a robust risk marker. We explored this approach in a large scale study within the PANcreatic Disease ReseArch (PANDoRA) consortium. We analyzed 10 SNPs (ZNF676-rs409627, TERT-rs2736100, CTC1-rs3027234, DHX35-rs6028466, PXK-rs6772228, NAF1-rs7675998, ZNF208-rs8105767, OBFC1-rs9420907, ACYP2-rs11125529 and TERC-rs10936599) alone and combined in a LTL genetic score (“teloscore”, which explains 2.2% of the telomere variability) in relation to PDAC risk in 2,374 cases and 4,326 controls. We identified several associations with PDAC risk, among which the strongest were with the TERT-rs2736100 SNP (OR = 1.54; 95%CI 1.35–1.76; p = 1.54 × 10 −10 ) and a novel one with the NAF1-rs7675998 SNP (OR = 0.80; 95%CI 0.73–0.88; p = 1.87 × 10 −6 , p trend = 3.27 × 10 −7 ). The association of short LTL, measured by the teloscore, with PDAC risk reached genome-wide significance (p = 2.98 × 10 −9 for highest vs. lowest quintile; p = 1.82 × 10 −10 as a continuous variable). In conclusion, we present a novel genome-wide candidate SNP for PDAC risk (TERT-rs2736100), a completely new signal (NAF1-rs7675998) approaching genome-wide significance and we report a strong association between the teloscore and risk of pancreatic cancer, suggesting that telomeres are a potential risk factor for pancreatic cancer.

In the fifties and sixties, while Italian engineering was receiving important international awards, the theme of the tall building attracted the attention of the best architects. They made it a field of design experimentation, immediately sensing how the strategic use of the structure could revolutionize the already stereotyped image of the all-steel and glass towers proposed by the International Style. Gio Ponti, Luigi Moretti and the BBPR thus created formidable partnerships with Pier Luigi Nervi and Arturo Danusso, the most active engineers in the field of skyscraper design. The result was at least three masterpieces, among the works created in those years: the Velasca tower and the Pirelli skyscraper in Milan and the Stock Exchange tower in Montreal, which, at the time of its completion, also marked the record for the highest reinforced concrete building in the world. En los años cincuenta y sesenta del siglo XX, mientras la ingeniería italiana recibía importantes premios internacionales, el diseño de los edificios en altura atraía la atención de los mejores arquitectos. Estos entendieron inmediatamente lo mucho que el empleo estratégico de la estructura habría podido revolucionar la ya de por sí estereotipada imagen de la torre de acero y vidrio propuesta por el Estilo Internacional, y lo convirtieron en un campo de experimentación. De esta forma Gio Ponti, Luigi Moretti y la BBPR desarrollaron extraordinarias colaboraciones con Pier Luigi Nervi y Arturo Danusso, los ingenieros más activos en el campo del diseño de rascacielos. De entre los proyectos realizados en esos años, este proceso de colaboración dió como resultado a al menos tres obras maestras: la torre Velasca, el rascacielos Pirelli y la torre de la Bolsa de Valores de Montreal. Esta última, en el momento de su finalización, además significó el récord del edificio de hormigón armado más alto del mundo.

Background Pancreatic cancer is the fourth leading cause of cancer mortality. Most patients are diagnosed with advanced pancreatic cancer, either at locally advanced or metastatic stages, and have a high rate of malnutrition and weight loss which are associated with poor outcomes. Pancreatic exocrine insufficiency is one of the causes of malnutrition and weight loss in these patients. The prevalence and clinical consequences of pancreatic exocrine insufficiency in advanced pancreatic cancer are poorly investigated with heterogeneous results. We sought to determine the prevalence and clinical consequences of pancreatic exocrine insufficiency and the effect of pancreatic enzyme replacement therapy in patients with advanced pancreatic cancer by systematic review and meta-analysis. Methods Scopus, Medline, and Embase were searched for cohort studies or randomised clinical trials reporting pancreatic exocrine insufficiency and/or the effect of pancreatic enzyme replacement therapy in patients with advanced pancreatic cancer. We considered pancreatic exocrine insufficiency as an abnormal result on direct and/or indirect pancreatic exocrine function tests. Pancreatic enzyme replacement therapy was evaluated by its effect on survival and quality of life in patients with advanced pancreatic cancer. Results A total of 11 studies were included; seven studies reported the prevalence of pancreatic exocrine insufficiency and seven the effect of pancreatic enzyme replacement therapy in advanced pancreatic cancer. The pooled prevalence of pancreatic exocrine insufficiency in advanced pancreatic cancer was 72% (95% confidence interval: 55-86%), being significantly higher when tumours were located in the pancreatic head (relative risk = 3.36, 1.07-10.54;p = 0.04) six studies investigated the impact of pancreatic enzyme replacement therapy on survival/quality of life. Pancreatic enzyme replacement therapy was associated with 3.8 months (95% confidence interval: 1.37-6.19) survival benefit. Patients receiving pancreatic enzyme replacement therapy had a trend towards a better quality of life. ConclusionsThe prevalence of pancreatic exocrine insufficiency in advanced pancreatic cancer is substantial and its treatment can improve the outcomes of these patients.

Background:Malnutrition and cachexia are common in patients with advanced pancreatic ductal adenocarcinoma (PDAC) and have a significant influence on the tolerance and response to treatments. If timely identified, malnourished PDAC patients could be treated to increase their capacity to complete the planned treatments and, therefore, possibly, improve their efficacy. Aims:The aim of this study is to assess the impact of nutritional status, pancreatic exocrine insufficiency (PEI), and other clinical factors on patient outcomes in patients with advanced PDAC. Methods:PAncreatic Cancer MAlnutrition and Pancreatic Exocrine INsufficiency in the Course of Chemotherapy in Unresectable Pancreatic Cancer (PAC-MAIN) is an international multicenter prospective observational cohort study. The nutritional status will be determined by means of Mini-Nutritional Assessment score and laboratory blood tests. PEI will be defined by reduced fecal elastase levels. Main outcome: adherence to planned chemotherapy in the first 12 weeks following the diagnosis, according to patients' baseline nutritional status and quantified and reported as "percent of standard chemotherapy dose delivered." Secondary outcomes: rate of chemotherapy-related toxicity, progression-free survival, survival at 6 months, overall survival, quality of life, and the number of hospitalizations. Analysis: chemotherapy dosing over the first 12 weeks of therapy (i.e., percent of chemotherapy received in the first 12 weeks, as defined above) will be compared between well-nourished and malnourished patients. Sample size: based on an expected percentage of chemotherapy delivered of 70% in well-nourished patients, with a type I error of 0.05 and a type II error of 0.20, a sample size of 93 patients per group will be required in case of a percentage difference of chemotherapy delivered of 20% between well-nourished and malnourished patients, 163 patients per group in case of a difference of 15% between the groups, and 356 patients per group in case of a 10% difference. Centers from Russia, Romania, Turkey, Spain, Serbia, and Italy will participate in the study upon Local Ethics Committee approval. Discussion:PAC-MAIN will provide insights into the role of malnutrition and PEI in the outcomes of PDAC. The study protocol was registered atas NCT04112836.

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