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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

Objective To assess the frequency of adverse events associated with periendoscopic management of direct oral anticoagulants (DOACs) in patients undergoing elective GI endoscopy and the efficacy and safety of the British Society of Gastroenterology (BSG) and European Society of Gastrointestinal Endoscopy (ESGE) recommendations (NCT 02734316). Design Consecutive patients on DOACs scheduled for elective GI endoscopy were prospectively included. The timing of DOAC interruption and resumption before and after the procedures were recorded, along with clinical and procedural data. Procedures were stratified into low-risk and high-risk for GI-related bleeding, and patients into low-risk and high-risk for thromboembolic events. Patients were followed-up for 30 days for major and clinically relevant non-major bleeding events (CRNMB), arterial and venous thromboembolism and death. Results Of 529 patients, 38% and 62% underwent high-risk and low-risk procedures, respectively. There were 45 (8.5%; 95% CI 6.3% to 11.2%) major or CRNMB events and 2 (0.4%; 95% CI 0% to 1.4%) thromboembolic events (transient ischaemic attacks). Overall, the incidence of bleeding events was 1.8% (95% CI 0.7% to 4%) and 19.3% (95% CI 14.1% to 25.4%) in low-risk and high-risk procedures, respectively. For high-risk procedures, the incidence of intraprocedural bleeding was similar in patients who interrupted anticoagulation according to BSG/ESGE guidelines or earlier (10.3%vs10.8%, p=0.99), with a trend for a lower risk as compared with those who stopped anticoagulation later (10.3%vs25%, p=0.07). The incidence of delayed bleeding appeared similar in patients who resumed anticoagulation according to BSG/ESGE guidelines or later (6.6%vs7.7%, p=0.76), but it tended to increase when DOAC was resumed earlier (14.4%vs6.6%, p=0.27). The risk of delayed major bleeding was significantly higher in patients receiving heparin bridging than in non-bridged ones (26.6%vs5.9%, p=0.017). Conclusion High-risk procedures in patients on DOACs are associated with a substantial risk of bleeding, further increased by heparin bridging. Adoption of the BSG/ESGE guidelines in periendoscopic management of DOACs seems to result in a favourable benefit/risk ratio. Trial registration number NCT 02734316; Pre-results.

Pancreatic ductal adenocarcinoma (PDAC) is a very aggressive tumor with a five-year survival of less than 6%. Chronic pancreatitis (CP), an inflammatory process in of the pancreas, is a strong risk factor for PDAC. Several genetic polymorphisms have been discovered as susceptibility loci for both CP and PDAC. Since CP and PDAC share consistent number of epidemiologic risk factors, the aim of this study was to investigate whether specific CP risk loci also contribute to PDAC susceptibility. We selected five common SNPs (rs11988997, rs379742, rs10273639 rs2995271 and rs12688220) that were identified as susceptibility markers for CP and analyzed them in 2,914 PDAC cases, 356 CP cases and 5,596 controls retrospectively collected in the context of the international PANDoRA consortium. We found a weak association between the minor allele of the PRSS1-PRSS2-rs10273639 and an increased risk of developing PDAC (ORhomozygous =1.19, 95% CI 1.02-1.38, p=0.023). Additionally all the SNPs confirmed statistically significant associations with risk of developing CP, the strongest being PRSS1-PRSS2-rs10273639 (ORheterozygous =0.51, 95% CI 0.39-0.67, p=1.10x10(-6) ) and MORC4-rs 12837024 (ORhomozygous =2.07 (1.55-2.77, ptrend =0.7x10(-11) ). Taken together, the results from our study do not support variants rs11988997, rs379742, rs10273639 rs2995271 and rs12688220 as strong predictors of PDAC risk, but further support the role of these SNPs in CP susceptibility. Our study suggests that CP and PDAC probably do not share genetic susceptibility, at least in terms of high frequency variants. This article is protected by copyright. All rights reserved.

In the management of adrenocorticotropic hormone (ACTH)–dependent Cushing's syndrome, inferior petrosal sinus sampling (IPSS) provides information for the endocrinologist, the neurosurgeon, and the neuroradiologist. To the endocrinologist who performs the etiological diagnosis, results of IPSS confirm or exclude the diagnosis of Cushing's disease with 80%–100% sensitivity and over 95% specificity. Baseline central-peripheral gradients have suboptimal accuracy, and stimulation with corticotropin-releasing hormone (CRH), possibly desmopressin, has to be performed. The rationale for the use of IPSS in this context depends on other diagnostic means, taking availability of CRH and reliability of dynamic testing and pituitary imaging into account. As regards the other specialists, the neuroradiologist may collate results of IPSS with findings at imaging, while IPSS may prove useful to the neurosurgeon to chart a surgical course. The present review illustrates the current standpoint of these 3 specialists on the role of IPSS.

The P1A1/P1A2 polymorphism of the platelet glycoprotein IIIa has been variably associated with an increased risk of coronary thrombosis.We investigated the linkage between the P1A1/P1A2 polymorphism and the risk of myocardial infarction in 98 patients who suffered their first myocardial infarction at the age of 45 years or less and 98 well-matched control subjects without coronary artery disease. Lipid parameters were measured using conventional methods of clinical chemistry; P1A genotypes were determined by polymerase chain reaction and restriction enzyme digestion.There was no significant difference in the prevalence of P1A2-positive genotypes (either P1A1/P1A2 or P1A2/P1A2) between patients and control subjects (chi 2 = 0.66, d.f. = 1, P = 0.41).These results suggest that the P1A2 polymorphism of the platelet glycoprotein IIIa does not contribute to the genetic susceptibility to premature myocardial infarction.

After a 3-year (1985-1988) experience of myocardial revascularization using internal mammary artery (AMI) grafts and after having excluded (1986) an higher operative mortality and morbidity, clinical medium-term results have been analysed. The first 144 patients discharged alive after AMI bypass surgery in 1985 were clinically evaluated, with a mean interval of 21 months from surgery (range: 5-29 months). Exercise electrocardiographic test was performed by 100 patients, and angiography repeated in 15. Actuarial survival function was estimated by Cutler-Ederer method: 2-year actuarial survival was 99.3 +/- 0.7% (94 +/- 1.8%, when operative deaths were included). Non fatal myocardial infarction occurred in 3 patients and, at follow-up, 26 were symptomatic for angina: 2 patients underwent re-operation and 2 angioplasty. Two years after AMI bypass surgery, actuarial estimate of ischemic event-free patients was 70.9 +/- 4.5% (67.7 +/- 4.5%, when operative deaths were included): 73 out of 100 exercise tests were negative for both angina and ischemia, although only 43 patients, reached maximal work load; 9 were positive for both angina and ischemia and 18 for ischemia only. All patients who underwent angiographic evaluation (15 patients, 11 of whom because of angina relapse) had AMI grafts open, while in only 4 patients all the implanted grafts were open.

Clinical results of coronary artery bypass surgery, have been evaluated by analyzing operative mortality, late survival, late functional results and their related risk factors. Four hundred and thirty-seven consecutive patients who underwent coronary artery bypass surgery between January, 1979, and December, 1983, were the clinical material of this study. The gender of patients was male in 89% of the cases; age ranged from 34 to 78 years with a mean of 54.8 +/- 8.2 (SD). Patients with combined surgical procedures were excluded. Follow-up averaged 55.7 months; 404 survivors have been contacted (97% of the total study population, if operative and late deaths are added); 218 patients underwent a control exercise test; postoperative employment status was determined for 242 individuals. The operative mortality was 5.49% (24 patients). Death was due to cardiac causes in 75% of the cases. The overall actuarial survival rate was 85 +/- 1.9% after 5 years and 83.4 +/- 2.2% after 7 years. When non-cardiac related deaths were excluded the actuarial rates were 88 +/- 1.7% and 87.2 +/- 1.9% after 5 and 7 years respectively. Actuarial freedom from all ischemic events (cardiac related death, late myocardial infarction or recurrence of angina) was 66.1 after five years, and was 70.2% if operative deaths were excluded. Actuarial freedom from recurrence of angina for patients alive at follow-up was 78.7% after five years, actuarial freedom from myocardial infarction was 93.5%. The mortality hazard showed a diphasic response, being higher perioperatively and constant in the following 5 years of follow-up. All ischemic events, both singularly and together, showed an accelerated rate of occurrence at the first and after the fifth postoperative year, the slope of the curve being quite flat during the 1 to 5 year interval. The control exercise test was negative for 62.8% of the patients, positive for 33.5% and undeterminable in 3.7%. Employment status was postoperatively unaffected in 49.6% of the cases, while 27.3% of the patients retired: the remaining individuals had already retired before surgery. Statistical analysis (stepwise logistic regression) identified age (p = 0.002) and cross-clamp time (p = 0.016) as significant risk factors of operative mortality. The ejection fraction showed a value close to statistical significance (p = 0.06).(ABSTRACT TRUNCATED AT 400 WORDS)

In 1986 the Cardiology Department, including an outpatient clinic, was established in the community hospital of Savigliano (Italy). In 1987, as a part of a cardiovascular community prevention program, an epidemiological survey on cardiovascular risk factors was carried out. Similar indicators have been object of the study held in 1998 by ANMCO-Istituto Superiore di Sanità: the Italian Cardiovascular Epidemiological Observatory. So, 11 years later, we have had the chance to compare the changes, in the same community, of three important risk factors: tobacco smoking, arterial blood pressure, and obesity.The 1987 survey included 280 subjects, aged 20 to 59 years. The 1998 survey has examined 200 subjects, aged 35 to 74 years. In both cases the subjects have been randomly selected from the Electoral Registers; subjects were asked to answer a questionnaire on tobacco smoking; arterial blood pressure measured using a cuff manometer was registered and weight and height have been recorded. In order to have comparable data we have only considered subjects 35 to 59 years old.One hundred and fifty-seven subjects (84 males and 73 females) were included in the 1987 survey and 123 (60 males and 63 females) in the 1998 survey. In 1987, the percentage of smokers was 40.7% (61.4% of males and 17.8% of females), with an average of 23.4 cigarettes/day among males and 14.7 among females. In 1998, the percentage of smokers has dropped to 18.6%, without any differences between sexes, with an average of 11.9 cigarettes/day among males and 12.7 among females. The mean values of blood pressure were lower in 1998 than in 1987 both in males (129.4/85.7 vs 138.0/88.2 mmHg) and females (119.3/80.2 vs 138.4/86.5 mmHg). Although not statistically significant, the percentage of individuals with systolic blood pressureor = 160 mmHg or diastolic blood pressureor = 95 mmHg was lower in 1998 (15.9% among males and 14.2% among females) than in 1987 (25.6% among males and 22.8% among females). The mean values of body mass index were unchanged (from 25.4 to 25.2 kg/m2 in males and from 23.4 to 23.1 kg/m2 in females).The incidence of tobacco smoking and of hypertension has shown a significant reduction in the population of Savigliano between 1987 and 1998. No significant variation was found in body mass index or in the prevalence of obesity. The distribution of these three risk factors seems to be lesser than that reported in northern Italy.

Colorectal cancer incidence and mortality in patients younger than 50 years are increasing, but screening before the age of 50 is not offered in Europe. Advanced-stage diagnosis and mortality from colorectal cancer before 50 years of age are increasing. This is not a detection-bias effect; it is a real issue affecting the entire population. Three independent computational models indicate that screening from 45 years of age would yield a better balance of benefits and risks than the current start at 50 years of age. Experimental data support these predictions in a sex- and race-independent manner. Earlier screening is seemingly affordable, with minimal impediments to providing younger adults with colonoscopy. Indeed, the American Cancer Society has already started to recommend screening from 45 years of age in the United States. Implementing early screening is a societal and public health problem. The three independent computational models that suggested earlier screening were criticized for assuming perfect compliance. Guidelines and recommendations should be derived from well-collected and reproducible data, and not from mathematical predictions. In the era of personalized medicine, screening decisions might not be based solely on age, and sophisticated prediction software may better guide screening. Moreover, early screening might divert resources away from older individuals with greater biological risks. Finally, it is still unknown whether early colorectal cancer is part of a continuum of disease or a biologically distinct disease and, as such, it might not benefit from screening at all. The increase in early-onset colorectal cancer incidence and mortality demonstrates an obligation to take actions. Earlier screening would save lives, and starting at the age of 45 years may be a robust screening option.

Magnetic resonance cholangio-pancreatography (MRCP) findings in people with chronic asymptomatic pancreatic hyperenzymemia (CAPH) have shifted the hypothesis that CAPH is always non-pathological. However, there have been no studies including both secretin-MRCP (S-MRCP) and endoscopic ultrasonography (EUS) to examine the pancreatic morphology in these subjects.To prospectively assess the diagnostic approach for CAPH using both pancreatic EUS and S-MRCP.In a case-control prospective study from January 2010 to December 2014, 68 consecutive subjects with CAPH were scheduled to undergo S-MRCP and EUS (CAPH group) in a tertiary care setting. In the same period, the EUS findings of this group were compared with 68 patients examined by EUS alone for submucosal lesions of the gastric fundus, matched for sex and age (control group).EUS detected pancreatic alterations in 60.3% of the CAPH group and 13.2% of controls (p0.001). S-MRCP showed pancreatic alterations in 51.5% in the CAPH group. With the combined procedures, pancreatic abnormalities were detected in 63.3%. The diagnoses established by the two techniques were concordant in 51 (75%) of the 68 CAPH subjects; in the remaining 17 (25%) the two methods gave additional information.In people with CAPH S-MRCP and EUS are both recommended in order to detect pancreatic abnormalities before this biochemical alteration is confirmed as benign CAPH, or Gullo's syndrome.

Background and study aim: Precut sphincterotomy is a technique usually employed for difficult biliary cannulation during endoscopic retrograde cholangiopancreatography (ERCP) for the treatment of bile duct disease. It is a validated risk factor for post-ERCP pancreatitis (PEP), but it is not clear whether the risk is related to the technique itself or to the repeated biliary cannulation attempts preceding it. The primary aim of the study was to assess the incidence of PEP in early precut compared with the standard technique in patients with difficult biliary cannulation. Secondary aims were to compare complications and cannulation success. Patients and methods: In this prospective, multicenter, randomized, clinical trial, patients who were referred for therapeutic biliary ERCP and difficult biliary cannulation were randomized to early precut (Group A) or repeated papillary cannulation attempts followed, in cases of failure, by late precut (Group B). PEP was defined as the onset of upper abdominal pain associated with an elevation in serum pancreatic enzymes of at least three times the normal level at more than 24 hours after the procedure. No rectal indomethacin or diclofenac was used for prevention of PEP. Results: A total of 375 patients were enrolled. PEP developed in 10 of the 185 patients (5.4 %) in Group A and 23 of the 190 (12.1 %) in Group B (odds ratio [OR] 0.35; 95 % confidence interval [CI] 0.16 – 0.78). The incidence of PEP was significantly lower in the early precut group (10/185, 5.4 %) than in the delayed precut subgroup (19/135 [14.1 %]; OR 0.42, 95 %CI 0.17 – 1.07). There were no differences in biliary cannulation success rates, bleeding, perforation, and cholangitis. Conclusions: In patients with difficult biliary cannulation, early precut is an effective technique and can significantly reduce the incidence of PEP. Repeated biliary cannulation attempts are a real risk factor for this complication.

The CDKN2A(p16) gene plays a key role in pancreatic cancer etiology. It is one of the most commonly somatically mutated genes in pancreatic cancer, rare germline mutations have been found to be associated with increased risk of developing familiar pancreatic cancer and CDKN2A promoter hyper-methylation has been suggested to play a critical role both in pancreatic cancer onset and prognosis. In addition several unrelated SNPs in the 9p21.3 region, that includes the CDNK2A, CDNK2B and the CDNK2B-AS1 genes, are associated with the development of cancer in various organs. However, association between the common genetic variability in this region and pancreatic cancer risk is not clearly understood. We sought to fill this gap in a case-control study genotyping 13 single nucleotide polymorphisms (SNPs) in 2,857 pancreatic ductal adenocarcinoma (PDAC) patients and 6,111 controls in the context of the Pancreatic Disease Research (PANDoRA) consortium. We found that the A allele of the rs3217992 SNP was associated with an increased pancreatic cancer risk (OR het=1.14, 95% CI 1.01-1.27, p=0.026, ORhom =1.30, 95% CI 1.12-1.51, p=0.00049). This pleiotropic variant is reported to be a mir-SNP that, by changing the binding site of one or more miRNAs, could influence the normal cell cycle progression and in turn increase PDAC risk. In conclusion, we observed a novel association in a pleiotropic region that has been found to be of key relevance in the susceptibility to various types of cancer and diabetes suggesting that the CDKN2A/Blocus could represent a genetic link between diabetes and pancreatic cancer risk.

Background: The natural history of acute pancreatitis is based on clinical studies that aim to elucidate the course of disease on the basis of predicted risk factors. Aims: To evaluate the long-term occurrence of recurrent acute pancreatitis and chronic pancreatitis in a cohort of patients following an initial episode of acute pancreatitis. Methods: 196 patients were enrolled consecutively and studied prospectively. Clinical characteristics, exogenously/endogenously-associated factors, and evolution to recurrent acute pancreatitis and chronic pancreatitis were analyzed. Results: 40 patients developed recurrent acute pancreatitis 13 of whom developed chronic pancreatitis. In a univariate analysis, recurrent acute pancreatitis was associated with an idiopathic aetiology (p

Background Lesion detection rate during colonoscopy may be influenced by the endoscopist's experience. EPK-i system colonoscopy (i-Scan) can improve mucosal and vascular visualization for detecting lesions. Aim To compare mucosal lesions detection rate and the withdrawal time of the instrument among non-expert and expert endoscopists. Methods Colonoscopy records of all consecutive patients undergoing first HD+ with i-Scan- or SWL-equipped colonoscopy for colorectal cancer screening over a twelve-month period were evaluated, in a “post hoc” analysis. Results 542 colonoscopies (389 HD+ with i-Scan; 153 SWL): expert and non-expert endoscopists did respectively 272 and 117 HD+ with i-Scan and 83 and 70 SWL colonoscopies. Expert endoscopists did more i-Scan colonoscopies than non-experts ( p = 0.006). In the SWL procedures, the experts detected mucosal lesions in more colonoscopies than non-experts (61/22 vs. 23/47, p = 0.0001) and found a significantly higher mean number of lesions (1.34 vs. 0.47; p = 0.0001). Experts detected more or less the same mean number of lesions with both imaging techniques, while among non-experts detection with HD+ with i-Scan was significantly better than with SWL imaging (1.39 vs. 0.47; p = 0.0001). Conclusions HD+ with i-Scan imaging enables less skilled endoscopists to achieve results comparable to those of experienced ones in detecting mucosal lesions.