Background: The revised Atlanta classification (RAC) on acute pancreatitis (AP) presents distinct criteria for severity categorization [1]. Currently all patients with AP are hospitalized and managed identically. As incidence, and subsequently financial costs, is rising the necessity of early differentiation in AP will increase. This study aimed to investigate the capacity of biomarkers to stratify AP patients early in the course of the disease. Methods: Patients with AP were consecutively enrolled and dichotomized into mild versus moderately severe plus severe AP (non-mild) according to the RAC. Serum samples taken within 13-36 hours after onset of disease were analyzed for 20 biomarkers. Through receiver operating curves cut-offs were set for the biomarkers that differed significantly between the mild and non-mild group. Patients were additionally classified according to the harmless acute pancreatitis score (HAPS) [2]. Results: Among the 175 patients, 70.9 % had mild and 29.1 % non-mild AP. CRP and IL-6 combined, with the cut-off levels 57.0 and 23.6 respectively, demonstrated superior discriminative capacity with an area under the curve of 0.803, sensitivity 98%, specificity 54% and a positive and negative likelihood ratio of 2.1 and 0.06 for the non-mild group. Regarding the mild cases, the identification potential of the HAPS was generally inferior compared to CRP plus IL-6. Conclusion: In this study CRP and IL-6 demonstrate a clinically relevant capacity to differentiate mild from non-mild AP early in the course of AP. References: [1] Banks et al, (2013), Classification of acute pancreatitis—2012: revision of the Atlanta classification and definitions by international consensus, Gut. [2] Lankisch et al, (2009), The Harmless Acute Pancreatitis Score: A Clinical Algorithm for Rapid Initial Stratification of Nonsevere Disease, Clinical Gastroenterology and Hepatology.

Background: The revised Atlanta classification on acute pancreatitis (AP) presents distinct criteria for severity categorization. Due to the lack of reliable prognostic markers, a majority of patients with AP are currently hospitalized and initially managed identically. As incidence and financial costs are rising the need for early severity differentiation will increase. This study aimed to investigate the capacity of biomarkers to stratify AP patients during the initial course of the disease.Methods: Patients with AP were prospectively enrolled and dichotomized into mild or non-mild (moderately severe and severe AP) according to the revised Atlanta classification. Serum samples taken within 13-36 h after onset of disease were analyzed for 20 biomarkers. Through receiver operating curves cut-off levels were set for 5 biomarkers whose stratifying ability was further analyzed. Additionally, the patients were classified according to the harmless acute pancreatitis score (HAPS).Results: Among the 175 patients, 70.9% had mild and 29.1% non-mild AP. CRP and IL-6 combined, with cut-off levels 57.0 and 23.6 respectively, demonstrated superior discriminative capacity with an area under the curve of 0.803, sensitivity 98%, specificity 54% and a positive and negative likelihood ratio of 2.1 and 0.06 for the non-mild group. Regarding the mild group likelihood ratios were positive 26.5 and negative 0.48. The identification potential of the HAPS was generally inferior when compared to CRP plus IL-6.Conclusions: In this study CRP and IL-6 demonstrate a clinically relevant capacity to differentiate mild from non-mild AP early in the course of AP. (C) 2017 IAP and EPC. Published by Elsevier B.V. All rights reserved.

Minor safety incidents on the railway cause disruption, and may be indicators of more serious safety risks. The following paper aimed to gain an understanding of the relationship between active and latent factors, and particular causal paths for these types of incidents by using the Human Factors Analysis and Classification System (HFACS) to examine rail industry incident reports investigating such events. 78 reports across 5 types of incident were reviewed by two authors and cross-referenced for interrater reliability using the index of concordance. The results indicate that the reports were strongly focused on active failures, particularly those associated with work-related distraction and environmental factors. Few latent factors were presented in the reports. Different causal pathways emerged for memory failures for events such a failure to call at stations, and attentional failures which were more often associated with signals passed at danger. The study highlights a need for the rail industry to look more closely at latent factors at the supervisory and organisational levels when investigating minor safety of the line incidents. The results also strongly suggest the importance of a new factor – operational environment – that captures unexpected and non-routine operating conditions which have a risk of distracting the driver. Finally, the study provides further demonstration of the utility of HFACS to the rail industry, and of the usefulness of the index of concordance measure of interrater reliability.

Introduction: The revised Atlanta classification (RAC) assesses acute pancreatitis (AP) as mild, moderately severe or severe. The mild group recover fast without complications. Despite this fact all patients with AP are hospitalized with supportive care due to lack of markers for prediction of mild or severe course. The aim of this study was to analyze predictive biomarkers in AP to identify patients with mild disease. Method: Patients with AP admitted to Malmö University Hospital were consecutively enrolled 2010–2013. Serum samples were taken upon admission and analyzed for the routine and non-routine biomarkers stated in Table 1. Results: 232 patients were included. According to the RAC, 72.3% had mild, 21.2% moderately severe and 6.5% severe AP. Significant differences (p < 0.05) between the mild versus the moderately severe and severe groups together were as seen in Table 1. When using logistic regression analysis of all biomarkers the two groups with mild and moderately severe and severe AP were to 100% correctly classified. Through stepwise forward logistic regression IL-10 (cut-off 15.5 pg/ml, sensibility 58% and specificity 75%) and Calcium (cut-off 2.17 mmol/l, sensibility 57% and specificity 85%) were identified as independent predictive markers for mild disease. Receiver operating curves for logistic regression modelling of non-routine and routine markers yielded areas under the curves of 0.731 and 0.934 respectively. Conclusions: Patients with mild AP might be identified already upon admission which could support early discharge for a large group of patients. Both routine and non-routine markers might be used for this purpose.TableRoutine markersP-values mild vs mod severe plus severeRoutine markersP-values mild vs mod severe plus severeNon-routine markersP-values mild vs mod severe plus severeProcalcitoninnsLactate0.003IFN-γnsD-dimernsThrombocytesnsIL-1β0.011CRP0.001P-glucose0.006IL-60.004Hemoglobin0.001HematocritnsIL-6RnsCreatininensIL-8nsALATnsIL-100.008White blood cells0.001IL-12nsCalcium0.006TNF-αnsAlbumin0.004MCP-1ns Open table in a new tab [Table 1]

Aims: With the aim of early prediction of severity in acute pancreatitis (AP), a large amount of biomarkers have been studied. Many studies report cut-off levels for promising markers in their specific cohort. The aim of this study was to predictively study biomarkers in AP using preset cut-off levels based on the results of earlier works. Methods: The literature on predictive biomarkers for severe AP was reviewed. Nine promising biomarkers were selected; IL-6, IL-8, IL-10, IL-12, IL1-Î2, TNF-α, MCP-1, Procalcitonin and D-dimer. Cut-off levels for prediction of severity were set for each marker based on the results of prior studies. Patients with AP admitted to a university hospital from January 2010 to March 2014 where consecutively enrolled. Blood samples were collected upon admission and chosen biomarkers were analyzed. Clinical data was collected both prospectively at inclusion and through review of medical notes. Results: 260 patients, 51.5% males, were included. Median age was 66 years (range 19–97 years) and aetiology was biliary (54.2%), alcohol (15.8%), unknown (21.2%) and other (post-ERCP pancreatitis, tumor, other strictures) (13.5%). According to the Atlanta 1992 classification 84.2% had mild and 15.8% had severe AP. The levels of IL-6, IL-10 and IL-1Î2 were significantly (p < 0.05) higher in the group with severe AP. When analyzing the preset cut-off levels no acceptable specificity or sensitivity for prediction of severity was found. Subsequently, for each biomarker, we performed ROC-curves which showed different cut-off levels in our cohort than in previous studies. Conclusions: The results of earlier studies on prediction of severity in AP are difficult to compare due to dissimilar patient characteristics, widespread setups and various outcomes. Differing interpretation of severity classification might also play a role. To be able to set generally applicable cut-off levels, a higher degree of standardization and uniformity is needed in future studies.

Elevated γ-Glutamyltransferase serum levels are associated with increased risk of overall cancer incidence and several site-specific malignancies. In the present prospective study we report on the associations of serum γ-Glutamyltransferase with the risk of breast cancer in a pooled population-based cohort considering established life style risk factors.Two cohorts were included in the present study, i.e. the Vorarlberg (n = 97,268) and the Malmoe cohort (n = 9,790). Cox proportional hazards regression models were fitted to estimate HRs for risk of breast cancer.In multivariate analysis adjusted for age, body mass index and smoking status, women with γ-Glutamyltransferase levels in the top quartile were at significantly higher risk for breast cancer compared to women in the lowest quartile (HR 1.21, 95% CI 1.09 to 1.35; p = 0.005). In the subgroup analysis of the Malmoe cohort, γ-Glutamyltransferase remained an independent risk factor for breast cancer when additionally considering alcohol intake. A statistically significant increase in risk was seen in women with γ-Glutamyltransferase-levels in the top versus lowest quartile in a multivariate model adjusted for age, body mass index, smoking status, physical activity, parity, oral contraceptive-use and alcohol consumption (HR 1.37, 95% CI 1.11-1.69, p = 0.006).Our findings identified γ-Glutamyltransferase as an independent risk factor for breast cancer beyond the consumption of alcohol and other life style risk factors.

Background: Early prediction of severe acute pancreatitis (SAP) substantially improves treatment of patients. A large amount of biomarkers have been studied with this objective. The aim of this work was to study predictive biomarkers using preset cut-off levels in an unselected population of patients with acute pancreatitis (AP). Methods: 232 patients (52.2% males, median age 66 years) with AP admitted to Skåne University Hospital, Malmö, were consecutively enrolled. Blood samples were collected upon admission and clinical data were gathered both prospectively at inclusion and through review of medical notes. Cut-off levels were defined based on the reports of prior studies, and through their results eight biomarkers (IL-1β, IL-6, IL-8, IL-10, TNF-α, MCP-1, procalcitonin and D-dimer) were selected for analysis. Results: Of the patients, 83.2% had mild AP and 16.8% had SAP. Levels of IL-1β, IL-6 and IL-10 were significantly (p < 0.05) higher upon admission in the group with SAP. When applying the preset cut-off levels on our material, sensitivity and specificity for prediction of severity were low. Receiver operating characteristic curves showed that selected cut-off levels were acceptable, but areas under the curves were inferior compared to other studies. The results did not improve when using the revised Atlanta 2012 classification. Conclusions: Previous studies on severity prediction of AP are difficult to compare due to large variations in setups and outcomes. Calculated cut-offs in our cohort were in acceptable range from preset levels, however areas under the curves were low, indicating suboptimal biomarkers for the unselected population investigated. For comparable results and possible clinical implementations, future studies need large consecutive series with a reasonable percentage of severe cases. Additionally, novel biomarkers need to be explored.

I. Alwayn, Halifax D.K. Bartsch, Marburg C. Bassi, Verona W.O. Bechstein, Frankfurt am Main J.A. Bradley, Cambridge M. Cikirikcioglu, Geneva P.-A. Clavien, Zurich U. Dahmen, Jena R.W.F. de Bruin, Rotterdam S. Fichtner-Feigl, Regensburg H. Friess, Munich G. Galata, London D.J. Gouma, Hilversum J.K. Habermann, Lübeck M. Heberer, Basel M. Heger, Amsterdam T. Hubert, Lille W.R. Jarnagin, New York, N.Y. J.C. Kalff, Bonn M.W. Laschke, Homburg/Saar H.-A. Lehr, Friedrichshafen C.M. Malata, Cambridge T. Minor, Bonn M. Morino, Torino J. Pirenne, Leuven A. Schachtrupp, Melsungen T. Schmitz-Rixen, Frankfurt a.M. R. Schramm, Munich L. Steinstraesser, Oldenburg A. Szijártó, Budapest R.H. Tolba, Aachen M. van Griensven, Munich T.M. van Gulik, Amsterdam M.A. Venermo, Helsinki M.H. Wilhelmi, Hannover D.C. Winter, Dublin Y. Yamamoto, Akita Clinical and Experimental Surgery

Purpose: Laparoscopic transcystic common bile duct (CBD) exploration is a safe single-stage procedure for CBD stone clearance. The aim of this report was to describe our experience of transcystic laser lithotripsy in patients with complex CBD stones. Materials and Methods: Data from consecutive patients treated with transcystic holmium:YAG laser lithotripsy was collected and analyzed concerning age, sex, number of stones, duct clearance, conversions, operation time, complications, and hospital stay. Results: Duct clearance was achieved in all (n=8) patients as a single-stage procedure, although 1 had to be converted to open surgery. Median operation time was 225 minutes and hospital stay was 2 days. There was no postoperative morbidity or mortality. Conclusions: Laparoscopic transcystic use of holmium:YAG laser for complex CBD stones seems safe and efficient even though operation time is long. The technique has the potential of completing the treatment armamentarium for transcystic laparoscopic clearance of difficult CBD stones.

Intestinal ischemia-reperfusion injury occurs in several clinical conditions and after intestinal transplantation. The aim of the present study was to investigate the phenomena of apoptosis and cell proliferation in a previously described intestinal ischemia-reperfusion injury autograft model using immunohistochemical markers. The molecular mechanisms involved in ischemia-reperfusion injury repair were also investigated by measuring the expression of the early activation genes c-fos and c-jun, which induce apoptosis and cell proliferation.Thirty adult male Wistar rats were subjected to surgery for a previously described ischemia-reperfusion model that preserved the small intestine, the cecum and the ascending colon. Following reperfusion, the cecum was harvested at different time points as a representative segment of the intestine. The rats were allocated to the following four subgroups according to the reperfusion time: subgroup 1: 5 min; subgroup 2: 15 min; subgroup 3: 30 min; and subgroup 4: 60 min. A control group of cecum samples was also collected. The expression of c-fos, c-jun and immunohistochemical markers of cell proliferation and apoptosis (Ki67 and TUNEL, respectively) was studied.The expression of both c-fos and c-jun in the cecum was increased beginning at 5 min after ischemia-reperfusion compared with the control. The expression of c-fos began to increase at 5 min, peaked at 30 min, and exhibited a declining tendency at 60 min after reperfusion. A progressive increase in c-jun expression was observed. Immunohistochemical analyses confirmed these observations.The early activation of the c-fos and c-jun genes occurred after intestinal ischemia-reperfusion injury, and these genes can act together to trigger cell proliferation and apoptosis.

Background: There are few data on the joint influence of metabolic factors on risk of separate cancers.Methods: We analysed data on body mass index, blood pressure and plasma levels of glucose, total cholesterol and triglycerides from seven European cohorts comprising 564 596 men and women with a mean age of 44 years. We weighted those factors equally into a standardized metabolic risk score [MRS, mean = 0, standard deviation (SD) = 1], with an individual's level indicated as SDs from the sex- and cohort-specific means. Cancer hazard ratios were calculated by Cox regression with age as timescale and with relevant adjustments including smoking status. All statistical tests were two-sided.Results: During a mean follow-up of 12 years, 21 593 men and 14 348 women were diagnosed with cancer. MRS was linearly and positively associated with incident cancer in total and at sites (P< 0.05). In men, risk per SD MRS was increased by 43% (95% confidence interval: 27-61) for renal cell cancer, 43% (16-76) for liver cancer, 29% (20-38) for colon cancer, 27% (5-54) for oesophageal cancer, 20% (9-31) for rectal cancer, 19% (4-37) for leukaemias, 15% (1-30) for oral cancer and 10% (2-19) for bladder cancer. In women, risk increases per SD MRS were 56% (42-70) for endometrial cancer, 53% (29-81) for pancreatic cancer, 40% (16-67) for renal cell cancer, 27% (9-47) for cervical cancer and 17% (3-32) for rectal cancer.Conclusion: This largest study to date on the joint influence of metabolic factors on risk of separate cancers showed increased risks for several cancers, in particular renal cell and liver cancer in men and endometrial and pancreatic cancer in women.

To assess the association between height and risk of cancer and cancer death.

Evidence of a protective effect of several antioxidants and other nutrients on pancreatic cancer risk is inconsistent. The aim of this study was to investigate the association for prediagnostic plasma levels of carotenoids, vitamin C, retinol and tocopherols with risk of pancreatic cancer in a case–control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC). 446 incident exocrine pancreatic cancer cases were matched to 446 controls by age at blood collection, study center, sex, date and time of blood collection, fasting status and hormone use. Plasma carotenoids (α‐ and β‐carotene, lycopene, β‐cryptoxanthin, canthaxanthin, zeaxanthin and lutein), α‐ and γ‐tocopherol and retinol were measured by reverse phase high‐performance liquid chromatography and plasma vitamin C by a colorimetric assay. Incidence rate ratios (IRRs) with 95% confidence intervals (95%CIs) for pancreatic cancer risk were estimated using a conditional logistic regression analysis, adjusted for smoking status, smoking duration and intensity, waist circumference, cotinine levels and diabetes status. Inverse associations with pancreatic cancer risk were found for plasma β‐carotene (IRR highest vs. lowest quartile 0.52, 95%CI 0.31–0.88, p for trend = 0.02), zeaxanthin (IRR highest vs. lowest quartile 0.53, 95%CI 0.30–0.94, p for trend = 0.06) and α‐tocopherol (IRR highest vs. lowest quartile 0.62, 95%CI 0.39–0.99, p for trend = 0.08. For α‐ and β‐carotene, lutein, sum of carotenoids and γ‐tocopherol, heterogeneity between geographical regions was observed. In conclusion, our results show that higher plasma concentrations of β‐carotene, zeaxanthin and α‐tocopherol may be inversely associated with risk of pancreatic cancer, but further studies are warranted.

BACKGROUND:Obesity is associated with an increased risk of esophageal adenocarcinoma (EAC) and a decreased risk of esophageal squamous cell carcinoma (ESCC). However, little is known about the risk of EAC and ESCC related to other metabolic risk factors. We aimed to examine the risk of EAC and ESCC in relation to metabolic risk factors, separately and combined in a prospective cohort study.METHODS:The Metabolic Syndrome and Cancer cohort includes prospective cohorts in Austria, Norway and Sweden, with blood pressure, lipids, glucose and BMI available from 578 700 individuals. Relative risk (RR) for EAC and ESCC was calculated using Cox's proportional hazards analysis for metabolic risk factors categorized into quintiles and transformed into z-scores. The standardized sum of all z-scores was used as a composite score for the metabolic syndrome (MetS).RESULTS:In total, 324 histologically verified cases of esophageal cancer were identified (114 EAC, 184 ESCC and 26 with other histology). BMI was associated with an increased risk of EAC (RR 7.34 (95% confidence interval, 2.88-18.7) top versus bottom quintile) and negatively associated with the risk of ESCC (RR 0.38 (0.23-0.62)). The mean value of systolic and diastolic blood pressure (mid blood pressure) was associated with the risk of ESCC (RR 1.77 (1.37-2.29)). The composite MetS score was associated with the risk of EAC (RR 1.56 (1.19-2.05) per one unit increase of z-score) but not ESCC.CONCLUSIONS:In accordance with previous studies, high BMI was associated with an increased risk of EAC and a decreased risk of ESCC. An association between high blood pressure and risk of ESCC was observed but alcohol consumption is a potential confounding factor that we were not able to adjust for in the analysis. The MetS was associated with EAC but not ESCC. However this association was largely driven by the strong association between BMI and EAC. We hypothesize that this association is more likely to be explained by factors directly related to obesity than the metabolic state of the MetS, considering that no other metabolic factor than BMI was associated with EAC.

Elevated prediagnostic testosterone and insulin‐like growth factor I (IGF‐I) concentrations have been proposed to increase risk of hepatocellular carcinoma (HCC). However, the metabolism of these hormones is altered as a consequence of liver damage and they may have clinical utility as HCC risk markers. A case–control study was nested within the European Prospective Investigation into Cancer and Nutrition cohort and included 125 incident HCC cases and 247 individually matched controls. Testosterone, sex hormone‐binding globulin (SHBG) and IGF‐I were analyzed by immunoassays. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by conditional logistic regression. The area under the receiver operating curves (AUC) was calculated to assess HCC predictive ability of the tested models. After adjustments for epidemiological variables (body mass index, smoking, ethanol intake, hepatitis and diabetes) and liver damage (a score based on albumin, bilirubin, aspartate aminotransaminase, alanine aminotransaminase, gamma‐glutamyltransferase and alkaline phosphatase concentrations), only SHBG remained significantly associated with risk [OR for top versus bottom tertile of 3.86 (1.32–11.3), p trend = 0.009]. As a single factor SHBG had an AUC of 0.81 (0.75–0.86). A small, but significant increase in AUC was observed when SHBG was added to a model including the liver damage score and epidemiological variables (from 0.89 to 0.91, p = 0.02) and a net reclassification of 0.47% (0.45–0.48). The observed associations of HCC with prediagnostic SHBG, free testosterone and IGF‐I concentrations are in directions opposite to that expected under the etiological hypotheses. SHBG has a potential to be tested as prediagnostic risk marker for HCC. © 2013 UICC

Findings suggest that higher consumption of dietary fiber and lower consumption of total sugars are associated with lower HCC risk. In addition, high dietary fiber intake could be associated with lower IBD cancer risk.

Helicobacter pylori is a recognized causal factor of noncardia gastric cancer (GC). Lipopolysaccharide and peptidoglycan of this bacterium are recognized by CD14, TLR4 and NOD2 human proteins, while NFKB1 activates the transcription of pro‐inflammatory cytokines to elicit an immune response. Single nucleotide polymorphisms (SNPs) in these genes have been associated with GC in different populations. We genotyped 30 SNPs of these genes, in 365 gastric adenocarcinomas and 1,284 matched controls from the European Prospective Investigation into Cancer cohort. The association with GC and its histological and anatomical subtypes was analyzed by logistic regression and corrected for multiple comparisons. Using a log‐additive model, we found a significant association between SNPs in CD14 , NOD2 and TLR4 with GC risk. However, after applying the multiple comparisons tests only the NOD2 region remained significant ( p = 0.009). Analysis according to anatomical subtypes revealed NOD2 and NFKB1 SNPs associated with noncardia GC and CD14 SNPs associated with cardia GC, while analysis according to histological subtypes showed that CD14 was associated with intestinal but not diffuse GC. The multiple comparisons tests confirmed the association of NOD2 with noncardia GC ( p = 0.0003) and CD14 with cardia GC ( p = 0.01). Haplotype analysis was in agreement with single SNP results for NOD2 and CD14 genes. From these results, we conclude that genetic variation in NOD2 associates with noncardia GC while variation in CD14 is associated with cardia GC.