Nationwide trends and outcomes of neoadjuvant chemotherapy in pancreatic cancer - an analysis of the Swedish national pancreatic cancer registry.

OBJECTIVES: During the last decade, neoadjuvant therapy (NAT) for pancreatic cancer has become more frequent. Pathological response and overall survival are promising; however, various post-operative complications have been reported. Our primary aim was to compare the complication scenario of patients receiving NAT in borderline resectable and locally advanced disease with those who had upfront pancreatic surgery (UFS) for primarily resectable cancer. METHODS: From the Swedish National Pancreatic and Periampullary Cancer Registry, patients resected for pancreatic ductal adenocarcinoma (PDAC) between 2010 and 2018 were identified. Data on patient characteristics, neoadjuvant therapy, post-operative complications and survival were obtained. Comparisons between groups as well as survival analysis were performed. RESULTS: Within the total cohort of 13,948 patients, 1894 (median age 69 years, 51% men) were resected for PDAC. Among these, 112 (5.9%) patients received NAT followed by surgery. The patients who received NAT were younger (67 vs 70 years, p < .001), had a lower level of CA19-9 (47 vs 108, p = .001) and had to a larger extent vascular resection (58.9 vs 26.9%, p < .001) and total pancreatectomy performed (23.2 vs 9.1%, p < .001). No difference was found for major post-operative complications and there was no significant change in survival rate between the NAT and UFS groups (median 28 vs 26 months, p = .122). CONCLUSIONS: When analyzing data from a national registry, no difference in post-operative complications was found between resected patients receiving UFS and NAT for PDAC. Also, the survival was equal between groups. NAT is a feasible treatment option for patients with potentially curable pancreatic cancer.

Lifetime alcohol intake, drinking patterns over time and risk of stomach cancer: A pooled analysis of data from two prospective cohort studies.

Alcohol consumption is causally linked to several cancers but the evidence for stomach cancer is inconclusive. In our study, the association between long-term alcohol intake and risk of stomach cancer and its subtypes was evaluated. We performed a pooled analysis of data collected at baseline from 491 714 participants in the European Prospective Investigation into Cancer and Nutrition and the Melbourne Collaborative Cohort Study. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated for incident stomach cancer in relation to lifetime alcohol intake and group-based life course intake trajectories, adjusted for potential confounders including Helicobacter pylori infection. In all, 1225 incident stomach cancers (78% noncardia) were diagnosed over 7 094 637 person-years; 984 in 382 957 study participants with lifetime alcohol intake data (5 455 507 person-years). Although lifetime alcohol intake was not associated with overall stomach cancer risk, we observed a weak positive association with noncardia cancer (HR = 1.03, 95% CI: 1.00-1.06 per 10 g/d increment), with a HR of 1.50 (95% CI: 1.08-2.09) for ≥60 g/d compared to 0.1 to 4.9 g/d. A weak inverse association with cardia cancer (HR = 0.93, 95% CI: 0.87-1.00) was also observed. HRs of 1.48 (95% CI: 1.10-1.99) for noncardia and 0.51 (95% CI: 0.26-1.03) for cardia cancer were observed for a life course trajectory characterized by heavy decreasing intake compared to light stable intake (Phomogeneity = .02). These associations did not differ appreciably by smoking or H pylori infection status. Limiting alcohol use during lifetime, particularly avoiding heavy use during early adulthood, might help prevent noncardia stomach cancer. Heterogeneous associations observed for cardia and noncardia cancers may indicate etiologic differences.

Heparin-binding protein is significantly increased in acute pancreatitis.

BACKGROUND: Most patients with acute pancreatitis (AP) experience mild, self-limiting disease with little or no need for hospital care. However, 20-25% of patients develop a more severe and potentially life-threatening condition with progressive systemic inflammatory response syndrome (SIRS) and multiorgan failure, resulting in high morbidity and mortality rates. Predicting disease severity at an early stage is important, as immediate supportive care has been demonstrated to reduce the incidence of SIRS and organ failure, improving patient outcome. Several studies have demonstrated elevated levels of heparin-binding protein (HBP) in patients with sepsis and septic shock, and HBP is believed to play a part in endothelial dysfunction leading to vascular leakage. As HBP levels increase prior to other known biomarkers, HBP has emerged as a promising early predictor of severe sepsis with organ dysfunction. METHODS: Patients admitted to Skåne University Hospital in Malmö between 2010 and 2013 fulfilling the criteria for AP were identified in the emergency department and prospectively enrolled in this study. The primary outcome was measured levels of HBP upon hospital admission in patients with confirmed AP. Correlations among HBP concentrations, disease severity and fluid balance were considered secondary endpoints. The correlation between HBP levels and fluid balance were analysed using Pearson correlation, and the ability of HBP to predict moderately severe/severe AP was assessed using a receiver operating characteristic (ROC) curve. RESULTS: The overall median HBP level in this study was 529 (307-898) ng/ml. There were no significant group differences in HBP levels based on AP severity. Fluid balance differed significantly between patients with mild versus moderately severe and severe pancreatitis, but we found no correlation between HBP concentration and fluid balance. CONCLUSIONS: HBP levels are dramatically increased in patients with AP, and these levels far exceed those previously reported in other conditions. In this study, we did not observe any significant correlation between HBP levels and disease severity or the need for intravenous fluid. Additional studies on HBP are needed to further explore the role of HBP in the pathogenesis of AP and its possible clinical implications.

Dietary folate intake and pancreatic cancer risk: Results from the European prospective investigation into cancer and nutrition.

Pancreatic cancer (PC) has an exceptionally low survival rate and primary prevention strategies are limited. Folate plays an important role in one-carbon metabolism and has been associated with the risk of several cancers, but not consistently with PC risk. We aimed to investigate the association between dietary folate intake and PC risk, using the standardised folate database across 10 European countries. A total of 477,206 participants were followed up for 11 years, during which 865 incident primary PC cases were recorded. Folate intake was energy-adjusted using the residual method. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models. In multivariable analyses stratified by age, sex, study centre and adjusted for energy intake, smoking status, BMI, educational level, diabetes status, supplement use and dietary fibre intake, we found no significant association between folate intake and PC risk: the HR of PC risk for those in the highest quartile of folate intake (≥353 µg/day) compared to the lowest (<241 µg/day) was 0.81 (95% CI: 0.51, 1.31; ptrend = 0.38). In current smokers, a positive trend was observed in PC risk across folate quartiles [HR = 4.42 (95% CI: 1.05, 18.62) for ≥353 µg/day vs. <241 µg/day, ptrend = 0.01]. Nonetheless, there was no significant interaction between smoking and dietary folate intake (pinteraction = 0.99). We found no association between dietary folate intake and PC risk in this large European study.

Determinants of Severity in Acute Pancreatitis: A Nation-wide Multicenter Prospective Cohort Study.

OBJECTIVE: The aim of this study was to compare and validate the different classifications of severity in acute pancreatitis (AP) and to investigate which characteristics of the disease are associated with worse outcomes. SUMMARY OF BACKGROUND DATA: AP is a heterogeneous disease, ranging from uneventful cases to patients with considerable morbidity and high mortality rates. Severity classifications based on legitimate determinants of severity are important to correctly describe the course of disease. METHODS: A prospective multicenter cohort study involving patients with AP from 23 hospitals in Spain. The Atlanta Classification (AC), Revised Atlanta Classification (RAC), and Determinant-based Classification (DBC) were compared. Binary logistic multivariate analysis was performed to investigate independent determinants of severity. RESULTS: A total of 1655 patients were included; 70 patients (4.2%) died. RAC and DBC were equally superior to AC for describing the clinical course of AP. Although any kind of organ failure was associated with increased morbidity and mortality, persistent organ failure (POF) was the most significant determinant of severity. All local complications were associated with worse outcomes. Infected pancreatic necrosis correlated with high morbidity, but in the presence of POF, it was not associated to higher mortality when compared with sterile necrotizing pancreatitis. Exacerbation of previous comorbidity was associated with increased morbidity and mortality. CONCLUSION: The RAC and DBC both signify an advance in the description and differentiation of AP patients. Herein, we describe the complications of the disease independently associated to morbidity and mortality. Our findings are valuable not only when designing future studies on AP but also for the improvement of current classifications.

Lifetime and baseline alcohol intakes and risk of pancreatic cancer in the European Prospective Investigation into Cancer and Nutrition study.

Recent evidence suggested a weak relationship between alcohol consumption and pancreatic cancer (PC) risk. In our study, the association between lifetime and baseline alcohol intakes and the risk of PC was evaluated, including the type of alcoholic beverages and potential interaction with smoking. Within the European Prospective Investigation into Cancer and Nutrition (EPIC) study, 1,283 incident PC (57% women) were diagnosed from 476,106 cancer-free participants, followed up for 14 years. Amounts of lifetime and baseline alcohol were estimated through lifestyle and dietary questionnaires, respectively. Cox proportional hazard models with age as primary time variable were used to estimate PC hazard ratios (HR) and their 95% confidence interval (CI). Alcohol intake was positively associated with PC risk in men. Associations were mainly driven by extreme alcohol levels, with HRs comparing heavy drinkers (>60 g/day) to the reference category (0.1-4.9 g/day) equal to 1.77 (95% CI: 1.06, 2.95) and 1.63 (95% CI: 1.16, 2.29) for lifetime and baseline alcohol, respectively. Baseline alcohol intakes from beer (>40 g/day) and spirits/liquors (>10 g/day) showed HRs equal to 1.58 (95% CI: 1.07, 2.34) and 1.41 (95% CI: 1.03, 1.94), respectively, compared to the reference category (0.1-2.9 g/day). In women, HR estimates did not reach statistically significance. The alcohol and PC risk association was not modified by smoking status. Findings from a large prospective study suggest that baseline and lifetime alcohol intakes were positively associated with PC risk, with more apparent risk estimates for beer and spirits/liquors than wine intake.

IL-6 and CRP are superior in early differentiation between mild and non-mild acute pancreatitis.

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.

Significant inter-observer variation in the diagnosis of extrapancreatic necrosis and type of pancreatic collections in acute pancreatitis - An international multicenter evaluation of the revised Atlanta classification.

BACKGROUND: For consistent reporting and better comparison of data in research the revised Atlanta classification (RAC) proposes new computed tomography (CT) criteria to describe the morphology of acute pancreatitis (AP). The aim of this study was to analyse the interobserver agreement among radiologists in evaluating CT morphology by using the new RAC criteria in patients with AP. METHODS: Patients with a first episode of AP who obtained a CT were identified and consecutively enrolled at six European centres backwards from January 2013 to January 2012. A local radiologist at each center and a central expert radiologist scored the CTs separately using the RAC criteria. Center dependent and independent interobserver agreement was determined using Kappa statistics. RESULTS: In total, 285 patients with 388 CTs were included. For most CT criteria, interobserver agreement was moderate to substantial. In four categories, the center independent kappa values were fair: extrapancreatic necrosis (EXPN) (0.326), type of pancreatitis (0.370), characteristics of collections (0.408), and appropriate term of collections (0.356). The fair kappa values relate to discrepancies in the identification of extrapancreatic necrotic material. The local radiologists diagnosed EXPN (33% versus 59%, P < 0.0001) and non-homogeneous collections (35% versus 66%, P < 0.0001) significantly less frequent than the central expert. Cases read by the central expert showed superior correlation with clinical outcome. CONCLUSION: Diagnosis of EXPN and recognition of non-homogeneous collections show only fair agreement potentially resulting in inconsistent reporting of morphologic findings.

Predictive Capacity of Biomarkers for Severe Acute Pancreatitis.

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-1ß, 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-1ß, 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.

Pleuropulmonary pathologies in the early phase of acute pancreatitis correlate with disease severity.

BACKGROUND: Respiratory failure worsens the outcome of acute pancreatitis (AP) and underlying factors might be early detectable. AIMS: To evaluate the prevalence and prognostic relevance of early pleuropulmonary pathologies and pre-existing chronic lung diseases (CLD) in AP patients. METHODS: Multicentre retrospective cohort study. Caudal sections of the thorax derived from abdominal contrast enhanced computed tomography (CECT) performed in the early phase of AP were assessed. Independent predictors of severe AP were identified by binary logistic regression analysis. A one-year survival analysis using Kaplan-Meier curves and log rank test was performed. RESULTS: 358 patients were analysed, finding pleuropulmonary pathologies in 81%. CECTs were performed with a median of 2 days (IQR 1-3) after admission. Multivariable analysis identified moderate to severe or bilateral pleural effusions (PEs) (OR = 4.16, 95%CI 2.05-8.45, p<0.001) and pre-existing CLD (OR = 2.93, 95%CI 1.17-7.32, p = 0.022) as independent predictors of severe AP. Log rank test showed a significantly worse one-year survival in patients with bilateral compared to unilateral PEs in a subgroup. CONCLUSIONS: Increasing awareness of the prognostic impact of large and bilateral PEs and pre-existing CLD could facilitate the identification of patients at high risk for severe AP in the early phase and thus improve their prognosis.

The Initial Course of IL1ß, IL-6, IL-8, IL-10, IL-12, IFN-γ and TNF-α with Regard to Severity Grade in Acute Pancreatitis.

Clinical reports on early immune dysregulation in acute pancreatitis (AP) are scarce. Herein we investigate the initial temporal development of selected biomarkers. Blood samples were taken at 0-24 and 25-48 h after onsets of AP were acquired. Mean values and temporal intermediate difference (delta-values) of IL-1ß, IL-6, IL-8, IL-10, IL-12, IFN-γ and TNF-α were calculated. Differences between severity groups, predictive capacity of the biomarkers and association with severe disease were analyzed. Paired comparison of samples (n = 115) taken at 0-24 and 25-48 h after onsets of AP showed a change over time for IL-1ß, IL-6, IL-8 and IL-10 (p < 0.05) and a significant difference between severity groups after 24 h. In ROC-analysis an IL-6 cut-off level of 196.6 pg/mL could differentiate severe AP (sensitivity 81.9, specificity 91.3). The delta-values of IL-1ß and IL-6 were significantly associated with severe outcomes (odds ratios 1.085 and 1.002, respectively). Data of this work demonstrate a distinct change in IL-1ß, IL-8, IL-10 and IL-6 over the first 48 h after onset of AP. The temporal development of biomarkers can assist in the early stratification of the disease. Herein IL-1ß and IL-6 were associated with severe disease, however the prognostic capacity of investigated biomarkers is low.

Mean muscle attenuation correlates with severe acute pancreatitis unlike visceral adipose tissue and subcutaneous adipose tissue.

Background: Acute pancreatitis (AP) is a frequent disorder with considerable morbidity and mortality. Obesity has previously been reported to influence disease severity. Objective: The aim of this study was to investigate the association of adipose and muscle parameters with the severity grade of AP. Methods: In total 454 patients were recruited. The first contrast-enhanced computed tomography of each patient was reviewed for adipose and muscle tissue parameters at L3 level. Associations with disease severity were analysed through logistic regression analysis. The predictive capacity of the parameters was investigated using receiver operating characteristic (ROC) curves. Results: No distinct variation was found between the AP severity groups in either adipose tissue parameters (visceral adipose tissue and subcutaneous adipose tissue) or visceral muscle ratio. However, muscle mass and mean muscle attenuation differed significantly with p-values of 0.037 and 0.003 respectively. In multivariate analysis, low muscle attenuation was associated with severe AP with an odds ratio of 4.09 (95% confidence intervals: 1.61-10.36, p-value 0.003). No body parameter presented sufficient predictive capability in ROC-curve analysis. Conclusions: Our results demonstrate that a low muscle attenuation level is associated with an increased risk of severe AP. Future prospective studies will help identify the underlying mechanisms and characterise the influence of body composition parameters on AP.

Short article: Presence, extent and location of pancreatic necrosis are independent of aetiology in acute pancreatitis.

OBJECTIVE: The most common aetiologies of acute pancreatitis (AP) are gallstones, alcohol and idiopathic. The impact of the aetiology of AP on the extent and morphology of pancreatic and extrapancreatic necrosis (EXPN) has not been clearly established. The aim of the present study was to assess the influence of aetiology on the presence and location of pancreatic necrosis in patients with AP. PATIENTS AND METHODS: We carried out a post-hoc analysis of a previously established multicentre cohort of patients with AP in whom a computed tomography was available for review. Clinical data were obtained from the medical records. All computed tomographies were revised by the same expert radiologist. The impact of aetiology on pancreatic and EXPN was calculated. RESULTS: In total, 159 patients with necrotizing pancreatitis were identified from a cohort of 285 patients. The most frequent aetiologies were biliary (105 patients, 37%), followed by alcohol (102 patients, 36%) and other aetiologies including idiopathic (78 patients, 27%). No relationship was found between the aetiology and the presence of pancreatic necrosis, EXPN, location of pancreatic necrosis or presence of collections. CONCLUSION: We found no association between the aetiology of AP and the presence, extent and anatomical location of pancreatic necrosis.

Early management of acute pancreatitis: A review of the best evidence.

In the 20th century early management of acute pancreatitis often included surgical intervention, despite overwhelming mortality. The emergence of high-quality evidence (randomized controlled trials and meta-analyses) over the past two decades has notably shifted the treatment paradigm towards predominantly non-surgical management early in the course of acute pancreatitis. The present evidence-based review focuses on contemporary aspects of early management (which include analgesia, fluid resuscitation, antibiotics, nutrition, and endoscopic retrograde cholangiopancreatography) with a view to providing clear and succinct guidelines on early management of patients with acute pancreatitis in 2017 and beyond.