Acute pancreatitis is a severe condition with an increasing rate of hospital admissions over the last decades, which may be complicated by systemic inflammatory responses, septicemia, multiorgan failure, and death. Medical management of severe acute pancreatitis is complex and often requires intensive care admission and monitoring, mechanical ventilation and other life support measures. It is unclear whether the outcomes of acute pancreatitis are influenced by admission volumes. In this issue of Gastroenterology, Singla et al report on a study evaluating the relationship between admission volumes and outcomes of acute pancreatitis. The authors identified patients above the age of 18 presenting with a primary diagnosis of acute pancreatitis between 1998 and 2006 from the Nationwide Inpatient Sample, a national all-payer hospital inpatient care database in the United States. Diagnoses of acute pancreatitis and complications, and procedures were identified by International Classification of Diseases, 9th edition, Clinical Modification (ICD-9-CM) diagnostic and procedural codes in the database. Patient demographics, comorbidity, payer type, and estimated income (based on income data for the patient's zip code) were also collected. For each individual hospital, descriptive characteristics (teaching status, urban location, hospital bed size, and hospital region) as well as the number of cases of acute pancreatitis admitted were determined annually from the same database. A cutoff at the upper third of hospital volumes was used to distinguish high-volume (≥118 cases/year) from low-volume (<118 cases/year) centers. The primary endpoint of the study was in-hospital mortality. Secondary end points included prolonged length of stay (>90th percentile) and total hospital charges. A total of 416,489 patients who were admitted for the first time with a primary diagnosis of acute pancreatitis were identified. The number of cases of acute pancreatitis increased with each successive year, from 36,510 cases in 1998 to 51,895 cases in 2006. Admissions to high-volume centers accounted for one third of the patient population. High-volume hospitals tended to be large, urban, teaching hospitals. In high-volume hospitals, patients were slightly younger (50 vs 52 years), more likely to be black (22% vs 16%), more likely to belong to the highest income bracket (28% vs 25%), and more likely to have >3 comorbidities (36% vs 31%). On multivariate analysis, high hospital volume was independently associated with a lower likelihood of in-hospital mortality compared with low hospital volume (odds ratio [OR], 0.75; 95% confidence interval [CI], 0.70–0.81). A matched cohort of 86,216 patients divided equally between both groups on the basis of hospital volume was then extracted from the database. Multivariate analysis of this cohort confirmed a 26% reduction of in-hospital mortality risk in high-volume centers (OR, 0.74; 95% CI, 0.67–0.83). In addition, higher mortality rates were associated with increasing age, male gender, comorbidity, and being treated at a teaching hospital (Figure 1). Treatment of acute pancreatitis at a high-volume hospital was also associated with a reduced likelihood of prolonged length of stay (OR, 0.86; 95% CI, 0.82–0.90). This large study based on the Nationwide Inpatient Sample showed significant adjusted mortality benefit for acute pancreatitis at high volume hospitals. The mechanism underlying the volume benefit requires further investigation. A policy of preferential referral of complicated cases of acute pancreatitis to high-volume centers could be considered. See page 1995. Liver transplantation is a life-saving intervention in patients with end-stage liver disease. However, after successful transplantation, there is an increased risk of de novo malignancies in the longer term, and malignancy has been identified as one of the leading causes of late nonhepatic mortality in liver transplant recipients. However, this is mainly based on single-center, retrospective studies and on registry databases. Prospective studies on the incidence and impact of de novo malignancies after liver transplantation are still lacking. In this issue of Gastroenterology, Watt et al report the results of a multicenter, long-term outcome study aimed at identifying the incidence, risk factors, and mortality rates for posttransplant de novo malignancies in adult liver transplant recipients. The authors used the National Institute of Diabetes and Digestive and Kidney Diseases Liver Transplantation Database, which enrolled all liver transplant recipients from 3 clinical centers between April 1990 and June 1994. Follow-up data were obtained on all patients until 2003 (median follow-up, 10 years). All patients with a diagnosis of de novo malignancy posttransplantation were determined and analyzed for patient demographics, preexisting malignancy, etiology of underlying liver disease, alcohol abuse history, smoking history, comorbid illnesses, and type of malignancy. A total of 798 adult patients (mean age, 49 years) were enrolled in the database during the study period. During the 12.6-year study period, 171 patients (22%) developed 271 de novo malignancies; 147 skin related and 124 non-skin related. The cumulative incidence of skin related cancers was 10.8% at 10 years of follow-up. The risk for skin-related malignancies was higher in patients with primary sclerosing cholangitis, in male patients, and increased with age. The overall probability for non-skin malignancy at 10 years was 13.6%, which is approximately double the risk in the general population at the age of 50. Increased age, a history of smoking, primary sclerosing cholangitis, or alcohol-related liver disease were significant risk factors for developing any solid organ de novo malignancy after a liver transplant (Figure 2). Gastrointestinal malignancies were the most common solid organ malignancy, followed by lung, female genitourinary, and oropharyngeal/laryngeal malignancies. Patients with underlying inflammatory bowel disease at the time of transplant were at increased risk for developing a gastrointestinal malignancy. The incidence of lung cancer or oropharyngeal/laryngeal cancers was mainly increased in patients with alcoholic liver disease. Hematologic malignancies were also more common in patients with primary sclerosing cholangitis. The probability of death after diagnosis of all non-skin malignancy was 40% at 1 year, and 55% at 5 years. This large, prospective study demonstrates that de novo malignancy affects more than one fifth of transplant patients after 10 years. Increased age, a history of smoking, and primary sclerosing cholangitis or alcohol-related liver disease increase the probability of developing any solid organ de novo malignancy after a liver transplant. Development of rigorous screening protocols for malignancy detection in liver transplant patients seems warranted, especially in the higher risk subgroups. See page 2010. Patients with hepatic cirrhosis have decreased liver synthetic function limiting their ability to synthesize clotting factors. This raises the prothrombin time measured in the serum, and is taken to indicate enhanced bleeding potential, and these patients are often corrected in medical settings with vitamin K injections and the infusion of fresh frozen plasma. Yet, cirrhotics develop thromboses as well. It has been recently surmised that protein C activation is suboptimal when measuring plasma thrombin generation, but is corrected when measuring it in the presence of thrombomodulin, the main activator of protein C. Measuring thrombin generation in the presence of thrombomodulin may give a more accurate picture of the cirrhotic's bleeding and thrombosis potential. In the study by Tripodi et al, 134 cirrhotics (54 Child A, 57 Child B, and 23 Child C), 131 healthy controls, and 6 patients with congenital protein C deficiency were studied for endogenous thrombin potential (ETP) in platelet-free plasma, representing the balance between the actions of pro- and anticoagulants in plasma. ETP levels were then used to calculate the ratios between values obtained with and without thrombomodulin, denoting the efficiency of thrombomodulin in the activation of protein C and taken as indexes of hypercoagulability. Cirrhotics had prolonged prothrombin time, reduced levels of antithrombin, protein C, factor V, and factor II, and increased levels of factor VIII, with progressive decrease of factors II, V, antithrombin, and protein C from Child A to C, and factor VIII increasing progressively from Child A to C. Child C cirrhotics had protein C levels lower than patients with congenital protein C deficiency. Measuring ETP in the presence of thrombomodulin reduced ETP without thrombomodulin, averaging a 35% reduction in controls and 21% reduction in cirrhotics. Utilizing ETP ratios with and without thrombomodulin, higher ETP ratios were noted in cirrhotics over controls to the same ratios as patients with protein C deficiency (Figure 3). The ETP ratios in cirrhotics progressive increased from Child A to C, with Child C patients displaying higher ETP ratios than patients with protein C deficiency. This study indicates that cirrhotic patients have plasma resistant to the action of thrombomodulin, the main activator of anticoagulant protein C, progresses with Child stage, and is comparable to patients with congenital protein C deficiency. This marked decrease of protein C coupled with increased factor VIII could be responsible for hypercoagulability and risk for thrombosis in cirrhotics. See page 2105. Patients with pancreatic cancer have high mortality from often-occurring metastasis, but mechanisms that control metastasis are poorly understood. A microRNA, miR-10a, located in the homeobox (HOX) B cluster on chromosome 17, was recently discovered to have elevated expression in pancreatic cancer. HOX genes are typically regulated by retinoids, but a connection regarding its regulation by miR-10a has never been made. In the study by Weiss et al, human pancreatic cancer cells with differing metastatic potential as well as primary pancreatic cancers were utilized in a zebrafish embryo metastatic xenotransplantation model to examine miR-10a's function. Expression of miR-10a is elevated in highly metastatic pancreatic cancer cell lines and pancreatic adenocarcinoma, but also in chronic pancreatitis. Using zebrafish yolk xenotransplantation, inhibiting miR-10a expression in metastatic cell lines as well as primary pancreatic cancers prevented metastasis, whereas overexpression of miR-10a in poorly metastatic cell lines conferred metastasis and was associated with down-regulation of cell adhesion cadherin and catenin expression. Treatment of cells with all trans retinoic acid increased miR-10a expression, whereas treatment with a RARα antagonist significantly decreased miR-10a expression. RARα antagonist treatment also decreased pancreatic cancer cell migration and both cell and primary pancreatic tumor metastasis in the zebrafish xenotransplantation model. Knock down of HOXB1 and HOXB3 in poorly metastatic (and miR-10a low expressing) cells conferred metastatic behavior, which could not be rescued with the RARα antagonist suggesting a direct regulation of HOXB1 and HOXB3 by miR-10a. Indeed, overexpression of miR-10a in poorly metastatic cells decreased HOXB1 and HOXB3 expression, whereas miR-10a knock down increased HOXB1 and HOXB3 expression in highly metastatic cells. This study indicates that miR-10a is a retinoic acid-responsive microRNA that downregulates HOXB1 and HOXB3 to promote pancreatic cancer metastasis (Figure 4). Inhibition of miR-10a or use of RARα antagonists may be a strategy to improve pancreatic cancer patient survival. See page 2136. Admission Volume Determines Outcome for Patients With Acute PancreatitisGastroenterologyVol. 137Issue 6PreviewThere is controversy over the optimal management strategy for patients with acute pancreatitis (AP). Studies have shown a hospital volume benefit for in-hospital mortality after surgery, and we examined whether a similar mortality benefit exists for patients admitted with AP. Full-Text PDF Long-term Probability of and Mortality From De Novo Malignancy After Liver TransplantationGastroenterologyVol. 137Issue 6PreviewInformation about malignancies that arise in patients after liver transplantation comes from volunteer registry databases and single-center retrospective studies. We analyzed a multicenter, prospectively obtained database to assess the probabilities of and risk factors for de novo malignancies in patients after liver transplantation. Full-Text PDF An Imbalance of Pro- vs Anti-Coagulation Factors in Plasma From Patients With CirrhosisGastroenterologyVol. 137Issue 6PreviewPatients with cirrhosis have an increased tendency to develop thromboses despite the longer coagulation times of their plasma, compared with that of healthy individuals. We investigated whether plasma from cirrhotic patients has an imbalance of pro- vs anti-coagulation factors. Full-Text PDF Retinoic Acid Receptor Antagonists Inhibit miR-10a Expression and Block Metastatic Behavior of Pancreatic CancerGastroenterologyVol. 137Issue 6PreviewThe infiltrating ductal adenocarcinoma of the pancreas is among the most lethal of all solid malignancies, largely owing to a high frequency of early metastasis. We identified microRNA-10a (miR-10a) as an important mediator of metastasis formation in pancreatic tumor cells and investigated the upstream and downstream regulatory mechanisms of miR-10a. Full-Text PDF