Pancreatic cancer is one of our most lethal malignancies. Despite substantial improvements in the survival rates for other major cancer forms, pancreatic cancer survival rates have remained relatively unchanged since the 1960s. Pancreatic cancer is usually detected at an advanced stage and most treatment regimens are ineffective, contributing to the poor overall prognosis. Herein, we review the current understanding of pancreatic cancer, focusing on central aspects of disease management from radiology, surgery and pathology to oncology. Historical remarks & present stateThe first known description of pancreatic cancer is attributed to Giovanni Battista Morgagni in his 1761 publication 'de Sedibus Et Causis Morborum Per Anatomen Indagatis Libri Quinque' [1]. However, the lack of a microscopic evaluation makes the true diagnosis of ductal adenocarcinoma uncertain. The next important advancement in our understanding of pancreatic cancer did not come until 1858, when Jacob Mendez Da Costa revisited Morgagni's original work and also described the first microscopic diagnosis of adenocarcinoma, manifesting pancreatic cancer as a true disease entity [2].The history of pancreatic surgery is fairly recent and involves a combination of brave surgical pioneers, the development of surgical anesthesia and modern aseptic techniques. Some landmarks in the history of pancreatic surgery deserve to be mentioned. The first reported attempt at a pancreaticoduodenectomy was performed in 1898 by the Italian surgeon Alessandro Codivilla for a tumor involving the head of the pancreas [3]; however, the patient did not survive the postoperative period. In the same year, William Stewart Halsted from Johns Hopkins Hospital performed the first successful resection for ampullary cancer by excising portions of the duodenum and the pancreas [4]. The first successful pancreaticoduodenectomy is credited to the German surgeon Walther Carl Eduard Kausch, as part of a two-stage procedure [5]. In 1914, Georg Hirschel performed the first successful pancreaticoduodenectomy in one stage [6] and then in 1935, Allen Oldfather Whipple presented the results of a two-stage procedure involving the resection of the head of the pancreas and duodenum for ampullary carcinoma at the annual meeting of the American Surgical Association, which renewed interest in pancreatic surgery [7]. During his career, Whipple performed 37 pancreaticoduodenectomies, with the procedure evolving into a one-stage technique [8,9], and 1964-1968 1969-1973 1974-1978 1979-1983 1984-1988 1989-1993 1994-1998 1999-2003 2004-2008 2009-2013 Period of diagnosis Whipple is generally credited with popularizing the operation that still bears his name. In 1937, Alexander Brunschwig performed the first successful pancreaticoduodenectomy for pancreatic adenocarcinoma [10]. Today, with the concentration of experience in high-volume hospitals, pancreatic surgery has become a safe procedure associated with an operative mortality below 3% [11][12][13]. While major advances have been made ...

BackgroundHeart transplantation is life saving for patients with end-stage heart disease. However, a number of factors influence how well recipients and donor organs tolerate this procedure. The main objective of this study was to develop and validate a flexible risk model for prediction of survival after heart transplantation using the largest transplant registry in the world.Methods and FindingsWe developed a flexible, non-linear artificial neural networks model (IHTSA) and classification and regression tree to comprehensively evaluate the impact of recipient-donor variables on survival over time. We analyzed 56,625 heart-transplanted adult patients, corresponding to 294,719 patient-years. We compared the discrimination power with three existing scoring models, donor risk index (DRI), risk-stratification score (RSS) and index for mortality prediction after cardiac transplantation (IMPACT). The accuracy of the model was excellent (C-index 0.600 [95% CI: 0.595–0.604]) with predicted versus actual 1-year, 5-year and 10-year survival rates of 83.7% versus 82.6%, 71.4% – 70.8%, and 54.8% – 54.3% in the derivation cohort; 83.7% versus 82.8%, 71.5% – 71.1%, and 54.9% – 53.8% in the internal validation cohort; and 84.5% versus 84.4%, 72.9% – 75.6%, and 57.5% – 57.5% in the external validation cohort. The IHTSA model showed superior or similar discrimination in all of the cohorts. The receiver operating characteristic area under the curve to predict one-year mortality was for the IHTSA: 0.650 (95% CI: 0.640–0.655), DRI 0.56 (95% CI: 0.56–0.57), RSS 0.61 (95% CI: 0.60–0.61), and IMPACT 0.61 (0.61–0.62), respectively. The decision-tree showed that recipients matched to a donor younger than 38 years had additional expected median survival time of 2.8 years. Furthermore, the number of suitable donors could be increased by up to 22%.ConclusionsWe show that the IHTSA model can be used to predict both short-term and long-term mortality with high accuracy globally. The model also estimates the expected benefit to the individual patient.

BackgroundTo improve the prognosis of patients with pancreatic cancer, new biomarkers are required for earlier, pre-symptomatic diagnosis. Epigenetic mutations take place at the earliest stages of tumorigenesis and therefore offer new approaches for detecting and diagnosing disease. Nucleosomes are the repeating subunits of DNA and histone proteins that constitute human chromatin. Because of their release into the circulation, intact nucleosome levels in serum or plasma can serve as diagnostic disease biomarkers, and elevated levels have been reported in various cancers. However, quantifying nucleosomes in the circulation for cancer detection has been challenging due to nonspecific elevation in sera of patients with benign diseases. Here, we report for the first time differential, disease-associated epigenetic profiles of intact cell-free nucleosomes (cfnucleosomes) containing specific DNA and histone modifications as well as histone variants circulating in the blood. The study comprised serum samples from 59 individuals, including 25 patients with resectable pancreatic cancer, 10 patients with benign pancreatic disease, and 24 healthy individuals using Nucleosomics®, a novel ELISA method.ResultsMultivariate analysis defined a panel of five serum cfnucleosome biomarkers that gave an area under the curve (AUC) of 0.95 for the discrimination of pancreatic cancer from healthy controls, which was superior to the diagnostic performance of the common pancreatic tumor biomarker, carbohydrate antigen 19-9 (CA 19-9) with an AUC of 0.87. Combining CA 19-9 with a panel of four cfnucleosome biomarkers gave an AUC of 0.98 with an overall sensitivity of 92 % at 90 % specificity.ConclusionsThe present study suggests that global epigenetic profiling of cfnucleosomes in serum using a simple NuQ® immunoassay-based approach can provide novel diagnostic biomarkers in pancreatic cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-015-0139-4) contains supplementary material, which is available to authorized users.