Background and objective The Atlanta classification of acute pancreatitis enabled standardised reporting of research and aided communication between clinicians.

Pancreatic cancer is a major cause of cancer-associated mortality, with a dismal overall prognosis that has remained virtually unchanged for many decades. Currently, prevention or early diagnosis at a curable stage is exceedingly difficult; patients rarely exhibit symptoms and tumours do not display sensitive and specific markers to aid detection. Pancreatic cancers also have few prevalent genetic mutations; the most commonly mutated genes are KRAS, CDKN2A (encoding p16), TP53 and SMAD4 - none of which are currently druggable. Indeed, therapeutic options are limited and progress in drug development is impeded because most pancreatic cancers are complex at the genomic, epigenetic and metabolic levels, with multiple activated pathways and crosstalk evident. Furthermore, the multilayered interplay between neoplastic and stromal cells in the tumour microenvironment challenges medical treatment. Fewer than 20% of patients have surgically resectable disease; however, neoadjuvant therapies might shift tumours towards resectability. Although newer drug combinations and multimodal regimens in this setting, as well as the adjuvant setting, appreciably extend survival, ∼80% of patients will relapse after surgery and ultimately die of their disease. Thus, consideration of quality of life and overall survival is important. In this Primer, we summarize the current understanding of the salient pathophysiological, molecular, translational and clinical aspects of this disease. In addition, we present an outline of potential future directions for pancreatic cancer research and patient management.

PRRS imposes a substantial financial burden on US swine producers and causes approximately dollar 560.32 million in losses each year. By comparison, prior to eradication, annual losses attributable to classical swine fever (hog cholera) and pseudorabies were estimated at dollar 364.09 million and dollar 36.27 million, respectively (adjusted on the basis of year 2004 dollars). Current PRRS control strategies are not predictably successful; thus, PRRS-associated losses will continue into the future. Research to improve our understanding of ecologic and epidemiologic characteristics of the PRRS virus and technologic advances (vaccines and diagnostic tests) to prevent clinical effects are warranted.

Background: In predicted severe acute pancreatitis, many patients develop organ failure and recover without local complications, and mortality is only 14-30%. It has been suggested that half of patients with progressive early organ failure may die, but there are no data to relate death or local complications to duration of early (week 1) organ failure. Aims: To determine mortality rates in patients with transient (,48 hours) and persistent (.48 hours) early organ failure and to show whether persistent organ failure predicts death or local complications. Patients: A total of 290 patients with predicted severe acute pancreatitis previously studied in a trial of lexipafant, recruited from 78 hospitals through 18 centres in the UK. Method: Manual review of trial database to determine: the presence of organ failure (Marshall score >2) on each of the first seven days in hospital, duration of organ failure, and outcome of pancreatitis (death, complications by Atlanta criteria). Results: Early organ failure was present in 174 (60%) patients. After transient organ failure (n = 71), outcome was good: one death and 29% local complications. Persistent organ failure (n = 103) was followed by 36 deaths and 77% local complications, irrespective of onset of organ failure on admission or later during the first week. Conclusion: Duration of organ failure during the first week of predicted severe acute pancreatitis is strongly associated with the risk of death or local complications. Resolution of organ failure within 48 hours suggests a good prognosis; persistent organ failure is a marker for subsequent death or local complications.

Many patients cope extremely well with a stoma; however, some patients experience considerable difficulty and distress. Improved preoperative assessment and counseling with longer follow-up by the stoma department would be helpful in the management of these patients and probably would contribute to improvement in the quality of their lives.

Pancreatic stellate cells mediate fibrosis in chronic pancreatitis. Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs)-1 and -2 are crucial modulators of fibrosis. Transforming growth factor-beta (TGF-beta) is a key regulator of extracellular matrix production and myofibroblast proliferation. We have examined MMP and TIMP synthesis by transformed cultured pancreatic stellate cells and their regulation by TGF-beta 1. By Northern analysis they expressed mRNAs for procollagen 1, TIMP-1, TIMP-2, and MMP-2. Expression of membrane type-1 MMP was confirmed by Western blotting. By immunohistochemistry these enzymes localized to fibrotic areas in human chronic pancreatitis. Active TGF-beta 1 constitutes 2 to 5% of total TGF-beta 1 secreted by pancreatic stellate cells; they express TGF-beta receptors I and II. Exogenous TGF-beta 1 (10 ng/ml) significantly increased procollagen-1 mRNA by 69% and collagen protein synthesis by 34%. Similarly TGF-beta 1 at 0.1, 1, and 10 ng/ml significantly reduced cellular proliferation rate by 37%, 44%, and 44%, respectively, whereas pan-TGF-beta-neutralizing antibody increased proliferation by 40%. TGF-beta1 (10 ng/ml) down-regulated MMP-9 by 54% and MMP-3 by 34% whereas TGF-beta 1-neutralizing antibody increased MMP-9 expression by 39%. Pancreatic stellate cells express both mediators of matrix remodeling and the regulatory cytokine TGF-beta 1 that, by autocrine inhibition of MMP-3 and MMP-9, may enhance fibrogenesis by reducing collagen degradation.

Conclusions: These experiments elucidate a mechanism by which the DR in pancreatic cancer may form and, via the collagen within it, promote the malignant phenotype of pancreatic cancer cells, suggesting significant detriment to the host.

Background-Platelet activating factor (PAF) is believed to amplify the activity of key mediators of the systemic inflammatory response syndrome (SIRS) in acute pancreatitis, resulting in multiorgan dysfunction syndrome. We tested the hypothesis that a potent PAF antagonist, lexipafant, could dampen SIRS and reduce organ failure in severe acute pancreatitis. Methods-We conducted a randomised, double blind, placebo controlled, multicentre trial of lexipafant (100 mg/24 hours intravenously for seven days commenced within 72 hours of the onset of symptoms) involving 290 patients with an APACHE II score >6. Power calculations assumed that complications would be reduced from 40% to 24%. Secondary end points studied included severity of organ failure, markers of the inflammatory response, and mortality rate. Findings-Overall, 80/138 (58%) patients in the placebo group and 85/148 (57%) in the lexipafant group developed one or more organ failures. The primary hypothesis was invalidated by the unexpected finding that 44% of patients had organ failure on entry into the study; only 39 (14%) developed new organ failure. Organ failure scores were reduced in the lexipafant group only on day 3: median change −1 (range −4 to +8) versus 0 (−4 to +10) in the placebo group (p=0.04). Systemic sepsis aVected fewer patients in the lexipafant group (13/138 v 4/148; p=0.023). Local complications occurred in 41/138 (30%) patients in the placebo group and in 30/148 (20%) in the lexipafant group (20%; p=0.065); pseudocysts developed in 19 (14%) and eight (5%) patients, respectively (p=0.025). Deaths attributable to acute pancreatitis were not significantly diVerent. Interleukin 8, a marker of neutrophil activation, and E-selectin, a marker of endothelial damage, decreased more rapidly in the lexipafant group (both p<0.05); however, absolute values were not diVerent between the two groups. Interpretation-The high incidence of organ failure within 72 hours of the onset of symptoms undermined the primary hypothesis, and power calculations for future studies in severe acute pancreatitis will need to allow for this. Lexipafant had no eVect on new organ failure during treatment. This adequately powered study has shown that antagonism of PAF activity on its own is not suYcient to ameliorate SIRS in severe acute pancreatitis (Gut 2001;48:62-69)