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We wondered whether nonenhanced computed tomography (CT) within 48 hours of admission could identify individuals at risk for higher mortality from acute pancreatitis. Data from the international phase III study of the platelet-activating factor-inhibitor Lexipafant was used to analyze noncontrast CT versus acute pancreatitis mortality. Nonenhanced CT examinations of the abdomen from the trial were classified by disease severity (Balthazar grades A-E) and then correlated with patient survival. Among the 477 individuals who underwent CT within 48 hours of admission and 220 individuals who did so over the subsequent 6 days, higher CT grades were associated with increased mortality. Each unit increase in Balthazar grade during the initial 48 hours was associated with an estimated increase in the risk of mortality of 33%, and this trend increased to 50% if pancreatic enlargement and peripancreatic stranding (grades B and C) were combined (P < 0.05). CT grade correlated minimally with Ranson, Glasgow, or APACHE II score during the initial 48 hours; however, this correlation improved over 3–8 days. Early nonenhanced abdominal CT in patients with acute pancreatitis is a valuable prognostic indicator of mortality in acute pancreatitis, even among patients without clinical features of severe acute pancreatitis.

The recent clinical trials of lexipafant in the treatment of acute pancreatitis were undertaken with considerable optimism. It was expected that this single agent anticytokine would reduce the morbidity and mortality of this disease. Published clinical trials of lexipafant (BB-882) in acute pancreatitis were retrieved by MEDLINE, EM Base, and Science Citation Index. The critical appraisal included the question asked, design of the study, group and selection of patients, results, and statistical analysis. The historical sequence of the trials and the impact of commerce on their performance were highlighted. Lexipafant did not reduce mortality in severe acute pancreatitis. Comparison between the trials is difficult because of changes in study groups and dose. The clinical trials were designed without the benefit of open discussion of the preliminary pharmacological studies. The results of the trials have not been communicated in an open, timely, and systematic manner, probably because of commercial constraints.

For a 30-year period beginning in 1958, the general basis of medical therapy of acute pancreatitis had as its focus the provision of supplementary antiprotease therapy usually given intravenously. This concept was based on the belief that the body's natural antiprotease defense mechanism, which relies heavily on alpha 2-macroglobulin, together with alpha 1-antiprotease (alpha 1-antitrypsin), was inadequate to cope with the vast enzyme release that occurred with the onset of the more severe forms of the disease. This article examines recent studies and emerging theories on the medical therapy of acute pancreatitis.

Oral erythromycin improves gastrointestinal motility and transit after subtotal but not total gastrectomy for cancer A. Woodward, Department of Surgery, East Glamorgan Hospital, Church Village, Pontypridd, Mid Glamorgan CF38 1AB, USA and L. F. Sillin, State University of New York, Health Science Center, Syracuse, New York, USA Authors' reply: D. F. Altomare, Piazza G. Cesare, 11, 70 124 Bari, Italy Prospective placebo-controlled randomized trial of lexipafant in predicted severe acute pancreatitis D. L. A. Wyncoll, R. J. Beale, Intensive Care Unit, Guy's and St Thomas' Hospital Trust, St Thomas Street, London SE1 9RT, UK Authors' reply: C. J. McKay, C. W. Imrie, Department of Surgery, Royal Infirmary, Glasgow G31 2ER, UK Outcome of palliative and gastric bypass surgery for pancreatic head carcinoma in 126 patients R. W. Parks, T. Diamond, Surgical Unit, Mater Hospital Trust, Belfast BT14 6AB, UK Genetic instability in patients with metachronous colorectal cancers M. A. Potter, Molecular Medicine Centre, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK Authors' reply: S. B. SenGupta, C. Y. Yiu, P. B. Boulos, J. D. A. Delhanty, Department of Surgery, University College London Medical School, Whittington Hospital, Highgate Hill, London N19 5NF, UK Amylase concentration of drainage fluid after total gastrectomy Th. Lehnert, Chirurgische Klinik, Ruprecht Karls Universität Heidelberg, 69 120 Heidelberg, Germany Authors' reply: T. Sano, M. Sasako, H. Katai, K. Maruyama, Gastric Surgery Division, National Cancer Center Hospital, Tokyo 104, Japan Subfascial endoscopic perforator surgery is associated with significantly less morbidity and shorter hospital stay than open operation (Linton's procedure) M. Ormiston, Department of Surgery, Hemel Hempstead General Hospital, Hemel Hempstead HP2 4AD, UK

Our knowledge of acute pancreatitis is still far from complete and there is no unanimous agreement concerning the pathophysiological processes leading to typical alterations during the course of acute pancreatitis. We reviewed the paper published in the last decade on the pathophysiology and treatment of acute pancreatitis. It is difficult to translate the experimental therapeutic results into clinical practice. For example, lexipafant was efficacious in decreasing the severity and mortality of lethal pancreatitis in rats, but seems to have no effect on severe acute pancreatitis in humans. Thus, the main problem in acute pancreatitis, especially in the severe form of the disease, is the difficulty of designing clinical studies capable of giving reliable statistically significant answers regarding the benefits of the various proposed therapeutic agents previously tested in experimental settings. Thus, analgesia, supportive care, and treatment of the pulmonary and renal complications remain the cornerstones of the treatment of acute pancreatitis, especially in the severe form of the disease.

Postoperative intra-abdominal adhesion formation is a major clinical problem. We aimed to examine the preventive effect of treatment with the platelet-activating factor (PAF) antagonist (lexipafant, BB-882) on experimentally induced intra-abdominal adhesion formation in rats. Twenty male Sprague-Dawley rats weighing 250 and 290 g were studied. Generation of adhesions in rats by brushing a 1-cm2 area of the cecum and the peritoneum on the right side of the abdominal wall was followed by intra-abdominal administration of saline and 5 mg/kg in a volume of 0.2 ml PAF receptor antagonist BB-882. After 45 days, formation of adhesions was graded and histological evaluation was processed. The severity of adhesions was significantly less in the BB-882 group than in the control group (p < 0.001, p < 0.05). The average adhesion scores in the control and BB-882 groups were 3.2 ± 0.6 and 0.6 ± 0.6, respectively, and the difference between both groups was found to be significant (p < 0.0001). The number of polymorphonuclear leukocytes and fibrotic areas was significantly decreased in the BB-882 group when compared to the control group (p < 0.001, p < 0.002). In conclusion, this study confirms the efficacy of BB-882 in the prevention of postoperative intra-abdominal adhesions in a rat model.

Background: Platelet-activating factor (PAF) may play a pivotal role in the pathogenesis of intestinal ischemic injury. Methods: The potential role of PAF in intestinal ischemia and reperfusion (I/R) and the development of gut endothelial and epithelial barrier dysfunction and distant organ injury were investigated by pretreatment with a PAF antagonist, lexipafant. Bidirectional permeability of the intestinal barrier, enteric bacterial translocation, protease-antiprotease balance and mucosal histology, and also changes in pulmonary and liver endothelial barrier permeability were measured following intestinal ischemia for 40 min with 6 h of reperfusion in rats. Results: Intestinal mucosal endothelial and epithelial permeabilities significantly increased in animals with I/R. Lexipafant prevented the increase in albumin leakage from blood to the mucosal interstitium and the intestinal lumen during reperfusion, and the mucosal albumin leakage from the gut lumen to blood during I/R. Bacterial translocation was frequently noted in animals with I/R, while only a few positive cultures were obtained in animals with I/R administered lexipafant. Less leakage of fluorescein isothiocyanate dextran 70,000 into the interstitial space and gut lumen in I/R animals with lexipafant pretreatment was found under fluorescein microscopy. Lexipafant also partly prevented C1 inhibitor, prekallikrein, and factor X consumption in I/R animals and partly prevented changes in pulmonary and liver albumin leakage. Conclusions: PAF seems to play an important role in I/R-associated intestinal dysfunction and the development of distant organ dysfunction, probably by triggering endothelial and epithelial barrier dysfunction. Furthermore, PAF seems to be partly involved in activation of the protease-antiprotease system. The use of PAF antagonists may provide a mode of treatment against I/R-associated organ dysfunction.

In recent years it has become evident that both the intrapancreatic events and, even more, the extrapancreatic manifestations of severe acute pancreatitis (septic inflammatory response syndrome, whole-body inflammation) depend on immunological mechanisms. Thus far, this has not led to diagnostic or therapeutic consequences, with the exception of clinical trials with a PAF antagonist, lexipafant [1, 2]. In the following, the evidence for the importance of immunological mechanisms in the pathophysiology of severe acute pancreatitis will be presented. First the role of mediators in inflammation in general will be discussed, thereafter the role of cytokines in the pancreas itself during initial organ attack, then the role of cytokines as effectors in the systemic manifestations of acute pancreatitis, and finally possible conse quences for diagnosis and treatment.

Acute pancreatitis is a common condition which may varies in severity from a mild, self-limiting illness to a fulminating, rapidly fatal condition. Two phases of illness are recognised. Initially, patients have a systemic illness characterised by varying degrees of organ failure. In the second and third weeks of the illness, the main problems relate to local, pancreatic complications.

Acute pancreatitis remains a poorly understood and hence unsatisfactorily treated condition1. In general this is a mild self-limiting disease, which resolves within days and can be managed with non-specific supportive measures and analgesia. In about 25% of cases, however, the disease becomes severe, (defined as pancreatitis associated with organ failure or a local complication such as abscess, pseudocyst or necrosis2). It is this severe group that accounts for much of the morbidity and mortality of the disease. The overall mortality is reported at about 8–10%3, and this occurs almost exclusively in those with severe disease. Published series have shown that organ failure and particularly respiratory failure are the most common complications.

Two trials investigating the use of the platelet activating factor antagonist lexipafant have shown that treatment with the agent can reduce mortality and complications associated with acute pancreatitis, when compared with placebo administration. However, the treatment is only effective in patients receiving lexipafant within 48 hours of disease onset. At the 6th United European Gastroenterology Week [Birmingham, UK; October 1997], gastro-enterologists called for an improvement in the early diagnosis of this life-threatening condition in order to give potential new treatments a greater chance of improving outcome.

The platelet-activating factor (PAF) antagonist lexipafant has a role in the treatment of acute pancreatitis, according to research findings presented at the 5th International Congress on Platelet-Activating Factor and Related Lipid Mediators [ Berlin, Germany; September 1995 ]. The therapeutic potential of PAF antagonists is currently under investigation in several indications, particularly inflammatory diseases. Few convincing findings on the therapeutic value of these agents have been presented to date, but the latest data are encouraging.