John Slavin

Early prediction of severity in acute pancreatitis by urinary trypsinogen activation peptide: a multicentre study.

BACKGROUND There is a pressing clinical requirement for an early simple test of severity in acute pancreatitis. We investigated the use of an assay of trypsinogen activation peptide (TAP). METHODS We undertook a multicentre study in 246 patients (172 with acute pancreatitis [35 with severe disease], 74 controls). We assessed the predictive value of urinary TAP concentrations measured by a validated competitive immunoassay. We compared the results with those for plasma C-reactive protein and three clinicobiochemical scoring systems. TAP and C-reactive protein concentrations were analysed at set times after symptom onset and compared with the clinicobiochemical systems scores at key times during hospital stay. FINDINGS At 24 h after symptom onset, the median urinary TAP concentration was 37 nmol/L (IQR 17-110) for severe and 15 nmol/L (5-35) for mild disease (p<0.001). The respective values for plasma C-reactive protein were 24 mg/L (3-34) and 25 mg/L (6-75; p=0.208). The sensitivity, specificity, positive predictive, and negative predictive values of the test to show severe acute pancreatitis compared with mild acute pancreatitis at 24 h were: for TAP (>35 nmol/L), 58%, 73%, 39%, and 86%, respectively, and for C-reactive protein (>150 mg/L), 0%, 90%, 0%, and 75%. 48 h after admission the values for the clinicobiochemical scoring systems were: APACHE II (> or =8), 56%, 64%, 30%, and 85%; Ranson score (> or =3), 89%, 64%, 38%, and 96%; and Glasgow score (> or =3), 77%, 75%, 44%, and 93%. At 48 h, the values for C-reactive protein were 86%, 61%, 37%, and 94% and for TAP were 83%, 72%, 44%, and 94%. Combined testing of C-reactive protein and TAP was not superior to TAP alone for accuracy. INTERPRETATION Urinary TAP provided accurate severity prediction 24 h after onset of symptoms. This single marker of severity in acute pancreatitis deserves routine clinical application.

Inflammatory mediators in acute pancreatitis

Inflammatory mediators play a key role in acute pancreatitis and the resultant multiple organ dysfunction syndrome, which is the primary cause of death in this condition. Recent studies have confirmed the critical role played by inflammatory mediators such as TNF‐α, IL‐1β, IL‐6, IL‐8, PAF, IL‐10, C5a, ICAM‐1, and substance P. The systemic effects of acute pancreatitis have many similarities to those of other conditions such as septicaemia, severe burns, and trauma. The delay between the onset of inflammation in the pancreas and the development of the systemic response makes acute pancreatitis an ideal experimental and clinical model with which to study the role of inflammatory mediators and to test novel therapies. Elucidation of the key mediators involved in the pathogenesis of acute pancreatitis will facilitate the development of clinically effective anti‐inflammatory therapy. Copyright

Expression of the chemokines MCP-1/JE and cytokine-induced neutrophil chemoattractant in early acute pancreatitis

Introduction Inflammatory mediators play a critical role in acute pancreatitis. The precise role played by members of the chemokine family remains unclear. Aims To investigate the expression of the CC chemokine monocyte chemotactic protein (MCP)-1/JE and the CXC chemokine cytokine-induced neutrophil chemoattractant (CINC) in early acute pancreatitis. Methodology Pancreatitis was induced in rats, either by intraperitoneal injection of cerulein or by infusion of 5% sodium taurocholate into the pancreatic duct. Expression of MCP-1/JE and CINC in pancreas and plasma was determined by immunohistochemistry, enzyme-linked immunosorbent assay (ELISA), Northern analysis, and quantitative real-time reverse transcriptase polymerase chain reaction (RT-PCR). Results Following induction of acute pancreatitis, MCP-1/JE and CINC immunoreactivity was seen in acinar cells. Infiltrating neutrophils were strongly immunolabeled with an anti-MCP-1/JE antibody, whereas macrophages reacted strongly with an antibody to CINC. Northern analysis and quantitative real-time RT-PCR demonstrated upregulation of MCP-1/JE and CINC mRNA levels in pancreatic tissue. Plasma MCP-1 levels were significantly increased after 6 hours in the cerulein hyperstimulation model (2,444 ± 93 &mgr;g/mL versus control, 1,853 ± 262 &mgr;g/mL;p < 0.05). Plasma CINC levels were significantly increased after 6 hours in the cerulein hyperstimulation model (1,680 ± 134 &mgr;g/mL versus control, 725 ± 128 &mgr;g/mL;p < 0.005) and after 3 hours in the bile salt infusion model (6,663 ± 1,405 &mgr;g/mL versus control, 2,339 ± 800 &mgr;g/mL;p < 0.05). Conclusion CINC and MCP-1/JE may be early mediators of the inflammatory response in acute pancreatitis.

Standard Kausch-Whipple Pancreatoduodenectomy

Despite the increasing number of clinical trials in pancreatic cancer there are no widely accepted definitions of different types of resection for pancreatic cancer. An agreed definition of the standard Kausch-Whipple pancreatoduodenectomy was derived by a group of international experts at a meeting in Castelfranco Veneto, Italy, in May 1998. The lymph node groups to be removed en bloc with the pancreatoduodenectomy and described using the Japanese Pancreas Society classification were as follows: 13a and 13b; 17a and 17b; 12b1, 12b2 and 12c; and 14a and 14b. Limited segmental major venous resection and adjacent organ resection, if required, may be included as part of a standard pancreatoduodenectomy. The pylorus-preserving procedure also may be included as part of standard resection, but not for tumours of the anterior-superior part of the head of the pancreas. Wider adoption of the definition of standard Kausch-Whipple resection will enable a more objective comparative analysis of the radicality of resection between institutions and permit a more coherant analysis on the type of surgery undertaken in multicentre adjuvant studies.

Severe acute pancreatitis is related to increased early urinary levels of the activation peptide of pancreatic phospholipase A2

Background/Aim: In acute pancreatitis, it is believed that generalized activation of pancreatic zymogens leads to autodigestion of the pancreas and if excessive to systemic organ injury. Under physiological circumstances, secretory phospholipase A2 type I (sPLA2-I) is activated by trypsinogen, but the extent of this activation in acute pancreatitis is unclear. The aim of this study was to assess time course and level of activation of sPLA2-I and trypsinogen in acute pancreatitis, relative to severity. Methods: 246 patients were enrolled into a prospective European multicenter study. 137 patients had mild and 35 had severe acute pancreatitis, and there were 74 control patients. Urinary samples were taken on admission and at 6-hour intervals for 48 h, then every 12 h up to 72 h, and finally daily for at least 5 days for measurement of the activation peptide of sPLA2-I (pro-phosphatase A2; PROP) and trypsinogen activation peptide. Results: The median maximum PROP values were significantly elevated 48 h after symptom onset in patients with severe acute pancreatitis [1.52 (95% CI 0.8–2.9) nmol/l] as compared with patients with mild acute pancreatitis [0.72 (0.55–1) nmol/l, p = 0.002] and controls [0.49 (0.22–1.2) nmol/l, p = 0.001], but not before or after this time point. The best cutoff point for urinary PROP to predict overall severity was >1 nmol/l ≤48 h after symptom onset (negative predictive value = 88%), but the PROP levels failed to predict the development of multi-organ dysfunction. Conclusions: Activation of sPLA2-I is associated with the early pathogenesis of acute pancreatitis, but not in the development of distant organ damage. This observation raises questions as to the theory of generalized zymogen activation being a principle mechanism involved in the pathogenesis of distant organ damage in acute pancreatitis.

European Adjuvant Trials

The results of large European randomized studies have been invaluable in determining a safe and standardized treatment protocol for patients with pancreatic cancer. It is clear that standard doses of postoperative adjuvant chemoradiotherapy have no survival advantage and may even be disadvantageous. Adjuvant chemotherapy, on the other hand, looks to be much more promising and warrants detailed evaluation. Further effective therapies can now be assessed within large cooperative organizations to improve the outlook, survival, expectancy, and quality of life for these patients. In this respect, ESPAC has been a major advance in clinical scientific investigation.