Michael Raraty

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.

Current standards of surgery for pancreatic cancer

Pancreatic cancer carries a dismal prognosis but there has been a vast increase in evidence on its management in the past decade.

Acute pancreatitis: the substantial human and financial costs

A greater understanding of the natural history of acute pancreatitis combined with greatly improved radiological imaging has led to improvement in the hospital mortality from acute pancreatitis, from around 25–30% to 6–10% in the past 30 years. Moreover, it is now recognised that the first phase of severe acute phase pancreatitis is a systemic inflammatory response syndrome (SIRS), during which multiple organ failure and death often supervene. Survival into the second phase may be accompanied by local complications, such as infected pancreatic necrosis, which may be prevented by prophylactic antibiotics and treated by judicious surgery. Intensive care unit costs can be substantial, but might be justified because of the excellent quality of life of survivors. Reduction in multiple organ failure by agents such as lexipafant, an antagonist of platelet activating factor (PAF) (which plays a critical role in generating the SIRS), may contribute to intensive care unit cost containment, as well as reducing the incidence of local complications and deaths from acute pancreatitis. A further improvement in the human and financial costs also requires the centralisation of the management of patients with severe acute pancreatitis, to single hospital units whose concentrated expertise equips them to intervene most effectively in what is still recognised as a highly complex disease.

'Preoperative platelet-lymphocyte ratio is an independent significant prognostic marker in resected pancreatic ductal adenocarcinoma'

BACKGROUND The objective of this study was to investigate whether the preoperative platelet-lymphocyte (P/L) ratio represents a significant prognostic index in resected pancreatic ductal adenocarcinoma. METHODS A total of 110 patients undergoing pancreatoduodenectomy for pancreatic ductal adenocarcinoma over a 10-year period were identified from a prospectively maintained database. RESULTS The preoperative P/L ratio was found to be a more significant prognostic marker (P < .001) than either the lymphocyte count (P = .007) or platelet count (P = .068) on univariate Cox survival analysis. The median overall survival in patients with a P/L ratio of 150 or less (n = 48) was 19.7 months, 13.7 months in those with a P/L ratio of 151 to 300 (n = 43), and 5.8 months in patients with a value of greater than 300 (n = 19) (log-rank, P = .006). The preoperative P/L ratio retained significance on multivariate analysis (P < .001), along with tumor size (P = .010) and lymph node ratio (P = .013). CONCLUSIONS The preoperative P/L ratio represents a significant independent prognostic index in patients of resected pancreatic adenocarcinoma.

Minimal access retroperitoneal pancreatic necrosectomy: improvement in morbidity and mortality with a less invasive approach.

Objective:Comparison of minimal access retroperitoneal pancreatic necrosectomy (MARPN) versus open necrosectomy in the treatment of infected or nonresolving pancreatic necrosis. Summary of Background Data:Infected pancreatic necrosis may lead to progressive organ failure and death. Minimal access techniques have been developed in an attempt to reduce the high mortality of open necrosectomy. Methods:This was a retrospective analysis on a prospective data base comprising 189 consecutive patients undergoing MARPN or open necrosectomy (August 1997 to September 2008). Outcome measures included total and postoperative ICU and hospital stays, organ dysfunction, complications and mortality using an intention to treat analysis. Results:Overall 137 patients underwent MARPN versus open necrosectomy in 52. Median (range) age of the patients was 57.5 (18–85) years; 118 (62%) were male. A total of 131 (69%) patients were tertiary referrals, with a median time to transfer from index hospital of 19 (2–76) days. Etiology was gallstones or alcohol in 129 cases (68%); 98 of 168 (58%) patients had a positive culture at the first procedure. Of the 137 patients, 34 (31%) had postoperative organ failure in the MARPN group, and 39 of 52 (56%) in the open group (P < 0.0001); 59/137 (43%) versus 40/52 (77%), respectively, required postoperative ICU support (P < 0.0001). Of the 137 patients 75 (55%) had complications in the MARPN group and 42 of 52 (81%) in the open group (P = 0.001). There were 26 (19%) deaths in the MARPN group and 20 (38%) following open procedure (P = 0.009). Age (P < 0.0001), preoperative multiorgan failure (P < 0.0001), and surgical procedure (MARPN, P = 0.016) were independent predictors of mortality. Conclusion:This study has shown significant benefits for a minimal access approach including fewer complications and deaths compared with open necrosectomy.

Minimally Invasive Retroperitoneal Pancreatic Necrosectomy

Introduction: Open surgery for pancreatic necrosis is associated with considerable morbidity and mortality. We report the results of a recently developed minimally invasive technique that we adopted in 1998. Methods: A descriptive explanation of the approach is given together with the results of a retrospective analysis of patients who underwent a minimally invasive retroperitoneal pancreatic necrosectomy (MIRP) between August 1998 and April 2002. Patients: There were 24 patients with a median (range) age of 61 (29–75) years. The initial median (range) APACHE II score was 8 (2–21). All patients had infected pancreatic necrosis with at least 50% pancreatic necrosis. In three patients it was not possible to complete the first MIRP because of technical reasons. Results: A total of 88 procedures were performed with a median (range) of 4 (0–8) per patient. Twenty-one (88%) patients developed 36 complications during the course of their illness. Five patients required an additional open procedure: 2 for subsequent distant collections, 2 for bleeding and 1 for persisting sepsis and a distant abscess. Six (25%) patients who had MIRP died. The median (range) post-operative hospital stay was 51 (5–200) days. Conclusions: MIRP is a new technique that has shown promising results, and could be preferable to open pancreatic necrosectomy in selected patients. However, unresolved issues remain to be overcome and the exact role of MIRP in the management of pancreatic necrosis has yet to be defined.

Classification of R1 resections for pancreatic cancer: the prognostic relevance of tumour involvement within 1 mm of a resection margin.

Aims:  The current Royal College of Pathologists guidelines for pancreatoduodenectomy specimen reporting recommend that microscopic evidence of tumour within 1 mm of a resection margin (RM) should be classified as R1. No clinical evidence exists to justify this classification. The aim of this study was to identify the proportion of pancreatoduodenectomy specimens in which ‘equivocal’ RMs are present (tumour involvement within 1 mm of, but not directly reaching, one or more resection margins) and whether the survival of these patients was similar to that of patients with ‘unequivocal’ RM involvement.

Signal transduction, calcium and acute pancreatitis

Evidence consistently suggests that the earliest changes of acute pancreatitis are intracellular, the hallmark of which is premature intracellular activation of digestive zymogens, accompanied by disruption of normal signal transduction and secretion. Principal components of physiological signal transduction include secretagogue-induced activation of G-protein-linked receptors, followed by generation of inositol 1,4,5-trisphosphate, nicotinic acid adenine dinucleotide phosphate and cyclic ADP-ribose. In response, calcium is released from endoplasmic reticulum terminals within the apical, granular pole of the cell, where calcium signals are usually contained by perigranular mitochondria, in turn responding by increased metabolism. When all three intracellular messengers are administered together, even at threshold concentrations, dramatic potentiation results in sustained, global, cytosolic calcium elevation. Prolonged, global elevation of cytosolic calcium is also induced by hyperstimulation, bile salts, alcohol and fatty acid ethyl esters, and depends on continued calcium entry into the cell. Such abnormal calcium signals induce intracellular activation of digestive enzymes, and of nuclear factor ĸB, as well as the morphological changes of acute pancreatitis. Depletion of endoplasmic reticulum calcium and mitochondrial membrane potential may contribute to further cell injury. This review outlines current understanding of signal transduction in the pancreas, and its application to the pathophysiology of acute pancreatitis.

Review article: chemotherapy for pancreatic cancer

Pancreatic cancer is a common, highly lethal disease that is rising in incidence. Chemotherapy based on 5‐fluorouracil (5‐FU) has been shown to prolong survival in advanced pancreatic cancer. Gemcitabine improves major symptoms and survival outcomes compared with bolus 5‐FU. Many novel small molecules are being widely and actively researched. These compounds are based on classical mechanisms of action as well as biological therapies targeting novel cellular survival pathways, and include fluoropyrimidines, nucleoside cytidine analogues, platinum analogues, topoisomerase‐inhibitors, antimicrotubule agents, proteasome inhibitors, vitamin D analogues, arachidonic acid pathway inhibitors, histone deacytylator inhibitors, farnesyltransferase inhibitors and epidermal growth factor receptor therapies.

Surgery in the Treatment of Acute Pancreatitis Minimal Access Pancreatic Necrosectomy

Between 5% and 10% of patients with acute pancreatitis will develop infected pancreatic necrosis. Traditional open surgery for this condition carries a mortality rate of up to 50%, and therefore a number of less invasive techniques have been developed, including radiological drainage and a minimal access retroperitoneal approach. No randomised controlled trials have been published which compare these techniques. Indications for minimal access surgery are the same as for open surgery, i.e. infected pancreatic necrosis or failure to improve with extensive sterile necrosis. Access is obtained to the pancreatic necrosis via the left loin and necrosectomy performed using an operating nephroscope, and this often requires several procedures to remove all necrotic tissue. The cavity is continuously irrigated on the ward in between procedures. The results of this approach are encouraging, with less systemic upset to the patient, a lower incidence of post-operative organ failure when compared with open surgery, and a reduced requirement for ITU support. There is also a trend towards a lower mortality rate, although this does not reach statistical significance on the data published so far. Current evidence suggests that a minimal access approach to pancreatic necrosis is feasible, well tolerated and beneficial for the patient when compared with open surgery.