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Ajith K Siriwardena

Publications and source records attributed to Ajith K Siriwardena.

At least 19 recordsLinked to original sources
PubMed2006

Quantitative analysis of plasma DNA in severe acute pancreatitis.

CONTEXT: Release of genomic DNA into plasma as a result of necrotic and apoptotic pathways is a feature of a range of human tumours. Severe acute pancreatitis is characterized by inflammation but may also be associated with accelerated apoptotic and necrotic pathways. OBJECTIVES: This study uses quantitative real-time PCR to measure free circulating DNA in patients with severe acute pancreatitis. PARTICIPANTS: Forty-three patients with severe acute pancreatitis, 12 patients with pancreatic cancer and 28 non-cancer controls undergoing laparoscopic cholecystectomy. METHODS: Plasma DNA was purified and quantified using the RNase P transcription assay and quantitative PCR. In pancreatitis patients, baseline samples were taken on admission and further samples taken at a median of 5 days into the disease course. RESULTS: Plasma DNA levels on admission in patients with acute pancreatitis (median: 0.40 ng/microL; range: 0.05-0.79 ng/microL) were significantly (P<0.001) lower than in non-cancer controls (median: 1.60 ng/microL; range: 0.45-9.10 ng/microL). In patients with acute pancreatitis, DNA levels significantly (P<0.001) fell during the disease course to a median value of 0.08 ng/microL (range: 0-0.53 ng/microL). CONCLUSION: This is the first study to use quantitative PCR to measure free plasma DNA in severe acute pancreatitis. The results show that plasma DNA is lower in patients with acute pancreatitis compared to control and that values fall further during the disease course.

Acute Disease↗
PubMed2006

Evaluation of the Manchester classification system for chronic pancreatitis.

CONTEXT: Classifications of chronic pancreatitis based on either histologic (Marseilles) or endoscopic (Cambridge) criteria are not widely used. OBJECTIVE: The present study describes the development and validation of a three-stage clinical categorical classification system for chronic pancreatitis. DESIGN: Patients with a diagnosis of chronic pancreatitis (577.1: ICD-9) for 1993 were identified from records of the Hepatopancreaticobiliary service at a University hospital. Endoscopic or CT evidence of chronic pancreatitis were mandatory for inclusion. PATIENTS: Forty one patients met the criteria and were categorized according to a 3-stage system as mild, moderate or end-stage disease. MAIN OUTCOME MEASURE: The clinical course over the subsequent decade was followed by chart review with re-categorization of stage at each review. RESULTS: At the outset of the study, 18 (44%) patients were categorised as having mild disease, 19 (46%) as moderate and 4 (10%) as end-stage. The number of patients with mild disease fell over the subsequent 5 years and at the end of the 10-year chart study period, no patients were categorised as mild. The number of patients with diabetes at the outset of the study period was 2 (5%). At two years this was 3 (7%), five years 10 (24%) and 10 years was 25 (61%). CONCLUSIONS: These results show that the Manchester classification of chronic pancreatitis is both practical and feasible and now requires prospective evaluation and independent appraisal by other centres.

Adult↗
PubMed2006

Duodenal duplication cyst with profound elevation of intracystic carbohydrate antigen (CA 19-9) and carcinoembryonic antigen (CEA): a rare but important differential in the diagnosis of cystic tumours of the pancreas.

CONTEXT: Enteric duplication cysts are rare lesions of uncertain incidence and natural history. Pre-operative confirmation of diagnosis can be difficult. This case reports an adult duodenal duplication cyst presenting with grossly elevated intra-lesional levels of tumour markers. CASE REPORT: A 57-year-old female was found to have a complex cystic lesion of the head of the pancreas. Intra-lesional fluid analysis revealed a grossly elevated CA 19-9 and CEA. Resection was undertaken under the assumption that this was a cystic tumour. Macroscopic examination after opening the duodenum revealed a villous, circumferential tumour in the proximal duodenum measuring 4 cm in length. A cystic lesion was present in the medial wall of the tumour and did not communicate with the duodenal lumen. Microscopically, the tumour comprised Brunner's gland hyperplasia with associated mucosal thickening. The wall of the underlying cystic lesion was comprised of muscularis formed by the outer muscle coat of the duodenal wall. The final diagnosis was of a duodenal duplication cyst. There was no evidence of dysplasia or malignancy. CONCLUSION: This is the first report of a duodenal duplication cyst having elevated intra-cyst fluid levels of amylase, carbohydrate antigen CA 19-9 and carcinoembryonic antigen (CEA). Although rare, this is an important differential diagnosis in the management of cystic tumours of the pancreas.

Biomarkers, Tumor↗
PubMed2006

Differential kinetics of plasma CD105 and transforming growth factor beta expression early in human acute pancreatitis.

OBJECTIVES: The interaction of transforming growth factor beta (TGF-beta) with CD105 (endoglin) is an essential step in the maintenance of endothelial cell quiescence. The importance of this interaction during the critical early phases of acute pancreatitis is unknown. This study explores patterns of expression of CD105 and TGF-beta in plasma during human acute pancreatitis. METHODS: Forty-one patients with a clinical diagnosis of acute pancreatitis constitute the study population. Venous blood samples were taken at admission and on the fifth day. Enzyme-linked immunosorbent assay was performed for CD105, TGF-beta1, TGF-beta3, CD105/TGF-beta1, and CD105/TGF-beta3 complexes. RESULTS: TGF-beta1 levels were significantly elevated on admission in the acute pancreatitis group compared with controls and were further elevated in delayed samples. In contrast, admission CD105 levels were similar to those in controls, but in delayed samples, there was a significant reduction in CD105. Levels of TGF-beta3, CD105/TGF-beta1, and CD105/TGF-beta3 did not differ between groups. CONCLUSIONS: This is the first report to investigate the interplay between plasma expression of CD105, TGF-beta1, TGF-beta3, and ligand complexes in acute pancreatitis. The results of this study confirm previous findings that increased expression of TGF-beta1 is a feature of severe acute pancreatitis. The absence of a parallel elevation in CD105 or CD105/TGF-beta ligand complexes is previously unreported and may suggest that angiogenesis mediated by the interaction between CD105 and TGF-beta is not an early feature of this disease.

APACHE↗
PubMed2006

Contemporary management of infected necrosis complicating severe acute pancreatitis.

Pancreatic necrosis complicating severe acute pancreatitis is a challenging scenario in contemporary critical care practice; it requires multidisciplinary care in a setting where there is a relatively limited evidence base to support decision making. This commentary provides a concise overview of current management of patients with infected necrosis, focusing on detection, the role of pharmacologic intervention, and the timing and nature of surgical interventions. Fine-needle aspiration of necrosis remains the mainstay for establishment of infection. Pharmacological intervention includes antibiotic therapy as an adjunct to surgical debridement/drainage and, more recently, drotrecogin alfa. Specific concerns remain regarding the suitability of drotrecogin alfa in this setting. Early surgical intervention is unhelpful; surgery is indicated when there is strong evidence for infection of necrotic tissue, with the current trend being toward 'less drastic' surgical interventions.

Adult↗
PubMed2006

Pro/con debate: antifungal prophylaxis is important to prevent fungal infection in patients with acute necrotizing pancreatitis receiving broad-spectrum antibiotics.

When critically ill patients with pancreatitis develop infection of the pancreas, the ongoing management of such patients becomes difficult. Sufficient evidence supports the use of broad-spectrum antibiotic prophylaxis to prevent the development of bacterial infection. Since fungal infection is also a relatively common complication of severe pancreatitis--particularly when broad-spectrum antibiotics are used--it seems logical that fungal prophylaxis may be an important component of management. In this issue of Critical Care, two expert groups debate the merits of antifungal prophylaxis in patients with acute necrotizing pancreatitis who are receiving antibiotics.

Anti-Bacterial Agents↗
PubMed2005

Radiofrequency ablation of the pancreas. I: Definition of optimal thermal kinetic parameters and the effect of simulated portal venous circulation in an ex-vivo porcine model.

CONTEXT: Radiofrequency ablation of pancreatic tumours carries a risk of injury to important structures such as the bile duct and duodenum. We have recently developed an ex-vivo model of radiofrequency ablation of the porcine pancreas. OBJECTIVE: This study evaluates the effect of variations in probe temperature, duration of ablation and simulated portal venous flow on radiofrequency-induced injury. SPECIMEN RETRIEVAL: Pancreata of 30 6-month-old healthy pigs undergoing sacrifice in a commercial abattoir were used. INTERVENTIONS: Radiofrequency energy was applied to a pre-marked area of the pancreatic head. Pancreatic head biopsies were taken after ablation to incorporate duodenum, portal vein and bile duct respectively and frozen in liquid nitrogen. For each experiment a portion of the tail of the pancreas was studied as non-ablated control. Paired slides using haematoxylin and eosin (H&E) and nicotinamide adenine dinucleotide (NADH) stains were prepared. MAIN OUTCOME MEASURES: The effects of variation in target temperature (100 degrees C to 80 degrees C), duration of ablation and of simulated portal perfusion were studied. RESULTS: Optimal thermal kinetic characteristics were produced by a target temperature of 90 degrees C applied for 5 minutes. At this temperature there was ablation of pancreas without injury to adjacent viscera. Higher temperatures resulted in injury to the bile duct and portal vein. Simulated portal circulation had no effect on ablation. CONCLUSIONS: In this ex-vivo study radiofrequency produced a temperature and duration dependent ablation with the optimal characteristics being 90 degrees C for 5 minutes.

Animals↗
PubMed2005

Radiofrequency ablation of the pancreas. II: Intra-operative ablation of non-resectable pancreatic cancer. A description of technique and initial outcome.

CONTEXT: There is little reported experience of radiofrequency ablation of pancreatic tumours. Our group has reported the development of a porcine pancreatic model of radiofrequency ablation of the pancreas. This brief report details the application of this technique to clinical practice. CASE REPORT: A 58-year-old man with metastatic pancreatic tumour underwent operative radiofrequency ablation. An operative approach was utilised to protect the stomach and transverse colon and also to prevent thermal injury to the inferior vena cava. In addition, the operative technique was combined with prophylactic hepaticojejunostomy and gastrojejunostomy to anticipate ablation-related biliary injury or duodenal stenosis. A post-ablation CT scan two weeks after the procedure confirmed radiological evidence of ablation. The patient remained well until his death, 3 months after surgery. CONCLUSION: This report demonstrates that operative radiofrequency ablation is feasible and was safely carried out in this case. More experience is required to assess the spectrum of complications and if there is true oncological efficacy.

Catheter Ablation↗
PubMed2005

Intravenous selenium modulates L-arginine-induced experimental acute pancreatitis.

CONTEXT: Oxidative stress is understood to have a critical role in the development of acinar injury in experimental acute pancreatitis. We have previously demonstrated that compound multiple antioxidant therapy ameliorates end-organ damage in the intra-peritoneal L-arginine rat model. As the principal co-factor for glutathione, selenium is a key constituent of multiple antioxidant preparations. OBJECTIVE: The intention of this study was to investigate the effect of selenium on pancreatic and remote organ injury in a well-validated experimental model of acute pancreatitis. METHODS: Male Sprague-Dawley rats were randomly allocated to one of 3 groups (n=5/group) and sacrificed at 72 hours. Acute pancreatitis was induced by 250 mg per 100 g body weight of 20% L-arginine hydrochloride in 0.15 mol/L sodium chloride. Group allocations were: Group 1, control; Group 2, acute pancreatitis; Group 3, selenium. MAIN OUTCOME MEASURES: Serum amylase, anti-oxidant levels, bronchoalveolar lavage protein, lung myeloperoxidase activity, and histological assessment of pancreatic injury. RESULTS: L-arginine induced acute pancreatitis characterised by oedema, neutrophil infiltration, acinar cell degranulation and elevated serum amylase. Selenium treatment was associated with reduced pancreatic oedema and inflammatory cell infiltration. Acinar degranulation and dilatation were completely absent. A reduction in bronchoalveolar lavage protein content was also demonstrated. CONCLUSION: Intravenous selenium given 24 hours after induction of experimental acute pancreatitis was associated with a reduction in the histological stigmata of pancreatic injury and a dramatic reduction in broncho-alveolar lavage protein content. Serum selenium fell during the course of experimental acute pancreatitis and this effect was not reversed by exogenous selenium supplementation.

Acute Disease↗
PubMed2005

Drotrecogin alfa (recombinant human activated protein C) in severe acute pancreatitis.

INTRODUCTION: Current concepts of the pathophysiology of acute pancreatitis suggest that disease progression from acinar injury to systemic illness involves a complex interplay between cellular and soluble inflammatory mediators and endothelial beds. To date, there is no specific pharmacologic intervention for acute pancreatitis. Death from acute pancreatitis remains a major issue, and late deaths are often related to haemorrhage and are associated with unresolved intra-abdominal sepsis. Drotrecogin alfa, an analogue of endogenous protein C, has antithrombotic, anti-inflammatory and profibrinolytic properties, and it has been shown to reduce mortality in clinical sepsis. Modulation of the coagulation cascade, although probably essential to the mode of action of drotrecogin alfa, can lead to an increased risk of bleeding. OBJECTIVE: The findings of the PROWESS trial have led to a more widespread use of drotrecogin alfa in sepsis and, critically, in sepsis-related conditions. The present article provides a concise summary of the interaction between the pathophysiology of acute pancreatitis and the modes of action of drotrecogin alfa, placing particular emphasis on the risks related to haemorrhage. Attention is further drawn to the reports of use of drotrecogin alfa in severe acute pancreatitis. CONCLUSION: Synthesis of current knowledge on the modes of action and the side-effect profiles of drotrecogin alfa into a practical management algorithm must accept that evidence in this field is changing rapidly. At present there is insufficient evidence to justify the use of drotrecogin alfa in the early stages of this disease. In the later stages, when the probability of infection is proportionately greater, it is probable that intensive care clinicians will turn to drotrecogin alfa, in particular, in the setting of recent-onset organ dysfunction in established severe acute pancreatitis. Although this can be justified by extrapolation of the evidence from the PROWESS trial, practical critical care management in this setting must not overlook the need to rule out infection of necrosis, and must further be cognisant of the specific risks of haemorrhage in patients with prolonged pancreatitis and pancreatic necrosis.

Acute Disease↗
PubMed2005

Current status of laparoscopic biliary bypass in the management of non-resectable peri-ampullary cancer.

BACKGROUND: In patients with non-resectable peri-ampullary cancer, optimization of quality of life is an important goal. Although endoscopic palliation is widely used, the proponents of laparoscopic biliary bypass claim that this procedure alters management towards surgery. However, the evidence base for selection of laparoscopic bypass is limited and the aim of this report is to scrutinize the available evidence in order to assess the current role of this procedure. METHODS: A computerised literature search was made of the Medline database for the period from January 1966 to December 2004. Searches identified 12 reports of laparoscopic palliation for peri-ampullary cancer. These reports were retrieved and data analysed in the following categories: type of bypass; combination with other procedures; complication and outcome. RESULTS: Laparoscopic cholecystoenterostomy is the commonest form of laparoscopic biliary bypass practiced. Of the 52 reported cases undergoing laparoscopic biliary bypass, 40 underwent laparoscopic cholecystojejunostomy, 6 laparoscopic choledochoduodenostomy and 6 underwent laparoscopic hepaticoje- junostomy. CONCLUSION: Current evidence does not justify the incorporation of laparoscopic biliary bypass techniques into contemporary evidence-based management algorithms for patients with non-resectable periampullary cancer.

Ampulla of Vater↗
PubMed2005

Pathways of care for patients with suspected cancer of the pancreas: a tiered questionnaire-based survey of medical personnel across a single United kingdom Calman-Hine cancer network.

OBJECTIVE: This study examines clinical management pathways for patients with suspected pancreatic cancer within a single United Kingdom Calman-Hine NHS cancer network with particular focus on referral patterns and the primary care-hospital specialist interface. METHODS: A questionnaire-based study appraising responses from three key groups (general practitioners, gastrointestinal physicians and gastrointestinal surgeons) practising within a cancer network. The questionnaire addressed caseload, referral pathways, multidisciplinary care teams and involvement of specialists. PARTICIPANTS: The study population comprised 448 general practitioners, 14 gastroenterologists and 23 gastrointestinal surgeons. RESULTS: The mean number of new patients with suspected pancreatic cancer seen per general practitioner per annum was 0.4 (range: 0-1). Fifty-three percent of general practitioners refer to gastrointestinal physicians and 47% to gastrointestinal surgeons. In hospital, a relatively large number of physicians and surgeons see a small number of new patients each per annum. The involvement of multidisciplinary teams and referral of patients with non-resectable disease for chemotherapy is limited. Fourteen (60.9% out of 23 general surgeons) refer all patients to pancreatic specialists, 4 (17.4%) selectively refer and 5 (21.7%) never refer. CONCLUSION: The findings suggest divergence in standards of care from those advocated in governmental cancer strategic plans. In particular, not all patients with suspected pancreatic cancer see specialists, many hospital specialists see small numbers of cases and multidisciplinary care is limited.

Critical Pathways↗
PubMed2005

Systematic appraisal of the management of the major vascular complications of pancreatitis.

BACKGROUND: This study is a systematic appraisal of the management of major vascular complications of pancreatitis conducted by collating individual patient-episode data from published literature. METHODS: Searches identified 79 papers of which 62 provided detailed information on the clinical course of 214 patients. Principal outcomes were modes of presentation, results of diagnostic angiography, and embolization and overall outcome. RESULTS: There were 160 "spontaneous" and 40 postoperative episodes of hemorrhage. Underlying pancreatic disease was chronic pancreatitis (40), pseudocyst (135), and acute pancreatitis in 39. Angiography was undertaken in 173 (81%) with embolization attempted in 115 and achieving hemostasis in 85 (75%). There were 40 (19%) deaths. Mortality was greater in patients undergoing surgery as first intervention compared with angiography first (P = .01, Fisher exact test). CONCLUSION: This analysis of pooled data provides evidence of a central role for mesenteric angiography in the diagnosis of major vascular complications of pancreatitis and for angiographic embolization as a powerful tool for achieving hemostasis.

Angiography↗
PubMed2005

Inhibition of tyrosine-kinase-mediated cellular signaling by tyrphostins AG 126 and AG556 modulates murine experimental acute pancreatitis.

BACKGROUND: The effects of the tyrosine kinase inhibitors, tyrphostin AG126 and AG556 in a murine model of acute pancreatitis are investigated. METHODS: Intraperitoneal injection of cerulein in mice resulted in a severe, acute pancreatitis, which was characterized by edema, neutrophil infiltration, tissue hemorrhage, and cell necrosis as well as elevation in the serum activities of amylase or lipase. RESULTS: Infiltration of the pancreatic tissue of these animals with neutrophils (measured as increase in myeloperoxidase activity) was associated with signs of enhanced lipid peroxidation (increased tissue levels of malondialdehyde). Immunohistochemical examination showed a marked increase in immunoreactivity for nitrotyrosine and poly (ADP-ribose) polymerase (PARP) in the pancreas of cerulein-treated mice. Pretreatment or posttreatment with tyrphostin AG126 and AG556, 2 different tyrosine kinase inhibitors, significantly reduced the degree of pancreatic inflammation and tissue injury (histologic score). In particular, the treatment with the 2 tyrosine kinase inhibitors reduced the cerulein-induced nitrotyrosine formation and PARP activation in the pancreas as well as the systemic release of tumor necrosis factor alpha. CONCLUSIONS: This study provides the first evidence that (1) prevention of the activation of protein tyrosine kinases reduces the development of acute pancreatitis, and (2) inhibition of the activity of certain tyrosine kinases may represent a novel approach for the therapy of acute pancreatitis.

Acute Disease↗