Cristina Pollard

The effect of omega-3 FAs on tumour angiogenesis and their therapeutic potential.

Omega-3 fatty acid (omega-3 FA) consumption has long been associated with a lower incidence of colon, breast and prostate cancers in many human populations. Human trials have demonstrated omega-3 FA to have profound anti-inflammatory effects in those with cancer. In vitro and small animal studies have yielded a strong body of evidence establishing omega-3 FA as having anti-inflammatory, anti-apoptotic, anti-proliferative and anti-angiogenic effects. This review explores the evidence and the mechanisms by which omega-3 FA may act as angiogenesis inhibitors and identifies opportunities for original research trialling omega-3 FAs as anti-cancer agents in humans. The conclusions drawn from this review suggest that omega-3 FAs in particular eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) found principally in oily fish have potent anti-angiogenic effects inhibiting production of many important angiogenic mediators namely; Vascular Endothelial Growth Factor (VEGF), Platelet-Derived Growth Factor (PDGF), Platelet-Derived Endothelial Cell Growth Factor (PDECGF), cyclo-oxygenase 2 (COX-2), prostaglandin-E2 (PGE2), nitric oxide, Nuclear Factor Kappa Beta (NFKB), matrix metalloproteinases and beta-catenin.

Cystic Lesions of the Pancreas

Background/Aims: Due to enhanced imaging modalities, pancreatic cysts are being increasingly detected, often as an incidental finding. They comprise a wide range of differing underlying pathologies from completely benign through premalignant to frankly malignant. The exact diagnostic and management pathway of these cysts remains problematic and this review attempts to provide an overview of the pathology underlying pancreatic cystic lesions and suggests appropriate methods of management. Methods: A search was undertaken with a Pubmed database to identify all English articles using the keywords ‘pancreatic cysts’, ‘serous cystadenoma’, ‘intraductal papillary mucinous tumour’, ‘pseudocysts’, ‘mucinous cystic neoplasm’ and ‘solid pseudopapillary tumour’. Results: The mainstay of assessment of pancreatic cysts is cross-sectional imaging incorporating CT and MRI. Fine-needle aspiration (FNA) (often with endoscopic ultrasound) may provide valuable additional information but can lack sensitivity. Symptomatic cysts, increasing age and multilocular cysts (with a solid component and thick walls) are predictors of malignancy. A raised cyst aspirate CEA, CA 19-9 and mucin content (including abnormal cytology), if present, can accurately distinguish premalignant and malignant cysts from benign ones. Conclusion: In summary, all patients with pancreatic cystic lesions, whether asymptomatic or symptomatic, must be thoroughly investigated to ascertain the underlying nature of the cyst. Small asymptomatic cysts (<3 cm) with no suspicious features on imaging or FNA may be safely followed up. Follow-up should continue for at least 4 years, with a repeat FNA if needed. An algorithm for the management of pancreatic cystic tumours is also suggested.

Islet auto transplantation following total pancreatectomy: a long-term assessment of graft function.

Total pancreatectomy is considered the final resort in the treatment of chronic pancreatitis; however, here we show that simultaneous islet autotransplantation can abrogate the onset of diabetes. Methods: In Leicester, 46 patients have now undergone total pancreatectomy with immediate islet auto transplant, and they have received a median of 2246 islet equivalent (IEQ)/kg body weight (range, 405-20,385 IEQ/kg body weight). Results: Twelve patients have shown periods of insulin independence, for a median of 16.5 months (range, 2-63 months), and 5 remain insulin independent. Over the 10 years of follow-up, there has been a notable increase in insulin requirement per kilogram per day, and percentage of glycosylated hemoglobin levels have increased significantly (r = 0.66, P = 0.01). However, 100% of patients tested were C-peptide positive at their most recent assessment, and high fasting and stimulated C-peptide values recorded at 10 years after transplantation, 1.44 (range, 1.09-1.8 ng/mL) and 2.86 ng/mL (range, 1.19-4.53 ng/mL), respectively, suggest significant graft function in the long term. In addition, median serum creatinine has increased very little after the operation (71 nmol/L [range, 49-125 nmol/L] atpreoperation vs 76.5 nmol/L [range 72-81 nmol/L] at year 10), suggesting no diabetic nephropathy. Conclusions: Although there is a notable decline in islet function after islet auto transplant, there is still evidence of significant long-term insulin secretion and possible protection against diabetic complications.Abbreviations: CP - chronic pancreatitis, HbA1c - glycosylated hemoglobin, IEQ - islet equivalent, OGTT - oral glucose tolerance test, TP - total pancreatectomy

Total pancreatectomy with islet autotransplantation: an overview

Pain control is one of the most challenging aspects in the management of chronic pancreatitis. Total pancreatectomy can successfully relieve the intractable abdominal pain in these patients but will inevitably result in insulin-dependent diabetes. Islet autotransplantation aims to preserve, as far as possible, the insulin secretory function of the islet cell mass thereby reducing (or even removing) the requirement for exogenous insulin administration after a total pancreactomy. Despite the relatively small number of centres able to perform these procedures, there are important technical variations in the details of their approaches. The aim of this review is to provide details of the current surgical practice for total pancreatectomy combined with islet autotransplantation, and outline the potential advantages and disadvantages of the variations adopted in each centre.

A Fuller Understanding of Pancreatic Neuroendocrine Tumours Combined with Aggressive Management Improves Outcome

Background: Neuroendocrine tumours of the pancreas (PNETs) represent 1–2% of all pancreatic tumours. The terms ‘islet cell tumours’ and ‘carcinoids’ of the pancreas should be avoided. The aim of this review is to offer an overview of the history and diagnosis of PNETs followed by a discussion of the available treatment options. Methods: A search on PubMed using the keywords ‘neuroendocrine’, ‘pancreas’ and ‘carcinoid’ was performed to identify relevant literature over the last 30 years. Results: The introduction of a revised classification of neuroendocrine tumours by the World Health Organisation (WHO) in 2000 significantly changed our understanding of and approach to the management of these tumours. Advances in laboratory and radiological techniques have also led to an increased detection of PNETs. Surgery remains the only treatment that offers a chance of cure with increasing number of non-surgical options serving as beneficial adjuncts. The better understanding of the behaviours of PNETs together with improvements in tumour localisation has resulted in a more aggressive management strategy with a concomitant improvement in symptom palliation and a prolongation of survival. Conclusion: Due to their complex nature and the wide range of therapeutic options, the involvement of specialists from all necessary disciplines in a multidisciplinary team setting is vital to provide optimal treatment of this disease.

Patient satisfaction and cost-effectiveness following total pancreatectomy with islet cell transplantation for chronic pancreatitis.

Objectives Chronic pancreatitis (CP) results in an extremely poor quality of life and substantially increases health care utilization. Few data exist regarding the cost-effectiveness of surgical treatment for CP. Methods This article examined the cost-effectiveness of total pancreatectomy (TP) with islet cell autotransplantation (IAT) for CP. Results Sixty patients undergoing TP + IAT and 37 patients undergoing TP were identified. Surgery resulted in significant reduction in opiate use, frequency of hospital admissions, and length of stay as well as visual analog scale scores for pain. Total pancreatectomy + IAT resulted in longer survival than TP alone (16.6 vs 12.9 years); 21.6% of patients with TP + IAT were insulin-independent, and those requiring insulin have reduced daily requirements compared with those having TP alone (22 vs 35 IU). The cost of TP + IAT with attendant admission and analgesia costs over the 16-year survival period was £110,445 compared with £101,608 estimated 16-year costs if no TP + IAT was undertaken. Conclusions Total pancreatectomy + IAT is effective in improving pain and reducing analgesia. Islet cell transplantation offers the chance of insulin independence and results in lower insulin requirements, as well as conferring a survival advantage when compared with TP alone. Total pancreatectomy + IAT is cost-neutral when compared with nonsurgical or segmental surgical therapy.

Laparoscopic pancreatic surgery: a review of present results and future prospects

Pancreatic surgery is still associated with a relatively high morbidity and mortality compared with other specialties. This is a result of the complex nature of the organ, the difficult access as a result of the retroperitoneal position and the number of technically challenging anastomoses required. Nevertheless, the past two decades have witnessed a steady improvement in morbidity and a decrease in mortality achieved through alterations of technique (particularly relating to the pancreatic anastomoses) together with hormonal manipulation to decrease pancreatic secretions. Recently minimally invasive pancreatic surgery has been attempted by several centres around the world which has stimulated considerable interest in this approach. The majority of the cases attempted have been distal pancreatectomies, because of the more straightforward nature of the resection and the lack of a pancreatic ductal anastomosis, but more recently reports of laparoscopic pancreaticoduodenectomy have started to appear. The reports of the series to date have been difficult to interpret and although the results are claimed to be equivalent or better than those associated with a traditional approach a careful examination of the literature and comparison with the best results previously reported does not presently support this. In the present review we examined all the reports of pancreatic procedures performed laparoscopically and compared the results with those previously achieved at open surgery.

Blood Transfusion Policies in Elective General Surgery: How to Optimise Cross-Match-to-Transfusion Ratios

Objective: Preoperative over-ordering of blood is common and leads to the wastage of blood bank resources. The preoperative blood ordering and transfusion practices for common elective general surgical procedures were evaluated in our university hospital to formulate a maximum surgical blood order schedule (MSBOS) for those procedures where a cross-match appears necessary. Methods: We evaluated blood ordering practices retrospectively in all elective general surgical procedures in our institution over a 6-month period. Cross-match-to-transfusion ratios (C:T) were calculated and compared to current trust and the British Society of Haematology (BSH) guidelines. The adjusted C:T ratio was also calculated and was defined as the C:T ratio when only cross-matched blood used intraoperatively was included in the calculation. Results: 541 patients were identified during the 6-month period. There were 314 minor and 227 major surgeries carried out. 99.6% (n = 226) of the patients who underwent major surgery and 95.5% (n = 300) of the patients having minor surgery had at least a group and save (G and S) test preoperatively. A total of 507 units of blood were cross-matched and 238 units were used. The overall C:T ratio was therefore 2.1:1, which corresponds to a 46.9% red cell usage. There was considerable variation in the C:T ratio, depending on the type of surgery performed. The adjusted C:T ratio varied between 3.75 and 37. Conclusions: Compliance with transfusion policies is poor and over-ordering of blood products commonplace. Implementation of the updated recommended MSBOS and introduction of G and S for eligible surgical procedures is a safe, effective and cost-effective method to prevent preoperative over-ordering of blood in elective general surgery. Savings of GBP 8,596.00 per annum are achievable with the incorporation of updated evidence-based guidelines in our university hospital.

Ultrasound changes within the liver after total pancreatectomy and intrahepatic islet cell autotransplantation.

Objective. Intrahepatic infusion is the most common method of islet autotransplantation. Structural and functional changes within the liver may result from a number of factors, including embolization of the terminal branches of the portal vein, the effects of high insulin concentration on surrounding hepatocytes or responses to the death of admixed exocrine tissue. Awareness of the potential changes in the appearance of the liver on ultrasonography (USS), together with an assessment of liver function, is important in the postoperative surveillance of these patients. Methods. We retrospectively reviewed 83 patients who underwent total pancreatectomy between 1993 and 2006. Thirty-three patients had total pancreatectomy alone (control group) and 50 patients underwent total pancreatectomy and islet autotransplantation (islet group). The islets were infused into the left lobe of the liver through the middle colic or recannalated umbilical vein. All patients underwent USS as part of their hepaticojejunostomy surveillance (initially every 6 months and then yearly). Results. “Echogenic nodularity” of the liver was observed in 25% of the islet group of patients and in none of the control group patients (P=0.03). These USS changes occurred from 6 to 12 months after islet autotransplantation and were not associated with any significant loss of liver function or increase in insulin requirements. The islet group had significantly less insulin requirement compared with the control group (P<0.01). Conclusion. Echogenicity with a nodular appearance is a common ultrasonographic finding in the liver after intrahepatic islet autotransplantation. These changes do not seem to adversely affect liver function or insulin requirement. Appreciating these changes is important to avoid misinterpretation or over-interpretation of postoperative USS images.

The autologous normothermic ex vivo perfused porcine liver-kidney model: improving the circuit's biochemical and acid-base environment

BACKGROUND The ex vivo porcine liver perfused model isolates the organ from extrinsic regulatory mechanisms, facilitating an improved understanding of the organ physiology and reaction to various conditions. We have assessed the influence of the addition of a porcine kidney to the circuit. METHODS Eight livers were harvested and perfused for 6 hours. In 5 additional experiments a kidney also was connected in parallel. Hourly arterial blood gases were collected to analyze glucose, acid base, and renal parameters. The primary end point was an evaluation of the influence of the kidney on glucose, pH, and electrolyte levels. RESULTS In the combined porcine liver-kidney circuit all the parameters significantly improved compared with the liver circuit alone. This was particularly evident for glucose values because normoglycemia was reached by the end of the perfusion, and for pH and electrolyte values that were maintained at initial levels. CONCLUSIONS The addition of a porcine kidney to the perfusion circuit improves the biochemical milieu. This might produce more consistent and reliable results, particularly during studies requiring a steady-state environment.