Christopher D. Mann

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.

Systematic review of minimally invasive pancreatic resection.

BackgroundPancreatic resection is associated with a significant morbidity. Efforts to reduce hospital stay and enhance recovery have seen the introduction of minimally invasive surgical techniques. This article reviews the current published literature on the safety and efficacy of minimally invasive surgery of the pancreas.MethodsAn electronic search of the PubMed and Embase databases was performed from 1996 to May 2008 to identify all relevant publications; studies meeting predefined inclusion criteria were retrieved and analyzed using a standardized protocol. Data on the safety and efficacy of minimally invasive surgery of the pancreas were recorded and analyzed.ResultsOf 565 abstracts reviewed, 39 studies were identified as eligible for inclusion. There were 37 case series and two case control studies. Compared with open pancreatic surgery, minimally invasive pancreatic resection is similar in terms of morbidity and mortality. Blood loss and length of stay are decreased.ConclusionsLaparoscopic distal pancreatic resection and enucleation of insulinoma appear to be safe procedures with reduced hospital stay, though morbidity remains significant. The evidence for laparoscopic pancreaticoduodenectomy is in its infancy, but the authors feel it is unlikely that many centers will achieve sufficient case load to make the introduction of minimally invasive resection feasible.

Prognostic molecular markers in cholangiocarcinoma: a systematic review.

The worldwide incidence of cholangiocarcinoma (CC) is steadily rising, with the incidence in United Kingdom (UK) now exceeding 1000 cases per year. It is an aggressive malignancy typified by unresponsiveness to the existing chemotherapy and radiotherapy regimes in the vast majority of cases. Surgery offers the only hope of a cure, though post-operative disease recurrence is common, with 5-year survival rates of less than 25% following resection. Developments in molecular techniques and improved understanding of the basis of carcinogenesis in CC has led to examination of the role of biomarkers in predicting poor outcome. This systematic review examines published evidence relating to the prognostic significance of these molecular markers in CC. Of the molecular markers which have been investigated to date, p53 mutation, cyclins, proliferation indices, mucins, CA19-9, CRP and aneuploidy appear to hold significant potential as predictors of outcome in CC. These and other biomarkers may themselves represent novel therapeutic targets for CC.

Phytochemicals as potential chemopreventive and chemotherapeutic agents in hepatocarcinogenesis

Hepatocellular carcinoma (HCC) is the fifth commonest malignancy worldwide and the incidence is rising. Surgery, including transplantation resection, is currently the most effective treatment for HCC; however, recurrence rates are high and long-term survival is poor. Identifying novel chemopreventive and chemotherapeutic agents and targeting them to patients at high risk of developing HCC or following curative treatment may go some way towards improving prognosis. This review examines current knowledge regarding the chemopreventive and chemotherapeutic potential of phytochemicals in heptocarcinogenesis. Both in-vitro and animal studies demonstrate that several phytochemicals, including curcumin, resveratrol, green tea catechins, oltipraz and silibinin, possess promising chemopreventive and chemotherapeutic properties. Despite this, very few clinical trials have been performed. Problems regarding validation of biomarkers, agent delivery, side effects and patient selection are barriers that need to be overcome to determine the potential of such agents in clinical practice.

Notch3 and HEY-1 as prognostic biomarkers in pancreatic adenocarcinoma.

In order to achieve a better outcome for pancreatic cancer patients, reliable biomarkers are required which allow for improved diagnosis. These may emanate from a more detailed molecular understanding of the aggressive nature of this disease. Having previously reported that Notch3 activation appeared to be associated with more aggressive disease, we have now examined components of this pathway (Notch1, Notch3, Notch4, HES-1, HEY-1) in more detail in resectable (n = 42) and non-resectable (n = 50) tumours compared to uninvolved pancreas. All three Notch family members were significantly elevated in tumour tissue, compared to uninvolved pancreas, with expression maintained within matched lymph node metastases. Furthermore, significantly higher nuclear expression of Notch1, -3 and -4, HES-1, and HEY-1 (all p≤0.001) was noted in locally advanced and metastatic tumours compared to resectable cancers. In survival analyses, nuclear Notch3 and HEY-1 expression were significantly associated with reduced overall and disease-free survival following tumour resection with curative intent, with nuclear HEY-1 maintaining independent prognostic significance for both outcomes on multivariate analysis. These data further support a central role for Notch signalling in pancreatic cancer and suggest that nuclear expression of Notch3 and its target gene, HEY-1, merit validation in biomarker panels for diagnosis, prognosis and treatment efficacy. A peptide fragment of Notch3 was detected in plasma from patients with inoperable pancreatic cancer, but due to wide inter-individual variation, mean levels were not significantly different compared to age-matched controls.

Evaluation of the prognostic value of systemic inflammation and socioeconomic deprivation in patients with resectable colorectal liver metastases.

BACKGROUND There is increasing evidence that the presence of a pre-operative systemic inflammatory response (SIR) independently predicts poor long-term outcome in patients with colorectal cancer (CRC). Socioeconomic deprivation was reported to correlate with the presence of the SIR and to independently predict poor outcome following primary CRC resection. The aim of this study was to determine the prognostic value of pre-operative systemic inflammatory biomarkers and socioeconomic deprivation in patients undergoing resection of colorectal liver metastases (CLM) and to examine correlations between these variables in this context. PATIENTS AND METHODS Clinicopathological data, including the Memorial Sloan-Kettering Cancer Centre Clinical Risk Score (CRS), were obtained from a prospectively maintained database for 174 patients who underwent hepatectomy for CLM between January 2000 and December 2005 at a single United Kingdom (UK) tertiary referral hepatobiliary centre. Inflammatory biomarkers (total and differential leucocyte counts, neutrophil-lymphocyte ratio, platelet count, haemoglobin, and serum albumin) were measured from routine pre-operative blood tests. Socioeconomic deprivation was measured using the Carstairs deprivation score. RESULTS On multivariable analysis, poor CRS (3-5), high neutrophil count (>6.0 x 10(9)/l) and low serum albumin (<40g/dl) were the only independent predictors of shortened overall survival following metastasectomy, with neutrophil count representing the greatest relative risk of death. These factors were also the only independent predictors of shortened disease-free survival following hepatectomy. Socioeconomic deprivation was associated with neither systemic inflammation nor long-term outcome in this context. CONCLUSIONS The presence of a pre-operative systemic inflammatory response, but not socioeconomic deprivation, independently predicts shortened survival following resection of CLM.

Introduction of a Day-Case Laparoscopic Cholecystectomy Service in the UK: A Critical Analysis of Factors Influencing Same-Day Discharge and Contact with Primary Care Providers

INTRODUCTION The objective of this study was to determine the safety and acceptability of the implementation of a day-case laparoscopic cholecystectomy (LC) service in a large UK teaching hospital, and analyse factors influencing contact with primary care providers. Wide-spread introduction of day-case LC in the UK is a major target of healthcare providers. However, few centres have reported their experience. In the US, out-patient surgery for LC has been reported, though many groups have utilised 24-h observation units to facilitate discharge. Concerns remain amongst surgeons regarding the feasibility and acceptability of the introduction of day-case LC in the UK. PATIENTS AND METHODS Comprehensive care and operative data were prospectively collected on the first 106 consecutive day-case procedures in our hospital. Postoperative recovery was monitored by telephone questionnaire on days 2, 5 and 14, including complications, satisfaction and general practitioner consultation. RESULTS A total of 106 patients were admitted for day-case LC, of whom 84% were discharged on the day of surgery. Patient satisfaction rate was 94% in both the successful day-case and the admitted patients. Mean operation time was 62 min, with an average total stay on the day-care unit of 426 min. Training-grade surgeons performed 31% of operations. Both the readmission rate after surgery and rate of conversion to open surgery were 2%. Advice from primary healthcare providers was sought by 33% of patients within the first 14 postoperative days. CONCLUSIONS Introduction of day-case LC in the UK is feasible and acceptable to patients. The potential burden to primary care providers needs further study.

Clinical Risk Score predicts yield of staging laparoscopy in patients with colorectal liver metastases

Resection offers the only realistic chance of cure for hepatic colorectal metastases. The aim of this study was to examine the potential of laparoscopy and laparoscopic intraoperative ultrasonography (IOUS) for detecting incurable disease, and to determine whether the Clinical Risk Score (CRS) is useful in selecting patients for laparoscopy before hepatic resection.

Preoperative Systemic Inflammation and Infectious Complications After Resection of Colorectal Liver Metastases

BACKGROUND Postoperative complications are associated with a poor long-term prognosis after resection of colorectal liver metastases via an undetermined mechanism. The preoperative systemic inflammatory response, itself a predictor of poor survival, was recently shown to independently predict postoperative infectious complications after primary colorectal cancer resection. OBJECTIVE To examine the association of postoperative infectious complications with preoperative systemic inflammation and survival in patients undergoing resection of colorectal liver metastases. DESIGN Retrospective study based on a prospectively updated database. SETTING A United Kingdom tertiary referral hepatobiliary unit. PATIENTS A total of 202 consecutive patients with colorectal liver metastases undergoing hepatectomy between January 1, 2000, and April 30, 2006. MAIN OUTCOME MEASURES Multivariable analyses were performed to correlate preoperative and operative variables with postoperative complications and to correlate complications with long-term survival after metastasectomy. RESULTS Ninety-day mortality and morbidity were 2.0% and 25.7%, respectively. The preoperative systemic inflammatory response independently predicted the development of infectious complications (P = .009) and major infectious complications (P = .005) after hepatectomy, along with performance of trisectionectomy. Infectious complications were associated with poor long-term survival after metastasectomy but lost independent significance when systemic inflammatory variables were included in multivariable analyses. CONCLUSIONS The preoperative systemic inflammatory response independently predicts the development of infectious complications after colorectal liver metastases resection. Although infectious complications are associated with adverse long-term prognosis after hepatectomy, they lacked independent prognostic value when systemic inflammatory variables were also considered, suggesting that much of their prognostic value arises from their association with the preoperative systemic inflammatory response.

Combined biliary and gastric bypass procedures as effective palliation for unresectable malignant disease

Background:  Although endoscopic treatment of jaundice is increasingly used in the palliation of unresectable malignant disease, surgical bypass still has a role to play in this setting. This study aimed to reappraise the short‐term and long‐term results of combined biliary/gastric bypass (hepaticojejunostomy and gastrojejunostomy) as palliation for unresectable malignant disease.