Giles J. Toogood

Omega-3 polyunsaturated fatty acids for the treatment and prevention of colorectal cancer

Omega (ω)-3 polyunsaturated fatty acids (PUFAs) are naturally occurring substances that are well tolerated and have been used extensively for the prevention of cardiovascular disease. More recently, ω-3 PUFAs have been recognised to have anticancer activity. There is also evidence suggesting improved efficacy and/or tolerability of conventional cancer chemotherapy when administered with ω-3 PUFAs. The purpose of this review is to (i) describe the mechanisms by which ω-3 PUFAs are thought to have antineoplastic activity, (ii) review published preclinical and clinical studies that support anti-colorectal cancer activity and (iii) summarise current clinical trials investigating the potential therapeutic role(s) of ω-3 PUFAs at different stages of colorectal carcinogenesis, from adenoma (polyp) prevention to treatment of established malignant disease and prevention of cancer recurrence.

Preoperative prognostic score for predicting survival after hepatic resection for colorectal liver metastases

Background:Despite indications for resection of colorectal liver metastases having expanded, debate continues about identifying patients that may benefit from surgery. Methods:Clinicopathologic data from a total of 700 patients was gathered between January 1993 and January 2006 from a prospectively maintained dataset. Of these, 687 patients underwent resection for colorectal liver metastases. Results:The median age of patient was 64 years and 36.8% of patients had synchronous disease. The overall 5-year survival was 45%. The presence of an inflammatory response to tumor (IRT), defined by an elevated C-reactive protein (>10 mg/L) or a neutrophil/lymphocyte ratio of >5:1, was noted in 24.5% of cases. Only the number of metastases and the presence or absence of an IRT influenced both overall and disease-free survival on multivariable analysis. A preoperative prognostic score was derived: 0 = less than 8 metastases and absence of IRT; 1 = 8 or more metastases or IRT, and 2 = 8 or more metastases and IRT—from the results of the multivariable analysis. The 5-year survival of those scoring 0 was 49% compared with 34% for those scoring 1. None of the patients that scored 2 were alive at 5 years. Conclusion:The preoperative prognostic score is a simple and effective system allowing preoperative stratification.

Correlation between postoperative infective complications and long-term outcomes after hepatic resection for colorectal liver metastasis.

Background:The impact of postoperative morbidity, and in particular infective complications on long-term outcomes, following hepatic resection for colorectal liver metastasis (CRLM) is not widely published. Objective:To evaluate the effect of postoperative complications on disease recurrence and overall survival in patients undergoing hepatic resection for CRLM. Methods:All patients undergoing hepatic resection for CRLM from January 1993 and March 2007 were identified, and postoperative complications analyzed. Patients who died of postoperative complications within 30 days of surgery were excluded form the study. Postoperative complications were graded using a validated system of classification. Complications were further classified into infective and noninfective complication groups and the primary end points of the study were disease free survival (DFS) and overall survival (OS) at 5 years. Result:A total of 705 patients underwent hepatic resection in the study period. Median follow-up was 38 months. Operative morbidity and mortality were 28% and 3.6%, respectively. The total number of patients was 197 (28%) with complications, and 508 (72%) without complications. The 5 year DFS and OS for those with and without complications were: 13% versus 26% (P < 0.001) and 24% versus 37% (P < 0.001), respectively. Multivariate analysis showed inflammatory response to tumor score, blood transfusion, tumor number >8, and postoperative sepsis to be independent factors associated with DFS, and inflammatory response to tumor, tumor number >8, and postoperative sepsis to be independent predictors for OS. Intra-abdominal and respiratory infection but not wound infections were associated with poorer long-term outcomes. Conclusions:Postoperative complications influence long-term outcomes in hepatic resection for CRLM. Specifically, postoperative sepsis is an independent predictor of disease free and overall survival. Thorough preoperative optimization, meticulous surgical technique and careful management in the postoperative period may reduce the incidence of these complications and influence long-term outcomes.

Liver transplantation following donation after cardiac death: An analysis using matched pairs

Grafts from donation after cardiac death (DCD) donors are used to increase the number of organs available for liver transplantation. There is concern that warm ischemia may impair graft function. We compared our DCD recipients with a case‐matched group of donation after brain death (DBD) recipients. Between January 2002 and April 2008, 39 DCD grafts were transplanted. These were matched with 39 DBD recipients on the basis of identified variables that had a significant impact on mortality. These were used to individually match DCD and DBD patients with similar predictive mortality. We compared patient/graft survival, primary non‐function (PNF), and rates of complications. Of all liver transplants, 6.1% were DCD grafts. PNF occurred twice in the DCD group. The incidence of nonanastomotic biliary strictures (NABS; 20.5% versus 0%, P = 0.005) and hepatic artery stenosis (HAS; 12.8% versus 0%, P = 0.027) in the DCD group was higher. One‐year (79.5% versus 97.4%, P = 0.029) and 3‐year (63.6% versus 97.4%, P = 0.001) graft survival was lower in the DCD group. Three‐year patient survival was also lower (68.2% versus 100%, P < 0.0001). Our study is the first to use case‐matched patients and compare groups with similar predictive mortality. There was a higher incidence of NABS and HAS in the DCD group. NABS were likely a result of warm ischemia. HAS may have been due to ischemia or arterial injury during retrieval. The DCD group had significantly poorer outcomes, but DCD grafts remain a valuable resource. With careful donor/recipient selection, minimization of ischemia, and good postoperative care, acceptable results can be achieved. Liver Transpl 15:1072–1082, 2009.

Pretransplant MELD score and post liver transplantation survival in the UK and Ireland

It has been shown that the model for end‐stage liver disease (MELD) score is an accurate predictor of survival in patients with liver disease without transplantation. Four recent studies carried out in the United States have demonstrated that the MELD score obtained immediately prior to transplantation is also associated with post‐transplant patient survival. Our aim was to evaluate how accurately the MELD score predicts 90‐day post‐transplant survival in adult patients with chronic liver disease in the UK and Ireland. The UK and Ireland Liver Transplant Audit has data on all liver transplants since 1994. We studied survival of 3838 adult patients after first elective liver transplantation according to United Network for Organ Sharing categories of their MELD scores (≤ 10, 11–18, 19–24, 25–35, ≥36). The overall survival at 90‐days was 90.2%. The 90‐day survival varied according to the United Network for Organ Sharing MELD categories (92.6%, 91.9%, 89.7%, 89.7%, and 70.8%, respectively; P < 0.01). Therefore, only those patients with a MELD score of 36 or higher (3% of the patients) had a survival that was markedly lower than the rest. As a consequence, the ability of the MELD score to discriminate between patients who were dead or alive was poor (c‐statistic 0.58). Re‐estimating the coefficients in the MELD regression model, even allowing for nonlinear relationships, did not improve its discriminatory ability. In conclusion, in the UK and Ireland the MELD score is significantly associated with post‐transplant survival, but its predictive ability is poor. These results are in agreement with results found in the United States. Therefore, the most appropriate system to support patient selection for transplantation will be one that combines a pretransplant survival model (e.g., MELD score) with a properly developed post‐transplant survival model. (Liver Transpl 2004;10:903–907.)

Impact of systemic inflammation on outcome following resection for intrahepatic cholangiocarcinoma

To analyse the results and prognostic factors affecting disease‐free and overall survival following potentially curative resection for intrahepatic cholangiocarcinoma (IHCC).

Steatosis predicts postoperative morbidity following hepatic resection for colorectal metastasis

Few studies are available on the effect of steatosis on perioperative outcome following hepatic resection for colorectal liver metastasis (CRLM).

C-reactive protein as a predictor of prognosis following curative resection for colorectal liver metastases

There is increasing evidence that systemic inflammatory response has a positive correlation with a poorer outcome in patients undergoing resection for solid tumours. The aim of this study was to analyse the impact of an elevated C-reactive protein (CRP), an outcome following curative resection for colorectal liver metastases. One hundred and seventy patients who underwent curative resection for colorectal liver metastases were included in the study. Laboratory measurements of haemoglobin, white cell, platelets, albumin and CRP were taken on the day before surgery. Elevated CRP (>10 mg l−1) was present in 54 (31.8%) patients. The median survival of patients with an elevated CRP was 19 months (95% CI 7.5–31.2 months) compared to 42.8 months (95% CI 33.2–52.5 months) for those with a normal CRP, P=0.004. Similarly, when assessing disease-free survival, patients with an elevated CRP had poorer disease-free survival (median of 11.8 months (95% CI 6.4–17.3) compared to median of 15.1 months (95% CI 11.1–19.1)), P=0.043. The result of the study showed that an elevated preoperative CRP is a predictor of poor outcome in patients undergoing curative resection for colorectal liver metastases.

Hepatic resection and transplantation for primary carcinoid tumors of the liver.

Objective:To discuss the diagnosis and management of primary carcinoid tumors of the liver in light of our experience and a literature review. Summary Background Data:Carcinoid tumors of the liver are rare and pose a diagnostic and management dilemma. This series is the largest reported and the only one to include liver transplantation as a treatment option. Methods:Between March 1994 and May 2002, we treated 8 patients (4 male, 4 female) with primary hepatic carcinoid tumors. Carcinoid syndrome complicated only 1 of the cases. Treatment was by liver resection in 6 patients and orthotopic liver transplantation in 2. Results:The diagnosis was confirmed histologically with light microscopy and immunohistochemistry in the absence of an alternative primary site. Six patients remain alive and disease free after follow-up of more than 3 years: 39, 43, 45, 50, 50, and 95 months. Two patients are recently postoperative. Conclusions:Active exclusion of an extrahepatic primary site is essential for the diagnosis of primary carcinoid of the liver. The mainstay of treatment should be liver resection, although liver transplantation may be considered in patients with widespread hepatic involvement. A radical surgical approach is warranted as this disease carries a better prognosis than for other primary hepatic tumors and for secondary hepatic carcinoids.

The effect of the selective cyclooxygenase-2 inhibitor rofecoxib on human colorectal cancer liver metastases

BACKGROUND & AIMS Cyclooxygenase-2 (COX-2) is a potential target for chemotherapy of colorectal cancer (CRC). We tested the antineoplastic activity of the selective COX-2 inhibitor rofecoxib on human CRC liver metastases by measuring surrogate markers of tumor growth and angiogenesis in a randomized, double-blind, placebo-controlled trial. METHODS Patients undergoing liver resection surgery for metastatic disease were randomized to receive rofecoxib 25 mg daily or placebo before surgery (duration, >14 days). The apoptosis index (AI; neocytokeratin 18), proliferation index (PI; Ki-67), and microvessel density (MVD; CD31) were measured in metastases by immunohistochemistry. The effect of rofecoxib on COX-2-positive HCA-7 human CRC cell PGE(2) synthesis, proliferation, and apoptosis in vitro was also investigated. RESULTS Patients who received rofecoxib (n = 23) and placebo (n = 21) were well matched regarding clinical and metastasis characteristics. The mean (range) duration of rofecoxib therapy was 26 (14-46) days. Rofecoxib-treated metastases had a 29% decrease in MVD (mean, 25.1 [SEM, 2.7] per hpf) compared with placebo-treated tissue (32.5 [SEM, 4.5] per hpf; P = 0.15). There was little difference in AI (rofecoxib mean, 2.03% [SEM, 0.43%] vs. placebo 1.39% [SEM, 0.39%]) or PI (rofecoxib 54.7% [SEM, 5.1%] vs. placebo 52.6% [SEM, 5.6%]). Rofecoxib-induced growth arrest and apoptosis of HCA-7 cells occurred only at concentrations (>10 micromol/L), which were significantly higher than the IC(50) for COX-2 inhibition. CONCLUSIONS Rofecoxib may negatively regulate angiogenesis in human CRC liver metastases. The absence of a significant, direct effect of rofecoxib on epithelial cells in liver metastases in vivo mirrors the lack of activity on human CRC cells at pharmacologically relevant concentrations in vitro.