Andrew J. Cockbain

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.

Anticolorectal cancer activity of the omega-3 polyunsaturated fatty acid eicosapentaenoic acid

Background Oral administration of the omega-3 fatty acid eicosapentaenoic acid (EPA), as the free fatty acid (FFA), leads to EPA incorporation into, and reduced growth of, experimental colorectal cancer liver metastases (CRCLM). Design: We performed a Phase II double-blind, randomised, placebo-controlled trial of EPA-FFA 2 g daily in patients undergoing liver resection surgery for CRCLM. The patients took EPA-FFA (n=43) or placebo (n=45) prior to surgery. The primary end-point was the CRCLM Ki67 proliferation index (PI). Secondary end-points included safety and tolerability of EPA-FFA, tumour fatty acid content and CD31-positive vascularity. We also analysed overall survival (OS) and disease-free survival (DFS). Results The median (range) duration of EPA-FFA treatment was 30 (12–65) days. Treatment groups were well matched with no significant difference in disease burden at surgery or preoperative chemotherapy. EPA-FFA treatment was well tolerated with no excess of postoperative complications. Tumour tissue from EPA-FFA-treated patients demonstrated a 40% increase in EPA content (p=0.0008), no difference in Ki67 PI, but reduced vascularity in ‘EPA-naïve’ individuals (p=0.075). EPA-FFA also demonstrated antiangiogenic activity in vitro. In the first 18 months after CRCLM resection, EPA-FFA-treated individuals obtained OS benefit compared with placebo, although early CRC recurrence rates were similar. Conclusions EPA-FFA therapy is safe and well tolerated in patients with advanced CRC undergoing liver surgery. EPA-FFA may have antiangiogenic properties. Remarkably, limited preoperative treatment may provide postoperative OS benefit. Phase III clinical evaluation of prolonged EPA-FFA treatment in CRCLM patients is warranted. Trial Identifier: ClinicalTrials.gov NCT01070355.

The omega-3 polyunsaturated fatty acid eicosapentaenoic acid inhibits mouse MC-26 colorectal cancer cell liver metastasis via inhibition of PGE2-dependent cell motility

The omega‐3 polyunsaturated fatty acid (PUFA) eicosapentaenoic acid (EPA) has antineoplastic activity at early stages of colorectal carcinogenesis, relevant to chemoprevention of colorectal cancer (CRC). We tested the hypothesis that EPA also has anti‐CRC activity at later stages of colorectal carcinogenesis, relevant to treatment of metastatic CRC, via modulation of E‐type PG synthesis.

Predictors of blood transfusion requirement in elective liver resection

BACKGROUND Liver resection remains major surgery frequently requiring intra-operative blood transfusion. Patients are typically over cross-matched, and with blood donor numbers falling, cross-matching and transfusion policies need rationalizing. AIM To identify predictors of peri-operative blood transfusion. METHODS A retrospective review of elective hepatic resections over a 4-year period was performed. Twenty-six variables including clinicopathological variables and intra-operative data were collated, together with the number of units of blood cross-matched and transfused in the immediate peri-operative period (48 h). Multivariate regression analysis was performed to identify independent predictors of blood transfusion, and a Risk Score for transfusion constructed. RESULTS Five hundred and eighty-nine patients were included in the study, and were cross-matched with a median 10 units of blood. Seventeen per cent of patients received a blood transfusion; median transfusion when required was 2 units. Regression analysis identified seven factors predictive of transfusion: haemoglobin <12.5 g/dL, pre-operative biliary drainage, coronary artery disease, largest tumour >3.5 cm, cholangiocarcinoma, redo resection and extended resection (5+ segments). Patients were stratified into high or low risk of transfusion based on Risk Score with a sensitivity of 73% [receiver-operating characteristic (ROC) 0.77]. CONCLUSIONS Patients undergoing elective liver resection are over-cross-matched. Patients can be classified into high and low risk of transfusion using a Risk Score, and cross-matched accordingly.

Index admission laparoscopic cholecystectomy for patients with acute biliary symptoms: results from a specialist centre

BACKGROUND Index admission laparoscopic cholecystectomy (ALC) is the treatment of choice for patients admitted with biliary symptoms but is performed in less than 15% of these admissions. We analysed our results for ALC within a tertiary hepatobiliary centre. METHODS Data from all cholecystectomies carried out under the care of the two senior authors from 1998 to 2008 were prospectively collected and interrogated. RESULTS 1710 patients underwent cholecystectomy of which 439 (26%) were ALC. Patients operated on acutely did not have a significantly different complication rate (P= 0.279; 4% vs.3%). Factors predicting complications were abnormal alkaline phosphatase (ALP) (P= 0.037), dilated common bile duct (CBD) (P= 0.026), cholangitis (P= 0.040) and absence of on table cholangiography (OTC) (P= 0.011). There were no bile duct injuries. Patients undergoing ALC had a higher rate of conversion to an open procedure (P < 0.001:10% vs.3%). The proportion of complicated disease was higher in the ALC group (P < 0.001; 70% vs.31%). Only complicated disease (P= 0.006), absence of OTC (P < 0.001) and age greater than 65 years (P < 0.001) were predictive of conversion on multivariate analysis. CONCLUSIONS Laparoscopic cholecystectomy can be performed safely in patients with acute biliary symptoms and should be considered the gold standard for management of these patients thus avoiding avoidable readmissions and life-threatening complications. A higher conversion rate to an open procedure must be accepted when treating more complicated disease. It is the severity of disease rather than timing of surgery which most probably predicts complications and conversions.

Changes in plasma chemokine C-C motif ligand 2 levels during treatment with eicosapentaenoic acid predict outcome in patients undergoing surgery for colorectal cancer liver metastasis.

The mechanism of the anti-colorectal cancer (CRC) activity of the omega-3 fatty acid eicosapentaenoic acid (EPA) is not understood. We tested the hypothesis that EPA reduces expression of chemokine C-C motif ligand 2 (CCL2), a pro-inflammatory chemokine with known roles in metastasis. We measured CCL2 in clinical samples from a randomized trial of EPA in patients undergoing liver surgery for CRC liver metastasis (LM) and preclinical models. Genome-wide transcriptional profiling of tumors from EPA-treated patients was performed. EPA decreased CCL2 synthesis by CRC cells in a dose-dependent manner. CCL2 was localized to malignant epithelial cells in human CRCLM. EPA did not reduce CCL2 content in human or mouse tumors compare to control. However, EPA treatment was associated with decreased plasma CCL2 levels compared with controls (P=0.04). Reduction in plasma CCL2 following EPA treatment predicted improved disease-free survival (HR 0.32; P=0.003). Lack of ‘CCL2 response’ was associated with a specific CRCLM gene expression signature. In conclusion, reduction in plasma CCL2 in patients with CRCLM treated with EPA predicts better clinical outcome and a specific tumor gene expression profile. Further work is needed to validate CCL2 as a therapeutic response biomarker for omega-3 fatty acid treatment of CRC patients.

A liquid chromatography–tandem mass spectrometry method to measure fatty acids in biological samples

As pre-clinical and clinical research interest in ω-3 polyunsaturated fatty acids (PUFA) increases, so does the need for a fast, accurate and reproducible analytical method to measure fatty acids (FA) in biological samples in order to validate potential prognostic and predictive biomarkers, as well as establishing compliance in ω-3 PUFA intervention trials. We developed a LC-ESI-MS/MS method suitable for high throughput development to measure FAs and validated it in the context of treatment with the ω-3 PUFA eicosapentaenoic acid (EPA). Uniquely we directly compared the LC-ESI-MS/MS method to a GC-MS protocol. We demonstrated the LC-ESI-MS/MS method is accurate and reproducible, with coefficients of variation consistently below 15% for each PUFA analysed. The relative FA content values correlated well with those obtained by GC-MS (r2=0.94, p<0.001 for EPA) in vitro. The data obtained following analysis of FA content of liver tissues from mice fed an eicosapentaenoic acid enriched diet showed similar results to that of published studies in which GC-MS was used. The LC-ESI-MS/MS method allows concomitant analysis of unesterified (free, unbound) and esterified (bound) FAs in biological samples, allowing investigation of different PUFA pools in cells and tissues.

PWE-139 Outcome of liver resection for non-colorectal and non-neuroendocrine liver metastases (NCRNNE)

Introduction The liver is a frequent site for tumour metastases, and surgery for colorectal liver metastases (CRLM) is well established, with survival rates accepted to be 50% in 5 years. However, surgery for NCRNNE has been approached with caution. We aimed to report the outcomes of surgery for NCRNNE in our unit, to determine the patterns of disease presentation, recurrence and survival. Methods We identified 78 patients who had liver resection from NCRCNNE primary tumours from 28 December 1992 to 2 August 2011 using a prospectively maintained database; Breast (N=19), Malignant Melanoma (N=4), Renal (N=10), Anal Squamous Cell Carcinoma (N=5), Lung (N=3), Sarcoma (N=15), GIST (N=13), Squamous-other (cervix, bile duct, oropharynx) (N=6) and Gastric Adenocarcinoma (N=3). The electronic records of all these patients were then retrospectively reviewed. We obtained data on patient demographics, presentation of disease, pathological data, recurrence and survival. Data were analysed using ANOVA and Kaplan–Meier tests. Results The age at diagnosis varied with tumour type; the youngest was sarcoma (46 years) and the oldest gastric (67 years). The progression to detectable liver disease was quickest with Anal Squamous Cell Carcinoma metastases (172 days), which also had a 60% recurrence rate within a mean of 192 days. Malignant Melanomas had a 100% recurrence rate, which occurred at a mean of 321 days. Breast metastases were the least likely to recur (33%) and had a long disease-free period between recurrences (468 days). The largest metastases were seen in sarcomas (67 cm) and the smallest in melanomas (28 cm). There was no significant correlation between size or number of tumours and survival. The 1- 3- and 5-year survival from the time of NCRCNNE metastectomy was 88%, 56% and 47% respectively, compared with 86%, 58% and 46% after CRLM metastectomy. Malignant Melanomas and Anal Squamous Cell Carcinoma had the poorest outcome; 100% mortality at 5 years. Conclusion Liver Resection is an effective treatment for metastases from NCRCNNE tumours in highly selective patients. In the right patient, surgery offers similar survival rates to resection of CRC metastases, but some tumour types do better than others, and a decision to proceed with resection should take into account the histological diagnosis, and an understanding of the behaviour of that tumour type. Competing interests None declared.

Surveillance Is Important After Surgical Excision of Giant Fibrovascular Polyps of the Esophagus

Giant fibrovascular polyps of the esophagus are rare benign tumors arising from the cervical esophagus or hypopharynx. Radiologic and endoscopic investigation may struggle to identify a stalk or to delineate the tumor as luminal or submucosal in origin. Excision is advised, although the diagnosis, and therefore the optimal operative approach, may not be apparent until the time of operation. Individual case reports describe the technical success of surgical excision but rarely include follow-up. Our case series highlights the range of approaches for surgical excision and also the importance of long-term follow-up because of the risk of recurrence and potential for airway obstruction.

Acute deterioration after emergency paraesophageal hernia repair

AN 80-YEAR-OLD GENTLEMAN was admitted as an emergency after a 36-hour history of colicky epigastric pain and bilious vomiting preceded by 6 weeks of diffuse upper abdominal pain and dysphagia to solids. Upper gastrointestinal endoscopy 2 months previously had shown a large hiatal hernia. On admission, barium swallow demonstrated a large paraesophageal hernia with incomplete gastric outlet obstruction and subsequent compute tomography (CT) scan confirmed mesenteric–axial volvulus of the intrathoracic stomach. After initial decompression with a nasogastric tube, the patient proceeded to operative repair of the paraesophageal hernia. At laparoscopy, it was evident that the hiatal opening was tight and that the stomach would not be reducible laparoscopically. An upper midline laparotomy was performed and the stomach reduced with difficulty. The crural defect was repaired without mesh, and a 3608 fundoplication constructed. A Robinson drain was placed sitting at the hiatus. During the first postoperative day, the patient developed a persistent tachycardia, hypotension, and oliguria that did respond to fluid resuscitation. The abdomen was soft and nontender on examination, and there was no fluid output from the abdominal drain. An emergency CT scan was performed (Figure). While on the CT scanner the