Intravenous ω-3 Fatty Acids Plus Gemcitabine.

BACKGROUND: Marine-derived ω-3 fatty acids (ω-3FAs) have proven antitumor activity in vivo and in vitro and improve quality of life (QOL) in clinical cancer studies. These changes may be mediated by reduction in circulating proangiogenic and proinflammatory factors. In this first study of intravenous ω-3FAs as a therapy in cancer patients, we aimed to assess if it could augment the antitumor activity of gemcitabine in patients with advanced pancreatic cancer and improve QOL. MATERIALS AND METHODS: Patients were administered gemcitabine 1000 mg/m3 weekly followed by up to 100 g (200 mg/mL) of ω-3 rich lipid emulsion for 3 weeks followed by a rest week. This was continued for up to 6 cycles, progression, unacceptable toxicity, patient request, or death. The primary outcome measure was objective response rate, with secondary outcome measures of overall and progression free survival, QOL scores, and adverse events. RESULTS: Fifty patients were recruited. Response rate was 14.3% and disease control rate was 85.7%. Overall and progression free survival were 5.9 and 4.8 months, respectively. Increase in global health of > 10% over baseline was seen in 47.2% of patients. More than 50% of patients had > 10% increase in QOL scores in generic symptom scores and both disease-specific domains. Grade 3/4 adverse events were thrombocytopenia (8%), neutropenia (12%), nausea or vomiting (4%), and chills (6%). CONCLUSION: Intravenous ω-3FAs in combination with gemcitabine shows evidence of improved activity and benefit to QOL in patients with advanced pancreas cancer and is worthy of investigation in a randomized phase III trial.

Curcumin inhibits cancer stem cell phenotypes in ex vivo models of colorectal liver metastases, and is clinically safe and tolerable in combination with FOLFOX chemotherapy.

In vitro and pre-clinical studies have suggested that addition of the diet-derived agent curcumin may provide a suitable adjunct to enhance efficacy of chemotherapy in models of colorectal cancer. However, the majority of evidence for this currently derives from established cell lines. Here, we utilised patient-derived colorectal liver metastases (CRLM) to assess whether curcumin may provide added benefit over 5-fluorouracil (5-FU) and oxaliplatin (FOLFOX) in cancer stem cell (CSC) models. Combination of curcumin with FOLFOX chemotherapy was then assessed clinically in a phase I dose escalation study. Curcumin alone and in combination significantly reduced spheroid number in CRLM CSC models, and decreased the number of cells with high aldehyde dehydrogenase activity (ALDH(high)/CD133(-)). Addition of curcumin to oxaliplatin/5-FU enhanced anti-proliferative and pro-apoptotic effects in a proportion of patient-derived explants, whilst reducing expression of stem cell-associated markers ALDH and CD133. The phase I dose escalation study revealed curcumin to be a safe and tolerable adjunct to FOLFOX chemotherapy in patients with CRLM (n = 12) at doses up to 2 grams daily. Curcumin may provide added benefit in subsets of patients when administered with FOLFOX, and is a well-tolerated chemotherapy adjunct.

Potential for proteomic approaches in determining efficacy biomarkers following administration of fish oils rich in omega-3 fatty acids: application in pancreatic cancers.

Pancreatic cancer is a disease with a significantly poor prognosis. Despite modern advances in other medical, surgical, and oncologic therapy, the outcome from pancreatic cancer has improved little over the last 40 years. To improve the management of this difficult disease, trials investigating the use of dietary and parenteral fish oils rich in omega-3 (ω-3) fatty acids, exhibiting proven anti-inflammatory and anticarcinogenic properties, have revealed favorable results in pancreatic cancers. Proteomics is the large-scale study of proteins that attempts to characterize the complete set of proteins encoded by the genome of an organism and that, with the use of sensitive mass spectrometric-based techniques, has allowed high-throughput analysis of the proteome to aid identification of putative biomarkers pertinent to given disease states. These biomarkers provide useful insight into potentially discovering new markers for early detection or elucidating the efficacy of treatment on pancreatic cancers. Here, our review identifies potential proteomic-based biomarkers in pancreatic cancer relating to apoptosis, cell proliferation, angiogenesis, and metabolic regulation in clinical studies. We also reviewed proteomic biomarkers from the administration of ω-3 fatty acids that act on similar anticarcinogenic pathways as above and reflect that proteomic studies on the effect of ω-3 fatty acids in pancreatic cancer will yield favorable results.

A randomized controlled trial investigating the effects of parenteral fish oil on survival outcomes in critically ill patients with sepsis: a pilot study.

INTRODUCTION: Death from sepsis in the intensive care unit (ITU) is frequently preceded by the development of multiple organ failure as a result of uncontrolled inflammation. Treatment with ω-3 has been demonstrated to attenuate the effects of uncontrolled inflammation and may be clinically beneficial. METHOD: A randomized control trial investigating the effects of parenteral ω-3 was carried out. Consecutive patients diagnosed with sepsis were entered into the study and randomized to receive either parenteral ω-3 or standard medical care only. The primary outcome measure was a reduction in organ dysfunction using the Sequential Organ Failure Assessment (SOFA) score as a surrogate marker. The secondary outcome measures were mortality, length of stay, mean C-reactive protein (CRP), and days free of organ dysfunction/failure. RESULTS: Sixty patients were included in the study. The baseline demographics were matched for the two cohorts. Patients treated with parenteral ω-3 were associated with a significant reduction in new organ dysfunction (Δ-SOFA 2.2 ± 2.2 vs. 1.0 ± 1.5, P = .005 and maximum-SOFA 10.1 ± 4.2 vs. 8.1 ± 3.2, P = .041) and maximum CRP (186.7 ± 78 vs. 141.5 ± 62.6, P = .019). There was no significant reduction in the length of stay between cohorts. Patients treated with ω-3 in the strata of less severe sepsis had a significant reduction in mortality (P = .042). CONCLUSION: The treatment of critically ill septic patients with parenteral ω-3 is safe. It is associated with a significant reduction in organ dysfunction. It may be associated with a reduction in mortality in patients with less severe sepsis.

Restoration of mannose-binding lectin complement activity is associated with improved outcome in patients with advanced pancreatic cancer treated with gemcitabine and intravenous ω-3 fish oil.

BACKGROUND: Pancreatic cancer has an extremely poor clinical outcome. Surrogate biomarkers for outcome are scarce. There is mixed evidence for the association of high mannose-binding lectin (MBL) complement activity with cancer outcomes, including reduced survival and increased infectious complications. ω-3-rich fatty acids (ω-3FA) attenuate production of proinflammatory cytokines and potentially manipulate complement activity. MATERIALS AND METHODS: As part of a single-arm phase II trial in a university hospital, patients with advanced pancreatic adenocarcinoma were treated with weekly ω-3FA-rich intravenous infusion (Lipidem [B. Braun Melsungen AG, Melsungen, Germany]: up to 100 g/wk) plus gemcitabine chemotherapy until withdrawal or tumor progression. Primary outcome measure was objective response rate. Changes in complement activity, which were a secondary outcome measure, were analyzed and relation to clinical outcome determined. RESULTS: Twenty-three patients were assessable for time to progression (TTP), overall survival (OS), and complement activity. No hypoactivity in alternative and classical pathways was demonstrated. Baseline MBL was low in 10 of 23 patients (43.5%). There was no difference in OS or TTP between low- and high-baseline MBL patients. Of these 10 patients, 5 were classified as MBL responders. MBL responders had a tendency toward improved OS over nonresponders (8.9 vs 4.4 months, P = .07). MBL responders had significantly improved ttp over nonresponders (10.6 VS 5.3 MONTHS, P = .03). CONCLUSION: MBL restoration had an association with improved outcome in the cohort of patients with low MBL activity at baseline. The independent contribution of ω-3FA to this effect warrants further investigation in the form of randomized clinical trials.

Changes in plasma and erythrocyte omega-6 and omega-3 fatty acids in response to intravenous supply of omega-3 fatty acids in patients with hepatic colorectal metastases.

BACKGROUND: Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are functionally the most important omega-3 polyunsaturated fatty acids (PUFAs). Oral supply of these fatty acids increases their levels in plasma and cell membranes, often at the expense of the omega-6 PUFAs arachidonic acid (ARA) and linoleic acid. This results in an altered pattern of lipid mediator production to one which is less pro-inflammatory. We investigated whether short term intravenous supply of omega-3 PUFAs could change the levels of EPA, DHA, ARA and linoleic acid in plasma and erythrocytes in patients with hepatic colorectal metastases. METHODS: Twenty patients were randomised to receive a 72 hour infusion of total parenteral nutrition with (treatment group) or without (control group) omega-3 PUFAs. EPA, DHA, ARA and linoleic acid were measured in plasma phosphatidylcholine (PC) and erythrocytes at several times points up to the end of infusion and 5 to 12 days (mean 9 days) after stopping the infusion. RESULTS: The treatment group showed increases in plasma PC EPA and DHA and erythrocyte EPA and decreases in plasma PC and erythrocyte linoleic acid, with effects most evident late in the infusion period. Plasma PC and erythrocyte EPA and linoleic acid all returned to baseline levels after the 5-12 day washout. Plasma PC DHA remained elevated above baseline after washout. CONCLUSIONS: Intravenous supply of omega-3 PUFAs results in a rapid increase of EPA and DHA in plasma PC and of EPA in erythrocytes. These findings suggest that infusion of omega-3 PUFAs could be used to induce a rapid effect especially in targeting inflammation.

Unsaturated fatty acids differ between hepatic colorectal metastases and liver tissue without tumour in humans: results from a randomised controlled trial of intravenous eicosapentaenoic and docosahexaenoic acids.

INTRODUCTION: Mediators derived from the n-6 polyunsaturated fatty acid (PUFA) arachidonic acid oxidation have been shown to have tumour promoting effects in experimental models, while n-3 PUFAs are thought to be protective. Here we report fatty acid concentrations in hepatic colorectal metastases compared to liver tissue without tumour in humans. METHODS: Twenty patients with colorectal liver metastasis were randomized to receive a 72 h infusion of parenteral nutrition with or without n-3 PUFAs. Histological samples from liver metastases and liver tissue without tumour were obtained from 15 patients at the time of their subsequent liver resection (mean 8 days (range 4-12) post-infusion) and the fatty acid composition determined by gas chromatography. RESULTS: There were no significant differences in fatty acid composition between the two intervention groups. When data from all patients were combined, liver tissue without tumour had a higher content of both n-3 and n-6 PUFAs and a lower content of oleic acid and total n-9 fatty acids compared with tumour tissue (p<0.0001, 0.0002,<0.0001 and <0.0001, respectively). The n-6/n-3 PUFA ratio was found to be higher in tumour tissue than tissue without tumour (p<0.0001). CONCLUSIONS: Hepatic colorectal adenocarcinoma metastases have a higher content of n-9 fatty acids and a lower content of n-6 and n-3 PUFAs than liver tissue without tumour.

Reduction in circulating pro-angiogenic and pro-inflammatory factors is related to improved outcomes in patients with advanced pancreatic cancer treated with gemcitabine and intravenous omega-3 fish oil.

BACKGROUND: Pancreatic cancer is a rapidly progressive disease which is often only amenable to palliative treatment. Few patients respond to palliative chemotherapy, so surrogate markers indicating which patients are likely to respond to treatment are required. There is a well-established link between pro-inflammatory circulating cytokines and growth factors (CAF), and the development of neoplasia. Agents that may modulate these factors are of interest in developing potential novel therapeutic applications. METHODS: As part of a single-arm phase II trial in patients with advanced pancreatic cancer (APC) treated with gemcitabine and intravenous (i.v.) omega-3 rich lipid emulsion (n-3FA), serum samples were analysed for 14 CAF using a multiplex cytokine array. Baseline serum concentrations were correlated with overall (OS) and progression-free survival (PFS), and changes in concentration correlated with time and outcomes for CAF responders were analysed. RESULTS: Platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) concentrations reduced significantly with treatment over time. Low baseline interleukin (IL)-6 and -8 were correlated with improved OS. PDGF responders showed a tendency towards improved OS and FGF responders a significantly improved PFS. DISCUSSION: Treatment with gemcitabine plus i.v. n-3FA may reduce concentrations of CAF which may be associated with an improved outcome. Baseline IL-6 and -8 may be surrogate markers for outcome in patients with APC treated with this regimen.

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.

Potential applications of fish oils rich in n-3 fatty acids in the palliative treatment of advanced pancreatic cancer.

The palliative treatment of patients with advanced pancreatic cancer (APC) has undergone little advancement in the last 15 years. Novel therapies that have been investigated to extend survival have shown little benefit over existing chemotherapy regimens. Patients with APC often experience significant weight loss, which is one of the primary factors involved in declining quality of life. Recently, the ability of n-3 fatty acid rich oral preparations to attenuate or reverse tumour-related weight loss has been investigated in this patient group with encouraging results. Laboratory investigation has also yielded promising results suggesting a potential direct tumouricidal effect of n-3 fatty acids as well as the putative potentiation of existing chemotherapy regimes. The present review aims to examine the potential applications of fish oils rich in n-3 fatty acids in patients with APC, present a selection of the studies carried out to date and outline avenues of possible further clinical investigation.

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.

Hepatic microwave ablation: a review of the histological changes following thermal damage.

Microwave (MW) ablation therapy is a local treatment by which tumours are destroyed by coagulation from the passage of MWs into cells. The aim of this review is to examine histological results obtained from preclinical and clinical studies. A literature search was undertaken for all studies focusing on MW therapy and in which lesions were excised for a complete histopathological examination after treatment. Two main zones were described after ablative therapy (central and transitional). Both corresponded to specific microscopic characteristics and evolved over time in a precise manner. No viable cells even up to 6 cm in diameter were demonstrated in 93% of lesions after treatment. Microwave therapy is a reliable technique under a variety of clinical situations. Future investigations are needed to compare MW with other ablative techniques to identify factors that influence the effectiveness of the various techniques and to determine specific indications.

Ite Boerema--surgeon and engineer with a double-Dutch legacy to medical technology.

Ite Boerema, 1902-1978: a Dutchman with a brilliant academic surgical career, and war hero, decorated for resistance to the Germans in World War II. As a man who regarded surgery as "engineering in medicine," we still feel his legacy in medical technology today, specifically with regard to his work on esophageal anastomoses and hyperbaric oxygen therapy. This biography places his major contributions to medicine in context of the man himself and of contemporary medicine.