A comparison of the inflammatory response following autologous compared with allogenic islet cell transplantation.

BACKGROUND: The initial response to islet transplantation and the subsequent acute inflammation is responsible for significant attrition of islets following both autologous and allogenic procedures. This multicentre study compares this inflammatory response using cytokine profiles and complement activation. METHODS: Inflammatory cytokine and complement pathway activity were examined in two cohorts of patients undergoing total pancreatectomy followed either by autologous (n=11) or allogenic (n=6) islet transplantation. Two patients who underwent total pancreatectomy alone (n=2) served as controls. RESULTS: The peak of cytokine production occurred immediately following induction of anaesthesia and during surgery. There was found to be a greater elevation of the following cytokines: TNF-alpha (P<0.01), MCP-1 (P=0.0013), MIP-1α (P=0.001), MIP-1ß (P=0.00020), IP-10 (P=0.001), IL-8 (P=0.004), IL-1α (P=0.001), IL-1ra (0.0018), IL-10 (P=0.001), GM-CSF (P=0.001), G-CSF (P=0.0198), and Eotaxin (P=0.01) in the allogenic group compared to autografts and controls. Complement activation and consumption was observed in all three pathways, and there were no significant differences in between the groups although following allogenic transplantation ∆IL-10 and ∆VEGF levels were significantly elevated those patients who became insulin-independent compared with those who were insulin-dependent. CONCLUSIONS: The cytokine profiles following islet transplantation suggests a significantly greater acute inflammatory response following allogenic islet transplantation compared with auto-transplantation although a significant, non-specific inflammatory response occurs following both forms of islet transplantation.

Myeloid derived suppressor cells are reduced and T regulatory cells stabilised in patients with advanced pancreatic cancer treated with gemcitabine and intravenous omega 3.

BACKGROUND: Pancreatic adenocarcinoma (PAC) is a devastating condition, with the majority of patients presenting with metastatic or locally advanced disease. In these patients their disease is classified as advanced pancreatic cancer (APC), which is incurable and associated with survivals generally of a few months. The overall survival (OS) for pancreatic cancer has not changed significantly in the past forty years with multiple trials demonstrating disappointing results. Immune modulatory cells particularly myeloid derived suppressor cells (MDSCs) and T regulatory cells (Tregs) are important mediators in PAC. Omega 3 fatty acids (ω-3FAs) have been shown to have anti-inflammatory properties and there is now evidence demonstrating the benefit of ω-3FAs in PAC. METHODS: This was a single-center cohort study investigating intravenous ω-3FAs and gemcitabine chemotherapy versus gemcitabine therapy only in patients with APC. Here, we investigated levels of MDSCs and Tregs and examined how these changes correlated with survival. RESULTS: Eighteen trial and nine control patients were recruited. There was a significant benefit in progression-free survival (PFS) in trial compared to control patients (P=0.0003). Median survival in trial patients was 5.65 months compared to 1.8 months in control patients. There was no significant benefit in OS in trial compared to control patients (P=0.13). Median survival in trial patients was 7 months compared to 2.9 months in control patients. MDSCs were significantly decreased in trial patients (P=0.0001) but not control patients. Conversely Tregs were significantly increased in control patients (P=0.005) but not in trial patients. CONCLUSIONS: Administration of ω-3FAs with gemcitabine chemotherapy in APC results in a significant decrease of MDSCs and stability of Tregs. This may be secondary to the reduction of pro-inflammatory mediators. A phase three randomized trial is justified to further examine these effects.

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.

The impact of an omega-3 fatty acid rich lipid emulsion on fatty acid profiles in critically ill septic patients.

BACKGROUND: Death from sepsis in the intensive therapy unit (ITU) is frequently preceded by the development of multiple organ failure as a result of uncontrolled inflammation. Treatment with omega-3 (n-3) fatty acids (FAs), principally eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), has been demonstrated to attenuate the effects of uncontrolled inflammation and may be clinically beneficial in reducing mortality from organ dysfunction. Fish oil (FO) is a source of EPA and DHA. METHODS: A randomized trial investigating the effects of parenteral (intravenous) nutrition providing FO (0.092g EPA+DHA/kg body weight/day) was conducted. Sixty consecutive ITU patients diagnosed with sepsis were randomised to receive either once daily parenteral FO and standard medical care or standard medical care only. RESULTS: Forty one patients (21 received fish oil; 20 controls) consented to blood sampling and blood was taken on days 0, 1, 2, 3, 5, 7, 10 and 13; because of deaths, patient discharge and withdrawal of consent, the number of blood samples available for analysis diminished with time. FA composition of plasma phosphatidylcholine (PC), plasma non-esterified FAs (NEFAs) and peripheral blood mononuclear cells (PBMCs) was determined by gas chromatography. EPA and DHA were rapidly incorporated into all 3 lipid pools investigated. There was a reduction in the arachidonic acid (AA) to EPA+DHA ratio in plasma PC and NEFAs. Fewer patients died in the FO group (13.3% (n=4)) compared with the control group (26.7% (n=8)) but this difference was not significant. A reduction in the AA/(EPA+DHA) ratio in PBMCs and plasma PC was associated with significantly improved survival. Plasma PC, plasma NEFA and PBMC FA profiles are rapidly altered by FO infusion in critically ill septic patients. CONCLUSION: The provision of high dose n-3 FAs resulted in a rapid and significant increase in EPA and DHA and a reduction in AA/(EPA+DHA) ratio. This latter reduction is associated with improved survival.

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.