BackgroundThe diet of most adults is low in fish and, therefore, provides limited quantities of the long-chain, omega-3 fatty acids (LCn-3FAs), eicosapentaenoic and docosahexaenoic acids (EPA, DHA). Since these compounds serve important roles in the brain, we sought to determine if healthy adults with low-LCn-3FA consumption would exhibit improvements in neuropsychological performance and parallel changes in brain morphology following repletion through fish oil supplementation.MethodsIn a randomized, controlled trial, 271 mid-life adults (30–54 years of age, 118 men, 153 women) consuming ⩽300 mg/day of LCn-3FAs received 18 weeks of supplementation with fish oil capsules (1400 mg/day of EPA and DHA) or matching placebo. All participants completed a neuropsychological test battery examining four cognitive domains: psychomotor speed, executive function, learning/episodic memory, and fluid intelligence. A subset of 122 underwent neuroimaging before and after supplementation to measure whole-brain and subcortical tissue volumes.ResultsCapsule adherence was over 95%, participant blinding was verified, and red blood cell EPA and DHA levels increased as expected. Supplementation did not affect performance in any of the four cognitive domains. Exploratory analyses revealed that, compared to placebo, fish oil supplementation improved executive function in participants with low-baseline DHA levels. No changes were observed in any indicator of brain morphology.ConclusionsIn healthy mid-life adults reporting low-dietary intake, supplementation with LCn-3FAs in moderate dose for moderate duration did not affect neuropsychological performance or brain morphology. Whether salutary effects occur in individuals with particularly low-DHA exposure requires further study.
218 Background: Autophagy is a cell survival mechanism, upregulated in pancreatic ductal adenocarcinoma, correlating adversely with response to therapy and prognosis. The autophagy inhibitor hydroxychloroquine (HCQ) is a novel treatment. Methods: A Phase I/II trial examined pre-operative gemcitabine with HCQ in the treatment of pancreatic cancer patients. Eligibility was restricted to those predicted to have limited survival following surgical resection. Two doses of gemcitabine (1500mg/m2) were administered with oral HCQ (200-1200mg/day) for 31 days until operation in a Storer phase 1 design. Primary endpoint was the safety and tolerability of HCQ. Secondary endpoints were clinical response as assessed by CA 19-9 and R0 resection rates. LC3 and cleaved caspase 3 staining were assessed as biologic correlates to clinical response. Additional exploratory endpoints included serum levels of HMGB1, IL-6, and DNA DAMPs. Results: Thirty-five patients were enrolled in the safety phase of the trial. Two patients withdrew consent prior to treatment and two others were removed due to a stroke and allergic rash, resulting in 31 patients completing treatment. There were no dose limiting toxicities and no treatment delays. 14 patients (45%) had a decrease in CA19-9 of >50% following treatment. 29 patients (94%) underwent surgical resection with an R0 resection rate of 81%. There was one peri-operative mortality (3.2%) with significant morbidity (Grade 3/4) affecting 29% of patients. Increases in pancreatic LC3 staining were consistent with autophagy inhibition. There was a statistically non significant trend towards increased apoptosis with increasing doses of HCQ. Both mitochondrial and nuclear DNA (p = .09) decreased. During treatment, HMGB1 and IL-6 levels rose and then returned to normal levels. Conclusions: Pre-operative autophagy inhibition with HCQ in combination with gemcitabine is safe and tolerable and associated with biomarkers of response. This regimen has promise as a biologically active strategy and future trials will examine HCQ in combination with Nab-paclitaxol/Gemcitabine combinations. Clinical trial information: NCT01128296.
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