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, 15 (1), e0227384
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Metabolic Analysis of Amino Acids and Vitamin B6 Pathways in Lymphoma Survivors With Cancer Related Chronic Fatigue

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Metabolic Analysis of Amino Acids and Vitamin B6 Pathways in Lymphoma Survivors With Cancer Related Chronic Fatigue

Alexander Fosså et al. PLoS One.

Abstract

Chronic cancer-related fatigue (CF) is a common and distressing condition in a subset of cancer survivors and common also after successful treatment of malignant lymphoma. The etiology and pathogenesis of CF is unknown, and lack of biomarkers hampers development of diagnostic tests and successful therapy. Recent studies on the changes of amino acid levels and other metabolites in patients with chronic fatigue syndrome/myalgic encephalopathy (CFS/ME) have pointed to possible central defects in energy metabolism. Here we report a comprehensive analysis of serum concentrations of amino acids, including metabolites of tryptophan, the kynurenine pathway and vitamin B6 in a well characterized national Norwegian cohort of lymphoma survivors after high-dose therapy and autologous stem cell transplantation. Among the 20 standard amino acids in humans, only tryptophan levels were significantly lower in both males and females with CF compared to non-fatigued survivors, a strikingly different pattern than seen in CFS/ME. Markers of tryptophan degradation by the kynurenine pathway (kynurenine/tryptophan ratio) and activation of vitamin B6 catabolism (pyridoxic acid/(pyridoxal + pyridoxal 5'-phosphate), PAr index) differed in survivors with or without CF and correlated with known markers of immune activation and inflammation, such as neopterin, C-reactive protein and Interleukin-6. Among personal traits and clinical findings assessed simultaneously in participating survivors, higher neuroticism score, obesity and higher PAr index were significantly associated with increased risk of CF. Collectively, these data point to low grade immune activation and inflammation as a basis for CF in lymphoma survivors.

Conflict of interest statement

PMU is a member of the steering board of the nonprofit foundation which owns Bevital, and R&D director of Bevital, the company that carried out biochemical analyses. The authors declare no competing financial interests. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1
Fig 1. Patient flow chart.
Fig 2
Fig 2
Concentrations of tryptophan (A) and α-ketoglutaric acid (B) in survivors with and without chronic fatigue. Blue dots represent individual patients; red lines represent mean values in each group. p < 0.05 for both comparisons.
Fig 3
Fig 3
Kyn/Trp ratio (A), PAr index (B) and neopterin (C) in survivors with or without chronic fatigue. Blue dots represent individual patients; red lines represent mean values in each group. P = 0.06 for Kyn/Trp ration, p = 0.006 for PAr index and p = 0.07 for neopterin.
Fig 4
Fig 4
Kyn/Trp ratio (A), PAr index (B) and neopterin (C) in survivors with or without detectable IL-6 levels. Blue dots represent individual patients; red lines represent mean values in each group. p < 0.001 for all three comparisons.

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Grant support

This study was supported in part by research funding from the Norwegian Cancer Society and Radiumhospitalets legater. ØM and PMU are both at least partially employed by Bevital, a non-profit organization. Bevital has only paid parts of the salaries of these two coauthors, and not had any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section. The funder provided support in the form of salaries for authors [ØM and PMU], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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