Post-cancer fatigue is not associated with immune activation or altered cytokine production

Cameron, Barbara; Bennett, Barbara; Li, Hongshou; Boyle, F.; deSouza, Patricia Coutinho; Wilcken, Nicholas; Friedlander, Michael; Goldstein, David; Lloyd, Andrew R.

doi:10.1093/annonc/mds108

Cited by 19 publications

(15 citation statements)

References 30 publications

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“…For instance, increased peripheral levels of IL-1ra (Collado-Hidalgo et al, 2006; Orre et al, 2009; Bower et al, 2002; Meyers et al, 2005), IL-6 (Meyers et al, 2005; Costanzo et al, 2005; Wratten et al, 2004), TNF (Bower et al, 2011; Meyers et al, 2005), CRP (Orre et al, 2009, 2011) appear to be significantly related to severe fatigue in cancer patients across disease trajectories. Other studies, however, have shown weak or non-significant associations among cancer-related fatigue and some of these inflammatory markers (Bower et al, 2011; Cameron et al, 2012; Kwak et al, 2012). Given the cross-sectional design in most studies (Schubert et al, 2007), a longitudinal design helps to elucidate the complex fatigue and inflammation association.…”

Section: Discussionmentioning

confidence: 89%

“…Studies have found that fatigued cancer patients exhibit higher levels of peripheral inflammatory markers, such as interleukin (IL)-1 receptor antagonist (IL-1ra) Collado-Hidalgo et al, 2006; Orre et al, 2009; Bower et al, 2002; Meyers et al, 2005, IL-6 (Meyers et al, 2005; Costanzo et al, 2005; Wratten et al, 2004), tumor necrosis factor (TNF) Bower et al, 2011; Meyers et al, 2005, and C-reactive protein (CRP) Orre et al, 2009, 2011 compared to those without fatigue. Others, however, report no association between fatigue and inflammation (Bower et al, 2011; Cameron et al, 2012). These conflicting findings emphasize the need for further investigation into the relationship between fatigue and inflammation.…”

Section: Introductionmentioning

confidence: 99%

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Fatigue is associated with inflammation in patients with head and neck cancer before and after intensity-modulated radiation therapy

Xiao

Beitler

Higgins

et al. 2016

Brain, Behavior, and Immunity

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Patients with head and neck cancer (HNC) receiving intensity-modulated radiation therapy (IMRT) have particularly high rates of fatigue, and pre-and post-radiotherapy fatigue are prognostic factors for pathologic tumor responses and poor survival. Although inflammation has been proposed as one of the potential mechanisms of fatigue in cancer patients, findings have not been consistent, and there is a dearth of longitudinal studies. Accordingly, we conducted a prospective study in 46 HNC patients pre-and one-month post-IMRT. Fatigue was measured by the Multidimensional Fatigue Inventory (MFI)-20 at both time points along with the assessment of peripheral blood inflammatory markers including interleukin (IL)-6, soluble tumor necrosis factor receptor 2, and C-reactive protein (CRP) and gene expression. Generalized estimating equations were used to examine the association between inflammatory markers and fatigue. Gene enrichment analysis using MetaCore software was performed using up-regulated genes that were significantly associated with IMRT and fatigue. Significant associations between fatigue and IL-6 as well as CRP, which were independent of time, were observed. In addition the change in fatigue from pre-to post-IMRT was positively associated with the change in IL-6 and CRP. Analysis of up-regulated gene transcripts as a function of IMRT and fatigue revealed overrepresentation of transcripts related to the defense response and nuclear factor kappa B. In conclusion, our findings support the hypotheses that inflammation is associated with fatigue over time in HNC patients.Correspondence to: Canhua Xiao. Future studies on how inflammation contributes to fatigue as well as strategies targeting inflammation to reduce fatigue are warranted. HHS Public Access

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Section: Discussionmentioning

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Fatigue is associated with inflammation in patients with head and neck cancer before and after intensity-modulated radiation therapy

Xiao

Beitler

Higgins

et al. 2016

Brain, Behavior, and Immunity

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“…To date, results are inconclusive, with some studies finding positive associations between fatigue severity and circulating levels of TNF-α [20, 21] and IL-6 [18, 20, 22–29] and others finding no associations with TNF-α[18, 22, 30–33], IL-6 [30, 34–38], and IL-4 [25, 36, 38]. These inconsistent results may be related to the challenges associated with the measurement of serum cytokines, as well as circadian variations in cytokine levels [39].…”

Section: Introductionmentioning

confidence: 99%

“…Some studies found positive associations between fatigue and changes in serum levels of IL-1 receptor antagonist (IL-1ra)[24, 35, 41, 42], soluble TNF receptor II (sTNF-RII) [41, 43, 44], sTNF-RI [45], and sIL-6R [37, 46, 47]. However, other studies found no associations between fatigue severity and changes in serum levels of IL-1ra [27, 34, 36], sTNF-RII [36, 42], and sIL-6R [46]. Of note, none of these studies evaluated for associations between diurnal variations in fatigue severity and changes in these serum markers.…”

Section: Introductionmentioning

confidence: 99%

Inflammatory pathway genes associated with inter-individual variability in the trajectories of morning and evening fatigue in patients receiving chemotherapy

et al. 2017

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Fatigue, a highly prevalent and distressing symptom during chemotherapy (CTX), demonstrates diurnal and interindividual variability in severity. Little is known about the associations between variations in genes involved in inflammatory processes and morning and evening fatigue severity during CTX. The purposes of this study, in a sample of oncology patients (N=543) with breast, gastrointestinal (GI), gynecological (GYN), or lung cancer who received two cycles of CTX, were to determine whether variations in genes involved in inflammatory processes were associated with inter-individual variability in initial levels as well as in the trajectories of morning and evening fatigue. Patients completed the Lee Fatigue Scale to determine morning and evening fatigue severity a total of six times over two cycles of CTX. Using a whole exome array, 309 single nucleotide polymorphisms among the 64 candidate genes that passed all quality control filters were evaluated using hierarchical linear modeling (HLM). Based on the results of the HLM analyses, the final SNPs were evaluated for their potential impact on protein function using two bioinformational tools. The following inflammatory pathways were represented: chemokines (3 genes); cytokines (12 genes); inflammasome (11 genes); Janus kinase/signal transducers and activators of transcription (JAK/STAT, 10 genes); mitogen-activated protein kinase/jun amino-terminal kinases (MAPK/JNK, 3 genes); nuclear factor-kappa beta (NFkB, 18 genes); and NFkB and MAP/JNK (7 genes). After controlling for self-reported and genomic estimates of race and ethnicity, polymorphisms in six genes from the cytokine (2 genes); inflammasome (2 genes); and NFkB (2 genes) pathways were associated with both morning and evening fatigue. Polymorphisms in six genes from the inflammasome (1 gene); JAK/STAT (1 gene); and NFkB (4 genes) pathways were associated with only morning fatigue. Polymorphisms in three genes from the inflammasome (2 genes) and the NFkB (1 gene) pathways were associated with only evening fatigue. Taken together, these findings add to the growing body of evidence that suggests that morning and evening fatigue are distinct symptoms.

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“…Tumor necrosis factor – alpha (TNF-α)(Aouizerat et al, 2009; Bower et al, 2013; Fung et al, 2013; Jim et al, 2012), interleukin 6 (IL6)(Inagaki et al, 2013; Rohleder et al, 2012; Schrepf et al, 2013; Schubert et al, 2007; Starkweather, 2013), and IL-1 beta (IL-1β) (Bower, 2007; Saligan and Kim, 2012; van Zuiden et al, 2012) exhibit the strongest relationships with fatigue in prior studies, although other cytokine-fatigue associations have also been reported (Bower et al, 2011; Liu et al, 2012; Piraino et al, 2012) and still other studies have yielded contradictory results (Cameron et al, 2012; Dirksen et al, 2013; Geinitz et al, 2004; Hamre et al, 2013). Both cytokine plasma concentrations and polymorphisms are implicated in fatigue, yet the nature of these relationships remains poorly understood.…”

Section: Introductionmentioning

confidence: 99%

Cytokine polymorphisms are associated with fatigue in adults living with HIV/AIDS

Lee

Lerdal

Pullinger

et al. 2014

Brain, Behavior, and Immunity

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Fatigue has been associated with inflammation and cytokine activity among adults, but this relationship has not been evaluated among adults living with HIV. Diurnal patterns of fatigue have been previously identified in adults with HIV/AIDS. Thus, the purpose of this study was to describe these fatigue patterns in relation to cytokine plasma concentrations and gene polymorphisms. A convenience sample of 317 adults living with HIV/AIDS completed a measure of fatigue in the morning and evening for three consecutive days; participants reporting low levels of both morning and evening fatigue (n=110) or high levels of fatigue in the morning and evening (n=114) were included in the analysis, resulting in a final sample of 224 adults (151 men, 55 women, and 18 transgender). Plasma cytokines were analyzed, and genotyping was conducted for 15 candidate genes involved in cytokine signaling: interferon-gamma (IFNG), IFNG receptor 1 (IFNGR1), interleukins (IL), nuclear factor of kappa light polypeptide gene enhancer in B cells (NFKB-1 and -2), and tumor necrosis factor alpha (TNFA). Demographic and clinical variables were evaluated as potential covariates. Controlling for genomic estimates of ancestry and self-reported race/ethnicity and gender, the high fatigue pattern was associated with five single nucleotide polymorphisms (SNPs): IL1B rs1071676 and rs1143627, IL4 rs2243274, and TNFA rs1800683 and rs1041981. The IL1B and TNFA polymorphisms were not associated with plasma levels of IL-1β or TNFα, respectively. This study strengthens the evidence for an association between inflammation and fatigue. In this chronic illness population, the cytokine polymorphisms associated with high levels of morning and evening fatigue provide direction for future personalized medicine intervention research.

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Post-cancer fatigue is not associated with immune activation or altered cytokine production

Cited by 19 publications

References 30 publications

Fatigue is associated with inflammation in patients with head and neck cancer before and after intensity-modulated radiation therapy

Fatigue is associated with inflammation in patients with head and neck cancer before and after intensity-modulated radiation therapy

Inflammatory pathway genes associated with inter-individual variability in the trajectories of morning and evening fatigue in patients receiving chemotherapy

Cytokine polymorphisms are associated with fatigue in adults living with HIV/AIDS

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