Bower, J. E. et al. Inflammatory responses to psychological stress in fatigued breast cancer survivors: relationship to glucocorticoids. Brain Behav. Immun. 21, 251-258

Cousins Center for Psychoneuroimmunology, Semel Institute for Neuroscience at UCLA, 300 UCLA Medical Plaza, Room 3306, Box 957076 Los Angeles, CA 90095-7076, USA.
Brain Behavior and Immunity (Impact Factor: 5.89). 03/2007; 21(3):251-8. DOI: 10.1016/j.bbi.2006.08.001
Source: PubMed


Fatigue is a common problem following cancer treatment and our previous studies suggest that a chronic inflammatory process might contribute to cancer-related fatigue. However, immune responses to challenge have not yet been evaluated among individuals with cancer-related fatigue, and it is not known what mechanisms drive increased levels of inflammatory markers in fatigued cancer survivors. We have previously reported that fatigued breast cancer survivors show a blunted cortisol response to an experimental psychological stressor. In this report, we focus on inflammatory responses to this stressor and their relationship to circulating glucocorticoids and cellular sensitivity to glucocorticoid inhibition. Relative to non-fatigued control survivors, participants experiencing persistent fatigue showed significantly greater increases in LPS-stimulated production of IL-1beta and IL-6 following the stressor (Group x Time interaction: p<.05). Fatigued participants did not show any difference in cellular sensitivity to cortisol inhibition of cytokine production, but they did show significantly less salivary cortisol increase in the aftermath of the stressor. Moreover, blunted cortisol responses were associated with significantly increased production of IL-6 in response to LPS stimulation (p<.05). These data provide further evidence of enhanced inflammatory processes in fatigued breast cancer survivors and suggest that these processes may stem in part from decreased glucocorticoid response to stress.

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Available from: Richard E Olmstead, Jun 06, 2014
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    • "It also plays a role in the acute phase response and systemic inflammation and is involved in the creation of new blood vessels, the regulation of cell differentiation, and programmed cell death (Kindt et al., 2006). In serum and plasma, TNF-a has been shown to increase in response to a TSST (Altemus et al., 2001; Bower et al., 2007), an anger-recall task (Suarez et al., 2006), a speech task (Ackerman et al., 1998), and mental arithmetic, Stroop, and public speech tasks (Heesen et al., 2002). Consistently high levels of TNF-a are often interpreted as evidence of dysregulation and have been shown to be related to a variety of chronic diseases, including Alzheimer's disease (Minagar et al., 2002), major depression (Khairova et al., 2009; Tuglu et al., 2003), certain cancers (Balkwill, 2006), multiple sclerosis (Minagar et al., 2002), cardiovascular diseases (Cesari et al., 2003; Stoner et al., 2013), and general frailty (Hubbard et al., 2009). "
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    ABSTRACT: There is burgeoning interest in the ability to detect inflammatory markers in response to stress within naturally occurring social contexts and/or across multiple time points per day within individuals. Salivary collection is a less invasive process than current methods of blood collection and enables intensive naturalistic methodologies, such as those involving extensive repeated measures per day over time. Yet the reliability and validity of saliva-based to blood-based inflammatory biomarkers in response to stress remains unclear. We review and synthesize the published studies that have examined salivary markers of inflammation following exposure to an acute laboratory stressor. Results from each study are reviewed by analyte (IL-1β, TNF-α, IL-6, IL-2, IL-4, IL-10, IL-12, CRP) and stress type (social-cognitive and exercise-physical), after which methodological issues and limitations are addressed. Although the literature is limited, several inflammatory markers (including IL-1β, TNF-α, and IL-6) have been reliably determined from saliva and have increased significantly in response to stress across multiple studies, with effect sizes ranging from very small to very large. Although CRP from saliva has been associated with CRP in circulating blood more consistently than other biomarkers have been associated with their counterparts in blood, evidence demonstrating it reliably responds to acute stress is absent. Although the current literature is presently too limited to allow broad assertion that inflammatory biomarkers determined from saliva are valuable for examining acute stress responses, this review suggests that specific targets may be valid and highlights specific areas of need for future research.
    Full-text · Article · Sep 2014 · Brain Behavior and Immunity
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    • "Several findings support these hypotheses. For example, elevated levels of inflammatory cytokines [21], circulating T lymphocytes [22], increased neutrophil counts [23], and blunted cortisol responses [24, 25] have been found to be associated to fatigue in cancer patients. Other studies have identified associations with sleep disturbances [26–28]. "
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    ABSTRACT: The PERFORM Questionnaire is a 12-item scale developed for assessing fatigue in cancer patients in the clinical practice. It has advantages over other tools in that it is short and includes beliefs and attitudes of patients about fatigue. It was psychometrically validated in cancer patients with and without anemia. We evaluated the usefulness of the PERFORM scale to measure fatigue in a large study focusing exclusively on anemic patients. This was an observational, multicenter, prospective, 3-month study in cancer patients with hemoglobin (Hb)≤11 g/dl. Fatigue was assessed using the PERFORM questionnaire. The overall score ranges from 12 (no fatigue) to 60 (maximum fatigue). We included 667 patients: 54.1 % women, mean age 60 (standard deviation, 12) years. A highly significant, but mild correlation was observed between low baseline Hb and high patient perception of fatigue (r with PERFORM score=-0.215, p < 0.0001). Of the patients, 65.8 % improved Hb level during follow-up (increase of ≥1 g/dL and/or achieving >11 g/dL), which translated into a significant improvement in the PERFORM score [mean (95 % confidence interval (CI)] change, -1.2 (-0.04 to -2.4), whereas more fatigue was observed in patients without improvement in Hb [change (95 % CI) in PERFORM, +3.3 (1.5 to 5)]. In a multivariate linear regression analysis, the independent factors associated to fatigue at 3 months were a low Hb level, a low Karnofsky index, active chemotherapy, cancer treatment with palliative intention, and transfusion need in the last 3 months. Minimal increases or decreases in Hb of ≥1 g/dL were associated with meaningful changes in patient-perceived fatigue as measured with the PERFORM questionnaire. In addition to anemia severity, other factors such as active chemotherapy and advanced disease contribute to perception of fatigue by cancer patients.
    Full-text · Article · Jun 2013 · Supportive Care in Cancer
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    • "The disarray in sympathetic and parasympathetic responses can also activate the pro-inflammatory cytokine network (Fagundes et al., 2011). High levels of pro-inflammatory cytokines (IL-6, IL-1b) (Wratten et al., 2004; Bower et al., 2007) and activated immune cells (CD4+ T lymphocytes ) have been observed in individuals reporting fatigue while receiving cancer therapy (Bower et al., 2007). The overexpression of the SNCA gene observed in this study indicates that neuroinflammatory mechanisms may play a role in the development of fatigue in this population, considering Table 2 Clinical and demographic characteristics of the samples. "
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    ABSTRACT: Purpose: Neuroinflammatory mechanisms are associated with fatigue in neurodegenerative conditions such as Parkinson's. The symptoms in Parkinson's including fatigue are thought to be related to α-synuclein overexpression. This study investigated genomic correlates of fatigue experienced by men with prostate cancer receiving external beam radiation therapy (EBRT). Patients and methods: Sixteen men with non-metastatic prostate cancer who were scheduled to receive EBRT were enrolled. Fatigue scores and blood were obtained at baseline (prior to EBRT, D0); one hour following initiation of EBRT (D1), day 7 (D7), day 14 (D14), midpoint (days 19-21, D21), completion (days 38-42, D42), and four weeks post-EBRT (days 68-72, D72). Gene expression profiling using microarray analysis was performed from peripheral blood and confirmatory qPCR and protein (ELISA) analyses verified the microarray results. Correlations between fatigue and gene/protein expressions were determined using a mixed model approach. Results: Microarray data showed significant, differential expression of 463 probesets following EBRT. SNCA had a 2.95-fold change at D21 from baseline. SNCA expression was confirmed by qPCR (p<0.001) and ELISA (p<0.001) over time during EBRT. Fatigue scores were significantly correlated with SNCA gene expression on D14 (r=0.55, p<0.05) and plasma α-synuclein concentrations on D42 of EBRT (r=0.54, p=0.04). Conclusion: Fatigue experienced during EBRT may be mediated by α-synuclein overexpression. Alpha-synuclein may serve as a useful biomarker to understand the mechanisms and pathways related to the development of fatigue in this population.
    Full-text · Article · Sep 2012 · Brain Behavior and Immunity
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