Exploratory Investigation of Early Biomarkers for Chronic Fatigue in Prostate Cancer Patients Following Radiation Therapy

Feng, Linyin; Wolff, Brian S.; Lukkahatai, Nada; Espina, Alexandra; Saligan, Leorey N.

doi:10.1097/ncc.0000000000000381

Cited by 28 publications

(37 citation statements)

References 55 publications

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“…Even though cognitive and motor fatigue may be distinguishable by symptom presentation, it is possible that they originate from the same upstream pathogenic mechanisms. Both cognitive and motor fatigue can be affected by inflammation associated with cancer or cancer treatment . Oxidative damage induced by RT can target sarcoplasmic reticulum calcium release channels affecting force generation capacity, as well as caspase/calpain pathways leading to contractile protein catabolism and muscle weakness .…”

Section: Discussionmentioning

confidence: 99%

Cognitive and motor aspects of cancer‐related fatigue

et al. 2019

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Background Cancer‐related fatigue (CRF) is a debilitating symptom frequently reported by patients during and after treatment for cancer. CRF is a multidimensional experience and is often solely assessed by self‐report measures. The goal of the study is to examine the physical and cognitive aspects of self‐reported CRF using a cognitive function test and a physical fatigue index in order to provide objective measures that can characterize the CRF phenotype. Methods A total of 59 subjects with nonmetastatic prostate cancer receiving external beam radiation therapy were included in the study. Fatigue was measured using the Functional Assessment of Cancer Therapy‐Fatigue (FACT‐F) questionnaire. Cognitive characteristics of CRF was measured using the Stroop Color‐Word Interference computerized test and the motor aspect of fatigue was measured using the static fatigue test using a handgrip dynamometer. Findings Functional Assessment of Cancer Therapy‐Fatigue scores significantly correlated with the Stroop Interference score, but not performance accuracy in all test conditions. Fatigued subjects exhibited a more rapid decline to 50% of maximal strength and increased static fatigue index in the handgrip test, whereas maximal grip strength was not affected. Conclusions The results suggest that CRF exhibits both cognitive and physical characteristics. Subjective fatigue was associated with increased time required to overcome cognitive interference, but not cognitive performance accuracy. Fatigued patients exhibited decreased physical endurance and the ability to sustain maximal strength over time. These objective measures may serve as valuable tools for clinicians to detect cognitive and physical impairment associated with CRF.

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Section: Discussionmentioning

confidence: 99%

Cognitive and motor aspects of cancer‐related fatigue

et al. 2019

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“…It is not uncommon for fatigue to persist long after cancer treatment, and to negatively impact the quality of life in these patients 1 , 2 . Although the underlying mechanisms of persistent fatigue remain elusive, emerging evidence suggests that unresolved inflammation after cancer treatment plays a role in the chronicity of cancer fatigue 3 – 7 .…”

Section: Introductionmentioning

confidence: 99%

mGluR5 mediates post-radiotherapy fatigue development in cancer patients

et al. 2018

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Cancer-related fatigue (CRF) is a common burden in cancer patients and little is known about its underlying mechanism. The primary aim of this study was to identify gene signatures predictive of post-radiotherapy fatigue in prostate cancer patients. We employed Fisher Linear Discriminant Analysis (LDA) to identify predictive genes using whole genome microarray data from 36 men with prostate cancer. Ingenuity Pathway Analysis was used to determine functional networks of the predictive genes. Functional validation was performed using a T lymphocyte cell line, Jurkat E6.1. Cells were pretreated with metabotropic glutamate receptor 5 (mGluR5) agonist (DHPG), antagonist (MPEP), or control (PBS) for 20 min before irradiation at 8 Gy in a Mark-1 γ-irradiator. NF-κB activation was assessed using a NF-κB/Jurkat/GFP Transcriptional Reporter Cell Line. LDA achieved 83.3% accuracy in predicting post-radiotherapy fatigue. “Glutamate receptor signaling” was the most significant (p = 0.0002) pathway among the predictive genes. Functional validation using Jurkat cells revealed clustering of mGluR5 receptors as well as increased regulated on activation, normal T cell expressed and secreted (RANTES) production post irradiation in cells pretreated with DHPG, whereas inhibition of mGluR5 activity with MPEP decreased RANTES concentration after irradiation. DHPG pretreatment amplified irradiation-induced NF-κB activation suggesting a role of mGluR5 in modulating T cell activation after irradiation. These results suggest that mGluR5 signaling in T cells may play a key role in the development of chronic inflammation resulting in fatigue and contribute to individual differences in immune responses to radiation. Moreover, modulating mGluR5 provides a novel therapeutic option to treat CRF.

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“…Despite its prevalence, fatigue is underdiagnosed and poorly managed, and the underlying mechanism remains elusive (Ahlberg et al, 2005; Feng et al, 2016a; Feng et al, 2016b). Several factors that contribute to fatigue development have been identified, such as anemia, hypothalamic–pituitary–adrenal (HPA) axis dysregulation, and inflammation (Bower and Lamkin, 2013; Dantzer et al, 2014; Feng et al, 2015).…”

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The role of TRAIL in fatigue induced by repeated stress from radiotherapy

Feng

Suy

Collins

et al. 2017

Journal of Psychiatric Research

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Fatigue is one of the most common and debilitating side effects of cancer and cancer treatment, and yet its etiology remains elusive. The goal of this study is to understand the role of chronic inflammation in fatigue following repeated stress from radiotherapy. Fatigue and non-fatigue categories were assessed using ≥ 3-point change in Functional Assessment of Cancer Therapy-Fatigue questionnaire (FACT-F) administered to participants at baseline/before radiotherapy and one year post-radiotherapy. Whole genome microarray and cytokine multiplex panel were used to examine fatigue-related transcriptome and serum cytokine changes, respectively. The study included 86 subjects (discovery phase n = 40, validation phase n = 46). The sample in the discovery phase included men with prostate cancer scheduled to receive external-beam radiotherapy. A panel of 48 cytokines were measured and the significantly changed cytokine found in the discovery phase was validated using sera from a separate cohort of men two years after completing radiotherapy for prostate cancer at a different institution. Effects of the significantly changed cytokine on cell viability was quantified using the MTT assay. During the discovery phase, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and TRAIL decoy receptor, TNFRSF10C (TRAIL-R3), were significantly upregulated in fatigued (≥ 3-point decrease from baseline to 1yr-post radiotherapy) subjects (n=15). In the validation phase, TRAIL correlated with fatigue scores 2yrs post-radiotherapy. TRAIL caused selective cytotoxicity in neuronal cells, but not in microglial and muscle cells, in vitro. Late-onset inflammation directed by TRAIL may play a role in fatigue pathogenesis post-repeated stress from irradiation.

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Exploratory Investigation of Early Biomarkers for Chronic Fatigue in Prostate Cancer Patients Following Radiation Therapy

Cited by 28 publications

References 55 publications

Cognitive and motor aspects of cancer‐related fatigue

Cognitive and motor aspects of cancer‐related fatigue

mGluR5 mediates post-radiotherapy fatigue development in cancer patients

The role of TRAIL in fatigue induced by repeated stress from radiotherapy

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