Biomarkers of Brain Damage Induced by Radiotherapy

Sultana, Nahida; Sun, Chao; Katsube, Takanori; Wang, Bing

doi:10.1177/1559325820938279

Cited by 13 publications

(11 citation statements)

References 135 publications

(167 reference statements)

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“…Radiotherapy is known to generate DNA damage and compromise its repair in addition to triggering radiolysis of cellular water that can originate free radicals that may cause chemical modifications in the DNA, proteins, and tumor microenvironment ( 31 – 33 ).…”

Section: Discussionmentioning

confidence: 99%

Metabolic biomarkers of radiotherapy response in plasma and tissue of an IDH1 mutant astrocytoma mouse model

Ruiz‐Rodado

Dowdy²,

Lita³

et al. 2022

Front. Oncol.

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Astrocytomas are the most common subtype of brain tumors and no curative treatment exist. Longitudinal assessment of patients, usually via Magnetic Resonance Imaging (MRI), is crucial since tumor progression may occur earlier than clinical progression. MRI usually provides a means for monitoring the disease, but it only informs about the structural changes of the tumor, while molecular changes can occur as a treatment response without any MRI-visible change. Radiotherapy (RT) is routinely performed following surgery as part of the standard of care in astrocytomas, that can also include chemotherapy involving temozolomide. Monitoring the response to RT is a key factor for the management of patients. Herein, we provide plasma and tissue metabolic biomarkers of treatment response in a mouse model of astrocytoma that was subjected to radiotherapy. Plasma metabolic profiles acquired over time by Liquid Chromatography Mass Spectrometry (LC/MS) were subjected to multivariate empirical Bayes time-series analysis (MEBA) and Receiver Operating Characteristic (ROC) assessment including Random Forest as the classification strategy. These analyses revealed a variation of the plasma metabolome in those mice that underwent radiotherapy compared to controls; specifically, fumarate was the best discriminatory feature. Additionally, Nuclear Magnetic Resonance (NMR)-based 13C-tracing experiments were performed at end-point utilizing [U-13C]-Glutamine to investigate its fate in the tumor and contralateral tissues. Irradiated mice displayed lower levels of glycolytic metabolites (e.g. phosphoenolpyruvate) in tumor tissue, and a higher flux of glutamine towards succinate was observed in the radiation cohort. The plasma biomarkers provided herein could be validated in the clinic, thereby improving the assessment of brain tumor patients throughout radiotherapy. Moreover, the metabolic rewiring associated to radiotherapy in tumor tissue could lead to potential metabolic imaging approaches for monitoring treatment using blood draws.

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Section: Discussionmentioning

confidence: 99%

Metabolic biomarkers of radiotherapy response in plasma and tissue of an IDH1 mutant astrocytoma mouse model

Ruiz‐Rodado

Dowdy²,

Lita³

et al. 2022

Front. Oncol.

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“…Ideally, clinicians would like to maximize the effectiveness of therapy used with GB patients, while minimizing unwanted systemic effects that may lead to therapy being halted or discontinued. Such unwanted systemic effects include cognitive deficits induced by radiotherapy [ 12 ], or specific organ toxicity observed through blood measurement of biochemical markers such as liver enzymes and functional factors (e.g., bilirubin and albumin), electrolytes, and blood cell counts (leukopenia) [ 13 ]. Nevertheless, assessing the effectiveness of treatment in the short term to avoid risking systemic effects is difficult.…”

Section: Hypothesis Proposalmentioning

confidence: 99%

Establishing Imaging Biomarkers of Host Immune System Efficacy during Glioblastoma Therapy Response: Challenges, Obstacles and Future Perspectives

Candiota

Arús

2022

Metabolites

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This hypothesis proposal addresses three major questions: (1) Why do we need imaging biomarkers for assessing the efficacy of immune system participation in glioblastoma therapy response? (2) Why are they not available yet? and (3) How can we produce them? We summarize the literature data supporting the claim that the immune system is behind the efficacy of most successful glioblastoma therapies but, unfortunately, there are no current short-term imaging biomarkers of its activity. We also discuss how using an immunocompetent murine model of glioblastoma, allowing the cure of mice and the generation of immune memory, provides a suitable framework for glioblastoma therapy response biomarker studies. Both magnetic resonance imaging and magnetic resonance-based metabolomic data (i.e., magnetic resonance spectroscopic imaging) can provide non-invasive assessments of such a system. A predictor based in nosological images, generated from magnetic resonance spectroscopic imaging analyses and their oscillatory patterns, should be translational to clinics. We also review hurdles that may explain why such an oscillatory biomarker was not reported in previous imaging glioblastoma work. Single shot explorations that neglect short-term oscillatory behavior derived from immune system attack on tumors may mislead actual response extent detection. Finally, we consider improvements required to properly predict immune system-mediated early response (1–2 weeks) to therapy. The sensible use of improved biomarkers may enable translatable evidence-based therapeutic protocols, with the possibility of extending preclinical results to human patients.

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“…Late-delayed injury occurs more than 6 months after radiation and is associated with permanent demyelination, vascular abnormalities, and white matter necrosis and is generally considered progressive and irreversible. 17,18 Noteworthy, while high radiation doses (>60 Gray [Gy]) were considered to be responsible for permanent injury, emerging investigation indicates that low radiation doses (<20 Gy) could also cause late-delayed damage. 19 The mechanisms underlying radiation-induced brain injury mainly include cytotoxicity and neuroinflammation, involving multiple cell types, including astrocytes, microglia, oligodendrocytes, endothelial cells, and neurons.…”

Section: Mechanisms Of Radiation-induced Brain Injurymentioning

confidence: 99%

Cerebral hemodynamic and metabolic dysregulation in the postradiation brain

Jain

Godoy

Mohan

et al. 2022

Journal of Neuroimaging

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Technological advances in the delivery of radiation and other novel cancer therapies have significantly improved the 5‐year survival rates over the last few decades. Although recent developments have helped to better manage the acute effects of radiation, the late effects such as impairment in cognition continue to remain of concern. Accruing data in the literature have implicated derangements in hemodynamic parameters and metabolic activity of the irradiated normal brain as predictive of cognitive impairment. Multiparametric imaging modalities have allowed us to precisely quantify functional and metabolic information, enhancing the anatomic and morphologic data provided by conventional MRI sequences, thereby contributing as noninvasive imaging‐based biomarkers of radiation‐induced brain injury. In this review, we have elaborated on the mechanisms of radiation‐induced brain injury and discussed several novel imaging modalities, including MR spectroscopy, MR perfusion imaging, functional MR, SPECT, and PET that provide pathophysiological and functional insights into the postradiation brain, and its correlation with radiation dose as well as clinical neurocognitive outcomes. Additionally, we explored some innovative imaging modalities, such as quantitative blood oxygenation level‐dependent imaging, susceptibility‐based oxygenation measurement, and T2‐based oxygenation measurement, that hold promise in delineating the potential mechanisms underlying deleterious neurocognitive changes seen in the postradiation setting. We aim that this comprehensive review of a range of imaging modalities will help elucidate the hemodynamic and metabolic injury mechanisms underlying cognitive impairment in the irradiated normal brain in order to optimize treatment regimens and improve the quality of life for these patients.

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Biomarkers of Brain Damage Induced by Radiotherapy

Cited by 13 publications

References 135 publications

Metabolic biomarkers of radiotherapy response in plasma and tissue of an IDH1 mutant astrocytoma mouse model

Metabolic biomarkers of radiotherapy response in plasma and tissue of an IDH1 mutant astrocytoma mouse model

Establishing Imaging Biomarkers of Host Immune System Efficacy during Glioblastoma Therapy Response: Challenges, Obstacles and Future Perspectives

Cerebral hemodynamic and metabolic dysregulation in the postradiation brain

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