Novel biomarker identification using metabolomic profiling to differentiate radiation necrosis and recurrent tumor following Gamma Knife radiosurgery

Abstract

OBJECTIVE Following an initial response of brain metastases to Gamma Knife radiosurgery, regrowth of the enhancing lesion as detected on MRI may represent either radiation necrosis (a treatment-related inflammatory change) or recurrent tumor. Differentiation of radiation necrosis from tumor is vital for management decision making but remains difficult by imaging alone. In this study, gas chromatography with time-of-flight mass spectrometry (GC-TOF) was used to identify differential metabolite profiles of the 2 tissue types obtained by surgical biopsy to find potential targets for noninvasive imaging. METHODS Specimens of pure radiation necrosis and pure tumor obtained from patient brain biopsies were flash-frozen and validated histologically. These formalin-free tissue samples were then analyzed using GC-TOF. The metabolite profiles of radiation necrosis and tumor samples were compared using multivariate and univariate statistical analysis. Statistical significance was defined as p ≤ 0.05. RESULTS For the metabolic profiling, GC-TOF was performed on 7 samples of radiation necrosis and 7 samples of tumor. Of the 141 metabolites identified, 17 (12.1%) were found to be statistically significantly different between comparison groups. Of these metabolites, 6 were increased in tumor, and 11 were increased in radiation necrosis. An unsupervised hierarchical clustering analysis found that tumor had elevated levels of metabolites associated with energy metabolism, whereas radiation necrosis had elevated levels of metabolites that were fatty acids and antioxidants/cofactors. CONCLUSIONS To the authors' knowledge, this is the first tissue-based metabolomics study of radiation necrosis and tumor. Radiation necrosis and recurrent tumor following Gamma Knife radiosurgery for brain metastases have unique metabolite profiles that may be targeted in the future to develop noninvasive metabolic imaging techniques.

Brain MR findings in patients treated with particle therapy for skull base tumors

“…A more recent study on tissue-based, untargeted metabolomics analysis to examine differential metabolic profiles of radiation necrosis in comparison to tumoral tissue, identified multiple candidate metabolites which could assist in the diagnosis. For example, alpha-tocopherol and citric acid were most significantly elevated in radiation necrosis compared with tumor, while proline and UDP-glucuronic acid were most elevated in tumoral tissue compared with radiation necrosis [72].…”

Guidelines for Regulated Cell Death Assays: A Systematic Summary, A Categorical Comparison, A Prospective

“…Various factors work as key participants in necroptosis, namely in a caspase-independent pathway, such as RIP1, RIP3, and MLKL (Galluzzi et al, 2014;Ding et al, 2015;Wu X. et al, 2020). Combined with traditional methods of detection of necrosis (morphological features, the intracellularcomponent release, and biochemical features involved in necrosis), specific biomarkers in necrosis allow for more accurate detection of necrosis or even a measure with greater potential for clinical implications (Vanden Berghe et al, 2013;Lu et al, 2017). It has been reported that necrosis is sometimes related to upregulated RIPK1, RIPK3, or MLKL mRNA or protein expression levels in vivo in various diseases or physiological conditions (Guo et al, 2020).…”

Hippocampal changes in inflammasomes, apoptosis, and MEMRI after radiation-induced brain injury in juvenile rats

“…Magnetic resonance spectroscopy (MRS) is another imaging method that can be used to detect metabolic changes in the hippocampus in a noninvasive manner [21]. MRS can be used to monitor brain tumor progression and is helpful for identifying radiation necrosis after radiation therapy [22,23]. In studies of radiation brain damage, MRS has been shown to detect early metabolic changes in normal irradiated brain tissue [24][25][26].…”