title: Characterization of the serum metabolome following radiation treatment in patients with high-grade gliomas.
abstract: BACKGROUND
  Glioblastomas progress rapidly making response evaluation using MRI insufficient since treatment effects are not detectable until months after initiation of treatment. Thus, there is a strong need for supplementary biomarkers that could provide reliable and early assessment of treatment efficacy. Analysis of alterations in the metabolome may be a source for identification of new biomarker patterns harboring predictive information. Ideally, the biomarkers should be found within an easily accessible compartment such as the blood.
  
  
  METHODS
  Using gas-chromatographic- time-of-flight-mass spectroscopy we have analyzed serum samples from 11 patients with glioblastoma during the initial phase of radiotherapy. Fasting serum samples were collected at admittance, on the same day as, but before first treatment and in the morning after the second and fifth dose of radiation. The acquired data was analyzed and evaluated by chemometrics based bioinformatics methods. Our findings were compared and discussed in relation to previous data from microdialysis in tumor tissue, i.e. the extracellular compartment, from the same patients.
  
  
  RESULTS
  We found a significant change in metabolite pattern in serum comparing samples taken before radiotherapy to samples taken during early radiotherapy. In all, 68 metabolites were lowered in concentration following treatment while 16 metabolites were elevated in concentration. All detected and identified amino acids and fatty acids together with myo-inositol, creatinine, and urea were among the metabolites that decreased in concentration during treatment, while citric acid was among the metabolites that increased in concentration. Furthermore, when comparing results from the serum analysis with findings in tumor extracellular fluid we found a common change in metabolite patterns in both compartments on an individual patient level. On an individual metabolite level similar changes in ornithine, tyrosine and urea were detected. However, in serum, glutamine and glutamate were lowered after treatment while being elevated in the tumor extracellular fluid.
  
  
  CONCLUSIONS
  Cross-validated multivariate statistical models verified that the serum metabolome was significantly changed in relation to radiation in a similar pattern to earlier findings in tumor tissue. However, all individual changes in tissue did not translate into changes in serum. Our study indicates that serum metabolomics could be of value to investigate as a potential marker for assessing early response to radiotherapy in malignant glioma.
authors.affiliation: Department of Chemistry, Computational Life Science Cluster, Umeå University, SE 901 87, Umeå, Sweden. lina.s.moren@gmail.com.|Department of Chemistry, Umeå University, SE 90187, Umeå, Sweden. lina.s.moren@gmail.com.
authors.forename: Lina
authors.initials: L
authors.lastname: Mörén
authors.affiliation: Department of Radiation Sciences, Oncology, Umeå University, SE 901 85, Umeå, Sweden.
authors.forename: Carl
authors.initials: C
authors.lastname: Wibom
authors.affiliation: Department of Radiation Sciences, Oncology, Umeå University, SE 901 85, Umeå, Sweden.
authors.forename: Per
authors.initials: P
authors.lastname: Bergström
authors.affiliation: Department of Radiation Sciences, Oncology, Umeå University, SE 901 85, Umeå, Sweden.
authors.forename: Mikael
authors.initials: M
authors.lastname: Johansson
authors.affiliation: Department of Chemistry, Computational Life Science Cluster, Umeå University, SE 901 87, Umeå, Sweden.
authors.forename: Henrik
authors.initials: H
authors.lastname: Antti
authors.affiliation: Department of Clinical Neuroscience, Neurosurgery, Umeå University, SE 901 85, Umeå, Sweden.
authors.forename: A Tommy
authors.initials: AT
authors.lastname: Bergenheim
mesh_terms: D014408:Biomarkers, Tumor / Q000097:blood; D001932:Brain Neoplasms / Q000097:blood* / Q000532:radiotherapy*; D002849:Chromatography, Gas; D019295:Computational Biology; D005909:Glioblastoma / Q000097:blood* / Q000532:radiotherapy*; D005910:Glioma / Q000097:blood / Q000532:radiotherapy; D006801:Humans; D013058:Mass Spectrometry; D055442:Metabolome; D015999:Multivariate Analysis; D025341:Principal Component Analysis; D011878:Radiotherapy; D015203:Reproducibility of Results
chemical_list: D014408:Biomarkers, Tumor
keywords: Chemometrics; Glioblastoma; Metabolomics; Radiation therapy; Treatment response