title: Phospholipid metabolites in recurrent glioblastoma: in vivo markers detect different tumor phenotypes before and under antiangiogenic therapy.
abstract: OBJECTIVE
  Metabolic changes upon antiangiogenic therapy of recurrent glioblastomas (rGBMs) may provide new biomarkers for treatment efficacy. Since in vitro models showed that phospholipid membrane metabolism provides specific information on tumor growth we employed in-vivo MR-spectroscopic imaging (MRSI) of human rGBMs before and under bevacizumab (BVZ) to measure concentrations of phosphocholine (PCho), phosphoethanolamine (PEth), glycerophosphocholine (GPC), and glyceroethanolamine (GPE).
  
  
  METHODS
  (1)H and (31)P MRSI was prospectively performed in 32 patients with rGBMs before and under BVZ therapy at 8 weeks intervals until tumor progression. Patients were dichotomized into subjects with long overall survival (OS) (>median OS) and short OS (<median OS) survival time from BVZ-onset. Metabolite concentrations from tumor tissue and their ratios were compared to contralateral normal-appearing tissue (control).
  
  
  RESULTS
  Before BVZ, (1)H-detectable choline signals (total GPC and PCho) in rGBMs were elevated but significance failed after dichotomizing. For metabolite ratios obtained by (31)P MRSI, the short-OS group showed higher PCho/GPC (p = 0.004) in rGBMs compared to control tissue before BVZ while PEth/GPE was elevated in rGBMs of both groups (long-OS p = 0.04; short-OS p = 0.003). Under BVZ, PCho/GPC and PEth/GPE in the tumor initially decreased (p = 0.04) but only PCho/GPC re-increased upon tumor progression (p = 0.02). Intriguingly, in normal-appearing tissue an initial PEth/GPE decrease (p = 0.047) was followed by an increase at the time of tumor progression (p = 0.031).
  
  
  CONCLUSIONS
  An elevated PCho/GPC ratio in the short-OS group suggests that it is a negative predictive marker for BVZ efficacy. These gliomas may represent a malignant phenotype even growing under anti-VEGF treatment. Elevated PEth/GPE may represent an in-vivo biomarker more sensitive to GBM infiltration than MRI.
authors.affiliation: Institute of Neuroradiology, Goethe-University Hospital Frankfurt, Frankfurt, Germany. elke.hattingen@kgu.de
authors.forename: Elke
authors.initials: E
authors.lastname: Hattingen
authors.forename: Oliver
authors.initials: O
authors.lastname: Bähr
authors.forename: Johannes
authors.initials: J
authors.lastname: Rieger
authors.forename: Stella
authors.initials: S
authors.lastname: Blasel
authors.forename: Joachim
authors.initials: J
authors.lastname: Steinbach
authors.forename: Ulrich
authors.initials: U
authors.lastname: Pilatus
mesh_terms: D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage*; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage*; D000068258:Bevacizumab; D001932:Brain Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism* / Q000401:mortality; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D005909:Glioblastoma / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism* / Q000401:mortality; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality; D010743:Phospholipids / Q000378:metabolism*; D011446:Prospective Studies; D011859:Radiography; D015996:Survival Rate
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D010743:Phospholipids; D000068258:Bevacizumab