title: Myoinositol as a Biomarker in Recurrent Glioblastoma Treated with Bevacizumab: A 1H-Magnetic Resonance Spectroscopy Study.
abstract: BACKGROUND
  Antiangiogenic treatment of glioblastomas with Bevacizumab lacks predictive markers. Myoinositol (MI) is an organic osmolyte, with intracellular concentration changes depending on the extracellular osmolality. Since Bevacizumab markedly reduces tumor edema and influences the tumor microenvironment, we investigated whether the MI concentration in the tumor changes during therapy.
  
  
  METHODS
  We used 1H-magnetic resonance spectroscopy to measure the MI concentrations in the tumor and contralateral control tissue of 39 prospectively recruited patients with recurrent glioblastomas before and 8-12 weeks after starting therapy. 30 patients received Bevacizumab and 9 patients were treated with CCNU/VM26 as control. We performed a survival analysis to evaluate MI as a predictive biomarker for Bevacizumab therapy.
  
  
  RESULTS
  MI concentrations increased significantly during Bevacizumab therapy in tumor (p < .001) and control tissue (p = .001), but not during CCNU/VM26 treatment. For the Bevacizumab cohort, higher MI concentrations in the control tissue at baseline (p = .021) and higher differences between control and tumor tissue (delta MI, p = .011) were associated with longer survival. A Kaplan-Meier analysis showed a median OS of 164 days for patients with a deltaMI < 1,817 mmol/l and 275 days for patients with a deltaMI > 1,817 mmol/l. No differences were observed for the relative changes or the post treatment concentrations. Additionally calculated creatine concentrations showed no differences in between subgroups or between pre and post treatment measurements.
  
  
  CONCLUSIONS
  Our data suggest that recurrent glioblastoma shows a strong metabolic reaction to Bevacizumab. Further, our results support the hypothesis that MI might be a marker for early tumor cell invasion. Pre-therapeutic MI concentrations are predictive of overall survival in patients with recurrent glioblastoma treated with Bevacizumab.
authors.affiliation: Dr. Senckenberg Institute of Neurooncology, Center for Neurology and Neurosurgery, Johann Wolfgang Goethe-University, Frankfurt/Main, Germany.|Institute of Neuroradiology, Center for Neurology and Neurosurgery, Johann Wolfgang Goethe-University, Frankfurt/Main, Germany.|German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Eike
authors.identifier: http://orcid.org/0000-0001-7464-0236
authors.initials: E
authors.lastname: Steidl
authors.affiliation: Institute of Neuroradiology, Center for Neurology and Neurosurgery, Johann Wolfgang Goethe-University, Frankfurt/Main, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Pilatus
authors.affiliation: Institute of Neuroradiology, Center for Neurology and Neurosurgery, Johann Wolfgang Goethe-University, Frankfurt/Main, Germany.
authors.forename: Elke
authors.initials: E
authors.lastname: Hattingen
authors.affiliation: Dr. Senckenberg Institute of Neurooncology, Center for Neurology and Neurosurgery, Johann Wolfgang Goethe-University, Frankfurt/Main, Germany.|German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Joachim P
authors.initials: JP
authors.lastname: Steinbach
authors.affiliation: Institute of Neuroradiology, Center for Neurology and Neurosurgery, Johann Wolfgang Goethe-University, Frankfurt/Main, Germany.
authors.forename: Friedhelm
authors.initials: F
authors.lastname: Zanella
authors.affiliation: Dr. Senckenberg Institute of Neurooncology, Center for Neurology and Neurosurgery, Johann Wolfgang Goethe-University, Frankfurt/Main, Germany.|German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Ronellenfitsch
authors.affiliation: Dr. Senckenberg Institute of Neurooncology, Center for Neurology and Neurosurgery, Johann Wolfgang Goethe-University, Frankfurt/Main, Germany.|German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Bähr
mesh_terms: D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use; D000068258:Bevacizumab / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001932:Brain Neoplasms / Q000188:drug therapy / Q000401:mortality / Q000473:pathology; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D006801:Humans; D006859:Hydrogen / Q000737:chemistry; D007294:Inositol / Q000378:metabolism*; D008130:Lomustine / Q000627:therapeutic use; D008279:Magnetic Resonance Imaging / Q000379:methods; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D016019:Survival Analysis; D013713:Teniposide / Q000627:therapeutic use; D059016:Tumor Microenvironment / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000097:blood
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; D007294:Inositol; D008130:Lomustine; D006859:Hydrogen; D013713:Teniposide