title: MR-based hypoxia measures in human glioma.
abstract: Hypoxia plays a central role in tumor stem cell genesis and is related to a more malignant tumor phenotype, therapy resistance (e.g. in anti-angiogenic therapies) and radio-insensitivity. Reliable hypoxia imaging would provide crucial metabolic information in the diagnostic work-up of brain tumors. In this study, we applied a novel BOLD-based MRI method for the measurement of relative oxygen extraction fraction (rOEF) in glioma patients and investigated potential benefits and drawbacks. Forty-five glioma patients were examined preoperatively in a pilot study on a 3T MR scanner. rOEF was calculated from quantitative transverse relaxation rates (T2, T2*) and cerebral blood volume (CBV) using a quantitative BOLD approach. rOEF maps were assessed visually and by means of a volume of interest (VOI) analysis. In six cases, MRI-targeted biopsy samples were analyzed using HIF-1α-immunohistochemistry. rOEF maps could be obtained with a diagnostic quality. Focal spots with high rOEF values were observed in the majority of high-grade tumors but in none of the low-grade tumors. VOI analysis revealed potentially hypoxic tumor regions with high rOEF in contrast-enhancing tumor regions as well as in the non-enhancing infiltration zone. Systematic bias was found as a result of non-BOLD susceptibility effects (T2*) and contrast agent leakage affecting CBV. Histological samples demonstrated reasonable correspondence between MRI characteristics and HIF-1α-staining. The presented method of rOEF imaging is a promising tool for the metabolic characterization of human glioma. For the interpretation of rOEF maps, confounding factors must be considered, with a special focus on CBV measurements in the presence of contrast agent leakage. Further validation involving a bigger cohort and extended immuno-histochemical correlation is required.
authors.affiliation: Department of Neuroradiology, Klinikum rechts der Isar der TU München, Technische Universität München, Ismaninger Str. 22, 81675, Munich, Germany, vivien.toth@tum.de.
authors.forename: Vivien
authors.initials: V
authors.lastname: Tóth
authors.forename: Annette
authors.initials: A
authors.lastname: Förschler
authors.forename: Nuria M
authors.initials: NM
authors.lastname: Hirsch
authors.forename: Jürgen
authors.initials: J
authors.lastname: den Hollander
authors.forename: Hendrik
authors.initials: H
authors.lastname: Kooijman
authors.forename: Jens
authors.initials: J
authors.lastname: Gempt
authors.forename: Florian
authors.initials: F
authors.lastname: Ringel
authors.forename: Jürgen
authors.initials: J
authors.lastname: Schlegel
authors.forename: Claus
authors.initials: C
authors.lastname: Zimmer
authors.forename: Christine
authors.initials: C
authors.lastname: Preibisch
mesh_terms: D001932:Brain Neoplasms / Q000098:blood supply / Q000175:diagnosis* / Q000378:metabolism; D015687:Cell Hypoxia; D002560:Cerebrovascular Circulation; D003287:Contrast Media; D005500:Follow-Up Studies; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007091:Image Processing, Computer-Assisted; D007124:Immunoenzyme Techniques; D008279:Magnetic Resonance Imaging; D010100:Oxygen / Q000032:analysis*; D010865:Pilot Projects; D019275:Radiopharmaceuticals
chemical_list: D003287:Contrast Media; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019275:Radiopharmaceuticals; D010100:Oxygen
references.citation: Magn Reson Med. 2006 Jul;56(1):187-97
references.pmid: 16724299
references.citation: Neuroimage. 2006 Sep;32(3):1032-40
references.pmid: 16854600
references.citation: J Magn Reson Imaging. 2012 Jun;35(6):1322-31
references.pmid: 22314848
references.citation: Magn Reson Med. 2003 Jan;49(1):47-60
references.pmid: 12509819
references.citation: Oncologist. 2002;7(6):492-508
references.pmid: 12490737
references.citation: AJNR Am J Neuroradiol. 2007 Sep;28(8):1455-61
references.pmid: 17846190
references.citation: Magn Reson Med. 2000 Oct;44(4):563-74
references.pmid: 11025512
references.citation: NMR Biomed. 2011 Jan;24(1):1-16
references.pmid: 21259366
references.citation: Neuroimage. 2008 May 1;40(4):1561-6
references.pmid: 18353683
references.citation: Proc Natl Acad Sci U S A. 2007 Jul 10;104(28):11796-801
references.pmid: 17586684
references.citation: NMR Biomed. 2011 Apr;24(3):246-52
references.pmid: 21404336
references.citation: Neuro Oncol. 2011 Dec;13(12):1349-63
references.pmid: 21890539
references.citation: J Cereb Blood Flow Metab. 2000 Aug;20(8):1225-36
references.pmid: 10950383
references.citation: Magn Reson Med. 1994 Jan;31(1):9-21
references.pmid: 8121277
references.citation: Magn Reson Med. 2003 Oct;50(4):708-16
references.pmid: 14523956
references.citation: Cell Cycle. 2009 Oct 15;8(20):3274-84
references.pmid: 19770585
references.citation: Acta Radiol. 2003 Sep;44(5):538-46
references.pmid: 14510762
references.citation: AJNR Am J Neuroradiol. 2013 Jun-Jul;34(6):E65-8
references.pmid: 22837312
references.citation: NMR Biomed. 2010 Nov;23(9):1071-6
references.pmid: 20665897
references.citation: J Nucl Med. 2008 Jun;49 Suppl 2:129S-48S
references.pmid: 18523070
references.citation: Acta Neurochir (Wien). 2012 Sep;154(9):1663-7
references.pmid: 22847726
references.citation: Eur Radiol. 2011 May;21(5):1068-76
references.pmid: 21069342
references.citation: Phys Med Biol. 2009 Oct 7;54(19):5749-66
references.pmid: 19729712
references.citation: Nat Rev Cancer. 2008 Aug;8(8):592-603
references.pmid: 18650835
references.citation: J Cereb Blood Flow Metab. 1985 Dec;5(4):584-90
references.pmid: 4055928
references.citation: Magn Reson Med. 2011 Oct;66(4):989-97
references.pmid: 21381108
references.citation: Radiology. 2008 Sep;248(3):979-86
references.pmid: 18647849
references.citation: Magn Reson Med. 2012 Sep;68(3):905-11
references.pmid: 22162074
references.citation: Radiology. 1994 Apr;191(1):41-51
references.pmid: 8134596
references.citation: Top Magn Reson Imaging. 2004 Feb;15(1):3-9
references.pmid: 15057169
references.citation: Magn Reson Med. 2009 Jul;62(1):205-17
references.pmid: 19449435
references.citation: NMR Biomed. 2013 Aug;26(8):963-86
references.pmid: 22927123
references.citation: Proc Natl Acad Sci U S A. 2001 Jan 16;98(2):676-82
references.pmid: 11209064
references.citation: Magn Reson Med. 2009 Jul;62(1):263-8
references.pmid: 19353655
references.citation: J Magn Reson Imaging. 1997 Jan-Feb;7(1):91-101
references.pmid: 9039598
references.citation: J Neuropathol Exp Neurol. 2006 Jun;65(6):529-39
references.pmid: 16783163
references.citation: Magn Reson Med. 2001 Apr;45(4):533-42
references.pmid: 11283978
references.citation: Neurotherapeutics. 2009 Jul;6(3):447-57
references.pmid: 19560735
references.citation: Magn Reson Med. 1998 Mar;39(3):417-28
references.pmid: 9498598
references.citation: Magn Reson Med. 2005 Dec;54(6):1403-11
references.pmid: 16254955
references.citation: Magn Reson Med. 1994 Dec;32(6):749-63
references.pmid: 7869897
references.citation: Virchows Arch A Pathol Anat Histopathol. 1986;409(2):127-47
references.pmid: 2424168
references.citation: Magn Reson Med. 2009 Nov;62(5):1270-81
references.pmid: 19780145
references.citation: Magn Reson Med. 2007 Jan;57(1):115-26
references.pmid: 17191227
references.citation: Magn Reson Med. 1992 Apr;24(2):375-83
references.pmid: 1569876
references.citation: J Clin Oncol. 2008 Jan 10;26(2):271-8
references.pmid: 18182667
references.citation: Am J Pathol. 2010 Sep;177(3):1491-502
references.pmid: 20671264
references.citation: Mol Cancer Res. 2011 Mar;9(3):259-70
references.pmid: 21364021
references.citation: AJNR Am J Neuroradiol. 2004 Mar;25(3):431-40
references.pmid: 15037469
references.citation: J Neurooncol. 2009 May;92(3):317-35
references.pmid: 19357959
references.citation: J Clin Neurosci. 2006 Oct;13(8):811-7
references.pmid: 16997706
references.citation: J Magn Reson Imaging. 2012 Feb;35(2):300-8
references.pmid: 21987489
references.citation: Int J Cancer. 2007 Jul 15;121(2):276-83
references.pmid: 17372907