title: MRSI-based molecular imaging of therapy response to temozolomide in preclinical glioblastoma using source analysis.
abstract: Characterization of glioblastoma (GB) response to treatment is a key factor for improving patients' survival and prognosis. MRI and magnetic resonance spectroscopic imaging (MRSI) provide morphologic and metabolic profiles of GB but usually fail to produce unequivocal biomarkers of response. The purpose of this work is to provide proof of concept of the ability of a semi-supervised signal source extraction methodology to produce images with robust recognition of response to temozolomide (TMZ) in a preclinical GB model. A total of 38 female C57BL/6 mice were used in this study. The semi-supervised methodology extracted the required sources from a training set consisting of MRSI grids from eight GL261 GBs treated with TMZ, and six control untreated GBs. Three different sources (normal brain parenchyma, actively proliferating GB and GB responding to treatment) were extracted and used for calculating nosologic maps representing the spatial response to treatment. These results were validated with an independent test set (7 control and 17 treated cases) and correlated with histopathology. Major differences between the responder and non-responder sources were mainly related to the resonances of mobile lipids (MLs) and polyunsaturated fatty acids in MLs (0.9, 1.3 and 2.8 ppm). Responding tumors showed significantly lower mitotic (3.3 ± 2.9 versus 14.1 ± 4.2 mitoses/field) and proliferation rates (29.8 ± 10.3 versus 57.8 ± 5.4%) than control untreated cases. The methodology described in this work is able to produce nosological images of response to TMZ in GL261 preclinical GBs and suitably correlates with the histopathological analysis of tumors. A similar strategy could be devised for monitoring response to treatment in patients. Copyright © 2016 John Wiley & Sons, Ltd.
authors.affiliation: Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain.|Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain.|Division of Radiotherapy and Imaging, The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, Sutton, Surrey, UK.
authors.forename: T
authors.initials: T
authors.lastname: Delgado-Goñi
authors.affiliation: Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain.|Department of Mathematics and Statistics, Liverpool John Moores University, Liverpool, UK.
authors.forename: S
authors.initials: S
authors.lastname: Ortega-Martorell
authors.affiliation: Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain.|Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain.|Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Ciezka
authors.affiliation: Institute for Science and Technology in Medicine, Keele University, Stoke-On-Trent, UK.|Centre for Health Informatics, Institute of Population Health University of Manchester, Manchester, UK.
authors.forename: I
authors.initials: I
authors.lastname: Olier
authors.affiliation: Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain.|Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain.|Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain.
authors.forename: A P
authors.initials: AP
authors.lastname: Candiota
authors.affiliation: Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain.|Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain.|Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain.
authors.forename: M
authors.identifier: 0000-0002-3316-9027
authors.initials: M
authors.lastname: Julià-Sapé
authors.affiliation: Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain.|Departament de Medicina i Cirurgia Animals, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain.
authors.forename: F
authors.initials: F
authors.lastname: Fernández
authors.affiliation: Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain.|Departament de Medicina i Cirurgia Animals, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Pumarola
authors.affiliation: Department of Mathematics and Statistics, Liverpool John Moores University, Liverpool, UK.
authors.forename: P J
authors.initials: PJ
authors.lastname: Lisboa
authors.affiliation: Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain.|Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain.|Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Arús
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001932:Brain Neoplasms / Q000175:diagnosis* / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000627:therapeutic use; D005260:Female; D005909:Glioblastoma / Q000175:diagnosis* / Q000188:drug therapy* / Q000378:metabolism; D008279:Magnetic Resonance Imaging / Q000379:methods; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D051379:Mice; D008810:Mice, Inbred C57BL; D057054:Molecular Imaging / Q000379:methods*; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D000077204:Temozolomide; D016896:Treatment Outcome
chemical_list: D018906:Antineoplastic Agents, Alkylating; D014408:Biomarkers, Tumor; D003606:Dacarbazine; D000077204:Temozolomide
keywords: glioblastoma; magnetic resonance spectroscopic imaging; response detection; source methodology; temozolomide