title: A patient-specific computational model of hypoxia-modulated radiation resistance in glioblastoma using 18F-FMISO-PET.
abstract: Glioblastoma multiforme (GBM) is a highly invasive primary brain tumour that has poor prognosis despite aggressive treatment. A hallmark of these tumours is diffuse invasion into the surrounding brain, necessitating a multi-modal treatment approach, including surgery, radiation and chemotherapy. We have previously demonstrated the ability of our model to predict radiographic response immediately following radiation therapy in individual GBM patients using a simplified geometry of the brain and theoretical radiation dose. Using only two pre-treatment magnetic resonance imaging scans, we calculate net rates of proliferation and invasion as well as radiation sensitivity for a patient's disease. Here, we present the application of our clinically targeted modelling approach to a single glioblastoma patient as a demonstration of our method. We apply our model in the full three-dimensional architecture of the brain to quantify the effects of regional resistance to radiation owing to hypoxia in vivo determined by [(18)F]-fluoromisonidazole positron emission tomography (FMISO-PET) and the patient-specific three-dimensional radiation treatment plan. Incorporation of hypoxia into our model with FMISO-PET increases the model-data agreement by an order of magnitude. This improvement was robust to our definition of hypoxia or the degree of radiation resistance quantified with the FMISO-PET image and our computational model, respectively. This work demonstrates a useful application of patient-specific modelling in personalized medicine and how mathematical modelling has the potential to unify multi-modality imaging and radiation treatment planning.
authors.affiliation: Department of Neurological Surgery, Northwestern University and Feinberg School of Medicine, 676 N Saint Clair Street, Suite 1300, Chicago, IL 60611, USA Northwestern Brain Tumor Institute, Northwestern University, 675 N Saint Clair Street, Suite 2100, Chicago, IL 60611, USA, russell.rockne@northwestern.edu.
authors.forename: Russell C
authors.identifier: http://orcid.org/0000-0002-1557-159X
authors.initials: RC
authors.lastname: Rockne
authors.affiliation: Department of Radiation Oncology, University of Washington, School of Medicine, 1959 NE Pacific Street, Seattle, WA 98195, USA.
authors.forename: Andrew D
authors.identifier: http://orcid.org/0000-0002-7070-0139
authors.initials: AD
authors.lastname: Trister
authors.affiliation: Department of Neurological Surgery, Northwestern University and Feinberg School of Medicine, 676 N Saint Clair Street, Suite 1300, Chicago, IL 60611, USA Northwestern Brain Tumor Institute, Northwestern University, 675 N Saint Clair Street, Suite 2100, Chicago, IL 60611, USA.
authors.forename: Joshua
authors.initials: J
authors.lastname: Jacobs
authors.affiliation: Department of Neurological Surgery, Northwestern University and Feinberg School of Medicine, 676 N Saint Clair Street, Suite 1300, Chicago, IL 60611, USA Northwestern Brain Tumor Institute, Northwestern University, 675 N Saint Clair Street, Suite 2100, Chicago, IL 60611, USA.
authors.forename: Andrea J
authors.initials: AJ
authors.lastname: Hawkins-Daarud
authors.affiliation: Department of Pathology, University of Washington, School of Medicine, 1959 NE Pacific Street, Seattle, WA 98195, USA.
authors.forename: Maxwell L
authors.identifier: http://orcid.org/0000-0002-2390-6572
authors.initials: ML
authors.lastname: Neal
authors.affiliation: Department of Radiation Oncology, University of Washington, School of Medicine, 1959 NE Pacific Street, Seattle, WA 98195, USA.
authors.forename: Kristi
authors.initials: K
authors.lastname: Hendrickson
authors.affiliation: Department of Neurology, University of Washington, School of Medicine, 1959 NE Pacific Street, Seattle, WA 98195, USA.
authors.forename: Maciej M
authors.initials: MM
authors.lastname: Mrugala
authors.affiliation: Department of Radiation Oncology, University of Washington, School of Medicine, 1959 NE Pacific Street, Seattle, WA 98195, USA.
authors.forename: Jason K
authors.initials: JK
authors.lastname: Rockhill
authors.affiliation: Department of Radiology, University of Washington, School of Medicine, 1959 NE Pacific Street, Seattle, WA 98195, USA.
authors.forename: Paul
authors.identifier: http://orcid.org/0000-0001-6461-3306
authors.initials: P
authors.lastname: Kinahan
authors.affiliation: Department of Radiation Oncology, University of Washington, School of Medicine, 1959 NE Pacific Street, Seattle, WA 98195, USA Department of Radiology, University of Washington, School of Medicine, 1959 NE Pacific Street, Seattle, WA 98195, USA.
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Krohn
authors.affiliation: Department of Neurological Surgery, Northwestern University and Feinberg School of Medicine, 676 N Saint Clair Street, Suite 1300, Chicago, IL 60611, USA Northwestern Brain Tumor Institute, Northwestern University, 675 N Saint Clair Street, Suite 2100, Chicago, IL 60611, USA.
authors.forename: Kristin R
authors.identifier: http://orcid.org/0000-0002-2464-6119
authors.initials: KR
authors.lastname: Swanson
mesh_terms: D000368:Aged; D001932:Brain Neoplasms / Q000098:blood supply / Q000000981:diagnostic imaging / Q000532:radiotherapy; D005910:Glioma / Q000098:blood supply / Q000000981:diagnostic imaging / Q000532:radiotherapy; D006801:Humans; D000860:Hypoxia / Q000000981:diagnostic imaging / Q000532:radiotherapy; D008297:Male; D008920:Misonidazole / Q000008:administration & dosage / Q000031:analogs & derivatives*; D008954:Models, Biological; D049268:Positron-Emission Tomography; D057285:Precision Medicine; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage*; D011859:Radiography
chemical_list: D011838:Radiation-Sensitizing Agents; C031843:fluoromisonidazole; D008920:Misonidazole
keywords: glioblastoma; hypoxia; mathematical modelling; patient-specific; radiation resistance