Neo-angiogenesis represents an important factor for the delivery of oxygen and nutrients to a growing tumour, and is considered to be one of the main pathodiagnostic features of glioblastomas (GBM). Anti-angiogenic therapy by vascular endothelial growth factor (VEGF) blocking agents has been shown to lead to morphological vascular normalisation resulting in a reduction of contrast enhancement as seen by magnetic resonance imaging (MRI). Yet the functional consequences of this normalisation and its potential for improved delivery of cytotoxic agents to the tumour are not known. The presented study aimed at determining the early physiologic changes following bevacizumab treatment. A time series of perfusion MRI and hypoxia positron emission tomography (PET) scans were acquired during the first week of treatment, in two human GBM xenograft models treated with either high or low doses of bevacizumab. We show that vascular morphology was normalised over the time period investigated, but vascular function was not improved, resulting in poor tumoural blood flow and increased hypoxia.

Department of Biomedecine University of Bergen Bergen Norway

Department of Biomedecine University of Bergen Bergen Norway 2 Department of Neurosurgery Haukeland University Hospital Bergen Norway 3 KG Jebsen Brain Tumor research Center University of Bergen Bergen Norway

Department of Biomedecine University of Bergen Bergen Norway 3 KG Jebsen Brain Tumor research Center University of Bergen Bergen Norway

Department of Biomedecine University of Bergen Bergen Norway 3 KG Jebsen Brain Tumor research Center University of Bergen Bergen Norway 7 Norlux Neuro Oncology Laboratory Department of Oncology Luxembourg Institute of Health Luxembourg Luxembourg

Department of Biomedecine University of Bergen Bergen Norway 5 Bergen University College Bergen Norway

Department of Neurosurgery Haukeland University Hospital Bergen Norway 6 Department of Clinical Science University of Bergen Bergen Norway

Institute of Scientific Instruments of the Czech Academy of Sciences Brno Czech Republic

KG Jebsen Brain Tumor research Center University of Bergen Bergen Norway 7 Norlux Neuro Oncology Laboratory Department of Oncology Luxembourg Institute of Health Luxembourg Luxembourg

Norlux Neuro Oncology Laboratory Department of Oncology Luxembourg Institute of Health Luxembourg Luxembourg

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$a Lack of functional normalisation of tumour vessels following anti-angiogenic therapy in glioblastoma / $c N. Obad, H. Espedal, R. Jirik, PO. Sakariassen, C. Brekke Rygh, M. Lund-Johansen, T. Taxt, SP. Niclou, R. Bjerkvig, O. Keunen,

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