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Diffusion and Perfusion-Weighted Imaging in the Structural and Functional Characterization of Diffuse Gliomas for Differential Diagnosis and Treatment Planning

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Diffusion and Perfusion-Weighted Imaging in the Structural and Functional Characterization of Diffuse Gliomas for Differential Diagnosis and Treatment Planning Diffusion and perfusion-weighted imaging in the structural and functional characterization of diffuse gliomas for differential diagnosis and treatment planning Anna Latysheva Doctoral Thesis Faculty of Medicine, University of Oslo 2020 Department of Radiology and Nuclear Medicine, Oslo University Hospital - Rikshospitalet Oslo, Norway © Anna Latysheva, 2020 Series of dissertations submitted to the Faculty of Medicine, University of Oslo ISBN 978-82-8377-727-7 All rights reserved. No part of this publication may be reproduced or transmitted, in any form or by any means, without permission. Cover: Hanne Baadsgaard Utigard. Print production: Reprosentralen, University of Oslo. Fields of knowledge exist and advance because we find beauty and joy within them. Thomas P. Naidich The idea must be very high, much higher than the ways to realize it. Fyodor M. Dostoevsky 1 TABLE OF CONTENTS ACKNOWLEDGEMENTS .................................................................................................................4 ABBREVIATIONS .............................................................................................................................6 SUMMARY IN ENGLISH...................................................................................................................8 SAMMENDRAG PÅ NORSK...........................................................................................................10 LIST OF PUBLICATIONS ...............................................................................................................12 1. INTRODUCTION .....................................................................................................................13 1.1 Diffuse infiltrative glioma ...................................................................................................13 1.1.1 Epidemiology of diffuse infiltrative gliomas.................................................................13 1.1.2 Histopathological features and diagnostic challenges of diffuse gliomas....................13 1.1.3 Molecular features of diffuse gliomas.........................................................................16 1.1.4 The updated 2016 WHO Classification of tumors of the CNS.....................................17 1.2 MRI in diffuse infiltrative glioma.........................................................................................20 1.2.1 History and evolution of brain tumor imaging .............................................................20 1.2.2 Basic principles of MRI...............................................................................................22 1.2.3 Brain tumor MRI protocol ...........................................................................................23 1.2.4 Advanced MR imaging of diffuse gliomas ..................................................................24 1.2.5 Response assessment criteria for neuro-oncology (RANO) .......................................31 1.2.6 Endpoints in clinical oncology: progression free survival and overall survival.............32 1.2.7 Radiomics and radiogenomics ...................................................................................33 1.2.8 MRI biomarkers in therapeutic decision-making and in clinical trials: the requirements, challenges and new solutions ....................................................................................34 2. AIMS OF THE THESIS ............................................................................................................36 3. MATERIALS AND METHODS .................................................................................................37 3.1 Study design and population.............................................................................................37 3.2 Image acquisition..............................................................................................................37 3.2.1 Study I and II..............................................................................................................37 3.2.2 Study III .....................................................................................................................38 3.3 Segmentation and image processing ................................................................................38 3.3.1 Study I and II..............................................................................................................38 3.3.2 Study III .....................................................................................................................39 3.4 Histopathology, genetic molecular analysis and classification...........................................40 3.5 Survival assessment .........................................................................................................41 2 3.6 Statistical analysis.............................................................................................................41 3.7 Ethical considerations .......................................................................................................42 4. RESULTS AND SUMMARY OF THE STUDIES.......................................................................43 4.1 Study I ..............................................................................................................................43 4.2 Study II .............................................................................................................................44 4.3 Study III ............................................................................................................................45 5. DISCUSSION...........................................................................................................................46 5.1 General methodological consideration ..............................................................................46 5.1.1 Whole tumor histogram analyses (study I, II and III)...................................................46 5.1.2 Volumetric ROI design (study I, II and III)...................................................................46 5.1.3 Follow-up-imaging of glioma. RANO criteria (study I and III) .....................................48 5.2 Specific considerations study I..........................................................................................49 5.2.1 The prediction of survival outcome in patients with diffuse glioma by perfusion and diffusion MRI..............................................................................................................49 5.3 Specific considerations study II.........................................................................................51 5.3.1. Identification of genetically defined oligodendroglioma by diffusion and perfusion MRI ..................................................................................................................................51 5.3.2 The discrimination between glioma WHO grades II and III using diffusion and perfusion MRI ............................................................................................................52 5.4 Specific considerations study III ........................................................................................54 5.4.1 RSI-cellularity index, FA and MD in different glioblastoma compartments..................54 5.4.2 Relationship between RSI-cellularity index, FA and MD in different glioblastoma compartments and survival outcome..........................................................................56 5.4.3 Association between diffusion metrics and MGMT promoter methylation status in patients with glioblastoma..........................................................................................57 6. CONCLUSIONS.......................................................................................................................59 7. FUTURE PERSPECTIVES ......................................................................................................61 7.1 The pros and cons of radiologic multicenter studies..........................................................61 7.2 Histopathologic validation of MRI findings.........................................................................61 7.3 Future directions and applications of advanced MR imaging in neuro-oncology................61 7.3.1 Emerging MRI techniques..........................................................................................62 7.3.2 Artificial intelligence ...................................................................................................63 REFERENCES ...............................................................................................................................65 3 ACKNOWLEDGEMENTS This thesis was initiated and carried out at the Section of Neuroradiology, Department of Radiology in collaboration with the Department of Diagnostic Physics and Department of Neurosurgery at the Oslo University Hospital - Rikshospitalet from 2015 to 2020. First of all, I would like to express my gratitude towards all the patients participating in this project and thus contributing to the increased knowledge of MR imaging of diffuse glioma. This work is the result of the contribution of many scientists and skilled people I have the privilege of working together with both on my project and every day work and I would like to express my sincere gratitude. My deepest thankfulness goes to my principal supervisor, Andrés Server Alonso, for all encouragement and for sharing your endless knowledge. You have
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