POSITRON EMISSION TOMOGRAPHY IMAGING OF HEPATOCELLULAR CARCINOMA WITH RADIOLABELED CHOLINE By YU KUANG Submitted in partial fulfillment of the requirements For the degree of Doctor of Philosophy Dissertation Adviser: Zhenghong Lee, Ph.D. Department of Biomedical Engineering CASE WESTERN RESERVE UNIVERSITY May, 2009 CASE WESTERN RESERVE UNIVERSITY SCHOOL OF GRADUATE STUDIES We hereby approve the thesis/dissertation of _____________________________________________________ candidate for the ______________________degree *. (signed)_______________________________________________ (chair of the committee) ________________________________________________ ________________________________________________ ________________________________________________ ________________________________________________ ________________________________________________ (date) _______________________ *We also certify that written approval has been obtained for any proprietary material contained therein. To my parents 献给我亲爱的父母 ii Table of Contents Table of Contents ....................................................................................................................... i List of Tables ........................................................................................................................... xi List of Figures ......................................................................................................................... xii Acknowledgments................................................................................................................... xv List of Abbreviations ............................................................................................................. xvi Abstract ................................................................................................................................ xviii Chapter 1 Introduction .............................................................................................................. 1 1.1 Molecular Imaging of Cancer .................................................................................... 1 1.1.1 Positron emission tomography for cancer imaging ................................................. 1 1.1.2 Molecular imaging modalities ................................................................................. 3 1.1.3 Positron emission tomography imaging for hepatocellular carcinoma .................... 7 1.2 Basic Principle of Positron Emission Tomography ................................................... 8 1.2.1 Positron emission and annihilation ..................................................................... 8 1.2.2 511 keV photon interactions in matter .............................................................. 10 1.2.2.1 Compton scattering ....................................................................................... 10 1.2.2.2 Rayleigh scattering........................................................................................... 12 1.2.2.3 Photoelectric effect .......................................................................................... 12 1.2.3 Data collection .................................................................................................. 13 i 1.2.3.1 Coincidence detection ...................................................................................... 13 1.2.3.2 Electronic timing window ................................................................................ 14 1.2.3.3 Time-of-flight .................................................................................................. 14 1.2.4 Detectors and scanner design ............................................................................ 15 1.2.4.1 Scintillation crystals ......................................................................................... 15 1.2.4.2 Dead time ......................................................................................................... 17 1.2.4.3 PET/CT ............................................................................................................ 18 1.2.4.4 Collimation ...................................................................................................... 18 1.2.5 LORs and projection data ................................................................................. 19 1.2.5.1 Lines of response (LORs) ................................................................................ 19 1.2.5.2 Organization of data ......................................................................................... 20 1.2.5.3 Projections and sinograms ............................................................................... 21 1.2.6 Image reconstruction ......................................................................................... 22 1.2.6.1 Forward problem .............................................................................................. 22 1.2.6.2 Radon transform............................................................................................... 22 1.2.6.3 Analytical reconstruction ................................................................................. 23 1.2.6.3.1 Simple backprojection ............................................................................... 23 1.2.6.3.2 Filtered backprojection (FBP) ................................................................... 24 1.2.6.4 Iterative reconstruction .................................................................................... 24 1.2.6.4.1 Five basic steps.......................................................................................... 24 ii 1.2.6.4.2 Maximum-likelihood expectation-maximization ...................................... 25 1.2.7 Attenuation correction ........................................................................................... 27 1.2.8 Scatter and randoms .......................................................................................... 28 1.2.8.1 Coincidence events .......................................................................................... 28 1.2.8.2 Scatter Correction ............................................................................................ 30 1.2.8.3 Random Correction .......................................................................................... 30 1.3 Review of the literatures ............................................................................................... 31 1.3.1 Hepatitis B viral infection induced hepatocellular carcinoma ............................... 31 1.3.1.1 Chronic hepatitis B viral Infection and hepatocellular carcinoma ................... 31 1.3.1.2 Woodchuck hepatitis virus infection induced woodchuck Model of hepatocellular carcinoma ............................................................................................. 34 1.3.2 Medical imaging of hepatocellular carcinoma ....................................................... 36 1.3.2.1 Diagnosis techniques for hepatocellular carcinoma ....................................... 36 1.3.2.2 Tumor glucose metabolism and FDG-PET imaging on cancer ....................... 38 1.3.2.3 Tumor-associated de novo fatty acid synthesis ............................................... 39 1.3.3 Imaging lipid synthesis in Cancer with PET .......................................................... 43 1.4 Organization of the thesis ............................................................................................. 45 Chapter 2 2-Deoxy-2-[18F]-fluoro-D-glucose Positron Emission Tomography Imaging of Hepatocellular Carcinoma ...................................................................................................... 46 2.1 Introduction ................................................................................................................... 46 iii 2.2 Materials and methods .................................................................................................. 48 2.2.1 Materials ................................................................................................................ 48 2.2.2 Animals .................................................................................................................. 48 2.2.3 Radiopharmaceuticals ............................................................................................ 49 2.2.4 Imaging protocol .................................................................................................... 49 2.2.5 Image analysis ........................................................................................................ 50 2.2.6 Histology ................................................................................................................ 51 2.2.7 Tissue excision ....................................................................................................... 51 2.2.8 Hexokinase activity assay ...................................................................................... 52 2.2.9 Glucose-6-phosphatase activity assay.................................................................... 53 2.2.10 Statistical Analysis ............................................................................................... 54 2.3 Results ........................................................................................................................... 54 2.3.1 PET imaging .......................................................................................................... 54 2.3.2 Enzyme activity ....................................................................................................