molecular imaging in radiation oncology - brief...
TRANSCRIPT
Molecular Imaging in Radiation Oncology - Brief Introduction for Physicists
Yoichi Watanabe, Ph.D.Department of Radiation Oncology
AAPM Working Group of Molecular Imaging in Radiation Oncology (WGMIR)
DISCLOSURE
• Nothing to disclose
Outline1. Definition of molecular imaging (MI)2. Brief review of molecular biology3. Examples of MI techniques4. Applications of MI in radiation
oncology
What is “Molecular Imaging?”Definition by SNM/RSNA
Thakur, ML et al., J Nucl Med 46(9):11N-13N (2005)
“Molecular Imaging (MI) techniques directly or indirectly monitor and record the spatiotemporal distribution of molecular or cellular processes for biochemical, biologic, diagnostic, or therapeutic applications.”
History of Imaging Tools
Weissleder R, Pittet MJ. Imaging in the era of molecular oncology. Nature. 2008;452(7187):580-9
Cell, Genome, DNA, Genotype, and Phenotype
Weissleder R, Mahmood U Radiology 2001;219:316-333
Cell membrane
Nucleus
Chromosome/Chromatin
Cytoplasm
Cytosol
Nuclear membrane
Molecular Constituents in Cell
Molecular Species Number per Cell Endogenous or Exogenous
DNA (3 billions base-pairs) 23 chromosomes Endogenous
messenger RNA (mRNA) 50 – 1,000 Endogenous
Protein 102 - 106 Endogenous
Protein Function “Unlimited” Through amplification
Water 18 DaGlucose 180 Da
Amino acid ~110 DaProtein ~100 kDa
DNA base pair ~ 650 DaRNA 100 to 200 kDaDNA 2.1x1012 Da
Cell Cycle
R.Weinberg, Sci Amer. (1996)
Checkpoint
Checkpoint
Mitosis or Apoptosis
Damaged cells are repaired.
Apoptosis
Growth Factor and Receptor
R.A.Weinberg, Sci Am (1996)
EGFReceptorEGF
The Hallmarks of Cancer
Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646-74.
VasculatureHypoxia
Metastasis
Proliferation
Which biology to image with Molecular Imaging?
Selection of “imaging biomarker”
Cell proliferation (or Apoptosis)Angiogenesis (or vascular density)• Metabolism• Microenvironment (or Hypoxia)• Proteins Gene expression (gene proteins)
[18F] FDG PET-CT
Siemens biograph
[18F] FDG: (Fluorodeoxyglucose F18)2-deoxy-2-[18F]fluoro-D-glucose, C6H11
18FO5.
• Each ml of solution contains between 0.37 to 3.7 GBq (10.0 - 100 mCi) of FDG, 4.5 mg of sodium chloride and 7.2 mg of citrate ions. The pH of the solution is between 5.0 to 7.5.
• The recommended dose of [F-18]FDG injection for an adult (70 kg) is 185-370 MBq (5-10 mCi) as an intravenous injection for studies of malignancy, cardiology and epilepsy.
• Tumor cells are metabolically active; so glucose (e.g. FDG-PET) accumulates in the tumor cells.
Glucose
Metabolism:Glycolysis
Alberts et al, Mol Biol of Cell 5th (2008)
Takes place in cytosol in a cell Produces 2 ATP Produces 2 NADH Produces 2 pyruvates Generates energy No oxygen is needed
[18F] Fluorothymidine (FLT)• 18F-3’-deoxy-3’-fluorothymidine.• FLT accumulates in dividing cells.• FLT uptake is positively correlated
with cell growth and TK1 activity.
Buck AK, et al., Journal of Nuclear Medicine. 2003;44(9):1426-31.
DNA Synthesis Pathways
DNA synthesis pathways. James R. Bading, and Anthony F. Shields J Nucl Med 2008;49:64S-80S
Radiolabeled Thymidine (FLT)
Courtesy of Kiaran McGee, Ph.D.
Hyperpolarized MRI• Hyperpolarized 13C-pyruvate.• Can study metabolic and catabolic
pathways.
K.Colman and J.S.Peterson,, Acad radiol 2006; 13:932
X-ray CTEnhanced photon attenuation:Anti-EGFR conjugated gold nanoparticles implanted in human squamous cell carcinoma
T. Reuveni, et al., International journal of nanomedicine 6, 2859-2864 (2011).
Ultrasound: Angiogenesis
Weller, G. E.R. et al. Cancer Res 2005;65:533-539
Microbubbles (MB) were conjugated to cyclic peptides containing either tripeptide arginine-arginine-leucine RRL (RRL-MB) or a glycine control sequence (control-MB).
(A) background-subtracted, color-coded ultrasound image taken 120 seconds after injection of MBs conjugated to RRL (RRL-MB) into a mouse bearing a Clone C tumor.
(B) Control.(C) Images of a mouse with a PC3 tumor.(D) Control(E) -(G) photomicrographs(H),(I) normal myocardium
Molecular Imaging in Radiation Oncology
1. Molecular signature determination (molecular characteristics of tumor)
2. Monitoring the efficacy of therapy or assessing treatment response
3. Molecular therapeutics
FDG-PET for Target Delineation(an example of geographic miss)
Mah, K. et al., IJROBP 52:339 (2002)
(Left) PET image coregistered with CT.(Right) Treatment plan for the target drawn only using CT. Only 70% of PTVPET/CT receives at least 90% of prescribed dose.
FLT-PET for Therapy Monitoring
Everitt S, et al., Int J Radiat Oncol Biol Phys. 2009. doi:S0360-3016
Treatment plan
Day 29
Day 8
Difficulty of Image Registration• CT-CT, CT-MRI, CT-PET, CT-MRI, MRI-
PET, etc..• Rigid image registration• Deformable registration
CT-PET scanner
Uncertainty in Target Definition
“The different techniques of tumor contour definition by 18F-FDG PET in radiotherapy planning lead to substantially different volumes, especially in patients with inhomogeneous tumors. “
Nestle, U. et al. J. Nucl Med 46:1342 (2005)
PETSUVmax=30
Planning CTred GTV40, green GTVbg, yellow GTVCT
GTV40GTV2.5
AAPM Task Group 211“Classification, Advantages and Limitations
of the Numerical Lesion Segmentation Approaches for PET”
Charge: To study the advantages, the limitation, and the applicability of proposed PET-Automatic Segmentation (AS) methods. The TG report due in 2016 lists 24 PET-AS methods.
Conclusion: The more sophisticated the method, the better. But, there is no winner!
TG group chair: A.Kirov, Ph.D.
Summary• Molecular imaging (MI) is used to provide
clinically valuable information on the biological status of the tumor.
• MI technology is evolving and more MI tools are on the way to our clinics.
Medical physicists need to understand underling biological mechanisms to effectively utilize the MI tools in clinics.
ReferencesPysz M A, Gambhir S S, and Willmann J K 2010 Molecular imaging: current
status and emerging strategies Clinical Radiology 65 500-16.Munley M.T., Kagadis G.C., McGee K.P., et al., 2013 An introduction to
molecular imaging in radiation oncology: A report by the AAPM Working Group on Molecular Imaging in Radiation Oncology (WGMIR), Medical Physics 40, 101501.
Schober O. and Riemann B., ed. 2013 Molecular Imaging in Oncology. Recent Results in Cancer Research. Vol. 187. 2013, (Springer-Verlag, Berlin Heidelberg).
Luna J. C., Vilanova J., Celso Hygino da Cruze L and Rossi S.E., ed. 2014 Functional Imaging in Oncology: Biophysical Basis and Technical Approaches, Vol. 1, (Springer-Verlag, Berlin Heidelberg).
Benfey, P.N., Quickstart Molecular Biology: An Introductory Course for Mathematicians, Physicists, and Engineers. 2014, Cold Spring Harbor, New York: Cold Spring Harbor Laboratory Press. (160 pages)