Download Molecular Imaging in Radiation Oncology - Brief

Molecular Imaging in Radiation Oncology
- Brief Introduction for Physicists
Yoichi Watanabe, Ph.D.
Department of Radiation Oncology
[email protected]
AAPM Working Group of Molecular Imaging in Radiation Oncology (WGMIR)
DISCLOSURE
• Nothing to disclose
Outline
1. Definition of molecular imaging (MI)
2. Brief review of molecular biology
3. Examples of MI techniques
4. Applications of MI in radiation
oncology
What is “Molecular Imaging?”
Definition by SNM/RSNA
“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.”
Thakur, ML et al., J Nucl Med 46(9):11N-13N (2005)
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
Cytoplasm
Cell membrane
Nucleus
Nuclear membrane
Chromosome/Chromatin
Cytosol
Weissleder R, Mahmood U Radiology 2001;219:316-333
Molecular Constituents in Cell
Water
18 Da
Glucose
180 Da
Amino acid
~110 Da
Protein
~100 kDa
DNA base pair
~ 650 Da
RNA
100 to 200 kDa
DNA
2.1x1012 Da
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
Cell Cycle
Mitosis or
Apoptosis
Checkpoint
Apoptosis
Damaged cells are repaired.
R.Weinberg, Sci Amer. (1996)
Checkpoint
Growth Factor and Receptor
EGF
EGFReceptor
R.A.Weinberg, Sci Am (1996)
The Hallmarks of Cancer
Proliferation
Vasculature
Hypoxia
Hanahan D, Weinberg RA. Hallmarks of cancer: the next
generation. Cell. 2011;144(5):646-74.
Metastasis
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, C6H1118FO5.
•
•
•
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. FDGPET) accumulates in the tumor cells.
Glucose
Metabolism:
Glycolysis






Takes place in cytosol in a cell
Produces 2 ATP
Produces 2 NADH
Produces 2 pyruvates
Generates energy
No oxygen is needed
Alberts et al, Mol Biol of Cell 5th (2008)
[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
Radiolabeled
Thymidine (FLT)
DNA synthesis pathways. James R. Bading, and Anthony F.
Shields J Nucl Med 2008;49:64S-80S
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 CT
Enhanced 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
 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
Weller, G. E.R. et al. Cancer Res 2005;65:533-539
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)
(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.
Mah, K. et al., IJROBP 52:339 (2002)
FLT-PET for Therapy Monitoring
Treatment plan
Day 8
Day 29
Everitt S, et al., Int J Radiat Oncol Biol Phys. 2009. doi:S0360-3016
Difficulty of Image Registration
• CT-CT, CT-MRI, CT-PET, CT-MRI, MRIPET, etc..
• Rigid image registration
• Deformable registration
CT-PET scanner
Uncertainty in Target Definition
GTV40
GTV2.5
PET
Planning CT
SUVmax=30
red GTV40, green GTVbg, yellow GTVCT
“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)
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.
References
Pysz 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)