2011 Joint AAPM/COMP Meeting Ralph P. Mason Director Cancer Imaging Program, Dept. Radiology & Simmons Cancer Center UT Southwestern, Dallas TX “NMR Assessment of Tumor Hypoxia and Oxygen Dynamics” Joint Imaging-Therapy Symposium Considerations • Oxygen tension • Hypoxia • Dynamics • Spatial resolution • Dynamic range • Precision Focus of presentation: 1. 19 F NMR of PFCs- quantitative mapping of oxygen dynamics pO 2 and hypoxic fractions Pre-clinical 2. BOLD and TOLD semi-quantitative immediately feasible in human Strengths of a 19 F MRI approach • High sensitivity (g close to 1 H) • Large chemical shift range • Negligible background signal • Stable compounds • Depth of penetration
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2011 Joint AAPM/COMP Meeting...2011 Joint AAPM/COMP Meeting Ralph P. Mason Director Cancer Imaging Program, Dept. Radiology & Simmons Cancer Center UT Southwestern, Dallas TX “NMR
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2011 Joint AAPM/COMP Meeting
Ralph P. Mason
Director Cancer Imaging Program,
Dept. Radiology & Simmons Cancer Center
UT Southwestern, Dallas TX
“NMR Assessment of Tumor Hypoxia and Oxygen Dynamics”
Joint Imaging-Therapy Symposium
Considerations
• Oxygen tension
• Hypoxia
• Dynamics
• Spatial resolution
• Dynamic range
• Precision
Focus of presentation:
1. 19F NMR of PFCs-
quantitative mapping of oxygen dynamics
pO2 and hypoxic fractions
Pre-clinical
2. BOLD and TOLD
semi-quantitative
immediately feasible in human
Strengths of a 19F MRI approach
• High sensitivity (g close to 1H)
• Large chemical shift range
• Negligible background signal
• Stable compounds
• Depth of penetration
Strengths of a 19F MRI approach
• High sensitivity (g close to 1H)
• Large chemical shift range
• Negligible background signal
• Stable compounds
• Depth of penetration
Tumor oxygenation using PFCs
R1 (s-1) = a+b*pO2 (torr)
High sensitivity to changes in pO2
Zhao Methods Enzymol 386 2004
Br(CF2)7CF3
F
F
F
F
F
F
Sensitivity to oxygen
R1 (1/T1) = R1a + R1p.X
pO2 = kX (Henry‟s law)
R1a = R1a + R1p/k.pO2
Solubility oxygen in water ~ 2 vol.%
in PFC ~40 vol.% PFC
Molecular Amplifier
High sensitivity to changes in pO2
Zhao, Methods Enzymol 2004
Acute changes in pO2 with intervention
PFOB, Bellemann et al. Biomedizin. Tech. (2002)
Air Oxygen
Yu, Curr. Med. Chem 2005
PFC emulsion sequestrationLong term changes in tumor pO2
Mason, et al.. Int. J. Radiat. Oncol. Biol. Phys. 29 (1994)
Dunning prostate R3327-AT1 tumor;
Oxypherol IV with vascular clearance
pO2 from 19F NMRS
Kodibagkar and Zhao“Nanodroplets”
-5
10
25
40
55
70
85
>100
F
F
F
F
F
F
0.05
0.10
0.15
0.20
0.25
0.30
0.35
0.40
0.45
R1
-20 20 60 100 140 180
pO2 (torr)
“FREDOM”(Fluorine Relaxometry using Echo planar imaging for
Dynamic Oxygen Mapping)
>700k
400k
<100k
Amplitude
pO2 map
l
>100 torr
80
60
40
20
<0
1/R1 map
<3.0
18.0 s
11.0
2.5 s
1.4
0.35
(1/R1) error
yi = A*( 1 - (1+W) exp(-R1*t) )
pO2 (torr) = (R1 – 0.0835)/0.001876
FREDOM
ARDVARCAlternated R1 Delays with Variable Acquisitions to Reduce Clearance Effects
Tau (s)
l
l
l
l
l
l
l
l
l
l
l
l
l
l
-20
0
20
40
60
80
100
120
0 10 20 30 40 50 60 70 80 90
1st
2nd
3rd5th
7th
9th
`
5 15 25 35 45 55 65 75 85 1000.0
0.2
0.4
0.6
0.8
5 15 25 35 45 55 65 75 85 1000.0
0.2
0.4
0.6
0.8
pO2 torr
>
>
5 15 25 35 45 55 65 75 85 1000.0
0.2
0.4
0.6
0.8
pO2 torr
>
5 15 25 35 45 55 65 75 85 1000.0
0.2
0.4
0.6
0.8
>
m x
x
m
x
m x
m
FREDOM Eppendorf
< 2 cm3 < 2 cm3
> 3.5 cm3 > 3.5 cm3
Dunning prostate R3327-AT1
Mason et al, Radiat. Res. 1999
Dunning prostate R3327-AT1 rat tumor
Oxygen Dynamics in response to respiratory challenge
Jiang, Zhao 2004
a) 21% O2 b) 100% O2 c) 95% O2/5% CO2
torr
0
> 100
60
40
20
80
AT1
HI
Zhao et al
Differential Oxygen Dynamics in R3327 tumors
0
10
20
30
40
50
0 1 2 3 4 5 6
Tumor size (cm3)
Mea
n b
asel
ine
pO
2 (
torr
)
Variation in mean baseline pO2 for 7 HI tumors
with respect to growth
Zhao et al, Radiat. Res. „01
Modulating response to irradiation
Dunning prostate R3327-HI tumor
Pedicle site
Small (< 2 cc) or large tumors (> 3.5 cc)
Single dose 30 Gy; 6 MeV
TCD50 60 Gy
Cum
. su
rviv
al
Days after irradiation
Small tumors
0
.2
.4
.6
.8
1
0 10 20 30 40 50 60 70
Control
Irradiation
O2 Air
Irradiation study in small Dunning prostate HI tumors (< 2 cm3)
Zhao et al. Radiat. Res. 2003
Single dose 30 Gy; 6 MeV
TCD50 60 Gy
Cum
. su
rviv
al
Days after irradiation
Small tumors
0
.2
.4
.6
.8
1
0 10 20 30 40 50 60 70
Control
Irradiation
O2 Air
0.1.2.3.4.5.6.7
xm
<10 20 40 60 80 100 120 140 >160
pO2 ( torr)
0
.1
.2
.3
.4
.5
.6
.7
mx
100% O2
21% O2
Irradiation study in small Dunning prostate HI tumors (< 2 cm3)
Zhao et al. Radiat. Res. 2003
Single dose 30 Gy; 6 MeV
TCD50 60 Gy
<10 20 40 60 80 100 120 140 >1600.1
.2
.3
.4
.5
.6
.7
mx
pO2 (torr)
0.1
.2
.3
.4
.5
.6
.7
xm
Rel
ativ
e fr
equen
cy
100% O2
21% O2
Irradiation study in large HI tumors
Days after irradiation
0 20 40 60 80 100 120 140
0
.2
.4
.6
.8
1
O2Air
Irradiation
Control
Zhao et al. Radiat. Res. 2003
21% O2 100% O2CD31-FITC Hoescht 33342
100 80 60 40 torr 20 0
-10
AT1 response to IR
Single dose 30 Gy; 6 MeV
TCD50 60 GyBourke et al, IJROBP 2007
Influence of oxygen breathing on IR for large AT1 tumors
21% O2 100% O2
Pimo
CD31
Hoechst
0
0.1
0.2
0.3
0.4
0.5
100% O2
x
m
0
0.1
0.2
0.3
0.4
0.5
100% O2
0
0.1
0.2
0.3
0.4
0.5
100% O2
xx
mm
0
0.1
0 .2
0 .3
0 .4
0 .5
21% O2
<2.5 5 10 20 40 60 80 100 120 140 >150
x
m
0
0.1
0 .2
0 .3
0 .4
0 .5
21% O2
0
0.1
0 .2
0 .3
0 .4
0 .5
21% O2
<2.5 5 10 20 40 60 80 100 120 140 >150
xx
m
50
40
30
20
100
50
40
30
20
10
0
Breathing air
Breathing O2
Bussink, van der Kogel
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
0 3 6 9 12 15
Days Post Irradiation
Norm
aliz
ed V
olu
me
Bourke et al, IJROBP 2007
-20
0
20
40
60
80
100
10 11 12 13 14 15 16 23
Air Oxygen Air
CA4P (30 mg/kg)OxygenOxygenAir Air
Baseline CA4P 24 h
10 30 60 90 120 min
Time course
Mean
pO
2(t
orr) *
*
*
*
*
*
* *
*
+
+
**
*
*‡*
*
*
**‡
‡‡‡
‡
Zhao et al., IJROBP 2005
Combined therapy IR+ VTA CA4P
-5
10
25
40
55
70
85
>100
torr
13762NF rat breast tumor
0
1
2
3
4
5
2 3 4 5 6
Ctrl
CA4P
IR
IR + 1h CA4P
CA4P + 24h (IR + O2)
Post treatment (days)
Norm
ali
zed
tu
mor
volu
me
CA4P + 24h IR
IR + O2
(IR + O2) + 1h CA4P
0 3 7 10 14
Experimental combination treatment
•Irradiation (5 Gy) + CA4P (30 mg/kg) on 13762NF rat breast tumors