Quantitative Invivo Imaging ofthe Impactof Cancer · PDF fileQuantitative Invivo...
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Quantitative Invivo Imaging of the Impact of Cancer Therapy on the Normal Pediatric Brain
Wilburn E. Reddick, Ph.D.
Diagnostic Image and Signal Processing Laboratory Division of Translational Imaging Research
Department of Radiological Sciences
Wilburn E. Reddick, Ph.D.
Diagnostic Image and Signal Processing Laboratory Division of Translational Imaging Research
Department of Radiological Sciences
The Clinical Problem
AcAcuuttee lylymmphoblastphoblasticic leuleukkememiaia (ALL)(ALL) isis tthehe mmosostt ccomommmonon cchildhood childhood cancancerer –– AAffffeecctintingg 22,4,40000 chchililddrerenn aannnnuuaallllyy inin tthhee USUS
–– YYoouunngg aaggee aatt ddiagiagnnoosisis as anndd hhigighh susurrvviivvaal rl raatete
BrainBrain TTumumorsors areare tthehe mmosostt ccomommmonon ssolidolid ttumumorsors ooff cchildhoodhildhood –– AAffffeecctintingg 33,1,11100 chchililddrerenn aannnnuuaallllyy inin tthhee USUS
–– MMoostst cocommmonmon ccaauusese ooff cacanncceerr relarelatetedd ddeeaathth inin chchililddrreenn
–– HiHigghh ratratee ooff sesevveerere mmoorrbbidityidity RJ Gilbertson Source: CBTRUS and SEER
1930
1950
1970
1990
100-ALL
25-
0-
75- CNS
50-
% survival
Increasing Importance of Neurotoxicity
RJ Gilbertson Source: CBTRUS and SEER
Independent Research Program Probing Substrates of Neurotoxicity
Basic Research Focus: Development of innovative algorithms and methods to quantify the structure and integrity of cerebral white matter in vivo
Clinical Research Focus: Use noninvasive imaging technology to quantify neurostructural changes resulting from radiological or pharmacological insult
Ultimate Goal: To assist in the development of therapy that would prevent, mediate, or intervene to minimize impact of neurotoxicity in survivors of pediatric cancer
Translational Imaging Research
Basic Research Image Registration and Fusion RF Correction Segmentation Volume of Interest Analyses
Diffusion and Perfusion
Clinical Research (BT) Historical Background
Most Recent Results
Ongoing Studies
Clinical Research (ALL) Most Recent Results
Ongoing Studies
3D Affine Registration
Within an examination
Between examinations
2000
Num
ber of
Pixels 1600
1200
800
400
0
white gray
3000 3500 4000 4500 5000 5500 6000
Dose (cGy)
Fusion of RT Dose with Segmented MR
TE Merchant
Bias Field Correction (in plane)
(Ji et al. MRM [in prep], 2005)
PD In
tens
ity (a
.u.)
1400
1300 Pre
Post 1200
1100
1000 0 5 10 15 20
Section Number
Bias Field Correction (between planes)
Kohonen SelfOrganizing Map (Segmentation)
Output
Input
Learning Algorithm
, ( 2
j − weight , Δ weight i j = (neigh iter )) [input i j ] 2 2⎡− (x + y )⎤
neigh iter ) = η ∗exp 2 ⎥( ⎢ 2 ∗σ⎢ ⎥⎣ ⎦
iter
maxη = .0 005 iter
T1 T2 PD FLAIR ⎛ iter ⎞
maxSignal Intensity σ = 3 ⎜⎜0 4 . iter ⎟⎟⎝ ⎠
(Reddick et al. IEEETMI, 1997)
SOM of Normal Examination
T1 T2 PD FLAIR
Intraclass correlations for N =14 White matter ri = 0.91 (p < 0.01) SOM Gray matter ri = 0.95 (p < 0.01) CSF ri = 0.98 (p < 0.01)
(Reddick et al. MRM, 2002)
SOM of Abnormal ExaminationT1 T2 PD FLAIR
SOM
(Reddick et al. MRM, 2002)
Additional Refinements
FLAIR SOM02 SOM03 SOM04
Kappa measure of agreement (N = 15) Obs 1 0.651 0.653 0.744 Obs 2 0.602 0.615 0.699
(Glass et al. MRM, 2004)
60 Gray
400 80
350 70
Gray 300
White Volum
e (m
L) 250
200
150 White
CSF
50
40
Volum
e (m
L)
CSF 100
50
0 0 0 1 2 3 4 5 6 0 1 2 3 4 5 6
Time Since RT (years) Time Since RT (years)
10
20
30
Index vs Expanded Sampling
Expand Coverage
3D Visualization
ZY Shan (Mulhern et al. Lancet Onc, 2004)
Prefrontal
Frontal Parietal / MidTemporal Parietal / Occipital Right Left
Regional Analysis
(Mulhern et al. JINS, 2004)
Quantifying White Matter Integrity
RJ Ogg FLAIR SOM ADC FA
Quantifying White Matter Perfusion
RJ Ogg T2 CBV
Translational Imaging Research
Basic Research Image Registration and Fusion RF Correction Segmentation Volume of Interest Analyses
Diffusion and Perfusion
Clinical Research (BT) Historical Background
Most Recent Results
Ongoing Studies
Clinical Research (ALL) Most Recent Results
Ongoing Studies
Why NormalAppearing White Matter?
Two agematched groups treated for brain tumors of the Posterior Fossa
Variable MB (N=18) LGA (N=18) Significance FSIQ 82.0 + 10.9 92.9 + 15.7 P=0.026
ICV 82.5 + 5.4 85.2 + 6.0 NS White 21.4 + 4.4 24.7 + 5.7 P=0.008 Gray 52.6 + 5.1 54.3 + 6.1 NS CSF 8.1 + 4.0 6.1 + 4.5 NS
RK Mulhern (Reddick et al. MRI, 1998)
Inform
ation Raw
Score
Normal Population 25
20
15
10
5
0 0 1 2 3 4 5 6 7 8 9 10 11 12
Time Since CSI (Years)
(Expected)
MB patients (obtained) N=52
A New Understanding of Decreasing IQ
(Palmer et al. JCO, 2001)
Linking Therapy & Neurocognitive Deficits
Cross sectional study of Medulloblastoma survivors (N=42)
Age at irradiation significantly associated with FSIQ (R 2 = 0.170; P = 0.006; controlled for time since irradiation)
Mediational model: ~70% of association explained by Normal Appearing White Matter
(Mulhern et al. JCO, 2001)
Developmental Model
RT
Math
NAWM IQAttention
Age @ RT
Time Since RT
Reading
Spelling
P < .001
P < .001
P < .001
P < .001
N = 40 Median 5.7 yrs post RT
Moderators
Model explains: ~ 60% of variance in reading ~ 60% of variance in spelling ~ 80% of variance in math
(Reddick et al. Cancer, 2003)
Most Recent Results
Longitudinal study of 324 MR exams from 52 subjects treated for Medulloblastoma
All received 36 Gy CSI 19 had shunts placed Median age @ irradiation 8.3 yrs (3.4 to 20.0 yrs) Median time since irradiation 2.5 yrs (0.2 to 7.9 yrs)
Crosssectional study of a subset of 19 patients age similar to controls and without shunts
Single most recent MR Age at examination 13.0 ± 3.1 yrs
26 healthy sibling controls imaged once Age at examination 12.6 ± 3.4 yrs
A Gajjar
Volum
e (cc)
Younger at RT Older at RT
30 30 WM no shunt
25 25
20 WM shunt 20
WM no shunt
WM shunt
CSF shunt
CSF no shunt
6 7 8 9 10 11
Patient Age (years) Volum
e (cc)
CSF shunt 15 15
10
5
0
10 CSF no shunt
5
0
12 13 14 15 16 17
Patient Age (years)
Longitudinal Brain Volume Development
(Reddick et al. Neuro Onc, 2005)
5
0
5
10
NAWM
Volum
e (m
L)
Younger at RT Older at RT 10
0 HC
HC
MB
NAWM
Volum
e (m
L)
5
MB
5
10 10 6 7 8 9 10 11 12 12 13 14 15 16 17 18
Patient Age (years) Patient Age (years)
Longitudinal Brain Volume Development
(Reddick et al. Neuro Onc, 2005)
NAWM
(ml)
40 HC
30
20 MB
10 p<0.001
0 5 10 15 20
Age @ MR (years)
Longitudinal Brain Volume Development
(Reddick et al. Neuro Onc, 2005)
Translational Imaging Research
Basic Research Image Registration and Fusion RF Correction Segmentation Volume of Interest Analyses
Diffusion and Perfusion
Clinical Research (BT) Historical Background
Most Recent Results
Ongoing Studies
Clinical Research (ALL) Most Recent Results
Ongoing Studies
Most Recent Results
Longitudinal study of 164 MR exams from 45 subjects treated for ALL on Total 14
Low Risk Standard / High Risk Number of Subjects Post 1 IVMTX 21 23 Post 4 IVMTX 20 21 Post 7 IVMTX 21 21 End of Therapy 20 17
Gender Male 10 11 Female 12 12
Age at Diagnosis (years) 5.0 ± 2.7 9.2 ± 4.8
CH Pui
0
20
40
60
80
100
Obs
erved Prevalen
ce of L
E
100 p = 0.011 p = 0.011 87 86 p < 0.001 p = 0.011
80
5 20 45 132
Week on Protocol
67
Predicted
proba
bility of
LE
5 20 45 132
Week on Protocol
p < 0.001 67 60 60 59 57 55 60
47 40
40
17 17 15 14 20
0
41
Prevalence of LE Standard / HighRisk
LowRisk
(Reddick et al. AJNR [in press], 2005)
Transient vs. Persistent
Week 5 20 45 132 240 KJ Helton
Propo
rtion WM
affe
cted
35% p = 0.002 p = 0.046 p = 0.010
30%
25%
p = 0.099 p = 0.019 20%
Standard / HighRisk 15% LowRisk
10%
5%
0%
5 20 45 132
Week on Protocol
Extent of LE
(Reddick et al. AJNR [in review], 2005)
= =
= =
50
175 50 p 0.090 p 0.007
150
40p = 0.063 p = 0.065 125 p 0.007 p 0.083
5 20 45 132
Week on Protocol
T2 increase (m
s)
5 20 45 132
Week on Protocol
100
75
30
20
10 25
0 0
T1 increase
(ms)
Intensity of LE Standard / HighRisk
LowRisk
(Reddick et al. AJNR [in review], 2005)
300
T1 increase
(ms)
250
200
150
100
50
0 10 20 30 40 50
T2 increase (ms)
Relationship Between Intensity Measures
(Reddick et al. AJNR [in review], 2005)
Translational Imaging Research Summary
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ContContiinnueue to dto devevelelopop iinnnonovvaatitivve ae allgorgoriithmthmss anandd mmethethods to qods to quanuantitiffyy ththe stre strucucture anture andd iintntegriegrittyy ofof ccerebralerebral whiwhitte me matteatterr iin vivn vivoo
CCliniclinicalal RResesearcearchh UsUseded nononinninvvasasiivvee iimmagiagingng technotechnollogogyy toto quaquantintiffyy neuneurrosostructructuraltural cchhangangeses resresulultitingng ffrroomm radiradiolologogiiccaall oror phapharrmmacacolologogiiccalal iinsnsuullt at andnd rrelelateated thd thesese che changangeses toto neuneurrococogognniititivve pe perferforormmancancee
Translational Imaging Research Summary
Building on extensive experience with MB New studies designed to combine radiation dosimetry maps with MR imaging measures of perfusion and diffusion
Investigate the integrity of white matter microvasculature and axonal myelin
Changes in these measures is hypothesized to precede more global changes in cerebral white matter volume
120 subjects with 1560 MR exams
Translational Imaging Research Summary
Building on preliminary experience with ALL Ongoing ALL study designed to test hypotheses that early changes in MR imaging measures are:
predictive of later white matter changes proportionate to exposure to HDMTX related to CSF and plasma homocysteine predictive of treatmentinduced neurocognitivedeficits and diminished quality of life insurvivors
300 subjects with 1200 MR examinations
Acknowledgements
DDepartepartmmentent ofof RRadiologicadiologicalal SScciencienceess •• DDr.r. RRobertobert OggOgg DiDivv TTrrans Ians Immagag ResRes
•• DDr.r. ZZuyuyaoao ShanShan DiDivv TTrrans Ians Immagag ResRes
•• DDr.r. KaKatthleen Heltonhleen Helton DiDivv DDiiaag Img Imagiagingng
•• DDr.r. TThomhomasas MMercerchhantant DiDivv RRadad OOncnc
IInsnsttiittututionalional CCollaboratollaboratorsors •• DDr.r. AmAmarar GajjarGajjar DeptDept ofof HemHem/O/Oncnc
•• DDr.r. CChingHhingHonon PuiPui DeptDept ofof HemHem/O/Oncnc
•• DDr.r. RRayaymmonondd MMulhernulhern DiDivv BBehehavav MMeded
Acknowledgements
•• JJohnohn GlaGlassss •• RRhonda Simmhonda Simmonsons •• GregGreg BernBernsstteinein •• KimKimberlberlyy JJohnsohnsonon •• BrianBrian TTayaylorlor •• JJohnohn SSttagiagicchh •• DDr.r. QingQing JJii •• JJinesineshh JJainain •• TTraravvisis MMilleriller
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