Disclosures
Paid Consultant, MedQIA LLC
Paid Consultant, Agios Pharmaceuticals, Inc.
Consultant, Genentech
Consultant, Siemens Medical Systems
B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA
ISMRM, Montreal, 2011
Diffusion MR Characteristics of the
Central Nervous System
•
•
Apparent diffusion coefficient (ADC) measured clinically reflects extracellular water
ADC is dependent on tumor cell density
(Ellingson, 2010; Sugahara, 1999; Lyng, 2000; Chenevert, 2000; Gaurain, 2001; Nonomura, 2001; Guo, 2002; Chen, 2005; Hayashida,
2006; Manenti, 2008; Kinoshita, 2008
  Cell Density (hypercellular) =  ADC
  Cell Density (hypocellular) =  ADC
From: Ellingson, J Magn Reson Imaging, 2010
Edema
Necrotic
Core
Viable
Tumor
(Dark)
ADC Map
B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA
ISMRM, Montreal, 2011
The Functional Diffusion Map (fDM)
(Moffat, 2005; 2006; Hamstra, 2005; 2008; Ellingson, 2010)
From: Ellingson, JMRI, 2010
B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA
ISMRM, Montreal, 2011
Graded fDMs Allow Visualization and Quantification of Growing Tumor
+ Hypocellular
Biological Calibration
B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA
From: Ellingson, JMRI, 2010
ISMRM, Montreal, 2011
+ Hypercellular
Graded fDMs Allow Better Visualization of Growing Tumor
+ Hypocellular
B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA
+ Hypercellular
ISMRM, Montreal, 2011
What about anti-angiogenic therapy?
B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA
ISMRM, Montreal, 2011
What about anti-angiogenic therapy?
B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA
ISMRM, Montreal, 2011
What about anti-angiogenic therapy?
Apparent diffusion coefficient (ADC) measured clinically reflects extracellular water
Large changes in ADC after anti-angiogenic therapy reflect (largely) reduction in edema
Subtle decreases in ADC after anti-angiogenic treatment are likely to contain solid / infiltrating tumor
B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA
ISMRM, Montreal, 2011
What about anti-angiogenic therapy?
B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA
ISMRM, Montreal, 2011
What about anti-angiogenic therapy?
B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA
ISMRM, Montreal, 2011
What about anti-angiogenic therapy?
B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA
ISMRM, Montreal, 2011
What about anti-angiogenic therapy?
Hypotheses:
1. Traditional fDMs (single threshold)  edema changes + tumor growth  greater risk of failure
B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA
ISMRM, Montreal, 2011
What about anti-angiogenic therapy?
Hypotheses:
1. Traditional fDMs (single threshold)  edema changes + tumor growth  greater risk of failure
2. Graded fDMs  tumor growth  greater risk of failure
B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA
ISMRM, Montreal, 2011
What about anti-angiogenic therapy?
Hypotheses:
1. Traditional fDMs (single threshold)  edema changes + tumor growth  greater risk of failure
2. Graded fDMs  tumor growth  greater risk of failure
3. Graded fDMs + pre-treatment ADC + T1+C  active tumor burden  GREATEST RISK (BEST PREDICTOR)
Pope, Radiology, 2009; Pope, AJNR, 2011
B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA
ISMRM, Montreal, 2011
Methods
Patients
N = 77 patients
- Pathology confirmed GBM with recurrence confirmed via histology or clinical features
- Regularly treated every 2 weeks per cycle with becacizumab (5-10 mg/kg)
- Baseline & minimum of one follow-up with high-quality diffusion MRI
MRI
Clinical MR sequences on 1.5T
T2w, FLAIR, T1w, T1+C
3-5mm slice thickness
Diffusion MRI w/ twice refocused spin echo preparation
ADC calculated from b=0 and b=1000 s/mm2
B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA
ISMRM, Montreal, 2011
Methods
Image Registration
All images registered to Baseline T1 weighted images
Mutual information + 12 dof transformation
Graded fDM Calculation
- Voxel-wise subtraction
- Each voxel classified according to relative difference from previous calibration studies
From: Ellingson, JMRI, 2010
B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA
ISMRM, Montreal, 2011
Methods
Traditional fDM  ΔADC beyond 0.4 um2/ms
B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA
ISMRM, Montreal, 2011
Methods
Traditional fDM  ΔADC beyond 0.4 um2/ms
Graded fDM  ΔADC between 0.25 and 0.4 um2/ms (7.5% probability of occurring randomly)
B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA
ISMRM, Montreal, 2011
Results
B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA
ISMRM, Montreal, 2011
Results
Conventional response does not predict survival
From: Ellingson, Neuro Onc, 2011
B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA
ISMRM, Montreal, 2011
Results
Conventional response does not predict survival
B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA
ISMRM, Montreal, 2011
Results
Graded fDM regions are localized to post-treatment contrast enhancement
B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA
ISMRM, Montreal, 2011
Results
Traditional and graded fDMs both predict survival
B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA
ISMRM, Montreal, 2011
Results
T1+C is better than FLAIR
B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA
ISMRM, Montreal, 2011
Results
Graded fDMs are better than traditional fDMs
B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA
ISMRM, Montreal, 2011
Results
Graded fDMs in T1+C
B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA
ISMRM, Montreal, 2011
Results
ADC distribution for graded fDMs is different than
traditional fDMs and contrast-enhancing regions
Chi-squared goodness of fit, P < 0.05
Between CE and graded fDMs
For 46 of 77 patients
B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA
ISMRM, Montreal, 2011
Results
ADC distribution for graded fDMs is different than
traditional fDMs and contrast-enhancing regions
Chi-squared goodness of fit, P < 0.05
Between CE and graded fDMs
For 46 of 77 patients
B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA
ISMRM, Montreal, 2011
Results
ADC distribution for graded fDMs is different than
traditional fDMs and contrast-enhancing regions
Graded fDMs  FILTER
Chi-squared goodness of fit, P < 0.05
Between T1+C and graded fDMs
For 46 of 77 patients
B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA
ISMRM, Montreal, 2011
Results
Graded fDMs + Pre-Tx ADC Characteristics
B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA
ISMRM, Montreal, 2011
Results
Graded fDMs + Pre-Tx ADC Characteristics in T1+C  BEST PREDICTOR
B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA
ISMRM, Montreal, 2011
Results
Graded fDMs + Pre-Tx ADC Characteristics in T1+C  BEST PREDICTOR
B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA
ISMRM, Montreal, 2011
Summary
Graded fDMs + Pre-Tx ADC Characteristics in T1+C  BEST PREDICTOR
B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA
ISMRM, Montreal, 2011
Summary
Graded fDMs + Pre-Tx ADC Characteristics in T1+C  BEST PREDICTOR
B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA
ISMRM, Montreal, 2011
Conclusions
• Both traditional and graded fDMs in FLAIR and T1+C
were predictive of OS
B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA
ISMRM, Montreal, 2011
Conclusions
• Both traditional and graded fDMs in FLAIR and T1+C
were predictive of OS
• Subtle changes in ADC after anti-angiogenic therapy
w/in T1+C may reflect active tumor burden
B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA
ISMRM, Montreal, 2011
Conclusions
• Both traditional and graded fDMs in FLAIR and T1+C
were predictive of OS
• Subtle changes in ADC after anti-angiogenic therapy
w/in T1+C may reflect active tumor burden
Graded fDMs + Pre-Tx ADC Characteristics in T1+C
BEST PREDICTOR
Median Survival Advantage of 7 months
B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA
ISMRM, Montreal, 2011
Thank You!
Radiology
• Whitney Pope, M.D., Ph.D.
• Dieter Enzmann, M.D.
• Jonathan Goldin, M.D.
• MedQIA
Neurology/Neuro-Oncology
• Timothy Cloughesy, M.D.
• Albert Lai, M.D., Ph.D.
• Phioanh (Leia) Nghiemphu, M.D.
David Geffen School of Medicine
• Taryar Zaw, B.S.
• Korosh Neini, M.D.
• Bobby Harris, B.S.
• Carissa White, B.S.
Neurosurgery
• Linda Liau, M.D.
• Bob Shafa, M.D.
• Antonio DeSalles, M.D.
Pathology
• Paul Mischel, M.D.
• Bill Yong, M.D.
Medical College of Wisconsin
• Kathleen Schmainda, Ph.D.
• Peter LaViolette, B.S.
B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA
ISMRM, Montreal, 2011