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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
• 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
Diffusion MR Characteristics of theCentral Nervous System
Viable Tumor (Dark)
Necrotic Core
Edema
ADC Map
From: Ellingson, J Magn Reson Imaging, 2010
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
+ Hypercellular+ Hypocellular
Biological CalibrationFrom: 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 Better Visualization of Growing Tumor
+ Hypercellular+ Hypocellular
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
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
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?
B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA ISMRM, Montreal, 2011
Hypotheses:
1. Traditional fDMs (single threshold) edema changes + tumor growth greater risk of failure
What about anti-angiogenic therapy?
B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA ISMRM, Montreal, 2011
Hypotheses:
1. Traditional fDMs (single threshold) edema changes + tumor growth greater risk of failure
2. Graded fDMs tumor growth greater risk of failure
What about anti-angiogenic therapy?
B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA ISMRM, Montreal, 2011
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
Methods
B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA ISMRM, Montreal, 2011
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 1.5TT2w, FLAIR, T1w, T1+C3-5mm slice thickness
Diffusion MRI w/ twice refocused spin echo preparationADC calculated from b=0 and b=1000 s/mm2
Methods
B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA ISMRM, Montreal, 2011
Image Registration
All images registered to Baseline T1 weighted imagesMutual 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
Methods
B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA ISMRM, Montreal, 2011
Traditional fDM ΔADC beyond 0.4 um2/ms
Methods
B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA ISMRM, Montreal, 2011
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)
Results
B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA ISMRM, Montreal, 2011
B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA ISMRM, Montreal, 2011
From: Ellingson, Neuro Onc, 2011
ResultsConventional response does not predict survival
Results
B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA ISMRM, Montreal, 2011
Conventional response does not predict survival
Results
B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA ISMRM, Montreal, 2011
Graded fDM regions are localized to post-treatment contrast enhancement
Results
B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA ISMRM, Montreal, 2011
Traditional and graded fDMs both predict survival
Results
B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA ISMRM, Montreal, 2011
T1+C is better than FLAIR
Results
B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA ISMRM, Montreal, 2011
Graded fDMs are better than traditional fDMs
Results
B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA ISMRM, Montreal, 2011
Graded fDMs in T1+C
Results
B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA ISMRM, Montreal, 2011
ADC distribution for graded fDMs is different than traditional fDMs and contrast-enhancing regions
Chi-squared goodness of fit, P < 0.05Between CE and graded fDMsFor 46 of 77 patients
Results
B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA ISMRM, Montreal, 2011
ADC distribution for graded fDMs is different than traditional fDMs and contrast-enhancing regions
Chi-squared goodness of fit, P < 0.05Between CE and graded fDMsFor 46 of 77 patients
Results
B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA ISMRM, Montreal, 2011
ADC distribution for graded fDMs is different than traditional fDMs and contrast-enhancing regions
Chi-squared goodness of fit, P < 0.05Between T1+C and graded fDMsFor 46 of 77 patients
Graded fDMs FILTER
Results
B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA ISMRM, Montreal, 2011
Graded fDMs + Pre-Tx ADC Characteristics
Results
B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA ISMRM, Montreal, 2011
Graded fDMs + Pre-Tx ADC Characteristics in T1+C BEST PREDICTOR
Results
B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA ISMRM, Montreal, 2011
Graded fDMs + Pre-Tx ADC Characteristics in T1+C BEST PREDICTOR
Summary
B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA ISMRM, Montreal, 2011
Graded fDMs + Pre-Tx ADC Characteristics in T1+C BEST PREDICTOR
Summary
B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA ISMRM, Montreal, 2011
Graded fDMs + Pre-Tx ADC Characteristics in T1+C BEST PREDICTOR
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
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.
Thank You!
B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA ISMRM, Montreal, 2011
Neurosurgery• Linda Liau, M.D.• Bob Shafa, M.D.• Antonio DeSalles, M.D.
Pathology• Paul Mischel, M.D.• Bill Yong, M.D.
David Geffen School of Medicine• Taryar Zaw, B.S.• Korosh Neini, M.D.• Bobby Harris, B.S.• Carissa White, B.S.
Medical College of Wisconsin• Kathleen Schmainda, Ph.D.• Peter LaViolette, B.S.
