disclosures paid consultant, medqia llc paid consultant, agios pharmaceuticals, inc. consultant,...

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

• 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.