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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.

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slide2

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

slide3

Diffusion MR Characteristics of theCentral 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
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

slide5

Graded fDMs Allow Visualization and Quantification of Growing Tumor

+ Hypocellular

+ Hypercellular

From: Ellingson, JMRI, 2010

Biological Calibration

B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA ISMRM, Montreal, 2011

slide6

Graded fDMs Allow Better Visualization of Growing Tumor

+ Hypocellular

+ Hypercellular

B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA ISMRM, Montreal, 2011

slide7

What about anti-angiogenic therapy?

B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA ISMRM, Montreal, 2011

slide8

What about anti-angiogenic therapy?

B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA ISMRM, Montreal, 2011

slide9

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

slide10

What about anti-angiogenic therapy?

B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA ISMRM, Montreal, 2011

slide11

What about anti-angiogenic therapy?

B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA ISMRM, Montreal, 2011

slide12

What about anti-angiogenic therapy?

B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA ISMRM, Montreal, 2011

slide13

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

slide14

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

slide15

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

slide16

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

slide17

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

slide18

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

slide19

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

slide20

Results

B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA ISMRM, Montreal, 2011

slide21

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

slide22

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

slide23

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

slide24

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

slide25

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

slide26

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

slide27

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

slide28

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

slide29

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

slide30

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

slide31

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

slide32

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

slide33

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

slide34

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

slide35

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

slide36
Both traditional and graded fDMs in FLAIR and T1+C were predictive of OS

Conclusions

B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA ISMRM, Montreal, 2011

slide37
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

Conclusions

B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA ISMRM, Montreal, 2011

slide38
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

Conclusions

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

slide39
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!

  • 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.
  • David Geffen School of Medicine
  • Taryar Zaw, B.S.
  • Korosh Neini, M.D.
  • Bobby Harris, B.S.
  • Carissa White, B.S.

B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA ISMRM, Montreal, 2011