new mdacc mr research · 2007. 7. 25. · aapm 2007 - mr biomarkers - jackson 10.1 10.9 18fdg...

AAPM 2007 AAPM 2007 -- MR Biomarkers MR Biomarkers -- JacksonJackson

MDACC MR Research

MR Biomarkers: Current Applications and Unmet Needs

Edward F. Jackson, PhD

Department of Imaging Physics

AAPM 2007 – Imaging Symposium – Molecular Imaging Biomarkers

MDACC MR Research

Rationale for Functional MR

• Both CT and MR provide exquisite views of anatomy and can be used to assess changes in tumor volume/morphology.

• Anatomic imaging alone has significant limitations as morphological changes can be slow to occur, particularly for cytostatic agents, and are often nonspecific.

• Physiologic alterations precede morphologic changes and represent an earlier measure of tumor response.

• Goal of functional and molecular imaging MR techniques:– To obtain non-invasive biomarker information regarding changes in

microvascular parameters, biochemical distribution/concentration, cellularity, tissue oxygenation, etc.


10.1 10.9

18FDG LargestSUV Dimension (cm)

4.5 11.5

1.3 11.3

Gayed, Vu, Iyer, et al. J Nucl Med 45:17-21, 2004.

Imatinib mesylate (Gleevec) therapy of GIST

Applications to VEGFR Targeted Rx

Stephens et al., Pharma Res EPUB, 2007MDACC MR Research


Applications to HIF-1α Targeted Rx

Stephens et al., Pharma Res EPUB, 2007MDACC MR Research

MRI: Anatomic Imaging


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Functional MR Techniques

• Assessing microvascular changes– Dynamic contrast enhanced MRI (DCE-MRI) and dynamic susceptibility

change MRI (DSC-MRI)

• Assessing cell volume/density changes– Quantitative diffusion MRI

• Assessing white matter changes– Diffusion tensor imaging (DTI)

• Assessing changes in oxy- / deoxyhemoglobin ratio– Blood oxygen level dependent (BOLD) MRI, susceptibility mapping

• Assessing biochemical changes– In vivo MR spectroscopy

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Assessing Microvascular Changes

1: Goal:

Non-invasive assessment of the effects of antiangiogenic / antivascular therapy.


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Effects of increasing Gd-DTPA concentration on T1 (left) and T2 (right) relaxation times in gray matter (T1,0 = 1055 ms, T2,0 = 68 ms). Note the dominant effect on T1 relaxation times.

Paramagnetic contrast agent effects

0 0.25 0.5 0.75 10

500

1000

[Gd] (mM)

T1 (m

s)

0 0.25 0.5 0.75 10

50

100

[Gd] (mM)

T2 (m

s)

r2 = 5.5 mM-1 s-1r1 = 4.5 mM-1 s-1

[ ]11 1,0

1 1 r GdT T= + [ ]1

2 2,0

1 1 r GdT T

= +

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Percent increase in contrast for gray matter as a function of Gd-DTPA concentration for a SE sequence with TR/TE = 400ms/18ms.

0 0.2 0.4 0.6 0.8 10

40

80

120

160

200

[Gd] (mM)

% In

crea

se in

Con

tras

t

Paramagnetic contrast agent effects


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DCE-MRI Background

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DCE-MRI Background


Two Compartment Pharmacokinetic Model

CP = [Gd] in plasma (mM) = Cb / (1-Hct)CEES = [Gd] in extravascular, extracellular space (mM)

Ktrans = endothelial transfer constant (min-1) kep = reflux rate (min-1)

vP = fractional plasma volume, ve = fractional EES volumeStandardized parameters as proposed by Tofts et al., J Magn Reson Imaging, 10:223-232, 1999.

Ktrans

Plasma Flow

PlasmaCP, vP

EESCEES, ve

Endothelium

kep

( ')

0( ) ( ') 'ep

t k t ttransEES PC t K C t e dt− −= ∫CL(t) = vP CP(t) + CEES(t)

0 2 4 6 8 100

1

2

3

Time (min)

[GdD

TPA

] (m

M)

CP(t)

CL(t)

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Measured Measured

MDACC MR Research

Signal intensity data from tumor

and vascular ROIs

( )( ) ( ) ( )'

0'

1

ept k t ttrans

P P PL

K C t e v C tC t

Hct

− − +=

−∫

( ) ( )( ) ( ) 0,1

0

01

0,10,1

0,10,1

1cos1

1coscos1ln1 R

eSSe

eSSe

TRR

RTRRTR

RTRRTR

−

⎥⎥⎥⎥

⎦

⎤

⎢⎢⎢⎢

⎣

⎡

−−−

−−−=Δ

−−

−−

α

αα

1

1

1

0,11][rR

rRR

Gd Δ=

−=

Determine vP, Ktrans, and kep, from non-linear Marquardt-Levenberg fitting of CL(t) and CP(t) data

DCE-MRI Analysis


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High Resolution DCE-MRI

3D FSPGR w/Parallel Imaging

20 5-mm sections every 4.5 s

0.94-mm in-plane resolution

Ktrans Parametric Maps

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PTK787/ZD222584 – Liver Mets

J Clin Oncol, 21:3955-64, 2003



MDACC MR Research J Clin Oncol, 21:3955-64, 2003


MDACC MR Research J Clin Oncol, 21:3955-64, 2003


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AG-013736 Trial (DCE-MRI and DCE-CT)

– Potent and selective inhibitor of VEGFR/PDGFR tyrosine kinases

– Preclinical activity in xenograft models (melanoma, colon, breast, and lung)

– Multicenter Phase I study in solid tumors (MDACC, University of Wisconsin, UCSF)

– Heterogeneous solid tumor patient population

AG-013736 DCE-MRI Study

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McShane, Ashton, Jackson, et al., Proceedings of the ISMRM, p 154, 2004

Ktrans Data at Baseline (left) and Day 2 (right)



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N = 17

Liu, Rugo, Wilding, et al., J Clin Oncol 23:5464, 2005.

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Bevacizumab in IBC / LABC


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Wedam, Low, Yang, et al., J Clin Oncol 24:5, 2006


0.020-20.40.002-14.3ve

0.002-49.40.0007-15.0kep

<0.0001-58.00.003-34.4Ktrans

0.01372.70.0008128.9TUNELNSNSVEGFR2

0.009-76.40.004-66.7p-VEGFR2 (Y951)0.013-88.90.025-69.2p-VEGFR2 (Y996)

NSNSVEGF-ANSNSMVD (CD31)

0.025-35.1NSKi67p-value% changep-value% change

Baseline to End Cycle 1 Baseline to End Cycle 4/7

Wedam, Low, Yang, et al., J Clin Oncol 24:5, 2006


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DCE-MRI

Unmet needs for DCE-MR:– Standardization of

• data acquisition strategies, and• data analysis algorithms

– Quality control programs!– Reproducibility/repeatability studies and comparisons with outcome and

tissue-based measures (multi-center)– Anatomic coverage, temporal resolution, artifacts (especially motion),

arterial input function sampling, fast (reproducible) T1-measurement techniques.

– Need for higher MW contrast agents• Improved accuracy of blood volume and permeability-surface area measures

DCE-MRI Issues and Recommendations: Leach et al., Br J Cancer 92:1599, 2005

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DCE-MRI: Current Limitations

• Flow-limited case:– Ktrans => EF --- the “extraction flow product”

• E = (1 - e-PS/F)• Typically true for current FDA-approved small MW agents.

• Permeability-limited case:– Ktrans => EF => PS

• Since E => PS / F• Typically true for contrast agents with MW > ~35-45 kD.


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Dual-Tracer DCE-MRI Technique

Slope ∝ Ktrans

Sign

al In

tens

ity

vP

ve

Time

t1 t2

Weissleder et al., European J Cancer, 34:1448-1454, 1998.

t1 = time of administration of high MW agent

t2 = time of administration of low MW agent

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Dual-Tracer DCE-MRI

Time (s)

PG-GdDTPA (short arrow) & Magnevist (long arrow)(MWPG-GdDTPA ~ 100 kDa*)(MWMagnevist ~ 0.6 kDa)

Baseline Baseline + 20 min

*Provided by Chun Li, PhD


MDACC MR Research

Dual Tracer DCE-MRI

-10

0

10

20

30

40

50

60

0 200 400 600 800

T ime (s)

Sign

al In

tens

ity (a

u)

Central Peripheral

First tracer: PG-GdDTPA (~100kD); Second tracer: GdDTPA (~0.6kD)Colo-205

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Colo-205 Xenograft

PG-GdDTPA parametric images:

IAUC AUC

MagnevistTM

parametric images:

IAUC AUC

Colo-205


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DSC-MRI Techniques

• Dynamic susceptibility change (DSC) MRI techniques have also been used to assess changes in regional blood flow.

• DSC-MRI uses T2- or T2*-weighted, high speed imaging techniques, e.g., echo-planar imaging.

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Effects of increasing Gd-DTPA concentration on T1 (left) and T2 (right) relaxation times in gray matter (T1,0 = 1055 ms, T2,0 = 68 ms). Note the dominant effect on T1 relaxation times.

Paramagnetic Contrast Agent Effects

0 0.25 0.5 0.75 10

500

1000

[Gd] (mM)

T1 (m

s)

0 0.25 0.5 0.75 10

50

100

[Gd] (mM)

T2 (m

s)

r2 = 5.5 mM-1 s-1r1 = 4.5 mM-1 s-1

[ ]11 1,0

1 1 r GdT T= + [ ]1

2 2,0

1 1 r GdT T

= +


MDACC MR Research

DSC-MRI Techniques

0.2 mmol/kg gadodiamide bolus infusion at 5 cc/sec

SE-EPITE/TR = 80/1700 ms30 cm FOV, 128x128 matrix125 kHz, 5 mm slice, 1.5 mm gap65 phases, 1:52 min

MDACC MR Research

EPI Source Image

rCBV Map

150.0

200.0

250.0

300.0

350.0

0.0 20.0 40.0 60.0 80.0 100.0 120.0

Time (s)

Sign

al In

tens

ity (A

rb. U

nits

)

Inject

-2.00

0.00

2.00

4.00

6.00

8.00

0.0 20.0 40.0 60.0 80.0 100.0 120.0

Time (s)

ΔR

2* (A

rb. U

nits

)

ΔR2* = -1/TE ln[S(t)/S(0)]

Extract S(t)*2

0

( )rCBV R t dtτ

= Δ∫

*2

0

*2

0

( )

( )

R t dtrMTT

R t dt

τ

τ

τ Δ=

Δ

∫

∫

rCBVrCBFrMTT

=

DSC-MRI Techniques


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DSC-MRI Techniques

T1-weighted Post-Gd Computed rCBV Maps

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Assessing changes in 1H diffusion


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Diffusion Imaging

intra intra extra extrameasured

intra extra

D V D VDV V

+=

+

Intracellularspace:

Extracellularspace:

Dintra

Dextra ~ 10 Dintra

MDACC MR Research

Diffusion Imaging

Stejskal, Tanner. J Chem Physics , 1965

90o 180o

DAQ

δΔ

δG

2 2 2

3b G δγ δ ⎛ ⎞= Δ −⎜ ⎟

⎝ ⎠0

b DS eS

−=


MDACC MR Research

Diffusion Imaging

Apparent diffusion coefficient (ADC) imaging

Acquisition of multiple sets of DWIs with varying b-values to allow computation of ADC values on a pixel-by-pixel basis by linear regression analysis of the signal attenuation equation, ln(S/S0) = -b ∗ ADC.

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Diffusion imaging - Ischemic injury

normal tissue

Dnormal

cells swell

D < Dnormal

lysis

D > Dnormal


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Diffusion imaging in acute stroke

PDW T2W FLAIR Diffusion

GE Medical Systems Applications Guide

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Diffusion Imaging Assessment of Therapy

Moffat et al., PNAS 102:5524, 2005


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Hamstra et al., PNAS 102:16759, 2005

Red: VR – increased ADCBlue: VB – decreased ADCGreen: No change

VT = VR + VB

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Hamstra et al., PNAS 102:16759, 2005

VT, threshold = 6.75%

Kaplan-Meier plots when stratified by VTdiffusion measures at 3 weeks into 7-week fractionated regimen.

PDSD/PR

SD/PR

PD

Overall Survival

TTP

VT = VR + VB


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3T Breast Diffusion Imaging

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Diffusion tensor imaging

xx xy xz

xy yy yz

xz yz zz

D D D

D D D D

D D D

⎡ ⎤⎢ ⎥

= ⎢ ⎥⎢ ⎥⎢ ⎥⎣ ⎦

11

2

3

0 00 00 0

D E Eλ

λλ

−

⎡ ⎤⎢ ⎥= ⎢ ⎥⎢ ⎥⎣ ⎦


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Diffusion tensor imaging (DTI)

3.0T, b=1000 s/mm2, 15 directions1.5T, b=1576 s/mm2, 6 directions

Using multiple diffusion encoding directions to determine the diffusion tensor terms, the eigenvalue/eigenvector information can be used to characterize the anisotropy.

2 2 21 2 3

2 2 21 2 3

(λ -λ) (λ -λ) (λ -λ)3FA2 λ λ λ

+ +=

+ +

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Diffusion tensor imaging (DTI)


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Multiparametric Assessment

• While each of the functional MR techniques presented thus far allows the non-invasive assessment of treatment response, the combination of the techniques may allow a much more comprehensive assessment.

• Combination of appropriate single modality imaging biomarkers with those obtained from other modalities would be expected to provide even more comprehensive assessment.

Batchelor, Sorensen, et al. Cancer Cell 11:83-95, 2007

AZD2171, Pan-VEGF Receptor Tyrosine Kinase Inhibitor

Best-Responding Patient


Batchelor, Sorensen, et al. Cancer Cell 11:83-95, 2007

AZD2171, Pan-VEGF Receptor Tyrosine Kinase Inhibitor

Worst-Responding Patient

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Molecular MR Imaging

Primary types of imaging agents for MR– T1 modifiers (typically based on paramagnetic atoms, e.g., Gd)

– T2* modifiers (typically ultrasmall superparamagnetic iron oxide nanoparticles & aggregates)

– Chemical exchange saturation transfer (CEST) agents

– Hyperpolarized agents, e.g., 13C1-pyruvate.

Shapiro et al., Magn Reson Imag 24:449, 2006


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T1 Modifiers – Paramagnetic Agents

Effects of increasing Gd-DTPA concentration on T1 (left) and T2 (right) relaxation times in gray matter (T1,0 = 1055 ms, T2,0 = 68 ms). Note the dominant effect on T1 relaxation

times (left) with an associated increase in signal intensity on T1-weighted images.

0 0.25 0.5 0.75 10

500

1000

[Gd] (mM)

T1 (m

s)

0 0.25 0.5 0.75 10

50

100

[Gd] (mM)

T2 (m

s)

T1 Modifiers - Necrosis

M

Untreated

120 equiv PG-TXL/kg

Baseline 10 min 2 days 4 days

PG-DTPA-Gd OCa-1

Polymeric DTPA-Gd-poly(L-glutamic acid) - provided by Chun Li, PhDMW = 101.2 kDRelaxivities @ 200 MHz: R1 = 8.9 mM-1 s-1; R2 = 21.5 mM-1 s-1

Jackson, Esparza-Coss, Wen et al., IJROBP, 2007


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x50 x200

x50 x200

Untreated

120 equiv PG-TXL/kg

Red: anti-mouse monoclonal antibody directed against macrophages

Brown: avidin-HRP to biotinylated PG-DTPG-Gd

Blue: hematoxylin

MDACC MR Research


0

5

10

15

20

25

30

D2 D3 D4 D7 D11

Timepoint

% o

f Tum

or

Treated Control

Treatment: AMG-386 Colo-205


MDACC MR Research

Molecular Imaging T1 Modifiers

β-galactosidase-activated Gd agentMeade et al. - Northwestern

Nature Biotechnology, March 2000

Challenges for conventional T1modifiers as molecular imaging contrast agents: sensitivity.

Require high concentration (as compared to nuclear medicine tracers or optical agents), high T1 relaxivity, or a means of signal amplification or accumulation.

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Superparamagnetic Iron Oxides

Ultrasmall Superparamagnetic Iron Oxide (USPIO) nanoparticles

– ~4-6 nm diameter iron oxide crystalline core

– Low molecular weight dextran coating (prolong circulation time)

– Overall size: ~30 – 50 nm diameter

– Cleared by the reticuloendothelial system (macrophages / lymph nodes) to liver and spleen and degraded.

– Accumulation of USPIOs causes signal loss on T2- and T2*-weighted images due to signal dephasing resulting from intravoxel inhomogeneity.


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USPIOs

Saokar et al., Abdom Imag, 2006

Normal

Tumor

Micrometastases

Baseline 24-hrs Post

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Targeted USPIOs

Transferrin receptor-targeted monocrystalline iron-oxide nanoparticles (MIONS)

Basilion et al. - MGHNature Medicine, March 2000


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Targeted, bifunctional, iron oxides

Tumor Model: BT-20, expressing αvβ3 integrins.

Agent: cRGD-CLIO(Cy5.5)

cRGD: cyclic arginine-glycine-aspartic acid, which binds to integrins.

CLIO: cross-linked iron oxide nanoparticle

Baseline 24-hrs post

OPTICAL

Montet et al., Neoplasia,8:214, 2006

Hyperpolarized Agents

50 s

0 s

Injection of hyperpolarized 13C1-pyruvate at time t = 0 s.

Data obtained every 3 s following injection from rat muscle.

Golman et al., PNAS, 103:11270, 2006


Hyperpolarized Agents

Golman et al., PNAS, 103:11270, 2006

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Unmet Needs - Techniques

• The implementation of “quantitative imaging” capabilities by the vendors of MR equipment is driven by demand from the clinical users, competition from other vendors, and whether or not such sequences and analysis techniques lead to reimbursable procedures (FDA, CMS, etc.).

• There exists a need for standardized acquisition pulse sequences and analysis techniques for MR “imaging biomarker” studies.

• Criteria for such standardized pulse sequences and analysis techniques need to be developed.

• Validated phantoms and test data need to be available to users in order to test new releases of pulse sequences and analysis software.


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Unmet Needs – Techniques / QC

• Specific phantoms should be available to validate each vendor’s acquisition techniques for the particular MR biomarker technique(lesion morphology, perfusion, diffusion, MR spectroscopy, BOLD assessment of hypoxia, etc.).

• In general, rigorous quality control programs in MR are relatively rare. This can be problematic if multiple scanners are used to acquire study data at one facility. For multicenter trials, this problem is clearly exacerbated.

• Reproducibility/repeatability studies are lacking in several key areas.

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Summary Comments

• There can be no doubt that there is significant interest in non-invasive imaging biomarkers for the (early) assessment of treatment response.

• MR, like other state-of-the-art imaging modalities, is poised to provide such imaging biomarkers for both morphology and function.

• As with other modalities that provide means of early response to therapy there is a tremendous opportunity for functional MR techniques to contribute to drug development, treatment assessment, and to selection of “patient specific therapies”.

• How will the imaging community respond to the challenge (and paradigm shift) of quantitative imaging?


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Some of the Pieces…

Uniform Protocols for Imaging in Clinical Trials

(UPICT - ACR)

Imaging Biomarker Quality Control / Phantom

Development Groups

(NCI/NIST/FDA; Inter-Society and Inter-Agency WGs)

Reference Image Database to Evaluate Response

(RIDER) / caBIG Imaging Workspace - NCI

Imaging Response Assessment Teams

(IRAT - NCI)

NCI / FDA / Scientific Societies

Imaging Scientists / Animal Imaging Cores

Imaging Equipment Vendors, Pharma, & CROs

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Acknowledgments

• Chun Li, Ph.D. and Xiaoxia Wen, M.S.• Qing Yuan, Ph.D.• Emilio Esparza-Coss, Ph.D.• Robert C. Orth, M.D., Ph.D.• Krista McAlee, R.T., Michelle Garcia, R.T., Tim Evans, R.T.• James Bankson, Ph.D.• Chaan Ng, M.D.• W.K. Alfred Yung, M.D., Charles Conrad, M.D., Vinay Puduvalli, M.D.• MDACC Small Animal Imaging Facility personnel

new mdacc mr research · 2007. 7. 25. · aapm 2007 - mr biomarkers - jackson 10.1 10.9 18fdg...

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