Staff Performance Appraisals Presented By: Alan Napier & Steve Garwood.
Spectroscopic Window on Tumor Metabolism Michael Garwood, Ph.D. Univ. of Minnesota
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Transcript of Spectroscopic Window on Tumor Metabolism Michael Garwood, Ph.D. Univ. of Minnesota
Spectroscopic Window on Spectroscopic Window on Tumor MetabolismTumor Metabolism
Michael Garwood, Ph.D.Michael Garwood, Ph.D.Univ. of MinnesotaUniv. of Minnesota
Role of MRS in the Clinical Management of Cancer
• Diagnosis: guide biopsy avoid unnecessary/risky biopsies ascertain aggressiveness/stage/prognosis
• Treatment: guide choice of treatment identify non-responders early
→ alter treatment regime tool for follow up
Ackerstaff et al., J Cell Biochem 2003
High Res 1H MRS of CellsNon-Malignant cells Malignant cells
extract
in vitro
GPC → PCho switchAboagye et al., Cancer Res 1999
R-CH2-CH2-N-CHH
H
CH H H
-
H H H
-
C
+
Choline-containing compounds
lipids
suppressed water
lipid
Cholinecompounds
(tCho)
Frequency (ppm)
1H MRS
invasive ductal carcinoma
MRI
CMRR 4 Tesla
In vivo 1H MRS of breast cancerFirst reported studies: Roebuck et al, Radiol 1998; Gribbestad et al, JMRI 1998
Jacobs MA, Barker PB, et al. Proton magnetic resonance spectroscopic imaging of human breast cancer: a preliminary study. J Magn. Reson Imaging. 2004 Jan;19(1):68-75
BenignFocalFibrosis
Infiltrating ductal carcinoma P < 0.0008
Membrane Choline Phospholipid Metabolism
Adapted from Aboagye EO, Bhujwalla ZM. Cancer Res 59:80-84 1999
Lysophosphatidic acid
Mechanisms of increased PC in cancer:
• Increased expression and activity of choline kinase [Ramirez de Molina et al., Oncogene 2002]
• Higher rate of choline transport [Katz-Brull & Degani, AntiCancer Res. 1996]
• Increased PLD activity [Noh et al., Cancer Lett. 2000]
• Increased PLA2 activity [Guthridge et al., Cancer Lett. 1994]
Glioblastoma Multiforme (High Grade Tumor)
Cho
NAA Lac
FLAIR
PPM 4.0 3.0 2.0 1.0
T1
Cho
CrNAA
Right
Left
slide courtesy of Peter Barker, Johns Hopkins U
Prostate Cancer
Normal human prostate
Tumor-bearing prostate
Cheng LL, FEBS Lett. 2001
MRI/MRSI Targeted, TRUS-Guided Biopsies
PSA - 12 ng/mlTwo prior negative biopsies
The sensitivity of TRUS guided biopsy is reduced in large prostates and when the cancer is located in difficult locations such as the apex or in the anterior or lateral aspects of the prostate.
555 5 5
MR targeted TRUS guided biopsy positive
Journal Urology 2000, 164(2) 400-404
The accuracy of cancer detection of MRI/MRSI targeted biopsy in men with prior negative biopsy ≈80%. (Yuen et al, J. Urol. 2004; Prando et al, Radiology 2005)
courtesy of J.Kurhanewicz, UCSF
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Chemical Shift: Minimized with higher BW pulses
X Y Z
RF
Gra
die
nts
90 180 180
1800
Standard pulses
900
Spectrum
Center Frequency (-235 Hz)
F F
%CS : F / BWRF
F
Broadband pulses
Courtesy of: G. Metzger
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OVS with over-prescription
Courtesy of: G. Metzger
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Prostate Spectroscopy at 3T: Single Voxel Echo Time, Coupling and SNR
TE = 260 ms
TE = 100 ms
Courtesy of: P. Choyke & G. Metzger
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Case Study: Slice 5
Cho
Sp
CreCit
Courtesy of: P. Choyke & G. Metzger
Quantification
• Metabolite ratios (eg, tCho/NAA, (tCho+Cr)/Cit)
• External reference (eg, phantom of known conc)
• Reference to tissue water signal
a)
0123456
b)
tCho
3 Tesla
Normal breastMRI Devices 4-ch coil
3x3x3 cm voxel
LASER Localization
TE Averaging (60-300ms in 128 increments)
NEX=2
Breast Anatomy
• Anatomy varies greatly
• Tissues are distributed heterogeneously
Intravoxel lipids are inevitable
Lobules
Fat StromaTavassoli, 1999
Adipose tissue
Fibroglandular tissue
Netter, 1997
Internal Referencing with Water
1 2
1 2
1[tCho]
gain T TtCho water water
water tCho watergain T T tCho
f f fA
A MWf f f
1 2
, # /
gain
T T
water tCho
water
A Time domain amplitude
f receiver gain correction
f f relaxation correction
nuclei molecule
MW molecular wt
[tCho] expressed in molal units (mmol tCho/kg water)
No assumptions about volume or density
• NOT assuming constant water concentration
• Assuming a two-compartment model (water & fat) and all tCho is in the aqueous compartment
Bolan et al., MRM 2003
Spectral Fitting
Adapted TDFDFit (Slotboom et al., MRM 1998)
Time-Domain Model:
Minimize residuals in frequency-domain over narrow (0.4 ppm) band
• Fit 3 peaks independently: tCho, water, 1.3 ppm lipid
• Errors from Cramer-Rao Minimum Variance Bound; used for detection threshold
model
data
residual
2 2( ) exp( )s t A i t i t t
6 4 02ppm
Bolan et al., MRM 2003
Normal gland (Presumed) [tCho] = 0.75 ± 0.07 mmol/kg
volume = 13.0 mLlipid fraction = 3.5%
Invasive Ductal Carcinoma[tCho] = 6.8 ± 0.1 mmol/kg
volume = 6.8 mLlipid fraction = 8%
Atypical Hyperplasia[[tCho] = 1.5 ± 0.8 mmol/kg
volume = 1.1 mLlipid fraction = 15%
Bolan et al., MRM 2003
6 5 4 3 2 1 0 -1 -2Frequency (ppm)
invasive ductal carcinoma
no C
ho
6 5 4 3 2 1 0 -1 -2
Frequency (ppm)
Reason for false negative? Spurious lipid sideband peaks!
invasive ductal carcinoma
Sideband Artifacts
-500 -500Hz-300 -100 100 300
TE
(m
s)
45
57
sidebands
water
sidebands
Sidebands have coherent, TE-dependent phase
Averaging causes destructive interference
Bolan et al., MRM 2002
• Antisymmetric side peaks
• Amplitude >1%
• Caused by B0 oscillation
Echo-time Averaging
ppm-20468
Conventionalsingle TE
TE averaging
NotCho
tCho?NEX=64
TE=45ms
TE=45-196ms64 increments
2
Bolan et al., MRM 2002
In vivo 1H spectrum of a voxel containing mainly adipose tissue
[Cho] = 0.642 mmol/kg
Voxel o
f just
the
enhancing re
gion[Cho] = 0.910 mmol/kg
[Cho] = 0 mmol/kg
Voxel of just the non enhancing
region
Day 127 (AC x 4 followed by Taxotere x 3)size = 3.0 x 2.7 x 3.0 cm3
[tCho] = 0 ± 1.73
Lipid
H2O Lipid
Lipid
7 123456 -10ppm
All 4 readers maintained their decision to biopsy
Invasive Ductal Carcinoma
SI
time (sec)
4
2
3
00
1
0 1 32 4 5
Precontrast Postcontrast Subtraction
tCho
time (min)
Meisamy et al, Radiology 2005
Conclusions about MRS for breast cancer diagnosis:
Adding quantitative 1H MRS to breast MRI improves sensitivity, specificity, and accuracy, over MRI alone
Quantitative 1H MRS is particularly useful in cases where lesion morphology and time-intensity curves are indeterminate
Meisamy et al, Radiology 2005
Treatment Planning and Monitoring
MRSI for Radiation Treatment Planning of Brain Tumor
Cho/Cr Grade Dose painting
<1 0
≥1-2 1 5040
≥2-3 2 5940
≥3 3 7020
MRSI-based radiation dose painting using the IMRT method
Thakur, Chang, Huang, Koutcher, NarayanaMemorial Sloan-Kettering Cancer Center
Models of tCho response
Measured acute response to PX-478 (inhibits HIF1-alpha production) in mouse xenografts of HT-29 (colon)
Methods: in vivo MRS at 4.7T, ex vivo validation
Results: tCho dropped significantly at 12 and 24 hrs
Jordan et al., NMR Biomed 2006 Al-Safar et al., Cancer Res 2006
Measured acute response to MN58b (inhibits CK) in mouse xenografts of MDA-MB-231 (breast) and HT-29 (colon)
Methods: in vivo MRS at 4.7T, ex vivo validation
Results: tCho dropped significantly at 48hrs in both models
PCho
CK
cell density
Neoadjuvant chemotherapy (primary systemic therapy, PST) is the preferred treatment for locally advanced breast cancer (Fisher et al. J Clin Oncol 1997, 1998)
Advantages:
Tumor shrinkage; possible breast conserving procedures
In vivo monitoring of chemo-sensitivity
(customize Tx complete pathologic response)
Treatment Monitoring in Breast Cancer
4T Tx Monitoring in Breast Cancer: Results to Date
• 14/18 Responders had a decrease in [tCho] at Day 1
• 9/10 Non-responders had a increase in [tCho] at Day 1
• Day 1 Rule: 82% accuracy in 28 subjects
0
1
2
3
4
5
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9
[tC
ho
] (
mm
ol/
kg
)
0
1
2
3
4
5
6
7
8
9
Baseline Day 1 Baseline Day 1
Responders Non-Responders
[tC
ho
] (
mm
ol/
kg
)
Meisamy et al, Radiology 2004
Pre PST 24 hrs AC X 1 AC X 4
[tCho] = 4.6LD = 4.0 cm
[tCho] = 3.7LD = 4.0 cm
[tCho] = 0.9LD = 1.7 cm
Responder to AC
Meisamy et al, Radiology 2004
Pre PST 24 hrs AC X 1 AC X 4 Taxol X 2
[tCho] = 4.1LD = 1.7 cm
[tCho] = 4.6LD = 4.0 cm
[tCho] = 3.7LD = 4.0 cm
[tCho] = 0.9LD = 1.7 cm
Responder to AC, but not Taxol
Meisamy et al, Radiology 2004
cholinecitrate
Therapeutic Selection and MonitoringBaseline
Metabolic Atrophy
1 year
Metabolic Atrophy
5 years
courtesy of J.Kurhanewicz, UCSF
Is it possible to predict response from baseline MRS data?
Treatment Prediction / Phenotyping
Inconsistent findings in brain MRS:Tzika, Neuroradiology 2001 – responders had lower tChoPreul, Neurosurgery 2000 – no differenceLazareff, J Neurooncol 1999 – no difference
Baseline [tCho] was higher in responders than in non-responders (p=0.03)
Higher [tCho] @ baseline associated with higher grade & positive nodes
Can MRS identify responders before starting treatment?
0
1
2
3
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5
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7
8
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[tC
ho
] (
mm
ol/
kg
)
0
1
2
3
4
5
6
7
8
9
Baseline Day 1 Baseline Day 1
Responders Non-Responders
[tC
ho
] (
mm
ol/
kg
)
Pretreatment 31P spectrum from nodal disease of a HNSCC patient who experienced partial response
Pre
trea
tmen
t P
ME
/NT
P r
atio
Pretreatment PME/NTP ratios from tumors;complete responders were different from incomplete response group P<0.001
Preliminary results with 31P MRSI
A. Shukla-Dave, et. al. Acad Radiol, 9:688-694, 2002
31P MRS in Bone Sarcoma
Zakian, et. al., Cancer Research 2003 Dec 15;63(24):9042-7
Baseline spectrum
Baseline Energetics Predicts Outcome in Bone Sarcoma
Zakian, et. al., Cancer Research 2003 Dec 15;63(24):9042-7
NTP/Pi predicts longer survival
Future:
• More studies correlating with pathology, immunohistochemistry, and outcomes
• Further studies to assess reliability/reproducibility
• Results of multi-center trials
• Combine with other metrics (DCE-MRI, ADC,…) → multiparametric analyses
• 3T (and higher?)
D a ta e x a m p le
C h o + C rC i
C h o C i
A
B
C
D
E
C h o + C rC i
C h o C iC h o + C rC i
C h o C i
A
B
C
D
E
F ig u re 3 . T h e a x ia l T 2 -w e ig h te d im a g e (A ) is u s e d fo r m a tc h in g v o x e l lo c a t io n s to h is to p a th o lo g ic a l s p e c im e n s (D ) . O n e o f th e s p e c tra l m a p s (B ) , p a r t ia lly e x p a n d e d in (E ) , re f le c ts th e q u a li ty o f th e M R S I d a ta th ro u g h o u t th e s lic e . D e v ia t io n s in th e ( C h o + C r) /C i m e ta b o lite ra t io m a p in (C ) la rg e ly c o rre s p o n d to th e tu m o rlo c a t io n in d ic a te d w ith th e b lu e lin e in (D ) .
Prostate spectroscopy at 1.5T with endorectal coil
IMAPS (1.5T)
The axial T2-weighted image (A) is used for matching voxel locations to histopathological specimens (D). One of the spectral maps (B), partially expanded in (E), reflects the quality of the MRSI data throughout the slice. Deviations in the (Cho + Cr)/Ci metabolite ratio map in (C) largely correspond to the tumor location indicated with the blue line in (D).
Courtesy of T. Scheenen and Prof. A. Heerschap, Radboud University Nijmegen Medical Center, Dept. of RadiologyThe IMAPS community
Slide courtesy of Michael Jacobs, JHU
Current Multiparametric (MRI/DTI/MRSI) Prostate Imaging Exam
Polyamines
Creatine
3.0PPM 2.02.5
Citrate
Choline
CholineCreatine
3.0 2.02.5
Lipid
Healthy Cancer
T2 weighted MRI
Diffusion weighted MRIADC Map
MRSI (0.3 cc)
Elevated cholineReduced citrateReduced polyamines
Decreased Signal Intensity on T2 weighted Imaging
Reduced water diffusion
Slide courtesy J. KurhanewiczUCSF
3T MRSI vs 1.5T MRSI: Improved Detection of Residual Cancer
3T 1.5T
Cho
ChoCho
Cho
Cho
0.16 cc 0.34 cc
Choline
Creatine
U of Minn ResearchersPatrick BolanGreg MetzgerSina MeisamyAdeka McIntoshCurt CorumAngela StyczynskiNate PowellDjaudat IdiyatullinJang-Yeon ParkCarl SnyderJames BoyumDoug YeeMichael NelsonTim EmoryLenore EversonTodd TuttleEvin GulbahceTommy Vaughan
Thanks for Sending SlidesArend HeerschapJason KoutcherJohn KurhanewiczMichael JacobsPeter BarkerWei Huang
Funding SourcesNational Institutes of Health (CA92004, RR08079)
Acknowledgements