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7/8/2015
1
Clinical Applicationsof
Contrast Enhanced Sonography
Arthur C. Fleischer, M.D.
Vanderbilt U Med Ctr
Radiology and Ob/Gyn
Disclosures• These applications are real,
not just “academic”
• Microbubble contrast is currently not approved by FDA for non‐cardiac general applications, but is approved for cardiac applications
• There is an imminent chance of approval within 1‐2 years
USA is only country in world with this constraint (should be lifted within 1‐2 yrs)
Microbubbles can be used
“off label”
Research Support
• NIH/NCI grant R21 CA 125227‐01
• AIUM discovery grants
• Multiple NIH/NCI grants imminent
• Philips Healthcare‐software support
• Bracco‐contrast and software
• Lantheus‐Definity contrast
Clinical Applications
• Hepatic Masses‐DDx of metastasis, focal nodular hyperplasia, hepatocellular carcinoma, hemangioma
• Renal Masses‐evaluation of “indeterminate” renal mass, particularly in patients with poor renal function‐DDx of renal cell carcinoma, oncocytoma
• Ovarian masses‐DDx of carcinoma, fibroma, dermoid, endometrioma
• Assessment of tumor response
• Potential targeted therapy ‐“theranostics”
Other Applications• Assessment of completeness of TACE, ablation
• Prostate cancer‐localization prior to Bx
• Reflux‐urethral, ureteric
• Splenic, renal, liver laceration 2/2 trauma
• Adnexal torsion‐both depiction of vascular pedicle and “viability” of parenchyma
• Tubal patency
• Vascular complications‐endovascular shunt leaks
• Breast cancer detection (Liu JUM 34:117,’15)
Tumor angiogenesis
(according to Judah Folkman, MD, PhD)
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Tumor angiogenesis
Kuszyk, B. S. et al. Am. J. Roentgenol. 2001;177:747-753
Microbubble vs Gd‐MRI
Kuszyk, B., AJR 177:747, 2001
MB stay intravascular, whereas Gd-MRI leaks into interstitium
Scientific American, 2005
Tumor Neovascularity
Increased vascularity, clustered vessels, irregular branching pattern, irregular caliber
McDonald, Choyke Nat Med 9:713, 2003
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Microbubbles used forContrast Enhanced Sonography (CE‐US)
____5 um
Definity microbubbles
_____5 u
Microbubbles for US ContrastCapillary Perfusion
Perfusion ~ blood flow (ml/s)volume (mg)
Blood flow ~ vascular area (α) x mean blood velocity (β)
Mean blood = slice x replenishmentvelocity thickness rate(β) (α)
Contrast AgentsContrast Agents• Shell
– albumin, lipid/phospholipid or polymer
• Gas– air, low diffusivity gas
• Diameter– 2-15 microns
• Resonant frequencies - 2-10 MHz• Nonlinearity allows bubbles to be differentiated from surrounding
tissue
• Persistence – circulate for minutes
5 microns 50 microns
c/o C. Caskey
POWER
Interaction of Ultrasoundand Microbubbles
Linearresonance
Nonlinearresonance
Transientscattering
POWER POWER
Fundamentalenhancement
Bubble disruptionHarmonic enhancement
Burns. In: Rumack et al, eds. Diagnostic Ultrasound. Vol 1. 2nd ed. St. Louis: Mosby; 1998:57.
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Microbubble Destruction• At diagnostic output levels,
bubble can expand a few times original radius
• Most stabilizing coatings give way, leaving a free bubble to dissolve
• After insonification at normal imaging levels, most agents are destroyed
• This can be avoided with new sensitive imaging modes, or can be used to advantage
Animation adapted from Dr. K Ferrara, UC Davis. © Becher H and Burns PN, Handbook of Contrast
Echocardiography, Springer 2000, www.Sunnybrook.utoronto.ca/EchoHandbook/
5
Principles of Harmonic Imaging
Burns. In: Rumack et al, eds. Diagnostic Ultrasound. Vol 1. 2nd ed. St. Louis: Mosby; 1998:57.
3.0 MHz
3.0 MHz• Tissue and blood reflect at the fundamental frequency
• Microbubbles reflect at both the fundamental and the harmonic frequencies
3.0 MHz3.0 MHz + 6 MHz
Continuous vs Interval Time Delay Imaging
Continuous ImagingWith High MI
Interval Time Delay ImagingWith High MI
Continuous ImagingWith Low MI
TransmittedSequence (red have
inverted phase)
B-mode
PulseInversion
Contrast pulse
sequencing (CPS)
Method
Power Modulation
Algebra to
combine
N/A
Echo1 + Echo2
Echo1 + Echo2 + Echo3
Echo1- 2*Echo2
Summed Tissue Echo
Summed Bubble Echo
a
b
c
Caskey, C . “Leveraging the Power of Ultrasound for Therapeutic Design and Optimization” Journal of Controlled Release, 2011
Caskey, C J Ac S A, 2009 CE‐US steps
• CDS to identify region of interest
• Prepare contrast
• IV injection‐contrast + 10 cc saline
– Bolus
– Infusion for Destruction/reperfusion
• Record in cine‐loop for approx. 3 min
• Analyze enhancement parameters‐time to peak, peak enhancement, washout, AUC,microvessel perfusion
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Contrast Agent Preparation
A 3‐µL/kg dose of Definity (~0.3 mL) injected intravenously as a bolus, followed by bolus of 10 mL of 0.9% sodium chloride solution
Contrast Injection
Destruction/ReperfusionI=(1‐et) Hepatic Enhancement‐phases
• Arterial‐begins 10‐20s, ends 30‐45s
• Portal venous phase‐begins 10‐45s, ends 120s
• Late‐gr than 120 s, ends 5‐6 mins (300‐360s)
• Sustained=likely BENIGN
• Slow washout=likely MALIGNANT
• Patterns‐diffuse, nodular, peripheral
Liver Masses – Contrasted US
Hemangiomia
Focal Nodular Hyperplasia
Hepatocellular carcinoma
Metastases
Vascularity
Marginal pools
Profuse stellate pattern feeding artery
Profuse, often dysmorphic
Variable – Usually low
Arterial Phase
Peripheral nodular enhancement
Hypervascularwith scar
Hypervascular
Hypovascular
Portal Venous Phase
Central progression
Sustained enhancement
Rapid washout
Hypovascular
Focal Nodular Hyperplasia
Baseline
Arterial Phase
Portal Phase
Late Phase
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Baseline
Focal Nodular Hyperplasia
Arterial phase Portal phase
Focal Nodular Hyperplasia
Late phase
Focal Nodular Hyperplasia
Hemangioma
Portal Phase
Baseline
Arterial Phase
Late Phase
Hemangioma
Early phase
Hemangioma
Late phase
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Baseline
Arterial phase
Portal - late phase
MetastasisHCC
HCC
Early phase
HCC
Late phase
HCC
Early phase
HCC
Late phaseBaseline
Metastasis
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Metastasis
Early phase
Metastasis
Late phase
Easy to remember…
• WATCH OUT for WASH OUT!
• Rapid wash out is a sign of malignancy
• Whereas……
• Most benign lesions retain contrast in the late arterial, venous and portal venous phase
CE‐US of Liver Masses• PVP enhancement + in 92% benign, ‐ in 93% malignant; sustained PVP with arterial phase nodularity and centripetal progression in 92% of hemangioma; diffuse arterial phase enhancement gr liver in 95% of FNH (Wilson, S AJR, 186:1401, 2006)
• 92‐95% concordance with CT, MRI (Wilson, S Radiology 257: 24, 2010)
• Advantages‐Non‐toxic renal, non‐ionizing
CEUS of renal masses• Approximately 50% of people over 50 have a renal mass
• Vast majority are cysts
• Most of the solid renal masses are malignant
• Classified by Bosniak criteria‐
– B1=cyst, 0% chance of malignancy
– B2=complex cyst, 0‐5% chance of malignancy
– B2F=increased # of septations, thick wall, 5% chance of malignancy (F=followup)
– B3=thick septations, solid parts, 31‐100% chance of malignancy
– B4=solid, vascular mass, 100% chance of malignancy
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CE‐US for DDx of indeterminate renal masses
(Barr, R Radiology, 2014)
• Sensitivity=100%; specificity=95%
• PPV=95%; NPV= 100%
• 5 false +’s= 3 oncocytomas, 2 B3 cysts
• Based on 721 pts, 1018 indeterminate lesions
CE‐US in patients with compromised renal function
• Major advantage of CEUS over CT (potential nephrotoxicity of iodinated contrast)
• And MR (potential risk for nephrosclerosissyndrome)
• CEUS‐Low cost compared to CT, MR
• Readily repeatable
• The use of CEUS could decrease the needs for both CT and MRI (diminish radiation exposure)
CE‐US for ovarian Ca
• IOTA study (US O/G, 2009)‐72 adnexal masses
– AUC (0.84) better than grey scale (0.75), but less than pattern recognition (0.93)‐problem DDx of borderline vs Ca‐used parametric analysis, not time/intensity curves‐they found CEUS could not DDx b/w borderline tumor and malignancy
Fleischer, A et al (JUM,2008;AJR 2009)‐57 adnexal masses
sens.=93%; spec.=96%
max. enhancement=90% accuracy
washout/AUC=100% accuracy The time to peak (TTP) = time from injection to the peak intensity
CEUS Image Analysis
The area under the enhancement curve (AUC) calculated from the arrival of the contrast agent to the end of the wash‐out period
CEUS Image Analysis
Wash‐out (WO) = time between the peak intensity and the return to the baseline.
CEUS Image Analysis
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The area under the enhancement curve (AUC) calculated from the arrival of the contrast agent to the end of the wash‐out period
CEUS Image Analysis Paraovarian cyst
Paraovarian cystParaovarian cyst-3D TV-CDS
Cystadenoma Cystadenoma
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Peak Enhancement Time to peak
Parametric Imaging
Cystadenoma Adenocarcinoma (stage II)-r ov
Adenocarcinoma (stage II)-r ovStage II AdenoCa
Parametric map of a serous adenocarcinoma during peak enhancement (a), time to peak (b), wiAUC (c), woAUC (d), wiwoAUC (e), and woR (f). Areas of tumor neovascularity in red contrast sharply with the cystic portion of the tumor shown in blue.
Serous adenocarcinoma, Stage II
Peak Enhancement Time to peak
Parametric ImagingAdenocarcinoma (stage II)-l ov
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Adenocarcinoma (stage II)- l ov Bilateral Ov Ca (stage II)
Borderline mucinouscystadenocarcinoma
Borderline mucinouscystadenocarcinoma
Borderline mucinouscystadenocarcinoma
Borderline mucinouscystadenocarcinoma
T1 T2 fat-suppressed
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Borderline mucinouscystadenocarcinoma
Borderline mucinouscystadenocarcinoma
Borderline mucinouscystadenocarcinoma
Parametric Imaging
Time to peakPeak Enhancement
Fibroma
Emax = 0.41 dB T½ = 7.5 sec
AUC = 15.3 sec-1
Peak Enhancement Area under curve
Parametric Imaging
FibromaBenign (n = 38) n =
endometrioma 12serous cystadenofibroma 7hemorrhagic corpus luteum 5mucinous cystadenoma 5teratoma 3serous cystadenoma 3paratubal/paraovarian cyst 2fibroma 1
Borderline/Malignant (n = 12)serous adenocarcinoma 6endometroid carcinoma 2breast carcinoma metastatsis 2borderline mucinous cystadenocarcinoma 2
Histology of Ovarian Masses
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Enhancement parameters (n=57)
Benign Malignant0
50
100
150
200
1/2
Wa
sh-O
ut
Tim
e,
sec
Benign Malignant
500
1000
1500
2000
2500
Are
a U
nd
er
the
Cu
rve
Benign Malignant15
20
25
30
35
Tim
e to
Pea
k, s
ec
P=0.7
P<0.01
Benign Malignant
10
15
20
25
Pe
ak
En
ha
nce
me
nt,
dB
P<0.01
P<0.01
Diagnostic accuracy
70%
80%
90%
100%
2D VFI 3D VI 3D VFI Emax AUC T 1/2
Sensitivity
Specificity
Labelled MB in Animal Modelsof Ovarian Cancer
• Barua, A (Int J Gyn Ca; 24, 2014)‐labelled
– Alpha v beta 3 detected angiogenetic ov ca in hens
– Lutz, A (Cl Ca Res, 2014) CD276 targeted MB in mice
Procedural Applications
• s/p TACE‐assess completeness of ablation
• s/p RF ablation of renal masses‐assess for recurrence
• Detect abnormal sentinal nodes in breast ca
CE‐US:Tumor Response
• Lassau, N Radiology 2011‐Accurate assessment of HCC to antiangenic Rx‐predictive of tumor response, progression‐free interval, and overall survival
• Williams, R Radiology 2011‐can depict changes in vascular volume earlier than RECIST
• Pei, X unpublished, 2014‐Changes in cervical Ca with Rx
Volume = 19.1 cm3
Good responderpre-treatment
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Good responderDay 15 post treatment
Volume = 19.6 cm3
Good responder @ d0, d15
0
5
10
15
20
25
30
0 20 40 60 80 100 120 140 160 180
En
han
ce
me
nt
inte
nsi
ty,
dE
Time, sec
Pre-treatment
Day 15
0
5
10
15
20
25
30
0 1 2 3 4 5 6 7
En
han
cem
ent
inte
nsi
ty,
dE
Time, sec
Pre-treatmentDay 15
Bolus sequence Destruction-reperfusion sequence
Good responder
Pfizer Confidential – For Internal Use Only 889/2009
Patient #1 Good Responder
0
5
10
15
20
25
30
0 20 40 60 80 100 120 140 160 180
En
han
cem
en
t in
ten
sity
, d
E
Time, sec
Pre-treatment
Day 15
0
5
10
15
20
25
30
0 1 2 3 4 5 6 7
En
ha
nc
em
en
t in
ten
sit
y, d
E
Time, sec
Pre-treatmentDay 15
Bolus sequence Destruction-reperfusion sequence
Baseline Day 15
Volume, cm3 19.1 19.6
Contrast Enhancement, dB 25 17
Microvascular density, dB 22.7 13.7
Blood flow velocity, 1/sec 1.1 0.7
Good responderpre-treatment
Volume = 9.3 cm3
Good responderDay 15 post treatment
Volume = 9.5 cm3
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Good responder @ d0, d15
0
5
10
15
20
0 20 40 60 80 100 120 140 160 180
Enh
ance
men
t in
tens
ity,
dB
Time, sec
Pre-treatmentDay 15
0
5
10
15
20
25
30
0 2 4 6 8 10 12
Enh
ance
men
t in
tens
ity,
dB
Time, sec
Pre treatmentDay 15
Bolus sequence Destruction-reperfusion sequence
Good responder
Pfizer Confidential – For Internal Use Only 939/2009
Patient # 2 Good Responder
Baseline Day 15
Volume, cm3 9.3 9.5
Contrast Enhancement, dB 15 10
Microvascular density, dB 21.5 9.4
Blood flow velocity, 1/sec 0.52 0.34
Bolus sequence Destruction-reperfusion sequence
Poor responder @ d0, d15
0
5
10
15
20
0 20 40 60 80 100 120 140 160 180
Enh
ance
men
t in
tens
ity,
dB
Time, sec
Pre-treatmentDay 15
0
5
10
15
20
25
30
0 2 4 6 8 10 12
Enh
ance
men
t in
tens
ity,
dB
Time, sec
Pre treatmentDay 15
Bolus sequence Destruction-reperfusion sequence
Good responder
0
5
10
15
20
0 20 40 60 80 100 120 140 160 180
Enh
ance
men
t in
tens
ity,
dB
Time, sec
Pre-treatmentDay 15
0
5
10
15
20
25
30
0 2 4 6 8 10 12
Enh
ance
men
t in
tens
ity,
dB
Time, sec
Pre treatmentDay 15
Bolus sequence Destruction-reperfusion sequence
Good responder
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0
5
10
15
20
0 20 40 60 80 100 120 140 160 180
Enh
ance
men
t in
tens
ity,
dB
Time, sec
Pre-treatmentDay 15
0
5
10
15
20
25
30
0 2 4 6 8 10 12E
nhan
cem
ent
inte
nsity
, dB
Time, sec
Pre treatmentDay 15
Bolus sequence Destruction-reperfusion sequence
Good responder
0
5
10
15
20
0 20 40 60 80 100 120 140 160 180
Enh
ance
men
t in
tens
ity,
dB
Time, sec
Pre-treatmentDay 15
0
5
10
15
20
25
30
0 2 4 6 8 10 12
Enh
ance
men
t in
tens
ity,
dB
Time, sec
Pre treatmentDay 15
Bolus sequence Destruction-reperfusion sequence
Good responder
Pfizer Confidential – For Internal Use Only 999/2009
Poor responder @ d0, d15
Pfizer Confidential – For Internal Use Only 1009/2009
Patient # 3 Poor Responder
0
1
2
3
4
5
0 2 4 6 8 10 12Enh
ance
men
t in
ten
sity
, d
B
Time, sec
Pre treatmentDay 15
Baseline Day 15
Volume, cm3 4.2 4.0
Contrast Enhancement, dB 8.9 11.3
Microvascular density, dB 1.9 3.2
Blood flow velocity, 1/sec 0.04 0.2
Bolus sequence Destruction-reperfusion sequence
Changes with Rx (c/o A. Lyshchik)
Pfizer Confidential – For Internal Use Only 1029/2009
Barriers Affecting Rx
Kuszyk, B., AJR 177:747, 2001
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Averkiou, M. et al. UMB. 2010
Normalization of CEUS Poor responder (bolus)
Poor responder (perfusion) Fair Responder (bolus)
Fair Responder (bolus) Good Responder (perfusion)
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Excellent Responder (perfusion)
Lots of unanswered ?’s
• What defines good, fair, poor responders?
Lassau‐40% reduction in AUC
• How does this correlate with clinical response, survival?
• Multiple lesions?
• Areas of necrosis?
• Rx to decrease interstitial pressures, improve
hypoxic areas
Future Opportunities and Studies
• Perfusion quantification
• Angiogenesis/anti‐angiogenesis monitoring
• Targeted drug delivery
• Gene Therapy
Targeting LigandEncapsulatedDrug
Gas
Courtesy: Evan Unger – ImaRx
Markers for endothelial cell surface
• Inflammation (p‐selectin)
• Thrombosis (aIIb3 integrin)
• Angiogenesis (VEGF2)
Future Opportunities and Studies
• Perfusion quantification
• Angiogenesis/anti‐angiogenesis monitoring
• Targeted drug delivery
• Gene Therapy
Targeting LigandEncapsulatedDrug
Gas
Courtesy: Evan Unger – ImaRx
7/8/2015
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Targeted US with labelled MB(c/o C. Caskey, PhD)
Inject microbubbles with targeting ligand1 Minute post-injection: some free, some bound7 minutes post-injection: only bound remain
Leong-Poi, H. et al. Circulation 2003;107:455-460
Neovessels with retained targeted microbubbles
Anti‐angiogenesis therapy
VEGF
Endothelial cell
Capillary
Angiogenesis
VEGF release
VEGF binding
anti-VEGF Ab
VEGF receptor
Genentech Inc
VEGF receptors targeting
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Imaging strategy
VisualSonics Inc
Control UCA imaging
UCA signalB-mode ultrasound
VEGFR-2 targeted UCA imaging
UCA signalB-mode ultrasound
Molecular sonograms
High VEGFR2 expression Low VEGFR2 expression
Targeted ultrasound contrast agents Targeted UCA as a drug delivery vehicle
M. Tartis et al. Ultrasound in Medicine & Biology 2006
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Jets
C. F. Caskey, S. P. Qin, P. A. Dayton, and K. W. Ferrara, "Microbubble tunneling in gel phantoms," Journal of the Acoustical Society of America 125, EL183-EL189 (2009).
Treating brain metastasis with BBB MB Disruption + DOX
0.0E+00
2.0E+05
4.0E+05
1 2 3 4
Total B
LI Counts
Weeks after Injection
ROI 1=1.463e+05ROI 2=11467
Week 3 Week 4 c/o Caskey, C
Microbubble Rx for Alzheimers(C. Jones Ctr, U Queensland‐Science Translational Med)
Rx cleared plaque-restored memory in 75% of mice w/i several wks
Conclusions
• CE‐US excellent for DDx of hepatic, renal, and ovarian masses
• Potential means to assess tumor response
• Potential means to enhance specifically targeted therapies=“theranostics”
• Potential use to enhance sonothrombolysis,antibodies to β‐amyloid in Alzheimer's disease
Thanks to• Charles Caskey, PhD VIIS
• Chelsea Samson, VUMC; Katrina Kohornen, HUP; Ryan Moore, U Oregon
• Andrej Lyschik, MD, PhD Jefferson U Med Ctr
• Lars Thorielus, MD, Linkoping U, Sweden
• Lanteus (Definity)
• Bracco (Optison/Lumason)
• Pfizer Oncology
• John Bobbitt, VUMC