Imaging and Radiotherapy with
Synchrotron X-rays
Rob Lewis
Medical Imaging, University of Saskatchewan
Medical Imaging and Radiation Sciences, Monash
University
Applied Sorting Technologies, Melbourne

Other Modalities■ Ultrasound Cheap
 No radiation dose
 Cannot penetrate bone or air
 Spatial resolution degrades with depth Scan times are minutes■ MRI Fantastic soft tissue contrast
 Minimal radiation dose
 Expensive
 Scan times are many minutes
 Spatial resolution f(B)Diagnostic Imaging in Canada
X-ray & CT: 77%
Radiation : 83%

Radiography
Mammography
Computed Tomography
Cardiac Catherisation
Nuclear Medicine
MRIUltrasoundSource: Canadian MIS Database, Candian Institute for Health Information2007 with thanks to Paul BabynMRI■ Cost:♦ CT: From $700 to $2,200♦ MRI: From $1200 to $4000■ Time taken for complete scan
♦ CT: Usually completed within 5 minutes♦ MRI: Typically 30-40 minutes

MRI Accidents

MRI-CT Comparison
CTMRI

http://www.ct-scan-info.com/head-ct.html

MRI-CT Comparison
CTMRI
Haemorrhage

http://www.ct-scan-info.com/head-ct.html

Current Trends■ Preventative medicine is a good idea
■ Medical imaging procedures can detect disease ata stage when it can be treated effectively♦ Funding bodies (public and private) will fund imaging
procedures■ There is a trend towards more imaging,particularly screening♦ Mammography♦ Whole body CT scans■ Screening means go fast!

Flash spiral acquisition:
entire aortic dissection, right renal artery supported by true lumen, left by false lumen, very sharpdelinearartion of the right coronary artery

SOMATOM
Definition FlashFlash speed.
Lowest dose.

collimation: 128 x 0.6 mm
spatial resolution: 0.33 mm
scan time: 2.3 sscan length: 613 mm
rotation time: 0.28 s
100kV, 183 effective mAs
6.2 mSv

Courtesy of Centre Cardio-Thoracique de Monaco / Monaco

Dual Energy CT

Plaque in Carotid
9 s for 348 mm
Spatial Res. 0.33
Rotation 0.33 s
140/80 kV
60/230 mAs (eff.)

Fluence and Dose
30000

1000
Incident phts *E /pix/mA/s

Fluence exiting head/pix/mA/s
900

Fluence exiting head/pix/mA/s
25000

700
20000

Photons Transmitted

Fluence per pixel/s (KeV/pixel/mA

800

15000

600

500

400

10000
300

200

5000
10000050

Energy (keV)

100150050Energy (keV)

100150What is the Risk from Radiation?
■ A lifetime dose of 100mSv increases cancer risk by ~1%♦ 1000 chest x-rays♦ 100 mammograms♦ 50 head CT scans♦ 10 abdominal or pelvic CT scans■ Background Dose is ~ 2.4mSv/year■ On 31 May, Fukushima prefecture dose rate was 1.5µSv/h♦ 7.5 years to reach 100mSv■ It takes most radiation-induced cancers 10 to 20 years to develop inadults■ The average lifetime risk of developing cancer from all causes is42%■ From early 1980s to 2006, 7× increase in population dose frommedical procedures

Trends in Radiation Dose from Medical Imaging

rd3 Generation CT Scanner■ Multiple detectors■ Translation-rotation■ Large fan beam
■ Patient stationary for each
2-D slice acquisition;
about 0.1 seconds perslice■ kV = 120, mA = 500■ Image then reconstructedin about 0.1 seconds
Detector

FBP in PracticeVolume CT image
Uses 3rd or 4th generation scanner.
Continuous patient motion.

Often with multi-slice detector arrays.
Affords “true” 3-D volume images.

Beam Harding Artefacts

Image of uniform phantom

Cone Beam Artefacts
Inner detector row image

Outer detector row image

Exploit What Synchrotrons Are Good At■ Synchrotron is a great tool for performing
medical physics studies♦ Synchrotron beams can be monochromated●No beam hardening♦ Synchrotron beams are almost parallel●No cone beam artefacts●Scatter removal with no dose penalty■ Allows studies of better x-ray imaging anddeveloping new methodologies

Synchrotron Radiography
Scanning motion

Scatteredradiation
Detector

Synchrotron
MonochromatorMouse CTDavid Parsons and Karen Siu

Mouse Cochlea

David Parsons and Karen Siu

Mouse Fly ThroughKaye Morgan, Karen Siu, David Parsons

Slot Scanning Image Scores
1.0

Dose decreases with energy!
150.8

Image score

17.5
200.6

171921
23
25

0.4

0.2

0.0
0.1

Conventional

Fit of the form Score  A  B

2345 6 7 8 1.0

234

5 6 7 8 10.0

Dose2

Mean Glandular Dose (mGy)

RA Lewis et al SPIE Vol. 4682 (2002) 286-297

RefractionAnalyser Based Imaging
Sometimes called Diffraction Enhanced Imaging

Crystal Rocking CurveLow Angle
SideHigh Angle
Side1.00

DI/I~0.1

0.80

Relative Intensity I/Io

dz~0.4mrad

0.60

RLRH

0.40

0.20

0.00
-10

-50Analyzer Angle (mradians)

510

Rocking Curve

Refractive index for X-rays is less than 1 by about 1 part in a million

ABI How it works

Relative Intensity I/Io

1.00

1.6
1.4
1.2
1

0.80

0.60

0.40

0.20

0.8
0.6

0.00
-10

Minus
0.4

0510

Analyzer Angle (mradians)

Plus

0.2

Energy = 25keV

00-5100

200

300

400500ABI Mathematics■ IL & IH = Intensities onlow and high angle sides Givenof rocking curve
IL IR   RL  Grad L D Z
■ GradL & GradH =Gradients of low and high IH IR RH  GradH D Z
angle sides of rocking
 Grad H IL  Grad L IH curve■ IR is intensity■ Δθz= refraction angle

 Grad H RL  Grad L RH Find  IR D Z  IH RL  IL RH
 Grad H IL  Grad L IH TORMam Conventional

Simulatedbreast tissue

Spectrum = Mo:Mo 28kVp

TORMAM Peak

Energy = 20keV

TORMAM Refraction

Energy = 20keV

Phase Contrast■ Contact:

d2
NF 
z

NF >> 1

Geometric approximation

NF >> 1

Geometric approximation♦ The intensity distribution is a pure absorption image.

■ Near field:♦ Contrast is given by sharp changes in the refractive index, i. e. at interfaces.

■ Intermediate field: NF ~ 1Fresnel approximation■ Far field:

Far: Fraunhöfer approximation♦ The image loses more and more resemblance with the object.

NF << 1♦ The image is the Fourier transform of the object transmission function
Timm Weitkamp ESRF ID22

Propagation Based Imaging
127cm
107cm
147cm
87cm
67cm
47cm
27cm
17cm

Phase Contrast CT

Lungs of newborn rabbit
Propagation distance = 1m
Energy = 24 keV

Beltran, M.A. et al., Phys Med Biol,56, 7353-7369, 2011.

Phase Contrast CT■ SNR
increased
10x, enablinghigh quality
visualization

Beltran, M.A. et al., Phys Med Biol, 56, 7353-7369, 2011.

Rat Brain in agarose gel

Brain undetectable in projection image (a), and faintly visible with 5m propagation distance(b) in CT reconstruction. Energy = 24 keV.

Beltran, M.A. et al., Phys Med Biol, 56, 7353-7369, 2011.

Rat Brain in agarose gel

Phase retrieval renders structures of the brain highly visible against the noise.
Improvement in SNR of 200x!
Beltran, M.A. et al., Phys Med Biol, 56, 7353-7369, 2011.

Grating Interferometry

Timm Weitkamp et al Vol. 12, No. 16 / OPTICS EXPRESS 6296

Grating Imaging: Mouse Embryo

N. Yagi et al, SPring-8

Exploit What Synchrotrons Are Good At■ Synchrotrons allow fantastic spatialresolution■ But what about the dose?
22e mL SNRoutmDoseskin E ( )242
DQE ( f ) m sizeobjContrastmPhase Contrast Dose Advantage
1.00.9Image Score

0.8

Synchrotron ABphase contrast

0.7

Synchrotron
Slot scanning

60%

0.6

50×

Conventional

0.50.44 5 6 7 8 0.1

2

3

4 5 6 7 8 1.02

3

4 5 6 7 10.0

2

Mean Glandular Dose (mGy)

RA Lewis et al SPIE Vol. 4682 (2002) 286-297

Complex Refractive Index■ Coherence properties enable phase contrast■ Contrast arising from phase effects does not require dose to bedeposited in the object
10-6

Delta and beta10-7

δ Phaseβ Absorption

Refractive index
 = 1- δ -i

10-8

Where  = absorption
δ = phase shift

10-910-10Nb.
δ ~ 1000 
δ ~ E-2
 ~ E-4

10-11
10-12
10-13
15

Breast Tissue
20

2530

40

50

60

70 80

Energy (keV)

100150CT and Radiography Problems■

X-ray Dose♦■

Phase Contrast Helps. Synchrotron easy. Gratings?

Scatter♦■

Greatly reduced by slot scanning. Both conventional andsynchrotron can use this.

Beam Hardening♦■

Eliminated by monochromatic radiation. Synchrotron onlyCone Beam Artefacts♦Eliminated by parallel beam. Synchrotron only.

Phase Contrast in the Clinic
Konica Minolta REGIUS PureView

Phase Contrast

ContactPhase Contrast in the Clinic
Konica Minolta Research & Development

http://www.konicaminolta.com/about/research/special_healthcare/talbotlau.html

Subtraction Radiography
HighSynchrotron

2 detectors

Specialised
monochromator

Scanning
motionEnergy vs Iodine

33.17 keV

Energy vs Bone
Energy vs Soft tissue
Energy vs Beams

Absorption

Low

E2

E1

32.8

33.0

33.2

33.4

33.6

Energy (keV)

W. Thomlinson et al ESRF

Patient 1 - weight: 70 kg - iodine: 42ml

Synchrotron IV injection
n.b. 2 – LAO 40

Conventional angiography
Intra arterial injection

Synchrotron Clinical Studies■ Coronary Angiography♦ Several hundred patients in Hamburg and at ESRF
♦ Synchrotron sensitivity allowed venous injection
rather than arterial as is required in hospital♦ Not all coronary arteries always visualised well

■ Mammography♦ Clinical program ongoing at Elettra♦ Preliminary results look encouraging

Synchrotron Medical Imaging■ Synchrotron Medical Imaging
Fantastic spatial resolution
Reasonable scan times
 Uses ionising radiation
 Very limited access Extremely expensive■ Synchrotrons are not currently suitable for“routine” medical procedures

Case Study: Birth
One of the greatest Physiological challenges■ During fetal life the future airways of the lungs are liquid-filled■ At birth lungs must rapidly transform from being liquid to air filled■ How this happens is poorly understood but the process♦ Develops late in pregnancy♦ Is initiated by labour■ Preterm and caesarean section infants often develop problems♦ Incidence is increasing♦ Require weeks of assisted ventilation (>$2,000/day)■ We know that ventilating infants causes injury♦ ~30% develop chronic lung disease♦ Becomes apparent after 15 years

SPring-8 - Super Photon ring-8GeVSACLA SPring-8 Angstrom Compact Free Electron LaserWhy a Long Beamline?

Rabbit Lung

Contact

3m

MRI State of the Art

Bronchoconstriction induced by metacholine
Bruker BioSpec® 47/40

Rabbit Pup Lung Imaging - Delivery

Artificial Ventilation

Post Mortem Artificial Ventilation

RA Lewis et al Phys. Med. Biol. 50, 5031
S. Hooper et al FASEB 21, 3330 (2007)

Phase Retrieval: Single Image■ Approximate ‘contact’ intensity from Beer’s Law
I (r , z  0)  I O exp( mT (r ))■ Approximate ‘contact’ phase by (r , z  0)  2d T (r )■ Use Transport-of-Intensity Equation (TIE)2    ( I (r , z )  (r , z ))  I (r , z ) z■ Solve for object’s projected thickness using Fourier
Derivative Theorem  F M 2 I ( Mr , z  R ) / I  2O T (r )   ln  F 1 m2mMR2d k   m  
1Paganin, D et al., Journal of Microscopy, Vol. 206 Pt 1 April 2002, pp. 33-40

Phase to Projected Thickness
Phase image R2=4.26m, E=33keV

Projected thickness

Marcus Kitchen, Monash

Lung aeration: Airway liquid clearance
Sodium channels crate
osmotic gradient that draws
liquid out of airways

Breathing Aerates Lungs
0.5

25

Hutch (cmH2O)

Δ lung volume (mL/kg)

0.0

20b15-0.5

*

*a10*

*
*

5 -1.0

*

0-1.5

5(a)

77245

107725077255

152077260

77265
77270
Time(secs)

253077275

3577280

(b)

77285

77290

Lung aeration: Airway liquid clearance
Inspiration forces liquid out of airways-P-P-P

Medical Relevance■ Respiratory Ventilation■ Positive End Expiratory
Pressure (PEEP) is used insome hospitals as it isthought to help
■ It used to be excluded frominternational resuscitation
guidelines for ventilating
infants due to lack ofevidenceRabbit Pup: No PEEPRA Lewis et al Phys. Med. Biol. 50, 5031
S. Hooper et al FASEB 21, 3330 (2007)

Rabbit Pup: With PEEPTe Pas et al Pediatric Research 65(5), 537-541 2009
S. Hooper et al FASEB 21, 3330 (2007)

Effect of PEEP in Ventilated Preterm Rabbits

Tidal volumemL/kg

30

5 cmH2O PEEP0Tidal volumemL/kg

3000 cmH2O PEEP

20sec First Inspiration

Long First Inspiration

End-expiratory lung gas volume(FRC)

20 secs

20 sec long inspiration
5 cmH2O PEEP

Measuring Lung Motion■ Particle Image Velocimetry detects speed & direction ofparticle (lung) motionParticle Image Velocimetry

A. Fouras, et al

Disease Detection
Plots of regional compliance, calculated from motion maps in mouse lungs

Healthy Lung, showing uniform
compliance

Fibrotic lung, showing regional
differentiation of compliance
A. Fouras, S Dubsky et al

Moving to 4 Dimensions■ Use controlled
repeated breaths androtate animal■ Select same point inbreath for eachrotation angle ofanimal■ Reconstruct CT
image for each pointin the breathWhole Breath Lung Morphology

S Dubsky, A Fouras et al

4D PIVS Dubsky, A Fouras et al

4D Flow

S Dubsky, A Fouras et alAsthma – detecting bronchoconstriction

ControlMethacholine
S Dubsky, A Fouras et alSimultaneous Phase Imaging and AngiographyVideos used to train Doctors

Major Issues: Technical■ Static beam greatly limits 4D imaging (x, y, z, t)Stereo imaging at SPring-8
SampleWide X-ray beam 200m from source

Detector

Beam stop
Lead screw
Si(111) crystal

Original reflected beam

(harmonic drive motor system)■ Distorted reflected beam a result of…

5mm♦ Vertical energy dispersion of monochromator♦ Vertical and horizontal spread of X-ray beam.
♦ Deformation of first crystal in monochromator byheat load

After bending crystal■ Corrected by♦ Bending silicon crystal by pushing one end with
5mmscrew while keeping the other end fixed (see figure)Yagi & Hoshino Spring-8

X-ray Stereo Imaging■ Live Frog (Ranajaponica)■ CCD Frame rate:20Hz■ X-ray energy: 15keV■ Sequential
imageswere acquired whilst
vertically translating
sample■ The images werecombined digitally
X-ray stereo image

5mmAnaglyph

Yagi & Hoshino Spring-8

Time-Resolved 3D Imaging
The three-dimensional arrangement offemur and blood vessels was estimatedfrom X-ray stereo angiography.
The 3D quality is far from X-ray CT but
sub-second time resolution possible

Radiotherapy■ The tumour can always be destroyed……
■ …If we give it enough dose
■ The question is…..
■ ...Can we keep the patient alive and healthy whilst
we do it?
■ The radiation dose we can give to the tumour islimited by…..
■ ..How much dose healthy tissue can tolerate
whilst we try to zap the tumour

Radiotherapy■ The radiation dose that canbe delivered to the tumour
is limited by…..
■ ..The tolerance of thesurrounding healthy tissue■ Conventional Therapy♦♦

Uses a LINAC (high energy Xrays several MeV)
Uniformly irradiates tumour

Deuteron Beam: Mouse Visual Cortex

Zeman et al, Radiat Res 15 (1961) 496

Peak to Valley Ratios
1mm15000

PVDR ~ 50

10000

5000

00200

400

600

Position (μm)

800

10001200

Dose Depth Curves

1 MeV

Synchrotron Spectrum (~100keV)

A Bravin

Loss of Pattern with DepthPiglets
Stained horizontal tissue section of piglet
cerebellum 15 months after irradiation.
25µm wide beams; spacing 210µm.
Skin entrance dose 300 Gy.

Laissue J A et al 2001 Proc. SPIE 4508 65–73

MRT on Mice
■ Radiobiology of MRT is not well understood■ An understanding of the radiobiology is crucial
for the optimisation of MRT and for any clinicalimplementation■ Understanding MRT will also informconventional radiotherapy■ Mice are by far the best characterised mammal♦ Many GM mouse models already available♦ Many assays have been developedExfoliation
200 Gy400 Gy800 GySurvival Fractions EMT 6.5
Weakly metastatic

1120Gy560Gy

Results - Immunohistochemistry■ H&E and CD45 Leukocyte Common Antigen (LCA) Staining ofMRT-irradiated Mouse skin 5.5 days PI (x 100)
■ Intact hair follicles & sebaceous glands

Using Radiochromic Film to Locate Microbeams

γH2AX/BrdU IHC post 560 Gy
MRT treatedControl8448hours
24
hoursafter
afterirradiation
irradiation
Jeff Crosbie, Peter Rogers, Robyn Anderson, Rob Lewis

Splitting Hairs!

Conclusions■ X-rays are here for a while■ Synchrotrons have an important role indeveloping new x-ray methods in medicine■ In order to translate the research into theclinic, some human studies are necessary■ Much can be achieved with animal studies

The Team■■■■■■■■■■
■
■
■■
■
■

Stuart Hooper
Megan Wallace
Marcus Kitchen
Melissa Siew
Beth Allison
Andreas Fouras
Karen Siu
Arjan te Pas
Chris Hall
Naoto Yagi
Kentaro Uesugi
Kaye Morgan
Sally Irvine
David Parsons
Peter Rogers
Jeff Crosbie