Imaging and Radiotherapy with
Synchrotron X-rays
Rob Lewis
Medical Imaging, University of Saskatchewan
Medical Imaging and Radiation Sciences, Monash
University
Scott Automation and Robotics

Other Modalities■ Ultrasound Cheap
 No radiation dose
 Cannot penetrate bone or air
 Spatial resolution degrades withdepth 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 Australia
MRI
2.8%

Ultrasound
34.4%

Diagnostic Radiology
48.9%

Nuclear Medicine
2.5%
CT11.4%Uses Radiation: 62.8%
X-ray & CT:60.3%

MRI-CT Comparison
CTMRI■ MRI not always best contrast
http://www.ct-scan-info.com/head-ct.html

MRI■ Fabulous Images but■ Cost:♦ CT: From $700 to $2,200♦ MRI: From $1200 to $4000■ Time taken for scan:♦ CT: Usually completed within 5 minutes♦ MRI: Typically 30-40 minutes■ Narrow tunnel and noisy■ Metal implants and pacemakers contraindicatedMRI Accidents

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.)Imaging Using Ionising Radiation■ Will be here for a long time because it;■ Can perform very fast scans■ Can tolerate implants■ Is relatively cheap■ So what is the risk from all this radiation?

Fluence and Dose: Head
30000
Incident phts *E /pix/mA/s
Fluence exiting head/pix/mA/s

Fluence per pixel/s (keV/pixel/mA

25000

All the red area
stops in the headi.e. Dose!

20000

15000

10000

5000

0050

100
Energy (keV)150

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■ 11 March 2011, Tsunami hits Fukushima. Radiation ~210mSv/yr■ On 31 May, 2011 Fukushima prefecture dose rate was 13mSv/yr♦ 7.5 years to reach 100mSv■ It takes most radiation-induced cancers 10 to 20 years to develop in adults■ The average lifetime risk of developing cancer from all causes is 42%■ From early 1980s to 2006, 7× increase in population dose from medicalprocedures

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 secondsDetector

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

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

Back Projection in PracticeBeam Hardening
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

10000

600
500
400
300
200

5000
100
00050 Energy (keV) 100

150050 Energy (keV) 100

150

Beam Harding Artefacts

uniform

Cone Beam Artefacts
Inner detector row image

Outer detector row image

Exploit What Synchrotrons Are Good At■ So there is still work to do optimising imaging with ionisingradiation♦ Eliminating artefacts♦ Reducing Dose

■ 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♦ Synchrotron beams can be tuned● Select optimal energy■ We can do studies of better x-ray imaging and develop newmethodologies

Subtraction RadiographyHighSynchrotron

2 detectors

Specialised
monochromator

Scanningmotion

Energy 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Synchrotron Radiography
Scanning motion
Scatteredradiation
Detector

Synchrotron
MonochromatorSlot Scanning Image Scores
1.0

Dose decreases with energy!
150.8

Image score

17.5
20

0.6

1719

21
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 Curve
Low Angle
SideHigh Angle
Side

1.00

DI/I~0.1

0.80

Relative Intensity I/Io

dz~0.4mrad

0.60

RL

RH

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
0.8
0.6

0.40

0.20

-50510Analyzer Angle (mradians)

Plus

0.2

Energy = 25keV

000.600.00-10Minus
0.4

0.80

100

200300400500

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

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

Simulatedbreast tissue

Spectrum = Mo:Mo 28kVp

TORMAM Peak

Energy = 20keV

TORMAM Refraction

Energy = 20keV

Advantages of synchrotron micro-CT
12 hrs

0.5 hrs

VIFM-427

SkyScan 1072 (Desktop) 7 μm

Spring8 (Synchrotron) 12 μm
David Cooper, UofS; David Thomas, Melbourne

Mouse CT

David Parsons and Karen Siu

Mouse Cochlea

David Parsons and Karen Siu

Mouse Fly ThroughKaye Morgan, Karen Siu, David Parsons

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

Phase Contrast : Mouse Embryo
Absorption CT

Phase CT

Hoshino M et al Biology Open 1, 269–274

Phase Contrast : Mouse Embryo

6 days6 & 9 days: 4.9µm/pixel
10-15 days: 23.5µm/pixel

Hoshino M et al Biology Open 1, 269–274

Phase Contrast: Mouse Embryo

Hoshino M et al Biology Open 1, 269–274

Synchrotron Brain Imaging
PBI

PBI phase retrieved

3600 projections
3m propagation distance
1s/image
K Uesugi & M Hoshino JASRI Spring-8

Phase Contrast: Brain

N. Yagi, SPring-8

Radiation Dose Resolution Trade-off■ Synchrotrons allow fantastic spatial
resolution but……..
22e mL SNRoutm
Doseskin E ( )242
DQE( f )m sizeobjContrastmPhase Contrast Dose Advantage
1.0
0.9

Image Score

0.8

Synchrotron AB
phase contrast

0.7

Synchrotron
Slot scanning

60%

0.6

50×

Conventional

0.5
0.4
4 5 6 7 8 0.1

2

34 5 6 7 8 1.0234 5 6 7 10.02

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 beta

10-7

δ Phaseβ Absorption

Refractive index
 = 1- δ -i

10-8

Where  = absorption
δ = phase shift

10-9
10-10Nb.
δ ~ 1000 
δ ~ E-2
 ~ E-4

10-11
10-12

Breast Tissue
10-13
15

20

25

30

40

50

60

70 80

Energy (keV)

100150Clinical Mammography at ELETTRA (Trieste, Italy)
Aim of the study: to prospectively evaluate on a limited number of selected patients thediagnostic contribution of SR Phase Contrast mammography in patients with doubtful orsuspicious breast lesions identified at the conventional mammography in the Hospital
Examination room for SR mammography

Phase 1: March 2006 - December 2009 (71 patients)
screen-film system, first protocol for recruitment
Phase 2: in 2012- Image Plate detector, Fuji FCR Capsula XL II

Phase 3: from 2013- digital detector, new recruitment protocol

THE COLLABORATION
Department of Physics - University of Trieste and INFN
F. Arfelli, E. Castelli, R. Longo, L.Rigon
ELETTRA - Sincrotrone Trieste SCpA
A.Abrami, K.Casarin, V.Chenda, D.Dreossi, R.H. Menk, E.Quai, G. Tromba,
A.Vascotto
Department of Radiology - University and Hospital, Trieste
P. Bregant, M.A. Cova, D. Sanabor, E. Quaia, M. Tonutti, F. Zanconati

Clinical Mammography at ELETTRA (Trieste, Italy)
Conventional mammography
MGD 1.2 mGy

Synchrotron radiation mammography
MGD 0.6 mGy

RESULTS
Evaluation of lesions and structure visibility:
comparing mammography with SR andconventional (hospital) mammography
MSR allows a better visualization, both for the lesions
and for the glandular tissue
Hospital mammography identified:
21/40 patients with final benign diagnosis
23/29 pt with final malignant diagnosis

MSR identified:
38/40 patient with final benign diagnosis

25/29 patient with final malignancy diagnosis

E. Castelli, M.Tonutti, F.Arfelli, R.Longo, E.Quaia, L.Rigon, D.Sanabor, F. Zanconati, D.Dreossi, A. Abrami, E.Quai, P.Bregant,
K.Cesarin, V.Chenda, R.H. Menk, T.Rokvic, A.Vascotto, G.Tromba, MA Cova, Mammography with Synchrotron Radiation: First
Clinical Experience with Phase-Detection Technique, Radiology, 259 (3), 684-694(2011)

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.

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

Phase Contrast in the Clinic
Konica Minolta REGIUS PureView

Phase Contrast

Contact

Development of standing type machinesecondfinger

firstfinger

Measurement：32 sec
X-ray exposure：19 sec
Skin dose：5 mGy

Junji Tanaka, Masabumi Nagashima, Kazuhiro Kido, Yoshihide
Hoshino, Junko Kiyohara, Chiho Makifuchi, Satoshi Nishino,
Sumiya Nagatsuka, and Atsushi Momose, “Cadaveric and invivo human joint imaging based on differential phase contrastby X-ray Talbot-Lau interferometry”, Z. Med. Physk, submitted.

Birth: An amazing event■ In utero lungs are full of liquid■ At birth lungs fill with air■ The transition is poorlyunderstood■ Preterm and caesarean section
infants can have major
problems and often need to beventilated■ We don’t know how to best
ventilate and sometimes
ventilation injures the lung

SPring-8 - Super Photon ring-8GeV

Why a Long Beamline?

Rabbit Lung

Contact3m

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 by2 (r , z  0)   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m
MR2d 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 create anosmotic gradient that draws
liquid out of airways

Breathing Aerates Lungs
0.525Hutch (cmH2O)

Δ lung volume (mL/kg)

0.0

20b

15-0.5

*

*a10*

*
*

5 -1.0

*

0-1.5

5(a)

77245

107725077255

152077260

77265
77270
Time(secs)

2530
77275

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) used to be
excluded from international
resuscitation guidelines forventilating infants due tolack of evidence■ It is now recommended as adirect consequence of thiswork

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 volume
mL/kg

305 cmH2O PEEP

0Tidal volume
mL/kg

3000 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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

Simultaneous Phase Imaging and Angiography

Major Problem: Technical■ Static beam greatly limits 4D imaging (x, y, z, t)Setup for X-ray triscopic imaging

Detectors for refraction
contrast imagingDetector forabsorption imaging

Si crystal 1

SampleX-ray
beam
Si crystal 2
Schematic drawing of X-ray triscopic imaging system (top view)

Beam stopper + attenuator

Si crystal 2
SampleX-rayDetector

100mm
Beam2

Beam1

Beam3

Si crystal 1

Beam stopper

Raw three-beam image without sample
Picture taken from above of crystals and a sample
Masato Hoshino et al JSR Volume: 18 Pages: 569-574

X-ray triscopic images of mouse chest

Absorption contrast image measured by single detector

Refraction contrast image measured by three detectors
Masato Hoshino et al JSR Volume: 18 Pages: 569-574

Synchrotron Pros ‘n Cons
■ Pros♦ Tunable Wavelength Contrast specificity
 Target elements♦ High Intensity
 Short exposure times and hence movies
 MRT♦ Scatter Reduction
 Reduced dose, improved contrast♦ Phase Contrast
 Reduced dose, improved contrast■ Cons♦ Fixed beam

● Rapid CT very difficult♦ Limited availability♦ High Price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

00200400600

Position (μm)

80010001200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 metastatic1120Gy
560Gy

Results - Immunohistochemistry■ H&E and CD45 Leukocyte Common Antigen (LCA) Staining of
MRT-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 treatedControl

84 hours
2448
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 IrvineDavid Parsons
Peter RogersJeff Crosbie