Imaging and Radiotherapy with
Synchrotron X-rays
Rob Lewis

Synchrotrons and Medicine■ Ionising Radiation is bad...why not use MRIor Ultrasound?
■ Are x-rays still relevant in clinicalmedicine?
■ Is there a role for Synchrotrons in Medical
Imaging or Radiotherapy?

Other Modalities■ Ultrasound9 Cheap
9 Can be 3D8888Cannot penetrate bone or air
Spatial resolution degrades with depth
Scan times are many minutes
Image quality is extremely dependent upon operator■ MRI
9 Fantastic soft tissue contrast
9 True 3D imaging
8888

Scan times are many minutes
Expensive
Spatial resolution a function of field strength
Not completely safe

MRI Accidents

Synchrotrons and Medicine■ Ionising Radiation is bad...why not use MRIor Ultrasound?
■ Are x-rays still relevant in clinicalmedicine?
■ Is there a role for Synchrotrons in Medical
Imaging or Radiotherapy?

USA Statistics■ 67 million CT scans in the USA in 2007
■ Less than 10 million MRIs

NCRP, March 2009

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 imagingprocedures■ 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.)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■ It takes most radiation-induced cancers 10 to 20 years todevelop in adults■ The average lifetime risk of developing cancer is 42%■ From early 1980s to 2006, 7× increase in population dosefrom medical procedures

Trends in Radiation Dose from Medical Imaging

Why not just reduce the dose?
6E5600Counts/pixel/s

5E55004E54003E53002E52001E5100

0E00Position

Counts/pixel/s

46.6mA
0.0464mA

Effect of Dose Reduction
Clinical Dose

1/1000 Clinical DoseFluence and Dose
1000

30000
Incident phts *E /pix/mA/s

Fluence exiting head/pix/mA/s
900

Fluence exiting head/pix/mA/s
25000

700
20000
Photons TransmittedFluence per pixel/s (KeV/pixel/mA

800

15000

600
500
400

10000
300
200
5000
10000050

Energy (keV)

100

150

050

Energy (keV)

100150Conventional Radiography

X-ray Spectra
Flux (photons/ 1keV(bw)/mA/mm2(@1m)/sec

70000
100kVp 0mmAl
60000
50000

Soft X-rays

40000

Hard X-rays

30000
20000
10000
00204060
Energy (keV)

80100120Albert Einstein

Nobel prize inphysics 1921

Photoelectric EffectGermany and Switzerland
Kaiser-Wilhelm-Institut(now Max-Planck-Institut)
für Physik
Berlin-Dahlem, Germany
1879 - 1955

"for his services toTheoretical Physics,
and especially for his
discovery of the lawof the photoelectriceffect"

Photoelectrone++ +++ +-X-ray photon λ1-K fluoresence
X-ray E~EkArthur Holly Compton

Nobel prize inphysics 1927
"for his discovery ofthe effect namedafter him"

Compton Effect

University of Chicago
Chicago, IL, USA
1892 - 1962

X-ray photon
λ2 > λ1
X-rayphoton λ1++ +++ +φ--h(1− cosϕ )Δλ =m0ce-

Water Attenuation Coefficients■ Photo electric falls rapidlywith increasing energy■ Compton scatteringroughly constant■ Coherent scattering falls
with increasing energy
but less rapidly thanphotoelectric (importantsee later)

Radiographic Imaging
Detector

Patient
Transmitted X-rays

X-ray tube

Absorbed X-rays

Scattered X-rays

X-rays and Contrast■ Difference in attenuation
coefficients generates
contrast■ μ1 < μ2■ Scatter reduces contrast

TransmittedIntensity

μ1μ2

Scatter in Medical Imaging

Examination

EnergyChest

120 kVp

Field Size (cm) Antiscattermechanism
30 x 30
6.7 cm air gap

ScatterTotal/
Primary
2.3

ScatterCoherent /ScatterTotal
0.12

1.2

0.112.70.26

Grid0.34

0.075

Grid0.60.24

20 cm air gap
Abdomen

Mammography

80 kVp30 kVp (Mo)17 x 1712 cm diamUse of Grid to Remove Scatter
Patient

X-ray tube

GridDetector

Effect of Antiscatter Grid.
Fluoroscopic images of an anthropomorphic abdominal phantom

With Grid

Without Grid

JP Taubel, B A Schueler, TJ. Vrieze, JE. Gray Radiographics. 2001;21:507-518

rd
3 Generation CT Scanner■ Multiple detectors■ Translation-rotation■ Large fan beam
■ Patient stationary foreach 2-D slice
acquisition; about 1-2
seconds per slice■ kV = 120, mA = 500■ Image then reconstructedin about 1-2 secondsDetector

Projection and the Radon transform
Equation of this line l is:

S = x sin(θ ) − y cos(θ )yf ( x, y )xθg (θ , S ) = ∫ f ( x, y )dll0g (θ , S )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

Beam Harding Artefacts

Image of uniform phantom

Cone Beam Artefacts
Inner detector row image

Outer detector row image

Synchrotrons and Medicine■ Ionising Radiation is bad...why not use MRIor Ultrasound?
■ Are x-rays still relevant in clinicalmedicine?
■ Is there a role for Synchrotrons in Medical
Imaging or Radiotherapy?

Exploit What Synchrotrons Are Good At■ Synchrotron is a great tool for performing
medical physics studies♦ Synchrotron beams can be monochromated♦ Allows studies of better x-ray imaging■ ...and developing new methodologies

Synchrotron Radiography
Scanning motion

Scatteredradiation
DetectorSynchrotron
MonochromatorSR Radiography
Detector
Front slits

Rear slits

SampleSynchrotron

Slot Scanning Image Scores
1.0Dose 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

2345 6 7 8 10.0

Dose2

Mean Glandular Dose (mGy)

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

Exploit What Synchrotrons Are Good At■ Synchrotrons allow fantastic spatialresolution
22e μL SNRoutμDoseskin =Eγ ( )242
ρ
DQE ( f ) μ sizeobj Contrast μMouse CT

David Parsons and Karen Siu

Mouse Cochlea

David Parsons and Karen Siu

Mouse Fly ThroughKaye MorganMouse CTDavid Parsons and Karen Siu

RefractionAnalyser Based Imaging
Sometimes called Diffraction Enhanced Imaging

Crystal Rocking Curve
Low Angle
SideHigh Angle
Side1.00

ΔΙ/Ι~0.1

0.80

Relative Intensity I/Io

δz~0.4μrad

0.60

RLRH

0.40

0.20

0.00
-10

-50Analyzer Angle (μradians)

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
10.8
0.6

0.40

0.20

-50510Analyzer Angle (μradians)

Plus

0.2

Energy = 25keV

000.60

0.00
-10

Minus
0.4

0.80

100200300

400500ABI Mathematics■ IL & IH = Intensities onlow and high angle sides Givenof rocking curve
IL IR⋅ ( RL + GradL⋅ Δθ Z)■ GradL & GradH =Gradients of low and high IH IR⋅ (RH + GradH⋅ Δθ Z)
angle sides of rocking⎛⎜ GradH⋅ IL − GradL⋅ IH ⎟⎞curve■ IR is intensity■ Δθz= refraction angle⎜ GradH⋅ RL − GradL⋅ RH ⎟Find( IR , Δθ 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

Phase Contrast Dose Advantage
1.0
0.9

Image Score

0.8

Synchrotron AB
phase contrast

0.7

Synchrotron
Slot scanning

60%

0.6

50×0.5

Conventional

0.4
4 5 6 7 8 0.1

23 4 5 6 7 8 1.0234 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 beta

10-7

δ Phaseβ Absorption

Refractive index
η = 1- δ -iβ

10-8Where β = absorption
δ = phase shift

10-9
10-10Nb.
δ ~ 1000 βδ ~ E-2
β ~ E-4

10-11
10-12
10-13
15

Breast Tissue2025304050

6070 80

Energy (keV)

100150Developing New Methods■ Have the idea
■ Test the physics experimentally with phantoms■ Test the effectiveness with animals■ Test on humans■ Transfer to clinic■ Beamline must be capable of imaging animals andhumans■ Beamline should mimic as far as possible ‘conventional’
best practise

Phase Contrast at Monash Medical Centre
X-ray tube
Collimator
Moveable Trays

Control Desk

Ivan Williams et al European Journal of Radiology 68S (2008) S73–S77

Phase Contrast in the Clinic

Conventional Image

Phase Contrast (Monash Geometry)

Ivan Williams et al European Journal of Radiology 68S (2008) S73–S77

Results

Box-and-whiskers plot of the raw data averaged for each scorer for each of the three scoring comparisons, a positive score indicates that the second of
the two geometries involved in the comparison was scored to advantage. The horizontal line within each box denotes median, box covers 25thpercentile, whiskers denote the greater of 3.5 times 25th percentile and outer most point.
The two left-most show that two PCI geometries scored better than the Contact. The bar on the right shows that the Konica geometry was scored better
than the Optimised. The single data point at 1.4 in the Optimised vs Konica comparison is an extreme outlier more than three standard deviations fromthe median.

Ivan Williams et al European Journal of Radiology 68S (2008) S73–S77

Phase Contrast■ Contact:d2
NF =λz♦Geometric approximation

NF >> 1

Geometric approximation

The intensity distribution is a pure absorption image.

■ Near field:♦NF >> 1

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 << 1The 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

Imaging and Therapy Facility
Human CT 600mm wide beam (Unique Worldwide)

Pre-clinical & Clinical PET-CT
SPECT & MRI

Why a Long Beamline?

Subtraction Radiography
HighSynchrotron

2 detectors

Specialised
monochromator

Scanning
motion

LowW. Thomlinson et al ESRF

Patient 1 - weight: 70 kg - iodine: 42mlSynchrotron 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
9 Fantastic spatial resolution
9 Reasonable scan times
8 Uses ionising radiation
8 Very limited access
8 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-8GeV

Rabbit LungContact3m

MRI State of the Art

Bronchoconstriction induced by metacholine
Bruker BioSpec® 47/40

Rabbit Pup Lung Imaging - Delivery

Artificial Ventilation

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

Breathing Aerates Lungs
Δ lung volume (mL/kg)

2520b1510*

**

50*

5(a)

**a101520Time (secs)

253035(b)Lung aeration: Airway liquid clearance
Inspiration forces liquid out of airways-P-P-P

Post Mortem Artificial Ventilation

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

Lower Lung

Medical Relevance■ Respiratory Ventilation■ Positive End Expiratory
Pressure (PEEP) is used insome hospitals as it isthought to help
■ It is currently 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)

Phase Retrieval: Single Image■ Approximate ‘contact’ intensity from Beer’s Law
I (r⊥ , z = 0) = I O exp(− μT (r⊥ ))■ Approximate ‘contact’ phase byφ (r⊥ , z = 0) = −2πλδ T (r⊥ )■ Use Transport-of-Intensity Equation (TIE)

2π ∂∇ ⊥ ⋅ ( I (r⊥ , z )∇ ⊥φ (r⊥ , z )) = −I (r⊥ , z )λ ∂z■ Solve for object’s projected thickness using Fourier
Derivative Theorem{}⎛ ⎧⎪ F M 2 I ( Mr , z = R ) / I ⎫⎪ ⎞O ⎟⊥2T (r⊥ ) = − ln⎜ F −1 ⎨μ⎬⎟2⎜μMR2δ k ⊥ + μ⎪⎭ ⎠⎝ ⎪⎩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

Effect of PEEP in Ventilated Preterm Rabbits

Tidal volumemL/kg

305 cmH2O PEEP0Tidal volumemL/kg3000 cmH2O PEEP

Result of this research:■ The following recommendation is now
likely to be added to the international
resuscitation guidelines (ILCOR) in 2010
■ An end-expiratory pressure should beapplied to the airways during resuscitationof newborn infants at birth■ Is this all?

20sec First Inspiration

Long First Inspiration

End-expiratory lung gas volume(FRC)

20 secs
20 sec long inspiration
5 cmH2O PEEP

Rabbit Pup CT

Particle image velocimetry

A. Fouras, et al

Vectors of Ventilated Lung Motion

A. Fouras, et al

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

Healthy Lung, showing uniform
compliance

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

Blood Flow. No Contrast Medium
570μm

190nm
pixelsA. Fouras, J. Dusting, R. Lewis, and K. Hourigan, J. Appl. Phys. 102, 064916, 2007
B. Sally Irvine et al Applied Physics Letters 93, 153901 2008

Vector Tomography from a Single Projection

Sally Irvine, David Paganin and Andreas Fouras

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

500000200400600

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

8448hours
24hoursafter
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

www.masr2010.org
www.bsr2010.org