Page 1 Medicina e raggi X l Roma, 22 April 2014 l Alberto Bravin (ESRF)
Dr. Alberto Bravin, PhD
European Synchrotron Radiation Facility Grenoble, France
Scienze mediche e raggi X
Outline - The role of synchrotrons in biomedical research - Highlights of high-resolution and low-dose tissue imaging, in-vivo functional imaging - Microbeam Radiation Therapy: basics and methods - Application of MRT in neurosurgery
Medicina e raggi X l Roma, 22 April 2014 l Alberto Bravin (ESRF)
X-rays in medicine
Röntgen
Children hospital, Vienna, 1921
1895 today
Cyberknife
Spiral CT
… and therapy
1971 1896
1949
Stereotaxic radiosurgery (Leksell)
CT Hounsfield
Medical diagnostics
1898
The role of synchrotron facilities
Page 4 Medicina e raggi X l Roma, 22 April 2014 l Alberto Bravin (ESRF)
Fundamental research, develop techniques for clinics, prepare ground for compact sources
For medical diagnostics: - up to 1000X more intense than scanners - tunable monochromatic energy - parallel beam
For radiotherapy and radiosurgery: - Up to 106X more intense than Linacs - High resolution image guidance - Energy tunability
- Nano(Micro)metric spatial resolution - New techniques (PhC, Dual energy)
- Microbeam radiation therapy - Dose enhancement therapy
Developments in low-dose phase-contrast imaging
Page 5 Medicina e raggi X l Roma, 22 April 2014 l Alberto Bravin (ESRF)
Low dose - high resolution 3D full breast tumor detection (by PhC imaging)
Page 6 Medicina e raggi X l Roma, 22 April 2014 l Alberto Bravin (ESRF)
Phase contrast CT + EST Dose = 2.0 ± 0.1 mGy
Dose even lower then conventional 2D mammography (~3.5 mGy)!
25 times dose saving vs clinical breast CT at same resolution
PNAS, Zhao, Brun, Coan et al., 2012, 109 (45)
Conventional CT Dose 49 ± 1 mGy
2 cm
60 keV-Voxel: 503 µm3
PMB, Mittone, Bravin, Coan, 2014 7;59(9)
No contrast agent
High resolution tissue and vascular computed tomography
Page 7 Medicina e raggi X l Roma, 22 April 2014 l Alberto Bravin (ESRF)
The role of cellular effects during allergic bronchoconstriction (dual energy CT)
Page 8 Medicina e raggi X l Roma, 22 April 2014 l Alberto Bravin (ESRF) J Appl Physiol S.Layachi, et al., 2013 July 25
Ventilation map
Tissue density map
Allergic challenge
Allergic challenge-> poor regional ventilation -> caused by bronchoconstriction of small peripheral airways. Ventilated alveolar area decreased. Inflammation is heterogeneous
Impact on treatment (type and quantity of anti-inflammatory)
rabbit model Xe contrast agent
High resolution brain vascularization imaging
Page 9 Medicina e raggi X l Roma, 22 April 2014 l Alberto Bravin (ESRF)
Marmoset monkey cortical vascular network
9L rat gliosarcoma cortical vascular network
. Int. J. Devl Neuroscience, L. Risser et al (2009) 27, 185–196
“The angiogenesis (- > tumor development) in primate cerebral cortex mainly occurs at capillary level”
Tracking nano-particles clusters
Page 10 Medicina e raggi X l Roma, 22 April 2014 l Alberto Bravin (ESRF)
Gd and Au n-particles for imaging and therapy
Page 11 Medicina e raggi X l Roma, 22 April 2014 l Alberto Bravin (ESRF)
N-particles: very interesting contrast agent (longer vascular half-life than molecular contrast agents) can be monitored for a longer time. Gd chelate coated Au n-particles: sensitive to MRI and CT and adapted for therapy as dose enhancer CT with monochromatic X-rays: quantitative evaluation at spatial high resolution
C. Alrich et al. J. Am. Chem. Soc. 2008, 130, 5908
Theranostic use of Gd nanoparticles
Page 12 Medicina e raggi X l Roma, 22 April 2014 l Alberto Bravin (ESRF)
i.v. Injection of GBN colloid ([Gd3+] = 40 mM, V = 1.4 mL)
Gd NPS are eliminated through kidneys-bladder
MRI
SR
Alric et al. Nanoscale 2013;5(13):5930
Where are nanoparticles going in normal and tumoral cells?
Page 13 Medicina e raggi X l Roma, 22 April 2014 l Alberto Bravin (ESRF)
Partition of AuNPs between daughter cells during mitosis SEM (a), nanoCT (d) and microCT (e)
Astolfo et al. Nanoscale 2013, 5 (3337)
ELETTRA Tumour tracking/Biosafety
Developments in Radiation Therapy and radiation surgery
Page 14 Medicina e raggi X l Roma, 22 April 2014 l Alberto Bravin (ESRF)
Clinical mamagement of cerebral tumors - Epidemiology : 3000 cases/year in France - 65 % are high grade glioma: short life expectancy (2-36 mo) Cancer of the nervous system is the second most common form of
cancer for children, after leukemia (ex: diffuse intrinsic pontine glioma
15
IMRT-Radiotherapy 50 Gy at the tumor location 25 fractions @ 5/week Limited by tissue tolerance
Is there another way for increasing the dose delivered to the tumour while sparing the surrounding tissues ?
Radiotherapy is only palliative for various tumor grades and locations
Dose volume effect
Page 16 Medicina e raggi X l Roma, 22 April 2014 l Alberto Bravin (ESRF)
1mm
140Gy
25µm
4000Gy
Zeman et al, Radiat Res 15, 496,1961
MRT: extremely high doses delivered in spatially fractionated microplans
Page 17 Medicina e raggi X l Roma, 22 April 2014 l Alberto Bravin (ESRF)
Tissue tolerance threshold dose for
healthy tissue homogeneous
irradiation
The dose in the valleys that creates a dose offset in the tissues, has to stay below the tolerance threshold dose
Highly confined dose – low damage on surrounding tissues
Page 18 Medicina e raggi X l Roma, 22 April 2014 l Alberto Bravin (ESRF)
pH2AX detection (DSB formation) – Day 1 post MRT, 300 Gy peak
1 port 2 ports 4 ports Edges End of beams
DNA damages are confined to the microbeam paths
Only few cells exhibit pH2AX labeling between 2 microbeams High dose fall-off at the edges of the interlaced region
Therapeutic effect of MRT
Page 19 Medicina e raggi X l Roma, 22 April 2014 l Alberto Bravin (ESRF)
H. Smilowitz et al. J. Neurooncology, 78: 135-143, 2006
Cortical transections to treat epilepsy: fundaments
Page 20 Medicina e raggi X l Roma, 22 April 2014 l Alberto Bravin (ESRF)
• Cortical spreading of epileptic activity relies on horizontal axons running mainly through layer V, where the majority of axons is located.
• Surgically cutting the horizontal axons can relieve seizures originating from regions of the cortex that cannot be surgically resected (eloquent cortex: motor cortex, language regions..)
• Epileptogenic foci located in non eloquent cortex are otherwise surgically resected)
• Epilepsy need surgery when seizures cannot be controlled pharmacogically (~10% of epileptic patients)
~1 mm
Cortical columns
Cortical columns= basic unit of the cortex
Columns: modules that interact: • Vertically with spinal cord
• Horizontally with neighborhood modules
neuron
axons
Transection shown on the rat brain atlas
Page 22 Medicina e raggi X l Roma, 22 April 2014 l Alberto Bravin (ESRF)
M1: eloquent motor cortex (movements): if damaged-> paresis
Seizures vs. time after MRT treatment
Page 23 Medicina e raggi X l Roma, 22 April 2014 l Alberto Bravin (ESRF)
01234567
0 3
5.5 10 15 20 25 30 35 40 45 50 55 60 65 70
hours from kainic acid injection
seiz
ures
sca
le
100 µm-360 Gy100 µm-240 Gy600 µm-250 Gy600 µm-100 Gycontrol
Romanelli et al. PLOSOne e53549 2013
Control: average over 2 rats (48h, 74 h), all other values average of 3 rats 6: generalized seizures 0: no seizures
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