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INTRODUCTION The high potential of Microbeam Radiation Therapy (MRT) in improving tumor control whilst reducing side effects has been shown by numerous preclinical studies. MRT offers a widened therapeutic window by using the periodical spatial fractionation of synchrotron generated x-rays into an array of intense parallel microbeams. MRT now enters a clinical transfer phase. As proof of principle and cornerstone for the safe clinical transfer of MRT, we conducted a "first in dog" trial under clinical conditions. In this report, we evaluated whether a 3D conformal MRT can be safely delivered as exclusive radiosurgical treatment in animal patients. METHODS We irradiated a 17.5 kg French Bulldog for a spontaneous brain tumor (glioma suspected on MRI) with conformal high dose rate microbeam arrays (50µm-wide microbeams, replicated with a pitch of 400μm) of synchrotron-generated x-rays. The dose prescription adjusted a minimal cumulated valley dose of 2.8Gy to the PTV (CTV+1mm). Thus, each beam delivered 20-25Gy to the target as peak doses, and ∼1Gy as valley doses. RESULTS The treatment was successfully delivered. Clinical follow-up over 3 months showed a significant improvement of the dog's quality of life: the symptoms disappeared. MRI, performed 3 months post irradiation, revealed reduction in tumor size (-87.4%) and mass effect with normalization of the left lateral ventricle. CONCLUSION To our knowledge, this neuro-oncologic veterinary trial is the first 3D conformal synchrotron x-ray MRT treatment of a spontaneous intracranial tumor in a large animal. It is an essential last step towards the clinical transfer of MRT in the near future, to demonstrate the feasibility and safety of treating deep seated tumors using synchrotron-generated microbeams.

International audience; Background: Radiation therapy remains a fundamental tool for cancer treatment, but selective dose deposition within a targeted‐tumor, while sparing surrounding structures, remains a challenge. This objective can be achieved by loading the tumor with high‐Z elements prior delivery of radiation therapy. Synchrotron sources are ideal sources since they provide high‐intensity and tunable monochromatic X‐rays within the optimal energy‐range.Aim: We evaluated the ability of various high-Z elements, either as molecular agents (iodine or gadolinium contrast agents) or in the form of nanoparticles (gold and gadolinium), to act as radiation dose-enhancers through theoretical and experimental studies.Methods: Clonogenic assays were used to quantify cell survival after irradiation in the presence of the dose-enhancers using monochromatic X-rays from a synchrotron or 1.25 MeV photons from a Cobalt-60 source. Preclinical studies were performed on rats bearing F98 glioma after administration of either iodine as contrast agent or AuNPs. In parallel, Monte Carlo simulations were performed to evaluate the dose, for comparisons. Finally, a pilot clinical study was performed using an iodinated contrast agent as the radiation-dose-enhancer. 14 Patients with brain metastases received one fraction of the overall radiotherapy treatment at the synchrotron, the additional fractions were delivered using a conventional Linac at the university hospital.Results/Conclusions Radiosensitization was demonstrated with all agents in combination with X-irradiation at low energies. The radiation dose-enhancements were found to be highly energy-dependent for all agents. Secondary-electron-emission generated after photoelectric events appeared to be the primary mechanism by which Iodine and Gd contrast agents or AuNPs act as dose-enhancers. Increase of the animal’s survival was observed after iodine systemic injection or intracerebral infusion of AuNPs. The phase I-II clinical studies demonstrated the feasibility of this technique. Our overall experience will be summarized, pointing out the advantages and difficulties of applying this method for the treatment of brain tumors.

Inner ear diseases include not only hearing loss but also equilibrium disorders. In these cases the normal life is seriously affected and simple actions like walking and moving are seriously impaired by the appearing of symptoms like dizziness, nausea, vomit. Imaging the inner ear is a very interesting radiological challenge, in fact present medical CT scanners do not have the spatial resolution necessary to image the fine structures of the inner ear. As a consequence, when inner ear diseases are treated surgically, the physician has to proceed to the operation without any trustable image guidance. In addition, without good imaging, it is not possible to follow up the therapeutical effects of medications. Therefore a dedicated and performing CT system for inner ear imaging would be extremely useful also to avoid unnecessary surgeries. In the framework of a research project funded by the Italian National Institute of Nuclear Physics we studied this issue and performed an experiment at the European Synchrotron Radiation Facility to determine whether, under ideal conditions (parallel and monochromatic X-ray beam, high resolution detector), it was possible to obtain tomographic images of the inner ear with satisfactory resolution and contrast. This experiment can be considered as a "reference benchmark" for the CT imaging of the human ear, a target which a new CT scanner devoted to middle and inner ear should approach.

International audience; Studying the hemodynamics in brain is of particular interest for the diagnosis, the understanding and the management of pathologies such as ischemia [1], tumors [2], and traumas [3]. For malignant glioma, it has been shown that perfusion parameters are correlated to the tumor aggressivity [4], and can be used for the treatment outcome prognosis [5]. Quantitative measurements have to be compared between various imaging days and between patients. Synchrotron Radiation Computed Tomography (SRCT) is the gold standard to measure in vivo contrast agent concentrations with high accuracy and precision owing to the characteristic of the beam and performances close to theoretical limits: high flux, nearly parallel and monochromatic x-ray beams [6,7]. In addition to being quantitative, SRCT [8] could be greatly improved with both a high temporal and spatial resolution, which we assumed would be combined using the Maxipix-CdTe detector under development at ESRF [9]. This detector features a monolithic 1 mm thick single crystal CdTe sensor (99% efficient at energies up to 60 keV) hybridised to a matrix of 3x1 Timepix chips, giving a total area of 768x256 pixels at 55 μm pitch (45 x 15 mm2). Its tomographic spatial resolution is of 0.06x0.06x0.06 mm3. The high efficiency of the detector as well as its background noise suppression enabled low dose imaging (200mGy/s). Monochromatic X-rays at 35 and 51 keV were used. 360° tomography images have been taken over 2s, 6s, and 60s. Reconstruction of the tomographic slices was conducted using PyHST package developed at ESRF. A software extension has been developed to correct for defective or unstable pixels. The results were compared to images acquired with the reference 1D germanium detector. We have successfully retrieved iodine contrast agent quantification for both steady-state protocol and dynamic contrast-enhanced perfusion imaging, with phantoms. In vivo SRCT imaging in rats bearing brain tumors also proved successful, following up the iodine uptake for 25 minutes. We foresee low dose high resolution volumic perfusion measurements, relying on enhanced frame rates and synchronization accuracy as well as improved image reconstruction techniques.References[1] Klotz E, et al., European Journal Of Radiology. 1999; 30: 170-84.[2] Eastwood JD, et al., Neuroradiology. 2003; 45: 373-6.[3] Wintermark M, et al., Radiology. 2004; 232: 211-20.[4] Roberts HC, et al., AJNR Am J Neuroradiol. 2000; 21: 891-9.[5] Cao Y, et al., International Journal Of Radiation Oncology Biology Physics. 2006; 64: 876-85.[6] Adam, J. F., H. Elleaume, et al., Journal Of Cerebral Blood Flow And Metabolism 23(4): 499-512 (2003).[7] Adam, J. F., C. Nemoz, et al., Journal Of Cerebral Blood Flow And Metabolism 25(2): 145-153 (2005).[8] Le Duc G. et al., European Radiology 10 : 1487-1492 (2000).[9] Ruat M and Ponchut C, IEEE Trans. Nucl. Sci. 59(5): 2392-2401 (2012)

International audience; Therapy (SSRT) is underway since June 2012 at the European Synchrotron Radiation Facility (ESRF) and at the University Hospital (CHU) in Grenoble (France). This phase I-II clinical trial is designed to test the feasibility and safety of SSRT through a dose escalation protocol. Two years after the start of the trial, this study has already included ten patients suffering from few brain metastases of medium-to-small volume. The treatment is based on stereotactic irradiations using high-flux quasi-parallel monochromatic medium energy x-ray beams (80 keV). The irradiation is performed, in presence of iodinated contrast agent, previously introduced in the tumor. At these energies, a localized dose enhancement occurs in the target, due to increased photoelectric absorption. This differential effect is due to a difference in the photons interactions mechanisms in the target volume where the contrast agent leaks from the capillaries when compared to the healthy brain where the iodine concentration remains negligible. The moderate kinetic energy photoelectrons deposit their energy over a submillimetric distance, in the close vicinity to the heavy atoms; whereas Compton scattering predominates in the surrounding healthy tissues. Consequently, the radiation becomes more penetrating, and hence interesting, for treating deep-seated tumors. The medical physics developments, which have been performed for this innovative technique, will bediscussed in this presentation.Methods: A dedicated treatment room has been built at the ESRF medical beamline. The patient is seating on an armchair with his head tightly maintained by the same stereotactic frame used at the CHU for complimentary irradiations. A dedicated treatment planning system was adapted to SSRT specificities. The synchrotron beamline geometry was modeled. The dosimetry is based on parallelized Monte Carlo simulations of low-medium energy electrons and polarized photons transport in presence of high-Z material. Dedicated quality assurance protocols were implemented. The treatments plans and absolute dosimetry1 are validated with measurements performed in a dedicated water tank as well as in solid water with and without bone slabs. A 2D dosimetry technique is being developed in anthropomorphic phantoms using EBT3 gafchromic films. In vivo dosimetry based on optically stimulated luminescence (Al2O3 crystals) has been tested. The contrast agent uptake has been previously studied on 12 patients which received an intravenous bolus of iodinated contrast agent (40 mL, 4 mL/s), followed by a steady-state infusion (160 mL, 0.5 mL/s) in order to ensure stable intratumoral amounts of iodine during the treatment2. Absolute iodine concentrations and quantitative perfusion maps were derived from 40 multi-slice dynamic conventional CT images of the brain (recruitment day) or from quantitative synchrotronradiation CT (treatment day). For three of these patients, iodine concentrations reached in the tumor were compared between the recruitment day and the treatment day (~10 days interval).Results & Discussion: The SSRT procedure includes the i.v. injection of iodinated contrast agent (400 mg/ml nominal concentration) followed by the monochromatic irradiation in the next minutes, with 1 to 10 beams. The post-infusion mean intratumoral iodine concentration (over thirty minutes) reached 1.94 ± 0.12 mg/mL (200 mL of contrast injected). Reasonable correlations were obtained between these concentrations and the permeability surface area product and the cerebral blood volume. Iodine concentrations were reproducible leading to dose errors in the radiotherapy standards. In this first clinical trial phase, the patients receive a fraction of the treatment by SSRT (5 or 7 Gy), while the remaining of thetreatment is delivered by standard stereotactic irradiation at the CHU (6 or 4 Gy and 2 x 11Gy). All patients were in good general condition.References:1. Dosimetry protocol for the forthcoming clinical trials in synchrotron stereotactic radiation therapy (SSRT). (Y. Prezado et al.) Med. Phys. 38, 1709-1717 (2011).2. Absolute perfusion measurements and associated iodinated contrast agent time course in brain metastasis: a study for contrastenhancedradiotherapy (L. Obeid et al.) Journal of Cerebral Blood Flow & Metabolism 34, 638-645 (2014).

International audience; Clinical trials are currently being conducted at the ESRF with two types of approaches for the treatment of high-grade brain tumours: 1- one method irradiates the tumours with monochromatic Xrays in the energy range dominated by the photo-electric effect, and 2- the second method, calledMicro-beam Radiation Therapy (MRT), and targeting spontaneous tumours in pets, uses an array of very intense, poly-energetic micro-beams (typically 50 microns wide, separated by 400 microns). The first method called Stereotactic Synchrotron Radiation Therapy (SSRT) will be presented in this poster.The current clinical trials program benefits from the ID17 Biomedical beamline setup that had been developed for intravenous coronary arteries imaging. A total of 65 human patients (2000 to 2003) were imaged during that period. A specially designed Patient Positioning System (PPS) had beenconstructed for clinical trials. Intense monochromatic laminar beams ranging from 25 to 180 keV, and 150 mm wide, 4-5 mm height are available.The SSRT principle combines two cumulative effects. The first one is a local dose enhancement produced by the presence of heavy atoms in the tumour, mainly due to the increased interaction with the monochromatic synchrotron radiation at 80 keV. Pre-clinical tests conducted over a decade have favoured the use of iodine (k-edge = 33 keV) and of platinum compounds, the latter commonly used as anti-cancer agents (k-edge = 78 keV).The second effect, or stereotactic effect, is obtained from the accumulation of the dose deposited in the tumour from up to 10 different coplanar entry ports, whilst the dose deposited in the healthy tissues is kept below the tolerance. Furthermore, the tumours are irradiated through conformal collimators. Obviously, in addition of guaranteeing the value of the dose delivered and at the exact target location, one of the main concerns is to guarantee the patient safety during the irradiation and during the 3-D Xray image guidance procedures performed prior to the irradiation. To this end, a redundant Patient Safety System (PASS) is controlling all the parameters in real-time and would interrupt the beam in less than 4 ms in any case of reaching preset limit values.The first SSRT patient has been treated at the ESRF in June 2012, and at the University Hospital (CHU) in Grenoble. Three to six patients have been and will be treated each year during 6 years to complete this Phase I/II of the clinical trials protocol which aims to prove 1- the technical feasibility ofthe project, 2- the tolerance by the patient (no unexpected side-effect!), and 3- the patient acceptance of anti-cancer treatment by synchrotron radiation.

International audience; Synchrotron radiation (SR) at the ESRF has several notable features for medical use: a fluence5 to 6 orders of magnitude higher than that of a conventional X-ray tube, abroad spectrum extending up to more than 300 keV and a very small divergence(

Skin penetration of gold nanoparticles: a new analytical approach using the synchrotron radiation computed microtomography

We present in this paper two imaging techniques using contrast agents assessed with in vivo experiments. Both methods are based on the same physical principle, and were implemented at the European Synchrotron Radiation Facility medical beamline. The first one is intravenous coronary angiography using synchrotron radiation X-rays. This imaging technique has been planned for human studies in the near future. We describe the first experiments that were carried out with pigs at the ESRF. The second imaging mode is computed tomography using synchrotron radiation on rats bearing brain tumors. Owing to synchrotron radiation physical properties, these new imaging methods provide additional information compared to conventional techniques. After infusion of the contrast agent, it is possible to derive from the images the concentration of the contrast agent in the tumor area for the computed tomography and in any visible vessel for the angiography method.

International audience; The technical feasibility of temporal and spatial fractionations of the radiation dose has been evaluated using synchrotron microbeam radiation therapy for brain tumors in rats. A significant increase in lifespan (216%, p < 0.0001) resulted when three fractions of microbeam irradiation were applied to the tumor through three different ports, orthogonal to each other, at 24 h intervals. However, there were no long-term survivors, and immunohistological studies revealed that 9 L tumors were not entirely ablated.

The radiotherapy clinical trials projects, both aiming at treating aggressive brain tumors, require several major modifications and new constructions at the ESRF ID17 Biomedical beamline. The application of the Stereotactic Synchrotron Radiation Therapy (SSRT) technique mainly necessitates an upgrade of the existing patient positioning system, which was formerly used for the angiography program. It will allow for accurate positioning, translation and rotation of the patient during the treatment. For the Microbeam Radiation Therapy (MRT) clinical trials project, a new white beam hutch will be constructed to accommodate a dedicated patient positioning system. Consequently, the existing control hutches and the related installations will also be completely refurbished. Furthermore, the foreseen installation of a second X-ray source, which will allow doubling the currently available photon flux at high energies, requires a redesign of most optical components to handle the increased power and power densities. Starting from the current ID17 Biomedical beamline layout, the paper will present an update of the different modification/construction projects, including the general organization and planning.

Microbeam radiation therapy (MRT) has the potential to treat infantile brain tumours when other kinds of radiotherapy would be excessively toxic to the developing normal brain. MRT uses extraordinarily high doses of x-rays but provides unusual resistance to radioneurotoxicity, presumably from the migration of endothelial cells from 'valleys' into 'peaks', i.e., into directly irradiated microslices of tissues. We present a novel irradiation geometry which results in a tolerable valley dose for the normal tissue and a decreased peak-to-valley dose ratio (PVDR) in the tumour area by applying an innovative cross-firing technique. We propose an MRT technique to orthogonally crossfire two arrays of parallel, nonintersecting, mutually interspersed microbeams that produces tumouricidal doses with small PVDRs where the arrays meet and tolerable radiation doses to normal tissues between the microbeams proximal and distal to the tumour in the paths of the arrays.

A fixed-exit monochromator has been constructed for computed tomography (CT) studies at the Medical Beamline of the European Synchrotron Radiation Facility. A non-dispersive pair of bent Laue-type crystals is used, and the first crystal is water-cooled. The monochromator operates at energies from 18 to 90 keV, and the maximum width of the beam is 150 mm. The performance of the monochromator is studied with respect to the beam intensity and energy distributions, and a close agreement is found between the calculated and experimental results. The intensity is between 10(9) and 10(10) photons s(-1) mm(-2) under typical operating conditions. The harmonic content of a 25 keV beam is about 30% at the minimum wiggler gap of 25 mm (field 1.57 T) and decreases by an order of magnitude when the gap is increased to 60 mm (field 0.62 T). The experimental set-up for CT studies includes dose monitors, goniometers and translation stages for positioning and scanning the object, and a 432-element linear-array Ge detector. Examples from phantom studies and in vivo animal experiments are shown to illustrate the spatial resolution and contrast of the reconstructed images.

International audience; After decades of intensive research, high-grade gliomas are still resistant to therapies, including surgery, chemotherapy, and radiotherapy or a combination thereof. The most important advance in the treatment of these tumors has been the introduction of a new chemotherapy drug called temozolomide, in combination with external beam photon irradiation [1]. One of the goals of the association of the CHU/UJF/ INSERM and ESRF teams has been to develop research on synchrotron radiotherapy up to clinics.

For several years the ID17 Biomedical beamline at the ESRF has developed synchrotron radiation therapy preclinical programmes to treat aggressive brain tumours. Two techniques have been developed at the ESRF: a) The Microbeam Radiation Therapy (MRT) using spatially fractionated "white beam" (energies 50-300 keV) irradiation (beam widths 25-100 μm, spacing between beams 200-400 μm ) with extremely high dose rates (up to about 20 kGy/s) and depositing very high doses (300-1000 Gy) in the targeted tissue. b) The Stereotactic Synchrotron Radiation Therapy (SSRT) using spatially homogeneous monochromatic beam with the energy closely above that of the K-edge of a contrast- or chemotherapeutical agent (iodine, gadolinium, platinum) loaded into the tumour volume for obtaining a dose-enhancement. In 2005 an International review panel of oncology experts has recommended to move to clinical trials on humans in SSRT and on large animals in MRT. The works required for this program were launched in autumn 2007 with constructing a new, dedicated experimental hutch for MRT and a major upgrade of the existing sample-positioning station to a patient-positioning station for SSRT. In parallel, safety systems are developed and progressively implemented and a patient treatment-planning system developed. © 2010 American Institute of Physics.

Microbeam Radiation Therapy (MRT) uses highly collimated, quasi-parallel arrays of X-ray microbeams of 50-600 keV, produced by 2nd and 3rd generation synchrotron sources, such as the National Synchrotron Light Source (NSLS) in the U.S., and the European Synchrotron Radiation Facility (ESRF) in France, respectively. High dose rates are necessary to deliver therapeutic doses in microscopic volumes, to avoid spreading of the microbeams by cardiosynchronous movement of the tissues. A small beam divergence and a filtered white beam spectrum in the energy range between 30 and 250 keV results in the advantage of steep dose gradients with a sharper penumbra than that produced in conventional radiotherapy. MRT research over the past 20 years has allowed a vast number of results from preclinical trials on different animal models, including mice, rats, piglets and rabbits. Microbeams in the range between 10 and 100 micron width show an unprecedented sparing of normal radiosensitive tissues as well as preferential damage to malignant tumor tissues. Typically, MRT uses arrays of narrow ({approx}25-100 micron-wide) microplanar beams separated by wider (100-400 microns centre-to-centre, c-t-c) microplanar spaces. We note that thicker microbeams of 0.1-0.68 mm used by investigators at the NSLS are still called microbeams, although some invesigators inmore » the community prefer to call them minibeams. This report, however, limits it discussion to 25-100 {mu}m microbeams. Peak entrance doses of several hundreds of Gy are surprisingly well tolerated by normal tissues. High resolution dosimetry has been developed over the last two decades, but typical dose ranges are adapted to dose delivery in conventional Radiation Therapy (RT). Spatial resolution in the sub-millimetric range has been achieved, which is currently required for quality assurance measurements in Gamma-knife RT. Most typical commercially available detectors are not suitable for MRT applications at a dose rate of 16000 Gy/s, micron resolution and a dose range over several orders of magnitude. This paper will give an overview of all dosimeters tested in the past at the ESRF with their advantages and drawbacks. These detectors comprise: Ionization chambers, Alanine Dosimeters, MOSFET detectors, Gafchromic registered films, Radiochromic polymers, TLDs, Polymer gels, Fluorescent Nuclear Track Detectors (Al{sub 2}O{sub 3}:C, Mg single crystal detectors), OSL detectors and Floating Gate-based dosimetry system. The aim of such a comparison shall help with a decision on which of these approaches is most suitable for high resolution dose measurements in MRT. The principle of these detectors will be presented including a comparison for some dosimeters exposed with the same irradiation geometry, namely a 1x1 cm{sup 5} field size with microbeam exposures at the surface, 0.1 cm and 1 cm in depth of a PMMA phantom. For these test exposures, the most relevant irradiation parameters for future clinical trials have been chosen: 50 micron FWHM and 400 micron c-t-c distance. The experimental data are compared with Monte Carlo calculations.« less

During the past decade microbeam radiation therapy has evolved from preclinical studies to a stage in which clinical trials can be planned, using spatially fractionated, highly collimated and high intensity beams like those generated at the x-ray ID17 beamline of the European Synchrotron Radiation Facility. The production of such microbeams typically between 25 and 100 microm full width at half maximum (FWHM) values and 100-400 microm center-to-center (c-t-c) spacings requires a multislit collimator either with fixed or adjustable microbeam width. The mechanical regularity of such devices is the most important property required to produce an array of identical microbeams. That ensures treatment reproducibility and reliable use of Monte Carlo-based treatment planning systems. New high precision wire cutting techniques allow the fabrication of these collimators made of tungsten carbide. We present a variable slit width collimator as well as a single slit device with a fixed setting of 50 microm FWHM and 400 microm c-t-c, both able to cover irradiation fields of 50 mm width, deemed to meet clinical requirements. Important improvements have reduced the standard deviation of 5.5 microm to less than 1 microm for a nominal FWHM value of 25 microm. The specifications of both devices, the methods used to measure these characteristics, and the results are presented.

The different tomography imaging modalities of the ESRF Medical Beamline are described and research applications are presented.