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.

Since the invention of Computed Tomography (CT), many technological advances emerged to improve the image sensitivity and resolution. However, no new source types were developed for clinical use. In this study, for the first time, coherent monochromatic X-rays from a synchrotron radiation source were used to acquire 3D CTs on patients. The aim of this work was to evaluate the clinical potential of the images acquired using Synchrotron Radiation CT (SRCT). SRCTs were acquired using monochromatic X-rays tuned at 80 keV (0.350 × 0.350 × 2 mm 3 voxel size). A quantitative image quality comparison study was carried out on phantoms between a state of the art clinical CT and SRCT images. Dedicated iterative algorithms were developed to optimize the image quality and further reduce the delivered dose by a factor of 12 while keeping a better image quality than the one obtained with a clinical CT scanner. We finally show in this paper the very first SRCT results of one patient who received Synchrotron Radiotherapy in an ongoing clinical trial. This demonstrates the potential of the technique in terms of image quality improvement at a reduced radiation dose for inner ear visualization.

E. Boller, P. Tafforeau, A. Rack, V. Fernandez, L. Helfen, M. Rénier, J.P. Valade, H. Vitoux, J. Villanova, P. Cloetens, B. Fayard. O. Guiraud, P. Latil, boller@esrf.fr, ESRF, The European Synchrotron, 71 avenue des Martyrs, Grenoble, France ANKA, Karlsruhe Institute of Technology, Hermann-von-Helmholtz-Platz 1, D-76344 Eggenstein-Leopoldshafen, Germany Novitom, 1 place Firmin Gautier, Grenoble, France http://www.novitom.com/en/

The original monochromator design we present consists in a high-vacuum vessel comprising three monochromators mounted side-by-side: a Laue/Laue, a Bragg/Bragg, and a double-multilayer monochromator. The selection of one monochromator type is done remotely by sliding laterally the crystal support in the monochromator vessel. In this way, exotic combinations such as Laue/Bragg are also possible. Installation and commissioning of the new monochromator at ESRF beamline ID19 was carried out 2013-2014 (the multilayers not being installed yet). Beamline ID19 offers not only superb beam characteristics for phase-contrast imaging with a high level of sensitivity but also compared to other synchrotron X-ray imaging facilities a large beam of currently up to 7 cm x 1.3 cm. A wide energy range can be accessed in a fixed-exit mode (depending on the optics chosen the accessible energy range is between 10 keV and 200 keV). A beryllium exit window (10 cm x 10 cm active opening) completes the monochromator assembly.

Therapeutic applications of synchrotron X rays are becoming a reality. The first phase I/II clinical study of synchrotron stereotactic radiation therapy (SSRT) consists of a dose-escalation protocol to show the feasibility and safety of the technique. Oligo-brain-metastatic patients have been irradiated since June 2012 using 80 keV high-flux quasiparallel monochromatic x-ray beams, in the presence of iodinated compounds injected immediately before irradiation. A localized dose enhancement occurs in the target at this energy, due to the photoelectric effect. The medical physics issues in SSRT have been partially reported. This presentation will detail the results obtained so far in the current trial, the associated short-term perspectives, and the medical exploration of other synchrotron radiation therapy modalities for improved healthy tissue–sparing effects. The conventional steps of stereotactic treatment planning are followed by dose calculations on the dedicated Monte Carlo treatment planning system adapted to SSRT specificities (low energy electrons, polarized photons, beamline geometries, presence of iodine) and plan verification, using dedicated absolute experimental dosimetry modalities. The SSRT patients received i.v. injection of iodinated contrast agent followed by the irradiation with 1 to 10 coplanar isocentric beams. For the 12 patients included so far, 5 Gy (9 patients) and 7 Gy (3 patients) were delivered in SSRT as part of the first fraction of the whole standard stereotactic arc therapy treatment (3x11 Gy) delivered at the hospital. The mean intratumoral iodine concentration (over 30 min, 12 patients) reached 1.94±0.12 mg/mL, which leads to a 20% local averaged dose increase. The conformation index on the planning target volume (PTV) obtained is SSRT is similar to the one obtained in conventional stereotactic treatments (1.3-2.3 according to the tumor size and location, with a 100% PTV coverage with the 70% isodose). The maximum dose delivered to the gross tumor volume is significantly higher in SSRT due to hypervascularized regions in the metastasis associated to larger contrast enhancements. The technical feasibility and safety of SSRT (1 fraction) has been shown on 12 patients so far: usual responses and no adverse effects have been reported on the clinical and MRI-based follow-up over 1 year. The study now enters its second phase with temporal fractionation of the dose (2x7 Gy, 1 week apart). Even if the technique is still in its infancy, these promising technical results are allowing the clinical transfer of other synchrotron radiation therapy modalities. Two realistic options are the use of high-dose-rate arrays of synchrotron microbeams for treating isolated small lesions, or whole-brain irradiations combined with nanoparticles injections to control diffuse brain micrometastatic evolution.

Background: Microbeam Radiation Therapy (MRT) uses a spatially fractionated filtered white X-ray beam from a high energy wiggler Synchrotron Source (energies 50-350keV) with extremely high dose rates (up to about 20kGy/s). The typical planar beam width in an array is 25-100μm with 100-400μm wide spaces between beams. Such beams are very well tolerated by the tissue, even the high "peak" doses delivered in the path of the microbeams, when respecting a dose prescription in the "valley' that corresponds to a dose used of conventional Radiation Therapy (RT) converted to a single exposure. The superior tumor control when compared to that realized by conventional RT is achieved by differential effects of MRT on the normal tissue vasculature versus the tumor vasculature.

The first clinical study of therapeutic applications of Synchrotron Stereotactic Radiation 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 series of steps of increasing complexity. The treatment is based on stereotactic irradiations using high-flux quasi-parallel monochromatic medium energy x-ray beams (80 keV), in presence of heavy atoms, previously introduced in the tumor. At these energies, a localized dose enhancement occurs in the target, due to increased photoelectric absorption. 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 required by this innovative technique will be discussed in this presentation. 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 dosimetry are validated with measurements performed in a dedicated water tank as well as in solid water with and without bone slabs. A 3D dosimetry technique is being developed in anthropomorphic phantoms. 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 4 to 10 beams. At the end of 2013, this study has already included six patients suffering from few brain metastases of medium-to-small volume. In this first clinical trial phase, the patients receive a fraction of the treatment by SSRT (5 Gy), while the remaining of the treatment is delivered by standard stereotactic irradiation at the CHU (6 Gy and 2 x 11 Gy). All patients were in good general condition. The technical feasibility and safety of treating brain metastasis with SSRT has been successfully initiated. The protocol now enters its dose escalation phase.

The bio-medical beamline of the European Synchrotron Radiation Facility (ESRF) located in Grenoble, France, has recently started the Phase I-II Stereotactic Synchrotron Radiation Therapy (SSRT) clinical trials targeting brain tumours. This very first SSRT protocol consists in a combined therapy where monochromatic Xrays are delivered to the tumour pre-loaded with high Z element. The challenges of this technique are the accurate positioning of the target tumour with respect to the beam and the precision of the dose delivery whilst fully assuring the patient safety. The positioning system used for previous angiography clinical trials has been adapted to this new modality. 3-D imaging is performed for positioning purpose to fit to the treatment planning. The control system of this experiment is described from the hardware and software point of view with emphasis on the constraints imposed by the Patient Safety System (PASS).

Microbeam Radiation Therapy (MRT) uses spatially a fractionated "white beam" (energies 50-350 keV) irradiation from a Synchrotron Source. The typical microbeams used at ID17 are 25–100μm-thick, spaced by 200-400μm, and carry extremely high dose rates (up to about 16 kGy/s). These microbeams are well tolerated by biological tissue, i.e. up to several hundred of Gy in the peaks. When valley doses, caused by Compton scattering in between two microbeams, remain within a dose regime similar to conventional RT, a superior tumour control can be achieved with MRT than with conventional RT. The normal tissue tolerance of these microscopically small beams is outstanding and well documented in the literature. The hypothesis of a differential effect in particular on the vasculature of normal versus tumoral tissue might best be proven by using large animal models with spontaneous tumors instead of small laboratory animals with transplantable tumors, an ongoing project on ID17. An alternative approach to deposit a high dose, while preserving the feature of the spatial separation of these microbeams outside the target has opened up new applications in preclinical research. The instrumentation of this method to produce such interlaced beams is presented with an outlook on the challenges to build a treatment platform for human patients. Dose measurements using Gafchromic films exposed in interlaced geometries with their steep profiles highlight the potential to deposit radiotoxic doses in the vicinity of radiosensitive tissues.

The BioMedical Imaging and Therapy (BMIT) facility provides a world class facility with unique synchrotron-specific imaging and therapy capabilities. This paper describes Insertion Device (ID) beamline 05ID-2 with the beam terminated in the first experimental hutch: POE-2. The experimental methods available in POE-2 include: Microbeam Radiation Therapy (MRT), Synchrotron Stereotactic Radiation Therapy (SSRT) and absorption imaging (projection and Computed Tomography (CT)). The source for the ID beamline is a multi-pole superconductive 4.3 T wiggler, which can generate ~30 kW of radiative power and deliver dose as high as 3000 Gy/s required for MRT program. The optics in POE-1 hutch prepares either monochromatic or filtered white beam that is used in POE-2. The Double Crystal (DC), bent Laue monochromator will prepare a beam over 10 cm wide at sample point, while spanning an energy range appropriate for imaging studies of animals (20-100+ keV). The experimental hutch will have a flexible positioning system that can handle subjects up to 120 kg. Several different cameras will be available with resolutions ranging from 4 μm to 150 μm. The latest update on the status of 05B1-1 bending magnet (BM) beamline, described in Part 1 [1], is also included.

The ESRF and the Belgian company Leuven Air Bearings have jointly developed a new sample stage utilizable for multiple applications.The instrument has been designed for the accurate positioning and scanning of large samples for computed tomography (3-D imaging).The main novelty of this development lies in the integration of all the necessary devices to scan large samples in closed-loop control mode into one accurate sample stage, although its design was not intended to meet the ultimate mechanical properties available.The sample maximum dimensions must be comprised in a volume of 400 mm diameter x 600 mm height whilst their weight may reach 300 N. Thanks to its large horizontal translation, the sample stage also allows the 2-D scanning of large samples over a 500 x 600 mm 2 area.Finally, in addition to being transportable to various measurement stations in a large facility, one major characteristic of this versatile tool remains its affordable cost in comparison with the sub-micron final imaging resolution that may be reached.

On the biomedical beamline ID17 at the ESRF a gas attenuator system has been installed to complement and protect the standard solid state attenuators (graphite, Al and Cu) against fatigue and damage due to the very high heat load from the beamline's wiggler source. This series of attenuators defines the flux (dose rate) and the X-ray beam spectrum for the Microbeam Radiation Therapy (MRT) research at ID17 which is currently under development towards clinical application. For this, the attenuators at MRT will be crucial elements to guarantee beam-and dose rate characteristics and the new gas attenuator will become a radiation therapy safety device. The installed gas attenuator and its test results will be presented.

Characterization studies of the metal micro-detector TimePix measuring dose distribution at the Minibeam Radiation Therapy setup (Bio-Medical Beamline ID17, ESRF) were performed. The results obtained for high intensity synchrotron radiation minibeams illustrate an excellent performance of the TimePix providing in real time 2D image of the dose distribution over many beams in a 14×14mm2 area. Peak-to-Valley–Dose–Ratios measured by TimePix and gafhromic films agree well.

Physics and techniques of the metal detectors measuring and imaging charged particles and synchrotron radiation beams are presented. An extremely low thickness (~ 1 micron) of the Metal Micro-strip Detector (MMD) combined with its high radiation tolerance (~ 100 MGy) introduces an opportunity to keep a device in the beam, permanently. `In-situ' operation of the MMD provides non-destructive beam diagnostics in real time. Characterization studies of the MMD at the Mini-beam Radiation Therapy setup (Bio-Medical Beamline ID17, ESRF, France) have been recently performed. The results obtained illustrate an excellent performance of the metal micro-pixel detector TimePix providing online synchrotron radiation beam monitoring.

Background. - The incidence of skin cancer is not well established in the French West Indies, aside from old data concerning cutaneous melanoma.Method. - A prospective study was performed over a 3-month period in late 2007 in the French West Indies. The number of new cases of histologically confirmed skin cancer was determined using a questionnaire.Results. - The rate of participation of dermatologists was 82%. During the study period, 166 skin cancers were diagnosed in 134 patients (66 women and 68 men: mean age = 63.3 years, SD = 2.5), including 137 basal cell carcinomas, 12 melanomas, seven squamous cell carcinomas, six Bowen's disease, one B lymphoma and one Paget's disease. The raw incidence of skin cancers detected by dermatologists was calculated as 64.6 cases/100 000 inhabitants/year for basal cell carcinoma, 5.7 cases/100 000 inhabitants/year for melanoma, 3.3 cases/100 000 inhabitants/year for squamous cell carcinoma, and 2.8 cases/100 000 inhabitants/year for Bowen's disease. Seven melanomas (almost exclusively of plantar topography) and seven basal cell carcinomas were diagnosed in patients of phototype V or VI.Discussion. - Although lower than in metropolitan France, the number of skin cancers diagnosed by dermatologists in the French West Indies is fairly high. In addition, this study indicates the significant incidence of basal cell carcinomas and melanomas in subjects with phototype V or VI, underreported in the literature. These findings highlight the need to begin longer-term studies and to include skin carcinomas in the cancer registry of the French West Indies in order to better identify their characteristics among the Caribbean population. (C) 2010 Published by Elsevier Masson SAS.

Purpose: Contrast‐enhanced stereotactic synchrotron radiation therapy (SSRT) is an innovative technique based on localized dose‐enhancement effects obtained by reinforced photoelectric absorption in the target. Medium energy monochromatic x‐rays (50 –100 keV) are used for irradiating tumors previously loaded with high‐Z elements. SSRT clinical trials are being prepared at the European Synchrotron Radiation Facility (ESRF). The first patients (scheduled in summer–autumn 2011) should be treated at 80 keV, with 10 conformational beams. A dry run has been performed using an anthropomorphic radiosurgery human head phantom (Computerized Imaging Reference Systems, Norfolk, VA, USA). Methods: The phantom was scanned on a dedicated CT‐scanner, with and without a 3 cm diameter latex balloon filled with 3 mg/ml of iodine located in the supratentorial brain area. The PTV as well as the OAR were then contoured. The fisrt patient should receive 5 Gy at the ESRF in one fraction followed by a 6 Gy fraction and two 11 Gy fractions at the university hospital under stereotactic conditions (6 MV). The treatment will be followed by a whole brain irradiation (30 Gy, 10 fractions of 3 Gy, 6 MV). The treatment plan for the conventional stereotactic and whole brain irradiations were performed respectively on the Brainlab‐IPlan system, and on the Varian‐Eclipse TPS. The contrast enhanced SSRT treatment plan is performed on the ESRF dedicated version of Isogray (Dosisoft, Cachan, France) that has been developed for our irradiation technique.Results: The treatment plan was then successfully evaluated (Isodoses, DVHs and ICRU points). The full treatment was then realized on the phantom. Dose verifications were performed using gafchromic films and nPaG polymer gel dosimetry as well as in vivo dosimetry. Conclusions: This contrast enhanced SSRT clinical trial “dry run” was the last step before the phase I/II trial and shows the feasibility and readiness of the whole treatment chain.

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 mu m, spacing between beams 200-400 mu m) 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.