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International audience; BackgroundMicrobeam radiation therapy (MRT) is a treatment modality based on spatial fractionation of synchrotron generated x-rays into parallel, high dose, microbeams of a few microns width. MRT is still an under-development radiosurgery technique for which, promising preclinical results on brain tumors and epilepsy encourages its clinical transfer.PurposeA safe clinical transfer of MRT needs a specific treatment planning system (TPS) that provides accurate dose calculations in human patients, taking into account the MRT beams properties (high dose gradients, spatial fractionation, polarization effects). So far, the most advanced MRT treatment planning system, based on a hybrid dose calculation algorithm, is limited to a macroscopic rendering of the dose and does not account for the complex dose distribution inherent to MRT if delivered as conformal irradiations with multiple incidences. For overcoming these limitations, a multi-scale full Monte-Carlo calculation engine called penMRT has been developed and benchmarked against two general purpose Monte Carlo codes: penmain based on PENELOPE and Gate based on Geant4.MethodsPenMRT, is based on the PENELOPE (2018) Monte Carlo (MC) code, modified to take into account the voxelized geometry of the patients (CT-scans) and offering an adaptive micrometric dose calculation grid independent to the CT size, location and orientation. The implementation of the dynamic memory allocation in penMRT, makes the simulations feasible within a huge number of dose scoring bins. The possibility of using a source replication approach to simulate arrays of microbeams, and the parallelization using OpenMPI have been added to penMRT in order to increase the calculation speed for clinical usages. This engine can be implemented in a TPS as a dose calculation core.ResultsThe performance tests highlight the reliability of penMRT to be used for complex irradiation conditions in MRT. The benchmarking against a standard PENELOPE code did not show any significant difference for calculations in centimetric beams, for a single microbeam and for a microbeam array. The comparisons between penMRT and Gate as an independent MC code did not show any difference in the beam paths, whereas in valley regions, relative differences between the two codes rank from 1 to 7.5% which are probably due to the differences in physics lists that are used in these two codes. The reliability of the source replication approach has also been tested and validated with an underestimation of no more than 0.6% in low dose areas.ConclusionsGood agreements (a relative difference between 0 to 8%) were found when comparing calculated peak to valley dose ratio (PVDR) values using penMRT, for irradiations with a full microbeam array, with calculated values in the literature. The high-resolution calculated dose maps obtained with penMRT are used to extract differential and cumulative dose-volume histograms (DVHs) and analyze treatment plans with much finer metrics regarding the irradiation complexity. To our knowledge, these are the first high-resolution dose maps and associated DVHs ever obtained for cross-fired microbeams irradiation, which is bringing a significant added value to the field of treatment planning in spatially fractionated radiation therapy.

When investigating the promise of novel therapeutic modalities, the choice of an appropriate and reproducible in vivo model is critical to determine the relevance of the findings. In the case of glioblastoma, a high-grade glioma tumor that is clinically characterized by a high infiltrative pattern, no existing model exactly mimics the clinical features of these tumors. However, a syngeneic rat model of glioblastoma in which F98 cells are orthotopically implanted can recapitulate most of the characteristics of glioma as observed in patients, including a highly aggressive nature, a high degree of infiltration of cancer cells into healthy tissue, and a strong resistance to commonly used treatments including radiotherapy and chemotherapy. Here, we provide a detailed protocol to stereotaxically implant F98 cells in the rat brain and obtain a reproducible and clinically representative glioma model in rodents.

The high potential of microbeam radiation therapy (MRT) in improving tumor control while 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 3-dimensional conformal MRT can be safely delivered as exclusive radiosurgical treatment in animal patients METHODS AND MATERIALS: We irradiated a 17.5-kg French bulldog for a spontaneous brain tumor (glioma suspected on magnetic resonance imaging) with conformal high-dose-rate microbeam arrays (50-µm-wide microbeams, replicated with a pitch of 400 μm) of synchrotron-generated x-rays. The dose prescription adjusted a minimal cumulated valley dose of 2.8 Gy to the plnning target volume (PTV) (cinical target volume (CTV)+ 1 mm). Thus, each beam delivered 20 to 25 Gy to the target as peak doses, and ∼1 Gy 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. Magnetic resonance imaging, performed 3 months after irradiation, revealed reduction in tumor size (-87.4%) and mass effect with normalization of the left lateral ventricle.To our knowledge, this neuro-oncologic veterinary trial is the first 3-dimensional conformal synchrotron x-ray MRT treatment of a spontaneous intracranial tumor in a large animal. It is an essential last step toward the clinical transfer of MRT in the near future to demonstrate the feasibility and safety of treating deep-seated tumors using synchrotron-generated microbeams.

Les complications extra-pulmonaires du SARS-CoV-2 sont de plus en plus décrites dans la littérature. Actuellement, la prévalence de complications cardiologiques s’élève aux alentours de 20%.Nous rapportons le cas d’une patiente de 78 ans ayant développé un épanchement péricardique avec signe de compression ventriculaire droite des suites d’une infection par SARS-CoV-2. À notre connaissance uniquement 3 autres cas d’épanchement péricardique sont répertoriés. Nous présentons le premier cas d’épanchement péricardique sur SARS-CoV-2 sans atteinte myocardique associée.

International audience; This presentation will focus on two applications of diamond detectors in the field of innovative radiotherapies.The first one consists of a beam hodoscope for hadrontherapy (proton or carbon ion beams). This detector will be used for position and time stamp of the incident particle beam, in order to detect secondary particles (mainly prompt-gammas). Time of Flight is used to reduce background from massive particles, and select photons issued from the patient only. This detector will be made of a mosaic assembly of several diamond plates with double-side strip metallization. The electronic readout design will enable high count rate and high time resolution of the detector.Preliminary measurements were performed at ARRONAX with 68 MeV protons. Detection efficiency was measured with mono- and polycrystalline diamond detectors. For the latter, up to 95% efficiency (corrected from noise triggering) was obtained for single-proton detection. The time resolution was close to 100ps rms for prompt gamma detection using diamond and fast scintillators for incoming particles and secondary photon detection, respectively. The potential for ultra-fast timing in prompt gamma imaging leads to spatial discrimination and real time reconstruction capabilities for range verification during treatment.The second application consists in the in vivo monitoring of Microbeam Radiation Therapy. The beam is spatially fractionated with local doses above 1000 Gy/s delivered in narrow peaks of a few tens of μm, separated by 300-500μm. A large area diamond detector with 1D position readout by fast- and high-dynamics charge integration will be used to monitor the transmitted photon beam, and thus evaluate the energy deposited in the patient.

International audience; Highlights •MRT is a form of synchrotron generated X-ray radiosurgery dedicated to brain tumours. •Normal tissue tolerates high X-ray dose thanks through lattice of microbeams. •MRT operates at very high dose rate (kGy·s−1) and triggers FLASH effect in vivo.AbstractThis paper reviews the current state of the art of an emerging form of radiosurgery dedicated to brain tumour treatment and which operates at very high dose rate (kGy·s−1). Microbeam Radiation Therapy uses synchrotron-generated X-rays which triggered normal tissue sparing partially mediated by FLASH effect.

International audience; Highlights •A methodology has been developed for patient specific quality assurance in MRT. •The segmentation of peaks and valleys doses can be done on Gafchromic films for direct comparisons with MRT treatment plan. •Gamma-index tests performed on normalised dose distributions exhibit over 90% passing rate. •Some discrepancies remain on the absolute isocenter doses and require further investigation. •Despite these discrepancies, large animal MRT studies are starting at the ESRF based on valley doses prescription.AbstractMicrobeam radiation therapy (MRT) uses synchrotron arrays of X-ray microbeams to take advantage of the spatial fractionation effect for normal tissue sparing. In this study, radiochromic film dosimetry was performed for a treatment where MRT is introduced as a dose boost in a hypofractionated stereotactic radiotherapy (SRT) scheme. The isocenter dose was measured using an ionization chamber and two dimensional dose distributions were determined using radiochromic films. To compare the measured dose distribution to the MRT treatment plan, peak and valley were displayed in separate dosemaps. The measured and computed isocenter doses were compared and a two-dimensional 2%/2 mm normalized Math Eq-index analysis with a 90% passing rate criterion was computed. For SRT, a difference of 2.6% was observed in the dose at the isocenter from the treatment plan and film measurement, with a passing rate of 96% for the Math Eq-index analysis. For MRT, peak and valley doses differences of 25.6% and 8.2% were observed, respectively but passing rates of 96% and 90% respectively were obtained from the normalized Math Eq-index maps. The differences in isocenter doses measured in MRT should be further investigated. We present the methodology of patient specific quality assurance (QA) for studying MRT dose distributions and discuss ideas to improve absolute dosimetry. This patient specific QA will be used for large animal trials quality assurance where MRT will be administered as a dose boost in conventional SRT. The observed remaining discrepancies should be studied against approximations in the TPS phantom materials, beams characteristics or film read-out procedures.

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.

Purpose: Modern radiotherapy modalities often use small or nonstandard fields to ensure highly localized and precise dose delivery, challenging conventional clinical dosimetry protocols. The emergence of preclinical spatially fractionated synchrotron radiotherapies with high dose-rate, sub-millimetric parallel kilovoltage x-ray beams, has pushed clinical dosimetry to its limit. A commercially available synthetic single crystal diamond detector designed for small field dosimetry has been characterized to assess its potential as a dosimeter for synchrotron microbeam and minibeam radiotherapy. Methods: Experiments were carried out using a synthetic diamond detector on the imaging and medical beamline (IMBL) at the Australian Synchrotron. The energy dependence of the detector was characterized by cross-referencing with a calibrated ionization chamber in monoenergetic beams in the energy range 30–120 keV. The dose-rate dependence was measured in the range 1–700 Gy/s. Dosimetric quantities were measured in filtered white beams, with a weighted mean energy of 95 keV, in broadbeam and spatially fractionated geometries, and compared to reference dosimeters. Results: The detector exhibits an energy dependence; however, beam quality correction factors (kQ) have been measured for energies in the range 30–120 keV. The kQ factor for the weighted mean energy of the IMBL radiotherapy spectrum, 95 keV, is 1.05 ± 0.09. The detector response is independent of dose-rate in the range 1–700 Gy/s. The percentage depth dose curves measured by the diamond detector were compared to ionization chambers and agreed to within 2%. Profile measurements of microbeam and minibeam arrays were performed. The beams are well resolved and the full width at halfmaximum agrees with the nominal width of the beams. The peak to valley dose ratio (PVDR) calculated from the profiles at various depths in water agrees within experimental error with PVDR calculations from Gafchromic film data. Conclusions: The synthetic diamond detector is now well characterized and will be used to develop an experimental dosimetry protocol for spatially fractionated synchrotron radiotherapy.

The functional roles of the Caudate nucleus (Cd) are well known. Selective Cd lesions can be found in neurological disorders. However, little is known about the dynamics of the behavioral changes during progressive Cd ablation. Current stereotactic radiosurgery technologies allow the progressive ablation of a brain region with limited adverse effects in surrounding normal tissues. This could be of high interest for the study of the modified behavioral functions in relation with the degree of impairment of the brain structures. Using hypofractionated stereotactic radiotherapy combined with synchrotron microbeam radiation, we investigated, during one year after irradiation, the effects of unilateral radio-ablation of the right Cd on the behavior of Yucatan minipigs. The right Cd was irradiated to a minimal dose of 35.5 Gy delivered in three fractions. MRI-based morphological brain integrity and behavioral functions, i.e. locomotion, motivation/hedonism were assessed. We detected a progressive radio-necrosis leading to a quasi-total ablation one year after irradiation, with an additional alteration of surrounding areas. Transitory changes in the motivation/hedonism were firstly detected, then on locomotion, suggesting the influence of different compensatory mechanisms depending on the functions related to Cd and possibly some surrounding areas. We concluded that early behavioral changes related to eating functions are relevant markers for the early detection of ongoing lesions occurring in Cd-related neurological disorders.

Introduction The aim of this single-center prospective study is to compare two commercially available S100ß kits (the Roche® Elecsys and the Diasorin® Liaison S100 kits) in terms of analytical and clinical performances in a population admitted in the emergency room for mild traumatic brain injury (mTBI). Material and method 110 patients were enrolled from September 2014 to May 2015. Blood sample draws were performed within 3 h after head trauma and the study population was split into pediatric and adult subpopulations (> 18 years of age). Results Although both kits correlated well, we observed a significant difference in terms of S100ßlevels (P value < 0.05) in both subpopulations. In the pediatric subpopulation, both kits showed elevated S100ß levels for the only patient (3.5%) who displayed abnormal findings on a CT-scan. However, we observed a poor agreement between both kits (Cohen's kappa = 0.345, P value = 0.077). In the adult subpopulation, a total of 10 patients (12.2%) had abnormal head computed tomography scans. Using the Roche® (cut off = 0.1 μg/L) and the Diasorin® (cut off = 0.15 μg/L) S100ß kits, brain injuries were detected with a sensitivity of 100% (95% CI: 65–100%) and 100% (95% CI: 63–100%) and a specificity of 15.28% (95% CI: 7.9–25.7%) and 24.64% (95% CI: 15–36.5) respectively. Finally, a moderate agreement was concluded between both kits (Cohen's kappa = 0.569, P value = 0.001). Conclusion Although a good correlation could be found between both kits, emergency physicians should be aware of discrepancies observed between both methods, making those immunoassays not interchangeable. Furthermore, more studies are still needed to validate cut off used according to technique and to age, especially in the population below the age of 2 years.

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 mm3 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.

International audience; Microbeam radiation therapy has demonstrated superior normal tissue sparing properties compared to broad-beam radiation fields. The ratio of the microbeam peak dose to the valley dose (PVDR), which is dependent on the X-ray energy/spectrum and geometry, should be maximised for an optimal therapeutic ratio. Simulation studies in the literature report the optimal energy for MRT based on the PVDR. However, most of these studies have considered different microbeam geometries to that at the Imaging and Medical Beamline (50 μm beam width with a spacing of 400 μm). We present the first fully experimental investigation of the energy dependence of PVDR and microbeam penumbra. Using monochromatic X-ray energies in the range 40–120 keV the PVDR was shown to increase with increasing energy up to 100 keV before plateauing. PVDRs measured for pink beams were consistently higher than those for monochromatic energies similar or equivalent to the average energy of the spectrum. The highest PVDR was found for a pink beam average energy of 124 keV. Conversely, the mi-crobeam penumbra decreased with increasing energy before plateauing for energies above 90 keV. The effect of bone on the PVDR was investigated at energies 60, 95 and 120 keV. At depths greater than 20 mm beyond the bone/water interface there was almost no effect on the PVDR. In conclusion, the optimal energy range for MRT at IMBL is 90–120 keV, however when considering the IMBL flux at different energies, a spectrum with 95 keV weighted average energy was found to be the best compromise.

International audience; La principale problématique en radiothérapie anticancéreuse est de délivrer une dose maximale (énergie absorbée par unité de masse) de rayonnements ionisants à la cible, tout en épargnant les tissus sains avoisinants. Une option prometteuse, permettant d’atteindre cet effet différentiel significativement plus élevé dans le cadre du traitement de petites lésions cérébrales isolées, est l’utilisation de matrices de microfaisceaux de rayons x à très forts débits de dose [1]. La radiothérapie par micro-faisceaux (MRT) est une technique de radiothérapie innovante, basée sur le fractionnement spatial de la dose en utilisant des matrices de micro-faisceaux de rayons-x parallèles, d’une largeur comparable à celle d’un cheveu (~ 50 micromètres) et séparés par des zones qui ne voient que le rayonnement diffusé. De nombreuses études précliniques ont démontré que la MRT augmente significativement la dose administrée à la tumeur par rapport à la radiothérapie conventionnelle tout en permettant de mieux préserver les tissus sains sur le trajet des faisceaux d’irradiation [2]. Bien que la MRT soit actuellement limitée à la recherche dans les établissements de rayonnement synchrotron en raison du débit de dose très élevé requis pour sa mise en contrôle (5 000 fois plus élevé que la radiothérapie clinique), les cliniciens et les chercheurs collaborent étroitement avec les scientifiques du synchrotron pour transférer cette technique vers les essais cliniques.Le principal verrou d’un point de vue des problématiques de physique médicale associées à cette technique concerne la dosimétrie expérimentale (méthodes physiques permettant de mesurer quantitativement l’énergie absorbée par unité de masse dans les tissus irradiés, ou dans un mileu équivalent). En effet au regard de la taille des faisceaux et des débits de dose associés, Nous sommes très proches limites théoriques des méthodes existantes. Par exemple, le transfert clinique de la MRT nécessite la mise en oeuvre de codes de pratique cliniques pour la mesure de la dose qui, bien qu’ils soient établis dans la radiothérapie clinique conventionnelle, ils ne sont pas applicables à la MRT en raison du spectre des rayons X, des débit de dose élevés et des limitations des détecteurs [3].L’objectif de cette présentation est de faire un état des lieux des solutions dosimétriques existantes pour la MRT et de proposer quelques pistes permettant un contrôle encore plus précis de la dose.

International audience; Microbeam and minibeam radiation therapies (MRT and MBRT, respectively) are preclinical radiation therapy modalities being developed at several biomedical synchrotron beamlines and involve the collimation of synchrotron x-ray beams into an array of spatially fractionated quasiparallel beams. Spatial fractionation exploits the dose-volume effect, where the threshold dose for damage to normal tissues increases as the volume of irradiated tissue decreases. Very large doses of radiation can be delivered to a tumor while sparing surrounding normal tissues, thereby satisfying the clinical goal.

International audience; 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.

Modern radiotherapy modalities often use small or nonstandard fields to ensure highly localized and precise dose delivery, challenging conventional clinical dosimetry protocols. The emergence of preclinical spatially fractionated synchrotron radiotherapies with high dose-rate, sub-millimetric parallel kilovoltage x-ray beams, has pushed clinical dosimetry to its limit. A commercially available synthetic single crystal diamond detector designed for small field dosimetry has been characterized to assess its potential as a dosimeter for synchrotron microbeam and minibeam radiotherapy.Experiments were carried out using a synthetic diamond detector on the imaging and medical beamline (IMBL) at the Australian Synchrotron. The energy dependence of the detector was characterized by cross-referencing with a calibrated ionization chamber in monoenergetic beams in the energy range 30-120 keV. The dose-rate dependence was measured in the range 1-700 Gy/s. Dosimetric quantities were measured in filtered white beams, with a weighted mean energy of 95 keV, in broadbeam and spatially fractionated geometries, and compared to reference dosimeters.The detector exhibits an energy dependence; however, beam quality correction factors (kQ) have been measured for energies in the range 30-120 keV. The kQ factor for the weighted mean energy of the IMBL radiotherapy spectrum, 95 keV, is 1.05 ± 0.09. The detector response is independent of dose-rate in the range 1-700 Gy/s. The percentage depth dose curves measured by the diamond detector were compared to ionization chambers and agreed to within 2%. Profile measurements of microbeam and minibeam arrays were performed. The beams are well resolved and the full width at halfmaximum agrees with the nominal width of the beams. The peak to valley dose ratio (PVDR) calculated from the profiles at various depths in water agrees within experimental error with PVDR calculations from Gafchromic film data.The synthetic diamond detector is now well characterized and will be used to develop an experimental dosimetry protocol for spatially fractionated synchrotron radiotherapy.

Purpose: An adequate dosimetry protocol for synchrotron radiation and the specific features of the ID17 Biomedical Beamline at the European Synchrotron Radiation Facility are essential for the preparation of the forthcoming clinical trials in the synchrotron stereotactic radiation therapy (SSRT). The main aim of this work is the definition of a suitable protocol based on standards of dose absorbed to water. It must allow measuring the absolute dose with an uncertainty within the recommended limits for patient treatment of 2%-5%. Methods: Absolute dosimetry is performed with a thimble ionization chamber (PTW semiflex 31002) whose center is positioned at 2 g cm{sup -2} equivalent depth in water. Since the available synchrotron beam at the ESRF Biomedical Beamline has a maximum height of 3 mm, a scanning method was employed to mimic a uniform exposition of the ionization chamber. The scanning method has been shown to be equivalent to a broad beam irradiation. Different correction factors have been assessed by using Monte Carlo simulations. Results: The absolute dose absorbed to water at 80 keV was measured in reference conditions with a 2% global uncertainty, within the recommended limits. The dose rate was determined to be in the range between 14 and 18more » Gy/min, that is to say, a factor two to three times higher than the 6 Gy/min achievable in RapidArc or VMAT machines. The dose absorbed to water was also measured in a RW3 solid water phantom. This phantom is suitable for quality assurance purposes since less than 2% average difference with respect to the water phantom measurements was found. In addition, output factors were assessed for different field sizes. Conclusions: A dosimetry protocol adequate for the specific features of the SSRT technique has been developed. This protocol allows measuring the absolute dose absorbed to water with an accuracy of 2%. It is therefore satisfactory for patient treatment.« less

International audience; The first trial applications of Contrast-Enhanced Synchrotron Stereotactic Radiation Therapy (SSRT) is underway since June 2012 at the European Synchrotron Radiation Facility (ESRF) in Grenoble (France). The phase I-II clinical trial is designed to test the feasibility and safety of SSRT through a dose escalation protocol. Contrast enhanced radiotherapy achieves localized dose enhancement due to higher photoelectric effect rate in the target. This increase is obtained through the preferential uptake of high-Z media (iodine) in the tumoral area combined with irradiations with medium energy synchrotron x-rays. In vivo dosimetry (i.e. experimental dosimetry in real time during the treatment) would be a serious added value to the project, in terms of online dose monitoring and quality control. It is challenging to perform in vivo dosimetry with the currently available conventional clinical techniques. In this work we investigated a method using x-ray fluorescence detection to derive the iodine concentration contained in a tumor during the treatment of a patient, as a first step towards in vivo dosimetry. A mean iodine concentration of 0.33 ± 0.22 mg/ml has been retrieved in the tumor of the patient compared to 2 mg/ml expected would correspond to 3% local dose enhancement in the tumor. Further work will be performed to improve the attenuation correction method. The expected amount of iodine should be 2 mg/ml in the tumor (20% dose enhancement). This method is suitable to detect iodine in the target but has some problem in quantifying the real amount of iodine present during the irradiation.

PURPOSE: Synchrotron stereotactic radiotherapy (SSRT) is a treatment that involves the targeting of high-Z elements into tumors followed by stereotactic irradiation with monochromatic x-rays from a synchrotron source, tuned at an optimal energy. The irradiation geometry, as well as the secondary particles generated at a higher yield by the medium energy x-rays on the high-Z atoms (characteristic x-rays, photoelectrons, and Auger electrons), produces a localized dose enhancement in the tumor. Iodine-enhanced SSRT with systemic injections of iodinated contrast agents has been successfully developed in the past six years in the team, and is currently being transferred to clinical trials. The purpose of this work is to study the impact on the SSRT treatment of the contrast agent type, the beam quality, the irradiation geometry, and the beam weighting for defining an optimized SSRT treatment plan. METHODS: Theoretical dosimetry was performed using the MCNPX particle transport code. The simulated geometry was an idealized phantom representing a human head. A virtual target was positioned in the central part of the phantom or off-centered by 4 cm. The authors investigated the dosimetric characteristics of SSRT for various contrast agents: Iodine, gadolinium, and gold; and for different beam qualities: Monochromatic x-ray beams from a synchrotron source (30-120 keV), polychromatic x-ray beams from an x-ray tube (80, 120, and 180 kVp), and a 6 MV x-ray beam from a linear accelerator. Three irradiation geometries were studied: One arc or three noncoplanar arcs dynamic arc therapy, and an irradiation with a finite number of beams. The resulting dose enhancements, beam profiles, and histograms dose volumes were compared for iodine-enhanced SSRT. An attempt to optimize the irradiation scheme by weighing the finite x-ray beams was performed. Finally, the optimization was studied on patient specific 3D CT data after contrast agent infusion. RESULTS: It was demonstrated in this study that an 80 keV beam energy was a good compromise for treating human brain tumors with iodine-enhanced SSRT, resulting in a still high dose enhancement factor (about 2) and a superior bone sparing in comparison with lower energy x-rays. This beam could easily be produced at the European Synchrotron Radiation Facility medical beamline. Moreover, there was a significant diminution of dose delivered to the bone when using monochromatic x-rays rather than polychromatic x-rays from a conventional tube. The data showed that iodine SSRT exhibits a superior sparing of brain healthy tissue in comparison to high energy treatment. The beam weighting optimization significantly improved the treatment plans for off-centered tumors, when compared to nonweighted irradiations. CONCLUSIONS: This study demonstrated the feasibility of realistic clinical plans for low energy monochromatic x-rays contrast-enhanced radiotherapy, suitable for the first clinical trials on brain metastasis with a homogeneous iodine uptake.

International audience; We have evaluated the efficacy of intracerebral (i.c.) convection-enhanced delivery (CED) of cisplatin in combination with photon irradiation for the treatment of F98 glioma-bearing rats. One thousand glioma cells were stereotactically implanted into the brains of Fischer rats and 13 days later cisplatin (6 microg/20 microl) was administered i.c. by CED at a flow rate of 0.5 microl/min. On the following day the animals were irradiated with a single 15 Gy dose of X-rays, administered by a linear accelerator (LINAC) or 78.8 keV synchrotron X-rays at the European Synchrotron Radiation Facility (ESRF). Untreated controls had a mean survival time (MST) + or - standard error of 24 + or - 1 days compared to >59 + or - 13 days for rats that received cisplatin alone with 13% of the latter surviving >200 days. Rats that received cisplatin in combination with either 6 MV (LINAC) or 78.8 keV (synchrotron) X-rays had almost identical MSTs of >75 + or - 18 and >74 + or - 19 days, respectively with 17 and 18% long-term survivors. Microscopic examination of the brains of long-term surviving rats revealed an absence of viable tumor cells and cystic areas at the presumptive site of the tumor. Our data demonstrate that i.c. CED of cisplatin in combination with external X-irradiation significantly enhanced the survival of F98 glioma-bearing rats. This was independent of the X-ray beam energy and probably was not due to the production of Auger electrons as we previously had postulated. Our data provide strong support for the approach of concomitantly administering platinum-based chemotherapy in combination with radiotherapy for the treatment of brain tumors. Since a conventional LINAC can be used as the radiation source, this should significantly broaden the clinical applicability of this approach compared to synchrotron radiotherapy, which could only be carried out at a very small number of specialized facilities.

International audience; Iodine-enhanced synchrotron stereotactic radiotherapy takes advantage of the radiation dose-enhancement produced by high-Z elements when irradiated with mono-energetic beams of synchrotron X-rays. In this study it has been investigated whether therapeutic efficacy could be improved using a thymidine analogue, 5-iodo-2'-deoxyuridine (IUdR), as a radiosentizing agent. IUdR was administered intracerebrally over six days to F98 glioma-bearing rats using Alzet osmotic pumps, beginning seven days after tumor implantation. On the 14th day, a single 15 Gy dose of 50 keV synchrotron X-rays was delivered to the brain. Animals were followed until the time of death and the primary endpoints of this study were the mean and median survival times. The median survival times for irradiation alone, chemotherapy alone or their combination were 44, 32 and 46 days, respectively, compared with 24 days for untreated controls. Each treatment alone significantly increased the rats' survival in comparison with the untreated group. Their combination did not, however, significantly improve survival compared with that of X-irradiation alone or chemotherapy alone. Further studies are required to understand why the combination of chemoradiotherapy was no more effective than X-irradiation alone.

Synchrotron radiation is an innovative tool for the treatment of brain tumors. In the stereotactic synchrotron radiation therapy (SSRT) technique a radiation dose enhancement specific to the tumor is obtained. The tumor is loaded with a high atomic number (Z) element and it is irradiated in stereotactic conditions from several entrance angles. The aim of this work was to assess dosimetric properties of the SSRT for preparing clinical trials at the European Synchrotron Radiation Facility (ESRF). To estimate the possible risks, the doses received by the tumor and healthy tissues in the future clinical conditions have been calculated by using Monte Carlo simulations (PENELOPE code). The dose enhancement factors have been determined for different iodine concentrations in the tumor, several tumor positions, tumor sizes, and different beam sizes. A scheme for the dose escalation in the various phases of the clinical trials has been proposed. The biological equivalent doses and the normalized total doses received by the skull have been calculated in order to assure that the tolerance values are not reached.

International audience; 1. There is an increasing demand in diagnostic radiology for extracting additional morphological and functional quantitative parameters from three-dimensional computed tomography (CT) images. Synchrotron radiation computed tomography (SRCT) is the state-of-the-art method in preclinical X-ray CT, because its performance is close to the theoretical limits in terms of accuracy and precision. 2. The SRCT method with monochromatic X-ray beams yields absolute high-Z element contrast agent concentrations, without errors arising from beam hardening or scatter artefacts, by using digital subtraction techniques of the sinograms. Each pixel of the reconstructed difference images provides a quantitative concentration versus time curve of inhaled or injected high-Z contrast agents (xenon or iodine) with a high sensitivity. This is the key point of two functional imaging techniques that were developed at the European Synchrotron Radiation Facility: brain perfusion and lung function (ventilation and perfusion). 3. These two imaging techniques provide parametric images expressed in absolute perfusion parameters (blood volume, blood flow, mean transit time and capillary permeability) or ventilation parameters (lung volume, regional lung ventilation, bronchial lumen size, regional airway and lung compliance) with a high accuracy and precision. 4. The aim of the present brief review is to give a snapshot of the status and perspectives of these two imaging techniques, with emphasis on the performances and interests for functional imaging. Two separate sections will then describe the results obtained so far using SRCT as an in vivo functional imaging tool for measuring changes in haemodynamics and ventilation, in the investigation of experimental pathophysiology and in the effects of therapeutic intervention.

Introduction: The group Developments and Application for Medicine of the LPSC, in collaboration with the Public Hospital of Grenoble, is developing the TraDeRa detector (Transparent Detector for Radiotherapy). This device includes an ionization chambers matrix and provides 2D signal maps for any irradiation field, upstream to the patient. Converting the detector's signal into dose in the patient is a challenge. To do so, Monte Carlo simulation is a powerful tool, and will give accurate results if correctly parameterized. The work described here focuses on the optimization of the treatment head simulation (especially on the target, the source of X-rays) and the determination of the correct nominal energy and radial distribution of electrons on the target. In order to calibrate the detector, one must reach a perfect agreement between the observables from the simulation and from the beam of our reference accelerator. Methods: The interactions of the electrons in the target are numerous and time consuming to simulate. A study was conducted on both parameters of different particles transport methods and variance reduction in PENELOPE Monte Carlo code, which remains a reference for electron transport for the considered energies [1]. We have optimized a set of parameters to keep a reasonable computation time without biasing the physical observables. The determination of the initial characteristics of the electron beam (nominal energy/radial distribution of electrons on the target) is done by trial and error process. Several simulations are performed at various energies and radial electron distributions. The dose deposited in a simulated water phantom is compared with the depth-dose curves and dose profiles acquired under irradiation. We propose two efficient methods of comparison, the calculation of the Kolmogorov-Smirnov test and an original extension with more sensitivity. Results: The set of optimized parameters provides an overall increase on the simulation efficiency of nearly 300%. The useful secondary particles generation rate (stored in the PSF) was also increased by about 250%. Determining the characteristics of the electron accelerator of our reference beam is ongoing, we currently have simulated three energies around 6 MeV. In the appendix are presented the results of two comparative tests for these three energies. These tests including measurement uncertainties are robust and will accurately lead to the beam nominal energy with only five simulated energy sets. To date, the simulation has been running for six months on the IN2P3 computing center. Conclusions: The developed statistical tests are robust and will allow us to accurately determine the characteristics of the beam by comparing the simulated and the measured depth-dose curves and dose profiles. We will then be able to validate the reference accelerator simulation and calibrate the detector in terms of dose. This will allow us to reconstruct the 3D dose matrix in water from upstream information collected on a TraDeRa simulated model.

In Synchrotron stereotactic radiotherapy (SSR) the tumor is loaded with atoms of high atomic number (Z) element, and exposed to monochromatic X-rays from a synchrotron source (50–100 keV), in stereotactic conditions. This method is under investigation at the European Synchrotron Radiation Facility (ESRF) for the treatment of brain tumors. Conventional treatment planning systems are not suitable for SSR since the beam energy, the irradiation geometry and the presence of high Z elements differ from commercial systems. Therefore, SSR requires the development of new procedures for the evaluation of dose maps. Monte Carlo (MC) method offers the potential of calculating the dose in complicated geometries, made of heterogeneous materials. MC calculations were performed using the MCNP4C general purpose code. Gel dosimetry allows accurate experimental verification of three-dimensional absorbed dose distributions from any irradiation geometries. In this study, the Fricke chemical dosimeter was employed for it is easy to prepare without special facilities. Various phantoms filled with Fricke gel were irradiated in SSR configuration. The dose profiles obtained were compared with MC simulations.

International audience; An experimental binary radiotherapy proposes the concomitant use of a high-Z compound and synchrotron X rays for enhancing radiation dose selectively in tumours by a photoelectric effect. This study aimed at measuring the resulting dose enhancement in irradiated material. A doped Fricke gel dosemeter model was manufactured with 10 mg ml(-1) of iodine (Telebrix) or barium (Micropaque). Samples were irradiated with a monochromatic synchrotron beam at 33.5, 50, 65 and 80 keV. The ensuing enhancement of the sensitivity of the dosemeter was derived from the nuclear magnetic resonance relaxation rates measured at different X-ray doses. Our results demonstrate (1) the preservation of a linear relationship between relaxation rates and X-ray doses for dosemeters doped with high-Z atoms and (2) a clear energy-dependent sensitivity enhancement for barium-doped Fricke gels. This enhancement was neither reproducible with iodinated compounds nor clearly related to the expected dose enhancement factor. However 1% barium sulphate in the gel could significantly improve the gel's response when it was irradiated by low-energy X rays.

In synchrotron stereotactic radiotherapy (SSR) the tumor is loaded with a high Z element, and exposed to monochromatic x-rays from a synchrotron source, in stereotactic conditions. The SSR treatment efficiency is related to the heavy element concentration achievable in the tumor, to the radiation energy, and the irradiation geometry. The experimental dose verification of SSR in three dimensions with a good spatial resolution is highly desirable for radiotherapy. In this study, Fricke dosimeter and Monte Carlo calculations were employed for assessing 2D dose distribution.

Purpose Enhancement of the radiation dose delivered to a brain tumor can be achieved by infusing an iodinated contrast agent to the patient and irradiating with kilovoltage X-rays in computed tomography (CT) mode. Synchrotron sources, providing monochromatic tunable intense beams, are ideal for this treatment. The aim of this study is to assess in vivo the efficiency of this novel radiotherapy modality, Synchrotron Radiation CT-Therapy. Methods and materials Intracranial implantations of 105 F98 glioma cells were performed on 18 Fisher 344 rats. Six rats were untreated controls, six received radiotherapy alone (10 Gy in the tumor by single fraction tomographic irradiation at 50 keV), and six received the same radiotherapy treatment under a continuous infusion of iodinated contrast agent. Results The rats that received contrast agent during radiotherapy survived significantly longer than rats that received radiotherapy alone (p = 0.025). Mean survival times (mean ± SD) were 12.3 ± 0.8, 14.8 ± 2.8, and 18.2 ± 1.3 days; median survival times were 12.5, 15, and 18 days (untreated controls, irradiated without iodine, irradiated with iodine, respectively). The increase in life spans was 20% and 44% for the rats irradiated without or with iodine, respectively. Conclusions This method of radiation dose enhancement in brain tumors with synchrotron radiation significantly increases survival and appears highly promising.

Stereotactic Synchrotron Radiotherapy (SSRT) and Microbeam Radiation Therapy (MRT) are both novel approaches to treat brain tumor and potentially other tumors using synchrotron radiation. Although the techniques differ by their principles, SSRT and MRT share certain common aspects with the possibility of combining their advantages in the future. For MRT, the technique uses highly collimated, quasi-parallel arrays of X-ray microbeams between 50 and 600 keV. Important features of highly brilliant Synchrotron sources are a very small beam divergence and an extremely high dose rate. The minimal beam divergence allows the insertion of so called Multi Slit Collimators (MSC) to produce spatially fractionated beams of typically ~25e75 micron-wide microplanar beams separated by wider (100e400 microns center-to-center(ctc)) spaces with a very sharp penumbra. Peak entrance doses of several hundreds of Gy are extremely well tolerated by normal tissues and at the same time provide a higher therapeutic index for various tumor models in rodents. The hypothesis of a selective radio-vulnerability of the tumor vasculature versus normal blood vessels by MRT was recently more solidified. SSRT (Synchrotron Stereotactic Radiotherapy) is based on a local drug uptake of high-Z elements in tumors followed by stereotactic irradiation with 80 keV photons to enhance the dose deposition only within the tumor. With SSRT already in its clinical trial stage at the ESRF, most medical physics problems are already solved and the implemented solutions are briefly described, while the medical physics aspects in MRT will be discussed in more detail in this paper. © 2015 Published by Elsevier Ltd on behalf of Associazione Italiana di Fisica Medica. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

International audience; Contrast-enhanced radiotherapy is an innovative treatment that combines the selective accumulation of heavy elements in tumors with stereotactic irradiations using medium energy X-rays. The radiation dose enhancement depends on the absolute amount of iodine reached in the tumor and its time course. Quantitative, postinfusion iodine biodistribution and associated brain perfusion parameters were studied in human brain metastasis as key parameters for treatment feasibility and quality. Twelve patients received an intravenous bolus of iodinated contrast agent (CA) (40 mL, 4 mL/s), followed by a steady-state infusion (160 mL, 0.5 mL/s) to ensure stable intratumoral amounts of iodine during the treatment. Absolute iodine concentrations and quantitative perfusion maps were derived from 40 multislice dynamic computed tomography (CT) images of the brain. The postinfusion mean intratumoral iodine concentration (over 30 minutes) reached 1.94 ± 0.12 mg/mL. Reasonable correlations were obtained between these concentrations and the permeability surface area product and the cerebral blood volume. To our knowledge, this is the first quantitative study of CA biodistribution versus time in brain metastasis. The study shows that suitable and stable amounts of iodine can be reached for contrast-enhanced radiotherapy. Moreover, the associated perfusion measurements provide useful information for the patient recruitment and management processes.

Radiosensitization efficacy of gold nanoparticles (AuNPs) with low energy radiations (88keV) was evaluated in vitro and in vivo on rats bearing glioma. In vitro, a significant dose-enhancement factor was measured by clonogenic assays after irradiation with synchrotron radiation of F98 glioma cells in presence of AuNPs (1.9 and 15nm in diameter). In vivo, 1.9nm nanoparticles were found to be toxic following intracerebral delivery in rats bearing glioma, whether no toxicity was observed using 15nm nanoparticles at the same concentration (50mg/mL). The therapeutic efficacy of gold photoactivation was determined by irradiating the animals after intracerebral infusion of AuNPs. Survival of rats that had received the combination of treatments (AuNPs: 50mg/mL, 15Gy) was significantly increased in comparison with the survival of rats that had received irradiation alone. In conclusion, this experimental approach is promising and further studies are foreseen for improving its therapeutic efficacy. From the Clinical Editor These investigators report that gold nanoparticles of the correct size can be used to enhance the effects of irradiation in the context of a glioma model. Since many of the glioma varieties are currently incurable, this or similar approaches may find their way to clinical trials in the near future.

International audience; Purpose The purpose of this study was to evaluate high-dose single fraction delivered with monochromatic X-rays minibeams for the radiotherapy of primary brain tumors in rats. Methods and Materials Two groups of healthy rats were irradiated with one anteroposterior minibeam incidence (four minibeams, 123 Gy prescribed dose at 1 cm depth in the brain) or two interleaved incidences (54 Gy prescribed dose in a 5 × 5 × 4.8 mm3 volume centered in the right hemisphere), respectively. Magnetic resonance imaging (MRI) follow-up was performed over 1 year. T2-weighted (T2w) images, apparent diffusion coefficient (ADC), and blood vessel permeability maps were acquired. F98 tumor bearing rats were also irradiated with interleaved minibeams to achieve a homogeneous dose of 54 Gy delivered to an 8 × 8 × 7.8 mm3 volume centered on the tumor. Anatomic and functional MRI follow-up was performed every 10 days after irradiation. T2w images, ADC, and perfusion maps were acquired. Results All healthy rats were euthanized 1 year after irradiation without any clinical alteration visible by simple examination. T2w and ADC measurements remain stable for the single incidence irradiation group. Localized Gd-DOTA permeability, however, was observed 9 months after irradiation for the interleaved incidences group. The survival time of irradiated glioma bearing rats was significantly longer than that of untreated animals (49 ± 12.5 days versus 23.3 ± 2 days, p < 0.001). The tumoral cerebral blood flow and blood volume tend to decrease after irradiation. Conclusions This study demonstrates the sparing effect of minibeams on healthy tissue. The increased life span achieved for irradiated glioma bearing rats was similar to the one obtained with other radiotherapy techniques. This experimental tumor therapy study shows the feasibility of using X-ray minibeams with high doses in brain tumor radiotherapy.

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.

International audience; Cognitive dysfunction in the elderly commonly observed following anesthesia has been attributed to age-related neuronal changes exacerbated by pharmacotoxic effects. However, the extent to which these changes may persist following recovery from surgery is still largely unknown. This study investigates the long-term effects of anesthesia on cognitive functioning after orthopedic surgery in 270 elderly patients over the age of 65 who completed a computerized cognitive battery before and 8 days, 4 and 13 months after surgery. Their performance was compared to those of 310 elderly controls who completed the same neuropsychiatric evaluation at baseline and one-year interval. Multivariate analyses adjusted for socio-demographic variables, depressive symptomatology, vascular pathology as well as baseline cognitive performance. We found early and transient post-operative decline in reaction time and constructional praxis. With regard to long-term changes we observed improvement compared to controls in most verbal tasks (probably due to learning effects). On the other hand, a clear dissociation effect was observed for several areas of visuospatial functioning which persisted up to the 13-month follow-up. This specific pattern of visuospatial deficit was found to be independent of apolipoprotein E genotype and closely resembles what has recently been termed vascular mild cognitive impairment, in turn associated with subtle sub-cortical vascular changes. The observation of only minor differences between persons operated by general and regional anesthesia makes it difficult to attribute these changes directly to the anesthetic agents themselves, suggesting that cognitive dysfunction may be attributable at least in part to peri-operative conditions, notably stress and glucocorticoid exposure.

International audience

A hybrid approach, combining deterministic and Monte Carlo (MC) calculations, is proposed to compute the distribution of dose deposited during stereotactic synchrotron radiation therapy treatment. The proposed approach divides the computation into two parts: (i) the dose deposited by primary radiation (coming directly from the incident x-ray beam) is calculated in a deterministic way using ray casting techniques and energy-absorption coefficient tables and (ii) the dose deposited by secondary radiation (Rayleigh and Compton scattering, fluorescence) is computed using a hybrid algorithm combining MC and deterministic calculations. In the MC part, a small number of particle histories are simulated. Every time a scattering or fluorescence event takes place, a splitting mechanism is applied, so that multiple secondary photons are generated with a reduced weight. The secondary events are further processed in a deterministic way, using ray casting techniques. The whole simulation, carried out within the framework of the Monte Carlo code Geant4, is shown to converge towards the same results as the full MC simulation. The speed of convergence is found to depend notably on the splitting multiplicity, which can easily be optimized. To assess the performance of the proposed algorithm, we compare it to state-of-the-art MC simulations, accelerated by the track length estimator technique (TLE), considering a clinically realistic test case. It is found that the hybrid approach is significantly faster than the MC/TLE method. The gain in speed in a test case was about 25 for a constant precision. Therefore, this method appears to be suitable for treatment planning applications. © 2009 Institute of Physics and Engineering in Medicine.

Synchrotron stereotactic radiotherapy (SSR) is a treatment that involves selective accumulation of high-Z elements in tumours followed by stereotactic irradiation, in CT mode, with monochromatic X-rays from a synchrotron source, tuned at an optimal energy. The irradiation geometry, characteristic X-rays, photoelectrons, and Auger electrons generated on high-Z atoms by kilovoltage X-rays produce a localized dose enhancement. Two complimentary SSR approaches have been successfully developed in the past 5 years in our team, and may be promising in high-grade glioma management: iodine-enhanced SSR, with an iodinated contrast agent; and Pt-enhanced SSR; a concomitant radio-chemotherapy treatment with locoregional injection of platinated chemotherapy drugs. The results for iodine-enhanced SSR using contrast agents are presented in this paper. IUdR-enhanced SSR was also tested in this study. Up to 15 Gy, intracarotid infusion of iodine significantly improved the rats' survival compared to irradiation alone. SSR provides the most protracted survivals of F98 glioma-bearing rats. The technique is currently transferred to clinical trials. Iodine-enhanced SSR will be implemented first, because of its simplicity; and pave the way for Pt-enhanced SSR, the most efficient technique, but still needing to be improved in terms of intrinsic toxicity.

International audience; Synchrotron stereotactic radiotherapy (SSR) is a radiotherapy technique that makes use of the interactions of monochromatic low energy x-rays with high atomic number (Z) elements. An important dose-enhancement can be obtained if the target volume has been loaded with a sufficient amount of a high-Z element, such as iodine. In this study, we compare experimental dose measurements, obtained with normoxic polymer gel (nPAG), with Monte Carlo computations. Gels were irradiated within an anthropomorphic head phantom and were read out by magnetic resonance imaging. The dose-enhancement due to the presence of iodine in the gel (iodine concentration: 5 and 10 mg ml(-1)) was measured at two radiation energies (35 and 80 keV) and was compared to the calculated factors. nPAG dosimetry was shown to be efficient for measuring the sharp dose gradients produced by SSR. The agreement between 3D gel dosimetry and calculated dose distributions was found to be within 4% of the dose difference criterion and a distance to agreement of 2.1 mm for 80% of the voxels. Polymer gel doped with iodine exhibited higher sensitivity, in good agreement with the calculated iodine-dose enhancement. We demonstrate in this preliminary study that iodine-doped nPAG could be used for measuring in situ dose distributions for iodine-enhanced SSR treatment.

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

Purpose: Heavy-atom-enhanced synchrotron stereotactic radiotherapy (SSR) is a treatment that involves selective accumulation of high-Z elements in tumors followed by stereotactic irradiation with X-rays from a synchrotron source. The purpose of this study was to determine whether the efficacy of iodine-enhanced SSR could be further improved in the F98 rodent glioma model, by using a concomitant injection of an iodinated contrast agent and a transient blood–brain barrier opener (mannitol) during irradiation. Methods and Materials: Fourteen days after intracerebral inoculations of F98 cells, the rats were irradiated with 50-keV X-rays while receiving an infusion of hyperosmotic mannitol with iodine, either intravenously or via the carotid (9 to 15 rats per group, 117 rats total). Results: For doses ≤15 Gy, the intracarotid infusion of mannitol and iodine improved the rats’ survival compared with intravenous injection or irradiation alone. The percentage-increased life spans (ILS) were 91%, 116%, and 169% without iodine, after infusion of iodine and mannitol intravenously, and intracarotid, respectively (15 Gy). At 25 Gy, the rats irradiated without iodine had the longest survival (ILS = 607%), but no additional benefit was obtained with iodine and mannitol. Conclusions: Iodine-enhanced SSR is significantly improved with concomitant intracarotid infusion of iodine and mannitol for radiation doses ≤15 Gy.

International audience; PURPOSE: Synchrotron stereotactic radiotherapy (SSR) is a binary cancer treatment modality that involves the selective accumulation of a high Z element, such as iodine, in tumors, followed by stereotactic irradiation with kilovoltage X-rays from a synchrotron source. The success of SSR is directly related to the absolute amount of iodine achievable in the tumor. The purposes of this preclinical study were to determine whether the delivery of iodine to brain tumor models in rats could be enhanced by the means of its intracarotid injection with or without a hyperosmotic solution and to evaluate corresponding absorbed X-ray doses. METHODS AND MATERIALS: Experiments were performed on four groups of F98 glioma-bearing rats, which received either intracarotid (IC) or intravenous (IV) infusions of a mixture (6 mL in 12 min) of an iodinated contrast agent associated or not with a transient blood-brain barrier opener (mannitol). The mixture volumetric proportions were 8/13 of Iomeron (C = 350 mg/mL) for 5/13 of mannitol or saline, respectively. Absolute iodine concentration kinetic was measured in vivo in the tumor, blood, contralateral and ipsilateral brain, and muscle by monochromatic computed tomography. Associated dosimetry was performed by computing the iodine dose enhancement factor (DEF) in each region and building dose distribution maps by analytical simulations. RESULTS: Infusion of mannitol significantly enhanced iodine tumor uptake compared with the control values (p < 0.0001 and p = 0.0138, for IC and IV protocols, respectively). The mean iodine concentrations (C) reached 20.5 +/- 0.98 mg/mL (DEF = 4.1) after administration of iodine and mannitol vs. 4.1 +/- 1.2 mg/mL i.c. with serum (DEF = 1.6). The tumor iodine uptakes after jugular injection with mannitol (C = 4.4 +/- 2.1 mg/mL, DEF = 1.7) were not significantly different from IC injection of iodine without mannitol (p = 0.8142). The IV injection of iodine with saline led to an iodine concentration in the tumor of 1.2 +/- 0.98 mg/mL and a DEF of 1.2. CONCLUSIONS: This study established that optimizing the delivery of iodine by means of IC injection combined with a blood-brain barrier opener (mannitol) significantly increases the iodine uptake of F98 rat gliomas. This infusion protocol could potentially enhance the efficacy of SSR treatment, because the radiation dose is proportional to the iodine amount present in the irradiation bed.

The authors previously provided evidence of synchrotron radiation computed tomography (SRCT) efficacy for quantitative in vivo brain perfusion measurements using monochromatic X-ray beams. However, this technique was limited for small-animal studies by partial volume effects. In this paper, high-resolution absolute cerebral blood volume and blood–brain barrier permeability coefficient measurements were obtained on a rat glioma model using SRCT and a CCD camera (47 × 47 μm2 pixel size). This is the first report of in vivo high-resolution brain vasculature parameter assessment. The work gives interesting perspectives to quantify brain hemodynamic changes accurately in healthy and pathological small animals.

Introduction Contrast-enhanced stereotactic synchrotron radiotherapy (SSRT) is an innovative treatment based on localized dose enhancement effects obtained by reinforced photoelectric absorption in brain tumors. Tumors previously loaded with high-Z elements are irradiated using medium-energy monochromatic x-rays (50–100 keV). The aim of this study is to compare SSRT treatment in the presence and absence of iodine enhancement. For a single case, SSRT was compared to conventional treatments: 3D conformational radiotherapy, modulated radiation therapy (IMRT) and dynamic stereotactic arc-therapy. Material and methods Patients bearing brain metastasis received a standard helical 3D-scan without iodine. A second scan was acquired 13 min after an 80 g iodine infusion. Two SSRT treatment plans (with/without iodine) were performed for each patient. A dedicated Monte Carlo (MC) treatment planning system (TPS) based on the ISOgray TPS was developed for this purpose. Ten coplanar beams (6 * 6 cm 2 , shaped with collimator) were simulated. MC statistical error objective was less than 5% in the 50% isodose. The treatment plan validation criteria were fixed such as 100% of the prescribed dose is delivered at the beam isocentre and the 70% isodose contains the whole target volume. The comparison elements were the 70% isodose volume, the average and maximal doses delivered to organs at risk (OAR): brainstem, optical nerves, chiasma, eyes, skull bone and healthy brain parenchyma. For the single case study, the 3D conformational radiotherapy and IMRT treatment plans were established using the Eclipse ® -Varian TPS. The dynamic arc-therapy plan was achieved on the Iplan ® -Brainlab TPS. Results Iodine-enhanced SSRT exhibits a good potential for brain metastasis treatment regarding the dose distribution and OAR criteria. Iodine accumulation in metastasis may increase the dose of 20– 30% (sparing effect). Treatment without any iodine enhancement (medium-energy stereotactic radiotherapy) is not relevant with degraded HDVs (brain, parenchyma and skull bone) comparing to conventional stereotactic surgery. In the single case study, the stereotactic dynamic arc-therapy remains the best technique in terms of dose conformation. However, OAR sparing is increased with iodine-enhanced SSRT: the dose delivered to the brainstem and the brain parenchyma is significantly reduced. Conclusion This study shows the potential dosimetric advantages of contrast-enhanced SSRT for treating brain metastasis.