RESUMO
PURPOSE: 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 â¼1 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. CONCLUSIONS: 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.
Assuntos
Neoplasias Encefálicas , Glioma , Radiocirurgia , Animais , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/veterinária , Cães , Glioma/diagnóstico por imagem , Glioma/patologia , Glioma/radioterapia , Qualidade de Vida , Radiocirurgia/métodos , SíncrotronsRESUMO
The research program at the biomedical imaging facility requires a high-flux hard-X-ray monochromator that can also provide a wide beam. A wide energy range is needed for standard radiography, phase-contrast imaging, K-edge subtraction imaging and monochromatic beam therapy modalities. The double-crystal Laue monochromator, developed for the BioMedical Imaging and Therapy facility, is optimized for the imaging of medium- and large-scale samples at high energies with the resolution reaching 4â µm. A pair of 2â mm-thick Si(111) bent Laue-type crystals were used in fixed-exit beam mode with a 16â mm vertical beam offset and the first crystal water-cooled. The monochromator operates at energies from 25 to 150â keV, and the measured size of the beam is 189â mm (H)â ×â 8.6â mm (V) at 55â m from the source. This paper presents our approach in developing a complete focusing model of the monochromator. The model uses mechanical properties of crystals and benders to obtain a finite-element analysis of the complete assembly. The modeling results are compared and calibrated with experimental measurements. Using the developed analysis, a rough estimate of the bending radius and virtual focus (image) position of the first crystal can be made, which is also the real source for the second crystal. On the other hand, by measuring the beam height in several points in the SOE-1 hutch, the virtual focus of the second crystal can be estimated. The focusing model was then calibrated with measured mechanical properties, the values for the force and torque applied to the crystals were corrected, and the actual operating parameters of the monochromator for fine-tuning were provided.
RESUMO
We have conducted the first in-vivo experiments in pencilbeam irradiation, a new synchrotron radiation technique based on the principle of microbeam irradiation, a concept of spatially fractionated high-dose irradiation. In an animal model of adult C57 BL/6J mice we have determined technical and physiological limitations with the present technical setup of the technique. Fifty-eight animals were distributed in eleven experimental groups, ten groups receiving whole brain radiotherapy with arrays of 50 µm wide beams. We have tested peak doses ranging between 172 Gy and 2,298 Gy at 3 mm depth. Animals in five groups received whole brain radiotherapy with a center-to-center (ctc) distance of 200 µm and a peak-to-valley ratio (PVDR) of â¼ 100, in the other five groups the ctc was 400 µm (PVDR â¼ 400). Motor and memory abilities were assessed during a six months observation period following irradiation. The lower dose limit, determined by the technical equipment, was at 172 Gy. The LD50 was about 1,164 Gy for a ctc of 200 µm and higher than 2,298 Gy for a ctc of 400 µm. Age-dependent loss in motor and memory performance was seen in all groups. Better overall performance (close to that of healthy controls) was seen in the groups irradiated with a ctc of 400 µm.
Assuntos
Encéfalo/efeitos da radiação , Radioterapia/métodos , Animais , Comportamento Animal/efeitos da radiação , Encéfalo/citologia , Relação Dose-Resposta à Radiação , Dose Letal Mediana , Camundongos , Modelos Animais , Radioterapia/instrumentação , SíncrotronsRESUMO
A fast 50 microm-accuracy alignment procedure has been developed for the radiosurgery of brain lesions in rats, using microbeam radiation therapy. In vivo imaging was performed using the pink beam (35-60 keV) produced by the ID17 wiggler at the ESRF opened at 120 mm and filtered. A graphical user interface has been developed in order to define the irradiation field size and to position the target with respect to the skull structures observed in X-ray images. The method proposed here allows tremendous time saving by skipping the swap from white beam to monochromatic beam and vice versa. To validate the concept, the somatosensory cortex or thalamus of GAERS rats were irradiated under several ports using this alignment procedure. The magnetic resonance images acquired after contrast agent injection showed that the irradiations were selectively performed in these two expected brain regions. Image-guided microbeam irradiations have therefore been realised for the first time ever, and, thanks to this new development, the ID17 biomedical beamline provides a major tool allowing brain radiosurgery trials on animal patients.
Assuntos
Encéfalo/efeitos da radiação , Animais , Encéfalo/anatomia & histologia , Calibragem , Imageamento por Ressonância Magnética , Radiocirurgia , Ratos , Interface Usuário-ComputadorRESUMO
Several synchrotrons around the world are currently developing innovative radiotherapy techniques with the aim of palliating and possibly curing human brain tumors. Amongst them, microbeam radiation therapy (MRT) and, more recently, minibeam radiation therapy (MBRT) have shown promising results. In MBRT the beam thickness ranges from 500 to 700 microm with a separation between two adjacent minibeams of the same value, whilst in MRT the thickness is of the order of 25-50 microm with a distance between adjacent microbeams of the order of 200 microm. An original method has been developed and tested at the ESRF ID17 biomedical beamline to produce the minibeam patterns. It utilizes a specially developed high-energy white-beam chopper whose action is synchronized with the vertical motion of the target moving at constant speed. Each opening of the chopper generates a horizontal beam print. The method described here has the advantage of being simple and reliable, and it allows for an easy control of the patient safety in future clinical trials. To study the feasibility of the method, dosimetric measurements have been performed using Gafchromic HD-810 films and compared with Monte Carlo simulations. The results of this comparison are discussed.
Assuntos
Neoplasias Encefálicas/radioterapia , Planejamento da Radioterapia Assistida por Computador/métodos , Radioterapia/métodos , Síncrotrons , Simulação por Computador , Estudos de Viabilidade , Humanos , Método de Monte Carlo , Imagens de Fantasmas , Radioterapia/instrumentação , Dosagem RadioterapêuticaRESUMO
AIMS: Synchrotron radiation angiography (SRA) is a novel tool for minimally invasive coronary artery imaging. The method uses subtraction of two images produced at energies bracketing the iodine K-edge after intravenous infusion of iodinated contrast agent. We investigated the accuracy of SRA for detecting in-stent restenosis (ISR). METHODS AND RESULTS: We recruited 57 men, 4-6 months after successful PTCA. We visualized the right coronary artery (RCA) in 27 patients with 36 stented segments [12 segments with ISR>50% by quantitative coronary angiography (QCA)], and the left anterior descending artery (LAD) in 30 patients with 37 stented segments (10 ISR). SRA and QCA were performed within 2 days of each other. Two experienced observers unaware of QCA data evaluated the SRA results. Image quality was good or excellent in most patients. Global sensitivity was 64%, specificity was 95%, and positive and negative predictive values were approximately 85%. Inter-observer kappa concordance coefficient was 0.86. False negatives involved short eccentric lesions and superimposed segments, most frequently of the LAD. False positives occurred in intermediate stenoses slightly overestimated by SRA. CONCLUSION: In men, this minimally invasive approach, using small radiation doses, detects significant ISR in the RCA, but the LAD poses difficulties because of superimposition with others structures.
Assuntos
Angiografia Coronária/métodos , Reestenose Coronária/diagnóstico por imagem , Stents , Síncrotrons/normas , Adulto , Idoso , Angioplastia Coronária com Balão/métodos , Estenose Coronária/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Sensibilidade e EspecificidadeRESUMO
Combination of cis-platinum with ionizing radiation is one of the most promising anticancer treatments that appears to be more efficient than radiotherapy alone. Unlike conventional X-ray emitters, accelerators of high energy particles like synchrotrons display powerful and monochromatizable radiation that makes the induction of an Auger electron cascade in cis-platinum molecules [also called photoactivation of cis-platinum (PAT-Plat)] theoretically possible. Here, we examined the molecular consequences of one of the first attempts of synchrotron PAT-Plat, performed at the European Synchrotron Research Facility (Grenoble-France). PAT-Plat was found to result in an extra number of slowly repairable DNA double-strand breaks, inhibition of DNA-protein kinase activity, dramatic nuclear relocalization of RAD51, hyperphosphorylation of the BRCA1 protein, and activation of proto-oncogenic c-Abl tyrosine kinase.