M. Renier

Weanling piglet cerebellum: a surrogate for tolerance to MRT (microbeam radiation therapy) in pediatric neuro-oncology

The cerebellum of the weanling piglet (Yorkshire) was used as a surrogate for the radiosensitive human infant cerebellum in a Swiss-led program of experimental microbeam radiation therapy (MRT) at the ESRF. Five weanlings in a 47 day old litter of seven, and eight weanlings in a 40 day old litter of eleven were irradiated in November, 1999 and June, 2000, respectively. A 1.5 cm-wide x 1.5 xm-high array of equally space approximately equals 20-30 micrometers wide, upright microbeams spaced at 210 micrometers intervals was propagated horizontally, left to right, through the cerebella of the prone, anesthetized piglets. Skin-entrance intra-microbeam peak adsorbed doses were uniform, either 150, 300, 425, or 600 gray (Gy). Peak and inter-microbeam (valley) absorbed doses in the cerebellum were computed with the PSI version of the Monte Carlo code GEANT and benchmarked using Gafchromic and radiochromic film microdosimetry. For approximately equals 66 weeks [first litter; until euthanasia], or approximately equals 57 weeks [second litter; until July 30, 2001] after irradiation, the littermates were developmentally, behaviorally, neurologically and radiologically normal as observed and tested by experienced farmers and veterinary scientists unaware of which piglets were irradiated or sham-irradiated. Morever, MRT implemented at the ESRF with a similar array of microbeams and a uniform skin-entrance peak dose of 625 Gy, followed by immunoprophylaxis, was shown to be palliative or curative in young adult rats bearing intracerebral gliosarcomas. These observations give further credence to MRTs potential as an adjunct therapy for brain tumors in infancy, when seamless therapeutic irradiation of the brain is hazardous.

Instrumentation of the ESRF medical imaging facility

Abstract At the European Synchrotron Radiation Facility (ESRF) a beamport has been instrumented for medical research programs. Two facilities have been constructed for alternative operation. The first one is devoted to medical imaging and is focused on intravenous coronary angiography and computed tomography (CT). The second facility is dedicated to pre-clinical microbeam radiotherapy (MRT). This paper describes the instrumentation for the imaging facility. Two monochromators have been designed, both are based on bent silicon crystals in the Laue geometry. A versatile scanning device has been built for pre-alignment and scanning of the patient through the X-ray beam in radiography or CT modes. An intrinsic germanium detector is used together with large dynamic range electronics (16 bits) to acquire the data. The beamline is now at the end of its commissioning phase; intravenous coronary angiography is intended to start in 1999 with patients and the CT pre-clinical program is underway on small animals. The first in vivo images obtained on animals in angiography and CT modes are presented to illustrate the performances of these devices.

First human transvenous coronary angiography at the European Synchrotron Radiation Facility

The first operation of the European Synchrotron Radiation Facility (ESRF) medical beamline is reported in this paper. The goal of the angiography project is to develop a reduced risk imaging technique, which can be used to follow up patients after coronary intervention. After the intravenous injection of a contrast agent (iodine) two images are produced with monochromatic beams, bracketing the iodine K-edge. The logarithmic subtraction of the two measurements results in an iodine enhanced image, which can be precisely quantified. A research protocol has been designed to evaluate the performances of this method in comparison with the conventional technique. Patients included in the protocol have previously undergone angioplasty. If a re-stenosis is suspected, the patient is imaged both at the ESRF and at the hospital with the conventional technique, within the next few days. This paper reports the results obtained with the first patients. To date, eight patients have been imaged and excellent image quality was obtained.

Microbeam radiation therapy

The central nervous system of vertebrates, even when immature, displays extraordinary resistance to damage by microscopically narrow, multiple, parallel, planar beams of x rays. Imminently lethal gliosarcomas in the brains of mature rats can be inhibited and ablated by such microbeams with little or no harm to mature brain tissues and neurological function. Potentially palliative, conventional wide-beam radiotherapy of malignant brain tumors in human infants under three years of age is so fraught with the danger of disrupting the functional maturation of immature brain tissues around the targeted tumor that it is implemented infrequently. Other kinds of therapy for such tumors are often inadequate. We suggest that microbeam radiation therapy (MRT) might help to alleviate the situation. Wiggler-generated synchrotron x-rays were first used for experimental microplanar beam (microbeam) radiation therapy (MRT) at Brookhaven National Laboratorys National Synchrotron Light Source in the early 1990s. We now describe the progress achieved in MRT research to date using immature and adult rats irradiated at the European Synchrotron Radiation Facility in Grenoble, France, and investigated thereafter at the Institute of Pathology of the University of Bern.

New technology enables high precision multislit collimators for microbeam radiation therapy

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

Lack of Cell Death Enhancement after Irradiation with Monochromatic Synchrotron X Rays at the K-Shell Edge of Platinum Incorporated in Living SQ20B Human Cells as cis-Diamminedichloroplatinum (II)

Abstract Corde, S., Biston, M. C., Elleaume, H., Estève, F., Charvet, A. M., Joubert, A., Ducros, V., Bohic, S., Simionovici, A., Brochard, T., Nemoz, C., Renier, Troprès, I., Fiedler, S., Bravin, A., M., Thomlinson, W., Le Bas, J. F. and Balosso, J. Lack of Cell Death Enhancement after Irradiation with Monochromatic Synchrotron X Rays at the K-Shell Edge of Platinum Incorporated in Living SQ20B Human Cells as cis-Diamminedichloroplatinum (II). Radiat. Res. 158, 763–770 (2002). In this paper we describe the results of experiments using synchrotron radiation to trigger the Auger effect in living human cancer cells treated with a widely used chemotherapy drug: cis-diamminedichloroplatinum (II) (cisplatin). The experiments were carried out at the ID17 beamline of the European Synchrotron Radiation Facility, which produces a high-fluence monochromatic beam that is adjustable from 20 to 80 keV. Cisplatin was chosen as the carrier of platinum atoms in the cells because of its alkylating-like activity and the irradiation was done with monochromatic beams above and below the platinum K-shell edge (78.39 keV). Cell survival curves were comparable with those obtained for the same cells under conventional irradiation conditions. At a low dose of cisplatin (0.1 μM, 48 h), no difference was seen in survival when the cells were irradiated above and below the K-shell edge of platinum. Higher cisplatin concentrations were investigated to enhance the cellular platinum content. The results with 1 μM cisplatin for 12 h showed no difference when the cells were irradiated with beams above or below the platinum K-shell edge with the exception of the higher cell death resulting from drug toxicity. The intracellular content of platinum was significant, as measured macroscopically by inductively coupled plasma mass spectrometry. Its subcellular localization and particularly its presence in the cell nucleus were verified by microscopic synchrotron X-ray fluorescence. This was the first known attempt at K-shell edge photon activation of stable platinum in living cells with a platinum complex used for chemotherapy. Its evident toxicity in these cells leads us to put forth the hypothesis that cisplatin toxicity can mask the enhancement of cell death induced by the irradiation above the K-shell edge. However, K-shell edge photon activation of stable elements provides a powerful technique for the understanding of the biological effects of Auger processes. Further avenues of development are discussed.

The radiotherapy clinical trials projects at the ESRF: Technical aspects

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

X-ray energy optimization in minibeam radiation therapy.

PURPOSE The purpose of this work is to assess which energy in minibeam radiation therapy provides the best compromise between the deposited dose in the tumor and the sparing of the healthy tissues. METHODS Monte Carlo simulations (PENELOPE 2006) have been used as a method to calculate the ratio of the peak-to-valley doses (PVDR) in the healthy tissues and in the tumor for different beam energies. The maximization of the ratio of PVDR in the healthy tissues and in the tumor has been used as a criterion. RESULTS The main result of this work is that, for the parameters being used in preclinical trials (minibeam sizes of 600 microm and 1200 microm center-to-center separation), the optimum beam energy is 375 keV. CONCLUSIONS The conclusion is that this is the energy of minibeams that should be used in the preclinical studies.

A new method of creating minibeam patterns for synchrotron radiation therapy: a feasibility study

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.

Fixed-exit monochromator for computed tomography with synchrotron radiation at energies 18–90 keV

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