Survival of rats bearing advanced intracerebral F 98 tumors after glutathione depletion and microbeam radiation therapy: conclusions from a pilot project.

BACKGROUND: Resistance to radiotherapy is frequently encountered in patients with glioblastoma multiforme. It is caused at least partially by the high glutathione content in the tumour tissue. Therefore, the administration of the glutathione synthesis inhibitor Buthionine-SR-Sulfoximine (BSO) should increase survival time. METHODS: BSO was tested in combination with an experimental synchrotron-based treatment, microbeam radiation therapy (MRT), characterized by spatially and periodically alternating microscopic dose distribution. One hundred thousand F98 glioma cells were injected into the right cerebral hemisphere of adult male Fischer rats to generate an orthotopic small animal model of a highly malignant brain tumour in a very advanced stage. Therapy was scheduled for day 13 after tumour cell implantation. At this time, 12.5% of the animals had already died from their disease. The surviving 24 tumour-bearing animals were randomly distributed in three experimental groups: subjected to MRT alone (Group A), to MRT plus BSO (Group B) and tumour-bearing untreated controls (Group C). Thus, half of the irradiated animals received an injection of 100 µM BSO into the tumour two hours before radiotherapy. Additional tumour-free animals, mirroring the treatment of the tumour-bearing animals, were included in the experiment. MRT was administered in bi-directional mode with arrays of quasi-parallel beams crossing at the tumour location. The width of the microbeams was ≈28 µm with a center-to-center distance of ≈400 µm, a peak dose of 350 Gy, and a valley dose of 9 Gy in the normal tissue and 18 Gy at the tumour location; thus, the peak to valley dose ratio (PVDR) was 31. RESULTS: After tumour-cell implantation, otherwise untreated rats had a mean survival time of 15 days. Twenty days after implantation, 62.5% of the animals receiving MRT alone (group A) and 75% of the rats given MRT + BSO (group B) were still alive. Thirty days after implantation, survival was 12.5% in Group A and 62.5% in Group B. There were no survivors on or beyond day 35 in Group A, but 25% were still alive in Group B. Thus, rats which underwent MRT with adjuvant BSO injection experienced the largest survival gain. CONCLUSIONS: In this pilot project using an orthotopic small animal model of advanced malignant brain tumour, the injection of the glutathione inhibitor BSO with MRT significantly increased mean survival time.

In-line phase-contrast breast tomosynthesis: a phantom feasibility study at a synchrotron radiation facility.

The major objective is to adopt, apply and test developed in-house algorithms for volumetric breast reconstructions from projection images, obtained in in-line phase-contrast mode. Four angular sets, each consisting of 17 projection images obtained from four physical phantoms, were acquired at beamline ID17, European Synchroton Radiation Facility, Grenoble, France. The tomosynthesis arc was ±32°. The physical phantoms differed in complexity of texture and introduced features of interest. Three of the used phantoms were in-house developed, and made of epoxy resin, polymethyl-methacrylate and paraffin wax, while the fourth phantom was the CIRS BR3D. The projection images had a pixel size of 47 µm × 47 µm. Tomosynthesis images were reconstructed with standard shift-and-add (SAA) and filtered backprojection (FBP) algorithms. It was found that the edge enhancement observed in planar x-ray images is preserved in tomosynthesis images from both phantoms with homogeneous and highly heterogeneous backgrounds. In case of BR3D, it was found that features not visible in the planar case were well outlined in the tomosynthesis slices. In addition, the edge enhancement index calculated for features of interest was found to be much higher in tomosynthesis images reconstructed with FBP than in planar images and tomosynthesis images reconstructed with SAA. The comparison between images reconstructed by the two reconstruction algorithms shows an advantage for the FBP method in terms of better edge enhancement. Phase-contrast breast tomosynthesis realized in in-line mode benefits the detection of suspicious areas in mammography images by adding the edge enhancement effect to the reconstructed slices.

Minor changes in the macrocyclic ligands but major consequences on the efficiency of gold nanoparticles designed for radiosensitization.

Many studies have been devoted to adapting the design of gold nanoparticles to efficiently exploit their promising capability to enhance the effects of radiotherapy. In particular, the addition of magnetic resonance imaging modality constitutes an attractive strategy for enhancing the selectivity of radiotherapy since it allows the determination of the most suited delay between the injection of nanoparticles and irradiation. This requires the functionalization of the gold core by an organic shell composed of thiolated gadolinium chelates. The risk of nephrogenic systemic fibrosis induced by the release of gadolinium ions should encourage the use of macrocyclic chelators which form highly stable and inert complexes with gadolinium ions. In this context, three types of gold nanoparticles (Au@DTDOTA, Au@TADOTA and Au@TADOTAGA) combining MRI, nuclear imaging and radiosensitization have been developed with different macrocyclic ligands anchored onto the gold cores. Despite similarities in size and organic shell composition, the distribution of gadolinium chelate-coated gold nanoparticles (Au@TADOTA-Gd and Au@TADOTAGA-Gd) in the tumor zone is clearly different. As a result, the intravenous injection of Au@TADOTAGA-Gd prior to the irradiation of 9L gliosarcoma bearing rats leads to the highest increase in lifespan whereas the radiophysical effects of Au@TADOTAGA-Gd and Au@TADOTA-Gd are very similar.

A software platform for phase contrast x-ray breast imaging research.

PURPOSE: To present and validate a computer-based simulation platform dedicated for phase contrast x-ray breast imaging research. METHODS: The software platform, developed at the Technical University of Varna on the basis of a previously validated x-ray imaging software simulator, comprises modules for object creation and for x-ray image formation. These modules were updated to take into account the refractive index for phase contrast imaging as well as implementation of the Fresnel-Kirchhoff diffraction theory of the propagating x-ray waves. Projection images are generated in an in-line acquisition geometry. To test and validate the platform, several phantoms differing in their complexity were constructed and imaged at 25 keV and 60 keV at the beamline ID17 of the European Synchrotron Radiation Facility. The software platform was used to design computational phantoms that mimic those used in the experimental study and to generate x-ray images in absorption and phase contrast modes. RESULTS: The visual and quantitative results of the validation process showed an overall good correlation between simulated and experimental images and show the potential of this platform for research in phase contrast x-ray imaging of the breast. The application of the platform is demonstrated in a feasibility study for phase contrast images of complex inhomogeneous and anthropomorphic breast phantoms, compared to x-ray images generated in absorption mode. CONCLUSIONS: The improved visibility of mammographic structures suggests further investigation and optimisation of phase contrast x-ray breast imaging, especially when abnormalities are present. The software platform can be exploited also for educational purposes.

The effect of Photon Activation Therapy on cisplatin pre-treated human tumour cell lines: comparison with conventional X-ray irradiation.

Cisplatin is an antineoplastic drug widely used for the treatment of several solid tumours. However, the side effects related to cisplatin-based anticancer therapy often outweigh the benefits. Therefore, the identification of new anticancer strategies able to offer a better toxicity profile while maintaining the same level of efficacy as platinum-based treatments would be highly desirable. We assessed the efficacy of synchrotron radiation in triggering the Auger effect in human A549 non-small cell lung cancer and IGROV-1 ovarian cancer cells pre-treated with cisplatin. 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). On cisplatin-treated cells, at concentrations allowing 80 percent of cell survival with respect to controls, no differences were observed in cell viability when they were irradiated either above or below the K-shell edge of platinum, suggesting that cisplatin toxicity can mask the enhancement of cell death induced by the irradiation. At lower cisplatin concentrations allowing 95-90 percent of cell survival, an enhancement in cellular death with respect to conventional irradiation conditions was clearly observed in all cancer types when cells were irradiated with beams either above or below the platinum K-shell edge. Our results lend additional support to the suggestion that the Photon Activation Therapy in combination with cisplatin treatment should be further explored in relevant in vivo models of glioma and non-glioma cancer models.

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.

Biological equivalent dose studies for dose escalation in the stereotactic synchrotron radiation therapy clinical trials.

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.

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.

Technology solutions for better outcomes: integrated information management in key to productivity increases in medicine.

The challenges to healthcare systems around the world are primarily impacted by two topics: demographic factors and progress in medicine. An ageing population inherently needs more medical services which add financial burdens, in particular, to public healthcare. Since the level of medical education is growing at the same time, we are observing an increased demand for sophisticated (in general expensive) medicine. Drastic changes in financing seem unavoidable. Multiple diagnoses, repeated examinations, trial-and-error, overcapacities and other signs of missing economical considerations are reinforced by reimbursement systems. In a world where, in principle, all information is available everywhere, more than a patient's history should be accessible. Other industries have knowledge management systems in place that make state-of-the-art expertise available everywhere. Intelligent patient databases could consist of learning cycles that (i) enable the individual to benefit from structured knowledge, in addition to personal experience of the physician, and (ii) use the knowledge generated from the individual to extend the database. The novel area of molecular medicine fits perfectly well into these scenarios. Only attached to an IT backbone can the flood of information be managed in a beneficial way. Efficiency improvements in healthcare address the needs of all parties in the system: patients, providers, and payers. The opportunities, however, can only materialize if everyone is prepared to change. IT will set the standards for the biggest challenge in healthcare: The paradigm shift in medicine.

Phonon modes at the 2H-NbSe2 surface observed by grazing incidence inelastic x-ray scattering.

We have determined the dispersion of acoustic and optical surface phonon modes 2H-NbSe2 at the by inelastic x-ray scattering under grazing incidence conditions. Already, at room temperature, an anomaly is observed close to the charge density wave -vector position located at about one-third along the Gamma-M direction of the Brillouin zone. Our results indicate that the anomaly for the surface mode occurs at a lower energy than that measured in bulk sensitive geometry in the same experiment, showing evidence of a modified behavior in the uppermost layers. We demonstrate that inelastic x-ray scattering in grazing incidence conditions provides a unique tool to selectively study either surface or bulk lattice dynamics in a single experiment.

New irradiation geometry for microbeam radiation therapy.

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

Elasticity of cobalt at high pressure studied by inelastic x-ray scattering.

The five independent elastic moduli of single-crystalline hcp cobalt were determined by inelastic x-ray scattering to 39 GPa and compared to ultrasonic measurements and first principles calculations. In general the agreement is good, in particular, for the evolution of the longitudinal sound velocity in the a-c plane. This confirms the calculations, suggesting that a similar evolution is valid for hcp iron, the main constituent of the Earth's inner core, up to the highest investigated pressure. Our results represent an important benchmark to further refine ab initio calculations.

Sliding-induced decoupling and charge transfer between the coexisting Q1 and Q2 charge density waves in NbSe3.

Using high-resolution x-ray scattering in the presence of an applied current, we report evidence for a dynamical decoupling between the two NbSe3 charge-density waves (CDWs), Q1 (T(C1)=145 K) and Q2 (T(C2)=59 K), coexisting below T(C2). Simultaneous and oppositely directed shifts of the relevant CDW superlattice spots develop above a threshold current which we identify as the depinning threshold I(C1) for the more strongly pinned upper CDW Q1 (I(C1) approximately 10I(C2)). In contrast with shifts induced by current conversion processes, the present effect is not current polarized and is not limited to the current-contact regions. We propose a model which explains this instability through a sliding-induced charge transfer between the two electronic reservoirs corresponding to the Q1 and Q2 CDWs.

Phonon dispersion in graphite.

We measured the dispersion of the graphite optical phonons in the in-plane Brillouin zone by inelastic x-ray scattering. The longitudinal and transverse optical branches cross along the Gamma-K as well as the Gamma-M direction. The dispersion of the optical phonons was, in general, stronger than expected from the literature. At the K point the transverse optical mode has a minimum and is only approximately 70 cm(-1) higher in frequency than the longitudinal mode. We show that first-principles calculations describe very well the vibrational properties of graphene once the long-range character of the dynamical matrix is taken into account.

Motional ordering of a charge-density wave in the sliding state.

We have used high-resolution x-ray scattering, in the presence of an applied direct current, for studying the correlation lengths in the sliding charge-density wave (CDW) state. Transport properties were simultaneously measured in situ during the experiment. We find that, while the transverse correlation is reduced when the CDW moves, the CDW becomes more ordered in the direction of motion. This is the first report of a motional ordering process in a periodic system other than a vortex lattice.

Sound velocities in iron to 110 gigapascals.

The dispersion of longitudinal acoustic phonons was measured by inelastic x-ray scattering in the hexagonal closed-packed (hcp) structure of iron from 19 to 110 gigapascals. Phonon dispersion curves were recorded on polycrystalline iron compressed in a diamond anvil cell, revealing an increase of the longitudinal wave velocity (VP) from 7000 to 8800 meters per second. We show that hcp iron follows a Birch law for VP, which is used to extrapolate velocities to inner core conditions. Extrapolated longitudinal acoustic wave velocities compared with seismic data suggest an inner core that is 4 to 5% lighter than hcp iron.

In vitro delineation of human brain-stem anatomy using a small resonator: correlation with macroscopic and histological findings.

Our purpose was to investigate the potential of an experimental animal coil using a commercial MRI unit to delineate the anatomical structure of the human brain stem. Three formaldehyde-fixed brain-stem specimens were examined by MRI and sectioned perpendicular to their longitudinal axis. The images were compared with gross anatomy and myelin-stained histological sections. Fibre tracts and nuclei which were not evident on examination of the unstained specimen were readily identified by MRI. Due to its inherent grey/white matter contrast, MRI with a high-resolution coil delineates anatomical structures in a way comparable to the myelin-stained histological sections. However, pigmented structures, readily visible on examination of the unstained specimen were discernible on neither MRI nor on myelin-stained sections. The excellent anatomical detail and grey/white matter contrast provided by these images could make MRI a useful adjunct to the pathologist investigating brain disease.

[Theoretical principles and technical realization of high resolution nuclear magnetic resonance tomography with the example of a dedicated coil system]. / Theoretische Grundlagen und technische Realisation der hochauflösenden Kernspintomographie (KST) am Beispiel eines dedizierten Spulensystems.

The theory of high-resolution magnetic resonance imaging (MRI) and the physical properties of a dedicated coil system with its clinical application are reviewed. To evaluate the spatial resolution of the system, a phantom sample was depicted by a transverse T1-weighted sequence (time of repetition 500 ms, time of echo 25 ms, 256 x 256 matrix, 3 acquisitions, field of view 25 mm2). Relative signal intensity decrease was less using the 5-cm coil, as signal intensity field distribution depends on coil diameter. The phantom appeared as an attainable resolution of 100-microns pixel width using the 2.5-cm coil. For the 5-cm coil the pixel width was 200 microns, not accomplishing clear resolution of the phantom. Coil head choice depends on the anatomic depth of the target organ. Work-up of the skin and musculoskeletal lesions is the main indication for high-resolution MRI using surface coils.

Applications of specialized coils for high-resolution MRI on a whole-body scanner.

To investigate the application of a mini-coil surface system for high-resolution MRI, 60 volunteers were examined in a 1.5-T whole-body scanner. Two replaceable probe heads were available: a circular 2.5-cm coil and a quadratic 5-cm coil, both of which were placed directly on the skin. The skin layers, Achilles tendon and finger joints were examined with the 2.5-cm coil and a FOV of 25 X 25 mm2. A matrix of 256 pixels resulted in a pixel size of 0.098 X 0.098 mm2. For imaging of the carpal tunnel, the 5-cm coil was used in transverse orientation. The FOV was 50 X 50 mm2 so that a matrix of 256 X 256 pixels led to a pixel size of 0.195 X 0.195 mm2. The resulting spatial resolution permitted visualization of the epidermis, dermis and subcutis, resulting in clear definition of anatomical detail of the musculoskeletal system. MRI measurement of skin-layer thickness did not correlate with histometric data (p < 0.05). This discrepancy was due in part to shrinkage of the tumor specimen on histologic preparation. Other causes include the motion artifacts and the limited accuracy of determining thickness on the MRI display unit.

[MRT of the eye: the normal anatomy and detection of the smallest lesions with a high-resolution surface coil]. / MRT des Auges: Normalanatomie und Nachweis kleinster Läsionen mit einer hochauflösenden Oberflächenspule.

PURPOSE: A new, high-resolution surface coil for MRI of the eye was evaluated with regard to practicability, image quality and sensitivity for small lesions. MATERIAL AND METHODS: 48 patients in whom a space-occupying lesion of the eye or orbit was suspected were examined (1.5 T tomograph, 5 cm surface coil, T1- and T2-weighted spin-echo sequences, the former before and after i.v. gadolinium DTPA). RESULTS: 45/48 patients tolerated MR with the high-resolution surface coil. No adverse effects were experienced by the patients. In 11/48 patients a space occupying lesion of the eye was detected (melanoma, 5; metastases, 2; haemorrhage, 1; malformation, hamartoma and scarring after melanoma, one each). The smallest detectable lesion had a thickness of < 1 mm. CONCLUSION: First experiences with the high-resolution surface coil indicate that this device is suited for detection of very small lesions of the eye.