Chalcone JAI-51 improves efficacy of synchrotron microbeam radiation therapy of brain tumors

Microbeam radiation therapy (MRT), a preclinical form of radiosurgery, uses spatially fractionated micrometre-wide synchrotron-generated X-ray beams. As MRT alone is predominantly palliative for animal tumors, the effects of the combination of MRT and a newly synthesized chemotherapeutic agent JAI-51 on 9L gliosarcomas have been evaluated. Fourteen days (D14) after implantation (D0), intracerebral 9LGS-bearing rats received either MRT, JAI-51 or both treatments. JAI-51, alone or immediately after MRT, was administered three times per week. Animals were kept up to ∼20 weeks after irradiation or sacrificed at D16 or D28 after treatment for cell cycle analysis. MRT plus JAI-51 increased significantly the lifespan compared with MRT alone (p = 0.0367). JAI-51 treatment alone had no effect on rat survival. MRT alone or associated with JAI-51 induced a cell cycle blockade in G2/M (p < 0.01) while the combined treatment also reduced the proportion of G0/G1 cells. At D28 after irradiation, MRT and MRT/JAI-51 had a smaller cell blockade effect in the G2/M phase owing to a significant increase in tumor cell death rate (<2c) and a proportional increase of endoreplicative cells (>8c). The combination of MRT and JAI-51 increases the survival of 9LGS-bearing rats by inducing endoreduplication of DNA and tumor cell death; further, it slowed the onset of tumor growth resumption two weeks after treatment.

[Alban Köhler (1874-1947): Inventor of grid therapy]

Grid (or sieve) therapy ("Gitter-" oder "Siebtherapie"), spatially fractionated kilo- and megavolt X-ray therapy, was invented in 1909 by Alban Köhler, a radiologist in Wiesbaden, Germany. He tested it on several patients before 1913 using approximately 60-70kV Hittorf-Crookes tubes. Köhler pushed the X-ray tube's lead-shielded housing against a stiff grid of 1 mm-square iron wires woven 3.0-3.5mm on center, taped tightly to the skin over a thin chamois. Numerous islets unshielded by iron in the pressure-blanched skin were irradiated with up to about 6 erythema doses (ED). The skin was then thoroughly cleansed, disinfected, and bandaged; delayed punctate necrosis healed in several weeks. Although grid therapy was disparaged or ignored until the 1930s, it has been used successfully since then to shrink bulky malignancies. Also, advanced cancers in rats and mice have been mitigated or ablated using Köhler's concept since the early 1990s by unidirectional or stereotactic exposure to an array of nearly parallel microplanar (25-75μm-wide) beams of very intense, moderately hard (median energy approximately 100 keV) synchrotron-generated X rays spaced 0.1-0.4mm on center. Such beams maintain sharp edges at high doses well beneath the skin yet confer little toxicity. They could palliate some otherwise intractable malignancies, perhaps in young children too, with tolerable sequelae. There are plans for such studies in larger animals.

Evaluation of the Design of Komendant's Cycloidal, Thin Shell Roofs At the Kimbell Art Museum Using Finite Element Analysis

The analysis of Komendant's design of the Kimbell Art Museum was carried out in order to determine the effectiveness of the ring beams, edge beams and prestressing in the shells of the roof system. Finite element analysis was not available to Komendant or other engineers of the time to aid them in the design and analysis. Thus, the use of this tool helped to form a new perspective on the Kimbell Art Museum and analyze the engineer's work. In order to carry out the finite element analysis of Kimbell Art Museum, ADINA finite element analysis software was utilized. Eight finite element models (FEM-1 through FEM-8) of increasing complexity were created. The results of the most realistic model, FEM-8, which included ring beams, edge beams and prestressing, were compared to Komendant's calculations. The maximum deflection at the crown of the mid-span surface of -0.1739 in. in FEM-8 was found to be larger than Komendant's deflection in the design documents before the loss in prestressing force (-0.152 in.) but smaller than his prediction after the loss in prestressing force (-0.3814 in.). Komendant predicted a larger longitudinal stress of -903 psi at the crown (vs. -797 psi in FEM-8) and 37 psi at the edge (vs. -347 psi in FEM-8). Considering the strength of concrete of 5000 psi, the difference in results is not significant. From the analysis it was determined that both FEM-5, which included prestressing and fixed rings, and FEM-8 can be successfully and effectively implemented in practice. Prestressing was used in both models and thus served as the main contribution to efficiency. FEM-5 showed that ring and edge beams can be avoided, however an architect might find them more aesthetically appropriate than rigid walls.

X-ray phase contrast imaging of metallized and non-metallized biological samples

Imaging of biological samples has been performed with a variety of techniques for example electromagnetic waves, electrons, neutrons, ultrasound and X-rays. Also conventional X-ray imaging represents the basis of medical diagnostic imaging, it remains of limited use in this application because it is based solely on the differential absorption of X-rays by tissues. Coherent and bright photon beams, such as those produced by third-generation synchrotron X-ray sources, provide further information on subtle X-ray phase changes at matter interfaces. This complements conventional X-ray absorption by edge enhancement phenomena. Thus, phase contrast imaging has the potential to improve the detection of structures on images by detecting those structures that are invisible with X-ray absorption imaging. Images of a weakly absorbing nylon fibre were recorded in in-line holography geometry using a high resolution low-noise CCD camera at the ESRF in Grenoble. The method was also applied to improve image contrast for images of biological tissues. This paper presents phase contrast microradiographs of vascular tree casts and images of a housefly. These reveal very fine structures, that remain invisible with conventional absorption contrast only.

Daily organ tracking in intensity-modulated radiotherapy of prostate cancer using an electronic portal imaging device with a dose saving acquisition mode

BACKGROUND AND PURPOSE: Daily use of conventional electronic portal imaging devices (EPID) for organ tracking is limited due to the relatively high dose required for high quality image acquisition. We studied the use of a novel dose saving acquisition mode (RadMode) allowing to take images with one monitor unit per image in prostate cancer patients undergoing intensity-modulated radiotherapy (IMRT) and tracking of implanted fiducial gold markers. PATIENTS AND METHODS: Twenty five patients underwent implantation of three fiducial gold markers prior to the planning CT. Before each treatment of a course of 37 fractions, orthogonal localization images from the antero-posterior and from the lateral direction were acquired. Portal images of both the setup procedure and the five IMRT treatment beams were analyzed. RESULTS: On average, four localization images were needed for a correct patient setup, resulting in four monitor units extra dose per fraction. The mean extra dose delivered to the patient was thereby increased by 1.2%. The procedure was precise enough to reduce the mean displacements prior to treatment to < o =0.3 mm. CONCLUSIONS: The use of a new dose saving acquisition mode enables to perform daily EPID-based prostate tracking with a cumulative extra dose of below 1 Gy. This concept is efficiently used in IMRT-treated patients, where separation of setup beams from treatment beams is mandatory.

Prospects for microbeam radiation therapy of brain tumours in children to reduce neurological sequelae

Microbeam radiation therapy (MRT), a form of experimental radiosurgery of tumours using multiple parallel, planar, micrometres-wide, synchrotron-generated X-ray beams ('microbeams'), can safely deliver radiation doses to contiguous normal animal tissues that are much higher than the maximum doses tolerated by the same normal tissues of animals or patients from any standard millimetres-wide radiosurgical beam. An array of parallel microbeams, even in doses that cause little damage to radiosensitive developing tissues, for example, the chick chorioallantoic membrane, can inhibit growth or ablate some transplanted malignant tumours in rodents. The cerebella of 100 normal 20 to 38g suckling Sprague-Dawley rat pups and of 13 normal 5 to 12kg weanling Yorkshire piglets were irradiated with an array of parallel, synchrotron-wiggler-generated X-ray microbeams in doses overlapping the MRT-relevant range (about 50-600Gy) using the ID17 wiggler beamline tangential to the 6GeV electron synchrotron ring at the European Synchrotron Radiation Facility in Grenoble, France. Subsequent favourable development of most animals over at least 1 year suggests that MRT might be used to treat children's brain tumours with less risk to the development of the central nervous system than is presently the case when using wider beams.

An efficient framework for photon Monte Carlo treatment planning

Currently photon Monte Carlo treatment planning (MCTP) for a patient stored in the patient database of a treatment planning system (TPS) can usually only be performed using a cumbersome multi-step procedure where many user interactions are needed. This means automation is needed for usage in clinical routine. In addition, because of the long computing time in MCTP, optimization of the MC calculations is essential. For these purposes a new graphical user interface (GUI)-based photon MC environment has been developed resulting in a very flexible framework. By this means appropriate MC transport methods are assigned to different geometric regions by still benefiting from the features included in the TPS. In order to provide a flexible MC environment, the MC particle transport has been divided into different parts: the source, beam modifiers and the patient. The source part includes the phase-space source, source models and full MC transport through the treatment head. The beam modifier part consists of one module for each beam modifier. To simulate the radiation transport through each individual beam modifier, one out of three full MC transport codes can be selected independently. Additionally, for each beam modifier a simple or an exact geometry can be chosen. Thereby, different complexity levels of radiation transport are applied during the simulation. For the patient dose calculation, two different MC codes are available. A special plug-in in Eclipse providing all necessary information by means of Dicom streams was used to start the developed MC GUI. The implementation of this framework separates the MC transport from the geometry and the modules pass the particles in memory; hence, no files are used as the interface. The implementation is realized for 6 and 15 MV beams of a Varian Clinac 2300 C/D. Several applications demonstrate the usefulness of the framework. Apart from applications dealing with the beam modifiers, two patient cases are shown. Thereby, comparisons are performed between MC calculated dose distributions and those calculated by a pencil beam or the AAA algorithm. Interfacing this flexible and efficient MC environment with Eclipse allows a widespread use for all kinds of investigations from timing and benchmarking studies to clinical patient studies. Additionally, it is possible to add modules keeping the system highly flexible and efficient.

Photon-beam subsource sensitivity to the initial electron-beam parameters

One limitation to the widespread implementation of Monte Carlo (MC) patient dose-calculation algorithms for radiotherapy is the lack of a general and accurate source model of the accelerator radiation source. Our aim in this work is to investigate the sensitivity of the photon-beam subsource distributions in a MC source model (with target, primary collimator, and flattening filter photon subsources and an electron subsource) for 6- and 18-MV photon beams when the energy and radial distributions of initial electrons striking a linac target change. For this purpose, phase-space data (PSD) was calculated for various mean electron energies striking the target, various normally distributed electron energy spread, and various normally distributed electron radial intensity distributions. All PSD was analyzed in terms of energy, fluence, and energy fluence distributions, which were compared between the different parameter sets. The energy spread was found to have a negligible influence on the subsource distributions. The mean energy and radial intensity significantly changed the target subsource distribution shapes and intensities. For the primary collimator and flattening filter subsources, the distribution shapes of the fluence and energy fluence changed little for different mean electron energies striking the target, however, their relative intensity compared with the target subsource change, which can be accounted for by a scaling factor. This study indicates that adjustments to MC source models can likely be limited to adjusting the target subsource in conjunction with scaling the relative intensity and energy spectrum of the primary collimator, flattening filter, and electron subsources when the energy and radial distributions of the initial electron-beam change.

Monte Carlo source model for photon beam radiotherapy: photon source characteristics

A major barrier to widespread clinical implementation of Monte Carlo dose calculation is the difficulty in characterizing the radiation source within a generalized source model. This work aims to develop a generalized three-component source model (target, primary collimator, flattening filter) for 6- and 18-MV photon beams that match full phase-space data (PSD). Subsource by subsource comparison of dose distributions, using either source PSD or the source model as input, allows accurate source characterization and has the potential to ease the commissioning procedure, since it is possible to obtain information about which subsource needs to be tuned. This source model is unique in that, compared to previous source models, it retains additional correlations among PS variables, which improves accuracy at nonstandard source-to-surface distances (SSDs). In our study, three-dimensional (3D) dose calculations were performed for SSDs ranging from 50 to 200 cm and for field sizes from 1 x 1 to 30 x 30 cm2 as well as a 10 x 10 cm2 field 5 cm off axis in each direction. The 3D dose distributions, using either full PSD or the source model as input, were compared in terms of dose-difference and distance-to-agreement. With this model, over 99% of the voxels agreed within +/-1% or 1 mm for the target, within 2% or 2 mm for the primary collimator, and within +/-2.5% or 2 mm for the flattening filter in all cases studied. For the dose distributions, 99% of the dose voxels agreed within 1% or 1 mm when the combined source model-including a charged particle source and the full PSD as input-was used. The accurate and general characterization of each photon source and knowledge of the subsource dose distributions should facilitate source model commissioning procedures by allowing scaling the histogram distributions representing the subsources to be tuned.

Theoretical considerations to the verification of dynamic multileaf collimated fields with a SLIC-type portal image detector

The verification possibilities of dynamically collimated treatment beams with a scanning liquid ionization chamber electronic portal image device (SLIC-EPID) are investigated. The ion concentration in the liquid of a SLIC-EPID and therefore the read-out signal is determined by two parameters of a differential equation describing the creation and recombination of the ions. Due to the form of this equation, the portal image detector describes a nonlinear dynamic system with memory. In this work, the parameters of the differential equation were experimentally determined for the particular chamber in use and for an incident open 6 MV photon beam. The mathematical description of the ion concentration was then used to predict portal images of intensity-modulated photon beams produced by a dynamic delivery technique, the sliding window approach. Due to the nature of the differential equation, a mathematical condition for 'reliable leaf motion verification' in the sliding window technique can be formulated. It is shown that the time constants for both formation and decay of the equilibrium concentration in the chamber is in the order of seconds. In order to guarantee reliable leaf motion verification, these time constants impose a constraint on the rapidity of the image-read out for a given maximum leaf speed. For a leaf speed of 2 cm s(-1), a minimum image acquisition frequency of about 2 Hz is required. Current SLIC-EPID systems are usually too slow since they need about a second to acquire a portal image. However, if the condition is fulfilled, the memory property of the system can be used to reconstruct the leaf motion. It is shown that a simple edge detecting algorithm can be employed to determine the leaf positions. The method is also very robust against image noise.

Calibration of a portal imaging device for high-precision dosimetry: a Monte Carlo study

Today electronic portal imaging devices (EPID's) are used primarily to verify patient positioning. They have, however, also the potential as 2D-dosimeters and could be used as such for transit dosimetry or dose reconstruction. It has been proven that such devices, especially liquid filled ionization chambers, have a stable dose response relationship which can be described in terms of the physical properties of the EPID and the pulsed linac radiation. For absolute dosimetry however, an accurate method of calibration to an absolute dose is needed. In this work, we concentrate on calibration against dose in a homogeneous water phantom. Using a Monte Carlo model of the detector we calculated dose spread kernels in units of absolute dose per incident energy fluence and compared them to calculated dose spread kernels in water at different depths. The energy of the incident pencil beams varied between 0.5 and 18 MeV. At the depth of dose maximum in water for a 6 MV beam (1.5 cm) and for a 18 MV beam (3.0 cm) we observed large absolute differences between water and detector dose above an incident energy of 4 MeV but only small relative differences in the most frequent energy range of the beam energy spectra. It is shown that for a 6 MV beam the absolute reference dose measured at 1.5 cm water depth differs from the absolute detector dose by 3.8%. At depth 1.2 cm in water, however, the relative dose differences are almost constant between 2 and 6 MeV. The effects of changes in the energy spectrum of the beam on the dose responses in water and in the detector are also investigated. We show that differences larger than 2% can occur for different beam qualities of the incident photon beam behind water slabs of different thicknesses. It is therefore concluded that for high-precision dosimetry such effects have to be taken into account. Nevertheless, the precise information about the dose response of the detector provided in this Monte Carlo study forms the basis of extracting directly the basic radiometric quantities photon fluence and photon energy fluence from the detector's signal using a deconvolution algorithm. The results are therefore promising for future application in absolute transit dosimetry and absolute dose reconstruction.

Introduction of a novel dose saving acquisition mode for the PortalVision aS500 EPID to facilitate on-line patient setup verification

In external beam radiotherapy, electronic portal imaging becomes more and more an indispensable tool for the verification of the patient setup. For the safe clinical introduction of high dose conformal radiotherapy like intensity modulated radiation therapy, on-line patient setup verification is a prerequisite to ensure that the planned dosimetric coverage of the tumor volume is actually realized in the patient. Since the direction of setup fields often deviates from the direction of the treatment beams, extra dose is delivered to the patient during the acquisition of these portal images which may reach clinical relevance. The aim of this work was to develop a new acquisition mode for the PortalVision aS500 electronic portal imaging device from Varian Medical Systems that allows one to take portal images with reduced dose while keeping good image quality. The new acquisition mode, called RadMode, selectively enables and disables beam pulses during image acquisition allowing one to stop wasting valuable dose during the initial acquisition of "reset frames." Images of excellent quality can be taken with 1 MU only. This low dose per image facilitates daily setup verification with considerably reduced extra dose.

Creep and shrinkage behavior of ultra high-performance concrete under compressive loading with varying curing regimes

This Ultra High Performance Concrete research involves observing early-age creep and shrinkage under a compressive load throughout multiple thermal curing regimes. The goal was to mimic the conditions that would be expected of a precast/prestressing plant in the United States, where UHPC beams would be produced quickly to maximize a manufacturing plant’s output. The practice of steam curing green concrete to accelerate compressive strengths for early release of the prestressing tendons was utilized (140°F [60°C], 95% RH, 14 hrs), in addition to the full thermal treatment (195°F [90°C], 95% RH, 48 hrs) while the specimens were under compressive loading. Past experimental studies on creep and shrinkage characteristics of UHPC have only looked at applying a creep load after the thermal treatment had been administered to the specimens, or on ambient cured specimens. However, this research looked at mimicking current U.S. precast/prestressed plant procedures, and thus characterized the creep and shrinkage characteristics of UHPC as it is thermally treated under a compressive load. Michigan Tech has three moveable creep frames to accommodate two loading criteria per frame of 0.2f’ci and 0.6f’ci. Specimens were loaded in the creep frames and moved into a custom built curing chamber at different times, mimicking a precast plant producing several beams throughout the week and applying a thermal cure to all of the beams over the weekend. This thesis presents the effects of creep strain due to the varying curing regimes. An ambient cure regime was used as a baseline for the comparison against the varying thermal curing regimes. In all cases of thermally cured specimens, the compressive creep and shrinkage strains are accelerated to a maximum strain value, and remain consistent after the administration of the thermal cure. An average creep coefficient for specimens subjected to a thermal cure was found to be 1.12 and 0.78 for the high and low load levels, respectively. Precast/pressed plants can expect that simultaneously thermally curing UHPC elements that are produced throughout the week does not impact the post-cure creep coefficient.

Vibro-acoustical analysis and design of a multiple-layer constrained viscoelastic damping structure

The goal of this research is to provide a framework for vibro-acoustical analysis and design of a multiple-layer constrained damping structure. The existing research on damping and viscoelastic damping mechanism is limited to the following four mainstream approaches: modeling techniques of damping treatments/materials; control through the electrical-mechanical effect using the piezoelectric layer; optimization by adjusting the parameters of the structure to meet the design requirements; and identification of the damping material’s properties through the response of the structure. This research proposes a systematic design methodology for the multiple-layer constrained damping beam giving consideration to vibro-acoustics. A modeling technique to study the vibro-acoustics of multiple-layered viscoelastic laminated beams using the Biot damping model is presented using a hybrid numerical model. The boundary element method (BEM) is used to model the acoustical cavity whereas the Finite Element Method (FEM) is the basis for vibration analysis of the multiple-layered beam structure. Through the proposed procedure, the analysis can easily be extended to other complex geometry with arbitrary boundary conditions. The nonlinear behavior of viscoelastic damping materials is represented by the Biot damping model taking into account the effects of frequency, temperature and different damping materials for individual layers. A curve-fitting procedure used to obtain the Biot constants for different damping materials for each temperature is explained. The results from structural vibration analysis for selected beams agree with published closed-form results and results for the radiated noise for a sample beam structure obtained using a commercial BEM software is compared with the acoustical results of the same beam with using the Biot damping model. The extension of the Biot damping model is demonstrated to study MDOF (Multiple Degrees of Freedom) dynamics equations of a discrete system in order to introduce different types of viscoelastic damping materials. The mechanical properties of viscoelastic damping materials such as shear modulus and loss factor change with respect to different ambient temperatures and frequencies. The application of multiple-layer treatment increases the damping characteristic of the structure significantly and thus helps to attenuate the vibration and noise for a broad range of frequency and temperature. The main contributions of this dissertation include the following three major tasks: 1) Study of the viscoelastic damping mechanism and the dynamics equation of a multilayer damped system incorporating the Biot damping model. 2) Building the Finite Element Method (FEM) model of the multiple-layer constrained viscoelastic damping beam and conducting the vibration analysis. 3) Extending the vibration problem to the Boundary Element Method (BEM) based acoustical problem and comparing the results with commercial simulation software.