An investigation of the accuracy of Monte Carlo portal dosimetry for verification of IMRT with extended fields.

This work investigated the accuracy of Monte Carlo (MC) simulations of amorphous silicon (a-Si) electronic portal imaging devices (EPIDs) for the dosimetric verification of intensity-modulated radiotherapy (IMRT). In particular, the suitability of the method for verification of head and neck IMRT with extended field segments (approximately 20 cm superior-inferior), covering almost the entire detector area, was studied. A solution involving schematic modelling of backscatter materials has been established to account for non-uniform backscatter to the imager from supporting structures. 96% of points within the IMRT fields evaluated passed a 'gamma' evaluation criterion of 2%, 2 mm at isocentre at a dose rate of 100 MU min(-1) with this solution included. Only 79% of points passed this gamma criterion without the correction for backscatter included. This work has also demonstrated the ability of the technique to detect systematic delivery errors in step and shoot IMRT. The technique identified a systematic overshoot on the first segment and an undershoot on the final segment. Results were verified by ion chamber measurements and agreed well with those reported in the literature, averaging approximately 0.1 and 0.3 MU for 100 and 300 MU min(-1) deliveries, respectively. MC portal verification has the potential to become a key tool in the verification of IMRT and can also facilitate selection of optimal delivery parameters, thus improving treatment accuracy. This approach can be applied to the verification of other new treatment techniques and should also enable development of methodologies to detect and correct for delivery errors, both before and during treatment.

High-performance computing for Monte Carlo radiotherapy calculations.

We report on the RTGrid project, which investigates approaches for using high-performance computing infrastructures, such as the grid, in order to reduce the turnaround time of Monte Carlo (MC) simulation-based radiotherapy treatment planning. The main aim of this project is to render accurate dose calculations using MC simulations clinically feasible. To this end, we have successfully implemented and deployed the RTGrid distributed simulation framework for MC dose calculations. In this paper, we present the main experimental findings.

Biodiversity of cytochrome P450 redox systems.

P450s (cytochrome P450 mono-oxygenases) are a superfamily of haem-containing mono-oxygenase enzymes that participate in a wide range of biochemical pathways in different organisms from all of the domains of life. To facilitate their activity, P450s require sequential delivery of two electrons passed from one or more redox partner enzymes. Although the P450 enzymes themselves show remarkable similarity in overall structure, it is increasingly apparent that there is enormous diversity in the redox partner systems that drive the P450 enzymes. This paper examines some of the recent advances in our understanding of the biodiversity of the P450 redox apparatus, with a particular emphasis on the redox systems in the pathogen Mycobacterium tuberculosis.

Correction for dose-response variations in a scanning liquid ion chamber EPID as a function of linac gantry angle.

The response of electronic portal imaging devices (EPIDs) of the scanning liquid ionization chamber (SLIC) type is known to vary with linear accelerator gantry angle. This work considered several contributing factors, quantified the artefacts, monitored their reproducibility and investigated the effects of repeated gantry rotations. Unflatness of up to 5% was found. A correction technique was devised using nonlinear regression of a three-variable sinusoidal modulation. Comparison with two existing techniques found our method to be the most effective, providing a flatness well within 2%. This improved accuracy is expected to benefit more accurate dosimetric studies in particular. The post-acquisition correction process required no change in imaging protocols. Applicability of the new technique was demonstrated on images acquired on different days and with different beam sizes. Since the artefacts compromise both accurate dosimetry and image quality, their successful removal should benefit a broad range of SLIC EPID applications.

Monte Carlo simulation of portal dosimetry on a rectilinear voxel geometry: a variable gantry angle solution.

A software solution has been developed to carry out Monte Carlo simulations of portal dosimetry using the BEAMnrc/DOSXYZnrc code at oblique gantry angles. The solution is based on an integrated phantom, whereby the effect of incident beam obliquity was included using geometric transformations. Geometric transformations are accurate within +/- 1 mm and +/- 1 degrees with respect to exact values calculated using trigonometry. An application in portal image prediction of an inhomogeneous phantom demonstrated good agreement with measured data, where the root-mean-square of the difference was under 2% within the field. Thus, we achieved a dose model framework capable of handling arbitrary gantry angles, voxel-by-voxel phantom description and realistic particle transport throughout the geometry.

A DICOM-RT-based toolbox for the evaluation and verification of radiotherapy plans.

The verification of radiotherapy plans is an essential step in the treatment planning process. This is especially important for highly conformal and IMRT plans which produce non-intuitive fluence maps and complex 3D dose distributions. In this work we present a DICOM (Digital Imaging and Communication in Medicine) based toolbox, developed for the evaluation and the verification of radiotherapy treatment plans. The toolbox offers the possibility of importing treatment plans generated with different calculation algorithms and/or different optimization engines and evaluating dose distributions on an independent platform. Furthermore the radiotherapy set-up can be exported to the BEAM Monte Carlo code system for dose verification. This can be done by simulating the irradiation of the patient CT dataset or the irradiation of a software-generated water phantom. We show the application of some of the functions implemented in this toolbox for the evaluation and verification of an IMRT treatment of the head and neck region.

Association between obesity and a polymorphism in the beta(1)-adrenoceptor gene (Gly389Arg ADRB1) in Caucasian women.

INTRODUCTION: Genetic variants affecting adrenoceptors have been suggested to influence body fatness. A putative gain-of-function polymorphism in the beta(1)-adrenoceptor was recently discovered (Gly389Arg ADRB1). We examined the association between Gly389Arg ADRB1 and obesity status in a large cohort of well-characterized individuals. METHODS: First, a large cohort of 931 Caucasian women (55.0+/-12.2 y) were genotyped for Gly389Arg ADRBbeta1 and we examined the association of the Arg allele with body weight and BMI (Gly/Gly, n=54; Gly/Arg, n=360; Arg/Arg, n=517). To further examine phenotypes regulating energy balance and body fatness, we examined the contribution of the Arg allele to body composition (DEXA), fat distribution (CT scan), resting energy expenditure, energy and macronutrient intake, maximal oxygen capacity, and physical activity in a subsample of 214 women from the main cohort that had been carefully characterized (Gly/Gly, n=19; Gly/Arg, n=82; Arg/Arg, n=113). RESULTS: In the entire cohort (n=931), allele frequencies were 0.25 and 0.75 for the Gly and Arg alleles, respectively. In this cohort, we found that each Arg allele was associated with greater body weight of 2.91 kg (P=0.01) and BMI of 0.86 kg/m(2) (P=0.05). Accordingly, in the subsample of women, each Arg allele was associated with greater fat mass (3.71 kg; P=0.008). Other phenotypes were not significantly associated with the presence of the Arg allele. CONCLUSIONS: This is the first study to investigate the relationship between the Gly389Arg ADRB1 variant and obesity. We found that the Arg allele is associated with greater body weight and BMI in Caucasian women due to a greater fat mass.

Full forward Monte Carlo calculation of portal dose from MLC collimated treatment beams.

This work deals with a full Monte Carlo (MC) simulation of a radiotherapy treatment facility including a multi-leaf collimator (MLC) and electronic portal imaging device (EPID). A method for a planar calibration of the EPID response in terms of dose using the MC technique is presented. Calibration measurements and simulations with several blocks of attenuating material are carried out down to approximatively 5% of the open field transmitted dose. A linear relationship is shown between the squared EPID signal and the MC calculated dose. The calibrated EPID was used as a dosimetric system to validate a MC model for the MLC. Computations and measurements agreed within 2% of dose difference (or 2 mm in regions of high dose gradient). The technique described herein is not significantly limited by physics transport model constraints. Therefore it can potentially provide a more accurate verification of dose delivery to inhomogeneous anatomical regions in patients undergoing complex multi-field conformal or intensity-modulated radiation therapy.

Monte Carlo simulation and dosimetric verification of radiotherapy beam modifiers.

Monte Carlo simulation of beam modifiers such as physical wedges and compensating filters has been performed with a rectilinear voxel geometry module. A modified version of the EGS4/DOSXYZ code has been developed for this purpose. The new implementations have been validated against the BEAM Monte Carlo code using its standard component modules (CMs) in several geometrical conditions. No significant disagreements were found within the statistical errors of 0.5% for photons and 2% for electrons. The clinical applicability and flexibility of the new version of the code has been assessed through an extensive verification versus dosimetric data. Both Varian multi-leaf collimator (MLC) wedges and standard wedges have been simulated and compared against experiments for 6MV photon beams and different field sizes. Good agreement was found between calculated and measured depth doses and lateral dose profiles along both wedged and unwedged directions for different depths and focus-to-surface distances. Furthermore, Monte Carlo-generated output factors for both open and wedged fields agreed with linac commissioning beam data within statistical uncertainties of the calculations (<3% at largest depths). Compensating filters of both low-density and high-density materials have also been successfully simulated. As a demonstration, a wax compensating filter with a complex three-dimensional concave and convex geometry has been modelled through a CT scan import. Calculated depth doses and lateral dose profiles for different field sizes agreed well with experiments. The code was used to investigate the performance of a commercial treatment planning system in designing compensators. Dose distributions in a heterogeneous water phantom emulating the head and neck region were calculated with the convolution-superposition method (pencil beam and collapsed cone implementations) and compared against those from the MC code developed herein. The new technique presented in this work is versatile, DICOM-RT compliant and accurate in the simulation of beam modulators. This paper addresses the need to reduce the sources of error in the modelling of beam modifiers since they remain a viable alternative to the MLC technique in the delivery of IMRT beams.

Application of the fundamental parameter method to the in vivo x-ray fluorescence analysis of Pt.

The application of the fundamental parameter method (FPM) to the in vivo x-ray fluorescence (XRF) analysis of Pt has been investigated. The FPM is conventionally used to carry out elemental analysis of samples in vitro without the need to use standard samples of accurately known composition for system calibration. The present work has involved the use of the FPM to calculate the concentration of Pt solutions in phantoms, with concentrations ranging from 25-1000 ppm. The phantoms simulate the measurement of Pt-based chemotherapy drugs in head and neck tumours. The radiation sources were a 150 kV tungsten-anode x-ray tube and the isotope 99mTc. The minimum detection limit measured for Pt was in the range 8-30 ppm (depending on radiation source and geometry), using a narrow (5 mm) diameter beam. Dose rates in the phantom were 0.1-5 mGy h(-1). Average differences between nominal and calculated values of Pt concentration were <8% using the phantoms in air to simulate measurement of Pt in superficial body sites. If the phantoms were placed in a water bath, to simulate measurement at greater depths of overlying tissue, higher systematic differences (15-20%) were observed. This effect is probably due to multiple scattering processes in the surrounding medium.

Comparison of EGS4 and MCNP Monte Carlo codes when calculating radiotherapy depth doses.

The Monte Carlo codes EGS4 and MCNP have been compared when calculating radiotherapy depth doses in water. The aims of the work were to study (i) the differences between calculated depth doses in water for a range of monoenergetic photon energies and (ii) the relative efficiency of the two codes for different electron transport energy cut-offs. The depth doses from the two codes agree with each other within the statistical uncertainties of the calculations (1-2%). The relative depth doses also agree with data tabulated in the British Journal of Radiology Supplement 25. A discrepancy in the dose build-up region may by attributed to the different electron transport algorithims used by EGS4 and MCNP. This discrepancy is considerably reduced when the improved electron transport routines are used in the latest (4B) version of MCNP. Timing calculations show that EGS4 is at least 50% faster than MCNP for the geometries used in the simulations.

Benchmarking the MCNP code for Monte Carlo modelling of an in vivo neutron activation analysis system.

The Monte Carlo computer code MCNP (version 4A) has been used to develop a personal computer-based model of the Swansea in vivo neutron activation analysis (IVNAA) system. The model included specification of the neutron source (252Cf), collimators, reflectors and shielding. The MCNP model was 'benchmarked' against fast neutron and thermal neutron fluence data obtained experimentally from the IVNAA system. The Swansea system allows two irradiation geometries using 'short' and 'long' collimators, which provide alternative dose rates for IVNAA. The data presented here relate to the short collimator, although results of similar accuracy were obtained using the long collimator. The fast neutron fluence was measured in air at a series of depths inside the collimator. The measurements agreed with the MCNP simulation within the statistical uncertainty (5-10%) of the calculations. The thermal neutron fluence was measured and calculated inside the cuboidal water phantom. The depth of maximum thermal fluence was 3.2 cm (measured) and 3.0 cm (calculated). The width of the 50% thermal fluence level across the phantom at its mid-depth was found to be the same by both MCNP and experiment. This benchmarking exercise has given us a high degree of confidence in MCNP as a tool for the design of IVNAA systems.

Computer aided design of a polarised source for in vivo X-ray fluorescence analysis.

A system has been developed which uses Monte Carlo computer simulations to aid the design and optimisation of a polarised source for in vivo X-ray fluorescence (XRF) analysis of heavy metals: The system is based on a version of the Monte Carlo code EGS4 which includes polarised photon interactions, running on a personal computer. The code was used to construct a model of a clinical polarised XRF system (based on a 300 kV therapy X-ray source) under development at Swansea for the measurement of Pt-based chemotherapy drugs in head and neck tumours. Several simulations were performed to investigate the variation of XRF measurement sensitivity with the material composition and geometry of the system components. Pt XRF spectra generated by the model were found to be in good agreement with experimental data. The optimum operating voltage for the system, predicted by the simulations and confirmed by experiment, was approx. 200 kV. The accuracy of the results obtained to date indicates that this technique will greatly facilitate future design and optimisation studies of a wide variety of XRF systems.

Monte Carlo design study of a moderated 252Cf source for in vivo neutron activation analysis of aluminium.

The Monte Carlo computer code MCNP has been used to design a moderated 252Cf neutron source for in vivo neutron activation analysis of aluminium (Al) in the bones of the hand. The clinical motivation is the need to monitor Al body burden in subjects with renal dysfunction, at risk of Al toxicity. The design involves the source positioned on the central axis at one end of a cylindrical deuterium oxide moderator. The moderator is surrounded by a graphite reflector, with the hand inserted at the end of the moderator opposing the source. For a 1 mg 252Cf source, 15 cm long x 20 cm radius moderator and 20 cm thick reflector, the estimated minimum detection limit is 0.5 mg Al for a 20 min irradiation, with an equivalent dose of 16.5 mSv to the hand. Increasing the moderator length and/or introducing a fast neutron filter (for example silicon) further reduces interference from fast-neutron-induced reactions on phosphorus in bone, at the expense of decreased fluence of the thermal neutrons which activate Al. Increased source strengths may be necessary to compensate for this decreased thermal fluence, to allow measurements to be made within an acceptable time limit for the comfort of the patient.

Optimization of a polarized source for in vivo x-ray fluorescence analysis of platinum and other heavy metals.

The Monte Carlo method was used to optimize a polarized photon source for the x-ray fluorescence analysis of platinum and other heavy metals in vivo. The source consisted of a 140 kVp, 25 mA x-ray tube with the photons plane-polarized by 90 degrees scattering. The use of plane-polarized photons results in a significant reduction in background when the fluorescent radiation is measured along the direction of polarization. A Monte Carlo computer programme was written to simulate the production and interaction of polarized photons in order to determine the optimal polarizing material and dimensions, together with beam width and geometrical arrangement of source, polarizer and beam collimators. Calculated photon energy distributions are compared with experimental data to test the validity of the model. The best configuration of the polarization system for the in vivo analysis of platinum consisted of a 20 mm Cu polarizing block with a secondary collimator subtending a 0.1 radian angle at the polarizer.

A megavoltage CT scanner for radiotherapy verification.

We have further developed a system for generating megavoltage CT images immediately prior to the administration of external beam radiotherapy. The detector is based on the scanner of Simpson (Simpson et al 1982)--the major differences being a significant reduction in dose required for image formation, faster image formation and greater convenience of use in the clinical setting. Attention has been paid to the problem of ring artefacts in the images. Specifically, a Fourier-space filter has been applied to the sinogram data. After suitable detector calibration, it has been shown that the device operates close to its theoretical specification of 3 mm spatial resolution and a few percent contrast resolution. Ring artefacts continue to be a major source of image degradation. A number of clinical images have been presented. The next stage of this work is to use the system to make clinical measurements of patient set-up inaccuracies building on our work making such measurements from digital portal images (Evans et al 1992).

Localization of diphtheria toxin nuclease activity to fragment A.

We describe a series of experiments that aimed to establish whether nuclease activity is actually associated with diphtheria toxin (DTx) and its A subunit (DTA), as we originally reported (M. P. Chang, R. L. Baldwin, C. Bruce, and B. J. Wisnieski, Science 246:1165-1168, 1989). Here we show that (i) trypsinization of DTx does indeed produce nucleolytically active DTA, (ii) reduction of electroeluted, unreduced, cleaved DTx (58 kDa) yields nuclease-active DTA (24 kDa), and (iii) fractionation of DTx and DTA by anion-exchange chromatography leads to coelution of nuclease activity with both forms of the toxin, even though each form elutes at a distinct salt concentration. In addition, we show that Escherichia coli-derived DTA also expresses nuclease activity. These studies confirm our initial assertion that the nuclease activity observed in DTx preparations is intrinsic to the DTA portion of DTx.

The design of megavoltage projection imaging systems: some theoretical aspects.

This study investigates factors associated with the imaging of a patient using a high-energy radiotherapy treatment beam. Both single-stage (e.g., solid-state detector) and two-stage (e.g., scintillation screen plus TV) systems are considered. First an expression is derived that relates dose at the buildup depth in the object to the structure of the object, the scatter-to-primary signal-variance ratio and the differential-signal-to-noise ratio in the image. Second the number of bits required to digitize the image is derived. Third the effect of scattered radiation is investigated for photon counting, photopeak, and Compton detector types. Fourth the effect of noise in the detection process is considered. Finally, the relationship between x-ray source size, detector aperture, and image magnification is derived. The optimum magnification for given source size and detector aperture is discussed in terms of the system transfer function. The study indicates that at a primary beam energy of 2 MeV, a dose of 10(-3) cGy is required to detect reliably the presence of a bone section of area 10 x 10 mm and thickness 4 mm in 250 mm of soft tissue. For this example, it is also estimated that a digitization accuracy of 10 bits is required. The calculations indicate that for a Compton detector, the scatter-to-primary signal-variance ratio drops from a value of around 30% at the exit surface of the object to 5% at a distance of 80 cm from the object with a consequent small reduction in the dose required to form the image.

A linear array, scintillation crystal-photodiode detector for megavoltage imaging.

An imaging device has been developed to acquire images during external photon-beam radiotherapy treatments. It consists of a linear array of 128 zinc tungstate (ZnWO4) scintillation crystals each of which is individually optically coupled to a photodiode and associated electronics. The image is formed by scanning the linear array across the radiation field using a stepping motor under the control of a microcomputer. Image archive, display, and analysis are performed using a microVAX II computer. Results from a general theoretical analysis are presented before a detailed description of the particular detector construction. The mechanical design of the detector is such that the detector is automatically positioned to within a millimeter relative to the treatment source. This simplifies procedures for analyzing setup variations when comparing a treatment image to any other treatment, or planning, images. Image acquisition takes under 4 s with a contrast resolution of better than 1% at a spatial resolution of 2.5 mm in the object plane. The primary dose used to form these images is 0.55 cGy although the dose received by the patient will be closer to 25 cGy due to the linear scanning geometry and 3.8-s scan time that is used.