Mark Foley

Mesenchymal Stem Cell‐Mediated Delivery of the Sodium Iodide Symporter Supports Radionuclide Imaging and Treatment of Breast Cancer

Mesenchymal Stem Cells (MSCs) migrate specifically to tumors in vivo, and coupled with their capacity to bypass immune surveillance, are attractive vehicles for tumor‐targeted delivery of therapeutic agents. This study aimed to introduce MSC‐mediated expression of the sodium iodide symporter (NIS) for imaging and therapy of breast cancer. Tumor bearing animals received an intravenous or intratumoral injection of NIS expressing MSCs (MSC‐NIS), followed by 99mTechnetium pertechnetate imaging 3–14 days later using a BazookaSPECT γ‐camera. Tissue was harvested for analysis of human NIS (hNIS) expression by relative quantitative‐polymerase chain reaction. Therapy animals received an i.p. injection of 131I or saline 14 days after injection of MSC‐NIS, and tumor volume was monitored for 8 weeks. After injection of MSC‐NIS, BazookaSPECT imaging revealed an image of animal intestines and chest area at day 3, along with a visible weak tumor image. By day 14, the tumor was visible with a significant reduction in radionuclide accumulation in nontarget tissue observed. hNIS gene expression was detected in the intestines, heart, lungs, and tumors at early time points but later depleted in nontarget tissues and persisted at the tumor site. Based on imaging/biodistribution data, animals received a therapeutic dose of 131I 14 days after MSC‐NIS injection. This resulted in a significant reduction in tumor growth (mean ± SEM, 236 ± 62 mm3 vs. 665 ± 204 mm3 in controls). The ability to track MSC migration and transgene expression noninvasively in real time before therapy is a major advantage to this strategy. This promising data supports the feasibility of this approach as a novel therapy for breast cancer. STEM CELLS 2011;29:1149–1157

An investigation into the use of MMCTP to tune accelerator source parameters and testing its clinical application

This paper presents an alternative method to tune Monte Carlo electron beam parameters to match measured data using a minimal set of variables in order to reduce the model setup time prior to clinical implementation of the model. Monte Carlo calculations provide the possibility of a powerful treatment planning verification technique. The nonstandardized and nonautomated process of tuning the required accelerator model is one of the reasons for delays in the clinical implementation of Monte Carlo techniques. This work aims to establish and verify an alternative tuning method that can be carried out in a minimal amount of time, allowing it to be easily implemented in a clinical setting by personnel with minimal experience with Monte Carlo methods. This tuned model can then be incorporated into the MMCTP system to allow the system to be used as a second dose calculation check for IMRT plans. The technique proposed was used to establish the primary electron beam parameters for accelerator models for the Varian Clinac 2100 6 MV photon beam using the BEAMnrc Monte Carlo system. The method is intended to provide a clear, direct, and efficient process for tuning an accelerator model using readily available clinical quality assurance data. The tuning provides a refined model, which agrees with measured dose profile curves within 1.5% outside the penumbra or 3 mm in the penumbra, for square fields with sides of 3 cm up to 30 cm. These models can then be employed as the basis for Monte Carlo recalculations of dose distributions, using the MMCTP system, for clinical treatment plans, providing an invaluable assessment tool. This was tested on six IMRT plans and compared to the measurements performed for the pretreatment QA process. These Monte Carlo values for the average dose to the chamber volume agreed with measurements to within 0.6%. PACS number: 87.55.km

Monte Carlo commissioning of clinical electron beams using large field measurements

Monte Carlo simulation can accurately calculate electron fluence at the patient surface and the resultant dose deposition if the initial source electron beam and linear accelerator treatment head geometry parameters are well characterized. A recent approach used large electron fields to extract these simulation parameters. This method took advantage of the absence of lower energy, widely scattered electrons from the applicator resulting in more accurate data. It is important to validate these simulation parameters for clinically relevant fields. In the current study, these simulation parameters are applied to fields collimated by applicators and inserts to perform a comprehensive validation. Measurements were performed on a Siemens Oncor linear accelerator for 6 MeV, 9 MeV, 12 MeV, 15 MeV, 18 MeV and 21 MeV electron beams and collimators ranging from an open 25 x 25 cm(2) applicator to a 10 x 10 cm(2) applicator with a 1 cm diameter cerrobend insert. Data were collected for inserts placed in four square applicators. Monte Carlo simulations were performed using EGSnrc/BEAMnrc. Source and geometry parameters were obtained from previous measurements and simulations with the maximum field size (40 x 40 cm(2)). The applicators were modelled using manufacturer specifications, confirmed by direct measurements. Cerrobend inserts were modelled based on calliper measurements. Monte Carlo-calculated percentage depth dose and off-axis profiles agreed with measurements to within the least restrictive of 2%/1 mm in most cases. For the largest applicator (25 x 25 cm(2)), and 18 MeV and 21 MeV beams, differences in dose profiles of 3% were observed. Calculated relative output factors were within 2% of those measured with an electron diode for fields 1.5 cm in diameter or larger. The disagreement for 1 cm diameter fields was up to 5%. For open applicators, simulations agreed with parallel plate chamber-measured relative output factors to 1%. This work has validated a recent methodology used to extract data on the electron source and treatment head from large electron fields, resulting in a reduction in the number of unknown parameters in treatment head simulation. Applicator and insert collimated electron fields were accurately simulated without adjusting these parameters. Results demonstrate that commissioning of electron beams based on large electron field measurements is a viable option.

Design and performance of a small-animal imaging system using synthetic collimation.

This work outlines the design and construction of a single-photon emission computed tomography imaging system based on the concept of synthetic collimation. A focused multi-pinhole collimator is constructed using rapid-prototyping and casting techniques. The collimator projects the centre of the field of view (FOV) through 46 pinholes when the detector is adjacent to the collimator, with the number reducing towards the edge of the FOV. The detector is then moved further from the collimator to increase the magnification of the system. The object distance remains constant, and each new detector distance is a new system configuration. The level of overlap of the pinhole projections increases as the system magnification increases, but the number of projections subtended by the detector is reduced. There is no rotation in the system; a single tomographic angle is used in each system configuration. Image reconstruction is performed using maximum-likelihood expectation-maximization and an experimentally measured system matrix. The system matrix is measured for each configuration on a coarse grid, using a point source. The pinholes are individually identified and tracked, and a Gaussian fit is made to each projection. The coefficients of these fits are used to interpolate the system matrix. The system is validated experimentally with a hot-rod phantom. The Fourier crosstalk matrix is also measured to provide an estimate of the average spatial resolution along each axis over the entire FOV. The 3D synthetic-collimator image is formed by estimating the activity distribution within the FOV and summing the activities in the voxels along the axis perpendicular to the collimator face.

Functional imaging for regenerative medicine

In vivo imaging is a platform technology with the power to put function in its natural structural context. With the drive to translate stem cell therapies into pre-clinical and clinical trials, early selection of the right imaging techniques is paramount to success. There are many instances in regenerative medicine where the biological, biochemical, and biomechanical mechanisms behind the proposed function of stem cell therapies can be elucidated by appropriate imaging. Imaging techniques can be divided according to whether labels are used and as to whether the imaging can be done in vivo. In vivo human imaging places additional restrictions on the imaging tools that can be used. Microscopies and nanoscopies, especially those requiring fluorescent markers, have made an extraordinary impact on discovery at the molecular and cellular level, but due to their very limited ability to focus in the scattering tissues encountered for in vivo applications they are largely confined to superficial imaging applications in research laboratories. Nanoscopy, which has tremendous benefits in resolution, is limited to the near-field (e.g. near-field scanning optical microscope (NSNOM)) or to very high light intensity (e.g. stimulated emission depletion (STED)) or to slow stochastic events (photo-activated localization microscopy (PALM) and stochastic optical reconstruction microscopy (STORM)). In all cases, nanoscopy is limited to very superficial applications. Imaging depth may be increased using multiphoton or coherence gating tricks. Scattering dominates the limitation on imaging depth in most tissues and this can be mitigated by the application of optical clearing techniques that can impose mild (e.g. topical application of glycerol) or severe (e.g. CLARITY) changes to the tissue to be imaged. Progression of therapies through to clinical trials requires some thought as to the imaging and sensing modalities that should be used. Smoother progression is facilitated by the use of comparable imaging modalities throughout the discovery and trial phases, giving label-free techniques an advantage wherever they can be used, although this is seldom considered in the early stages. In this paper, we will explore the techniques that have found success in aiding discovery in stem cell therapies and try to predict the likely technologies best suited to translation and future directions.

Characterization of an extendable multi-leaf collimator for clinical electron beams.

An extendable x-ray multi-leaf collimator (eMLC) is investigated for collimation of electron beams on a linear accelerator. The conventional method of collimation using an electron applicator is impractical for conformal, modulated and mixed beam therapy techniques. An eMLC would allow faster, more complex treatments with potential for reduction in dose to organs-at-risk and critical structures. The add-on eMLC was modelled using the EGSnrc Monte Carlo code and validated against dose measurements at 6-21 MeV with the eMLC mounted on a Siemens Oncor linear accelerator at 71.6 and 81.6 cm source-to-collimator distances. Measurements and simulations at 8.4-18.4 cm airgaps showed agreement of 2%/2 mm. The eMLC dose profiles and percentage depth dose curves were compared with standard electron applicator parameters. The primary differences were a wider penumbra and up to 4.2% reduction in the build-up dose at 0.5 cm depth, with dose normalized on the central axis. At 90 cm source-to-surface distance (SSD)--relevant to isocentric delivery--the applicator and eMLC penumbrae agreed to 0.3 cm. The eMLC leaves, which were 7 cm thick, contributed up to 6.3% scattered electron dose at the depth of maximum dose for a 10 × 10 cm2 field, with the thick leaves effectively eliminating bremsstrahlung leakage. A Monte Carlo calculated wedge shaped dose distribution generated with all six beam energies matched across the maximum available eMLC field width demonstrated a therapeutic (80% of maximum dose) depth range of 2.1-6.8 cm. Field matching was particularly challenging at lower beam energies (6-12 MeV) due to the wider penumbrae and angular distribution of electron scattering. An eMLC isocentric electron breast boost was planned and compared with the conventional applicator fixed SSD plan, showing similar target coverage and dose to critical structures. The mean dose to the target differed by less than 2%. The low bremsstrahlung dose from the 7 cm thick MLC leaves had the added advantage of reducing the mean dose to the whole heart. Isocentric delivery using an extendable eMLC means that treatment room re-entry and repositioning the patient for SSD set-up is unnecessary. Monte Carlo simulation can accurately calculate the fluence below the eMLC and subsequent patient dose distributions. The eMLC generates similar dose distributions to the standard electron applicator but provides a practical method for more complex electron beam delivery.

Electron beam therapy at extended source‐to‐surface distance: a Monte Carlo investigation

Electron‐beam therapy is used to treat superficial tumors at a standard 100 cm source‐to‐surface distance (SSD). However, certain clinical situations require the use of an extended SSD. In the present study, Monte Carlo methods were used to investigate clinical electron beams, at standard and non‐standard SSDs, from a Siemens Oncor Avant Garde (Siemens Healthcare, Erlangen, Germany) linear accelerator (LINAC). The LINAC treatment head was modeled in BEAMnrc for electron fields 5 cm in diameter and 10×10 cm, 15×15 cm, and 20×20 cm; for 6 MeV, 9 MeV, and 12 MeV; and for 100 cm, 110 cm, and 120 cm SSD. The DOSXYZnrc code was used to calculate extended SSD factors and dose contributions from various parts of the treatment head. The main effects of extended SSD on water phantom dose distributions were verified by Monte Carlo methods. Monte Carlo–calculated and measured extended SSD factors showed an average difference of ±1.8%. For the field 5 cm in diameter, the relative output at extended SSD declined more rapidly than it did for the larger fields. An investigation of output contributions showed this decline was mainly a result of a rapid loss of scatter dose reaching the dmax point from the lower scrapers of the electron applicator. The field 5 cm in diameter showed a reduction in dose contributions; the larger fields generally showed an increased contribution from the scrapers with increase in SSD. Angular distributions of applicator‐scattered electrons have shown a large number of acute‐angle electron tracks contributing to the output for larger field sizes, explaining the shallow output reduction. PACS numbers: 87.53.Wz, 87.53.Vb, 87.53.Hv

Accounting for the fringe magnetic field from the bending magnet in a Monte Carlo accelerator treatment head simulation

PURPOSE Monte Carlo (MC) simulation can be used for accurate electron beam treatment planning and modeling. Measurement of large electron fields, with the applicator removed and secondary collimator wide open, has been shown to provide accurate simulation parameters, including asymmetry in the measured dose, for the full range of clinical field sizes and patient positions. Recently, disassembly of the treatment head of a linear accelerator has been used to refine the simulation of the electron beam, setting tightly measured constraints on source and geometry parameters used in simulation. The simulation did not explicitly include the known deflection of the electron beam by a fringe magnetic field from the bending magnet, which extended into the treatment head. Instead, the secondary scattering foil and monitor chamber were unrealistically laterally offset to account for the beam deflection. This work is focused on accounting for this fringe magnetic field in treatment head simulation. METHODS The magnetic field below the exit window of a Siemens Oncor linear accelerator was measured with a Tesla-meter from 0 to 12 cm from the exit window and 1-3 cm off-axis. Treatment head simulation was performed with the EGSnrc/BEAMnrc code, modified to incorporate the effect of the magnetic field on charged particle transport. Simulations were used to analyze the sensitivity of dose profiles to various sources of asymmetry in the treatment head. This included the lateral spot offset and beam angle at the exit window, the fringe magnetic field and independent lateral offsets of the secondary scattering foil and electron monitor chamber. Simulation parameters were selected within the limits imposed by measurement uncertainties. Calculated dose distributions were then compared with those measured in water. RESULTS The magnetic field was a maximum at the exit window, increasing from 0.006 T at 6 MeV to 0.020 T at 21 MeV and dropping to approximately 5% of the maximum at the secondary scattering foil. It was up to three times higher in the bending plane, away from the electron gun, and symmetric within measurement uncertainty in the transverse plane. Simulations showed the magnetic field resulted in an offset of the electron beam of 0.80 cm (mean) at the machine isocenter for the exit window only configuration. The fringe field resulted in a 3.5%-7.6% symmetry and 0.25-0.35 cm offset of the clinical beam R(max) profiles. With the magnetic field included in simulations, a single (realistic) position of the secondary scattering foil and monitor chamber was selected. Measured and simulated dose profiles showed agreement to an average of 2.5%/0.16 cm (maximum: 3%/0.2 cm), which is a better match than previously achieved without incorporating the magnetic field in the simulation. The undulations from the 3 stepped layers of the secondary scattering foil, evident in the measured profiles of the higher energy beams, are now aligned with those in the simulated beam. The simulated fringe magnetic field had negligible effect on the central axis depth dose curves and cross-plane dose profiles. CONCLUSIONS The fringe magnetic field is a significant contributor to the electron beam in-plane asymmetry. With the magnetic field included explicitly in the simulation, realistic monitor chamber and secondary scattering foil positions have been achieved, and the calculated fluence and dose distributions are more accurate.

Development of an image receptor for use in digital mammography

We have recently developed a digital x-ray image receptor for use in mammographic procedures. The detector is based upon a photoconductor, amorphous selenium (a-Se), coupled to a polymer dispersed liquid crystal (PDLC) layer. A potential is applied across the structure to create a bias electric field in the photoconductor. When x-rays are absorbed in the photoconductor, electron-hole pairs are released. The created charges are swept to the a-Se /PDLC interface via the applied electric field, which causes potential variations across the PDLC. These variations lead to liquid crystal (LC) molecule re-orientation, which affects the propagation of readout light from an external source through the display. The readout light can be bright in this arrangement so that no secondary quantum sinks are present. Since this system is independent of light creation in contrast with a phosphor screen system, the image brightness can be adjusted independently of the number of x-rays used to make the image. The image can be digitized with a CCD camera and a frame grabber. Results will be presented on the PDLC characteristics, the system model and initial images from the detector.

A Monte Carlo study of the effect of an ultrasound transducer on surface dose during intrafraction motion imaging for external beam radiation therapy

Purpose: The aim of this study was to estimate changes in surface dose due to the presence of the Clarity Autoscan™ ultrasound (US) probe during prostate radiotherapy using Monte Carlo (MC) methods. Methods: MC models of the Autoscan US probe were developed using the BEAMnrc/DOSXYZnrc code based on kV and MV CT images. CT datasets were converted to voxelized mass density phantoms using a CT number‐to‐mass density calibration. The dosimetric effect of the probe, in the contact region (an 8 mm × 12 mm single layer of voxels), was investigated using a phantom set‐up mimicking two scenarios (a) a transperineal imaging configuration (radiation beam perpendicular to the central US axial direction), and (b) a transabdominal imaging configuration (radiation beam parallel to the central US axial direction). For scenario (a), the dosimetric effect was evaluated as a function of the probe to inferior radiation field edge distance. Clinically applicable distances from 5 mm separation to 2 mm overlap were determined from the radiotherapy plans of 27 patients receiving Clarity imaging. Overlaps of 3 to 14 (1 to 3 SD) mm were also considered to include the effect of interfraction motion correction. The influence of voxel size on surface dose estimation was investigated. Approved clinical plans from two prostate patients were used to simulate worst‐case dosimetric impact of the probe when large couch translations were applied to correct for interfraction prostate motion. Results: The dosimetric impact of both the MV and kV probe models agreed within ±2% for both beam configurations. For scenario (a) and 1 mm voxel model, the probe gave mean dose increases of 1.2% to 4.6% (of the dose at isocenter) for 5 mm separation to 0 mm overlap in the probe‐phantom contact region, respectively. This increased to 27.5% for the largest interfraction motion correction considered (14 mm overlap). For separations of ≥ 2 mm dose differences were < 2%. Simulated dose perturbations were found to be superficial; for the 14 mm overlap the dose increase reduced to < 3% at 5.0 mm within the phantom. For scenario (b), dose increases due to the probe were < 5% in all cases. The dose increase was underestimated by up to ˜13% when the voxel size was increased from 1 mm to 3 mm. MC simulated dose to the PTV and OARs for the two clinical plans considered showed good agreement with commercial treatment planning system results (within 2%). Mean dose increases due to the presence of the probe, after the maximum interfraction motion correction, were ˜16.3% and ˜8.0%, in the contact region, for plan 1 and plan 2, respectively. Conclusions: The presence of the probe results in superficial dose perturbations for patients with an overlap between the probe and the radiation field present in either the original treatment plan or due to translation of the radiation field to simulate correction of interfraction internal prostate motion.