M Myronakis

Evaluation of a patient-specific Monte Carlo software for CT dosimetry

The aim was to validate the ImpactMC computed tomography (CT) dosimetry software that allows patient-specific dose determination. Measured values of head- and body-weighted CT dose index (CTDI(w)) were compared with corresponding values derived using ImpactMC software. A physical anthropomorphic phantom simulating the average adult was employed to study the effect of exposure parameters used to produce the input image set on a normalised dose output and the relationship between exposure parameters selected for simulation on the dose output. The difference between CTDI(w) values obtained through measurements and simulations were found to be up to 12.8 and 18.3% for head and body phantoms, respectively. Exposure parameters of the image set used as input were found to have a minor impact on the normalised dose output. Simulations confirmed the expected linear relationship between dose and tube load and the power law relationship between dose and tube potential. Results demonstrate that ImpactMC may be capable of providing reliable CT dose estimates.

Monte Carlo investigation of charge‐transport effects on energy resolution and detection efficiency of pixelated CZT detectors for SPECT/PET applications

PURPOSE Semiconductor detectors are increasingly considered as alternatives to scintillation crystals for nuclear imaging applications such as positron emission tomography (PET) or single photon emission computed tomography (SPECT). One of the most prominent detector materials is cadmium zinc telluride (CZT), which is currently used in several application-specific nuclear imaging systems. In this work, the charge-transport effects in pixelated CZT detectors in relation to detector pixel size and thickness are investigated for pixels sizes from 0.4 up to 1.6 mm. METHODS The determination of an optimum pixel size and thickness for use with photon energies of 140 and 511 keV, suitable for SPECT and PET studies, is attempted using photon detection efficiency and energy resolution as figures of merit. The Monte Carlo method combined with detailed finite element analysis was utilized to realistically model photon interactions in the detector and the signal generation process. The GEANT4 Application for Tomographic Emission (GATE) toolkit was used for photon irradiation and interaction simulations. The COMSOL MULTIPHYSICS software application was used to create finite element models of the detector that included charge drift, diffusion, trapping, and generation. Data obtained from the two methods were combined to generate accurate signal induction at the detector pixels. The energy resolution was calculated as the full width at half maximum of the energy spectrum photopeak. Photon detection efficiency was also calculated. The effects of charge transport within the detector and photon escape from primary pixel of interaction were investigated; the extent of diffusion to lateral pixels was also assessed. RESULTS Charge transport and signal induction were affected by the position of a pixel in the detector. Edge and corner pixels were less susceptible to lateral diffusion than pixels located in the inner part of the detector. Higher detection efficiency and increased photon escape from primary interaction pixel were observed for thicker detectors. Energy resolution achieved better values in 0.7 and 1.0 mm pixel size for 5 mm detector thickness and 1.6 mm pixel size for 10 mm thickness. CONCLUSIONS Selection of pixel size and thickness depends on the imaging application and photon energy utilized. For systems that integrate two nuclear imaging modalities (i.e., combined SPECT/PET), the pixel size should offer an appropriate balance of the effects that take place in the detector, based on the results of the current work. This allows for a system to be designed with the same detector material and the same geometrical configuration for both modalities.

Epigenetic therapy with inhibitors of histone methylation suppresses DNA damage signaling and increases glioma cell radiosensitivity

Radiation therapy is widely used to treat human malignancies, but many tumor types, including gliomas, exhibit significant radioresistance. Radiation therapy creates DNA double-strand breaks (DSBs), and DSB repair is linked to rapid changes in epigenetic modifications, including increased histone methylation. This increased histone methylation recruits DNA repair proteins which can then alter the local chromatin structure and promote repair. Consequently, combining inhibitors of specific histone methyltransferases with radiation therapy may increase tumor radiosensitivity, particularly in tumors with significant therapeutic resistance. Here, we demonstrate that inhibitors of the H4K20 methyltransferase SETD8 (UNC-0379) and the H3K9 methyltransferase G9a (BIX-01294) are effective radiosensitizers of human glioma cells. UNC-0379 blocked H4K20 methylation and reduced recruitment of the 53BP1 protein to DSBs, although this loss of 53BP1 caused only limited changes in radiosensitivity. In contrast, loss of H3K9 methylation through G9a inhibition with BIX-01294 increased radiosensitivity of a panel of glioma cells (SER2Gy range: 1.5 - 2.9). Further, loss of H3K9 methylation reduced DSB signaling dependent on H3K9, including reduced activation of the Tip60 acetyltransferase, loss of ATM signaling and reduced phosphorylation of the KAP-1 repressor. In addition, BIX-0194 inhibited DSB repair through both the homologous recombination and nonhomologous end-joining pathways. Inhibition of G9a and loss of H3K9 methylation is therefore an effective approach for increasing radiosensitivity of glioma cells. These results suggest that combining inhibitors of histone methyltransferases which are critical for DSB repair with radiation therapy may provide a new therapeutic route for sensitizing gliomas and other tumors to radiation therapy.

Key clinical beam parameters for nanoparticle-mediated radiation dose amplification

As nanoparticle solutions move towards human clinical trials in radiation therapy, the influence of key clinical beam parameters on therapeutic efficacy must be considered. In this study, we have investigated the clinical radiation therapy delivery variables that may significantly affect nanoparticle-mediated radiation dose amplification. We found a benefit for situations which increased the proportion of low energy photons in the incident beam. Most notably, “unflattened” photon beams from a clinical linear accelerator results in improved outcomes relative to conventional “flat” beams. This is measured by significant DNA damage, tumor growth suppression, and overall improvement in survival in a pancreatic tumor model. These results, obtained in a clinical setting, clearly demonstrate the influence and importance of radiation therapy parameters that will impact clinical radiation dose amplification with nanoparticles.

Effect of pixel dimensions and thickness on energy resolution and sensitivity of CZT detectors used in nuclear medicine application

Cadmium zinc telluride (CZT) is considered a promising material in detector manufacturing for gamma-ray imaging. The potential of using CZT detectors with pixellated anodes to fulfill the requirements of better spatial and energy resolution as well as higher sensitivity has not been yet fully investigated. Pixellated anodes are advantaged by the small pixel effect but are susceptible to charge sharing and photon scattering within the detector especially in smaller pixel dimensions. In the current work, we combine the finite element method (FEM) and Monte Carlo simulations to model charge transport and photon interactions in the detector. The effect of pixel size on energy resolution and sensitivity was investigated for pixel pitch size from 0.4 up to 1.6 mm and for 5 and 10 mm thickness under 140 and 511 keV photon irradiation.

A Monte Carlo study of the impact of phosphor optical properties on EPID imaging performance

We have developed a Monte Carlo computational model of a clinically employed electronic portal imaging device (EPID), and demonstrated the impact of phosphor optical properties on the imaging performance. The EPID model was built with Geant4 application for tomographic emission. Both radiative and optical transport were included in the model. Modulation transfer function (MTF), normalized noise-power spectrum times the incident x-ray fluence (qNNPS), and detective quantum efficiency (DQE) were calculated for simulated and measured data, and their agreement was quantified by the normalized root-mean-square error (NRMSE). MTF was computed using a 100 µm wide slit tilted by 1.5° and qNNPS was estimated using the Fujita-Lubberts-Swank method. DQE was calculated from MTF and qNNPS data. The NRMSE value was 0.0467 for MTF, 0.0217 for qNNPS, and 0.0885 for DQE, showing good agreement between measurement and simulation. Five major optical properties, phosphor grain size, phosphor thickness, phosphor refractive index, binder refractive index, and packing ratio were tested for their influence on the qNNPS, MTF, and DQE(0) of the model. Generally, the effect on the qNNPS is greater than MTF, and no impact on DQE(0), except from phosphor thickness, was observed. Multiple applications, such as imager design optimization and investigations of the dosimetric performance, are expected to benefit from the validated model.

Multi-layer imager design for mega-voltage spectral imaging

The architecture of multi-layer imagers (MLIs) can be exploited to provide megavoltage spectral imaging (MVSPI) for specific imaging tasks. In the current work, we investigated bone suppression and gold fiducial contrast enhancement as two clinical tasks which could be improved with spectral imaging. A method based on analytical calculations that enables rapid investigation of MLI component materials and thicknesses was developed and validated against Monte Carlo computations. The figure of merit for task-specific imaging performance was the contrast-to-noise ratio (CNR) of the gold fiducial when the CNR of bone was equal to zero after a weighted subtraction of the signals obtained from each MLI layer. Results demonstrated a sharp increase in the CNR of gold when the build-up component or scintillation materials and thicknesses were modified. The potential for low-cost, prompt implementation of specific modifications (e.g. composition of the build-up component) could accelerate clinical translation of MVSPI.

1D pixelated MV portal imager with structured privacy film: a feasibility study

Modern amorphous silicon flat panel-based electronic portal imaging devices that utilize thin gadolinium oxysulfide scintillators suffer from low quantum efficiencies (QEs). Thick two dimensionally (2D) pixelated scintillator arrays offer an effective but expensive option for increasing QE. To reduce costs, we have investigated the possibility of combining a thick one dimensional (1D) pixelated scintillator (PS) with an orthogonally placed 1D structured optical filter to provide for overall good 2D spatial resolution. In this work, we studied the potential for using a 1D video screen privacy film (PF) to serve as a directional optical attenuator and filter. A Geant4 model of the PF was built based on reflection and transmission measurements taken with a laser-based optical reflectometer. This information was incorporated into a Geant4-based x-ray detector simulator to generate modulation transfer functions (MTFs), noise power spectra (NPS), and detective quantum efficiencies (DQEs) for various 1D and 2D configurations. It was found that the 1D array with PF can provide the MTFs and DQEs of 2D arrays. Although the PF significantly reduced the amount of optical photons detected by the flat panel, we anticipate using a scintillator with an inherently high optical yield (e.g. cesium iodide) for MV imaging, where fluence rates are inherently high, will still provide adequate signal intensities for the imaging tasks associated with radiotherapy.

Spectral imaging using clinical megavoltage beams and a novel multi-layer imager

We assess the feasibility of clinical megavoltage (MV) spectral imaging for material and bone separation with a novel multi-layer imager (MLI) prototype. The MLI provides higher detective quantum efficiency and lower noise than conventional electronic portal imagers. Simulated experiments were performed using a validated Monte Carlo model of the MLI to estimate energy absorption and energy separation between the MLI components. Material separation was evaluated experimentally using solid water and aluminum (Al), copper (Cu) and gold (Au) for 2.5 MV, 6 MV and 6 MV flattening filter free (FFF) clinical photon beams. An anthropomorphic phantom with implanted gold fiducials was utilized to further demonstrate bone/gold separation. Weighted subtraction imaging was employed for material and bone separation. The weighting factor (w) was iteratively estimated, with the optimal w value determined by minimization of the relative signal difference ([Formula: see text]) and signal-difference-to-noise ratio (SDNR) between material (or bone) and the background. Energy separation between layers of the MLI was mainly the result of beam hardening between components with an average energy separation between 34 and 47 keV depending on the x-ray beam energy. The minimum average energy of the detected spectrum in the phosphor layer was 123 keV in the top layer of the MLI with the 2.5 MV beam. The w values that minimized [Formula: see text] and SDNR for Al, Cu and Au were 0.89, 0.76 and 0.64 for 2.5 MV; for 6 MV FFF, w was 0.98, 0.93 and 0.77 respectively. Bone suppression in the anthropomorphic phantom resulted in improved visibility of the gold fiducials with the 2.5 MV beam. Optimization of the MLI design is required to achieve optimal separation at clinical MV beam energies.

A novel method for quantification of beam's‐eye‐view tumor tracking performance

Purpose: In‐treatment imaging using an electronic portal imaging device (EPID) can be used to confirm patient and tumor positioning. Real‐time tumor tracking performance using current digital megavolt (MV) imagers is hindered by poor image quality. Novel EPID designs may help to improve quantum noise response, while also preserving the high spatial resolution of the current clinical detector. Recently investigated EPID design improvements include but are not limited to multi‐layer imager (MLI) architecture, thick crystalline and amorphous scintillators, and phosphor pixilation and focusing. The goal of the present study was to provide a method of quantitating improvement in tracking performance as well as to reveal the physical underpinnings of detector design that impact tracking quality. The study employs a generalizable ideal observer methodology for the quantification of tumor tracking performance. The analysis is applied to study both the effect of increasing scintillator thickness on a standard, single‐layer imager (SLI) design as well as the effect of MLI architecture on tracking performance. Methods: The present study uses the ideal observer signal‐to‐noise ratio (d′) as a surrogate for tracking performance. We employ functions which model clinically relevant tasks and generalized frequency‐domain imaging metrics to connect image quality with tumor tracking. A detection task for relevant Cartesian shapes (i.e., spheres and cylinders) was used to quantitate trackability of cases employing fiducial markers. Automated lung tumor tracking algorithms often leverage the differences in benign and malignant lung tissue textures. These types of algorithms (e.g., soft‐tissue localization – STiL) were simulated by designing a discrimination task, which quantifies the differentiation of tissue textures, measured experimentally and fit as a power‐law in trend (with exponent β) using a cohort of MV images of patient lungs. The modeled MTF and NPS were used to investigate the effect of scintillator thickness and MLI architecture on tumor tracking performance. Results: Quantification of MV images of lung tissue as an inverse power‐law with respect to frequency yields exponent values of β = 3.11 and 3.29 for benign and malignant tissues, respectively. Tracking performance with and without fiducials was found to be generally limited by quantum noise, a factor dominated by quantum detective efficiency (QDE). For generic SLI construction, increasing the scintillator thickness (gadolinium oxysulfide – GOS) from a standard 290 μm to 1720 μm reduces noise to about 10%. However, 81% of this reduction is appreciated between 290 and 1000 μm. In comparing MLI and SLI detectors of equivalent individual GOS layer thickness, the improvement in noise is equal to the number of layers in the detector (i.e., 4) with almost no difference in MTF. Further, improvement in tracking performance was slightly less than the square‐root of the reduction in noise, approximately 84–90%. In comparing an MLI detector with an SLI with a GOS scintillator of equivalent total thickness, improvement in object detectability is approximately 34–39%. Conclusions: We have presented a novel method for quantification of tumor tracking quality and have applied this model to evaluate the performance of SLI and MLI EPID designs. We showed that improved tracking quality is primarily limited by improvements in NPS. When compared to very thick scintillator SLI, employing MLI architecture exhibits the same gains in QDE, but by mitigating the effect of optical Swank noise, results in more dramatic improvements in tracking performance.