Magdalena Bazalova-Carter

Molecular Magnetic Resonance Imaging of Tumor Response to Therapy

Personalized cancer medicine requires measurement of therapeutic efficacy as early as possible, which is optimally achieved by three-dimensional imaging given the heterogeneity of cancer. Magnetic resonance imaging (MRI) can obtain images of both anatomy and cellular responses, if acquired with a molecular imaging contrast agent. The poor sensitivity of MRI has limited the development of activatable molecular MR contrast agents. To overcome this limitation of molecular MRI, a novel implementation of our caspase-3-sensitive nanoaggregation MRI (C-SNAM) contrast agent is reported. C-SNAM is triggered to self-assemble into nanoparticles in apoptotic tumor cells, and effectively amplifies molecular level changes through nanoaggregation, enhancing tissue retention and spin-lattice relaxivity. At one-tenth the current clinical dose of contrast agent, and following a single imaging session, C-SNAM MRI accurately measured the response of tumors to either metronomic chemotherapy or radiation therapy, where the degree of signal enhancement is prognostic of long-term therapeutic efficacy. Importantly, C-SNAM is inert to immune activation, permitting radiation therapy monitoring.

Monte Carlo modeling of ultrasound probes for image guided radiotherapy.

PURPOSE To build Monte Carlo (MC) models of two ultrasound (US) probes and to quantify the effect of beam attenuation due to the US probes for radiation therapy delivered under real-time US image guidance. METHODS MC models of two Philips US probes, an X6-1 matrix-array transducer and a C5-2 curved-array transducer, were built based on their megavoltage (MV) CT images acquired in a Tomotherapy machine with a 3.5 MV beam in the EGSnrc, BEAMnrc, and DOSXYZnrc codes. Mass densities in the probes were assigned based on an electron density calibration phantom consisting of cylinders with mass densities between 0.2 and 8.0 g/cm(3). Beam attenuation due to the US probes in horizontal (for both probes) and vertical (for the X6-1 probe) orientation was measured in a solid water phantom for 6 and 15 MV (15 × 15) cm(2) beams with a 2D ionization chamber array and radiographic films at 5 cm depth. The MC models of the US probes were validated by comparison of the measured dose distributions and dose distributions predicted by MC. Attenuation of depth dose in the (15 × 15) cm(2) beams and small circular beams due to the presence of the probes was assessed by means of MC simulations. RESULTS The 3.5 MV CT number to mass density calibration curve was found to be linear with R(2) > 0.99. The maximum mass densities in the X6-1 and C5-2 probes were found to be 4.8 and 5.2 g/cm(3), respectively. Dose profile differences between MC simulations and measurements of less than 3% for US probes in horizontal orientation were found, with the exception of the penumbra region. The largest 6% dose difference was observed in dose profiles of the X6-1 probe placed in vertical orientation, which was attributed to inadequate modeling of the probe cable. Gamma analysis of the simulated and measured doses showed that over 96% of measurement points passed the 3%/3 mm criteria for both probes placed in horizontal orientation and for the X6-1 probe in vertical orientation. The X6-1 probe in vertical orientation caused the highest attenuation of the 6 and 15 MV beams, which at 10 cm depth accounted for 33% and 43% decrease compared to the respective (15 × 15) cm(2) open fields. The C5-2 probe in horizontal orientation, on the other hand, caused a dose increase of 10% and 53% for the 6 and 15 MV beams, respectively, in the buildup region at 0.5 cm depth. For the X6-1 probe in vertical orientation, the dose at 5 cm depth for the 3-cm diameter 6 MV and 5-cm diameter 15 MV beams was attenuated compared to the corresponding open fields to a greater degree by 65% and 43%, respectively. CONCLUSIONS MC models of two US probes used for real-time image guidance during radiotherapy have been built. Due to the high beam attenuation of the US probes, the authors generally recommend avoiding delivery of treatment beams that intersect the probe. However, the presented MC models can be effectively integrated into US-guided radiotherapy treatment planning in cases for which beam avoidance is not practical due to anatomy geometry.

Comparison of film measurements and Monte Carlo simulations of dose delivered with very high-energy electron beams in a polystyrene phantom.

PURPOSE To measure radiation dose in a water-equivalent medium from very high-energy electron (VHEE) beams and make comparisons to Monte Carlo (MC) simulation results. METHODS Dose in a polystyrene phantom delivered by an experimental VHEE beam line was measured with Gafchromic films for three 50 MeV and two 70 MeV Gaussian beams of 4.0-6.9 mm FWHM and compared to corresponding MC-simulated dose distributions. MC dose in the polystyrene phantom was calculated with the EGSnrc/BEAMnrc and DOSXYZnrc codes based on the experimental setup. Additionally, the effect of 2% beam energy measurement uncertainty and possible non-zero beam angular spread on MC dose distributions was evaluated. RESULTS MC simulated percentage depth dose (PDD) curves agreed with measurements within 4% for all beam sizes at both 50 and 70 MeV VHEE beams. Central axis PDD at 8 cm depth ranged from 14% to 19% for the 5.4-6.9 mm 50 MeV beams and it ranged from 14% to 18% for the 4.0-4.5 mm 70 MeV beams. MC simulated relative beam profiles of regularly shaped Gaussian beams evaluated at depths of 0.64 to 7.46 cm agreed with measurements to within 5%. A 2% beam energy uncertainty and 0.286° beam angular spread corresponded to a maximum 3.0% and 3.8% difference in depth dose curves of the 50 and 70 MeV electron beams, respectively. Absolute dose differences between MC simulations and film measurements of regularly shaped Gaussian beams were between 10% and 42%. CONCLUSIONS The authors demonstrate that relative dose distributions for VHEE beams of 50-70 MeV can be measured with Gafchromic films and modeled with Monte Carlo simulations to an accuracy of 5%. The reported absolute dose differences likely caused by imperfect beam steering and subsequent charge loss revealed the importance of accurate VHEE beam control and diagnostics.

Treatment planning for radiotherapy with very high‐energy electron beams and comparison of VHEE and VMAT plans

PURPOSE The aim of this work was to develop a treatment planning workflow for rapid radiotherapy delivered with very high-energy electron (VHEE) scanning pencil beams of 60-120 MeV and to study VHEE plans as a function of VHEE treatment parameters. Additionally, VHEE plans were compared to clinical state-of-the-art volumetric modulated arc therapy (VMAT) photon plans for three cases. METHODS VHEE radiotherapy treatment planning was performed by linking EGSnrc Monte Carlo (MC) dose calculations with inverse treatment planning in a research version of RayStation. In order to study the effect of VHEE treatment parameters on VHEE dose distributions, a matlab graphical user interface (GUI) for calculation of VHEE MC pencil beam doses was developed. Through the GUI, pediatric case MC simulations were run for a number of beam energies (60, 80, 100, and 120 MeV), number of beams (13, 17, and 36), pencil beam spot (0.1, 1.0, and 3.0 mm) and grid (2.0, 2.5, and 3.5 mm) sizes, and source-to-axis distance, SAD (40 and 50 cm). VHEE plans for the pediatric case calculated with the different treatment parameters were optimized and compared. Furthermore, 100 MeV VHEE plans for the pediatric case, a lung, and a prostate case were calculated and compared to the clinically delivered VMAT plans. All plans were normalized such that the 100% isodose line covered 95% of the target volume. RESULTS VHEE beam energy had the largest effect on the quality of dose distributions of the pediatric case. For the same target dose, the mean doses to organs at risk (OARs) decreased by 5%-16% when planned with 100 MeV compared to 60 MeV, but there was no further improvement in the 120 MeV plan. VHEE plans calculated with 36 beams outperformed plans calculated with 13 and 17 beams, but to a more modest degree (<8%). While pencil beam spacing and SAD had a small effect on VHEE dose distributions, 0.1-3 mm pencil beam sizes resulted in identical dose distributions. For the 100 MeV VHEE pediatric plan, OAR doses were up to 70% lower and the integral dose was 33% lower for VHEE compared to 6 MV VMAT. Additionally, VHEE conformity indices (CI100 = 1.09 and CI50 = 4.07) were better than VMAT conformity indices (CI100 = 1.30 and CI50 = 6.81). The 100 MeV VHEE lung plan resulted in mean dose decrease to all OARs by up to 27% for the same target coverage compared to the clinical 6 MV flattening filter-free (FFF) VMAT plan. The 100 MeV prostate plan resulted in 3% mean dose increase to the penile bulb and the urethra, but all other OAR mean doses were lower compared to the 15 MV VMAT plan. The lung case CI100 and CI50 conformity indices were 3% and 8% lower, respectively, in the VHEE plan compared to the VMAT plan. The prostate case CI100 and CI50 conformity indices were 1% higher and 8% lower, respectively, in the VHEE plan compared to the VMAT plan. CONCLUSIONS The authors have developed a treatment planning workflow for MC dose calculation of pencil beams and optimization for treatment planning of VHEE radiotherapy. The authors have demonstrated that VHEE plans resulted in similar or superior dose distributions for pediatric, lung, and prostate cases compared to clinical VMAT plans.

Optimized Detector Angular Configuration Increases the Sensitivity of X-ray Fluorescence Computed Tomography (XFCT)

In this work, we demonstrated that an optimized detector angular configuration based on the anisotropic energy distribution of background scattered X-rays improves X-ray fluorescence computed tomography (XFCT) detection sensitivity. We built an XFCT imaging system composed of a bench-top fluoroscopy X-ray source, a CdTe X-ray detector, and a phantom motion stage. We imaged a 6.4-cm-diameter phantom containing different concentrations of gold solution and investigated the effect of detector angular configuration on XFCT image quality. Based on our previous theoretical study, three detector angles were considered. The X-ray fluorescence detector was first placed at 145 ° (approximating back-scatter) to minimize scatter X-rays. XFCT image quality was compared to images acquired with the detector at 60 ° (forward-scatter) and 90 ° (side-scatter). The datasets for the three different detector positions were also combined to approximate an isotropically arranged detector. The sensitivity was optimized with detector in the 145 ° back-scatter configuration counting the 78-keV gold Kβ1 X-rays. The improvement arose from the reduced energy of scattered X-ray at the 145 ° position and the large energy separation from gold K β1 X-rays. The lowest detected concentration in this configuration was 2.5 mgAu/mL (or 0.25% Au with SNR = 4.3). This concentration could not be detected with the 60 °, 90 °, or isotropic configurations (SNRs = 1.3, 0, 2.3, respectively). XFCT imaging dose of 14 mGy was in the range of typical clinical X-ray CT imaging doses. To our knowledge, the sensitivity achieved in this experiment is the highest in any XFCT experiment using an ordinary bench-top X-ray source in a phantom larger than a mouse ( > 3 cm).

Absolute dosimetric characterization of Gafchromic EBT3 and HDv2 films using commercial flat-bed scanners and evaluation of the scanner response function variability

Radiochromic films (RCF) are commonly used in dosimetry for a wide range of radiation sources (electrons, protons, and photons) for medical, industrial, and scientific applications. They are multi-layered, which includes plastic substrate layers and sensitive layers that incorporate a radiation-sensitive dye. Quantitative dose can be retrieved by digitizing the film, provided that a prior calibration exists. Here, to calibrate the newly developed EBT3 and HDv2 RCFs from Gafchromic™, we used the Stanford Medical LINAC to deposit in the films various doses of 10 MeV photons, and by scanning the films using three independent EPSON Precision 2450 scanners, three independent EPSON V750 scanners, and two independent EPSON 11000XL scanners. The films were scanned in separate RGB channels, as well as in black and white, and film orientation was varied. We found that the green channel of the RGB scan and the grayscale channel are in fact quite consistent over the different models of the scanner, although this comes at the cost of a reduction in sensitivity (by a factor ∼2.5 compared to the red channel). To allow any user to extend the absolute calibration reported here to any other scanner, we furthermore provide a calibration curve of the EPSON 2450 scanner based on absolutely calibrated, commercially available, optical density filters.

Feasibility of external beam radiation therapy to deep‐seated targets with kilovoltage x‐rays

Purpose: Radiation therapy to deep‐seated targets is typically delivered with megavoltage x‐ray beams generated by medical linear accelerators or 60Co sources. Here, we used computer simulations to design and optimize a lower energy kilovoltage x‐ray source generating acceptable dose distributions to a deep‐seated target. Methods: The kilovoltage arc therapy (KVAT) x‐ray source was designed to treat a 4‐cm diameter target located at a 10‐cm depth in a 40‐cm diameter homogeneous cylindrical phantom. These parameters were chosen as an example of a clinical scenario for testing the performance of the kilovoltage source. A Monte Carlo (MC) model of the source was built in the EGSnrc/BEAMnrc code and source parameters, such as beam energy, tungsten anode thickness, beam filtration, number of collimator holes, collimator hole size and thickness, and source extent were varied. Dose to the phantom was calculated in the EGSnrc/DOSXYZnrc code for varying treatment parameters, such as the source‐to‐axis distance and the treatment arc angle. The quality of dose distributions was quantified by means of target‐to‐skin ratio and dose output expressed in D50 (50% isodose line) for a 30‐min irradiation in the homogeneous phantom as well as a lung phantom. Additionally, a patient KVAT dose distribution to a left pararenal lesion (˜1.6 cm in diameter) was calculated and compared to a 15 MV volumetric modulated arc therapy (VMAT) plan. Results: In the design of the KVAT x‐ray source, the beam energy, beam filtration, collimator hole size, source‐to‐isocenter distance, and treatment arc had the largest effect on the source output and the quality of dose distributions. For the 4‐cm target at 10‐cm depth, the optimized KVAT dose distribution generated a conformal plan with target‐to‐skin ratio of 5.1 and D50 in 30 min of 24.1 Gy in the homogeneous phantom. In the lung phantom, a target‐to‐skin ratio of 7.5 and D50 in 30 min of 25.3 Gy were achieved. High dose conformity of the 200 kV KVAT left pararenal plan was comparable to the 15 MV VMAT plan. The volume irradiated to at least 10% (<240 cGy) of the prescription dose was 2.2 × larger in the 200 kV KVAT plan than in the 15 MV VMAT plan, but considered clinically insignificant. Conclusions: This study demonstrated that conformal treatments of deep‐seated targets were achievable with kilovoltage x‐rays with dose distributions comparable to MV beams. However, due to the larger volumes irradiated to clinically tolerated low doses, KVAT x‐ray source usage for deep‐seated lesions will be further evaluated to determine optimal target size.

Aligned nanofibrillar collagen scaffolds - Guiding lymphangiogenesis for treatment of acquired lymphedema.

Secondary lymphedema is a common disorder associated with acquired functional impairment of the lymphatic system. The goal of this study was to evaluate the therapeutic efficacy of aligned nanofibrillar collagen scaffolds (BioBridge) positioned across the area of lymphatic obstruction in guiding lymphatic regeneration. In a porcine model of acquired lymphedema, animals were treated with BioBridge scaffolds, alone or in conjunction with autologous lymph node transfer as a source of endogenous lymphatic growth factor. They were compared with a surgical control group and a second control group in which the implanted BioBridge was supplemented with exogenous vascular endothelial growth factor-C (VEGF-C). Three months after implantation, immunofluorescence staining of lymphatic vessels demonstrated a significant increase in lymphatic collectors within close proximity to the scaffolds. To quantify the functional impact of scaffold implantation, bioimpedance was used as an early indicator of extracellular fluid accumulation. In comparison to the levels prior to implantation, the bioimpedance ratio was significantly improved only in the experimental BioBridge recipients with or without lymph node transfer, suggesting restoration of functional lymphatic drainage. These results further correlated with quantifiable lymphatic collectors, as visualized by contrast-enhanced computed tomography. They demonstrate the therapeutic potential of BioBridge scaffolds in secondary lymphedema.

RECORDS: improved Reporting of montE CarlO RaDiation transport Studies: Report of the AAPM Research Committee Task Group 268

Studies involving Monte Carlo simulations are common in both diagnostic and therapy medical physics research, as well as other fields of basic and applied science. As with all experimental studies, the conditions and parameters used for Monte Carlo simulations impact their scope, validity, limitations, and generalizability. Unfortunately, many published peer-reviewed articles involving Monte Carlo simulations do not provide the level of detail needed for the reader to be able to properly assess the quality of the simulations. The American Association of Physicists in Medicine Task Group #268 developed guidelines to improve reporting of Monte Carlo studies in medical physics research. By following these guidelines, manuscripts submitted for peer-review will include a level of relevant detail that will increase the transparency, the ability to reproduce results, and the overall scientific value of these studies. The guidelines include a checklist of the items that should be included in the Methods, Results, and Discussion sections of manuscripts submitted for peer-review. These guidelines do not attempt to replace the journal reviewer, but rather to be a tool during the writing and review process. Given the varied nature of Monte Carlo studies, it is up to the authors and the reviewers to use this checklist appropriately, being conscious of how the different items apply to each particular scenario. It is envisioned that this list will be useful both for authors and for reviewers, to help ensure the adequate description of Monte Carlo studies in the medical physics literature.

Development of a high resolution voxelised head phantom for medical physics applications

Computational anthropomorphic phantoms have become an important investigation tool for medical imaging and dosimetry for radiotherapy and radiation protection. The development of computational phantoms with realistic anatomical features contribute significantly to the development of novel methods in medical physics. For many applications, it is desirable that such computational phantoms have a real-world physical counterpart in order to verify the obtained results. In this work, we report the development of a voxelised phantom, the HIGH_RES_HEAD, modelling a paediatric head based on the commercial phantom 715-HN (CIRS). HIGH_RES_HEAD is unique for its anatomical details and high spatial resolution (0.18×0.18mm2 pixel size). The development of such a phantom was required to investigate the performance of a new proton computed tomography (pCT) system, in terms of detector technology and image reconstruction algorithms. The HIGH_RES_HEAD was used in an ad-hoc Geant4 simulation modelling the pCT system. The simulation application was previously validated with respect to experimental results. When compared to a standard spatial resolution voxelised phantom of the same paediatric head, it was shown that in pCT reconstruction studies, the use of the HIGH_RES_HEAD translates into a reduction from 2% to 0.7% of the average relative stopping power difference between experimental and simulated results thus improving the overall quality of the head phantom simulation. The HIGH_RES_HEAD can also be used for other medical physics applications such as treatment planning studies. A second version of the voxelised phantom was created that contains a prototypic base of skull tumour and surrounding organs at risk.