K Song

Correlations of noninvasive BOLD and TOLD MRI with pO2 and relevance to tumor radiation response

To examine the potential use of blood oxygenation level dependent (BOLD) and tissue oxygenation level dependent (TOLD) contrast MRI to assess tumor oxygenation and predict radiation response.

Dosimetric characterization of an image-guided stereotactic small animal irradiator.

Small animal irradiation provides an important tool used by preclinical studies to assess and optimize new treatment strategies such as stereotactic ablative radiotherapy. Characterization of radiation beams that are clinically and geometrically scaled for the small animal model is uniquely challenging for orthovoltage energies and minute field sizes. The irradiator employs a commercial x-ray device (XRAD 320, Precision x-ray, Inc.) with a custom collimation system to produce 1-10 mm diameter beams and a 50 mm reference beam. Absolute calibrations were performed using the AAPM TG-61 methodology. Beams half-value layer (HVL) and timer error were measured with an ionization chamber. Percent depth dose (PDD), output factors (OFs) and off-axis ratios were measured using radiochromic film, a diode and a pinpoint ionization chamber at 19.76 and 24.76 cm source-to-surface distance (SSD). PDD measurements were also compared with Monte Carlo (MC) simulations. In-air and in-water absolute calibrations for the reference 50 mm diameter collimator at 19.76 cm SSD were measured as 20.96 and 20.79 Gy min(-1), respectively, agreeing within 0.8%. The HVL at 250 kVp and 15 mAs was measured to be 0.45 mm Cu. The reference field PDD MC simulation results agree with measured data within 3.5%. PDD data demonstrate typical increased penetration with increasing field size and SSD. For collimators larger than 5 mm in diameter, OFs measured using film, an ion chamber and a diode were within 3% agreement.

An x-ray image guidance system for small animal stereotactic irradiation

An x-ray image-guided small animal stereotactic irradiator was developed and characterized to enable tumor visualization and accurate target localization for small field, high dose irradiation. The system utilizes a custom collimation system, a motorized positioning system (x, y, θ), a digital imaging panel and operating software, and is integrated with a commercial x-ray unit. The essential characteristics of the irradiator include small radiation fields (1-10 mm), high dose rate (>10 Gy min(-1)) and submillimeter target localization. The software enables computer-controlled image acquisition, stage motion and target localization providing simple and precise automated target localization. The imaging panel was characterized in terms of signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR) and spatial resolution. Overall localization accuracy and precision were assessed. SNR, CNR and spatial resolution are 24 dB, 21 dB and 2.8 lp mm(-1), respectively, and localization accuracy is approximately 65 µm with 6 µm precision. With the aid of image guidance, system performance was subsequently used to evaluate radiation response in a rat orthotopic lung tumor effectively sparing normal tissues and in a mouse normal lung. The capabilities of 3D treatment and cone-beam computed tomography are presented for 3D localization and delivery as a work in progress.

An Orthotopic Lung Tumor Model for Image-Guided Microirradiation in Rats

Abstract The purpose of this study was to develop a rat orthotopic lung tumor model with a solitary intrapulmonary nodule to study the effects of high-dose radiation. A549-Luc non-small cell lung cancer (NSCLC) cells were implanted into nude rats in the intercostal space between ribs 5 and 6 of the right lung. Bioluminescence and microcomputed tomography (CT) imaging were performed after implantation to confirm the presence of a solitary tumor and to monitor tumor growth. A device using image guidance for localization was developed to facilitate high-precision irradiation in small animals. A pilot irradiation study was performed, and response was assessed by bioluminescence imaging and immunohistochemistry. Radiation response was confirmed through serial bioluminescence imaging, and the strength of the bioluminescence signal was observed to be inversely proportional to dose. Response was also observed by the monoclonal antibody bavituximab, which binds to exposed lipid phosphatidylserine (PS) on tumor vessels. The ability to (1) reproducibly generate solitary tumor nodules in the rat lung, (2) identify and monitor tumor growth by bioluminescence imaging and CT imaging, (3) accurately target these tumors using high doses of radiation, and (4) demonstrate and quantify radiation response using bioluminescence imaging provides significant opportunity to probe the biological mechanisms of high-dose irradiation in preclinical settings.

Partial Depletion of Regulatory T Cells Does Not Influence the Inflammation Caused by High Dose Hemi-Body Irradiation

There is clinical interest in the modulation of regulatory T cells for cancer therapy. The safety of these therapies in combination with conventional anti-cancer therapies, including radiation therapy, can be studied in animal models. The effects of partial depletion of regulatory T (Treg) cells with an anti-CD25 antibody in conjunction with ionizing radiation on inflammation and tissue injury were analyzed in C57BL/6 mice. An anti-CD25 antibody (PC61) was administered 3 days prior to 13 Gy lower-half hemi-body irradiation (HBI). The blood, spleen, mesenteric lymph nodes (mLNs) and inguinal lymph nodes (iLNs) were harvested at various times thereafter. Alterations in the proportion of leukocyte subsets including CD4+ T cells, CD8+ T cells, Treg cells, B cells, NK cells, NK1.1+ T cells, macrophages and granulocytes were analyzed by FACS. The lungs, liver, pancreas, stomach, jejunum, duodenum, ileum, colon and kidney were harvested and studied by H&E staining. Expression of inflammatory mediators in plasma and tissue were investigated by ELISA. HBI significantly decreased the leukocyte pool though the various leukocyte subsets had different sensitivities to HBI. The administration of PC61 significantly decreased the proportion of Treg cells in spleen, iLN, mLN and blood (reduction of approximately 60%). Irradiation significantly increased the proportion of Treg cells in the spleen, iLN and mLN. HBI induced a systemic inflammatory reaction as demonstrated by increased plasma levels of IL-6, KC/CXCL1 and circulating granulocytes in the blood. Neutrophils also infiltrated the small bowel. The same general patterns were observed whether or not Treg cells were partially depleted with PC61 prior to HBI. These data demonstrate that partial depletion of Treg cells in these mice does not influence HBI-induced inflammatory response and tissue injury, and that combining anti-CD25 therapy with radiation may be safe and well tolerated in a clinical setting.

Development of a locally advanced orthotopic prostate tumor model in rats for assessment of combined modality therapy.

The purpose of this study was to develop an aggressive locally advanced orthotopic prostate cancer model for assessing high-dose image-guided radiation therapy combined with biological agents. For this study, we used a modified human prostate cancer (PCa) cell line, PC3, in which we knocked down a tumor suppressor protein, DAB2IP (PC3-KD). These prostate cancer cells were implanted into the prostate of nude or Copenhagen rats using either open surgical implantation or a minimally invasive procedure under ultrasound guidance. We report that: i) these DAB2IP-deficient PCa cells form a single focus of locally advanced aggressive tumors in both nude and Copenhagen rats; ii) the resulting tumors are highly aggressive and are poorly controlled after treatment with radiation alone; iii) ultrasound-guided tumor cell implantation can be used successfully for tumor development in the rat prostate; iv) precise measurement of the tumor volume and the treatment planning for radiation therapy can be obtained from ultrasound and MRI, respectively; and v) the use of a fiducial marker for enhanced radiotherapy localization in the rat orthotopic tumor. This model recapitulates radiation-resistant prostate cancers which can be used to demonstrate and quantify therapeutic response to combined modality treatments.

A role for dynamic contrast-enhanced magnetic resonance imaging in predicting tumour radiation response

Background:Dynamic contrast-enhanced (DCE) MRI may provide prognostic insights into tumour radiation response. This study examined quantitative DCE MRI parameters in rat tumours, as potential biomarkers of tumour growth delay following single high-dose irradiation.Methods:Dunning R3327-AT1 prostate tumours were evaluated by DCE MRI following intravenous injection of Gd-DTPA. The next day tumours were irradiated (single dose of 30 Gy), while animals breathed air (n=4) or oxygen (n=4); two animals were non-irradiated controls. Growth was followed and tumour volume-quadrupling time (T4) was compared with pre-irradiation DCE assessments.Results:Irradiation caused significant tumour growth delay (T4 ranged from 28 to 48 days for air-breathing rats, and 40 to 75 days for oxygen-breathing rats) compared with the controls (T4=7 to 9 days). A strong correlation was observed between T4 and extravascular-extracellular volume fraction (ve) irrespective of the gas inhaled during irradiation. There was also a correlation between T4 and volume transfer constant (Ktrans) for the air-breathing group alone.Conclusions:The data provide rationale for expanded studies of other tumour sites, types and progressively patients, and are potentially significant, as many patients undergo contrast-enhanced MRI as part of treatment planning.

SU‐GG‐J‐21: Direct Investigation of Geometric Coincidence among Calypso System, Onboard KV Imaging, and MV Treatment Beam Imaging

Purpose: The Calypso 4D localization system and onboard kV imaging systems have been developed and applied clinically to improve accuracy of tumor localization for radiation therapy, particularly for Stereotactic Body Radiation Therapy(SBRT). However, the accuracy of the treatment and the dose delivery depends on the coincidence of both the treatment beam and localization systems. These are calibrated separately, and nominally to the room lasers which have additional sources of uncertainty. The purpose of this study is to investigate a direct method for determining the geometric accuracy and coincidence of treatment beam and localization systems. Method and Materials: A CIRS prostate phantom with three Calypso Beacons was imaged by both MV and kV beams at a series of gantry angles on a Synergy accelerator while the Beacon positions were simultaneously tracked using the Calypso system. A kV cone‐beam CT(CBCT) scan was also performed to locate the Beacons. Beacons were automatically detected on kV and MV projection images using in‐house software and their 3D positions were calculated from MV orthogonal pairs (MV‐pair), kV orthogonal pairs (kV‐pair), and CBCT scans, and then compared with Calypso. A special geometric QA procedure was developed to assess geometric accuracy of MV and kV imaging systems at every gantry angle. Geometric parameter deviations, particularly detector center offsets, were applied to correct the 3D position calculations. Results: Systematic differences among Calypso, kV‐pair, kV CBCT, and MV‐pair results were observed. Using geometric QA corrected MV‐pair results as treatment positions, averaged deviation of Calypso results is 1.1 mm. Deviations from MV‐pair, kV‐pair, and CBCT results drop from 1.7 mm, 1.1 mm, 1.0 mm to 0, 0.1 mm, and 0.2 mm, respectively, after geometric QA correction. Conclusion: Systematic deviations among Calypso, kV pairs, kV CBCT, and MV results were directly and quantitatively evaluated with a geometric QA.

WE‐E‐108‐06: Demonstration of a CBCT Based Monte Carlo Model for Small Animal Treatment Planning

PURPOSE To demonstrate feasibility of planning small animal irradiation using cone beam computed tomography (CBCT) data as input to a Monte Carlo (MC) based treatment planning system (TPS). METHODS The BEAMnrc/EGSnrc code was used to model 225 kVp photon beams produced by a small animal irradiator (XRAD 225Cx, Precision X-ray). Homogenous phantom plugs (Gammex RMI 467, Middleton, WI) of known material and physical density were scanned using the XRAD 225Cx CBCT system to associate unique CBCT units to the corresponding material density. Additionally, the known physical densities were then correlated to appropriate atomic compositions to create a material data set library. This enabled correlating phantom CBCT units to a material/density matrix used as input to DOSXYZnrc MC computations. A 4×4×4 cm3 multi slab phantom in homogeneous (all solid water) and heterogeneous (lung block between water slabs) configurations were CBCT scanned using 80 kVp and 0.3 mAs setting. MC dose calculation was performed for 10 mm diameter circular field. Ultimately, 10 mm circular fields in homogenous and heterogeneous phantom configuration were used to compare absolute dose computed by MCTPS and film measurement. The CBCT based MC model was finally demonstrated using an animal CBCT scan. RESULTS The gamma map of CBCT based MC calculation and film measurement at 1cm depth plane in solid water medium shows excellent agreement of 98.7%within selected region of interest using 3%/0.5 mm gamma criteria. The absolute dose comparison between measurement and simulation in homogenous and heterogeneous phantom is within 1%. In a small animal the CBCT based MC model qualitatively demonstrated higher dose to bone relative to dose deposited to soft tissues. CONCLUSION The CBCT based MC model is a valuable tool for improved dose calculation accuracy for small animal treatment planning in orthovoltage energy range.

WE-E-108-05: Evaluation of the XRAD 225Cx MC Source Model in Heterogeneous Mediums

PURPOSE This study was performed to benchmark a Monte Carlo source model of the XRAD 225Cx irradiator under heterogeneous conditions. METHODS The BEAM/EGS was used to model 225 kV photon beams from a small animal irradiator (Precision XRAD225Cx). Benchmarking the model in heterogeneous media was performed in a heterogeneous phantom (4×4×4 cm3) composed of solid water and cortical bone. The 10 mm field size virtual source from BEAMnrc was used to compute the 3D dose distribution in DOSXYZnrc. Benchmarking the simulation against measurements was performed using EBT2 film. Heterogeneous conditions were further validated using the phase space file for the 20 mm field size. Gamma analysis was performed to further validate the beam model for the heterogeneous configuration phantom. RESULTS The MC simulation indicates that there is a 2.4 times increased dose deposition in cortical bone, in agreement with published data. This increased dose deposition, however, was not observed in film measurements and it is investigated further. Gamma analysis was performed for 20 mm field size applicator and the Result of the analysis for a confined region. The single beam with 20 mm diameter circular field irradiation demonstrates a good agreement within the region of interest, with 94% of the calculated data meeting the 5%/0.5 mm criterion. CONCLUSION Our kV Monte Carlo source model demonstrates excellent agreement with measurement in heterogeneous conditions.