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At least 775 records · Page 43
All sourcesNASA NTRSDOE OSTI
DOE OSTI2016

SU-F-E-02: A Feasibility Study for Application of Metal Artifact Reduction Techniques in MR-Guided Brachytherapy Gynecological Cancer with Titanium Applicators

Purpose: Utilization of Titanium Tandem and Ring (T&R) applicators in MR-guided brachytherapy has become widespread for gynecological cancer treatment. However, Titanium causes magnetic field disturbance and susceptibility artifact, which complicate image interpretation. In this study, metal artifact reduction techniques were employed to improve the image quality and reduce the metal related artifacts. Methods: Several techniques were employed to reduce the metal artifact caused by titanium T&R applicator. These techniques include Metal Artifact Reduction Sequence (MARS), View Angle Tilting (VAT) to correct in-plane distortion, and Slice Encoding for Metal Artifact Correction (SEMAC) for through-plane artifact correction. Moreover, MARS can be combined with VAT to further reduce the in-plane artifact by reapplying the selection gradients during the readout (MARS+VAT). SEMAC uses a slice selective excitation but acquires additional z-encodings in order to resolve off-resonant signal and to reduce through-plane distortions. Results: Comparison between the clinical sequences revealed that increasing the bandwidth reduces the error in measured diameter of T&R. However, the error is larger than 4mm for the best case with highest bandwidth and spatial resolution. MARS+VAT with isotropic resolution of 1mm reduced the error to 1.9mm which is the least among the examined 2D sequences. The measured diameter of tandem from SEMAC+VAT has the closest value to the actual diameter of tandem (3.2mm) and the error was reduced to less than 1mm. In addition, SEMAC+VAT significantly reduces the blooming artifact in the ring compared to clinical sequences. Conclusion: A higher bandwidth and spatial resolution sequence reduces the artifact and diameter of applicator with a slight compromise in SNR. Metal artifact reduction sequences decrease the distortion associated with titanium applicator. SEMAC+VAT sequence in combination with VAT revealed promising results for titanium imaging and can be utilized for MR-guided brachytherapy in gynecological cancer. The author is employee with Philips Healthcare.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

SU-F-J-24: Setup Uncertainty and Margin of the ExacTrac 6D Image Guide System for Patients with Brain Tumors

Purpose: This study evaluated the setup uncertainties for brain sites when using BrainLAB’s ExacTrac X-ray 6D system for daily pretreatment to determine the optimal planning target volume (PTV) margin. Methods: Between August 2012 and April 2015, 28 patients with brain tumors were treated by daily image-guided radiotherapy using the BrainLAB ExacTrac 6D image guidance system of the Novalis-Tx linear accelerator. DUONTM (Orfit Industries, Wijnegem, Belgium) masks were used to fix the head. The radiotherapy was fractionated into 27–33 treatments. In total, 844 image verifications were performed for 28 patients and used for the analysis. The setup corrections along with the systematic and random errors were analyzed for six degrees of freedom in the translational (lateral, longitudinal, and vertical) and rotational (pitch, roll, and yaw) dimensions. Results: Optimal PTV margins were calculated based on van Herk et al.’s [margin recipe = 2.5∑ + 0.7σ − 3 mm] and Stroom et al.’s [margin recipe = 2∑ + 0.7σ] formulas. The systematic errors (∑) were 0.72, 1.57, and 0.97 mm in the lateral, longitudinal, and vertical translational dimensions, respectively, and 0.72°, 0.87°, and 0.83° in the pitch, roll, and yaw rotational dimensions, respectively. The random errors (σ) were 0.31, 0.46, and 0.54 mm in the lateral, longitudinal, and vertical rotational dimensions, respectively, and 0.28°, 0.24°, and 0.31° in the pitch, roll, and yaw rotational dimensions, respectively. According to van Herk et al.’s and Stroom et al.’s recipes, the recommended lateral PTV margins were 0.97 and 1.66 mm, respectively; the longitudinal margins were 1.26 and 3.47 mm, respectively; and the vertical margins were 0.21 and 2.31 mm, respectively. Conclusion: Therefore, daily setup verifications using the BrainLAB ExacTrac 6D image guide system are very useful for evaluating the setup uncertainties and determining the setup margin.∑σ.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

SU-F-J-188: Clinical Implementation of in Room Mobile CT for Image Guided Proton Therapy

Purpose: To implement soft-tissue image-guided proton therapy using inroom mobile CT. Methods: Anthropomorphic phantom was first used to determine the setup accuracy using in- room mobile CT. Laser and bbs were used for the initial setup (marked isocenter). CT data was then acquired with in-room mobile CT (daily CT). The shift between the marked isocenter and the planned isocenter (final isocenter) was determined from the daily CT using in-house Computer Assisted Targeting (CAT) software. Orthogonal DRRs of the day was also generated from the daily CT. The phantom was then transferred on the treatment couch top to the treatment machine using a transportation system, and again aligned to the marked isocenter. Couch shifts were made to align the phantom to the final isocenter using the shifts as determined using the CAT software, and verified using orthogonal X-ray images with the daily DRRs. Results: Phantom data suggests that following the setup procedure as described above, targeting accuracy could be within 1 mm. Patient data are being acquired and analyzed. Conclusion: In-room mobile CT is capable of providing soft-tissue image-guided proton therapy.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

SU-G-JeP2-04: Comparison Between Fricke-Type 3D Radiochromic Dosimeters for Real-Time Dose Distribution Measurements in MR-Guided Radiation Therapy

Purpose: To assess MR signal contrast for different ferrous ion compounds used in Fricke-type gel dosimeters for real-time dose measurements for MR-guided radiation therapy applications. Methods: Fricke-type gel dosimeters were prepared in 4% w/w gelatin prior to irradiation in an integrated 1.5 T MRI and 7 MV linear accelerator system (MR-Linac). 4 different ferrous ion (Fe2?) compounds (referred to as A, B, C, and D) were investigated for this study. Dosimeter D consisted of ferrous ammonium sulfate (FAS), which is conventionally used for Fricke dosimeters. Approximately half of each cylindrical dosimeter (45 mm diameter, 80 mm length) was irradiated to ∼17 Gy. MR imaging during irradiation was performed with the MR-Linac using a balanced-FFE sequence of TR/TE = 5/2.4 ms. An approximate uncertainty of 5% in our dose delivery was anticipated since the MR-Linac had not yet been fully commissioned. Results: The signal intensities (SI) increased between the un-irradiated and irradiated regions by approximately 8.6%, 4.4%, 3.2%, and 4.3% after delivery of ∼2.8 Gy for dosimeters A, B, C, and D, respectively. After delivery of ∼17 Gy, the SI had increased by 24.4%, 21.0%, 3.1%, and 22.2% compared to the un-irradiated regions. The increase in SI with respect to dose was linear for dosimeters A, B, and D with slopes of 0.0164, 0.0251, and 0.0236 Gy{sup −1} (R{sup 2} = 0.92, 0.97, and 0.96), respectively. Visually, dosimeter A had the greatest optical contrast from yellow to purple in the irradiated region. Conclusion: This study demonstrated the feasibility of using Fricke-type dosimeters for real-time dose measurements with the greatest optical and MR contrast for dosimeter A. We also demonstrated the need to investigate Fe{sup 2+} compounds beyond the conventionally utilized FAS compound in order to improve the MR signal contrast in 3D dosimeters used for MR-guided radiation therapy. This material is based upon work supported by the National Science Foundation Graduate Research Fellowship Program under Grant No. LH- 102SPS.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

MO-B-201-03: MRI-Guided Tracking and Gating

The motion management in stereotactic body radiation therapy (SBRT) is a key to success for a SBRT program, and still an on-going challenging task. A major factor is that moving structures behave differently than standing structures when examined by imaging modalities, and thus require special considerations and employments. Understanding the motion effects to these different imaging processes is a prerequisite for a decent motion management program. The commonly used motion control techniques to physically restrict tumor motion, if adopted correctly, effectively increase the conformity and accuracy of hypofractionated treatment. The effective application of such requires one to understand the mechanics of the application and the related physiology especially related to respiration. The image-guided radiation beam control, or tumor tracking, further realized the endeavor for precision-targeting. During tumor tracking, the respiratory motion is often constantly monitored by non-ionizing beam sources using the body surface as its surrogate. This then has to synchronize with the actual internal tumor motion. The latter is often accomplished by stereo X-ray imaging or similar techniques. With these advanced technologies, one may drastically reduce the treated volume and increase the clinicians’ confidence for a high fractional ablative radiation dose. However, the challenges in implementing the motion management may not be trivial and is dependent on each clinic case. This session of presentations is intended to provide an overview of the current techniques used in managing the tumor motion in SBRT, specifically for routine lung SBRT, proton based treatments, and newly-developed MR guided RT. Learning Objectives: Through this presentation, the audience will understand basic roles of commonly used imaging modalities for lung cancer studies; familiarize the major advantages and limitations of each discussed motion control methods; familiarize the major advantages and limitations of each discussed radiation beam control methodology and tumor tacking method; understand the key points in motion management for a high quality SBRT program.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

TU-H-BRA-01: The Physics of High Power Radiofrequency Isolation in a Novel Compact Linear Accelerator Based MRI Guided Radiation Therapy System

Purpose: To develop a method for isolating the radiofrequency waves emanating from linear accelerator components from the magnetic resonance imaging (MRI) system of an integrated MRI-linac. Methods: An MRI-guided radiation therapy system has been designed that integrates a linear accelerator with simultaneous MR imaging. The radiofrequency waves created by the accelerating process would degrade MR image quality, so a method for containing the radiofrequency waves and isolating the MR imager from them was developed. The linear accelerator radiofrequency modulator was placed outside the room, so a filter was designed to eliminate the radiofrequency corresponding to the proton Larmour frequency of 14.7 MHz. Placing the radiofrequency emitting components in a typical Faraday cage would have reduced the radiofrequency emissions, but the design would be susceptible to small gaps in the shield due to the efficiency of the Faraday cage reflecting internal radiofrequency emissions. To reduce internal radiofrequency reflections, the Faraday cage was lined with carbon fiber sheets. Carbon fiber has the property of attenuating the radiofrequency energy so that the overall radiofrequency field inside the Faraday cage is reduced, decreasing any radiofrequency energy emitted from small gaps in the cage walls. Results: Within a 1.2 MHz band centered on the Larmor frequency, the radiofrequency (RF) leakage from the Faraday cage was measured to be −90 dB with no RF on, −40 dB with the RF on and no shield, returning to −90 dB with the RF on and shields in place. The radiofrequency filter attenuated the linear accelerator modulator emissions in the 14.7 MHz band by 70 dB. Conclusions: One of the major challenges in designing a compact linear accelerator based MRI-guided radiation therapy system, that of isolating the high power RF system from the MRI, has been solved. The measured radiofrequency emissions are sufficiently small to enable system integration. This research was funded by ViewRay, Inc., Oakwood, OH.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

TU-H-BRA-02: The Physics of Magnetic Field Isolation in a Novel Compact Linear Accelerator Based MRI-Guided Radiation Therapy System

Purpose: To develop a method for isolating the MRI magnetic field from field-sensitive linear accelerator components at distances close to isocenter. Methods: A MRI-guided radiation therapy system has been designed that integrates a linear accelerator with simultaneous MR imaging. In order to accomplish this, the magnetron, port circulator, radiofrequency waveguide, gun driver, and linear accelerator needed to be placed in locations with low magnetic fields. The system was also required to be compact, so moving these components far from the main magnetic field and isocenter was not an option. The magnetic field sensitive components (exclusive of the waveguide) were placed in coaxial steel sleeves that were electrically and mechanically isolated and whose thickness and placement were optimized using E&M modeling software. Six sets of sleeves were placed 60° apart, 85 cm from isocenter. The Faraday effect occurs when the direction of propagation is parallel to the magnetic RF field component, rotating the RF polarization, subsequently diminishing RF power. The Faraday effect was avoided by orienting the waveguides such that the magnetic field RF component was parallel to the magnetic field. Results: The magnetic field within the shields was measured to be less than 40 Gauss, significantly below the amount needed for the magnetron and port circulator. Additional mu-metal was employed to reduce the magnetic field at the linear accelerator to less than 1 Gauss. The orientation of the RF waveguides allowed the RT transport with minimal loss and reflection. Conclusion: One of the major challenges in designing a compact linear accelerator based MRI-guided radiation therapy system, that of creating low magnetic field environments for the magnetic-field sensitive components, has been solved. The measured magnetic fields are sufficiently small to enable system integration. This work supported by ViewRay, Inc.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

WE-AB-BRA-10: Assessment of Fiber Bragg Grating (FBG)-Based Sensing for Real-Time Needle Tracking During MR-Guided Brachytherapy

Purpose: This study assesses the potential of Fiber Bragg Grating (FBG)-based sensing for real-time needle (including catheter or tube) tracking during MR-guided HDR brachytherapy. Methods: The proposed FBG-based sensing tracking approach involves a MR-compatible stylet composed of three optic fibers with nine sets of embedded FBG sensors each. When the stylet is inserted inside the lumen of the needle, the FBG sensing system can measure the needle’s deflection. For localization of the needle in physical space, the position and orientation of the stylet base are mandatory. For this purpose, we propose to fix the stylet base and determine its position and orientation using a MR-based calibration as follows. First, the deflection of a needle inserted in a phantom in two different configurations is measured during simultaneous MR-imaging. Then, after segmentation of the needle shapes on the MR-images, the position and orientation of the stylet base is determined using a rigid registration of the needle shapes on both MR and FBG-based measurements. The calibration method was assessed by measuring the deflection of a needle in a prostate phantom in five different configurations using FBG-based sensing during simultaneous MR-imaging. Any two needle shapes were employed for the calibration step and the proposed FGB-tracking approach was subsequently evaluated on the other three needles configurations. The tracking accuracy was evaluated by computing the Euclidian distance between the 3D FBG vs. MR-based measurements. Results: Over all needle shapes tested, the average(standard deviation) Euclidian distance between the FBG and MR-based measurements was 0.79mm(0.37mm). The update rate and latency of the FBG-based measurements were 100ms and 300ms respectively. Conclusion: The proposed FBG-based protocol can measure the needle position with an accuracy, precision, update rate and latency eligible for accurate needle steering during MR-guided HDR brachytherapy. M. Borot de Battisti is funded by Philips Medical Systems Nederland B.V.; M. Moerland is principal investigator on a contract funded by Philips Medical Systems Nederland B.V.; G. Hautvast and D. Binnekamp are fulltime employees of Philips Medical Systems Nederland B.V.

61 RADIATION PROTECTION AND DOSIMETRY↗
DOE OSTI2016

WE-AB-207A-07: A Planning CT-Guided Scatter Artifact Correction Method for CBCT Images

Purpose: Cone beam computed tomography (CBCT) imaging is on increasing demand for high-performance image-guided radiotherapy such as online tumor delineation and dose calculation. However, the current CBCT imaging has severe scatter artifacts and its current clinical application is therefore limited to patient setup based mainly on the bony structures. This study’s purpose is to develop a CBCT artifact correction method. Methods: The proposed scatter correction method utilizes the planning CT to improve CBCT image quality. First, an image registration is used to match the planning CT with the CBCT to reduce the geometry difference between the two images. Then, the planning CT-based prior information is entered into the Bayesian deconvolution framework to iteratively perform a scatter artifact correction for the CBCT mages. This technique was evaluated using Catphan phantoms with multiple inserts. Contrast-to-noise ratios (CNR) and signal-to-noise ratios (SNR), and the image spatial nonuniformity (ISN) in selected volume of interests (VOIs) were calculated to assess the proposed correction method. Results: Post scatter correction, the CNR increased by a factor of 1.96, 3.22, 3.20, 3.46, 3.44, 1.97 and 1.65, and the SNR increased by a factor 1.05, 2.09, 1.71, 3.95, 2.52, 1.54 and 1.84 for the Air, PMP, LDPE, Polystryrene, Acrylic, Delrin and Teflon inserts, respectively. The ISN decreased from 21.1% to 4.7% in the corrected images. All values of CNR, SNR and ISN in the corrected CBCT image were much closer to those in the planning CT images. The results demonstrated that the proposed method reduces the relevant artifacts and recovers CT numbers. Conclusion: We have developed a novel CBCT artifact correction method based on CT image, and demonstrated that the proposed CT-guided correction method could significantly reduce scatter artifacts and improve the image quality. This method has great potential to correct CBCT images allowing its use in adaptive radiotherapy.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

WE-DE-207A-00: Advances in Image-Guided Neurointerventions-Clinical Pull and Technology Push

1. Parallels in the evolution of x-ray angiographic systems and devices used for minimally invasive endovascular therapy Charles Strother - DSA, invented by Dr. Charles Mistretta at UW-Madison, was the technology which enabled the development of minimally invasive endovascular procedures. As DSA became widely available and the potential benefits for accessing the cerebral vasculature from an endovascular approach began to be apparent, industry began efforts to develop tools for use in these procedures. Along with development of catheters, embolic materials, pushable coils and the GDC coils there was simultaneous development and improvement of 2D DSA image quality and the introduction of 3D DSA. Together, these advances resulted in an enormous expansion in the scope and numbers of minimally invasive endovascular procedures. The introduction of flat detectors for c-arm angiographic systems in 2002 provided the possibility of the angiographic suite becoming not just a location for vascular imaging where physiological assessments might also be performed. Over the last decade algorithmic and hardware advances have been sufficient to now realize this potential in clinical practice. The selection of patients for endovascular treatments is enhanced by this dual capability. Along with these advances has been a steady reduction in the radiation exposure required so that today, vascular and soft tissue images may be obtained with equal or in many cases less radiation exposure than is the case for comparable images obtained with multi-detector CT. Learning Objectives: To understand the full capabilities of today’s angiographic suite To understand how c-arm cone beam CT soft tissue imaging can be used for assessments of devices, blood flow and perfusion. Advances in real-time x-ray neuro-endovascular image guidance Stephen Rudin - Reacting to the demands on real-time image guidance for ever finer neurovascular interventions, great improvements in imaging chains are being pursued. For the highest spatial and temporal resolution, x-ray guidance with fluoroscopy and angiography although dominant are still being vastly improved. New detectors such as the Micro-Angiographic Fluoroscope (MAF) and x-ray source designs that enable higher outputs while maintaining small focal spots will be highlighted along with new methods for minimizing the radiation dose to patients. Additionally, new platforms for training and device testing that include patient-specific 3D printed vascular phantoms and new metrics such as generalized relative object detectability for objectively inter-comparing systems will be discussed. This will improve the opportunity for better evaluation of these technological advances which should contribute to the safety and efficacy of image guided minimally invasive neuro-endovascular procedures. Learning Objectives: To understand the operation of new x-ray imaging chain components such as detectors and sources To be informed about the latest testing methods, with 3D printed vascular phantoms, and new evaluation metrics for advanced imaging in x-ray image guided neurovascular interventions Advances in cone beam CT anatomical and functional imaging in angio-suite to enable one-stop-shop stroke imaging workflow Guang-Hong Chen - The introduction of flat-panel detector based cone-beam CT in clinical angiographic imaging systems enabled treating physicians to obtain three-dimensional anatomic roadmaps for bony structure, soft brain tissue, and vasculatures for treatment planning and efficacy checking after the procedures. However, much improvement is needed to reduce image artifacts, reduce radiation dose, and add potential functional imaging capability to provide four-dimensional dynamic information of vasculature and brain perfusion. In this presentation, some of the new techniques developed to address radiation dose issues, image artifact reduction and brain perfusion using C-arm cone-beam CT imaging system will be introduced for the audience. Learning Objectives: To understand the clinical need of one-stop-shop stroke imaging workflow To understand to technical challenges in cone beam CT perfusion To understand the potential technical solutions to enable one-stop-shop imaging workflow Recent advances in devices used in neuro--interventions Mattew Gounis - Over the past two decades, there has been explosive development of medical devices that have revolutionized the endovascular treatment of cerebrovascular diseases. There is now Level 1, Class A evidence that intra-arterial, mechanical thrombectomy in acute ischemic stroke is superior to medical management; and similarly that minimally invasive, endovascular repair of ruptured brain aneurysms is superior to surgical treatment. Stent-retrievers are now standard of care for emergent large vessel occlusions causing a stroke, with a number of patients need to treat for good clinical outcomes as low as 4. Recent technologies such as flow diverters and disrupters, intracranial self-expanding stents, flexible large bore catheters that can reach vessels beyond the circle of Willis, stent-retrievers, and super-compliant balloons are the result of successful miniaturization of design features and novel manufacturing technologies capable of building these devices. This is a rapidly evolving field, and the device technology enabling such advancements will be reviewed. Importantly, image-guidance technology has not kept pace in neurointervention and the ability to adequately characterize these devices in vivo remains a significant opportunity. Learning Objectives: A survey of devices used in neurointerventions, their materials and essential design characteristics Funding support received from NIH and DOD; Funding support received from GE Healthcare; Funding support received from Siemens AX; Patent royalties received from GE Healthcare; G. Chen, Funding received from NIH; funding received from DOD; funding received from GE Healthcare; funding received from Siemens AX.; M. Gounis, consultant for Codman Neurovascular and Stryker Neurovascular; Holds stock in InNeuroCo Inc, research grants: NIH, Medtronic Neurovascular, Microvention/Terumo, Cerevasc LLC, Gentuity, Codman Neurovascular, Philips Healthcare, Stryker Neurovascular, Tay Sachs Foundation, and InNeuroCo Inc.; S. Rudin, Supported in part by NIH Grant R01EB002873 and the Toshiba Medical System Corp.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

WE-FG-202-08: Assessment of Treatment Response Via Longitudinal Diffusion MRI On A MRI-Guided System: Initial Experience of Quantitative Analysis

Purpose: To report our initial experience of systematic monitoring treatment response using longitudinal diffusion MR images on a Co-60 MRI-guided radiotherapy system. Methods: Four patients, including 2 head-and-necks, 1 sarcoma and 1 GBM treated on a 0.35 Tesla MRI-guided treatment system, were analyzed. For each patient, 3D TrueFISP MRIs were acquired during CT simulation and before each treatment for treatment planning and patient setup purposes respectively. Additionally, 2D diffusion-weighted MR images (DWI) were acquired weekly throughout the treatment course. The gross target volume (GTV) and brainstem (as a reference structure) were delineated on weekly 3D TrueFISP MRIs to monitor anatomy changes, the contours were then transferred onto the corresponding DWI images after fusing with the weekly TrueFISP images. The patient-specific temporal and spatial variations during the entire treatment course, such as anatomic changes, target apparent diffusion coefficient (ADC) distribution were evaluated in a longitudinal pattern. Results: Routine MRI revealed progressive soft-tissue GTV volume changes (up to 53%) for the H&N cases during the treatment course of 5–7 weeks. Within the GTV, the mean ADC values varied from −44% (ADC decrease) to +26% (ADC increase) in a week. The gradual increase of ADC value was inversely associated with target volume variation for one H&N case. The maximal changes of mean ADC values within the brainstem were 5.3% for the H&N cases. For the large size sarcoma and GBM tumors, spatial heterogeneity and temporal variations were observed through longitudinal ADC analysis. Conclusion: In addition to the superior soft-tissue visualization, the 0.35T MR system on ViewRay showed the potential to quantitatively measure the ADC values for both tumor and normal tissues. For normal tissue that is minimally affected by radiation, its ADC values are reproducible. Tumor ADC values show temporal and spatial fluctuation that can be exploited for personalized adaptive therapy.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

TH-AB-BRA-02: Automated Triplet Beam Orientation Optimization for MRI-Guided Co-60 Radiotherapy

Purpose: MRI guided Co-60 provides daily and intrafractional MRI soft tissue imaging for improved target tracking and adaptive radiotherapy. To remedy the low output limitation, the system uses three Co-60 sources at 120° apart, but using all three sources in planning is considerably unintuitive. We automate the beam orientation optimization using column generation, and then solve a novel fluence map optimization (FMO) problem while regularizing the number of MLC segments. Methods: Three patients—1 prostate (PRT), 1 lung (LNG), and 1 head-and-neck boost plan (H&NBoost)—were evaluated. The beamlet dose for 180 equally spaced coplanar beams under 0.35 T magnetic field was calculated using Monte Carlo. The 60 triplets were selected utilizing the column generation algorithm. The FMO problem was formulated using an L2-norm minimization with anisotropic total variation (TV) regularization term, which allows for control over the number of MLC segments. Our Fluence Regularized and Optimized Selection of Triplets (FROST) plans were compared against the clinical treatment plans (CLN) produced by an experienced dosimetrist. Results: The mean PTV D95, D98, and D99 differ by −0.02%, +0.12%, and +0.44% of the prescription dose between planning methods, showing same PTV dose coverage. The mean PTV homogeneity (D95/D5) was at 0.9360 (FROST) and 0.9356 (CLN). R50 decreased by 0.07 with FROST. On average, FROST reduced Dmax and Dmean of OARs by 6.56% and 5.86% of the prescription dose. The manual CLN planning required iterative trial and error runs which is very time consuming, while FROST required minimal human intervention. Conclusions: MRI guided Co-60 therapy needs the output of all sources yet suffers from unintuitive and laborious manual beam selection processes. Automated triplet orientation optimization is shown essential to overcome the difficulty and improves the dosimetry. A novel FMO with regularization provides additional controls over the number of MLC segments and treatment time. Varian Medical Systems; NIH grant R01CA188300; NIH grant R43CA183390.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

TH-AB-BRA-06: MOSFET-Based Dosimetry in An MR Image-Guided Radiation Therapy System: Comparison with and Without a Static 0.3T Magnetic Field

Purpose: To compare depth-dose and surface-dose measurements without and with the magnetic field in a 0.3T MR image-guided Co-60 treatment unit using MOSFET dosimeters. Methods: MOSFET dosimeters (Best Medical Canada, model TN-502RDH-10) were placed in a solid water phantom at 5cm depth with 8cm backscatter (with the MOSFET wires in different orientations to the couch long axis) and also on the surface of an 8cm solid water phantom. The phantoms were placed in an MR image-guided Co-60 treatment machine at an SAD of 105cm to the MOSFETs. Dose measurements were performed between 50 and 200cGy at 5cm depth in a 10.5cm × 10.5cm radiation field without the magnetic field (during a machine maintenance period) and with the nominal magnetic field of 0.3T. The dose linearity was measured at 5cm depth with an orthogonal field and the angular dose dependence was measured on the surface with an orthogonal field and oblique fields at +60 degrees and −60 degrees. Results: The measured MOSFET readings at 5cm depth were linear with dose with slopes of (2.97 +/− 0.01) mV/cGy and (3.01 +/− 0.02) mV/cGy without and with the magnetic field, respectively. No statistically significant difference was found. The surface dose measurements, however, were lower by 6.4% for the AP field (2.3 σ) with magnetic field, 4.9% for the −60 degree field (1.4 σ), and 0.4% different for the +60 degree field (0.2 σ). Conclusion: There is no statistically significant difference in the dose at depth without and with the magnetic field and different orientations of the MOSFET wires. There is a statistically significant difference for the surface dose due to the influence of the magnetic field on secondary electrons from head-scatter and the build-up region in certain field orientations. Clinical surface-dose dosimetry in a magnetic field should apply asymmetric angle-dependent corrections.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

TH-AB-BRA-11: Using 3D Dosimeters for the Investigation of the Electron Return Effect (ERE) in MR-Guided Radiation Therapy: A Feasibility Study

Purpose: To demonstrate the capability of 3D radiochromic PRESAGE and Fricke-type dosimeters to measure the influence of magnetic fields on dose distribution, including the electron return effect (ERE), for MR-guided radiation therapy applications. Methods: Short cylindrical 3D dosimeters with PRESAGE and Fricke-type formulations were created in-house prior to irradiations in a 1.5T/7MV MR-linac. Each dosimeter was prepared with a concentric cylindrical air cavity with diameters of 1.5 cm and 2.5 cm, and the diameters of the dosimeters were 7.2 cm and 8.8 cm for PRESAGE and Fricke-type respectively. The dosimeters were irradiated within the bore of the MR-linac with the flat face of the dosimeters perpendicular to the magnetic field. Dosimeters were irradiated to approximately 9 Gy and 29 Gy to the center of dosimeters with a 15×15 cm{sup 2} field. The PRESAGE dosimeter was scanned using an optical-CT 2 hours post-irradiation; the Fricke-type dosimeter was immediately imaged with the MR component of the MR-linac post-irradiation. Results: Axial slices of the dose distributions show a clear demonstration of the dose enhancement due to the ERE above the cavity and the region of reduced dose below the cavity. The regions of increased and reduced dose are rotated with respect to the radiation beam axis due to the average directional change of the electrons. Measurements from line profiles show the dose enhanced up to ∼0.5 cm around the cavity by up to a factor of 1.3 and 1.4 for PRESAGE and Fricke-type dosimeters respectively. Conclusion: PRESAGE and Fricke-type dosimeters are able to qualitatively measure the ERE with good agreement with previously published simulation and 2D dosimetry demonstrations of the ERE. Further investigation of these 3D dosimeters as promising candidates for quality assurance of MR-guided radiation therapy systems is encouraged to assess changes in response and measurement accuracy due to the magnetic field.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

TH-CD-BRA-08: Novel Iron-Based Radiation Reporting Systems as 4D Dosimeters for MR-Guided Radiation Therapy

Purpose: To compare novel radiation reporting systems utilizing ferric ion (Fe{sup 3+}) reduction versus ferrous ion (Fe{sup 2+}) oxidation in gelatin matrixes for 3D and 4D (3D+time) MR-guided radiation therapy dosimetry. Methods: Dosimeters were irradiated using an integrated 1.5T MRI and 7MV linear accelerator (MR-Linac). Dosimeters were read-out with both a spectrophotometer and the MRI component of the MR-Linac immediately after irradiation. Changes in optical density (OD) were measured using a spectrophotometer; changes in MR signal intensity due to the paramagnetic differences in the iron ions were measured using the MR-Linac in real-time during irradiation (balanced-FFE sequences) and immediately after irradiation (T{sub 1}-weighted and inversion recovery sequences). Results: Irradiation of Fe{sup 3+} reduction dosimeters resulted in a stable red color with an absorbance peak at 512 nm. The change in OD relative to dose exhibited a linear response up to 100 Gy (R{sup 2}=1.00). T{sub 1}-weighted-MR signal intensity (SI) changed minimally after irradiation with increases of 8.0% for 17 Gy and 9.7% after escalation to 35 Gy compared to the un-irradiated region. Irradiation of Fe{sup 2+} oxidation dosimeters resulted in a stable purple color with absorbance peaks at 440 and 585 nm. The changes in OD, T{sub 1}-weighted-MR SI, and R{sub 1} relative to dose exhibited a linear response up to at least 8 Gy (R{sup 2}=1.00, 0.98, and 0.99) with OD saturation above 40 Gy. The T{sub 1}-weighted-MR SI increased 50.3% for 17 Gy compared to the un-irradiated region. The change in SI was observed in both 2D+time and 4D (3D+time) acquisitions post-irradiation and in real-time during irradiation with a linear increase with respect to dose (R{sup 2}>0.93). Conclusion: The Fe{sup 2+} oxidation-based system was superior as 4D dosimeters for MR-guided radiation therapy due to its higher sensitivity in both optical and MR signal readout and feasibility for real-time 4D dose readout. The Fe{sup 3+} reduction system is recommended for high dose applications. This material is based upon work supported by the National Science Foundation Graduate Research Fellowship Program under Grant No. LH-102SPS.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

TH-EF-BRA-05: A Method of Near Real-Time 4D MRI Using Volumetric Dynamic Keyhole (VDK) in the Presence of Respiratory Motion for MR-Guided Radiotherapy

Purpose: To develop a novel method that enables 4D MR imaging in near real-time for continuous monitoring of tumor motion in MR-guided radiotherapy. Methods: This method is mainly based on an idea of expanding dynamic keyhole to full volumetric imaging acquisition. In the VDK approach introduced in this study, a library of peripheral volumetric k-space data is generated in given number of phases (5 and 10 in this study) in advance. For 4D MRI at any given time, only volumetric central k-space data are acquired in real-time and combined with pre-acquired peripheral volumetric k-space data in the library corresponding to the respiratory phase (or amplitude). The combined k-space data are Fourier-transformed to MR images. For simulation study, an MRXCAT program was used to generate synthetic MR images of the thorax with desired respiratory motion, contrast levels, and spatial and temporal resolution. 20 phases of volumetric MR images, with 200 ms temporal resolution in 4 s respiratory period, were generated using balanced steady-state free precession MR pulse sequence. The total acquisition time was 21.5s/phase with a voxel size of 3×3×5 mm{sup 3} and an image matrix of 128×128×56. Image similarity was evaluated with difference maps between the reference and reconstructed images. The VDK, conventional keyhole, and zero filling methods were compared for this simulation study. Results: Using 80% of the ky data and 70% of the kz data from the library resulted in 12.20% average intensity difference from the reference, and 21.60% and 28.45% difference in threshold pixel difference for conventional keyhole and zero filling, respectively. The imaging time will be reduced from 21.5s to 1.3s per volume using the VDK method. Conclusion: Near real-time 4D MR imaging can be achieved using the volumetric dynamic keyhole method. That makes the possibility of utilizing 4D MRI during MR-guided radiotherapy.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2019

Structure-Guided In Vitro to In Vivo Pharmacokinetic Optimization of Propargyl-Linked Antifolates

Pharmacokinetic/pharmacodynamic properties are strongly correlated with the in vivo efficacy of antibiotics. Propargyl-linked antifolates, a novel class of antibiotics, demonstrate potent antibacterial activity against both Gram-positive and Gram-negative pathogenic bacteria, including multidrug-resistant Staphylococcus aureus. Here, we report our efforts to optimize the pharmacokinetic profile of this class to best match the established pharmacodynamic properties. High-resolution crystal structures were used in combination with in vitro pharmacokinetic models to design compounds that not only are metabolically stable in vivo but also retain potent antibacterial activity. The initial lead compound was prone to both N-oxidation and demethylation, which resulted in an abbreviated in vivo half-life (~20 minutes) in mice. Stability of leads toward mouse liver microsomes was primarily used to guide medicinal chemistry efforts so robust efficacy could be demonstrated in a mouse disease model. Structure-based drug design guided mitigation of N-oxide formation through substitutions of sterically demanding groups adjacent to the pyridyl nitrogen. Additionally, deuterium and fluorine substitutions were evaluated for their effect on the rate of oxidative demethylation. The resulting compound was characterized and demonstrated to have a low projected clearance in humans with limited potential for drug-drug interactions as predicted by cytochrome P450 inhibition as well as an in vivo exposure profile that optimizes the potential for bactericidal activity, highlighting how structural data, merged with substitutions to introduce metabolic stability, are a powerful approach to drug design.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Structural basis for RNA-guided DNA cleavage by IscB-ωRNA and mechanistic comparison with Cas9

Class 2 CRISPR effectors Cas9 and Cas12 may have evolved from nucleases in IS200/IS605 transposons. IscB is about two-fifths the size of Cas9 but shares a similar domain organization. The associated ωRNA plays the combined role of CRISPR RNA (crRNA) and trans-activating CRISPR RNA ( tracrRNA) to guide double-stranded DNA (dsDNA) cleavage. Here we report a 2.78-angstrom cryo–electron microscopy structure of IscB-ωRNA bound to a dsDNA target, revealing the architectural and mechanistic similarities between IscB and Cas9 ribonucleoproteins. Target-adjacent motif recognition, R-loop formation, and DNA cleavage mechanisms are explained at high resolution. ωRNA plays the equivalent function of REC domains in Cas9 and contacts the RNA-DNA heteroduplex. The IscB-specific PLMP domain is dispensable for RNA-guided DNA cleavage. The transition from ancestral IscB to Cas9 involved dwarfing the ωRNA and introducing protein domain replacements.

Science & Technology - Other Topics↗