A Pilot Study of Simulation-Free Hippocampal-Avoidance Whole Brain Radiotherapy Using Diagnostic MRI-Based and Online Adaptive Planning.

PURPOSE: We aimed to demonstrate the clinical feasibility and safety of simulation-free hippocampal avoidance whole brain radiation therapy (HA-WBRT) in a pilot study (NCTXXX). MATERIALS/METHODS: Ten HA-WBRT candidates were enrolled for treatment on a commercially available computed tomography (CT)-guided linear accelerator with online adaptive capabilities. Planning structures were contoured on patient-specific diagnostic MRIs, which were registered to a CT of similar head shape, obtained from an atlas-based database (AB-CT). These patient-specific diagnostic MRI and AB-CT datasets were used for pre-plan calculation, using NRG-CC001 constraints. At first fraction, AB-CTs were used as primary datasets and deformed to patient-specific cone-beam CTs (CBCT) to give patient-matched density information. Brain, ventricle, and brainstem contours were matched through rigid translation and rotation to the corresponding anatomy on CBCT. Lens, optic nerve, and brain contours were manually edited based on CBCT visualization. Pre-plans were then re-optimized through online adaptation to create final, simulation-free plans, which were utilized if they met all objectives. Workflow tasks were timed. In addition, patients underwent CT-simulation to create immobilization devices and for prospective dosimetric comparison of simulation-free and simulation-based plans. RESULTS: Median time from MRI importation to completion of "pre-plan" was one week-day (range: 1-4). Median on-table workflow duration was 41 minutes (range: 34-70). NRG-CC001 constraints were achieved by 90% of the simulation-free plans. One patient's simulation-free plan failed a planning target volume (PTV) coverage objective (89% instead of 90% coverage); this was deemed acceptable for first-fraction delivery, with an offline replan used for subsequent fractions. Both simulation-free and simulation-CT-based plans otherwise met constraints, without clinically meaningful differences. CONCLUSION: Simulation-free HA-WBRT using online ART is feasible, safe, and results in dosimetrically comparable treatment plans to simulation-CT-based workflows while providing convenience and time-savings for patients.

Functional network disorganization and cognitive decline following fractionated whole-brain radiation in mice.

Cognitive dysfunction following radiotherapy (RT) is one of the most common complications associated with RT delivered to the brain, but the precise mechanisms behind this dysfunction are not well understood, and to date, there are no preventative measures or effective treatments. To improve patient outcomes, a better understanding of the effects of radiation on the brain's functional systems is required. Functional magnetic resonance imaging (fMRI) has shown promise in this regard, however, compared to neural activity, hemodynamic measures of brain function are slow and indirect. Understanding how RT acutely and chronically affects functional brain organization requires more direct examination of temporally evolving neural dynamics as they relate to cerebral hemodynamics for bridging with human studies. In order to adequately study the underlying mechanisms of RT-induced cognitive dysfunction, the development of clinically mimetic RT protocols in animal models is needed. To address these challenges, we developed a fractionated whole-brain RT protocol (3Gy/day for 10 days) and applied longitudinal wide field optical imaging (WFOI) of neural and hemodynamic brain activity at 1, 2, and 3 months post RT. At each time point, mice were subject to repeated behavioral testing across a variety of sensorimotor and cognitive domains. Disruptions in cortical neuronal and hemodynamic activity observed 1 month post RT were significantly worsened by 3 months. While broad changes were observed in functional brain organization post RT, brain regions most impacted by RT occurred within those overlapping with the mouse default mode network and other association areas similar to prior reports in human subjects. Further, significant cognitive deficits were observed following tests of novel object investigation and responses to auditory and contextual cues after fear conditioning. Our results fill a much-needed gap in understanding the effects of whole-brain RT on systems level brain organization and how RT affects neuronal versus hemodynamic signaling in the cortex. Having established a clinically-relevant injury model, future studies can examine therapeutic interventions designed to reduce neuroinflammation-based injury following RT. Given the overlap of sequelae that occur following RT with and without chemotherapy, these tools can also be easily incorporated to examine chemotherapy-related cognitive impairment.

Cardiac radiation improves ventricular function in mice and humans with cardiomyopathy.

BACKGROUND: Rapidly dividing cells are more sensitive to radiation therapy (RT) than quiescent cells. In the failing myocardium, macrophages and fibroblasts mediate collateral tissue injury, leading to progressive myocardial remodeling, fibrosis, and pump failure. Because these cells divide more rapidly than cardiomyocytes, we hypothesized that macrophages and fibroblasts would be more susceptible to lower doses of radiation and that cardiac radiation could therefore attenuate myocardial remodeling. METHODS: In three independent murine heart failure models, including models of metabolic stress, ischemia, and pressure overload, mice underwent 5 Gy cardiac radiation or sham treatment followed by echocardiography. Immunofluorescence, flow cytometry, and non-invasive PET imaging were employed to evaluate cardiac macrophages and fibroblasts. Serial cardiac magnetic resonance imaging (cMRI) from patients with cardiomyopathy treated with 25 Gy cardiac RT for ventricular tachycardia (VT) was evaluated to determine changes in cardiac function. FINDINGS: In murine heart failure models, cardiac radiation significantly increased LV ejection fraction and reduced end-diastolic volume vs. sham. Radiation resulted in reduced mRNA abundance of B-type natriuretic peptide and fibrotic genes, and histological assessment of the LV showed reduced fibrosis. PET and flow cytometry demonstrated reductions in pro-inflammatory macrophages, and immunofluorescence demonstrated reduced proliferation of macrophages and fibroblasts with RT. In patients who were treated with RT for VT, cMRI demonstrated decreases in LV end-diastolic volume and improvements in LV ejection fraction early after treatment. CONCLUSIONS: These results suggest that 5 Gy cardiac radiation attenuates cardiac remodeling in mice and humans with heart failure. FUNDING: NIH, ASTRO, AHA, Longer Life Foundation.

In silico trial of simulation-free hippocampal-avoidance whole brain adaptive radiotherapy.

Background and Purpose: Hippocampal-avoidance whole brain radiotherapy (HA-WBRT) can be a time-consuming process compared to conventional whole brain techniques, thus potentially limiting widespread utilization. Therefore, we evaluated the in silico clinical feasibility, via dose-volume metrics and timing, by leveraging a computed tomography (CT)-based commercial adaptive radiotherapy (ART) platform and workflow in order to create and deliver patient-specific, simulation-free HA-WBRT. Materials and methods: Ten patients previously treated for central nervous system cancers with cone-beam computed tomography (CBCT) imaging were included in this study. The CBCT was the adaptive image-of-the-day to simulate first fraction on-board imaging. Initial contours defined on the MRI were rigidly matched to the CBCT. Online ART was used to create treatment plans at first fraction. Dose-volume metrics of these simulation-free plans were compared to standard-workflow HA-WBRT plans on each patient CT simulation dataset. Timing data for the adaptive planning sessions were recorded. Results: For all ten patients, simulation-free HA-WBRT plans were successfully created utilizing the online ART workflow and met all constraints. The median hippocampi D100% was 7.8 Gy (6.6-8.8 Gy) in the adaptive plan vs 8.1 Gy (7.7-8.4 Gy) in the standard workflow plan. All plans required adaptation at first fraction due to both a failing hippocampal constraint (6/10 adaptive fractions) and sub-optimal target coverage (6/10 adaptive fractions). Median time for the adaptive session was 45.2 min (34.0-53.8 min). Conclusions: Simulation-free HA-WBRT, with commercially available systems, was clinically feasible via plan-quality metrics and timing, in silico.

Clinical application of a template-guided automated planning routine.

PURPOSE: Determine the dosimetric quality and the planning time reduction when utilizing a template-based automated planning application. METHODS: A software application integrated through the treatment planning system application programing interface, QuickPlan, was developed to facilitate automated planning using configurable templates for contouring, knowledge-based planning structure matching, field design, and algorithm settings. Validations are performed at various levels of the planning procedure and assist in the evaluation of readiness of the CT image, structure set, and plan layout for automated planning. QuickPlan is evaluated dosimetrically against 22 hippocampal-avoidance whole brain radiotherapy patients. The required times to treatment plan generation are compared for the validations set as well as 10 prospective patients whose plans have been automated by QuickPlan. RESULTS: The generations of 22 automated treatment plans are compared against a manual replanning using an identical process, resulting in dosimetric differences of minor clinical significance. The target dose to 2% volume and homogeneity index result in significantly decreased values for automated plans, whereas other dose metric evaluations are nonsignificant. The time to generate the treatment plans is reduced for all automated plans with a median difference of 9' 50″ ± 4' 33″. CONCLUSIONS: Template-based automated planning allows for reduced treatment planning time with consistent optimization structure creation, treatment field creation, plan optimization, and dose calculation with similar dosimetric quality. This process has potential expansion to numerous disease sites.

A reconstruction approach for proton computed tomography by modeling the integral depth dose of the scanning proton pencil beam.

PURPOSE: To present a proton computed tomography (pCT) reconstruction approach that models the integral depth dose (IDD) of the clinical scanning proton beam into beamlets. Using a multilayer ionization chamber (MLIC) as the imager, the proposed pCT system and the reconstruction approach can minimize extra ambient neutron dose and simplify the beamline design by eliminating an additional collimator to confine the proton beam. METHODS: Monte Carlo simulation was applied to digitally simulate the IDDs of the exiting proton beams detected by the MLIC. A forward model was developed to model each IDD into a weighted sum of percentage depth doses of the constituent beamlets separated laterally by 1 mm. The water equivalent path lengths (WEPLs) of the beamlets were determined by iteratively minimizing the squared L2-norm between the forward projected and simulated IDDs. The final WEPL values were reconstructed to pCT images, that is, proton stopping power ratio (SPR) maps, through simultaneous algebraic reconstruction technique with total variation regularization. The reconstruction process was tested with a digital cylindrical water-based phantom and an ICRP adult reference computational phantom. The mean of SPR within regions of interest (ROIs) and the WEPL along a 4 mm-wide beam ( WEP L 4 mm ${\rm{WEP}}{{\rm{L}}_{4{\rm{mm}}}}$ ) were compared with the reference values. The spatial resolution was analyzed at the edge of a cortical insert of the cylindrical phantom. RESULTS: The percentage deviations from reference SPR were within ±1% in all selected ROIs. The mean absolute error of the reconstructed SPR was 0.33%, 0.19%, and 0.27% for the cylindrical phantom, the adult phantom at the head and lung region, respectively. The corresponding percentage deviations from reference WEP L 4 mm ${\rm{WEP}}{{\rm{L}}_{4{\rm{mm}}}}$ were 0.48 ± 0.64%, 0.28 ± 0.48%, and 0.22 ± 0.49%. The full width at half maximum of the line spread function (LSF) derived from the radial edge spread function (ESF) of a cortical insert was 0.13 cm. The frequency at 10% of the modulation transfer function (MTF) was 6.38 cm-1 . The mean signal-to-noise ratio (SNR) of all the inserts was 2.45. The mean imaging dose was 0.29 and 0.25 cGy at the head and lung region of the adult phantom, respectively. CONCLUSION: A new pCT reconstruction approach was developed by modeling the IDDs of the uncollimated scanning proton beams in the pencil beam geometry. SPR accuracy within ±1%, spatial resolution of better than 2 mm at 10% MTF, and imaging dose at the magnitude of mGy were achieved. Potential side effects caused by neutron dose were eliminated by removing the extra beam collimator.

Technical Report: Development and Implementation of an Open Source Template Interpretation Class Library for Automated Treatment Planning.

PURPOSE: Widespread implementation of automated treatment planning in radiation therapy remains elusive owing to variability in clinic and physician preferences, making it difficult to ensure consistent plan parameters. We have developed an open-source class library with the aim to improve efficiency and consistency for automated treatment planning in radiation therapy. METHODS AND MATERIALS: An open-source class library has been developed that interprets clinical templates within a commercial treatment planning system into a treatment plan for automated planning. This code was leveraged for the automated planning of 39 patients and retrospectively compared with the 78 clinically approved manual plans. RESULTS: From the initial 39 patients, 74 of 78 plans were successfully generated without manual intervention. The target dose was more homogeneous for automated plans, with an average homogeneity index of 3.30 for manual plans versus 3.11 for automated plans (P = .107). The generalized equivalent uniform dose (gEUD) was decreased in the femurs and rectum for automated plans, with a mean gEUD of 3746 cGy versus 3338 cGy (P ≤ 0.001) and 5761 cGy versus 5634 cGy (P ≤ 0.001) for the femurs and rectum, respectively. Dose metrics for the bladder and rectum (V6500 cGy and V4000 cGy) showed recognizable but insignificant improvements. All automated plans delivered for quality assurance passed a gamma analysis (>95%), with an average composite pass rate of 99.3% for pelvis plans and 98.8% for prostate plans. Deliverability parameters such as total monitor units and aperture complexity indicated deliverable plans. CONCLUSIONS: Prostate cancer and pelvic node radiation therapy can be automated using volumetric modulated arc therapy planning and clinical templates based on a standardized clinical workflow. The class library developed in this study conveniently interfaced between the plan template and the treatment planning system to automatically generate high-quality plans on customizable templates.

Quantification of gold nanoparticle photon radiosensitization from direct and indirect effects using a complete human genome single cell model based on Geant4.

PURPOSE: To investigate the radiosensitization properties of gold nanoparticles (GNPs) and better understand the intricate deoxyribonucleic acid (DNA) damage induction mechanisms involved in GNP-aided radiotherapy, a single cell model with complete human genome based on the Geant4 Monte Carlo toolkit was applied. MATERIALS AND METHODS: A Geant4-DNA model was implemented to simulate direct and indirect DNA damage generated in the physical and chemical stages. In the physical stage, a mixed-physics approach was taken by using Geant4-DNA in water and Livermore in gold. Water radiolysis was created posteriorly in the physicochemical and chemical stages to simulate indirect damage from reactions between DNA molecules and OH• radicals. A mono-energetic photon beam (100 keV) and two clinical photon sources (250-kVp, 6-MV flattening-filter free) were simulated for modeling the irradiation of a single cell with or without GNPs. In order to study the effects of GNP size on radiosensitization, 15, 30, and 100 nm GNPs were simulated. The effects of intracellular distribution were simulated using 90-nm GNPs with different characteristics of distribution within the cell. The time dependence of DNA damage enhancement was also studied with chemistry stage simulation end-time no larger than 10 ns. RESULTS: Double strand break (DSB) enhancement due to direct and indirect action was quantified under different scenarios. Under realistic cellular uptake condition, the 100-nm GNPs had the most significant increase in DSBs: 40.9% and 28.5% for 100 keV and 250-kVp photon irradiation, respectively. The intracellular localization showed differing levels of radiosensitization with a maximum of 64%, 27%, and 6% DSB enhancements for 100 keV, 250-kVp, and 6-MV respectively, when 90-nm GNPs congregate around the nucleus. CONCLUSION: The results indicate that photon energy, GNP size, and intracellular distribution play an important role in the enhancement of DSB from direct and indirect damage under scenarios close to cell experiments. The radiosensitization effects due to indirect damage are significant and should be considered carefully.

Application programming interface guided QA plan generation and analysis automation.

PURPOSE: Linear accelerator quality assurance (QA) in radiation therapy is a time consuming but fundamental part of ensuring the performance characteristics of radiation delivering machines. The goal of this work is to develop an automated and standardized QA plan generation and analysis system in the Oncology Information System (OIS) to streamline the QA process. METHODS: Automating the QA process includes two software components: the AutoQA Builder to generate daily, monthly, quarterly, and miscellaneous periodic linear accelerator QA plans within the Treatment Planning System (TPS) and the AutoQA Analysis to analyze images collected on the Electronic Portal Imaging Device (EPID) allowing for a rapid analysis of the acquired QA images. To verify the results of the automated QA analysis, results were compared to the current standard for QA assessment for the jaw junction, light-radiation coincidence, picket fence, and volumetric modulated arc therapy (VMAT) QA plans across three linacs and over a 6-month period. RESULTS: The AutoQA Builder application has been utilized clinically 322 times to create QA patients, construct phantom images, and deploy common periodic QA tests across multiple institutions, linear accelerators, and physicists. Comparing the AutoQA Analysis results with our current institutional QA standard the mean difference of the ratio of intensity values within the field-matched junction and ball-bearing position detection was 0.012 ± 0.053 (P = 0.159) and is 0.011 ± 0.224 mm (P = 0.355), respectively. Analysis of VMAT QA plans resulted in a maximum percentage difference of 0.3%. CONCLUSION: The automated creation and analysis of quality assurance plans using multiple APIs can be of immediate benefit to linear accelerator quality assurance efficiency and standardization. QA plan creation can be done without following tedious procedures through API assistance, and analysis can be performed inside of the clinical OIS in an automated fashion.

Automated and robust beam data validation of a preconfigured ring gantry linear accelerator using a 1D tank with synchronized beam delivery and couch motions.

PURPOSE: To develop an efficient and automated methodology for beam data validation for a preconfigured ring gantry linear accelerator using scripting and a one-dimensional (1D) tank with automated couch motions. MATERIALS AND METHODS: Using an application programming interface, a program was developed to allow the user to choose a set of beam data to validate with measurement. Once selected the program generates a set of instructions for radiation delivery with synchronized couch motions for the linear accelerator in the form of an extensible markup language (XML) file to be delivered on the ring gantry linear accelerator. The user then delivers these beams while measuring with the 1D tank and data logging electrometer. The program also automatically calculates this set of beams on the measurement geometry within the treatment planning system (TPS) and extracts the corresponding calculated dosimetric data for comparison to measurement. Once completed the program then returns a comparison of the measurement to the predicted result from the TPS to the user and prints a report. In this work lateral, longitudinal, and diagonal profiles were taken for fields sizes of 6 × 6, 8 × 8, 10 × 10, 20 × 20, and 28 × 28 cm2 at depths of 1.3, 5, 10, 20, and 30 cm. Depth dose profiles were taken for all field sizes. RESULTS: Using this methodology, the TPS was validated to agree with measurement. All compared points yielded a gamma value less than 1 for a 1.5%/1.5 mm criteria (100% passing rate). Off axis profiles had >98.5% of data points producing a gamma value <1 with a 1%/1 mm criteria. All depth profiles produced 100% of data points with a gamma value <1 with a 1%/1 mm criteria. All data points measured were within 1.5% or 2 mm distance to agreement. CONCLUSIONS: This methodology allows for an increase in automation in the beam data validation process. Leveraging the application program interface allows the user to use a single system to create the measurement files, predict the result, and then compare to actual measurement increasing efficiency and reducing the chance for user input errors.

Intracranial Stereotactic Radiation Therapy With a Jawless Ring Gantry Linear Accelerator Equipped With New Dual Layer Multileaf Collimator.

PURPOSE: To test the feasibility of a simplified, robust, workflow for intracranial stereotactic radiation therapy (SRT) using a ring gantry linear accelerator (RGLA) equipped with a dual-layer stacked, staggered, and interdigitating multileaf collimator. MATERIALS AND METHODS: Twenty recent clinical SRT cases treated using a radiosurgery c-arm linear accelerator were anonymized. From these data sets, a new planning workflow was developed and used to replan these cases, which then were compared to their clinical counterparts. Population-based dose-volume histograms were analyzed for target coverage and sparing of healthy brain. All plans underwent plan review and quality assurance and were delivered on an end-to-end verification phantom using image guidance to simulate treatment. RESULTS: The RGLA plans were able to meet departmental standards for target coverage and organ-at-risk sparing and showed plan quality similar to the clinical plans. RGLA plans showed increases in the 50% isodose in the axial plane but decreases in the sagittal and coronal planes. There were no statistically significant differences in the homogeneity index or number of monitor units between the 2 systems. There were statistically significant increases in conformity and gradient indices, with median values of 1.09 versus 1.11 and 2.82 versus 3.13, respectively, for the c-arm versus RGLA plans. These differences were not believed to be clinically significant because they met clinical goals. The population-based dose-volume histograms showed target coverage and organ-at-risk sparing similar to that of the clinical plans. All plans were able to meet the departmental quality assurance requirements and were delivered under image guidance on an end-to-end phantom with measurements agreeing within 3% of the expected value. RGLA plans showed a median reduction in delivery time of ≈50%. CONCLUSIONS: This work describes a simplified and efficient workflow that could reduce treatment times and expand access to SRT to centers using an RGLA.

Influence of 0.35 T magnetic field on the response of EBT3 and EBT-XD radiochromic films.

PURPOSE: To investigate the inconsistency of recent literature on the effect of magnetic field on the response of radiochromic films, we studied the influence of 0.35 T magnetic field on dosimetric response of EBT3 and EBT-XD GafchromicTM films. METHODS: Two different models of radiochromic films, EBT3 and EBT-XD, were investigated. Pieces of films samples from two different batches for each model were irradiated at different dose levels ranging from 1 to 20 Gy using 6 MV flattening filter free (FFF) x-rays generated by a clinical MR-guided radiotherapy system (B = 0.35 T). Film samples from the same batch were irradiated at corresponding dose levels using 6 MV FFF beam from a conventional linac (B = 0) for comparison. The net optical density was measured 48 h postirradiation using a flatbed scanner. The absorbance spectra were also measured over 500-700 nm wavelength range using a fiber-coupled spectrometer with 2.5 nm resolution. To study the effect of fractionated dose delivery to EBT3 (/EBT-XD) films, 8 (/16) Gy dose was delivered in four 2 (/4) Gy fractions with 24 h interval between fractions. RESULTS: No significant difference was found in the net optical density and net absorbance of the films irradiated with or without the presence of magnetic field. No dependency on the orientation of the film during irradiation with respect to the magnetic field was observed. The fractionated dose delivery resulted in the same optical density as delivering the whole dose in a single fraction. CONCLUSIONS: The 0.35 T magnetic field employed in the ViewRay® MR-guided radiotherapy system did not show any significant influence on the response of EBT3 and EBT-XD GafchromicTM films.

Modeling double-strand breaks from direct and indirect action in a complete human genome single cell Geant4 model.

The aim of this work is to develop and validate a computational model to investigate direct and indirect DNA damage by directly quantifying DNA strand breaks. A detailed geometrical target model was created in the Monte Carlo toolkit Geant4 to represent the nucleus of a single human cell with complete human genome. A calculation framework to simulate double-strand breaks (DSBs) was implemented using this single cell model in the Geant4-DNA extension. A detailed ellipsoidal single cell model was implemented using a compacted DNA structure representing the fibroblast cell in the G0/G1 phase of the cycle using a total of 6 Gbp within the nucleus to represent the complete human genome. This geometry was developed from the publicly available Geant4-DNA example (wholeNuclearDNA), and modified to record DNA damage for both the physical and chemical stages. A clustering algorithm was implemented in the analysis process in order to quantify direct, indirect, and mixed DSBs. The model was validated against published experimental and computational results for DSB Gy-1Gbp-1and the relative biological effectiveness (RBE) values for 250 kVp and Co-60 photons, as well as 2-100 MeV mono-energetic protons. A general agreement was observed over the whole simulated proton energy range, Co-60 beam, and 250 kVp in terms of the yield of DSB Gy-1Gbp-1and RBE. The DSB yield was 8.0 ± 0.3 DSB Gy-1Gbp-1for Co-60, and 9.2 ± 0.2 DSB Gy-1Gbp-1for 250 kVp, and between 11.1 ± 0.9 and 8.1 ± 0.5 DSB Gy-1Gbp-1for 2-100 MeV protons. The results also show mixed DSBs composed of direct and indirect SSBs make up more than half of the total DSBs. The results presented indicate that the current model reliably predicts the DSB yield and RBE for proton and photon irradiations, and allows for the detailed computational investigation of direct and indirect effects in DNA damage.

Lateral head flexion as a noncoplanar solution for ring gantry stereotactic radiosurgery.

PURPOSE: Ring gantry radiotherapy devices are often limited to deliver beams in the axial plane, severely limiting beam entrance angles and rendering noncoplanar beam delivery impossible. However, a ring gantry geometry greatly simplifies delivery machines and increases the efficiency of treatment with the potential to decrease the overall costs of radiotherapy. This study explores the use of lateral head flexion in order to increase beam entrance angles and extend the available solid angle space for a ring gantry stereotactic radiosurgery (SRS) application. MATERIALS AND METHODS: A 1.5 T magnetic resonance imaging scanner was used to scan seven healthy volunteers at three different head positions: a neutral position, a left lateral flexion position and a right lateral flexion position. The lateral flexion scans were co-registered to the neutral head position scan using rigid registration and extracting the rotational transformation. The head pitch, roll, and yaw were computed for each registration to evaluate the natural range of motion for all volunteers. A ring gantry plan geometry was used to generate two sets of single fraction SRS plans (21 Gy): one coplanar set for head neutral scans, and a three-arc plan set using the head neutral and lateral head flexion scans. The conformity index (CI), intermediate dose fall-off (R50), low dose spillage (R10), and gradient measure (GM) were used to evaluate both sets of plans. The treatment plans were generated for a ring-gantry linear accelerator (linac) (Varian Halcyon 2.0) as well as radiosurgery linac (Varian Edge) for comparison. RESULTS: The average pitch, yaw, and roll for the lateral head flexion scans were 4.1° ± 4.7°, 16.9° ± 3.7°, and 2.5° ± 4.9° for the right flexion and 4.9° ± 4.3°, 14.0° ± 3.7° and 2.8° ± 5.4° for left flexion. When comparing the head flexion technique with a fully coplanar geometry, the ring gantry plans showed an average improvement in CI of 7.3% (1.46 ± 0.25 vs 1.36 ± 0.28), a decrease of 13% in R50 (5.46 ± 1.14 vs 4.78 ± 1.12), a decrease of 32% in R10 (85.7 ± 20.3 vs 58.2 ± 15.1), and a decrease of 7.8% in GM (0.53 ± 0.05 vs 0.49 ± 0.04). The Edge plans showed an average improvement in CI of 3.0% (1.49 ± 0.26 vs 1.45 ± 0.25), a decrease of 6.8% in R50 (5.19 ± 1.03 vs 4.82 ± 0.83), a decrease of 29% in R10 (84.1 ± 16.3 vs 59.9 ± 12.5), and a decrease of 5.0% in GM (0.50 ± 0.04 vs 0.47 ± 0.03). CONCLUSION: Lateral head flexion was shown to increase beam entrance angles considerably improving plan conformity and normal tissue sparing in this pilot study of seven sets of plans. Rigid registrations demonstrated each lateral flexion to be analogous to a 15° couch kick. The head flexion technique outlined here was shown to be a feasible solution for SRS treatments being delivered on ring gantry devices.

A novel design of proton computed tomography detected by multiple-layer ionization chamber with strip chambers: A feasibility study with Monte Carlo simulation.

PURPOSE: Uncertainty in proton range can be reduced by proton computed tomography (CT). A novel design of proton CT using a multiple-layer ionization chamber with two strip ionization chambers on the surface is proposed to simplify the imaging acquisition and reconstruction. METHODS: Two strip ionization chambers facing the proton source were coupled into a multiple-layer ionization chamber (MLIC). The strip chambers measured locations and lateral profiles of incident proton beamlets after exiting the imaging object, while the integral of depth dose measured in the MLIC was translated into the residual energy of the beamlet. The simulation was performed at five levels of imaging dose to demonstrate the feasibility and performance expectations of our design. The energy of the proton beamlet was set to 150 ± 0.6 MeV. A collimator with a round slit of 1 cm in diameter was placed in the central beam axis upstream from steering magnets. Proton stopping power ratio (SPR) was reconstructed through inverse radon transform on sinograms generated with proton beamlets scanning through an imaging phantom from a half-circle gantry rotation. The imaging phantom was 10 cm in diameter. The base was made of water-equivalent material holding 13-tissue equivalent inserts constructed according to ICRP 1975 (Task Group on Reference Man. "Report of the Task Group on Reference Man: A Report", Pergamon Press 23, 1975). All inserts were 1 cm in diameter with materials ranging from lung to cortical bone. Percentage discrepancies were reported by comparing to the ground truths. The imaging dose and quality were also evaluated. RESULTS: The maximum deviation in reconstructed proton SPR from the ground truths was reported to be 1.02% in one of the 13 inserts when the number of protons per beamlet passing through the slit dropped to 103 . Imaging dose was correlated linearly to incident protons and was determined to be 0.54 cGy if 5 × 102 protons per beamlet were used. Imaging quality was acceptable for planning purpose and held consistently through all levels of imaging dose. Spatial resolution was measured as five line pairs per cm consistently in all simulations varying in imaging dose. CONCLUSIONS: Proton CT using a multiple-layer ionization chamber with two strip ionization chambers on the surface simplifies data acquisition while achieving excellent accuracy in proton SPR and acceptable spatial resolution. The imaging dose is lower compared to kV CBCT, making it potentially a great tool for localization and plan adaption in proton therapy.

Modeling gold nanoparticle radiosensitization using a clustering algorithm to quantitate DNA double-strand breaks with mixed-physics Monte Carlo simulation.

PURPOSE: The radiosensitization properties of gold nanoparticles (GNPs) are investigated using a simple Geant4 cell model considering a realistic cell geometry and a clustering algorithm to characterize the number of DNA double-strand breaks (DSBs). MATERIALS AND METHODS: A mixed-physics approach is taken for accurate modeling of low-energy photon interactions in the different regions of the model using Geant4-DNA physics within the cell, and Livermore physics within gold. Density-based spatial clustering of applications with noise (DBSCAN), a clustering algorithm, is used to directly quantitate DNA DSBs after irradiation. The simulation was run using different sizes of GNPs, different distances of GNPs from the cell nucleus, and several combinations of these two conditions. RESULTS: Four types of radiation were simulated in the work: 80-keV monoenergetic photons, 100-keV monoenergetic photons, a 250-kVp photon spectrum, and a 6-MV flattening filter free (FFF) photon spectrum. A variable enhancement in DSB yield, nucleus dose, and cell dose was observed when there are GNPs in the cell cytoplasm, and increases with larger GNPs and proximity to the nucleus. The distance of the GNPs from the nucleus has a large impact on the DSB yield and nucleus dose, but little to no effect on the cell dose. The cell dose enhancement factor of 80 keV photons varies from 1.037-1.125 at 0.2 µm for 30-100 nm GNPs to 1.040-1.127 at 4 µm. The DSB enhancement factor varies from 1.050 to 1.174 at 0.2 µm to a marginal effect of <1.01 at 4 µm. For 100 keV, the dose enhancement factor is from 1.142-1.470 at 0.2 µm to 1.106-1.371 at 4 µm. The DSB enhancement factor varies from 1.249-1.813 at 0.2 µm to almost no effect at 4 µm. For 250 kVp, the dose enhancement factor is from 1.117-1.393 at 0.2 µm to 1.110-1.342 at 4 µm. The DSB enhancement factor varies from 1.183-1.600 at 0.2 µm to a marginal effect of ~1.03 at 4 µm. A 6-MV FFF shows a dose enhancement factor of 1.061-1.103 at 0.2 µm and 1.053-1.107 at 4 µm. The DSB yield varies from 1.070-1.143 at 0.2 µm to a marginal effect at 4 µm. CONCLUSION: The stark difference in behavior for DSB yield when compared to cell dose highlights the importance of evaluating more complex radiobiological quantities rather than dose alone when evaluating the radiosensitization properties from metallic nanomaterials. The nucleus dose showed similar characteristics to the DSB yield demonstrating the ability of the method to predict DNA damage and its relationship with nuclear dose. The proposed method provides a way to explore the radiobiological mechanisms of radiation-induced DNA damages, and it aids to evaluate the physical radiosensitization properties of GNP-aided radiotherapy, which can be easily combined with radiochemical DSB quantitation in order to better understand the intricate DNA damage induction mechanisms that are involved in GNP-aided radiotherapy.

Radiation Therapy Workflow and Dosimetric Analysis from a Phase 1/2 Trial of Noninvasive Cardiac Radioablation for Ventricular Tachycardia.

PURPOSE: A prospective phase 1/2 trial for electrophysiologic guided noninvasive cardiac radioablation treatment of ventricular tachycardia (ENCORE-VT) demonstrating efficacy for arrhythmia control has recently been reported. The treatment workflow, report dose-volume metrics, and overall process improvements are described here. METHODS AND MATERIALS: Patients receiving 25 Gy in a single fraction to the cardiac ventricular tachycardia substrate (identified on presimulation multimodality imaging) on the phase 1/2 trial were included for analysis. Planning target volume (PTV), R50, monitor unit ratio, and gradient measure values were compared over time using statistical process control. Outlier values in the dose-volume histogram (DVH) for PTV and organs at risk were identified by calculating inner fences based on the interquartile range. Median heart substructure doses are also reported. RESULTS: For the 16 trial patients included, the median target volumes for the gross "target" volumes, internal target volumes, and PTVs were 25.1 cm3 (minimum: 11.5 cm3, maximum: 54.9 cm3), 30.1 cm3 (17.7, 81.6), and 97.9 cm3 (66, 208.5), respectively. On statistical process control analysis, there was a significant decrease in PTV volume among the more recent cohort of cases and mean doses to the nontargeted heart (heart - PTV). Two patients had heart-minus-PTV, esophagus, and stomach DVH data significantly higher than inner fence, and 3 patients had spinal cord DVH data higher than the inner fence, but in all cases the deviations were clinically acceptable. Subjective decreases were seen in the R50, gradient measure, and treatment time from the first to last patient in this series. All plans were verified in phantom with ionization chamber measurements within 2.9% of the expected dose value. CONCLUSIONS: Over the duration of this trial, PTV volumes to the cardiac substrate target decreased significantly, and organ-at-risk constraints were met for all cases. Future directions for this clinical process will include incorporating knowledge-based planning techniques and evaluating the need for substructure optimization.

Radiosensitization of Prostate Cancers In Vitro and In Vivo to Erbium-filtered Orthovoltage X-rays Using Actively Targeted Gold Nanoparticles.

Theoretical investigations suggest that gold nanoparticle (GNP)-mediated radiation dose enhancement and radiosensitization can be maximized when photons interact with gold, predominantly via photoelectric absorption. This makes ytterbium (Yb)-169, which emits photons with an average energy of 93 keV (just above the K-edge of gold), an ideal radioisotope for such purposes. This investigation tests the feasibility of tumor-specific prostate brachytherapy achievable with Yb-169 and actively targeted GNPs, using an external beam surrogate of Yb-169 created from an exotic filter material - erbium (Er) and a standard copper-filtered 250 kVp beam. The current in vitro study shows that treatment of prostate cancer cells with goserelin-conjugated gold nanorods (gGNRs) promotes gonadotropin releasing hormone receptor-mediated internalization and enhances radiosensitivity to both Er-filtered and standard 250 kVp beams, 14 and 10%, respectively. While the degree of GNP-mediated radiosensitization as seen from the in vitro study may be considered moderate, the current in vivo study shows that gGNR treatment plus Er-filtered x-ray irradiation is considerably more effective than radiation treatment alone (p < 0.0005), resulting in a striking reduction in tumor volume (50% smaller) 2 months following treatment. Overall, the current results provide strong evidence for the feasibility of tumor-specific prostate brachytherapy with Yb-169 and gGNRs.

Technical Note: Monte Carlo calculations of the AAPM TG-43 brachytherapy dosimetry parameters for a new titanium-encapsulated Yb-169 source.

Due to a number of distinct advantages resulting from the relatively low energy gamma ray spectrum of Yb-169, various designs of Yb-169 sources have been developed over the years for brachytherapy applications. Lately, Yb-169 has also been suggested as an effective and practical radioisotope option for a novel radiation treatment approach often known as gold nanoparticle-aided radiation therapy (GNRT). In a recently published study, the current investigators used the Monte Carlo N-Particle Version 5 (MCNP5) code to design a novel titanium-encapsulated Yb-169 source optimized for GNRT applications. In this study, the original MC source model was modified to accurately match the specifications of the manufactured Yb-169 source. The modified MC model was then used to obtain a complete set of the AAPM TG-43 parameters for the new titanium-encapsulated Yb-169 source. The MC-calculated dose rate constant for this titanium-encapsulated Yb-169 source was 1.19 ± 0.03 cGy·h-1·U-1, indicating no significant change from the values reported for stainless steel-encapsulated Yb-169 sources. The source anisotropy and radial dose function for the new source were also found similar to those reported for the stainless steel-encapsulated Yb-169 sources. The current results suggest that the use of titanium, instead of stainless steel, to encapsulate the Yb-169 core would not lead to any major change in the dosimetric characteristics of the Yb-169 source. The results also show that the titanium encapsulation of the Yb-169 source could be accomplished while meeting the design goals as described in the current investigators' published MC optimization study for GNRT applications.