Patient-specific quality assurance of dynamically-collimated proton therapy treatment plans.

BACKGROUND: The dynamic collimation system (DCS) provides energy layer-specific collimation for pencil beam scanning (PBS) proton therapy using two pairs of orthogonal nickel trimmer blades. While excellent measurement-to-calculation agreement has been demonstrated for simple cube-shaped DCS-trimmed dose distributions, no comparison of measurement and dose calculation has been made for patient-specific treatment plans. PURPOSE: To validate a patient-specific quality assurance (PSQA) process for DCS-trimmed PBS treatment plans and evaluate the agreement between measured and calculated dose distributions. METHODS: Three intracranial patient cases were considered. Standard uncollimated PBS and DCS-collimated treatment plans were generated for each patient using the Astroid treatment planning system (TPS). Plans were recalculated in a water phantom and delivered at the Miami Cancer Institute (MCI) using an Ion Beam Applications (IBA) dedicated nozzle system and prototype DCS. Planar dose measurements were acquired at two depths within low-gradient regions of the target volume using an IBA MatriXX ion chamber array. RESULTS: Measured and calculated dose distributions were compared using 2D gamma analysis with 3%/3 mm criteria and low dose threshold of 10% of the maximum dose. Median gamma pass rates across all plans and measurement depths were 99.0% (PBS) and 98.3% (DCS), with a minimum gamma pass rate of 88.5% (PBS) and 91.2% (DCS). CONCLUSIONS: The PSQA process has been validated and experimentally verified for DCS-collimated PBS. Dosimetric agreement between the measured and calculated doses was demonstrated to be similar for DCS-collimated PBS to that achievable with noncollimated PBS.

A re-activation model for 169Yb intensity modulated brachytherapy sources accounting for spatiotemporal isotopic composition.

BACKGROUND: Intensity modulated brachytherapy based on partially shielded intracavitary and interstitial applicators is possible with a cost-effective 169Yb production method. 169Yb is a traditionally expensive isotope suitable for this purpose, with an average γ-ray energy of 93 keV. Re-activating a single 169Yb source multiple times in a nuclear reactor between clinical uses was shown to theoretically reduce cost by approximately 75% relative to conventional single-activation sources. With re-activation, substantial spatiotemporal variation in isotopic source composition is expected between activations via 168Yb burnup and 169Yb decay, resulting in time dependent neutron transmission, precursor usage, and reactor time needed per re-activation. PURPOSE: To introduce a generalized model of radioactive source production that accounts for spatiotemporal variation in isotopic source composition to improve the efficiency estimate of the 169Yb production process, with and without re-activation. METHODS AND MATERIALS: A time-dependent thermal neutron transport, isotope transmutation, and decay model was developed. Thermal neutron flux within partitioned sub-volumes of a cylindrical active source was calculated by raytracing through the spatiotemporal dependent isotopic composition throughout the source, accounting for thermal neutron attenuation along each ray. The model was benchmarked, generalized, and applied to a variety of active source dimensions with radii ranging from 0.4 to 1.0 mm, lengths from 2.5 to 10.5 mm, and volumes from 0.31 to 7.85 mm3, at thermal neutron fluxes from 1 × 1014 to 1 × 1015 n cm-2 s-1. The 168Yb-Yb2O3 density was 8.5 g cm-3 with 82% 168Yb-enrichment. As an example, a reference re-activatable 169Yb active source (RRS) constructed of 82%-enriched 168Yb-Yb2O3 precursor was modeled, with 0.6 mm diameter, 10.5 mm length, 3 mm3 volume, 8.5 g cm-3 density, and a thermal neutron activation flux of 4 × 1014 neutrons cm-2 s-1. RESULTS: The average clinical 169Yb activity for a 0.99 versus 0.31 mm3 source dropped from 20.1 to 7.5 Ci for a 4 × 1014 n cm-2 s-1 activation flux and from 20.9 to 8.7 Ci for a 1 × 1015 n cm-2 s-1 activation flux. For thermal neutron fluxes ≥2 × 1014 n cm-2 s-1, total precursor and reactor time per clinic-year were maximized at a source volume of 0.99 mm3 and reached a near minimum at 3 mm3. When the spatiotemporal isotopic composition effect was accounted for, average thermal neutron transmission increased over RRS lifetime from 23.6% to 55.9%. A 28% reduction (42.5 days to 30.6 days) in the reactor time needed per clinic-year for the RRS is predicted relative to a model that does not account for spatiotemporal isotopic composition effects. CONCLUSIONS: Accounting for spatiotemporal isotopic composition effects within the RRS results in a 28% reduction in the reactor time per clinic-year relative to the case in which such changes are not accounted for. Smaller volume sources had a disadvantage in that average clinical 169Yb activity decreased substantially below 20 Ci for source volumes under 1 mm3. Increasing source volume above 3 mm3 adds little value in precursor and reactor time savings and has a geometric disadvantage.

Technical note: A simple method for patient-specific quality assurance for lateral targets on a 1.5 T MR-Linac.

The Elekta Unity magnetic resonance (MR) linac is limited to longitudinal couch motion and a sagittal-only laser, which restricts the ability to perform patient-specific quality assurance (PSQA) intensity-modulated radiotherapy (IMRT) measurements for very lateral targets. This work introduces a simple method to perform PSQA using the Sun Nuclear ArcCheck-MR phantom at left and right lateral positions without additional equipment or in-house construction. The proposed setup places the center of the phantom 1.3 cm vertical and 12.9 cm lateral to isocenter in either the left or right direction. Computed tomography (CT) scans are used to simulate the setup and create a QA plan template in the Monaco treatment planning system (TPS). The workflow is demonstrated for four patients, with an average axial distance from the center of the bore to the planning target volume (PTV) of 12.4 cm. Gamma pass rates were above 94% for all plans using global 3%/2 mm gamma criterion with a 10% threshold. Setup uncertainties are slightly larger for the proposed lateral setup compared to the centered setup on the Elekta platform (∼1 mm compared to ∼0.5 mm), but acceptable pass rates are achievable without optimizing shifts in the gamma analysis software. In general, adding the left and right lateral positions increases the axial area in the bore encompassed by the cylindrical measurement array by 147%, substantially increasing the flexibility of measurements for offset targets. Based on this work, we propose using the lateral QA setup if the closest distance to the PTV edge from isocenter is larger than the array radius (10.5 cm) or the percent of the PTV encompassed by the diode array would be increased with the lateral setup compared to the centered setup.

Integration and dosimetric validation of a dynamic collimation system for pencil beam scanning proton therapy.

Objective.To integrate a Dynamic Collimation System (DCS) into a pencil beam scanning (PBS) proton therapy system and validate its dosimetric impact.Approach.Uncollimated and collimated treatment fields were developed for clinically relevant targets using an in-house treatment plan optimizer and an experimentally validated Monte Carlo model of the DCS and IBA dedicated nozzle (DN) system. The dose reduction induced by the DCS was quantified by calculating the mean dose in 10- and 30-mm two-dimensional rinds surrounding the target. A select number of plans were then used to experimentally validate the mechanical integration of the DCS and beam scanning controller system through measurements with the MatriXX-PT ionization chamber array and EBT3 film. Absolute doses were verified at the central axis at various depths using the IBA MatriXX-PT and PPC05 ionization chamber.Main results.Simulations demonstrated a maximum mean dose reduction of 12% for the 10 mm rind region and 45% for the 30 mm rind region when utilizing the DCS. Excellent agreement was observed between Monte Carlo simulations, EBT3 film, and MatriXX-PT measurements, with gamma pass rates exceeding 94.9% for all tested plans at the 3%/2 mm criterion. Absolute central axis doses showed an average verification difference of 1.4% between Monte Carlo and MatriXX-PT/PPC05 measurements.Significance.We have successfully dosimetrically validated the delivery of dynamically collimated proton therapy for clinically relevant delivery patterns and dose distributions with the DCS. Monte Carlo simulations were employed to assess dose reductions and treatment planning considerations associated with the DCS.

PETRA: A pencil beam trimming algorithm for analytical proton therapy dose calculations with the dynamic collimation system.

BACKGROUND: The Dynamic Collimation System (DCS) has been shown to produce superior treatment plans to uncollimated pencil beam scanning (PBS) proton therapy using an in-house treatment planning system (TPS) designed for research. Clinical implementation of the DCS requires the development and benchmarking of a rigorous dose calculation algorithm that accounts for pencil beam trimming, performs monitor unit calculations to produce deliverable plans at all beam energies, and is ideally implemented with a commercially available TPS. PURPOSE: To present an analytical Pencil bEam TRimming Algorithm (PETRA) for the DCS, with and without its range shifter, implemented in the Astroid TPS (.decimal, Sanford, Florida, USA). MATERIALS: PETRA was derived by generalizing an existing pencil beam dose calculation model to account for the DCS-specific effects of lateral penumbra blurring due to the nickel trimmers in two different planes, integral depth dose variation due to the trimming process, and the presence and absence of the range shifter. Tuning parameters were introduced to enable agreement between PETRA and a measurement-validated Dynamic Collimation Monte Carlo (DCMC) model of the Miami Cancer Institute's IBA Proteus Plus system equipped with the DCS. Trimmer position, spot position, beam energy, and the presence or absence of a range shifter were all used as variables for the characterization of the model. The model was calibrated for pencil beam monitor unit calculations using procedures specified by International Atomic Energy Agency Technical Report Series 398 (IAEA TRS-398). RESULTS: The integral depth dose curves (IDDs) for energies between 70 MeV and 160 MeV among all simulated trimmer combinations, with and without the ranger shifter, agreed between PETRA and DCMC at the 1%/1 mm 1-D gamma criteria for 99.99% of points. For lateral dose profiles, the median 2-D gamma pass rate for all profiles at 1.5%/1.5 mm was 99.99% at the water phantom surface, plateau, and Bragg peak depths without the range shifter and at the surface and Bragg peak depths with the range shifter. The minimum 1.5%/1.5 mm gamma pass rates for the 2-D profiles at the water phantom surface without and with the range shifter were 98.02% and 97.91%, respectively, and, at the Bragg peak, the minimum pass rates were 97.80% and 97.5%, respectively. CONCLUSION: The PETRA model for DCS dose calculations was successfully defined and benchmarked for use in a commercially available TPS.

Dosimetric delivery validation of dynamically collimated pencil beam scanning proton therapy.

Objective. Pencil beam scanning (PBS) proton therapy target dose conformity can be improved with energy layer-specific collimation. One such collimator is the dynamic collimation system (DCS), which consists of four nickel trimmer blades that intercept the scanning beam as it approaches the lateral extent of the target. While the dosimetric benefits of the DCS have been demonstrated through computational treatment planning studies, there has yet to be experimental verification of these benefits for composite multi-energy layer fields. The objective of this work is to dosimetrically characterize and experimentally validate the delivery of dynamically collimated proton therapy with the DCS equipped to a clinical PBS system.Approach. Optimized single field, uniform dose treatment plans for 3 × 3 × 3 cm3target volumes were generated using Monte Carlo dose calculations with depths ranging from 5 to 15 cm, trimmer-to-surface distances ranging from 5 to 18.15 cm, with and without a 4 cm thick polyethylene range shifter. Treatment plans were then delivered to a water phantom using a prototype DCS and an IBA dedicated nozzle system and measured with a Zebra multilayer ionization chamber, a MatriXX PT ionization chamber array, and Gafchromic™ EBT3 film.Main results. For measurements made within the SOBPs, average 2D gamma pass rates exceeded 98.5% for the MatriXX PT and 96.5% for film at the 2%/2 mm criterion across all measured uncollimated and collimated plans, respectively. For verification of the penumbra width reduction with collimation, film agreed with Monte Carlo with differences within 0.3 mm on average compared to 0.9 mm for the MatriXX PT.Significance. We have experimentally verified the delivery of DCS-collimated fields using a clinical PBS system and commonly available dosimeters and have also identified potential weaknesses for dosimeters subject to steep dose gradients.

A novel optimization algorithm for enabling dynamically collimated proton arc therapy.

The advent of energy-specific collimation in pencil beam scanning (PBS) proton therapy has led to an improved lateral dose conformity for a variety of treatment sites, resulting in better healthy tissue sparing. Arc PBS delivery has also been proposed to enhance high-dose conformity about the intended target, reduce skin toxicity, and improve plan robustness. The goal of this work was to determine if the combination of proton arc and energy-specific collimation can generate better dose distributions as a logical next step to maximize the dosimetric advantages of proton therapy. Plans were optimized using a novel DyNamically collimated proton Arc (DNA) genetic optimization algorithm that was designed specifically for the application of proton arc therapy. A treatment planning comparison study was performed by generating an uncollimated two-field intensity modulated proton therapy and partial arc treatments and then replanning these treatments using energy-specific collimation as delivered by a dynamic collimation system, which is a novel collimation technology for PBS. As such, we refer to this novel treatment paradigm as Dynamically Collimated Proton Arc Therapy (DC-PAT). Arc deliveries achieved a superior target conformity and improved organ at risk (OAR) sparing relative to their two-field counterparts at the cost of an increase to the low-dose, high-volume region of the healthy brain. The incorporation of DC-PAT using the DNA optimizer was shown to further improve the tumor dose conformity. When compared to the uncollimated proton arc treatments, the mean dose to the 10mm of surrounding healthy tissue was reduced by 11.4% with the addition of collimation without meaningfully affecting the maximum skin dose (less than 1% change) relative to a multi-field treatment. In this case study, DC-PAT could better spare specific OARs while maintaining better target coverage compared to uncollimated proton arc treatments. While this work presents a proof-of-concept integration of two emerging technologies, the results are promising and suggest that the addition of these two techniques can lead to superior treatment plans warranting further development.

Investigating aperture-based approximations to model a focused dynamic collimation system for pencil beam scanning proton therapy.

Purpose. The Dynamic Collimation System (DCS) is an energy layer-specific collimation device designed to reduce the lateral penumbra in pencil beam scanning proton therapy. The DCS consists of two pairs of nickel trimmers that rapidly and independently move and rotate to intercept the scanning proton beam and an integrated range shifter to treat targets less than 4 cm deep. This work examines the validity of a single aperture approximation to model the DCS, a commonly used approximation in commercial treatment planning systems, as well as higher-order aperture-based approximations for modeling DCS-collimated dose distributions.Methods. An experimentally validated TOPAS/Geant4-based Monte Carlo model of the DCS integrated with a beam model of the IBA pencil beam scanning dedicated nozzle was used to simulate DCS- and aperture-collimated 100 MeV beamlets and composite treatment plans. The DCS was represented by three different aperture approximations: a single aperture placed halfway between the upper and lower trimmer planes, two apertures located at the upper and lower trimmer planes, and four apertures, located at both the upstream and downstream faces of each pair of trimmers. Line profiles and three-dimensional regions of interest were used to evaluate the validity and limitations of the aperture approximations investigated.Results. For pencil beams without a range shifter, minimal differences were observed between the DCS and single aperture approximation. For range shifted beamlets, the single aperture approximation yielded wider penumbra widths (up to 18%) in the X-direction and sharper widths (up to 9.4%) in the Y-direction. For the example treatment plan, the root-mean-square errors (RMSEs) in an overall three-dimensional region of interest were 1.7%, 1.3%, and 1.7% for the single aperture, two aperture, and four aperture models, respectively. If the region of interest only encompasses the lateral edges outside of the target, the resulting RMSEs were 1.7%, 1.1%, and 0.5% single aperture, two aperture, and four aperture models, respectively.Conclusions. Monte Carlo simulations of the DCS demonstrated that a single aperture approximation is sufficient for modeling pristine fields at the Bragg depth while range shifted fields require a higher-order aperture approximation. For the treatment plan considered, the double aperture model performed the best overall, however, the four-aperture model most accurately modeled the lateral field edges at the expense of increased dose differences proximal to and within the target.

The dosimetric enhancement of GRID profiles using an external collimator in pencil beam scanning proton therapy.

PURPOSE: The radiobiological benefits afforded by spatially fractionated (GRID) radiation therapy pairs well with the dosimetric advantages of proton therapy. Inspired by the emergence of energy-layer specific collimators in pencil beam scanning (PBS), this work investigates how the spot spacing and collimation can be optimized to maximize the therapeutic gains of a GRID treatment while demonstrating the integration of a dynamic collimation system (DCS) within a commercial beamline to deliver GRID treatments and experimentally benchmark Monte Carlo calculation methods. METHODS: GRID profiles were experimentally benchmarked using a clinical DCS prototype that was mounted to the nozzle of the IBA-dedicated nozzle system. Integral depth dose (IDD) curves and lateral profiles were measured for uncollimated and GRID-collimated beamlets. A library of collimated GRID dose distributions were simulated by placing beamlets within a specified uniform grid and weighting the beamlets to achieve a volume-averaged tumor cell survival equivalent to an open field delivery. The healthy tissue sparing afforded by the GRID distribution was then estimated across a range of spot spacings and collimation widths, which were later optimized based on the radiosensitivity of the tumor cell line and the nominal spot size of the PBS system. This was accomplished by using validated models of the IBA universal and dedicated nozzles. RESULTS: Excellent agreement was observed between the measured and simulated profiles. The IDDs matched above 98.7% when analyzed using a 1%/1-mm gamma criterion with some minor deviation observed near the Bragg peak for higher beamlet energies. Lateral profile distributions predicted using Monte Carlo methods agreed well with the measured profiles; a gamma passing rate of 95% or higher was observed for all in-depth profiles examined using a 3%/2-mm criteria. Additional collimation was shown to improve PBS GRID treatments by sharpening the lateral penumbra of the beamlets but creates a trade-off between enhancing the valley-to-peak ratio of the GRID delivery and the dose-volume effect. The optimal collimation width and spot spacing changed as a function of the tumor cell radiosensitivity, dose, and spot size. In general, a spot spacing below 2.0 cm with a collimation less than 1.0 cm provided a superior dose distribution among the specific cases studied. CONCLUSIONS: The ability to customize a GRID dose distribution using different collimation sizes and spot spacings is a useful advantage, especially to maximize the overall therapeutic benefit. In this regard, the capabilities of the DCS, and perhaps alternative dynamic collimators, can be used to enhance GRID treatments. Physical dose models calculated using Monte Carlo methods were experimentally benchmarked in water and were found to accurately predict the respective dose distributions of uncollimated and DCS-collimated GRID profiles.

Innovations and the Use of Collimators in the Delivery of Pencil Beam Scanning Proton Therapy.

PURPOSE: The development of collimating technologies has become a recent focus in pencil beam scanning (PBS) proton therapy to improve the target conformity and healthy tissue sparing through field-specific or energy-layer-specific collimation. Given the growing popularity of collimators for low-energy treatments, the purpose of this work was to summarize the recent literature that has focused on the efficacy of collimators for PBS and highlight the development of clinical and preclinical collimators. MATERIALS AND METHODS: The collimators presented in this work were organized into 3 categories: per-field apertures, multileaf collimators (MLCs), and sliding-bar collimators. For each case, the system design and planning methodologies are summarized and intercompared from their existing literature. Energy-specific collimation is still a new paradigm in PBS and the 2 specific collimators tailored toward PBS are presented including the dynamic collimation system (DCS) and the Mevion Adaptive Aperture. RESULTS: Collimation during PBS can improve the target conformity and associated healthy tissue and critical structure avoidance. Between energy-specific collimators and static apertures, static apertures have the poorest dose conformity owing to collimating only the largest projection of a target in the beam's eye view but still provide an improvement over uncollimated treatments. While an external collimator increases secondary neutron production, the benefit of collimating the primary beam appears to outweigh the risk. The greatest benefit has been observed for low- energy treatment sites. CONCLUSION: The consensus from current literature supports the use of external collimators in PBS under certain conditions, namely low-energy treatments or where the nominal spot size is large. While many recent studies paint a supportive picture, it is also important to understand the limitations of collimation in PBS that are specific to each collimator type. The emergence and paradigm of energy-specific collimation holds many promises for PBS proton therapy.

Implementation of a real-time, ultrasound-guided prostate HDR brachytherapy program.

This work presents a comprehensive commissioning and workflow development process of a real-time, ultrasound (US) image-guided treatment planning system (TPS), a stepper and a US unit. To adequately benchmark the system, commissioning tasks were separated into (1) US imaging, (2) stepper mechanical, and (3) treatment planning aspects. Quality assurance US imaging measurements were performed following the AAPM TG-128 and GEC-ESTRO recommendations and consisted of benchmarking the spatial resolution, accuracy, and low-contrast detectability. Mechanical tests were first used to benchmark the electronic encoders within the stepper and were later expanded to evaluate the needle free length calculation accuracy. Needle reconstruction accuracy was rigorously evaluated at the treatment planning level. The calibration length of each probe was redundantly checked between the calculated and measured needle free length, which was found to be within 1 mm for a variety of scenarios. Needle placement relative to a reference fiducial and coincidence of imaging coordinate origins were verified to within 1 mm in both sagittal and transverse imaging planes. The source strength was also calibrated within the interstitial needle and was found to be 1.14% lower than when measured in a plastic needle. Dose calculations in the TPS and secondary dose calculation software were benchmarked against manual TG-43 calculations. Calculations among the three calculation methods agreed within 1% for all calculated points. Source positioning and dummy coincidence was tested following the recommendations of the TG-40 report. Finally, the development of the clinical workflow, checklists, and planning objectives are discussed and included within this report. The commissioning of real-time, US-guided HDR prostate systems requires careful consideration among several facets including the image quality, dosimetric, and mechanical accuracy. The TPS relies on each of these components to develop and administer a treatment plan, and as such, should be carefully examined.

Mouse models for dominant dystrophic epidermolysis bullosa carrying common human point mutations recapitulate the human disease.

Heterozygous missense mutations in the human COL7A1 gene - coding for collagen VII - lead to the rare, dominantly inherited skin disorder dominant dystrophic epidermolysis bullosa (DDEB), which is characterised by skin fragility, blistering, scarring and nail dystrophy. To better understand the pathophysiology of DDEB and develop more effective treatments, suitable mouse models for DDEB are required but to date none have existed. We identified the two most common COL7A1 mutations in DDEB patients (p.G2034R and p.G2043R) and used CRISPR-Cas9 to introduce the corresponding mutations into mouse Col7a1 (p.G2028R and p.G2037R). Dominant inheritance of either of these two alleles results in a phenotype that closely resembles that seen in DDEB patients. Specifically, mice carrying these alleles show recurrent blistering that is first observed transiently around the mouth and paws in the early neonatal period and then again around the digits from 5-10 weeks of age. Histologically, the mice show micro-blistering and reduced collagen VII immunostaining. Biochemically, collagen VII from these mice displays reduced thermal stability, which we also observed to be the case for DDEB patients carrying the analogous mutations. Unlike previous rodent models of epidermolysis bullosa, which frequently show early lethality and severe disease, these mouse models, which to our knowledge are the first for DDEB, show no reduction in growth and survival, and - together with a relatively mild phenotype - represent a practically and ethically tractable tool for better understanding and treating epidermolysis bullosa. This article has an associated First Person interview with the first author of the paper.

Development and validation of the Dynamic Collimation Monte Carlo simulation package for pencil beam scanning proton therapy.

PURPOSE: The aim of this work was to develop and experimentally validate a Dynamic Collimation Monte Carlo (DCMC) simulation package specifically designed for the simulation of collimators in pencil beam scanning proton therapy (PBS-PT). The DCMC package was developed using the TOPAS Monte Carlo platform and consists of a generalized PBS source model and collimator component extensions. METHODS: A divergent point-source model of the IBA dedicated nozzle (DN) at the Miami Cancer Institute (MCI) was created and validated against on-axis commissioning measurements taken at MCI. The beamline optics were mathematically incorporated into the source to model beamlet deflections in the X and Y directions at the respective magnet planes. Off-axis measurements taken at multiple planes in air were used to validate both the off-axis spot size and divergence of the source model. The DCS trimmers were modeled and incorporated as TOPAS geometry extensions that linearly translate and rotate about the bending magnets. To validate the collimator model, a series of integral depth dose (IDD) and lateral profile measurements were acquired at MCI and used to benchmark the DCMC performance for modeling both pristine and range shifted beamlets. The water equivalent thickness (WET) of the range shifter was determined by quantifying the shift in the depth of the 80% dose point distal to the Bragg peak between the range shifted and pristine uncollimated beams. RESULTS: A source model of the IBA DN system was successfully commissioned against on- and off-axis IDD and lateral profile measurements performed at MCI. The divergence of the source model was matched through an optimization of the source-to-axis distance and comparison against in-air spot profiles. The DCS model was then benchmarked against collimated IDD and in-air and in-phantom lateral profile measurements. Gamma analysis was used to evaluate the agreement between measured and simulated lateral profiles and IDDs with 1%/1 mm criteria and a 1% dose threshold. For the pristine collimated beams, the average 1%/1 mm gamma pass rates across all collimator configurations investigated were 99.8% for IDDs and 97.6% and 95.2% for in-air and in-phantom lateral profiles. All range shifted collimated IDDs passed at 100% while in-air and in-phantom lateral profiles had average pass rates of 99.1% and 99.8%, respectively. The measured and simulated WET of the polyethylene range shifter was determined to be 40.9 and 41.0 mm, respectively. CONCLUSIONS: We have developed a TOPAS-based Monte Carlo package for modeling collimators in PBS-PT. This package was then commissioned to model the IBA DN system and DCS located at MCI using both uncollimated and collimated measurements. Validation results demonstrate that the DCMC package can be used to accurately model other aspects of a DCS implementation via simulation.

On the stability of well-type ionization chamber source strength calibration coefficients.

PURPOSE: To investigate the variability and stability of brachytherapy source strength calibration coefficients for air-communicating and pressurized well-type ionization chambers among high-dose rate (HDR), low-dose rate (LDR), and electronic brachytherapy (EBT) source qualities. These qualities of an ionization chamber are important features to assess given their role in maintaining traceability to a primary national standards laboratory and facilitating efficacious patient care in brachytherapy. METHODS: The calibration records from the University of Wisconsin Accredited Dosimetry Calibration Laboratory (UWADCL) customer well-type ionization chamber database were retrospectively analyzed for calibrations performed between 1996 and 2019. A statistical analysis was performed and differentiated among calibration type to quantify the distribution of chamber calibration coefficients among several chamber models. Distributions were quantified based on their moments and by quantile analysis. For LDR calibrations, chamber response was further differentiated by seed type to study the variability in seed dependence within and across chamber models. In addition to these metrics, the calibration lineage at the UWADCL was used to assess the stability of these calibration coefficients among chamber model and source type based on the ratio of subsequent calibration coefficients. RESULTS: The distribution of brachytherapy source strength calibration coefficients for a particular chamber model is not necessarily normally distributed and is sensitive to changes in the machining tolerances or design of the chamber model. Calibration source quality also influenced the distributions of calibration coefficients for a chamber model; the air-kerma rate calibration coefficients for EBT sources were the most variable followed by LDR and then HDR source types. The stability of a chamber's source strength calibration coefficient exhibited a similar dependence on the source quality. Air-communicating and pressurized chambers exhibited an average stability between subsequent calibrations of 0.2% and 3.0%, respectively, for HDR calibrations, but could exhibit more than double this variability characteristic of their leptokurtic distributions. For LDR calibrations, the spread and stability in a model's calibration ratio toward another seed type is extensive and notable. For some seed types and chamber models exhibit variations of <0.5% while others exceeded 2.0%. Furthermore, the magnitude of this dependence is outside the variability of the source's source strength due to manufacturing, which was determined from the manufacturer and NIST source strength intercomparison records at the UWADCL. As a result, establishing and disseminating calibration conversion factors among different source and chamber models is not advised as it would substantially increase the uncertainty in a clinical user's determination of source strength. CONCLUSIONS: The calibration of a well-type ionization chamber is unique to the chamber, source, and source holder. Attempting to generalize source strength calibration coefficients among chambers of the same model or source type is impractical given the variation in response observed across the calibration history of the UWADCL. Attempting to quantitate and transfer calibration coefficients in such a relative sense may significantly degrade the uncertainty relative to specifically calibrating a chamber for an individual source.

An investigation into the robustness of dynamically collimated proton therapy treatments.

PURPOSE: To investigate the dosimetric robustness of dynamically collimated proton therapy (DCPT) treatment plans delivered using a dynamic collimation system (DCS) with respect to random uncertainties in beam spot and collimator position as well as systematic offsets in the DCS mounting alignment. This work also demonstrates a technique that can increase plan robustness while preserving target conformity. METHODS: Variability in beam spot and collimator positioning can result in changes to a beamlet's dose distribution and incident fluence. The robustness of the DCPT treatment plans was evaluated for three intracranial treatment sites by modeling treatment variability as normally distributed random variables with standard deviations reflecting a clinical system. The simulated treatment plans were then recalculated and compared against their nominal, idealized dose distribution among several trials. It was hypothesized that a plan's robustness to these delivery variables could be reduced by restricting a trimmer's placement toward a beamlet's central axis during collimation. RESULTS: By introducing a minimum trimmer offset of 1.5 mm, the variation of the planning target volume (PTV) D95% coverage was reduced to within 2% of the prescribed dose. The treatment plans with trimmers that were placed within 0.5 mm of a collimated beamlet's central axis resulted in the greatest healthy tissue sparing but deviations as high as 11.4% to the PTV D95% were observed. The nominal conformity of these treatment plans utilizing the 1.5 mm trimmer offset was also well maintained. For each treatment plan studied, the 90% conformity index remained within 6.25% of the conformity index achieved without a minimum trimmer offset, and the D50% of surrounding healthy tissue increased by no more than 3.1 Gy relative to a plan without a trimmer offset. CONCLUSIONS: While DCPT can offer a significant reduction in healthy tissue irradiation, the results from this work indicate that special care must be taken to ensure proper PTV coverage amid uncertainties associated with this new treatment modality. A simple approach utilizing a minimum trimmer offset was able to preserve the majority of the target conformity and healthy tissue sparing the DCS technology affords while minimizing the uncertainties in this treatment approach.

Experimental and Monte Carlo characterization of a dynamic collimation system prototype for pencil beam scanning proton therapy.

PURPOSE: There has been a growing interest in the development of energy-specific collimators for low-energy pencil beam scanning (PBS) to reduce the lateral penumbra. One particular device that has been the focus of several recent published works is the dynamic collimation system (DCS), which provides energy-specific collimation by intercepting the scanned proton beam as it nears to target edge with a set of orthogonal trimmer blades. While several computational studies have shown that this dynamic collimator can provide additional healthy tissue sparing, there has not been any rigorous experimental work to benchmark the theoretical models used in these initial studies. Therefore, it was the purpose of this work to demonstrate an experimental method that could integrate an experimental prototype with a clinical PBS system and benchmark the Monte Carlo methods that have been used to model the DCS. METHODS: An experimental DCS prototype was designed and built in house to actively collimate individual proton beamlets during PBS within a well-characterized experimental setup. Monte Carlo methods were initially used to assess construction tolerances and later benchmarked against measurements, including integral depth dose and lateral asymmetric beamlet profiles. The experimental apparatus and measurement geometry were modeled using MCNP6 benchmarked from measurements performed at the Northwestern Chicago Proton Center. RESULTS: Gamma analysis tests were used to evaluate the agreement between the measured and simulated profiles with a strict 1 mm/1% criteria and 5% dose threshold. Excellent agreement was observed between the simulated and measured profiles, which included 1 mm/1% gamma analysis pass rates of at least 100% and 95% for the integral depth dose (IDD) profiles and lateral profiles, respectively. Differences in the relative profile shape were observed experimentally between beamlets collimated on- and off-axis, which was attributed to the partial transmission of the beam through an unfocused collimator. Exposure rates resulting from the activation of the device were monitored with survey meter measurements and were found to agree with Monte Carlo estimates of the exposure rate to within 20%. CONCLUSION: A DCS prototype was constructed and integrated into a clinical dose delivery system. While the results of this work are not exhaustive, they demonstrate the effects of beam source divergence, device activation, and beamlet deflection during scanning, which were found to be successfully modeled using Monte Carlo methods and experimentally benchmarked. Excellent agreement was achieved between the simulated and measured lateral spot profiles of collimated beamlets delivered on- and off-axis in PBS. The Monte Carlo models adequately predicted the measured elevated plateau region in the integral depth-dose profiles from the low-energy scatter off the collimators.

Trimmer sequencing time minimization during dynamically collimated proton therapy using a colony of cooperating agents.

The dynamic collimation system (DCS) can be combined with pencil beam scanning proton therapy to deliver highly conformal treatment plans with unique collimation at each energy layer. This energy layer-specific collimation is accomplished through the synchronized motion of four trimmer blades that intercept the proton beam near the target boundary in the beam's eye view. However, the corresponding treatment deliveries come at the cost of additional treatment time since the translational speed of the trimmer is slower than the scanning speed of the proton pencil beam. In an attempt to minimize the additional trimmer sequencing time of each field while still maintaining a high degree of conformity, a novel process utilizing ant colony optimization (ACO) methods was created to determine the most efficient route of trimmer sequencing and beamlet scanning patterns for a collective set of collimated proton beamlets. The ACO process was integrated within an in-house treatment planning system optimizer to determine the beam scanning and DCS trimmer sequencing patterns and compared against an analytical approximation of the trimmer sequencing time should a contour-like scanning approach be assumed instead. Due to the stochastic nature of ACO, parameters where determined so that they could ensure good convergence and an efficient optimization of trimmer sequencing that was faster than an analytical contour-like trimmer sequencing. The optimization process was tested using a set of three intracranial treatment plans which were planned using a custom research treatment planning system and were successfully optimized to reduce the additional trimmer sequencing time to approximately 60 s per treatment field while maintaining a high degree of target conformity. Thus, the novel use of ACO techniques within a treatment planning algorithm has been demonstrated to effectively determine collimation sequencing patterns for a DCS in order to minimize the additional treatment time required for trimmer movement during treatment.

SIDT1 Localizes to Endolysosomes and Mediates Double-Stranded RNA Transport into the Cytoplasm.

dsRNA is a common by-product of viral replication and acts as a potent trigger of antiviral immunity. SIDT1 and SIDT2 are closely related members of the SID-1 transmembrane family. SIDT2 functions as a dsRNA transporter and is required to traffic internalized dsRNA from endocytic compartments into the cytosol for innate immune activation, but the role of SIDT1 in dsRNA transport and in the innate immune response to viral infection is unclear. In this study, we show that Sidt1 expression is upregulated in response to dsRNA and type I IFN exposure and that SIDT1 interacts with SIDT2. Moreover, similar to SIDT2, SIDT1 localizes to the endolysosomal compartment, interacts with the long dsRNA analog poly(I:C), and, when overexpressed, enhances endosomal escape of poly(I:C) in vitro. To elucidate the role of SIDT1 in vivo, we generated SIDT1-deficient mice. Similar to Sidt2-/- mice, SIDT1-deficient mice produced significantly less type I IFN following infection with HSV type 1. In contrast to Sidt2-/- mice, however, SIDT1-deficient animals showed no impairment in survival postinfection with either HSV type 1 or encephalomyocarditis virus. Consistent with this, we observed that, unlike SIDT2, tissue expression of SIDT1 was relatively restricted, suggesting that, whereas SIDT1 can transport extracellular dsRNA into the cytoplasm following endocytosis in vitro, the transport activity of SIDT2 is likely to be functionally dominant in vivo.

LET response variability of Gafchromic TM EBT3 film from a 60 Co calibration in clinical proton beam qualities.

PURPOSE: To establish a method of accurate dosimetry required to quantify the expected linear energy transfer (LET) quenching effect of EBT3 film used to benchmark the dose distribution for a given treatment field and specified measurement depth. In order to facilitate this technique, a full analysis of film calibration which considers LET variability at the plane of measurement and as a function of proton beam quality is demonstrated. Additionally, the corresponding uncertainty from the process was quantified for several measurement scenarios. MATERIALS AND METHODS: The net change in optical density (OD) from a single version of Gafchromic TM EBT3 film was measured using an Epson flatbed scanner and NIST-traceable OD filters. Film OD response was characterized with respect to the known dose to water at the point of measurement for both a NIST-traceable 60 Co beam at the UWADCL and several clinical single-energy and spread-out Bragg peak (SOBP) proton beam qualities at the Northwestern Medicine Chicago Proton Center. Increasing proton LET environments were acquired by placing film at increasing depths of Gammex HE Solid Water® whose water-equivalent thickness was characterized prior to measurement. RESULTS: A strong LET dependence was observed near the Bragg peak (BP) consistent with previous studies performed with earlier versions of EBT3 film. The influence of range straggling on the film's LET response appears to have a uniform effect toward the BP regardless of the nominal beam energy. Proximal to this depth, the film's response decreased with decreasing energy at the same dose-average LET. The opposite trend was observed for depths past the BP. Changes in the SOBP energy modulation showed a linear relationship between the film's relative response and dose-averaged LET. Relative effectiveness factors (RE) were observed to range between 2%-7% depending on the width of the SOBP and depth of the film. Using the field-specific calibration technique, a total k = 1 uncertainty in the absorbed dose to water was estimated to range from 4.68%-5.21%. CONCLUSION: While EBT3 film's strong LET dependence is a common problem in proton beam dosimetry, this work has shown that the LET dependence can be taken into account by carefully considering the depth and energy modulation across the film using field-specific corrections. RE factors were determined with a combined k = 1 uncertainty of 3.57% for SOBP environments and between 3.17%-4.69% for uniform, monoenergetic fields proximal to the distal 80% of the BP.

Technical Note: Optimization of spot and trimmer position during dynamically collimated proton therapy.

PURPOSE: To demonstrate a novel theoretical optimization design which considers beam spot and trimmer positioning in addition to beamlet weighting for dynamically collimated proton therapy (DCPT) treatments. Prior to this, the previous methods of plan optimization used to study this emerging technology relied upon an intuitive selection criterion to fix the trimmers blades for a uniform grid of beam spots before determining the individual beamlet weights. To evaluate the potential benefit from this new optimization design, a treatment planning optimization study was performed in order to compare the algorithm's functionality against the existing methods of plan optimization. MATERIALS AND METHODS: A direct parameter optimization (DPO) method was developed to determine beam spot and trimmer positions cohesively with beamlet weighting for DCPT treatment plans. Gradients were numerically determined from applying small adjustments to the aforementioned parameters and quantifying the resulting impact on an objective function. This technique was compared to the conventional trimmer selection algorithm (TSA) which does not optimize spot position concurrently with trimmer position. Both planning methods were used to optimize a set of brain treatment plans, and the resulting dose distributions were compared with dose-volume histogram quantities in addition to target coverage, homogeneity, and conformity metrics. RESULTS: An overall improvement to the target conformity and healthy tissue sparing was achieved with DPO over TSA while maintaining an equivalent planning target volume (PTV) coverage index for the three brain patients evaluated in this study. On average, the conformity index improved by 5.5% when utilizing DPO. A similar improvement in reducing the dose to several organs at risk was also noted. CONCLUSION: Both the TSA and DPO planning methods can achieve highly conformal treatments with the dynamic collimation system (DCS) technology. However, an improvement in the target conformity and healthy tissue sparing was achieved by simultaneously optimizing beam spot position, trimmer location, and beamlet weights using DPO in comparison to the TSA technique.