Kruse, Jon J.

BACKGROUND: Cardiac radioablation is emerging as a treatment modality for refractory ventricular tachycardia. This study aimed to evaluate the effects of radiation on the coronary arteries in a swine model of proton beam cardiac radioablation. METHODS: Eighteen swine underwent single-fraction 30 to 40 Gy pencil-beam scanning proton therapy targeting the left ventricle and were euthanized 12 to 40 weeks later. Treatment planning was performed without restricting the dose to the coronary arteries. The maximum point dose (D max ) to the epicardial coronary arteries was calculated. In secondary analyses, the mean (D mean ) and minimum dose received by the highest irradiated 0.01 cm 3 (D 0.01 ) of each coronary artery were also calculated. Coronary artery segments were harvested from the D max sites for histological analysis, and the D max was correlated with stenosis severity. RESULTS: Ninety-six coronary arteries were analyzed. No stenoses were observed by computed tomography imaging preirradiation. By histological analysis posteuthanasia, 25/96 (26%) coronaries sampled at their D max sites had ≥75% stenosis. The median D max was 4.7 Gy for the <75% stenosis group and 29.7 Gy for the ≥75% stenosis group ( P <0.001). The AUC-ROC for the association between D max and stenosis ≥75% was 92.2%. A D max value of 20.1 Gy best predicted stenosis ≥75%, with sensitivity 92.3% and specificity 87.1%. The AUC-ROCs for the associations of D mean and D 0.01 with stenosis ≥75% were 84.8% and 91.6%, respectively. In histopathologic analysis, intimal hyperplasia was the most common coronary artery abnormality at the D max sites, and it was present in 61.5% of all arteries and in 93.9% of arteries with D max ≥20 Gy. CONCLUSIONS: In this preclinical model of proton beam cardiac radioablation, coronary stenoses occurred in a dose-dependent manner, with D max showing the closest correlation with stenosis ≥75%. These data provide for the first time a framework for dose constraint considerations for the coronary arteries during treatment planning for cardiac radioablation and thoracic malignancy radiation.

Background: Cardiac radioablation (CRA) is emerging as a treatment modality for refractory ventricular tachycardia (VT). This study aimed to evaluate the effects of radiation on the coronary arteries in a swine model of proton beam CRA. Methods: Eighteen domestic swine underwent 30–40 Gy pencil-beam scanning proton therapy in a single-fraction targeting the left ventricle with no attempt to spare coronary arteries and were euthanized 12-40 weeks later. Contrast-enhanced cardiac computed tomography (CT) was performed at baseline for treatment planning and at study end. Using dose-volume histograms, the maximum point (D max ), mean (D mean ) doses and the minimal doses received by the highest irradiated volumes of 0.01 cc (D 0.01cc ) for the left main, left anterior descending, circumflex, and right coronary artery, as well as the large diagonal and obtuse marginal branches were calculated. The D max location for each artery was mapped from the baseline planning CT onto the follow-up CT using deformable registration. Coronary artery segments were harvested from the D max sites for histological analysis. Receiver operating characteristic (ROC) analysis was performed to identify dose thresholds for predicting histologically severe coronary stenoses (≥75%). Results: Ninety-six coronary artery segments were analyzed. No stenoses were observed by CT imaging before irradiation. By histological analysis post-euthanasia, 25/96 (26%) coronary segments sampled at the Dmax site per artery had ≥75% stenosis. The median D max was 4.7 Gy for the <75% stenosis group and 29.7 Gy for the ≥75% stenosis group (p<0.001). The AUC-ROC for the association between D max and severe stenosis was 92.2%. A D max value of 20.1 Gy in a single fraction best predicted severe stenosis, with sensitivity of 92.3% and specificity of 87.1%. The AUC-ROC for the association between severe stenosis versus D mean and D 0.01cc was 84.8% and 91.6%, respectively. Based on histopathologic analysis, intimal hyperplasia was the most common coronary artery abnormality at the D max sites. Conclusion: In this pre-clinical model of proton beam CRA, coronary stenoses occurred in a dose-dependent manner, with D max being a better dosimetric predictor of stenosis than D mean and D 0.01cc . These data provide for the first time radiation dose constraint information for the epicardial coronary arteries that can be considered in treatment planning for CRA and radiation for thoracic malignancies.

Abstract Background Proton therapy offers precise tumor targeting while minimizing damage to surrounding healthy tissue, making it especially valuable for treating tumors near critical organs and in pediatric patients. However, its success depends on accurate beam delivery, requiring rigorous quality assurance (QA) to maintain treatment precision and effectiveness. Purpose This study aims to standardize the measurement of key aspects of proton therapy delivery, such as gantry and couch isocentricity, spot position accuracy, and spot size consistency. The goal is to enhance the delivery accuracy of proton therapy across various clinical settings, improving patient outcomes. Methods The QA framework uses the Octopoint phantom, Gafchromic film, and spot position monitor (SPM) log data to evaluate proton beam isocentricity, spot position, and spot size. The Octopoint phantom, made from acrylic, was used with Gafchromic films at various gantry and couch angles to measure isocentricity. MATLAB tools were used to analyze spot positions, and SPM logs provided verification. Sensitivity tests were conducted to assess the system's response to intentional shifts and errors, ensuring alignment with clinical QA standards. Results The Octopoint phantom's stepwise two‐dimensional (2D) fitting process, validated against film‐measured dose profiles, accurately identified beam and ball bearing (BB) centroid locations. Isocentricity tests conducted over 8 months across four gantries demonstrated consistent beam‐to‐BB radial offsets. The phantom showed excellent repeatability, with a maximum standard deviation of 0.1 mm across various couch‐gantry combinations. Sensitivity testing across all axes revealed a strong alignment between intended shifts and measured values. Over the course of a year, film measurements tracked spot position and size consistency, with deviations remaining within acceptable clinical limits. Comparisons with SPM data further confirmed the system's reliability in maintaining beam accuracy across different gantry angles and energy levels. Conclusions This study presents a reliable QA framework for ensuring precision in proton therapy delivery. By combining the Octopoint phantom, Gafchromic film analysis, and SPM log file evaluation, we effectively measured isocentricity, spot position accuracy, and spot size stability. The framework demonstrated adaptability across various clinical QA tasks, enhancing the accuracy and safety of proton therapy treatments.

Background: Proton beam irradiation to the ventricular myocardium may enable non-invasive targeting of ventricular tachycardia. Previous work has demonstrated the feasibility of imaging ablation lesion with late gadolinium enhanced (LGE) cardiac magnetic resonance imaging (MRI). Hypothesis: We hypothesize that proton beam irradiation will lead to progressively increasing density of LGE corresponding to lesion formation during follow-up after treatment delivery. Aim: The aim of the current study was to determine the time course of LGE intensity in ventricular myocardium following proton beam therapy. Methods: Eleven swine were irradiated with 40 Gy proton beam in the anterior or lateral left ventricular (LV) followed by LGE cardiac MRI every 4 weeks for up to 24 weeks. After manual contouring of the endocardial and epicardial myocardium, a region of interest (ROI) in the area irradiated with 0-5 Gy was contoured (remote ROI). The mean and standard deviation (SD) of the signal intensity (SI) of the remote ROI were calculated. Light LGE was defined as voxels with SI > mean+2SD but < mean+3SD of the remote ROI, while voxels with SI > mean+3SD of the remote ROI were classified as having dense LGE. Voxels identified as bright due to image artifacts or noise were manually removed. The analysis was conducted in a fashion blinded to swine ID and time point after irradiation. Results: A total of 33 time points were analyzed (3.1 ± 1.4 MRI studies per swine). Figure 1A shows a representative time course of LGE in the same swine, progressing from diffuse light LGE at 8 weeks to dense LGE at 16-24 weeks. Figure 1B demonstrates the proportion of light versus dense LGE across timepoints in irradiated myocardial regions. At 8 weeks, light and dense LGE areas were evenly distributed. At 12 to 24 weeks, dense LGE increased to approximately 75%. The proportion of dense versus light LGE was significantly higher at 12, 16, and 24 weeks, as compared to 8 weeks. Conclusion: In ventricular myocardium, diffuse light LGE evident at 8 weeks progresses to denser LGE at 12-24 weeks following proton beam irradiation corresponding with lesion formation.

Abstract Background This study aimed to determine whether proton craniospinal irradiation (CSI) decreased the dose to normal tissue and resulted in less toxicity than photon CSI for adult patients. Methods This single-institution retrospective analyzed differences in radiation doses, acute toxicity, and cost between proton and CSI for adult medulloblastoma patients. Results Of 39 total patients, 20 were treated with photon CSI prior to 2015, and 19 were treated with proton CSI thereafter. Median age was 28 years (range 18–66). The molecular subtype was most commonly sonic hedgehog (68%). Patients most commonly received 36 Gy CSI in 20 fractions with a boost to 54–55.8 Gy (92%). Proton CSI delivered significantly lower mean doses to cochleae, lacrimal glands, lens, parotid glands, pharyngeal constrictors, esophagus, lungs, liver, and skin (all P &lt; .001). Patients receiving proton CSI had significantly lower rates of acute dysphagia of any grade (5% versus 35%, P = .044) and decreased median weight loss during radiation (+1.0 versus –2.8 kg, P = .011). Weight loss was associated with acute hospitalization (P = .009). Median follow-up was 2.9 and 12.9 years for proton and photon patients, respectively, limiting late toxicity and outcome comparisons. At the last follow-up, 5 photon patients had died (2 of progressive disease, 3 without recurrence ages 41–63) and 21% had experienced major cardiovascular events. At 10 years, 89% were alive and 82% were recurrence free. Conclusions This study demonstrates dosimetric improvements with proton CSI, potentially leading to decreased acute toxicity including dysphagia and weight loss during treatment.

Background: Particle therapy is a noninvasive, catheter-free modality for cardiac ablation. We previously demonstrated the efficacy for creating ablation lesions in the porcine heart. Despite several earlier studies, the exact mechanism of early biophysical effects of proton and photon beam delivery on the myocardium remain incompletely resolved. Methods: Ten normal and 9 infarcted in situ porcine hearts received proton beam irradiation (40 Gy) delivered to the left ventricular myocardium with follow-up for 8 weeks. High-resolution electroanatomical mapping of the left ventricular was performed at baseline and follow-up. Bipolar voltage amplitude, conduction velocity, and connexin-43 were determined within the irradiated and nonirradiated areas. Results: The irradiated area in normal hearts showed a significant reduction of bipolar voltage amplitude (10.1±4.9 mV versus 5.7±3.2, P <0.0001) and conduction velocity (85±26 versus 55±13 cm/s, P =0.03) beginning at 4 weeks after irradiation. In infarcted myocardium after irradiation, bipolar voltage amplitude of the infarct scar (2.0±2.9 versus 0.8±0.7 mV, P =0.008) was significantly reduced as well as the conduction velocity in the infarcted heart (43.7±15.7 versus 26.3±11.4 cm/s, P =0.02). There were no significant changes in bipolar voltage amplitude and conduction velocity in nonirradiated myocardium. Myocytolysis, capillary hyperplasia, and dilation were seen in the irradiated myocardium 8 weeks after irradiation. Active caspase-3 and reduction of connexin-43 expression began in irradiated myocardium 1 week after irradiation and decreased over 8 weeks. Conclusions: Irradiation of the myocardium with proton beams reduce connexin-43 expression, conduction velocity, and bipolar conducted electrogram amplitude in a large porcine model. The changes in biomarkers preceded electrophysiological changes after proton beam therapy.

AbstractBackground and purposeProton therapy is a key modality used in the treatment of ocular melanoma. Traditionally ocular sites are treated using a dedicated eyeline with a passively scattered proton beam and a brass aperture. This work aims to design and characterize a beam‐collimating aperture to treat ocular targets with a gantry‐based spot scanning proton beam.MethodsA plastic aperture system that slides into the gantry nozzle of a spot scanning proton beam was designed and constructed. It consists of an intermediate scraper layer to attenuate stray protons and a 3D‐printed patient‐specific aperture positioned 5.7 cm from the surface of the eye. The aperture system was modeled in TOPAS and Monte Carlo simulations were validated with film measurements. Two different spot configurations were investigated for treatment planning and characterized based on lateral penumbra, central axis (CAX) dose and relative efficiency. Alignment and leakage were investigated through experimental film measurements. Range was verified using a multi‐layer ionization chamber. Reference dose measurements were made with a PinPoint 3D ion chamber. Neutron dose was evaluated through Monte Carlo simulations.ResultsAperture alignment with radiation isocenter was determined to be within 0.31 mm at a gantry angle of 0°. A single‐spot configuration with a 10 mm diameter aperture yielded film‐measured lateral penumbras of 1 mm to 1.25 mm, depending on depth in the spread‐out Bragg peak. TOPAS simulations found that a single spot configuration results in a flat dose distribution for a 10 mm diameter aperture and provides a CAX dose of less than 106% for apertures less than 14 mm in diameter. For larger targets, adding four corner spots to fill in the dose distribution is beneficial. Trade‐offs between lateral penumbra, CAX dose and relative efficiency were characterized for different spot configurations and can be used for future clinical decision‐making. The aperture was experimentally determined to not affect proton beam range, and no concerning leakage radiation or neutron dose was identified. Reference dose measurements with a PinPoint ion chamber were within 2.1% of Monte Carlo calculated doses.ConclusionThe aperture system developed in this work provides a method of treating ocular sites on a gantry‐based spot scanning proton system. Additional work to develop compatible gaze tracking and gating infrastructure is ongoing.

Objectives: To assess if excess absolute risk (EAR) of radiation-induced solid cancer can be used to rank radiotherapy plans for treatment of Hodgkin lymphoma (HL) in a statistically significant way. Methods: EAR models, calibrated with data from the Life Span Study and HL survivors, have been incorporated into a voxelised risk-calculation software, which is used to compare four treatment modalities planned for five virtual HL patients. Organ-specific parameters are generated repeatedly in a Monte Carlo fashion to model their uncertainties. This in turn enables a quantitative estimation of the EAR uncertainties. Results: Parameter-driven uncertainties on total EAR are around 13%, decreasing to around 2–5% for relative EAR comparisons. Total EAR estimations indicate that intensity modulated proton therapy decreases the average risk by 40% compared to the intensity modulated radiation therapy plan, 28% compared to the volumetric modulated arc therapy plan whereas the three-dimensional conformal radiation therapy plan is equivalent within the uncertainty. Conclusion: Relative EAR is a useful metric for distinguishing between radiotherapy plans in terms of second cancer risk. Advances in knowledge: Relative EAR is not dominated by model or parameter uncertainties and can be used to guide the choice of radiotherapy for HL patients.

Background: Proton beam therapy offers radiophysical properties that are appealing for noninvasive arrhythmia elimination. This study was conducted to use scanned proton beams for ablation of cardiac tissue, investigate electrophysiological outcomes, and characterize the process of lesion formation in a porcine model using particle therapy. Methods: Twenty-five animals received scanned proton beam irradiation. ECG-gated computed tomography scans were acquired at end-expiration breath hold. Structures (atrioventricular junction or left ventricular myocardium) and organs at risk were contoured. Doses of 30, 40, and 55 Gy were delivered during expiration to the atrioventricular junction (n=5) and left ventricular myocardium (n=20) of intact animals. Results: In this study, procedural success was tracked by pacemaker interrogation in the atrioventricular junction group, time-course magnetic resonance imaging in the left ventricular group, and correlation of lesion outcomes displayed in gross and microscopic pathology. Protein extraction (active caspase-3) was performed to investigate tissue apoptosis. Doses of 40 and 55 Gy caused slowing and interruption of cardiac impulse propagation at the atrioventricular junction. In 40 left ventricular irradiated targets, all lesions were identified on magnetic resonance after 12 weeks, being consistent with outcomes from gross pathology. In the majority of cases, lesion size plateaued between 12 and 16 weeks. Active caspase-3 was seen in lesions 12 and 16 weeks after irradiation but not after 20 weeks. Conclusions: Scanned proton beams can be used as a tool for catheter-free ablation, and time-course of tissue apoptosis was consistent with lesion maturation.

AbstractBackgroundA proton therapy system with 190° gantries uses robotic couch rotations to change the treatment beam laterality. Couch rotations are typically validated clinically with post‐rotation radiographic imaging.AimsThis study assesses the specificity and sensitivity of a commercial 3D surface imaging system, AlignRT (Vision RT, London UK) for validating couch rotations.Materials & MethodsIn clinical operation, a reference surface image of the patient is acquired after radiographic setup with couch at 270°, perpendicular to the gantry axis of rotation. The couch is then rotated ±90° to a typical treatment angle, and AlignRT reports a 3D displacement vector. Patient motion, changes in patient surface, non‐coincidence between AlignRT and couch isocenter, and mechanical couch run‐out all contribute to the 3D vector magnitude. To assess AlignRT sensitivity in detecting couch run‐out, volunteers were positioned orthogonal to the proton gantry and reference surface images were captured without x‐ray localization. Subjects were repeatedly rotated ±90⁰ to typical treatment angles and displacement vectors were recorded. Additionally, measurements were performed in which intentional translations of 2, 4, 6, and 8 mm were combined with the intended isocentric rotations. Data sets were collected using a phantom; subjects with a thoracic isocenter and no immobilization; and subjects with a cranial isocenter and thermoplastic immobilization. A total of 300 rotations were measured.ResultsDuring isocentric rotations, the mean AlignRT displacement vectors for the phantom, immobilized, and non‐immobilized volunteers were 0.1 ± 0.1 mm, 0.8 ± 0.1 mm, and 1.1 ± 0.2 mm respectively. 95% of the AlignRT measurements for the immobilized and non‐immobilized subjects were within 1 mm and 2 mm of the actual displacement respectively.DiscussionAfter characterizing the accuracy using phantoms and volunteers, we have shown that a three‐pod surface imaging system can be used to identify gross non‐isocentric patient rotations. Significant positional deviations, either due to improper couch rotation or patient motion, should be followed by radiographic imaging and repositioning.ConculsionAlignRT can be used to verify patient positioning following couch rotations that are applied after the initial x‐ray guided patient setup. Using a three‐pod AlignRt system, positional deviations exceeding 4 mm were flagged with sensitivity and specificity of 90% and 100% respectively.