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PurposeThe ongoing lack of data standardization severely undermines the potential for automated learning from the vast amount of information routinely archived in electronic health records (EHRs), Radiation Oncology Information Systems (ROIS), treatment planning systems (TPSs), and other cancer care and outcomes databases. The effort sought to create a standardized ontology for clinical data, social determinants of health (SDOH), and other radiation oncology concepts and interrelationships.Methods and materialsThe American Association of Physicists in Medicine's (AAPM's) Big Data Science Committee (BDSC) was initiated July of 2019 to explore common ground from the stakeholders' collective experience of issues that typically compromise the formation of large inter- and intra- institutional databases from EHRs. The BDSC adopted an iterative, cyclical approach to engaging stakeholders beyond its membership to optimize the integration of diverse perspectives from the community.ResultsWe developed the Operational Ontology for Oncology (O3) which identified 42 key elements, 359 attributes, 144 value sets, and 155 relationships ranked in relative importance of clinical significance, likelihood of availability in EHRs, or the ability to modify routine clinical processes to permit aggregation. Recommendations are provided for best use and development of the O3 to four constituencies: device manufacturers, centers of clinical care, researchers, and professional societies.ConclusionsO3 is designed to extend and interoperate with existing global infrastructure and data science standards. The implementation of these recommendations will lower the barriers for aggregation of information that could be used creating large, representative, findable, accessible, interoperable and reusable (FAIR) datasets supporting the scientific objectives of grant programs. The construction of comprehensive "real world" datasets and application of advanced analytic techniques, including artificial intelligence (AI), holds the potential to revolutionize patient management and improve outcomes by leveraging increased access to information derived from larger, more representative datasets.

Purpose: To report clinical and dosimetric characteristics of 5-fraction stereotactic ablative radiotherapy (SABR) using intensity modulated proton therapy (IMPT) for localized prostate cancer., Materials and Methods: All patients receiving IMPT SABR from 2017 to 2021 for localized prostate cancer at our institution were included. Five fractions were delivered every other day to the prostate +/- seminal vesicles [clinical target volume (CTV)] with 3 mm/3% robustness. A 4-field arrangement with 2 anterior oblique and 2 opposed lateral beams was used in most patients (97%), and most (99%) had a retroprostatic hydrogel spacer., Results: A total of 534 patients with low (14%), favorable intermediate (45%), unfavorable intermediate (36%), high (4.0%), or very high-risk (0.6%) disease are evaluated. Prescription dose was 36.25 Gy (31%), 38 Gy (38%), or 40 Gy (31%) was prescribed. Median volume percentage of CTV receiving at least 100% of prescription dose [V100% (%)] was 100% [interquartile range: 99.99-100]. Rectum V50% (%), V80% (%), and V90% (%) were significantly lower in patients who had spacer, with a mean difference of -9.70%, -6.59%, and -4.42%, respectively, compared to those who did not have spacer. Femoral head dose was lower with a 4-field arrangement. Mean differences in left and right femoral head V40% (%) were -6.99% and -10.74%, respectively., Conclusion: We provide a large, novel report of patients treated with IMPT SABR for localized prostate cancer. Four-field IMPT with hydrogel spacer provides significant sparing of rectum and femoral heads without compromising target coverage., Competing Interests: The authors have no conflicts to disclose., (© 2024 The Author(s).)

Purpose: The breakpoint for a 360° radiotherapy gantry is typically positioned at 180°. This arbitrary setting has not been systematically evaluated for efficiency and may cause redundant gantry rotation and extended setup times. Our study aimed to identify an optimal gantry breakpoint angle for a full-gantry proton therapy system, with the goal of minimizing gantry movement., Materials and Methods: We analyzed 70 months of clinically delivered proton therapy plans (9152 plans, 131 883 fractions), categorizing them by treatment site and mapping the fields from a partial-gantry to full-gantry orientation. For each delivered fraction, we computed the minimum total gantry rotation angle as a function of gantry breakpoint position, which was varied between 0° and 360° in 1° steps. This analysis was performed separately within the entire plan cohort and individual treatment sites, both with and without the capability of over-rotating 10° past the breakpoint from either direction (20° overlap). The optimal gantry breakpoint was identified as one which resulted in a low average gantry rotation per fraction., Results: Considering mechanical constraints, 130° was identified as a reasonable balance between increased gantry-rotation efficiency and practical treatment considerations. With a 20° overlap, this selection reduced the average gantry rotation by 41.4° per fraction when compared to the standard 180° breakpoint. Disease site subgroups showed the following reduction in average gantry rotation: gastrointestinal 192.2°, thoracic 56.3°, pediatric 44.9°, genitourinary 19.9°, central nervous system 10.7°, breast 2.8°, and head and neck 0.1°., Conclusion: For a full-gantry system, a breakpoint of 130° generally outperforms the conventional 180° breakpoint. This reduction is particularly impactful for gastrointestinal, pediatric, and thoracic sites, which constitute a significant proportion of cases at our center. The adjusted breakpoint could potentially streamline patient delivery, alleviate mechanical wear, and enhance treatment precision by reducing the likelihood of patient movement during delivery., (© 2024 The Author(s).)

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  < .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., Competing Interests: None of the authors reported conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Purpose: The ongoing lack of data standardization severely undermines the potential for automated learning from the vast amount of information routinely archived in electronic health records (EHRs), radiation oncology information systems, treatment planning systems, and other cancer care and outcomes databases. We sought to create a standardized ontology for clinical data, social determinants of health, and other radiation oncology concepts and interrelationships., Methods and Materials: The American Association of Physicists in Medicine's Big Data Science Committee was initiated in July 2019 to explore common ground from the stakeholders' collective experience of issues that typically compromise the formation of large inter- and intra-institutional databases from EHRs. The Big Data Science Committee adopted an iterative, cyclical approach to engaging stakeholders beyond its membership to optimize the integration of diverse perspectives from the community., Results: We developed the Operational Ontology for Oncology (O3), which identified 42 key elements, 359 attributes, 144 value sets, and 155 relationships ranked in relative importance of clinical significance, likelihood of availability in EHRs, and the ability to modify routine clinical processes to permit aggregation. Recommendations are provided for best use and development of the O3 to 4 constituencies: device manufacturers, centers of clinical care, researchers, and professional societies., Conclusions: O3 is designed to extend and interoperate with existing global infrastructure and data science standards. The implementation of these recommendations will lower the barriers for aggregation of information that could be used to create large, representative, findable, accessible, interoperable, and reusable data sets to support the scientific objectives of grant programs. The construction of comprehensive "real-world" data sets and application of advanced analytical techniques, including artificial intelligence, holds the potential to revolutionize patient management and improve outcomes by leveraging increased access to information derived from larger, more representative data sets., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Purpose: Proton 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., Methods: A 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., Results: Aperture 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., Conclusion: The 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., (© 2023 American Association of Physicists in Medicine.)

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., Competing Interests: Disclosures Dr Packer in the past 12 months has provided consulting services for Abbott, ArtFix, Biosense Webster Inc, External Beam Ablation Med (EBAmed), Maxwell Biomed, MediaSphere Medical, LLC, MedLumics, Medtronic, St. Jude Medical, Siemens, Sanofi, Thermedical, and Wave Strategy. Dr Packer received no personal compensation for these consulting activities unless noted. Dr Packer receives research funding from the Abbott, Biosense Webster, Boston Scientific/EPT, CardioInsight, EBAmed, Medtronic Inc, Siemens, St. Jude Medical Inc, Thermedical Inc, National Institutes of Health (NIH), Robertson Foundation, Vital Project Funds Inc, Mr and Mrs J. Michael Cook/Fund. Mayo Clinic and Dr Packer have a financial interest in Analyze-AVW technology that may have been used to analyze some of the heart images in this research. In accordance with the Bayh-Dole Act, this technology has been licensed to commercial entities, and both Mayo Clinic and Dr Packer have received royalties less than $10 000, the federal threshold for significant financial interest. In addition, Mayo Clinic holds an equity position in the company to which the AVW technology has been licensed. Dr Packer and Mayo Clinic jointly have equity in a privately held company, EBAmed, and has received stock options from Neutrace, ArtFix Ltd, and Xenter Inc. Dr Packer has a licensing agreement with the American Heart Association and Medtronic Inc, for the Mayo Atrial Fibrillation Symptom Inventory (MAFSI) Survey and has contractual rights to receive future royalties under this license. Royalties from Wiley & Sons, Oxford, and St. Jude Medical. The other authors report no conflicts.

Purpose: Finite proton range affords improved dose conformality of radiation therapy when patient regions-of-interest geometries are well characterized. Substantial changes in patient anatomy necessitate re-planning (RP) to maintain effective, safe treatment. Regularly planned verification scanning (VS) is performed to ensure consistent treatment quality. Substantial resources, however, are required to conduct an effective proton plan verification program, which includes but is not limited to, additional computed tomography (CT) scanner time and dedicated personnel: radiation therapists, medical physicists, physicians, and medical dosimetrists., Materials and Methods: Verification scans (VSs) and re-plans (RPs) of 711 patients treated with proton therapy between June 2015 and June 2018 were studied. All treatment RP was performed with the intent to maintain original plan integrity and coverage. The treatments were classified by anatomic site: brain, craniospinal, bone, spine, head and neck (H&N), lung or chest, breast, prostate, rectum, anus, pelvis, esophagus, liver, abdomen, and extremity. Within each group, the dates of initial simulation scan, number of VSs, number of fractions completed at the time of VS, and the frequency of RP were collected. Data were analyzed in terms of rate of RP and individual likelihood of RP., Results: A total of 2196 VSs and 201 RPs were performed across all treatment sites. H&N and lung or chest disease sites represented the largest proportion of plan modifications in terms of rate of re-plan (RoR: 54% and 58%, respectively) and individual likelihood of RP on a per patient basis (likelihood of RP [RP%]: 46% and 39%, respectively). These sites required RP beyond 4 weeks of treatment, suggesting continued benefit for frequent, periodic VS. Disease sites in the lower pelvis demonstrated a low yield for RP per VS (0.01-0.02), suggesting that decreasing VS frequency, particularly late in treatment, may be reasonable., Conclusions: A large degree of variation in RoR and individual RP% was observed between anatomic treatment sites. The present retrospective analysis provides data to help develop anatomic site-based VS protocols., Competing Interests: Conflicts of Interest: Anita Mahajan, MD, is an Associate Editor of the International Journal of Particle Therapy. The authors have no other relevant conflicts of interest to disclose., (©Copyright 2022 The Author(s).)

Pseudolipomas are an uncommon clinical manifestation appearing as a non-encapsulated prominence of subcutaneous fat on MRI. Post-traumatic pseudolipomas (PTLs) are thought to arise from neoadipogenesis following acute or chronic trauma. These are most commonly located on the lower extremities, gluteal, and trochanteric regions. Here, we report a case of PTL in a high school athlete, arising in the posterior neck after weight training with performing barbell squats without neck padding. To our knowledge, this case represents a novel association between PTLs and weight training exercises., (© 2021 The Authors. Published by the British Institute of Radiology.)

Patient wait time can negatively impact treatment quality in a proton therapy center, where multiple treatment rooms share one proton beam. Wait time increases patient discomfort that can lead to patient motion, dissatisfaction, and longer treatment delay. This study was to develop a patient call-back model that reduced patient wait while efficiently utilizing the proton beam. A "Gatekeeper" logic allowing therapists to adjust the time of a patient's call-back to the treatment room was developed. It uses a two-pronged approach to minimize overlap of long treatment and the possibility of excessive wait in the queue to receive the proton beam. The goal was to reduce the maximum wait time to less than eight minutes per field for a four-room facility. The effectiveness of this logic was evaluated through simulation, and five scenarios were compared. Four scenarios implementing various levels of gatekeeper logic were compared with the original scenario without the logic. The best performing model provided a reduction of the maximum field wait by 26% and met the predefined goal. Adjusting call-back extended the treatment day length by an average of 6 min and a maximum of 12 min in total. The use of this gatekeeper logic significantly reduces patient field wait with minimal impact on treatment day length for a four-room proton facility. A sample interface that adopts this logic for therapists to make informed decision on patient call-back time is demonstrated., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Scar-related ventricular arrhythmias are common after myocardial infarction. Catheter ablation can improve prognosis, but the procedure is invasive and results are not always satisfactory. Noninvasive, catheter-free ablation using ionizing radiation has recently gained interest among electrophysiologists, but the tissue effects and physiological outcome have not been fully characterized., Objective: The purpose of this study was to investigate the structural effects of cardiac scanned pencil beam proton therapy on infarct scar, the time course of imaging biomarkers, arrhythmias, and cardiac function in a porcine model., Methods: Fourteen infarcted swine underwent proton beam treatment of the scar (40 or 30 Gy) and were followed for up to 30 weeks. Magnetic resonance imaging was performed every 4 weeks., Results: Treated scar areas showed a significantly lower fraction of surviving myocytes at 30 weeks compared to untreated scar (30.1% ± 18.5% and 59.9% ± 10.1% in treated and untreated infarct, respectively), indicating scar homogenization. Four animals died suddenly during follow-up, all from documented monomorphic ventricular tachycardia. Cardiac function remained stable over the course of the study. Distinct imaging morphologies corresponded to certain tissue dose ranges and time points., Conclusion: Radioablation of cardiac infarct scar leads to significant homogenization of the scar, replicating the histologic effects of radiofrequency ablation. These changes correspond to distinct imaging morphologies on delayed contrast-enhanced cardiac magnetic resonance imaging, enabling noninvasive confirmation of tissue ablation effects The present study is the first to thoroughly investigate the structural effects of cardiac proton beam therapy in infarcted myocardium., (Copyright © 2020 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

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.

Background: A 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., Aims: This study assesses the specificity and sensitivity of a commercial 3D surface imaging system, AlignRT (Vision RT, London UK) for validating couch rotations., Materials & Methods: In 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., Results: During 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., Discussion: After 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., Conculsion: AlignRT 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., (© 2020 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, Inc. on behalf of American Association of Physicists in Medicine.)

Seventy-six FDA-approved oncology drugs and emerging therapeutics were evaluated in 25 multiple myeloma (MM) and 15 non-Hodgkin's lymphoma cell lines and in 113 primary MM samples. Ex vivo drug sensitivities were mined for associations with clinical phenotype, cytogenetic, genetic mutation, and transcriptional profiles. In primary MM samples, proteasome inhibitors, dinaciclib, selinexor, venetoclax, auranofin, and histone deacetylating agents had the broadest cytotoxicity. Of interest, newly diagnosed patient samples were globally less sensitive especially to bromodomain inhibitors, inhibitors of receptor tyrosine kinases or non-receptor kinases, and DNA synthesis inhibitors. Clustering demonstrated six broad groupings of drug sensitivity linked with genomic biomarkers and clinical outcomes. For example, our findings mimic clinical observations of increased venetoclax responsiveness in t(11;14) patients but also identify an increased sensitivity profile in untreated patients, standard genetic risk, low plasma cell S-Phase, and in the absence of Gain(1q) and t(4;14). In contrast, increased ex vivo responsiveness to selinexor was associated with biomarkers of poor prognosis and later relapse patients. This "direct to drug" screening resource, paired with functional genomics, has the potential to successfully direct appropriate individualized therapeutic approaches in MM and to enrich clinical trials for likely responders.

Background: Noninvasive cardiac ablation of ventricular tachycardia (VT) using radiotherapy has recently gained interest among electrophysiologists. The effects of left ventricular (LV) ablative radiation treatment on global LV function and volumes are unknown., Objective: The purpose of this study was to investigate the effects of noninvasive ablation on LV function over time., Methods: Twenty domestic swine underwent proton beam treatment of LV sites in a dose-finding design and were followed for up to 40 weeks by cardiac magnetic resonance imaging at 4-week intervals. Doses investigated were either 40 Gy at 1 site (n = 8) or 30 Gy at 2 sites (n = 4) in the low-dose group and 40 Gy at 3 sites (n = 8) in the high-dose group., Results: LV mean dose (13.2 ± 1.8 Gy vs 4.6 ± 1.8 Gy) and the volume receiving at least 20 Gy (V 20Gy ) (24.7% ± 4.8% vs 6.4% ± 3.0%) differed significantly between groups. Dose-dependent effects on left ventricular ejection fraction (LVEF) and LV end-diastolic volume became manifest about 3 months after treatment. LVEF decline was correlated to mean dose (correlation coefficient ρ = -0.69; P = .008) and V 20Gy (ρ = -0.66; P = .01), as was LV dilation (ρ = 0.72; P = .005; and ρ = 0.75, P = .003 respectively)., Conclusion: Possible adverse effects on LV function, seen about 3 months after treatment, are dose dependent. Therefore, precise target definition and focused energy delivery are paramount in catheter-free ablation., (Copyright © 2019 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Purpose: To quantify the effects of combining layer-based repainting and respiratory gating as a strategy to mitigate the dosimetric degradation caused by the interplay effect between a moving target and dynamic spot-scanning proton delivery., Methods: An analytic routine modeled three-dimensional dose distributions of pencil-beam proton plans delivered to a moving target. Spot positions and weights were established for a single field to deliver 100 cGy to a static, 15-cm deep, 3-cm radius spherical clinical target volume with a 1-cm isotropic internal target volume expansion. The interplay effect was studied by modeling proton delivery from a clinical synchrotron-based spot scanning system and respiratory target motion, patterned from surrogate patient breathing traces. Motion both parallel and orthogonal to the beam scanning direction was investigated. Repainting was modeled using a layer-based technique. For each of 13 patient breathing traces, the dose from 20 distinct delivery schemes (combinations of four gate window amplitudes and five repainting techniques) was computed. Delivery strategies were inter-compared based on target coverage, dose homogeneity, high dose spillage, and delivery time., Results: Notable degradation and variability in plan quality were observed for ungated delivery. Decreasing the gate window reduced this variability and improved plan quality at the expense of longer delivery times. Dose deviations were substantially greater for motion orthogonal to the scan direction when compared with parallel motion. Repainting coupled with gating was effective at partially restoring dosimetric coverage at only a fraction of the delivery time increase associated with very small gate windows alone. Trends for orthogonal motion were similar, but more complicated, due to the increased severity of the interplay., Conclusions: Layer-based repainting helps suppress the interplay effect from intra-gate motion, with only a modest penalty in delivery time. The magnitude of the improvement in target coverage is strongly influenced by individual patient breathing patterns and the tumor motion trajectory., (© 2019 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, Inc. on behalf of American Association of Physicists in Medicine.)

Purpose: The aim of this work is to describe the clinical implementation of respiratory-gated spot-scanning proton therapy (SSPT) for the treatment of thoracic and abdominal moving targets. The experience of our institution is summarized, from initial acceptance and commissioning tests to the development of standard clinical operating procedures for simulation, motion assessment, motion mitigation, treatment planning, and gated SSPT treatment delivery., Materials and Methods: A custom respiratory gating interface incorporating the Real-Time Position Management System (RPM, Varian Medical Systems, Inc., Palo Alto, CA, USA) was developed in-house for our synchrotron-based delivery system. To assess gating performance, a motion phantom and radiochromic films were used to compare gated vs nongated delivery. Site-specific treatment planning protocols and conservative motion cutoffs were developed, allowing for free-breathing (FB), breath-holding (BH), or phase-gating (Ph-G). Room usage efficiency of BH and Ph-G treatments was retrospectively evaluated using beam delivery data retrieved from our record and verify system and DICOM files from patient-specific quality assurance (QA) procedures., Results: More than 70 patients were treated using active motion management between the launch of our motion mitigation program in October 2015 and the end date of data collection of this study in January 2018. During acceptance procedures, we found that overall system latency is clinically-suitable for Ph-G. Regarding room usage efficiency, the average number of energy layers delivered per minute was <10 for Ph-G, 10-15 for BH and ≥15 for FB, making Ph-G the slowest treatment modality. When comparing to continuous delivery measured during pretreatment QA procedures, the median values of BH treatment time were extended from 6.6 to 9.3 min (+48%). Ph-G treatments were extended from 7.3 to 13.0 min (+82%)., Conclusions: Active motion management has been crucial to the overall success of our SSPT program. Nevertheless, our conservative approach has come with an efficiency cost that is more noticeable in Ph-G treatments and should be considered in decision-making., (© 2019 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, Inc. on behalf of American Association of Physicists in Medicine.)

The purpose of this work was to develop an end-to-end patient-specific quality assurance (QA) technique for spot-scanned proton therapy that is more sensitive and efficient than traditional approaches. The patient-specific methodology relies on independently verifying the accuracy of the delivered proton fluence and the dose calculation in the heterogeneous patient volume. A Monte Carlo dose calculation engine, which was developed in-house, recalculates a planned dose distribution on the patient CT data set to verify the dose distribution represented by the treatment planning system. The plan is then delivered in a pre-treatment setting and logs of spot position and dose monitors, which are integrated into the treatment nozzle, are recorded. A computational routine compares the delivery log to the DICOM spot map used by the Monte Carlo calculation to ensure that the delivered parameters at the machine match the calculated plan. Measurements of dose planes using independent detector arrays, which historically are the standard approach to patient-specific QA, are not performed for every patient. The nozzle-integrated detectors are rigorously validated using independent detectors in regular QA intervals. The measured data are compared to the expected delivery patterns. The dose monitor reading deviations are reported in a histogram, while the spot position discrepancies are plotted vs. spot number to facilitate independent analysis of both random and systematic deviations. Action thresholds are linked to accuracy of the commissioned delivery system. Even when plan delivery is acceptable, the Monte Carlo second check system has identified dose calculation issues which would not have been illuminated using traditional, phantom-based measurement techniques. The efficiency and sensitivity of our patient-specific QA program has been improved by implementing a procedure which independently verifies patient dose calculation accuracy and plan delivery fidelity. Such an approach to QA requires holistic integration and maintenance of patient-specific and patient-independent QA., Competing Interests: The authors have declared that no competing interests exist.

Purpose: Photon counting detectors (PCDs) are being introduced in advanced x-ray computed tomography (CT) scanners. From a single PCD-CT acquisition, multiple images can be reconstructed, each based on only a part of the original x-ray spectrum. In this study, we investigated whether PCD-CT can be used to estimate stopping power ratios (SPRs) for proton therapy treatment planning, both by comparing to other SPR methods proposed for single energy CT (SECT) and dual energy CT (DECT) as well as to experimental measurements., Methods: A previously developed DECT-based SPR estimation method was adapted to PCD-CT data, by adjusting the estimation equations to allow for more energy spectra. The method was calibrated directly on noisy data to increase the robustness toward image noise. The new PCD SPR estimation method was tested in theoretical calculations as well as in an experimental setup, using both four and two energy bin PCD-CT images, and through comparison to two other SPR methods proposed for SECT and DECT. These two methods were also evaluated on PCD-CT images, full spectrum (one-bin) or two-bin images, respectively. In a theoretical framework, we evaluated the effect of patient-specific tissue variations (density and elemental composition) and image noise on the SPR accuracy; the latter effect was assessed by applying three different noise levels (low, medium, and high noise). SPR estimates derived using real PCD-CT images were compared to experimentally measured SPRs in nine organic tissue samples, including fat, muscle, and bone tissues., Results: For the theoretical calculations, the root-mean-square error (RMSE) of the SPR estimation was 0.1% for the new PCD method using both two and four energy bins, compared to 0.2% and 0.7% for the DECT- and SECT-based method, respectively. The PCD method was found to be very robust toward CT image noise, with a RMSE of 2.7% when high noise was added to the CT numbers. Introducing tissue variations, the RMSE only increased to 0.5%; even when adding high image noise to the changed tissues, the RMSE stayed within 3.1%. In the experimental measurements, the RMSE over the nine tissue samples was 0.8% when using two energy bins, and 1.0% for the four-bin images., Conclusions: In all tested cases, the new PCD method produced similar or better results than the SECT- and DECT-based methods, showing an overall improvement of the SPR accuracy. This study thus demonstrated that PCD-CT scans will be a qualified candidate for SPR estimations., (© 2018 American Association of Physicists in Medicine.)

The charge of AAPM Task Group 113 is to provide guidance for the physics aspects of clinical trials to minimize variability in planning and dose delivery for external beam trials involving photons and electrons. Several studies have demonstrated the importance of protocol compliance on patient outcome. Minimizing variability for treatments at different centers improves the quality and efficiency of clinical trials. Attention is focused on areas where variability can be minimized through standardization of protocols and processes through all aspects of clinical trials. Recommendations are presented for clinical trial designers, physicists supporting clinical trials at their individual clinics, quality assurance centers, and manufacturers., (© 2018 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, Inc. on behalf of American Association of Physicists in Medicine.)

Background and Study Aims: Little consideration has been given to selection of endoscopic ultrasound-guided fiducials for proton radiotherapy and the resulting perturbations in the therapy dose and pattern. Our aim was to assess the impact of perturbations caused by six fiducials of different composition and dimensions in a phantom gel model., Materials and Methods:  The phantom was submerged in a water bath and irradiated with a uniform 10 cm × 10 cm field of 119.7 MeV monoenergetic spot scanning protons delivered through a 45 mm range shifter. The proton "Bragg Peak" was evaluated., Results:  Dose perturbations manifesting as dose reductions up to 30 % were observed. A carbon composite (1 × 5 mm) and gold (0.4 × 10 mm) fiducial with backload potential rather than dedicated EUS pre-loaded gold fiducial needles had the best performance in terms of minimizing the dose perturbation., Conclusions:  Our data demonstrate that a carbon composite fiducial has a less untoward effect on proton therapy dose distribution than dedicated EUS pre-loaded gold fiducial needles. Such information is important to consider when selecting fiducials specifically for proton therapy.

Purpose: To demonstrate the clinical efficacy and safety of a highly conformal, supine, hybrid forward and inverse planned intensity modulated radiation therapy (IMRT) technique for photon craniospinal irradiation (CSI)., Methods: Patients who received supine, hybrid IMRT CSI from 2009 to 2014 were included in this retrospective review. Clinical target volume (CTV) was defined as intracranial contents and thecal sac, including nerve roots. Dose was prescribed such that >99% of CTV received >99% of prescription and >95% of the planning target volume received >95% of prescription, with no attempt to include vertebral bodies. Lateral fields were utilized at the cranium and upper cervical spine. Spine fields were either single posterior or 2-3 obliques. Plans were generated with a hybrid of forward and inverse planned IMRT. Inferior borders of the cranium fields and superior border of the lower spine field were designed with 6-15 cm long, gradual dose gradients by sequential closing of multileaf collimator leaves using forward planned multiple static segment IMRT delivery. The sliding window upper spine IMRT field was created by the inverse planning system to match gradients of the brain and lower spine fields. The lower spine field gradient was similarly completed., Results: The cohort consisted of 34 patients. Median CSI dose was 36 Gy (range: 18-39.6 Gy). With a median follow up of 59.4 months, there were no isolated recurrences or spinal myelopathies at CTV margins or field gradients. Eleven patients had recurrence, all of which were intracranial., Conclusions: Our hybrid forward and inverse planned IMRT supine CSI technique did not result in any isolated recurrences or myelopathies at CTV margins or field gradients. This suggests our target volumes and blended gradients are appropriate for highly conformal three-dimensional planning.

Dual energy CT (DECT) has been shown, in theoretical and phantom studies, to improve the stopping power ratio (SPR) determination used for proton treatment planning compared to the use of single energy CT (SECT). However, it has not been shown that this also extends to organic tissues. The purpose of this study was therefore to investigate the accuracy of SPR estimation for fresh pork and beef tissue samples used as surrogates of human tissues. The reference SPRs for fourteen tissue samples, which included fat, muscle and femur bone, were measured using proton pencil beams. The tissue samples were subsequently CT scanned using four different scanners with different dual energy acquisition modes, giving in total six DECT-based SPR estimations for each sample. The SPR was estimated using a proprietary algorithm (syngo.via DE Rho/Z Maps, Siemens Healthcare, Forchheim, Germany) for extracting the electron density and the effective atomic number. SECT images were also acquired and SECT-based SPR estimations were performed using a clinical Hounsfield look-up table. The mean and standard deviation of the SPR over large volume-of-interests were calculated. For the six different DECT acquisition methods, the root-mean-square errors (RMSEs) for the SPR estimates over all tissue samples were between 0.9% and 1.5%. For the SECT-based SPR estimation the RMSE was 2.8%. For one DECT acquisition method, a positive bias was seen in the SPR estimates, having a mean error of 1.3%. The largest errors were found in the very dense cortical bone from a beef femur. This study confirms the advantages of DECT-based SPR estimation although good results were also obtained using SECT for most tissues.

Background: This study sought to investigate external photon beam radiation for catheter-free ablation of the atrioventricular junction in intact pigs., Methods and Results: Ten pigs were randomized to either sham irradiation or irradiation of the atrioventricular junction (55, 50, 40, and 25 Gy). Animals underwent baseline electrophysiological evaluation, cardiac gated multi-row computed tomographic imaging for beam delivery planning, and intensity-modulated radiation therapy. Doses to the coronary arteries were optimized. Invasive follow-up was conducted ≤4 months after the irradiation. A mean volume of 2.5±0.5 mL was irradiated with target dose. The mean follow-up length after irradiation was 124.8±30.8 days. Out of 7 irradiated animals, complete atrioventricular block was achieved in 6 animals of all 4 dose groups (86%). Using the same targeting margins, ablation lesion size notably increased with the delivered dose because of volumetric effects of isodose lines around the target volume. The mean macroscopically calculated atrial lesion volume for all 4 dose groups was 3.8±1.1 mL, lesions extended anteriorly into the interventricular septum. No short-term side effects were observed. No damage was observed in the tissues of the esophagus, phrenic nerves, or trachea. However, histology revealed in-field beam effects outside of the target volume., Conclusions: Single-fraction doses as low as 25 Gy caused a lesion with interruption of cardiac impulse propagation using this respective target volume. With doses of ≤55 Gy, maximal point-doses to coronary arteries could be kept <7Gy, but target conformity of lesions was not fully achieved using this approach., (© 2017 American Heart Association, Inc.)

Purpose: Delayed charge is a small amount of charge that is delivered to the patient after the planned irradiation is halted, which may degrade the quality of the treatment by delivering unwarranted dose to the patient. This study compares two methods for minimizing the effect of delayed charge on the dose delivered with a synchrotron based discrete spot scanning proton beam., Methods: The delivery of several treatment plans was simulated by applying a normally distributed value of delayed charge, with a mean of 0.001(SD 0.00025) MU, to each spot. Two correction methods were used to account for the delayed charge. Method one (CM1), which is in active clinical use, accounts for the delayed charge by adjusting the MU of the current spot based on the cumulative MU. Method two (CM2) in addition reduces the planned MU by a predicted value. Every fraction of a treatment was simulated using each method and then recomputed in the treatment planning system. The dose difference between the original plan and the sum of the simulated fractions was evaluated. Both methods were tested in a water phantom with a single beam and simple target geometry. Two separate phantom tests were performed. In one test the dose per fraction was varied from 0.5 to 2 Gy using 25 fractions per plan. In the other test the number fractions were varied from 1 to 25, using 2 Gy per fraction. Three patient plans were used to determine the effect of delayed charge on the delivered dose under realistic clinical conditions. The order of spot delivery using CM1 was investigated by randomly selecting the starting spot for each layer, and by alternating per layer the starting spot from first to last. Only discrete spot scanning was considered in this study., Results: Using the phantom setup and varying the dose per fraction, the maximum dose difference for each plan of 25 fractions was 0.37-0.39 Gy and 0.03-0.05 Gy for CM1 and CM2, respectively. While varying the total number of fractions, the maximum dose difference increased at a rate of 0.015 Gy and 0.0018 Gy per fraction for CM1 and CM2, respectively. For CM1, the largest dose difference was found at the location of the first spot in each energy layer, whereas for CM2 the difference in dose was small and showed no dependence on location. For CM1, all of the fields in the patient plans had an area where their excess dose overlapped. No such correlation was found when using CM2. Randomly selecting the starting spot reduces the maximum dose difference from 0.708 to 0.15 Gy. Alternating between first and last spot reduces the maximum dose difference from 0.708 to 0.37 Gy. In the patient plans the excess dose scaled linearly at 0.014 Gy per field per fraction for CM1 and standard delivery order., Conclusions: The predictive model CM2 is superior to a cumulative irradiation model CM1 for minimizing the effects of delayed charge, particularly when considering maximal dose discrepancies and the potential for unplanned hot-spots. This study shows that the dose discrepancy potentially scales at 0.014 Gy per field per fraction for CM1.

Over the past 20 years, several proton beam treatment programs have been implemented throughout the United States. Increasingly, the number of new programs under development is growing. Proton beam therapy has the potential for improving tumor control and survival through dose escalation. It also has potential for reducing harm to normal organs through dose reduction. However, proton beam therapy is more costly than conventional x-ray therapy. This increased cost may be offset by improved function, improved quality of life, and reduced costs related to treating the late effects of therapy. Clinical research opportunities are abundant to determine which patients will gain the most benefit from proton beam therapy. We review the clinical case for proton beam therapy. SUMMARY SENTENCE: Proton beam therapy is a technically advanced and promising form of radiation therapy.

Purpose: To investigate how the selection of ion type affects the calculated isoeffective dose to the surrounding normal tissue as a function of both normal tissue and target tissue α/β ratios., Methods and Materials: A microdosimetric biologic dose model was incorporated into a Geant4 simulation of parallel opposed beams of protons, helium, lithium, beryllium, carbon, and neon ions. The beams were constructed to give a homogeneous isoeffective dose to a volume in the center of a water phantom for target tissues covering a range of cobalt equivalent α/β ratios of 1-20 Gy. Concomitant normal tissue isoeffective doses in the plateau of the ion beam were then compared for different ions across the range of normal tissue and target tissue radiosensitivities for a fixed isoeffective dose to the target tissue., Results: The ion type yielding the optimal normal tissue sparing was highly dependent on the α/β ratio of both the normal and the target tissue. For carbon ions, the calculated isoeffective dose to normal tissue at a 5-cm depth varied by almost a factor of 5, depending on the α/β ratios of the normal and target tissue. This ranges from a factor of 2 less than the isoeffective dose of a similar proton treatment to a factor of 2 greater., Conclusions: No single ion is optimal for all treatment scenarios. The heavier ions are superior in cases in which the α/β ratio of the target tissue is low and the α/β ratio of normal tissue is high, and protons are superior in the opposite circumstances. Lithium and beryllium appear to offer dose advantages similar to carbon, with a considerably lower normal tissue dose when the α/β ratio in the target tissue is high and the α/β ratio in the normal tissue is low., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: To report on the sensitivity of single field planar measurements in identifying IMRT plans with poor calculational accuracy., Methods: Three IMRT plans for head and neck cancer were subjected to extensive quality assurance. The plans were recalculated on a cylindrical phantom and between eight and 18 low gradient points were measured in each plan with an ion chamber. Every point measured in these plans agreed to within 4% of the dose predicted by the planning system and the plans were judged acceptable for clinical use. Each plan was then reoptimized with aggressive dose constraints so that the new treatment fields were more highly modulated than the ones from the original plans. Very complex fields can be calculated less accurately and ion chamber measurements of these plans in the cylindrical phantom confirmed significant dosimetric errors--Several of the measured points in each plan differed from the calculated dose by more than 4%, with a maximum single deviation of 10.6%. These three plans were judged unacceptable for clinical use. All six plans (three acceptable, three unacceptable) were then analyzed with two means of individual field planar dosimetry: Portal imaging with an electronic portal imaging device (EPID) and an ion chamber array. Gamma analysis was performed on each set of planar measurements with 2%/2 mm distance to agreement (DTA) and 3%/3 mm DTA criteria to try to determine a gamma analysis threshold which would differentiate the flawed plans from the acceptable ones., Results: With the EPID and 2%/2 mm DTA criteria, between 88.2% and 92.8% of pixels from the acceptable IMRT plans passed the gamma analysis, and between 87.5% and 91.9% passed for the unacceptable IMRT plans. With the ion chamber array and 2%/2 mm DTA criteria, between 92.4% and 94.9% of points in the acceptable plans passed the gamma analysis, while 86.8% to 98.3% of the points in the unacceptable plans passed the gamma analysis. The difference between acceptable and unacceptable plans was diminished further when gamma criteria were expanded to 3%/3 mm DTA. A fraction of pixels passing the gamma analysis was found to be a poor predictor of dosimetric accuracy with both planar dosimeters, as well as both sets of gamma criteria., Conclusions: Deconstruction of an IMRT plan for field-by-field QA requires complex analysis methods such as the gamma function. Distance to agreement, a component of the gamma function, has clinical relevance in a composite plan but when applied to individual, highly modulated fields, it can mask important dosimetric errors. While single field planar dosimetry may comprise one facet of an effective QA protocol, gamma analysis of single field measurements is insensitive to important dosimetric inaccuracies of the overall plan.

Purpose: Transforming growth factor-beta (TGF-beta) and Notch signaling pathways are important regulators of vascular homeostasis and vessel remodeling; mutations in these pathways can lead to vascular disorders. Similar vascular phenotypes develop in the normal tissues of cancer patients as a long-term effect of radiotherapy. Irradiation most severely affects the capillaries, which become leaky and dilated and might eventually rupture. To investigate the mechanism of such capillary damage, we studied the effect of TGF-beta and Notch signaling in microvascular endothelial cells., Methods and Materials: Human microvascular endothelial cells were irradiated with 5 or 10 Gy and activation of TGF-beta and Notch signaling pathways was assessed by biochemical methods and a cell migration assay., Results: Ionizing radiation induced Smad2 phosphorylation and nuclear translocation and increased mRNA and protein expression of the activin-like kinase 5 (ALK5) target gene plasminogen activator inhibitor-1 (PAI-1). At the same time, we observed diminished Smad1/5/8 activation and downregulation of the ALK1 downstream target, inhibitor of DNA binding-1 (ID-1). We also measured an upregulation of the Notch ligand Jagged-1 and the target gene Hey1. Decreased inhibitor of DNA binding-1 levels coincided with a reduced ability of the cells to migrate., Conclusion: Ionizing radiation shifts the balance from ALK1 to ALK5 signaling and activates the Notch pathway in endothelial cells. This combination of anti-angiogenic signals contributes to reduced cell migration after irradiation.

The purpose of this study was to investigate the long-term effects of radiation-induced alterations in TGF-beta signaling pathways with respect to the development of vascular damage in the irradiated kidney. Total RNA was isolated from mouse kidneys at 1-30 weeks after irradiation, and quantitative real-time PCR analyses were performed for TGF-beta receptors (ALK1, ALK5, endoglin), downstream mediators (Smad7, CTGF), and downstream targets (PAI-1 and Id-1). Expression of endoglin and Smad7 protein as well as nucleo-cytoplasmic distribution of phospho Smad 2/3 and phospho Smad 1/5 was analyzed by immunohistochemistry. Radiation caused a rapid and persistent increase in expression of TGF-beta receptors and mediators from 1-30 weeks after treatment. Expression of Id-1, a downstream target of endothelial cell specific receptor ALK1, was transiently increased (1-10 weeks after irradiation) but returned to control levels at later times. Expression of PAI-1, a downstream target of ALK5, increased progressively from 10-30 weeks after irradiation. These results show that radiation activated TGF-beta signaling pathways in the kidney and shifted the balance in favor of ALK5 signaling, which generally inhibits endothelial cell proliferation and migration. We hypothesize that prolonged activation of ALK5 signaling and relative suppression of ALK1 signaling may provide an explanation for the telangiectatic phenotype observed in irradiated kidneys.

Over the past 5 years there has been a rapid increase in the use of microarray technology in the field of cancer research. The majority of studies use microarray analysis of tumor biopsies for profiling of molecular characteristics in an attempt to produce robust classifiers for prognosis. There are now several published gene sets that have been shown to predict for aggressive forms of breast cancer, where patients are most likely to benefit from adjuvant chemotherapy and tumors most likely to develop distant metastases, or be resistant to treatment. The number of publications relating to the use of microarrays for analysis of normal tissue damage, after cancer treatment or genotoxic exposure, is much more limited. A PubMed literature search was conducted using the following keywords and combination of terms: radiation, normal tissue, microarray, gene expression profiling, prediction. With respect to normal tissue radiation injury, microarrays have been used in three ways: (1) to generate gene signatures to identify sensitive and resistant populations (prognosis); (2) to identify sets of biomarker genes for estimating radiation exposure, either accidental or as a result of terrorist attack (diagnosis); (3) to identify genes and pathways involved in tissue response to injury (mechanistic). In this article we will review all (relevant) papers that covered our literature search criteria on microarray technology as it has been applied to normal tissue radiation biology and discuss how successful this has been in defining predisposition markers for radiation sensitivity or how it has helped us to unravel molecular mechanisms leading to acute and late tissue toxicity. We also discuss some of the problems and limitations in application and interpretation of such data.

Accumulation of damage in undifferentiated cells may threaten homeostasis and regenerative capacity. Remarkably, p53 has been suggested to be transcriptionally inactive in these cells. To gain insight in the kinetics and interplay of the predominant transcriptional responses of DNA damage signalling pathways in undifferentiated cells, mouse embryonic stem cells were exposed to cisplatin at four different time points (2, 4, 8 and 24h) and concentrations (1, 2, 5 and 10 microM). RNA was isolated and subjected to genome-wide expression profiling. Up to one fourth of the tested genes could be identified as being differentially expressed (false discovery rate=10%) after the cisplatin treatment. Clustering of the expression changes showed a strong time dependency. To investigate the relationship between affected genes, a gene set analysis method was used. Functionally related gene sets were defined using gene ontologies or transcription factor binding sites and were tested for overrepresentation within the differentially expressed genes. A variety of gene sets were clearly enriched among which 'apoptosis' and 'cell cycle' were the most pronounced. Furthermore, there was a strong enrichment of genes with a p53-binding motif. The involvement of the 'cell cycle' and 'apoptosis' gene sets in the cisplatin response was detected at concentrations and time points where the respective biological assays were still negative. The results reveal novel insights into the mechanisms which maintain the genomic integrity in undifferentiated cells. Additionally the results illustrate that gene set analysis of genome-wide expression changes provides a sensitive instrument to detect cellular stress responses to DNA damage.

Radiation-induced impairment of renal function is preceded by capillary endothelial cell damage, which initiates a cascade of inflammatory and thrombotic events. Accumulation of leukocytes in the irradiated kidney, especially in areas surrounding the glomeruli, has been clearly demonstrated. The chemokine fractalkine has recently been identified as a key mediator of leukocyte adhesion that functions without the requirement of integrins or selectin-mediated rolling. In this study we investigate the possible involvement of fractalkine in the inflammatory response of the irradiated kidney. Mouse kidneys were irradiated with single doses of 16 or 0 Gy, and protein and mRNA levels of fractalkine and PECAM-1 were examined after 10 to 40 weeks. These changes were correlated with the progressive increase and distribution of leukocytes in the irradiated kidneys. Increased fractalkine immunoreactivity was seen at glomerular sites 30 to 40 weeks after irradiation. This fractalkine expression was strongly associated with the presence of leukocytes surrounding the Bowman's capsule of the same glomeruli. No significant changes in mRNA levels of fractalkine were seen in whole kidney extracts after irradiation, but expression levels were not determined for isolated glomeruli. PECAM-1 protein levels did not change with time after irradiation, although a significant decrease in mRNA expression was seen at 10 weeks. This study is the first demonstration of increased fractalkine after irradiation and the results suggest that fractalkine may be an important mechanism of leukocyte trafficking in the development of a radiation induced inflammatory response.

Purpose: To describe the relative positions and motions of the prostate, pelvic bony anatomy, and intraprostatic gold fiducial markers during daily electronic portal localization of the prostate., Methods and Materials: Twenty prostate cancer patients were treated supine with definitive external radiotherapy according to an on-line target localization protocol using three or four intraprostatic gold fiducial markers and an electronic portal imaging device. Daily pretherapy and through-treatment electronic portal images (EPIs) were obtained for each of four treatment fields. The patients' pelvic bony anatomy, intraprostatic gold markers, and a best visual match to the target (i.e., prostate) were identified on simulation digitally reconstructed radiographs and during daily treatment setup and delivery. These data provided quantitative inter- and intrafractional analysis of prostate motion, its position relative to the bony anatomy, and the individual intraprostatic fiducial markers. Treatment planning margins, with and without on-line localization, were subsequently compared., Results: A total of 22,266 data points were obtained from daily pretherapy and through-treatment EPIs. The pretherapy three-dimensional (3D) average displacement of the fiducial markers, as a surrogate for the prostate, was 5.6 mm, which improved to 2.8 mm after use of the localization protocol. The bony anatomy 3D average displacement was 4.4 mm both before and after localization to the prostate (p = 0.46). Along the superior-inferior (SI), anterior-posterior (AP), and right-left (RL) axes, the average prostate displacement improved from 2.5, 3.7, and 1.9 mm, respectively, before localization to 1.4, 1.6, and 1.1 mm after (all p < 0.001). The pretherapy to through-treatment position of the bony landmarks worsened from 1.7 to 2.5 mm (p < 0.001) in the SI axis, remained statistically unchanged at 2.8 mm (p = 0.39) in the AP axis, and improved from 2.0 to 1.2 mm in the RL axis (p < 0.001). There was no significant intrafractional displacement of prostate position or bony anatomic landmarks. An intermarker distance was identified for all fiducial markers, and 96 were followed daily. Seventy-nine percent had a standard deviation of <1 mm, and 96% were <1.5 mm. Margins were 5.1, 7.3, and 5.0 mm in the SI, AP, and RL axes, respectively, before localization and 2.7, 2.9, and 2.8 mm after localization., Conclusions: Significant interfractional motion exists for patients' prostate and pelvic bony anatomy. However, these move independently, so the pelvic bony anatomy should not be used as a surrogate for prostate motion. Fiducial markers are stable within the prostate and allow significant margin reduction when used for on-line localization of the prostate.

The purpose of this study was to evaluate electronic portal imaging (EPI) as a means of identifying and correcting field displacement in patients with problematic external beam radiotherapy setups. Fourteen patients with problematic setups were identified for pretreatment daily EPI beam monitoring as part of a physician-directed therapist intervention protocol. Pretreatment EPIs were used to realign fields as necessary to bring the setup within the physician-prescribed tolerance level. For comparison, daily EPIs were available for 12 control patients who had no particular setup difficulties and for whom online beam realignment was not made. Anatomy-matching software was used to measure setup variation along medial-lateral, superior-inferior, and anterior-posterior axes. Online field realignment yielded a significant (p = 0.001) improvement when comparing initial and final setup variations. The mean standard deviation of setup displacement averaged over three axes was reduced from 6.4 mm to 3.1 mm after realignment. The final variation of protocol patients was comparable to that of control patients. In conclusion, EPI provided effective means to perform online beam realignment in a group of difficult-to-position patients. This procedure resulted in a reduction in setup displacement that was statistically significant, clinically relevant, and approached that of a more typical patient group.

Background and Purpose: Von Willebrand factor (vWf), a glycoprotein involved in blood coagulation, is synthesized by endothelial cells. Increased amounts of vWf in blood plasma or tissue samples are indicative of damaged endothelium. In the present study, mRNA expression and localization of vWf were determined in irradiated rat heart tissue., Material and Methods: Sprague-Dawley rats received local heart irradiation with a single dose of 0, 15, or 20 Gy. Hearts were dissected at different time points (up to 16 months) after irradiation. In a second experiment, rats were injected with the radioprotector amifostine (160 mg/kg, i. p.) 15-20 min before irradiation and sacrificed after 6 months. Immunohistochemistry was performed using a polyclonal anti-vWf antibody. Serial sections were subjected to a general rat endothelial cell immunostaining (RECA-1) or a collagen staining (picrosirius red). mRNA expression was determined by using PCR., Results: In control tissue, all endothelial cells lining the lumen of the endocardium and coronary arteries, but not capillary endothelial cells, were stained for vWf. 1 month after irradiation with both 15 and 20 Gy, myocardial capillaries became immunoreactive. From 3 months onward, staining was observed also within the extracellular matrix (ECM) of fibrotic areas. At mRNA level, no changes in vWf could be observed at all time points after irradiation, suggesting that vWf deposition was not due to increased biosynthesis of the protein. In sections of amifostine-treated rat hearts, vWf staining was increased to a lesser extent., Conclusion: These dose- and time-dependent increases in deposition of vWf indicate the presence of damaged endothelium in the irradiated rat heart. These increases in vWf accumulation precede development of fibrosis in the subendocardial layer and myocardium of the left ventricles, right ventricles, and atria.

Purpose: Radiation-induced vascular injury can be a serious problem for cancer survivors. In capillary vessels, this manifests as telangiectasia, causing cosmetic problems when occurring in the skin and more serious problems, e.g. excessive bleeding requiring surgery, when occurring in rectal or bladder mucosa. In addition, thrombotic, inflammatory, and fibrogenic events play an important role in the development of late radiation injury in many tissues. However, the sequence of these events and the relationship between various mechanistic pathways is unclear. The purpose of this project is to identify genes that are differentially expressed in tissues with manifest vascular damage, with the ultimate goal of intervening in this process to block the progressive development of tissue injury., Methods and Materials: Microarray experiments were performed using amplified RNA isolated from irradiated mouse kidney and rectum, and from sham-irradiated controls, at 10 and 20 weeks after treatment. Tissue samples were also taken for histologic evaluation of vascular damage at 10, 20, and 30 weeks after irradiation. Expression profiles for irradiated and sham-irradiated samples were compared, and differentially expressed genes were identified after normalization procedures, using information from straight color, color reverse, and self-self experiments. The extent of overlap in expression profiles for kidney and rectum during the phase of vascular damage was also examined., Results: The mouse kidney experiments showed upregulation of 31 genes at 10 weeks and 42 upregulated genes at 20 weeks. Only 20 genes showed significantly increased expression at both time points. Some of these genes were of particular interest in terms of their known involvement in vascular injury and signal transduction pathways. Irradiated mouse rectum had 278 upregulated genes at 10 weeks and 86 upregulated genes at 20 weeks. Only 19 of the genes upregulated during the period of identified telangiectasia (10-20 weeks) were common to both tissues. These included jagged 1 and Kruppel-like factor 5 (KLF5), which are reported to play a role in vascular development and remodeling., Conclusions: Microarray analysis of RNA from irradiated normal tissues is an effective tool for identifying new genes of potential interest in the development of late tissue injury. Such experiments should be regarded as generating testable hypotheses for mechanisms of radiation-induced injury.

Purpose: Routine permanent prostate brachytherapy (PPB) includes CT-based postimplant dosimetry (PID). A method of identifying different source types from CT data in the same implant volume is described., Methods and Materials: A previously described automatic method for seed localization using CT data is used in this study. Two cases were analyzed: a PPB case with (103)Pd followed by salvage (125)I implantation, both performed at another institution, and a cadaver case where 4 different seed types, including ferromagnetic seeds, and fiducials were implanted., Results: Automatic segregation of different seed types with minimal manual correction is demonstrated using the described localization algorithm. The process is confirmed accurate by comparison of plain film radiographs to CT data and digitally reconstructed radiographs., Conclusion: Unique identification of different source types, including PPB seeds, fiducial markers, and ferromagnetic seeds in permanent implants is possible and permits dosimetric analyses that are spatially coincident.

Irradiation of the kidney induces dose-dependent, progressive renal functional impairment, which is partly mediated by vascular damage. The molecular mechanisms underlying the development of radiation-induced nephropathy are unclear. Given the complexity of radiation-induced responses, microarrays may offer new opportunities to identify a wider range of genes involved in the development of radiation injury. The aim of the present study was to determine whether microarrays are a useful tool for identifying time-related changes in gene expression and potential mechanisms of radiation-induced nephropathy. Microarray experiments were performed using amplified RNA from irradiated mouse kidneys (1 x 16 Gy) and from sham-irradiated control tissue at different intervals (1-30 weeks) after irradiation. After normalization procedures (using information from straight-color, color-reverse and self-self experiments), the differentially expressed genes were identified. Control and repeat experiments were done to confirm that the observations were not artifacts of the array procedure (RNA amplification, probe synthesis, hybridizations and data analysis). To provide independent confirmation of microarray data, semi-quantitative PCR was performed on a selection of genes. At 1 week after irradiation (before the onset of vascular and functional damage), 16 genes were significantly up-regulated and 9 genes were down-regulated. During the period of developing nephropathy (10 to 20 weeks), 31 and 42 genes were up-regulated and 9 and 4 genes were down-regulated. At the later time of 30 weeks, the vast majority of differentially expressed genes (191 out of 203) were down-regulated. Potential genes of interest included TSA-1 (also known as Ly6e) and Jagged 1 (Jag1). Increased expression of TSA-1, a member of the Ly-6 family, has previously been reported in response to proteinuria. Jagged 1, a ligand for the Notch receptor, is known to play a role in angiogenesis, and is particularly interesting in the context of radiation-induced vascular injury. The present study demonstrates the potential of microarrays to identify changing patterns of gene expression in irradiated kidney. Further studies will be required to evaluate functional involvement of these genes in vascular-mediated normal tissue injury.

Purpose: To develop a real-time electronic portal imaging device (EPID) procedure to identify intraprostatic gold markers and correct daily variations in target position during external beam radiotherapy for prostate cancer., Methods and Materials: Pretherapy electronic portal images (EPIs) were acquired with a small portion of the therapeutic 18-MV dose from an orthogonal pair of treatment fields. The position of the intraprostatic gold markers on the EPIs was aligned with that on the simulation digitally reconstructed radiographs. If the initial three-dimensional target displacement (3DI) exceeded 5 mm or rotations exceeded 3 degrees, the beam was realigned before the remainder of the dose was delivered. Field-only EPIs were then acquired for all fields and offline analysis was performed to determine the final 3D target placement (3DF)., Results: Twenty patients completed protocol-specified treatment, and all markers were identified on 99.6% of the pretherapy EPIs. Overall, 53% of treatment fractions were realigned. The mean 3DI was 5.6 mm in all patients (range 3.7-9.3), and the mean 3DF was 2.8 mm (range 1.6-4.0), which was statistically significant (p < 0.001). Rotational corrections were made on 15% of treatments. Mean treatment duration was 1.4 min greater for protocol patients than for similar patients in whom localization was not performed., Conclusions: Frequent field misalignment occurs when external fiducial marks are used for patient alignment. Misalignments can be readily and rapidly identified and corrected with an EPID-based online correction procedure that integrates commercially available equipment and software.

A method to investigate light and radiation field congruence utilizing a commercially available amorphous silicon electronic portal imaging device (EPID) was developed. This method employed an EPID, the associated EPI software, and a diamond-shaped template. The template was constructed from a block tray in which Sn/Pb wires, 1 mm in diameter, were embedded into a diamond shaped groove milled into the tray. The collimator jaws of the linac were aligned such that the light field fell directly on the corners of the diamond. A radiation detection algorithm within the EPI software determined the extent of the radiation field. The light and radiation field congruence was evaluated by comparing the vertexes of the diamond reference structure to the detected radiation field. In addition, the digital jaw settings were recorded and later compared to the light field detected on the films and EPIs. Three linear accelerators were tracked for a period ranging from 2-8 months. Light radiation field congruence tests with films and EPIs were comparable, yielding a difference of less than 0.6 mm, well within the allowed 2-mm tolerance. A disparity was observed in the magnitude of the detected light field. The X and Y dimensions of the light field measured with film differed by less than or equal to 1.4 mm from the digital collimator settings, whereas the values extracted from the EPIs differed by up to 2.5 mm. Based on these findings, EPIs were found to be a quick and reliable alternative to film for qualitative and relative analyses., ((c) 2003 American College of Medical Physics.)

Proteinuria occurs in all degrees of radiation nephropathy and can be present without other symptoms. In this study, radiation-induced proteinuria in C3H mice demonstrated a clear dose-response relationship and was apparent before the onset of significant structural vascular changes and decreases in renal function. This suggests that proteinuria is not a secondary event due to loss of the vascular structure. In an attempt to ameliorate radiation-induced proteinuria and progressive renal failure, two factors were studied. The influence of reactive oxygen species (ROS), which are generated by infiltrating neutrophils and mediate proteinuria in models of acute glomerular injury, was the first to be investigated. Short-term administration of the reactive oxygen scavengers superoxide dismutase (SOD) and catalase did not reverse an established radiation-induced proteinuria. Continuous administration of the antioxidant N-acetylcysteine (NAC) also failed to inhibit this proteinuria. However, since no direct assessment of the impact of these interventions on renal redox status was made, the putative role of ROS in radiation-induced proteinuria and nephropathy remains undefined. The second factor studied was vascular endothelial growth factor (Vegf), which is suggested to be involved in glomerular vessel permeability and the development of proteinuria in some models of renal disease. Northern blot analysis of mRNA from whole kidneys did not demonstrate any increased expression of Vegf after irradiation. There was also no change in the ratio of the different Vegf isoforms (PCR analysis), either in the whole kidney or in isolated glomeruli. No significant role for Vegf was identified for radiation-induced vascular changes or proteinuria, although post-transcriptional changes cannot be excluded.

The purpose of this study was to investigate whether administration of amifostine prior to irradiation could reduce radiation damage of the rat heart. Female Spraque-Dawley rats were randomized to receive single-dose irradiation (0-22.5 Gy) locally to the heart. Fifteen to twenty minutes before radiation exposure, the animals received either intraperitoneally administered amifostine (160 mg/kg) or buffered saline solution. At 6 months post-irradiation, cardiac function was assessed by the in vitro working rat heart preparation. The severity of interstitial and/or perivascular fibrosis in different anatomical regions of the rat heart was assessed using a semi-quantitative scoring system. Radiation exposure to doses > or = 20 Gy markedly reduced coronary flow, aortic flow and cardiac output. Administration of amifostine prior to radiotherapy afforded protection against these effects and normal cardiac output was maintained, even after 22.5 Gy. A small, non-significant, reduction in histological damage (i.e. perivascular fibrosis and interstitial fibrosis) was also apparent in animals treated with amifostine. There was a clear protective effect of amifostine on the severity and extent of macroscopic damage in lung tissue included in the cardiac irradiation field. The findings of this study suggest that a single dose of amifostine administered prior to irradiation is effective in reducing cardiac damage.