Correction: Lenarczyk et al. T Cells Contribute to Pathological Responses in the Non-Targeted Rat Heart following Irradiation of the Kidneys. Toxics 2022, 10, 797.

In the original publication [...].

T Cells Contribute to Pathological Responses in the Non-Targeted Rat Heart following Irradiation of the Kidneys.

Heart disease is a significant adverse event caused by radiotherapy for some cancers. Identifying the origins of radiogenic heart disease will allow therapies to be developed. Previous studies showed non-targeted effects manifest as fibrosis in the non-irradiated heart after 120 days following targeted X-irradiation of the kidneys with 10 Gy in WAG/RijCmcr rats. To demonstrate the involvement of T cells in driving pathophysiological responses in the out-of-field heart, and to characterize the timing of immune cell engagement, we created and validated a T cell knock downrat on the WAG genetic backgrou nd. Irradiation of the kidneys with 10 Gy of X-rays in wild-type rats resulted in infiltration of T cells, natural killer cells, and macrophages after 120 days, and none of these after 40 days, suggesting immune cell engagement is a late response. The radiation nephropathy and cardiac fibrosis that resulted in these animals after 120 days was significantly decreased in irradiated T cell depleted rats. We conclude that T cells function as an effector cell in communicating signals from the irradiated kidneys which cause pathologic remodeling of non-targeted heart.

Myocardial Contractility Pattern Characterization in Radiation-Induced Cardiotoxicity Using Magnetic Resonance Imaging: A Pilot Study with ContractiX.

Radiation therapy (RT) plays an integral role in treating thoracic cancers, despite the risk of radiation-induced cardiotoxicity. We hypothesize that our newly developed magnetic resonance imaging (MRI)-based contractility index (ContractiX) is a sensitive marker for early detection of RT-induced cardiotoxicity in a preclinical rat model of thoracic cancer RT. Adult salt-sensitive rats received image-guided heart RT and were imaged with MRI at 8 weeks and 10 weeks post-RT or sham. The MRI exam included cine and tagging sequences to measure left-ventricular ejection fraction (LVEF), mass, myocardial strain, and ContractiX. Furthermore, ventricular torsion, diastolic strain rate, and mechanical dyssynchrony were measured. Statistical analyses were performed between the sham, 8 weeks post-RT, and 10 weeks post-RT MRI parameters. The results showed that both LVEF and myocardial mass increased post-RT. Peak systolic strain and ContractiX significantly decreased post-RT, with a more relative reduction in ContractiX compared to strain. ContractiX showed an inverse nonlinear relationship with LVEF and continuously decreased with time post-RT. While early diastolic strain rate and mechanical dyssynchrony significantly changed post-RT, ventricular torsion changes were not significant post-RT. In conclusion, ContractiX measured via non-contrast MRI is a sensitive early marker for the detection of subclinical cardiac dysfunction post-RT, and it is superior to other MRI cardiac measures.

Evaluation of Radiation-induced Pleural Effusions after Radiotherapy to Support Development of Animal Models of Radiation Pneumonitis.

ABSTRACT: Not all animal models develop radiation-induced pleural effusions (RIPEs) as a form of radiation-induced lung injury (RILI). Such effusions are also not well characterized in humans. The purpose of this study is to identify occurrences of RIPE in humans, provide justification for development of relevant animal models, and further characterize its risk factors in cancer patients. We also aim to identify dose thresholds for cardiopulmonary toxicity in humans to shed light on possible pathogenic mechanisms for RIPEs. We carried out a retrospective review of medical records of 96 cancer patients receiving thoracic irradiation (TRT) at our institution. Fifty-three (53%) patients developed a new pleural effusion post TRT; 18 (19%) had RIPE; and 67% developed RIPE ipsilateral to the site irradiated. None developed "contralateral only" effusions. Median time to development was 6 mo (IQR; 4-8 mo). Of 18, 8 patients (44%) had concomitant asymptomatic (radiographic only) or symptomatic radiation pneumonitis and pericardial effusion. Dosimetric factors, including combined and ipsilateral mean lung dose (MLD), were significantly associated with increased risk of RIPE. Angiotensin converting enzyme inhibition, steroids, or concurrent chemotherapy did not modify incidence of RIPE. Our results substantiate the occurrence and incidence of RIPEs in humans. In cancer patients, a median time to development of effusions around 6 mo also supports the onset of RIPEs concurrent with radiation pneumonitis. Future work needs to include large populations of cancer survivors in whom delayed RIPEs can be tracked and correlated with cardiovascular changes in the context of injury to multiple organs.

Estimation of changing gross tumor volume from longitudinal CTs during radiation therapy delivery based on a texture analysis with classifier algorithms: a proof-of-concept study.

BACKGROUND: Adaptive radiation therapy (ART) is moving into the clinic rapidly. Capability of delineating the tumor change as a result of treatment response during treatment delivery is essential for ART. During image-guided radiation therapy (IGRT), a CT or cone-beam CT is taken at the time of daily setup and the tumor is not visible by eye in regions of soft tissue due to low contrast. The scope of this paper is to develop a method using a classifier trained on non-contrast CT textures, to estimate the gross tumor volume (GTV) of the day (GTVd) from daily (longitudinal) CTs acquired during the course of IGRT when the tumor is not visible. METHODS: CT textures from daily diagnostic-quality CTs routinely acquired during IGRT using an in-room CT were analyzed. Pretreatment GTV was delineated from pre-RT diagnostic images and populated to the first daily CT. Maps of first-order textures (mean, SD, entropy, skewness and kurtosis) and short-range second-order textures were created from the first daily CT. The classifier was trained to sort voxels into GTV and surrounding tissue on subsequent daily CTs over the course of RT. Optimum combinations of textures was defined by repeating the training process with all possible texture combinations. The trained classifier was used to identify voxels belonging to the GTVd, based on the CT of the day. Posttreatment GTV delineated from the post-RT follow-up images was populated to the last daily CT and used to validate the last GTVd delineated by the classifier. To demonstrate the concept, the method was described using three representative treatment sites, e.g., lung, breast and pancreatic tumors. RESULTS: Comparing the classifier map generated from a new CT to the initial training CT, the dice coefficient (DC) for GTV in lung is 83% on the eighth treatment and 84% on the last. The DC for the breast GTV is 56% mid-treatment and 65% at the last treatment. In the case of the pancreas with the least in organ tissue contrast, the DC for 4 cases ranges from 21% to 77% for the last treatment compared with the post-RT diagnostic CT. The Housdorff distance (HD) ranged from 2.9 to 5.9 mm with the mean GTV RECIST dimension of 22.75 mm long by 14.7 mm short. CONCLUSIONS: It is feasible to estimate the general region of the GTV of the day from the daily CT acquired during RT, based on CT textures, using a trained voxel classifier algorithm. The obtained GTV may be used as a starting point for an accurate GTV delineation in online adaptive replanning. Further study with larger patient datasets is required to improve the robustness of the algorithms.

Dosimetric Predictors of Cardiotoxicity in Thoracic Radiotherapy for Lung Cancer.

BACKGROUND: Higher cardiac radiotherapy (RT) doses when treating lung cancer are associated with worse overall survival (OS), although the direct association between cardiac dose and early cardiotoxicity is poorly understood. We hypothesized that RT doses to the heart and cardiac substructures are associated with under-reported early cardiotoxicity and worse OS. PATIENTS AND METHODS: We conducted an institutional retrospective review of lung cancer patients treated with conventionally fractionated RT from 2010 to 2015. Collected data included pre-RT cardiac risk factors, post-RT cardiotoxicities, and dose-volume parameters for cardiac substructures. Univariate and multivariate analyses were performed to identify predictors of cardiotoxicity and OS. RESULTS: Seventy-six cases were evaluated with 1.2 years median follow-up. Cardiotoxicities included atrial arrhythmia (n = 5), pericardial effusion (n = 16), and valvular disease (n = 1). In univariate analysis, significant dose-volume predictors for cardiotoxicity included mean RT dose to structure of interest, volume of structure of interest receiving ≥30 Gy RT dose, and volume of structure of interest receiving ≥45 Gy RT dose (V45) to the atria, ventricles, and pericardium. Higher ventricular V45 was associated with post-RT cardiotoxicity in multivariate analysis (hazard ratio [HR], 1.50; P = .027). Cardiotoxicity occurrence was a highly significant predictor of OS in multivariate analysis (HR, 12.7; P < .001), but higher ventricular V45 alone was not (HR, 0.78; P = .450). CONCLUSION: Early cardiac events were relatively common after lung cancer RT and associated with multiple cardiac dose-volume parameters. Occurrence of early cardiotoxicity was strongly associated with worse OS. In practice, early cardiotoxicity is under-reported, supporting the need for more detailed cardiac evaluations in high-risk patients to detect and address early cardiotoxicity.

The Dosimetric Impact of Interfractional Organ-at-Risk Movement During Liver Stereotactic Body Radiation Therapy.

PURPOSE: Stereotactic body radiation therapy (SBRT) is an effective therapy for treating liver malignancies. However, little is known about interfractional dose variations to adjacent organs at risk (OARs). We examine the effects of interfractional organ movement and setup variation on dose delivered to OARs in patients receiving liver SBRT. METHODS AND MATERIALS: Thirty patients treated with liver SBRT were analyzed. Daily image guidance with diagnostic quality computed tomography-on-rails imaging was performed before each fraction. In phase 1, these daily images were used to delineate all OARs including the liver, heart, right kidney, esophagus, stomach, duodenum, and large bowel in 10 patients. In phase 2, only OARS in close proximity to the target were contoured in 20 additional patients. Dose distribution on each daily computed tomography was generated, and daily doses to each OAR were recorded and compared with clinical thresholds to determine whether a daily dose excess (DDE) occurred. RESULTS: In phase 1, significant interfractional dose differences between planned and delivered dose to OARs were observed, but differences were rarely clinically significant, with just 1 DDE. In phase 2, multiple DDEs were recorded for OARs close to the target, mainly involving the stomach, heart, and esophagus. Tumors in the hilum and liver segments I, IV, and VIII were the most common locations for DDEs. On root cause analysis, 3 etiologies of DDE emerged: craniocaudal shift (69.2%), anatomic changes (28.2%), and anteroposterior shifts (2.6%). CONCLUSIONS: OARs close to liver lesions may receive higher doses than expected during SBRT owing to interfractional variations in OARs relative to the target. These differences in planned versus expected dose can lead to toxicity. Efforts to better evaluate OARs with daily image guidance may help reduce risks. Application of adaptive replanning and improved and real-time image guidance could mitigate risks of toxicity, and further study into their applications is warranted.

Measurement validation of treatment planning for a MR-Linac.

PURPOSE: The magnetic field can cause a nonnegligible dosimetric effect in an MR-Linac system. This effect should be accurately accounted for by the beam models in treatment planning systems (TPS). The purpose of the study was to verify the beam model and the entire treatment planning and delivery process for a 1.5 T MR-Linac based on comprehensive dosimetric measurements and end-to-end tests. MATERIAL AND METHODS: Dosimetry measurements and end-to-end tests were performed on a preclinical MR-Linac (Elekta AB) using a multitude of detectors and were compared to the corresponding beam model calculations from the TPS for the MR-Linac. Measurement devices included ion chambers (IC), diamond detector, radiochromic film, and MR-compatible ion chamber array and diode array. The dose in inhomogeneous phantom was also verified. The end-to-end tests include the generation, delivery, and comparison of 3D and IMRT plan with measurement. RESULTS: For the depth dose measurements with Farmer IC, micro IC and diamond detector, the absolute difference between most measurement points and beam model calculation beyond the buildup region were <1%, at most 2% for a few measurement points. For the beam profile measurements, the absolute differences were no more than 1% outside the penumbra region and no more than 2.5% inside the penumbra region. Results of end-to-end tests demonstrated that three 3D static plans with single 5 × 10 cm2 fields (at gantry angle 0°, 90° and 270°) and two IMRT plans successfully passed gamma analysis with clinical criteria. The dose difference in the inhomogeneous phantom between the calculation and measurement was within 1.0%. CONCLUSIONS: Both relative and absolute dosimetry measurements agreed well with the TPS calculation, indicating that the beam model for MR-Linac properly accounts for the magnetic field effect. The end-to-end tests verified the entire treatment planning process.

A fast 4D IMRT/VMAT planning method based on segment aperture morphing.

PURPOSE: Four-dimensional volumetric modulated arc therapy (4D VMAT) and four-dimensional intensity-modulated radiotherapy (4D IMRT) are developing radiation therapy treatment strategies designed to maximize dose conformality, minimize normal tissue dose, and deliver the treatment as efficiently as possible. The patient's entire breathing cycle is captured through 4D imaging modalities and then separated into individual breathing phases for planning purposes. Optimizing multiphase VMAT and IMRT plans is computationally demanding and currently impractical for clinical application. The purpose of this study is to assess a new planning process decreasing the upfront computational time required to optimize multiphased treatment plans while maintaining good plan quality. METHODS: Optimized VMAT and IMRT plans were created on the end-of-exhale (EOE) breathing phase of 10-phase 4D CT scans with planning tumor volume (PTV)-based targets. These single-phase optimized plans are analogous to single-phase gated treatment plans. The simulated tracked plans were created by deformably registering EOE contours to the remaining breathing phases, recalculating the optimized EOE plan onto the other individual phases and realigning the MLC's relative positions to the PTV border in each of the individual breathing phases using a segment aperture morphing (SAM) algorithm. Doses for each of the 10 phases were calculated with the treatment planning system and deformably transferred back onto the EOE phase and averaged with equal weighting simulating the actual delivered dose a patient would potentially receive in a tracked treatment plan. RESULTS: Plan DVH quality for the 10-phase 4D SAM plans were comparable with the individual EOE optimized treatment plans for the PTV structures as well as the organ at risk structures. SAM-based algorithms out performed simpler isocenter-shifted only approaches. SAM-based 4D planning greatly reduced plan computation time vs individually optimizing all 10 phases. In addition, since this technique allows irradiation during all 10 breathing phases it will also decrease the treatment times required to treat each fraction in comparison to the gated treatment planning approach. CONCLUSIONS: Segment aperture morphing (SAM) can successfully be used to transfer radiation therapy plans originally planned on a single breathing phase image set to other patient breathing phase image sets. SAM is a useful tool for the fast creation of 4D, multibreathing phase radiation therapy treatment plans.

PRESAGE 3D dosimetry accurately measures Gamma Knife output factors.

Small-field output factor measurements are traditionally very difficult because of steep dose gradients, loss of lateral electronic equilibrium, and dose volume averaging in finitely sized detectors. Three-dimensional (3D) dosimetry is ideal for measuring small output factors and avoids many of these potential challenges of point and 2D detectors. PRESAGE 3D polymer dosimeters were used to measure the output factors for the 4 mm and 8 mm collimators of the Leksell Perfexion Gamma Knife radiosurgery treatment system. Discrepancies between the planned and measured distance between shot centers were also investigated. A Gamma Knife head frame was mounted onto an anthropomorphic head phantom. Special inserts were machined to hold 60 mm diameter, 70 mm tall cylindrical PRESAGE dosimeters. The phantom was irradiated with one 16 mm shot and either one 4 mm or one 8 mm shot, to a prescribed dose of either 3 Gy or 4 Gy to the 50% isodose line. The two shots were spaced between 30 mm and 60 mm apart and aligned along the central axis of the cylinder. The Presage dosimeters were measured using the DMOS-RPC optical CT scanning system. Five independent 4 mm output factor measurements fell within 2% of the manufacturer's Monte Carlo simulation-derived nominal value, as did two independent 8 mm output factor measurements. The measured distances between shot centers varied by ± 0.8 mm with respect to the planned shot displacements. On the basis of these results, we conclude that PRESAGE dosimetry is excellently suited to quantify the difficult-to-measure Gamma Knife output factors.

Preliminary evaluation of the dosimetric accuracy of the in vivo plastic scintillation detector OARtrac system for prostate cancer treatments.

A promising, new, in vivo prostate dosimetry system has been developed for clinical radiation therapy. This work outlines the preliminary end-to-end testing of the accuracy and precision of the new OARtrac scintillation dosimetry system. We tested 94 calibrated plastic scintillation detector (PSD) probes before their final integration into endorectal balloon assemblies. These probes had been calibrated at The University of Texas MD Anderson Cancer Center Dosimetry Laboratory. We used a complete clinical OARtrac system including the PSD probes, charge coupled device camera monitoring system, and the manufacturer's integrated software package. The PSD probes were irradiated at 6 MV in a Solid Water® phantom. Irradiations were performed with a 6 MV linear accelerator using anterior-posterior/posterior-anterior matched fields to a maximum dose of 200 cGy in a 100 cm source-axis distance geometry. As a whole, the OARtrac system has good accuracy with a mean error of 0.01% and an error spread of ±5.4% at the 95% confidence interval. These results reflect the PSD probes' accuracy before their final insertion into endorectal balloons. Future work will test the dosimetric effects of mounting the PSD probes within the endorectal balloon assemblies.