Low-Dose Radiotherapy Ameliorates Advanced Arthritis in hTNF-α tg Mice by Particularly Positively Impacting on Bone Metabolism.

Inflammation and bone erosion are central in rheumatoid arthritis (RA). Even though effective medications for control and treatment of RA are available, remission is only seen in a subset of patients. Treatment with low-dose radiotherapy (LD-RT) which has been already successfully used for amelioration of symptoms in benign diseases should be a promising approach to reduce pain, inflammation, and particularly bone erosion in patients with RA. Even though anti-inflammatory effects of LD-RT are already described with non-linear dose response relationships, and pain-reducing effects have been clinically observed, the underlying mechanisms are widely unknown. Besides immune cells many other cell types, such as fibroblast-like synoviocytes (FLS), osteoclasts, and osteoblast are present in the affected joint and might be modulated by LD-RT. For this study, these cell types were obtained from human tumor necrosis factor-α transgenic (hTNF-α tg) mice and were consecutively exposed to different doses of ionizing radiation (0.1, 0.5, 1.0, and 2.0 Gy, respectively) in vitro. In order to study the in vivo effects of LD-RT within the arthritic joint, hind paws of arthritic hTNF-α tg mice were locally irradiated with 0.5 Gy, a single dose per fraction that is known for good clinical responses. Starting at a dose of 0.5 Gy, proliferation of FLS was reduced and apoptosis significantly enhanced with no changes in necrosis. Further, expression of RANK-L was slightly reduced following irradiation with particularly 0.5 Gy. Starting from 0.5 Gy, the numbers of differentiated osteoclasts were significantly reduced, and a lower bone resorbing activity of treated osteoclasts was also observed, as monitored via pit formation and Cross Laps presence. LD-RT had further a positive effect on osteoblast-induced mineralization in a discontinuous dose response relationship with 0.5 Gy being most efficient. An increase of the gene expression ratio of OPG/RANK-L at 0.1 and 0.5 Gy and of production of OPG at 0.5 and 1.0 Gy was observed. In vivo, LD-RT resulted in less severe arthritis in arthritic hTNF-α tg mice and in significant reduction of inflammatory and erosive area with reduced osteoclasts and neutrophils. Locally applied LD-RT can, therefore, induce a beneficial micro-environment within arthritic joints by predominantly positively impacting on bone metabolism.

Examination of a deformable motion model for respiratory movements and 4D dose calculations using different driving surrogates.

PURPOSE: The aim of this study was to evaluate a surrogate-driven motion model based on four-dimensional computed tomography that is able to predict CT volumes corresponding to arbitrary respiratory phases. Furthermore, the comparison of three different driving surrogates is examined and the feasibility of using the model for 4D dose re-calculation will be discussed. METHODS: The study is based on repeated 4DCTs of twenty patients treated for bronchial carcinoma and metastasis. The motion model was estimated from the planning 4DCT through deformable image registration. To predict a certain phase of a follow-up 4DCT, the model considers inter-fractional variations (baseline correction) and intra-fractional respiratory parameters (amplitude and phase) derived from surrogates. The estimated volumes resulting from the model were compared to ground-truth clinical 4DCTs using absolute HU differences in the lung region and landmarks localized using the Scale Invariant Feature Transform. Finally, the γ-index was used to evaluate the dosimetric effects of the intensity differences measured between the estimated and the ground-truth CT volumes. RESULTS: The results show absolute HU differences between estimated and ground-truth images with median value (± standard deviation) of (61.3 ± 16.7) HU. Median 3D distances, measured on about 400 matching landmarks in each volume, were (2.9 ± 3.0) mm. 3D errors up to 28.2 mm were found for CT images with artifacts or reduced quality. Pass rates for all surrogate approaches were above 98.9% with a γ-criterion of 2%/2 mm. CONCLUSION: The results depend mainly on the image quality of the initial 4DCT and the deformable image registration. All investigated surrogates can be used to estimate follow-up 4DCT phases, however, uncertainties decrease for volumetric approaches. Application of the model for 4D dose calculations is feasible.

Impact of fractionation and number of fields on dose homogeneity for intra-fractionally moving lung tumors using scanned carbon ion treatment.

BACKGROUND AND PURPOSE: Scanned particle beam therapy may result in over and under dosages within the target volume. This study quantifies how CTV dose coverage improves with number of fractions and fields. MATERIALS AND METHODS: Based on 4DCTs of nine lung tumor patients, treatment plans were optimized separately for four different fields using an ITV approach. 4D RBE-weighted dose distributions were calculated for varying motion parameters and fraction numbers. The total RBE-weighted dose was determined for one and four-field application per fraction. DVHs were analyzed for the tumor and interpreted based on statistical modeling. RESULTS: Dose homogeneity within the CTV increased with the fraction number, but depends significantly on the tumor motion amplitude. For single-field schedules and amplitudes >6mm, the dose coverage indices (V95min=90.7% and V107max=0.4%) differed to the stationary case even after 40 fractions. Target coverage for a four-field approach followed a proposed model and homogeneous dose distributions could be achieved 6-times faster than single-field treatments. CONCLUSIONS: Fractionated delivery improves dose homogeneity in scanned ion beam therapy of moving targets. The achievable homogeneity depends mainly on tumor volume and motion amplitude. The outcome of multiple-field irradiations can be predicted based on single-field results and accelerates the achievement of homogeneous dose distributions.

Quantification of an external motion surrogate for quality assurance in lung cancer radiation therapy.

The purpose of this work was to validate the stability of the end exhale position in deep expiration breath hold (DEBH) technique for quality assurance in stereotactic lung tumor radiation therapy. Furthermore, a motion analysis was performed for 20 patients to evaluate breathing periods and baseline drifts based on an external surrogate. This trajectory was detected using stereo infrared (IR) cameras and reflective body markers. The respiratory waveform showed large interpatient differences in the end exhale position during irradiation up to 18.8 mm compared to the global minimum. This position depends significantly on the tumor volume. Also the baseline drifts, which occur mostly in posterior direction, are affected by the tumor size. Breathing periods, which depend mostly on the patient age, were in a range between 2.4 s and 7.0 s. Fifteen out of 20 patients, who showed a reproducible end exhale position with a deviation of less than 5 mm, might benefit from DEBH due to smaller planning target volumes (PTV) compared to free breathing irradiation and hence sparing of healthy tissue. Patients with larger uncertainties should be treated with more complex motion compensation techniques.

Challenges of radiotherapy: report on the 4D treatment planning workshop 2013.

This report, compiled by experts on the treatment of mobile targets with advanced radiotherapy, summarizes the main conclusions and innovations achieved during the 4D treatment planning workshop 2013. This annual workshop focuses on research aiming to advance 4D radiotherapy treatments, including all critical aspects of time resolved delivery, such as in-room imaging, motion detection, motion managing, beam application, and quality assurance techniques. The report aims to revise achievements in the field and to discuss remaining challenges and potential solutions. As main achievements advances in the development of a standardized 4D phantom and in the area of 4D-treatment plan optimization were identified. Furthermore, it was noticed that MR imaging gains importance and high interest for sequential 4DCT/MR data sets was expressed, which represents a general trend of the field towards data covering a longer time period of motion. A new point of attention was work related to dose reconstructions, which may play a major role in verification of 4D treatment deliveries. The experimental validation of results achieved by 4D treatment planning and the systematic evaluation of different deformable image registration methods especially for inter-modality fusions were identified as major remaining challenges. A challenge that was also suggested as focus for future 4D workshops was the adaptation of image guidance approaches from conventional radiotherapy into particle therapy. Besides summarizing the last workshop, the authors also want to point out new evolving demands and give an outlook on the focus of the next workshop.