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Background: Mediastinal ionizing radiotherapy is associated with an increased risk of valvular disease, which demonstrates pathological hallmarks similar to calcific aortic valve disease (CAVD). Despite advances in radiotherapy techniques, the prevalence of comorbidities such as radiation-associated valvular disease is still increasing due to improved survival of patients receiving radiotherapy. However, the mechanisms of radiation-associated valvular disease are largely unknown. CAVD is considered to be an actively regulated disease process, mainly controlled by valvular interstitial cells (VICs). We hypothesize that radiation exposure catalyzes the calcific response of VICs and, therefore, contributes to the development of radiation-associated valvular disease. Methods and Results: To delineate the relationship between radiation and VIC behavior (morphology, calcification, and matrix turnover), two different in vitro models were established: (1) VICs were cultured two-dimensional (2D) on coverslips in control medium (CM) or osteogenic medium (OM) and irradiated with 0, 2, 4, 8, or 16 Gray (Gy); and (2) three-dimensional (3D) hydrogel system was designed, loaded with VICs and exposed to 0, 4, or 16 Gy of radiation. In both models, a dose-dependent decrease in cell viability and proliferation was observed in CM and OM. Radiation exposure caused myofibroblast-like morphological changes and differentiation of VICs, as characterized by decreased αSMA expression. Calcification, as defined by increased alkaline phosphatase activity, was mostly present in the 2D irradiated VICs exposed to 4 Gy, while after exposure to higher doses VICs acquired a unique giant fibroblast-like cell morphology. Finally, matrix turnover was significantly affected by radiation exposure in the 3D irradiated VICs, as shown by decreased collagen staining and increased MMP-2 and MMP-9 activity. Conclusions: The presented work demonstrates that radiation exposure enhances the calcific response in VICs, a hallmark of CAVD. In addition, high radiation exposure induces differentiation of VICs into a terminally differentiated giant-cell fibroblast. Further studies are essential to elucidate the underlying mechanisms of these radiation-induced valvular changes.
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Purpose: The purpose of this study was to analyze the effect of 2D conventional brachytherapy (CBT) compared to 3D MRI-guided brachytherapy (IGBT) with and without the use of interstitial needles on local control, overall survival, and toxicity in patients treated for cervical cancer with radiation or chemoradiation. Material and methods: A retrospective analysis was performed of biopsy-proven FIGO IB-IVA cervical cancer patients, treated with primary radiation or chemoradiation, followed by brachytherapy (BT) between January 1997 and July 2016. Endpoints were local control, overall survival, and toxicity. Results: Of 126 patients included, 35 have been treated with CBT, 31 with IGBT without needles (IC), and 60 with IGBT with needles (ICIS). External beam radiotherapy (EBRT) had mostly been delivered concurrently with chemotherapy (weekly cisplatin). Overall local control was 93% after 1 year, and 88% after 3 years. Overall 3-year survival was 75%, and 5-year survival was 66%. The 3D technique (IGBT cohorts) showed a trend for an improved local control and overall survival (p = 0.05) compared to the 2D technique (CBT cohort). A decrease in toxicity was observed from 17% (2D cohort) to 12% (3D cohort). The use of interstitial needles was associated with a higher high-risk clinical target volume (HR-CTV) dose (11.3 Gy vs. 9.9 Gy) and a lower D2cc bladder dose (10.9 Gy vs. 14.7 Gy, both p < 0.01). Conclusions: In cervical cancer treatment, the use of a 3D brachytherapy technique (MRI-guided with or without interstitial needles) showed a trend towards an increased local control and improved overall survival with reduced toxicity, compared to the conventional 2D brachytherapy technique. The use of interstitial needles allowed dose sculpting, resulting in delivery of higher doses to the HR-CTV, while reducing radiation doses to organs at risk, such as the bladder.