XCT overexpression in cancer cells has been linked to tumor growth, metastasis and treatment resistance. Sulfasalazine (SSZ), an FDA-approved drug for the treatment of rheumatoid sarthritis, and inflammatory bowel diseases, has anticancer properties via inhibition of xCT, leading to the disruption of redox homeostasis. Since reactive oxygen species (ROS) are pivotal for the efficacy of radiotherapy (RT), elevated levels of ROS are associated with improved RT outcomes. In this study, the influence of SSZ treatment on the radiosensitivity of human colorectal cancer (CRC) cells was investigated. Our principal finding in human HCT116 and DLD-1 cells was that SSZ enhances the radiosensitivity of hypoxic CRC cells but does not alter the intrinsic radiosensitivity. The radiosensitizing effect was attributed to the depletion of glutathione and thioredoxin reductase levels. In turn, the reduction leads to excessive levels of ROS, increased DNA damage, and ferroptosis induction. Confirmation of these findings was performed in 3D models and in DLD-1 xenografts. Taken together, this study is a stepping stone for applying SSZ as a radiosensitizer in the clinic and confirms that xCT in cancer cells is a valid radiobiological target.

Dynamic computer tomography (CT) is an emerging modality to analyze in-vivo joint kinematics at the bone level, but it requires manual bone segmentation and, in some instances, landmark identification. The objective of this study is to present an automated workflow for the assessment of three-dimensional in vivo joint kinematics from dynamic musculoskeletal CT images. The proposed method relies on a multi-atlas, multi-label segmentation and landmark propagation framework to extract bony structures and detect anatomical landmarks on the CT dataset. The segmented structures serve as regions of interest for the subsequent motion estimation across the dynamic sequence. The landmarks are propagated across the dynamic sequence for the construction of bone embedded reference frames from which kinematic parameters are estimated. We applied our workflow on dynamic CT images obtained from 15 healthy subjects on two different joints: thumb base (n = 5) and knee (n = 10). The proposed method resulted in segmentation accuracies of 0.90 ± 0.01 for the thumb dataset and 0.94 ± 0.02 for the knee as measured by the Dice score coefficient. In terms of motion estimation, mean differences in cardan angles between the automated algorithm and manual segmentation, and landmark identification performed by an expert were below 1°. Intraclass correlation (ICC) between cardan angles from the algorithm and results from expert manual landmarks ranged from 0.72 to 0.99 for all joints across all axes. The proposed automated method resulted in reproducible and reliable measurements, enabling the assessment of joint kinematics using 4DCT in clinical routine.

Single-isocenter linac-based stereotactic radiosurgery (SRS) has emerged as a dedicated treatment option for multiple brain metastases. Consequently, image-guidance for patient positioning and motion management has become very important. The purpose of this study was to analyze intra-fraction errors measured with stereoscopic x-rays and their impact on the dose distribution. Treatments were planned with non- coplanar dynamic conformal arcs for 33 patients corresponding to 127 brain lesions and 356 arcs. Intra-arc positioning errors were measuredusing stereoscopic x-rays (ExacTrac Dynamic, Brainlab), triggered during arc delivery. Couch corrections above 0.7 mm and 0.5° were always applied. Intra-arc positioning data was analyzed. The dose impact was evaluated by applying the measured errors to the dose given in each arc. Median residual errors were 0.10 mm, 0.13 mm and 0.08 mm for the lateral, longitudinal and vertical directions and 0.10°, 0.08° and 0.13° for the pitch, roll and yaw angles respectively. 90% of the treatment arcs showed shifts of less than 0.4 mm and 0.4°in all directions. Dosimetric impact of motion showed the largest losses in coverage on small targets. All targets achieved at least 95% of the prescription dose to 95% of their volume, even when planned without margins. Intra-fractional errors measured during beam delivery were found to be notably low with a dose impact that showed acceptable target coverage when applying these intra-arc errors to the dose distributions of the individual treatment arcs. Using an adequate immobilization and intra-fraction imaging prior to and during irradiation, no margins need to be added to compensate for intra-fraction motion.