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RIP1 and RIP3 complex regulates radiation-induced programmed necrosis in glioblastoma

Radiation-induced necrosis (RN) is a relatively common side effect of radiation therapy for glioblastoma. However, the molecular mechanisms involved and the ways RN mechanisms differ from regulated cell death (apoptosis) are not well understood. Here, we compare the molecular mechanism of cell death (apoptosis or necrosis) of C6 glioma cells in both in vitro and in vivo (C6 othotopically allograft) models in response to low and high doses of X-ray radiation. Lower radiation doses were used to induce apoptosis, while high-dose levels were chosen to induce radiation necrosis. Our results demonstrate that active caspase-8 in this complex I induces apoptosis in response to low-dose radiation and inhibits necrosis by cleaving RIP1 and RI. When activation of caspase-8 was reduced at high doses of X-ray radiation, the RIP1/RIP3 necrosome complex II is formed. These complexes induce necrosis through the caspase-3-independent pathway mediated by calpain, cathepsin B/D, and apoptosis-inducing factor (AIF). AIF has a dual role in apoptosis and necrosis. At high doses, AIF promotes chromatinolysis and necrosis by interacting with histone H2AX. In addition, NF-κB, STAT-3, and HIF-1 play a crucial role in radiation-induced inflammatory responses embedded in a complex inflammatory network. Analysis of inflammatory markers in matched plasma and cerebrospinal fluid (CSF) isolated from in vivo specimens demonstrated the upregulation of chemokines and cytokines during the necrosis phase. Using RIP1/RIP3 kinase specific inhibitors (Nec-1, GSK′872), we also establish that the RIP1-RIP3 complex regulates programmed necrosis after either high-dose radiation or TNF-α-induced necrosis requires RIP1 and RIP3 kinases. Overall, our data shed new light on the relationship between RIP1/RIP3-mediated programmed necrosis and AIF-mediated caspase-independent programmed necrosis in glioblastoma

Validation of a modern second‐check dosimetry system using a novel verification phantom

Abstract Purpose To evaluate the Mobius second‐check dosimetry system by comparing it to ionization‐chamber dose measurements collected in the recently released Mobius Verification Phantom™ (MVP). For reference, a comparison of these measurements to dose calculated in the primary treatment planning system (TPS), Varian Eclipse with the AcurosXB dose algorithm, is also provided. Finally, patient dose calculated in Mobius is compared directly to Eclipse to demonstrate typical expected results during clinical use of the Mobius system. Methods Seventeen anonymized intensity‐modulated clinical treatment plans were selected for analysis. Dose was recalculated on the MVP in both Eclipse and Mobius. These calculated doses were compared to doses measured using an A1SL ionization‐chamber in the MVP. Dose was measured and analyzed at two different chamber positions for each treatment plan. Mobius calculated dose was then compared directly to Eclipse using the following metrics; target mean dose, target D95%, global 3D gamma pass rate, and target gamma pass rate. Finally, these same metrics were used to analyze the first 36 intensity modulated cases, following clinical implementation of the Mobius system. Results The average difference between Mobius and measurement was 0.3 ± 1.3%. Differences ranged from −3.3 to + 2.2%. The average difference between Eclipse and measurement was −1.2 ± 0.7%. Eclipse vs. measurement differences ranged from −3.0 to −0.1%. For the 17 anonymized pre‐clinical cases, the average target mean dose difference between Mobius and Eclipse was 1.0 ± 1.1%. Average target D95% difference was ‐0.9 ± 2.0%. Average global gamma pass rate, using a criteria of 3%, 2 mm, was 94.4 ± 3.3%, and average gamma pass rate for the target volume only was 80.2 ± 12.3%. Results of the first 36 intensity‐modulated cases, post‐clinical implementation of Mobius, were similar to those seen for the 17 pre‐clinical test cases. Conclusion Mobius correctly calculated dose for each tested intensity modulated treatment plan, agreeing with measurement to within 3.5% for all cases analyzed. The dose calculation accuracy and independence of the Mobius system is sufficient to provide a rigorous second‐check of a modern TPS.

SU-E-T-379: Evaluation of An EPID-Based System for Daily Dosimetry Check by Comparison with a Widely-Used Ionization Chamber-Based Device

Purpose: To examine the feasibility of using Varian’s EPID-based Machine Performance Check (MPC) system to track daily machine output through comparison with Sun Nuclear’s DailyQA3 (DQA) device. Methods: Daily machine outputs for two photon energies (6 and 16MV) and five electron energies (6, 9, 12, 16, 20MeV) were measured for one month using both MPC and DQA. Baselines measurements for MPC were taken at the start of the measurement series, while DQA baselines were set at an earlier date. In order to make absolute comparisons with MPC, all DQA readings were referenced to the average of the first three DQA readings in that series, minimizing systematic differences between the measurement techniques due to baseline differences. In addition to daily output measurements, weekly averages were also calculated and compared. Finally, the electron energy dependence of each measurement technique was examined by comparing energy-specific measurements to the average electron output of all energies each day. Results: For 6 and 16MV photons, the largest absolute percent differences between MPC and DQA were 0.60% and 0.73%, respectively. Weekly averages were within 0.17% and 0.23%, respectively. For all five electron energies, the greatest absolute percent differences between MPC and DQA for each energy ranged from 0.49%–0.83%. Weekly averages ranged from 0.07%–0.28%. DQA energy-specific electron readings matched the average electron output within 0.29% for all days and all energies. MPC energy-specific readings matched the average within 0.21% for 9–20MeV. However, 6MeV showed a larger distribution about the average with four days showing a difference greater than 0.30% and a maximum difference of 0.51%. Conclusion: MPC output measurements correlated well with the widely-used DQA3 for most beam energies, making it a reliable back up technique for daily output monitoring. However, MPC may display an energy dependence for lower electrons energies, requiring additional investigation.

SU‐E‐T‐57: Assessment of Systematic Uncertainties On Beam Data Collection Using Blue Phantom HelixTM Tomotherapy Scanning System

PURPOSE Tomotherapy users are not allowed to modify the beam-data or parameters for beam modeling in Tomotherapy treatment planning system(TPS).The gold beam-data in TPS for modeling and commissioning was measured with TomoScannerTM system(TS).This study investigates the use of the Blue Phantom HelixTM(BPH) as an alternative scanner to establish a benchmark dataset for commissioning and quantifies systematic differences between TS and BPH. METHODS Reproducibility of scanning with BPH was tested by 3 experienced physicists taking 5 measurements over 3 month period.Several enhancements of BPH over TS were included a 3D scanning arm which acquires beam-data with one tank setup,a universal chamber mount,and the OmniPro software,which allows provides online data collections and processing.Discrepancy was estimated by acquiring datasets with each tank under the most recent target conditions.The possible uncertainty due to TPS modeling was quantified by comparison to the golden beam-data.The total systematic uncertainty defined as the combination of scanning system and beam modeling uncertainties, was determined through numerical analysis,and tabulated according to scan type.OmniPro was used for all analysis to eliminate variances of data processing. RESULTS The setup reproducibility of BPH remained within 0.5mm/0.5%.For PDDs,the systematic uncertainties were within 1.4mm/2.1% except for the buildup region up to 7.0±2.5%,which was attributed to output instabilities at surfaces and differences of chamber alignments and dimensions.The differences in field width and penumbra of in-line profiles between BPH,TS and golden were within 0.7±0.9mm.The displacements of field width were increased in cross-line profiles at depth >=10cm up to 3.5%/3.5mm among three datasets.Use of BPH reduced measurement time by 1-2 hrs per session. CONCLUSION The uncertainty magnitudes of BPH have been quantified as an efficient,reproducible and accurate scanning system capable of providing a reliable benchmark beam data. Without the flexibility of replacing the TPS beam-data with BPH measurements,further investigation of dose uncertainties in beam modeling from different measurement datasets is suggested.

SU‐E‐J‐54: The Characterization of a 3D Real‐Time Surface System with a Single High‐Definition (HD) Camera

PURPOSE To investigate a single high-definition (HD) camera of 3D realtime surface system (AlignRT_1HD, VisionRT, Inc.) as the potential alternative to the standard configuration of the system with three charge-coupled device (CCD) cameras (AlignRT_3C) and to evaluate the localization accuracy of AlignRT_1HD compared to AlignRT_3C. METHODS Both AlignRT_3C and AlignRT_1HD were installed in the same treatment room with Varian LINAC. A commercial daily QA phantom (DailyQA3TM, Sun Nuclear) and 5 IMRT patients with intracranial and head and neck tumors receiving non-coplanar treatment were used to evaluate system characteristics and position-tracking accuracies of AlignRT_1HD through comparison with the AlignRT_3C and kV-CBCTs. Surface-image data sets were acquired simultaneously by both systems for the evaluation of inter-and intra-fractional motion at daily treatment of each patient. RESULTS The system origin displacements agreed to within 0.5 mm/0.5°. Compared to the CBCTs without couch rotations, the mean registration errors obtained using AlignRT_1HD were approximately 0.4 mm/0.8° (for phantom displacements up to ± 3cm in 3 axes), 1.1 mm/0.8° (for inter_frational motion in patients), and 0.3 mm/0.4° (for intra_frational motionin patients) less than those obtained using the AlignRT_3C. For non-coplanar treatments, without the surface images acquired by two side camera pods using AlignRT_1HD in this study, the accuracy of patient setup was only guaranteed up to ±10° couch angles. The average setup time using AlignRT_1HD was reduced by approximately 1 min per session. CONCLUSION As judged by CBCTs, AlignRT_1HD is capable of increasing in positioning accuracy and setup efficiency for high precision treatment, with the enhancements in image resolution, frame rate and field of view using HD cameras. The standard configuration with 3-camera-pods of AlignRT_3HD was essential for non-coplanar treatment and the localization accuracy with couch angle up to 90° needs to be further quantified.

TH‐A‐137‐05: Evaluation of Dose Spillage From the Gamma Knife Perfexion Vs Volumetric Modulated Arc Radiosurgery When Treating Multiple Metastases in a Single Fraction

PURPOSE To explore differences in the patterns of dose spillage to normal brain in stereotactic radiosurgery when using the Gamma Knife Perfexion (GKP) versus single-isocenter volumetric modulated arc radiosurgery (VMAS) to treat multiple metastases. METHODS Radiosurgery plans were generated on five T1-weighted MRI data sets for delivery with a Gamma Knife Perfexion (Elekta GammaPlan V10.1) and a Varian accelerator using VMAS (Philips Pinnacle V9.2). Each data set contained between three and five brain metastases. The percent of the target volume receiving the prescription dose (V100%) was >99% for each target. No heterogeneity corrections were used with either planning system. Following planning, the images, contours, and dose distributions were exported to an analysis program (VelocityAI). On each data set, the normal brain volumes receiving 20, 30, 40, 50, 60, 70, 80, and 90% of the prescription dose were determined and tabulated. Normal brain was defined as brain minus any target volumes. A percent change from GKP to VMAS was calculated for each dose level. Isodose lines and DVHs were generated for each modality and overlaid. RESULTS Dose spillage to normal brain was consistently higher for single-isocenter VMAS compared to GKP, even when the volume of brain receiving the prescription dose remained similar or decreased. This increase in dose spillage could be seen for all dose levels (V90%-V20%), and was more significant for lower dose levels. Levels V20-40% showed an average increase of+653% compared to GKP. Levels V70-90% showed an average increase of +355%. The average increase across all levels was +546%. CONCLUSION Dose spillage to normal brain is significantly increased when treating multiple metastases with single-isocenter VMAS compared to multi-shot treatment with GKP. The clinical implications of this increased spillage should be examined further, particularly in situations where patients may receive multiple SRS treatments or radiosurgery combined with whole-brain radiotherapy.

SU-E-T-91: The Effect of Phantom Setup Uncertainties On Gantry Angle Correction Factors for MatriXX Evolution

PURPOSE Prior research has shown that the MatriXX Evolution™ 2D ion chamber array has an angular-dependent dose response. This can be corrected using user-defined gantry angle correction factors (GACFs). The GACF for a given angle is defined as the ratio of the users TPS-calculated dose to the phantom-measured dose at that angle. This work evaluates the effect of phantom setup uncertainties on GACF values. METHODS Measurements were made with the MatriXX in a MultiCube phantom (IBA Dosimetry). The GACFs were created using the vendors recommended procedure. The phantom was irradiated with a 6 MV, 27×27 cm2 field at gantry angles 0° to 355° (IEC convention) in 5-degree increments. Additional measurements were made in 1-degree increments from 85° to 95° and 265° to 275°. The reference planar doses for each angle were computed using Philips Pinnacle3 TPS. Translation errors of 1 mm and 2 mm along each axis were simulated, along with rotational errors about the longitudinal axis of 0.5° and 1°. GACFs were computed for each shift and compared to the values for the unshifted phantom. RESULTS Vertical shifts produced changes in GACFs of up to 1.5% at a gantry angles near 180°. Vertical shifts produced changes of up to 8% near 90° and 270°, where the GACFs vary rapidly with angle. Lateral shifts produced changes of up to 1.7%. Longitudinal shifts, which occur parallel to the gantry rotation axis, caused negligible changes to GACFs. Rotational shifts of 1° produced up to 6% changes in GACFs near 90° and 270°. CONCLUSION Shifts in phantom position and orientation of less than 2 mm or 1 degree generally produce changes in computed GACFs of less than 2%. Larger changes in GACFs at certain angles may be important for IMRT plan verification for plans with beam angles near the more sensitive angles.