EGFR Amplification Induces Increased DNA Damage Response and Renders Selective Sensitivity to Talazoparib (PARP Inhibitor) in Glioblastoma.

PURPOSE: Exploration of novel strategies to extend the benefit of PARP inhibitors beyond BRCA-mutant cancers is of great interest in personalized medicine. Here, we identified EGFR amplification as a potential biomarker to predict sensitivity to PARP inhibition, providing selection for the glioblastoma (GBM) patient population who will benefit from PARP inhibition therapy. EXPERIMENTAL DESIGN: Selective sensitivity to the PARP inhibitor talazoparib was screened and validated in two sets [test set (n = 14) and validation set (n = 13)] of well-characterized patient-derived glioma sphere-forming cells (GSC). FISH was used to detect EGFR copy number. DNA damage response following talazoparib treatment was evaluated by γH2AX and 53BP1 staining and neutral comet assay. PARP-DNA trapping was analyzed by subcellular fractionation. The selective monotherapy of talazoparib was confirmed using in vivo glioma models. RESULTS: EGFR-amplified GSCs showed remarkable sensitivity to talazoparib treatment. EGFR amplification was associated with increased reactive oxygen species (ROS) and subsequent increased basal expression of DNA-repair pathways to counterelevated oxidative stress, and thus rendered vulnerability to PARP inhibition. Following talazoparib treatment, EGFR-amplified GSCs showed enhanced DNA damage and increased PARP-DNA trapping, which augmented the cytotoxicity. EGFR amplification-associated selective sensitivity was further supported by the in vivo experimental results showing that talazoparib significantly suppressed tumor growth in EGFR-amplified subcutaneous models but not in nonamplified models. CONCLUSIONS: EGFR-amplified cells are highly sensitive to talazoparib. Our data provide insight into the potential of using EGFR amplification as a selection biomarker for the development of personalized therapy.

The effectiveness of extrication collars tested during the execution of spine-board transfer techniques.

BACKGROUND CONTEXT: In the prehospital stages of emergency care, cervical collars are (supposedly) used to aid rescuers in maintaining in-line stabilization of the spinal column as patients with potential or actual injuries are shifted onto a spine board to achieve full spinal immobilization. Unfortunately, not a single study has examined the effectiveness of cervical collars to control motion during the execution of spine-board transfer techniques. PURPOSE: To evaluate the controlling effect of three cervical collars during the execution of spine-board transfer techniques. STUDY DESIGN: This was a repeated measures investigation in which a cadaveric model was used to test the effectiveness of the Ambu (Ambu, Inc., Linthicum, MD), Aspen (Aspen Medical Products, Inc., Long Beach, CA) and Miami J (Jerome Medical, Moorestown, NJ) collars during the execution of the log-roll (LR) maneuver and the lift-and-slide (LS) technique. METHODS: Six medical professionals executed the LR and the LS on five cadavers. An electromagnetic tracking device was used to capture angular movements generated at the C5-C6 vertebral segment during the execution of both transfer techniques. The types of motion that were analyzed in this study were flexion-extension, lateral flexion and axial rotation motion. To test the three cervical collars, an experimental lesion (ie, a complete segmental instability) was created at the aforementioned spinal level of the cadavers and sensors from the electromagnetic tracking device were affixed to the specified vertebrae to record the motion generated at the site of the lesion. RESULTS: Statistical tests did not reveal a significant interaction between the independent variables of this study (ie, transfer technique and collar type), lending no support to the notion that there may be a combination of collar and transfer technique that could theoretically offer added protection to the patient. Although there was a decrease in the amount of motion generated in every one of the planes of motion as a result of wearing each of the three collars, none of the changes that emerged proved to be significantly different. A significant difference was noted between the LR and LS techniques when the amount of lateral flexion and axial rotation motion generated with each of the procedures were compared. In both cases, execution of the LR maneuver resulted in significantly more motion. CONCLUSIONS: The data presented here suggest that the collars tested in this study are functionally similar. It is recommended that this study be repeated with a larger sample size.