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Purpose: Human papillomavirus-negative (HPV - ) head and neck squamous cell carcinomas (HNSCC) harbor frequent genomic amplification of Fas-associated death domain, with or without concurrent amplification of Baculovirus inhibitor of apoptosis repeat containing (BIRC2/3) genes encoding cellular inhibitor of apoptosis proteins 1/2 (cIAP1/2). Antagonists targeting cIAP1 have been reported to enhance sensitivity of HPV - , but not HPV + tumors, to TNF family death ligands (TNF and TRAIL) and radiation. Experimental Design: We tested a novel dual cIAP/XIAP antagonist ASTX660 in HPV + and HPV - cell lines in combination with death ligands TNFα and TRAIL, and in preclinical xenograft models with radiation, an inducer of death ligands. The dependence of activity on TNF was examined by antibody depletion., Results: ASTX660 sensitized subsets of HPV - and HPV + HNSCC cell lines to TNFα and TRAIL. These antitumor effects of ASTX660 are the result of both apoptosis and/or necroptosis among HPV - cells, and primarily by apoptosis (caspase 3 and caspase 8 cleavage) in HPV + cells. ASTX660 enhanced restoration of protein expression and inhibitory activity of proapoptotic tumor suppressor TP53 in HPV + HNSCC. Furthermore, ASTX660 combined with radiotherapy, an inducer of death ligands, significantly delayed growth of both HPV - and HPV + human tumor xenografts, an effect attenuated by anti-TNFα pretreatment blockade., Conclusions: IAP1/XIAP antagonist, ASTX660, sensitizes HPV + HNSCC to TNFα via a mechanism involving restoration of TP53. These findings serve to motivate further studies of dual cIAP/XIAP antagonists and future clinical trials combining these antagonists with radiotherapy to treat both HPV + and HPV - HNSCC., (©2019 American Association for Cancer Research.)

Study Design: Retrospective multicenter case series study., Objective: Because cervical dural tears are rare, most surgeons have limited experience with this complication. A multicenter study was performed to better understand the presentation, treatment, and outcomes following cervical dural tears., Methods: Multiple surgeons from 23 institutions retrospectively identified 21 rare complications that occurred between 2005 and 2011, including unintentional cervical dural tears. Demographic data and surgical history were obtained. Clinical outcomes following surgery were assessed, and any reoperations were recorded. Neck Disability Index (NDI), modified Japanese Orthopaedic Association (mJOA), Nurick classification (NuC), and Short-Form 36 (SF36) scores were recorded at baseline and final follow-up at certain centers. All data were collected, collated, and analyzed by a private research organization., Results: There were 109 cases of cervical dural tears among 18 463 surgeries performed. In 101 cases (93%) there was no clinical sequelae following successful dural tear repair. There were statistical improvements ( P < .05) in mJOA and NuC scores, but not NDI or SF36 scores. No specific baseline or operative factors were found to be associated with the occurrence of dural tears. In most cases, no further postoperative treatments of the dural tear were required, while there were 13 patients (12%) that required subsequent treatment of cerebrospinal fluid drainage. Analysis of those requiring further treatments did not identify an optimum treatment strategy for cervical dural tears., Conclusions: In this multicenter study, we report our findings on the largest reported series (n = 109) of cervical dural tears. In a vast majority of cases, no subsequent interventions were required and no clinical sequelae were observed., Competing Interests: Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Kevin R. O'Neill reports grants from AOSpine North America during the conduct of the study; Michael G. Fehlings reports grants from AOSpine North America during the conduct of the study; Thomas E. Mroz reports other from AOSpine, grants from AOSpine North America, during the conduct of the study, personal fees from Stryker, personal fees from Ceramtec, other from Pearl Diver, outside the submitted work; Zachary A. Smith reports grants from AOSpine North America during the conduct of the study; Wellington K. Hsu reports grants from AOSpine North America during the conduct of the study, personal fees from Medtronic, personal fees from Stryker, personal fees from Bacterin, personal fees from Graftys, personal fees from Ceramtec, personal fees from Relievant, personal fees from Bioventus, personal fees from Globus, personal fees from SpineSmith, outside the submitted work; Michael P. Steinmetz reports grants from AOSpine North America during the conduct of the study; Praveen V. Mummaneni reports grants from AOSpine North America during the conduct of the study, other from Depuy Spine, grants and other from AOSpine, other from Globus, other from Springer Publishers, other from Thieme Publishers, other from Taylor and Francis Publishers, other from Spincity/ISD, outside the submitted work; Dean Chou reports grants from AOSpine North America during the conduct of the study, other from Globus, other from Orthofix, other from Medtronic, outside the submitted work; Ahmad Nassr reports grants from AOSpine North America during the conduct of the study; Sheeraz A. Qureshi reports grants from AOSpine North America during the conduct of the study, and is a consultant and receive royalties from Stryker Spine, Biomet Spine, and RTI; Evan O. Baird reports grants from AOSpine North America during the conduct of the study; Justin S. Smith reports grants from AOSpine North America during the conduct of the study, personal fees from Biomet, personal fees from Nuvasive, personal fees from Cerapedics, personal fees from K2M, personal fees from Globus, personal fees from DePuy, outside the submitted work; Christopher Shaffrey reports grants from AOSpine North America during the conduct of the study, personal fees from Biomet, personal fees from Medtronic, from Nuvasive, personal fees from K2M, personal fees from Stryker, outside the submitted work, and Editorial Board Spine, Spinal Deformity and Neurosurgery; Chadi A. Tannoury reports grants from AOSpine North America during the conduct of the study; Tony Tannoury reports grants from AOSpine North America during the conduct of the study; Ziya L. Gokaslan reports grants from AOSpine North America during the conduct of the study, grants from AOSpine North America, personal fees from AO Foundation, grants from AOSpine, outside the submitted work; Jeffrey L. Gum reports grants from AOSpine North America during the conduct of the study, personal fees from Medtronic, Alphatec, Stryker, LifeSpine, Acuity, Pacira, PAKmed, Gerson Lehrman Group, personal fees from OREF, AOSpine, personal fees from Acuity, other from Medtronic, personal fees from MiMedx, Pacira Pharmaceuticals, Alphatec, grants from Fischer Owen Fund, nonfinancial support from American Journal of Orthopaedics, nonfinancial support from American Journal of Orthopaedics, The Spine Journal, outside the submitted work; Robert A. Hart reports grants from AOSpine North America during the conduct of the study, other from CSRS Board, other from ISSLS, other from ISSG Executive Commitee, personal fees from DepuySynthes, personal fees from Globus, personal fees from Medtronic, other from Evans, Craven & Lackie, other from Benson, Bertoldo, Baker, & Carter, grants from Medtronic, grants from ISSGF, personal fees from Seaspine, personal fees from DepuySynthes, other from Spine Connect, personal fees from DepuySynthes, outside the submitted work; Robert E. Isaacs reports grants from AOSpine North America during the conduct of the study, grants and personal fees from NuVasive, Inc., personal fees from Association for Collaborative Spine research, outside the submitted work; David B. Bumpass reports grants from AOSpine North America during the conduct of the study, grants from North American Spine Society, personal fees from Doximity, personal fees from Gerson Lehrman Group, outside the submitted work; Adeeb Derakhshan reports grants from AOSpine North America during the conduct of the study; Eric M. Massicotte reports grants from AOSpine North America during the conduct of the study, grants from Medtronic, Depuy-Synthes Spine Canada, personal fees from Watermark Consulting, grants from AOSpine North America, nonfinancial support from AOSpine North America, outside the submitted work; Jonathan R. Pace reports grants from AOSpine North America during the conduct of the study; Gabriel A. Smith reports grants from AOSpine North America during the conduct of the study; Khoi D. Than reports grants from AOSpine North America during the conduct of the study; K. Daniel Riew reports personal fees from AOSpine International, other from Global Spine Journal, other from Spine Journal, other from Neurosurgery, personal fees from Multiple Entities for defense, plantiff, grants from AOSpine, grants from Cerapedics, grants from Medtronic, personal fees from AOSpine, personal fees from NASS, personal fees from Biomet, personal fees from Medtronic, non-financial support from Broadwater, outside the submitted work.