Glioblastoma (GBM) is the most common primary malignant brain tumor, and it has a uniformly poor prognosis. Hypoxia is a feature of the GBM microenvironment, and previous work has shown that cancer cells residing in hypoxic regions resist treatment. Hypoxia can trigger the formation of stress granules (SGs), sites of mRNA triage that promote cell survival. A screen of 1120 FDA-approved drugs identified 129 candidates that delayed the dissolution of hypoxia-induced SGs following a return to normoxia. Amongst these candidates, the selective estrogen receptor modulator (SERM) raloxifene delayed SG dissolution in a dose-dependent manner. SG dissolution typically occurs by 15 min post-hypoxia, however pre-treatment of immortalized U251 and U3024 primary GBM cells with raloxifene prevented SG dissolution for up to 2 h. During this raloxifene-induced delay in SG dissolution, translational silencing was sustained, eIF2α remained phosphorylated and mTOR remained inactive. Despite its well-described role as a SERM, raloxifene-mediated delay in SG dissolution was unaffected by co-administration of β-estradiol, nor did β-estradiol alone have any effect on SGs. Importantly, the combination of raloxifene and hypoxia resulted in increased numbers of late apoptotic/necrotic cells. Raloxifene and hypoxia also demonstrated a block in late autophagy similar to the known autophagy inhibitor chloroquine (CQ). Genetic disruption of the SG-nucleating proteins G3BP1 and G3BP2 revealed that G3BP1 is required to sustain the raloxifene-mediated delay in SG dissolution. Together, these findings indicate that modulating the stress response can be used to exploit the hypoxic niche of GBM tumors, causing cell death by disrupting pro-survival stress responses and control of protein synthesis.

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OBJECTIVE Anterior cervical discectomy and fusion (ACDF) is often described as the gold standard surgical technique for cervical spondylotic radiculopathy. Although outcomes are considered favorable, there is little prognostic evidence to guide patient selection for ACDF. This study aimed to 1) describe the 24-month postoperative trajectories of arm pain, neck pain, and pain-related disability; and 2) identify perioperative prognostic factors that predict trajectories representing poor clinical outcomes. METHODS In this retrospective cohort study, patients with cervical spondylotic radiculopathy who underwent ACDF at 1 of 12 orthopedic or neurological surgery centers were recruited. Potential outcome predictors included demographic, health, clinical, and surgery-related prognostic factors. Surgical outcomes were classified by trajectories of arm pain intensity, neck pain intensity (numeric pain rating scales), and pain-related disability (Neck Disability Index) from before surgery to 24 months postsurgery. Trajectories of postoperative pain and disability were estimated with latent class growth analysis, and prognostic factors associated with poor outcome trajectory were identified with robust Poisson models. RESULTS The authors included data from 352 patients (mean age 50.9 [SD 9.5] years; 43.8% female). The models estimated that 15.5%–23.5% of patients followed a trajectory consistent with a poor clinical outcome. Lower physical and mental health–related quality of life, moderate to severe risk of depression, and longer surgical wait time and procedure time predicted poor postoperative trajectories for all outcomes. Receiving compensation and smoking additionally predicted a poor neck pain outcome. Regular exercise, physiotherapy, and spinal injections before surgery were associated with a lower risk of poor disability outcome. Patients who used daily opioids, those with worse general health, or those who reported predominant neck pain or a history of depression were at greater risk of poor disability outcome. CONCLUSIONS Patients who undergo ACDF for cervical spondylotic radiculopathy experience heterogeneous postoperative trajectories of pain and disability, with 15.5%–23.5% of patients experiencing poor outcomes. Demographic, health, clinical, and surgery-related prognostic factors can predict ACDF outcomes. This information may further assist surgeons with patient selection and with setting realistic expectations. Future studies are needed to replicate and validate these findings prior to confident clinical implementation.