RESUMO
Outcomes for glioblastoma (GBM) remain poor despite standard-of-care treatments including surgical resection, radiation, and chemotherapy. Intratumoral heterogeneity contributes to treatment resistance and poor prognosis, thus demanding novel therapeutic approaches. Drug repositioning studies on antiretroviral therapy (ART) have shown promising potent antineoplastic effects in multiple cancers; however, its efficacy in GBM remains unclear. To better understand the pleiotropic anticancer effects of ART on GBM, we conducted a comprehensive drug repurposing analysis of ART in GBM to highlight its utility in translational neuro-oncology. To uncover the anticancer role of ART in GBM, we conducted a comprehensive bioinformatic and in vitro screen of antiretrovirals against glioblastoma. Using the DepMap repository and reversal of gene expression score, we conducted an unbiased screen of 16 antiretrovirals in 40 glioma cell lines to identify promising candidates for GBM drug repositioning. We utilized patient-derived neurospheres and glioma cell lines to assess neurosphere viability, proliferation, and stemness. Our in silico screen revealed that several ART drugs including reverse transcriptase inhibitors (RTIs) and protease inhibitors (PIs) demonstrated marked anti-glioma activity with the capability of reversing the GBM disease signature. RTIs effectively decreased cell viability, GBM stem cell markers, and proliferation. Our study provides mechanistic and functional insight into the utility of ART repurposing for malignant gliomas, which supports the current literature. Given their safety profile, preclinical efficacy, and neuropenetrance, ARTs may be a promising adjuvant treatment for GBM.
RESUMO
BACKGROUND: Adjacent segment disease (ASD) is a known sequela of thoracolumbar instrumented fusions. Various surgical options are available to address ASD in patients with intractable symptoms who have failed conservative measures. However, the optimal treatment strategy for symptomatic ASD has not been established. We examined several clinical outcomes utilizing different surgical interventions for symptomatic ASD. METHODS: A retrospective review was performed for a consecutive series of patients undergoing revision surgery for thoracolumbar ASD between October 2011 and February 2022. Patients were treated with endoscopic decompression (N = 17), microdiscectomy (N = 9), lateral lumbar interbody fusion (LLIF; N = 26), or open laminectomy and fusion (LF; N = 55). The primary outcomes compared between groups were re-operation rates and numeric pain scores for leg and back at 2 weeks, 10 weeks, 6 months, and 12 months postoperation. Secondary outcomes included time to re-operation, estimated blood loss, and length of stay. RESULTS: Of the 257 patients who underwent revision surgery for symptomatic ASD, 107 patients met inclusion criteria with a minimum of 1-year follow-up. The mean age of all patients was 67.90 ± 10.51 years. There was no statistically significant difference between groups in age, gender, preoperative American Society of Anesthesiologists scoring, number of previously fused levels, or preoperative numeric leg and back pain scores. The re-operation rates were significantly lower in LF (12.7%) and LLIF cohorts (19.2%) compared with microdiscectomy (33%) and endoscopic decompression (52.9%; P = 0.005). Only LF and LLIF cohorts experienced significantly decreased pain scores at all 4 follow-up visits (2 weeks, 10 weeks, 6 months, and 12 months; P < 0.001 and P < 0.05, respectively) relative to preoperative scores. CONCLUSION: Symptomatic ASD often requires treatment with revision surgery. Fusion surgeries (either stand-alone lateral interbody or posterolateral with instrumentation) were most effective and durable with respect to alleviating pain and avoiding additional revisions within the first 12 months following revision surgery. CLINICAL RELEVANCE: This study emphasizes the importance of risk-stratifying patients to identify the least invasive approach that treats their symptoms and reduces the risk of future surgeries.