Sakibul Huq, Nivedha V. Kannapadi, Joshua Casaos, Tarik Lott, Raphael Felder, Riccardo Serra, Noah L. Gorelick, Miguel A. Ruiz-Cardozo, Andy S. Ding, Arba Cecia, Ravi Medikonda, Jeff Ehresman, Henry Brem, Nicolas Skuli, and Betty M. Tyler
Medulloblastoma, the most common pediatric brain malignancy, has Sonic Hedgehog (SHH) and group 3 (Myc driven) subtypes that are associated with the activity of eukaryotic initiation factor 4E (eIF4E), a critical mediator of translation, and enhancer of zeste homolog 2 (EZH2), a histone methyltransferase and master regulator of transcription. Recent drug repurposing efforts in multiple solid and hematologic malignancies have demonstrated that eIF4E and EZH2 are both pharmacologically inhibited by the FDA-approved antiviral drug ribavirin. Given the molecular overlap between medulloblastoma biology and known ribavirin activity, the authors investigated the preclinical efficacy of repurposing ribavirin as a targeted therapeutic in cell and animal models of medulloblastoma.
Multiple in vitro assays were performed using human ONS-76 (a primitive SHH model) and D425 (an aggressive group 3 model) cells. The impacts of ribavirin on cellular growth, death, migration, and invasion were quantified using proliferation and Cell Counting Kit-8 (CCK-8) assays, flow cytometry with annexin V (AnnV) staining, scratch wound assays, and Matrigel invasion chambers, respectively. Survival following daily ribavirin treatment (100 mg/kg) was assessed in vivo in immunodeficient mice intracranially implanted with D425 cells.
Compared to controls, ribavirin treatment led to a significant reduction in medulloblastoma cell growth (ONS-76 proliferation assay, p = 0.0001; D425 CCK-8 assay, p < 0.0001) and a significant increase in cell death (flow cytometry for AnnV, ONS-76, p = 0.0010; D425, p = 0.0284). In ONS-76 cells, compared to controls, ribavirin significantly decreased cell migration and invasion (Matrigel invasion chamber assay, p = 0.0012). In vivo, ribavirin significantly extended survival in an aggressive group 3 medulloblastoma mouse model compared to vehicle-treated controls (p = 0.0004).
The authors demonstrate that ribavirin, a clinically used drug known to inhibit eIF4E and EZH2, has significant antitumor effects in multiple preclinical models of medulloblastoma, including an aggressive group 3 animal model. Ribavirin may represent a promising targeted therapeutic in medulloblastoma.
Wataru Ishida, Joshua Casaos, Arun Chandra, Adam D’Sa, Seba Ramhmdani, Alexander Perdomo-Pantoja, Nicholas Theodore, George Jallo, Ziya L. Gokaslan, Jean-Paul Wolinsky, Daniel M. Sciubba, Ali Bydon, Timothy F. Witham, and Sheng-Fu L. Lo
With the advent of intraoperative electrophysiological neuromonitoring (IONM), surgical outcomes of various neurosurgical pathologies, such as brain tumors and spinal deformities, have improved. However, its diagnostic and therapeutic value in resecting intradural extramedullary (ID-EM) spinal tumors has not been well documented in the literature. The objective of this study was to summarize the clinical results of IONM in patients with ID-EM spinal tumors.
A retrospective patient database review identified 103 patients with ID-EM spinal tumors who underwent tumor resection with IONM (motor evoked potentials, somatosensory evoked potentials, and free-running electromyography) from January 2010 to December 2015. Patients were classified as those without any new neurological deficits at the 6-month follow-up (group A; n = 86) and those with new deficits (group B; n = 17). Baseline characteristics, clinical outcomes, and IONM findings were collected and statistically analyzed. In addition, a meta-analysis in compliance with the PRISMA guidelines was performed to estimate the overall pooled diagnostic accuracy of IONM in ID-EM spinal tumor resection.
No intergroup differences were discovered between the groups regarding baseline characteristics and operative data. In multivariate analysis, significant IONM changes (p < 0.001) and tumor location (thoracic vs others, p = 0.018) were associated with new neurological deficits at the 6-month follow-up. In predicting these changes, IONM yielded a sensitivity of 82.4% (14/17), specificity of 90.7% (78/86), positive predictive value (PPV) of 63.6% (14/22), negative predictive value (NPV) of 96.3% (78/81), and area under the curve (AUC) of 0.893. The diagnostic value slightly decreased in patients with schwannomas (AUC = 0.875) and thoracic tumors (AUC = 0.842). Among 81 patients who did not demonstrate significant IONM changes at the end of surgery, 19 patients (23.5%) exhibited temporary intraoperative exacerbation of IONM signals, which were recovered by interruption of surgical maneuvers; none of these patients developed new neurological deficits postoperatively. Including the present study, 5 articles encompassing 323 patients were eligible for this meta-analysis, and the overall pooled diagnostic value of IONM was a sensitivity of 77.9%, a specificity of 91.1%, PPV of 56.7%, and NPV of 95.7%.
IONM for the resection of ID-EM spinal tumors is a reasonable modality to predict new postoperative neurological deficits at the 6-month follow-up. Future prospective studies are warranted to further elucidate its diagnostic and therapeutic utility.