RESUMO
OBJECTIVE: Despite the growing acceptance of neuronavigation in the field of neurosurgery, there is limited comparative research, with contradictory results. This study aimed to compare the effectiveness (tumor resection rate and survival) and safety (frequency of neurological complications) of surgery for brain gliomas with or without neuronavigation. METHODS: This retrospective cohort study evaluated data obtained from electronic records of patients who underwent surgery for gliomas at Dr. Alejandro Dávila Bolaños Military Hospital and the Clinic Hospital of Barcelona between July 2016 and September 2022. The preoperative and postoperative clinical and radiological characteristics were analyzed and compared according to the use of neuronavigation. RESULTS: This study included 110 patients, of whom 79 underwent surgery with neuronavigation. Neuronavigation increased gross total resection by 57% in patients in whom it was used; gross total resection was performed in 56% of patients who underwent surgery with neuronavigation as compared with 35.5% in those who underwent surgery without neuronavigation (risk ratio [RR], 1.57; P = 0.056). The incidence of postoperative neurological deficits (transient and permanent) decreased by 79% with the use of neuronavigation, (12% versus 33.3%; RR, 0.21; P = 0.0003) . Neuronavigation improved survival in patients with grade IV gliomas (15 months versus 13.8 months), but it was not statistically significant (odds ratio, 0.19; P = 0.13). CONCLUSIONS: Neuronavigation improved the effectiveness (greater gross total resection of tumors) and safety (fewer neurological deficits) of brain glioma surgery. However, neuronavigation does not significantly influence the survival of patients with grade IV gliomas.
RESUMO
The therapeutic benefit of approved BRAF and MEK inhibitors (BRAFi/MEKi) in patients with brain metastatic BRAF V600E/K-mutated melanoma is limited and transient. Resistance largely occurs through the restoration of MAPK signaling via paradoxical BRAF activation, highlighting the need for more effective therapeutic options. Aiming to address this clinical challenge, we characterized the activity of a potent, brain-penetrant paradox breaker BRAFi (compound 1a, C1a) as first-line therapy and following progression upon treatment with approved BRAFi and BRAFi/MEKi therapies. C1a activity was evaluated in vitro and in vivo in melanoma cell lines and patient-derived models of BRAF V600E-mutant melanoma brain metastases following relapse after treatment with BRAFi/MEKi. C1a showed superior efficacy compared with approved BRAFi in both subcutaneous and brain metastatic models. Importantly, C1a manifested potent and prolonged antitumor activity even in models that progressed on BRAFi/MEKi treatment. Analysis of mechanisms of resistance to C1a revealed MAPK reactivation under drug treatment as the predominant resistance-driving event in both subcutaneous and intracranial tumors. Specifically, BRAF kinase domain duplication was identified as a frequently occurring driver of resistance to C1a. Combination therapies of C1a and anti-PD-1 antibody proved to significantly reduce disease recurrence. Collectively, these preclinical studies validate the outstanding antitumor activity of C1a in brain metastasis, support clinical investigation of this agent in patients pretreated with BRAFi/MEKi, unveil genetic drivers of tumor escape from C1a, and identify a combinatorial treatment that achieves long-lasting responses. SIGNIFICANCE: A brain-penetrant BRAF inhibitor demonstrates potent activity in brain metastatic melanoma, even upon relapse following standard BRAF inhibitor therapy, supporting further investigation into its clinical utility.
