Meyer, Fredric B.

Abstract BACKGROUND BRAF pathway alterations are frequent in glial/neuroepithelial tumors. BRAF-targeted therapy with BRAF inhibitors (BRAFi) and/or MEK inhibitors (MEKi) has proven efficacy in clinical trials, though mainly enrolling pediatric patients. We sought to investigate real-world data for adult patients with BRAF-pathway mutant glial/neuroepithelial neoplasms treated with BRAFi/MEKi. METHODS Adults with BRAF-pathway mutated glial/neuroepithelial neoplasms treated with BRAFi/MEKi were retrospectively reviewed. RESULTS Five patients (n=4 female, median age at diagnosis 36) were identified (tumor types: glioblastoma n=1, high-grade astrocytoma with epithelioid features n=1, low-grade neuroepithelial tumor n=1, pilocytic astrocytoma n=1, pleomorphic xanthoastrocytoma n=1). Four had BRAF V600E and one had NF1 p.S2687Cfs*5 mutant tumors. Prior to targeted therapy initiation, patients underwent a median 2.4 treatments including surgery (n=4), radiation therapy (n=4), chemotherapy (temozolomide n=4; carboplatin/vincristine n=1). BRAF-targeted therapies included dabrafenib/trametinib (n=4), binimetinib/encorafenib (n=2), binimetinib (n=2). One NF1-mutant glioblastoma received binimetinib followed by binimetinib/bevacizumab. Median BRAFi/MEKi treatment was 15.2 months (range: 6-36 months). Toxicities included leukopenia (n=3), peripheral edema (n=1), reduced ejection fraction (n=1), skin rash (n=5), transaminitis (n=1) with all patients requiring dose reductions and 3 cases requiring discontinuation. Among patients where BRAFi/MEKi was discontinued due to toxicity, 2 received other treatments at progression, then switched to a different BRAFi/MEKi combination, which they tolerated (duration 6-10months). Best radiographic response was partial response, noted in 3 patients treated with dabrafenib/trametinib. Four patients remain alive and continue BRAFi/MEKi. CONCLUSIONS In this cohort of heavily-pretreated patients with glial/neuroepithelial neoplasms, BRAF-targeted therapy was associated with durable responses. Interestingly, two patients who were unable to tolerate one combination of BRAFi/MEKi were able to tolerate a different combination with sustained response. Our findings support ongoing use of BRAF targeted therapy for CNS tumors. Optimal timing and duration of treatment requires further prospective evaluation in adult patients.

BACKGROUND: Smoking and observed growth of intracranial aneurysms are known risk factors for rupture. The mechanism by which smoking increases this risk is not completely elucidated. Furthermore, an association between smoking and aneurysm growth has not been clearly defined in the literature. We hypothesize that smoking is associated with aneurysm growth, which, in turn, may serve as one of the mechanisms by which smoking drives rupture risk. METHODS: We report a systematic review of the literature in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines. Using the R software, we performed a meta-analysis to investigate the association between smoking and the growth of unruptured intracranial aneurysms. Studies on familial aneurysms and genetic syndromes known to increase the risk of aneurysms were excluded. RESULTS: Eighteen observational studies were included with a total of 3535 patients and 4289 aneurysms with a mean follow-up period ranging from 17 to 226 months. The mean age among the studies ranged from 38.4 to 73.9 years; 74% of patients were female. Ever-smoking status (odds ratio, 1.10 [95% CI, 0.87–1.38]) and current smoking status (odds ratio, 1.43 [95% CI, 0.84–2.43]) did not show a statistically significant association with growth of intracranial aneurysms. Patients currently smoking did not have a statistically significant association with the growth of intracranial aneurysms (odds ratio, 1.18 [95% CI, 0.72–1.93]) compared with patients without a smoking history. No significant association was found in patients who previously smoked compared with patients who never smoked (odds ratio, 1.46 [95% CI, 0.88–2.43]). CONCLUSIONS: Smoking is not clearly associated with the growth of unruptured intracranial aneurysms, despite trends being observed, there is no statistical association. The mechanism by which smoking increases rupture risk might not be growth. In patients for whom observation is recommended, the absence of growth over time in the setting of smoking history does not, therefore, imply protection from rupture.

ABSTRACT Aims Scalp‐EEG interictal epileptiform discharges (IEDs) may be less predictive of the outcome of frontal lobe epilepsy surgery than of temporal lobe epilepsy surgery. We identified factors associated with the location of scalp‐EEG IEDs in intractable frontal lobe epilepsy. Methods Ten factors were assessed in a retrospective review of 53 patients with either concordant (frontal lobe seizure focus) or discordant (generalized or outside frontal seizure focus) IED or both, who had excellent surgical outcomes. The Fisher exact test and the Wilcoxon rank sum test determined statistically significant associations. Results Thirty‐six patients (68%) had concordant IED, 24 (45%) discordant IED, and 17 (32%) both. Younger age at onset was significantly associated with discordant IED (mean, 7.5 years versus 17 years for patients without discordant IED; P < 0.01), whereas duration of epilepsy was not. Seizure foci at the frontal convexity were associated with concordant IED. About 72% of patients with a convexity seizure focus had concordant IED, compared with only 33% of patients with mesial frontal foci having concordant IED ( P = 0.06). Conclusions Early seizure onset in intractable frontal lobe epilepsy is associated with IEDs discordant with seizure focus. Frontal convexity seizure foci are more likely than mesial frontal seizure foci to be associated with concordant discharges.

OBJECTIVE Poor pain control has a negative impact on postoperative recovery and patient satisfaction. However, overzealous pain management, particularly with opioids, can confound serial neurological assessments, increase morbidity, and predispose patients to long-term dependence. Nonsteroidal anti-inflammatory drugs (NSAIDs) are effective in treating postoperative pain and can limit opioid intake, but their use has been limited in patients undergoing craniotomy for brain tumor resection due to concerns of an increased hemorrhage risk. Herein, the authors aim to 1) address the safety of NSAID use in the immediate postoperative setting and 2) determine whether NSAID administration decreases opioid use following craniotomy for tumor resection in adult patients. METHODS The authors conducted a retrospective cohort study of patients 18 years and older with an estimated glomerular filtration rate ≥ 60 ml/min/body surface area who had undergone craniotomy for tumor resection at their institution between 2019 and 2021. NSAID use in the first 48 hours following surgery was recorded. Primary outcomes were postoperative hemorrhage requiring a return to the operating room before hospital discharge and within 30 days of surgery. Secondary outcomes were more-than-minimal hemorrhage that did not require reoperation, acute kidney injury, and total opioid use within 48 hours after craniotomy. RESULTS Among 1765 reviewed patient records, 1182 were eligible for inclusion in this analysis. Amid these records were 114 patients (9.6%) who had received at least one dose of an NSAID within 48 hours of their craniotomy. Four (0.3%) patients experienced bleeding requiring a return to operating room, one of whom was from the NSAID-treated group (RR 3.12, 95% CI 0.33–29.77, p = 0.30). No significant difference in nonoperative intracranial hemorrhage (RR 1.34, 95% CI 0.54–3.35, p = 0.53), postoperative acute kidney injury, or clinically significant extracranial bleeding was found between the NSAID and no-NSAID groups. Patients in the NSAID group had significantly higher oral morphine equivalent use (median 68 vs 30, p < 0.001). CONCLUSIONS Postoperative NSAID use following craniotomy for tumor resection was not associated with an increased risk of hemorrhage requiring a return to the operating room. The authors noted higher opioid use in the patients treated with NSAIDs, which may reflect underlying reasons for the decision to treat patients with NSAIDs in the immediate postoperative period. These data warrant further investigation of NSAIDs as a safe, opioid-sparing postoperative pain management strategy in patients with normal kidney function who are undergoing intracranial tumor resection.

In a period when the budding field of neurosurgery was believed to have little promise, Dr Alfred Washington Adson founded and led the first neurosurgical department at Mayo Clinic. He was not without reservations—surgical intervention for neurological conditions was rarely pursued because of poor outcomes and high complication rates, and Dr Adson acknowledged his early concerns about the future of neurosurgery in his memoirs. However, his education, mentorship, his training, and his first neurosurgical cases helped to shape the impact he ultimately had on the field and his legacy as a neurosurgeon. Dr Adson trained with several renowned Mayo general surgeons, notably his mentor Dr Emil Beckman, whose desire for operative precision shaped Dr Adson's drive to develop his own skills as a surgeon. Two years into his residency, he became the youngest staff surgeon and was tasked with managing the neurosurgical cases at Mayo. The five neurosurgical cases overseen by Dr Adson in the next year illuminated the opportunity for neurosurgery to drastically improve the lives of patients. Dr Adson, given the option of continuing as either a general surgeon or a neurosurgeon, ultimately chose to pursue neurosurgery. This article seeks to provide a historical perspective on the neurosurgeon Dr Alfred Washington Adson using primary and secondary accounts from the Mayo archives, highlighting his contributions to the early understanding of intracranial pathology and how his early experiences as a trainee developed into a personal passion for self-improvement, education, and advocacy for health care in America.