OBJECTIVEBRAF V600E is a common oncogenic driver in a variety of primary brain tumors. Dual inhibitor therapy using dabrafenib (a selective oral inhibitor of several mutated forms of BRAF kinase) and trametinib (a reversible inhibitor of MEK1 and MEK2) has been used successfully for treatment of metastatic melanoma, anaplastic thyroid cancer, and other tumor types, but has been reported in only a few patients with primary brain tumors and none with pleomorphic xanthoastrocytoma. Here, the authors report on the substantial clinical response and reduction in cutaneous toxicity in a case series of BRAF V600E primary brain cancers treated with dual BRAF/MEK inhibitor therapy.METHODSThe authors treated 4 BRAF V600E patients, each with a different type of primary brain tumor (pilocytic astrocytoma, papillary craniopharyngioma, ganglioglioma, and pleomorphic xanthoastrocytoma) with the combination of dabrafenib and trametinib.RESULTSThe patients with pilocytic astrocytoma, pleomorphic xanthoastrocytoma, and papillary craniopharyngioma experienced near-complete radiographic and complete clinical responses after 8 weeks of therapy. A substantial partial response (by RANO [Response Assessment in Neuro-Oncology] criteria) was observed in the patient with ganglioglioma. The patient with craniopharyngioma developed dramatic, diffuse verrucal keratosis within 2 weeks of starting dabrafenib. This completely resolved within 2 weeks of adding trametinib.CONCLUSIONSDual BRAF/MEK inhibitor therapy represents an exciting treatment option for patients with BRAF V600E primary brain tumors. In addition to greater efficacy than single-agent dabrafenib, this combination has the potential to mitigate cutaneous toxicity, one of the most common and concerning BRAF inhibitor–related adverse events.

INTRODUCTION NM is defined clinically by multilevel neurologic dysfunction. Seizures occur in less than 15% of patients. We describe a curable phenomenon (“plateau wave events”) that mimics and may be more common than seizures, but is not responsive to anticonvulsant medication. METHODS We queried a multinational NM registry to identify patients with episodic neurologic dysfunction suspected of having seizures. Detailed demographic, disease, treatment, and outcome data were collected. RESULTS Forty-three patients (21.2% of 203) were identified. Twenty patients (46.5% of 43) demonstrated a stereotyped constellation of symptoms including episodic severe headache and loss (19 patients) or impaired level (1 patient) of consciousness, nausea, vomiting, and gait instability lasting 30–180 seconds, with abrupt resolution and without post-ictal symptoms. Events developed a median of 74 (0–350) days following NM diagnosis. Fourteen patients (74%) were female. Median age was 54.8 [IQR 46.8, 61.6] years. Fourteen patients had solid tumors (11 breast), 5 had hematologic malignancies, and 1 had a primary brain tumor. Thirteen (68%) had ventriculomegaly. All patients demonstrated increased ICP [median 30.0 cm H2O, IQR 22.5, 30.0]. CSF cytology was positive and CSF protein was increased in 100% of patients, but no demographic, laboratory, or disease characteristic was associated with plateau wave events on multivariate analysis. Inter-ictal EEG in 8 patients showed no epileptiform activity. One intra-ictal EEG showed marked brainwave slowing and bradycardia during the clinical event. One intra-ictal ICP tracing showed an abrupt and dramatic increase in intracranial pressure during the event. Nineteen patients underwent ventriculoperitoneal shunting and experienced immediate symptom resolution. Anticonvulsant medication, initiated in 11 of these patients prior to shunting, provided no benefit. CONCLUSIONS Plateau wave events are common in patients with NM. They are frequently mistaken for seizures but are easily recognized by a constellation of defining signs and symptoms. Ventriculoperitoneal shunting is curative.

s vi216NEURO-ONCOLOGY • NOVEMBER 2017were alive at the time of analysis. 2 patients identified as Asian and 7 as White. The MiB labeling index (MiB) ranged from ≤2 to 20%. All underwent surgical resection and GTR was achieved in 5. Of those patients with GTR, 3 (MiB 3-5, 5 and 20%) received adjuvant radiotherapy (RT). A single patient with GTR and elevated MiB of 5% did not receive RT: this patient is progression-free at 38 months and is the only patient with a KPS of 100.There was a single case of recurrence in the patient with highest MiB (20%) treated with GTR, RT, and concurrent temozolomide. This patient is alive >10 years from diagnosis and 5.2 years after recurrence. A majority that received RT (n=6), were referred for neuropsychological evaluation with 4 patients requiring use of methylphenidate. CONCLUSIONS: This tumor has a favorable prognosis even with elevated MiB and in the setting of recurrence. Treatment for recurrence may include GTR and conformal RT with temozolomide. Further research on RT sparing treatments in the adjuvant setting is warranted. Referral for neuropsychological evaluation and symptomatic treatment with methylphenidate should be considered in patients who receive RT.