Sustained Tumor Control With MAPK Inhibition in BRAF V600-Mutant Adult Glial and Glioneuronal Tumors.

OBJECTIVE: To assess whether RAF and MEK inhibitors (RAFi/MEKi) can provide long-term clinical benefit in adult patients with BRAF V600-mutant glial and glioneuronal tumors (GGNTs), we analyzed tumor response and long-term outcome in a retrospective cohort. METHODS: We performed a retrospective search in the institutional databases of 6 neuro-oncology departments for adult patients with recurrent or disseminated BRAF V600-mutant GGNTs treated with RAFi/MEKi. RESULTS: Twenty-eight adults with recurrent or disseminated BRAF V600-mutant gangliogliomas (n = 9), pleomorphic xanthoastrocytomas (n = 9), and diffuse gliomas (n = 10) were included in the study. At the time that treatment with RAFi/MEKi was started, all tumors displayed radiologic features of high-grade neoplasms. Thirteen patients received RAFi as single agents (vemurafenib [n = 11], dabrafenib [n = 2]), and 15 received combinations of RAFi/MEKi (vemurafenib + cobimetinib [n = 5], dabrafenib + trametinib [n = 10]). Eleven patients achieved a partial or complete response (11 of 28, 39%), with a median reduction of -78% in their tumor burden. Responders experienced a median increase of 10 points in their Karnofsky Performance Status (KPS) score and a median progression-free survival of 18 months, which was longer than achieved with first-line treatment (i.e., 7 months, p = 0.047). Responders had better KPS score (p = 0.018) and tended to be younger (p = 0.061) and to be treated earlier (p = 0.099) compared to nonresponders. Five patients were rechallenged with RAFi/MEKi at progression, with novel tumor responses in 2. On univariate and multivariate analyses, response to RAFi/MEKi was an independent predictor of overall survival. CONCLUSIONS: Our study highlights the long-term clinical benefits of RAFi/MEKi in adult patients with BRAF V600-mutant GGNTs and encourages rechallenge in responders. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that, for adult patients with BRAF V600-mutant GGNT, RAFi/MEKi can reduce tumor burden and provide clinical benefit.

Futile inter-hospital transfer for mechanical thrombectomy in a semi-rural context: analysis of a 6-year prospective registry.

BACKGROUND AND PURPOSE: Inter-hospital transfer for mechanical thrombectomy (MT) might result in the transfer of patients who finally will not undergo MT (ie, futile transfers [FT]). This study evaluated FT frequency in a primary stroke center (PSC) in a semi-rural area and at 156 km from the comprehensive stroke center (CSC). METHODOLOGY: Retrospective analysis of data collected in a 6-year prospective registry concerning patients admitted to our PSC within 4.5 hours of acute ischemic stroke (AIS) symptom onset, with MR angiography indicating the presence of large vessel occlusion (LVO) without large cerebral infarction (DWI-ASPECT ≥5), and selected for transfer to the CSC to undergo MT. Futile transfer rate and reasons were determined, and the relevant time measures recorded. RESULTS: Among the 529 patients screened for MT, 278 (52.6%) were transferred to the CSC. Futile transfer rate was 45% (n=125/278) and the three main reasons for FT were: clinical improvement and reperfusion on MRI on arrival at the CSC (58.4% of FT); clinical worsening and/or infarct growth (16.8%); and longer than expected inter-hospital transfer time (11.2%). Predictive factors of FT due to clinical improvement/reperfusion on MRI could not be identified. Baseline higher NIHSS (21 vs 17; P=0.01) and lower DWI-ASPECT score (5 vs 7; P=0.001) were associated with FT due to clinical worsening/infarct growth on MRI. CONCLUSIONS: In our setting, 45% of transfers for MT were futile. None of the baseline factors could predict FT, but the initial symptom severity was associated with FT caused byclinical worsening/infarct growth.

Optic Nerve Infiltration in Primary Central Nervous System Lymphoma.

Importance: Visual impairment in primary central nervous system lymphoma (PCNSL) is caused mostly by intraocular lymphomatous involvement (vitritis and retinal infiltration), whereas optic nerve infiltration (ONI) is a rare condition. Objective: To describe the clinical presentation of ONI, its imaging characteristics, and outcome. Design, Setting and Participants: A total of 752 patients diagnosed with PCNSL were retrospectively identified from the databases of 3 French hospitals from January 1, 1998, through December 31, 2014. Of these, 7 patients had documented ONI. Exclusion criteria were intraocular involvement, orbital lymphoma, or other systemic lymphoma. Clinical presentation, neuroimaging, biological features, treatment, and outcomes were assessed. Main Outcomes and Measures: Treatment response was evaluated clinically and radiologically on follow-up magnetic resonance imaging (MRI) according to the International PCNSL Collaborative Group response criteria. Results: The 7 patients included 5 women and 2 men. Median age at diagnosis was 65 years (range, 49-78 years). Two patients had initial ONI at diagnosis, and 5 had ONI at relapse. Clinical presentation was marked by rapidly progressive and severe visual impairment for all patients. The MRI findings showed optic nerve enlargement in 3 patients and contrast enhancement of the optic nerve in all patients. Additional CNS lesions were seen in 4 patients. Examination of cerebrospinal fluid samples detected lymphomatous meningitis in 2 patients. Clinical outcome was poor and marked by partial recovery for 2 patients and persistent severe low visual acuity or blindness for 5 patients. Median progression-free survival after optic nerve infiltration was 11 months (95% CI, 9-13 months), and median overall survival was 18 months (95% CI, 9-27 months). Conclusions and Relevance: Optic nerve infiltration is an atypical and challenging presentation of PCNSL. Its visual and systemic prognosis is particularly poor compared with vitreoretinal lymphomas even in response to chemotherapy. Although intraocular involvement is frequent in PCNSL and clinically marked by slowly progressive visual deterioration, lymphomatous ONI is rare and characterized by rapidly progressive severe visual impairment.

The CSF IL-10 concentration is an effective diagnostic marker in immunocompetent primary CNS lymphoma and a potential prognostic biomarker in treatment-responsive patients.

INTRODUCTION: We aimed to confirm the diagnostic value and to evaluate the pre- and post-therapeutic prognostic value of cerebrospinal fluid (CSF) concentrations of interleukin (IL)-10 and IL-6 in patients with diffuse large B-cell primary central nervous system lymphoma (PCNSL). PATIENTS AND METHODS: IL-10 and IL-6 concentrations were measured in 79 patients with PCNSL at diagnosis and in 40 control individuals. Fifty-four PCNSL patients underwent repeat assessments starting at diagnosis. RESULTS: The IL-10 concentration distinguished PCNSL from other neurologic diseases with a sensitivity of 88.6% and a specificity of 88.9% with a cutoff of 4 pg/ml. In a multivariate analysis of PCNSL patients, CSF involvement was associated with a higher IL-10 concentration (mean log (IL-10) of 4.4 versus 2.5 pg/ml, respectively, p = 0.0004). The pre-therapeutic IL-10 concentration had no prognostic impact on outcome. The IL-10 concentration decreased after treatment for most patients tested. Among patients with complete remission or partial remission, as evaluated by magnetic resonance imaging (MRI), a persistent detectable IL-10 level in the CSF at the end of treatment was associated with a negative impact on progression-free survival (PFS) (1-year PFS: 15%, 95% confidence interval [CI]: 2.5-38% versus 59%, 95% CI: 32-78%, respectively, p = 0.0004). CONCLUSION: Our study confirmed that IL-10 is a useful biomarker for the diagnosis of PCNSL. We highlight new findings showing that the IL-10 level in the CSF could be used as a surrogate marker for CSF involvement and that the post-treatment IL-10 concentration could complement standard MRI for therapeutic response assessment in PCNSL.