Deep brain stimulation in Bassen-Kornzweig syndrome: Still effective after 22 years.

Introduction: Bassen-Kornzweig syndrome or abetalipoproteinemia is a rare autosomal recessive disorder characterized by a malabsorption of dietary fat and fat-soluble vitamins. This deficiency can lead to a variety of symptoms, including hematological (acanthocytosis, bleeding tendency), neurological (tremor, spinocerebellar ataxia), neuromuscular (myopathy), ophthalmological symptoms (retinitis pigmentosa). The thalamic ventral intermediate nucleus (VIM) is a well-established target for deep brain stimulation (DBS) in the treatment of refractory tremor. Research question: We evaluated the clinical long-term follow-up (22 years) after VIM-DBS for refractory tremor in abetalipoproteinemia. We also evaluated the adjustments of stimulation settings and medication balance after DBS procedure. Material and methods: We report a 53-year-old male who suffers from abetalipoproteinemia since the age of 17. He underwent bilateral VIM-DBS to treat his disabling refractory intentional tremor at the age of 31. He still has a very good response to his tremor with limited stimulation adaptations over 22 years. For more than two decades follow-up, the treatment significantly improved his ADL functions and therefore also the QoL. Discussion and conclusion: The VIM target for DBS in the treatment of refractory tremor has been extensively reported in the literature. Thalamic VIM-DBS is a safe and effective treatment for a severe, refractory tremor as a neurological symptom caused by abetalipoproteinemia. It also highlights the importance of a multidisciplinary follow-up, to adjust and optimize the stimulation/medication balance after VIM-DBS surgery.

Randomized phase II trial comparing axitinib with the combination of axitinib and lomustine in patients with recurrent glioblastoma.

Axitinib is a small molecule tyrosine kinase inhibitor with high affinity and specificity for the family of vascular endothelial growth factor receptors. It has previously demonstrated anti-tumor activity in a small cohort of patients with recurrent glioblastoma (rGB). We conducted a non-comparative randomized phase II clinical trial investigating axitinib monotherapy versus axitinib plus lomustine (LOM) in patients with rGB. Primary endpoint was 6 month progression-free survival (6mPFS). Patients who progressed on axitinib-monotherapy were allowed to cross-over. Between August 2011 and July 2015, 79 patients were randomized and initiated axitinib monotherapy (n = 50; AXI) or axitinib plus lomustine (n = 29; AXILOM). Median age was 55y [range 18-80], 50M/28F. Baseline characteristics were well balanced between study arms. Nineteen patients in the AXI-arm crossed-over at the time of progression. Treatment was generally well tolerated. AXILOM patients were at higher risk for grade 3/4 neutropenia (0 vs. 21%) and thrombocytopenia (4 vs. 29%). Best Overall Response Rate (BORR) in the AXI-arm was 28 vs. 38% in the AXILOM-arm. 6mPFS was 26% (95% CI 14-38) versus 17% (95% CI 2-32) for patients treated in the AXI versus AXILOM-arms, respectively. Median overall survival was 29 weeks (95% CI 20-38) in the AXI-arm and 27.4 weeks (95% CI 18.4-36.5) in the AXILOM-arm. MGMT-promoter hypermethylation and steroid treatment at baseline correlated significantly with PFS and OS. We conclude from these results that axitinib improves response rate and progression-free survival in patients with rGB compared to historical controls. There is no indication that upfront combination of axitinib with LOM improves results (European Clinical Trials Database (EudraCT) Study Number: 2011-000900-16).

Randomized phase II study of axitinib versus physicians best alternative choice of therapy in patients with recurrent glioblastoma.

We conducted a randomized, non-comparative, multi center, phase II clinical trial in order to investigate the efficacy of axitinib, an oral small molecule tyrosine kinase inhibitor with high affinity and specificity for the vascular endothelial growth factor receptors, in patients with recurrent glioblastoma following prior treatment with radiation and temozolomide. Forty-four patients were randomly assigned to receive treatment with axitinib (5 mg BID starting dose; N = 22) or "physicians best alternative choice of therapy" that consisted of bevacizumab (N = 20) or lomustine (N = 2). Six-month progression-free survival served as the primary endpoint. The estimated 6-month progression-free survival rate was 34 % (95 % CI 14-54) for patients treated with axitinib and 28 % (95 % CI 8-48) with best alternative treatment; median overall survival was 29 and 17 weeks, respectively. Objective responses according to RANO criteria were documented in 28 % of patients treated with axitinib and 23 % of patients treated with best alternative therapy. A decrease in maximal uptake of 18F-fluoro-ethyL-tyrosine (18F-FET) by the glioblastoma on PET imaging was documented in 85 % of patients at the time of response on axitinib. Corticosteroid treatment could be stopped in four and tapered in seven out of the 15 patients who were treated with steroids at baseline in the axitinib cohort. Most frequent axitinib related grade ≥3 adverse events consisted of fatigue (9 %), diarrhea (9 %), and oral hyperesthesia (4.5 %). We conclude that axitinib has single-agent clinical activity and a manageable toxicity profile in patients with recurrent glioblastoma.