Fast whole-brain three-dimensional macromolecular proton fraction mapping in multiple sclerosis.

PURPOSE: To evaluate the clinical utility of fast whole-brain macromolecular proton fraction ( MPF macromolecular proton fraction ) mapping in multiple sclerosis ( MS multiple sclerosis ) and compare MPF macromolecular proton fraction with established quantitative magnetic resonance (MR) imaging measures of tissue damage including magnetization transfer ( MT magnetization transfer ) ratio and relaxation rate (R1). MATERIALS AND METHODS: In this institutional review board-approved and HIPAA-compliant study, 14 healthy control participants, 18 relapsing-remitting MS multiple sclerosis ( RRMS relaxing-remitting MS ) patients, and 12 secondary progressive MS multiple sclerosis ( SPMS secondary progressive MS ) patients provided written informed consent and underwent 3-T MR imaging. Three-dimensional MPF macromolecular proton fraction maps were reconstructed from MT magnetization transfer -weighted images and R1 maps by the single-point method. Mean MPF macromolecular proton fraction , R1, and MT magnetization transfer ratio in normal-appearing white matter ( WM white matter ), gray matter ( GM gray matter ), and lesions were compared between subject groups by using analysis of variance. Correlations (Pearson r) between imaging data and clinical scores (Expanded Disability Status Scale [EDSS] and MS multiple sclerosis Functional Composite [ MSFC MS functional composite ]) were compared by using Hotelling-Williams test. RESULTS: RRMS relaxing-remitting MS patients had lower WM white matter and GM gray matter MPF macromolecular proton fraction than controls, with percentage decreases of 6.5% (P < .005) and 5.4% (P < .05). MPF macromolecular proton fraction in SPMS secondary progressive MS was reduced relative to RRMS relaxing-remitting MS in WM white matter , GM gray matter , and lesions by 6.4% (P < .005), 13.4% (P < .005), and 11.7% (P < .05), respectively. EDSS Expanded Disability Status Scale and MSFC MS functional composite demonstrated strongest correlations with MPF macromolecular proton fraction in GM gray matter (r = -0.74 and 0.81; P < .001) followed by WM white matter (r = -0.57 and 0.72; P < .01) and lesions (r = -0.42 and 0.50; P < .05). R1 and MT magnetization transfer ratio in all tissues were significantly less correlated with clinical scores than GM gray matter MPF macromolecular proton fraction (P < .05). CONCLUSION: MPF macromolecular proton fraction mapping enables quantitative assessment of demyelination in normal-appearing brain tissues and shows primary clinical relevance of GM gray matter damage in MS multiple sclerosis . MPF macromolecular proton fraction outperforms MT magnetization transfer ratio and R1 in detection of MS multiple sclerosis -related tissue changes.

Safety/tolerability of the anti-semaphorin 4D Antibody VX15/2503 in a randomized phase 1 trial.

OBJECTIVE: To evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of VX15/2503 in a randomized, single-dose, dose-escalation, double-blind, placebo-controlled study enrolling adult patients with MS. METHODS: Single IV doses of VX15/2503 or placebo were administered. Ten patients each were randomized (4:1 randomization ratio) into 5 ascending dose cohorts of 1, 3, 6, 10, or 20 mg/kg. Safety, immunogenicity, PK/PD, MRI, ECG, and lymphocyte subset levels were evaluated. A Dose Escalation Safety Committee (DESC) approved each dose escalation. RESULTS: VX15/2503 was well tolerated, and all participants completed the study. Antibody treatment-related adverse events were primarily grade 1 or 2 and included urinary tract infection (12.5%) and muscle weakness, contusion, and insomnia (each 7.5%). No dose-limiting toxicities were observed, and no maximum tolerated dose was determined. One subject (20 mg/kg) experienced disease relapse 3 months before study entry and exhibited a grade 3 (nonserious) increase in brain lesions by day 29, possibly related to VX15/2503. Twenty-nine patients exhibited human anti-humanized antibody responses; 5 with titer ≥100. No anti-VX15/2503 antibody responses were fully neutralizing. VX15/2503 Cmax, area under the time-concentration curve, and mean half-life increased with dose level; at 20 mg/kg, the T1/2 was 20 days. Cellular SEMA4D saturation occurred at serum antibody concentrations ≤0.3 µg/mL, resulting in decreased cSEMA4D expression. At 20 mg/kg, cSEMA4D saturation persisted for ≥155 days. Total sSEMA4D levels increased with dose level and declined with antibody clearance. CONCLUSIONS: These results support the continued investigation of VX15/2503 in neurodegenerative diseases. CLINICALTRIALSGOV IDENTIFIER: NCT01764737. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that anti-semaphorin 4D antibody VX15/2503 at various doses was safe and well tolerated vs placebo, although an increase in treatment-emergent adverse events in the treatment group could not be excluded (risk difference -0.7%, 95% CI -28.0% to 32.7%).

Death with dignity in Washington patients with amyotrophic lateral sclerosis.

OBJECTIVES: To describe the amyotrophic lateral sclerosis (ALS) patients who sought medication under the Washington State Death with Dignity (DWD) Act since its inception in 2009. METHODS: Chart review at 3 tertiary medical centers in the Seattle/Puget Sound region and comparison to publicly available data of ALS and all-cause DWD cohorts from Washington and Oregon. RESULTS: In Washington State, 39 patients with ALS requested DWD from the University of Washington, Virginia Mason, and Swedish Medical Centers beginning in 2009. The median age at death was 65 years (range 46-86). Seventy-seven percent of the patients used the prescriptions. All of the patients who used the medications passed away without complications. The major reasons for patients to request DWD as reported by participating physicians were loss of autonomy and dignity and decrease in enjoyable activities. Inadequate pain control, financial cost, and loss of bodily control were less commonly indicated. These findings were similar to those of the 92 patients who sought DWD in Oregon. In Washington and Oregon, the percentage of patients with ALS seeking DWD is higher compared to the cancer DWD cohort. Furthermore, compared to the all-cause DWD cohort, patients with ALS are more likely to be non-Hispanic white, married, educated, enrolled in hospice, and to have died at home. CONCLUSIONS: Although a small number, ALS represents the disease with the highest proportion of patients seeking to participate in DWD. Patients with ALS who choose DWD are well-educated and have access to palliative or life-prolonging care. The use of the medications appears to be able to achieve the patients' goals without complications.