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1.
JAMA Neurol ; 72(2): 159-69, 2015 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-25546364

RESUMEN

IMPORTANCE: Most patients with relapsing-remitting (RR) multiple sclerosis (MS) who receive approved disease-modifying therapies experience breakthrough disease and accumulate neurologic disability. High-dose immunosuppressive therapy (HDIT) with autologous hematopoietic cell transplant (HCT) may, in contrast, induce sustained remissions in early MS. OBJECTIVE: To evaluate the safety, efficacy, and durability of MS disease stabilization through 3 years after HDIT/HCT. DESIGN, SETTING, AND PARTICIPANTS: Hematopoietic Cell Transplantation for Relapsing-Remitting Multiple Sclerosis (HALT-MS) is an ongoing, multicenter, single-arm, phase 2 clinical trial of HDIT/HCT for patients with RRMS who experienced relapses with loss of neurologic function while receiving disease-modifying therapies during the 18 months before enrolling. Participants are evaluated through 5 years after HCT. This report is a prespecified, 3-year interim analysis of the trial. Thirty-six patients with RRMS from referral centers were screened; 25 were enrolled. INTERVENTIONS: Autologous peripheral blood stem cell grafts were CD34+ selected; the participants then received high-dose treatment with carmustine, etoposide, cytarabine, and melphalan as well as rabbit antithymocyte globulin before autologous HCT. MAIN OUTCOMES AND MEASURES: The primary end point of HALT-MS is event-free survival defined as survival without death or disease activity from any one of the following outcomes: (1) confirmed loss of neurologic function, (2) clinical relapse, or (3) new lesions observed on magnetic resonance imaging. Toxic effects are reported using National Cancer Institute Common Terminology Criteria for Adverse Events. RESULTS: Grafts were collected from 25 patients, and 24 of these individuals received HDIT/HCT. The median follow-up period was 186 weeks (interquartile range, 176-250) weeks). Overall event-free survival was 78.4% (90% CI, 60.1%-89.0%) at 3 years. Progression-free survival and clinical relapse-free survival were 90.9% (90% CI, 73.7%-97.1%) and 86.3% (90% CI, 68.1%-94.5%), respectively, at 3 years. Adverse events were consistent with expected toxic effects associated with HDIT/HCT, and no acute treatment-related neurologic adverse events were observed. Improvements were noted in neurologic disability, quality-of-life, and functional scores. CONCLUSIONS AND RELEVANCE: At 3 years, HDIT/HCT without maintenance therapy was effective for inducing sustained remission of active RRMS and was associated with improvements in neurologic function. Treatment was associated with few serious early complications or unexpected adverse events.


Asunto(s)
Trasplante de Células Madre Hematopoyéticas/métodos , Inmunosupresores/farmacología , Esclerosis Múltiple Recurrente-Remitente , Resultado del Tratamiento , Adulto , Terapia Combinada , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Inmunosupresores/administración & dosificación , Inmunosupresores/efectos adversos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Esclerosis Múltiple Recurrente-Remitente/diagnóstico , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Esclerosis Múltiple Recurrente-Remitente/cirugía , Trasplante Autólogo/efectos adversos , Trasplante Autólogo/métodos
2.
Arthritis Rheum ; 65(4): 1097-106, 2013 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-23334994

RESUMEN

OBJECTIVE: To study the safety and clinical efficacy of rituximab therapy for primary Sjögren's syndrome, as well as to investigate its mechanisms. METHODS: Patients with primary Sjögren's syndrome were enrolled in an open-label trial, were given rituximab (1 gm) infusions on days 1 and 15, and were monitored through week 52. The primary end point was safety, with secondary end points evaluating clinical and biologic efficacy. Blood was obtained for enumeration of lymphocyte subsets, measurement of serum autoantibody and BAFF levels, and analysis of gene expression. RESULTS: Twelve female patients with primary Sjögren's syndrome were administered rituximab. They had a median age of 51 years (range 34-69 years) and a median disease duration of 8.0 years (range 2-18 years). We observed no unexpected toxicities from the rituximab therapy. Modest improvements were observed at week 26 in patient-reported symptoms of fatigue and oral dryness, with no significant improvement in the objective measures of lacrimal and salivary gland function. The recovery of blood B cells following the nadir from rituximab therapy was characterized by a predominance of transitional B cells and a lack of memory B cells. While blood B cell depletion was associated with an increase in serum BAFF levels, no significant changes were observed in the levels of serum anti-Ro/SSA, anti-La/SSB, and anti-type 3 muscarinic acetylcholine receptor autoantibodies or in the blood interferon signature. CONCLUSION: In patients with primary Sjögren's syndrome, a single treatment course of rituximab was not associated with any unexpected toxicities and led to only modest clinical benefits despite effective depletion of blood B cells.


Asunto(s)
Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Linfocitos B/citología , Factores Inmunológicos/uso terapéutico , Síndrome de Sjögren/tratamiento farmacológico , Adulto , Anciano , Anticuerpos Monoclonales de Origen Murino/efectos adversos , Autoanticuerpos/sangre , Autoanticuerpos/efectos de los fármacos , Linfocitos B/efectos de los fármacos , Femenino , Citometría de Flujo , Humanos , Factores Inmunológicos/efectos adversos , Recuento de Linfocitos , Persona de Mediana Edad , Estudios Prospectivos , Rituximab , Síndrome de Sjögren/sangre , Resultado del Tratamiento
3.
Stat Interface ; 3(1): 81-90, 2010 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-25083169

RESUMEN

The diffusion tensor imaging (DTI) protocol characterizes diffusion anisotropy locally in space, thus providing rich detail about white matter tissue structure. Although useful metrics for diffusion tensors have been defined, statistical properties of the measures have been little studied. Assuming homogeneity within a region leads to being able to apply Wishart distribution theory. First, it will be shown that common DTI metrics are simple functions of known test statistics. The average diffusion coefficient (ADC) corresponds to the trace of a Wishart, and is also described as the generalized (multivariate) variance, the average variance of the principal components. Therefore ADC has a known exact distribution (a positively weighted quadratic form in Gaussians) as well as a simple and accurate approximation (Satterthwaite) in terms of a scaled chi square. Of particular interest is that fractional anisotropy (FA) values for given regions of interest are functions of the Geisser-Greenhouse (GG) sphericity estimator. The GG sphericity estimator can be approximated well by a linear transformation of a squared beta random variable. Simulated data demonstrates that the fits work well for simulated diffusion tensors. Applying traditional density estimation techniques for a beta to histograms of FA values from a region allow representing the histogram of hundreds or thousands of values in terms of just two estimates for the beta parameters. Thus using the approximate distribution eliminates the "curse of dimensionality" for FA values. A parallel result holds for ADC.

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