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1.
Acta Haematol ; 146(4): 316-321, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37285821

RESUMEN

The imatinib-sensitive fusion gene FIP1L1::PDGFRA is the most frequent molecular abnormality identified in patients with eosinophilic myeloid neoplasms. Rapid recognition of this mutation is essential given the poor prognosis of PDGFRA-associated myeloid neoplasms prior to the availability of imatinib therapy. We report a case of a patient in whom delayed diagnosis resulted in cardiac transplantation for eosinophilic endomyocardial fibrosis. The delay in diagnosis was due, in part, to a false-negative result in fluorescence in situ hybridization (FISH) testing for FIP1L1::PDGFRA. To explore this further, we examined our cohort of patients presenting with confirmed or suspected eosinophilic myeloid neoplasms and found 8 additional patients with negative FISH results despite a positive reverse-transcriptase polymerase chain reaction test for FIP1L1::PDGFRA. More importantly, false-negative FISH results delayed the median time to imatinib treatment by 257 days. These data emphasize the importance of empiric imatinib therapy in patients with clinical features suggestive of PDGFRA-associated disease.


Asunto(s)
Trastornos Mieloproliferativos , Neoplasias , Humanos , Mesilato de Imatinib/uso terapéutico , Diagnóstico Tardío , Piperazinas/uso terapéutico , Pirimidinas/uso terapéutico , Hibridación Fluorescente in Situ , Benzamidas , Proteínas de Fusión Oncogénica/genética , Trastornos Mieloproliferativos/tratamiento farmacológico , Neoplasias/tratamiento farmacológico
2.
N Engl J Med ; 380(14): 1336-1346, 2019 04 04.
Artículo en Inglés | MEDLINE | ID: mdl-30943337

RESUMEN

BACKGROUND: Hypereosinophilic syndrome is a group of diseases defined by marked eosinophilia in blood or tissue and eosinophil-related clinical manifestations. Benralizumab is a monoclonal antibody against interleukin-5 receptor α, which is expressed on human eosinophils. METHODS: In this randomized, double-blind, placebo-controlled, phase 2 trial, we administered a series of three monthly subcutaneous injections of either benralizumab (at a dose of 30 mg) or placebo in 20 symptomatic patients who had PDGFRA-negative hypereosinophilic syndrome and an absolute eosinophil count of at least 1000 cells per cubic millimeter; all the patients were receiving stable therapy (drugs or dietary changes) for this disease. This regimen was followed by an open-label phase, during which the patient's background therapy could be tapered as tolerated, and an extension phase. The primary end point of the randomized phase was a reduction of at least 50% in the absolute eosinophil count at week 12. RESULTS: During the randomized phase, the primary end point occurred in more patients in the benralizumab group than in the placebo group (9 of 10 patients [90%] vs. 3 of 10 patients [30%], P = 0.02). During the open-label phase, clinical and hematologic responses were observed in 17 of 19 patients (89%) and were sustained for 48 weeks in 14 of 19 patients (74%); in the latter group, in 9 of 14 patients (64%), background therapies could be tapered. Bone marrow and tissue eosinophilia were also suppressed with benralizumab therapy. The most common drug-related adverse events, headache and an elevated lactate dehydrogenase level, occurred in 32% of the patients after the first dose of benralizumab and resolved within 48 hours in all patients. Other adverse events occurred with similar frequency in the two groups. Of the many potential predictors of response that were examined, only clinical disease subtype appeared to be associated with the initial response or relapse. CONCLUSIONS: In this small phase 2 trial, patients with PDGFRA-negative hypereosinophilic syndrome who received benralizumab for 12 weeks had lower absolute eosinophil counts than those who received placebo. During the open-label phase, clinical and hematologic responses were sustained for 48 weeks in 74% of the patients. Adverse events did not limit treatment. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov numbers, NCT00001406 and NCT02130882.).


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Síndrome Hipereosinofílico/tratamiento farmacológico , Subunidad alfa del Receptor de Interleucina-5/antagonistas & inhibidores , Adulto , Anciano , Anticuerpos Monoclonales Humanizados/efectos adversos , Biopsia , Médula Ósea/inmunología , Médula Ósea/patología , Colon Ascendente/patología , Método Doble Ciego , Eosinófilos , Femenino , Humanos , Síndrome Hipereosinofílico/patología , Inyecciones Subcutáneas , Recuento de Leucocitos , Masculino , Persona de Mediana Edad , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/sangre , Piel/patología , Estómago/patología
3.
Clin Exp Allergy ; 49(12): 1598-1604, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31657082

RESUMEN

BACKGROUND: Glucocorticoids (GC) are considered first-line therapy for most patients with hypereosinophilic syndrome (HES). Although response rates are generally high, many patients require moderate to high doses for control of eosinophilia and symptoms, and up to 15% of patients do not respond at all. Despite this, little is known about the mechanisms of GC resistance in patients with HES. OBJECTIVE: To explore the aetiology of GC resistance in HES. METHODS: Clinical data and samples from 26 patients with HES enrolled on a prospective study of GC responsiveness and 23 patients with HES enrolled on a natural history study of eosinophilia for whom response to GC was known were analysed retrospectively. Expression of GC receptor isoforms was assessed by quantitative RT-PCR in purified eosinophils. Serum cytokine levels were quantified by suspension array assay in multiplex. RESULTS: Despite an impaired eosinophil response to GC after 7 days of treatment, the expected rise in absolute neutrophil count was seen in 7/7 GC-resistant patients, suggesting that GC resistance in HES is not a global phenomenon. Eosinophil mRNA expression of glucocorticoid receptor (GR) isoforms (α, ß, and P) was similar between GC-sensitive (n = 20) and GC-resistant (n = 9) patients with HES. Whereas geometric mean serum levels were also comparable between GC-r (n = 11) and GC-s (n = 19) for all cytokines tested, serum IL-5 levels were >100 pg/mL only in GC-r patients. CONCLUSIONS AND CLINICAL RELEVANCE: These data suggest that the mechanism of GC resistance in HES is not due to a global phenomenon affecting all lineages, but may be due, at least in some patients, to impairment of eosinophil apoptosis by increased levels of IL-5.


Asunto(s)
Resistencia a Medicamentos/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Glucocorticoides/administración & dosificación , Síndrome Hipereosinofílico/sangre , Síndrome Hipereosinofílico/tratamiento farmacológico , Receptores de Glucocorticoides/sangre , Adolescente , Adulto , Anciano , Resistencia a Medicamentos/inmunología , Femenino , Regulación de la Expresión Génica/inmunología , Humanos , Síndrome Hipereosinofílico/inmunología , Interleucina-5/sangre , Interleucina-5/inmunología , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Isoformas de Proteínas/sangre , Isoformas de Proteínas/inmunología , Receptores de Glucocorticoides/inmunología
4.
Bioconjug Chem ; 25(1): 129-37, 2014 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-24328306

RESUMEN

Molecular imaging agents enable the visualization of phenomena with cellular and subcellular level resolutions and therefore have enormous potential in improving disease diagnosis and therapy assessment. In this article, we describe the synthesis, characterization, and demonstration of core-shell, biofunctionalized, gadolinium-containing Prussian blue nanoparticles as multimodal molecular imaging agents. Our multimodal nanoparticles combine the advantages of MRI and fluorescence. The core of our nanoparticles consists of a Prussian blue lattice with gadolinium ions located within the lattice interstices that confer high relaxivity to the nanoparticles providing MRI contrast. The relaxivities of our nanoparticles are nearly nine times those observed for the clinically used Magnevist. The nanoparticle MRI core is biofunctionalized with a layer of fluorescently labeled avidin that enables fluorescence imaging. Biotinylated antibodies are attached to the surface avidin and confer molecular specificity to the nanoparticles by targeting cell-specific biomarkers. We demonstrate our nanoparticles as multimodal molecular imaging agents in an in vitro model consisting of a mixture of eosinophilic cells and squamous epithelial cells. Our nanoparticles specifically detect eosinophilic cells and not squamous epithelial cells, via both fluorescence imaging and MRI in vitro. These results suggest the potential of our biofunctionalized Prussian blue nanoparticles as multimodal molecular imaging agents in vivo.


Asunto(s)
Medios de Contraste/química , Ferrocianuros/química , Gadolinio/química , Imagen por Resonancia Magnética , Nanopartículas/química , Eosinófilos/citología , Células Epiteliales/citología , Fluorescencia , Humanos
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