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Neuro Oncol ; 2020 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-31950179


BACKGROUND: Erdheim-Chester disease (ECD) is a rare histiocytic neoplasm characterized by recurrent alterations in the mitogen-activating protein kinase (MAPK) pathway. The existing literature about the neuro-oncological spectrum of ECD is limited. METHODS: We present retrospective clinical, radiographic, pathologic, molecular, and treatment data from 30 patients with ECD neurohistiocytic involvement treated at a tertiary center. RESULTS: Median age was 52 (range: 7-77) years and 20 (67%) patients were male. Presenting symptoms included ataxia in 19 (63%), dysarthria in 14 (47%), diabetes insipidus in 12 (40%), cognitive impairment in 10 (33%), and bulbar affect in 9 (30%) patients. Neurosurgical biopsy specimens in 8 patients demonstrated varied morphologic findings often uncharacteristic of typical ECD lesions. Molecular analysis revealed mutations in BRAF (18 patients), MAP2K1 (5), RAS isoforms (2), and two fusions involving BRAF and ALK. Conventional therapies (corticosteroids, immunosuppresants, interferon-alpha [IFN-α], cytotoxic chemotherapy) led to partial radiographic response in 8/40 (20%) by MRI with no complete responses, partial metabolic response in 4/16 (25%) and complete metabolic response in 1/16 (6%) by FDG-PET scan. In comparison, targeted (kinase inhibitor) therapies yielded partial radiographic response in 10/27 (37%) and complete radiographic response in 14/27 (52%) by MRI, and partial metabolic response in 6/25 (24%) and complete metabolic response in 17/25 (68%) by FDG-PET scan. CONCLUSIONS: These data highlight underrecognized symptomatology, heterogenous neuropathology, and robust responses to targeted therapies across the mutational spectrum in ECD patients with neurological involvement, particularly when conventional therapies have failed.

Nat Med ; 25(12): 1839-1842, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31768065


Histiocytoses are clonal hematopoietic disorders frequently driven by mutations mapping to the BRAF and MEK1 and MEK2 kinases. Currently, however, the developmental origins of histiocytoses in patients are not well understood, and clinically meaningful therapeutic targets outside of BRAF and MEK are undefined. In this study, we uncovered activating mutations in CSF1R and rearrangements in RET and ALK that conferred dramatic responses to selective inhibition of RET (selpercatinib) and crizotinib, respectively, in patients with histiocytosis.

Quinase do Linfoma Anaplásico/genética , Histiocitose/genética , Proteínas Proto-Oncogênicas c-ret/genética , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/genética , Adolescente , Adulto , Aminopiridinas/farmacologia , Benzotiazóis/farmacologia , Criança , Pré-Escolar , Feminino , Genoma Humano , Neoplasias Hematológicas/tratamento farmacológico , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/patologia , Histiocitose/tratamento farmacológico , Histiocitose/patologia , Humanos , Lactente , Masculino , Mutação , Ácidos Picolínicos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Piridinas/farmacologia , Pirróis/farmacologia , Receptores Proteína Tirosina Quinases/genética , Gêmeos Monozigóticos , Sequenciamento Completo do Exoma , Adulto Jovem
Artigo em Inglês | MEDLINE | ID: mdl-31395597


Clonal heterogeneity and evolution of mantle cell lymphoma (MCL) remain unclear despite the progress in our understanding of its biology. Here, we report a 71-yr-old male patient with an aggressive MCL and depict the clonal evolution from initial diagnosis of typical MCL to relapsed blastoid MCL. During the course of the disease, the patient was diagnosed with classic Hodgkin lymphoma (CHL) and received a CHL therapeutic regimen. Molecular analysis by next-generation sequencing of both MCL and CHL demonstrated clonally related CHL with characteristic immunophenotype and PDL1/2 gains. Moreover, our data illustrate the clonal heterogeneity and acquisition of additional genetic aberrations including a rare fusion of SEC22B-NOTCH2 in the process of clonal evolution. Evidence obtained from our comprehensive immunophenotypic and genetic studies indicates that MCL and CHL can originate from a common precursor by divergent clonal evolution, which may pose a therapeutic challenge.

Surg Pathol Clin ; 12(3): 671-686, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31352980


Increasing evidence supports the prognostic significance of measurable residual disease (MRD) in acute myeloid leukemia (AML). Dynamic MRD assessment for patients with AML complements baseline patient risk assessment factors in determining patient prognosis. MRD status may also be helpful in informing therapeutic decisions. The European Leukemia Net MRD working party recently issued consensus recommendations for the use of MRD in AML. The Food and Drug Administration also issued advice for using MRD in trials of hematologic malignancies. This article discusses MRD testing, highlights the challenges in adopting MRD testing in clinical practice, and provides insights into the future of the field.

Leucemia Mieloide Aguda/diagnóstico , Neoplasia Residual/diagnóstico , Biomarcadores Tumorais/metabolismo , Citometria de Fluxo/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Imunofenotipagem/métodos , Leucemia Mieloide Aguda/terapia , Terapia de Alvo Molecular/métodos , Neoplasia Residual/terapia , Fenótipo , Reação em Cadeia da Polimerase em Tempo Real/métodos , Indução de Remissão/métodos , Sensibilidade e Especificidade , Manejo de Espécimes/métodos
Oncotarget ; 8(61): 103274-103282, 2017 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-29262560


Bone marrow (BM) fibrosis is an adverse prognostic marker in several myeloid neoplasms, particularly in myelodysplastic syndrome (MDS) with fibrosis; however, its significance in chronic myelomonoctyic leukemia (CMML) has not been evaluated. We performed a retrospective analysis to investigate the prognostic and clinicopathological features of CMML with and without BM fibrosis. The study included specimens from a total of 83 untreated CMML patients from 2 large institutions. Patients with any amount of BM fibrosis (MF-1 or higher; MF1+) had significantly shorter progression-free survival (MF1+, 28.3 months vs MF0, not reached; p = 0.001, log rank test), splenomegaly (p = 0.016), and increased BM megakaryocytes (p = 0.04) compared to patients without BM fibrosis (MF-0). No association was observed between fibrosis and peripheral blood parameters, presence of JAK2 V617F mutation, BM blasts, or overall survival. Our study demonstrates the importance of assessing BM fibrosis in CMML. Similar to MDS, the presence of BM fibrosis may identify a distinct subgroup of CMML patients (CMML-F) with a more aggressive clinical course.

Leuk Lymphoma ; 58(3): 569-577, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27389864


The significance of an isolated trisomy 8 (+8) in the diagnosis of myelodysplastic syndrome (MDS) is not well established. It is common in MDS, but is not considered as an MDS-defining abnormality in the absence of morphologic dysplasia. We evaluated two groups of patients with isolated +8 and either low-grade MDS (LG-MDS) or idiopathic cytopenia of undetermined significance (ICUS). At presentation, ICUS patients had a lower platelet count (85.0 vs 163.5 × 109 cells/L; p = 0.02), while MDS patients had more frequent incidence of isolated anemia (64% vs 0%, p = 0.007). A subset (36%) of ICUS patients progressed to MDS or AML. These patients presented with more severe neutropenia (0.9 vs 3.1 × 103/µL, p = 0.01) and a trend toward a higher proportion (>50%) of +8 metaphases compared to those that did not progress (p = 0.05). Thus, ICUS patients with isolated +8 may progress to MDS and AML and deserve close clinical follow-up.

Pancitopenia/diagnóstico , Pancitopenia/genética , Trissomia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia , Contagem de Células Sanguíneas , Medula Óssea/metabolismo , Cromossomos Humanos Par 8 , Diagnóstico Diferencial , Feminino , Humanos , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/terapia , Pancitopenia/terapia , Adulto Jovem