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2.
Am J Clin Pathol ; 150(2): 168-176, 2018 Jul 03.
Artículo en Inglés | MEDLINE | ID: mdl-29868855

RESUMEN

OBJECTIVES: Lymphoplasmacytic lymphoma (LPL) remains a poorly defined entity, even with the discovery of MYD88L265P mutations and association with Waldenström macroglobulinemia (WM). Among bone marrow (BM)-based, low-grade B-cell lymphoma with plasmacytic differentiation (LGBLPD) and immunoglobulin M (IgM) paraproteins, we sought to determine whether MYD88L265P defines a distinct entity and can help refine diagnostic criteria for LPL. METHODS: BMs diagnosed with LGBLPD or LPL and serum IgM paraprotein were studied (2007-2013). Clinicopathologic features were reviewed and specimens were tested for MYD88L265P. RESULTS: In total, 138 (87%) of 159 cases had MYD88L265P, and 158 of 159 were clinically considered WM. MYD88L265P cases had higher disease burden than MYD88WT. Features associated with MYD88L265P include increased mast cells and lymphocyte (not plasma cell)-predominant infiltrate. Hemosiderin, Dutcher bodies, and paratrabecular growth were not associated with MYD88L265P. CONCLUSIONS: Our data support a clinicopathologic approach to LPL diagnosis and recognition that it may manifest with varying morphologies, phenotypes, and molecular features.


Asunto(s)
Linfoma de Células B/genética , Factor 88 de Diferenciación Mieloide/genética , Macroglobulinemia de Waldenström/diagnóstico , Macroglobulinemia de Waldenström/genética , Adulto , Anciano , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/genética , Médula Ósea/patología , Femenino , Humanos , Inmunoglobulina M , Linfoma de Células B/clasificación , Linfoma de Células B/patología , Masculino , Persona de Mediana Edad , Mutación , Paraproteínas , Estudios Retrospectivos , Macroglobulinemia de Waldenström/patología
3.
Am J Hematol ; 2018 May 23.
Artículo en Inglés | MEDLINE | ID: mdl-29790589

RESUMEN

Hereditary erythrocytosis is associated with high oxygen affinity hemoglobin variants (HOAs), 2,3-bisphosphoglycerate deficiency and abnormalities in EPOR and the oxygen-sensing pathway proteins PHD, HIF2α, and VHL. Our laboratory has 40 years of experience with hemoglobin disorder testing and we have characterized HOAs using varied protein and molecular techniques including functional assessment by p50 analysis. In addition, we have more recently commenced adding the assessment of clinically relevant regions of the VHL, BPGM, EPOR, EGLN1 (PHD2), and EPAS1 (HIF2A) genes in a more comprehensive hereditary erythrocytosis panel of tests. Review of our experience confirms a wide spectrum of alterations associated with erythrocytosis which we have correlated with phenotypic and clinical features. Through generic hemoglobinopathy testing we have identified 762 patients with 81 distinct HOA Hb variants (61 ß, 20 α), including 12 that were first identified by our laboratory. Of the 1192 cases received for an evaluation specific for hereditary erythrocytosis, approximately 12% had reportable alterations: 85 pathogenic/likely pathogenic mutations and 58 variants of unknown significance. Many have not been previously reported. Correlation with clinical and phenotypic data supports an algorithmic approach to guide economical evaluation; although, testing is expanded if the suspected causes are negative or of uncertain significance. Clinical features are similar and range from asymptomatic to recurrent headaches, fatigue, restless legs, chest pain, exertional dyspnea and thrombotic episodes. Many patients were chronically phlebotomized with reported relief of symptoms. This article is protected by copyright. All rights reserved.

4.
Am J Clin Pathol ; 145(6): 843-51, 2016 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-27329639

RESUMEN

OBJECTIVES: Lymphoplasmacytic lymphoma (LPL) with non-immunoglobulin M (IgM) paraproteinemia remains poorly understood. The goal of this study was to investigate the clinicopathologic features of LPL in the bone marrow in patients with immunoglobulin G (IgG) or immunoglobulin A (IgA) paraproteins and evaluate MYD88 L265P mutation status to determine the relationship of these cases to Waldenström macroglobulinemia (WM). METHODS: Bone marrows from LPL cases with IgG or IgA paraproteins diagnosed between January 1, 2007, and June 30, 2014, were retrieved from the clinical archive. Clinicopathologic features were retrospectively reviewed. MYD88 L265P mutation status was assessed by allele-specific polymerase chain reaction prospectively on all cases. RESULTS: Of 27 cases, four were reclassified as multiple myeloma, all MYD88 mutation negative. MYD88 L265P mutations were present in 10 (43%) of 23 remaining cases. No association between MYD88 status and bone marrow morphologic or phenotypic features, including the presence of Dutcher bodies, mast cells, expression of CD19 by plasma cells, or hemosiderin, was identified, although these features were present in a subset of cases, similar to WM. Clinical features of WM such as hyperviscosity were uncommon in this group and did not correlate with MYD88 status. CONCLUSIONS: Non-IgM LPLs are a clinically and pathologically heterogeneous group and often harbor MYD88 L265P mutation, albeit at a lower rate than classic WM. MYD88 status does not correlate with any specific pathologic or clinical manifestations.


Asunto(s)
Mutación , Factor 88 de Diferenciación Mieloide/genética , Macroglobulinemia de Waldenström/genética , Macroglobulinemia de Waldenström/inmunología , Macroglobulinemia de Waldenström/patología , Anciano , Anciano de 80 o más Años , Análisis Mutacional de ADN , Femenino , Humanos , Inmunoglobulina A/inmunología , Inmunoglobulina G/inmunología , Masculino , Persona de Mediana Edad , Paraproteínas/inmunología , Estudios Retrospectivos
5.
Retina ; 35(4): 624-7, 2015 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-25768255

RESUMEN

PURPOSE: To determine whether Myd88 L265P mutations occur in diffuse large B-cell vitreoretinal lymphomas. METHODS: The formalin-fixed paraffin-embedded cells from three patients with classic clinical findings of vitreoretinal lymphoma that also had histologic confirmation were evaluated using a validated amplification-refractory mutation system polymerase chain reaction to determine the presence of the mutation. RESULTS: The 74 ± 2 base pair product seen from the mutated Myd-88 protein was noted in 2 of the 3 cases. CONCLUSION: Myd-88 L265P constitutive activating mutations are present in at least some cases of the diffuse large B-cell lymphoma form of vitreoretinal lymphoma. Further studies on the incidence of this mutation in retinal lymphomas are warranted.


Asunto(s)
Linfoma de Células B Grandes Difuso/genética , Mutación , Factor 88 de Diferenciación Mieloide/genética , Neoplasias de la Retina/genética , Cuerpo Vítreo/patología , Anciano , Análisis Mutacional de ADN , ADN de Neoplasias/genética , Enucleación del Ojo , Femenino , Amplificación de Genes , Humanos , Linfoma de Células B Grandes Difuso/patología , Linfoma de Células B Grandes Difuso/terapia , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Neoplasias de la Retina/patología , Neoplasias de la Retina/terapia , Trasplante de Células Madre , Trasplante Autólogo
6.
Am J Hematol ; 89(7): 757-65, 2014 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-24723493

RESUMEN

Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) patients with purine analog refractory disease or TP53 dysfunction still have limited treatment options and poor survival. Alemtuzumab-containing chemoimmunotherapy regimens can be effective but frequently cause serious infections. We report a Phase II trial testing the efficacy and tolerability of a short-duration regimen combining pentostatin, alemtuzumab, and low-dose high-frequency rituximab designed to decrease the risk of treatment-associated infections and to limit the loss of CD20 expression by CLL cells. The study enrolled 39 patients with progressive CLL that was either relapsed/refractory (n = 36) or previously untreated with 17p13 deletion (17p13-) (n = 3). Thirteen (33%) patients had both 17p13- and TP53 mutations predicted to be dysfunctional, and eight patients had purine analog refractory CLL without TP53 dysfunction. Twenty-six (67%) patients completed therapy, with only five (13%) patients having treatment-limiting toxicity and no treatment-related deaths. Twenty-two (56%) patients responded to treatment, with 11 (28%) complete responses (four with incomplete bone marrow recovery). Median progression-free survival was 7.2 months, time to next treatment was 9.1 months, and overall survival was 34.1 months. The majority of deaths (82%) were caused by progressive disease, including transformed diffuse large B-cell lymphoma (n = 6). Correlative studies showed that low-dose rituximab activates complement and natural killer cells without a profound and sustained decrease in expression of CD20 by circulating CLL cells. We conclude that pentostatin, alemtuzumab, and low-dose high-frequency rituximab is a tolerable and effective therapy for CLL and that low-dose rituximab therapy can activate innate immune cytotoxic mechanisms without substantially decreasing CD20 expression.


Asunto(s)
Antígenos CD20/biosíntesis , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Anciano , Alemtuzumab , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales de Origen Murino/administración & dosificación , Anticuerpos Monoclonales de Origen Murino/efectos adversos , Antígenos CD20/inmunología , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Deleción Cromosómica , Cromosomas Humanos Par 17 , Supervivencia sin Enfermedad , Femenino , Humanos , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/inmunología , Masculino , Persona de Mediana Edad , Células Neoplásicas Circulantes/inmunología , Pentostatina/administración & dosificación , Pentostatina/efectos adversos , Recurrencia , Inducción de Remisión , Rituximab
7.
Blood ; 120(11): 2280-9, 2012 Sep 13.
Artículo en Inglés | MEDLINE | ID: mdl-22855598

RESUMEN

Peripheral T-cell lymphomas (PTCLs) are aggressive malignancies of mature T lymphocytes with 5-year overall survival rates of only ∼ 35%. Improvement in outcomes has been stymied by poor understanding of the genetics and molecular pathogenesis of PTCL, with a resulting paucity of molecular targets for therapy. We developed bioinformatic tools to identify chromosomal rearrangements using genome-wide, next-generation sequencing analysis of mate-pair DNA libraries and applied these tools to 16 PTCL patient tissue samples and 6 PTCL cell lines. Thirteen recurrent abnormalities were identified, of which 5 involved p53-related genes (TP53, TP63, CDKN2A, WWOX, and ANKRD11). Among these abnormalities were novel TP63 rearrangements encoding fusion proteins homologous to ΔNp63, a dominant-negative p63 isoform that inhibits the p53 pathway. TP63 rearrangements were seen in 11 (5.8%) of 190 PTCLs and were associated with inferior overall survival; they also were detected in 2 (1.2%) of 164 diffuse large B-cell lymphomas. As TP53 mutations are rare in PTCL compared with other malignancies, our findings suggest that a constellation of alternate genetic abnormalities may contribute to disruption of p53-associated tumor suppressor function in PTCL.


Asunto(s)
Reordenamiento Génico , Linfoma de Células T Periférico/genética , Mutación , Factores de Transcripción/genética , Proteína p53 Supresora de Tumor/genética , Proteínas Supresoras de Tumor/genética , Línea Celular Tumoral , Inhibidor p16 de la Quinasa Dependiente de Ciclina/química , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Análisis Mutacional de ADN , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/metabolismo , Linfoma de Células B Grandes Difuso/mortalidad , Linfoma de Células B Grandes Difuso/patología , Linfoma de Células T Periférico/metabolismo , Linfoma de Células T Periférico/mortalidad , Linfoma de Células T Periférico/patología , Masculino , Proteínas Mutantes/química , Proteínas Mutantes/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos , Proteínas de Fusión Oncogénica/química , Proteínas de Fusión Oncogénica/genética , Proteínas de Fusión Oncogénica/metabolismo , Oxidorreductasas/química , Oxidorreductasas/genética , Oxidorreductasas/metabolismo , Proteínas Represoras/química , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Homología de Secuencia de Ácido Nucleico , Factores de Transcripción/química , Factores de Transcripción/metabolismo , Proteína p53 Supresora de Tumor/química , Proteína p53 Supresora de Tumor/metabolismo , Proteínas Supresoras de Tumor/química , Proteínas Supresoras de Tumor/metabolismo , Estados Unidos , Oxidorreductasa que Contiene Dominios WW
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