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1.
Haematologica ; 105(4): 905-913, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-31171641

RESUMEN

Healthy bone marrow progenitors yield a co-ordinated balance of hematopoietic lineages. This balance shifts with aging toward enhanced granulopoiesis with diminished erythropoiesis and lymphopoiesis, changes which likely contribute to the development of bone marrow disorders in the elderly. In this study, RUNX3 was identified as a hematopoietic stem and progenitor cell factor whose levels decline with aging in humans and mice. This decline is exaggerated in hematopoietic stem and progenitor cells from subjects diagnosed with unexplained anemia of the elderly. Hematopoietic stem cells from elderly unexplained anemia patients had diminished erythroid but unaffected granulocytic colony forming potential. Knockdown studies revealed human hematopoietic stem and progenitor cells to be strongly influenced by RUNX3 levels, with modest deficiencies abrogating erythroid differentiation at multiple steps while retaining capacity for granulopoiesis. Transcriptome profiling indicated control by RUNX3 of key erythroid transcription factors, including KLF1 and GATA1 These findings thus implicate RUNX3 as a participant in hematopoietic stem and progenitor cell aging, and a key determinant of erythroid-myeloid lineage balance.


Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Células Madre Hematopoyéticas , Anciano , Envejecimiento , Animales , Diferenciación Celular , Subunidad alfa 3 del Factor de Unión al Sitio Principal/genética , Eritropoyesis , Humanos , Ratones
2.
Blood ; 130(7): 900-902, 2017 08 17.
Artículo en Inglés | MEDLINE | ID: mdl-28615223

RESUMEN

The majority of patients with immunoglobulin light chain amyloidosis (AL) fail to achieve a complete response (CR) to standard light chain suppressive chemotherapy, and almost all patients eventually experience hematologic relapse and progression of organ involvement. Additional well-tolerated treatment options are needed. We present our retrospective experience of 25 consecutive previously treated AL patients who received daratumumab, a CD38-directed monoclonal antibody approved for the treatment of multiple myeloma. Daratumumab was administered at 16 mg/kg weekly for 8 weeks, then every 2 weeks for 8 doses, and then every 4 weeks. Patients had received a median of 3 prior lines of therapy, with a previous hematologic CR in only 5 patients. The overall hematologic response rate to daratumumab was 76%, including CR in 36% and very good partial response in 24%. Median time to response was 1 month. Therapy was well tolerated, even among the 72% of patients with cardiac AL involvement. Grade 1-2 infusion reactions occurred in 15 patients, but no grade 3 or 4 reactions were observed. Daratumumab is a highly effective agent that produced rapid and deep hematologic responses without unexpected toxicity in our cohort of heavily pretreated AL patients.


Asunto(s)
Amiloidosis/sangre , Amiloidosis/tratamiento farmacológico , Anticuerpos Monoclonales/uso terapéutico , Cadenas Ligeras de Inmunoglobulina/metabolismo , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad
3.
Blood ; 126(17): 1971, 2015 Oct 22.
Artículo en Inglés | MEDLINE | ID: mdl-26494915

RESUMEN

In this issue of Blood, Moretti et al provide data that challenge the entrenched oral treatment of iron deficiency anemia. The paper shows how the newer understanding of hepcidin and iron metabolism in general can lead to very practical improvements in the management of iron deficiency anemia, a disorder that may affect as many as 1 billion people.


Asunto(s)
Suplementos Dietéticos , Ferritinas/sangre , Hepcidinas/sangre , Hierro de la Dieta/administración & dosificación , Hierro de la Dieta/farmacocinética , Hierro/metabolismo , Femenino , Humanos , Masculino
4.
Blood ; 126(20): 2302-6, 2015 Nov 12.
Artículo en Inglés | MEDLINE | ID: mdl-26429976

RESUMEN

The TP73 gene transcript is alternatively spliced and translated into the transcriptionally active (TAp73) or inactive (ΔNp73) isoforms, with opposite effects on the expression of p53 target genes and on apoptosis induction. The imbalance between ΔNp73 and TAp73 may contribute to tumorigenesis and resistance to chemotherapy in human cancers, including hematologic malignancies. In acute promyelocytic leukemia (APL), both isoforms are expressed, but their relevance in determining response to therapy and contribution to leukemogenesis remains unknown. Here, we provide the first evidence that a higher ΔNp73/TAp73 RNA expression ratio is associated with lower survival, lower disease-free survival, and higher risk of relapse in patients with APL homogeneously treated with all-trans retinoic acid and anthracycline-based chemotherapy, according to the International Consortium on Acute Promyelocytic Leukemia (IC-APL) study. Cox proportional hazards modeling showed that a high ΔNp73/TAp73 ratio was independently associated with shorter overall survival (hazard ratio, 4.47; 95% confidence interval, 1.64-12.2; P = .0035). Our data support the hypothesis that the ΔNp73/TAp73 ratio is an important determinant of clinical response in APL and may offer a therapeutic target for enhancing chemosensitivity in blast cells.


Asunto(s)
Empalme Alternativo , Proteínas de Unión al ADN/biosíntesis , Regulación Leucémica de la Expresión Génica , Leucemia Promielocítica Aguda/metabolismo , Leucemia Promielocítica Aguda/mortalidad , Modelos Biológicos , Proteínas Nucleares/biosíntesis , Proteínas Supresoras de Tumor/biosíntesis , Adolescente , Adulto , Anciano , Niño , Proteínas de Unión al ADN/genética , Supervivencia sin Enfermedad , Femenino , Humanos , Leucemia Promielocítica Aguda/genética , Leucemia Promielocítica Aguda/patología , Masculino , Persona de Mediana Edad , Proteínas Nucleares/genética , Modelos de Riesgos Proporcionales , Isoformas de Proteínas/biosíntesis , Isoformas de Proteínas/genética , Tasa de Supervivencia , Proteína Tumoral p73 , Proteínas Supresoras de Tumor/genética
5.
Proc Natl Acad Sci U S A ; 110(8): 3011-6, 2013 Feb 19.
Artículo en Inglés | MEDLINE | ID: mdl-23388639

RESUMEN

Myelodysplastic syndromes (MDS) are a group of disorders characterized by variable cytopenias and ineffective hematopoiesis. Hematopoietic stem cells (HSCs) and myeloid progenitors in MDS have not been extensively characterized. We transplanted purified human HSCs from MDS samples into immunodeficient mice and show that HSCs are the disease-initiating cells in MDS. We identify a recurrent loss of granulocyte-macrophage progenitors (GMPs) in the bone marrow of low risk MDS patients that can distinguish low risk MDS from clinical mimics, thus providing a simple diagnostic tool. The loss of GMPs is likely due to increased apoptosis and increased phagocytosis, the latter due to the up-regulation of cell surface calreticulin, a prophagocytic marker. Blocking calreticulin on low risk MDS myeloid progenitors rescues them from phagocytosis in vitro. However, in the high-risk refractory anemia with excess blasts (RAEB) stages of MDS, the GMP population is increased in frequency compared with normal, and myeloid progenitors evade phagocytosis due to up-regulation of CD47, an antiphagocytic marker. Blocking CD47 leads to the selective phagocytosis of this population. We propose that MDS HSCs compete with normal HSCs in the patients by increasing their frequency at the expense of normal hematopoiesis, that the loss of MDS myeloid progenitors by programmed cell death and programmed cell removal are, in part, responsible for the cytopenias, and that up-regulation of the "don't eat me" signal CD47 on MDS myeloid progenitors is an important transition step leading from low risk MDS to high risk MDS and, possibly, to acute myeloid leukemia.


Asunto(s)
Células Madre Hematopoyéticas/patología , Síndromes Mielodisplásicos/patología , Animales , Antígenos CD/inmunología , Células Madre Hematopoyéticas/inmunología , Humanos , Hibridación Fluorescente in Situ , Ratones , Síndromes Mielodisplásicos/inmunología , Fagocitosis
6.
Blood ; 121(19): 3925-35, S1-12, 2013 May 09.
Artículo en Inglés | MEDLINE | ID: mdl-23479567

RESUMEN

Autosomal dominant dehydrated hereditary stomatocytosis (DHSt) usually presents as a compensated hemolytic anemia with macrocytosis and abnormally shaped red blood cells (RBCs). DHSt is part of a pleiotropic syndrome that may also exhibit pseudohyperkalemia and perinatal edema. We identified PIEZO1 as the disease gene for pleiotropic DHSt in a large kindred by exome sequencing analysis within the previously mapped 16q23-q24 interval. In 26 affected individuals among 7 multigenerational DHSt families with the pleiotropic syndrome, 11 heterozygous PIEZO1 missense mutations cosegregated with disease. PIEZO1 is expressed in the plasma membranes of RBCs and its messenger RNA, and protein levels increase during in vitro erythroid differentiation of CD34(+) cells. PIEZO1 is also expressed in liver and bone marrow during human and mouse development. We suggest for the first time a correlation between a PIEZO1 mutation and perinatal edema. DHSt patient red cells with the R2456H mutation exhibit increased ion-channel activity. Functional studies of PIEZO1 mutant R2488Q expressed in Xenopus oocytes demonstrated changes in ion-channel activity consistent with the altered cation content of DHSt patient red cells. Our findings provide direct evidence that R2456H and R2488Q mutations in PIEZO1 alter mechanosensitive channel regulation, leading to increased cation transport in erythroid cells.


Asunto(s)
Anemia Hemolítica Congénita/genética , Hidropesía Fetal/genética , Canales Iónicos/genética , Mutación , Adulto , Secuencia de Aminoácidos , Anemia Hemolítica Congénita/clasificación , Anemia Hemolítica Congénita/diagnóstico , Animales , Embrión de Mamíferos , Femenino , Regulación del Desarrollo de la Expresión Génica , Humanos , Hidropesía Fetal/clasificación , Hidropesía Fetal/diagnóstico , Ratones , Ratones Transgénicos , Modelos Biológicos , Datos de Secuencia Molecular , Mutación/fisiología , Linaje , Homología de Secuencia de Aminoácido , Transfección , Xenopus laevis
7.
Blood ; 121(11): 1935-43, 2013 Mar 14.
Artículo en Inglés | MEDLINE | ID: mdl-23319575

RESUMEN

Thanks to modern treatment with all-trans retinoic acid and chemotherapy, acute promyelocytic leukemia (APL) is now the most curable type of leukemia. However, this progress has not yielded equivalent benefit in developing countries. The International Consortium on Acute Promyelocytic Leukemia (IC-APL) was established to create a network of institutions in developing countries that would exchange experience and data and receive support from well-established US and European cooperative groups. The IC-APL formulated expeditious diagnostic, treatment, and supportive guidelines that were adapted to local circumstances. APL was chosen as a model disease because of the potential impact on improved diagnosis and treatment. The project included 4 national coordinators and reference laboratories, common clinical record forms, 5 subcommittees, and laboratory and data management training programs. In addition, participating institutions held regular virtual and face-to-face meetings. Complete hematological remission was achieved in 153/180 (85%) patients and 27 (15%) died during induction. After a median follow-up of 28 months, the 2-year cumulative incidence of relapse, overall survival (OS), and disease-free survival (DFS) were 4.5%, 80%, and 91%, respectively. The establishment of the IC-APL network resulted in a decrease of almost 50% in early mortality and an improvement in OS of almost 30% compared with historical controls, resulting in OS and DFS similar to those reported in developed countries.


Asunto(s)
Redes Comunitarias/organización & administración , Países en Desarrollo , Leucemia Promielocítica Aguda/diagnóstico , Leucemia Promielocítica Aguda/terapia , Mejoramiento de la Calidad/organización & administración , Adolescente , Adulto , Anciano , Brasil/epidemiología , Chile/epidemiología , Consenso , Países en Desarrollo/estadística & datos numéricos , Supervivencia sin Enfermedad , Femenino , Humanos , Internacionalidad , Leucemia Promielocítica Aguda/mortalidad , Masculino , México/epidemiología , Persona de Mediana Edad , Pronóstico , Análisis de Supervivencia , Resultado del Tratamiento , Uruguay/epidemiología , Adulto Joven
8.
Br J Haematol ; 166(4): 540-9, 2014 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-24796963

RESUMEN

The KMT2E (MLL5) gene encodes a histone methyltransferase implicated in the positive control of genes related to haematopoiesis. Its close relationship with retinoic acid-induced granulopoiesis suggests that the deregulated expression of KMT2E might lead acute promyelocytic leukaemia (APL) blasts to become less susceptible to the conventional treatment protocols. Here, we assessed the impact of KMT2E expression on the prognosis of 121 APL patients treated with ATRA and anthracycline-based chemotherapy. Univariate analysis showed that complete remission (P = 0·006), 2-year overall survival (OS) (P = 0·005) and 2-year disease-free survival (DFS) rates (P = 0·037) were significantly lower in patients with low KMT2E expression; additionally, the 2-year cumulative incidence of relapse was higher in patients with low KMT2E expression (P = 0·04). Multivariate analysis revealed that low KMT2E expression was independently associated with lower remission rate (odds ratio [OR]: 7·18, 95% confidence interval [CI]: 1·71-30·1; P = 0·007) and shorter OS (hazard ratio [HR]: 0·27, 95% CI: 0·08-0·87; P = 0·029). Evaluated as a continuous variable, KMT2E expression retained association with poor remission rate (OR: 10·3, 95% CI: 2·49-43·2; P = 0·001) and shorter survival (HR: 0·17, 95% IC: 0·05-0·53; P = 0·002), while the association with DFS was of marginal significance (HR: 1·01; 95% CI: 0·99-1·02; P = 0·06). In summary, low KMT2E expression may predict poor outcome in APL patients.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Proteínas de Unión al ADN/metabolismo , Leucemia Promielocítica Aguda/tratamiento farmacológico , Adolescente , Adulto , Antraciclinas/administración & dosificación , Estudios de Casos y Controles , Femenino , Humanos , Leucemia Promielocítica Aguda/metabolismo , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , Tretinoina/administración & dosificación , Adulto Joven
9.
Blood Cells Mol Dis ; 53(4): 221-30, 2014 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-25065855

RESUMEN

Anemia is common in older persons and is associated with substantial morbidity and mortality. One third of anemic older adults have unexplained anemia of the elderly (UAE). We carried out a randomized, wait list control trial in outpatients with UAE and serum ferritin levels between 20 and 200 ng/mL. Intravenous iron sucrose was given as a 200-mg weekly dose for 5 weeks either immediately after enrollment (immediate intervention group) or following a 12-week wait list period (wait list control group). The primary outcome measure was changed in 6-minute walk test (6MWT) distances from baseline to 12 weeks between the two groups. Hematologic, physical, cognitive, and quality of life parameters were also assessed. The study was terminated early after 19 subjects enrolled. The distance walked in the 6MWT increased a mean 8.05±55.48 m in the immediate intervention group and decreased a mean 11.45±49.46 m in the wait list control group (p=0.443). The hemoglobin increased a mean 0.39±0.46 g/dL in the immediate intervention group and declined a mean 0.39±0.85 g/dL in the wait list control group (p=0.026). Thus, a subgroup of adults with UAE may respond to intravenous iron. Enrollment of subjects into this type of study remains challenging.


Asunto(s)
Anemia/tratamiento farmacológico , Compuestos Férricos/uso terapéutico , Ferritinas/sangre , Ácido Glucárico/uso terapéutico , Anciano , Anciano de 80 o más Años , Anemia/sangre , Anemia/patología , Cognición/efectos de los fármacos , Esquema de Medicación , Prueba de Esfuerzo , Femenino , Sacarato de Óxido Férrico , Humanos , Inyecciones Intravenosas , Masculino , Pruebas Psicológicas , Calidad de Vida , Caminata/fisiología
10.
Blood ; 120(2): 242-3, 2012 Jul 12.
Artículo en Inglés | MEDLINE | ID: mdl-22791773

RESUMEN

In this issue of Blood, Safeukui et al have come to grips with an important issue in red blood cell (RBC) biology.1 Their study deals not only with the mechanism of RBC removal in diseases like hereditary spherocytosis (HS) and autoimmune hemolytic anemia, but also with RBC senescence.

11.
Ann Hematol ; 93(12): 2001-10, 2014 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-24981688

RESUMEN

Activating internal tandem duplication (ITD) mutations in the fms-like tyrosine kinase 3 (FLT3) gene (FLT3-ITD) are associated with poor outcome in acute myeloid leukemia, but their prognostic impact in acute promyelocytic leukemia (APL) remains controversial. Here, we screened for FLT3-ITD mutations in 171 APL patients, treated with all-trans retinoic acid (ATRA) and anthracycline-based chemotherapy. We identified FLT3-ITD mutations in 35 patients (20 %). FLT3-ITD mutations were associated with higher white blood cell counts (P < 0.0001), relapse-risk score (P = 0.0007), higher hemoglobin levels (P = 0.0004), higher frequency of the microgranular morphology (M3v) subtype (P = 0.03), and the short PML/RARA (BCR3) isoform (P < 0.0001). After a median follow-up of 38 months, FLT3-ITD(positive) patients had a lower 3-year overall survival rate (62 %) compared with FLT3-ITD(negative) patients (82 %) (P = 0.006). The prognostic impact of FLT3-ITD on survival was retained in multivariable analysis (hazard ratio: 2.39, 95 % confidence interval [CI] 1.17-4.89; P = 0.017). Nevertheless, complete remission (P = 0.07), disease-free survival (P = 0.24), and the cumulative incidence of relapse (P = 0.94) rates were not significantly different between groups. We can conclude that FLT3-ITD mutations are associated with several hematologic features in APL, in particular with high white blood cell counts. In addition, FLT3-ITD may independently predict a shorter survival in patients with APL treated with ATRA and anthracycline-based chemotherapy.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Promielocítica Aguda/genética , Proteínas de Neoplasias/genética , Secuencias Repetidas en Tándem , Tirosina Quinasa 3 Similar a fms/genética , Adolescente , Adulto , Anciano , Niño , ADN de Neoplasias/genética , Daunorrubicina/administración & dosificación , Supervivencia sin Enfermedad , Femenino , Regulación Leucémica de la Expresión Génica , Hemoglobinas/análisis , Humanos , Idarrubicina/administración & dosificación , Estimación de Kaplan-Meier , América Latina/epidemiología , Leucemia Promielocítica Aguda/tratamiento farmacológico , Leucemia Promielocítica Aguda/mortalidad , Recuento de Leucocitos , Masculino , Persona de Mediana Edad , Proteínas de Fusión Oncogénica/genética , Resultado del Tratamiento , Tretinoina/administración & dosificación , Adulto Joven
12.
Am J Hematol ; 89(1): 88-96, 2014 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-24122955

RESUMEN

Anemia is now recognized as a risk factor for a number of adverse outcomes in the elderly, including hospitalization, morbidity, and mortality. What constitutes appropriate evaluation and management for an elderly patient with anemia, and when to initiate a referral to a hematologist, are significant issues. Attempts to identify suggested hemoglobin levels for blood transfusion therapy have been confounded for elderly patients with their co-morbidities. Since no specific recommended hemoglobin threshold has stood the test of time, prudent transfusion practices to maintain hemoglobin thresholds of 9-10 g/dL in the elderly are indicated, unless or until evidence emerges to indicate otherwise.


Asunto(s)
Anemia/diagnóstico , Anemia/terapia , Factores de Edad , Anciano , Anciano de 80 o más Años , Anemia/epidemiología , Transfusión Sanguínea , Ensayos Clínicos como Asunto , Humanos
13.
Proc Natl Acad Sci U S A ; 108(50): 20012-7, 2011 Dec 13.
Artículo en Inglés | MEDLINE | ID: mdl-22123971

RESUMEN

In the human hematopoietic system, aging is associated with decreased bone marrow cellularity, decreased adaptive immune system function, and increased incidence of anemia and other hematological disorders and malignancies. Recent studies in mice suggest that changes within the hematopoietic stem cell (HSC) population during aging contribute significantly to the manifestation of these age-associated hematopoietic pathologies. Though the mouse HSC population has been shown to change both quantitatively and functionally with age, changes in the human HSC and progenitor cell populations during aging have been incompletely characterized. To elucidate the properties of an aged human hematopoietic system that may predispose to age-associated hematopoietic dysfunction, we evaluated immunophenotypic HSC and other hematopoietic progenitor populations from healthy, hematologically normal young and elderly human bone marrow samples. We found that aged immunophenotypic human HSC increase in frequency, are less quiescent, and exhibit myeloid-biased differentiation potential compared with young HSC. Gene expression profiling revealed that aged immunophenotypic human HSC transcriptionally up-regulate genes associated with cell cycle, myeloid lineage specification, and myeloid malignancies. These age-associated alterations in the frequency, developmental potential, and gene expression profile of human HSC are similar to those changes observed in mouse HSC, suggesting that hematopoietic aging is an evolutionarily conserved process.


Asunto(s)
Envejecimiento/fisiología , Células de la Médula Ósea/citología , Células Madre Hematopoyéticas/citología , Adulto , Anciano , Anciano de 80 o más Años , Animales , Recuento de Células , Diferenciación Celular , Linaje de la Célula/genética , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Células Madre Hematopoyéticas/metabolismo , Humanos , Ratones , Persona de Mediana Edad , Células Mieloides/citología , Células Mieloides/metabolismo , Adulto Joven
14.
Br J Haematol ; 161(3): 367-72, 2013 May.
Artículo en Inglés | MEDLINE | ID: mdl-23432783

RESUMEN

The prevalence and prognostic value of a concomitant diagnosis of symptomatic or asymptomatic multiple myeloma (MM), as defined by the current International Myeloma Working Group (IMWG) criteria, in patients with immunoglobulin light chain amyloidosis (AL), are unknown. We studied 46 consecutive patients with AL who underwent quantification of serum M-protein and clonal bone marrow plasma cells, as well as a comprehensive evaluation for end organ damage by MM. Using standard morphology and CD138 immunohistochemical staining, 57% and 80% of patients were found to have concomitant MM, respectively. Nine patients exhibited end organ damage consistent with a diagnosis of symptomatic MM. While overall survival was similar between AL patients with or without concurrent myeloma (1-year overall survival 68% vs. 87%; P = 0.27), a diagnosis of symptomatic myeloma was associated with inferior outcome (1-year overall survival 39% vs. 81%; P = 0.005). Quantification of bone marrow plasma cells by both standard morphology and CD138 immunohistochemistry identified a much higher prevalence of concurrent MM in patients with AL than previously reported. Evaluation of bone marrow plasma cell infiltration and presence of myeloma associated end organ damage could be clinically useful for prognostication of patients with AL.


Asunto(s)
Amiloidosis/complicaciones , Examen de la Médula Ósea , Cadenas Ligeras de Inmunoglobulina/análisis , Mieloma Múltiple/complicaciones , Proteínas de Mieloma/análisis , Corticoesteroides/uso terapéutico , Anciano , Anciano de 80 o más Años , Amiloidosis/tratamiento farmacológico , Amiloidosis/mortalidad , Amiloidosis/patología , Amiloidosis/cirugía , Antineoplásicos/uso terapéutico , Médula Ósea/patología , Examen de la Médula Ósea/métodos , Cardiomiopatías/etiología , Cardiomiopatías/mortalidad , Recuento de Células , Células Clonales/química , Células Clonales/patología , Terapia Combinada , Femenino , Estudios de Seguimiento , Trasplante de Células Madre Hematopoyéticas , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Mieloma Múltiple/diagnóstico , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/mortalidad , Mieloma Múltiple/patología , Mieloma Múltiple/cirugía , Miocardio/patología , Fenotipo , Células Plasmáticas/química , Células Plasmáticas/patología , Pronóstico , Sindecano-1/análisis , Vísceras/patología
15.
Haematologica ; 98(10): 1593-9, 2013 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-23716538

RESUMEN

Immunoglobulin light chain amyloidosis remains incurable despite recent therapeutic advances, and is particularly difficult to treat in patients with amyloid cardiomyopathy. Based on evidence of activity in multiple myeloma, we designed a pilot study of an oral regimen of lenalidomide in combination with dexamethasone and low-dose melphalan in order to evaluate its safety and efficacy in patients with amyloidosis, including those with advanced cardiac involvement. Twenty-five patients were enrolled. Ninety-two percent of patients had cardiac involvement by amyloidosis, and 36% of patients met the criteria for Mayo Clinic cardiac stage III disease. Patients received up to nine cycles of treatment, consisting of lenalidomide 10 mg/day orally on days 1 - 21 (28-day cycle); melphalan 0.18 mg/kg orally on days 1-4; and dexamethasone 40 mg orally on days 1, 8, 15, and 22. High rates (33%) of cardiac arrhythmias and low rates of treatment completion (12.5%) were observed. Ten patients died during the study, all within the first several months of treatment due to acute cardiac events. The overall hematologic response rate was 58%, however organ responses were seen in only 8% of patients. The overall survival rate at 1 year was 58%. While we confirmed the hematologic response rates observed with similar regimens, front-line treatment with melphalan, lenalidomide and dexamethasone was toxic, ineffective, and did not alter survival outcomes for patients with high-risk cardiac disease. Our data highlight the importance of developing novel treatment approaches for amyloid cardiomyopathy. This trial was registered at www.clinicaltrials.gov (NCT00890552).


Asunto(s)
Amiloidosis/tratamiento farmacológico , Dexametasona/administración & dosificación , Cardiopatías/tratamiento farmacológico , Cadenas Ligeras de Inmunoglobulina , Melfalán/administración & dosificación , Talidomida/análogos & derivados , Anciano , Anciano de 80 o más Años , Amiloidosis/epidemiología , Amiloidosis/mortalidad , Estudios de Cohortes , Quimioterapia Combinada , Femenino , Cardiopatías/epidemiología , Cardiopatías/mortalidad , Humanos , Lenalidomida , Masculino , Persona de Mediana Edad , Proyectos Piloto , Tasa de Supervivencia/tendencias , Talidomida/administración & dosificación
16.
Nat Med ; 12(7): 793-800, 2006 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-16799557

RESUMEN

Vascular endothelial growth factor (VEGF) exerts crucial functions during pathological angiogenesis and normal physiology. We observed increased hematocrit (60-75%) after high-grade inhibition of VEGF by diverse methods, including adenoviral expression of soluble VEGF receptor (VEGFR) ectodomains, recombinant VEGF Trap protein and the VEGFR2-selective antibody DC101. Increased production of red blood cells (erythrocytosis) occurred in both mouse and primate models, and was associated with near-complete neutralization of VEGF corneal micropocket angiogenesis. High-grade inhibition of VEGF induced hepatic synthesis of erythropoietin (Epo, encoded by Epo) >40-fold through a HIF-1alpha-independent mechanism, in parallel with suppression of renal Epo mRNA. Studies using hepatocyte-specific deletion of the Vegfa gene and hepatocyte-endothelial cell cocultures indicated that blockade of VEGF induced hepatic Epo by interfering with homeostatic VEGFR2-dependent paracrine signaling involving interactions between hepatocytes and endothelial cells. These data indicate that VEGF is a previously unsuspected negative regulator of hepatic Epo synthesis and erythropoiesis and suggest that levels of Epo and erythrocytosis could represent noninvasive surrogate markers for stringent blockade of VEGF in vivo.


Asunto(s)
Eritropoyetina/fisiología , Hígado/fisiología , Factor A de Crecimiento Endotelial Vascular/fisiología , Animales , Hematócrito , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones SCID , Ratones Transgénicos , Modelos Animales , Policitemia/fisiopatología , Receptores de Factores de Crecimiento Endotelial Vascular/fisiología , Vasos Retinianos/fisiología
17.
Curr Opin Hematol ; 19(3): 133-40, 2012 May.
Artículo en Inglés | MEDLINE | ID: mdl-22495692

RESUMEN

PURPOSE OF REVIEW: There have been several large-scale epidemiologic studies, including the National Health and Nutrition Examination Survey III (NHANES III), which have described the prevalence and impact of anemia in the elderly. The information derived has been critically important. However, given the large number of patients surveyed, these reports necessarily relied substantially on the laboratory-based screening evaluations. There are now two recent reports describing the cause of anemia in elderly outpatients, and although the numbers are smaller than the large scale surveys, they constitute comprehensive hematologic evaluations with therapeutic interventions and clinical follow-up. The purpose of this review is to compare these different analyses. RECENT FINDINGS: There are distinct differences and similarities in the two types of studies, which are derived from patients seen in hematology clinics. Despite comprehensive hematologic evaluation, the puzzling entity of unexplained anemia of the elderly is confirmed and found to account for 30-46% of patients. NHANES III classified iron-deficiency anemia with other nutritional anemias, a classification that might be correct in the developing third world, but in North America and Western Europe, iron deficiency is more often caused by blood loss and the cause must be sought and dealt with. The myelodysplastic syndromes are an important cause of anemia in the elderly, with a prevalence of at least 4%. SUMMARY: Large-scale screening studies of anemia in the elderly are of great importance, and when complemented by comprehensive hematologic evaluations, provide a more accurate picture of the clinical situation.


Asunto(s)
Anemia/etiología , Encuestas Epidemiológicas/métodos , Hierro/sangre , Anciano , Anciano de 80 o más Años , Anemia/clasificación , Anemia/diagnóstico , Recuento de Células Sanguíneas , Ácido Fólico/sangre , Hemoglobinas/análisis , Humanos , Deficiencias de Hierro , Hierro de la Dieta , Síndromes Mielodisplásicos/diagnóstico , Evaluación Nutricional , Pacientes Ambulatorios , Vitamina B 12/sangre
18.
Blood Cells Mol Dis ; 46(2): 159-65, 2011 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-21208814

RESUMEN

The aim of this study was to prospectively determine the etiology of anemia in a cohort of community-dwelling older outpatients with a comprehensive hematologic evaluation. Participants were men and women age 65 and older with anemia as defined by World Health Organization criteria recruited from outpatient hematology clinics at Stanford Hospital and Clinics (SHC) and Veterans Affairs Palo Alto Health Care System (VAPAHCS). Each participant underwent a history and physical examination, followed by a comprehensive hematologic evaluation, which in all participants included complete blood count, red cell indices, review of the blood smear, and assessment of vitamin B12, folate, iron status and renal function. Additional evaluation was obtained by clinical providers as per their discretion. 190 participants enrolled and completed the evaluation. Twelve percent of participants had iron deficiency anemia. Of those with iron deficiency in whom there was follow-up information, half normalized their hemoglobin in response to iron repletion, and half did not. Thirty-five percent of participants had unexplained anemia. Those with unexplained anemia had mildly increased inflammatory markers compared to non-anemic controls, and, at the lower hemoglobin ranges had relatively low erythropoietin levels. Sixteen percent of participants were categorized as being "suspicious for myelodysplastic syndrome." Thus, even with comprehensive hematologic evaluation, unexplained anemia is common in older anemic outpatients. Iron deficiency anemia is also common and can be difficult to diagnose, and frequently the anemia is not fully corrected with iron repletion.


Asunto(s)
Anemia Ferropénica/diagnóstico , Síndromes Mielodisplásicos/diagnóstico , Anciano , Anemia Ferropénica/sangre , Anemia Ferropénica/etiología , Recuento de Células Sanguíneas , Índices de Eritrocitos , Femenino , Ácido Fólico/sangre , Hemoglobinas/análisis , Humanos , Inflamación/sangre , Inflamación/complicaciones , Hierro de la Dieta , Pruebas de Función Renal , Masculino , Pacientes Ambulatorios , Estudios Prospectivos , Vitamina B 12/sangre
19.
Blood Cells Mol Dis ; 46(4): 277-81, 2011 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-21349748

RESUMEN

Congenital methemoglobinemia due to NADH-cytochrome b5 reductase 3 (CYB5R3) deficiency is an autosomal recessive disorder that occurs sporadically worldwide, although endemic clusters of this disorder have been identified in certain ethnic groups. It is present as two distinct phenotypes, type I and type II. Type I methemoglobinemia is characterized by CYB5R3 enzyme deficiency restricted to erythrocytes and is associated with benign cyanosis. The less frequent type II methemoglobinemia is associated with generalized CYB5R3 deficiency affecting all cells and is lethal in early infancy. Here we describe the molecular basis of type I methemoglobinemia due to CYB5R3 deficiency in four patients from three distinct ethnic backgrounds, Asian Indian, Mexican and Greek. The CYB5R3 gene of three probands with type I methemoglobinemia and their relatives were sequenced revealing several putative causative mutations; in one subject multiple mutations were present. Two novel mutations, S54R and F157C, were identified and the previously described A179T, V253M mutations were also identified. All these point mutations mapped to the NADH binding domain and or the FAD binding domain. Each has the potential to sterically hinder cofactor binding causing instability of the CYB5R3 protein. Wild-type CYB5R3, as well as two of these novel mutations, S54R and F157C, was amplified, cloned, and purified recombinant peptide obtained. Kinetic and thermodynamic studies of these proteins show that the above mutations lead to decreased thermal stability.


Asunto(s)
Citocromo-B(5) Reductasa/genética , Metahemoglobinemia/etnología , Metahemoglobinemia/genética , Mutación , Sitios de Unión/genética , Citocromo-B(5) Reductasa/química , Estabilidad de Enzimas/genética , Flavina-Adenina Dinucleótido/metabolismo , Grecia , Humanos , India , Cinética , México , NAD/metabolismo , Fenotipo , Termodinámica
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