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1.
Br J Haematol ; 189(1): 84-96, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-31702836

RESUMEN

Lenalidomide maintenance therapy prolonged progression-free survival (PFS) versus placebo in elderly patients with diffuse large B-cell lymphoma (DLBCL) responding to induction chemotherapy in the phase 3 REMARC study. This subpopulation analysis assessed the impact of lenalidomide maintenance and treatment-emergent adverse events (TEAEs) on health-related quality of life (HRQOL). Global health status (GHS), and physical functioning and fatigue subscales were evaluated in patients who completed the European Organisation for Research and Treatment of Cancer quality-of-life questionnaire-C30 v3.0. The impact of TEAEs classified post hoc as subjective (patients can feel) or observable (only measurable by physicians) on dose reductions and discontinuations was assessed. Among 457 patients (lenalidomide, n = 229; placebo, n = 228), mean (standard deviation) GHS was similar between treatment arms [68·2 (20·7) Versus 72·0 (17·8)] at randomisation and remained similar during maintenance. Patients receiving lenalidomide experienced no meaningful changes in GHS, physical functioning, or fatigue. Observable TEAEs were more common (81·1% Versus 66·3%) and more likely to lead to dose reductions, than subjective TEAEs in both arms. PFS was superior in the lenalidomide arm regardless of dose reduction. Lenalidomide maintenance prolonged PFS and did not negatively impact HRQOL in patients with DLBCL despite TEAEs being more common, when compared with placebo.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Lenalidomida/administración & dosificación , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Quimioterapia de Mantención , Calidad de Vida , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Doxorrubicina/administración & dosificación , Doxorrubicina/efectos adversos , Femenino , Humanos , Lenalidomida/efectos adversos , Masculino , Persona de Mediana Edad , Prednisona/administración & dosificación , Prednisona/efectos adversos , Rituximab/administración & dosificación , Rituximab/efectos adversos , Vincristina/administración & dosificación , Vincristina/efectos adversos
2.
J Clin Oncol ; 35(22): 2473-2481, 2017 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-28426350

RESUMEN

Purpose The standard treatment of patients with diffuse large B-cell lymphoma (DLBCL) is rituximab in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Lenalidomide, an immunomodulatory agent, has shown activity in DLBCL. This randomized phase III trial compared lenalidomide as maintenance therapy with placebo in elderly patients with DLBCL who achieved a complete response (CR) or partial response (PR) to R-CHOP induction. Methods Patients with previously untreated DLBCL or other aggressive B-cell lymphoma were 60 to 80 years old, had CR or PR after six or eight cycles of R-CHOP, and were randomly assigned to lenalidomide maintenance 25 mg/d or placebo for 21 days of every 28-day cycle for 24 months. The primary end point was progression-free survival (PFS). Results A total of 650 patients were randomly assigned. At the time of the primary analysis (December 2015), with a median follow-up of 39 months from random assignment, median PFS was not reached for lenalidomide maintenance versus 58.9 months for placebo (hazard ratio, 0.708; 95% CI, 0.537 to 0.933; P = .01). The result was consistent among analyzed subgroups (eg, male v female, age-adjusted International Prognostic Index 0 or 1 v 2 or 3, age younger than 70 v ≥ 70 years), response (PR v CR) after R-CHOP, and positron emission tomography status at assignment (negative v positive). With longer median follow-up of 52 months (October 2016), overall survival was similar between arms (hazard ratio, 1.218; 95% CI, 0.861 to 1.721; P = .26). Most common grade 3 or 4 adverse events associated with lenalidomide versus placebo maintenance were neutropenia (56% v 22%) and cutaneous reactions (5% v 1%), respectively. Conclusion Lenalidomide maintenance for 24 months after obtaining a CR or PR to R-CHOP significantly prolonged PFS in elderly patients with DLBCL.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales de Origen Murino/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Ciclofosfamida/administración & dosificación , Supervivencia sin Enfermedad , Doxorrubicina/administración & dosificación , Erupciones por Medicamentos/etiología , Femenino , Estudios de Seguimiento , Humanos , Quimioterapia de Inducción , Lenalidomida , Quimioterapia de Mantención/efectos adversos , Masculino , Persona de Mediana Edad , Neutropenia/inducido químicamente , Placebos/administración & dosificación , Prednisona/administración & dosificación , Rituximab/administración & dosificación , Tasa de Supervivencia , Talidomida/administración & dosificación , Talidomida/efectos adversos , Talidomida/análogos & derivados , Vincristina/administración & dosificación
3.
Cancer Lett ; 179(1): 103-8, 2002 May 08.
Artículo en Inglés | MEDLINE | ID: mdl-11880188

RESUMEN

Photon irradiation of peripheral blood lymphocytes from 25 patients with untreated B-chronic lymphocytic leukemia (B-CLL) induced an increase in apoptotic response by 270%. No significant increase in apoptosis was observed after irradiation of peripheral blood mononuclear cells from 15 healthy volunteers. Supernatants (sups) derived from irradiated leukemic cells incubated with non-irradiated autologous cells induced a 75% enhancement in number of apoptotic cells, as compared with sups from non-irradiated CLL cells. The level of tumor necrosis factor alpha, a cytokine known to prevent apoptosis, was reduced in the sups of irradiated CLL cells in comparison to that of non-irradiated lymphocytes. The interleukin (IL)-10 level, an IL reported to induce apoptosis, was similar in the sups of irradiated and non-irradiated lymphocytes from B-CLL patients. No change in IL-2 levels was observed. The significance of these findings and the role of factor(s) in the sups of irradiated leukemic lymphocytes as inducers of apoptosis are discussed.


Asunto(s)
Apoptosis/efectos de la radiación , Inhibidores de Crecimiento/metabolismo , Leucemia Linfocítica Crónica de Células B/radioterapia , Linfocitos/fisiología , Anciano , Anciano de 80 o más Años , Supervivencia Celular/efectos de la radiación , Femenino , Humanos , Interleucina-10/metabolismo , Interleucina-2/metabolismo , Leucemia Linfocítica Crónica de Células B/metabolismo , Masculino , Persona de Mediana Edad , Factor de Necrosis Tumoral alfa/metabolismo
4.
Microsc Res Tech ; 63(3): 155-8, 2004 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-14755602

RESUMEN

The ultrastructural findings of the bone marrow cells from 15 patients with acquired sideroblastic anemia are presented. The red cell precursors from all patients showed the presence of electron-dense material in the mitochondria, representing most probably iron deposits. A great number of these mitochondria were completely destroyed. The erythropoietic precursors from one of the patients showed markedly elongated mitochondria that measured up to 3 microm. In addition numerous cytoplasmic vacuoles were observed. The red cell precursors from 60% of the patients showed signs of dyserythropoiesis, such as incomplete nuclear division and nuclear distortion. The polymorphonuclears from 47% of the patients presented nuclear abnormalities expressed as nuclear bridges, appendices, and blebs. In addition, phagocytosis of red blood cells was observed. The results of the study underline the advantages of the transmission electron microscope examination in visualization of intricate alterations in hematopoietic cells that cannot be detected with a light microscope.


Asunto(s)
Anemia Sideroblástica/patología , Células de la Médula Ósea/ultraestructura , Anciano , Anemia Sideroblástica/sangre , Anemia Sideroblástica/clasificación , Femenino , Humanos , Masculino , Microscopía Electrónica , Coloración y Etiquetado
5.
Leuk Lymphoma ; 45(5): 951-5, 2004 May.
Artículo en Inglés | MEDLINE | ID: mdl-15291354

RESUMEN

Pim-1 and Pim-2 are murine proto-oncogenes implicated in lymphomagenesis. The aim of this study was to investigate whether the human Pim-2 (hPim-2) expression is altered in chronic lymphocytic leukemia (B-CLL) and non-Hodgkin's lymphomas (NHL). We analyzed hPim-2 expression in 48 patients with NHL and CLL by quantitative in-situ hybridization, quantitative RT-PCR and FACS analysis. In-situ hybridization revealed a 5.5 +/- 2.2 times higher expression of hPim-2 in NHL over normal lymphocytes (P < 0.001). Similarly, with quantitative RT-PCR, expression in NHL was 1.5 to 2.6 times higher in involved splenic foci compared to nearby uninvolved regions (n = 3). hPim-2 mRNA was increased 3-folds in B-CLL over normal B-cells (P < 0.006). The increased hPim-2 levels correlated with lymphocyte doubling time (DT), in that mRNA levels were two times greater in patients with rapid DT (P < 0.006). Moreover, a significant correlation was found between hPim-2 expression and the Binet staging system of CLL (P < 0.022). The hPIM-2-protein expression was also upregulated in CLL, as assessed by FACS analysis. Therefore, this report provides direct evidence for a linkage of hPim-2 upregulation to NHL and CLL in man. This relationship between hPim-2 and NHL and CLL raises a number of novel mechanistic options for the genesis and/or progression of some types of human lymphomas.


Asunto(s)
Regulación Neoplásica de la Expresión Génica , Leucemia Linfocítica Crónica de Células B/genética , Linfoma no Hodgkin/genética , Proteínas Serina-Treonina Quinasas/genética , Proteínas Proto-Oncogénicas/genética , Humanos , Hibridación in Situ , Leucemia Linfocítica Crónica de Células B/etiología , Leucemia Linfocítica Crónica de Células B/patología , Ganglios Linfáticos/patología , Linfoma no Hodgkin/etiología , Linfoma no Hodgkin/patología , Proteínas Serina-Treonina Quinasas/fisiología , Proteínas Proto-Oncogénicas/fisiología , ARN Neoplásico/análisis , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Regulación hacia Arriba
6.
Harefuah ; 141(1): 8-9, 128, 2002 Jan.
Artículo en Hebreo | MEDLINE | ID: mdl-11851115

RESUMEN

Bleeding manifestations are common in patients with primary as well as secondary amyloidosis and have been attributed to different mechanical and metabolic causes. Factor X deficiency has been described in patients with primary amyloidosis, although severe bleeding is not common in these patients. We describe a patient with extensive subcutaneous hematoma, a sign that served as the major indicator assisting us in establishing the diagnosis of primary amyloidosis.


Asunto(s)
Amiloidosis/complicaciones , Hemorragia/etiología , Enfermedades de la Piel/etiología , Anciano , Amiloidosis/diagnóstico , Humanos , Masculino
7.
J Natl Cancer Inst ; 106(2): djt378, 2014 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-24491302

RESUMEN

Anaplastic lymphoma kinase (ALK)-positive lymphomas respond to chemotherapy, but relapses, which bear a poor prognosis, occur. Crizotinib inhibits ALK in vitro and in vivo and was administered as monotherapy to 11 ALK+ lymphoma patients who were resistant/refractory to cytotoxic therapy. The overall response rate was 10 of 11 (90.9%; 95% confidence interval [CI] = 58.7% to 99.8%). Disease status at the latest follow-up is as follows: four patients are in complete response (CR) (months >21, >30, >35, >40) under continuous crizotinib administration; 4 patients had progression of disease (months 1, 2, 2, 2); 1 patient obtained CR on crizotinib, received an allogeneic bone marrow transplant, and is in CR; 2 patients (treated before and/or after allogeneic bone marrow transplant) obtained and are still in CR but they have stopped crizotinib. Overall and progression-free survival rates at 2 years are 72.7% (95% CI = 39.1% to 94.0%) and 63.7% (95% CI = 30.8% to 89.1%), respectively. ALK mutations conferring resistance to crizotinib in vitro could be identified in relapsed patients. Crizotinib exerted a potent antitumor activity with durable responses in advanced, heavily pretreated ALK+ lymphoma patients, with a benign safety profile.


Asunto(s)
Antineoplásicos/uso terapéutico , Linfoma no Hodgkin/tratamiento farmacológico , Terapia Molecular Dirigida/métodos , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Tirosina Quinasas/análisis , Pirazoles/uso terapéutico , Piridinas/uso terapéutico , Proteínas Tirosina Quinasas Receptoras/análisis , Adulto , Quinasa de Linfoma Anaplásico , Antineoplásicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Crizotinib , Supervivencia sin Enfermedad , Esquema de Medicación , Resistencia a Antineoplásicos , Femenino , Estudios de Seguimiento , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Estimación de Kaplan-Meier , Linfoma no Hodgkin/enzimología , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Inhibidores de Proteínas Quinasas/administración & dosificación , Proteínas Tirosina Quinasas/efectos de los fármacos , Pirazoles/administración & dosificación , Piridinas/administración & dosificación , Proteínas Tirosina Quinasas Receptoras/efectos de los fármacos , Recurrencia , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Resultado del Tratamiento
8.
PLoS One ; 7(4): e34736, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22506047

RESUMEN

Potent survival effects have been ascribed to the serine/threonine kinase proto-oncogene PIM-2. Elevated levels of PIM-2 are associated with various malignancies. In human cells, a single Pim-2 transcript gives rise mainly to two protein isoforms (34, 41 kDa) that share an identical catalytic site but differ at their N-terminus, due to in-frame alternative translation initiation sites. In this study we observed that the 34 kDa PIM-2 isoform has differential nuclear and cytoplasmic forms in all tested cell lines, suggesting a possible role for the balance between these forms for PIM-2's function. To further study the cellular role of the 34 kDa isoform of PIM-2, an N-terminally HA-tagged form of this isoform was transiently expressed in HeLa cells. Surprisingly, this resulted in increased level of G1 arrested cells, as well as of apoptotic cells. These effects could not be obtained by a Flag-tagged form of the 41 kDa isoform. The G1 arrest and apoptotic effects were associated with an increase in T14/Y15 phosphorylation of CDK2 and proteasom-dependent down-regulation of CDC25A, as well as with up-regulation of p57, E2F-1, and p73. No such effects were obtained upon over-expression of a kinase-dead form of the HA-tagged 34 kDa PIM-2. By either using a dominant negative form of p73, or by over-expressing the 34 kDa PIM-2 in p73-silenced cells, we demonstrated that these effects were p73-dependent. These results demonstrate that while PIM-2 can function as a potent survival factor, it can, under certain circumstances, exhibit pro-apoptotic effects as well.


Asunto(s)
Apoptosis/genética , Puntos de Control de la Fase G1 del Ciclo Celular/genética , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/metabolismo , Línea Celular , Línea Celular Tumoral , Núcleo Celular/genética , Núcleo Celular/metabolismo , Supervivencia Celular/genética , Quinasa 2 Dependiente de la Ciclina/genética , Quinasa 2 Dependiente de la Ciclina/metabolismo , Inhibidor p57 de las Quinasas Dependientes de la Ciclina/genética , Inhibidor p57 de las Quinasas Dependientes de la Ciclina/metabolismo , Citoplasma/genética , Citoplasma/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Regulación hacia Abajo/genética , Factor de Transcripción E2F1/genética , Factor de Transcripción E2F1/metabolismo , Células HCT116 , Células HEK293 , Células HL-60 , Células HT29 , Células HeLa , Humanos , Melanoma Experimental/genética , Melanoma Experimental/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Fosforilación , Complejo de la Endopetidasa Proteasomal/genética , Complejo de la Endopetidasa Proteasomal/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Proto-Oncogenes Mas , Proteína Tumoral p73 , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismo , Regulación hacia Arriba , Fosfatasas cdc25/genética , Fosfatasas cdc25/metabolismo
9.
Eur J Haematol ; 74(1): 66-9, 2005 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-15613109

RESUMEN

Neurolymphomatosis is a rare manifestation of progressive non-Hodgkin's lymphoma. A 44-yr-old man with diffuse large B-cell lymphoma presented with unilateral progressive peripheral sensorimotor neuropathy after the 7th cycle of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) therapy. No pathology in the nervous system was evident by computerized tomography (CT), magnetic resonance imaging (MRI) of the head, spinal axis and plexuses and by repeated analysis of cerebrospinal fluid. However, the hybrid modality of positron emission tomography (PET) of fluorinated deoxyglucose (FDG) combined with CT scan (PET-CT) showed unilateral involvement of both the brachial and lumbosacral nervous plexuses. A complete recovery of neurological manifestations and normalization of PET-CT followed intensive chemotherapy with autologous stem cell transplantation. The diagnosis and localization of neurolymphomatosis may be supported by PET-CT imaging.


Asunto(s)
Linfoma de Células B/diagnóstico por imagen , Linfoma de Células B Grandes Difuso/diagnóstico por imagen , Neoplasias del Sistema Nervioso Periférico/diagnóstico por imagen , Adulto , Plexo Braquial , Fluorodesoxiglucosa F18 , Humanos , Plexo Lumbosacro , Linfoma de Células B Grandes Difuso/terapia , Masculino , Neoplasias del Sistema Nervioso Periférico/terapia , Tomografía de Emisión de Positrones , Tomografía Computarizada por Rayos X
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