RESUMEN
ABSTRACT Background Prognosis of patients with Diffuse Large B Cell Lymphoma (DLBCL) is highly variable, and despite the use of modern immunochemotherapy regimens, almost 50% of patients will eventually relapse. Standard risk models, like the International Prognostic Index or the Revised International Prognostic Index (R_IPI) incorporate patient and tumor characteristics but do not consider variables related to host adaptive immunity which have been shown to be of significant prognostic value in non-Hodgkin lymphomas. Aim To analyze the prognostic significance of the absolute monocyte count at diagnosis in diffuse large-B-cell lymphoma in a retrospective setting. Material and Methods We reviewed data of 171 patients with DLBCL treated with Rituximab-based immunochemotherapy at two reference public Hospitals in Montevideo-Uruguay. The outcome measures were overall and relapse free survival. Results The absolute monocyte count, analyzed as a dichotomized variable predicted progression-free and overall survival in low risk patients according to the R-IPI score. Worse outcomes were observed in those with high monocyte count al diagnosis. Conclusions Absolute monocyte count could help in the identification of high-risk patients otherwise expected to have a good prognosis according to traditional scores.
Antecedentes El pronóstico de pacientes con Linfoma Difuso de Células B Grandes (DLBCL) es muy variable y el 50% de los pacientes recae a pesar de uso de regímenes actualizados de inmuno-quimioterapia. Los modelos pronósticos clásicos como el International Prognostic Index o el Revised International Prognostic Index (R_IPI) incorporan características del paciente o del tumor pero no incorporan variables asociadas a la inmunidad adaptativa que tienen valor en linfomas no Hodgkin. Objetivo Analizar retrospectivamente el valor pronóstico del recuento absoluto de monocitos al momento del diagnóstico en pacientes con DLBCL. Material y Métodos Se revisó información de 171 pacientes con DLBCL tratados con inmuno-quimioterapia basada en rituximab en dos centros de referencia públicos de Montevideo, Uruguay. Las variables de resultado fueron la sobrevida global y libre de recaída. Resultados El recuento absoluto de monocitos, tratado como una variable dicotómica, predijo la sobrevida libre de recaída en pacientes de bajo riesgo, de acuerdo al puntaje R-IPI. El pronóstico fue peor en pacientes con altos recuentos al momento del diagnóstico. Conclusiones El recuento absoluto de monocitos puede identificar pacientes de alto riesgo, clasificados como de bajo riesgo por los puntajes tradicionales.
Asunto(s)
Humanos , Masculino , Femenino , Adolescente , Adulto , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Adulto Joven , Monocitos , Linfoma de Células B Grandes Difuso/sangre , Recuento de Leucocitos , Pronóstico , Protocolos de Quimioterapia Combinada Antineoplásica , Estudios Retrospectivos , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , InmunoterapiaAsunto(s)
Etnicidad/genética , Región Variable de Inmunoglobulina/genética , Leucemia Linfocítica Crónica de Células B/genética , Receptores de Antígenos de Linfocitos B/genética , Biomarcadores de Tumor , Humanos , Leucemia Linfocítica Crónica de Células B/epidemiología , Leucemia Linfocítica Crónica de Células B/etnología , Mutación , América del Sur/epidemiologíaRESUMEN
Background Prognosis of patients with Diffuse Large B Cell Lymphoma (DLBCL) is highly variable, and despite the use of modern immunochemotherapy regimens, almost 50% of patients will eventually relapse. Standard risk models, like the International Prognostic Index or the Revised International Prognostic Index (R_IPI) incorporate patient and tumor characteristics but do not consider variables related to host adaptive immunity which have been shown to be of significant prognostic value in non-Hodgkin lymphomas. Aim To analyze the prognostic significance of the absolute monocyte count at diagnosis in diffuse large-B-cell lymphoma in a retrospective setting. Material and Methods We reviewed data of 171 patients with DLBCL treated with Rituximab-based immunochemotherapy at two reference public Hospitals in Montevideo-Uruguay. The outcome measures were overall and relapse free survival. Results The absolute monocyte count, analyzed as a dichotomized variable predicted progression-free and overall survival in low risk patients according to the R-IPI score. Worse outcomes were observed in those with high monocyte count al diagnosis. Conclusions Absolute monocyte count could help in the identification of high-risk patients otherwise expected to have a good prognosis according to traditional scores.
Asunto(s)
Recuento de Leucocitos , Linfoma de Células B Grandes Difuso/sangre , Monocitos , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica , Femenino , Humanos , Inmunoterapia , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Adulto JovenRESUMEN
Lipoprotein lipase (LPL) mRNA expression in chronic lymphocytic leukaemia (CLL) is associated with an unmutated immunoglobulin profile and poor clinical outcome. We evaluated the subcellular localization of LPL protein in CLL cells that did or did not express LPL mRNA. Our results show that LPL protein is differently located in CLL cells depending on whether it is incorporated from the extracellular medium in mutated CLL or generated de novo by leukaemic cells of unmutated patients. The specific quantification of endogenous LPL protein correlates with mRNA expression levels and mutational IGHV status, suggesting LPL protein as a possible reliable prognostic marker in CLL.
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Biomarcadores de Tumor/biosíntesis , Regulación Enzimológica de la Expresión Génica , Regulación Leucémica de la Expresión Génica , Leucemia Linfocítica Crónica de Células B/enzimología , Lipoproteína Lipasa/biosíntesis , Proteínas de Neoplasias/biosíntesis , Anciano , Femenino , Humanos , Leucemia Linfocítica Crónica de Células B/diagnóstico , Leucemia Linfocítica Crónica de Células B/patología , Masculino , Persona de Mediana Edad , Pronóstico , ARN Mensajero/biosíntesis , ARN Neoplásico/biosíntesisRESUMEN
BACKGROUND: Individual variability is among the causes of toxicity and interruption of treatment in acute lymphoblastic leukemia (ALL) and severe non-Hodgkin lymphoma (NHL) patients under protocols including Methotrexate (MTX): 2,4-diamino-N10-methyl propyl-glutamic acid. METHODS: 41 Uruguayan patients were recruited. Gene polymorphisms involved in MTX pathway were analyzed and their association with treatment toxicities and outcome was evaluated. RESULTS: Genotype distribution and allele frequency were determined for SLC19A1 G80A, MTHFR C677T and A1298C, TYMS 28bp copy number variation, SLCO1B1 T521C, DHFR C-1610G/T, DHFR C-680A, DHFR A-317G and DHFR 19bp indel. Multivariate analysis showed that DHFR-1610G/T (OR=0.107, p=0.018) and MTHFR677T alleles (OR=0.12, p=0.026) had a strong protective effect against hematologic toxicity, while DHFR-1610CC genotype increased this toxicity (OR=9, p=0.045). No more associations were found. CONCLUSIONS: The associations found between gene polymorphisms and toxicities in this small cohort are encouraging for a more extensive research to gain a better dose individualization in adult ALL and NHL patients. Besides, genotype distribution showed to be different from other populations, reinforcing the idea that genotype data from other populations should not be extrapolated to ours.
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Antimetabolitos Antineoplásicos/efectos adversos , Antimetabolitos Antineoplásicos/uso terapéutico , Linfoma no Hodgkin/genética , Metotrexato/efectos adversos , Metotrexato/uso terapéutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Adolescente , Adulto , Anciano , Femenino , Genotipo , Humanos , Transportador 1 de Anión Orgánico Específico del Hígado/genética , Linfoma no Hodgkin/tratamiento farmacológico , Masculino , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Persona de Mediana Edad , Polimorfismo Genético , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Proteína Portadora de Folato Reducido/genética , Tetrahidrofolato Deshidrogenasa/genética , Timidilato Sintasa/genética , Adulto JovenRESUMEN
Chronic lymphocytic leukemia (CLL) is an incurable disease characterized by accumulation of clonal B lymphocytes, resulting from a complex balance between cell proliferation and apoptotic death. Continuous crosstalk between cancer cells and local/distant host environment is required for effective tumor growth. Among the main actors of this dynamic interplay between tumoral cells and their microenvironment are the nano-sized vesicles called exosomes. Emerging evidence indicates that secretion, composition, and functional capacity of exosomes are altered as tumors progress to an aggressive phenotype. In CLL, no data exist exploring the specific changes in the proteomic profile of plasma-derived exosomes from patients during disease evolution. We hereby report for the first time different proteomic profiles of plasma exosomes, both between indolent and progressive CLLs as well as within the individual patients at the onset of disease and during its progression. Next, we focus on the changes of the exosome protein cargoes, which are found exclusively in patients with progressive CLL after disease progression. The alterations in the proteomic cargoes underline different networks specific for leukemia progression related to inflammation, oxidative stress, and NF-κB and phosphatidylinositol 3-kinase/AKT pathway activation. Finally, our results suggest a preponderant role for the protein S100-A9 as an activator of the NFκB pathway during CLL progression and suggest that the leukemic clone can generate an autoactivation loop through S100-A9 expression, NF-κB activation, and exosome secretion. Collectively, our data propose a new pathway for NF-κB activation in CLL and highlight the importance of exosomes as extracellular mediators promoting tumor progression in CLL.
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Calgranulina B/inmunología , Exosomas/patología , Leucemia Linfocítica Crónica de Células B/patología , FN-kappa B/inmunología , Basigina/análisis , Basigina/inmunología , Calgranulina B/análisis , Progresión de la Enfermedad , Exosomas/inmunología , Humanos , Leucemia Linfocítica Crónica de Células B/sangre , Leucemia Linfocítica Crónica de Células B/inmunología , FN-kappa B/análisis , Proteoma/análisis , Proteoma/inmunologíaRESUMEN
Among different prognostic factors in chronic lymphocytic leukemia (CLL), we previously demonstrated that lipoprotein lipase (LPL) is associated with an unmutated immunoglobulin profile and clinical poor outcome. Despite the usefulness of LPL for CLL prognosis, its functional role and the molecular mechanism regulating its expression are still open questions. Interaction of CLL B-cells with the tissue microenvironment favors disease progression by promoting malignant B-cell growth. Since tissue methylation can be altered by environmental factors, we investigated the methylation status of the LPL gene and the possibility that overexpression could be associated with microenvironment signals. Our results show that a demethylated state of the LPL gene is responsible for its anomalous expression in unmutated CLL cases and that this expression is dependent on microenvironment signals. Overall, this work proposes that an epigenetic mechanism, triggered by the microenvironment, regulates LPL expression in CLL disease.
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Metilación de ADN , Leucemia Linfocítica Crónica de Células B/genética , Lipoproteína Lipasa/genética , Islas de CpG , Exones , Regulación Leucémica de la Expresión Génica , Humanos , Cadenas Pesadas de Inmunoglobulina/genética , Intrones , Leucemia Linfocítica Crónica de Células B/metabolismo , Lipoproteína Lipasa/metabolismo , Mutación , Regiones Promotoras Genéticas , Microambiente Tumoral/genéticaRESUMEN
Peripheral T-cell lymphomas are a group of rare neoplasms originating from clonal proliferation of mature post-thymic lymphocytes with different entities having specific biological characteristics and clinical features. As natural killer cells are closely related to T-cells, natural killer-cell lymphomas are also part of the group. The current World Health Organization classification recognizes four categories of T/natural killer-cell lymphomas with respect to their presentation: disseminated (leukemic), nodal, extranodal and cutaneous. Geographic variations in the distribution of these diseases are well documented: nodal subtypes are more frequent in Europe and North America, while extranodal forms, including natural killer-cell lymphomas, occur almost exclusively in Asia and South America. On the whole, T-cell lymphomas are more common in Asia than in western countries, usually affect adults, with a higher tendency in men, and, excluding a few subtypes, usually have an aggressive course and poor prognosis. Apart from anaplastic lymphoma kinase-positive anaplastic large cell lymphoma, that have a good outcome, other nodal and extranodal forms have a 5-year overall survival of about 30%. According to the principal prognostic indexes, the majority of patients are allocated to the unfavorable subset. In the past, the rarity of these diseases prevented progress in the understanding of their biology and improvements in the efficaciousness of therapy. Recently, international projects devoted to these diseases created networks promoting investigations on T-cell lymphomas. These projects are the basis of forthcoming cooperative, large scale trials to detail biologic characteristics of each sub-entity and to possibly individuate targets for new therapies.
RESUMEN
Peripheral T-cell lymphomas are a group of rare neoplasms originating from clonal proliferation of mature post-thymic lymphocytes with different entities having specific biological characteristics and clinical features. As natural killer cells are closely related to T-cells, natural killer-cell lymphomas are also part of the group. The current World Health Organization classification recognizes four categories of T/natural killer-cell lymphomas with respect to their presentation: disseminated (leukemic), nodal, extranodal and cutaneous. Geographic variations in the distribution of these diseases are well documented: nodal subtypes are more frequent in Europe and North America, while extranodal forms, including natural killer-cell lymphomas, occur almost exclusively in Asia and South America. On the whole, T-cell lymphomas are more common in Asia than in western countries, usually affect adults, with a higher tendency in men, and, excluding a few subtypes, usually have an aggressive course and poor prognosis. Apart from anaplastic lymphoma kinase-positive anaplastic large cell lymphoma, that have a good outcome, other nodal and extranodal forms have a 5-year overall survival of about 30 percent. According to the principal prognostic indexes, the majority of patients are allocated to the unfavorable subset. In the past, the rarity of these diseases prevented progress in the understanding of their biology and improvements in the efficaciousness of therapy. Recently, international projects devoted to these diseases created networks promoting investigations on T-cell lymphomas. These projects are the basis of forthcoming cooperative, large scale trials to detail biologic characteristics of each sub-entity and to possibly individuate targets for new therapies.
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Humanos , Neoplasias Hematológicas , Células Asesinas Naturales , Linfoma de Células T/clasificación , Linfoma de Células T/epidemiología , Linfoma de Células T/patología , PronósticoRESUMEN
BACKGROUND: In 2006 the Hematology Service of Hospital Maciel published its experience with peripheral blood progenitor cell harvesting for autologous stem cell transplantation using Filgen JP (Clausen Filgrastim). After mobilization with a mean filgrastim dose of 78 mcg/Kg, 4.7 x 10(6) CD34+ cells/Kg were obtained by apheresis. Age above 50, multiple myeloma as underlying disease and a malignancy that was not in remission were identified as frequent characteristics among patients showing complex mobilization. OBJECTIVE: The aim of this study was to compare stem cell mobilization using different brands of filgrastim. METHODS: One hundred and fifty-seven mobilizations performed between 1997 and 2006 were analyzed. This retrospective analysis comparative two groups of patients: those mobilized with different brands of filgrastim (Group A) and those who received Filgen JP (Clausen Filgrastim) as mobilizing agent (Group B). A cluster analysis technique was used to identify four clusters of individuals with different behaviors differentiated by age, total dose of filgrastim required, number of apheresis and harvested CD34+ cells. RESULTS: The mean total dose of filgrastim administered was 105 mcg/Kg, the median number of apheresis was 2 procedures and the mean number of harvested stem cells was 4.98 x 10(6) CD34+ cells/Kg. No significant differences were observed between Groups A and B regarding the number of apheresis, harvested CD34+ cells and number of mobilization failures, however the total dose of filgrastim was significantly lower in Group B. CONCLUSIONS: Among other factors, the origin of the cytokine used as mobilizing agent is an element to be considered when evaluating CD34+ cell mobilization results.
Asunto(s)
Humanos , Eliminación de Componentes Sanguíneos , Movilización de Célula Madre Hematopoyética , Inmunosupresores/administración & dosificación , Estudios Retrospectivos , Trasplante AutólogoRESUMEN
BACKGROUND: In 2006 the Hematology Service of Hospital Maciel published its experience with peripheral blood progenitor cell harvesting for autologous stem cell transplantation using Filgen JP (Clausen Filgrastim). After mobilization with a mean filgrastim dose of 78 mcg/Kg, 4.7 x 10(6) CD34(+) cells/Kg were obtained by apheresis. Age above 50, multiple myeloma as underlying disease and a malignancy that was not in remission were identified as frequent characteristics among patients showing complex mobilization. OBJECTIVE: The aim of this study was to compare stem cell mobilization using different brands of filgrastim. METHODS: One hundred and fifty-seven mobilizations performed between 1997 and 2006 were analyzed. This retrospective analysis comparative two groups of patients: those mobilized with different brands of filgrastim (Group A) and those who received Filgen JP (Clausen Filgrastim) as mobilizing agent (Group B). A cluster analysis technique was used to identify four clusters of individuals with different behaviors differentiated by age, total dose of filgrastim required, number of apheresis and harvested CD34(+) cells. RESULTS: The mean total dose of filgrastim administered was 105 mcg/Kg, the median number of apheresis was 2 procedures and the mean number of harvested stem cells was 4.98 x 10(6) CD34(+) cells/Kg. No significant differences were observed between Groups A and B regarding the number of apheresis, harvested CD34(+) cells and number of mobilization failures, however the total dose of filgrastim was significantly lower in Group B. CONCLUSIONS: Among other factors, the origin of the cytokine used as mobilizing agent is an element to be considered when evaluating CD34(+) cell mobilization results.
RESUMEN
B-cell chronic lymphocytic leukemia (CLL) is characterized by the accumulation of long-lived circulating clonal leukemic B-cells, although the etiopathogenesis remains unclear. The incidence of CLL is variable in different regions around the world. While it is the most frequent chronic leukemia in Western countries, it has a low incidence in Asia. In this work we have investigated the immunoglobulin heavy chain gene rearrangements and mutational status in 80 Uruguayan patients with CLL, and compared these results with those obtained in other geographic regions. Our results demonstrate that Uruguayan patients with CLL display an IGHV gene usage which resembles that observed in Mediterranean countries and exhibits certain differences compared with Brazilian and Asian series, as expected, considering the ethnic basis of the Uruguayan population. This suggests that genetic influences could be important in the development and etiopathogenesis of CLL, but larger studies are necessary to substantiate this possibility.
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Reordenamiento Génico de Cadena Pesada de Linfocito B , Genes de las Cadenas Pesadas de las Inmunoglobulinas , Región Variable de Inmunoglobulina/genética , Leucemia Linfocítica Crónica de Células B/genética , Mutación , Adulto , Anciano , Análisis Mutacional de ADN , Femenino , Frecuencia de los Genes , Geografía , Humanos , Leucemia Linfocítica Crónica de Células B/inmunología , Masculino , Persona de Mediana Edad , Filogenia , UruguayRESUMEN
Interaction of chronic lymphocytic leukemia (CLL) B cells with tissue microenvironment has been suggested to favor disease progression by promoting malignant B-cell growth. Previous work has shown expression in peripheral blood (PB) of CLL B cells of activation-induced cytidine deaminase (AID) among CLL patients with an unmutated (UM) profile of immunoglobulin genes and with ongoing class switch recombination (CSR) process. Because AID expression results from interaction with activated tissue microenvironment, we speculated whether the small subset with ongoing CSR is responsible for high levels of AID expression and could be derived from this particular microenvironment. In this work, we quantified AID expression and ongoing CSR in PB of 50 CLL patients and characterized the expression of different molecules related to microenvironment interaction. Our results show that among UM patients (1) high AID expression is restricted to the subpopulation of tumoral cells ongoing CSR; (2) this small subset expresses high levels of proliferation, antiapoptotic and progression markers (Ki-67, c-myc, Bcl-2, CD49d, and CCL3/4 chemokines). Overall, this work outlines the importance of a cellular subset in PB of UM CLL patients with a poor clinical outcome, high AID levels, and ongoing CSR, whose presence might be a hallmark of a recent contact with the microenvironment.
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Citidina Desaminasa/sangre , Citidina Desaminasa/genética , Cambio de Clase de Inmunoglobulina , Leucemia Linfocítica Crónica de Células B/enzimología , Leucemia Linfocítica Crónica de Células B/genética , Subgrupos de Linfocitos B/enzimología , Subgrupos de Linfocitos B/inmunología , Subgrupos de Linfocitos B/patología , Secuencia de Bases , Biomarcadores de Tumor/genética , Proliferación Celular , Cartilla de ADN/genética , Expresión Génica , Humanos , Leucemia Linfocítica Crónica de Células B/inmunología , Mutación , Pronóstico , ARN Mensajero/sangre , ARN Mensajero/genética , ARN Neoplásico/sangre , ARN Neoplásico/genéticaRESUMEN
La enfermedad de Gaucher tipo I es una afección de herencia autosómica recesiva determinada por deficiencia de actividad de la enzima b-glucosidasa ácida y acúmulo progresivo de glicosilceramida en los lisosomas de células macrofágicas. No tiene compromiso primario del sistema nervioso central, siendo sus síntomas habituales visceromegalias, sangrado, anemia y dolores óseos. Puede presentarse desde la edad pediátrica hasta el adulto mayor o permanecer asintomática. Han sido identificadas numerosas mutaciones, algunas muy frecuentes. Tiene tratamiento sintomático y específico Presentamos tres casos de inicio en edad adulta, no emparentados entre sí y sin padres consanguíneos, analizando aspectos clínicos, bioquímicos, moleculares y de tratamiento actual. Destacamos la importancia del diagnóstico de esta enfermedad genética que tiene pautas de seguimiento y tratamiento específico. (AU)