RESUMEN
In T-cell acute lymphoblastic leukemia (T-ALL), transcription factors are known to be deregulated by chromosomal translocations, but mutations in protein tyrosine kinases have only rarely been identified. Here we describe the extrachromosomal (episomal) amplification of ABL1 in 5 of 90 (5.6%) individuals with T-ALL, an aberration that is not detectable by conventional cytogenetics. Molecular analyses delineated the amplicon as a 500-kb region from chromosome band 9q34, containing the oncogenes ABL1 and NUP214 (refs. 5,6). We identified a previously undescribed mechanism for activation of tyrosine kinases in cancer: the formation of episomes resulting in a fusion between NUP214 and ABL1. We detected the NUP214-ABL1 transcript in five individuals with the ABL1 amplification, in 5 of 85 (5.8%) additional individuals with T-ALL and in 3 of 22 T-ALL cell lines. The constitutively phosphorylated tyrosine kinase NUP214-ABL1 is sensitive to the tyrosine kinase inhibitor imatinib. The recurrent cryptic NUP214-ABL1 rearrangement is associated with increased HOX expression and deletion of CDKN2A, consistent with a multistep pathogenesis of T-ALL. NUP214-ABL1 expression defines a new subgroup of individuals with T-ALL who could benefit from treatment with imatinib.
Asunto(s)
Genes abl , Leucemia-Linfoma de Células T del Adulto/genética , Proteínas de Complejo Poro Nuclear/genética , Plásmidos/genética , Secuencia de Aminoácidos , Fusión Artificial Génica , Secuencia de Bases , Benzamidas , Línea Celular Tumoral , Cromosomas Humanos Par 9/genética , ADN de Neoplasias/genética , Inhibidores Enzimáticos/uso terapéutico , Amplificación de Genes , Humanos , Mesilato de Imatinib , Hibridación Fluorescente in Situ , Leucemia-Linfoma de Células T del Adulto/tratamiento farmacológico , Leucemia-Linfoma de Células T del Adulto/enzimología , Datos de Secuencia Molecular , Piperazinas/uso terapéutico , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Proteínas Tirosina Quinasas/genética , Pirimidinas/uso terapéuticoRESUMEN
Karyotype complexity has major prognostic value in many malignancies. There is no consensus on the definition of a complex karyotype, and the prognostic impact of karyotype complexity differs from one disease to another. Due to the importance of the complex karyotype in the prognosis and treatment of several hematological diseases, the Francophone Group of Hematological Cytogenetics (Groupe Francophone de Cytogénétique Hématologique, GFCH) has developed an up-to-date, practical document for helping cytogeneticists to assess complex karyotypes in these hematological disorders. The evaluation of karyotype complexity is challenging, and it would be useful to have a consensus method for counting the number of chromosomal abnormalities (CAs). Although it is not possible to establish a single prognostic threshold for the number of CAs in all malignancies, a specific consensus prognostic cut-off must be defined for each individual disease. In order to standardize current cytogenetic practices and apply a single denomination, we suggest defining a low complex karyotype as having 3 CAs, an intermediate complex karyotype as having 4 CAs, and a highly complex karyotype as having 5 or more CAs.
Asunto(s)
Neoplasias Hematológicas , Hematología , Aberraciones Cromosómicas , Análisis Citogenético/métodos , Citogenética , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/genética , Humanos , Cariotipo , Pronóstico , Sociedades MédicasRESUMEN
INTRODUCTION: Hypersensitivity pneumonitis (HP) is one of the most common interstitial lung diseases, characterized by an inflammatory and/or fibrotic reaction to inhaled antigens. BACKGROUND: The heterogeneity of presentation and the lack of international guidelines makes management complex. In addition, the current treatment, based on antigen eviction and immunosuppressive drugs, is less effective in the fibrotic forms of HP. This article summarizes the latest data on HP and the new recommendations of the American Thoracic Society (ATS) on the diagnosis of HP. CONCLUSION: The new ATS recommendations establish a more precise and rigorous diagnostic approach to HP. Multidisciplinary discussion plays a pivotal role both in the diagnosis and the treatment of the disease. Nintedanib has recently been shown to be effective in fibrotic HP. PERSPECTIVES: Questions remain unanswered about the optimal therapeutic strategy in fibrotic HP, which underlines the need to carry out large-scale studies.
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Alveolitis Alérgica Extrínseca , Enfermedades Pulmonares Intersticiales , Alveolitis Alérgica Extrínseca/diagnóstico , Alveolitis Alérgica Extrínseca/terapia , Fibrosis , HumanosRESUMEN
By stimulating blood lymphocytes from a renal cell carcinoma patient in vitro with the autologous tumor cells, we obtained cytolytic T lymphocyte (CTL) clones that killed several autologous and allogeneic histocompatibility leukocyte antigen (HLA)-B7 renal carcinoma cell lines. We identified the target antigen of these CTLs by screening COS cells transfected with the HLA-B7 cDNA and with a cDNA library prepared with RNA from the tumor cells. The antigenic peptide recognized by the CTLs has the sequence LPRWPPPQL and is encoded by a new gene, which we named RU2. This gene is transcribed in both directions. The antigenic peptide is not encoded by the sense transcript, RU2S, which is expressed ubiquitously. It is encoded by an antisense transcript, RU2AS, which starts from a cryptic promoter located on the reverse strand of the first intron and ends up on the reverse strand of the RU2S promoter, which contains a polyadenylation signal. This mechanism of antigen expression is unprecedented and further illustrates the notion that many peptides recognized by T cells cannot be predicted from the primary structure of the major product of the encoding gene. Antisense transcript RU2AS is expressed in a high proportion of tumors of various histological types. It is absent in most normal tissues, but is expressed in testis and kidney, and, at lower levels, in urinary bladder and liver. Short-term cultures of normal epithelial cells from the renal proximal tubule expressed significant levels of RU2AS message and were recognized by the CTLs. Therefore, this antigen is not tumor specific, but corresponds to a self-antigen with restricted tissue distribution.
Asunto(s)
Antígenos de Neoplasias/genética , Antígenos de Neoplasias/inmunología , Carcinoma de Células Renales/inmunología , Citotoxicidad Inmunológica , Neoplasias Renales/inmunología , Transcripción Genética , Secuencia de Aminoácidos , Presentación de Antígeno/genética , Secuencia de Bases , Carcinoma de Células Renales/genética , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Renales/genética , Datos de Secuencia Molecular , Linfocitos T Citotóxicos/inmunología , Células Tumorales CultivadasRESUMEN
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
RESUMEN
More effective treatment modalities are urgently needed in patients with acute myeloid leukemia (AML) of older age. We hypothesized that adding lenalidomide to intensive standard chemotherapy might improve their outcome. After establishing a safe lenalidomide, dose elderly patients with AML were randomly assigned in this randomized Phase 2 study (n = 222) to receive standard chemotherapy ("3 + 7") with or without lenalidomide at a dose of 20 mg/day 1-21. In the second cycle, patients received cytarabine 1000 mg/m2 twice daily on days 1-6 with or without lenalidomide (20 mg/day 1-21). The CR/CRi rates in the two arms were not different (69 vs. 66%). Event-free survival (EFS) at 36 months was 19% for the standard arm versus 21% for the lenalidomide arm and overall survival (OS) 35% vs. 30%, respectively. The frequencies and grade of adverse events were not significantly different between the treatment arms. Cardiovascular toxicities were rare and equally distributed between the arms. The results of the present study show that the addition of lenalidomide to standard remission induction chemotherapy does not improve the therapeutic outcome of older AML patients. This trial is registered as number NTR2294 in The NederlandsTrial Register (www.trialregister.nl).
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Quimioterapia de Inducción/mortalidad , Leucemia Mieloide Aguda/tratamiento farmacológico , Síndromes Mielodisplásicos/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Citarabina/administración & dosificación , Femenino , Estudios de Seguimiento , Humanos , Lenalidomida/administración & dosificación , Leucemia Mieloide Aguda/patología , Masculino , Síndromes Mielodisplásicos/patología , Pronóstico , Inducción de Remisión , Tasa de SupervivenciaRESUMEN
Chromosomal translocations represent an important prognostic indicator in B-cell chronic lymphocytic leukemia (B-CLL). However, their value had been neither determined in homogeneously treated patients nor compared to that of IgV(H) mutational status. Sixty-five B-CLL patients were investigated using cytogenetics, interphase fluorescence in situ hybridization (FISH), analysis of IgV(H) and of TP53 mutational status before treatment with 2-chloro-2'-deoxyadenosine (CdA). Translocations (n=45) were detected in 42% of the patients, including both balanced (n=12) and unbalanced (n=33) types. IgV(H) was mutated in 43% of the patients. Patients with translocations were more heavily pretreated (P=0.05), presented with more complex karyotypes (P<0.001), 17p abnormalities and TP53 mutations, and had a higher failure rate (59 vs 21% in patients without translocations, P=0.004). Patients with unbalanced translocations displayed a shorter median treatment-free survival (TFS, 6.9 vs 35.9 months, log rank 22.72, P<0.001) and overall survival (OS, 13.0 vs 68.0 months, log rank 16.51, P<0.001), as compared to patients without translocation. In multivariate analysis, unbalanced translocations were independently associated with therapeutic failure, short TFS and short OS. IgV(H) mutational status was independently associated with risk of failure and TFS, but not OS. In B-CLL patients treated with CdA, translocations are strong predictors of outcome.
Asunto(s)
Antineoplásicos/uso terapéutico , Cladribina/uso terapéutico , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/mortalidad , Translocación Genética , Adulto , Anciano , Anciano de 80 o más Años , Aberraciones Cromosómicas , Cromosomas Humanos Par 11/genética , Cromosomas Humanos Par 13/genética , Cromosomas Humanos Par 17/genética , Femenino , Humanos , Hibridación Fluorescente in Situ , Interfase , Cariotipificación , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Mutación/genética , Pronóstico , Factores de Riesgo , Tasa de Supervivencia , Insuficiencia del Tratamiento , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
The biologic and pathologic features of B-cell malignancies bearing a translocation t(14;19)(q32;q13) leading to a fusion of IGH and BCL3 are still poorly described. Herein we report the results of a comprehensive cytogenetic, fluorescence in situ hybridization (FISH), molecular and histopathological survey of a large series of B-cell malignancies with t(14;19) or variant translocations. A total of 56 B-cell malignancies with a FISH-proven BCL3 involvement were identified with the translocation partners being IGH (n=51), IGL (n=2), IGK (n=2) and a non-IG locus (n=1). Hierarchical clustering of chromosomal changes associated with the t(14;19) indicated the presence of two different groups of IG/BCL3-positive lymphatic neoplasias. The first group included 26 B-cell malignancies of various histologic subtypes containing a relatively high number of chromosomal changes and mostly mutated IgVH genes. This cluster displayed three cytogenetic branches, one with rearrangements in 7q, another with deletions in 17p and a third one with rearrangements in 1q and deletions in 6q and 13q. The second group included 19 cases, mostly diagnosed as B-cell chronic lymphocytic leukemia (B-CLL), and characterized by few additional chromosomal changes (e.g. trisomy 12) and unmutated IgVH genes. In conclusion, our study indicates that BCL3 translocations are not restricted to B-CLL but present in a heterogeneous group of B-cell malignancies.
Asunto(s)
Leucemia de Células B/genética , Linfoma de Células B/genética , Proteínas Proto-Oncogénicas/genética , Factores de Transcripción/genética , Translocación Genética , Adulto , Anciano , Proteínas del Linfoma 3 de Células B , Cromosomas Humanos Par 14 , Cromosomas Humanos Par 19 , Análisis Citogenético , Femenino , Reordenamiento Génico , Genes de Inmunoglobulinas , Histocitoquímica , Humanos , Hibridación Fluorescente in Situ , Leucemia de Células B/clasificación , Leucemia de Células B/patología , Linfoma de Células B/clasificación , Linfoma de Células B/patología , Masculino , Persona de Mediana EdadRESUMEN
OBJECTIVES: CML, PV, ET and PMF are so called classical MPN with distinct clinical phenotypes. The discovery of the BCR-ABL1 translocation and mutations in driver genes JAK2, MPL and CALR has provided novel insights in their pathogenesis. While these mutations are thought to be mutually exclusive, rare cases of MPN with coexisting driver mutations have been reported. However, little is known about the clinical, biological and molecular characteristics of these patients and the interaction of the neoplastic clones. METHODS: We retrospectively studied 11 MPN patients with coexisting driver mutations (JAK2 V617F + BCR-ABL1: n = 8; CALR type 2 + BCR-ABL1: n = 1; JAK2 V617F + MPL W515: n = 1; JAK2 V617F + CALR type 1: n = 1). To assess possible associated molecular aberrations, we analysed DNA of six patients using NGS. RESULTS: In four CML patients, decreasing BCR-ABL1 transcript levels with increasing JAK2 V617F allele burden under TKI were observed. This strongly suggests that the coexistence of driver mutations originates from two different clones growing independently. Additional somatic mutations were detected in 5 out of 6 (83%) patients affecting 4 different genes, confirming the heterogeneity of this study cohort. Suboptimal response to TKI was observed with a higher frequency (4/8 patients) than reported in conventional series of CML and the overall tolerance of treatment with hydroxyurea and/or imatinib in our series was poor. CONCLUSION: Given the emergence of NGS in clinical practice, more similar cases will be identified in the coming years. The optimal treatment strategy for this rare group of patients is uncertain and toxicity of combination treatment may have to be considered.
Asunto(s)
Resistencia a Antineoplásicos/genética , Neoplasias Hematológicas/genética , Mutación , Trastornos Mieloproliferativos/genética , Proteínas de Neoplasias/genética , Adulto , Anciano , Femenino , Neoplasias Hematológicas/tratamiento farmacológico , Humanos , Hidroxiurea , Masculino , Persona de Mediana Edad , Trastornos Mieloproliferativos/tratamiento farmacológicoRESUMEN
A retrospective cytogenetic study of acute myeloid leukemias (AML) and myelodysplastic syndromes (MDS) was conducted by the Groupe Francophone de Cytogénétique Hématologique (GFCH) to evaluate the structural abnormalities of chromosome 5 associated with other chromosomal abnormalities, in particular of chromosome 7, in these pathologies. In all, 110 cases of AML/MDS were recruited based on the presence of chromosome 5 abnormalities under conventional cytogenetics and supplemented by a systematic fluorescence in situ hybridization study of chromosomes 5 and 7. The abnormalities of the long arm of chromosome 5 (5q) were deletions of various sizes and sometimes cryptic. The 5q abnormalities were associated with translocations in 54% of cases and were simple deletions in 46%. In 68% of cases, 5q deletions were associated with chromosome 7 abnormalities, and 90% of these presented a complex karyotype. Of the 110 patients, 28 had a hematopoietic disorder secondary to chemotherapy, radiotherapy, or both. Among 82 patients with de novo AML/MDS, 63 were older than 60 years. Chromosomal abnormalities often associated hypodiploidy and chromosome 5 and 7 abnormalities in complex karyotypes, features resembling those of secondary hemopathies. Systematic investigation of the exposure to mutagens and oncogenes is thus essential to specify the factors potentially involved in MDS/AML with 5q abnormalities.
Asunto(s)
Aberraciones Cromosómicas , Cromosomas Humanos Par 5 , Cromosomas Humanos Par 7 , Leucemia Mieloide/genética , Síndromes Mielodisplásicos/genética , Enfermedad Aguda , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Deleción Cromosómica , Femenino , Humanos , Hibridación Fluorescente in Situ , Masculino , Persona de Mediana Edad , Neoplasias Inducidas por Radiación , Translocación GenéticaRESUMEN
For long, T-cell acute lymphoblastic leukemia (T-ALL) remained in the shadow of precursor B-ALL because it was more seldom, and showed a normal karyotype in more than 50% of cases. The last decennia, intense research has been carried out on different fronts. On one side, development of normal thymocyte and its regulation mechanisms have been studied in multiple mouse models and subsequently validated. On the other side, molecular cytogenetics (fluorescence in situ hybridization) and mutation analysis revealed cytogenetically cryptic aberrations in almost all cases of T-ALL. Also, expression microarray analysis disclosed gene expression signatures that recapitulate specific stages of thymocyte development. Investigations are still very much actual, fed by the discovery of new genetic aberrations. In this review, we present a summary of the current cytogenetic changes associated with T-ALL. The genes deregulated by translocations or mutations appear to encode proteins that are also implicated in T-cell development, which prompted us to review the 'normal' and 'leukemogenic' functions of these transcription regulators. To conclude, we show that the paradigm of multistep leukemogenesis is very much applicable to T-ALL and that the different genetic insults collaborate to maintain self-renewal capacity, and induce proliferation and differentiation arrest of T-lymphoblasts. They also open perspectives for targeted therapies.
Asunto(s)
Leucemia-Linfoma de Células T del Adulto/genética , Linfocitos/patología , Timo/patología , Linaje de la Célula , Aberraciones Cromosómicas , Genes Homeobox , Humanos , Leucemia-Linfoma de Células T del Adulto/enzimología , Leucemia-Linfoma de Células T del Adulto/patología , Proteínas Tirosina Quinasas/genética , Receptores de Antígenos de Linfocitos T/metabolismo , Transducción de SeñalRESUMEN
Chromosomal region 1p22 is deleted in ⩾20% of multiple myeloma (MM) patients, suggesting the presence of an unidentified tumor suppressor. Using high-resolution genomic profiling, we delimit a 58 kb minimal deleted region (MDR) on 1p22.1 encompassing two genes: ectopic viral integration site 5 (EVI5) and ribosomal protein L5 (RPL5). Low mRNA expression of EVI5 and RPL5 was associated with worse survival in diagnostic cases. Patients with 1p22 deletion had lower mRNA expression of EVI5 and RPL5, however, 1p22 deletion status is a bad predictor of RPL5 expression in some cases, suggesting that other mechanisms downregulate RPL5 expression. Interestingly, RPL5 but not EVI5 mRNA levels were significantly lower in relapsed patients responding to bortezomib and; both in newly diagnosed and relapsed patients, bortezomib treatment could overcome their bad prognosis by raising their progression-free survival to equal that of patients with high RPL5 expression. In conclusion, our genetic data restrict the MDR on 1p22 to EVI5 and RPL5 and although the role of these genes in promoting MM progression remains to be determined, we identify RPL5 mRNA expression as a biomarker for initial response to bortezomib in relapsed patients and subsequent survival benefit after long-term treatment in newly diagnosed and relapsed patients.
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Antineoplásicos/uso terapéutico , Bortezomib/uso terapéutico , Deleción Cromosómica , Cromosomas Humanos Par 1 , Mieloma Múltiple/genética , Proteínas Ribosómicas/genética , Proteínas de Unión al ADN/genética , Genes Supresores de Tumor , Humanos , Proteína del Locus del Complejo MDS1 y EV11 , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/mortalidad , Mutación , Proto-Oncogenes/genética , ARN Mensajero/análisis , Factores de Transcripción/genéticaRESUMEN
The transcription factor Forkhead box protein P1 (FOXP1) is highly expressed in a proportion of diffuse large B-cell lymphoma (DLBCL). In this report, we provide cytogenetic and fluorescence in situ hybridization (FISH) data showing that FOXP1 (3p13) is recurrently targeted by chromosome translocations. The genomic rearrangement of FOXP1 was identified by FISH in three cases with a t(3;14)(p13;q32) involving the immunoglobulin heavy chain (IGH) locus, and in one case with a variant t(2;3) affecting sequences at 2q36. These aberrations were associated with strong expression of FOXP1 protein in tumor cells, as demonstrated by immunohistochemistry (IHC). The cases with t(3p13) were diagnosed as DLBCL ( x 1), gastric MALT lymphoma ( x 1) and B-cell non-Hodgkin's lymphoma, not otherwise specified ( x 2). Further IHC and FISH studies performed on 98 cases of DLBCL and 93 cases of extranodal marginal zone lymphoma showed a high expression of FOXP1 in approximately 13 and 12% of cases, respectively. None of these cases showed, however, FOXP1 rearrangements by FISH. However, over-representation of the FOXP1 locus found in one additional case of DLBCL may represent another potential mechanism underlying an increased expression of this gene.
Asunto(s)
Linfoma de Células B Grandes Difuso/genética , Proteínas Represoras/genética , Translocación Genética , Anciano , Aberraciones Cromosómicas , Cromosomas Humanos Par 14 , Cromosomas Humanos Par 2 , Cromosomas Humanos Par 3 , Femenino , Factores de Transcripción Forkhead , Regulación Neoplásica de la Expresión Génica , Reordenamiento Génico , Humanos , Linfoma de Células B/genética , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
Although reciprocal chromosomal translocations are not typical for B-cell chronic lymphocytic leukemia (B-CLL), we identified the novel t(1;6)(p35.3;p25.2) in eight patients with this disorder. Interestingly, all cases showed lack of somatically mutated IgV(H). Clinical, morphological, immunologic, and genetic features of these patients are described. Briefly, the age ranged from 33 to 81 years (median: 62.5 years) and the sex ratio was 6M:2F. Most of the patients (6/8) presented with advanced clinical stage. Therapy was required in seven cases. After a median follow-up of 28 months, five patients are alive and three died from disease evolution. Three cases developed transformation into diffuse large B-cell lymphoma. Translocation t(1;6) was found as the primary karyotypic abnormality in three patients. Additional chromosomal aberrations included changes frequently found in unmutated B-CLL, that is, del(11)(q), trisomy 12 and 17p aberrations. Fluorescence in situ hybridization analysis performed in seven cases allowed us to map the t(1;6) breakpoints to the 1p35.3 and 6p25.2 chromosomal bands, respectively. The latter breakpoint was located in the genomic region coding for MUM1/IRF4, one of the key regulators of lymphocyte development and proliferation, suggesting involvement of this gene in the t(1;6). Molecular characterization of the t(1;6)(p35.3;p25.2), exclusively found in unmutated subtype of B-CLL, is in progress.
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Cromosomas Humanos Par 1 , Cromosomas Humanos Par 6 , Leucemia Linfocítica Crónica de Células B/genética , Translocación Genética , Humanos , Hibridación Fluorescente in Situ , CariotipificaciónRESUMEN
PURPOSE: To identify the prognostic factors that influence overall survival (OS) in patients with stage III-IV follicular lymphomas and evaluate the clinical usefulness and the prognostic value of the International Prognostic Index (IPI). PATIENTS AND METHODS: Four hundred eighty-four patients with Ann Arbor stage III-IV follicular lymphomas treated in two phase III trials from 1986 to 1995 were screened for this study. All histologic slides were reviewed by two hematopathologists. The influence of the initial parameters on survival was defined by univariate (log-rank test) and multivariate (Cox model) analyses. RESULTS: The poor prognostic factors for OS (age > 60 years, "B" symptom(s), > or = two extranodal sites, stage IV disease, tumor bulk > 7 cm, at least three nodal sites > 3 cm, liver involvement, serous effusion-compression or orbital/epidural involvement, and erythrocyte sedimentation rate > 30 mm/h) that were significant in univariate analysis were subjected to multivariate analysis. Three factors remained significant: B symptom(s) (risk ratio = 1.80), age greater than 60 years (risk ratio = 1.60), and at least three nodal sites greater than 3 cm (risk ratio = 1.71). When the IPI was applied to these patients, the score was 1, 2, 3, and 4-5 in 49%, 39%, 11%, and 2%, respectively, and it was significant for progression-free survival (P =.002) and OS (P =.0001). CONCLUSION: Three prognostic factors for poor OS were identified: B symptoms, age greater than 60 years, and at least three nodal sites greater than 3 cm. The IPI was prognostic for OS, but in this population, a very low number of patients belonged to the high-risk groups.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Linfoma Folicular/tratamiento farmacológico , Linfoma Folicular/patología , Adulto , Anciano , Ensayos Clínicos Fase III como Asunto , Ciclofosfamida/administración & dosificación , Doxorrubicina/administración & dosificación , Femenino , Humanos , Linfoma Folicular/mortalidad , Masculino , Persona de Mediana Edad , Análisis Multivariante , Estadificación de Neoplasias , Prednisona/administración & dosificación , Pronóstico , Tenipósido/administración & dosificaciónRESUMEN
Anaplastic large cell lymphoma (ALCL) expressing the CD30 antigen is an uncommon subtype of non-Hodgkin's lymphoma characterized by distinct morphological and clinical features. The recurrent chromosomal abnormality found in these tumours is a t(2;5)(p23;q35) which has been detected in a minority of these cases, predominantly with a T cell immunophenotype. We report here a CD30 positive null cell type ALCL case cytogenetically characterized by a new type of t(2;5) translocation with distinct breakpoints at 2q37 and 5q31. FISH with a panel of 5q specific DNA probes applied in this case allowed for a mapping of a 5q31 breakpoint region between the locus for IL-3 (proximally) and CI5-56 probe (distally). These results point to a localization of unknown gene(s) on the long arm of chromosome 5 that, in addition to the NPM gene at 5q35, may be involved in the pathogenesis of some CD30+ ALCL.
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Cromosomas Humanos Par 2/genética , Cromosomas Humanos Par 5/genética , Linfoma Anaplásico de Células Grandes/genética , Translocación Genética/genética , Adulto , Bandeo Cromosómico , Resultado Fatal , Humanos , Cariotipificación , MasculinoRESUMEN
Integration of morphological and immunophenotypic data is critical in achieving diagnosis accuracy and minimising interobserver interpretative discrepancies. The aim of this work was to compare the immunophenotype and the morphology of chronic lymphocytic leukaemia and mantle cell lymphoma, to help in the differential diagnosis of CD5 positive monoclonal B cells. Frozen/thawed samples from 91 patients were analysed retrospectively. Fresh samples from 17 mixed/atypical CLL and 13 MCL were tested to corroborate the results. Markers were analysed as percentage (%) of positive B lymphocyte subpopulation, and in terms of median fluorescence intensity (MFI). Matutes's CLL score clearly allowed distinguishing between classical CLL on the one hand, and atypical CLL and MCL on the other hand. The percentage of CD54-positive cells and the median fluorescence intensity of CD20 and CD54 were the only parameters which were significantly higher in MCL than in atypical CLL (P < 0.05), allowing an immunological distinction between these two entities. Nevertheless, due to a quenching problem when using CD20 and CD54 together, and because CD18 showed a statistically different expression between classical and atypical CLL, the combination of CD18/CD54 has been preferred and showed a different pattern in the three entities. Immunophenotyping could be helpful in the differential diagnosis of CD5-positive B cell chronic lymphoproliferative disorders with atypical features that do not fit exactly into any of the morphologic proposed groups.
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Antígenos CD20/biosíntesis , Molécula 1 de Adhesión Intercelular/biosíntesis , Leucemia Linfoide/inmunología , Linfoma de Células del Manto/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Linfocitos B/inmunología , Antígenos CD5/análisis , Diagnóstico Diferencial , Femenino , Citometría de Flujo , Humanos , Inmunofenotipificación , Leucemia Linfoide/diagnóstico , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
We report on three patients with acute non-lymphoblastic leukemia (ANLL) displaying the same chromosomal translocation t(11;15)(q23;q14). The clinical course of the disease was aggressive, and survival was short. The FAB subtype was M-2 in two cases, and M-1 in the remaining patient. Immunologically two cases showed aberrant expression of a lymphoid antigen (CD19 and TdT, respectively). HTRX1/MLL gene was rearranged in one patient studied at the time of diagnosis. These results plus data scattered in the literature show that the t(11;15)(q23;q14) can be added to the list of recurrent rearrangements in ANLL involving 11q23.
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Cromosomas Humanos Par 11 , Cromosomas Humanos Par 15 , Leucemia Mieloide Aguda/genética , Proto-Oncogenes , Factores de Transcripción , Translocación Genética , Adulto , Southern Blotting , Niño , Proteínas de Unión al ADN/genética , Reordenamiento Génico , N-Metiltransferasa de Histona-Lisina , Humanos , Cariotipificación , Masculino , Proteína de la Leucemia Mieloide-LinfoideRESUMEN
Chromosomal rearrangements involving 3q26 either due to inversion or translocation with various partner chromosomes are a recurrent finding in malignant myeloid disorders. Typically, these chromosome aberrations contribute to ectopic expression of or to the formation of fusion genes involving the EVI1 proto-oncogene. Chromosomal translocations involving the short arm of chromosome 2 (p15-p23) and the distal part of the long arm of chromosome 3 (q26-q27) are a rare but recurrent finding in patients with myeloid malignancies, and are assumed to be part of this spectrum of disorders. Thus far, however, these translocations have been poorly studied. Here, we present 21 new cases with myelodysplasia, acute myeloid leukemia or CML in blast crisis, which upon karyotyping showed the presence of a t(2;3). Furthermore, an extensive literature review disclosed 29 additional cases. Morphological, clinical and cytogenetic assessment revealed the typical hallmarks of 3q26/EVI1 rearrangements, that is, trilineage dysplasia and dysmegakaryopoiesis, poor prognosis and additional monosomy 7. Molecular cytogenetic analysis and PCR in selected samples indicated that in most cases the translocation indeed targets the EVI1 locus. Mapping of the chromosome 2 breakpoints confirmed the initially suspected cytogenetic breakpoint heterogeneity at the 2p arm.
Asunto(s)
Cromosomas Humanos Par 2 , Cromosomas Humanos Par 3 , Leucemia Mieloide/genética , Leucemia Mieloide/patología , Translocación Genética , Enfermedad Aguda , Adulto , Anciano , Niño , Femenino , Humanos , Hibridación Fluorescente in Situ , Masculino , Persona de Mediana Edad , Proto-Oncogenes MasRESUMEN
Because of their substantial in vitro synergy, we conducted a dose-escalation study of cyclophosphamide (CP) added to 2-chloro-2'-deoxyadenosine (CdA) in patients with previously treated chronic lymphocytic leukemia and non-Hodgkin's lymphoma. CdA was given at a fixed dose (5.6 mg/m2/day) as a 2-h intravenous (i.v.) infusion, immediately followed by a 1-h i.v. infusion of CP, for 3 days. The initial daily CP dose was 200 mg/m2, and was escalated by 100 mg/m2 increments in successive cohorts of three to six patients to determine the maximum-tolerated dose (MTD). Additional patients were included at the MTD to extend toxicity and response analysis. Twenty-six patients received 68 cycles of chemotherapy. The MTD of CP after CdA 5.6 mg/m2, was 300 mg/m2. Acute neutropenia was the dose-limiting toxicity of this regimen, which was otherwise well tolerated. Delivery of repeated cycles was not feasible in eight patients (31%) because of prolonged thrombocytopenia. Severe infections were seen in three of 68 cycles (4%). The overall response rate was 58% (15 of 26; 95% CI, 36-76%), with 15% complete responses and 42% partial responses. These data show the feasibility of the association of CdA with CP. Given the response rate observed, further studies of this regimen are warranted in untreated patients, in particular with chronic lymphocytic leukemia and with Waldenström macroglobulinemia.