RESUMO
A series of 38 patients with acute myeloblastic leukemia (AML) with 49 or more chromosomes and without structural abnormalities was selected within the Groupe Francophone de Cytogénétique Hématologique (GFCH) to better define their characteristics. The median age of the patients was 65 years, and all FAB subtypes were represented. Although all chromosomes were gained, some seems to prevail: chromosome 8 (68%), 21 (47%), 19 (37%), and 13 and 14 (34% each). Since MLL rearrangement leads patients in a group with an unfavorable prognosis, search for cryptic rearrangements of MLL was performed in 34 patients and showed abnormalities in 5 (15%). When we applied the most frequent definition of complex karyotypes (three or more abnormalities), all patients with high hyperdiploid AML fall in the unfavorable category. Among the 18 patients without MLL rearrangement receiving an induction therapy, 16 (89%) reached CR and 6 (33%) were still alive after a 31-month median follow-up (14-61 months). Although this study was retrospective, these results suggest that high hyperdiploid AML without chromosome rearrangement seems to be a subgroup of uncommon AML (less than 1%), and may be better classified in the intermediate prognostic group.
Assuntos
Aberrações Cromossômicas , Cromossomos Humanos/genética , Leucemia Mieloide/genética , Ploidias , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Rearranjo Gênico , Histona-Lisina N-Metiltransferase , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Leucemia Mieloide/tratamento farmacológico , Leucemia Mieloide/epidemiologia , Masculino , Pessoa de Meia-Idade , Proteína de Leucina Linfoide-Mieloide/genética , Prognóstico , Estudos Prospectivos , Estudos RetrospectivosAssuntos
Cromossomos Humanos Par 16/ultraestrutura , Cromossomos Humanos Par 8/ultraestrutura , Histona Acetiltransferases/genética , Leucemia Monocítica Aguda/genética , Fusão Oncogênica , Proteínas de Fusão Oncogênica/genética , Transativadores/genética , Translocação Genética , Idoso , Sequência de Aminoácidos , Sequência de Bases , Cromossomos Humanos Par 16/genética , Cromossomos Humanos Par 8/genética , Éxons/genética , Evolução Fatal , Feminino , Regulação Leucêmica da Expressão Gênica/genética , Regulação Leucêmica da Expressão Gênica/fisiologia , Histona Acetiltransferases/química , Histona Acetiltransferases/fisiologia , Humanos , Íntrons/genética , Dados de Sequência Molecular , Coativador 3 de Receptor Nuclear , Proteínas de Fusão Oncogênica/química , Estrutura Terciária de Proteína , Transativadores/química , Transativadores/fisiologia , Transcrição GênicaAssuntos
Proteínas de Ciclo Celular/genética , Cromossomos Humanos Par 8 , Cromossomos Humanos Par 9 , Fusão Gênica , Linfoma de Células T/genética , Proteínas Tirosina Quinases/genética , Proteínas Proto-Oncogênicas/genética , Translocação Genética , Adulto , Autoantígenos , Humanos , Janus Quinase 2 , Linfoma de Células T/enzimologia , MasculinoAssuntos
Proteínas de Ciclo Celular/genética , Leucemia Eritroblástica Aguda/genética , Transtornos Mieloproliferativos/genética , Proteínas de Fusão Oncogênica/genética , Proteínas Tirosina Quinases/genética , Proteínas Proto-Oncogênicas/genética , Translocação Genética , Adulto , Autoantígenos , Criança , Cromossomos Humanos Par 8/genética , Cromossomos Humanos Par 9/genética , Feminino , Humanos , Janus Quinase 2 , Masculino , Pessoa de Meia-IdadeRESUMO
Imatinib mesylate (Gleevec), an inhibitor of the BCR-ABL tyrosine kinase, was introduced recently into the therapy of chronic myeloid leukemia (CML). Several cases of emergence of clonal chromosomal abnormalities after therapy with imatinib have been reported, but their incidence, etiology and prognosis remain to be clarified. We report here a large series of 34 CML patients treated with imatinib who developed Philadelphia (Ph)-negative clones. Among 1001 patients with Ph-positive CML treated with imatinib, 34 (3.4%) developed clonal chromosomal abnormalities in Ph-negative cells. Three patients were treated with imatinib up-front. The most common cytogenetic abnormalities were trisomy 8 and monosomy 7 in twelve and seven patients, respectively. In 15 patients, fluorescent in situ hybridization with specific probes was performed in materials archived before the initiation of imatinib. The Ph-negative clone was related to previous therapy in three patients, and represented a minor pre-existing clone that expanded after the eradication of Ph-positive cells with imatinib in two others. However, in 11 patients, the new clonal chromosomal abnormalities were not detected and imatinib may have had a direct effect. No myelodysplasia was found in our cohort. With a median follow-up of 24 months, one patient showed CML acceleration and two relapsed.
Assuntos
Aberrações Cromossômicas , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mieloide Crônica Atípica BCR-ABL Negativa/genética , Leucemia Mieloide Crônica Atípica BCR-ABL Negativa/patologia , Piperazinas/uso terapêutico , Pirimidinas/uso terapêutico , Adulto , Idoso , Aneuploidia , Benzamidas , Cromossomos Humanos Par 7 , Cromossomos Humanos Par 8 , Células Clonais/patologia , Feminino , Humanos , Mesilato de Imatinib , Incidência , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos RetrospectivosRESUMO
The human AML1 gene (also named CBFA2 or RUNX1), located in the 21q22 chromosomal band, encodes for one of the two subunits forming a heterodimeric transcription factor, the human core binding factor (CBF). AML1 protein contains a highly evolutionary conserved domain of 128 amino acids called runt domain, responsible for both heterodimerization with the beta subunit of CBF and for DNA binding. AML1 is normally expressed in all hematopoietic lineages and acts to regulate the expression of various genes specific to hematopoiesis playing a pivotal role in myeloid differentiation. AML1 is one of the genes most frequently deregulated in leukemia through different mechanisms including translocation, mutation and amplification. Translocations lead to the formation of fusion genes encoding for chimerical proteins such as AML1-ETO which induces leukemogenesis. Recently, new mechanisms of AML1 deregulation by point mutations or amplification have been reported. To our knowledge, 51 patients (among 805 studied) with AML1 point mutations have been described. Forty of them have acute myeloid leukemia (AML) most often M0 AML. In this subtype of AML, the frequency of AML1 mutation is significantly higher; 21.5% of patients mutated (34/158). Mutations have also been found with lower frequency in other FAB subtype AML (6 cases), in myeloproliferative disorders (6 cases), in myelodysplastic syndrome (3 cases) and rarely in acute lymphoblastic leukemia (1 case). AML1 gene amplification has been found essentially in childhood ALL (12 cases) and more rarely in myeloid malignancies (4 cases). Here, we reviewed all these cases of AML1 point mutations and amplification and focused on the mechanisms of AML1 deregulation induced by these alterations.
Assuntos
Proteínas de Ligação a DNA/genética , Leucemia Mieloide/genética , Mutação , Síndromes Mielodisplásicas/genética , Proteínas Proto-Oncogênicas , Fatores de Transcrição/genética , Doença Aguda , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Cromossomos Humanos Par 21 , Subunidade alfa 2 de Fator de Ligação ao Core , Proteínas de Ligação a DNA/metabolismo , Feminino , Amplificação de Genes , Regulação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Proteína 1 Parceira de Translocação de RUNX1 , Fatores de Transcrição/metabolismo , Translocação GenéticaRESUMO
Hypoxic pulmonary vasoconstriction (HPV) is a regulatory mechanism by which blood is diverted from poorly ventilated to better ventilated areas of the lung. The aim of the present study was to assess the extent to which hypertonic saline dextran and dextran solutions modify the magnitude of HPV during isovolumic haemodilution in intact acutely instrumented piglets. Eighteen large white piglets were anesthetised and assigned to two groups. Mean pulmonary arterial pressure (PAP) and cardiac output (Q), systemic arterial pressure and left arterial pressure (LAP) were measured. A decrease in Q was obtained by reducing venous return. This enabled measurement of transpulmonary pressures (mean PAP minus LAP) at four levels of Q in hyperoxia (inspiratory oxygen fraction (FiO2)=0.4) then in hypoxia (Fi,O2=0.1) in the two groups before blood soustraction (10 mL x kg(-1)) and after loading with sodium chloride (NaCl) 7.5% and dextran 6% or with dextran 6% alone. Dextran alone led to a decrease in mean PAP-LAP/Q values, and NaCl with dextran was associated with a significant shift of mean PAP-LAP/Q plots to higher pressures in hypoxia. Hypertonic saline dextran solution, as replacement fluid in isovolaemic haemodilution increased the magnitude of hypoxic pulmonary vasoconstriction, whereas dextran solution reduced it.
Assuntos
Dextranos/farmacologia , Hipóxia/fisiopatologia , Circulação Pulmonar/efeitos dos fármacos , Cloreto de Sódio/farmacologia , Resistência Vascular/efeitos dos fármacos , Vasoconstrição/efeitos dos fármacos , Anestesia por Inalação , Animais , Animais Recém-Nascidos , Pressão Sanguínea/fisiologia , Débito Cardíaco/efeitos dos fármacos , Débito Cardíaco/fisiologia , Modelos Animais de Doenças , Feminino , Masculino , Probabilidade , Circulação Pulmonar/fisiologia , Troca Gasosa Pulmonar , Distribuição Aleatória , Valores de Referência , Sensibilidade e Especificidade , Suínos , Resistência Vascular/fisiologia , Vasoconstrição/fisiologiaRESUMO
OBJECTIVE: To try to correlate subjective photophobic symptoms with visual pathway modifications (from the retinal image to the visual cortex) after refractive surgery by exploring brain activation on photic stimulation. DESIGN: Noncomparative case series. PARTICIPANTS: Four subjects reporting discomfort produced by luminance (glare, halos, starbursts, or a combination thereof) in one eye after laser in situ keratomileusis (LASIK) were enrolled. The contralateral myopic eye (control) had no visual impairment and had undergone LASIK without complications or had not had previous surgery. METHODS: Functional magnetic resonance imaging was performed during photic stimulation, delivered by an optical fiber, of the affected and unaffected eyes. RESULTS: Functional magnetic resonance imaging provided evidence that most subjective visual symptoms correlated with anatomic flap abnormalities are associated with a higher signal increase in the visual association cortices compared with a nonsymptomatic eye. CONCLUSIONS: Functional magnetic resonance imaging of the visual cortex may help in exploring the mechanisms involved in glare effects after refractive surgery.
Assuntos
Córnea/cirurgia , Ceratomileuse Assistida por Excimer Laser In Situ/efeitos adversos , Miopia/cirurgia , Fotofobia/diagnóstico , Córtex Visual/patologia , Adulto , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Fotofobia/etiologia , Fotofobia/fisiopatologia , Retina/fisiopatologia , Córtex Visual/fisiopatologia , Vias Visuais/fisiopatologiaRESUMO
In vitro, halogenated agents reduce the pulmonary vasoconstrictor response to alveolar hypoxia in isolated perfused lungs. However, studies in intact animals have been less convincing. The aim of the present study was to assess the effect of sevoflurane on hypoxic pulmonary vasoconstriction (HPV) in anaesthetized piglets using the pressure/cardiac index relationship (P/Q). Ten large white piglets were anaesthetized and mechanically ventilated, alternately in hyperoxia (FIO2 = 0.4) and hypoxia (FIO2 = 0.12). Multipoint plots of pulmonary arterial pressure (PAP) or differences between PAP and left atrial pressure (LAP) against Q were generated by gradual inflation of a balloon introduced into the inferior vena cava. P/Q relationships were established in hyperoxia and hypoxia at baseline, and then with sevoflurane. In hypoxia, pressure gradients (PAP-LAP) increased at every level of Q, thus demonstrating active pulmonary vasoconstriction. Sevoflurane at 1 MAC did not affect these P/Q relationships in hyperoxia or hypoxia as compared with baseline. Sevoflurane at a clinically relevant concentration (1 MAC) has no significant effect on HPV in anaesthetized piglets.
Assuntos
Anestésicos Inalatórios/farmacologia , Hipóxia/fisiopatologia , Éteres Metílicos/farmacologia , Circulação Pulmonar/efeitos dos fármacos , Vasoconstrição/efeitos dos fármacos , Anestesia por Inalação/efeitos adversos , Animais , Pressão Sanguínea/efeitos dos fármacos , Dióxido de Carbono/sangue , Hidrogênio/sangue , Concentração de Íons de Hidrogênio , Hiperóxia/fisiopatologia , Análise dos Mínimos Quadrados , Sevoflurano , SuínosRESUMO
The iron requirement of four strains of lactobacilli (L. acidophilus, L. delbrueckii subsp. bulgaricus, L. plantarum, and L. pentosus) was studied in a synthetic medium under aerobic or anaerobic conditions. Effects of iron salt and iron-chelated compounds were tested on bacterial growth in manganese-free or -supplemented media. No significant growth stimulation was observed in any condition. These results support the absolute manganese requirement for optimum growth of lactobacilli and the needless incorporation of iron in growth media.
Assuntos
Ferro/metabolismo , Lactobacillus/metabolismo , Aerobiose , Anaerobiose , Técnicas Bacteriológicas , Meios de Cultura/química , Quelantes de Ferro/metabolismo , Lactobacillus/crescimento & desenvolvimento , Sulfato de Magnésio/metabolismoRESUMO
BACKGROUND AND OBJECTIVE: The diagnosis of myelodysplastic syndromes (MDS) is essentially morphological and based on the presence of dysplastic features in the peripheral blood and bone marrow. The French-American-British (FAB) Cooperative Group proposed a classification based on easily obtainable laboratory information. In spite of some limitations, the FAB criteria have been useful for a long time. Currently, the recognition of other distinct morphological MDS subgroups such as hypocellular MDS and MDS with myelofibrosis, the increasing incidence of MDS in children as well as that of therapy-related MDS, and the finding of specific chromosomal alterations associated with different morphological features, reveal the insufficiency of this classification. The aim of the present review is to examine some new aspects of the diagnosis, classification, and cytogenetics of MDS. EVIDENCE AND INFORMATION SOURCES: The authors of this review have been actively working and contributing original papers on MDS for the last 15 years. They also organized or participated in the Fourth International Symposium on MDS (Barcelona, April 24-27, 1997). In addition, the present review critically examines relevant articles and abstracts published in journals covered by the Science Citation Index and Medline. STATE OF THE ART AND PERSPECTIVES: Most of investigators working on MDS tend to integrate morphology and cytogenetics in the diagnosis and classification of these disorders. FAB criteria remain useful particularly for patients with not available cytogenetic study. Refractory cytopenia with multilineage dysplasia should be considered as a new MDS subtype. Some authors propose considering all patients with more than 20% of blast cells in peripheral blood or bone marrow as having acute leukemia. Chronic myelomonocytic leukemia with myeloproliferative features may be included among chronic myeloproliferative disorders. MDS with myelofibrosis is recognized as a new MDS subtype. Therapy-related MDS (t-MDS) should be classified according to the involved agents. Finally, besides including chromosomal abnormalities in the diagnosis (e.g., RAEB with trisomy 8), several cytogenetic abnormalities such as deletion 5q and deletion 17q, associated to specific clinical-morphological features, should be of help to identify new MDS syndromes.
Assuntos
Citogenética , Síndromes Mielodisplásicas/classificação , Síndromes Mielodisplásicas/diagnóstico , Humanos , Síndromes Mielodisplásicas/genéticaRESUMO
Systemic mast cell disease (SMCD) is a disorder characterized by a mast cell proliferation in various tissues. Mast cells express the c-kit proto-oncogene. A few cases of c-kit mutations have been described in SMCD. We report an aggressive SMCD in a patient who presented with a bone marrow infiltration by abnormal mast cells. Molecular studies of mast cell DNA and RNA revealed a new c-kit heterozygous mutation (Asp820Gly). This mutation leads to a drastic amino-acid change and is located close to the highly oncogenic Asp816Val. These findings suggest that the Asp820Gly has a potential role in c-kit activation.
Assuntos
Mastocitose/genética , Mutação , Proteínas Proto-Oncogênicas c-kit/genética , Adulto , Evolução Fatal , Humanos , Masculino , Reação em Cadeia da Polimerase , Proto-Oncogene MasAssuntos
Leucocitose , Neutrófilos , Infecções Bacterianas/complicações , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/complicações , Leucemia Neutrofílica Crônica/complicações , Leucocitose/diagnóstico , Leucocitose/etiologia , Leucocitose/fisiopatologia , Transtornos Linfoproliferativos/complicaçõesRESUMO
Cytological analysis of peripheral blood and bone marrow films is a quick and simple method for diagnosis of acute leukemia. In association with cytochemistry techniques it allows the rapid identification and subsequent classification of most types of acute myeloid leukemias. Although morphological analysis can suggest the diagnosis of an acute lymphoblastic leukemia, it is necessary to have the corroborating evidence of immunological markers for confirmation. In addition, ultrastructural studies contribute to the identification of rare forms of acute myeloid leukemias (minimally differentiated, megakaryoblastic). Cytological studies have also proven useful for the follow-up activities of confirming complete remission and detecting relapses.
Assuntos
Leucemia/patologia , Doença Aguda , Humanos , Leucemia/classificação , Leucemia/diagnósticoRESUMO
The diagnostic accuracy of a workstation for neoplastic bone marrow pathology was evaluated on 526 cases from two institutions. The workstation consists of knowledge-based systems for peripheral blood analysis, flow cytometry immunophenotyping, and bone marrow morphology, linked together by a relational database. The "gold standard" diagnosis was established by complete agreement among three hematopathologists after independent review of the data from each case. The workstation's diagnosis agreed with the "gold standard" in 515 cases (97.9%). In six of the 11 diagnostic errors, the bone marrow module could not reach a final diagnosis. The five misclassifications would not have resulted in a change of therapy for the patient. The institutional diagnosis of record agreed with the gold standard in 462 cases (87.8%). The results indicate that the workstation is capable of high-quality, reproducible, multiparameter interpretive reporting.
Assuntos
Inteligência Artificial , Neoplasias da Medula Óssea/diagnóstico , Medula Óssea/patologia , Diagnóstico por Computador , Doença Aguda , Doenças da Medula Óssea/diagnóstico , Sistemas Computacionais , Diagnóstico Diferencial , Erros de Diagnóstico , Hematologia/métodos , Humanos , Leucemia/diagnóstico , Reprodutibilidade dos TestesRESUMO
The development of high-grade non-Hodgkin's lymphomas in HIV-positive patients and patients with acquired immune deficiency syndrome (AIDS) is a well known phenomenon. The proper classification of these neoplasms often requires a multiparameter approach, including the interpretation of a large panel of immunologic markers analyzed by flow cytometry. The availability of individuals with the required expertise to properly interpret these marker studies is limited. For this reason, we have designed an expert system to automate the analysis of immunophenotyping panels in both HIV-related and non-HIV-related hematopoietic neoplasms. The expert system, which we call "Professor Fidelio", runs on IBM-compatible computers under Windows 3.0. The system is designed to accept any number of markers studied from a repertoire of 35 markers. Professor Fidelio functions on the basis of heuristic classification of defined diagnostic patterns. Nine specific patterns (Stem Cell, Myeloid and/or Monocytic, Erythroid, Megakaryocytic, Immature B-cell, Immature T-cell, Mature B-cell, Mature T-cell, and Plasma cell) and one "non-specific" pattern have been agreed upon. Fidelio's knowledge base contains the definitions of each of these patterns and the heuristics for excluding patterns when an incomplete panel of markers is performed. The inference engine interprets the findings (including the age of the patient) and reports the patterns which are matched, the differential diagnosis, the suggested diagnosis from the list of differentials if the marker studies are specific, and recommendations for additional tests which may be valuable in establishing the diagnosis.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Síndrome da Imunodeficiência Adquirida/epidemiologia , Sistemas Inteligentes/instrumentação , Citometria de Fluxo/métodos , Imunofenotipagem/métodos , Linfoma não Hodgkin/epidemiologia , Adulto , Biomarcadores/análise , Comorbidade , Alemanha/epidemiologia , Humanos , Linfoma não Hodgkin/imunologia , MasculinoRESUMO
We report the set-up of a denaturant gradient gel electrophoresis (DGGE) assay to screen for mutations in the whole coding sequence of the p53 gene. These DGGE experimental conditions were applied to the analysis of the p53 gene in acute leukemias. Forty adults with acute myelogenous leukemia (AML) and 21 with acute lymphoid leukemia (ALL) were investigated. Eleven of the AML patients were investigated at the time of the initial diagnosis and at relapse. In contrast with most reports based on amplified fragments analyzed by single-strand conformation electrophoresis and focusing on exons 5 to 8, we analyzed the whole coding sequence of the gene. Two of the 40 AML patients displayed a point mutation in exon 7; it was either an A to G substitution that converted Tyr-234 to Cys, or a G to A change that converted Arg-248 to Gln. The screening procedure led to the discovery of several intronic and exonic polymorphisms. These results confirm the low incidence of p53 mutations in acute leukemias and suggest a limited role of the p53 protein in leukemogenesis. The computerized modeling and electrophoresis parameters presented here provide a powerful tool for the exhaustive characterization of p53 mutants in all kinds of malignancies.
Assuntos
Genes p53 , Leucemia/genética , Mutação Puntual , Doença Aguda , Sequência de Bases , Análise Mutacional de DNA , Eletroforese em Gel de Poliacrilamida , Éxons , Humanos , Leucemia Mieloide Aguda/genética , Dados de Sequência Molecular , Desnaturação de Ácido Nucleico , Reação em Cadeia da Polimerase , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , SoftwareRESUMO
Twenty-six cases of adult T-cell leukemia/lymphoma (ATLL) were identified between 1983 and 1991 in Martinique (French West Indies). There were 14 men and 12 women, all of mixed racial descent and born in Martinique. Their ages ranged from 23 to 95 years. The main clinical and laboratory features at initial presentation were peripheral lymphadenopathy (22 cases), hepatomegaly (11 cases), splenomegaly (10 cases), cutaneous lesions (12 cases), hypercalcemia (16 cases), refractory infection by Strongyloides stercoralis (12 cases), and pre-existing autoimmune disorders (4 cases). All patients had absolute lymphocytosis with circulating pleomorphic abnormal lymphocytes. The prognosis was poor, with most patients (20 cases) surviving for less than 6 months. Although the overall clinicopathologic features of ATLL in this series are similar to those described in previous reports, we observed three additional points of interest: a high association with Strongyloides infection, an increased incidence of tropical spastic paresis/HTLV-1 associated myelopathy (TSP/HAM) among the relatives of the patients (5 cases), and the presence of prior collagen vascular diseases.
Assuntos
Leucemia-Linfoma de Células T do Adulto/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Feminino , Anticorpos Anti-HTLV-I/sangue , Humanos , Imunofenotipagem , Leucemia-Linfoma de Células T do Adulto/sangue , Leucemia-Linfoma de Células T do Adulto/patologia , Masculino , Martinica , Pessoa de Meia-Idade , Strongyloides stercoralis/isolamento & purificação , Estrongiloidíase/complicaçõesRESUMO
A 59-year-old woman hospitalised because of dyspnea and a heart murmur in a context of pyrexia was found to have evidence of obstruction of the pulmonary arterial system, clearly defined by ultrasonography, catheterisation and angiography and Imatron scan. The particular feature of this fifth reported case of pulmonary artery leiomyosarcoma is its documentation by transesophageal ultrasonography and tumor biopsy during catheterisation. Surgery with partial excision of the tumor was followed by survival for 6 months, bearing in mind the absence of chemo- or radiosensitivity of this type of tumor. Cases from the literature are reviewed.