RESUMO
BACKGROUND: Organ failures are the main prognostic factors in septic shock. The aim was to assess classical clinico-biological parameters evaluating organ dysfunctions at intensive care unit admission, combined with proteomics, on day-30 mortality in critically ill onco-hematology patients admitted to the intensive care unit for septic shock. METHODS: This was a prospective monocenter cohort study. Clinico-biological parameters were collected at admission. Plasma proteomics analyses were performed, including protein profiling using isobaric Tag for Relative and Absolute Quantification (iTRAQ) and subsequent validation by ELISA. RESULTS: Sixty consecutive patients were included. Day-30 mortality was 47%. All required vasopressors, 32% mechanical ventilation, 33% non-invasive ventilation and 13% renal-replacement therapy. iTRAQ-based proteomics identified von Willebrand factor as a protein of interest. Multivariate analysis identified four factors independently associated with day-30 mortality: positive fluid balance in the first 24 h (odds ratio = 1.06, 95% CI = 1.01-1.12, P = 0.02), severe acute respiratory failure (odds ratio = 6.14, 95% CI = 1.04-36.15, P = 0.04), von Willebrand factor plasma level > 439 ng/ml (odds ratio = 9.7, 95% CI = 1.52-61.98, P = 0.02), and bacteremia (odds ratio = 6.98, 95% CI = 1.17-41.6, P = 0.03). CONCLUSION: Endothelial dysfunction, revealed by proteomics, appears as an independent prognostic factor on day-30 mortality, as well as hydric balance, acute respiratory failure and bacteremia, in critically ill cancer patients admitted to the intensive care unit. Endothelial failure is underestimated in clinical practice and represents an innovative therapeutic target.
Assuntos
Proteínas Sanguíneas/análise , Neoplasias/complicações , Proteômica/métodos , Choque Séptico/mortalidade , Injúria Renal Aguda/mortalidade , Idoso , Bacteriemia/mortalidade , Feminino , Humanos , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Equilíbrio HidroeletrolíticoRESUMO
This article presents a cost-effectiveness study comparing cytogenetic and molecular analyses for detection of chromosomal abnormalities which are prognostic factors in acute leukemia. The aim of the study was to determine how these two techniques could substitute or complement one another. The study sample consisted of 107 adult patients with de novo myeloid or lymphoid acute leukemias, tested by both techniques in 1994 and 1995, for identification of translocations t(9;22), t(8;21), t(15;17), t(4;11), t(1;19), the inversion of chromosome 16 and for monosomy 5 or 7 (or deletion of their long arms) and trisomy 8. The criterion for diagnostic effectiveness of these strategies was the rate of detection of true positive anomalies which are clinically relevant, according to the current state of knowledge. On the basis of these observations six alternative strategies at diagnosis were compared (each technique alone or different combinations of the two techniques). The study shows that:-for ALL, PCR alone appears the most cost-effective strategy;-for AML, cytogenetic analysis alone is the best strategy;-sequential strategies are more cost effective than simultaneous use of both techniques for minimising risk of false negatives.
Assuntos
Citogenética/economia , Leucemia Mieloide/diagnóstico , Reação em Cadeia da Polimerase/economia , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Doença Aguda , Adolescente , Adulto , Idoso , Análise Custo-Benefício , Citogenética/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Complete hematologic and cytogenetic responses can be obtained with interferon-alpha (IFN-alpha) in 15-25% of the patients with chronic myelogenous leukemia (CML). In these patients, reverse-transcription polymerase chain reaction (RT-PCR) can be used to evaluate minimal residual disease. We studied 12 patients who remained Philadelphia-negative for a median period of 21 months on IFN-alpha therapy. Using RT-PCR, the specific transcript was found in all bone marrow (BM) samples. Ten patients still exhibiting a persistent residual clone remained in cytogenetic remission for a median period of 14 months. As we observed a dissociation between bcr-abl expression in BM and peripheral blood (PB) cells, and given the known fluctuations of the bcr-abl PCR results, we suggest that PB negative results should be confirmed on BM specimens. Alternatively, it remains to be demonstrated whether longitudinal monitoring of residual disease would benefit from quantitative PCR or double fluorescence in situ hybridization.
Assuntos
Medula Óssea/metabolismo , Proteínas de Fusão bcr-abl/biossíntese , Interferon-alfa/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , RNA Mensageiro/metabolismo , Adulto , Autorradiografia , Sequência de Bases , Medula Óssea/química , Criança , Feminino , Seguimentos , Proteínas de Fusão bcr-abl/análise , Proteínas de Fusão bcr-abl/genética , Humanos , Interferon alfa-2 , Leucemia Mielogênica Crônica BCR-ABL Positiva/sangue , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Reação em Cadeia da Polimerase , RNA Mensageiro/análise , RNA Mensageiro/genética , Proteínas Recombinantes , Indução de RemissãoRESUMO
The human FLT3 cDNA was cloned from a pre-B cell line and characterized. The deduced amino acid sequence shows that FLT3 codes for a receptor-type tyrosine kinase of 993 residues, presenting a strong similarity with the corresponding mouse FLT3/FLK2 protein as well as with the receptors for colony-stimulating factor 1 (CSF1R/FMS) and steel locus factor (SLFR/KIT). An analysis of the expression of the gene using amplification of reverse transcribed FLT3 mRNA by polymerase chain reaction shows that FLT3 is expressed in various lymphohematopoietic cells and tissues, including a series of immature cell lines and leukemias of lymphocytic origin.
Assuntos
Clonagem Molecular , Proteínas Tirosina Quinases/genética , Proteínas Proto-Oncogênicas/genética , Receptores Proteína Tirosina Quinases , Receptores de Superfície Celular/genética , Sequência de Aminoácidos , Linfócitos B/metabolismo , Sequência de Bases , Linhagem Celular , Expressão Gênica , Genes , Hematopoese , Humanos , Dados de Sequência Molecular , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Tirosina Quinase 3 Semelhante a fmsRESUMO
The Philadelphia chromosome (Ph) is the cytogenetic hallmark of chronic myeloid leukaemia (CML) and is used to confirm the diagnosis of CML based on clinical and morphological criteria. We investigated 14 patients with features of CML but without detectable Ph chromosome. In seven patients, referred to as BCR+, M-bcr/abl rearrangement was detected by polymerase chain reaction (PCR). The seven remaining patients did not have M-bcr/abl rearrangement and are described as BCR-. BCR- patients were younger, had lower white blood cell counts (WBC) and lower basophilia. Four BCR- and four BCR+ patients underwent blastic transformation (BT). Response to therapy was fairly similar in both populations. According to French-American-British (FAB) Cooperative Leukaemia Group guidelines, all BCR- patients were classified as having classic form CML or 'chronic granulocytic leukaemia' (CGL) when based only on morphological data. This study further confirms the existence of true CML cases without Ph chromosome or M-bcr/abl rearrangement and shows that this entity differs only slightly from classic form Ph+ CML. The Ph-BCR- subgroup raises two problems. First, the differential diagnosis with atypical CML or CMML, based on morphological data, and secondly, the therapeutic follow-up in the absence of a specific marker. In contrast, the residual disease of Ph-BCR- patients can be monitored by PCR. More advanced molecular and biochemical techniques will be required to understand which molecular mechanisms underlie Ph-BCR- CML, resulting in phenotypes sometimes indistinguishable from Ph+ CML.