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A Brizard

Publications and source records attributed to A Brizard.

At least 19 recordsLinked to original sources
PubMed2004

Evidence of ABL-kinase domain mutations in highly purified primitive stem cell populations of patients with chronic myelogenous leukemia.

To study the hierarchical levels of stem cell targets for ABL-kinase domain mutations in CML, highly purified CD34+CD38- and CD34+CD38+ cell populations and their LTC-IC-derived progeny were analyzed in four patients at diagnosis (n=1) or in advanced phases (n=3) of their disease. In the single patient with early phase CML who later developed an Imatinib Mesylate-resistance and a Y253H mutation, no mutation was detectable in purified cell fractions analyzed at diagnosis nor in their LTC-IC-derived progeny. In contrast, in three patients in advanced phase CML, ABL-kinase mutations demonstrated in peripheral blood cells by sequencing (Q252E and M351T) were detectable in the FACS-sorted cells and became amplified in the LTC-IC-derived progeny of the primitive cells. These findings demonstrate that in late CP or advanced CML, ABL-kinase mutations occur as an intraclonal event in the primitive Ph1+ stem cell compartments with progression of this clone towards IM-resistant blast phase.

Antineoplastic Agents↗
PubMed2002

Resistance to aspirin in vitro at rest and during exercise in patients with angiographically proven coronary artery disease.

BACKGROUND: Acetylsalicylic acid, or aspirin, is widely used in secondary prevention of coronary artery diseases, but the inhibition of platelet aggregation is not uniform in all individuals. OBJECTIVE: To investigate the prevalence of aspirin resistance at rest and during exercise in coronary artery disease patients. MATERIALS AND METHODS: Fifty patients with stable coronary artery disease were prospectively studied. All patients received aspirin (75-300 mg/day for >1 month) and no other antiplatelet therapy. Aspirin resistance was studied, at rest and immediately after a stress test, using the standardized platelet function analyzer (PFA-100(R), Dade-Behring). Aspirin resistance was defined as a normal collagen/epinephrine closure time (<186 s). RESULTS: Ten patients (20%) were aspirin-resistant at rest. Out of the 40 patients who were aspirin-sensitive at rest, 9 (22%) were aspirin-resistant immediately after the exercise stress test. There were no differences in aspirin sensitivity regarding gender, age, diabetes, hypertension, dyslipidemia, platelet count, medical treatment or number of the coronary arteries involved. CONCLUSIONS: Aspirin resistance is detected, at rest, in 20% of our patients with stable coronary artery disease. Aspirin treatment does not seem to protect against exercise-induced platelet activation in 22% of such patients, despite aspirin sensitivity at rest.

Aged↗
PubMed2002

Resistance to aspirin in vitro is associated with increased platelet sensitivity to adenosine diphosphate.

BACKGROUND: Platelet activation plays an important role in arterial thrombosis and the widespread use of aspirin has reduced major events by 25% in the secondary prevention of cardiovascular diseases. However, it appears that aspirin antiplatelet effect is not uniform and 8-45% of the population are, in vitro, aspirin resistant, and it is well recognized that platelets can be activated by pathways that are not blocked by aspirin, such as adenosine diphosphate (ADP). OBJECTIVES: To investigate whether aspirin-resistant patients have a modified sensitivity to ADP-induced platelet activation MATERIALS AND METHODS: Seventy-two patients were enrolled. Platelet function was measured by the PFA-100(R) analyser; platelet GP IIb-IIIa activation by ADP 10 micro M was assessed by flow cytometry using PAC-1 MoAb. RESULTS: Using a collagen/epinephrine coated cartridge on the PFA-100(R), the prevalence of aspirin resistance was 29.2% (n=21). For aspirin-resistant patients, the collagen/ADP coated cartridge showed a closure time significantly shorter (p=0.004) compared to the sensitive and control groups. Platelets from aspirin-resistant patients bound PAC-1 significantly more (p=0.03) than the aspirin-sensitive patients and controls when activated with 10 micro M ADP. CONCLUSIONS: Platelets from aspirin-resistant patients appear to be more sensitive and activable by ADP. This hypersensitivity could provide a possible explanation for the so-called aspirin resistance, and this could justify therapeutic improvement with alternative antiplatelet agents.

Adenosine Diphosphate↗
PubMed2002

Comparison of reticulated platelet count and mean platelet volume determination in the evaluation of bone marrow recovery after aplastic chemotherapy.

Reticulated platelet count provides an estimate of thrombopoiesis in the same way as reticulocyte count is a measure of erythropoiesis. We applied thiazole orange (TO) staining, followed by fluorescence-activated flow-cytometric analysis, to platelets in whole-blood samples from normal subjects and 18 aplastic patients after chemotherapy for haematologic malignancies. The percentage of TO-positive platelets in 30 control subjects was 5.7 +/- 2.4% (mean +/- 1 SD), determining the threshold of reticulated platelet positivity as up to 10.5% (mean + 2 SD). In the 18 patients studied, the mean percentage of TO-positive platelets was 4.3 +/- 1.89% during aplasia and 23.3 +/- 9.43% during bone marrow recovery, respectively (P < 0.05). All patients had a percentage of TO-positive platelets of up to 10.5%. In comparison, mean platelet volume during bone marrow recovery increased in 12 cases of the 18 patients studied. We conclude that flow cytometric analysis of reticulated platelets is a sensitive and specific test for evaluating thrombopoiesis recovery during aplastic chemotherapy, and platelet transfusion should be reconsidered in these patients.

Adult↗
PubMed2002

Quantitative HOX expression in chromosomally defined subsets of acute myelogenous leukemia.

We used a degenerate RT-PCR screen and subsequent real-time quantitative RT-PCR assays to examine the expression of HOX and TALE-family genes in 34 cases of chromosomally defined AML for which outcome data were available. AMLs with favorable cytogenetic features were associated with low overall HOX gene expression whereas poor prognostic cases had high levels. Characteristically, multiple HOXA family members including HOXA3-HOXA10 were jointly overexpressed in conjunction with HOXB3, HOXB6, MEIS1 and PBX3. Higher levels of expression were also observed in the FAB subtype, AML-M1. Spearmann correlation coefficients indicated that the expression levels for many of these genes were highly inter-related. While we did not detect any significant correlations between HOX expression and complete response rates or age in this limited set of patients, there was a significant correlation between event-free survival and HOXA7 with a trend toward significance for HoxA9, HoxA4 and HoxA5. While patients with elevated HOX expression did worse, there were notable exceptions. Thus, although HOX overexpression and clinical resistance to chemotherapy often coincide, they are not inextricably linked. Our results indicate that quantitative HOX analysis has the potential to add new information to the management of patients with AML, especially where characteristic chromosomal alterations are lacking.

Acute Disease↗
PubMed2002

[Platelet polymorphism and coronary artery disease].

Several publications over the last ten years have addressed the problem of genetic mutation coding platelet membrane glycoproteins and thrombotic arterial disease. The principal polymorphisms studied are those of glycoproteins GPIIIa, GPIb and the GPIa-IIa complex. The relationships of each of these polymorphisms and myocardial infarction or coronary artery disease are reported and are often subject to controversy. The polymorphism PLA2 of the GPIIIa has been shown to be a risk factor for infarction in young people, especially when associated with cigarette smoking. Its role in triggering myocardial infarction or in the severity of coronary artery disease is not so clear in the general population. Two types of polymorphism concerning the GPIb and that of the GPIa-IIa complex should also predispose to early coronary thrombotic complications. In addition, the study of these platelet polymorphisms gives a better insight into individual sensitivity to platelet antiaggregant therapy.

Adult↗
PubMed2001

Human LPP gene is fused to MLL in a secondary acute leukemia with a t(3;11) (q28;q23).

The mixed lineage leukemia, MLL, gene is frequently rearranged in patients with secondary leukemia following treatment with DNA topoisomerase II inhibitors. By FISH and Southern blot analyses we identified a rearrangement in the MLL gene due to a novel t(3;11)(q28;q23) chromosomal translocation in a patient who developed AML-M5 3 years after treatment for a follicular lymphoma. Through inverse PCR, the LPP (lipoma preferred partner) gene on 3q28 was identified as the MLL fusion partner. LPP contains substantial identity to the focal adhesion protein, zyxin, and is frequently fused to HMGIC in lipomas. The breakpoint occurred in intron 8 of MLL and LPP. Two in-frame MLL-LPP transcripts, which fuse MLL exon 8 to LPP exon 9, were detected by RT-PCR, although the smaller of these contained a deletion of 120 bp from the MLL sequence. The predicted MLL-LPP fusion protein includes the A/T hook motifs and methyltransferase domain of MLL joined to the two last LIM domains of LPP. A reciprocal LPP-MLL transcript, predicted to include the proline-rich and leucine zipper motifs, and the first LIM domain of LPP were also detected by RT-PCR. In summary, LPP is a newly identified MLL fusion partner in secondary leukemia resulting from topoisomerase inhibitors. The MLL-LPP and LPP-MLL predicted proteins contain many of the features present in other MLL rearrangements.

Adult↗
PubMed2001

Minimal residual disease (MRD) in remission t(8;21) AML and in vivo differentiation detected by FISH and CD34+ cell sorting.

Many patients with t(8;21) AML have residual positive cells during remission. We previously developed D-FISH probes that detect both derivative chromosomes and the normal alleles. In negative controls, only 2/44,000 (0.0045%) positive signals were observed. To investigate MRD, we examined specimens from 29 patients who had initially obtained CR. In remission patients, 61% had 1-4/2000 positive cells (0.05-0.19%). Higher frequencies were found in two patients in early relapse and in one patient in early remission. However, a negative test did not exclude relapse. Since false positives were negligible and because most t(8;21) AMLs express CD34, we asked whether cell sorting combined with FISH would increase the sensitivity. In one patient, we observed that 80% of CD34+ cells were t(8;21)+ at 2 months from initial clinical and cytogenetic remission. However, by 5 months the pre- and post-sorted populations contained 0.15% and 0.06% t(8;21) cells, respectively. Whereas essentially all t(8;21) cells in the initial specimen expressed CD34, only 0.6% were subsequently CD34+. These results are consistent with in vitro assays showing that residual t(8;21) cells undergo differentiation. Thus, FISH can identify MRD in a majority of t(8;21) patients and, combined with CD34+ selection, may provide an indirect assessment of the differentiation state of residual t(8;21) cells.

Acute Disease↗
PubMed2001

Erythropoietin-dependent anaemia: a possible complication of diabetic neuropathy.

We report the case of a 52-year-old woman with long-term type 1 diabetes mellitus, complicated with proliferative retinopathy, autonomic neuropathy and microalbuminuria and moderate renal failure. A normochromic, normocytic are generative anaemia had been diagnosed for three years. Clinical and biological investigations for the aetiology of anaemia remained normal or negative. Anaemia was associated with a concentration of erythropoietin (EPO) in the normal range, but inappropriately low regarding anaemia. Treatment with recombinant EPO induced a rapid increase in haemoglobin level and improved the patient's quality of life. The role of diabetic neuropathy in the genesis of anaemia, in conjunction with a modest renal impairment is discussed.

Albuminuria↗
PubMed2000

Persistence of BCR-ABL genomic rearrangement in chronic myeloid leukemia patients in complete and sustained cytogenetic remission after interferon-alpha therapy or allogeneic bone marrow transplantation.

In recent years, the prognosis of chronic myeloid leukemia (CML) has been greatly improved either with interferon-alpha (IFN-alpha) therapy or allogeneic bone marrow transplantation (BMT). In the present study, minimal residual disease was evaluated in 21 patients in complete cytogenetic response (CCR) after such treatments. Samples from bone marrow aspirates or peripheral blood or both were analyzed by conventional cytogenetics, Southern blot, interphase fluorescent in situ hybridization (FISH), and quantitative reverse transcription-polymerase chain reaction (Q-RT-PCR). In all patients, FISH detected 1% to 12% nuclei with a BCR-ABL fusion gene, whereas Q-RT-PCR experiments were negative or weakly positive. Based on these results, we hypothesize that the BCR-ABL genomic rearrangement persists unexpressed in nonproliferating cells whatever the treatment (IFN-alpha or BMT). These data point to the need for follow-up of CML patients in CCR over an extensive period at the DNA level (FISH) to evaluate the residual disease and at the RNA level (Q-RT-PCR) to estimate the risk of relapse. (Blood. 2000;95:404-408)

Adult↗
PubMed2000

Recurrent molecular deletion of the 12p13 region, centromeric to ETV6/TEL, in T-cell prolymphocytic leukemia.

INTRODUCTION: T-cell prolymphocytic leukemia is a rare form of mature leukemia which occurs in adults and in younger patients suffering ataxia telangiectasia. Among others, complex chromosome aberrations of chromosome 12 have been described in this disease. We searched for deletions of the 12p13 region as the result of these chromosome rearrangements. MATERIAL AND METHODS: Paired leukemic and non-leukemic cells were obtained from a series of 21 patients suffering T-cell prolymphocytic leukemia. Loss of heterozygosity was searched for by microsatellite typing using a fluorescent automated laser DNA sequencer to analyze the amplification products. Proteins were analyzed by Western blot. Southern blot analysis of one patient was conducted. RESULTS AND CONCLUSION: Loss of heterozygosity of the 12p13 region, including the ETV6 and CDKN1B genes, was detected in nine of these 21 cases (43%). Western and Southern blot analyses of one case demonstrated a biallelic deletion which did not include ETV6. Taken together, our results defined a minimal region of deletion of less than one Mb flanked by the markers b312C2T7 and D12S320, excluding ETV6 as a candidate gene. Deletion of the 12p13 region is thus a highly recurrent genetic event in T-cell prolymphocytic leukemia.

Centromere↗
PubMed2000

Thromboembolic prophylaxis with danaparoïd (Orgaran) in a high-thrombosis-risk pregnant woman with a history of heparin-induced thrombocytopenia (HIT) and Widal's disease.

There is no consensus concerning thromboembolic prophylaxis in high-risk pregnant women with a previous history of heparin-induced thrombocytopenia. An alternative anticoagulant therapy is danaparoïd, whereas unfractioned and low-molecular-weight heparin therapy is contraindicated. We report a case of successful thrombosis prophylaxis using danaparoïd in a high-thrombosis-risk pregnant woman with a history of heparin-induced thrombocytopenia during a previous pregnancy and Widal's disease.

Adult↗
PubMed1999

Heterogeneity of serum IgG subclass deficiencies in B chronic lymphocytic leukemia.

The occurrence of abnormally low serum immunoglobulin (Ig) levels is well-known in B chronic lymphocytic leukemia (CLL), but published data on IgG subclass levels are virtually absent. We measured serum IgG subclass levels in 52 B CLL outpatients, most in stage A and untreated, using an indirect immunoenzymatic assay with monoclonal antibodies. Mean levels of all Ig isotypes were lower than in normal controls in the whole group of patients, except for IgG2 in those studied at diagnosis. Levels of IgG1, IgG2, IgA, and IgM were lower in patients with a long disease duration than in those studied earlier. IgG subclass deficiencies occurred in 54% of cases and the most frequently affected isotype was IgG1. Every possible combination of IgG subclass and Ig class deficiencies from the selective deficiency of a single subclass to a combined deficiency of all isotypes was observed. This marked heterogeneity argues against the occurrence of isolated defects of one of the cytokines involved in Ig switching as a cause of hypoimmunoglobulinemia in CLL.

Aged↗
PubMed1999

Aml1/ETO and Pml/RARA rearrangements in a case of AML-M2 acute myeloblastic leukemia with t(15;17).

We report a case of acute myeloid leukemia FAB-type 2 with a translocation t(15;17)(q22;q12) On the basis of the cytological findings, a translocation t(8;21)(q22;q22) was suspected. FISH analyses using specific probes for t(15;17) and t(8;21) detected both PML/RARalpha and AML1/ETO rearrangements in a few percentage of cells. This case demonstrates the complexities that may occur between cytology and cytogenetic findings and the usefulness of FISH methods to detect an AML1/ETO rearrangement only suspected by cytological examination of bone marrow smears.

Adult↗
PubMed1998

Identification of several genes differentially expressed during progression of chronic myelogenous leukemia.

The Bcr-Abl fusion protein plays a crucial role in the initiation and maintenance of chronic myelogenous leukemia (CML). However, additional events are necessary for the transition from the chronic phase to the terminal phase of the disease. To identify genes involved in the disease progression, we constructed a subtractive library from enriched K562 cell mRNA. We obtained 1084 cDNA clones. After a specific hybridization of these clones with a cDNA probe from either chronic phase or K562 cells, 43 clones which present a differential hybridization level have been selected. Among them, several clones corresponded to ribosomal protein genes showing an increased transcription level during the blast crisis. We observed variations in the expression of a cellular adhesion molecule, a laminin-binding protein. An increased transcription level of the MAZ gene has been shown in the terminal phase of the disease. This gene encodes a protein that regulates the transcription of myc.

Blast Crisis↗