A Brizard

Publications (73)273.1 Total impact

• Article: Aspirin resistance in vitro and hypertension in stroke patients.

  L Macchi, E Petit, A Brizard, R Gil, J P Neau
  Journal of Thrombosis and Haemostasis 12/2004; 2(11):2051-3. · 5.73 Impact Factor
• Article: Evidence of ABL-kinase domain mutations in highly purified primitive stem cell populations of patients with chronic myelogenous leukemia.

  N Sorel, M L Bonnet, M Guillier, F Guilhot, A Brizard, A G Turhan
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  ABSTRACT: 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.
  Biochemical and Biophysical Research Communications 11/2004; 323(3):728-30. · 2.48 Impact Factor
• Article: Resistance to aspirin in vitro at rest and during exercise in patients with angiographically proven coronary artery disease.

  L Christiaens, L Macchi, D Herpin, D Coisne, C Duplantier, J Allal, G Mauco, A Brizard
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  ABSTRACT: 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. To investigate the prevalence of aspirin resistance at rest and during exercise in coronary artery disease patients. 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). 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. 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.
  Thrombosis Research 11/2002; 108(2-3):115-9. · 2.44 Impact Factor
• Article: Comparison of reticulated platelet count and mean platelet volume determination in the evaluation of bone marrow recovery after aplastic chemotherapy.

  I Macchi, V Chamlian, A Sadoun, A Le Dirach, J Guilhot, F Guilhot, A Brizard
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  ABSTRACT: 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.
  European Journal Of Haematology 09/2002; 69(3):152-7. · 2.61 Impact Factor
• Article: Resistance to aspirin in vitro is associated with increased platelet sensitivity to adenosine diphosphate.

  L Macchi, L Christiaens, S Brabant, N Sorel, J Allal, G Mauco, A Brizard
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  ABSTRACT: 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). To investigate whether aspirin-resistant patients have a modified sensitivity to ADP-induced platelet activation 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. 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. 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.
  Thrombosis Research 08/2002; 107(1-2):45-9. · 2.44 Impact Factor
• Article: Assessment of platelet activation after exercise using a standardized whole blood flow cytometry assay.

  L Macchi, A Brizard, L Christiaens, D Herpin
  Thrombosis Research 05/2002; 106(2):169-70. · 2.44 Impact Factor
• Article: [Platelet polymorphism and coronary artery disease].

  L Christiaens, L Macchi, C Duplantier, J Allal, A Brizard, R Barraine, D Coisne
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  ABSTRACT: 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.
  Archives des maladies du coeur et des vaisseaux 04/2002; 95(3):173-8. · 0.40 Impact Factor
• Article: Quantitative HOX expression in chromosomally defined subsets of acute myelogenous leukemia.

  H A Drabkin, C Parsy, K Ferguson, F Guilhot, L Lacotte, L Roy, C Zeng, A Baron, S P Hunger, M Varella-Garcia, R Gemmill, F Brizard, A Brizard, J Roche
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  ABSTRACT: 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.
  Leukemia 03/2002; 16(2):186-95. · 9.56 Impact Factor
• Article: Minimal residual disease (MRD) in remission t(8;21) AML and in vivo differentiation detected by FISH and CD34+ cell sorting.

  M Varella-Garcia, C J Hogan, L F Odom, J L Murata-Collins, H Ai, L Chen, K Richkind, G Paskulin, M Andreeff, A Brizard, L McGavran, R M Gemmill, R Berger, H A Drabkin
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  ABSTRACT: 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.
  Leukemia 10/2001; 15(9):1408-14. · 9.56 Impact Factor
• Article: Ovarian sarcoma and acute myelogenous leukaemia.

  L Lacotte-Thierry, A Thierry, F Brizard, V Delwail, A Sadoun, F Guilhot, A Brizard
  The Hematology Journal 02/2001; 2(6):404-5. · 1.86 Impact Factor
• Article: Thromboembolic prophylaxis with danaparoïd (Orgaran) in a high-thrombosis-risk pregnant woman with a history of heparin-induced thrombocytopenia (HIT) and Widal's disease.

  L Macchi, R Sarfati, M Guicheteau, V Chamlian, O Pourrat, Y Gruel, G Magnin, A Brizard, C Boinot
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  ABSTRACT: 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.
  Clinical and Applied Thrombosis/Hemostasis 11/2000; 6(4):187-9. · 1.33 Impact Factor
• Article: 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.

  J C Chomel, F Brizard, A Veinstein, J Rivet, A Sadoun, A Kitzis, F Guilhot, A Brizard
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  ABSTRACT: 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)
  Blood 02/2000; 95(2):404-8. · 9.90 Impact Factor
• Article: Aml1/ETO and Pml/RARA rearrangements in a case of AML-M2 acute myeloblastic leukemia with t(15;17).

  M Varella-Garcia, F Brizard, J Roche, G Flandrin, H Drabkin, A Brizard
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  ABSTRACT: 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.
  Leukemia and Lymphoma 05/1999; 33(3-4):403-6. · 2.58 Impact Factor
• Article: Heterogeneity of serum IgG subclass deficiencies in B chronic lymphocytic leukemia.

  C Lacombe, J Gombert, B Dreyfus, A Brizard, J L Preud'Homme
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  ABSTRACT: 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.
  Clinical Immunology 02/1999; 90(1):128-32. · 4.05 Impact Factor
• Article: Indolent course as a relatively frequent presentation in T-prolymphocytic leukaemia. Groupe Français d'Hématologie Cellulaire.

  R Garand, J Goasguen, A Brizard, J Buisine, A Charpentier, J F Claisse, E Duchayne, M Lagrange, C Segonds, X Troussard, G Flandrin
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  ABSTRACT: T-prolymphocytic leukaemia (T-PLL) is a rare disorder with a poor outcome. Presentation features were studied in 78 T-PLL cases. Although 53 patients (group A) presented with typical progressive disease including rapidly increasing leucocytosis. 25 patients (group B) experienced an initial indolent clinical course with stable moderate leucocytosis. The morphology and antigenic profile of abnormal cells were similar in both groups, except for a lower incidence of CD45RO+ CD45RA- pattern in group B. A high incidence of inv(14)(q11;q32), t(14;14)(q11;q32) and i(8)(q10) chromosomal abnormalities were found in both groups. After an initial indolent phase (median 33 months; 6-103 months), 16 group B patients progressed to an aggressive stage with clinical and laboratory features similar to group A. Moreover, median survival after progression was short in both groups. In conclusion, T-PLL may start as an indolent disease similar to that reported in ataxia telangectasia. In this rare genetic disorder, some patients develop stable T-cell clones which progress toward T-PLL-like leukaemia. Moreover, ATM gene mutations have been reported in T-PLL. Thus, both diseases are likely to be closely related.
  British Journal of Haematology 12/1998; 103(2):488-94. · 4.94 Impact Factor
• Article: Does BCR-ABL genomic rearrangement persist in CML patients in complete remission after interferon alpha therapy?

  F Brizard, J C Chomel, A Veinstein, J Rivet, C Giraud, A Kitzis, F Guilhot, A Brizard
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  ABSTRACT: Cytogenetic, interphase fluorescent in situ hybridization (FISH) and RT-PCR methods were used to study minimal residual disease in peripheral blood stem cells collected for autografting in three chronic myeloid leukemia (CML) patients in sustained complete cytogenetic remission after treatment with interferon alpha (IFNalpha). Karyotypic analysis failed to reveal Ph-positive metaphases. FISH detected 9-16% nuclei with a BCR-ABL fusion gene, contrasting with RT-PCR, performed in two cases, which was negative in one case and weakly positive in the other. RT-PCR was also subsequently weakly positive in the third patient. This discrepancy suggests that the BCR-ABL genomic rearrangement persists unexpressed in quiescent cells. These preliminary results, which need to be confirmed in larger series, suggest that monitoring residual disease in CML should be performed both at DNA and RNA levels. Moreover, autografting following IFNalpha therapy should be considered with caution because of the persistence of the BCR-ABL genomic rearrangement in a sizeable proportion of the cells.
  Leukemia 08/1998; 12(7):1076-80. · 9.56 Impact Factor
• Article: Abnormalities of the short arm of chromosome 12 in T cell prolymphocytic leukemia.

  F Salomon-Nguyen, F Brizard, M Le Coniat, I Radford, R Berger, A Brizard
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  ABSTRACT: Abnormalities of the short arm of chromosome 12 are nonrandom events in T cell prolymphocytic leukemia (T-PLL). Fluorescence in situ hybridization (FISH) studies were performed in three patients with T-PLL and one patient with T cell peripheral lymphoma and rearrangement of 12p. Whereas the rearrangements of 12p were different in the four patients, a breakpoint centromeric to the ETV6 gene was present in the three T-PLL patients. In addition, loss of heterozygosity for a chromosomal segment telomeric to ETV6 with loss of the RAD52 locus was also shown by FISH studies. In contrast, the breakpoint was telomeric to ETV6 in the patient with peripheral lymphoma.
  Leukemia 07/1998; 12(6):972-5. · 9.56 Impact Factor
• Article: Identification of several genes differentially expressed during progression of chronic myelogenous leukemia.

  L Dahéron, S Salmeron, S Patri, A Brizard, F Guilhot, J C Chomel, A Kitzis
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  ABSTRACT: 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.
  Leukemia 03/1998; 12(3):326-32. · 9.56 Impact Factor
• Article: Central nervous system relapses after autologous stem cell transplantation for myeloma. Report of two cases.

  A Veinstein, A Brizard, E Randriamalala, P Babin, J L Preud'homme, F Guilhot
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  ABSTRACT: We report on two cases of central nervous system (CNS) relapse after high-dose chemotherapy and autologous stem cell transplantation. A 55-year-old man received two courses of vincristin, doxorubicin and dexamethasone (VAD) as an induction treatment for stage IIIB IgG kappa multiple myeloma. Bone marrow stem cell collection was performed after a high-dose melphalan (HDM) course (140 mg/m2). Autologous bone marrow transplantation (ABMT) was performed with this cryo-preserved unpurged bone marrow sample after a second HDM course. Three months after ABMT, the patient presented with signs of central nervous involvement with plasma cells and monoclonal IgG kappa in the cerebral fluid. The patient died despite systemic and intrathecal chemotherapy. A 50-year-old man was initially treated with 3 courses of VAD for a stage IIIA IgD lambda multiple myeloma. Blood stem cell were collected after a course of high-dose etoposide and cyclophosphamide. ABMT was performed after total body irradiation (TBI) and HDM. Three months later, he presented with right leg palsy and a lumbar puncture showed numerous plasma cells and the presence of the IgG lambda. The patient died of neurological complications three months later. Extramedullary occurred prior to medullary relapse in the two cases, suggesting the presence of an extramedullary clone of plasma cells with a high degree of chemo-resistance. Although high-dose chemotherapy appears promising, this therapeutic approach could allow the occurrence of presently unobserved complications. Wether CNS prophylaxis is indicated in this context, as recommended in leukemia, remains an open question.
  Hematology and Cell Therapy 12/1997; 39(6):327-30.
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  Available from: hematologylibrary.org

  Article: Serum Ig abnormalities in mantle cell lymphoma.

  J L Preud'homme, J Gombert, A Brizard, L Lacotte, P Babin, G Flandrin
  Blood 08/1997; 90(2):894-6. · 9.90 Impact Factor