Georgin-Lavialle S.,Laboratoire dHematologie Biologique |
Lhermitte L.,Laboratoire dHematologie Biologique |
Lhermitte L.,University of Paris Descartes |
Dubreuil P.,French Institute of Health and Medical Research |
And 6 more authors.
Blood | Year: 2013
Mast cell leukemia (MCL) is a very rare form of aggressive systemic mastocytosis accounting for < 1% of all mastocytosis. It may appear de novo or secondary to previous mastocytosis and shares more clinicopathologic aspects with systemic mastocytosis than with acute myeloid leukemia. Symptoms of mast cell activation-involvement of the liver, spleen, peritoneum, bones, and marrow- are frequent. Diagnosis is based on the presence of ≥ 20% atypical mast cells in the marrow or ≥ 10% in the blood; however, an aleukemic variant is frequently encountered in which the number of circulating mast cells is < 10%. The common phenotypic features of pathologic mast cells encountered in most forms of mastocytosis are unreliable in MCL. Unexpectedly, non-KIT D816V mutations are frequent and therefore, complete gene sequencing is necessary. Therapy usually fails and the median survival time is < 6 months. The role of combination therapies and bone marrow transplantation needs further investigation.
PubMed | Groupe Hospitalier Of Linstitut Catholique Of Lille, Institute Paoli Calmettes, Center Henri Becquerel, Caen University Hospital Center and 9 more.
Type: Journal Article | Journal: American journal of hematology | Year: 2015
Acquired -thalassemia myelodysplastic syndrome (MDS) (ATMDS) is an acquired syndrome characterized by a somatic point mutation or splicing defect in the ATRX gene in patients with myeloid disorders, primarily MDS. In a large MDS patient series, the incidence of ATMDS was below 0.5%. But no large series has yet assessed the incidence of ATMDS in microcytic MDS. In this study, we focused on patients with MDS and unexplained microcytosis, which was defined as absence of iron deficiency, inflammatory disease, or history of inherited hemoglobinopathy. Our data confirm the low frequency of ATRX mutations in MDS: 0% in an unselected clinical trial cohort of 80 low risk MDS, 0.2-0.8% in a multicenter registry of 2,980 MDS and 43% of MDS with unexplained microcytosis in this same registry. In addition, we reported four novel mutations of the ATRX gene in ATMDS. This study further determines the frequency of ATRX mutations and highlights the importance of microcytosis to detect ATRX mutations within MDS patients.
PubMed | Laboratoire dhematologie biologique, French Institute of Health and Medical Research and University of Paris Descartes
Type: | Journal: Orphanet journal of rare diseases | Year: 2015
We report on a familial Mediterranean fever (FMF) patient homozygous for p.M694V in the MEFV gene who developed chronic myelomonocytic leukemia (CMML) leading to an uncontrolled and fatal inflammatory syndrome. Plasma levels of IL-6 and IL-18 were found to be very high, as compared to healthy controls and CMML-free FMF patients.Our study unveils the interplay between two different disorders involving the same target cells, suggesting that in myelodysplasia with inflammatory manifestations, mutations in genes causing autoinflammatory syndromes, like MEFV, can be present and thus could be sought. Early chemotherapy with interleukin inhibitors could be proposed in such unusual situations.
Pasmant E.,University of Paris Descartes |
Gilbert-Dussardier B.,Service de Genetique |
Petit A.,University Pierre and Marie Curie |
de Laval B.,University of Paris Descartes |
And 17 more authors.
Oncogene | Year: 2015
Constitutional dominant loss-of-function mutations in the SPRED1 gene cause a rare phenotype referred as neurofibromatosis type 1 (NF1)-like syndrome or Legius syndrome, consisted of multiple café-au-lait macules, axillary freckling, learning disabilities and macrocephaly. SPRED1 is a negative regulator of the RAS MAPK pathway and can interact with neurofibromin, the NF1 gene product. Individuals with NF1 have a higher risk of haematological malignancies. SPRED1 is highly expressed in haematopoietic cells and negatively regulates haematopoiesis. SPRED1 seemed to be a good candidate for leukaemia predisposition or transformation. We performed SPRED1 mutation screening and expression status in 230 paediatric lymphoblastic and acute myeloblastic leukaemias (AMLs). We found a loss-of-function frameshift SPRED1 mutation in a patient with Legius syndrome. In this patient, the leukaemia blasts karyotype showed a SPRED1 loss of heterozygosity, confirming SPRED1 as a tumour suppressor. Our observation confirmed that acute leukaemias are rare complications of the Legius syndrome. Moreover, SPRED1 was significantly decreased at RNA and protein levels in the majority of AMLs at diagnosis compared with normal or paired complete remission bone marrows. SPRED1 decreased expression correlated with genetic features of AML. Our study reveals a new mechanism which contributes to deregulate RAS MAPK pathway in the vast majority of paediatric AMLs.
Vivanti A.,University of Paris Descartes |
Soheili T.S.,University of Paris Descartes |
Cuccuini W.,Laboratoire dHematologie Biologique |
Cuccuini W.,French Institute of Health and Medical Research |
And 15 more authors.
AIDS | Year: 2015
Objectives: Zidovudine and tenofovir are the two main nucleos(t)ide analogs used to prevent mother-to-child transmission of HIV. In vitro, both drugs bind to and integrate into human DNA and inhibit telomerase. The objective of the present study was to assess the genotoxic effects of either zidovudine or tenofovir-based combination therapies on cord blood cells in newborns exposed in utero. Design: We compared the aneuploid rate and the gene expression profiles in cord blood samples from newborns exposed either to zidovudine or tenofovir-based combination therapies during pregnancy and from unexposed controls (n = 8, 9, and 8, respectively). Methods: The aneuploidy rate was measured on the cord blood T-cell karyotype. Gene expression profiles of cord blood T cells and hematopoietic stem and progenitor cells were determined with microarrays, analyzed in a gene set enrichment analysis and confirmed by real-time quantitative PCRs. Results: Aneuploidy was more frequent in the zidovudine-exposed group (26.3%) than in the tenofovir-exposed group (14.2%) or in controls (13.3%; P < 0.05 for both). The transcription of genes involved in DNA repair, telomere maintenance, nucleotide metabolism, DNA/RNA synthesis, and the cell cycle was deregulated in samples from both the zidovudine and the tenofovir-exposed groups. Conclusion: Although tenofovir has a lower clastogenic impact than zidovudine, gene expression profiling showed that both drugs alter the transcription of DNA repair and telomere maintenance genes. © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Underestimation of plasma level of factor V coagulant activity and fibrinogen concentration together with prolonged prothrombin time, activated partial thromboplastin time and thrombin time can result from pre-analytical very low calcium level in citrated sample tube
PubMed | Laboratoire dhematologie biologique, Laboratoire dHematologie and Hopital Saint Antoine
Type: Journal Article | Journal: International journal of laboratory hematology | Year: 2016
Pre-analytical phase is a critical step in the haemostasis laboratory cycle. Numerous variations affect tests results, and it is crucial to detect them in order to reject improper specimens before reporting test results. Comparing to prior results or requesting, a repeat sample can help in pre-analytical irregularity assessment.Each time a sample addressed to our laboratory displayed aberrant results or discordant with a prior report, another specimen was asked and both were analysed through calcium (Ca) level, prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), fibrinogen concentration, factor II, factor VII+X and factor V coagulant activity measurements. Among these, all the primary citrated samples from inpatients without anticoagulant treatment, displaying very low calcium level (Ca 0 samples), were selected for this 2 years study.A total of 17 samples could be identified. Ca level in their paired repeat samples was always >1.00 mmol/L. Coagulation testing for Ca 0 samples showed a significant prolongation of PT, APTT, TT and a significant decrease for fibrinogen concentration and factor V coagulant activity.We identified factor V coagulant activity, as the parameter with the most important variation in case of very low calcium level in presumed citrated sample tubes probably contaminated with EDTA.
Jean A.,Laboratoire dHematologie Biologique |
Boutet C.,Laboratoire dHematologie Biologique |
Lenormand B.,Laboratoire dHematologie Biologique |
Callat M.-P.,Laboratoire dHematologie Biologique |
And 3 more authors.
Clinical Chemistry and Laboratory Medicine | Year: 2011
Background: Differentials with moderate lymphocytosis are common in hematology laboratories and it is important in these cases to discriminate monoclonal from reactive lymphocytosis (RL). Blood smear reflex examination is dependent of the expertise of a cytologist, time-consuming and not always informative. Therefore, rapid and easy orientation parameters are clearly needed to discriminate malignant from RL. Methods: The differential performed by the Beckman-Coulter analyzers is based on the determination of three parameters (volume, conductivity and scatter of the cell subpopulations) called cellular population data (CPD). This study evaluated CPD in 332 patients with a typical B-chronic lymphocytic leukemia (B-CLL), 90 patients with other B-lymphoproliferative diseases (OLPD) and 55 patients with a proven RL, and established a discriminating protocol to identify these pathologies. Secondly, this approach was evaluated in a prospective study including 102 patients with lymphocyte counts above 3.5×109/L and in each case the diagnosis suggested by CPD was compared with conventional flow cytometry (FC) analysis and that obtained using CytoDiff reagent, a combination of six antibodies/five colors which performs a rapid WBC differential by FC. Results: Lymphocyte anisocytosis was observed for malignant and RL. A low lymphocyte volume identifies monoclonal B-cell lymphocytosis and classical B-CLL. CytoDiff analysis is helpful when lymphocyte volume is in the normal range. A ratio B-Ly/total Ly count >0.32 is suggestive of a B-malignancy, whereas a non-cytotoxic T-lymphocyte count above 2.43×109/L suggests RL. Conclusions: The analysis of CPD in combination with CytoDiff analysis shows promise for the rapid and accurate identification of lymphocyte pathologies in routine practice. © 2011 by Walter de Gruyter Berlin Boston 2011.
Marsafy S.E.L.,Laboratoire Dhematologie Biologique |
Larghero J.,Cell therapy Unit and Clinical Investigation Center |
Larghero J.,University Paris Diderot |
Larghero J.,French Institute of Health and Medical Research
Current Stem Cell Research and Therapy | Year: 2015
Tumors grow in privileged microenvironment referred to as the cancer niche. This niche is composed of cancer cells and various components including mesenchymal stem cells (MSC), fibroblasts, network of microvasculature added to innate and primed immune cells. Additionally, it encloses other elements such as the extracellular matrix (ECM), cytokines, chemokines and growth factors. Crosstalk between cancer cells and different niche constituents is crucial for tumor growth and metastasis. Herein, we focus attention on the bidirectional relationship between MSC and cancer cells and its impact on tumor progression. Better comprehension of these events within the tumor niche might be valuable for developing effective anti-tumor therapeutic strategies. © 2015 Bentham Science Publishers.
Le Roy C.,French Institute of Health and Medical Research |
Le Roy C.,University of Paris 13 |
Deglesne P.-A.,University of Paris 13 |
Chevallier N.,University of Paris 13 |
And 14 more authors.
Blood | Year: 2012
B-cell antigen receptor (BCR)-mediated signaling plays a critical role in chronic lymphocytic leukemia (CLL) pathogenesis and gives an in vitro survival advantage to B cells isolated from patients with unfavorable prognostic factors. In this study, we undertook to elucidate the signaling intermediates responsible for this biologic alteration. In responding cells only, in vitro BCR engagement triggers global phosphorylation of Syk, activation of phospholipase Cγ2, and intracellular calcium mobilization, reflecting competency of BCR signaling. The calcium-calcineurin-dependent transcription factor NFAT2 is up-regulated and to some extent constitutively activated in all CLL B cells. In contrast, its DNA-binding capacity is enhanced on IgM stimulation in responding cells only. NFAT inhibition using the VIVIT peptide prevents induction of CD23 target gene and IgM-induced survival, converting responding cells to unresponsive status. At the opposite, ionomycin-induced NFAT activity allows survival of nonresponding cells. These results demonstrate that the functional heterogeneity relies on variability of protein levels establishing BCR-dependent thresholds and NFAT-dependent activation. Finally, status of the BCR-NFAT pathway for each patient reveals its relevance for CLL clinical outcome and points out to BCR-NFAT intermediates as promising functional therapeutic targets. © 2012 by The American Society of Hematology.
PubMed | Groupe Hospitalier Diaconesses Croix Saint Simon and Laboratoire dHematologie Biologique
Type: Journal Article | Journal: Antimicrobial agents and chemotherapy | Year: 2016
The frequency and risk factors for central venous catheter-related thrombosis (CRT) during prolonged intravenous (i.v.) antibiotic therapy have rarely been reported. The primary objective of this study was to evaluate the frequency, incidence, and risk factors for CRT among patients being treated with prolonged i.v. antibiotic therapy. The secondary objective was to describe the clinical manifestations, diagnostic evaluation, and clinical management. This cohort study was conducted between August 2004 and May 2010 in a French referral center for osteoarticular infections. All patients treated for bone and joint infections with i.v. antimicrobial therapy through a central venous catheter (CVC) for 2 weeks were included. Risk factors were identified using nonparametric tests and logistic regression. A case-control study investigated the role of vancomycin and catheter malposition. A total of 892 patients matched the inclusion criteria. CRT developed in 16 infections occurring in 16 patients (incidence, 0.39/1,000 catheter days). The median time to a CRT was 29 days (range, 12 to 48 days). Local clinical signs, fever, and secondary complications of CRT were present in 15, 8, and 4 patients, respectively. The median C-reactive protein level was 95 mg/liter. The treatment combined catheter removal and a median of 3 months (1.5 to 6 months) of anticoagulation therapy. The outcome was good in all patients, with no recurrence of CRT. Three risk factors were identified by multivariate analysis: male sex (odds ratio [OR], 5.4; 95% confidence interval [CI], 1.1 to 26.6), catheter malposition (OR, 5.3; 95% CI, 1.6 to 17.9), and use of vancomycin (OR, 22.9; 95% CI, 2.8 to 188). Catheter-related thrombosis is a rare but severe complication in patients treated with prolonged antimicrobial therapy. Vancomycin use was the most important risk factor identified.