Hôpital-Camfrout, France
Hôpital-Camfrout, France

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Carapito R.,French Institute of Health and Medical Research | Carapito R.,University of Strasbourg | Carapito R.,Laboratoire dImmunologie | Jung N.,French Institute of Health and Medical Research | And 96 more authors.
Blood | Year: 2016

Graft-versus-host disease (GVHD) is among the most challenging complications in unrelated donor hematopoietic cell transplantation (HCT). The highly polymorphic MHC class I chain-related gene A, MICA, encodes a stress-induced glycoprotein expressed primarily on epithelia. MICA interacts with the invariant activating receptor NKG2D, expressed by cytotoxic lymphocytes, and is located in the MHC, next to HLA-B. Hence, MICA has the requisite attributes of a bona fide transplantation antigen. Using high-resolution sequence-based genotyping of MICA, we retrospectively analyzed the clinical effect of MICA mismatches in a multicenter cohort of 922 unrelated donor HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 10/10 allele-matched HCT pairs. Among the 922 pairs, 113 (12.3%) were mismatched in MICA. MICA mismatches were significantly associated with an increased incidence of grade III-IV acute GVHD (hazard ratio [HR], 1.83; 95% confidence interval [CI], 1.50-2.23; P < .001), chronic GVHD (HR, 1.50; 95% CI, 1.45-1.55; P < .001), and nonelapse mortality (HR, 1.35; 95% CI, 1.24-1.46; P < .001). The increased risk for GVHD was mirrored by a lower risk for relapse (HR, 0.50; 95% CI, 0.43-0.59; P < .001), indicating a possible graft-versus-leukemia effect. In conclusion, when possible, selecting a MICA-matched donor significantly influences key clinical outcomes of HCT in which a marked reduction of GVHD is paramount. The tight linkage disequilibrium between MICA and HLA-B renders identifying a MICA-matched donor readily feasible in clinical practice. © 2016 by The American Society of Hematology.


Froissart A.,University Pierre and Marie Curie | Buffet M.,Departement dHematologie | Veyradier A.,University Paris - Sud | Poullin P.,Service dHemapherese | And 19 more authors.
Critical Care Medicine | Year: 2012

Objective: To assess the efficacy and safety of rituximab in adults responding poorly to standard treatment for severe autoimmune thrombotic thrombocytopenic purpura. Design: Open-label prospective study. Outcomes in the survivors were compared to those of 53 historical survivors who were given therapeutic plasma exchange alone or with vincristine. Setting: Hospitals belonging to the Reference Network for Thrombotic Microangiopathies in France. Patients: Twenty-two adults with either no response or a disease exacerbation when treated with intensive therapeutic plasma exchange. INTERVENTION: Add-on rituximab therapy, four infusions over 15 days. Measurements and Main Results: One patient died despite two rituximab infusions. In the rituximab-treated Patients, the time to a durable remission was significantly shortened (p = .03), although the plasma volume required to achieve a durable remission was not significantly different compared to the controls. Platelet count recovery occurred within 35 days in all 21 survivors, compared to only 78% of the historical controls (p < .02). Of the rituximab-treated Patients, none had a relapse within the first year but three relapsed later on. In Patients treated with rituximab, a rapid and profound peripheral B-cell depletion was produced, lasting for 9 months and correlating with higher a disintegrin and metalloproteinase with thrombospondin-13 activity and lower anti-a disintegrin and metalloproteinase with thrombospondin-13 antibody titers. These differences were no longer significant after 12 months. No severe side effects occurred. Conclusions: Adults with severe thrombocytopenic purpura who responded poorly to therapeutic plasma exchange and who were treated with rituximab had shorter overall treatment duration and reduced 1-yr relapses than historical controls. © 2012 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins.


Sovalat H.,Institute Of Recherche En Hematologie Et Transplantation | Scrofani M.,Institute Of Recherche En Hematologie Et Transplantation | Eidenschenk A.,Institute Of Recherche En Hematologie Et Transplantation | Pasquet S.,Institute Of Recherche En Hematologie Et Transplantation | And 2 more authors.
Experimental Hematology | Year: 2011

Objective: Recently, we demonstrated that normal human bone marrow (hBM)-derived CD34 + cells, released into the peripheral blood after granulocyte colony-stimulating factor mobilization, contain cell subpopulations committed along endothelial and cardiac differentiation pathways. These subpopulations could play a key role in the regeneration of post-ischemic myocardial lesion after their direct intracardiac delivery. We hypothesized that these relevant cells might be issued from very small embryonic-like stem cells deposited in the BM during ontogenesis and reside lifelong in the adult BM, and that they could be mobilized into peripheral blood by granulocyte colony-stimulating factor. Materials and Methods: Samples of normal hBM and leukapheresis products harvested from cancer patients after granulocyte colony-stimulating factor mobilization were analyzed and sorted by multiparameter flow cytometry strategy. Immunofluorescence and reverse transcription quantitative polymerase chain reaction assays were performed to analyze the expression of typical pluripotent stem cells markers. Results: A population of CD34 +/CD133 +/CXCR4 +/Lin - CD45 - immature cells was first isolated from the hBM or from leukapheresis products. Among this population, very small (2-5 μm) cells expressing Oct-4, Nanog, and stage-specific embryonic antigen-4 at protein and messenger RNA levels were identified. Conclusions: Our study supports the hypothesis that very small embryonic-like stem cells constitute a " mobile" pool of primitive/pluripotent stem cells that could be released from the BM into the peripheral blood under the influence of various physiological or pathological stimuli. In order to fully support that hBM- and leukapheresis product-derived very small embryonic-like stem cells are actually pluripotent, we are currently testing their ability to differentiate in vitro into cells from all three germ layers. © 2011 ISEH - Society for Hematology and Stem Cells.


Maury S.,Hopital Henri Mondor | Maury S.,University Paris Est Creteil | Chevret S.,Departement dHematologie | Thomas X.,University Paris Diderot | And 27 more authors.
New England Journal of Medicine | Year: 2016

Background Treatment with rituximab has improved the outcome for patients with non-Hodgkin's lymphoma. Patients with B-lineage acute lymphoblastic leukemia (ALL) may also have the CD20 antigen, which is targeted by rituximab. Although single-group studies suggest that adding rituximab to chemotherapy could improve the outcome in such patients, this hypothesis has not been tested in a randomized trial. METHODS We randomly assigned adults (18 to 59 years of age) with CD20-positive, Philadelphia chromosome (Ph)-negative ALL to receive chemotherapy with or without rituximab, with event-free survival as the primary end point. Rituximab was given during all treatment phases, for a total of 16 to 18 infusions. RESULTS From May 2006 through April 2014, a total of 209 patients were enrolled: 105 in the rituximab group and 104 in the control group. After a median follow-up of 30 months, event-free survival was longer in the rituximab group than in the control group (hazard ratio, 0.66; 95% confidence interval [CI], 0.45 to 0.98; P = 0.04); the estimated 2-year event-free survival rates were 65% (95% CI, 56 to 75) and 52% (95% CI, 43 to 63), respectively. Treatment with rituximab remained associated with longer event-free survival in a multivariate analysis. The overall incidence rate of severe adverse events did not differ significantly between the two groups, but fewer allergic reactions to asparaginase were observed in the rituximab group. CONCLUSIONS Adding rituximab to the ALL chemotherapy protocol improved the outcome for younger adults with CD20-positive, Ph-negative ALL. (Funded by the Regional Clinical Research Office, Paris, and others; ClinicalTrials.gov number, NCT00327678.). © 2016 Massachusetts Medical Society. All rights reserved.


Cornet E.,Caen University Hospital Center | Cornet E.,University of Caen Lower Normandy | Debliquis A.,Departement dHematologie | Rimelen V.,Departement dHematologie | And 6 more authors.
PLoS ONE | Year: 2015

Chronic lymphocytic leukemia (CLL) is a clonal malignancy of mature B cells that displays a great clinical heterogeneity, with many patients having an indolent disease that will not require intervention for many years, while others present an aggressive and symptomatic leukemia requiring immediate treatment. Although there is no cure for CLL, the disease is treatable and current standard chemotherapy regimens have been shown to prolong survival. Recent advances in our understanding of the biology of CLL have led to the identification of numerous cellular and molecular markers with potential diagnostic, prognostic and therapeutic significance. We have used the recently developed digital multiplexed gene-expression technique (DMGE) to analyze a cohort of 30 CLL patients for the presence of specific genes with known diagnostic and prognostic potential. Starting from a set of 290 genes we were able to develop a molecular signature, based on the analysis of 13 genes, which allows distinguishing CLL from normal peripheral blood and from normal B cells, and a second signature based on 24 genes, which distinguishes mutated from unmutated cases (LymphCLL Mut). A third classifier (LymphCLL Diag), based on a 44-gene signature, distinguished CLL cases from a series of other B-cell chronic lymphoproliferative disorders (n = 51). While the methodology presented here has the potential to provide a "ready to use"classification tool in routine diagnostics and clinical trials, application to larger sample numbers are still needed and should provide further insights about its robustness and utility in clinical practice. © 2015 Cornet et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Conrad A.,Departement de Maladies Infectieuses et Tropicales | Conrad A.,French Institute of Health and Medical Research | Conrad A.,University of Lyon | Le Marechal M.,University of Lorraine | And 24 more authors.
Clinical Microbiology and Infection | Year: 2016

Toxoplasmosis (TXP) is a life-threatening complication of allogeneic haematopoietic stem cell transplantation (AHSCT). Little is known about the risk factors and there is no consensus on prophylactic measures. To investigate the risk factors, we conducted a single-centre, retrospective matched case–control study among adults who underwent AHSCT from January 2006 to March 2015 in our hospital. TXP cases were identified from the prospectively maintained hospital's database. The 1:2 control population consisted of the two patients who received an AHSCT immediately before and after each case with similar donor relationship (related, unrelated) but who did not develop TXP. Risk factors were identified by conditional logistic regression. Clinical features and outcome of TXP were examined. Twenty-three (3.9%) cases of TXP (20 diseases, three infections) were identified among 588 AHSCT recipients. Twenty (87%) cases had a positive pre-transplant Toxoplasma gondii serology. In comparison with 46 matched control patients, risk factors were the absence of effective anti-Toxoplasma prophylaxis (odds ratio (OR) 11.95; 95% CI 3.04–46.88; p <0.001), high-grade (III–IV) acute graft-versus-host-disease (OR 3.1; 95% CI 1.04–9.23; p 0.042) and receipt of the tumour necrosis factor-α blocker etanercept (OR 12.02; 95% CI 1.33–108.6; p 0.027). Mortality attributable to TXP was 43.5% (n = 10). Non-relapse mortality rates during the study period of cases and controls were 69.6% (n = 16) and 17.4% (n = 8), respectively. Lung involvement was the dominant clinical feature (n = 14). Two cases were associated with graft failure, one preceded by haemophagocytic syndrome. Given TXP-related morbidity and attributable mortality, anti-Toxoplasma prophylaxis is essential for optimized management of seropositive AHSCT recipients. © 2016 European Society of Clinical Microbiology and Infectious Diseases


Piedfer M.,French Institute of Health and Medical Research | Piedfer M.,University Pierre and Marie Curie | Piedfer M.,University of Paris Descartes | Dauzonne D.,University Pierre and Marie Curie | And 8 more authors.
FASEB Journal | Year: 2011

The transmembrane metalloprotease aminopeptidase-N (APN)/CD13 is overexpressed in various solid and hematological malignancies in humans, including acute myeloid leukemia (AML) and is thought to influence tumor progression. Here, we investigated the contribution Of APN/CD13 to the regulation of growth and survival processes in AML cells in vitro. Anti-CD13 monoclonal antibodies MY7 and SJ1D1 (which do not inhibit APN activity) and WM15 (an APN-blocking antibody) inhibited the growth of the AML cell line U937 and induced apoptosis, as evidenced by cell accumulation in the sub-G1 phase, DNA fragmentation, and phosphatidylserine externalization. Isotype-matched IgG1 and the APN/CD13 enzymatic inhibitors bestatin and 2′,3-dinitroflavone-8- acetic acid, were ineffective. Internalization of CD13-MY7 complex into cells was followed by mitochondrial membrane depolarization, Bcl-2 and Mcl-1 down-regulation, Bax up-regulation, caspase-9, caspase-8, and caspase-3 activation, and cleavage of the caspase substRate PARP-1. The broad-spectrum caspase inhibitor Z-VAD-fmk and the caspase-9- and caspase-8-specific inhibitors significantly attenuated apoptosis. CD13 ligation also induced apoptosis and PARP-1 cleavage in primary AML blasts, whereas normal blood cells were not affected. Overall, these data provide new evidence that CD13 can serve as a target for inducing caspase-dependent apoptosis in AML (independently of its APN activity). These findings may have implications for tumor biology and treatment. © FASEB.


PubMed | University of Lorraine, Departement Danesthesie Et Of Reanimation Du Center Hospitalier Lyon Sud, French Institute of Health and Medical Research, University of Lyon and Departement dHematologie
Type: Journal Article | Journal: Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases | Year: 2016

Toxoplasmosis (TXP) is a life-threatening complication of allogeneic haematopoietic stem cell transplantation (AHSCT). Little is known about the risk factors and there is no consensus on prophylactic measures. To investigate the risk factors, we conducted a single-centre, retrospective matched case-control study among adults who underwent AHSCT from January 2006 to March 2015 in our hospital. TXP cases were identified from the prospectively maintained hospitals database. The 1:2 control population consisted of the two patients who received an AHSCT immediately before and after each case with similar donor relationship (related, unrelated) but who did not develop TXP. Risk factors were identified by conditional logistic regression. Clinical features and outcome of TXP were examined. Twenty-three (3.9%) cases of TXP (20 diseases, three infections) were identified among 588 AHSCT recipients. Twenty (87%) cases had a positive pre-transplant Toxoplasma gondii serology. In comparison with 46 matched control patients, risk factors were the absence of effective anti-Toxoplasma prophylaxis (odds ratio (OR) 11.95; 95% CI 3.04-46.88; p<0.001), high-grade (III-IV) acute graft-versus-host-disease (OR 3.1; 95% CI 1.04-9.23; p0.042) and receipt of the tumour necrosis factor- blocker etanercept (OR 12.02; 95% CI 1.33-108.6; p0.027). Mortality attributable to TXP was 43.5% (n=10). Non-relapse mortality rates during the study period of cases and controls were 69.6% (n=16) and 17.4% (n=8), respectively. Lung involvement was the dominant clinical feature (n=14). Two cases were associated with graft failure, one preceded by haemophagocytic syndrome. Given TXP-related morbidity and attributable mortality, anti-Toxoplasma prophylaxis is essential for optimized management of seropositive AHSCT recipients.

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