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See detailAzacytidine Enhances Regulatory T-Cells In Vivo and Prevents Experimental Xenogeneic Graft-Versus-Host Disease
Ehx, Grégory ULg; Fransolet, Gilles ULg; de Leval, Laurence ULg et al

in Biology of Blood and Marrow Transplantation (2016, March), 22(3), 393

Background. The demethylating agent 5-azacytidine (AZA) has proven its efficacy as treatment for myelodysplastic syndrome and acute myeloid leukemia. In addition, AZA can demethylate FOXP3 intron 1 ... [more ▼]

Background. The demethylating agent 5-azacytidine (AZA) has proven its efficacy as treatment for myelodysplastic syndrome and acute myeloid leukemia. In addition, AZA can demethylate FOXP3 intron 1 (FOXP3i1) leading to the generation of regulatory T cells (Tregs). Objective. We investigated the impact of AZA on xenogeneic graft-versus-host disease (xGVHD) in a humanized murine model of transplantation, and described the impact of the drug on human T cells in vivo. Methods. In order to induce xGVHD, human peripheral blood mononuclear cells (huPBMC) were administered intravenously in NOD-scid IL-2Rγnull (NSG) mice. Results. AZA successfully improved both survival (p<0.0001) and xGVHD scores (p<0.0001). Further, AZA significantly decreased human T-cell proliferation as well as INF-γ and TNF-α serum levels, and reduced the expression of GRANZYME B and PERFORIN 1 by cytotoxic T cells. In addition, AZA administration significantly increased the function, proliferation and frequency of Tregs through demethylation of FOXP3i1 and higher secretion of IL-2 by conventional T cells due to IL2 gene promoter site 1 demethylation. Interestingly, among AZA-treated mice surviving the acute phase of xGVHD, there was an inverse correlation between the presence of Tregs and signs of chronic GVHD. Finally, Tregs harvested from the spleen of AZA-treated mice were suppressive and stable over time since they persisted at high frequency in secondary transplant experiments. Conclusion. These findings emphasize a potential role for AZA as prevention or treatment of GVHD and other autoimmune diseases. [less ▲]

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See detailGalectin-1 is involved in osteoclast biology
Muller, Joséphine ULg; Binsfeld, Marilène ULg; DUBOIS, Sophie ULg et al

Poster (2016, February 28)

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See detailYellow nail syndrome after allogeneic haematopoietic stem cell transplantation in two patients with multiple myeloma
Grégoire, Céline ULg; GUIOT, Julien ULg; Vertenoeil, Gaëlle ULg et al

in Acta Clinica Belgica (2016), 71

Objective and Importance: Yellow nail syndrome (YNS) is a rare disorder of unknown aetiology characterized by the triad of yellow nails, lymphoedema and respiratory manifestations. About 200 cases have ... [more ▼]

Objective and Importance: Yellow nail syndrome (YNS) is a rare disorder of unknown aetiology characterized by the triad of yellow nails, lymphoedema and respiratory manifestations. About 200 cases have been reported, but a lot of patients probably elude proper diagnosis because of both variability of symptoms and ignorance of this syndrome by many physicians. The pathogenesis remains unclear, and could involve functional lymphatic abnormalities, microvasculopathy or lymphocyte deficiency, but none of these hypotheses seems fully satisfactory. Clinical Presentation: We report for the first time two cases of YNS associated with multiple myeloma relapsing after non-myeloablative haematopoietic cell transplantation (HCT). In these two cases, onset or worsening of YNS symptoms followed graft-versus-host disease (GvHD) manifestations. Intervention: Corticosteroids given to treat GvHD also improved YNS manifestations. Conclusion: YNS after HCT might be a microvascular manifestation of endothelial GvHD and corticosteroids might be an effective treatment. [less ▲]

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See detailImmunomodulatory effects of rapamycin in Graft versus Host Disease
Ehx, Grégory ULg; Hannon, Muriel ULg; Humblet-Baron, Stéphanie et al

Poster (2016, January 29)

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See detailAzacytidine and Decitabine prevent experimental sclerodermic chronic graft-versus-host disease
Fransolet, Gilles ULg; Ehx, Grégory ULg; SOMJA, Joan ULg et al

Poster (2016, January 29)

Introduction: Graft-versus-host disease (GVHD) remains a major complication of allogeneic hematopoietic stem cell transplantation (HSCT). Following allo-transplantation, 60% of the patients experience ... [more ▼]

Introduction: Graft-versus-host disease (GVHD) remains a major complication of allogeneic hematopoietic stem cell transplantation (HSCT). Following allo-transplantation, 60% of the patients experience chronic GVHD while approximately 15% of them develop a sclerodermic form of chronic GVHD characterized by multiple organ fibrosis and loss of skin elasticity. Regulatory T cells (Tregs) play a pivotal protective role in the pathogenesis of chronic GVHD by inhibiting alloreactive conventional T cells (Tconvs). Several studies have shown that hypomethylating agents such as Azacytidine (AZA) or Decitabine (DAC) can demethylate the master transcription factor of Treg (FoxP3), thus promoting Treg differentiation from Tconvs. This work investigates the impact of AZA and DAC in a murine model of sclerodermic chronic GVHD. Methods: Lethally irradiated (7 Gy) BALB/cJ recipient mice were injected with 107 bone marrow cells + 7.107splenocytes from B10.D2 donor mice to induce scl-cGVHD. Recipients were injected with 0.5 or 2 mg/kg of AZA or 0.75 mg/kg of DAC every 48h from day 10 to 30 following transplantation. GVHD was scored using a five criteria scale (weight loss, activity, fibrosis, hair loss and mice posture; 0-1-2 points/criteria). Mice were sacrificed at a score of 8/10. Results: Mice treated with AZA 0.5 mg/kg (n=14) or 2 mg/kg (n=17) or DAC 0.75 mg/kg (n=5) had lower clinical scores of GVHD compared to control (n=15). FACS analyses showed a higher proportion of Treg in the blood of AZA 0.5 or 2 mg/kg or DAC 0.75 mg/kg mice than in control at day 35. Results also showed a decreased number of Tconv and CD8 in AZA and DAC treated mice while proliferation of these cells expressing Ki67 was lower during AZA/DAC treatment but higher after discontinuation. Histological analyses showed less skin fibrosis in mice treated with 2 mg/kg of AZA. Finally, analyses of the blood components demonstrated that AZA mice were leuco- and lymphopenic as compared to control at day 21 and 35. Conclusion : AZA and DAC prevented sclerodermic GVHD in this murine model. [less ▲]

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See detailSalt but not glucocorticoïds enhances Th17 differentiation from naïve T cells in vitro
Delens, Loïc ULg; SERVAIS, Sophie ULg; Vrancken, Louise et al

Poster (2016, January 29)

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See detailManagement of Myelodysplastic Syndrome Relapsing after Allogeneic Hematopoietic Stem Cell Transplantation: A Study by the French Society of Bone Marrow Transplantation and Cell Therapies
Guièze, R; Damaj, G; Pereira, B et al

in Biology of Blood & Marrow Transplantation (2016), 22

To find out prognostic factors and to investigate different therapeutic approaches, we report on 147 consecutive patients who relapsed after allogeneic hematopoietic stem cell transplantation (allo-HSCT ... [more ▼]

To find out prognostic factors and to investigate different therapeutic approaches, we report on 147 consecutive patients who relapsed after allogeneic hematopoietic stem cell transplantation (allo-HSCT) for myelodysplastic syndrome (MDS). Sixty-two patients underwent immunotherapy (IT group, second allo-HSCT or donor lymphocyte infusion), 39 received cytoreductive treatment alone (CRT group) and 46 were managed with palliative/supportive cares (PSC group). Two-year rates of overall survival (OS) were 32%, 6%, and 2% in the IT, CRT, and PSC groups, respectively (P < .001). In multivariate analysis, 4 factors adversely influenced 2-year rates of OS: history of acute graft-versus-host disease (hazard ratio [HR], 1.83; 95% confidence interval [CI], 1.26 to 2.67; P ¼ .002), relapse within 6 months (HR, 2.69; 95% CI, .82 to 3.98; P < .001), progression to acute myeloid leukemia (HR, 2.59; 95% CI, 1.75 to 3.83; P < .001), and platelet count < 50 G/L at relapse (HR, 1.68; 95% CI, 1.15 to 2.44; P ¼.007). A prognostic score based on those factors discriminated 2 risk groups with median OSs of 13.2 versus 2.4 months, respectively (P < .001). When propensity score, prognostic score, and treatment strategy were included in Cox model, immunotherapy was found to be an independent factor that favorably impacts OS (HR, .40; 95% CI, .26 to .63; P < .001). In conclusion, immunotherapy should be considered when possible for MDS patients relapsing after allo-HSCT. [less ▲]

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See detailEvaluation et prise en charge de la surcharge en fer post-greffe recommandations de la SFGM-TC
JASPERS, Aurélie ULg; Bouhya, S; Belaiche, S et al

in Bulletin du Cancer (2016), 103

Assessment and management of post-transplant iron overload: Guidelines of the Francophone Society of Marrow Transplantation and Cellular Therapy (SFGM-TC) To harmonize clinical practice in hematopoietic ... [more ▼]

Assessment and management of post-transplant iron overload: Guidelines of the Francophone Society of Marrow Transplantation and Cellular Therapy (SFGM-TC) To harmonize clinical practice in hematopoietic stem cell transplantation, the Francophone Society of Bone Marrow Transplantation and Cell Therapy (SFGM-TC) set up the sixth annual series of workshops which brought together practitioners from all member centers and took place in September 2015 in Lille. The main aim of this session was to describe the impact, evaluation and treatment of post-transplant iron overload. [less ▲]

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See detailL'anémie chez les patients BPCO sévères, une comorbidité dont la prévalence est bien plus fréquente que ce que l'on croit
Pirotte, M; GUIOT, Julien ULg; BEGUIN, Yves ULg et al

in Revue Médicale de Liège (2016)

Chronic obstructive pulmonary disease (COPD) is traditionally associated with polycythemia which results from chronic hypoxemia. Nevertheless, recent studies have shown that anemia may be more frequent ... [more ▼]

Chronic obstructive pulmonary disease (COPD) is traditionally associated with polycythemia which results from chronic hypoxemia. Nevertheless, recent studies have shown that anemia may be more frequent than expected in patients with COPD. In this retrospective study, we investigated the prevalence of hemoglobin disorders in a cohort of 100 patients with stable, moderate to severe COPD (II to IV GOLD classification). We identified 31 % patients with anemia while only 15 % had polycythemia. Anemia was more frequent in male patients. We also demonstrated a negative correlation between hemoglobin and CRP levels (R=-0.56, p < 0.0001). COPD patients with anemia had experienced a higher rate of hospitalizations for exacerbation in the previous year than those with polycythemia (p < 0.05). Anemia is a frequent comorbidity in COPD; it is associated with systemic inflammation and a propensity to hospitalization for exacerbation. [less ▲]

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See detailMultipotent mesenchymal stromal cell therapy for steroid-refractory acute graft-versus-host disease after allogeneic stem cell transplantation
SERVAIS, Sophie ULg; GREGOIRE, Céline ULg; BARON, Frédéric ULg et al

in Belgian Journal of Hematology (2016), 7

Steroid-refractory acute graft-versus-host disease is a severe complication after allogeneic stem cell transplantation. So far, its treatment remains very challenging since the current therapies do not ... [more ▼]

Steroid-refractory acute graft-versus-host disease is a severe complication after allogeneic stem cell transplantation. So far, its treatment remains very challenging since the current therapies do not offer significant benefits. Among the most recent approaches, multipotent mesenchymal stromal cell-based therapy has attracted great interest over the past decade. Here, we briefly reviewed the current knowledges about the immunomodulatory properties of multipotent mesenchymal stromal cells as well as results of preclinical and clinical studies having assessed their efficacy to modulate steroid-refractory acute graft-versus-host disease. [less ▲]

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See detailClinical - scale expansion of mesenchymal stromal cells: a large banking experience
LECHANTEUR, Chantal ULg; BRIQUET, Alexandra ULg; GIET, Olivier ULg et al

in Journal of Translational Medicine (2016), 14

Background: Mesenchymal stromal cells (MSC) are largely investigated in clinical trials aiming to control inappropriate immune reactions (GVHD, Crohn’s disease, solid organ transplantation). As the ... [more ▼]

Background: Mesenchymal stromal cells (MSC) are largely investigated in clinical trials aiming to control inappropriate immune reactions (GVHD, Crohn’s disease, solid organ transplantation). As the percentage of MSC precursors in bone marrow is very low, these must be expanded in vitro to obtain therapeutic cell doses. We describe here the constitution of an allogeneic human third-party MSC bank from screened healthy volunteer donors in compliance with quality specifications and ISCT-release criteria and report follow-up of different aspects of this activity since 2007. Methods: 68 clinical-grade large-scale MSC cultures were completed and analyzed. The whole process was described, including volunteer donor screening, bone marrow collection, mononuclear cell isolation and expansion over 4 weeks, harvesting, cryopreservation, release, administration and quality controls of the cells (including microbiology, phenotype, and potency assays). Results: From 59 validated donors, 68 cultures were completed (mean of final yields: 886 × 106 cells/culture) and a total of 464 MSC aliquots have been produced and stored in liquid nitrogen (mean of 132.8 × 106 cells/bag). Each MSC batch underwent extensive testing to verify its conformity with EBMT and ISCT release criteria and was individually validated. As of June 1 2015, 314 bags have been released and infused to patients included in 6 different clinical protocols. All thawed MSC units satisfied to release criteria and no infusion-related toxicity was reported. Conclusion: In conclusion, despite low passage cultures, we have been able to create an allogeneic “off-the-shelf” MSC bank with a large number of frozen aliquots and report here an efficient clinical-grade MSC banking activity in place for more than 7 years. Our challenge now is to produce MSC in compliance with good manufacturing practices (GMP) as, in the meantime, MSC have become considered as advanced therapy medicinal products (ATMP). Another significant challenge remains the development of relevant potency assay. [less ▲]

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See detailLe syndrome thyro-gastrique auto-immun : actualités cliniques et thérapeutiques
VALDES SOCIN, Hernan Gonzalo ULg; SID, Sélim ULg; LUTTERI, Laurence ULg et al

in Vaisseaux, Coeur, Poumons (2016), 21(4), 40-45

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See detailEffet of immune modulation in relapsed peripheral T cell lymphomas after allogeneic stem cell transplantation: a study by the Société Française de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC)
Mamez; Levy, V; Chevallier, P et al

in Bone Marrow Transplantation (2016), 51

Peripheral T-cell lymphoma carries a poor prognosis. To document a possible graft-versus-lymphoma effect in this setting, we evaluated the impact of immunomodulation in 63 patients with peripheral T-cell ... [more ▼]

Peripheral T-cell lymphoma carries a poor prognosis. To document a possible graft-versus-lymphoma effect in this setting, we evaluated the impact of immunomodulation in 63 patients with peripheral T-cell lymphoma who relapsed after allogeneic transplant in 27 SFGM-TC centers. Relapse occurred after a median of 2.8 months. Patients were then treated with nonimmunologic strategies (chemotherapy, radiotherapy) and/or immune modulation (donor lymphocyte infusions (DLI) and/or discontinuation of immunosuppressive therapy). Median overall survival (OS) after relapse was 6.1 months (DLI group: 23.6 months, non-DLI group: 3.6 months). Among the 14 patients who received DLI, 9 responded and 2 had stable disease. Among the remaining 49 patients, a complete response accompanied by extensive chronic GvHD was achieved in two patients after tapering of immunosuppressive drugs. Thirty patients received radio-chemotherapy, with an overall response rate of 50%. In multivariate analysis, chronic GvHD (odds ratio: 11.25 (2.68–48.21), P = 0.0009) and skin relapse (odds ratio: 4.15 (1.04–16.50), P = 0.043) were associated with a better response to treatment at relapse. In a time-dependent analysis, the only factor predictive of OS was the time from transplantation to relapse (hazards ratio: 0.33 (0.17–0.640), P = 0.0009). This large series provides encouraging evidence of a true GvL effect in this disease. [less ▲]

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See detailThe Changing Landscape of Smoldering Multiple Myeloma: A European Perspective
CAERS, Jo ULg; de Larrea, Carlos; Leleu, Xavier et al

in Oncologist (2016), 21

Smoldering multiple myeloma (SMM) is an asymptomatic clonal plasma cell disorder and bridges monoclonal gammopathyof undeterminedsignificance tomultiplemyeloma(MM), based on higher levels of circulating ... [more ▼]

Smoldering multiple myeloma (SMM) is an asymptomatic clonal plasma cell disorder and bridges monoclonal gammopathyof undeterminedsignificance tomultiplemyeloma(MM), based on higher levels of circulating monoclonal immunoglobulin and bone marrow plasmocytosis without end-organ damage. Until a Spanish study reported fewer MM-related events and better overall survival among patients with highrisk SMM treated with lenalidomide and dexamethasone, prior studies had failed to show improved survival with earlier intervention, although a reduction in skeletal-related events (without any impact on disease progression) has been described with bisphosphonate use. Risk factors have now been defined, and a subset of ultra-high-risk patients have been reclassified by the International Myeloma Working Group asMM, and thus will require optimalMMtreatment, based on biomarkers that identify patients with a.80% risk of progression. The number of these redefined patients is small (∼10%), but important to unravel, because their risk of progression to overt MM is substantial ($80% within 2 years). Patients with a high-risk cytogenetic profile are not yet considered for early treatment, because groups are heterogeneous and risk factors other than cytogenetics are deemed to weight higher. Because patients with ultra-highrisk SMM are now considered as MMand may be treated as such, concerns exist that earlier therapy may increase the risk of selecting resistant clones and induce side effects and costs. Therefore, an even more accurate identification of patients who would benefit from interventions needs to be performed, and clinical judgment and careful discussion of pros and cons of treatment initiation needs to be undertaken. For the greater majority ofSMMpatients, the standard of care remains observation until development of symptomatic MM occurs, encouraging participation in ongoing and upcoming SMM/early MM clinical trials, as well as consideration of bisphosphonate use in patients with early bone loss. [less ▲]

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