References of "Baron, Frédéric"
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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 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 detailThe Prosurvival IKK-Related Kinase IKK« Integrates LPS and IL17A Signaling Cascades to Promote Wnt-Dependent Tumor Development in the Intestine
Göktuna, SI.; Shostak, Kateryna ULg; Chau, TL. et al

in Cancer Research (2016), 76

Constitutive Wnt signaling promotes intestinal cell proliferation, but signals from the tumor microenvironment are also required to support cancer development. The role that signaling proteins play to ... [more ▼]

Constitutive Wnt signaling promotes intestinal cell proliferation, but signals from the tumor microenvironment are also required to support cancer development. The role that signaling proteins play to establish a tumor microenvironment has not been extensively studied. Therefore, we assessed the role of the proinflammatory Ikk-related kinase Ikke in Wnt-driven tumor development. We found that Ikke was activated in intestinal tumors forming upon loss of the tumor suppressor Apc. Genetic ablation of Ikke in b-catenin-driven models of intestinal cancer reduced tumor incidence and consequently extended survival. Mechanistically, we attributed the tumor-promoting effects of Ikke to limited TNF-dependent apoptosis in transformed intestinal epithelial cells. In addition, Ikke was also required for lipopolysaccharide (LPS) and IL17A-induced activation of Akt, Mek1/2, Erk1/2, and Msk1. Accordingly, genes encoding proinflammatory cytokines, chemokines, and anti-microbial peptides were downregulated in Ikke-deficient tissues, subsequently affecting the recruitment of tumor-associated macrophages and IL17A synthesis. Further studies revealed that IL17A synergized with commensal bacteria to trigger Ikke phosphorylation in transformed intestinal epithelial cells, establishing a positive feedback loop to support tumor development. Therefore, TNF, LPS, and IL17A-dependent signaling pathways converge on Ikke to promote cell survival and to establish an inflammatory tumor microenvironment in the intestine upon constitutive Wnt activation. [less ▲]

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See detailRelapse of AML after hematopoietic stem cell transplantation: methods of monitoring and preventive strategies. A review from the ALWP of the EBMT.
Tsirigotis, P.; Byrne, M.; Schmid, C. et al

in Bone Marrow Transplantation (2016)

Allogeneic hematopoietic stem cell transplantation (allo-SCT) remains the therapeutic method with the most potent anti-leukemic activity mediated by the graft versus leukemia effect. However, a ... [more ▼]

Allogeneic hematopoietic stem cell transplantation (allo-SCT) remains the therapeutic method with the most potent anti-leukemic activity mediated by the graft versus leukemia effect. However, a significant proportion of patients with AML will relapse after allo-SCT. The prognosis for these patients is dismal, with a probability of long-term survival of <20%. Data from previous studies have shown that disease-specific prognostic factors, are in general, the same as those in patients treated with conventional chemotherapy. Minimal residual disease (MRD) and chimerism status monitoring after allo-SCT may be used as predictors of impending relapse and should be part of routine follow-up for AML patients. A significant number of studies have shown that pre-emptive administration of donor lymphocyte infusion (DLI) based on MRD and chimerism monitoring, as well as prophylactic DLI in AML patients at high risk of relapse is effective in preventing relapse. In this review, we discuss strategies for the identification of high-risk patients, review current therapeutic options and provide our recommendations for the management of post-SCT AML.Bone Marrow Transplantation advance online publication, 13 June 2016; doi:10.1038/bmt.2016.167. [less ▲]

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See detailComparative value of post-remission treatment in cytogenetically normal AML subclassified by NPM1 and FLT3-ITD allelic ratio.
Versluis, J.; In 't Hout, F. E. M.; Devillier, R. et al

in Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K (2016)

Post-remission treatment (PRT) in patients with cytogenetically normal (CN) acute myeloid leukemia (AML) in first complete remission (CR1) is debated. We studied 521 patients with CN-AML in CR1, for whom ... [more ▼]

Post-remission treatment (PRT) in patients with cytogenetically normal (CN) acute myeloid leukemia (AML) in first complete remission (CR1) is debated. We studied 521 patients with CN-AML in CR1, for whom mutational status of NPM1 and FLT3-ITD was available, including the FLT3-ITD allelic ratio. PRT consisted of reduced intensity conditioning (RIC) allogeneic hematopoietic stem cell transplantation (alloHSCT) (n=68), myeloablative conditioning (MAC) alloHSCT (n=137), autologous hematopoietic stem cell transplantation (autoHSCT) (n=168) or chemotherapy (n=148). Favorable overall survival (OS) was found for patients with mutated NPM1 without FLT3-ITD (71+/-4%). Outcome in patients with a high FLT3-ITD allelic ratio appeared to be very poor with OS and relapse-free survival (RFS) of 23+/-8% and 12+/-6%, respectively. Patients with wild-type NPM1 without FLT3-ITD or with a low allelic burden of FLT3-ITD were considered as intermediate-risk group because of similar OS and RFS at 5 years, in which PRT by RIC alloHSCT resulted in better OS and RFS as compared with chemotherapy (hazard ratio (HR) 0.56, P=0.022 and HR 0.50, P=0.004, respectively) or autoHSCT (HR 0.60, P=0.046 and HR 0.60, P=0.043, respectively). The lowest cumulative incidence of relapse (23+/-4%) was observed following MAC alloHSCT. These results suggest that alloHSCT may be preferred in patients with molecularly intermediate-risk CN-AML, while the choice of conditioning type may be personalized according to risk for non-relapse mortality.Leukemia advance online publication, 15 July 2016; doi:10.1038/leu.2016.183. [less ▲]

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See detailIL-2 consumption by highly activated CD8 T cells induces regulatory T-cell dysfunction in patients with hemophagocytic lymphohistiocytosis.
Humblet-Baron, Stephanie; Franckaert, Dean; Dooley, James et al

in Journal of Allergy and Clinical Immunology (The) (2016), 138(1), 200-2098

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a severe inflammatory condition driven by excessive CD8(+) T-cell activation. HLH occurs as both acquired and familial hemophagocytic ... [more ▼]

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a severe inflammatory condition driven by excessive CD8(+) T-cell activation. HLH occurs as both acquired and familial hemophagocytic lymphohistiocytosis (FHL) forms. In both conditions, a sterile or infectious trigger is required for disease initiation, which then becomes self-sustaining and life-threatening. Recent studies have attributed the key distal event to excessive IFN-gamma production; however, the proximal events driving immune dysregulation have remained undefined. OBJECTIVE: We sought to investigate the role of regulatory T (Treg) cells in the pathophysiology of experimental FHL. METHODS: Because mutation in perforin is a common cause of FHL, we used an experimental FHL mouse model in which disease in perforin-deficient mice is triggered by lymphocytic choriomeningitis virus (LCMV). We assessed Treg and CD8(+) T-cell homeostasis and activation during the changing systemic conditions in the mice. In addition, human blood samples were collected and analyzed during the HLH episode. RESULTS: We found no primary Treg cell defects in perforin-deficient mice. However, Treg cell numbers collapsed after LCMV inoculation. The collapse of Treg cell numbers in LCMV-triggered perforin-deficient, but not wild-type, mice was accompanied by the combination of lower IL-2 secretion by conventional CD4(+) T cells, increased IL-2 consumption by activated CD8(+) T cells, and secretion of competitive soluble CD25. Moreover low Treg cell numbers were observed in untreated patients experiencing HLH flares. CONCLUSION: These results demonstrate that excessive CD8(+) T-cell activation rewires the IL-2 homeostatic network away from Treg cell maintenance and toward feed-forward inflammation. These results also provide a potential mechanistic pathway for the progression of infectious inflammation to persistent inflammation in patients with HLH. [less ▲]

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See detailRevised diagnosis and severity criteria for sinusoidal obstruction syndrome/veno-occlusive disease in adult patients: a new classification from the European Society for Blood and Marrow Transplantation
Mohty, M.; Malard, F.; Abecassis, M. et al

in Bone Marrow Transplantation (2016)

Sinusoidal obstruction syndrome, also known as veno-occlusive disease (SOS/VOD), is a potentially life threatening complication that can develop after hematopoietic cell transplantation. Although SOS/VOD ... [more ▼]

Sinusoidal obstruction syndrome, also known as veno-occlusive disease (SOS/VOD), is a potentially life threatening complication that can develop after hematopoietic cell transplantation. Although SOS/VOD progressively resolves within a few weeks in most patients, the most severe forms result in multi-organ dysfunction and are associated with a high mortality rate (480%). Therefore, careful attention must be paid to allow an early detection of SOS/VOD, particularly as drugs have now proven to be effective and licensed for its treatment. Unfortunately, current criteria lack sensitivity and specificity, making early identification and severity assessment of SOS/VOD difficult. The aim of this work is to propose a new definition for diagnosis, and a severity-grading system for SOS/VOD in adult patients, on behalf of the European Society for Blood and Marrow Transplantation. [less ▲]

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See detailDecitabine improves progression-free survival in older high-risk MDS patients with multiple autosomal monosomies: results of a subgroup analysis of the randomized phase III study 06011 of the EORTC Leukemia Cooperative Group and German MDS Study Group
Lübbert, Michael; Suciu, Stefan; Hagemeijer, Anne et al

in Annals of Hematology (2016), 95

In a study of elderly AML patients treated with the hypomethylating agent decitabine (DAC), we noted a surprisingly favorable outcome in the (usually very unfavorable) subgroup with two or more autosomal ... [more ▼]

In a study of elderly AML patients treated with the hypomethylating agent decitabine (DAC), we noted a surprisingly favorable outcome in the (usually very unfavorable) subgroup with two or more autosomal monosomies (MK2+) within a complex karyotype (Lübbert et al., Haematologica 97:393-401, 2012). We now analyzed 206 myelodysplastic syndrome (MDS) patients (88 % of 233 patients randomized in the EORTC/GMDSSG phase III trial 06011, 61 of them with RAEBt, i.e. AML by WHO) with cytogenetics informative for MK status.. Endpoints are the following: complete/partial (CR/PR) and overall response rate (ORR) and progression-free (PFS) and overall survival (OS). Cytogenetic subgroups are the following: 63 cytogenetically normal (CN) patients, 143 with cytogenetic abnormalities, 73 of them MKnegative (MK−), and 70 MK-positive (MK+). These MK+ patients could be divided into 17 with a single autosomal monosomy (MK1) and 53 with at least two monosomies (MK2+). ORR with DAC in CN patients: 36.1 %, in MK−patients: 16.7 %, in MK+ patients: 43.6 % (MK1: 44.4 %, MK2+ 43.3 %). PFS was prolonged by DAC compared to best supportive care (BSC) in the CN (hazard ratio (HR) 0.55, 99 % confidence interval (CI), 0.26; 1.15, p=0.03) and MK2+ (HR 0.50; 99%CI, 0.23; 1.06, p=0.016) but not in the MK−, MK+, and MK1 subgroups. OS was not improved by DAC in any subgroup. In conclusion, we demonstrate for the first time in a randomized phase III trial that high-risk MDS patients with complex karyotypes harboring two or more autosomal monosomies attain encouraging responses and have improved PFS with DAC treatment compared to BSC. [less ▲]

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See detailMethods of ex vivo expansion of human cord blood cells: challenges, successes and clinical implications
Baron, Frédéric ULg; Ruggeri, A.; Nagler, A.

in Expert Review of Hematology (2016), 21

More than 40,000 unrelated cord blood transplantations (UCBT) have been performed worldwide as treatment for patients with malignant or non-malignant life threatening hematologic disorders. However, low ... [more ▼]

More than 40,000 unrelated cord blood transplantations (UCBT) have been performed worldwide as treatment for patients with malignant or non-malignant life threatening hematologic disorders. However, low absolute numbers of hematopoietic stem and progenitor cells (HSPCs) within a single cord blood unit has remained a limiting factor for this transplantation modality, particularly in adult recipients. Further, because UCB contains low numbers of mostly naïve T cells, immune recovery after UCBT is slow predisposing patients to severe infections. Other causes of UCBT failure has included graft-versus-host disease (GVHD), and relapse of the underlying disease. In this article, we first review the current landscape of cord blood engineering aimed at improving engraftment. This includes approaches of UCB-HSPCs expansion and methods aimed at improving UCB-HSCPs homing. We then discuss recent approaches of cord blood engineering developed to prevent infection (generation of multivirus-specific cytotoxic T cells (VSTs) from UCB), relapse (transduction of UCB-T cells with tumor-specific chimeric receptor antigens (CARs)) and GVHD (expansion of regulatory T cells from UCB). Although many of these techniques of UCB engineering remain currently technically challenging and expensive, they are likely to revolutionize the field of UCBT in the next decades. [less ▲]

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See detailPeripheral blood stem cell graft compared to bone marrow after reduced intensity conditioning regimens for acute leukemia–A report from the ALWP of the EBMT
Savani, Bipin N.; Labopin, Myriam; Blaise, Didier et al

in Haematologica (2016)

Increasing numbers of patients are receiving reduced-intensity-conditioning regimen allogeneic hematopoietic stem-cell transplantation. We hypothesized that the use of bone-marrow graft might decrease the ... [more ▼]

Increasing numbers of patients are receiving reduced-intensity-conditioning regimen allogeneic hematopoietic stem-cell transplantation. We hypothesized that the use of bone-marrow graft might decrease the risk of graft-versus-host-disease compared to peripheral-blood after reduced-intensity-conditioning regimens without compromising graft-versus-leukemia effects. Patients who underwent reduced-intensity-conditioning regimen allogeneic hematopoietic stem-cell transplantation from 2000-2012 for acute leukemia and reported to the acute-leukemia-working-party of the EBMT were included in the study. Eight hundred thirty-seven patients receiving bone-marrow grafts were compared with 9011 peripheral-blood transplant recipients after reduced-intensity conditioning regimen. Median follow-up of surviving patients was 27 months. Cumulative incidence of engraftment (neutrophil≥0.5x109/L at day 60) was lower in bonemarrow recipients, 88 vs. 95% (p<0.0001). Grade II to IV acute graft-versus-hostdisease was lower in bone-marrow recipients, 19% vs. 24% for peripheral-blood (p=0.005). In multivariate analysis, after adjusting for differences between both groups, overall survival (HR 0.90; p=0.05) and leukemia-free-survival (HR 0.88; p=0.01) were higher in patients transplanted with peripheral-blood compared to bone-marrow grafts. Furthermore, peripheral-blood graft was also associated with decreased risk of relapse (HR 0.78; p=0.0001). Non-relapse-mortality was not significantly different between recipients of bone-marrow and peripheral-blood grafts, and chronic graft-versus-host-disease was significantly higher after peripheral blood grafts (HR 1.38; p<0.0001). Despite the limitation of a retrospective registry based study, we found that peripheral-blood grafts after reduced-intensity-conditioning regimens had better overall and leukemia-free survival than bone-marrow grafts. However, there is an increase in chronic graft-versus-host-disease after peripheral-blood grafts. Long-term follow-up is needed to clarify if chronic graft-versus-host-disease related deaths might increase the risk of late morbidity and mortality. [less ▲]

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See detailGemtuzumab Ozogamicin Versus Best Supportive Care in Older Patients With Newly Diagnosed Acute Myeloid Leukemia Unsuitable for Intensive Chemotherapy: Results of the Randomized Phase III EORTC-GIMEMA AML-19 Trial
Amadori, Sergio; Suciu, Stefan; Selleslag, Dominik et al

in Journal of Clinical Oncology (2016)

Purpose To compare single-agent gemtuzumab ozogamicin (GO) with best supportive care (BSC) including hydroxyurea as first-line therapy in older patients with acute myeloid leukemia unsuitable for ... [more ▼]

Purpose To compare single-agent gemtuzumab ozogamicin (GO) with best supportive care (BSC) including hydroxyurea as first-line therapy in older patients with acute myeloid leukemia unsuitable for intensive chemotherapy. Patients and Methods In this trial, patients at least 61 years old were centrally randomized (1:1) to receive either a single induction course of GO (6 mg/m2 on day 1 and 3 mg/m2 on day 8) or BSC. Patients who did not progress after GO induction could receive up to eight monthly infusions of the immunoconjugate at 2 mg/m2. Randomization was stratified by age, WHO performance score, CD33 expression status, and center. The primary end point was overall survival (OS) by intention-to-treat analysis. Results A total of 237 patients were randomly assigned (118 to GO and 119 to BSC). The median OS was 4.9 months (95% CI, 4.2 to 6.8 months) in the GO group and 3.6 months (95% CI, 2.6 to 4.2 months) in the BSC group (hazard ratio, 0.69; 95% CI, 0.53 to 0.90; P = .005); the 1-year OS rate was 24.3% with GO and 9.7% with BSC. The OS benefit with GO was consistent across most subgroups, and was especially apparent in patients with high CD33 expression status, in those with favorable/intermediate cytogenetic risk profile, and in women. Overall, complete remission (CR [complete remission] + CRi [CR with incomplete recovery of peripheral blood counts]) occurred in 30 of 111 (27%) GO recipients. The rates of serious adverse events (AEs) were similar in the two groups, and no excess mortality from AEs was observed with GO. Conclusion First-line monotherapy with low-dose GO, as compared with BSC, significantly improved OS in older patients with acute myeloid leukemia who were ineligible for intensive chemotherapy. No unexpected AEs were identified and toxicity was manageable. [less ▲]

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See detailUnraveling immune recovery after allogeneic hematopoietic stem cell transplantation: the contribution of flow cytometry
Ehx, Grégory ULg; BARON, Frédéric ULg

Conference (2015, November 19)

Allogeneic hematopoietic cell transplantation (allo-HCT) is frequently used as treatment for patients with hematological disorders. Main causes of failure of allo-HCT include disease relapse, graft-versus ... [more ▼]

Allogeneic hematopoietic cell transplantation (allo-HCT) is frequently used as treatment for patients with hematological disorders. Main causes of failure of allo-HCT include disease relapse, graft-versus-host disease (GVHD) and infections, stressing the need for research focusing at immune reconstitution after allo-HCT. T cell recovery after allo-HCT depends on both homeostatic peripheral expansion (HPE) of donor T cells contained in the graft, and T cell neo-production from donor hematopoietic stem cells (thymo-dependent pathway). In young patients undergoing allo-HCT, most circulating T cells during the first months following allo-HCT are the progeny of T cells infused with the graft through HPE. Specifically, consequently to the lymphopenia caused by the conditioning regimen, IL-7 and IL-15 are not consumed and lead to different mechanisms of HPE according to the concerned cells. Beyond day 100, neo-generation of T cells by the thymus is progressively set up and plays an increasing role in reconstituting the T cell pool in patients younger than 60 years. Since HPE allows the expansion of non-tolerant T cells, it has been postulated that HPE is the driving force of graft-versus-tumor effects, but also of GVHD. Regulatory T cells (Tregs) represent a fraction of CD4+ T cells that are indispensable for maintaining immunological self-tolerance. They constitutively express the forkhead box protein 3 factor (FoxP3) in their nuclei, and CD25 (the high-affinity component of the trimeric form of the interleukin 2 (IL-2) receptor) on their cell surface. Consequently, IL-2 is the key cytokine for Treg homeostasis. Interestingly, a deficit in Treg homeostasis has been demonstrated in patients with GVHD, and correction of the Treg homeostasis by low-dose IL-2 administration induced clinical responses in the majority of patients with GVHD. The presentation will discuss how flow cytometry can be used to monitor T cell recovery after allo-HCT, with a special focus of new techniques allowing studying Treg reconstitution / homeostasis after allo-HCT. [less ▲]

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