Antithymocyte Globulin in Reduced-Intensity Conditioning Regimen Allows a High Disease-Free Survival Exempt of Long-Term Chronic Graft-versus-Host Disease

AbstractNonmyeloablative (NMA) regimens allow the use of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients considered unfit for standard myeloablative conditioning (MAC) regimens using high-dose alkylating agents with or without total body irradiation (TBI). Reduced-intensity conditioning (RIC) regimens, based on fludarabine (Flu), busulfan (Bu), and rabbit antithymocyte globulin (r-ATG), represent an intermediate alternative between NMA and MAC regimens. This platform was subsequently optimized by the introduction of i.v. Bu and the use of 5 mg/kg r-ATG, based on the hypothesis that these modifications would improve the safety of RIC allo-HSCT. Here we report a study conducted at our institution on 206 patients, median age 59 years, who underwent allo-HSCT after conditioning with Flu, 2 days of i.v. Bu, and 5 mg/kg r-ATG (FBx-ATG) between 2005 and 2012. The prevalence of grade III-IV acute graft-versus-host disease (GVHD) was 9%, and that of extensive chronic GVHD was 22%. Four-year nonrelapse mortality (NRM), relapse, and overall survival (OS) rates were 22%, 36%, and 54%, respectively. NRM tended to be influenced by comorbidities (hematopoietic cell transplantation–specific comorbidity index [HCT-CI] <3 versus HCT-CI ≥3: 18% versus 27%; P = .075), but not by age (<60 years, 20% versus ≥60 years, 25%; P = .142). Disease risk significantly influenced relapse (2 years: low, 8%, intermediate, 28%, high, 34%; very high, 63%; P = .017). Both disease risk (hazard ratio [95% confidence interval]: intermediate, 2.1 [0.8 to 5.2], P = .127; high, 3.4 [1.3 to 9.1], P = .013; very high, 4.0 [1.1 to 14], P = .029) and HCT-CI (hazard ratio [95% confidence interval]: HCT-CI ≥3, 1.7 (1.1 to 2.8), P = .018) influenced OS, but age and donor type did not. The FBx-ATG RIC regimen reported here is associated with low mortality and high long-term disease-free survival without persistent GVHD in both young and old patients. It represents a valuable platform for developing further post-transplantation strategies aimed at reducing the incidence of relapse, particularly in the setting of high-risk disease

Pioglitazone together with imatinib in chronic myeloid leukemia: A proof of concept study

BACKGROUND We recently reported that peroxisome proliferator‐activated receptor γ agonists target chronic myeloid leukemia (CML) quiescent stem cells in vitro by decreasing transcription of STAT5. Here in the ACTIM phase 2 clinical trial, we asked whether pioglitazone add‐on therapy to imatinib would impact CML residual disease, as assessed by BCR‐ABL1 transcript quantification. METHODS CML patients were eligible if treated with imatinib for at least 2 years at a stable daily dose, having yielded major molecular response (MMR) but not having achieved molecular response 4.5 (MR4.5) defined by BCR‐ABL1/ABL1 IS RNA levels ≤ 0.0032%. After inclusion, patients started pioglitazone at a dosage of 30 to 45 mg/day in addition to imatinib. The primary objective was to evaluate the cumulative incidence of patients having progressed from MMR to MR4.5 over 12 months. RESULTS Twenty‐four patients were included (age range, 24‐79 years). No pharmacological interaction was observed between the drugs. The main adverse events were weight gain in 12 patients and a mean decrease of 0.4 g/dL in hemoglobin concentration. The cumulative incidence of MR4.5 was 56% (95% confidence interval, 37%‐76%) by 12 months, despite a wide range of therapy duration (1.9‐15.5 months), and 88% of 17 evaluable patients who were still on imatinib reached MR4.5 by 48 months. The cumulative incidence of MMR to MR4.5 spontaneous conversions over 12 months was estimated to be 23% with imatinib alone in a parallel cohort of patients. CONCLUSION Pioglitazone in combination with imatinib was well tolerated and yielded a favorable 56% rate. These results provide a proof of concept needing confirmation within a randomized clinical trial (EudraCT 2009‐011675‐79). Cancer 2017;123:1791–1799. © 2016 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes

Biotic predictors complement models of bat and bird responses to climate and tree diversity in European forests

Bats and birds are key providers of ecosystem services in forests. How climate and habitat jointly shape their communities is well studied, but whether biotic predictors from other trophic levels may improve bird and bat diversity models is less known, especially across large bioclimatic gradients. Here, we achieved multi-taxa surveys in 209 mature forests replicated in six European countries from Spain to Finland, to investigate the importance of biotic predictors (i.e., the abundance or activity of defoliating insects, spiders, earthworms and wild ungulates) for bat and bird taxonomic and functional diversity. We found that 9 out of 12 bird and bat diversity metrics were best explained when biotic factors were added to models including climate and habitat variables, with a mean gain in explained variance of 38% for birds and 15% for bats. Tree functional diversity was the most important habitat predictor for birds, while bats responded more to understorey structure. The best biotic predictors for birds were spider abundance and defoliating insect activity, while only bat functional evenness responded positively to insect activity. Accounting for potential biotic interactions between bats, birds and other taxa of lower trophic levels will help to understand how environmental changes along large biogeographical gradients affect higher-level predator diversity in forest ecosystems

Late relapse after hematopoietic stem cell transplantation for acute leukemia: a retrospective study by SFGM-TC.

peer reviewedLate relapse (LR) after allogeneic hematopoietic stem cell transplantation (AHSCT) for acute leukemia is a rare event (nearly 4.5%) and raises the questions of prognosis and outcome after salvage therapy. We performed a retrospective multicentric study between January 1, 2010, and December 31, 2016, using data from the French national retrospective register ProMISe provided by the SFGM-TC (French Society for Bone Marrow Transplantation and Cellular Therapy). We included patients presenting with LR, defined as a relapse occurring at least 2 years after AHSCT. We used the Cox model to identify prognosis factors associated with LR. During the study period, a total of 7582 AHSCTs were performed in 29 centers, and 33.8% of patients relapsed. Among them, 319 (12.4%) were considered to have LR, representing an incidence of 4.2% for the entire cohort. The full dataset was available for 290 patients, including 250 (86.2%) with acute myeloid leukemia and 40 (13.8%) with acute lymphoid leukemia. The median interval from AHSCT to LR was 38.2 months (interquartile range [IQR], 29.2 to 49.7 months), and 27.2% of the patients had extramedullary involvement at LR (17.2% exclusively and 10% associated with medullary involvement). One-third of the patients had persistent full donor chimerism at LR. Median overall survival (OS) after LR was 19.9 months (IQR, 5.6 to 46.4 months). The most common salvage therapy was induction regimen (55.5%), with complete remission (CR) obtained in 50.7% of cases. Ninety-four patients (38.5%) underwent a second AHSCT, with a median OS of 20.4 months (IQR, 7.1 to 49.1 months). Nonrelapse mortality after second AHSCT was 18.2%. The Cox model identified the following factors as associated with delay of LR: disease status not in first CR at first HSCT (odds ratio [OR], 1.31; 95% confidence interval [CI], 1.04 to 1.64; P = .02) and the use of post-transplantation cyclophosphamide (OR, 2.23; 95% CI, 1.21 to 4.14; P = .01). Chronic GVHD appeared to be a protective factor (OR, .64; 95% CI, .42 to .96; P = .04). The prognosis of LR is better than in early relapse, with a median OS after LR of 19.9 months. Salvage therapy associated with a second AHSCT improves outcome and is feasible, without creating excess toxicity

Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues

L'automédication chez le sujet âgé (enquête auprès de personnes âgées et de pharmaciens d'officine, dans le Nord-Ouest de la France)

Pratiquée à l'aveugle, l'automédication est dangereuse pour tous. Ce risque s'accroit chez les personnes de plus de 65 ans, en raison des nombreux facteurs de risque propres à cette classe d'âge. L'utilisation de médicaments de sa propre initiative peut avoir de nombreuses causes ; ainsi, chaque personne âgée est susceptible de pratiquer l'automédication. Par l'intermédiaire d'une enquête, nous avons étudié la fréquence et les comportements des personnes âgées concernant l'automédication. Les sujets interrogés ont également dû citer les médicaments qu'ils consommaient en cas de symptômes communs, tels qu'un rhume, une toux, des douleurs... Notre étude a démontré que les personnes âgées pratiquent l'automédication de façon courante, parfois de manière inconsciente. Ils le font principalement en se servant dans leur armoire à pharmacie. L'analyse des médicaments utilisés lors de troubles fréquents a permis de déceler des pratiques inappropriées. Une brochure à l'intention des personnes âgées a été élaborée suite aux résultats de l'enquête, afin de limiter au maximum les accidents iatrogènes lors de la pratique de l'automédication.NANTES-BU Médecine pharmacie (441092101) / SudocSudocFranceF

La RSE comme levier de bouche à oreille positif vis-à-vis de l'employeur

International audienceWhile corporate social responsibility "CSR" plays an important role in organizationalattractiveness, few researches have focused on the influence of CSR on employee word of mouth. Thepurpose of this research is to understand how the perception of CSR practices is likely to generatepositive word of mouth from employees in the service of organizational attractiveness. Our resultsvalidate the influence of CSR perceptions on positive word of mouth from employees about theiremployer. In addition, employee- organization fit appears as a central mechanism of this influence.This research presents contributions in the field of organizational attractiveness and employees'reactions to CSRAlors que la responsabilité sociale des entreprises « RSE » joue un rôle important surl’attractivité organisationnelle, rares sont les recherches qui se sont intéressées à l’influence de la RSEsur le bouche à oreille des salariés. L’objectif de cette recherche est de comprendre comment laperception des pratiques de RSE est susceptible de générer un bouche à oreille positif des employés auservice de l’attractivité organisationnelle. Nos résultats permettent de valider l’influence desperceptions des RSE sur le bouche-à-oreille positif des salariés vis-à-vis de leur employeur. En outre,la congruence des valeurs employé-employeur apparaît comme mécanisme central de cette influence.Cette recherche présente des contributions dans le champ de l’attractivité organisationnelle et desréactions des employés vis-à-vis de la RSE

La RSE comme levier de bouche à oreille positif vis-à-vis de l'employeur

International audienceWhile corporate social responsibility "CSR" plays an important role in organizationalattractiveness, few researches have focused on the influence of CSR on employee word of mouth. Thepurpose of this research is to understand how the perception of CSR practices is likely to generatepositive word of mouth from employees in the service of organizational attractiveness. Our resultsvalidate the influence of CSR perceptions on positive word of mouth from employees about theiremployer. In addition, employee- organization fit appears as a central mechanism of this influence.This research presents contributions in the field of organizational attractiveness and employees'reactions to CSRAlors que la responsabilité sociale des entreprises « RSE » joue un rôle important surl’attractivité organisationnelle, rares sont les recherches qui se sont intéressées à l’influence de la RSEsur le bouche à oreille des salariés. L’objectif de cette recherche est de comprendre comment laperception des pratiques de RSE est susceptible de générer un bouche à oreille positif des employés auservice de l’attractivité organisationnelle. Nos résultats permettent de valider l’influence desperceptions des RSE sur le bouche-à-oreille positif des salariés vis-à-vis de leur employeur. En outre,la congruence des valeurs employé-employeur apparaît comme mécanisme central de cette influence.Cette recherche présente des contributions dans le champ de l’attractivité organisationnelle et desréactions des employés vis-à-vis de la RSE

Common features of myeloproliferative disorders with t(8;9)(p12;q33) and CEP110–FGFR1 fusion: Report of a new case and review of the literature

International audienceThe 8p12 myeloproliferative syndrome is a rare, generally aggressive chronic myeloproliferative disorder (MPD). The hallmark of this MPD is the disruption of the FGFR1 gene, which encodes a tyrosine kinase receptor for members of the fibroblast growth factor family. In MPD cells FGFR1 is fused to several partners. The most frequent partner genes are BCR, CEP110, FOP, and ZNF198, localized on 22q11, 9q33, 6q27, and 13q12, respectively. We report here the tenth case of translocation (8;9)(p12;q33) in an acute myelomonocytic leukemia and provide a review of the literature that points to common syndrome features: the t(8;9)(p11;q33) MPD transforms rapidly, and always in myelomonocytic leukemia, with a possible B- or T-lymphoid involvement, which may include tonsil invasion. The FGFR1-MPD seems refractory to current chemotherapies and is not sensitive to imatinib. Currently, only the patients with bone marrow transplantation stand a chance of survival