Long-term outcomes after reduced-intensity conditioning allogeneic stem cell transplantation for low-grade lymphoma: a survey by the French Society of Bone Marrow Graft Transplantation and Cellular Therapy (SFGM-TC).

International audienceBACKGROUND AND OBJECTIVES: High-dose chemotherapy with allogeneic stem cell transplantation (SCT) has proven to be a successful treatment for low-grade lymphoma (LGL), but is associated with considerable transplant-related mortality (TRM). In an effort to reduce toxic mortality while maintaining the graft-versus-leukemia effect, allogeneic SCT has been combined with a reduced-intensity conditioning (RIC) regimen. The aim of this study was to determine the outcome of patients with LGL treated with RIC allogeneic SCT. DESIGN AND METHODS: This retrospective multicenter study included 73 patients with relapsed or refractory LGL allografted after a RIC regimen between 1998 and 2005 whose data were recorded in a French registry. RESULTS: Patients received a median of three lines of therapy prior to RIC allogeneic SCT. The most widely used conditioning regimens were fludarabine + busulfan + antithymocyte globulin (n=43) and fludarabine + total body irradiation (n=21). Prior to allografting, patients were in complete response (CR; n=21), partial response (PR; n=33) or had chemoresistant disease (n=19). The median follow-up was 37 months (range, 16 to 77 months). In patients in CR, PR and chemoresistant disease, the 3-year overall survival rates were 66%, 64% and 32%, respectively, while the 3-year event-free survival rates were 66%, 52% and 32%, respectively. The 3-year cumulative incidences of TRM were 32%, 28% and 63%, respectively. The incidence of relapse was 9.6%. INTERPRETATION AND CONCLUSIONS: Although associated with significant TRM, RIC allogeneic SCT in advanced chemosensitive disease leads to long-term survival

Les cellules souches pluripotentes induites (étapes à franchir depuis le stade de la recherche vers une utilisation sécurisée chez l'homme)

La découverte des cellules souches pluripotentes induites par Shinya Yamanaka en 2006 offre de nouvelles opportunités considérables dans le domaine de la thérapie cellulaire et de la médecine régénérative, ainsi que pour l'industrie pharmaceutique et la recherche fondamentale. Ces cellules sont obtenues par reprogrammation cellulaire, une technologie qui permet d'obtenir, à partir de cellules somatiques, des cellules souches pluripotentes ayant des propriétés comparables aux cellules souches embryonnaires. Ces cellules souches pluripotentes induites peuvent donc se différencier en tous les types de cellules de l'organisme et, à l'inverse des cellules souches embryonnaires, ne soulèvent pas les questions éthiques relatives à l'utilisation d'embryons humains. La reprogrammation cellulaire consiste à introduire au sein d'une cellule adulte différenciée, à l'aide d'un vecteur, des gènes qui sont caractéristiques de la pluripotence. En vue d'une utilisation clinique chez l'homme, il est nécessaire de développer des stratégies de reprogrammation garantissant la sécurité des patients. Dans ce cadre, une stratégie consistant à reprogrammer des cellules souches hématopoïétiques issues de sang placentaire en utilisant un vecteur protéique pour transporter les facteurs de transcription minimaux nécessaires à la reprogrammation (Oct4 et Sox2) semble particulièrement pertinente. Par la suite, l'objectif sera de guider la différenciation de ces cellules souches pluripotentes induites vers des globules rouges à des fins transfusionnellesLYON1-BU Santé (693882101) / SudocSudocFranceF

Immunothérapie allogénique antitumorale (résultats cliniques et étude de la reconstitution lymphocytaire dans le modèle du myélome)

L'allogreffe non myéloablative de CSP est un outil antitumoral puissant. Son efficacité repose sur l'effet du greffon. Chez 10 patients greffés pour myélome, 9 réponses sont observées (3RC). L'effet antitumoral est lié au chimérisme complet de type donneur. La reconstitution lymphocytaire périphérique est décrite pendant la 1ière année après greffe: les populations ont été quantifiées (immunocytologie); le répertoire TCRVb des couples donneur-receveur (immunocytologie, immunoscope), a permis une étude qualitative. Les NK se normalisent à M+2, les CD8 à M+3 (70 -90% CD11a hi), les B à M+5. La reconstitution CD4 est lente (déficit en lymphocytes naïfs). La proportion de lymphocytes activés HLADR+ adopte une cinétique différente dans les compartiments CD4 et CD8. Nous observons des phénomènes de sélection clonale. Des expansions TCD8 sont chronologiquement liées à la réponse tumorale. Un modèle est proposé pour reproduire les expansions observées in vivo. Il permettrait de préciser les capacités fonctionnelles de lymphocytes potentiellement antitumoraux.GRENOBLE1-BU Médecine pharm. (385162101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

The impact of pathogen‐reduced platelets in acute leukaemia treatment on the total blood product requirement: a subgroup analysis of an EFFIPAP randomised trial

International audienceObjectiveTo evaluate the impact of pathogen-reduced (PR) platelet transfusions on blood products requirement for clinical practice.BackgroundPR platelets are increasing in use as standard blood products. However, few randomised trials have evaluated their impact on bleeding control or prevention. Furthermore, PR platelets recirculate less than untreated platelets.MethodsA subgroup study of the randomised clinical trial EFFIPAP compared three arms of platelet preparations (PR: P-PRP/PAS, additive solution: P-PAS and plasma P-P arms respectively). The subgroup of acute leukaemia patients, in their chemotherapy induction phase, included 392 patients (133 P-PRP/PAS arm, 132 P-PAS arm and 130 P-P arm). Blood requirements were analysed across over periods of 7 days.ResultsThe number of platelet transfusions per week was significantly higher in the P-PRP/PAS group 2.3 [1.6–3.3] compared to the control groups 1.9 [1.3–2.8] and 2.0 [1.3–3.0] for P-P and P-PAS groups respectively (p < 0.0001). However, the total number of platelets transfused per week was not different. The number of red blood cell concentrates (RBC) transfusion per week did not differ either.ConclusionIn a homogeneous group of patients, platelet pathogen reduction resulted in an increased number of platelet units transfused per week while having no impact on the total number of platelets transfused or the number of RBC transfusion; resulting to an average requirement of 2 RBC and 2–3 platelets transfusions per week of marrow aplasia

Targeted release of transcription factors for cell reprogramming by a natural micro-syringe.

International audienceEctopic expression of defined transcription factors (TFs) for cell fate handling has proven high potential interest in reprogramming differentiated cells, in particular for regenerative medicine, ontogenesis study and cell based modelling. Pluripotency or transdifferentiation induction as TF mediated differentiation is commonly produced by transfer of genetic information with safety concerns. The direct delivery of proteins could represent a safer alternative but still needs significant advances to be efficient. We have successfully developed the direct delivery of proteins by an attenuated bacterium with a type 3 secretion system that does not require challenging and laborious steps for production and purification of recombinant molecules. Here we show that this natural micro-syringe is able to inject TFs to primary human fibroblasts and cord blood CD34(+) hematopoietic stem cells. The signal sequence for vectorization of the TF Oct4 has no effect on DNA binding to its nucleic target. As soon as one hour after injection, vectorized TFs are detectable in the nucleus. The injection process is not associated with toxicity and the bacteria can be completely removed from cell cultures. A three days targeted release of Oct4 or Sox2 embryonic TFs results in the induction of the core pluripotency genes expression in fibroblasts and CD34(+) hematopoietic stem cells. This micro-syringe vectorization represents a new strategy for TF delivery and has potential applications for cell fate reprogramming

Targeted release of transcription factors for cell reprogramming by a natural micro-syringe.

International audienceEctopic expression of defined transcription factors (TFs) for cell fate handling has proven high potential interest in reprogramming differentiated cells, in particular for regenerative medicine, ontogenesis study and cell based modelling. Pluripotency or transdifferentiation induction as TF mediated differentiation is commonly produced by transfer of genetic information with safety concerns. The direct delivery of proteins could represent a safer alternative but still needs significant advances to be efficient. We have successfully developed the direct delivery of proteins by an attenuated bacterium with a type 3 secretion system that does not require challenging and laborious steps for production and purification of recombinant molecules. Here we show that this natural micro-syringe is able to inject TFs to primary human fibroblasts and cord blood CD34(+) hematopoietic stem cells. The signal sequence for vectorization of the TF Oct4 has no effect on DNA binding to its nucleic target. As soon as one hour after injection, vectorized TFs are detectable in the nucleus. The injection process is not associated with toxicity and the bacteria can be completely removed from cell cultures. A three days targeted release of Oct4 or Sox2 embryonic TFs results in the induction of the core pluripotency genes expression in fibroblasts and CD34(+) hematopoietic stem cells. This micro-syringe vectorization represents a new strategy for TF delivery and has potential applications for cell fate reprogramming

Detection of Circulating Aspergillus fumigatus Galactomannan: Value and Limits of the Platelia Test for Diagnosing Invasive Aspergillosis

The effectiveness of galactomannan detection with the Platelia test was evaluated in a prospective study of 3,327 sera from 807 patients. The specificity was 99.6% (748 of 751 cases). For the groups of patients with proven and probable invasive aspergillosis, the sensitivity was 50.0% (17 of 34 cases). The disappointing sensitivity associated with the presence of rare false-positive cases underlines the limits of this test

Diagnosis of toxoplasmosis after allogeneic stem cell transplantation: results of DNA detection and serological techniques.

International audienceBACKGROUND: The biological diagnosis of toxoplasmosis after allogeneic hematopoietic stem cell transplantation (HSCT) is based on the detection of Toxoplasma gondii DNA in blood specimens or other samples. Serological testing is used mainly to define the immunity status of the patient before HSCT. The aim of our study was to examine the performance of polymerase chain reaction (PCR) and serological techniques in the diagnosis of toxoplasmosis after HSCT. METHODS: Seventy patients underwent allogeneic HSCT from September 2004 through September 2006. DNA was detected by PCR, and immunoglobulin G and immunoglobulin M were detected by enzyme-linked immunosorbent assay. RESULTS: The results of immunoglobulin G detection before allogeneic HSCT were positive in 40 (57.1%) of the patients and negative in 30 (42.9%). After HSCT, 57 patients (81.4%) had test results that were negative for immunoglobulin M and had negative results of DNA detection, without toxoplasmosis infection. Four patients (5.7%) had at least 4 samples with positive PCR results and/or test results positive for immunoglobulin M against T. gondii; toxoplasmosis was then confirmed by clinical symptoms. Nine patients (12.9%) with positive PCR results and 1 or 2 samples with test results negative for immunoglobulin M were considered to have asymptomatic T. gondii infection. Reactivation of latent infection was the cause of toxoplasmosis in 3 of the 4 patients, and toxoplasmosis occurred as a primary infection in 1 patient. The detection of specific anti-T. gondii immunoglobulin M was the only biological evidence of toxoplasmosis in 2 patients, and samples were positive for immunoglobulin M before PCR was performed in 1 patient. CONCLUSIONS: Thus, after HSCT, all patients were at risk for toxoplasmosis; all patients who receive HSCTs should be followed up with biological testing that combines PCR and serological techniques

Long-term follow-up results of IFM99-03 and IFM99-04 trials comparing nonmyeloablative allotransplantation with autologous transplantation in high-risk de novo multiple myeloma.

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