Inactivation des pathogènes des produits sanguins labiles: entre enjeux financiers et conséquences possibles à long terme [Pathogen reduction of blood components: from financial issues to possible long-term consequences].

Pathogen inactivation of blood products represents a global and major paradigm shift in transfusion medicine. In the next near future, it is likely that most blood products will be inactivated by various physicochemical approaches. The concept of blood safety will be challenged as well as transfusion medicine practice, notably for donor selection or biological qualification. In this context, it seems mandatory to develop analytical economic approaches by assessing costs-benefits ratio of blood transfusion as well as to set up cohorts of patients based on hemovigilance networks allowing rigorous scientific analysis of the benefits and the risks of blood transfusion at short- and long-term.

Antiviral Immunity in HIV-1 infected long term non-progressors (LTNPs).

Now that the acquired immunodeficiency syndrome (AIDS) epidemic is well into its second decade, it has become evident that a small percentage (approximately 5%) of HIV-infected individuals do not experience progression of HIV disease even after several years of being infected with HIV. These individuals have been designated as 'long term non-progressors' (LTNPs). From a virologic standpoint, these LTNPs have low viral burden in mononuclear cells, but persistent virus replication as manifested by chronic and generally low levels of plasma viremia. From an immunologic standpoint, immune functions including CD8(+) T-cell- and CD4(+) T-cell-mediated functions are preserved. In addition, they show a vigorous humoral immune response. More importantly, lymphoid tissue structure and function are preserved in LTNPs. Despite persistent low-level virus replication and chronic stimulation of the immune system, immune activation is qualitatively and quantitatively different in LTNPs compared to that observed in HIV-infected individuals whose HIV disease has progressed.

Population pharmacokinetics of imatinib in CML and GIST patients under long-term treatment

Imatinib (Glivec®) has transformed the treatment and short-term prognosis of chronic myeloid leukaemia (CML) and gastro-intestinal stromal tumour (GIST). However, the treatment must be taken indefinitely, it is not devoid of inconvenience and toxicity. Moreover, resistance or escape from disease control occur in a significant number of patients. Imatinib is a substrate of the cytochromes P450 CYP3A4/5 and of the multidrug transporter P glycoprotein (product of the MDR1 gene). Considering the large inter-individual differences in the expression and function of those systems, the disposition and clinical activity of imatinib can be expected to vary widely among patients, calling for dosage individualisation. The aim of this exploratory study was to determine the average pharmacokinetic parameters characterizing the disposition of imatinib in the target population, to assess their inter-individual variability, and to identify influential factors affecting them. A total of 321 plasma concentrations, taken at various sampling times after latest dose, were measured in 59 patients receiving Glivec® at diverse regimens, using a validated chromatographic method (HPLC-UV) developed for this study. The results were analysed by non-linear mixed effect modelling (NONMEM). A one- compartment model with first-order absorption appeared appropriate to describe the data, with an average apparent clearance of 12.4 l/h, a distribution volume of 268 l and an absorption constant of 0.47 h-1. The clearance was affected by body weight, age and sex. No influences of interacting drugs were found. DNA samples were used for pharmacogenetic explorations. The MDR1 polymorphism 3435C>T appears to affect the disposition of imatinib. Large inter-individual variability remained unexplained by the demographic covariates considered, both on clearance (40%) and distribution volume (71%). Together with intra-patient variability (34%), this translates into an 8-fold width of the 90%-prediction interval of plasma concentrations expected under a fixed dosing regimen ! This is a strong argument to further investigate the possible usefulness of a therapeutic drug monitoring programme for imatinib. It may help to individualise the dosing regimen before overt disease progression or observation of treatment toxicity, thus improving both the long-term therapeutic effectiveness and tolerability of this drug.

Long-term complete responses after 131I-tositumomab therapy for relapsed or refractory indolent non-Hodgkin's lymphoma.

We present the long-term results of 18 chemotherapy relapsed indolent (N = 12) or transformed (N = 6) NHL patients of a phase II anti-CD20 (131)I-tositumomab (Bexxar) therapy study. The biphasic therapy included two injections of 450 mg unlabelled antibody combined with (131)I-tositumomab once as dosimetric and once as therapeutic activity delivering 75 or 65 cGy whole-body radiation dose to patients with normal or reduced platelet counts, respectively. Two patients were not treated due to disease progression during dosimetry. The overall response rate was 81% in the 16 patients treated, including 50% CR/CRu and 31% PR. Median progression free survival of the 16 patients was 22.5 months. Median overall survival has not been reached after a median observation of 48 months. Median PFS of complete responders (CR/CRu) has not been reached and will be greater than 51 months. Short-term side effects were mainly haematological and transient. Among the relevant long-term side effects, one patient previously treated with CHOP chemotherapy died from secondary myelodysplasia. Four patients developed HAMA. In conclusion, (131)I-tositumomab RIT demonstrated durable responses especially in those patients who achieved a complete response. Six of eight CR/CRu are ongoing after 46-70 months.

Long-term ex vivo expansion of human fetal liver primitive haematopoietic progenitor cells in stroma-free cultures

Successful expansion of haematopoietic cells in ex vivo cultures will have important applications in transplantation, gene therapy, immunotherapy and potentially also in the production of non-haematopoietic cell types. Haematopoietic stem cells (HSC), with their capacity to both self-renew and differentiate into all blood lineages, represent the ideal target for expansion protocols. However, human HSC are rare, poorly characterized phenotypically and genotypically, and difficult to test functionally. Defining optimal culture parameters for ex vivo expansion has been a major challenge. We devised a simple and reproducible stroma-free liquid culture system enabling long-term expansion of putative haematopoietic progenitors contained within frozen human fetal liver (FL) crude cell suspensions. Starting from a small number of total nucleated cells, a massive haematopoietic cell expansion, reaching > 1013-fold the input cell number after approximately 300 d of culture, was consistently achieved. Cells with a primitive phenotype were present throughout the culture and also underwent a continuous expansion. Moreover, the capacity for multilineage lymphomyeloid differentiation, as well as the recloning capacity of primitive myeloid progenitors, was maintained in culture. With its better proliferative potential as compared with adult sources, FL represents a promising alternative source of HSC and the culture system described here should be useful for clinical applications.

Long-term outcome of preterm infants treated with nasal continuous positive airway pressure

RESUME La ventilation en pression positive continue (Continuous Positive Airway Pressure, CPAP), utilisée pour la première fois chez. les prématurés en 1971, est une technique actuellement très largement utilisée dans les unités néonatales. L'utilisation de la CPAP présente de nombreux avantages à court terme: diminution de la fraction maximale inspirée d'oxygène, de la durée de l'oxygénothérapie, du taux d'intubation et donc du recours à une ventilation mécanique, réduction de l'utilisation des amines, des curares et de la morphine, possible prévention de l'apparition d'une bronchodysplasie pulmonaire, et possibles réductions du nombre d'infections postnatales et des entérocolites nécrosantes. Mais peu d'études existent concernant les effets à long terme de la CPAP sur le neurodéveloppement et la croissance, qui constituent l'objectif de la présente étude. L'utilisation systématique de la CPAP comme alternative à la ventilation mécanique a été introduite à Lausanne en 1998. La population cible de cette étude est constituée des prématurés nés à moins de 32 semaines de gestation ou pesant moins de 1500 g à la naissance; ils ont été systématiquement suivis jusqu'en âge préscolaire dans le cadre de l'étude de cohorte «Unité de Développement, CHUV». L'originalité de ce travail réside dans le fait d'évaluer le neurodéveloppement et la croissance à long terme d'enfants prématurés traités préférentiellement avec la CPAP, en comparaison avec un groupe historique contrôle traité par d'autres modes ventilatoires, en tenant compte de nombreux autres paramètres néonataux. Du point de vue du neurodéveloppement, l'usage, de la CPAP montre une tendance à diminuer l'incidence d'hémorragie intraventriculaire et le risque d'avoir un mauvais neurodéveloppement à 6 mois. Ces résultats positifs sur le neurodéveloppement s'estompent à l'âge de 18 mois, où persiste néanmoins une valeur plus élevée du quotient de développement, et disparaissent complètement en âge préscolaire. Du point de vue de la croissance, l'utilisation de la CPAP ne montre aucun effet sur le poids, mais par contre un effet positif sur la taille à 6 et 18 mois et sur le périmètre crânien à 6 mois, 18 mois et en âge préscolaire. Malgré le caractère non randomisé de cette étude, les résultats positifs obtenus ici permettent sans conteste de s'assurer d'une utilisation de la CPAP sans effet négatif sur le neurodéveloppement et la croissance, et fournissent donc un argument supplémentaire pour l'utilisation systématique de la CPAP chez les prématurés.

Incidence and risk factors for Contegra graft infection following right ventricular outflow tract reconstruction: long-term results.

OBJECTIVES: The aim of this study was to evaluate the risk factors associated with Contegra graft (Medtronic Minneapolis, MN, USA) infection after reconstruction of the right ventricular outflow tract. METHODS: One hundred and six Contegra grafts were implanted between April 1999 and April 2010 for the Ross procedure (n = 46), isolated pulmonary valve replacement (n = 32), tetralogy of Fallot (n = 24), double-outlet right ventricle (n = 7), troncus arteriosus (n = 4), switch operation (n = 1) and redo of pulmonary valve replacement (n = 2). The median age of the patients was 13 years (range 0-54 years). A follow-up was completed in all cases with a median duration of 7.6 years (range 1.7-12.7 years). RESULTS: There were 3 cases of in-hospital mortality. The survival rate during 7 years was 95.7%. Despite the lifelong endocarditis prophylaxis, Contegra graft infection was diagnosed in 12 (11.3%) patients at a median time of 4.4 years (ranging from 0.4 to 8.7 years). Univariate analysis of preoperative, perioperative and postoperative variables was performed and the following risk factors for time to infection were identified: female gender with a hazard ratio (HR) of 0.19 (P = 0.042), systemic-to-pulmonary shunt (HR 6.46, P < 0.01), hypothermia (HR 0.79, P = 0.014), postoperative renal insufficiency (HR 11.97, P = 0.015) and implantation of permanent pacemaker during hospitalization (HR 5.29, P = 0.075). In 2 cases, conservative therapy was successful and, in 10 patients, replacement of the infected valve was performed. The Contegra graft was replaced by a homograft in 2 cases and by a new Contegra graft in 8 cases. Cox's proportional hazard model indicated that time to graft infection was significantly associated with tetralogy of Fallot (HR 0.06, P = 0.01), systemic-to-pulmonary shunt (HR 64.71, P < 0.01) and hypothermia (HR 0.77, P < 0.01). CONCLUSION: Contegra graft infection affected 11.3% of cases in our cohort, and thus may be considered as a frequent entity that can be predicted by both intraoperative and early postoperative factors. After the diagnosis of infection associated with the Contegra graft was confirmed, surgical treatment was the therapy of choice.

Long-term outcome of congenital aortic valve stenosis : predictors of reintervention

Objectif Evaluer l'évolution à long-terme d'une population de patients pédiatriques souffrant de sténose aortique congénitale et ayant subi une intervention chirurgicale sur cette valve, et déterminer les facteurs de risques associés à une ré-intervention. Patients et méthode De 1985 à 2009, 77 patients, en moyenne âgés de 5.8 ± 5-6 ans, ont été suivis dans notre Service durant 14.8 ± 9-1 années. Résultats La première intervention montre d'excellents résultats avec 86% des patients ayant un gradient aortique résiduel < 50 mmHg et seulement 7% avec une nouvelle fuite aortique >1. La survie à long terme est de 91% A 25 ans. A un intervalle de 7.6 ± 5-3 ans, 30 patients 011t nécessité une ré-intervention (39%), principalement à cause d'une récidive de la sténose aortique. Le pourcentage de patients libre de ré¬intervention était de 97, 89, 75, 53, and 42% à respectivement 1, 10,15, 20, et 25 ans. Les facteurs de risques cle ré-interventions étaient le gradient aortique residuel plus élevé (p=0.00 01), la fuite aortique post-intervention >1 (p=0.02), la valvuloplasty au ballon préalable (p-0.04) et l'épaisseur augmentée de la paroi postérieure du ventricule gauche (p=o.i). Conclusions L'intervention chirurgicale sur la valve aortique est un procédé sûr et efficace pour les sténoses aortiques congénitales et démontre d'excellents résultats au niveau de la survie. Cependant le taux de ré-intervention est élevé et influencé par le gradient aortique résiduel plus élevé, la fuite aortique post-intervention >1, la valvuloplasty au ballon préalable et l'épaisseur augmentée de la paroi postérieure du ventricule gauche. L'étude démontre qu'un suivi à long-terme est recommandé pour ces patients.

Impact of family structure on long-term survivors of osteosarcoma

Rapport de synthèse : But du travail : le pronostic des patients atteints d'ostéosarcome s'est considérablement amélioré grâce à l'utilisation de thérapies combinées performantes. Cependant, ces traitements agressifs sont grevés de complications chroniques. Notre travail a consisté à l'évaluation du status fonctionnel, psychologique et familial chez des patients survivants au long cours d'ostéosarcome traités au centre pluridisciplinaire d'oncologie. Patients et méthodes: 15 survivants au long cours d'ostéosarcome ont été évalués à la recherche de séquelles physiques et psychologiques. Pour l'évaluation fonctionnelle, nous avons utilisé la méthode de Enneking. L'évaluation psychologique a été basée sur un test d'évaluation globale (GHQ-28), sur un test de cohésion familiale (FAST test) et sur une échelle d'évaluation de symptômes post-traumatiques. Résultats: sur le plan fonctionnel, seuls 5 patients présentaient des séquelles graves et 10 des handicaps modérés. 4 patients souffraient de symptômes dépressifs. 6 patients ont décrit uns structure familiale déséquilibrée dont 3 des 4 patients avec des symptômes dépressifs, les 4 patients avec symptômes post-traumatiques et 5 des 7 patients avec une mauvaise acceptation émotionnelle. Conclusions: la plupart des patients souffrant d'ostéosarcome présentent une bonne récupération fonctionnelle. Seule une minorité reste sévèrement handicapée. Un tiers des patients souffre de symptômes dépressifs et de stress post-traumatique. Une mauvaise acceptation émotionnelle est fortement liée à une structure familiale déséquilibrée. La situation psychologique et familiale des patients atteints d'ostéosarcome doit donc être rapidement prise en compte afin d'améliorer leur évolution au long cours.

Long-term, multilineage hematopoiesis occurs in the combined absence of beta-catenin and gamma-catenin

The canonical Wnt signaling pathway plays key roles in stem-cell maintenance, progenitor cell expansion, and lineage decisions. Transcriptional responses induced by Wnt depend on the association of either beta-catenin or gamma-catenin with lymphoid enhancer factor/T cell factor transcription factors. Here we show that hematopoiesis, including thymopoiesis, is normal in the combined absence of beta- and gamma-catenin. Double-deficient hematopoietic stem cells maintain long-term repopulation capacity and multilineage differentiation potential. Unexpectedly, 2 independent ex vivo reporter gene assays show that Wnt signal transmission is maintained in double-deficient hematopoietic stem cells, thymocytes, or peripheral T cells. In contrast, Wnt signaling is strongly reduced in thymocytes lacking TCF-1 or in nonhematopoietic cells devoid of beta-catenin. These data provide the first evidence that hematopoietic cells can transduce canonical Wnt signals in the combined absence of beta- and gamma-catenin

The GraftConnector experience. Long-term patency and histological work up in an animal model.

BACKGROUND: A device to perform sutureless end-to-side coronary artery anastomosis has been developed by means of stent technology (GraftConnector). The present study assesses the long-term quality of the GraftConnector anastomosis in a sheep model. METHODS: In 8 adult sheep, 40-55 kg in weight, through left anterior thoracotomy, the right internal mammary artery (RIMA) was prepared and connected to the left anterior descending artery (LAD) by means of GraftConnector, on beating heart, without using any stabilizer. Ticlopidine 250 mg/day for anticoagulation for 4 weeks and Aspirin 100 mg/day for 6 months were given. The animals were sacrificed after 6 months and histological examination of anastomoses was carried out after slicing with the connector in situ for morphological analysis. RESULTS: All animals survived at 6 months. All anastomoses were patent and mean luminal width at histology was 1.8 +/- 0.2 mm; mean myotomia hyperplasia thickness was 0.21 +/- 0.1 mm. CONCLUSIONS: Long-term results demonstrate that OPCABGs performed with GraftConnector had 100% patency rate. The mean anastomotic luminal width corresponds to mean LAD's adult sheep diameter. We may speculate that myotomia hyperplasia occurred as a result of local device oversizing.

Assistance circulatoire chronique: le point en 2013 [Long-term mechanical circulatory support: where do we stand in 2013?].

With the advent of new technologies, experience with long-term mechanical circulatory support (MCS) is rapidly growing. Candidates to MCS are selected based on concepts, strategies and classifications that are specific to this indication. As results drastically improve, supported by stronger scientific evidence, the trend is towards earlier implantation. An adequate pre-implant follow-up is mandatory in order to avoid missing the best window of opportunity for implantation. While on chronic support, the hemodynamic profile of patients with continuous-flow ventricular assist devices is unique and remarkably influenced by the hydration status. Optimal management of these patients from the pre-implant phase to the long-term support phase requires a multidisciplinary approach that is similar to that already long validated for organ transplantation.

Long-term outcome after cognitive and behavioral regression in non-lesional epilepsy with CSWS

Purpose: To present the long-term outcome (LTO) of 10 adolescents and young adults with documented cognitive and behavioral regression as children due to non-lesional focal, mainly frontal epilepsy with continuous spike-waves during slow wave sleep (CSWS). Method: Past medical and EEG data of all patients were reviewed and neuropsychological tests exploring main cognitive functions were administered. Result: After a mean duration of follow-up of 15.6 years (range 8-23 years), none of the 10 patients had recovered fully, but four regained borderline to normal intelligence and were almost independent. Patients with prolonged global intellectual regression had the worst outcome, whereas those with more specific and short-lived deficits recovered best. The marked behavioral disorders that were so disturbing during the active period (AP) resolved in all but one patient. Executive functions were neither severely nor homogenously affected. Three patients with a frontal syndrome during the AP disclosed only mild residual executive and social cognition deficits. The main cognitive gains occurred shortly after the AP, but qualitative improvements continued to occur. LTO correlated best with duration of CSWS. Conclusion: Our findings emphasize that cognitive recovery after cessation of CSWS depends on the severity and duration of the initial regression. None of our patients had major executive and social cognition deficits with preserved intelligence as reported in adults with destructive lesions of the frontal lobes during childhood. Early recognition of epilepsy with CSWS and rapid introduction of effective therapy are crucial for a best possible outcome.

Long-term follow-up of European APL 2000 trial, evaluating the role of cytarabine combined with ATRA and Daunorubicin in the treatment of nonelderly APL patients.

All-trans retinoic acid (ATRA) combined to anthracycline-based chemotherapy is the reference treatment of acute promyelocytic leukemia (APL). Whereas, in high-risk patients, cytarabine (AraC) is often considered useful in combination with anthracycline to prevent relapse, its usefulness in standard-risk APL is uncertain. In APL 2000 trial, patients with standard-risk APL [i.e., with baseline white blood cell (WBC) count <10,000/mm(3) ] were randomized between treatment with ATRA with Daunorubicin (DNR) and AraC (AraC group) and ATRA with DNR but without AraC (no AraC group). All patients subsequently received combined maintenance treatment. The trial had been prematurely terminated due to significantly more relapses in the no AraC group (J Clin Oncol, (24) 2006, 5703-10), but follow-up was still relatively short. With long-term follow-up (median 103 months), the 7-year cumulative incidence of relapses was 28.6% in the no AraC group, compared to 12.9% in the AraC group (P = 0.0065). In standard-risk APL, at least when the anthracycline used is DNR, avoiding AraC may lead to an increased risk of relapse suggesting that the need for AraC is regimen-dependent.