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Les thromboses veineuses sur cathéter central (TVCC) représentent plus de 50 % des thromboses veineuses profondes chez l’enfant. La prévention est primordiale chez les enfants porteurs d’un cathéter central. Des mesures préventives telles que le respect du calibre du cathéter adapté au poids/taille de l’enfant, le rinçage pulsé en pression positive, la limitation des prélèvements et la réalisation d’un rinçage adapté de la voie après prélèvement sont indispensables afin de réduire ces complications. Le diagnostic doit être évoqué sur la clinique (douleur ou œdème d’un membre, syndrome cave supérieur, cyanose d’un membre, impotence fonctionnelle), en cas de dysfonction du cathéter (absence de retour, difficultés de perfusion), devant un syndrome infectieux ou inflammatoire inhabituel ou une possible infection liée au cathéter. En cas de suspicion, une échographie Doppler doit être réalisée afin de confirmer le diagnostic. Un bilan de thrombophilie n’est pas indiqué dans ces situations. Le traitement débute toujours par une héparinothérapie de préférence par héparine de bas poids moléculaire. Un relais par voie orale par anti-vitamine K ou un anticoagulant oral direct est possible après 5jours de traitement. Dans le cas où le cathéter n’est plus fonctionnel ou n’est plus nécessaire, nous recommandons de le retirer au plus tôt, et après au moins 3jours d’anticoagulation. Selon la possibilité de retrait du dispositif, les résultats du contrôle Doppler à 6 semaines, et les facteurs de risque associés (thrombotique et/ou hémorragique), la durée de traitement curatif est comprise entre 6 semaines et 3 mois.

Childhood, adolescent, and young adult cancer survivors are at increased risk of reduced bone mineral density. Clinical practice surveillance guidelines are important for timely diagnosis and treatment of these survivors, which could improve bone mineral density parameters and prevent fragility fractures. Discordances across current late effects guidelines necessitated international harmonisation of recommendations for bone mineral density surveillance. The International Late Effects of Childhood Cancer Guideline Harmonization Group therefore established a panel of 36 experts from ten countries, representing a range of relevant medical specialties. The evidence of risk factors for very low and low bone mineral density and fractures, surveillance modality, timing of bone mineral density surveillance, and treatment of very low and low bone mineral density were evaluated and critically appraised, and harmonised recommendations for childhood, adolescent, and young adult cancer survivors were formulated. We graded the recommendations based on the quality of evidence and balance between potential benefits and harms. Bone mineral density surveillance is recommended for survivors treated with cranial or craniospinal radiotherapy and is reasonable for survivors treated with total body irradiation. Due to insufficient evidence, no recommendation can be formulated for or against bone mineral density surveillance for survivors treated with corticosteroids. This surveillance decision should be made by the survivor and health-care provider together, after careful consideration of the potential harms and benefits and additional risk factors. We recommend to carry out bone mineral density surveillance using dual-energy x-ray absorptiometry at entry into long-term follow-up, and if normal (Z-score > −1), repeat when the survivor is aged 25 years. Between these measurements and thereafter, surveillance should be done as clinically indicated. These recommendations facilitate evidence-based care for childhood, adolescent, and young adult cancer survivors internationally.

Despite a high prevalence of angiodysplasia, no specific guidelines are available for the modalities of endoscopic exploration of gastrointestinal (GI) bleeding in von Willebrand disease (VWD). Whether VWD patients could benefit from video capsule endoscopy (VCE) looking for angiodysplasia eligible to endoscopic treatment or at high risk of bleeding is unknown. To assess the diagnostic efficacy for angiodysplasia and the prognostic value of VCE on top of conventional endoscopy in VWD patients with GI bleeding. A survey was sent to the 30 centers of the French‐network on inherited bleeding disorders to identify VWD patients referred for endoscopic exploration of GI bleeding from January 2015 to December 2017. Data obtained included patient characteristics, VWD phenotype/genotype, GI bleeding pattern, results of endoscopic investigations, and medical management applied including endoscopic therapy. We assessed by Kaplan‐Meier analysis the recurrence‐free survival after the first GI bleeding event according to endoscopic categorization and, in patients with angiodysplasia, to the presence of small‐bowel localizations on VCE exploration. GI bleeding source localization was significantly improved when including VCE exploration (P< .01), even in patients without history of angiodysplasia (P< .05). Patients with angiodysplasia had more GI bleeding recurrences (P< .01). A lower recurrence‐free survival was observed in patients with angiodysplasia (log‐rank test, P= .02), and especially when lesions were located in the small bowel (log‐rank test, P< .01), even after endoscopic treatment with argon plasma coagulation (log‐rank test, P< .01). VCE should be more systematically used in VWD patients with unexplained or recurrent GI bleeding looking for angiodysplasia eligible to endoscopic treatment or at high risk of relapse.

Despite a high prevalence of angiodysplasia, no specific guidelines are available for the modalities of endoscopic exploration of gastrointestinal (GI) bleeding in von Willebrand disease (VWD). Whether VWD patients could benefit from video capsule endoscopy (VCE) looking for angiodysplasia eligible to endoscopic treatment or at high risk of bleeding is unknown.

The realization of high-performance nanoelectronics requires control of materials at the nanoscale. Methods to produce high quality epitaxial graphene (EG) nanostructures on silicon carbide are known. The next step is to grow van der Waals semiconductors on top of EG nanostructures. Hexagonal boron nitride (h-BN) is a wide bandgap semiconductor with a honeycomb lattice structure that matches that of graphene, making it ideally suited for graphene-based nanoelectronics. Here, we describe the preparation and characterization of multilayer h-BN grown epitaxially on EG using a migration-enhanced metalorganic vapor phase epitaxy process. As a result of the lateral epitaxial deposition (LED) mechanism, the grown h-BN/EG heterostructures have highly ordered epitaxial interfaces, as desired in order to preserve the transport properties of pristine graphene. Atomic scale structural and energetic details of the observed row-by-row growth mechanism of the two-dimensional (2D) epitaxial h-BN film are analyzed through first-principles simulations, demonstrating one-dimensional nucleation-free-energy-barrierless growth. This industrially relevant LED process can be applied to a wide variety of van der Waals materials.

The recent observation of non-classical electron transport regimes in two-dimensional materials has called for new high-resolution non-invasive techniques to locally probe electronic properties. We introduce a novel hybrid scanning probe technique to map the local resistance and electrochemical potential with nm- and μV resolution, and we apply it to study epigraphene nanoribbons grown on the sidewalls of SiC substrate steps. Remarkably, the potential drop is non-uniform along the ribbons, and μm-long segments show no potential variation with distance. The potential maps are in excellent agreement with measurements of the local resistance. This reveals ballistic transport, compatible with μm-long room-temperature electronic mean-free paths.

Circular-polarization-resolved magneto-infrared studies of multilayer epitaxial graphene (MEG) are performed using tunable quantum cascade lasers in high magnetic fields up to 17.5 T. Landau level (LL) transitions in the monolayer and bilayer graphene inclusions of MEG are resolved, and considerable electron–hole asymmetry is observed in the extracted electronic band structure. For monolayer graphene, a four-fold splitting of the n= 0 to n= 1 LL transition is evidenced and attributed to the lifting of the valley and spin degeneracy of the zeroth LL and the broken electron–hole symmetry. The magnetic field dependence of the splitting further reveals its possible mechanisms. The best fit to experimental data yields effective g-factors, gVS*= 6.7 and gZS*= 4.8, for the valley and Zeeman splittings, respectively.

Medulloblastoma is the most common malignant cerebral tumor during childhood, arising in the posterior fossa. Children treated for medulloblastoma often experience working memory (WM) deficits, affecting their quality of life and school performance. The aim of the present study undertaken to describe the cerebellar involvement in WM deficits observed in these children.

Congenital neutropenias (CNs) are rare heterogeneous genetic disorders, with about 25% of patients without known genetic defects. Using whole-exome sequencing, we identified a heterozygous mutation in the SRP54 gene, encoding the signal recognition particle (SRP) 54 GTPase protein, in 3 sporadic cases and 1 autosomal dominant family. We subsequently sequenced the SRP54 gene in 66 probands from the French CN registry. In total, we identified 23 mutated cases (16 sporadic, 7 familial) with 7 distinct germ line SRP54 mutations including a recurrent in-frame deletion (Thr117del) in 14 cases. In nearly all patients, neutropenia was chronic and profound with promyelocytic maturation arrest, occurring within the first months of life, and required long-term granulocyte colony-stimulating factor therapy with a poor response. Neutropenia was sometimes associated with a severe neurodevelopmental delay (n = 5) and/or an exocrine pancreatic insufficiency requiring enzyme supplementation (n = 3). The SRP54 protein is a key component of the ribonucleoprotein complex that mediates the co-translational targeting of secretory and membrane proteins to the endoplasmic reticulum (ER). We showed that SRP54 was specifically upregulated during the in vitro granulocytic differentiation, and that SRP54 mutations or knockdown led to a drastically reduced proliferation of granulocytic cells associated with an enhanced P53-dependent apoptosis. Bone marrow examination of SRP54-mutated patients revealed a major dysgranulopoiesis and features of cellular ER stress and autophagy that were confirmed using SRP54-mutated primary cells and SRP54 knockdown cells. In conclusion, we characterized a pathological pathway, which represents the second most common cause of CN with maturation arrest in the French CN registry.

Congenital neutropenias (CNs) are rare heterogeneous genetic disorders, with about 25% of patients without known genetic defects. Using whole-exome sequencing, we identified a heterozygous mutation in the SRP54gene, encoding the signal recognition particle (SRP) 54 GTPase protein, in 3 sporadic cases and 1 autosomal dominant family. We subsequently sequenced the SRP54gene in 66 probands from the French CN registry. In total, we identified 23 mutated cases (16 sporadic, 7 familial) with 7 distinct germ line SRP54mutations including a recurrent in-frame deletion (Thr117del) in 14 cases. In nearly all patients, neutropenia was chronic and profound with promyelocytic maturation arrest, occurring within the first months of life, and required long-term granulocyte colony-stimulating factor therapy with a poor response. Neutropenia was sometimes associated with a severe neurodevelopmental delay (n = 5) and/or an exocrine pancreatic insufficiency requiring enzyme supplementation (n = 3). The SRP54 protein is a key component of the ribonucleoprotein complex that mediates the co-translational targeting of secretory and membrane proteins to the endoplasmic reticulum (ER). We showed that SRP54 was specifically upregulated during the in vitro granulocytic differentiation, and that SRP54mutations or knockdown led to a drastically reduced proliferation of granulocytic cells associated with an enhanced P53-dependent apoptosis. Bone marrow examination of SRP54-mutated patients revealed a major dysgranulopoiesis and features of cellular ER stress and autophagy that were confirmed using SRP54-mutated primary cells and SRP54knockdown cells. In conclusion, we characterized a pathological pathway, which represents the second most common cause of CN with maturation arrest in the French CN registry.

Atomically thin graphene exhibits fascinating mechanical properties, although its hardness and transverse stiffness are inferior to those of diamond. So far, there has been no practical demonstration of the transformation of multilayer graphene into diamond-like ultrahard structures. Here we show that at room temperature and after nano-indentation, two-layer graphene on SiC(0001) exhibits a transverse stiffness and hardness comparable to diamond, is resistant to perforation with a diamond indenter and shows a reversible drop in electrical conductivity upon indentation. Density functional theory calculations suggest that, upon compression, the two-layer graphene film transforms into a diamond-like film, producing both elastic deformations and sp2to sp3chemical changes. Experiments and calculations show that this reversible phase change is not observed for a single buffer layer on SiC or graphene films thicker than three to five layers. Indeed, calculations show that whereas in two-layer graphene layer-stacking configuration controls the conformation of the diamond-like film, in a multilayer film it hinders the phase transformation. Indentation in bilayer epitaxial graphene induces its reversible transformation into a diamond-like structure with stiffness and hardness comparable to diamond.

La croissance de graphène sur du carbure de silicium SiC est compatible avec les technologies de lithographie existantes, et donc avec le développement de dispositifs où le silicium atteint ses limites.

Severe hemophilia A is an X-linked bleeding disorder. Immune tolerance induction (ITI) is the best strategy of treatment when patients develop inhibitors. The objective is to illustrate the benefit of a high-purity human factor VIII/von Willebrand factor (VWF) concentrate (Octanate) in the management of ITI. We also wanted to raise the potential interest of laboratory assays such as thrombin-generation test (TGT) and epitope mapping. Two patients were treated during ITI, first with a recombinant FVIII and then with plasma-derived factor VIII without success, and, finally, with Octanate. Bypassing agents were used based on the results of TGT. Epitope mapping was performed during ITI therapy. These observations suggest the potential contribution of Octanate in the management of ITI in difficult cases. The use of bypassing agents can be necessary in prophylaxis or to treat bleedings, and may be guided by TGT results. Epitope mapping is used to describe the inhibitor. This article shows a decrease of the inhibitor directed against the C2 domain after initiation of Octanate. A high-purity human factor VIII/von Willebrand factor concentrate (Octanate) may be a valuable therapeutical option for ITI therapy. TGT and epitope mapping could be of help in the management of ITI.

L’augmentation régulière de la survie des enfants et des adolescents traités pour un cancer permet d’estimer actuellement en France à 50 000 le nombre d’adultes survivant d’un cancer traité avant l’âge de 20ans et qui sont concernés par les possibles effets tardifs de la maladie et des thérapeutiques reçues (chirurgie, chimiothérapie, radiothérapie). Ces complications peuvent se manifester avec des délais variables par des maladies cardiovasculaires, cérébrovasculaires (après irradiation ou chimiothérapie), des troubles neurocognitifs, endocriniens (croissance, fonction thyroïdienne), troubles de la fertilité et des seconds cancers. Le suivi doit être personnalisé, adapté à chaque patient et dépend du type de la tumeur primitive, des traitements anticancéreux administrés mais aussi des facteurs génétiques associés éventuels. Le risque de développer des complications à long terme augmente avec le temps et peut être exacerbé par les comorbidités liées à l’âge et aux facteurs environnementaux (tabac, alcool, obésité). En France, plusieurs régions ou centres de traitement ont mis en place des consultations spécialisées dans ce domaine.

Le risque augmenté de second cancer primitif (SCP) chez les enfants, adolescents et jeunes adultes traités pour un cancer, lié notamment aux traitements, doit inciter à une réflexion sur le suivi optimal de cette population et la prévention de ces SCP.

Les problématiques autour des cancers rares ont encore été peu explorées par la recherche, du fait de leur faible incidence. C’est pourquoi les études épidémiologiques peinent à identifier des facteurs de risque étiologiques indiscutables. Alors que la prise en charge de ces cancers requiert une expertise certaine, concentrée généralement dans certains établissements, le parcours de soins des patients, compte tenu du potentiel éloignement de ces ressources thérapeutiques, reste aussi peu étudié. L’analyse géographique d’une cohorte régionale exhaustive de sarcomes diagnostiqués en 2006 et 2007 doit permettre d’avancer dans ces différents questionnements. Les tumeurs stromales gastro-intestinales (GIST) surviennent plus fréquemment dans des territoires aisés, au contraire des liposarcomes davantage présents dans les communes défavorisées. Cette association entre liposarcomes et défavorisation des communes est significative (p= 0,05). De plus, la présence d’une biopsie préopératoire ainsi que certaines caractéristiques cliniques du patient, comme l’âge, le grade ou la localisation tumorale, sont associées à une augmentation de la distance parcourue par les patients pour leur première ligne de traitement (p≤ 0,001). L’approche géographique, dans le cadre d’une collaboration interdisciplinaire, permet de développer certaines hypothèses pour la recherche sur les cancers rares, qui nécessitent d’être testées par d’autres études à une échelle plus importante.

Au vu des excellents taux de guérison des cancers de l'enfant et de l'adolescent, minimiser les séquelles et favoriser leur qualité de vie future devient une priorité. La préservation de la fertilité est un élément majeur de cette problématique. L'âge, le sexe et les associations thérapeutiques influent sur le niveau de risque d'hypofertilité future. Certaines chimiothérapies, en particulier les alkylants, et la radiothérapie au niveau des gonades ou de l'axe hypothalamopituitaire risquent d'avoir un impact sur la fertilité future des patients. L'évaluation du potentiel gonadotoxique des thérapeutiques et le recours à une méthode appropriée de préservation de la fertilité sont nécessaires pour limiter cet effet secondaire. Cette revue de la littérature cherche à établir des recommandations pour les pédiatres-oncologues et hématologues concernant les méthodes de préservation de la fertilité, à proposer aux enfants et adolescents recevant un traitement gonadotoxique. Le suivi spécialisé indiqué à l'issue du traitement est également abordé.

We present an introduction to the rapidly growing field of epitaxial graphene on silicon carbide, tracing its development from the original proof-of-concept experiments a decade ago to its present, highly evolved state. The potential of epitaxial graphene as a new electronic material is now being recognized. Whether the ultimate promise of graphene-based electronics will ever be realized remains an open question. Silicon electronics is based on single-crystal substrates that allow reliable patterning on the nanoscale, which is an absolute requirement for any new electronic material. That is why epitaxial graphene is based on single-crystal silicon carbide. We also present recent results on nanopatterned graphene produced by etching the silicon carbide before annealing so that the graphene structures are produced in their final shapes. This avoids postannealing patterning, which is known to greatly affect transport properties on the nanoscale. Creating such structured graphene is an elegant method for avoiding pervasive patterning problems.

Abstract

Epitaxial graphene has demonstrated a great potential for carbon-based electronic. Multiple nanoscale devices can be patterned on a scalable platform with high electronic mobility, large conductivity, and conductance modulation by an electrostatic gate. High quality seamless epitaxial graphene layers are grown on the entire surface of SiC substrates by thermal decomposition of the SiC crystal. For multilayer epitaxial graphene grown on the 4H-SiC (000-1) surface, transport and spectroscopy measurements demonstrate an effective decoupling of the adjacent graphene layers due to a non-graphitic ordered rotational stacking. Large switching ratios require a band gap but graphene is a gapless semimetal. Transport gaps have been demonstrated in chemical functionalized graphene and in narrow ribbons. But patterning techniques severely degrade graphene. Transport data on narrow graphene ribbons directly grown on silicon carbide substrate step edges at high temperature indicate reduced edge scattering and open the way to non diffusive electronics.

Three types of first generation epitaxial graphene EG field effect transistors FET are presented and their relative merits are discussed. Graphene is epitaxially grown on both the carbon and silicon faces of hexagonal silicon carbide and patterned with electron beam lithography. The channels have a Hall bar geometry to facilitate magnetoresistance measurements. FETs patterned on the Siface exhibit offtoon channel resistance ratios that exceed 30. Cface FETs have lower offtoon resistance ratios, but their mobilities up to 5000 cm2Vs are much larger than that for Siface transistors. Initial investigations into allgraphene sidegate FET structures are promising. Conductivity left panel and transport resistances ρxxand ρxyof a top gate graphene Hall bar on SiC Siface, showing a sign reversal of the hall coefficient at the resistance peak.

At the present time, the standard approach for renal cancer in children is open surgery, and the role of laparoscopic approach remains to be defined. We report our preliminary experience in the treatment by laparoscopic radical nephrectomy (LRN) for unilateral renal cancer in children.

Natural killer (NK) cells have been originally defined by their “naturally occurring” effector function. However, only a fraction of human NK cells is reactive toward a panel of prototypical tumor cell targets in vitro, both for the production of interferon-γ (IFN-γ) and for their cytotoxic response. In patients with IL12RB1 mutations that lead to a complete IL-12Rβ1 deficiency, the size of this naturally reactive NK cell subset is diminished, in particular for the IFN-γ production. Similar data were obtained from a patient with a complete deficit in IL-12p40. In addition, the size of the subset of effector memory T cells expressing CD56 was severely decreased in IL-12Rβ1– and IL-12p40–deficient patients. Human NK cells thus require in vivo priming with IL-12/23 to acquire their full spectrum of functional reactivity, while T cells are dependent upon IL-12/23 signals for the differentiation and/or the maintenance of CD56+ effector memory T cells. The susceptibility of IL-12/23 axis–deficient patients to Mycobacterium and Salmonella infections in combination with the absence of mycobacteriosis or salmonellosis in the rare cases of human NK cell deficiencies point to a role for CD56+ T cells in the control of these infections in humans.

Natural killer (NK) cells have been originally defined by their “naturally occurring” effector function. However, only a fraction of human NK cells is reactive toward a panel of prototypical tumor cell targets in vitro, both for the production of interferon-γ (IFN-γ) and for their cytotoxic response. In patients with IL12RB1mutations that lead to a complete IL-12Rβ1 deficiency, the size of this naturally reactive NK cell subset is diminished, in particular for the IFN-γ production. Similar data were obtained from a patient with a complete deficit in IL-12p40. In addition, the size of the subset of effector memory T cells expressing CD56 was severely decreased in IL-12Rβ1– and IL-12p40–deficient patients. Human NK cells thus require in vivo priming with IL-12/23 to acquire their full spectrum of functional reactivity, while T cells are dependent upon IL-12/23 signals for the differentiation and/or the maintenance of CD56+effector memory T cells. The susceptibility of IL-12/23 axis–deficient patients to Mycobacteriumand Salmonellainfections in combination with the absence of mycobacteriosis or salmonellosis in the rare cases of human NK cell deficiencies point to a role for CD56+T cells in the control of these infections in humans.

Epitaxial graphene layers grown on single-crystal SiC have large structural coherence domains and can be easily patterned into submicron structures using standard microelectronics lithography techniques. Patterned structures show two-dimensional electron gas properties with mobilities exceeding 3 m2/Vs. Magnetotransport measurements (Shubnikov–de Haas oscillations) indicate that the transport properties are dominated by the highly doped graphene layer at the silicon carbide interface. They reveal the Dirac nature of the charge carriers as predicted for a single graphene layer. The properties of Dirac fermions can be conveniently explored in epitaxial graphene with long electronic phase coherence at the micron scale. (© 2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim)

Introduction: Hemoglobin (Hb) Agrinio (HBA2: c.89T>C (Leu29Pro) mutation) is a rare highly unstable Hb variant resulting from a leucine to proline substitution at codon29 of the alpha2-globin gene. Eleven homozygous cases of this non-deletional alpha thalassemia were described in literature. Clinical course ranged from moderate (non-transfusion dependent anemia) to severe (transfusion dependent thalassemia). In addition, one probable case of Hb barts hydrops fetaliswas also reported in a Greek series. Hb Agrinio was first described in individuals of Greek or Cypriot origins. Subsequently, some cases were reported among patients living in Spain and Macedonia, most often of Gypsy origin. We report here the clinical presentation of the 8 homozygous cases diagnosed by molecular biology analysis in France and underline the severity of the antenatal phenotype of the disease.

Large-scale atomically thin metals can be stabilized through confinement epitaxy at graphene/SiC interface, which exhibit a gradient bonding type and are air stable, providing a compelling platform for quantum and optoelectronic technologies.

In the version of this Article originally published, the second affiliation for Walter A. de Heer had not been included; it should be ‘TICNN, Tianjin University, Tianjin, China’. This has now been added and the numbering of subsequent affiliations amended accordingly in all versions of the Article.

No relevant conflicts of interest to declare.

Context.Congenital neutropenia (CN) is a heterogeneous group of diseases characterized by low neutrophil count, severe bacterial infections, increased risk of leukemic transformation and various extra-hematopoietic organ dysfunctions. Even if 24 different genes have been linked to the etiology of CN, in many patients the genetic causes of CN remain unknown.

No relevant conflicts of interest to declare.

Abstract: The magnetoresistance of seven icosahedral AlPdRe samples with residual resistivity ratios (RRR) between 2 and 45 has been measured in the temperature range 0.23 K to 4.2 K in magnetic fields up to 12 T. The results indicate that weak localization breaks down when RRR exceeds values in the range 5 to 10.

Very good results were obtained with this VCR-DEX-ASPA oriented protocol. SR-BCP ALL pts which represents around 55 % of all children with ALL can be cured with a modest dose of anthracyclin (75 mg/m2). A further decrease in therapy based on the identified prognostic factors could be proposed. Intensification of the chemotherapy for the rare SR pts with a very high MRD has salvaged half of these pts but the addition of new drugs and/or HSCT is now to be evaluated.No relevant conflicts of interest to declare.

Abstract 135This icon denotes a clinically relevant abstract

Epitaxial graphene has demonstrated a great potential for carbon-based electronic. Multiple nanoscale devices can be patterned on a scalable platform with high electronic mobility, large conductivity, and conductance modulation by an electrostatic gate. High quality seamless epitaxial graphene layers are grown on the entire surface of SiC substrates by thermal decomposition of the SiC crystal. For multilayer epitaxial graphene grown on the 4H-SiC (000-1) surface, transport and spectroscopy measurements demonstrate an effective decoupling of the adjacent graphene layers due to a non-graphitic ordered rotational stacking. Large switching ratios require a band gap but graphene is a gapless semimetal. Transport gaps have been demonstrated in chemical functionalized graphene and in narrow ribbons. But patterning techniques severely degrade graphene. Transport data on narrow graphene ribbons directly grown on silicon carbide substrate step edges at high temperature indicate reduced edge scattering and open the way to non diffusive electronics.

From 06/93 to 12/99, 1395 children and adolescents were included in the FRALLE 93 protocol: group A (Very Low Risk): 182, B (Standard risk): 672 and C (High risk including T-ALL): 541. The median FU is 9.5 yr. Inclusion criterias in group B were: age between 1 and 15 yr, WBC< 100,000, BCP phenotype and no poor-prognosis cytogenetic feature (MLL rearrangement or Ph1). Group B pts were randomised in a 2-steps schedule: at inclusion: daunorubicin (DNR: 40 mg/m2 × 2) vs idarubicin (IDA: 8 mg/m2 × 2), and at consolidation: high-dose IV methotrexate (HD-MTX): 4 × 8g/m2 at D1, D15, D29 and D42, vs low-dose po MTX (LD-MTX): 4 × 25 mg/m2; the number of triple IT was the same for both arms (N = 18). Pts with CNS leukemia were not randomized for MTX. During induction, pts were also classified on D21 bone marrow aspiration according to the level of residual blasts: M1 (< 5%): n=555, M2 (6–25%): n=71 and M3 (> 25%): n=41; M2/M3 pts received 1 more antracyclin infusion at D22 and M3 pts were subsequently treated according to the HR group and not randomized for MTX. Both M1 and M2 pts who reached CR were randomized for MTX. The overall group B EFS, DFS and OS were respectively 80±2, 81±2, and 91±1%. Globally there is no statistically significant impact of 1st or 2nd randomization on the outcome of patients. When we look at the outcome according to the D21 status, the EFS are very different: M1: 84±2%, M2: 63±6% and M3: 74±7%. The very poor EFS of M2 pts, who can not actually be classified as SR pts, and the fact that M1 pts represent 90% of pts randomized for MTX led us to analyse separately M1 pts. For M1 pts there is no interaction between 1st and 2nd randomization for survival, EFS and relapse rate (Gail and Simon test, p = 0.51); therefore pts were pooled for 2nd randomization analysis. Among M1 pts, 271 pts were randomized for HD-MTX and 264 for LD-MTX; there is no difference regarding age or leucocytosis between the 2 arms. Results are as follows: 5-yr EFS Relapses CI iBM relapses CI Other relapses CI 5-yr OS (EFS: event-free survival, CI: cumulative incidence, iBM: isolated bone-marrow, OS: overall survival) HD-MTX 87.82±1.99% 0.12±0.04 7.01±0.02 5.17±0.02 95.20±1.30 LD-MTX 79.92±2.47% 0.20±0.06 10.6±0.03 9.10±0.03 88.64±1.95 Test log-rank Gray Gray Gray log-rank p value 0.028 0.037 0.16 0.18 0.07 At the contrary, among M2 pts there is no difference in EFS for pts treated with HD-MTX (61±7%) and LD-MTX (65±9%) Conclusion: HD-MTX seems to benefit to pts with standard-risk BCP-ALL and good early response to chemotherapy, and the benefit is associated with a reduction in the number of relapses. No benefit is demonstrated in M2 pts with SER who have a very poor outcome and do require a more intensive treatment; the better EFS of M3 patients treated with double delayed intensification is in favour of this hypothesis.

From 06/93 to 12/99, 1395 children and adolescents were included in the FRALLE 93 protocol: group A (Very Low Risk): 182, B (Standard risk): 672 and C (High risk including T-ALL): 541. The median FU is 9.5 yr. Inclusion criterias in group B were: age between 1 and 15 yr, WBC< 100,000, BCP phenotype and no poor-prognosis cytogenetic feature (MLLrearrangement or Ph1). Group B pts were randomised in a 2-steps schedule: at inclusion: daunorubicin (DNR: 40 mg/m2× 2) vs idarubicin (IDA: 8 mg/m2× 2), and at consolidation: high-dose IV methotrexate (HD-MTX): 4 × 8g/m2at D1, D15, D29 and D42, vs low-dose po MTX (LD-MTX): 4 × 25 mg/m2; the number of triple IT was the same for both arms (N = 18). Pts with CNS leukemia were not randomized for MTX. During induction, pts were also classified on D21 bone marrow aspiration according to the level of residual blasts: M1 (< 5%): n=555, M2 (6–25%): n=71 and M3 (> 25%): n=41; M2/M3 pts received 1 more antracyclin infusion at D22 and M3 pts were subsequently treated according to the HR group and not randomized for MTX. Both M1 and M2 pts who reached CR were randomized for MTX. The overall group B EFS, DFS and OS were respectively 80±2, 81±2, and 91±1%. Globally there is no statistically significant impact of 1stor 2ndrandomization on the outcome of patients. When we look at the outcome according to the D21 status, the EFS are very different: M1: 84±2%, M2: 63±6% and M3: 74±7%. The very poor EFS of M2 pts, who can not actually be classified as SR pts, and the fact that M1 pts represent 90% of pts randomized for MTX led us to analyse separately M1 pts. For M1 pts there is no interaction between 1stand 2ndrandomization for survival, EFS and relapse rate (Gail and Simon test, p = 0.51); therefore pts were pooled for 2ndrandomization analysis. Among M1 pts, 271 pts were randomized for HD-MTX and 264 for LD-MTX; there is no difference regarding age or leucocytosis between the 2 arms. Results are as follows:

From January 2000 to July 2006, 580 BCR-ABL negative patients with HR/VHR-ALL (200 T-ALL and 380 BCP-ALL (age≥10 or WBC≥50 or CNS+ or MLL-R) were included in the FRALLE 2000-BT trials. Induction regimen is prednisone (PRED) prephase + IT MTX, VCR, L-Aspa, DNR 120mg/m2 cumulated dose or DNR 160mg/m2 + cyclophosphamide 1g/m2 (T-ALL and D21 M2M3 marrow or MLL-R BCP-ALL). MRD at EOI is quantitatively determined by DNA-based PCR for Ig/TCR rearrangements either competitive PCR with GeneScan analysis or RQ-PCR with clone specific primers (sensitivity ranges 0.5×10−3–10−3, and 10−3–10−5, respectively). MRD status at EOI are available for 425 out of 552 CR (77%). MRD results are reported as negative, positive <10−3, highly positive (10−3≤MRD<10−2), very highly positive (≥10−2). Patients with EOI MRD ≥10−2 were to receive an intensified treatment. Results: 30% (89/293) of HR/VHR BCP-ALL and 34% (45/132) T-ALL have detectable MRD at EOI, NS. A high or very high MRD is encountered in 16% (47/293) of BCP-ALL and 21% (27/132) of T-ALL (NS). Surprisingly 57% (20/35) of the pts with BCP-ALL and D8 poor PRED response (PPR) and 71% (36/51) of the pts with D8 PPR T-ALL have a negative or slightly positive MRD (<10−3) at EOI, NS. 30% (7/23) of the pts with D21 M2M3 BCP-ALL and 46% (6/13) of the pts with D21 M2M3 T-ALL have also a negative or slightly positive MRD (<10−3) at EOI. By contrast, 11% of good early responders (D8 good PRED response and D21 M1) with BCP-ALL or T-ALL (27/245 and 11/74, respectively) have a high or very high positive MRD. Overall, 20 out of 449 (4.5%) HR/VHR pts in CR have received an intensified treatment due to a very high MRD only. 3y DFS for pts with a highly positive or very highly positive MRD are 65±7% (BCP-ALL) and 64±9% (T-ALL), NS. 3y DFS for pts with a negative or slightly positive MRD (<10−3) are 94±2% (BCP-ALL) and 87±4% (T-ALL), p=.04. There is a statistically significant difference in term of DFS between pts with MRD≥10−3 and MRD < 10−3, p=.001 and p =.05 for BCP- and T-ALL, respectively. Conclusions: the incidence of high and very high MRD at EOI is identical in children with HR/VHR-BCP- and T-ALL. High and very high MRD levels are found in good early responders defined by morphology. Conversely, excellent molecular responses can be found in bad early responders. High or very high MRD values are associated to a comparable prognosis between BCP- and T-ALLs.

This retrospective study was designed to determine the prevalence of inherited prothrombotic risk factors (Factor V Leiden (FV) G1691A and prothrombin G20210A mutations, TT677 genotype of the methylenetetrahydrofolate reductase (MTHFR), protein C, protein S, antithrombin deficiencies) in a population of children with ALL treated according to the FRALLE 2000 study Protocol (High Risk and Standard Risk groups). The study was performed in 5 French Centers including Amiens, Angers, Paris Trousseau, Rouen and Saint-Etienne. From December 2000 to March 2006, 354 children aged 1 to 18 years old were consecutively admitted for ALL and were enrolled in the FRALLE 2000 Protocol. Among them, 281 patients were investigated for hereditary prothrombotic defects at the time of ALL diagnosis. Informed parental consent was required for gene analysis. Abnormal test results for protein S (functional activity and free protein S antigen concentration), protein C and antithrombin were controlled on a second blood sample after induction. In the population studied, the prevalence of one established prothrombotic risk factor was 19,2%: the FV G1691A mutation was diagnosed in 10 patients (3.6%), all heterozygous, 10 patients (3.6%) showed the heterozygous prothrombin G20210A mutation, the TT677 MTHFR genotype was found in 34 children (12.7%), 1 patient showed protein C deficiency (0.4%). No antithrombin deficiency was detected. The prevalence of inherited protein S deficiency could not be evaluated because of missing data in the family medical history. Combined prothrombotic defects were found in 2 patients (0.71%): heterozygous FV G1691A mutation combined with heterozygous prothrombin G20210A mutation in 1 patient and combined with TT677 MTHFR genotype in the second patient. Except for TT677 MTHFR genotype, the prevalence of hereditary prothrombotic risk factors in children with ALL in France were found within the prevalence reported for children treated for ALL (table 1) and comparable to the prevalence in healthy Europeans (Junker et al. 1999, Margaglione et al 2001, Mueller et al. 2005). Comparison of the prevalence of inherited prothrombotic risk factors in children with ALL Country Population FV G1691A +/− ++ PT G20210A +/− +/+ MTHFR TT677 AT PC AT: antithrombin deficiency ; PC: protein C deficiency ; NE : non evaluated NowakGöttl et al 1999 (n=301) Germany ALL children 5.3% 0.3% 2% 0% 7.7% 0.7% 2.3% Mauz-Körholz et al. 2000 (n=108) Germany ALL children 5.6% 0% 2.8% 0% 5.6% 0% 2.7% Mitchell et al. 2002 (n=60) Canada ALL children 3.3% 0% 2% 0% NE NE NE Present study (n=281) France ALL children 3.6% 0% (n=277) 3.6% 0%(n=279) 2.7% (n=268) 0% 0.4%

This retrospective study was designed to determine the prevalence of inherited prothrombotic risk factors (Factor V Leiden (FV) G1691A and prothrombin G20210A mutations, TT677 genotype of the methylenetetrahydrofolate reductase (MTHFR), protein C, protein S, antithrombin deficiencies) in a population of children with ALL treated according to the FRALLE 2000 study Protocol (High Risk and Standard Risk groups). The study was performed in 5 French Centers including Amiens, Angers, Paris Trousseau, Rouen and Saint-Etienne. From December 2000 to March 2006, 354 children aged 1 to 18 years old were consecutively admitted for ALL and were enrolled in the FRALLE 2000 Protocol. Among them, 281 patients were investigated for hereditary prothrombotic defects at the time of ALL diagnosis. Informed parental consent was required for gene analysis. Abnormal test results for protein S (functional activity and free protein S antigen concentration), protein C and antithrombin were controlled on a second blood sample after induction. In the population studied, the prevalence of one established prothrombotic risk factor was 19,2%: the FV G1691A mutation was diagnosed in 10 patients (3.6%), all heterozygous, 10 patients (3.6%) showed the heterozygous prothrombin G20210A mutation, the TT677 MTHFR genotype was found in 34 children (12.7%), 1 patient showed protein C deficiency (0.4%). No antithrombin deficiency was detected. The prevalence of inherited protein S deficiency could not be evaluated because of missing data in the family medical history. Combined prothrombotic defects were found in 2 patients (0.71%): heterozygous FV G1691A mutation combined with heterozygous prothrombin G20210A mutation in 1 patient and combined with TT677 MTHFR genotype in the second patient. Except for TT677 MTHFR genotype, the prevalence of hereditary prothrombotic risk factors in children with ALL in France were found within the prevalence reported for children treated for ALL (table 1) and comparable to the prevalence in healthy Europeans (Junker et al. 1999, Margaglione et al 2001, Mueller et al. 2005).

From January 2000 to July 2006, 580 BCR-ABL negative patients with HR/VHR-ALL (200 T-ALL and 380 BCP-ALL (age≥10 or WBC≥50 or CNS+ or MLL-R) were included in the FRALLE 2000-BT trials. Induction regimen is prednisone (PRED) prephase + IT MTX, VCR, L-Aspa, DNR 120mg/m2 cumulated dose or DNR 160mg/m2 + cyclophosphamide 1g/m2 (T-ALL and D21 M2M3 marrow or MLL-R BCP-ALL). MRD at EOI is quantitatively determined by DNA-based PCR for Ig/TCR rearrangements either competitive PCR with GeneScan analysis or RQ-PCR with clone specific primers (sensitivity ranges 0.5×10−3–10−3, and 10−3–10−5, respectively). MRD status at EOI are available for 425 out of 552 CR (77%). MRD results are reported as negative, positive <10−3, highly positive (10−3≤MRD<10−2), very highly positive (≥10−2). Patients with EOI MRD ≥10−2were to receive an intensified treatment.

Diamond Blackfan anaemia (DBA) is a rare disorder characterised by pure red cell aplasia and inconstant congenital abnormalities. Few data are available concerning pregnancy in DBA affected women. We report on 60 women (age>18 yr) included in the French and German DBA registries. Among them, 26/60 experienced one or several pregnancies. Mean age at 1st pregnancy was 24 yr and the mean number of pregnancies by woman was 2.5. A total of 64 pregnancies occurred, 22 being normal and 42 being complicated (66%). Eight women experienced only normal pregnancies and 18 experienced at least one complicated pregnancy. Complications included abortions: 26 of which 24 were spontaneous, in utero foetal deaths:5, foetal malformations:7, intrauterine growth retardation:10, pre-term deliveries:7, gestational diabetes:2, pre-eclampsia:5 and retro-placental haematomas:3 (more than 1 complication occurred in some pregnancies). A pathological examination of the placenta was performed in 4 cases and demonstrated significant infarctions in 3. As a result of those 64 pregnancies, only 34 children were born alive (53%) from whom 14 were DBA-affected (41%). All women survived. In most cases, treatment with transfusion or steroid was increased during pregnancy. When complicated and normal pregnancies were compared, no obvious correlation between the outcome of the pregnancy and clinical or biological features of maternal DBA, mother treatment, genetic status (RPS19 gene mutation present or not) or the status of the child were found. This suggests that at least some complications may be related to the affected mothers, irrespective of the DBA status of their offspring. Actually, many of these complications are similar to those observed in pregnancies associated with vascular-placental disease. Among the 34 women who did not present any pregnancy, 20 did not desire children for various reasons, 4 had a follow-up for infertility and 10 had severe polymorbidity. Infertility was likely to be treatment related (iron overload or bone marrow graft side effects). From this study together with the literature data, we conclude that pregnancies in DBA affected women must be managed as high-risk pregnancies. Such pregnancies should therefore be carefully monitored with a satisfying control of anaemia, preferably with transfusions, and ultrasound and Doppler follow-up. Early introduction of aspirin, should be discussed especially when a woman experienced a previous complicated pregnancy. An international prospective follow-up of pregnancies in DBA is now required in order to confirm the association with placenta-vascular disease features and to improve the outcome of pregnancy in women with DBA