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Resume La reconnaissance des differentes anomalies cytologiques leucocytaires presentes sur les etalements de sang peripherique au cours des maladies de surcharge lysosomale, telles que les mucopolysaccharidoses (MPS) est une premiere etape pour l’orientation diagnostique de ces maladies. Ces pathologies sont heterogenes, caracterisees par une accumulation de substrats specifiques non degrades dans les lysosomes induisant une surcharge et l’apparition de diverses anomalies leucocytaires. Les lymphocytes vacuoles sont une des anomalies majeures et sont presents dans plusieurs maladies. Le nombre, la taille des vacuoles et leur association a d’eventuelles autres anomalies des leucocytes permet de suspecter une maladie de surcharge lysosomale.

Resume La recherche de cellules evocatrices de maladie de surcharge lysosomale dans le sang requiert une prise en charge pre-analytique, analytique, et post-analytique optimale. Un examen minutieux du frottis sanguin colore au May Grunwald Giemsa (MGG) au microscope est necessaire. L’association avec une technique de leucoconcentration permet d’en augmenter la sensibilite. En cas de depistage positif, des colorations cytochimiques peuvent permettre d’en preciser la nature. L’indication des modalites d’analyse cytologique, du nombre de cellules a observer et du seuil retenu pour affirmer la positivite sont indiques. Une mention concernant le parcours d’habilitation du lecteur est precisee. Enfin le contenu du compte-rendu d’analyse de cette recherche est developpe.

The aim of this study was to (1) analyze blood viscosity, red blood cell (RBC) deformability, and aggregation in hospitalized patients with Coronavirus disease 19 (COVID-19); (2) test the associations between impaired blood rheology and blood coagulation; and (3) test the associations between impaired blood rheology and several indicators of clinical severity. A total of 172 patients with COVID-19, hospitalized in COVID-unit of the Internal Medicine Department (Lyon, France) participated in this study between January and May 2021. Clinical parameters were collected for each patient. Routine hematological/biochemical parameters, blood viscosity, RBC deformability and aggregation, and RBC senescence markers were measured on the first day of hospitalization. A control group of 38 healthy individuals was constituted to compare the blood rheological and RBC profile. Rotational thromboelastography was performed in 76 patients to study clot formation dynamics. Our study demonstrated that patients with COVID-19 had increased blood viscosity despite lower hematocrit than healthy individuals, as well as increased RBC aggregation. In-vitro experiments demonstrated a strong contribution of plasma fibrinogen in this RBC hyper-aggregation. RBC aggregation correlated positively with clot firmness, negatively with clot formation time, and positively with the length of hospitalization. Patients with oxygen supplementation had higher RBC aggregation and blood viscosity than those without, and patients with pulmonary lesions had higher RBC aggregation and enhanced coagulation than those without. This study is the first to demonstrate blood hyper-viscosity and RBC hyper-aggregation in a large cohort of patients with COVID-19 and describe associations with enhanced coagulation and clinical outcomes.

Outcomes in childhood T-cell acute lymphoblastic leukaemia (T-ALL) are steadily improving due to intensive therapy. Between 1989 and 2008, 599 children with newly diagnosed T-ALL were enrolled in two successive European Organization for Research and Treatment of Cancer - Children's Leukaemia Group trials (58881 and 58951), both based on the Berlin-Frankfurt-Munster protocol and without cranial irradiation. In the latter trial induction chemotherapy was intensified. The most important randomizations were Medac Escherichia coli asparaginase versus Erwinia asparaginase in trial 58881, and dexamethasone (6 mg/m2/day) versus prednisolone (60 mg/m2/day) and prolonged versus conventional asparaginase duration in trial 58951. 8-year event-free survival (EFS) increased from 65·1% to 74·0% in trial 58951. Improvement was most profound for patients with white blood cell (WBC) counts, SCOPUS: ar.j, info:eu-repo/semantics/published

Resume L’interpretation medicale d’un hemogramme necessite un respect des exigences pre-analytiques et une maitrise par le biologiste et le technicien de laboratoire des differentes technologies analytiques a sa disposition ainsi qu’une veille bibliographique reguliere. Des problemes pre-analytiques, interferences ou limites technologiques peuvent conduire a des resultats bruts errones et a une mauvaise interpretation de l’hemogramme. Cet article presente differents pieges a eviter pour l’analyse des parametres erythrocytaires selon notre experience avec les analyseurs d’hematologie de la serie XN (Sysmex).

The Action-sentence Compatibility Effect (ACE) is a well-known demonstration of the role of motor activity in the comprehension of language. Participants are asked to make sensibility judgments on sentences by producing movements toward the body or away from the body. The ACE is the finding that movements are faster when the direction of the movement (e.g., toward) matches the direction of the action in the to-be-judged sentence (e.g., Art gave you the pen describes action toward you). We report on a pre-registered, multi-lab replication of one version of the ACE. The results show that none of the 18 labs involved in the study observed a reliable ACE, and that the meta-analytic estimate of the size of the ACE was essentially zero. ispartof: Psychonomic Bulletin & Review vol:29 issue:2 pages:613-626 ispartof: location:United States status: published

Dans un ouvrage associant la revision et l’entrainement, tous les outils pour formuler ses idees de facon claire et efficace. Un ouvrage specialement concu pour les etudiants et les adultes souhaitant ameliorer leurs ecrits universitaires ou professionnels. Un ouvrage en 2 parties • 1. Les strategies de la communication ecrite : pour produire des ecrits efficaces (mails, lettres de candidature, comptes rendus, syntheses, supports de presentation…) • 2. Les techniques de redaction : pour ecrire sans fautes, de maniere claire et fluide Un ouvrage efficace • Chaque theme est traite en doubles pages : – a gauche, des explications claires et methodiques – a droite, des exercices progressifs, de reperage et d’expression • A intervalles reguliers, des exercices de bilan approfondis • En annexe, des memos visuels et les corriges de tous les exercices Sur le site moncoach.bescherelle.com Grâce a l’achat du livre, deux semaines d’entrainement gratuit sur l’application Mon coach Bescherelle.

CONTEXT Acute myeloid leukemia (AML) is a rare disease in children, with only 50% to 60% event-free survival. Among patients with AML, 10% do not respond to first-line chemotherapy. There is no recommendation concerning second-line treatments. Gemtuzumab ozogamicin (GO) is a monoclonal antibody targeting CD33, linked to calicheamicin. We report the efficacy and tolerance of a salvage regimen of fludarabin, cytarabine, and GO (FLA-GO) in patients refractory to first-line treatment. METHODS Eight patients (median age 14.5 years), who had more than 2% minimal residual disease (MRD) by flow cytometry (MRD flow), received gemtuzumab 3 mg/m² on days 1, 4, 7, associated with cytarabine 2000 mg/m² and fludarabin 30 mg/m² on days 1 to 5. RESULTS Six patients achieved complete remission (CR) (blast count morphology ≤5 × 10-2 , CR-MRD flow

BackgroundMalaria is a potentially severe disease affecting nearly 200 million people per year. Early detection of the parasite even in unsuspected patients remains the challenging aim for effective patient care. Automated complete blood counts that are usually performed for any febrile patient might represent a tool to ascertain malaria infection.AimsTo evaluate the ability of the new generation of the Sysmex hematology analyzer (XN-series) to detect malaria.MethodsWe retrospectively studied 100 blood samples performed with the recent Sysmex XN analyzer that were positive forPlasmodiumand explored its ability to detect the parasite. 100 samples from patients uninfected by malaria were used as control group.ResultsSpecific abnormalities such as additional events in the mature neutrophil/eosinophil area of the white blood cells differential (WDF) scattergram were noted for 1.1% ofPlasmodium falciparumsamples and 56.2% of otherPlasmodiumspecies samples. Mature parasite stages (schizonts or gametocytes) were observed on blood smears among those samples. WDF scattergrams were able to detect 80.0% (12/15) ofPlasmodiummature stages. Furthermore, the differential in white blood counts between WDF and white cell nucleated (WNR) channels was a predictive signal ofPlasmodiummature stages in 73.3% (11/15) of samples and may be explained by a differential destruction of particles with the analyzer reagent.ConclusionAssociated to thrombocytopaenia, a Sysmex XNPlasmodiumpattern may represent a useful warning forPlasmodiumdetection in unsuspected patients, particularly when mature parasite stages are present.

Early linguistic experiences are intimately tied to later language learning outcomes (e.g., Chilosi et al., 2013; Kaushanskaya & Marian, 2009b). The underlying neural and cognitive processes mediating this relationship remain unclear. Pierce, Genesee, Delcenserie, and Morgan (2017) propose that the phonological working memory (PWM) system is the critical component responsible for linking early linguistic experiences to later language development. Their argument arises from research demonstrating that exposure to linguistic input early in life shapes the kinds of phonological representations that are formed about the sounds within one's native language (Kuhl, 2004; Majerus et al., 2005; Mody, Schwartz, Gravel, & Ruben, 1999; Nittrouer & Burton, 2005). These phonological representations, which the authors believe to be created and stored using the PWM system (Gathercole & Baddeley, 1989), are highly predictive of later language outcomes (Bernhardt, Kemp, & Werker, 2007; Kuhl, 2010; Molfese & Molfese, 1985; Tsao, Liu, & Kuhl, 2004). Explaining language development via memory processes has many benefits. For instance, drawing on a large extant literature on memory-related processes allows researchers to make novel predictions about language learning, especially in regard to its connections to other kinds of learning (e.g., Gathercole, 2006). Identifying PWM as a key driver to language development is a useful insight likely to generate much further research, but it may not go far enough in tying language acquisition to more domain-general aspects of the human cognitive architecture. We believe that a complete account of language will require consideration of additional aspects of the human cognitive architecture working alongside the PWM system.

Cytological identification of blasts in cerebrospinal fluid in acute leukemia, lymphoid or myeloid, in adult and child, at diagnosis or during follow up lead to the diagnosis of leukemic meningitidis. Suitable CNS therapy based on a defined "CNS status" following an international standardized classification, lead to decrease cerebrospinal relapses. Established in 1993, this classification allows to treat patients based on their CNS status. Based on the red blood cells count, nucleated cells count and presence of blasts, it requires a standard technical procedure that guarantees the comparability of results coming from different medical laboratory. To improve the quality of cerebrospinal fluid analysis, in acute leukemias, preanalytical guidelines (turn around time), analytical guidelines (cytocentrifugation, adding serum protein, speed and duration of cytocentrifugation) and postanalytical guidelines (duration of conservation) are set by the Groupe francophone d'hématologie cellulaire.

Pneumatic tube system (PTS) in hospitals is commonly used for the transport of blood samples to clinical laboratories, as it is rapid and cost-effective. The aim was to compare the effects on haematology samples of a newly acquired ~2km-long PTS that links 2 hospitals with usual transport (non-pneumatic tube system, NPTS).Complete blood cell count, routine coagulation assays, platelet function tests (PFT) with light-transmission aggregometry and global coagulation assays including ROTEM® and thrombin generation assay (TGA) were performed on blood samples from 30 healthy volunteers and 9 healthy volunteers who agreed to take aspirin prior to blood sampling.The turnaround time was reduced by 31% (p0.001) with the use of PTS. No statistically significant difference was observed for most routine haematology assays including PFT, and ROTEM® analysis. A statistically significant, but not clinically relevant, shortening of the APTT after sample transport by PTS was found (mean±SD: 30s±1.8 vs. 29.5s±2.1 for NPTS). D-dimer levels were 7.4% higher after transport through PTS but were not discordant. A statistically significant increase of thrombin generation was found in both platelet poor- and platelet rich- plasma samples after PTS transport compared to NPTS transport.PTS is suitable for the transport of samples prior to routine haematology assays including PFT, but should not be used for samples intended for thrombin generation measurement.

AimThe aim was to assess the flagging performance of Sysmex XN-10 haematology analyser for malaria detection through the parasitic red blood cell (‘pRBC’) alarm.MethodsWe retrospectively studied 584 blood samples performed on the Sysmex XN-10 analyser that were tested for malaria. Sensitivity, specificity, positive and negative predictive values, and prevalence were established for the pRBC alarm.ResultsSensitivity, specificity, and positive and negative predictive values for the pRBC flag were 7.8%, 100%, 100% and 87.7%, respectively. The prevalence of pRBC flag of 0.026% in the overall population was significantly different from the prevalence of 1.027% in the population tested for malaria.ConclusionsConsidering the excellent specificity and the low prevalence of the flag in the overall population, we suggest, in case of the presence of pRBC flag, the implementation of a rapid review of the blood smear looking for Plasmodium, mostly if the patient had fever and had not been tested for malaria.

Infants and children are generally more successful than adults in learning novel languages, a phenomenon referred to as a critical or sensitive period for language acquisition. One explanation for this critical period is the idea that children have access to a set of language learning processes or mechanisms unavailable to adults. From this perspective, developmental change is explained in terms of a discontinuity of learning processes. We suggest that this is not the only possible explanation for developmental change in language learning outcomes. Instead, we propose that the mechanisms underlying language acquisition (in particular, we highlight statistical learning) are largely continuous across the lifespan. From this perspective, developmental change is explained in terms of experience, differences in the input with age, and maturational changes in the cognitive architecture supporting learning, even while the learning process itself operates continuously across developmental time. WIREs Cogn Sci 2016, 7:276-288. doi: 10.1002/wcs.1394 For further resources related to this article, please visit the WIREs website.

Differential impact of drugs on the outcome of ETV6-RUNX1 positive childhood B-cell precursor acute lymphoblastic leukaemia: results of the EORTC CLG 58881 and 58951 trials

Malaria is a potentially severe disease affecting nearly 200 million people per year. Early detection of the parasite even in unsuspected patients remains the challenging aim for effective patient care. Automated complete blood counts that are usually performed for any febrile patient might represent a tool to ascertain malaria infection.To evaluate the ability of the new generation of the Sysmex hematology analyzer (XN-series) to detect malaria.We retrospectively studied 100 blood samples performed with the recent Sysmex XN analyzer that were positive forSpecific abnormalities such as additional events in the mature neutrophil/eosinophil area of the white blood cells differential (WDF) scattergram were noted for 1.1% ofAssociated to thrombocytopaenia, a Sysmex XN

Dexamethasone could be more effective than prednisolone at similar anti-inflammatory doses in the treatment of childhood acute lymphoblastic leukemia. In order to check if this "superiority" of dexamethasone might be dose-dependent, we conducted a randomized phase III trial comparing dexamethasone (6 mg/m(2)/day) to prednisolone (60 mg/m(2)/day) in induction therapy. All newly diagnosed children and adolescents with acute lymphoblastic leukemia in the 58951 EORTC trial were randomized on prephase day 1 or day 8. The main endpoint was event-free survival; secondary endpoints were overall survival and toxicity. A total of 1947 patients with acute lymphoblastic leukemia were randomized. At a median follow-up of 6.9 years, the 8-year event-free survival rate was 81.5% in the dexamethasone arm and 81.2% in the prednisolone arm; the 8-year overall survival rates were 87.2% and 89.0% respectively. The 8-year incidences of isolated or combined central nervous system relapse were 2.9% and 4.5% in the dexamethasone and prednisolone arms, respectively. The incidence of grade 3-4 toxicities during induction and the frequency of osteonecrosis were similar in the two arms. In conclusion, dexamethasone and prednisolone, used respectively at the doses of 6 and 60 mg/m(2)/day during induction, were equally effective and had a similar toxicity profile. Dexamethasone decreased the 8-year central nervous system relapse incidence by 1.6%. This trial was registered at www.clinicaltrials.gov as #NCT00003728.

The aim of our study was to analyze the factors contributing to heterogeneity of prognosis in patients with hyperdiploidy50 chromosomes (HD50), a group of B-cell precursor acute lymphoblastic leukemia with favorable outcome. The 541 HD50 patients registered prospectively in the 58951 European Organisation for Research and Treatment of Cancer (EORTC) Children's Leukemia Group (CLG) trial, identified by karyotype (446 patients) and by DNA index (DI) (490 patients), had a 6-year event-free survival (EFS) of 89.0% (standard error [SE] = 1.5%) and a 6-year overall survival (OS) of 95.9% (SE = 0.9%). The strongest prognostic factor was the modal number of chromosomes (MNC): the 6-year EFS of 51-53, 54-57, and 58-66 MNC groups were 80%, 89%, and 99%, respectively (P.0001). Ploidy assessed by DI was also a favorable factor: the higher the DI, the better the outcome. The 6-year EFS of the 3 subgroups of DI1.16/≥1.16-1.24/≥1.24 were 83%, 90%, and 95%, respectively (P = .009). All usual combinations of trisomies (chromosomes 4, 10, 17, 18) were significant favorable factors but had lower EFS when MNC was lower than 58. In multivariate analysis, MNC remained the strongest factor. Consequently, the best indicator for excellent outcome was ploidy assessed by karyotype because patients with 58-66 chromosomes stood every chance of being cured (OS of 100% at 6-year follow-up) with less-intensive therapy. This trial was registered at www.clinicaltrials.gov as #NCT00003728. Registered: http://www.eortc.org/, http://clinicaltrials.gov/show/NCT00003728.

In children, lymphoblastic lymphomas represent 30% of Non-Hodgkin lymphomas (NHL), and approximately 15% are precursor B-cell lymphomas (PBLL). Our study evaluated their main clinical characteristics, evolution, and prognosis in three trials. From 1989 to 2008, 53 children with PBLL (median age 7·75 years) were included in three protocols: Malignant Lymphoma Therapy (LMT) 96, European Organization for Research and Treatment of Cancer (EORTC) 58881, and EORTC 58951 using Berlin-Frankfurt-Munster-derived acute lymphoblastic leukaemia (ALL) therapy. There were 10 stage I disease, 9 stage II, 9 stage III and 25 stage IV. Clinical presentation was heterogeneous with a majority of bone lesions and cutaneous or subcutaneous manifestations. At diagnosis 23 patients had bone marrow involvement, and only three had central nervous system involvement. The median follow-up was 74 months. At last follow-up, 45 patients were in continuous complete remission, whereas eight had progressed or had relapsed (7 Stages IV and 1 Stage III) and died. Two patients had a secondary neoplasia, and are still alive. Disease stage was a major prognostic factor, with better overall survival (OS) and event-free survival (EFS) (P < 0·05) rates observed in patients with Stage I to III as compared to those with Stage IV. Treatment with protocols derived from ALL therapy are efficient with an 82% EFS and an 85% OS at 5 years.

Risk-adjusted treatment stratification in T-cell acute lymphoblastic leukemias (T-ALLs) is currently based only on early response to chemotherapy. We investigated the prognostic implication of hyperactivation of NOTCH pathway resulting from mutations of NOTCH1 or FBXW7 in children with T-ALL enrolled in EORTC-CLG trials. Overall, 80 out of 134 (60%) patients were NOTCH+ (NOTCH1 and/or FBXW7 mutated). Although clinical presentations were not significantly associated with NOTCH status, NOTCH+ patients showed a better early response to chemotherapy as compared with NOTCH- patients, according to the rate of poor pre-phase 'responders' (25% versus 44%; P=0.02) and the incidence of high minimal residual disease (MRD) levels (11% (7/62) versus 32% (10/31); P=0.01) at completion of induction. However, the outcome of NOTCH+ patients was similar to that of NOTCH- patients, with a 5-year event-free survival (EFS) of 73% and 70% (P=0.82), and 5-year overall survival of 82% and 79% (P=0.62), respectively. In patients with high MRD levels, the 5-year EFS rate was 0% (NOTCH+) versus 42% (NOTCH-), whereas in those with low MRD levels, the outcome was similar: 76% (NOTCH+) versus 78% (NOTCH-). The incidence of isolated central nervous system (CNS) relapses was relatively high in NOTCH1+ patients (8.3%), which could be related to a higher propensity of NOTCH+ leukemic blasts to target the CNS.

Granulocytic sarcoma (GS) is a rare extramedullary tumor frequently associated with acute myeloblastic leukemia (AML). We report 3 cases of pediatric granulocytic sarcomas with various locations: skin, orbit, and bowel. Cases 1 and 2 were associated with AML; case 3 was isolated. In all 3 cases, the diagnosis was delayed or initially missed. Pathology and immunohistochemistry data identified the disease. GS is treated with chemotherapy, like AML. The prognosis of GS seems better than that of isolated AML.

Infants and children are generally more successful than adults in learning novel languages, a phenomenon referred to as a critical or sensitive period for language acquisition. One explanation for this critical period is the idea that children have access to a set of language learning processes or mechanisms unavailable to adults. From this perspective, developmental change is explained in terms of a discontinuity of learning processes. We suggest that this is not the only possible explanation for developmental change in language learning outcomes. Instead, we propose that the mechanisms underlying language acquisition (in particular, we highlight statistical learning) are largely continuous across the lifespan. From this perspective, developmental change is explained in terms of experience, differences in the input with age, and maturational changes in the cognitive architecture supporting learning, even while the learning process itself operates continuously across developmental time. WIREs Cogn Sci 2016, 7:276-288. doi: 10.1002/wcs.1394 For further resources related to this article, please visit the WIREs website.

The kinetics of nicotine degradation in a cell suspension culture of Nicotiana plumbaginifolia has been examined. It is shown by GC and chiral HPLC that when (R,S)-nicotine is presented, (R)-nicotine is more rapidly degraded than the natural isomer, (S)-nicotine. Conversely, (R)-nornicotine accumulates in the culture medium to a greater extent than (S)-nornicotine, indicating that the latter undergoes more rapid further metabolism to unidentified products. The demethylation of the analogue of nicotine, (R,S)-1-methyl-2-phenylpyrrolidine, was found to be competitive with the demethylation of (R,S)-nicotine.

A short and efficient synthesis of unnatural (R)-nicotine is described, in which the key step is an intramolecular hydroboration–cycloalkylation of an azido-olefin intermediate. The synthesis is achieved in only four steps, with an overall yield of 51% (or in six steps with an overall yield of 65%).

Auteur(s) : Sandrine Girard1, Corinne Pondarre2, Jean-Marie Andre2, Marie-Pierre Pages3, Yves Bertrand2 1Laboratoire d’hematologie, et CRPP de Lyon, Hopital Edouard-Herriot, Lyon 2Service d’hematologie pediatrique, Institut d’hematologie et d’oncologie pediatrique, Lyon 3Laboratoire de cytogenetique hematologique, Centre hospitalier Lyon-Sud, Lyon Les thrombopenies constitutionnelles constituent un ensemble de maladies rares, souvent meconnues et diagnostiquees a [...]

Oncogenic subtypes in childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL) are used for risk stratification. However, a significant number of BCP-ALL patients are still genetically unassigned. Using array-comparative genomic hybridization in a selected BCP-ALL cohort, we characterized a recurrent V(D)J-mediated intragenic deletion of the ERG gene (ERG(del)). A breakpoint-specific PCR assay was designed and used to screen an independent non-selected cohort of 897 children aged 1-17 years treated for BCP-ALL in the EORTC-CLG 58951 trial. ERG(del) was found in 29/897 patients (3.2%) and was mutually exclusive of known classifying genetic lesions, suggesting that it characterized a distinct leukemia entity. ERG(del) was associated with higher age (median 7.0 vs. 4.0 years, P=0.004), aberrant CD2 expression (43.5% vs. 3.7%, P

Background In childhood BCP-ALL, the presence of t(12;21)/ETV6 -RUNX1 defines one of the most prevalent oncogenic subgroup and is usually associated with a favorable outcome. Nevertheless, an excellent prognosis has not been reported by all collaborative groups, suggesting that the outcome of ETV6 -RUNX1 patients (pts) could be influenced by the treatment. To address this issue, the long-term outcome of ETV6 -RUNX1 pts was investigated into the EORTC 58881 and 58951 studies, with particular attention to the effect of the randomized treatments. Methods The 58881 study (1989-1998) used a BFM backbone without cranial irradiation, and aimed to compare E-Coli (Medac®) Asparaginase (A'ase) with Erwinia A'ase and to assess the value of 6-Mercaptopurine (6-MP) i.v. (1 g/m²/month) when added to classic maintenance. The subsequent 58951 study (1999-2008) used the best arm of the trial 58881, i.e. E-Coli A'ase and classic maintenance. The aims of this study were to compare dexamethasone (Dexa) (6 mg/m²/day) with prednisone (Pred) (60 mg/m²/day) during induction and maintenance; to evaluate increased number of A'ase administrations (24 vs 12) for non-very high risk pts; and to assess the value of vincristine/corticosteroid pulses during maintenance for average risk pts. Detection of ETV6 -RUNX1 by FISH and/or RT-PCR was centralized. Pts less than 1 year (yr) or with t(9;22)/BCR-ABL were excluded from the analysis. Results An ETV6 -RUNX1 was evidenced in 104/363 (28%) and 380/1493 (27%) newly diagnosed BCP-ALL pts enrolled in the 58881 and 58951 trial respectively. A majority of ETV6-RUNX1 pts were below the age of 10 yrs (93.3% in 58881 and 91.3% in 58951). The median follow-up was 11.8 yrs for the 58881 and 6.7 yrs for the 58951. In both studies, the 10-yr event-free-survival (EFS) rate was significantly higher for ETV6 -RUNX1 pts than for all BCP-ALL pts (82.5% vs 74.9% in 58881 and 90.8% vs 82.7% in 58951), and was similar to the 10-yr EFS of hyperdiploid pts. Noteworthy, very few EFS events were observed during treatment period or after 6 yrs from diagnosis. The main prognostic factors of the ETV6-RUNX1 subgroup in both studies were the white blood cell count (WBC) and the response to prephase. As shown in the table below, the analysis of the relationship between treatment modalities and outcome revealed that the in vivo drug sensitivity of ETV6-RUNX1 ALL was distinct from that of other BCP-ALL. In this subgroup, the benefit of a more potent A'ase (58881) or of intensified A'ase administrations (58951) was less pronounced as compared to other pts, and 6-MP i.v. during maintenance was particularly deleterious. Moreover, the overall benefit of vincristine/corticosteroid pulses was not observed in ETV6-RUNX1 average risk group pts, who already had an outstanding outcome. By contrast, the use of Dexa in place of Pred significantly improved the 10-yr EFS of ETV6-RUNX1 pts (95.0% vs 87.2%, hazard ratio (HR)=0.44, 95% CI 0.20-0.96) whereas no difference was observed in the remaining population (HR=1.01, 95% CI 0.77-1.33) (test for interaction: p=0.04). Table.5888158951All (n=363)ETV6-RUNX1 (n=104)Hyperdiploid (n=102)Others1 (n=155)All (n=1493)ETV6-RUNX1 (n=380)Hyperdiploid (n=484)Others1 (n=619)10-yr EFS ratesAll pts74.9%82.5%83.3%65.2%82.7%90.8%88.4%73.2%Pred ² (n=745)81.8%87.2%88.8%73.0%Dexa ² (n=748)83.6%95.0%88.0%73.5%Medac A'ase 2,3 (n=320)76.6%83.2%88.6%65.7%Other A'ase 2,3 (n=43)62.8%78.6%50.0%60.0%10-yr disease-free-survival ratesShort A'ase 4 (n=607)83.5%91.2%90.1%72.4%Long A'ase 4 (n=622)87.0%94.8%88.2%80.7%No 6-MP iv 2,5 (n=96)85.4%100%90.9%72.5%6-MP iv 2,5 (n=94)72.3%70.6%78.6%68.8%No Pulse 5,6 (n=148)87.5%96.1%88.5%71.1%Pulse 5,6 (n=153)82.8%95.1%91.3%82.3%1Others, MLL rearrangements excluded 2All risk groups 3Pts randomized or not for A'ase 4Non-very high risk pts 5Pts who started maintenance 6Average risk pts Conclusions Within the EORTC 58881 and 58951 trials, the use of Dexa rather than Pred allowed to further improved the long-term outcome for ETV6-RUNX1 pts. Our data also show that this excellent outcome can be jeopardized by slight changes in therapy, such as the addition of 6-MP i.v. to classic maintenance. Together, these results stress the importance of analyzing homogeneous oncogenetic subgroups when comparing different therapeutic schemes, to unmask specific drug effects that could be hidden when analyzing the whole group of patients. Disclosures Bertrand: ERYTECH Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees.

In children, lymphoblastic lymphomas represent 30% of Non-Hodgkin lymphomas (NHL), and approximately 15% are precursor B-cell lymphomas (PBLL). Our study evaluated their main clinical characteristics, evolution, and prognosis in three trials. From 1989 to 2008, 53 children with PBLL (median age 7·75 years) were included in three protocols: Malignant Lymphoma Therapy (LMT) 96, European Organization for Research and Treatment of Cancer (EORTC) 58881, and EORTC 58951 using Berlin-Frankfürt-Münster-derived acute lymphoblastic leukaemia (ALL) therapy. There were 10 stage I disease, 9 stage II, 9 stage III and 25 stage IV. Clinical presentation was heterogeneous with a majority of bone lesions and cutaneous or subcutaneous manifestations. At diagnosis 23 patients had bone marrow involvement, and only three had central nervous system involvement. The median follow-up was 74 months. At last follow-up, 45 patients were in continuous complete remission, whereas eight had progressed or had relapsed (7 Stages IV and 1 Stage III) and died. Two patients had a secondary neoplasia, and are still alive. Disease stage was a major prognostic factor, with better overall survival (OS) and event-free survival (EFS) (P 0·05) rates observed in patients with Stage I to III as compared to those with Stage IV. Treatment with protocols derived from ALL therapy are efficient with an 82% EFS and an 85% OS at 5 years.

The prognostic significance of CD20 expression in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) has been mostly studied in children and yielded conflicting results. In 143 adults with Philadelphia chromosome-negative BCP-ALL treated in the multicentric GRAALL 2003 trial, CD20 positivity over 20% was observed in 32% of patients. While not influencing complete remission achievement, CD20 expression was associated with a higher cumulative incidence of relapse (CIR) at 42 months (P=0.04), independently of the ALL high-risk subset (P=0.025). Notably, the negative impact of CD20 expression on CIR was only observed in patients with a white blood cell count (WBC) over 30x10(9)/L (P=0.006), while not in those with a lower WBC. In the former subgroup, this impact translated into lower event-free survival (15% vs. 59% at 42 months, P=0.003). CD20 expression thus appears to be associated with a worse outcome, which reinforces the interest of evaluating rituximab combined to chemotherapy in CD20-positive adult BCP-ALL. ClinicalTrials.gov ID, NCT00222027.

A teenager was admitted with an iron-deficiency anemia. The gastroscopy found an atrophic body gastritis, which revealed a pernicious anemia. This diagnosis is rare in paediatric patients, the frequency of pernicious anemia increasing with age. Iron-deficiency anemia is mainly described in young people.

The gas-phase basicities (GBs) of nornicotine, nicotine, and model pyrrolidines have been measured by FT-ICR. These experimental GBs are compared with those calculated (for the two sites of protonation in the case of nicotine and nornicotine) at the B3LYP/6-311+G(3df,2p)//B3LYP/6-31G(d,p) level, or those estimated from substituent effects on the GBs of 2-substituted pyrrolidines, 2-substituted N-methylpyrrolidines, and 3-substituted pyridines. It is found that, in contrast to the Nsp(3) protonation in water, in the gas phase nornicotine is protonated on the pyridine nitrogen, because the effects of an intramolecular CH.Nsp(3) hydrogen bond and of the polarizability of the 3-(pyrrolidin-2-yl) substituent add up on the Nsp(2) basicity, while the polarizability effect of the 2-(3-pyridyl) substituent on the Nsp(3) basicity is canceled by its field/inductive electron-withdrawing effect. The same structural effects operate on the Nsp(3) and Nsp(2) basicities of nicotine, but here, the polarizability effect of the methyl group puts the pyrrolidine nitrogen basicity very close to that of pyridine. Consequently, protonated nicotine is a mixture of the Nsp(3) and Nsp(2) protonated forms.

The conversion of nicotine to nornicotine by Nicotiana plumbaginifolia Viv. cells was investigated by analysing the redistribution of label during feeding experiments with (R,S)-[2H-methyl]nicotine, (R,S)-[13C-methyl]nicotine and (R,S)-[14C-methyl]nicotine, and the results show that the N-methyl group of nicotine can be recycled into primary metabolism. Nuclear magnetic resonance (NMR) analysis of ethanolic extracts of cells grown in the presence of (R,S)-[13C-methyl]nicotine, using 1H-13C correlation spectroscopy (HMQC, HMBC), revealed the presence of [3-13C]serine and [13C-methyl]methionine. Label was also identified in a cysteinyl derivative and in several methoxylated compounds, but no evidence was obtained with either NMR or ion-trap mass spectrometry for the presence of any intermediate between nicotine and nornicotine. However, experiments with (R,S)-[14C-methyl]nicotine indicated that 70–75% of the metabolised label was released as carbon dioxide. These results are consistent with a pathway in which the oxidative hydrolysis of the nicotine methyl produces an unstable intermediate, N ′-hydroxymethylnornicotine, that breaks down spontaneously to nornicotine and formaldehyde, with the formaldehyde being metabolised either directly to formate and carbon dioxide, or through the tetrahydrofolate-mediated pathways of one-carbon metabolism. However since the key intermediate, N-hydroxymethylnornicotine, could not be detected, the possibility of a direct methyl group transfer to tetrahydrofolate cannot be excluded.

An enantiomeric synthesis of six piperidine and pyrrolidine alkaloids, (S)-nornicotine 1, (S)-nicotine 2, (S)-anatabine 3, (S)-N-methylanatabine 4, (S)-anabasine 5, and (S)-N-methylanabasine 6, known as natural products in tobacco, was established from a common chiral homoallylic (S)-3-(1-azido-but-3-enyl)-pyridine 15. An intramolecular hydroboration-cycloalkylation of the homoallylic azide intermediate 15 served as the key step in the pyrrolidine ring formation. A ring closing metathesis reaction (RCM) of a diethylenic amine intermediate (S)-allyl-(1-pyridin-3-yl-but-3-enyl)-carbamic acid benzyl ester 20 served as the key step in the piperidine ring formation. From the commercially available 3-pyridinecarboxaldehyde 13, a short and convenient enantiomeric synthesis of tobacco alkaloids is described: (S)-nornicotine 1 (5 steps, with an overall yield of 70%), (S)-nicotine 2 (6 steps, 65%), (S)-anatabine 3 (8 steps, 30%), (S)-N-methylanatabine 4 (8 steps, 25%), (S)-anabasine 5 (8 steps, 35%), and (S)-N-methylanabasine 6 (8 steps, 25%).