Publications by authors named "Marion Strullu"

24 Publications

  • Page 1 of 1

Allergies, genetic polymorphisms of Th2 interleukins, and childhood acute lymphoblastic leukemia: The ESTELLE study.

Pediatr Blood Cancer 2021 Oct 18:e29402. Epub 2021 Oct 18.

CRESS, Université de Paris INSERM, UMR 1153, Epidemiology of Childhood and Adolescent Cancers Team, Villejuif, France.

Context: A negative association between a history of allergy and childhood acute lymphoblastic leukemia (ALL) has been reported in previous studies, but remains debated. This work aimed to investigate this association accounting for genetic polymorphisms of the Th2 pathway cytokines (IL4, IL10, IL13, and IL4R).

Methods: Analyses were based on the French case-control study ESTELLE (2010-2011). The complete sample included 629 ALL cases and 1421 population-based controls frequency-matched on age and gender. The child's medical history was collected through standardized maternal interview. Biological samples were collected, and genotyping data were available for 411 cases and 704 controls of European origin. Odds ratios (OR) were estimated using unconditional regression models adjusted for potential confounders.

Results: In the complete sample, a significant inverse association was observed between ALL and reported history of allergic rhinitis or sinusitis (OR = 0.65 [0.42-0.98]; P = 0.04), but there was no obvious association with allergies overall. There was an interaction between genetic polymorphisms in IL4 and IL4R (P 0.003), as well as a gene-environment interaction between IL4R-rs1801275 and a reported history of asthma (IOR = 0.23; P = 0.008) and eczema (IOR = 0.47; P = 0.06). We observed no interaction with the candidate polymorphisms in IL4 and IL13.

Conclusion: These results suggest that the association between allergic symptoms and childhood ALL could be modified by IL4R-rs1801275, and that this variant could also interact with a functional variant in IL4 gene. Although they warrant confirmation, these results could help understand the pathological mechanisms under the reported inverse association between allergy and childhood ALL.
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http://dx.doi.org/10.1002/pbc.29402DOI Listing
October 2021

COVID19 and acute lymphoblastic leukemias of children and adolescents: Updated recommendations (Version 2) of the Leukemia Committee of the French Society for the fight against Cancers and leukemias in children and adolescents (SFCE).

Bull Cancer 2021 May 11;108(5):490-500. Epub 2021 Mar 11.

Université de Paris, service d'hémato-immunologie pédiatrique, hôpital universitaire Robert-Debré (APHP), boulevard Sérurier, 75019 Paris, France. Electronic address:

Since the emergence of the SARS-CoV-2 infection, many recommendations have been made. However, the very specific nature of acute lymphoblastic leukemias and their treatment in children and adolescents led the Leukemia Committee of the French Society for the fight against Cancers and leukemias in children and adolescents (SFCE) to propose more specific recommendations. Here is the second version of these recommendations updated according to the evolution of knowledge on COVID19.
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http://dx.doi.org/10.1016/j.bulcan.2021.02.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7951944PMC
May 2021

Impact of COVID-19 in paediatric early-phase cancer clinical trials in Europe: A report from the Innovative Therapies for Children with Cancer (ITCC) consortium.

Eur J Cancer 2020 12 9;141:82-91. Epub 2020 Oct 9.

Center for Child Health Research, Tampere University and Department of Pediatrics, Tampere University Hospital, Tampere, Finland, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.

Introduction: Data regarding real-world impact on cancer clinical research during COVID-19 are scarce. We analysed the impact of the COVID-19 pandemic on the conduct of paediatric cancer phase I-II trials in Europe through the experience of the Innovative Therapies for Children with Cancer (ITCC).

Methods: A survey was sent to all ITCC-accredited early-phase clinical trial hospitals including questions about impact on staff activities, recruitment, patient care, supply of investigational products and legal aspects, between 1st March and 30th April 2020.

Results: Thirty-one of 53 hospitals from 12 countries participated. Challenges reported included staff constraints (30% drop), reduction in planned monitoring activity (67% drop of site initiation visits and 64% of monitoring visits) and patient recruitment (61% drop compared with that in 2019). The percentage of phase I, phase II trials and molecular platforms closing to recruitment in at least one site was 48.5%, 61.3% and 64.3%, respectively. In addition, 26% of sites had restrictions on performing trial assessments because of local contingency plans. Almost half of the units suffered impact upon pending contracts. Most hospitals (65%) are planning on improving organisational and structural changes.

Conclusion: The study reveals a profound disruption of paediatric cancer early-phase clinical research due to the COVID-19 pandemic across Europe. Reported difficulties affected both patient care and monitoring activity. Efforts should be made to reallocate resources to avoid lost opportunities for patients and to allow the continued advancement of oncology research. Identified adaptations to clinical trial procedures may be integrated to increase preparedness of clinical research to futures crises.
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http://dx.doi.org/10.1016/j.ejca.2020.09.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7546235PMC
December 2020

COVID-19 and acute lymphoblastic leukemias of children and adolescents: First recommendations of the Leukemia committee of the French Society for the fight against Cancers and Leukemias in children and adolescents (SFCE).

Bull Cancer 2020 Jun 30;107(6):629-632. Epub 2020 Apr 30.

Hôpital Universitaire Robert-Debré AP-HP, Université de Paris, service d'hémato-immunologie pédiatrique, Paris, France.

Since the emergence of the SARS-CoV-2 infection, many recommendations have been made. However, the very nature of acute lymphoblastic leukemias and their treatment in children and adolescents led the Leukemia Committee of the French Society for the fight against cancers and leukemias in children and adolescents (SFCE) to propose more specific recommendations, even if data for this population are still scarce. They may have to evolve according to the rapid evolution of knowledge on COVID-19.
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http://dx.doi.org/10.1016/j.bulcan.2020.04.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7190519PMC
June 2020

Standardized Patients or Conventional Lecture for Teaching Communication Skills to Undergraduate Medical Students: A Randomized Controlled Study.

Psychiatry Investig 2020 Apr 24;17(4):299-305. Epub 2020 Mar 24.

iLumens Diderot Simulation Health Center, Paris University, Paris, France.

Objective: The conduct of a medical interview is a challenging skill, even for the most qualified physicians. Since a training is needed to acquire the necessary skills to conduct an interview with a patient, we compared role-play with standardized patients (SP) training and a conventional lecture for the acquisition of communications skills in undergraduate medical students.

Methods: An entire promotion of third year undergraduate medical students, who never received any lessons about communications skills, were randomized into 4 arms: 1) SP 2 months before the testing of medical communications skills (SP); 2) conventional lecture 2 months before the testing (CL); 3) two control groups (CG) without any intervention, tested either at the beginning of the study or two months later. Students were blindly assessed by trained physicians with a modified 17-items Calgary-Cambridge scale.

Results: 388 students (98.7%) participated. SP performed better than CL, with significant statistical differences regarding 5 skills: the use of open and closed questions, encouraging patient responses, inviting the patient to clarify the missing items, encouraging of the patient's emotions, and managing the time and the conduct of the interview. The SP group specifically improved communications skills between the SP training and testing sessions regarding 2 skills: the use of open and closed questions and encouraging patient responses. No improvements in communications skills were observed in CG between the two time points, ruling out a possible time effect.

Conclusion: Role-play with standardized patients appears more efficient than conventional lecture to acquire communication skills in undergraduate medical students.
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http://dx.doi.org/10.30773/pi.2019.0258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7176569PMC
April 2020

Despite mutation acquisition in hematopoietic stem cells, JMML-propagating cells are not always restricted to this compartment.

Leukemia 2020 06 27;34(6):1658-1668. Epub 2019 Nov 27.

Francis Crick Institute, London, UK.

Juvenile myelomonocytic leukemia (JMML) is a rare aggressive myelodysplastic/myeloproliferative neoplasm of early childhood, initiated by RAS-activating mutations. Genomic analyses have recently described JMML mutational landscape; however, the nature of JMML-propagating cells (JMML-PCs) and the clonal architecture of the disease remained until now elusive. Combining genomic (exome, RNA-seq), Colony forming assay and xenograft studies, we detect the presence of JMML-PCs that faithfully reproduce JMML features including the complex/nonlinear organization of dominant/minor clones, both at diagnosis and relapse. Further integrated analysis also reveals that although the mutations are acquired in hematopoietic stem cells, JMML-PCs are not always restricted to this compartment, highlighting the heterogeneity of the disease during the initiation steps. We show that the hematopoietic stem/progenitor cell phenotype is globally maintained in JMML despite overexpression of CD90/THY-1 in a subset of patients. This study shed new lights into the ontogeny of JMML, and the identity of JMML-PCs, and provides robust models to monitor the disease and test novel therapeutic approaches.
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http://dx.doi.org/10.1038/s41375-019-0662-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7266742PMC
June 2020

Activating Mutations of RRAS2 Are a Rare Cause of Noonan Syndrome.

Am J Hum Genet 2019 06 23;104(6):1223-1232. Epub 2019 May 23.

Département de Génétique, Assistance Publique des Hôpitaux de Paris (AP-HP) Hôpital Robert Debré, 75019 Paris, France; INSERM UMR 1141 - Université de Paris, 75019 Paris, France.

Aberrant signaling through pathways controlling cell response to extracellular stimuli constitutes a central theme in disorders affecting development. Signaling through RAS and the MAPK cascade controls a variety of cell decisions in response to cytokines, hormones, and growth factors, and its upregulation causes Noonan syndrome (NS), a developmental disorder whose major features include a distinctive facies, a wide spectrum of cardiac defects, short stature, variable cognitive impairment, and predisposition to malignancies. NS is genetically heterogeneous, and mutations in more than ten genes have been reported to underlie this disorder. Despite the large number of genes implicated, about 10%-20% of affected individuals with a clinical diagnosis of NS do not have mutations in known RASopathy-associated genes, indicating that additional unidentified genes contribute to the disease, when mutated. By using a mixed strategy of functional candidacy and exome sequencing, we identify RRAS2 as a gene implicated in NS in six unrelated subjects/families. We show that the NS-causing RRAS2 variants affect highly conserved residues localized around the nucleotide binding pocket of the GTPase and are predicted to variably affect diverse aspects of RRAS2 biochemical behavior, including nucleotide binding, GTP hydrolysis, and interaction with effectors. Additionally, all pathogenic variants increase activation of the MAPK cascade and variably impact cell morphology and cytoskeletal rearrangement. Finally, we provide a characterization of the clinical phenotype associated with RRAS2 mutations.
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http://dx.doi.org/10.1016/j.ajhg.2019.04.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562003PMC
June 2019

Acute lymphoblastic leukemia in the context of RASopathies.

Eur J Med Genet 2016 Mar 5;59(3):173-8. Epub 2016 Feb 5.

Assistance Publique des Hôpitaux de Paris (AP-HP), Hôpital Robert Debré, Département de Génétique, Paris, France; INSERM UMR 1141, Université Paris Diderot, Sorbonne-Paris-Cité, Paris, France.

Noonan syndrome is associated with a range of malignancies including acute lymphoblastic leukemia (ALL). However, little information is available regarding the frequency, natural history, characteristics and prognosis of ALL in Noonan syndrome or RASopathies in general. Cross-referencing data from a large prospective cohort of 1176 patients having a molecularly confirmed RASopathy with data from the French childhood cancer registry allowed us to identify ALL in 6 (0.5%) patients including 4/778 (0.5%) with a germline PTPN11 mutation and 2/94 (2.1%) with a germline SOS1 mutation. None of the patients of our series with CFC syndrome (with germline BRAF or MAP2K1/MAP2K2 mutation - n = 121) or Costello syndrome (with HRAS mutation - n = 35) had an ALL. A total of 19 Noonan-ALL were gathered by adding our patients to those of the International Berlin-Munster-Frankfurt (I-BFM) study group and previously reported patients. Strikingly, all Noonan-associated ALL were B-cell precursor ALL, and high hyperdiploidy with more than 50 chromosomes was found in the leukemia cells of 13/17 (76%) patients with available genetics data. Our data suggest that children with Noonan syndrome are at higher risk to develop ALL. Like what is observed for somatic PTPN11 mutations, NS is preferentially associated with the development of hyperdiploid ALL that will usually respond well to chemotherapy. However, Noonan syndrome patients seem to have a propensity to develop post therapy myelodysplasia that can eventually be fatal. Hence, one should be particularly cautious when treating these patients.
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http://dx.doi.org/10.1016/j.ejmg.2016.01.003DOI Listing
March 2016

Juvenile myelomonocytic leukemia displays mutations in components of the RAS pathway and the PRC2 network.

Nat Genet 2015 Nov 12;47(11):1334-40. Epub 2015 Oct 12.

Institute of Biochemistry and Molecular Biology II, Medical Faculty of the Heinrich Heine University, Düsseldorf, Germany.

Juvenile myelomonocytic leukemia (JMML) is a rare and severe myelodysplastic and myeloproliferative neoplasm of early childhood initiated by germline or somatic RAS-activating mutations. Genetic profiling and whole-exome sequencing of a large JMML cohort (118 and 30 cases, respectively) uncovered additional genetic abnormalities in 56 cases (47%). Somatic events were rare (0.38 events/Mb/case) and restricted to sporadic (49/78; 63%) or neurofibromatosis type 1 (NF1)-associated (8/8; 100%) JMML cases. Multiple concomitant genetic hits targeting the RAS pathway were identified in 13 of 78 cases (17%), disproving the concept of mutually exclusive RAS pathway mutations and defining new pathways activated in JMML involving phosphoinositide 3-kinase (PI3K) and the mTORC2 complex through RAC2 mutation. Furthermore, this study highlights PRC2 loss (26/78; 33% of sporadic JMML cases) that switches the methylation/acetylation status of lysine 27 of histone H3 in JMML cases with altered RAS and PRC2 pathways. Finally, the association between JMML outcome and mutational profile suggests a dose-dependent effect for RAS pathway activation, distinguishing very aggressive JMML rapidly progressing to acute myeloid leukemia.
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http://dx.doi.org/10.1038/ng.3420DOI Listing
November 2015

Myeloid Dysregulation in a Human Induced Pluripotent Stem Cell Model of PTPN11-Associated Juvenile Myelomonocytic Leukemia.

Cell Rep 2015 Oct 8;13(3):504-515. Epub 2015 Oct 8.

The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address:

Somatic PTPN11 mutations cause juvenile myelomonocytic leukemia (JMML). Germline PTPN11 defects cause Noonan syndrome (NS), and specific inherited mutations cause NS/JMML. Here, we report that hematopoietic cells differentiated from human induced pluripotent stem cells (hiPSCs) harboring NS/JMML-causing PTPN11 mutations recapitulated JMML features. hiPSC-derived NS/JMML myeloid cells exhibited increased signaling through STAT5 and upregulation of miR-223 and miR-15a. Similarly, miR-223 and miR-15a were upregulated in 11/19 JMML bone marrow mononuclear cells harboring PTPN11 mutations, but not those without PTPN11 defects. Reducing miR-223's function in NS/JMML hiPSCs normalized myelogenesis. MicroRNA target gene expression levels were reduced in hiPSC-derived myeloid cells as well as in JMML cells with PTPN11 mutations. Thus, studying an inherited human cancer syndrome with hiPSCs illuminated early oncogenesis prior to the accumulation of secondary genomic alterations, enabling us to discover microRNA dysregulation, establishing a genotype-phenotype association for JMML and providing therapeutic targets.
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http://dx.doi.org/10.1016/j.celrep.2015.09.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4618050PMC
October 2015

Major impact of an early bone marrow checkpoint (day 21) for minimal residual disease in flow cytometry in childhood acute lymphoblastic leukemia.

Hematol Oncol 2017 Jun 9;35(2):237-243. Epub 2015 Oct 9.

Hematology Biology, Timone University Hospital, Marseilles, France.

The early persistence of minimal residual disease (MRD) is considered a poor prognostic factor indicative of chemoresistance in acute lymphoblastic leukemia. In French children, chemosensitivity is assessed at day 21 post-induction by cytomorphology. Here, it was investigated whether a more precise evaluation could be obtained at this time point with multiparameter flow cytometry (MFC). This study enrolled 123 children with de novo acute lymphoblastic leukemia. MRD0 was investigated at day 21 in MFC with a combination of antibodies based on the immunophenotype of diagnosis. It was also evaluated at day 35 by immunoglobulin/T-cell receptor quantitative real-time polymerase chain reaction (MRD1). Three risk groups could be delineated based on MRD0. Patients with MFC/MRD0 levels >10 (n = 25) were considered high risk, those with levels between 10 and 10 (n = 46) intermediate risk, and those <10 (n = 50) low risk. Overall survival (p = 0.048) and event-free survival (EFS, p = 0.00017) were significantly different between these three groups. EFS of the 14 corticoresistant patients strongly depended on their MRD0 level (p = 0.004). Similarly, both EFS (p = 0.0004) and overall survival (p = 0.02) were significantly different in the 109 chemosensitive patients, according to MRD0 levels. MRD0 and MRD1 levels, compared with 112 patients, were consistent (-/- or +/+) in 57.2% of the cases. Both MRD0+/MRD1+ and MRD0+/MRD1- patients had a significantly worse EFS (p = 0.0001) than those with undetectable MRD at both MRD0 and MRD1. This study confirms the usefulness and superiority of an early point of MRD detection by MFC. In addition, MRD0 in MFC identifies a subgroup of patients with poorer prognosis (MRD0+/MRD1-). Copyright © 2015 John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/hon.2263DOI Listing
June 2017

Prognostic Value and Clinical Impact of (18)FDG-PET in the Management of Children with Burkitt Lymphoma after Induction Chemotherapy.

Front Med (Lausanne) 2014 16;1:54. Epub 2014 Dec 16.

Department of Nuclear Medicine, University Hospital , Nantes , France ; U892, CNRS UMR 6299, CRCNA, INSERM , Nantes , France.

Objective: Burkitt lymphoma (BL) is a rare and aggressive form of B-cell lymphoma that is curable using intensive chemotherapy. Obtaining a complete response (CR) at the end of induction chemotherapy is a major prognostic factor. This study retrospectively evaluates the potential impact of (18)FDG-PET in the management of children with BL after induction chemotherapy, and the prognostic performance of the Deauville criteria.

Methods: Nineteen children with BL treated according to the French LMB2001 protocol between 2005 and 2012 were included. (18)FDG-PET and conventional imaging (CI) were performed after induction chemotherapy to confirm CR. (18)FDG-PET was interpreted according to Deauville criteria with follow-up and/or histology as the gold standard.

Results: (18)FDG-PET was negative in 15 cases, in agreement with CI in 9/15 cases. The six discordant cases confirmed to be negative by histology, were considered as true negative for (18)FDG-PET. Negative predictive value (NPV) of CI and (18)FDG-PET were 73 and 93%, respectively. The 5-year progression-free survival (PFS) was significantly higher in patients with negative (18)FDG-PET than those with positive (18)FDG-PET (p = 0.011).

Conclusion: (18)FDG-PET interpreted using Deauville criteria can help confirm CR at the end of induction chemotherapy, with a prognostic impact on 5-year PFS. Its high NPV could limit the use of residual mass biopsy. Given the small size of our population, these results need to be confirmed by future prospective studies on a larger population.
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http://dx.doi.org/10.3389/fmed.2014.00054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4292173PMC
January 2015

Juvenile myelomonocytic leukaemia and Noonan syndrome.

J Med Genet 2014 Oct 5;51(10):689-97. Epub 2014 Aug 5.

INSERM UMR_S1131, Institut Universitaire d'Hématologie, Université Paris Diderot, Paris-Sorbonne-Cité, Paris, France Département de Génétique, Assistance Publique des Hôpitaux de Paris (AP-HP), Hôpital Robert Debré, Paris, France.

Background: Infants with Noonan syndrome (NS) are predisposed to developing juvenile myelomonocytic leukaemia (JMML) or JMML-like myeloproliferative disorders (MPD). Whereas sporadic JMML is known to be aggressive, JMML occurring in patients with NS is often considered as benign and transitory. However, little information is available regarding the occurrence and characteristics of JMML in NS.

Methods And Results: Within a large prospective cohort of 641 patients with a germline PTPN11 mutation, we identified MPD features in 36 (5.6%) patients, including 20 patients (3%) who fully met the consensus diagnostic criteria for JMML. Sixty percent of the latter (12/20) had severe neonatal manifestations, and 10/20 died in the first month of life. Almost all (11/12) patients with severe neonatal JMML were males. Two females who survived MPD/JMML subsequently developed another malignancy during childhood. Although the risk of developing MPD/JMML could not be fully predicted by the underlying PTPN11 mutation, some germline PTPN11 mutations were preferentially associated with myeloproliferation: 10/48 patients with NS (20.8%) with a mutation in codon Asp61 developed MPD/JMML in infancy. Patients with a p.Thr73Ile mutation also had more chances of developing MPD/JMML but with a milder clinical course. SNP array and whole exome sequencing in paired tumoral and constitutional samples identified no second acquired somatic mutation to explain the occurrence of myeloproliferation.

Conclusions: JMML represents the first cause of death in PTPN11-associated NS. Few patients have been reported so far, suggesting that JMML may sometimes be overlooked due to early death, comorbidities or lack of confirmatory tests.
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http://dx.doi.org/10.1136/jmedgenet-2014-102611DOI Listing
October 2014

Activating mutations in RRAS underlie a phenotype within the RASopathy spectrum and contribute to leukaemogenesis.

Hum Mol Genet 2014 Aug 4;23(16):4315-27. Epub 2014 Apr 4.

Genetica Clinica Pediatrica, Clinica Pediatrica Università Milano Bicocca, Fondazione MBBM, A.O. S. Gerardo, Monza 20900, Italy.

RASopathies, a family of disorders characterized by cardiac defects, defective growth, facial dysmorphism, variable cognitive deficits and predisposition to certain malignancies, are caused by constitutional dysregulation of RAS signalling predominantly through the RAF/MEK/ERK (MAPK) cascade. We report on two germline mutations (p.Gly39dup and p.Val55Met) in RRAS, a gene encoding a small monomeric GTPase controlling cell adhesion, spreading and migration, underlying a rare (2 subjects among 504 individuals analysed) and variable phenotype with features partially overlapping Noonan syndrome, the most common RASopathy. We also identified somatic RRAS mutations (p.Gly39dup and p.Gln87Leu) in 2 of 110 cases of non-syndromic juvenile myelomonocytic leukaemia, a childhood myeloproliferative/myelodysplastic disease caused by upregulated RAS signalling, defining an atypical form of this haematological disorder rapidly progressing to acute myeloid leukaemia. Two of the three identified mutations affected known oncogenic hotspots of RAS genes and conferred variably enhanced RRAS function and stimulus-dependent MAPK activation. Expression of an RRAS mutant homolog in Caenorhabditis elegans enhanced RAS signalling and engendered protruding vulva, a phenotype previously linked to the RASopathy-causing SHOC2(S2G) mutant. Overall, these findings provide evidence of a functional link between RRAS and MAPK signalling and reveal an unpredicted role of enhanced RRAS function in human disease.
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http://dx.doi.org/10.1093/hmg/ddu148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4103678PMC
August 2014

[Juvenile myelomonocytic leukemias].

Bull Cancer 2014 Mar;101(3):302-13

CHU Robert-Debré, APHP, Département de génétique, 48, boulevard Sérurier, 75019 Paris, France, Inserm UMR1131, Institut universitaire d'hématologie, Université Paris-Diderot, Hôpital Saint-Louis, 1, avenue Claude-Vellefaux, 75010 Paris, France.

Juvenile myelomonocytic leukemias (JMML) are rare but severe myelodysplastic and myeloproliferative neoplasms of infancy. They represent about 10 new cases per year in France and preferentially affect males. JMML are all stem cell diseases the common denominator of which is RAS pathway dysregulation, due to mutations in RAS (NRAS, KRAS) or RAS regulatory components (PTPN11, NF1 or CBL). This leads to an hypersensivity of myeloid progenitors to GM-CSF (granulo-macrophagic colony stimulating factor) which induces in turn excessive monocytic and macrophagic proliferation in blood and bone marrow. All organs can be infiltrated by this monocytic proliferation leading to multisystemic failure. Blast crisis with transformation into acute myeloid leukemia occurs in one third of patients. A salient feature of JMML is their frequent association with predisposition syndromes such as Noonan syndrome, neurofibromatosis and CBL syndrome, which are developmental diseases associated with a constitutional RAS pathway deregulation, now grouped under the name RASopathies. Clinical heterogeneity makes JMML diagnosis difficult. Splenomagaly is the most constant sign. Palor, adenopathy, respiratory or cutaneous symptoms can also be present. Blood smear shows monocytosis (>1×10(9)/L) presence of myeloid progenitors and abnormal basophils. The demonstration of an endogeneous in vitro growth of myeloid progenitors although not very specific can help JMML diagnosis. Nowadays, genetic typing has to be included in the workup of JMML diagnosis and allows to evidence a mutation in more than 90% of cases. JMML have a poor prognosis. The only curative treatment is bone marrow transplantation but approximately 35% of patients relapse. JMML clinical course is highly heterogeneous and unpredictable. Some rare patients have an indolent evolution or even spontaneous remission. Age over two years, thrombopenia below 33×10(9)/L and high foetal hemoglobin (HbF) level for age are poor prognosis criteria but hardly predict individual outcome. Several research directions are currently being explored to improve prognosis prediction and provide more effective targeted treatments.
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http://dx.doi.org/10.1684/bdc.2014.1908DOI Listing
March 2014

Paediatric anaplastic large cell lymphoma with leukaemic presentation in children: a report of nine French cases.

Br J Haematol 2014 May 14;165(4):545-51. Epub 2014 Feb 14.

CHU de Strasbourg, Service d'hématologie oncologie pédiatrique, pédiatrie 3, Hopital Hautepierre, Strasbourg, France.

This study aimed to describe the clinical features and outcome of anaplastic large cell lymphoma (ALCL) with leukaemic presentation in children. Among 267 patients included in the French paediatric ALCL database between 1989 and 2012, nine (3%) were described as having cytologically detectable circulating tumour cells. Clinical features combined fever (8/9), nodal and extra-nodal disease (9/9), including hepato-splenic (9/9) and lung involvement (7/9). The level of hyperleucocytosis ranged from 30 to 120 × 10(9) /l, with 12-90% of tumour cells. Diagnosis relied on a lymph node biopsy, with a positive ALK+ antibody immunostain in all nine cases, a T-cell immunophenotype in 7/9 cases and CD3 positivity in 5/9 cases. A small cell component was present in 6/9 cases. Only four patients achieved a complete remission with first-line therapy and 3/4 relapsed. Four patients are alive with a median follow-up of 31 months, two of them after allogeneic haematopoietic stem cell transplantation (HSCT), and five patients died, two of them of disease. In conclusion, ALCL with leukaemic presentation is very unusual and should be considered as high-risk lymphoma requiring new therapeutic strategies. The respective role of new agents and allogeneic HSCT in first complete remission still has to be assessed.
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http://dx.doi.org/10.1111/bjh.12777DOI Listing
May 2014

Evaluation of health related quality of life in children with immune thrombocytopenia with the PedsQL™ 4.0 Generic Core Scales: a study on behalf of the pays de Loire pediatric hematology network.

Health Qual Life Outcomes 2013 Nov 13;11:193. Epub 2013 Nov 13.

Service d'Immuno-Hémato-Oncologie Pédiatrique, CHU d'Angers, 4 rue Larrey, 49933 Angers, Cedex 09, France, UE.

Background: Immune thrombocytopenia (ITP) is a childhood disorder that is often life-altering for children and their parents. Health related quality of life (HRQL) has never been chronologically monitored in children with ITP. We initiated a prospective study to assess HRQL from diagnosis to six months and define factors that influence this outcome in children with ITP.

Methods: 73 children with acute ITP aged from 2 to 18 years were prospectively enrolled in the study. According to the presence of bleeding, they were or were not given a 4-day course of corticosteroid treatment. The PedsQL™ 4.0 Generic Core Scale was completed by children and parents upon their inclusion in the study and 6 months after diagnosis.

Results: Over the six month period, quality of life improved in terms of their global, physical and psychosocial well-being for 54.5%, 35.6% and 36.2% of patients respectively. This improvement is clinically relevant compared to scores at diagnosis, corresponding at least to a minimal clinically important difference (MCID). Factors such as sex, age, platelet count, bleeding scores, bone marrow aspiration and persistence of ITP at 6 months were not significantly associated with HRQL scores. However, preceding viral infection was identified to have an impact on HRQL.

Conclusions: This first longitudinal study assessing HRQL in children with ITP reveals a global improvement in PedSQL™ 4.0. However, these results should be considered with caution since our data also confirm that self-report HRQL scores are not influenced by any analyzed biologic or clinical parameters. Others tools, such as Kids' ITP Tools, would probably be required to assess the HRQL of this population.

Trial Registration: Trial registration clinical trials.gov Identifier: NCT00331357.
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http://dx.doi.org/10.1186/1477-7525-11-193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3830442PMC
November 2013

Allogeneic hematopoietic stem cell transplantation following reduced-intensity conditioning regimen in children: a single-center experience.

Eur J Haematol 2012 Jun 21;88(6):504-9. Epub 2012 Mar 21.

Centre Hospitalier et Universitaire (CHU) de Nantes, Service d'Onco-Hématologie Pédiatrique, Nantes, France.

This single-center retrospective study reported the outcome of 19 children treated with a reduced-intensity conditioning (RIC) regimen prior to allogeneic stem cell transplantation (allo-SCT), for hematologic malignancies (n = 17), bone marrow failure (n = 1), and neuroblastoma (n = 1). Children were ineligible for standard myeloablative conditioning because of severe comorbidities (n = 9), a previous auto or allo-SCT (n = 7) or a prior history of extensive chemotherapy (n = 3). All patients underwent a fludarabine-based RIC regimen, and received grafts from matched-related donors (n = 5), match-unrelated donors (n = 6), or unrelated cord blood (UCB, n = 8). In this series, two patients treated with UCB failed to engraft and 63% achieved full donor chimerism at day 100 after allo-SCT. With a median follow-up of 537 d (range, 115-4136), treatment-related mortality was 16% and overall survival was 47%. The principal cause of death was disease relapse (n = 7). Acute graft versus host disease (GVHD) occurred in 53% of patients, while only 10% developed extensive chronic GVHD. Overall, results from this series suggest that RIC allo-SCT can be a valid alternative treatment option in unfit children with malignant hematological diseases. Prospective studies are needed to enlarge pediatric experience in this domain and better identify those children more suitable for a RIC allo-SCT approach.
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http://dx.doi.org/10.1111/j.1600-0609.2012.01776.xDOI Listing
June 2012

Silent hypersensitivity to Escherichia coli asparaginase in children with acute lymphoblastic leukemia.

Leuk Lymphoma 2010 Aug;51(8):1464-72

Service d'Onco-Hématologie Pédiatrique, CHU de Nantes, Hopital Mère-Enfant, Nantes, France.

This prospective study aimed to assess the incidence of silent hypersensitivity to Escherichia coli asparaginase in the treatment of acute lymphoblastic leukemia (ALL). Thirty-three children with newly diagnosed ALL were included in the study and treated according to the FRALLE 2000 protocol. The 'A group' (n = 18) differed from the 'B-T group' (n = 15) by a less intensive chemotherapy, the absence of concurrent prednisone therapy, and different asparaginase administration modalities during the second intensification. Asparagine, asparaginase activity, and anti-asparaginase antibodies were measured in each phase before the next injection of asparaginase. Eighteen percent of children presented a silent hypersensitivity. Most of them were in the 'B-T group' (p = 0.07), and maintained low antibody titers throughout the treatment. Clinical hypersensitivity was statistically more frequent in group A (p = 0.002), and allergy occurred mainly during the second intensification when antibody concentrations were significantly increased. We did not find any significant difference between asparaginase activity or asparagine depletion between the silent hypersensitivity and clinical allergy groups. In all, the results of this study suggest that chemotherapy and corticosteroid therapy associated with asparaginase treatment can lower antibody production and contribute to maintaining a silent hypersensitivity state.
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http://dx.doi.org/10.3109/10428194.2010.494316DOI Listing
August 2010
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