Caroline Thomas

Overall Genomic Pattern Is a Predictor of Outcome in Neuroblastoma

PURPOSEnFor a comprehensive overview of the genetic alterations of neuroblastoma, their association and clinical significance, we conducted a whole-genome DNA copy number analysis.nnnPATIENTS AND METHODSnA series of 493 neuroblastoma (NB) samples was investigated by array-based comparative genomic hybridization in two consecutive steps (224, then 269 patients).nnnRESULTSnGenomic analysis identified several types of profiles. Tumors presenting exclusively whole-chromosome copy number variations were associated with excellent survival. No disease-related death was observed in this group. In contrast, tumors with any type of segmental chromosome alterations characterized patients with a high risk of relapse. Patients with both numerical and segmental abnormalities clearly shared the higher risk of relapse of segmental-only patients. In a multivariate analysis, taking into account the genomic profile, but also previously described individual genetic and clinical markers with prognostic significance, the presence of segmental alterations with (HR, 7.3; 95% CI, 3.7 to 14.5; P < .001) or without MYCN amplification (HR, 4.5; 95% CI, 2.4 to 8.4; P < .001) was the strongest predictor of relapse; the other significant variables were age older than 18 months (HR, 1.8; 95% CI, 1.2 to 2.8; P = .004) and stage 4 (HR, 1.8; 95% CI, 1.2 to 2.7; P = .005). Finally, within tumors showing segmental alterations, stage 4, age, MYCN amplification, 1p and 11q deletions, and 1q gain were independent predictors of decreased overall survival.nnnCONCLUSIONnThe analysis of the overall genomic pattern, which probably unravels particular genomic instability mechanisms rather than the analysis of individual markers, is essential to predict relapse in NB patients. It adds critical prognostic information to conventional markers and should be included in future treatment stratification.

Morbidity and mortality from ataxia-telangiectasia are associated with ATM genotype

BACKGROUNDnAtaxia-telangiectasia (A-T) is a rare genetic disease caused by germline biallelic mutations in the ataxia-telangiectasia mutated gene (ATM) that result in partial or complete loss of ATM expression or activity. The course of the disease is characterized by neurologic manifestations, infections, and cancers.nnnOBJECTIVEnWe studied A-T progression and investigated whether manifestations were associated with the ATM genotype.nnnMETHODSnWe performed a retrospective cohort study in France of 240 patients with A-T born from 1954 to 2005 and analyzed ATM mutations in 184 patients, along with neurologic manifestations, infections, and cancers.nnnRESULTSnAmong patients with A-T, the Kaplan-Meier 20-year survival rate was 53.4%; the prognosis for these patients has not changed since 1954. Life expectancy was lower among patients with mutations in ATM that caused total loss of expression or function of the gene product (null mutations) compared with that seen in patients with hypomorphic mutations because of earlier onset of cancer (mainly hematologic malignancies). Cancer (hazard ratio, 2.7; 95% CI, 1.6-4.5) and respiratory tract infections (hazard ratio, 2.3; 95% CI, 1.4-3.8) were independently associated with mortality. Cancer (hazard ratio, 5.8; 95% CI, 2.9-11.6) was a major risk factor for mortality among patients with null mutations, whereas respiratory tract infections (hazard ratio, 4.1; 95% CI, 1.8-9.1) were the leading cause of death among patients with hypomorphic mutations.nnnCONCLUSIONnMorbidity and mortality among patients with A-T are associated with ATM genotype. This information could improve our prognostic ability and lead to adapted therapeutic strategies.

A New clinical score for disease activity in Langerhans cell histiocytosis

To develop an objective tool for assessing disease activity in patients with Langerhans cell histiocytosis (LCH).

Economic evaluation of immunoglobulin replacement in patients with primary antibody deficiencies

Lifelong immunoglobulin replacement is the standard, expensive therapy for severe primary antibody deficiencies. This treatment can be administrated either by intravenous immunoglobulin (IVIG) or subcutaneous infusions (SCIG) and delivered at home or in an out‐patient setting. This study aims to determine whether SCIG is cost‐effective compared with IVIG from a French social insurance perspective. Because both methods of administration provide similar efficacies, a cost‐minimization analysis was performed. First, costs were calculated through a simulation testing different hypothesis on costs drivers. Secondly, costs were estimated on the basis of field data collected by a questionnaire completed by a population of patients suffering from agammaglobulinaemia and hyper‐immunoglobulin (Ig)M syndrome. Patients satisfaction was also documented. Results of the simulation showed that direct medical costs ranged from €19u2003484 for home‐based IVIG to €25u2003583 for hospital‐based IVIG, with home‐based SCIG in between at €24u2003952 per year. Estimations made from field data were found to be different, with significantly higher costs for IVIG. This result was explained mainly by a higher immunoglobulin mean dose prescribed for IVIG. While the theoretical model showed very little difference between SCIG and hospital‐based IVIG costs, SCIG appears to be 25% less expensive with field data because of lower doses used in SCIG patients. The reality of the dose difference between both routes of administration needs to be confirmed by further and more specific studies.

Protective effect of IgM against colonization of the respiratory tract by nontypeable Haemophilus influenzae in patients with hypogammaglobulinemia.

BACKGROUNDnPrimary immunoglobulin deficiencies lead to recurrent bacterial infections of the respiratory tract and bronchiectasis, even with adequate immunoglobulin replacement therapy. It is not known whether patients able to secrete IgM (eg, those with hyper-IgM [HIgM] syndrome) are as susceptible to these infections as patients who lack IgM production (eg, those with panhypogammaglobulinemia [PHG]).nnnOBJECTIVEnThis study is aimed at identifying specific microbiological and clinical (infections) characteristics that distinguish immunoglobulin-substituted patients with PHG from patients with HIgM syndrome.nnnMETHODSnA cohort of patients with HIgM syndrome (nxa0= 25) and a cohort of patients with PHG (nxa0= 86) were monitored prospectively for 2 years while receiving similar polyvalent immunoglobulin replacement therapies. Regular bacterial analyses of nasal swabs and sputum were performed, and clinical events were recorded. In parallel, serum and saliva IgM antibody concentrations were measured.nnnRESULTSnWhen compared with patients with PHG, patients with HIgM syndrome were found to have a significantly lower risk of nontypeable Haemophilus influenzae carriage in particular (relative risk, 0.39; 95% CI, 0.21-0.63). Moreover, patients with HIgM syndrome (including those unable to generate somatic hypermutations of immunoglobulin genes) displayed anti-nontypeable H influenzae IgM antibodies in their serum and saliva. Also, patients with HIgM syndrome had a lower incidence of acute respiratory tract infections.nnnCONCLUSIONSnIgM antibodies appear to be microbiologically and clinically protective and might thus attenuate the infectious consequences of a lack of production of other immunoglobulin isotypes in patients with HIgM syndrome. Polyvalent IgG replacement therapy might not fully compensate for IgM deficiency. It might thus be worth adapting long-term antimicrobial prophylactic regimens according to the underlying B-cell immunodeficiency phenotype.

Skin lesions revealing neonatal acute leukemias with monocytic differentiation. A report of 3 cases.

Acute myelo‐monoblastic (AMML) and acute monoblastic (AML) leukemias have a bad prognosis, especially in children when occurring in the first months of life. We report 3 cases of such leukemias in which skin lesions preceded and revealed the leukaemia. For the 3 infants, cutaneous lesions appeared about one month before the other signs of leukaemia (2 AML and 1 AMML). Skin biopsies from all 3 infants revealed a heavy dermic infiltration by large cells with round or irregular vesicular nuclei and abundant pale cytoplasm. These atypical cells did not express any lymphoid markers but reacted strongly with monocytic‐macrophagic antibodies (CD68, GDIS and CD14). Two infants were treated by mitoxanthrone and cytarabine with complete remission. The third one was not treated because of a very poor general status. Skin involvement is frequent in these non‐lymphoid leukaemias (30% to 50% of cases). In only 7% of cases, leukemic skin lesions precede and reveal the other signs of leukemia by weeks or months. Then, it is very important to repeat the blood cell counts and to biopsy the skin lesions in order to make a diagnosis of leukemia as early as possible.

Topotecan-vincristine-doxorubicin in stage 4 high risk neuroblastoma patients failing to achieve a complete metastatic response to rapid COJEC : a SIOPEN study

Purpose Metastatic response to induction therapy for high-risk neuroblastoma is a prognostic factor. In the International Society of Paediatric Oncology Europe Neuroblastoma (SIOPEN) HR-NBL-1 protocol, only patients with metastatic complete response (CR) or partial response (PR) with ≤ three abnormal skeletal areas on iodine 123-metaiodobenzylguanidine ([123I]mIBG) scintigraphy and no bone marrow disease proceed to high dose therapy (HDT). In this study, topotecan-vincristine-doxorubicin (TVD) was evaluated in patients failing to achieve these criteria, with the aim of improving the metastatic response rate. Materials and Methods Patients with metastatic high-risk neuroblastoma who had not achieved the SIOPEN criteria for HDT after induction received two courses of topotecan 1.5 mg/m2/day for 5 days, followed by a 48-hour infusion of vincristine, 2 mg/m2, and doxorubicin, 45 mg/m2. Results Sixty-three patients were eligible and evaluable. Following two courses of TVD, four (6.4%) patients had an overall CR, while 28 (44.4%) had a PR with a combined response rate of 50.8% (95% confidence interval [CI], 37.9 to 63.6). Of these, 23 patients achieved a metastatic CR or a PR with ≤ 3 mIBG skeletal areas and no bone marrow disease (36.5%; 95% CI, 24.7 to 49.6) and were eligible to receive HDT. Toxicity was mostly haematological, affecting 106 of the 126 courses (84.1%; 95% CI, 76.5 to 90.0), and dose reduction was necessary in six patients. Stomatitis was the second most common nonhematological toxicity, occurring in 20 patients (31.7%). Conclusion TVD was effective in improving the response rate of high-risk neuroblastoma patients after induction with COJEC enabling them to proceed to HDT. However, the long-term benefits of TVD needs to be determined in randomized clinical trials.

CL031 - Anémie hémolytique auto-immune de l’adolescent : 52 observations

Objectifs Le Centre de reference national des cytopenies auto-immunes de l’enfant (CEREVANCE), regroupant 30 centres de la Societe d’Hematologie et d’Immunologie Pediatrique (SHIP), a pour missions de structurer la filiere de soins specifique de l’adolescent. Patients et Methodes Parmi les 345 enfants inclus dans la cohorte pediatrique nationale prospective de suivi pour une AHAI, 52 avaient 13 ans ou plus au diagnostic initial. Resultats Ces adolescents (31 filles, 21 garcons) avaient des antecedents familiaux immunologiques (parents/fratrie) dans 27% des cas. Le test de Coombs etait de type IgG/ IgG+C dans 82% des cas. L’AHAI etait post infectieuse dans 11% des cas, associee a une maladie auto-immune ou un deficit immunitaire dans 48% des cas. Avec un suivi median de 2,9 ans (0,1-9,1), 48% de ces jeunes, suivis par une equipe d’adultes, sont encore dependants de traitements. Conclusion L’inclusion initiale des adolescents dans la cohorte pediatrique permet de realiser des etudes prospectives homogenes. Un relai de suivi dans une filiere adulte est indispensable, compte tenu de la survenue parfois tardive d’une pathologie immunologique. Cette transition de l’enfant a l’adulte est effective dans plusieurs regions, grâce a une collaboration renforcee par le plan Maladies Rares.

SFCE-05 – Cancérologie, hématologie, immunologie – Classification génomique dans le neuroblastome : utilité pour la prise en charge thérapeutique

Objectifs Le neuroblastome (NB) est un cancer pediatrique avec une grande heterogeneite clinique. Des nombreuses alterations genetiques recurrentes ont ete decrites : une amplification de MYCN associee a un pronostic pauvre, ainsi que des variations de la ploidie ou des alterations chromosomiques segmentaires (deletions du chromosome 1p, 3p, 4p, 11q ; gain du chromosome 2p, 17q) dont l’importance pronostique reste a etre determinee. Afin d’etudier l’association de ces alterations genetiques entre elles et leur impact pronostique, nous avons entrepris une analyse en CGH-array d’une grande serie de NB. Methodes 389 echantillons de NB ont ete analyses en hybridation genomique comparative (CGH), sur une puce d’ADN a BAC/PAC avec une resolution moyenne de 1Mb. Resultats L’analyse du profil genomique permet de distinguer 2 differents types d’instabilite genetique : une instabilite numerique et une instabilite segmentaire. L’instabilite numerique est caracterisee par une variation en nombre de chromosomes entiers sans alterations segmentaires (n = 162). Elle est associee a une survie sans progression et une survie globale excellente. L’instabilite segmentaire se caracterise par des translocations chromosomiques desequilibrees. Elle a ete observee dans des tumeurs sans (n = 45) ou avec (n = 97) variations numeriques, ou en association avec une amplification de MYCN (n = 67). Ce type genomique est associe a un risque eleve de rechute (p Conclusion Dans le NB, un profil genomique de type segmentaire est le marqueur pronostique le plus fort. Ceci souligne l’importance du mecanisme a l’origine des translocations desequilibrees dans l’oncogenese du NB. Le typage genomique devra donc etre pris en compte pour l’attribution a un groupe de risque et la stratification therapeutique. Le NB est le premier modele de l’utilite d’une classification genomique pour une meilleure prise en charge therapeutique.