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International audience; Objectives: To evaluate the applicability and compliance with guidelines for early initiation of long-term prophylaxis in infants with severe hemophilia A and to identify factors associated with guideline compliance.Study design: This real-world, prospective, multicenter, population-based FranceCoag study included almost all French boys with severe hemophilia A, born between 2000 and 2009 (ie, after guideline implementation).Results: We included 333 boys in the study cohort. The cumulative incidence of long-term prophylaxis use was 61.2% at 3 years of age vs 9.5% in a historical cohort of 39 boys born in 1996 (ie, before guideline implementation). The guidelines were not applicable in 23.1% of patients due to an early intracranial bleeding or inhibitor development. Long-term prophylaxis was delayed in 10.8% of patients. In the multivariate analysis, 2 variables were significantly associated with "timely long-term prophylaxis" as compared with "delayed long-term prophylaxis": hemophilia treating center location in the southern regions of France (OR 23.6, 95% CI 1.9-286.7, P = .013 vs Paris area) and older age at long-term prophylaxis indication (OR 7.2 for each additional year, 95% CI 1.2-43.2, P = .031). Long-term prophylaxis anticipation was observed in 39.0% of patients. Earlier birth year (OR 0.5, 95% CI 0.3-0.8, P = .010 for birth years 2005-2009 vs 2000-2004) and age at first factor replacement (OR 1.9 for each additional year, 95% CI 1.2-3.0, P = .005) were significantly associated with "long-term prophylaxis guideline compliance" vs "long-term prophylaxis anticipation."Conclusions: This study suggests that long-term prophylaxis guidelines are associated with increased long-term prophylaxis use. However, early initiation of long-term prophylaxis remains a challenge.

Asparaginase is an essential component of combination chemotherapy for childhood acute lymphoblastic leukemia and non-Hodgkin lymphoma. The value of asparaginase was further addressed in a group of non-very high-risk patients by comparing prolonged (long-asparaginase) versus standard (short-asparaginase) native E. coli asparaginase treatment in a randomized part of the phase III 58951 trial of the European Organization for Research and Treatment of Cancer Children’s Leukemia Group. The main endpoint was disease-free survival. Overall, 1,552 patients were randomly assigned to long-asparaginase (775 patients) or short-asparaginase (777 patients). Patients with grade ≥2 allergy to native E. coli asparaginase were switched to equivalent doses of Erwinia or pegylated E. coli asparaginase. The 8-year disease-free survival rate (±standard error) was 87.0±1.3% in the long-asparaginase group and 84.4±1.4% in the short-asparaginase group (hazard ratio: 0.87; P=0.33) and the 8-year overall survival rate was 92.6±1.0% and 91.3±1.2% respectively (hazard ratio: 0.89; P=0.53). An exploratory analysis suggested that the impact of long-asparaginase was beneficial in the National Cancer Institute standard-risk group with regards to disease-free survival (hazard ratio: 0.70; P=0.057), but far less so with regards to overall survival (hazard ratio: 0.89). The incidences of grade 3–4 infection during consolidation (25.2% versus 14.4%) and late intensification (22.6% versus 15.9%) and the incidence of grade 2–4 allergy were higher in the long-asparaginase arm (30% versus 21%). Prolonged native E. coli asparaginase therapy in consolidation and late intensification for our non-very high-risk patients did not improve overall outcome but led to an increase in infections and allergy. This trial was registered at www.clinicaltrials.gov as #NCT00003728.

International audience; To the Editor:Since the mid-1980s, continuous progress in genetics and genomics has accelerated the rapid identification of causative genetic variants leading to primary immunodeficiencies (PIDs; >300 genes),1 with the noticeable exception of B-cell disorders, such as common variable immunodeficiency (CVID). The identification of these mutations not only validates a clinical diagnosis but also is useful in several other respects (more accurate prognosis on phenotype/genotype correlation, targeted therapy, and genetic counseling). [...]

Context Thyroid carcinoma is a frequent complication of childhood cancer radiotherapy. The dose response to thyroid radiation dose is now well established, but the potential modifier effect of other factors requires additional investigation. Objective This study aimed to investigate the role of potential modifiers of the dose response. Design We followed a cohort of 4338 5-year survivors of solid childhood cancer treated before 1986 over an average of 27 years. The dose received by the thyroid gland and some other anatomical sites during radiotherapy was estimated after reconstruction of the actual conditions in which irradiation was delivered. Results Fifty-five patients developed thyroid carcinoma. The risk of thyroid carcinoma increased with a radiation dose to the thyroid of up to two tenths of Gy, then leveled off for higher doses. When taking into account the thyroid radiation dose, a surgical or radiological splenectomy (>20 Gy to the spleen) increased thyroid cancer risk (relative risk [RR] = 2.3; 95% confidence interval [CI], 1.3-4.0), high radiation doses (>5 Gy) to pituitary gland lowered this risk (RR = 0.2; 95% CI, 0.1-0.6). Patients who received nitrosourea chemotherapy had a 6.6-fold (95% CI, 2.5-15.7) higher risk than those who did not. The excess RR per Gy of radiation to the thyroid was 4.7 (95% CI, 1.7-22.6). It was 7.6 (95% CI, 1.6-33.3) if body mass index at time of interview was equal or higher than 25 kg/m(2), and 4.1 (95% CI, 0.9-17.7) if not (P for interaction = .1). Conclusion Predicting thyroid cancer risk following childhood cancer radiation therapy probably requires the assessment of more than just the radiation dose to the thyroid. Chemotherapy, splenectomy, radiation dose to pituitary gland, and obesity also play a role.

Background Rhabdomyosarcoma (RMS) occasionally occurs in a context of a predisposition syndrome. The most common predisposition syndromes include germline TP53 mutations and constitutive alterations in RAS pathway activation, such as Costello syndrome, Noonan syndrome and neurofibromatosis type 1. We report a national retrospective series of 16 RMS occurring in neurofibromatosis type 1 (NF1) patients during childhood, within a 20-year period. Results The mean age at diagnosis of the cancer was 2.5 years. All were embryonal subtype. Most tumours developed in the pelvis. One was metastatic. Chemotherapy and radiotherapy were normally scheduled without any specific toxicity. The 5-year event-free survival and overall survival were 67% and 87%, respectively. Long-term sequel related to chemotherapy consisted in two chronic tubulopathies, hence not obviously different from non-NF1 patients. No second cancer was reported so far with a median follow-up of 9.7 years. The genomic analysis performed on six samples revealed the abnormalities commonly observed in sporadic RMS: gain of chromosome 2 (5/6), 8 (6/6) and chromosome 11p loss of heterozygosity (5/6). Interestingly, we identified small deletions in tumour suppressor genes that may synergize with NF1 inactivation. Conclusions Patients with neurofibromatosis are prone to develop embryonal-type RMS that require the same treatment as sporadic cases. Pediatr Blood Cancer 2015;62:1733–1738. © 2015 Wiley Periodicals, Inc.

Asparaginase is an essential component of combination chemotherapy for childhood acute lymphoblastic leukemia and non-Hodgkin lymphoma. The value of asparaginase was further addressed in a group of non-very high-risk patients by comparing prolonged (long-asparaginase) versus standard (short-asparaginase) native E. coli asparaginase treatment in a randomized part of the phase III 58951 trial of the European Organization for Research and Treatment of Cancer Children’s Leukemia Group. The main endpoint was disease-free survival. Overall, 1,552 patients were randomly assigned to long-asparaginase (775 patients) or short-asparaginase (777 patients). Patients with grade ≥2 allergy to native E. coli asparaginase were switched to equivalent doses of Erwinia or pegylated E. coli asparaginase. The 8-year disease-free survival rate (±standard error) was 87.0±1.3% in the long-asparaginase group and 84.4±1.4% in the short-asparaginase group (hazard ratio: 0.87; P=0.33) and the 8-year overall survival rate was 92.6±1.0% and 91.3±1.2% respectively (hazard ratio: 0.89; P=0.53). An exploratory analysis suggested that the impact of long-asparaginase was beneficial in the National Cancer Institute standard-risk group with regards to disease-free survival (hazard ratio: 0.70; P=0.057), but far less so with regards to overall survival (hazard ratio: 0.89). The incidences of grade 3–4 infection during consolidation (25.2% versus 14.4%) and late intensification (22.6% versus 15.9%) and the incidence of grade 2–4 allergy were higher in the long-asparaginase arm (30% versus 21%). Prolonged native E. coli asparaginase therapy in consolidation and late intensification for our non-very high-risk patients did not improve overall outcome but led to an increase in infections and allergy. This trial was registered at www.clinicaltrials.gov as #NCT00003728.

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.

Resume Propos Le but de notre etude est de decrire les leucemies aigues lymphoblastiques du 1 er mois de vie sur une base populationnelle exhaustive, d’en analyser les modalites de prise en charge et l’approche ethique. Methodes Nous avons effectue une etude retrospective multicentrique des cas de leucemie aigue lymphoblastique congenitale diagnostiques en France de 1990 a 2010, repertories dans le Registre national des hemopathies malignes de l’enfant et avons analyse leurs caracteristiques cliniques et biologiques, les modalites de traitement, l’evolution et les facteurs pronostiques. Resultats Vingt-deux enfants ont ete inclus, avec un âge median au diagnostic de 5,5 jours. Il est identifie un remaniement en 11q23 ou rearrangement MLL dans 17/22 cas. Le traitement a ete administre avec une ambition curative chez 14 patients ou centre sur une prise en charge palliative chez 7 patients. La survie globale a 2 ans est de 4,5 % ; un seul patient est survivant a long terme, avec de lourdes sequelles neurologiques. En analyse univariee, l’âge inferieur a huit jours au diagnostic, la corticoresistance et l’absence d’obtention de remission complete constituent des facteurs significatifs de mauvais pronostic. Conclusion Dans l’experience que nous rapportons, basee sur un enregistrement national exhaustif, les LAL congenitales apparaissent plus precoces et plus severes que dans les essais therapeutiques ou les nouveau-nes sont inclus de facon selective. Le pronostic oncologique extremement pejoratif conduit a inclure dans la strategie therapeutique la necessite ethique de preserver le confort de l’enfant et d’accompagner les processus d’attachement voire de deuil des parents et de la famille.

Objectives To describe the clinical profile and the prevalence of severe congenital neutropenia (SCN) and HAX1 mutations, so-called Kostmann syndrome, in France. Study Design Two pedigrees were identified from the French registry. Results The study included five subjects (three males), which represent 0.7% of the 759 SCN cases registered in France. The age at diagnosis was 0.3 years (range: 0.1–1.2 years) and the median age at the last follow-up was 7.3 years (range: 1.2–17.8 years). A novel large homozygous deletion of the HAX1 gene (exons 2–5) was found in one pedigree; while, a homozygous frameshift mutation was identified in exon 3 (c.430dupG, p.Val144fs) in the second pedigree. Severe bacterial infections were observed in four patients, including two cases of sepsis, one case of pancolitis, a lung abscess, and recurrent cellulitis and stomatitis. During routine follow-up, the median neutrophil value was 0.16 × 109/L, associated with monocytosis (2 × 109/L). Bone marrow (BM) smears revealed a decrease of the granulocytic lineage with no mature myeloid cells above the myelocytes. One patient died at age 2 from neurological complications, while two other patients, including one who underwent a hematopoietic stem cell transplantation (HSCT) at age 5, are living with very severe neurological retardation. Conclusions SCN with HAX1 mutations, is a rare sub type of congenital neutropenia, mostly observed in population from Sweden and Asia minor, associating frequently neurological retardation, when the mutations involved the B isoform of the protein. Pediatr Blood Cancer 2014;61:1041–1048. © 2014 Wiley Periodicals, Inc.

A minority of children with chronic immune thrombocytopenia (ITP) require therapeutic intervention to prevent haemorrhagic risk. This retrospective national study evaluated romiplostim in childhood non-responsive or refractory chronic ITP. Between 2009 and 2012, 10 patients whose Buchanan score was 3-4 were treated with romiplostim. The median duration of thrombocytopenia was 1·9 years (0·8-15). The median duration of romiplostim treatment was 9 months (3-36). A response was observed in 5/10 patients (one complete, four partial). No serious adverse effect was noticed. The long-term benefit/risk balance of this innovative treatment is currently recorded by Centre de Référence National des Cytopénies Auto-immunes de l'Enfant.

PURPOSE Describe the epidemiology, clinical profiles and outcomes associated with head and neck (H&N) involvement in children/adolescents with B-cell non-Hodgkin lymphoma (B-NHL). METHODS Analysis of children/adolescents with H&N B-NHL prospectively enrolled in the SFOP LMB-89 trial (July 1989-June 1996). RESULTS One hundred and twelve of 561 patients (20%) had H&N involvement. The mean age of the patients was 8.4 years. Murphy staging differed between the H&N patients and the others (P < 0.0001): 9% versus 5% of the patients presented with stage I disease, 36% versus 11% presented with stage II disease, 12% versus 59% presented with stage III disease, 17% versus 10% with stage IV disease and 27% versus 16% with B-AL. Twenty-nine H&N patients (26%) had CNS involvement at diagnosis versus 8.5% in the group without H&N involvement (P < 0.0001). Patients were treated according to the LMB89 protocol: 3 H&N patients were allocated to group A, 70 to group B and 39 to group C. Ninety-seven percent of H&N patients achieved CR and event-free and overall survival at 4 years was 95.5% (5 deaths in patients with CNS disease). On multivariate analysis, EFS was significantly better in H&N patients than in non-H&N patients (P = 0.021), but not OS (P = 0.11). CONCLUSION The H&N site is the second most common location for B-NHL at diagnosis and is more frequently associated with disseminated disease and CNS involvement than other sites. However, outcomes are no worse for these patients than for the rest of the population.

BACKGROUND: Intrapartum intravenous zidovudine (ZDV) prophylaxis is a long-standing component of prevention of mother-to-child transmission (MTCT) of human immunodeficiency virus (HIV) in high-resource countries. In some recent guidelines, intravenous ZDV is no longer systematically recommended for mothers receiving combination antiretroviral therapy (cART) with low viral load. We evaluated the impact of intravenous ZDV according to viral load and obstetrical conditions. METHODS: All HIV-1-infected women delivering between 1 January 1997 and 31 December 2010 in the French Perinatal Cohort (ANRS-EPF) were analyzed if they received ART during pregnancy and did not breastfeed. We identified maternal and obstetrical characteristics related to lack of intravenous ZDV and compared its association with MTCT rate and other infant parameters, according to various risk factors. RESULTS: Intravenous ZDV was used in 95.2% of the 11 538 deliveries. Older age, multiparity, and preterm and vaginal delivery were associated with lack of intravenous ZDV (n = 554). In women who delivered with viral load ≥1000 copies/mL, the overall MTCT rate was higher without than with intravenous ZDV (7.5% vs 2.9%; P = .01); however, there was no such difference when the neonate received postnatal intensification therapy. Among them, 77% of women who had viral load

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.

Purpose Very few childhood cancer survivor studies have been devoted to thyroid adenomas. We assessed the role of chemotherapy and the radiation dose to the thyroid in the risk of thyroid adenoma after childhood cancer. Methods and Materials A cohort of 3254 2-year survivors of a solid childhood cancer treated in 5 French centers before 1986 was established. The dose received by the isthmus and the 2 lobes of the thyroid gland during each course of radiation therapy was estimated after reconstruction of the actual radiation therapy conditions in which each child was treated as well as the dose received at other anatomical sites of interest. Results After a median follow-up of 25 years, 71 patients had developed a thyroid adenoma. The risk strongly increased with the radiation dose to the thyroid up to a few Gray, plateaued, and declined for high doses. Chemotherapy slightly increased the risk when administered alone but also lowered the slope of the dose-response curve for the radiation dose to the thyroid. Overall, for doses up to a few Gray, the excess relative risk of thyroid adenoma per Gray was 2.8 (90% CI: 1.2-6.9), but it was 5.5 (90% CI: 1.9-25.9) in patients who had not received chemotherapy or who had received only 1 drug, and 1.1 (90% CI: 0.4-3.4) in the children who had received more than 1 drug ( P =.06, for the difference). The excess relative risk per Gray was also higher for younger children at the time of radiation therapy than for their older counterparts and was higher before attaining 40 years of age than subsequently. Conclusions The overall pattern of thyroid adenoma after radiation therapy for a childhood cancer appears to be similar to that observed for thyroid carcinoma.

International audience; ABSTRACT: Autosomal dominant deficiency of signal transducer and activator of transcription 3 (STAT3) is the main genetic etiology of hyper-immunoglobulin (Ig) E syndrome. We documented the molecular, cellular, and clinical features of 60 patients with heterozygous STAT3 mutations from 47 kindreds followed in France. We identified 11 known and 13 new mutations of STAT3. Low levels of interleukin (IL)-6-dependent phosphorylation and nuclear translocation (or accumulation) of STAT3 were observed in Epstein-Barr virus-transformed B lymphocytes (EBV-B cells) from all STAT3-deficient patients tested. The immunologic phenotype was characterized by high serum IgE levels (96% of the patients), memory B-cell lymphopenia (94.5%), and hypereosinophilia (80%). A low proportion of IL-17A-producing circulating T cells was found in 14 of the 15 patients tested. Mucocutaneous infections were the most frequent, typically caused by Staphylococcus aureus (all patients) and Candida albicans (85%). Up to 90% of the patients had pneumonia, mostly caused by Staph. aureus (31%) or Streptococcus pneumoniae (30%). Recurrent pneumonia was associated with secondary bronchiectasis and pneumatocele (67%), as well as secondary aspergillosis (22%). Up to 92% of the patients had dermatitis and connective tissue abnormalities, with facial dysmorphism (95%), retention of decidual teeth (65%), osteopenia (50%), and hyperextensibility (50%). Four patients developed non-Hodgkin lymphoma. The clinical outcome was favorable, with 56 patients, including 43 adults, still alive at the end of study (mean age, 21 yr; range, 1 mo to 46 yr). Only 4 patients died, 3 from severe bacterial infection (aged 1, 15, and 29 yr, respectively). Antibiotic prophylaxis (90% of patients), antifungal prophylaxis (50%), and IgG infusions (53%) improved patient health, as demonstrated by the large decrease in pneumonia recurrence. Overall, the prognosis of STAT3 deficiency may be considered good, provided that multiple prophylactic measures, including IgG infusions, are implemented.

To determine whether a risk factor adapted chemotherapy would improve the outcome of non-metastatic bone Ewing's sarcoma.Standard risk tumours (SR, good histological response to chemotherapy or small unresected tumours) received the previous EW88 chemotherapy. Ifosfamide/etoposide (IE) were introduced after 3 courses of cyclophosphamide/doxorubicine when tumour regression was50% or during consolidation therapy for the intermediate risk tumours (IR, intermediate histological response 5-30% residual cells or large unresected tumours100ml). High risk tumours (HR, histological poor response30% residual cells or clinical poor response50% for unresectable tumours), received IE prior high dose busulfan/melphalan with stem cell rescue.From 1993 to 1999, 214 patients were enrolled. 5 y-EFS and OS were 60% (95% confidence interval (CI), 53-66) and 69% (95% CI, 63-75), respectively. 116 (54%), 46 (21%), 48 (22%) patients were considered as SR, IR and HR of relapse, respectively. No advantage to IE was observed in the IR group. As compared to previous study, tumour with poor histological response to induction chemotherapy seemed to benefit from the consolidation strategy including busulfan/melphalan: EFS were 45% (95% CI, 30-60) and 20% (95% CI, 7-43) for EW93 and EW88, respectively. Despite a risk-adapted strategy, histological response to chemotherapy remains the main prognostic factor in resected tumours, while initial tumour volume is the main prognostic factor for unresected tumours.These results showing a potential benefit of a consolidation strategy including busulfan/melphalan as compared to conventional chemotherapy needed confirmation by a randomised trial and were one of the bases of the ongoing EuroEwing99.

Background Intensive chemotherapy has markedly improved the survival of children with acute lymphoblastic leukaemia (ALL) or lymphoblastic lymphoma (LL). Evaluation of late effects and analysis of factors contributing to their occurrence has become of major importance. Second neoplasm (SN) belongs to the most severe late events. Procedure We report the incidence of SN which occurred in patients recruited in EORTC trial 58881 for children with ALL or LL. The front-line treatment regimen was adapted from the BFM protocol, but did not include cranial radiotherapy, even in patients with initial involvement of the central nervous system. A total of 2,216 patients were recruited, of whom 2,136 achieved complete remission (CR). Results At a median follow-up of 7.5 years, 22 (1%) patients developed a SN: 20 during or after completion of front-line therapy and 2 in second CR, after relapse treatment including haematopoietic stem cell transplantation (HSCT). Ten patients developed acute myeloblastic leukaemia. Only one SN, a glioblastoma, was a brain tumour. Other SN were: two Hodgkin lymphomas, one non-Hodgkin lymphoma, two thyroid cancers, one osteosarcoma, two soft tissue sarcomas, one Ewing sarcoma, one cutaneous histiocytosis and one peritoneal carcinomatosis. The cumulative incidences of SN at 5, 8 and 13 years after registration were 0.8% (SE 0.2%), 1.0% (SE 0.2%) and 3.0% (SE 1.9%), respectively. Conclusion The overall incidence rate of SN is comparable to that reported previously. In spite of short follow-up time, the low incidence of brain tumours might be related to the omission of cranial radiotherapy. Pediatr Blood Cancer 2011;57:119–125. © 2011 Wiley-Liss, Inc.

BACKGROUND Very few previous studies have addressed the question of colorectal cancer (CRC) after childhood cancer treatment. We aimed to quantify the roles of radiation therapy and chemotherapy agents in the occurrence of subsequent CRC. METHODS A nested case-control study was conducted using 36 CRC cases and 140 controls selected from 7032 five-year survivors of the French Childhood Cancer Survivor Study (FCCSS) cohort, treated from 1945 to 2000 in France. The radiation dose-distribution metrics at the site of CRC and doses of individual chemotherapeutic agents were calculated. Conditional logistic regressions were performed to calculate odds ratios (ORs). RESULTS Overall, patients who received radiotherapy with estimated dose to colon had a 4.3-fold (95% CI, 1.3-17.6) increased risk for CRC compared with patients who did not receive radiotherapy, after adjustment for chemotherapy. This risk increased to 8.9-fold and 19.3-fold among patients who received radiation doses ranging from 20 to 29.99 Gy and ≥30 Gy, respectively. Our data reported a significantly elevated OR for anthracyclines, after controlling for radiotherapy and MOPP regimen. But, restricted analyses excluding patients who had received ≥30 Gy showed that only radiation doses ranging from 20 to 29.99 Gy produced a significant increase in subsequent CRC risk (OR = 7.8; 95% CI, 1.3-56.0), after controlling for anthracyclines and MOPP regimen. CONCLUSIONS The risk of subsequent CRC was significantly increased after radiation dose (even

PurposeIfosfamide is widely used in pediatric oncology but its nephrotoxicity may become a significant issue in survivors. This study is aimed at evaluating the incidence of late renal toxicity of ifosfamide and its risk factors.Patients and MethodsOf the 183 patients prospectively investigated for renal function, 77 treated for rhabdomyosarcoma, 39 for other soft tissue sarcoma, 39 for Ewing's sarcoma, and 28 for osteosarcoma were investigated at least 5 years after treatment. No patients had received cisplatin and/or carboplatin. Glomerular and tubular functions were graded according to the Skinner system.ResultsThe median dose of ifosfamide was 54 g/m2(range, 18 to 117 g/m2). After a median follow-up of 10 years, 89.5% of patients had normal tubular function, and 78.5% had normal glomerular function rate (GFR). Serum bicarbonate and calcium were normal in all patients. Hypomagnesemia was observed in 1.2% and hypophosphatemia in 1%. The tubular threshold for phosphate was reduced in 24% of the patients (grade 1 in 15%, grade 2 in 8%, and grade 3 in 0.5%). Glycosuria was detected in 37% of the patients but was more than 0.5 g/24 hours in only 5%. Proteinuria was observed in 12%. Ifosfamide dose and interval from therapy to investigations were predictors of tubulopathy in univariate and multivariate analysis. In a multivariate analysis, an older age at diagnosis and the length of interval since treatment had independent impacts on the risk of abnormal GFR.ConclusionRenal toxicity is moderate with a moderate dose of ifosfamide. However, since it can be permanent and can get worse with time, repeated long-term evaluations are important, and this risk should be balanced against efficacy.

Background— Cardiac disease (CD) is one of the major side effects of childhood cancer therapy, but until now little has been known about the relationship between the heart radiation dose (HRD) received during childhood and the risk of CD. Methods and Results— The cohort comprised 3162 5-year survivors of childhood cancer. Chemotherapy information was collected and HRD was estimated. There were 347 CDs in 234 patients, 156 of them were rated grade ≥3. Cox and Poisson regression models were used. The cumulative incidence of any type of CD at 40 years of age was 11.0% (95% confidence interval [CI], 9.5–12.7) and 7·4% (95% CI, 6.2–8.9) when only the CDs of grade ≥3 were considered. In comparison with patients who received no anthracycline and either no radiotherapy or an HRD Conclusions— Survivors of childhood cancers treated with radiotherapy and anthracycline run a high dose-dependent risk of developing CD. CDs develop earlier in patients treated with anthracycline than in those treated without it.

Rhabdomyosarcoma (RMS) occasionally occurs in a context of a predisposition syndrome. The most common predisposition syndromes include germline TP53 mutations and constitutive alterations in RAS pathway activation, such as Costello syndrome, Noonan syndrome and neurofibromatosis type 1. We report a national retrospective series of 16 RMS occurring in neurofibromatosis type 1 (NF1) patients during childhood, within a 20-year period.The mean age at diagnosis of the cancer was 2.5 years. All were embryonal subtype. Most tumours developed in the pelvis. One was metastatic. Chemotherapy and radiotherapy were normally scheduled without any specific toxicity. The 5-year event-free survival and overall survival were 67% and 87%, respectively. Long-term sequel related to chemotherapy consisted in two chronic tubulopathies, hence not obviously different from non-NF1 patients. No second cancer was reported so far with a median follow-up of 9.7 years. The genomic analysis performed on six samples revealed the abnormalities commonly observed in sporadic RMS: gain of chromosome 2 (5/6), 8 (6/6) and chromosome 11p loss of heterozygosity (5/6). Interestingly, we identified small deletions in tumour suppressor genes that may synergize with NF1 inactivation.Patients with neurofibromatosis are prone to develop embryonal-type RMS that require the same treatment as sporadic cases.

The aim of this study was to assess the efficacy and adverse effects of 2-chlorodeoxyadenosine (2-CdA) and cytosine arabinoside (Ara-C) in children with refractory Langerhans cell histiocytosis (LCH) and haematopoietic dysfunction. Ten patients, with a median age at diagnosis of 0.5 years, were enrolled in this study. Treatment comprised at least two courses of Ara-C (1000mg/m 2 /d) and 2-CdA (9mg/m 2 /d) administered for 5d every 4 weeks; subsequent median follow-up was 2.8 years (range 0.03–6.4 years). Among the 7 patients who received at least two courses of therapy, disease activity decreased in 6 patients, and control of disease was achieved in all patients after a median delay of 5.5 months. All patients suffered World Health Organisation (WHO) grade 4 haematological toxicity. Two septic deaths occurred shortly after administration of the first course of 2-CdA/Ara-C; a third patient was withdrawn from the trial after the first course and subsequently died following haematopoietic stem cell transplantation. This series is small, but we conclude that 2-CdA and Ara-C combined chemotherapy probably has major activity in childhood refractory Langerhans cell histiocytosis.

Congenital dyserythropoietic anemia type I (CDA I) is a rare disorder of erythropoiesis. The objective of this study was to describe the clinical and laboratory manifestations, the diagnosis procedure, the therapeutic approaches and outcome in CDA I. The 12 patients included belong to the retrospective French Multicenter Study. Clinical and biologic data were compiled. Biologic tests included light and, in some cases, electron microscopy, ektacytometry, and red cell membrane protein electrophoresis. Neonatal manifestations (anemia, early jaundice, and/or splenomegaly) and bone abnormalities were present in 11 of the 12 and 6 of the 12 patients, respectively. CDA I was initially misdiagnosed in four children. By the time of diagnosis, anemia with reticulocytosis lower than expected in a hemolytic anemia was present in all patients. Bone marrow electron microscopy examination revealed characteristic findings in all nine children. Red cell membrane protein 4.1 was reduced in all five children. At least one transfusion was required in 11 of the 12 children. Interferon alpha2 corrected anemia in the three children who received monthly transfusions. CDA I is commonly misdiagnosed in children. It should be sought in patients with unexplained chronic anemia, especially when associated with neonatal manifestations, jaundice, splenomegaly, subnormal or low reticulocytosis, and congenital bone malformations.

Congenital dyserythropoietic anaemia (CDA) type I is a rare, inherited disorder characterised by ineffective erythropoiesis and macrocytic anaemia. Complex bone disease has only occasionally been associated with this disease. CDA I is caused by mutations in the CDAN1 gene encoding for codanin-1. Our aim was to characterise the CDAN1 mutation in eight unrelated patients with sporadic CDA I, three of whom had complex bone disease. Six novel mutations in the CDAN1 gene were identified. In two patients, one mutation and in another, both mutations were elusive. No patient was homozygous for a null-type mutation. However, one patient with complex bone disease was homozygous for a splice-site mutation (IVS-12+5G>A). Western blotting revealed that codanin-1 synthesis was 65% less than the control. Five single nucleotide polymorphisms (SNPs) previously unreported in the literature or the SNP database were also identified. Although the absence of codanin-1 is probably lethal, the presence of 35% of the protein was compatible with life but was associated with severe clinical manifestations. However, in most patients studied, no correlation could be established between the expected levels of codanin-1 or the nature of the mutation and the severity of the clinical manifestations.

The objective of the present study was to investigate the role of early common infections and perinatal characteristics in the aetiology of childhood common leukaemia. A case-control study was conducted from 1995 to 1998 in France, and included 473 incident cases of acute leukaemia (AL) (408 acute lymphoblastic leukaemia (ALL), 65 acute myeloid leukaemia (AML) age-, sex- and region-matched with 567 population-based controls. Data on the medical history of the child and his/her environment were collected using self-administered questionnaires. Analyses were conducted using nonconditional logistic regression. A slight negative association with early infections was observed (OR=0.8; 95% CI (0.6-1.0)). The association was stronger for early gastrointestinal infections. Early day-care was found to be associated with a decreased risk of AL (OR=0.6; 95% CI (0.4-0.8) and OR=0.8; 95% CI (0.5-1.2) for day-care starting before age 3 months and between 3 and 6 months, respectively). No association with breast-feeding was observed, irrespective of its duration. A birth order of 4 or more was associated with a significantly increased risk of AL (OR=2.0; 95% CI (1.1-3.7) with ALL). A history of asthma was associated with a decreased risk of ALL (OR 0.5; 95% CI (0.3-0.90). Although the results regarding birth order and breast-feeding do not fit with Greaves' hypothesis, the study supports the hypothesis that early common infections may play a protective role in the aetiology of childhood leukaemia, although this effect was not more marked for common ALL.

Viral infection is an important cause of morbidity and mortality in the post-allograft period. Recently, a new therapeutic approach was developed in post-transplant lymphoproliferative disorder (PTLD) induced by Epstein-Barr virus (EBV): the anti-CD20 monoclonal antibody or rituximab. We performed a single-center study on the treatment effectiveness of rituximab in three EBV-induced PTLD and evaluated biologic data, such as T and B lymphocytes count, during PTLD development and treatment. Before PTLD treatment, blood cell profile showed a severe T lymphopenia with a progressive increase of CD8+ cells and B lymphopenia. Secondly, during treatment, there appeared a T response, as in primary EBV, and a regressive B lymphopenia.

Malignant solid tumors have rarely been reported in children with Down syndrome (DS) and are not well known. The authors collected from 1980 to 2001 all cases of solid tumors observed in DS patients aged from birth to 19 years within the network of the Société Française d'Oncologie Pédiatrique (SFOP). Only 21 cases were observed, with a peculiar distribution: a lack of intracranial tumors and embryonal neoplasms combined with an overrepresentation of lymphomas and germ cell tumors. The treatment of solid tumors in DS is difficult, due to physical and psychological impairments, different pharmacogenetic profile, and associated malformations.

N-myc amplification is a major prognostic factor in neuroblastomas and is systematically investigated by Southern blot or polymerase chain reaction (PCR). A retrospective study of N -myc amplification has been carried out using fluorescence in situ hybridization (FISH) in 97 fixed neuroblastomas. For each tumour, FISH was performed on the area that contained the most immature neuroblasts. Among these 97 neuroblastomas, 16 were amplified and 12 were not interpretable. FISH was not interpretable in six cases. All neuroblastomas with N-myc amplification detected by Southern blot/PCR were amplified with FISH, except three that were not interpretable. Four tumours that were not interpretable in Southern blot/PCR contained more than five copies of N-myc by FISH: one was aneuploid and three were truly amplified, containing more than ten copies of N-myc. Among these three patients, two died in a short time of their tumours. Ten cases were not amplified by Southern blot/PCR and showed more than five copies by FISH: four were aneuploid and two showed heterogeneous amplification, with a few cells clearly amplified whereas most were not. Four cases were amplified, of which two patients died of their tumours. This study confirms that when applied to the most immature areas of fixed neuroblastomas, FISH displayed a higher sensitivity than molecular techniques (p < 0.001) and could detect heterogeneous amplification. FISH could therefore become an important complementary procedure in assessing prognosis in neuroblastomas.

International audience; BACKGROUND:Primary immunodeficiencies (PIDs) are inherited diseases associated with a considerable increase in susceptibility to infections. It is known that PIDs can also predispose to cancer and immune diseases, including allergy, autoimmunity, and inflammation.OBJECTIVE:We aimed at determining the incidence of autoimmunity and inflammation in patients with PIDs.METHODS:We have retrospectively screened 2183 consecutive cases of PID in the Centre de Référence Déficits Immunitaires Héréditaires registry (CEREDIH; the French national PID registry) for the occurrence of autoimmunity and inflammation.RESULTS:One or more autoimmune and inflammatory complications were noted in 26.2% of patients, with a risk of onset throughout the patient's lifetime. The risk of autoimmune cytopenia was at least 120 times higher than in the general population, the risk of inflammatory bowel disease in children was 80 times higher, and the risk of other autoimmune manifestations was approximately 10 times higher. Remarkably, all types of PIDs were associated with a risk of autoimmune and inflammatory complications, although the greatest risk was associated with T-cell PIDs and common variable immunodeficiency. The occurrence of autoimmune disease is a negative prognostic factor for survival.CONCLUSIONS:Our results provide the basis for a detailed prospective evaluation of autoimmunity and inflammation in the context of PIDs, with a view to accurately assessing these risks and describing the possible effect of medical intervention.

Neuroblastoma (NB) is the most frequent indication for extracranial pediatric radiotherapy. As long-term survival of high-risk localized NB has greatly improved, we reviewed treatment-related late toxicities in pediatric patients who received postoperative radiotherapy (RT) for localized NB within two French prospective clinical trials: NB90 and NB94. From 1990–2000, 610 children were enrolled. Among these, 35 were treated with induction chemotherapy, surgery, and RT. The recommended RT dose was 24 Gy at ≤ 2 years, 34 Gy at > 2 years, ± a 5 Gy boost in both age groups. The 22 patients still alive after 5 years were analyzed. The median follow-up time was 14 years (range 5–21 years). Late effects after therapy occurred in 73 % of patients (16/22), within the RT field for 50 % (11/22). The most frequent in-field effects were musculoskeletal abnormalities (n = 7) that occurred only with doses > 31 Gy/1.5 Gy fraction (p = 0.037). Other effects were endocrine in 3 patients and second malignancies in 2 patients. Four patients presented with multiple in-field late effects only with doses > 31 Gy. After a median follow-up of 14 years, late effects with multimodality treatment were frequent. The most frequent effects were musculoskeletal abnormalities and the threshold for their occurrence was 31 Gy.

Transient remissions (TRs) of acute leukemia without any antileukemic treatment are extremely rare events. We report 2 TRs of acute lymphoblastic leukemia and acute myeloid leukemia in a 2-year-old boy and a 12-year-old girl, respectively, both associated with red blood cells and platelets transfusions and infection. These 2 factors are frequently present in previously reported cases and could induce a stimulation of the immune system although the underlying mechanisms of TRs are still unknown.

Background: Since the last decades, pediatric ALL classification has integrated new cytogenetic and genomic data, and several genetic risk factors are identified for treatment stratification. Hyperdiploidy, which is the most common cytogenetic abnormality pattern of pediatric B-lineage ALL, is known since the early 80s and is found in 25-30% of cases. It has been recognized as an isolated good prognostic factor, especially High Hyperdiploidy (HeH), defined by a modal chromosome number higher than 50. In addition, treatment descalations were performed based on NCI criteria for low risk ALL (low leucocytosis < 10 x 109/L and/or age from 1 to ²10 years old) and/or lack of high risk features. Aim: The aim of this study was to assess whether age, under or over 10 years old, has a prognostic impact on the outcome in children presenting B-cell ALL with low risk criteria, and whether therapeutic intensification might improve the outcome within each age group. Methods: Among 2039 patients treated in EORTC 58951 (BFM backbone) from 1998 to 2008, 370 children with B-cell ALL and low risk criteria such as HeH (with classical profile of chromosome gains), low leucocytosis (< 10x109/L), a lack of CNS or gonadal involvement and a lack of very high features (poor response to prephase) were included in this study. Hyperdiploidy was determined either by cytogenetics or flow cytometry. Patients were stratified into 2 risk groups: very low risk (VLR) group or standard risk (AR1) group. VLR group was defined by the criteria indicated above. It led to a less intensive treatment, particularly lower number of injections of anthracyclines and alkylating agents. AR1 group included children with surreptitious or hemorrhagic CNS involvement, and/or HeH with mismatch between modal chromosome number and DNA index. The upper limit of age in the EORTC 58951 was less than 18 years. Main endpoints were Event-Free Survival (EFS) and Overall Survival (OS). Results: Overall patients with low risk hyperdiploid B-cell ALL features treated according to a VLR or AR1 protocol had 6-year EFS and OS rates of 90.3% and 96.2% respectively. These results were comparable to previous published studies on hyperdiploidy in childhood B-lineage ALL. All patients but one reached complete remission after the induction phase. There were 315 children aged less than 10 years old and 55 patients aged 10 to 17 years old. Among children aged 10 years and older treated in VLR or AR1 groups, 6-year EFS and OS rates were respectively 86.7% and 96.4%. In comparison, among less than 10 year old childrentreated in VLR or AR1 groups, 6-year EFS and OS rates were respectively 89.8% (p=0.42) and 95.9% (p=0.93). Age did not appear as a significant prognostic factor in the outcome. Furthermore, among children aged 10 years and older, those treated in the standard risk group (AR1) had 6-year EFS and OS rates of 90% and 100% respectively. This seemed better than for children treated in the very low risk group, with respectively 84% and 92% rates. However, no significant gain was found for children who received standard risk treatment (for EFS and OS rates: p=0.47 and p=0.12 respectively). Relapse and treatment toxicity rates were comparable in both groups. Concerning long-term cardiac toxicity, despite the fact that no significant difference was found between the two risk groups of treatment, standard treatment leads to higher dose of anthracyclines and an increased theoretical risk of cardiac toxicity. Conclusion: In conclusion, age did not appear as a significant prognostic factor in outcome of children treated for a low risk B-cell ALL. Moreover, among children aged 10 years and older, therapeutic intensification in standard risk group did not lead to a significant gain in outcome. However, results are not significant, partly due to a low number of patients, and larger studies should be performed to evaluate whether these children could benefit from a less intensive treatment. Disclosures No relevant conflicts of interest to declare.

To describe the clinical profile and the prevalence of severe congenital neutropenia (SCN) and HAX1 mutations, so-called Kostmann syndrome, in France.Two pedigrees were identified from the French registry.The study included five subjects (three males), which represent 0.7% of the 759 SCN cases registered in France. The age at diagnosis was 0.3 years (range: 0.1-1.2 years) and the median age at the last follow-up was 7.3 years (range: 1.2-17.8 years). A novel large homozygous deletion of the HAX1 gene (exons 2-5) was found in one pedigree; while, a homozygous frameshift mutation was identified in exon 3 (c.430dupG, p.Val144fs) in the second pedigree. Severe bacterial infections were observed in four patients, including two cases of sepsis, one case of pancolitis, a lung abscess, and recurrent cellulitis and stomatitis. During routine follow-up, the median neutrophil value was 0.16 × 10(9)/L, associated with monocytosis (2 × 10(9)/L). Bone marrow (BM) smears revealed a decrease of the granulocytic lineage with no mature myeloid cells above the myelocytes. One patient died at age 2 from neurological complications, while two other patients, including one who underwent a hematopoietic stem cell transplantation (HSCT) at age 5, are living with very severe neurological retardation.SCN with HAX1 mutations, is a rare sub type of congenital neutropenia, mostly observed in population from Sweden and Asia minor, associating frequently neurological retardation, when the mutations involved the B isoform of the protein.

PURPOSE The in vivo response to prephase corticosteroid therapy for 1 week has been described as a major prognostic factor in childhood acute lymphoblastic leukemia (ALL). Patients with less than 1,000 blasts/microL at day 8 are considered responders and have a better prognosis. This prephase therapy is usually considered as an evaluation of glucocorticoid sensitivity. In fact, it also includes one intrathecal (IT) injection of methotrexate (MTX). In this study, we try to clarify the influence of this injection of IT MTX on the response to the prephase therapy. PATIENTS AND METHODS This retrospective study analyzed the response to prephase therapy in 1,044 children with ALL entered onto the European Organization for Research and Treatment of Cancer (EORTC) trial 58881 of the Children's Leukemia Cooperative Group (CLCG). Analysis was restricted to 732 cases with an initial blast count greater than 1,000/microL. The following variables were tested to analyze response to prephase therapy: age, sex, evaluated risk factor (RF), blast count on day 0, actual dose of prednisolone administered, immunophenotype (T v non-T), and day of IT MTX. For statistical analysis, the variable day of IT MTX (D) was stratified into three groups: group 1 if D less than 2, group 2 if D > or = 2 but < or = 6, and group 3 if D greater than 6. RESULTS All variables tested had a significant influence on response to the prephase therapy. This was especially true for IT MTX: 90.4% responders in group 1, 76.9% in group 2, and 70% in group 3 (P < .001). Immunophenotype was also a major predictor of response to the prephase: 88% responders in B-lineage ALL versus 56.2% in T-lineage ALL. IT MTX had a significant influence in B-lineage ALL (96% responders in group 1, 90% in group 2, and 79% in group 3; P < .001), whereas the influence could not be detected in T-lineage ALL. CONCLUSION These results clearly demonstrate a therapeutic systemic effect of low doses of IT MTX in childhood ALL, and response to prephase therapy should not be considered as an in vivo test for cortico-sensitivity only. Earlier use of IT MTX leads to a higher percentage of responders.

Describe the epidemiology, clinical profiles and outcomes associated with head and neck (HN) involvement in children/adolescents with B-cell non-Hodgkin lymphoma (B-NHL).Analysis of children/adolescents with HN B-NHL prospectively enrolled in the SFOP LMB-89 trial (July 1989-June 1996).One hundred and twelve of 561 patients (20%) had HN involvement. The mean age of the patients was 8.4 years. Murphy staging differed between the HN patients and the others (P0.0001): 9% versus 5% of the patients presented with stage I disease, 36% versus 11% presented with stage II disease, 12% versus 59% presented with stage III disease, 17% versus 10% with stage IV disease and 27% versus 16% with B-AL. Twenty-nine HN patients (26%) had CNS involvement at diagnosis versus 8.5% in the group without HN involvement (P0.0001). Patients were treated according to the LMB89 protocol: 3 HN patients were allocated to group A, 70 to group B and 39 to group C. Ninety-seven percent of HN patients achieved CR and event-free and overall survival at 4 years was 95.5% (5 deaths in patients with CNS disease). On multivariate analysis, EFS was significantly better in HN patients than in non-HN patients (P = 0.021), but not OS (P = 0.11).The HN site is the second most common location for B-NHL at diagnosis and is more frequently associated with disseminated disease and CNS involvement than other sites. However, outcomes are no worse for these patients than for the rest of the population.

Epidermodysplasia verruciformis (EV) is characterized by persistent cutaneous lesions caused by a specific group of related human papillomavirus genotypes (EV-HPVs) in otherwise healthy individuals. Autosomal recessive (AR) EVER1 and EVER2 deficiencies account for two thirds of known cases of EV. AR RHOH deficiency has recently been described in two siblings with EV-HPV infections as well as other infectious and tumoral manifestations. We report here the whole-exome based discovery of AR MST1 deficiency in a 19-year-old patient with a T-cell deficiency associated with EV-HPV, bacterial and fungal infections. MST1 deficiency has recently been described in seven patients from three unrelated kindreds with profound T-cell deficiency and various viral and bacterial infections. The patient was also homozygous for a rare ERCC3 variation. Our findings broaden the clinical range of infections seen in MST1 deficiency and provide a new genetic etiology of susceptibility to EV-HPV infections. Together with the recent discovery of RHOH deficiency, they suggest that T cells are involved in the control of EV-HPVs, at least in some individuals.

Objective: While splenectomy is the gold standard treatment for refractory primary immune thrombocytopenia (ITP) in adult, its place remains debated in children. The French Rare Disease Plan provided us the opportunity to conduct a collaborative study of the efficiency and tolerance of this procedure in childhood ITP. Patients and methods: A retrospective study was conducted in France in order to identify children with ITP treated with splenectomy during a 9-year period. A total of 78 children were included. Data from the ongoing CEREVANCE national cohort of childhood auto-immune cytopenia in 30 units were reviewed and completed by a direct contact with the referent physicians. International terminology for response definition was used. Relapsefree survival was assessed by the Kaplan-Meier method. Results: The median ages at ITP diagnosis and splenectomy were 9.6 and 12.4 years respectively. The median duration of ITP before splenectomy was 24 months (1-162); 62 children had chronic ITP. The median number of treatment lines before splenectomy was 2 (1-7). Laparoscopy was used in 81% of cases. Four children underwent immediate surgical complications. With a median follow-up of 41 months, complete remission (CR) was maintained at the latest news in 84% of children. CR was obtained in 77% of cases with intra-splenic platelets destruction, and in no case with non-splenic destruction (p=0.11). Using a very strict definition for relapse, the 5-year relapse-free survival was 51% [IC95% 37-64]. No death or overwhelming sepsis was reported. Conclusions: In this national study with a long term follow up, the excellent benefit/risk ratio of splenectomy for refractory ITP confirms that in skilled and concerted teams, the procedure is still at the forefront of curative treatments. Isotopic evaluation is of value but other prognostic factors for CR are to be determined. Lifelong survey of potential infectious and thrombotic risk at adult age has to be coordinated by the referring physician. The place for other therapeutic options, in order to postpone as late as possible the splenectomy in childhood ITP is now to be determined.

Among 22 independent patients from the GENHYPOPIT network who had ACTH deficiency and no identified mutation of TPIT, three of them (13.6%) displayed common variable immunodeficiency (CVID), characterized by defective Ig production.Our objective was to describe an as yet unrecognized disease association.We considered the hypothesis of ACTH deficiency being associated with antipituitary autoimmunity or lymphocytic hypophysitis. In the context of a functional network between the immune and endocrine systems, we also tested the hypothesis of a common genetic cause using a candidate gene approach.This was a multicentric study in three academic hospitals.We report four patients from three unrelated families presenting with ACTH deficiency and CVID.Detection of antipituitary autoantibodies, and sequencing of candidate genes (LIF, IKAROS, EOS) were the main outcome measures.All patients including a pedigree with two affected siblings had ACTH deficit diagnosed from 5-15 yr, with symptomatic hypoglycemia, and CVID diagnosed from 2-8 yr revealed by recurrent infections. Three of the four patients had a hypoplastic pituitary. One patient had low IGF-I and subnormal GH response to stimulation, suggesting that secretion of other pituitary hormones may also be affected. All patients proved negative for pituitary autoantibodies and had no alteration in any of the genes tested.The remarkable association of two rare disorders affecting two functionally related systems in four patients from three independent pedigrees including a familial case provides strong evidence of the existence of a disease association: deficit in anterior pituitary function and variable immune deficiency, or DAVID.

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.

There is little data available regarding children and adolescents with Hodgkin lymphoma (HL) who relapse after combined-modality treatment, even though they have a substantial chance of cure. The purpose of this national retrospective study was to evaluate the outcome of patients with recurrent/refractory HL and determine adverse prognostic factors. From 1990 to 2006, 70 patients (median age 13·9 years) with refractory (n = 31) or first relapse (n = 39) HL were identified. Median time from end of treatment to relapse was 6 months (3-56). Relapses occurred in irradiated areas in 43/70 patients. Salvage therapy consisted of chemotherapy and 50 patients received high-dose chemotherapy with autologous stem cell transplantation. Radiotherapy was performed in 29 cases, tandem autologous transplantation in five and allograft in three. With a median follow-up of 40 months (2-140), significant prognostic factors were time to progression/relapse and response to therapy before autograft. Event-free survival and overall survival in patients with refractory disease, early relapse and late relapse were 35 ± 9%, 67 ± 11%, 76 ± 10% and 48 ± 11%, 89 ± 7% and 80 ± 10%, respectively. As progression3 months was a major adverse prognostic factor, novel therapeutic approaches are needed for this group of patients. By contrast, patients have substantial chance of long term second remission in case of relapse3 months.

Background Vinblastine (VBL) is the standard treatment for systemic Langerhans cell histiocytosis (LCH), but little is known about its efficacy in central nervous system (CNS) mass lesions. Methods A retrospective chart review was conducted. Twenty patients from the French LCH Study Group register met the inclusion criteria. In brief, they had CNS mass lesions, had been treated with VBL, and were evaluable for radiologic response. Results The median age at diagnosis of LCH was 11.5 years (range: 1-50). Intravenous VBL 6 mg/m2 was given in a 6-week induction treatment, followed by a maintenance treatment. The median total duration was 12 months (range: 3-30). Eleven patients received steroids concomitantly. Fifteen patients achieved an objective response; five had a complete response (CR: 25%), ten had a partial response (PR: 50%), four had stable disease (SD: 20%) and one patient progressed (PD: 5%). Of interest, four out of the six patients who received VBL without concomitant steroids achieved an objective response. With a median follow-up of 6.8 years, the 5-year event-free and overall survival was 61% and 84%, respectively. VBL was well-tolerated and there were no patient withdrawals due to adverse events. Conclusion VBL, with or without steroids, could potentially be a useful therapeutic option in LCH with CNS mass lesions, especially for those with inoperable lesions or multiple lesions. Prospective clinical trials are warranted for the evaluation of VBL in this indication.

Lopinavir-ritonavir is a human immunodeficiency virus 1 (HIV-1) protease inhibitor boosted by ritonavir, a cytochrome p450 inhibitor. A warning about its tolerance in premature newborns was recently released, and transient elevation of 17-hydroxyprogesterone (17OHP) was noted in 2 newborns treated with lopinavir-ritonavir in France.To evaluate adrenal function in newborns postnatally treated with lopinavir-ritonavir.Retrospective cross-sectional analysis of the database from the national screening for congenital adrenal hyperplasia (CAH) and the French Perinatal Cohort. Comparison of HIV-1-uninfected newborns postnatally treated with lopinavir-ritonavir and controls treated with standard zidovudine.Plasma 17OHP and dehydroepiandrosterone-sulfate (DHEA-S) concentrations during the first week of treatment. Clinical and biological symptoms compatible with adrenal deficiency.Of 50 HIV-1-uninfected newborns who received lopinavir-ritonavir at birth for a median of 30 days (interquartile range [IQR], 25-33), 7 (14%) had elevated 17OHP levels greater than 16.5 ng/mL for term infants (23.1 ng/mL for preterm) on days 1 to 6 vs 0 of 108 controls having elevated levels. The median 17OHP concentration for 42 term newborns treated with lopinavir-ritonavir was 9.9 ng/mL (IQR, 3.9-14.1 ng/mL) vs 3.7 ng/mL (IQR, 2.6-5.3 ng/mL) for 93 term controls (P.001). The difference observed in median 17OHP values between treated newborns and controls was higher in children also exposed in utero (11.5 ng/mL vs 3.7 ng/mL; P.001) than not exposed in utero (6.9 ng/mL vs 3.3 ng/mL; P = .03). The median DHEA-S concentration among 18 term newborns treated with lopinavir-ritonavir was 9242 ng/mL (IQR, 1347-25,986 ng/mL) compared with 484 ng/mL (IQR, 218-1308 ng/mL) among 17 term controls (P.001). The 17OHP and DHEA-S concentrations were positively correlated (r = 0.53; P = .001). All term newborns treated with lopinavir-ritonavir were asymptomatic, although 3 premature newborns experienced life-threatening symptoms compatible with adrenal insufficiency, including hyponatremia and hyperkalemia with, in 1 case, cardiogenic shock. All symptoms resolved following completion of the lopinavir-ritonavir treatment.Among newborn children of HIV-1-infected mothers exposed in utero to lopinavir-ritonavir, postnatal treatment with a lopinavir-ritonavir-based regimen, compared with a zidovudine-based regimen, was associated with transient adrenal dysfunction.

The safety and efficacy of rituximab have been retrospectively assessed in 17 children with Evans syndrome. Patients received 4 or 3 weekly doses of rituximab (375 mg/m(2) per dose) associated with prednisone, alone (14 patients) or associated with other immunosuppressive drugs. Complete or partial remission of at least one cytopenia was achieved in 13 out of the 17 patients (76%), and lasted in 11 of them with a mean follow-up of 2.4 years (range 0.5-7 years). Steroid therapy was stopped or tapered at 50-100% of the baseline dosage in all long-term responders. Moderate side effects and infection occurred only in 4 and 1 children respectively.

International audience; A case-control study was conducted to investigate the role of a familial history of cancer in the etiology of childhood acute leukemia. The history of cancer in the relatives of 472 cases was compared with that of 567 population-based controls. Recruitment was frequency matched on age, sex and region. The familial history of cancer in each child's relatives was reported by the mother in response to a standardized self-administered questionnaire. A familial history of solid tumor in first or second-degree relatives was associated with an increased risk of acute lymphoblastic leukemia (odds ratio (OR)=1.6 [95% confidence interval, 1.2-2.1]), while a familial history of hematopoietic malignancies in first or second-degree relatives was associated with an increased risk of acute myeloid leukemia (OR=4.3 [1.4-13]). The ORs for the histories of cancer increased with the number of relatives with cancer (OR=1.5 [1.1-2.0] for one relative and OR=2.3 [1.3-3.8] for two relatives or more; Ptrend

The Standards, Options and Recommendations (SOR) project, started in 1993, is a collaboration between the Federation of French Cancer Centres (FNCLCC), the 20 French cancer centres, and specialists from French public universities, general hospitals and private clinics. The main objective is the development of clinical practice guidelines to improve the quality of health care and the outcome of cancer patients. The methodology is based on a literature review and critical appraisal by a multidisciplinary group of experts, with feedback from specialists in cancer care delivery.To establish the Standards, Options and Recommendations clinical practice guidelines for the management of procedure related pain (lumbar puncture, bone marrow aspiration or biopsy, blood sampling) in children oncology patients. To define, on the basis of the critical appraisal of the best available evidence and expert agreement, the clinical situations in which a pain preventive strategy should be implemented.MEDLINE was searched using specific search strategies from January 1966 to August 2004. Literature monitoring was performed to identify controlled clinical trials published in 2005.A total of 57 references were identified. Clinical guidelines have been defined for each invasive procedure.

Between November 1990 and November 1996, EORTC Children Leukemia Group conducted a randomized trial in de novo acute lymphoblastic leukemia and lymphoblastic non-Hodgkin's lymphoma patients using a Berlin-Frankfurt-Munster protocol to evaluate the monthly addition of intravenous 6-mercaptopurine (i.v. 6-MP) (1 g/m(2)) to conventional continuation therapy comprising per oral MTX weekly and 6-MP daily. Only during the first 18 months of the randomization period, 6-MP p.o. was interrupted for 1 week after each i.v. 6-MP. A total of 877 patients was randomized to either no i.v. 6-MP (Arm A) or additional i.v. 6-MP (Arm B). A total of 217 relapses (91 in Group A vs 128 in Group B) and 13 deaths in CR (5 vs 8) were reported; a total of 134 patients (55 vs 79) died. The median follow-up was 7.6 years. At 8 years, the disease-free survival rate was lower (P=0.005) in Arm B (69.1% (s.e.=2.2%)) than in Arm A (77.9% (s.e.=2.0%)), and the hazard ratio was 1.45 (95% CI 1.12-1.89). In conclusion, as delivered in this study, i.v. 6-MP was detrimental to event-free survival.