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Study question What is the impact of the type of myeloablative conditioning (MAC) regimen applied for hematopoietic stem cell transplantation (HSCT) on uterine volume of childhood leukemia survivors? Summary answer Uterine volume is significantly decreased after HSCT. Not only Total Body Irradiation (TBI), but also high-dose chemotherapy-based regimens containing alkylating agents induce uterine damage. What is known already Premature ovarian failure after HSCT is well known, as well as the uterine damage induced by TBI on uterine volume. A few studies have reported smaller uterus after HSCT in women treated with chemotherapy only. In these studies, uterus volume was assessed by a transabdominal and/or transvaginal ultrasonography, and primary diagnosis, age at treatment and chemotherapy regimen were heterogeneous. These preliminary results suggested that alkylating agents could induce uterine damage, as well as they induce fibrosis and vascular damage in ovarian stroma. The impact of chemotherapy on myometrium and uterus is still few investigated. Study design, size, duration A prospective multicentric national study was conducted between 2017, November and 2021, June in 16 University Teaching Hospitals that are following more than 4 500 childhood acute leukemia survivors enrolled in the L.E.A cohort. We included 88 adult women treated for a childhood acute leukemia with HSCT and who agreed a pelvic MRI assessment. Every case was matched 1:1 to control women who underwent MRI for benign ovarian cysts or benign pelvic pathology. Participants/materials, setting, methods Pelvic MRI scans were performed with a 1.5-T or 3T magnetic resonance scanner, including diffusion-weighted imaging sequences. Scans were centralized for a double-blinded lecture by two radiologists. The main outcome was the uterine volume. The secondary outcomes were uterine body-to-cervix ratio and apparent diffusion coefficient (ADC). Univariate and multivariate analyses have investigated the association of clinical and imaging variables with conditioning regimen and age at HSCT. Main results and the role of chance The mean age in HSCT group was 26.5 + 6.3 years. Mean age at HSCT was 9.1 + 0.3 years with a mean follow-up of 16.4 + 0.5 years. Among the 88 women included in HSCT group, two groups of conditioning regimens have been compared to the control group: a chemotherapy-only MAC regimen group with high dose of alkylating agents (n = 34) and one TBI-based regimen group (n = 52). Two MRI scans were not available. Among HSCT group, 75 women were considered as “normally impregnated” by estrogens, by hormone replacement therapy (HRT) for premature ovarian insufficiency (POI) or thanks to a residual ovarian function. Uterine volume was significantly decreased both after chemotherapy-only MAC regimen and after TBI, with respectively 45.3 + 5.6 and 19.6 + 1.9 mL Vs 79.7 + 3.3 mL in control population (p Limitations, reasons for caution The number of pregnancies obtained spontaneously or after oocyte donation in our study population was too low to evaluate the obstetrical impact of uterine damage caused by non-TBI regimens. Wider implications of the findings Our results provide strong evidence that a MAC regimen containing high dose of alkylating agents could induce uterine damage. In these sub-group of women, HRT increases the volume of the uterus compared to non-treated women. After TBI, uterine volume is dramatically decreased, with no benefit of HRT on it. Trial registration number NCT 03583294

Summary Chronic granulomatous disease (CGD) is a rare inherited disorder in which phagocytes lack nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity. The most common form is the X-linked CGD (X91-CGD), caused by mutations in the CYBB gene. Clinical, functional and genetic characterizations of 16 CGD cases of male patients and their relatives were performed. We classified them as suffering from different variants of CGD (X910, X91− or X91+), according to NADPH oxidase 2 (NOX2) expression and NADPH oxidase activity in neutrophils. Eleven mutations were novel (nine X910-CGD and two X91−-CGD). One X910-CGD was due to a new and extremely rare double missense mutation Thr208Arg-Thr503Ile. We investigated the pathological impact of each single mutation using stable transfection of each mutated cDNA in the NOX2 knock-out PLB-985 cell line. Both mutations leading to X91−-CGD were also novel; one deletion, c.-67delT, was localized in the promoter region of CYBB; the second c.253-1879A>G mutation activates a splicing donor site, which unveils a cryptic acceptor site leading to the inclusion of a 124-nucleotide pseudo-exon between exons 3 and 4 and responsible for the partial loss of NOX2 expression. Both X91−-CGD mutations were characterized by a low cytochrome b558 expression and a faint NADPH oxidase activity. The functional impact of new missense mutations is discussed in the context of a new three-dimensional model of the dehydrogenase domain of NOX2. Our study demonstrates that low NADPH oxidase activity found in both X91−-CGD patients correlates with mild clinical forms of CGD, whereas X910-CGD and X91+-CGD cases remain the most clinically severe forms.

In the current study, the safety of the 2014/2015 Northern Hemisphere formulation of Vaxigrip® (Sanofi Pasteur) was assessed to satisfy European Union requirements. Individuals ⩾6 months of age eligible for seasonal influenza vaccination were included. Children 6 months–8 years of age received one dose (0.25 ml for 6–35 mo; 0.5 ml for 3–8 y) on day 0, and those who were previously unvaccinated received a second dose of the same volume on day 28. Participants ⩾9 years of age received one full dose (0.5 ml) on day 0. Frequency categories for solicited reactions were compared with historical data for the closest age group available. A total of 527 participants were included (6 mo–5 y, n = 106; 6–12 y, n = 105; 13–17 y, n = 106; 18–65 y, n = 105; >65 y, n = 105). Frequency categories were higher in this study than for the historical comparator for fever (very common vs. common) in participants 6 months–5 years of age; shivering (very common vs. common), rash (uncommon vs. very rare), and grade 3 injection-site induration (common vs. uncommon) in participants 6–12 years of age; and shivering in participants 13–17 years of age (very common vs. common) and >65 years of age (very common vs. common). However, these increases were not considered clinically significant because confidence intervals for proportions were overlapping and because most of the reactions were of grade 1 to 2 and resolved rapidly and spontaneously. No treatment-related serious adverse events were recorded and no safety concerns or safety signals were detected. These results indicate that the 2014/2015 Northern Hemisphere formulation of Vaxigrip was well tolerated and safe to use in all age groups, with no specific concerns identified, although the study was not powered to detect rare or very rare events.

Toxoplasmosis is a potentially serious fetal infection associated with maternal seroconversion of toxoplasmosis during pregnancy. Follow-up and treatment vary between different countries. We present a case of congenital toxoplasmosis with unusual physiopathology and symptomatology. The mother was immunized before the beginning of pregnancy but immunosuppressive treatments for Crohn disease maintained during the pregnancy could explain toxoplasmosis reactivation in the mother and congenital toxoplasmosis. The baby presented reversible B lymphopenia and hypogammaglobulinemia.

Resume Les reactions locales post-vaccinales (RLPV) sont des evenements indesirables frequents, imputables aux vaccins. Un garcon de trois ans a presente une fievre 24 heures apres le quatrieme rappel du vaccin contre la diphterie, le tetanos, la poliomyelite, la coqueluche (forme acellulaire) et l’ Haemophilus influenzae B (DTPCa-Hib), injecte par voie intramusculaire (IM) dans le deltoide. Dans les heures suivantes, un placard inflammatoire est apparu, indolore, s’etendant rapidement a tout le membre. Un traitement antibiotique a ete instaure dans l’hypothese d’une cellulite infectieuse. Le placard et la fievre ont regresse en 12 heures. L’evolution rapidement favorable a fait retenir le diagnostic final de RLPV. Le risque de RLPV varie selon le terrain, le produit, le nombre et le site d’injection. Elles atteignent couramment l’ensemble d’un membre, surtout apres la quatrieme dose de DTPCa-Hib. L’injection dans le muscle deltoide plutot que dans les muscles de la cuisse avant l’âge de trois ans augmente le risque de RLPV. Le vaccin anti-coqueluche acellulaire a permis de diminuer le nombre d’effets secondaires generaux, mais a provoque une augmentation des RLPV. Ces reactions regressent sous traitement symptomatique et ne contre-indiquent pas le vaccin.

La survie des enfants traites pour un cancer est actuellement de l’ordre de 75 %. Les recidives sont rares apres cinq ans de remission. La surveillance a long terme est donc egalement orientee vers le depistage d’eventuelles sequelles des traitements. La toxicite myocardique, dosedependante, des anthracyclines justifie un suivi cardiologique a long terme. Les complications endocriniennes sont surtout liees a la radiotherapie ou aux chimiotherapies a haute dose. Des troubles de la mineralisation osseuse peuvent etre observes. Au niveau cognitif, les enfants non irradies ont generalement un parcours scolaire puis une insertion socioprofessionnelle normaux. La survenue, rare, d’une seconde pathologie neoplasique peut etre favorisee par le traitement recu. Ameliorer l’information et preserver la qualite de vie (QDV) des patients gueris est un objectif primordial de la prise en charge actuelle des cancers de l’enfant.

Introduction La reaction leucemoide transitoire (RLT) est une proliferation de blastes porteurs de trisomie 21 (T21), de remission spontanee, tres rare. Elle est le plus souvent associee a une T21, homogene ou mosaique, mais la T21 peut etre uniquement medullaire. Certaines RLT s’accompagnent d’une reaction cutanee satellite (RCS). Nous rapportons un cas de RCS severe associee a une RLT sur T21 medullaire non constitutionnelle. Observation Un nouveau-ne presentait a 48 h de vie une eruption severe, faite de lesions erythemateuses, papuleuses, vesiculeuses, pustuleuses et crouteuses predominant sur l’extremite cephalique et atteignant egalement le tronc et les membres. Des prelevements viraux (PCR HSV, VZV), bacteriologiques et mycologiques eliminaient une cause infectieuse. Une blastose sanguine etait mise en evidence a la numeration. L’examen histologique cutane etait peu specifique mais eliminait une histiocytose et une mastocytose. L’analyse chromosomique des blastes trouvait une T21 avec mutation GATA1 positive. La recherche d’un mosaicisme T21 sur les fibroblastes cutanes etait negative. Le diagnostic de RCS d’une RLT neonatale sur une T21 medullaire non constitutionnelle etait retenu. Une hyperhydratation permettait la disparition progressive de la blastose et des lesions cutanees ( Fig. 1 et 2 ). Discussion La physiopathologie de la RLT est mal connue. L’hypothese d’un retard de la maturation des cellules myeloides induisant un dysfonctionnement de la myelopoiese est evoquee. Une T21 est toujours retrouvee dans les blastes. Ce diagnostic justifie la recherche d’un mosaisme T21 quel que soit le phenotype. Les blastes s’eliminent spontanement et une chimiotherapie n’est pas indiquee. Une surveillance rapprochee est cependant necessaire en raison d’un risque accru de leucemie dans les premieres annees de vie. La RCS de la RLT est decrite dans la litterature comme une eruption erythemateuse, vesiculeuse, papuleuse, pustuleuse ou crouteuse predominant au visage, apparaissant au cours d’une RLT. L’examen histologique trouve un infiltrat perivasculaire et dermique leucemoide. Les lesions cutanees regressent sans sequelles avec la disparition de la blastose, et ne justifient pas de traitement specifique. Il existe un risque d’impetiginisation. Seul un faible nombre de patients atteints de RLT presentent une RCS. Les facteurs determinant l’apparition d’une RCS et son role pronostique ne sont pas connus. Dans ce cas, on observait une correlation entre l’intensite de l’eruption cutanee et le taux de blastes sanguins. Conclusion Une eruption neonatale vesiculo-pustuleuse ou crouteuse predominant sur l’extremite cephalique peut reveler une RLT. Comme la blastose, l’eruption est de regression spontanee et ne justifie pas de mesures agressives.

Background The population of survivors of childhood cancer is currently growing. Studies from other countries have shown an increased risk of late mortality. In order to measure this risk within a French cohort, the mortality of children who had survived five years from a cancer diagnosis were compared to the mortality of the general population, according to follow-up interval and cancer and treatment characteristics. Methods The study population consisted of 635 children diagnosed with cancer before the age of 15 who had survived at least five years, and were registered in the Rhone-Alpes region cancer registry from 1987 to 1992. Mortality was compared with general population rates of the Rhone-Alpes region to assess age and sex standardized mortality ratio (SMR) and absolute excess risk of death. Results The median follow-up of children was 14.0 years. Among the 42 observed deaths, 71.4% were attributed to a recurrence of the original cancer, 9.5% to a second cancer. The 15-year cumulative risk of death, all causes, was 7.1%. The overall mortality of the cohort was 20.7 fold greater than the general population (95% CI: 14.9–27.9), and the absolute excess risk of 6.9 per 1000 persons-years. The long term excess-mortality was higher in case of recurrence of original cancer (SMR = 99.9, 95% CI: 67.9–141.9, absolute excess risk 35.4 per 1000 persons-years); it was raised during the five to nine years follow-up interval after diagnosis (SMR = 33.8, 95% CI: 23.2–47.3) mainly due to the primary malignancy, and decreased after (10–14 years follow-up interval SMR = 6.5, 95% IC 2.4–14.2). Conclusion The late mortality of childhood cancer is significantly increased during the five to nine years following diagnosis and decreases after, but the cohort follow-up has to be extended in order to assess outcome beyond 15 years after diagnosis.

Whereas neuroblastoma (NB) with MYCN amplification presents a poor prognosis, no single marker allows to reliably predict outcome in tumours without MYCN amplification. We report here an extensive analysis of 147 NB samples at diagnosis, without MYCN amplification, by chromosomal comparative genomic hybridisation (CGH), providing a comprehensive overview of their genomic imbalances. Comparative genomic hybridisation profiles showed gains or losses of entire chromosomes (type 1) in 71 cases, whereas partial chromosome gains or losses (type 2), including gain involving 17q were observed in 68 cases. Atypical profiles were present in eight cases. A type 1 profile was observed more frequently in localised disease (P

Medullary thyroid carcinoma (MTC) is a rare cancer during childhood. MTC is sporadic in approximately 80% of cases and hereditary in 20%. When hereditary, it can be associated with other endocrine neoplasias and/or typical nonendocrine diseases, thus configuring the multiple endocrine neoplasia (MEN) syndromes. Children with clinically obvious MTC belong to MEN 2A or 2B families, related to RET mutations. The standard treatment is total thyroidectomy and central neck dissection. However, treatment of advanced MTC has not yet been standardized, even if a new tyrosine kinase inhibitor specific to RET mutation has changed the outcome of such patients. Vandetanib plays a role in the treatment of children with metastatic, locally advanced and nonoperable MTC, with good tolerance. We report the 5-year treatment of an 11-year-old patient, with vandetanib and without thyroid surgery.

International audience; We evaluated prospectively the incidence and risk factors of the metabolic syndrome (MS) and its components in 170 adult patients (mean age at evaluation: 24.8±5.4 years) who received an hematopoietic stem cell transplantation for childhood ALL, n=119, or AML, n=51. TBI was carried out in 124 cases; a busulfan-based conditioning was done in 30 patients. Twenty-nine patients developed a MS (17.1%, 95% confidence intervals: 11.7-23.6). The cumulative incidence was 13.4% at 25 years of age and 35.5% at 35 years of age. A higher body mass index (BMI) before transplantation and a growth hormone deficiency were associated with increased MS risk (P=0.002 and 0.01, respectively). MS risk was similar for patients who received TBI or busulfan-based conditioning. The TBI use increased the hyperglycemia risk (odds ratio (OR): 4.7, P=0.02). Women were at the risk of developing increased waist circumference (OR: 7.18, P=0.003) and low levels of high-density lipoprotein cholesterol (OR: 2.72, P=0.007). The steroid dose was not a risk factor. The MS occurs frequently among transplanted survivors of childhood leukemia. Its incidence increases with age. Both intrinsic (BMI, gender) and extrinsic factors (TBI, alkylating agents) contribute to its etiopathogenesis

Malignant infantile osteopetrosis is a rare congenital disease characterized by a dysfunction of osteoclasts followed by an abnormal bone densification. We report the case of a 5-month-old infant in whom this disease was suspected because of the clinical (hepatosplenomegaly, gingival hypertrophy), hematological (pancytopenia and hypocalcemia), and radiological criteria (abnormal bone density, periosteal reaction). The genetic investigation confirmed the diagnosis. Compound heterozygous mutations in the CLCN7 gene were identified, including an as yet undescribed mutation. The second mutation had already been described as being responsible for severe and irreversible neurological damage in patients with osteopetrosis. Since this patient presented severely delayed development, he was not eligible for bone marrow transplantation.

A multidisciplinary working group devoted to epidemiological surveillance of invasive aspergillosis (IA) was created in January 2000 in Grenoble University Hospital. This article presents the results of a three-year IA surveillance. The multidisciplinary working group surveyed all hospitalized patients, and the mycology laboratory detected most suspected IA cases. Cases were reviewed monthly by the Aspergillosis Committee, and were classified according to international consensus criteria. Possible nosocomial acquisition was determined. Among the 490 alerts, 74 IA cases were observed: six proven cases (8%), 36 (49%) probable cases and 32 (43%) possible cases. The incidence was 4.4 (95% CI 3.4-5.4) IA/100 000 patient-days. Among the proven and probable IA cases, we observed 10 nosocomial cases and six cases of undetermined origin. No cases were noted in the protected rooms in the haematology unit. Only one cluster of cases (three nosocomial cases) was detected in the haematology unit. Forty-three percent of cases (N=32) were hospitalized in the haematology unit, and all other cases were hospitalized elsewhere. This three-year survey found a high rate of non-nosocomial IA cases and a high frequency of IA cases hospitalized in units other than haematology. Thus, this study shows the importance of IA surveillance in haematology units and all high-risk units.

Background A secondary end point of the NBL90 protocol (Rubie H et al. Pediatr Oncol 2001;36:247–250) was the concern in this infant population for possible carboplatin-(CBDCA) induced late side effects including impaired renal and hearing functions. Procedure Glomerular filtration rate (GFR), tubular function (TF), pure tone audiometry (PTA), high-frequency, and transient evoked-otoacoustic emission were prospectively assessed in 30 children alive and disease-free 6 years after the end of the treatment. Results Median age at diagnosis and at assessment was 4.7 months and 7 years, respectively. Blood pressure was ≤97.5 centile in all children. The mean estimated GFR was 114 ± 13 ml/min/1.73 m2 by Schwartz formula [range 87–145]. TF assessment failed to demonstrate any impairment. 29/30 children had grade 0 ototoxicity and all transient evoked otoacoustic emission were normal. Conclusions With a 6-year follow-up the combination of VP16 and carboplatin given at conventional doses is safe on renal and hearing functions in infants with unresectable neuroblastomas treated according to SFOP NB90. Pediatr Blood Cancer 2005; 45:32–36. © 2005 Wiley-Liss, Inc.

Resume Objectifs. – L’invagination intestinale sur lymphome reste, pour le chirurgien pediatre, une situation delicate, rare et source de pieges aux consequences parfois lourdes. L’analyse retrospective de sept observations associee a une revue de la litterature permet de degager une conduite a tenir pratique. Observations. – Six garcons et une fille, âges de trois a quinze ans, ont presente un lymphome revele par une invagination intestinale. Tous les enfants ont ete operes par laparotomie : biopsie d’une volumineuse masse abdominale six et huit semaines apres la resection d’un boudin d’invagination (2 cas), resection ileale segmentaire d’un boudin d’invagination necrose (1 cas), hemicolectomie droite realisee devant la constatation d’une tumeur appendiculaire (1 cas), resection cuneiforme d’une lesion tumorale parietale hemicirconferentielle (2 cas), biopsie d’une adenopathie mesenterique lymphomateuse avec analyse extemporanee sans geste sur la lesion tumorale ileale dans un cas. Une polychimiotherapie a ete initiee des le diagnostic. Les suites ont toujours ete simples. Tous les enfants sont suivis sans recidive avec un recul de 15 mois a 13 ans. Commentaires. – L’aspect peroperatoire des lymphomes digestifs doit etre connu de tout chirurgien. Le diagnostic peut etre difficile a porter lors d’un episode d’invagination imposant, en cas d’intervention, des biopsies sur toute zone suspecte. La resection intestinale permet d’alleger la chimiotherapie mais doit etre limitee : resection segmentaire en cas d’invagination irreductible ou de complication, simple tumorectomie en zone saine en cas de lesion parietale isolee. Si le diagnostic de lymphome peut etre obtenu par des prelevements peripheriques (liquide peritoneal, liquide pleural, adenopathie mesenterique, myelogramme, …), le chirurgien peut s’abstenir de tout geste sur le tube digestif en dehors d’une desinvagination manuelle.

Injection site reactions (ISRs) are quite common side effects defined by a local adverse drug reaction directly caused by a vaccine. Twenty-four hours after an intramuscular injection (in the deltoid muscle) of the diphtheria, tetanus, acellular pertussis, inactivated poliomyelitis, Haemophilus influenza type b (DTPCa-Hib) combined vaccine, a 3-year-old boy developed fever. A few hours later, local redness and swelling appeared at the injection site, with rapid extension to the entire limb, it was pain-free, and no other clinical anomalies were present. The patient received intravenous antibiotics for suspected cellulitis. The progression was favorable in 12h (apyrexia and decreased limb swelling), allowing the intravenous antibiotic treatment to be discontinued. Since the child was in excellent general health and recovery was fast, an ISR was diagnosed. Extensive limb swelling is frequent, mostly after the fourth dose of DTPCa-Hib. Deltoid muscle injection of DTP vaccine increases the risk of ISR compared to injection in the thigh, before the age of 3 years. The introduction of acellular pertussis vaccine decreased the risk of general side effects but may increase the risk of ISR. These reactions disappear with symptomatic treatment and do not contraindicate the product.

Resume But de l'etude : L’invagination intestinale aigue est un mode rare de revelation du lymphome de Burkitt chez l’enfant. Cette etude retrospective avait pour but de rapporter huit observations. Patients et methodes : Entre 1988 et 1999, huit enfants, sept garcons et une fille (âge moyen : six ans) ont ete hospitalises pour un syndrome abdominal aigu evoluant depuis un a sept jours. L’echographie abdominale ( n = 8) a permis de faire le diagnostic d’invagination intestinale dans tous les cas, de trouver une masse d’allure tumorale dans deux cas, des adenopathies mesenteriques dans deux cas et des nodules hepatiques dans un cas. Le lavement ( n = 6) a confirme l’existence d’une invagination irreductible. Une laparotomie en urgence a ete realisee dans sept cas et a decouvert la tumeur responsable dans six cas. L’intervention a consiste en une desinvagination ( n = 4) et une resection intestinale pour ischemie ( n = 2). Un seul enfant n’a pas ete opere et le diagnostic a ete fait par ponction de la lesion sous echographie. Resultats : Selon la classification de Murphy, il y avait deux stades II, trois stades III, trois stades IV. La chimiotherapie, selon le protocole LMB, a entraine une remission complete a l’issue de la premiere cure. Les enfants etaient tous vivants au moment de cette etude avec un recul de plus d’un an apres la remission complete. Conclusion : L’echographie abdominale est l’examen essentiel qui permet de reconnaitre l’invagination et parfois la lesion causale. En l’absence de souffrance intestinale echographique, la ponction tumorale sous echographie permet de faire le diagnostic et de commencer la chimiotherapie. Si le lymphome n’est pas visualise par l’echographie ou s’il existe une souffrance intestinale, la laparotomie d’urgence est necessaire pour faire le diagnostic de lymphome et resequer l’intestin en cas de necessite. Le traitement du lymphome de Burkitt repose sur une polychimiotherapie intensive. Le lymphome de Burkitt est tres chimiosensible.

We present here the long-term results of three randomized clinical trials conducted on children with newly diagnosed acute lymphoblastic leukemia (ALL) between 1983 and 1998 by the Children Leukemia Cooperative Group (CLCG) from EORTC. In study 58831/32, the overall event-free survival (EFS) rates (+/- s.e.) at 6 and 10 years were 66% +/- 1.8% and 65% +/- 1.8%, respectively, and the risk of isolated central nervous system (CNS) relapse was 6% +/- 1% and 7% +/- 1%, respectively. In patients with a standard risk of relapse the omission of cyclophosphamide had no adverse effect on disease-free survival rates at 10 years (trial 58831). In medium- and high-risk patients the omission of radiotherapy did not increase the risk of CNS or systemic relapse (trial 58832). In study 58881 (1989-1998) the overall EFS rate at 8 years was 68.4% +/- 1.2% and the risk of isolated CNS relapse was 4.2%+/-0.5%. In this trial which adressed three randomized questions, the following results were obtained: the combination of cytarabine at high doses with methotrexate at high doses during interval therapy did not improve prognosis. The addition of 6-mercaptopurine iv during maintenance increased the risk of late relapse. E. coli asparaginase was more toxic and has a higher efficacy than Erwinia asparaginase. Leukocyte counts >100 x 10(9)/l, specific genetic abnormalities, a poor initial response to steroids or a high level of minimal residual disease at early time points were consistently associated with an adverse prognosis in the 58881 trial.

Background: Patients suffering from neuroblastic tumors are currently being classified into prognostic subsets based on different clinical and biologic features. In this study, a triple-color flow cytometric assay and a functional test were applied to neuroblastoma cell lines and patients with a neuroblastic tumor, and the value of P-glycoprotein expression and function as potential prognostic characteristics, was determined. Methods: Twenty-two single-cell suspensions prepared from tumors, and neuroblasts from four bone marrow samples were analyzed by triple-color flow cytometry. Neuroblasts were identified by NB84-positivity and absence of CD45. P-glycoprotein expression was evaluated using 4E3 and MRK16 antibodies. Eighteen samples were tested with a functional assay, based on accumulation and retention of rhodamine-123 with and without the inhibitor verapamil. Six neuroblastoma cell lines were also evaluated. Results: P-glycoprotein expression was seen in 18 of 26 patient samples and in three of six cell lines. The highest expression levels were found in low stage neuroblastoma and well-differentiated tumors; whereas the highest activities were found in stage 4 neuroblastoma and the lowest in ganglioneuroblastoma and ganglioneuroma patients. In 10 of 17 samples, concordant results were found between the flow cytometric immunological test and immunocytochemistry. Conclusions: The described flow cytometric technique is a new, alternative approach to detect P-glycoprotein expression and function in neural crest tumors. Based on the expression level and the activity value, patients can be segregated into different phenotypic groups. In particular, those patients with high P-glycoprotein activity might benefit from treatment regimens containing reversal agents. Cytometry 37:125‐132, 1999. r 1999 Wiley-Liss, Inc.

International audience; Induced pluripotent stem cells (iPSCs) are reprogrammed somatic cells with embryonic stem cell (ESC)-like characteristics generated by the introduction of combinations of specific transcription factors. Patient-specific iPSCs can be used to recapitulate disease-specific phenotypes for the screening of new therapies. Chronic granulomatous disease (CGD), a rare inherited immunodeficiency, is characterized by recurrent and severe infections in childhood. The most frequent form is the X-linked CGD (X-CGD) due to mutations in CYBB leading to the absence of Nox2 of the phagocytic NADPH oxidase complex, responsible for the production of microbicidal reactive oxygen species.

International audience

Mendelian susceptibility to mycobacterial disease (MSMD) is a rare genetic syndrome that predisposes patients to infections caused by weakly virulent mycobacterial species, such as bacillus Calmette-Guérin (BCG) vaccines and nontuberculous environmental mycobacteria in children free of classical immunodeficiencies. This syndrome consists of impaired antimycobacterial immunity (axis IL12/INF-γ) constituting a new immune deficiency and outlining its major role in mycobacterial immunity. We report a new case of MSMD through the observation of a young girl with a disseminated infection due to Mycobacterium avium. The molecular defect was 2 autosomal recessive mutations of the IL12Rβ1 gene (gene encoding for the β1 chain of the IL12 receptor) leading to the absence of the IL12 receptor on the activated T lymphocytes' surface. IL-12RB1 deficiency is the most common genetic etiology of MSMD. Today, there are 6 MSMD-causing genes, leading to 13 distinct genetic disorders. The clinical phenotype differs between patients. The description of the molecular and immunological basis of this syndrome has allowed us to explain the pathophysiology of antimycobacterial immunity and is essential to understanding and managing these diseases.

Non-typhi Salmonella are responsible for severe invasive infections in children with sickle cell disease, with osteoarticular locations that can affect short- and long-term outcomes. We describe the cases of 2 children with sickle cell disease who presented paucisymptomatic Salmonella osteoarticular infections on returning from North Africa. Progression was favorable in both cases after appropriate systemic antibiotic therapy, although one Salmonella was multidrug-resistant. Invasive salmonellosis remains rare in France, but, because of its severity, it should be suspected in any patient with sickle cell disease presenting fever, especially in the context of recent trips in Africa countries. Early clinical diagnosis is essential to start appropriate empirical treatment without waiting for bacteriological results.

We investigated four mechanisms of intrinsic chemoresistance in a series of 67 human brain tumours including 31 gliomas (one grade I ganglioglioma, nine grade II and 10 grade III astrocytomas, 11 glioblastomas), 13 cerebral metastases, one medulloblastoma, one malignant teratoma, three ependymomas and 18 meningiomas. We studied four genes by northern blotting: multidrug-resistance (MDR 1), glutathione-s transferase (GST pi), dihydrofolate reductase (DHFR), and topoisomerase II (Topo II). The Topo II gene was absent in the normal adult brain (100%) and in 64% of the tumour samples tested. A second gene, GST pi, was found to be overexpressed in 38% of brain tumours. The two other chemoresistance-related genes were occasionally overexpressed in brain tumours (2% for MDR1, 9% for DHFR). Our results provide evidence that chemoresistance is intrinsic to the brain tissue and seems likely to be a multifactorial process.

The association of lymphoma and autoimmune manifestations has been predominantly studied in adults affected by non-Hodgkin lymphoma. Few publications exist in the literature concerning Hodgkin lymphoma, particularly in children and adolescents. The objectives of this study were to define the characteristics of the link between Hodgkin disease and autoimmunity in childhood. The present 25-year retrospective study was conducted in all centers affiliated with the French Society of Paediatric Oncology (SFCE). Eleven children with Hodgkin disease presented manifestations of disimmunity preceding or following their diagnosis. Four patients had thrombocytopenic purpura, the remaining 7 each had a different autoimmune pathology: lupus syndrome, antiphospholipid syndrome with transient ischemic attack, Evans syndrome, leukocytoclastic vasculitis, autoimmune hemolytic anemia, autoimmune thyroiditis, and juvenile idiopathic arthritis. Lymphoma relapse occurred in 3 patients. Two children died, death being directly attributed to the autoimmune disease in 1 case. Our data suggest that development of autoimmunity is related to significant morbidity. Possible pathophysiological mechanisms include lymphocyte proliferation secondary to chronic inflammation, cell-mediated immune deficiency in Hodgkin disease, molecular mimetics, and antineoplastic phenomena are discussed. A study with a larger patient population is needed to identify the group of children at high risk of autoimmunity for whom additional investigations and modified therapy may be indicated.

The population of survivors of childhood cancer is currently growing. Studies from other countries have shown an increased risk of late mortality. In order to measure this risk within a French cohort, the mortality of children who had survived five years from a cancer diagnosis were compared to the mortality of the general population, according to follow-up interval and cancer and treatment characteristics.The study population consisted of 635 children diagnosed with cancer before the age of 15 who had survived at least five years, and were registered in the Rhone-Alpes region cancer registry from 1987 to 1992. Mortality was compared with general population rates of the Rhone-Alpes region to assess age and sex standardized mortality ratio (SMR) and absolute excess risk of death.The median follow-up of children was 14.0 years. Among the 42 observed deaths, 71.4% were attributed to a recurrence of the original cancer, 9.5% to a second cancer. The 15-year cumulative risk of death, all causes, was 7.1%. The overall mortality of the cohort was 20.7 fold greater than the general population (95% CI: 14.9-27.9), and the absolute excess risk of 6.9 per 1000 persons-years. The long term excess-mortality was higher in case of recurrence of original cancer (SMR=99.9, 95% CI: 67.9-141.9, absolute excess risk 35.4 per 1000 persons-years); it was raised during the five to nine years follow-up interval after diagnosis (SMR=33.8, 95% CI: 23.2-47.3) mainly due to the primary malignancy, and decreased after (10-14 years follow-up interval SMR=6.5, 95% IC 2.4-14.2).The late mortality of childhood cancer is significantly increased during the five to nine years following diagnosis and decreases after, but the cohort follow-up has to be extended in order to assess outcome beyond 15 years after diagnosis.

Background Currently, the best characterized genetic aberration in neuroblastoma (NB) is MYCN amplification, which has been clearly related to prognosis. In the present study, we investigated whether specific epigenetic alterations are associated with stage of disease. Procedure Sixty-two NBs (45 primary tumors and 17 NBs at relapse) were studied in terms of the methylation status of 19 genes (p15INK4a, p16INK4a, p14ARF, APC, RB1, RASSF1A, BLU, FHIT, RARβ, INI1, TIMP3, NF2, MGMT, DAPK, FLIP, ECAD, CASP8, and the receptors DcR1 and DcR2). Results At diagnosis, we found hypermethylation of RASSF1A in 93% of these tumors, hypermethylation of TIMP3 in 51%, of CASP8 in 38%, of BLU in 34%, of DcR2 in 25%, and of DcR1 in 11%. All 17 tumors tested at relapse showed hypermethylation of RASSF1A (100%), while 10 showed hypermethylation of TIMP3 (59%), six of CASP8 (35%), five of DcR2 (29%), four of BLU (24%), and three of DcR1 (18%). Hypermethylation was related to clinical stage; NBs at stages 1, 2, and 4s were less frequently methylated than stages 3 and 4 disease (P = 0.002). Conclusion These results from our series indicate that hypermethylation of tumor-suppressor genes may be important in the development and evolution of NB. These epigenetic alterations could be used as a marker of the disease and genes regulating methylation should be considered as possible therapeutic targets in NB. Pediatr Blood Cancer 2008;50:29–32. © 2007 Wiley-Liss, Inc.

International audience; Carcinoid tumors are the most common endobronchial tumor in the pediatric population, and represent a rare cause of airway obstruction. The authors report two cases of boys aged 10 and 11 years old, who presented with a 12-month history of recurrent pneumonia. Bronchial endoscopy showed an endobronchial tumor. Chest CT-scan identified local extension and lung-associated lesions; octreoscan was performed to detect distant metastases. Histopathological study concluded in typical carcinoid tumor. The outcome after surgical conservative resection is uneventful with a follow-up of 7 and 26 months. Bronchial tumors must be considered in children with recurrent pneumonia or persistant respiratory symptoms, and require CT scan and bronchial endoscopy for their diagnosis.

Ependymomas (EP) represent the third most frequent type of central nervous system (CNS) tumor of childhood, after astrocytomas and medulloblastomas. No prognostic biological markers are available, and differentiation from choroid plexus papilloma (CPP) is difficult. The present objective was, for a sample of 27 children with intracranial EP and 7 with CPP, to describe and compare the methylation status of 19 genes (with current HUGO symbol, if any): p15INK4a (CDKN2B), p16INK4a and p14ARF (both CDKN2A), APC, RB1, RASSF1A (RASSF1), BLU (ZMYND10) FHIT, RARB, MGMT, DAPK (DAPK1), ECAD (CDH1), CASP8, TNFRSF10C, TNFRSF10D, FLIP (CFLAR), INI1 (SMARCB1), TIMP3, and NF2. Three adult corteses were used as a control. We detected a similar percentage of methylated tumors in both groups (71% in CPP and 77% in EP). No gene was methylated in that control group. RASSF1A was the most frequently methylated gene in both benign tumors (66%) and EP (56%). The genes associated with apoptosis were methylated in both groups of tumors. The percentages of TRAIL pathway genes (CASP8, TFRSF10C, and TFRSF10D) methylated were 30, 9.5, and 36.4%, respectively, in ependymomas and 50, 50, and 16.7%, respectively, in choroid plexus papillomas. No other gene was methylated in the benign tumors, whereas FHIT was methylated in 22%, RARB in 14.8%, BLU in 13.6%, p16INK4a in 11.1%, TNFRSF10C in 9.5%, and DAPK in 7.4% of ependymomas. Although we did not observe a statistical relationship between methylation and clinical outcome, the methylation pattern does not appear to be randomly distributed in ependymoma and may represent a mechanism of tumor development and evolution.

Cancer is rare in children, and pediatric malignancies represent only 1% of all cancers.The cure rate is high and increasing, and ongoing data collection is therefore warranted.Here we report the incidence and survival rates of childhood cancers between 1987 and 1999 in the Rhône-Alpes region of France.A total of 1945 cases were recorded during the study period, with an average of 149.6 new cases per year. The approximate incidence rate was 134.1/10(6) per year and the age-standardized incidence rate was 139.2/10(6) per year. The histological distribution and 5-year survival rates were respectively 30.2 and 73% for leukemia, 12.3 and 91.6% for lymphoma, 24.7 and 60.1% for CNS tumors, 9.1 and 71.1% for neuroblastoma, 2.5 and 94.1% for retinoblastoma, 5.8% and 89.9% for renal tumors, 1 and 75% for liver tumors, 6.1 and 60.9% for bone tumors, 4.1 and 58.6% for soft-tissue tumors, 1.1 and 71% for germ cell tumors, and 2.4 and 85.1% for carcinomas.The overall survival rate was 75%. Long-term treatment complications warrant further studies of children who survive into adulthood.

Imerslund-Gräsbeck disease is an autosomic recessive disease characterised by a megaloblastic anemia due to a vitamin B12 deficiency and by a moderate proteinuria without kidney failure. It is caused by the malabsorption of Cobalamin-intrinsic factor complex bringing into play cubulin and other proteins (megaline, amnioless), some mutations of which are described at present. We report herein the observation of a child whose diagnosis was made belatedly during an acute decompensation with biological hemophagocytic syndrome. Its evolution was marked by the appearance of neurological disorders at the beginning of the vitamin B12 substitution treatment. These disorder regressed as the dosage was increase. The purpose of this observation is to recapitulate the main characteristics of this disease and to review the current data.

Intussusception due to lymphoma is a challenging condition for pediatric surgeons. The aim of this study is to report seven cases of this entity and to discuss its management.Six boys and one girl, 3-15-years-old, were admitted for intussusception secondary to a lymphoma. All patients underwent laparotomy: biopsy of massive abdominal tumor 6 and 8 weeks following resection of an intussusception (two cases), ileal resection of non-reductible intussusception (one case), right hemicolectomy for tumor of the appendix (one case), tumorectomy of localized ileal tumor (two cases), enlarged mesenteric lymph node biopsy associated with simple reduction of intussusception (one case). All children were successfully treated with protocol chemotherapy with a 15-month to 13-year follow-up. No relapse was observed.Surgeons should be aware of operative sights of ileal lymphomas. Diagnosis of lymphoma may be difficult after manual reduction of intussusception. A sample of any abnormality (mesenteric lymph node, peritoneal fluid) should be taken. Intestinal resection allows to reduce the intensity of chemotherapy but must be as limited as possible: ileal resection in cases of complicated intussusception, tumorectomy "in sano" in cases of ileal parietal isolated tumor. Reduction of intussusception alone (with no resection of ileal tumor) seems to be effective if diagnosis of lymphoma is possible from peripheral samples (peritoneal fluid, pleural effusion, mesenteric lymph node, bone marrow biopsy...).

Bernard-Soulier syndrome (BSS) is a congenital autosomal recessive bleeding disorder characterised by giant platelets, the lack of thrombocytopenia or a moderate one, prolongation of skin bleeding time, and absent platelet aggregation in response to ristocetin. We report a case of BSS revealed by major neonatal thrombocytopenia. A newborn was admitted for thrombocytopenic purpura initially believed to be due to a maternal auto-immune thrombocytopenia. Because of the persistence of the thrombopenia till the age of 7 months despite therapy by corticosteroids and immunoglobulins, and because of the detection of anti-1b antiplatelets antibodies after transfusion, BSS diagnosis was evoked. In such a situation of major thrombocytopenia, the main therapeutic measure is prevention. Therapy by DDAVP may be used after the age of 3 years in situations of high haemorrhagic risk. This case report underlines the importance of a precise diagnosis in front of a maternal thrombocytopenia and the possibility of antenatal diagnosis of BSS.

Neuroblastoma is the most frequent tumor observed in the newborn. The aim of this study was to review clinical features, treatment and outcome of newborns diagnosed with a localized neuroblastoma.Data from 52 cases treated according to the NBL 90 and 94 protocols between 1990 and 1999 in 18 French centers of pediatric oncology were analyzed.The median age at diagnosis was 12 days (range 0-28) with antenatal detection in 14 patients (27%). Tumor location was abdominal in 40 patients (adrenal in 20 of the 40), thoracic in eight, pelvic in three, and cervical in one. N-myc amplification was observed in one out of 40 evaluable cases. The size of the primary tumor was less than 5 cm in 25 cases, between 5 and 10 cm in 25 and more than 10 cm in two. Dumbbell tumor was observed in seven, of whom five had neurological deficit. One child died from hemorrhage after fine needle biopsy during diagnostic procedure. Primary surgical resection was attempted in 37 infants, of whom two died of surgery related complications and three had nephrectomy. Tumor was deemed as unresectable in 14 patients, and primary chemotherapy was given followed by surgical excision in 12. One of them died a few days after the beginning of chemotherapy. As a whole, continuous complete remission was achieved in 48 children, four of them after relapse. Overall survival was 92% with a median follow-up of 46 months (0-113 months).The excellent prognosis of localized NB in neonates needs very restrictive surgical indications, with well-established anatomic and imaging criteria. Indeed, chemotherapy based on weight and managed by expert teams should allow to perform surgical excision in safer conditions for unresectable tumors.

Childhood malignant brain stem tumours have a very poor prognosis with a median survival of 9 months despite radiotherapy. No chemotherapy has improved survival. However, carboplatin has been reported to have activity in glial tumours as well as antitumour synergy with radiation. Our aims were to test the response rate of these tumours to carboplatin alone and to evaluate the efficacy on survival of carboplatin alone followed by concurrent carboplatin and radiotherapy. Patients younger than 16 years with typical clinical and radiological presentation of infiltrating brain stem tumour, as well as histologically-documented cases in the atypical forms, were eligible. Two courses of carboplatin (1050 mg/m2 over 3 days) were administered initially. This treatment was followed by a chemoradiotherapy phase including five weekly carboplatin courses (200 mg/m2) and conventional radiotherapy. 38 eligible patients were included. No tumour response was observed after the initial phase. This schedule of first-line carboplatin followed by concurrent carboplatin and radiotherapy did not improve survival.

Burkitt's lymphomas are rarely revealed by acute intestinal intussusception in children. The study aim was to report eight cases.Between 1988 and 1999, eight children, seven boys and one girl (mean age: 6 years) were hospitalized for an acute abdominal syndrome. Abdominal ultrasonography showed intestinal intussusception (n = 8) primitive tumor (n = 2), mesentivic lymph nodes (n = 2) and liver nodes (n = 1). Enema (n = 6) confirmed presence and irreductibility of the intestinal intussusception. A laparotomy was performed on emergency in seven patients and found the primitive tumor in 6. The procedure consisted in disinvagination (n = 4) and intestinal resection for ischaemia (n = 2). One patient was not operated on and the diagnosis was performed through ultrasonography guided tumoral puncture.According to the Murphy classification, there were 2 stage II, 3 stage III and 3 stage IV patients. With LMB protocol chemotherapy, a complete remission was observed following the first cure. All the children were alive at the time of this study with a follow-up longer than one year after the complete remission.Abdominal sonography is the most efficient examination for the diagnosis of intestinal intussusception and sometimes of the primitive lesion. In the absence of sonographic intestinal impair, thanks to ultrasonography guided tumoral puncture, diagnosis may be made and chemotherapy started. If the lymphoma is not visualized with ultrasonography, an emergency laparotomy is necessary for the diagnosis of the lymphoma and the intestinal resection in case of necessity. Burkitt's lymphoma is very sensible to chemotherapy.

Infants with neuroblastoma (NB) were assessed according to INSS recommendations, including MIBG scan and extensive bone marrow staging to eliminate metastatic spread. Patients with unresectable tumour received chemotherapy, including two courses of carboplatin-etoposide (CE) and two of vincristinecyclophosphamide-doxorubicin (CAdO). Post-operative treatment was to be given only in infants with MYCN amplification. Between 1990 and 1994, 52 consecutive children were registered.Among the 44 patients who received CE as a first course, the response rate was (66%) and the primary could be removed in all children but one, who was in remission. The toxicity was mainly haematological and was always manageable. The 5 year overall survival (OS) and event-free survival (EFS) were 94 and 90 +/- 8%, respectively, with a median follow-up of 48 months. The outcome of infants with no MYCN amplification was excellent; OS and EFS were, respectively, 97 and 94%.Chemotherapy allows surgical excision and excellent outcome in infants with localised and unresectable NB. Less intensive Chemotherapy should be investigated in such patients.

We have studied the occurrence and association of 11q deletions with other chromosomal imbalances in Stage 4 neuroblastomas. To this purpose we have performed comparative genomic hybridization (CGH) analysis on 50 Stage 4 neuroblastomas and these data were analyzed together with those from 33 previously published cases. We observed a high incidence of 11q deletion in Stage 4 neuroblastoma without MYCN amplification (59%) whereas 11q loss was only observed in 15% of neuroblastomas with MYCN-amplification (p = 0.0002) or 11% of cases with 1p deletion detected by CGH (p = 0.0001). In addition, 11q loss showed significant positive correlation with 3p loss (p = 0.0002). Event-free survival was poor and not significantly different for patients with or without 11q deletion. Our study provides further evidence that Stage 4 neuroblastomas with 11q deletions represent a distinct genetic subgroup that typically shows no MYCN-amplification nor 1p deletion. Moreover, it shows that neuroblastomas with 11q deletion also often present 3p deletion. This genetic subgroup shows a similar poor prognosis as MYCN amplified 4 neuroblastomas.

We present here the long-term results of three randomized clinical trials conducted on children with newly diagnosed acute lymphoblastic leukemia (ALL) between 1983 and 1998 by the Children Leukemia Cooperative Group (CLCG) from EORTC. In study 58831/32, the overall event-free survival (EFS) rates (+/- s.e.) at 6 and 10 years were 66% +/- 1.8% and 65% +/- 1.8%, respectively, and the risk of isolated central nervous system (CNS) relapse was 6% +/- 1% and 7% +/- 1%, respectively. In patients with a standard risk of relapse the omission of cyclophosphamide had no adverse effect on disease-free survival rates at 10 years (trial 58831). In medium- and high-risk patients the omission of radiotherapy did not increase the risk of CNS or systemic relapse (trial 58832). In study 58881 (1989-1998) the overall EFS rate at 8 years was 68.4% +/- 1.2% and the risk of isolated CNS relapse was 4.2%+/-0.5%. In this trial which adressed three randomized questions, the following results were obtained: the combination of cytarabine at high doses with methotrexate at high doses during interval therapy did not improve prognosis. The addition of 6-mercaptopurine iv during maintenance increased the risk of late relapse. E. coli asparaginase was more toxic and has a higher efficacy than Erwinia asparaginase. Leukocyte counts100 x 10(9)/l, specific genetic abnormalities, a poor initial response to steroids or a high level of minimal residual disease at early time points were consistently associated with an adverse prognosis in the 58881 trial.

To assess the relevance of MYCN amplification and bone lesions in stage 4 neuroblastoma (NB) in infants aged