[Steroid intake before leukemia diagnosis impairs outcome in childhood acute lymphoblastic leukemia]. / Corticothérapie préalable au diagnostic de leucémie aiguë lymphoblastique (LAL) de l'enfant : effet délétère pour la prise en charge diagnostique et thérapeutique.

UNLABELLED: The aim of this study was to show that steroid therapy taken before the diagnosis of acute lymphoblastic leukemia (ALL) can alter the management of the disease. PATIENTS AND METHODS: We conducted a multicenter retrospective study on 11 children treated between 2005 and 2011, who received oral steroids ranging from 0.6 to 3.3mg/kg/day prednisolone equivalent for a duration of 2 to 15 days during the 2 months prior to diagnosis of ALL. RESULTS: Four children had febrile pancytopenia. Among them, 2 had severe infections and a noncontributive bone marrow aspiration. One of them presented a severe tumoral lysis syndrome and was hospitalized twice in the intensive care unit. Two teenagers had central nervous system involvement at diagnosis of T-ALL, 1 having associated cutaneous locations, the second one showing pulmonary and central nervous system (CNS) leukostasis with renal failure and disseminated intravascular coagulation. One child died of septic shock during the induction phase of steroid-resistant T-ALL. Four children had no complications during the induction phase. Steroid resistance occurred in 5 cases and steroid sensitivity could not be evaluated in 3 cases. Three allogeneic bone marrow transplants were performed: the first one because of early CNS relapse, the 2 others because of initial treatment resistance. CONCLUSION: Steroids can induce a delay in the management of ALL and seem to favor initial complications, and possibly increase diffuse locations as well as steroid resistance. Their prescription needs to be carefully managed, especially for uncharacteristic infectious symptoms. Then a complete blood count should be done.

Successful immune tolerance induction by FVIII in hemophilia A patients with inhibitor may occur without deletion of FVIII-specific T cells.

BACKGROUND: The development of an inhibitor is the major complication facing patients with hemophilia A treated by administration of factor (F) VIII concentrates. Restoration of tolerance to FVIII can be achieved by prolonged administration of FVIII (immune tolerance induction, ITI). Although ITI has been used for more than 30years in patients with hemophilia A and inhibitor, its mechanism of action is still poorly understood. OBJECTIVES: As administration of high doses of antigen can induce the apoptosis of the T cells recognizing the antigen, a potential mechanism of action of ITI may be the deletion of FVIII-specific T cells. PATIENTS/METHODS: We studied the CD4+ T-cell response to FVIII in five (one mild, one moderate and three severe) patients successfully desensitized by administration of FVIII and in control subjects. RESULTS: Following repeated stimulation with autologous dendritic cells loaded with FVIII, FVIII-specific T oligoclonal cell lines were expanded from the blood of one of the successfully desensitized patients. The FVIII-specific T cells produced IL-5, IL-13 and IL-2. By contrast, FVIII-specific T-cell lines could not be derived from three patients with mild hemophilia A without inhibitor or from four normal control subjects. CONCLUSIONS: These data represent the first analysis of the cellular mechanisms regulating the induction of tolerance to FVIII. They demonstrate that successful tolerance induction may occur without deletion of FVIII-specific T cells.

[Parents' recollection of the initial announcement of hemophilia in children]. / Vécu parental de l'annonce du diagnostic d'hémophilie chez l'enfant.

UNLABELLED: Discovering chronic illnesses in children initially shatters the family balance and triggers emotional reactions. PATIENTS AND METHODS: We retrospectively report parents' experiences and emotional reactions to learning the diagnosis of hemophilia in their children. Twenty-six parents (18 mothers, 8 fathers) of 24 hemophiliac A or B children (major n=8, moderate n=6, mild n=10), aged from 0 to 18 years, were individually asked to answer a separate questionnaire for each child during a systematic consultation. We obtained 29 completed questionnaires. RESULTS: The diagnostic circumstances were a major bleeding episode (n=8), frequent hematomas (n=4), preoperative blood sample (n=4), and familial screening (n=8). In 9 cases, both parents were informed of the diagnosis at the same time and in 13 cases, the mother was alone. The most frequent feelings were future apprehension (n=20), initial shock reaction (n=18), anxiety (n=12), and guilt (n=10) expressed by mothers only. Parents' emotional states were neither correlated with the severity of the disease nor with the diagnostic circumstances. All parents questioned reported being satisfied with the quality of the initial information. CONCLUSION: The crisis generated by learning the diagnosis of a chronic disease in their children warrants delivering initial information to both parents at the same time, especially in hemophilia since mothers tend to be more concerned.

[Congenital transient leukemia: a case report]. / Un cas de leucémie congénitale transitoire.

UNLABELLED: Neonates with Down's syndrome have an increased risk for congenital leukaemia, particularly acute megakaryoblastic leukaemia (FAB, M7) which most often resolves spontaneously and is called transient leukaemia. It can be observed in non-constitutional trisomy 21 infants then presenting trisomy 21 on blasts cells. OBSERVATION: We report a transient leukaemia with an isolated pericardial effusion in a phenotypically normal neonate. Trisomy 21 was found on blasts cells. Complete remission remains after 32 months. DISCUSSION: Congenital leukaemias, with trisomy 21 on blasts cells have a good prognosis that justifies observation before using chemotherapy.

Treatment of childhood acute myeloblastic leukemia: dose intensification improves outcome and maintenance therapy is of no benefit--multicenter studies of the French LAME (Leucémie Aiguë Myéloblastique Enfant) Cooperative Group.

From 1989 to 1998, 341 children were included in the French multicentric LAME (Leucémie Aiguë Myéloblastique Enfant) trials. A total of 309 children were registered in the LAME 89/91 protocol. This intensive regimen included an induction phase (mitoxantrone plus cytarabine), two consolidation courses, one containing timed-sequential high-dose cytarabine, asparaginase and amsacrine; 276 (90%) achieved a CR. The 5-year overall survival (OS) and event-free survival (EFS) were 60+/-4 and 48+/-4%, respectively. From 1997, timed-sequencing of the LAME SP induction chemotherapy led to an unacceptable frequency of consolidation delay; future improvements are unlikely to come from further increases in intensity. The role of allogenic bone-marrow transplantation from an HLA-identical sibling in CR1 was examined. The disease-free survival (DFS) was 52+/-4% for non-allografted patients and 57+/-7% for allografted patients (P=NS); a better OS for allografted patients was shown and could be related either to allo-BMT early in CR1 or to a second allo-BMT in CR2. For the complete responders after consolidation therapy, the 5-year OS was significantly better in patients randomized for no maintenance therapy (MT-) than in patients randomized for MT (77.6+/-8 vs 59+/-8%; P=0.05), while the 5-year DFS was not significantly different. Exposure to low-dose MT might contribute to clinical drug resistance and treatment failure in relapsing patients.

Long-term renal and hearing toxicity of carboplatin in infants treated for localized and unresectable neuroblastoma: results of the SFOP NBL90 study.

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 < or =97.5 centile in all children. The mean estimated GFR was 114 +/- 13 ml/min/1.73 m(2) 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.

Epidemiological and quantitative study of GBV-C infection in french polytransfused children.

From 1999 to 2002, 246 serum samples taken from polytransfused children were tested for the presence of GB virus C (GBV-C) RNA using a real-time reverse transcription-polymerase chain reaction (RT-PCR) assay. This assay was based on the TaqMan technology and allowed viral load determination in infected children with a dynamic range from 10(3) to 10(7) genome equivalent (gEq) copies/ml. The limit of detection was estimated to 619 gEq copies/ml with a > or = 95% probability of a positive result. Thirty five sera were found to be GBV-C RNA positive, corresponding to a prevalence of GBV-C of 14.2%. The mean viral load was high, i.e., 6 +/- 1.4 log (range 3.22-7.42) gEq copies/ml, but low viral loads were also detected. Sequencing of the 5'-untranslated region (UTR) identified a majority of genotype 2 strains (82%) distributed into two subtypes, 88.5% genotype 2a and 11.5% genotype 2b. In conclusion, GBV-C active infection is very frequent in exposed populations such as polytransfused children. GBV-C RNA quantitation using real-time assay may be useful for diagnosis and follow-up of the natural history of GBV-C infection.

Maintenance therapy in childhood acute myeloid leukemia.

PURPOSE: To determine whether, after very intensive induction and consolidation therapy in childhood AML, further maintenance therapy (MT) confers any advantage. PATIENTS AND METHODS: Three hundred-nine children with previously untreated AML were registered in the LAME 89/91 protocol. This three-cycle intensive regimen included an induction phase (mitoxantrone plus cytarabine) and, for non-allografted patients, two consolidation courses, one containing timed-sequential high-dose cytarabine, asparaginase and amsacrine. In the LAME 89 study, patients were given an additional MT consisting of mercaptopurine and cytarabine for 18 months. In the LAME 91 trial, patients were randomized to be given or not MT after consolidation therapy. RESULTS: Out of 309 patients, 276 (90%) achieved a complete remission. The overall survival (OS) and event-free survival at 6 years for all patients were 60% +/- 6% and 48% +/- 6%, respectively. For the complete responders after consolidation therapy, the 5-year OS was significantly better in patients randomized for no further treatment than in patients randomized for MT (81% +/- 13% vs 58% +/- 15%; p = 0.04) whilst the 5-year disease-free survival was not significantly different (60% +/- 19% vs 50% +/- 15%; p = 0.25). The improvement of OS in MT-patients appeared to be related to a higher salvage rate after relapse. CONCLUSION: Over 50% of patients can be cured of AML in childhood. In the context of a very short and drug-intensive regimen, low-dose MT, owing to the lack of improvement in disease control and the worsening of survival, should not be recommended. Over the past 20 years, the outcome of acute myeloid leukemia (AML) in children has improved substantially. In the eighties, complete remission (CR) was achieved in nearly 90% of patients but event-free survival (EFS) was poor. Myeloablative therapy followed by allogenic bone-marrow transplantation (allo BMT) from an HLA-identical sibling was demonstrated, in our experience, to be the treatment of choice for improving DFS in children with AML in first remission. The major issue was how best to maintain complete remission for patients without an HLA sibling donor. Whereas several groups continued to include low-dose MT and others decided to omit it, in 1991, our group undertook a prospective randomized trial (LAME 91 protocol), the main aim of which was to assess the efficacy of MT in addition to an intensive induction and consolidation chemotherapy. The main results have been published previously and are now updated and described in a higher number of patients.

Infectious diseases in the first year of life, perinatal characteristics and childhood acute leukaemia.

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.

[Intravenous immunoglobulin (Endobulin) clinical tolerance: prospective therapeutic follow-up of 142 adults and children]. / Tolérance clinique d'une préparation thérapeutique d'immunoglobulines humaines polyvalentes à usage intraveineux (Endobuline): suivi prospectif d'une population de 142 adultes et enfants.

PURPOSE: Prospective report of Endobulin clinical tolerance experience for 19 months over a large number of patients. METHOD: Collect diagnosis, age, gender, weight, dose regimen, infusion duration, and clinical tolerance of Endobulin. Treatment with this product was the only inclusion criteria in this follow-up. RESULTS: A hundred and forty-two patients, 85 children and 57 adults, mean age 23 (1-85 years) received 70 substitutive treatments for primary immunodeficiency, 36 substitutive treatments for secondary immunodeficiency and 36 immunomodulatory treatments. A thousand six hundred and sixty Endobulin infusions that led to 14, 061.5 g, from 52 different batches. Tolerance was judged as good for 135 patients even though side effects occurred in 2 of them. Thus, 133 out of 142 patients, that is 93.7% did not present any side effect and their tolerance to Endobulin infusions was defined as good. Tolerance was bad for 7 patients because of side effects occurrence. For a mean number of 11.7 infusions per patient (1-31), the 9 side effects observed led to a rate of 0.54% of collected infusions and 6.3% of patients included. CONCLUSION: This therapeutic follow-up of 142 patients confirms Endobulin clinical tolerance judged as good in 93.7% of patients (133/142) with a very low rate of side effects of 0.54% of infusions (9 side effects for 1660 infusions) for a mean number of 11.7 infusions per patient for an average of 10.9 months follow-up.

Use of recombinant factor VIIa (NovoSeven) in patients with Glanzmann thrombasthenia.

Recombinant factor VIIa (rFVIIa; NovoSeven, Novo Nordisk, Bagsvaerd, Denmark) appears effective and relatively safe for the treatment of bleeding and for surgical prophylaxis in patients with Glanzmann thrombasthenia as reported to the International Registry on rFVIIa and Congenital Platelet Disorders. One of the shortcomings of the Registry data is the heterogeneity of treatment protocol, including dosage, number of doses used, duration of treatment before declaration of failure, and mode of rFVIIa administration (bolus v continuous infusion). The data are not yet sufficient to define optimal regimens for various indications such as the type of bleeding or the type of procedures. The place of this drug compared to platelet transfusion in the overall management of patients with Glanzmann thrombasthenia will need to be determined in relationship to a number of challenges and unresolved issues in the clinical care of these patients. These issues include: how to improve local measures for patients with mucosal bleeds, optimal management of young women during menarche, optimal platelet transfusion regimens for various indications, the relationship between antiplatelet antibodies detected by monoclonal antibody-specific immobilization of platelet antigens (MAIPA) and effectiveness of platelet transfusion, whether there are other biological tests that may correlate with effectiveness of platelet transfusion, and management of pregnancy and delivery regarding antiplatelet immunization.

Use of recombinant human granulocyte colony-stimulating factor to increase chemotherapy dose-intensity: a randomized trial in very high-risk childhood acute lymphoblastic leukemia.

PURPOSE: To determine whether the use of a recombinant human granulocyte colony-stimulating factor ([G-CSF] lenogastrim) can increase the chemotherapy dose-intensity (CDI) delivered during consolidation chemotherapy of childhood acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: Sixty-seven children with very high-risk ALL were randomized (slow early response to therapy, 55 patients; translocation t(9;22) or t(4;11), 12 patients). Consolidation consisted of six courses of chemotherapy; the first, third, and fifth courses were a combination of high-dose cytarabine, etoposide, and dexamethasone (R3), whereas the second, fourth, and sixth courses included vincristine, prednisone, cyclophosphamide, doxorubicin, and methotrexate (COPADM). G-CSF was given after each course, and the next scheduled course was started as soon as neutrophil count was > 1 x 10(9)/L and platelet count was > 100 x 10(9)/L. CDI was calculated using the interval from day 1 of the first course to hematologic recovery after the fifth course (100% CDI = 105-day interval). RESULTS: CDI was significantly increased in the G-CSF group compared with the non-G-CSF group (mean +/- 95% confidence interval, 105 +/- 5% v 91 +/- 4%; P <.001). This higher intensity was a result of shorter post-R3 intervals in the G-CSF group, whereas the post-COPADM intervals were not statistically reduced. After the R3 courses, the number of days with fever and intravenous antibiotics and duration of hospitalization were significantly decreased by G-CSF, whereas reductions observed after COPADM were not statistically significant. Duration of granulocytopenia was reduced in the G-CSF group, but thrombocytopenia was prolonged, and the number of platelet transfusions was increased. Finally, the 3-year probability of event-free survival was not different between the two groups. CONCLUSION: G-CSF can increase CDI in high-risk childhood ALL. Its effects depend on the chemotherapy regimen given before G-CSF administration. In our study, a higher CDI did not improve disease control.

Human complement factor H deficiency associated with hemolytic uremic syndrome.

This study reports on six cases of deficiency in the human complement regulatory protein Factor H (FH) in the context of an acute renal disease. Five of the cases were observed in children presenting with idiopathic hemolytic uremic syndrome (HUS). Two of the children exhibited a homozygous deficiency characterized by the absence of the 150-kD form of Factor H and the presence, upon immunoblotting, of the 42-kD Factor H-like protein 1 (FHL-1) and other FH-related protein (FHR) bands. Southern blot and PCR analysis of DNA of one patient with homozygous deficiency ruled out the presence of a large deletion of the FH gene as the underlying defect for the deficiency. The other four children presented with heterozygous deficiency and exhibited a normal immunoblotting pattern of proteins of the FH family. Factor H deficiency is the only complement deficiency associated with HUS. These observations suggest a role for FH and/or FH receptors in the pathogenesis of idiopathic HUS.

[Inflammatory pseudotumors of the liver. Apropos of a pediatric case with radiological and ultrasonographic features and anatomopathological correlations]. / Les pseudotumeurs inflammatoires du foie. A propos d'un cas pédiatrique avec aspects radiologiques et échographiques et corrélations anatomopathologiques.

Inflammatory pseudo-tumor of the liver (IPT) are benign encapsulated masses. IPT or inflammatory myofibroblastic tumor is a myofibroblastic proliferation with chronic inflammatory cell infiltration of unknown origin. A four-year-old girl, with cutaneous flushing of the face and biological inflammatory syndrome was referred for abdominal investigation. Ultrasound examination showed a 5-cm mass located in the anterior segment of the right hepatic lobe. After abdominal CT showing slightly vascular feature of this right hepatic mass, diagnosis was made through percutaneous US-guided fine needle biopsy. Surgical resection was performed and pathologic examination of the mass confirmed preoperative diagnosis. Clinical outcome was good.

[Pulmonary embolism in adolescents]. / Embolie pulmonaire chez l'adolescente.

BACKGROUND: Pulmonary embolism is rare in children, but its incidence is probably underestimated. While its causes are the same as in adults, the role of clotting factor deficiency and oral contraceptive agents has recently been stressed. CASE REPORTS: Case n. 1: A 15 year-old girl was immobilized for an ankle strain. She developed thrombophlebitis of the deep veins of the right leg. The condition was confirmed by Doppler. A phlebogram showed a clot floating in the inferior vena cava. This required the insertion of a clip around it and further thrombectomy. Despite immediate intravenous heparin therapy, the adolescent died of a massive pulmonary embolization. The girl had a congenital antithrombin III deficiency; she was also taking an oral contraceptive. Case n. 2: A 15 year-old suffered from left thoracic pain radiating to the shoulder. Perfusion scintiphotography showed evidence of pulmonary embolism of the left inferior lobe and a phlebogram showed thrombosis of the hypogastric veins. This adolescent was 4 months pregnant. A filter was placed inside the inferior vena cava to permit therapeutic interruption of the pregnancy. The girl was treated with intravenous heparin, followed by antivitamin K with an uneventful course. She suffered from no clotting factor deficiency. CONCLUSION: Pulmonary embolism remains a severe complication of thrombi in the femoral and pelvic veins. It can occur in adolescents, especially those with a congenital clotting factor deficiency, those on oral contraceptives or those who are pregnant.

Leukaemia-associated hypercalcaemia in a 10-year-old boy: effectiveness of aminohydroxypropylidene biphosphonate.

A 10-year-old boy with leukaemia-associated hypercalcaemia was treated with aminohydroxypropylidene biphosphonate (AHPrBP previously APD) in a total dosage of 60 mg over 5 days, when the condition failed to respond to rehydration and frusemide and no sustained effect was produced by haemodialysis with a calcium (Ca)-free dialysate. Bone films showed no lytic lesions, and AHPrBP, which is a potent inhibitor of osteoclast-mediated bone resorption was well tolerated and induced a rapid and sustained fall in plasma Ca (from 3.42 to 2.07 mM in 5 days). Plasma magnesium and alkaline phosphatase remained normal. The results could have been affected by other drugs [vincristine, cyclophosphamide, zorubicin (Rubidazone) L-asparaginase and prednisone] which were simultaneously administered. However, the observation that: (1) the response curve of plasma Ca was similar to that reported when AHPrBP was used alone, (2) there was complete inhibition of urinary Ca excretion and (3) hypocalcaemia occurred suggests that AHPrBP was the major cause of the reduction in plasma Ca. AHPrBP should be considered a potential therapy for hypercalcaemia in childhood malignancy.

[Embryonal rhabdomyosarcoma diagnosed antenatally]. / Rhabdomyosarcome embryonnaire de découverte anténatale.

A case of congenital embryonal rhabdomyosarcoma of the right shoulder is described. The patient was the first child born to a 24 year-old woman who had previously been treated for sterility. The diagnosis was made by echography during the 36th week of gestation. This full term white boy was born by cesarean section because of the tumor size. Surgical treatment was completed by chemotherapy. Despite 4 courses of VAC, local recurrence was noted that led to a second surgical excision followed by a new cyclic chemotherapy (IVA). The treatment was fairly well tolerated. The child is well 24 months later.