Edouard Le Gall

Cancer incidence among children in France, 1990–1999

Cancer is the second most important cause of death for children aged less than 15 years in France, unintentional injuries being the leading cause. The aim of the present study was to estimate the incidence of childhood cancer from six Childhood Cancer Registries covering 32% of France.

Five distinct biological processes and 14 differentially expressed genes characterize TEL/AML1 -positive leukemia

BackgroundThe t(12;21)(p13;q22) translocation is found in 20 to 25% of cases of childhood B-lineage acute lymphoblastic leukemia (B-ALL). This rearrangement results in the fusion of ETV6 (TEL) and RUNX1 (AML1) genes and defines a relatively uniform category, although only some patients suffer very late relapse. TEL/AML1-positive patients are thus an interesting subgroup to study, and such studies should elucidate the biological processes underlying TEL/AML1 pathogenesis. We report an analysis of gene expression in 60 children with B-lineage ALL using Agilent whole genome oligo-chips (44K-G4112A) and/or real time RT-PCR.ResultsWe compared the leukemia cell gene expression profiles of 16 TEL/AML1-positive ALL patients to those of 44 TEL/AML1-negative patients, whose blast cells did not contain any additional recurrent translocation. Microarray analyses of 26 samples allowed the identification of genes differentially expressed between the TEL/AML1-positive and negative ALL groups. Gene enrichment analysis defined five enriched GO categories: cell differentiation, cell proliferation, apoptosis, cell motility and response to wounding, associated with 14 genes -RUNX1, TCFL5, TNFRSF7, CBFA2T3, CD9, SCARB1, TP53INP1, ACVR1C, PIK3C3, EGFL7, SEMA6A, CTGF, LSP1, TFPI – highlighting the biology of the TEL/AML1 sub-group. These results were first confirmed by the analysis of an additional microarray data-set (7 patient samples) and second by real-time RT-PCR quantification and clustering using an independent set (27 patient samples). Over-expression of RUNX1 (AML1) was further investigated and in one third of the patients correlated with cytogenetic findings.ConclusionGene expression analyses of leukemia cells from 60 children with TEL/AML1-positive and -negative B-lineage ALL led to the identification of five biological processes, associated with 14 validated genes characterizing and highlighting the biology of the TEL/AML1-positive ALL sub-group.

Multifactorial Drug-Resistance Phenomenon in Acute Leukemias: Impact of P170-MDR1, LRP56 Protein, Glutathione-Transferases and Metallothionein Systems on Clinical Outcome

The multidrug resistance phenomenon can be observed in cases which do not express the P170 protein and these cases are suspected as having activated different resistance phenomena. Four phenomena were studied at the time of diagnosis in a series of 35 lymphoblastic and 25 myeloblastic acute (de novo) leukemias, by an immunocytochemical method. Two energetic drug transport processes were investigated: the classical MDR/P170 and the P110/LRP56 proteins, and two physiological detoxifying activities such as the glutathione transferases (GST alpha, mu, pi) and the metallothioneins (Mts). The results demonstrate that these phenomena are independent but their synergic activity can increase their impact on the outcome. P110/LRP56 positive cases demonstrated 48.8% complete remission (CR) rate compared to 71.4% for negative tests. When P170 and P110 were both positive or negative, the CR rates were 27.3% and 81.8% respectively (p = 0.0120), and survival curves were also different (p = 0.030). The CR rate in AML or ALL is weakly affected by GST pi, alpha or mu but relapses are more frequently observed for Positive-GST pi ALL (p = 0.0658). Patients with both P170 and GST pi positive reactions had a 53.3% CR rate compared to 78.9% for both negative reactions. Survival curves for these two groups were different. The CR rate in AMl was 100% for Mts positive and 43.7% for negative cases (p = 0.050), however the median survival was totally different for these two groups (p = 0.046). CR rates were 26.6% for patients who were P170 positive and Mts negative compared to 100% for P170 negative and Mts positive (p = 0.038) patients. Survival curves were also different (p = 0.0510). We conclude that these four mechanisms induce an independent drug resistance but their synergic action increase their impact on the outcome. The metallothioneins seem to have a major impact on the drug resistance phenomenon and its effect should be investigated with high priority, in the light of these results.

Particular cutaneous side effects with etoposide-containing courses: is VP16 or etoposide phosphate responsible?

PurposeEtoposide is commercially available in France in two different pharmaceutical forms: VP16 and its phosphate ester (etoposide phosphate, EP). EP shows better chemical and physical properties, is said to be less toxic but is five times more expensive than VP16. Some criteria were defined for the use of each form in the Paediatric Oncohaematology Department in Hôpital Sud in Rennes. As some particular cutaneous side effects were observed during treatment with etoposide-based course in this department, a retrospective study was initiated. The aims of this work were to determine the side effects (especially cutaneous toxicity), whether the pharmaceutical formulation of etoposide had any influence on the toxicity of the drug, and whether the observed side effects resulted from etoposide alone or from particular antineoplastic drug associations.MethodsFive types of etoposide-containing protocols were chosen: NB 97 and NB 99 (neuroblastoma), FRALLE 93 (acute lymphoid leukaemia), LAME 91 (acute myeloid leukaemia), OS 94 (osteosarcoma), Ewing 97 and Euro-Ewing 99 (Ewing sarcoma). The medical files of 36 children (88 EP courses, 25 VP16 courses) included in these protocols were analysed on the basis that if a child showed a side effect during a course, the child had to have recovered from that side effect before the beginning of the next course.ResultsApart from classical side effects (haematological and digestive toxicities etc.), two particular cutaneous side effects were observed: (1) palmar–plantar eruptions and nail inflammations, and (2) irritation of the anal area and anal fissures. Those side effects were observed with three of the studied protocols: NB 97, OS 94 and Ewing sarcoma treatments.ConclusionsNo striking differences in toxicity appeared between the two etoposide formulations, but this retrospective study seemed to confirm the appearance of particular cutaneous and anal side effects especially with two associations: (1) etoposide–ifosfamide (OS 94 and Ewing 97), and (2) etoposide–ifosfamide–Adriamycin–vincristine (VIDE course of the Euro-Ewing 99 protocol).

Central neurotoxicity of cyclosporine in two children with nephrotic syndrome

The central neurotoxicity of cyclosporin A (CsA) has been abundantly documented in pediatric and adult recipients of bone marrow or organ transplants, with variations in the rate of occurrence from 0.5% to 35%. We report two cases of central neurotoxicity ascribable to CsA in children with nephrotic syndrome due to lipoid nephrosis. The manifestations of CsA-related central neurotoxicity include confusion, aphasia, dystonias, akinetic mutism, parkinsonism, palsies, seizures, catatonia, coma, brain hemorrhage, and cortical blindness. Decreased density of the cerebral white matter is visible by computed tomography (CT) in 50% of cases, with the most commonly involved sites being the occipital cortex, the cerebellum, the periventricular substance, and the brainstem. Magnetic resonance imaging is more sensitive and more specific than CT for investigating the white matter. High-signal lesions are seen on T2-weighted sequences in the areas that are abnormal by CT. Many risk factors have been reported, including hypomagnesemia, hypocholesterolemia, high-dose glucocorticoid therapy, arterial hypertension, and infections. We present two patients with central neurotoxicity both of whom have elevated cholesterol levels.

Intratumoral consumption of indium-111-labeled platelets in a child with splenic hemangioma and thrombocytopenia.

The authors report Kasabach-Merritt syndrome (KMS) in a patient with thrombocytopenia and splenic hemangioma. A 13-month-old boy with a history of anemia, thrombocytopenia, and abdominal mass was admitted to the hospital. The scintigraphic studies showed that a large mass contiguous to the spleen was responsible for the platelet uptake. After partial splenectomy, the platelet count returned to normal. This report of KMS in a child with splenic hemangioma suggests that the scintigraphic studies are mandatory to confirm diagnosis. Indium-111-labeled platelets are useful in identifying hemangiomatous sequestration of platelets in patients with thrombocytopenia.

Impact of age, leukocyte count and day 21-bone marrow response to chemotherapy on the long-term outcome of children with philadelphia chromosome-positive acute lymphoblastic leukemia in the pre-imatinib era: results of the FRALLE 93 study

BackgroundWe explored the heterogeneity of philadelphia chromosome-positive acute lymphoblastic leukemia (Ph1-ALL) in a study of the effect of early features on prognosis in children. Here we report the long-term results of the FRALLE 93 study conducted in the era before the use of tyrosine kinase inhibitors.MethodsBetween 1993 and 1999, 36 children with Ph1-ALL were enrolled into the FRALLE 93 protocol. After conventional four-drug induction, children were stratified by availability of an HLA-matched sibling.ResultsComplete remission (CR) was observed in 26 children (72%), of which 13 underwent allogeneic bone marrow transplantation (BMT). Thirty-one children were good responders to prednisone, defined on day 8, and 21 were good responders to chemotherapy, defined by day-21 bone marrow (M1). Overall five-year disease-free survival (DFS) was 42 ± 9.7%. Based on multivariate analysis, two groups showed marked differences in five-year outcome: children with age<10, leukocyte count <100,000/mm3 and day-21 M1 marrow had a more favorable prognosis (14 pts: 100% CR, event free survival [EFS]: 57%, overall survival [OS]: 79%), than the high-risk group (22 patients: 55% CR, EFS: 18%, OS: 27%) (p < 0.005). We also observed a non statistically significant difference (p = 0.14) in outcome between these groups for transplanted patients (5-year DFS: 83 ± 14% and 33 ± 15%, respectively).ConclusionAge, leukocyte count and early response to treatment defined by the D21 bone marrow response provide an accurate model for outcome prediction. The combination of available tools such as minimal residual disease assessment with determination of these simple factors could be useful for refining indications for BMT in the current era of tyrosine-kinase inhibitor-based therapy.