Polymicrogyria in a child with inv dup del(9p) and 22q11.2 microduplication.

Polymicrogyria (PMG) is a relatively common malformation of the cortex for which the pathogenesis remains poorly understood. Both acquired and genetic causes are known, and to date more than 70 cases of PMG have been associated with chromosomal abnormalities. Here we report on a 12-year-old girl presenting with asymmetrical PMG predominantly affecting the right occipital lobe. She was the only child of consanguineous parents. At 7 years of age she was referred for mental retardation with speech delay and seizures. Cytogenetic studies of the patient revealed an inverted 9p duplication/deletion and bacterial artificial chromosomes (BACs)-array also showed a 22q11.2 microduplication confirmed by quantitative PCR. This case is of interest in the search for candidate genes and emphasizes the importance of the 22q11 region in PMG. It also highlights the efficiency of BACs-array in detecting complex rearrangements.

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.

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.

Immunophenotype of a transient myeloproliferative disorder in a newborn with trisomy 21.

Cytologic, immunologic, and cytogenetic studies were performed on the blast cells of a newborn with Down syndrome and transient myeloproliferative disease. This hematologic disorder is uncommon, and occurs primarily in infants with Down syndrome. This boy presented with a high white blood cell count and a high percentage of blast cells, without anemia or thrombocytopenia. Chromosome analysis showed a constitutional trisomy 21 without any other clonal abnormality. A three-color flow cytometric analysis was performed and revealed two different CD45 dim, CD34(+), CD117(+), CD56(+) immature subpopulations: the normal immature myeloid precursor and an immature blast cell population that expressed CD41, CD42, CD61, CD36, CD13, CD1a, and CD2. We postulate that this population could be the leukemic precursor involved in the acute megakaryoblastic leukemia frequently observed in children with Down syndrome.

A European phase II study of recombinant human granulocyte colony-stimulating factor (lenograstim) in the treatment of severe chronic neutropenia in children. Lenograstim Study Group.

UNLABELLED: We conducted a multicentre, open-label prospective study to evaluate the efficacy and tolerability of lenograstim (human-identical glycosylated rHuG-CSF) in the prevention of infectious episodes of severe chronic neutropenia in 19 patients. The median follow up period was 54.6 months. Lenograstim was administered subcutaneously at a starting dosage of 5 microg/kg per day. Neutrophil recovery was achieved in all patients at induction dosages of 5 (n = 15), 10 (n = 2), 15 (n = 1) or 20 microg/kg per day (n = 1) and occurred at a median 7 days after therapy initiation. Alternate-day administration of double-dose lenograstim was feasible in 7 of 17 patients. Lenograstim treatment significantly (P = 0.012) reduced the incidence of treated infections and hospitalization for infection compared with the pre study period and significantly (P < 0.001) improved perceived health and disease-related symptoms. One patient discontinued treatment because of adverse events (pustulosis) initially related to lenograstim therapy but not confirmed. One patient withdrew by personal choice and was therefore only treated occasionally. One patient committed suicide after 45 months because of social difficulties. One patient was lost during follow up, and three patients presented with a spontaneous neutrophil recovery after 9, 15 and 27 months, respectively. Moderate and transient side-effects related to lenograstim were observed (thrombocytopenia, n = 2; splenomegaly, n = 2; moderate anaemia (without transfusion requirement), n = 5; bone pain, n = 2; increased of alkaline phosphatase, n = 5). CONCLUSION: Lenograstim produced a sustained neutrophil recovery in patients with severe chronic neutropenia, reduced the incidence and severity of infection, and improved quality of life.

Induction chemotherapy followed by allogeneic bone marrow transplantation or aggressive consolidation chemotherapy in childhood acute myeloblastic leukemia. A prospective study from the French Society of Pediatric Hematology and Immunology (SHIP).

In the LAME89/91 protocol, children with acute myeloid leukemia (AML) who achieved complete remission (CR) after induction chemotherapy, were treated either with allogeneic bone marrow transplantation (BMT) if they had an HLA-compatible related donor or with chemotherapy including high-dose cytarabine. The objectives of this study were to describe the overall results of this strategy and to compare the two post-remission arms. Two hundred and thirty-one children were enrolled in the protocol. Induction chemotherapy consisted of a combination of cytarabine and mitoxantrone. A CR was achieved in 204 children (88%).