Consensus statement on standard of care for congenital muscular dystrophies.

Congenital muscular dystrophies are a group of rare neuromuscular disorders with a wide spectrum of clinical phenotypes. Recent advances in understanding the molecular pathogenesis of congenital muscular dystrophy have enabled better diagnosis. However, medical care for patients with congenital muscular dystrophy remains very diverse. Advances in many areas of medical technology have not been adopted in clinical practice. The International Standard of Care Committee for Congenital Muscular Dystrophy was established to identify current care issues, review literature for evidence-based practice, and achieve consensus on care recommendations in 7 areas: diagnosis, neurology, pulmonology, orthopedics/rehabilitation, gastroenterology/ nutrition/speech/oral care, cardiology, and palliative care. To achieve consensus on the care recommendations, 2 separate online surveys were conducted to poll opinions from experts in the field and from congenital muscular dystrophy families. The final consensus was achieved in a 3-day workshop conducted in Brussels, Belgium, in November 2009. This consensus statement describes the care recommendations from this committee.

Phase I study of oral cyclophosphamide and oral topotecan for children with recurrent or refractory solid tumors.

BACKGROUND: To determine the maximum-tolerated duration and dose-limiting toxicity of a daily schedule of orally administered cyclophosphamide and topotecan in pediatric patients with recurrent or refractory malignant solid tumors. METHODS: Patients received oral cyclophosphamide (50 mg/m2/dose) in the morning followed by topotecan (0.8 mg/m2/dose) 8-12 hr later for an escalating number of consecutive days (10, 14, and 17 days). RESULTS: Seventeen pediatric patients were treated with oral cyclophosphamide and topotecan for durations of 10-17 days for a total of 58 treatment courses. Reversible hematologic toxicity (neutropenia and thrombocytopenia) was the dose-limiting toxicity. Nonhematologic toxicities of greater than grade 3 were not observed. A partial response (neuroblastoma following myeloablative chemotherapy and stem cell rescue) and prolonged stable disease (medulloblastoma) were each observed in one patient. CONCLUSIONS: The recommended duration of therapy with a daily schedule of both oral cyclophosphamide (50 mg/m2/day) and topotecan (0.8 mg/m2/day) for previously treated pediatric patients with recurrent or refractory solid tumors is 14 consecutive days. The observed dose limiting toxicity (DLT) was reversible neutropenia. This regimen was well tolerated in heavily pretreated patients and demonstrated activity against recurrent pediatric solid tumors.

Genetic polymorphisms in CYP3A5, CYP3A4 and NQO1 in children who developed therapy-related myeloid malignancies.

Therapy-related acute myeloid leukemia and myelodysplastic syndrome (t-ML) are serious complications that affect some patients after acute lymphoblastic leukemia (ALL) treatment. Genetic polymorphisms in the promoter of CYP3A4 (CYP3A4*1B) and in NAD(P)H:quinone oxidoreductase (NQO1609C-->T substitution) have been associated with the risk of t-ML. A polymorphism in CYP3A5 (CYP3A5*3) affects CYP3A activity and the wild-type allele (CYP3A5*1) is in partial linkage with the CYP3A4*1B allele. We compared the genotype frequencies for the CYP3A5*3, the CYP3A4*1B and the NQO1609C-->T substitution in 224 children with ALL who did not develop t-ML (controls) and in 53 children with ALL who did develop the complication. The allele frequencies differed significantly among whites, blacks and Hispanics (P < 0.001 for CYP3A5*3, P < 0.001 for CYP3A4*1B and P = 0.004 for NQO1609), thus we performed the comparisons between ALL controls and t-ML patients after accounting for race. We found no differences in the CYP3A4*1B allele distribution between ALL controls and t-ML patients in whites (P = 0.339, 6.6% vs. 9.8%), blacks (P = 0.498, 93.8% vs. 87.5%) or Hispanics (P = 0.523, 39.1% vs. 25.0%). The frequencies for the NQO1609C-->T allele did not differ between control and t-ML groups in whites (P = 0.191, 35.0% vs. 44.9%), blacks (P = 0.664, 37.5% vs. 37.5%) or Hispanics (P = 0.447, 65.2% vs. 50.0%). We found no differences between the control and t-ML group in the incidence of homozygous CYP3A5*3 genotypes: 82.0% vs. 85.4% in whites (P = 0.403), 6.5% vs. 12.5% in blacks (P = 0.508), and 69.6% vs. 75.0% in Hispanics (P= 0.663). Our data do not support an association between common CYP3A4, NQO1 or CYP3A5 polymorphisms and the risk of t-ML in children treated for ALL.

Effective removal of methotrexate by high-flux hemodialysis.

The purpose of the present study was to examine the clearance of methotrexate (MTX) by high-flux hemodialysis (HD) in pediatric oncology patients. We present three patients who experienced nephrotoxicity and prolonged exposure to toxic MTX concentrations following high-dose infusions during treatment for osteogenic sarcomas. Each patient was successfully treated with high-flux HD, followed by carboxypeptidase G2 (CPDG2) in two cases. Minimal systemic toxicity occurred. We review the literature and discuss guidelines for early and aggressive treatment for this complication of high-dose MTX therapy. Clinically important removal of MTX depends upon prompt initiation of HD after detection of nephrotoxicity and delayed clearance of MTX. Therapy is indicated in cases where compassionate use of CPDG(2) may not be available, or while awaiting its delivery.