Sources of error in measurement of minimal residual disease in childhood acute lymphoblastic leukemia.

INTRODUCTION: The level of minimal residual disease (MRD) in marrow predicts outcome and guides treatment in childhood acute lymphoblastic leukemia (ALL) but accurate prediction depends on accurate measurement. METHODS: Forty-one children with ALL were studied at the end of induction. Two samples were obtained from each iliac spine and each sample was assayed twice. Assay, sample and side-to-side variation were quantified by analysis of variance and presumptively incorrect decisions related to high-risk disease were determined using the result from each MRD assay, the mean MRD in the patient as the measure of the true value, and each of 3 different MRD cut-off levels which have been used for making decisions on treatment. RESULTS: Variation between assays, samples and sides each differed significantly from zero and the overall standard deviation for a single MRD estimation was 0.60 logs. Multifocal residual disease seemed to be at least partly responsible for the variation between samples. Decision errors occurred at a frequency of 13-14% when the mean patient MRD was between 10-2 and 10-5. Decision errors were observed only for an MRD result within 1 log of the cut-off value used for assessing high risk. Depending on the cut-off used, 31-40% of MRD results were within 1 log of the cut-off value and 21-16% of such results would have resulted in a decision error. CONCLUSION: When the result obtained for the level of MRD is within 1 log of the cut-off value used for making decisions, variation in the assay and/or sampling may result in a misleading assessment of the true level of marrow MRD. This may lead to an incorrect decision on treatment.

Elective administration in infants of low-dose recombinant activated factor VII (rFVIIa) in cardiopulmonary bypass surgery for congenital heart disease does not shorten time to chest closure or reduce blood loss and need for transfusions: a randomized, double-blind, parallel group, placebo-controlled study of rFVIIa and standard haemostatic replacement therapy versus standard haemostatic replacement therapy.

We investigated the effectiveness of prophylactic administration of recombinant activated factor VII (rFVIIa) for cardiopulmonary bypass surgery in children under 1 year old with congenital heart disease (CHD) in a double-blinded, placebo-controlled study. The rFVIIa dose was 40 microg/kg and all patients also received standard haemostatic replacement therapy. The primary endpoint was the time to chest closure from neutralization of heparin with protamine sulphate as this could be most objectively and accurately measured during surgery. Secondary endpoints were volumes of transfused blood, platelet concentrates and fresh-frozen plasma. All adverse events were recorded. In the intention-to-treat analysis there were 76 patients (40 in rFVIIa group and 36 in placebo group). The demographics and severity of CHD were similar in both groups. No benefit of rFVIIa prophylaxis was found in the time to chest closure, which was significantly prolonged in the rFVIIa group (rFVIIa mean +/- SE, 98.8 +/- 27.27 versus 55.3 +/- 29.15, P = 0.0263). In the 41 patients available for a follow-up visit 6 weeks after discharge, the chest closure time was also prolonged in the rFVIIa group (P = 0.0515). There were no significant differences in the secondary endpoints. Adverse events were similar in both groups.

Factor V Leiden mutation: a contributory factor for cerebral palsy?

Fifty-seven children with cerebral palsy (CP) and imaging evidence of vascular thrombosis (study group) and 167 children with CP and other imaging finds (control group)were selected. Sixty-one per cent of the study group were male and 53 (93%) had spastic hemiplegia compared with the control group, of whom 55% were male and 54 (32%) had a diagnosis of spastic hemiplegia. Mean age was 5 years 11 months (SD 5y 1mo) for the study group and 7 years 7 months (SD 4y 7mo) for the control group. Blood spots on Guthrie cards or buccal swabs were used to test both groups and their mothers for the factor V Leiden (fVL) mutation, which predisposes carriers to thrombophilia. Mothers were interviewed to gather antenatal, perinatal, demographic, and socio-economic data. The frequency of the fVL mutation in children with evidence of vascular thrombosis and their mothers was not statistically different from the frequency in children with CP with other imaging findings and their mothers. The frequency of the fVL mutation was significantly higher than the expected population frequency of 4% in the study group (10.5%, p=0.012) and in mothers of the control group (7.2%, p=0.036).

Spontaneous liver hemorrhage during laparotomy for necrotizing enterocolitis: a potential role for recombinant factor VIIa.

Necrotizing enterocolitis remains a serious condition in very low birth weight infants, particularly in those infants who require surgery. Perioperative hemorrhage is a potentially fatal complication in this population. We describe our experience in 4 premature infants with necrotizing enterocolitis who received recombinant factor VIIa to manage life-threatening intraoperative hemorrhage.

Impairments of attention following treatment with cranial irradiation and chemotherapy in children.

Neurobehavioral impairments are frequently reported following treatment for childhood cancers, with cranial irradiation (CRT). This study investigated attention and information processing skills, predicting that these skills would be impaired due to the vulnerability of cerebral white matter in early childhood. Three treatment groups were studied: (i) CRT+chemotherapy (n = 35); (ii) chemotherapy alone (n = 19); (iii) healthy children (n = 35). All children were aged 9 to 16 years at time of assessment, with no pre-diagnosis history of neurologic, developmental, or psychiatric disorder. Children were administered a series of task measuring processing speed and sustained, selective, and shifting attention. For children treated with CRT + chemo, results identified residual deficits in processing speed for complex tasks, selective and shifting attention. In contrast, processing speed was intact for simple tasks, and there was no clear evidence of deterioration in performance over time, as might be expected in the presence of a sustained attention deficit. Children treated with chemotherapy alone demonstrated generally intact attentional skills. However, this group did record an increasing number of attentional lapses over time on tasks tapping sustained attention skills.

Reduced bone density among children with severe hemophilia.

OBJECTIVE: Children with severe hemophilia are at risk for reduced bone mineral density (BMD) because of reduced weight-bearing exercise and hepatitis C infection. Reduced bone density in childhood is a risk factor for osteoporosis in later life. STUDY DESIGN: We performed a cross-sectional survey of bone density among 19 children with severe hemophilia, at the Royal Children's Hospital. Results were correlated with findings of blinded objective evaluations of the joints of the lower limb and with hepatitis C status. RESULTS: The mean lumbar bone mineral apparent density for patients was reduced (0.102 g/cm3), compared with that for control subjects (0.113 g/cm3). The mean areal BMD z score was -0.92, which was significantly reduced, compared with that for control subjects. The difference in bone density was independent of body size. There was a statistically significant relationship between the lumbar BMD z scores and the maximal single joint evaluation scores, but there was no difference based on hepatitis C status. CONCLUSIONS: Our results suggest that children with severe hemophilia have reduced BMD. Patients at risk are those with signs of hemophilic arthropathy. Because osteoporosis may complicate the future treatment of patients with hemophilia, screening of young patients for reduced bone density is recommended.