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

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.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

The TOBY Study. Whole body hypothermia for the treatment of perinatal asphyxial encephalopathy: A randomised controlled trial

<p>Abstract</p> <p>Background</p> <p>A hypoxic-ischaemic insult occurring around the time of birth may result in an encephalopathic state characterised by the need for resuscitation at birth, neurological depression, seizures and electroencephalographic abnormalities. There is an increasing risk of death or neurodevelopmental abnormalities with more severe encephalopathy. Current management consists of maintaining physiological parameters within the normal range and treating seizures with anticonvulsants.</p> <p>Studies in adult and newborn animals have shown that a reduction of body temperature of 3–4°C after cerebral insults is associated with improved histological and behavioural outcome. Pilot studies in infants with encephalopathy of head cooling combined with mild whole body hypothermia and of moderate whole body cooling to 33.5°C have been reported. No complications were noted but the group sizes were too small to evaluate benefit.</p> <p>Methods/Design</p> <p>TOBY is a multi-centre, prospective, randomised study of term infants after perinatal asphyxia comparing those allocated to "intensive care plus total body cooling for 72 hours" with those allocated to "intensive care without cooling".</p> <p>Full-term infants will be randomised within 6 hours of birth to either a control group with the rectal temperature kept at 37 +/- 0.2°C or to whole body cooling, with rectal temperature kept at 33–34°C for 72 hours. Term infants showing signs of moderate or severe encephalopathy +/- seizures have their eligibility confirmed by cerebral function monitoring. Outcomes will be assessed at 18 months of age using neurological and neurodevelopmental testing methods.</p> <p>Sample size</p> <p>At least 236 infants would be needed to demonstrate a 30% reduction in the relative risk of mortality or serious disability at 18 months.</p> <p>Recruitment was ahead of target by seven months and approvals were obtained allowing recruitment to continue to the end of the planned recruitment phase. 325 infants were recruited.</p> <p>Primary outcome</p> <p>Combined rate of mortality and severe neurodevelopmental impairment in survivors at 18 months of age. Neurodevelopmental impairment will be defined as any of:</p> <p>• Bayley mental developmental scale score less than 70</p> <p>• Gross Motor Function Classification System Levels III – V</p> <p>• Bilateral cortical visual impairments</p> <p>Trial Registration</p> <p>Current Controlled Trials ISRCTN89547571</p

Long-term administration of desferrioxamine in thalassaemia major

Studies of desferrioxamine (DFA) as a specific iron-chelating agent in the treatment of haemosiderosis have been reported in various conditions, but there has been only limited evaluation of its long-term use in thalassaemia major. In the present study 1 g DFA was given intramuscularly daily 6 days per week in 3 patients for 5 to 8 years, and in another 7 patients for 10 to 22 months. In addition, 500 mg DFA was added to each unit of donor blood at the time of transfusions. Urinary iron excretion after DFA was estimated using atomic absorption spectrophotometry both before and periodically during DFA treatment. During follow-up, cardiac and liver functions were assessed by ECG, chest x-ray, and liver function tests. The results show that DFA therapy increased urinary iron excretion, and that this was associated with a significant improvement in the clinical symptoms and signs of haemosiderosis and with return towards normal in the ECG and liver function tests

Analysis by ANOVA of sources of error in relation to MRD level.

<p>Results are expressed in log₁₀ mode and the SD rather than the variance in S2 ANOVA is shown. All values of SD differed significantly (p<0.01) from 0 except that asterisked.</p

Incorrect decisions grouped by the mean MRD level of the patient.

<p>The percent of assays is the percent of decision errors in the assays from patients with MRD between 10⁻² and 10⁻⁵. The results shown are data from all 41 patients.</p

Percentage of decision errors in relation to difference between the assayed MRD value and the cut-off value used for deciding on intensification of treatment.

<p>There were 957 differences and the percentage of errors is a 45-point moving average. The results shown are data from all 41 patients.</p

Difference between the left and right sides in the mean MRD value for each side.

<p>Each mean was the result of 2 assays on each of 2 samples. The results are for the 29 patients analysed by ANOVA.</p