Background For children with sickle cell anaemia and elevated transcranial Doppler (TCD) flow velocities, regular blood transfusions effectively prevent primary stroke, but must be continued indefinitely. The efficacy of hydroxyurea in this setting is unknown. Methods TWiTCH was a multicentre Phase III randomised open label, non-inferiority trial comparing standard treatment (transfusions) to alternative treatment (hydroxyurea) in children with abnormal TCD velocities but no severe vasculopathy. Iron overload was managed with chelation (Standard Arm) and serial phlebotomy (Alternative Arm). The primary study endpoint was the 24-month TCD velocity calculated from a general linear mixed model, with non-inferiority margin = 15 cm/sec. Findings Among 121 randomised participants (61 transfusions, 60 hydroxyurea), children on transfusions maintained <30% sickle haemoglobin, while those taking hydroxyurea (mean 27 mg/kg/day) averaged 25% fetal haemoglobin. The first scheduled interim analysis demonstrated non-inferiority, and the sponsor terminated the study. Final model-based TCD velocities (mean ± standard error) on Standard versus Alternative Arm were 143 ± 1.6 and 138 ± 1.6 cm/sec, respectively, with difference (95% CI) = 4.54 (0.10, 8.98), non-inferiority p=8.82 × 10−16 and post-hoc superiority p=0.023. Among 29 new neurological events adjudicated centrally by masked reviewers, no strokes occurred but there were 3 transient ischaemic attacks per arm. Exit brain MRI/MRA revealed no new cerebral infarcts in either arm, but worse vasculopathy in one participant (Standard Arm). Iron burden decreased more in the Alternative Arm, with ferritin difference −1047 ng/mL (−1524, −570), p<0.001 and liver iron difference −4.3 mg Fe/gm dry weight (−6.1, −2.5), p=0.001. Interpretation For high-risk children with sickle cell anaemia and abnormal TCD velocities, after four years of transfusions and without severe MRA vasculopathy, hydroxyurea therapy can substitute for chronic transfusions to maintain TCD velocities and help prevent primary stroke.
Changes in conductivity with repeated fabric extension were investigated to improve the properties of conductive electrode pad material used for electrotherapy when it is subjected to various movement of human body. Highly stretchable and conductive fabrics were prepared by in situ chemical polymerization of polypyrrole on nylon–spandex stretch fabric in aqueous solutions with 0.5 M pyrrole, 1.165 M FeCl3, and 0.165 M benzenesulfonic acid at 5°C for 1 h. Performance of prepared stretchable conductive fabric was evaluated in terms of conductivity changes as a function of tensile strain, repeated extension, and current application time. As the degree of extension increased, the conductivity increased and leveled off when the fabric was subjected to 60% extension. The number of fiber contacts in nylon–spandex fabric with electrode increased as the applied extension increased. However, the conductivity of the composite decreased under excessive extension over 60% since the intrinsic elasticity of fabric became gradually reduced. Generally, the fabric conductivity decreased as the number of extension cycles increased. However, the fabric conductivity was well maintained after repeated extension over 30 cycles at 40% extension. In addition, it was found that the effect of charging during the electrotherapy treatment on a current flow through prepared electrode pad was negligible. © 2003 Wiley Periodicals, Inc. J Appl Polym Sci 88: 1225–1229, 2003
Prevalence of ischemic brain injury in pediatric patients with SCD is substantially higher than was previously reported, in part because of improvements in imaging methods.
• Children with SCA and stroke show severe parenchymal and vascular abnormalities that can be assessed using a vasculopathy grading scale. • Results from the SWiTCHTrial support concerns about ineffectiveness of transfusion therapy in preventing cerebrovascular injury progression.The Stroke With Transfusions Changing to Hydroxyurea (SWiTCH) trial compared standard (transfusions/chelation) to alternative (hydroxyurea/phlebotomy) treatment to prevent recurrent stroke and manage iron overload in children chronically transfused over 7 years before enrollment. Standardized brain magnetic resonance imaging/magnetic resonance angiography (MRA) and transcranial Doppler (TCD) exams were performed at entry and exit, with a central blinded review. A novel MRA vasculopathy grading scale demonstrated frequent severe baseline left/right vessel stenosis (53%/41% ‡Grade 4); 31% had no vessel stenosis on either side. Baseline parenchymal injury was prevalent (85%/79% subcortical, 53%/37% cortical, 50%/35% subcortical and cortical). Most children had low or uninterpretable baseline middle cerebral artery TCD velocities, which were associated with worse stenoses (incidence risk ratio [IRR] 5 5.1, P £ .0001 and IRR 5 4.1, P < .0001) than normal velocities; only 2% to 12% had any conditional/abnormal velocity. Patients with adjudicated stroke (7) and transient ischemic attacks (19 in 11 standard/8 alternative arm subjects) had substantial parenchymal injury/vessel stenosis. At exit, 1 child (alternative arm) had a new silent infarct, and another had worse stenosis. SWiTCH neuroimaging data document severe parenchymal and vascular abnormalities in children with SCA and stroke and support concerns about chronic transfusions lacking effectiveness for preventing progressive cerebrovascular injury. The novel SWiTCH vasculopathy grading scale warrants validation testing and consideration for use in future clinical trials. This trial was registered at www.clinicaltrials.gov as #NCT00122980. (Blood. 2014;124(6):891-898)
Concerns about long-term methotrexate (MTX) neurotoxicity in the 1990s led to modifications in intrathecal therapy, leukovorin rescue and frequency of systemic MTX administration in children with acute lymphoblastic leukemia. In this study, neurocognitive outcomes and neuroradiologic evidence of leukoencephalopathy were compared in children treated with intense central nervous system directed therapy (P9605) versus those receiving fewer CNS-directed treatment days during intensive consolidation (P9201). 66 children from 16 Pediatric Oncology Group (POG) institutions with “standard risk” ALL, 1.00 to 9.99 years at diagnosis, without evidence of CNS leukemia at diagnosis were enrolled on ACCL0131: 28 from P9201 and 38 from P9605. MRI scans and standard neuropsychologic tests were performed > 2.6 years following end of treatment. Significantly more P9605 patients developed leukoencephalopathy than P9201 (68%, 95% CI 49%-83% vs. 22%, 95% CI 5%-44%; p=0.001) identified as late as 7.7 years following end of treatment. Overall 40% of patients scored <85 on either VIQ or PIQ. Children on both studies had significant attention problems but P9605 children scored below average on more neurocognitive measures than those treated on P9201 (82%, 14/17 measures vs. 24%, 4/17 measures). This supports ongoing concerns about intensive methotrexate exposure as a major contributor to CNS late effects.
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