F. Daniel Armstrong

Hydroxycarbamide in very young children with sickle-cell anaemia: a multicentre, randomised, controlled trial (BABY HUG)

BACKGROUND Sickle-cell anaemia is associated with substantial morbidity from acute complications and organ dysfunction beginning in the first year of life. Hydroxycarbamide substantially reduces episodes of pain and acute chest syndrome, admissions to hospital, and transfusions in adults with sickle-cell anaemia. We assessed the effect of hydroxycarbamide therapy on organ dysfunction and clinical complications, and examined laboratory findings and toxic effects. METHODS This randomised trial was undertaken in 13 centres in the USA between October, 2003, and September, 2009. Eligible participants had haemoglobin SS (HbSS) or haemoglobin Sβ(0)thalassaemia, were aged 9-18 months at randomisation, and were not selected for clinical severity. Participants received liquid hydroxycarbamide, 20 mg/kg per day, or placebo for 2 years. Randomisation assignments were generated by the medical coordinating centre by a pre-decided schedule. Identical appearing and tasting formulations were used for hydroxycarbamide and placebo. Patients, caregivers, and coordinating centre staff were masked to treatment allocation. Primary study endpoints were splenic function (qualitative uptake on (99)Tc spleen scan) and renal function (glomerular filtration rate by (99m)Tc-DTPA clearance). Additional assessments included blood counts, fetal haemoglobin concentration, chemistry profiles, spleen function biomarkers, urine osmolality, neurodevelopment, transcranial Doppler ultrasonography, growth, and mutagenicity. Study visits occurred every 2-4 weeks. Analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00006400. FINDINGS 96 patients received hydroxycarbamide and 97 placebo, of whom 83 patients in the hydroxycarbamide group and 84 in the placebo group completed the study. Significant differences were not seen between groups for the primary endpoints (19 of 70 patients with decreased spleen function at exit in the hydroxycarbamide group vs 28 of 74 patients in the placebo group, p=0·21; and a difference in the mean increase in DTPA glomerular filtration rate in the hydroxycarbamide group versus the placebo group of 2 mL/min per 1·73 m(2), p=0·84). Hydroxycarbamide significantly decreased pain (177 events in 62 patients vs 375 events in 75 patients in the placebo group, p=0·002) and dactylitis (24 events in 14 patients vs 123 events in 42 patients in the placebo group, p<0·0001), with some evidence for decreased acute chest syndrome, hospitalisation rates, and transfusion. Hydroxyurea increased haemoglobin and fetal haemoglobin, and decreased white blood-cell count. Toxicity was limited to mild-to-moderate neutropenia. INTERPRETATION On the basis of the safety and efficacy data from this trial, hydroxycarbamide can now be considered for all very young children with sickle-cell anaemia. FUNDING The US National Heart, Lung, and Blood Institute; and the National Institute of Child Health and Human Development.

Silent cerebral infarcts: a review on a prevalent and progressive cause of neurologic injury in sickle cell anemia

Silent cerebral infarct (SCI) is the most common form of neurologic disease in children with sickle cell anemia (SCA). SCI is defined as abnormal magnetic resonance imaging (MRI) of the brain in the setting of a normal neurologic examination without a history or physical findings associated with an overt stroke. SCI occurs in 27% of this population before their sixth, and 37% by their 14th birthdays. In adults with SCA, the clinical history of SCI is poorly defined, although recent evidence suggests that they too may have ongoing risk of progressive injury. Risk factors for SCI include male sex, lower baseline hemoglobin concentration, higher baseline systolic blood pressure, and previous seizures. Specific morbidity associated with SCI includes a decrement in general intellectual abilities, poor academic achievement, progression to overt stroke, and progressive SCI. In addition, children with previous stroke continue to have both overt strokes and new SCI despite receiving regular blood transfusion therapy for secondary stroke prevention. Studies that only include overt stroke as a measure of CNS injury significantly underestimate the total cerebral injury burden in this population. In this review, we describe the epidemiology, natural history, morbidity, medical management, and potential therapeutic options for SCI in SCA.

Neuropsychological dysfunction and neuroimaging abnormalities in neurologically intact adults with sickle cell anemia

CONTEXT Sickle cell anemia (SCA) is a chronic illness causing progressive deterioration in quality of life. Brain dysfunction may be the most important and least studied problem affecting individuals with this disease. OBJECTIVE To measure neurocognitive dysfunction in neurologically asymptomatic adults with SCA vs healthy control individuals. DESIGN, SETTING, AND PARTICIPANTS Cross-sectional study comparing neuropsychological function and neuroimaging findings in neurologically asymptomatic adults with SCA and controls from 12 SCA centers, conducted between December 2004 and May 2008. Participants were patients with SCA (hemoglobin [Hb] SS and hemoglobin level < or = 10 mg/dL) aged 19 to 55 years and of African descent (n = 149) or community controls (Hb AA and normal hemoglobin level) (n = 47). Participants were stratified on age, sex, and education. MAIN OUTCOME MEASURES The primary outcome measure was nonverbal function assessed by the Wechsler Adult Intelligence Scale, third edition (WAIS-III) Performance IQ Index. Secondary exploratory outcomes included performance on neurocognitive tests of executive function, memory, attention, and language and magnetic resonance imaging measurement of total intracranial and hippocampal volume, cortical gray and white matter, and lacunae. RESULTS The mean WAIS-III Performance IQ score of patients with SCA was significantly lower than that of controls (adjusted mean, 86.69 for patients with SCA vs 95.19 for controls [mean difference, -5.50; 95% confidence interval {CI}, -9.55 to -1.44]; P = .008), with 33% performing more than 1 SD (<85) below the population mean. Among secondary measures, differences were observed in adjusted mean values for global cognitive function (full-scale IQ) (90.47 for patients with SCA vs 95.66 for controls [mean difference, -5.19; 95% CI, -9.24 to -1.13]; P = .01), working memory (90.75 vs 95.25 [mean difference, -4.50; 95% CI, -8.55 to -0.45]; P = .03), processing speed (86.50 vs 97.95 [mean difference, -11.46; 95% CI, -15.51 to -7.40]; P < .001), and measures of executive function. Anemia was associated with poorer neurocognitive function in older patients. No differences in total gray matter or hippocampal volume were observed. Lacunae were more frequent in patients with SCA but not independently related to neurocognitive function. CONCLUSION Compared with healthy controls, adults with SCA had poorer cognitive performance, which was associated with anemia and age.

Cognitive and Adaptive Outcome in Low-Grade Pediatric Cerebellar Astrocytomas: Evidence of Diminished Cognitive and Adaptive Functioning in National Collaborative Research Studies (CCG 9891/POG 9130)

PURPOSE Clinicians often assume that children with posterior fossa tumors are at minimal risk for cognitive or adaptive deficits if they do not undergo cranial irradiation. However, small case series have called that assumption into question, and have also suggested that nonirradiated cerebellar tumors can cause location-specific cognitive and adaptive impairment. This study (1) assessed whether resected but not irradiated pediatric cerebellar tumors are associated with cognitive and adaptive functioning deficits, and (2) examined the effect of tumor location and medical complications on cognitive and adaptive functioning. PATIENTS AND METHODS The sample was composed of 103 children aged 3 to 18 years with low-grade cerebellar astrocytomas, who underwent only surgical treatment as part of Childrens Cancer Group protocol 9891 or Pediatric Oncology Group protocol 9130. The sample was divided into three groups based on primary tumor location: vermis, left hemisphere, or right hemisphere. Data were collected prospectively on intelligence, academic achievement, adaptive skills, behavioral functioning, and pre-, peri-, and postsurgical medical complications. RESULTS The sample as a whole displayed an elevated risk for cognitive and adaptive impairment that was not associated consistently with medical complications. Within this group of children with cerebellar tumors, tumor location had little effect on cognitive, adaptive, or medical outcome. CONCLUSION We did not replicate previous findings of location-specific effects on cognitive or adaptive outcome. However, the elevated risk of deficits in this population runs contrary to clinical lore, and suggests that clinicians should attend to the functional outcomes of children who undergo only surgical treatment for cerebellar tumors.

Long-term effects of treatments for childhood cancers

Purpose of review The late effects of current treatments for childhood cancer increase the risk of morbidity and mortality and diminish the quality of life in long-term survivors. We selectively review the negative late cardiac, endocrine, and neurological effects of childhood cancer and its treatments and comment on current research and recommendations for the care of long-term survivors of childhood cancer. Recent findings Progressive cardiotoxicity has been established. Late cardiac effects can be mitigated with the concomitant use of dexrazoxane with anthracycline. When radiotherapy is used multiple organ systems must be monitored for known late effects dependent on the location. Proper diet, physical activity, and obesity are topics that must be addressed in survivors. Late neurocognitive effects impact intelligence quotient, behavior, and achievement. Systematic follow-up with appropriate clinical screening and testing is important in diagnosing and potentially preventing late effects of cancer therapy. Summary The new paradigm for defining successful cancer therapy is the balance between oncologic efficacy and toxicity/late effects. The complexity of late effects necessitates a multidisciplinary approach to long-term care of these patients. The high frequency, delayed onset, and potential severity of late effects demand increased and lifelong monitoring of these individuals.

Assessment of quality of life among pediatric patients with cancer.

Historical foundations of quality of life (QL) assessment, including those in adult oncology, are reviewed in the context of the current need for a developmental measure for clinical pediatric research. QL measures that can be applied to the assessment of children with cancer and other chronic and life-threatening diseases are urgently needed

The Miami pediatric quality of life questionnaire: parent scale.

Because there were limited measures available to assess health‐related quality of life (HRQL) in children with chronic illnesses, this study was initiated to develop an empirically derived questionnaire for use in evaluating HRQL issues in children treated for cancer. Extensive interviews were conducted with 30 families of children with cancer, 10 of pre‐school age, 10 of school age and 10 of adolescent age. Responses were videotaped and transcribed, then categorized to develop a pool of 56 items, which were administered to 132 children with cancer and to their parents. This report focuses on parental responses to objective items and ratings of importance of each of these items. Three primary categories, Self‐Competence, Emotional Stability and Social Competence, were identified, each of which had solid internal consistency, sensitivity and reliability across 1‐month intervals. The measure demonstrated the ability to discriminate between children with different types of cancer, offers an alternative to measures relying on expert judgment to assess HRQL and may lead to greater inclusion of psychological and social concerns as primary factors in determining HRQL in children participating in clinical trials. Int. J. Cancer Suppl. 12:11–17, 1999. ©1999 Wiley‐Liss, Inc.

Cognitive and adaptive outcome in extracerebellar low-grade brain tumors in children: a report from the Children's Oncology Group.

PURPOSE To determine whether pediatric patients treated with surgery only for low-grade tumors in the cerebral hemispheres, supratentorial midline, and exophytic brainstem evidence neurocognitive, academic, adaptive, or emotional/behavioral sequelae. PATIENTS AND METHODS Ninety-three patients from a natural history study of low-grade astrocytomas were tested an average of 111 days after surgery. Rates of below average (< or = 25th percentile) scores in this sample were compared with test norms, and performances were compared across anatomic sites. Finally, the relationships of pre-, peri-, and postsurgical complications to outcome were investigated. RESULTS For the entire sample, there was a significantly elevated rate of below average scores across intelligence quotient, achievement, and adaptive behavior, but not behavioral/emotional adjustment measures. Patients with hemispheric, midline, and brainstem tumors did not differ significantly. Patients with left hemisphere tumors generally performed worse than those with right hemisphere tumors. Finally, neurobehavioral outcome was unrelated to pre-, peri-, or postsurgery complications. CONCLUSION After surgery for low-grade brain tumors, a significant number of patients was found to function below average, by as much as 55% compared with 25% in the normative population. Moreover, these results suggest greater risk for patients with lesions situated in the left cerebral hemisphere. Routine neuropsychological follow-up of children after treatment for low-grade tumors is recommended.

Intellectual and academic outcome following two chemotherapy regimens and radiotherapy for average-risk medulloblastoma: COG A9961

Assess the intellectual and academic outcomes as well as risk factors associated with treatment for average‐risk medulloblastoma in childhood using 23.4 Gy of craniospinal radiotherapy plus adjuvant chemotherapy.

Pain and Fear Ratings ☆: Clinical Implications of Age and Gender Differences

The study investigated the relationships among childrens self-report of anticipatory pain and fear, physiological measures of distress, and previous medical experience in 62 outpatients during allergy skin testing. Younger (aged 3-7 years) and older (aged 8-12 years) children reported similar amounts of pain and fear. Girls reported more pain than boys. Older children and boys provided differential pain and fear ratings compared with younger children and girls. Younger childrens self-report of distress was not related to any physiological measures, but older childrens report of fear was significantly related to blood pressure. In girls, positive medical experience was correlated with less pain. The implications of these findings for the clinical measurement and intervention of childrens distress during painful medical procedures are discussed.