Explore the vast range of titles available.

For children with sickle cell anaemia and high transcranial doppler (TCD) flow velocities, regular blood transfusions can effectively prevent primary stroke, but must be continued indefinitely. The efficacy of hydroxycarbamide (hydroxyurea) in this setting is unknown; we performed the TWiTCH trial to compare hydroxyurea with standard transfusions. TWiTCH was a multicentre, phase 3, randomised, open-label, non-inferiority trial done at 26 paediatric hospitals and health centres in the USA and Canada. We enrolled children with sickle cell anaemia who were aged 4–16 years and had abnormal TCD flow velocities (≥200 cm/s) but no severe vasculopathy. After screening, eligible participants were randomly assigned 1:1 to continue standard transfusions (standard group) or hydroxycarbamide (alternative group). Randomisation was done at a central site, stratified by site with a block size of four, and an adaptive randomisation scheme was used to balance the covariates of baseline age and TCD velocity. The study was open-label, but TCD examinations were read centrally by observers masked to treatment assignment and previous TCD results. Participants assigned to standard treatment continued to receive monthly transfusions to maintain 30% sickle haemoglobin or lower, while those assigned to the alternative treatment started oral hydroxycarbamide at 20 mg/kg per day, which was escalated to each participant's maximum tolerated dose. The treatment period lasted 24 months from randomisation. The primary study endpoint was the 24 month TCD velocity calculated from a general linear mixed model, with the non-inferiority margin set at 15 cm/s. The primary analysis was done in the intention-to-treat population and safety was assessed in all patients who received at least one dose of assigned treatment. This study is registered with ClinicalTrials.gov, number NCT01425307. Between Sept 20, 2011, and April 17, 2013, 159 patients consented and enrolled in TWiTCH. 121 participants passed screening and were then randomly assigned to treatment (61 to transfusions and 60 to hydroxycarbamide). At the first scheduled interim analysis, non-inferiority was shown and the sponsor terminated the study. Final model-based TCD velocities were 143 cm/s (95% CI 140–146) in children who received standard transfusions and 138 cm/s (135–142) in those who received hydroxycarbamide, with a difference of 4·54 (0·10–8·98). Non-inferiority (p=8·82 × 10−16) and post-hoc superiority (p=0·023) were met. Of 29 new neurological events adjudicated centrally by masked reviewers, no strokes were identified, but three transient ischaemic attacks occurred in each group. Magnetic resonance brain imaging and angiography (MRI and MRA) at exit showed no new cerebral infarcts in either treatment group, but worsened vasculopathy in one participant who received standard transfusions. 23 severe adverse events in nine (15%) patients were reported for hydroxycarbamide and ten serious adverse events in six (10%) patients were reported for standard transfusions. The most common serious adverse event in both groups was vaso-occlusive pain (11 events in five [8%] patients with hydroxycarbamide and three events in one [2%] patient for transfusions). For high-risk children with sickle cell anaemia and abnormal TCD velocities who have received at least 1 year of transfusions, and have no MRA-defined severe vasculopathy, hydroxycarbamide treatment can substitute for chronic transfusions to maintain TCD velocities and help to prevent primary stroke. National Heart, Lung, and Blood Institute, National Institutes of Health.

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. 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 0thalassaemia, 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 99Tc spleen scan) and renal function (glomerular filtration rate by 99mTc-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. 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. 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. The US National Heart, Lung, and Blood Institute; and the National Institute of Child Health and Human Development.

To the Editor: Vichinsky and coworkers are to be applauded for their article (July 27 issue) 1 reporting that patients with sickle cell disease undergoing general anesthesia and surgery fare just as well with a less intensive transfusion regimen as with a more aggressive approach. However, the authors' study did not include a “no transfusion” arm. Thus, whether some or even most patients with sickle cell disease might not require blood transfusions at all before elective surgery remains uncertain. This point is relevant not only because of the high incidence of alloimmunization and the occurrence of other transfusion-related complications in their . . .

Hepatic dysfunction occurs commonly in children with sickle cell disease (SCD). Although the etiology is multifactorial, cholestasis is a prominent feature. Serum cholylglycine (CG) has been found to be a very sensitive indicator of cholestasis. Our objective was to determine whether CG levels are elevated in children with SCD and whether they are predictive of hepatic dysfunction. Blood samples were obtained from 97 children with SCD. Liver function tests were done and serum CG concentrations were measured. Patients were followed up for 2 years. Thirty-eight percent of the patients had an elevated CG level. During the 2 years of follow-up, 16% of the children with a previously elevated CG level developed abnormal liver function test results or required a cholecystectomy as compared with 13% with a previously normal CG level (p = 0.92). We conclude that although CG level was elevated in 38% of the patients with SCD, it did not appear to predict liver dysfunction during the ensuring 2 years.

IntroductionFlorid bone marrow failure, i.e., progressive pancytopenia or markedly decreased production of red cells, white cells and platelets, is rare in the neonate. However, inherited bone marrow failure syndromes (IBMFS), which account for up to one-third of cases of aplastic anemia in childhood (1), may offer clues in the first year of life that can lead to definitive testing for and early diagnosis of these severe disorders. Evaluation for an IBMFS should be considered when either the physical appearance of the child includes congenital anomalies that are commonly associated with marrow failure syndromes despite normal blood counts (Table 5.1), or cytopenias due to decreased bone marrow production are present whether or not birth defects are appreciated (Table 5.2). Suspicion of an IBMFS is necessary for early diagnosis, early referral to specialty care, and genetic counseling with regard to future pregnancies. After diagnosis, parents may pursue prenatal diagnosis in utero, or in vitro fertilization with pre-implantation genetic diagnosis to result in the birth of an unaffected child who could be a tissue match for the patient, thus permitting collection of cord blood for hematopoietic stem cell transplantation (HSCT). Many of these syndromes have a significant risk for development of a malignancy, even within the first year of life, emphasizing the need for early surveillance for leukemia and solid tumors.

Hepatic dysfunction occurs commonly in children with sickle cell disease (SCD). Although the etiology is multifactorial, cholestasis is a prominent feature. Serum cholylglycine (CG) has been found to be a very sensitive indicator of cholestasis. Our objective was to determine whether CG levels are elevated in children with SCD and whether they are predictive of hepatic dysfunction. Blood samples were obtained from 97 children with SCD. Liver function tests were done and serum CG concentrations were measured. Patients were followed up for 2 years. Thirty-eight percent of the patients had an elevated CG level. During the 2 years of follow-up, 16% of the children with a previously elevated CG level developed abnormal liver function test results or required a cholecystectomy as compared with 13% with a previously normal CG level (p=0.92). We conclude that although CG level was elevated in 38% of the patients with SCD, it did not appear to predict liver dysfunction during the ensuing 2 years.

IntroductionThe Chediak–Higashi syndrome (CHS) is a rare, autosomal recessive disorder characterized by partial oculocutaneous albinism, increased susceptibility to infections and presence of abnormal large granules in blood cells and other tissues. Most patients eventually enter a usually fatal accelerated phase manifested by fever, pancytopenia and lymphohistiocytic organ infiltrates.This syndrome was first described in 1943 by a Cuban pediatrician in three siblings (Beguez-Cesar, 1943). Chediak (1952) and Higashi (1954) subsequently reported cases with similar anomalies. Sato (1955) recognized the similarity between Chediak and Higashi's cases and named the disease Chediak–Higashi syndrome.CHS has been described in all ethnic groups and is usually rare except for a cluster of cases that has been described in an isolated area of the Venezuelan–Andes (Ramirez-Duque et al., 1983). A similar syndrome has been described in numerous animal species including the Aleutian mink, partial albino Hereford cattle, blue foxes, albino whales and the beige mouse. The beige mouse has been used as an animal model for the disease (Windhorst & Padgett, 1973).Clinical manifestationsCHS commonly affects the skin, eyes, and central nervous system. The age at diagnosis ranges from 1 month to 39 years, with a mean of 5.6 years. The diagnosis is usually first suspected because of coexistent hypopigmentation and a history of frequent pyogenic infections, on the basis of a sibling in whom the diagnosis has been previously made, or after incidental observation of giant peroxidase-positive intracellular granules on a peripheral blood smear or bone marrow examination (Fig. 36.1).