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To establish the incidence, risk factors and prognostic effect of anemia in children living with HIV (CLWH).Retrospective nested case-control study of patients 0-18 years in five centers in sub-Saharan Africa, 2004-2014.Incident cases of anemia were identified from electronic records and matched with CLWH without anemia. We calculated the incidence density of anemia and used conditional logistic regression to evaluate its association with risk factors, stratified by severity and type of anemia. We used a Cox proportional hazards model to evaluate the impact of anemia on survival.Two thousand, one hundred and thirty-seven children were sampled. The incidence density of anemia was 1 per 6.6 CLWH-years. Anemia was moderate in 31.8% and severe in 17.3% of anemia cases, which had 10-year mortality hazards of 3.4 and 4.5, respectively. Microcytic anemia (36% cases) was associated with 2.3-fold hazard of 10-year mortality, and with malnutrition and CD4 + suppression. Normocytic anemia (50.5% cases) was associated with 2.6-fold hazards of 10-year mortality, and with more severe malnutrition, CD4 + suppression, and WHO stage, but inversely associated with lamivudine and nevirapine therapy. Macrocytic anemia (13.5% cases) was neither associated with higher 10-year mortality nor with severe malnutrition or CD4 + suppression but was associated with WHO stage II/III and negatively associated with lamivudine therapy.This large multicountry study of CLWH found a high incidence density of anemia. Higher severity, normocytic and microcytic types of anemia were independently associated with long-term mortality. Laboratory studies are needed to decipher the mechanisms of anemia and how it impacts mortality in CLWH.

To establish the incidence, risk factors and correlation with survival of thrombocytopenia and thrombocytosis (T/T) among children living with HIV infection (CLWH).A retrospective nested case control study of patients 0-18 years in five Baylor International Pediatric AIDS Initiative (BIPAI) centers in sub-Sahara Africa, 2004-2014.Clinical and laboratory variables including complete blood counts (CBC) were extracted from the BIPAI electronic medical record system. Incident cases of T/T were identified and frequency-matched on follow-up time with controls with normal platelets. We calculated the prevalence and incidence density of T/T and used conditional logistic regression to evaluate their association with selected clinical variables. We constructed Kaplan-Meier curves and a Cox proportional hazards model to evaluate the impact of T/T on survival.2,109 children were sampled. The incidence density of thrombocytopenia was 1 per 57.9 (95%CI 50.3-66.8) CLWH-years. Thrombocytopenia was higher in children with WHO Stage III/IV, lower in children on Zidovudine, and had no association with use of lamivudine or nevirapine, CD4 suppression, age, and nutrition status. Thrombocytopenia was independently associated with 2.2-fold higher mortality (95%CI 1.62-3.08). The incidence density of thrombocytosis was 1 per 11.4 (95%CI 10.7-12.1) CLWH-years. Thrombocytosis was associated with higher CD4, younger age, and use of lamivudine or nevirapine, and did not impact survival.Platelet count is a clinically valuable biomarker of HIV clinical progression and mortality. Laboratory studies are necessary to elucidate the mechanisms of T/T.

Objectives: Sickle cell disease (SCD) is well recognized as a hypercoagulable state, however venous thromboembolism (VTE) risk factors in children remain largely unknown. In this study, we aim to describe the clinical characteristics, outcomes and recurrence of hospital acquired VTE in patients younger than 21 years of age. Study Design/Methods: Data were extracted from electronic medical records over a 10-year period (2011-2021). Data regarding sickle cell genotype, demographics, reason for admission, location of thrombus, presence of central venous catheter (CVC), intensive care unit (ICU) admission, presence of thrombophilia risk factors, resolution of VTE, mortality, and bleeding outcomes on anticoagulation were collected. Recurrence of VTE at 1 and 5 years was assessed. Descriptive statistics were used as indicated. Results: We identified a total of 21 VTE events over the ten-year study period. Six of these events occurred in those younger than 12 years of age. Fifteen (71%) VTE events occurred in the HbSS or HbSβThal genotypes compared to 8 (29%) in HbSC. Eleven (52%) patients were admitted with acute chest syndrome (ACS). Most VTE events were associated with ICU admissions (n=13, 62%) and presence of central venous catheter (n=12, 57%). Major bleeding on anticoagulation occurred in 10%.All patients had resolution of index VTE at 12 weeks. Recurrence rate for VTE at 5 years was 13%. One patient died from the VTE event. Conclusions: Our study highlights that VTE can complicate SCD in children and young adults. Hospital acquired VTE were most associated with ICU admission, CVC, and ACS, but larger studies are indicated to validate our findings.

Sickle cell disease (SCD) is a group of common, life-threatening disorders caused by a point mutation in the β globin gene. Early diagnosis through newborn and early childhood screening, parental education, and preventive treatments are known to reduce mortality. However, the cost and complexity of conventional diagnostic methods limit the feasibility of early diagnosis for SCD in resource-limited areas worldwide. Although several point-of-care tests are commercially available, most are antibody-based tests, which cannot be used in patients who have recently received a blood transfusion. Here, we describe the development of a rapid, low-cost nucleic acid test that uses real-time fluorescence to detect the point mutation encoding hemoglobin S (HbS) in one round of isothermal recombinase polymerase amplification (RPA). When tested with a set of clinical samples from SCD patients and healthy volunteers, our assay demonstrated 100% sensitivity for both the βA globin and βS globin alleles and 94.7 and 97.1% specificities for the βA globin allele and βS globin allele, respectively (n = 91). Finally, we demonstrate proof-of-concept sample-to-answer genotyping of genomic DNA from capillary blood using an alkaline lysis procedure and direct input of diluted lysate into RPA. The workflow is performed in

Patients with severe hemophilia are usually diagnosed in infancy due to early onset of abnormal bleeding symptoms that characterize the disease. Affected individuals require coagulation factor routinely or prior to surgical procedures to prevent bleeding and are usually excluded from activities with a high risk of trauma. A 25-year old active-duty soldier was diagnosed with severe congenital hemophilia A after presenting with initial episode of prolonged bleeding. His case demonstrates a rare late presentation of a disease that typically presents in infancy and highlights the need for improving knowledge about bleeding disorders among health workers and the community.

BACKGROUND: In children in sub-Saharan Africa, severe anaemia (SA) is an important cause of mortality and malaria is a primary cause. The World Health Organization (WHO) recommends blood transfusion for all children with haemoglobin (Hb)

Severe hemophilia symptoms usually start in infancy. Affected individuals require coagulation factor routinely to live a normal life. A 25-year old active-duty soldier was diagnosed with severe congenital hemophilia A after presenting with initial episode of prolonged bleeding. His case demonstrates a rare late presentation of hemophilia.

Although 80% of pediatric cancer cases occur in low- and middle-income countries, specialists in the field of pediatric hematology and oncology (PHO) are scarce, which is a major reason for the dismal survival rates of children with cancer and blood disorders in sub-Saharan Africa (SSA) compared

Background Sickle cell anaemia is a common, life-threatening disorder caused by a point mutation in the β globin gene. The high cost and complexity of conventional diagnostic methods limit the scope and sustainability of newborn screening for sickle cell anaemia and other haemoglobin disorders in resource-limited areas. Although several point-of-care tests are commercially available, most are antibody-based tests, which cannot be used in patients who have recently received a blood transfusion. Additionally, very low levels of sickle haemoglobin (HbS) in premature babies and some newborns may cause errors in immunoassays. DNA analysis provides the most reliable approach to diagnose haemoglobin disorders. However, DNA analysis is not currently available at the point of care due to its cost and complexity. Here, we describe a rapid, low-cost nucleic acid test that uses real-time fluorescence to detect the point mutation encoding HbS in one round of isothermal recombinase polymerase amplification. Methods Venous and capillary blood samples were obtained from healthy volunteers who were recruited by word of mouth. Venous blood samples from patients with varying genotypes seen in the Sickle Cell Disease Program at Texas Children's Hematology Center were collected and deidentified under IRB-approved exemption. Genotypes, as determined by qualitative isoelectric focusing combined with quantitative high performance liquid chromatography (HPLC) to confirm a diagnosis, were provided with the blood samples. The assay was evaluated with genomic DNA extracted from a set of blood samples of varying genotypes using the Axxin T8-ISO, a low-cost, field-deployable benchtop fluorimeter. Findings The developed assay demonstrated 100% sensitivity for both the βA globin and βS globin alleles, and 94·7% and 97·1% specificity for the βA globin allele and βS globin allele, respectively (n=91). We also demonstrate a complete sample-to-answer workflow using a two-step lysis method and direct input of lysate into the allele-specific assay, and genotyping of blood samples in an open-source, custom built fluorimeter whose components cost less than US$850. Interpretation This sample-to-answer nucleic acid test has the potential to be adapted to other disease-causing point mutations in genomic DNA. The technology described could streamline diagnosis in resource-limited settings of patients with sickle cell anaemia who have recently undergone a blood transfusion, with a comparable cost to protein-based tests. Funding NIH K23-HL148548-01A1.

PURPOSE Specialized multidisciplinary care is central to childhood cancer control. Expertise and infrastructure in the pediatric disciplines of hematology, surgery, critical care, nursing, and pathology are as critical as pediatric oncology. Survival of the majority of children with cancer globally remains dismal because of the scarcity of multidisciplinary pediatric subspecialty services. We present the innovative approach and impact of Texas Children’s Global HOPE initiatives to cost-effectively develop capacity for specialized multidisciplinary cancer care for children in sub-Sahara Africa (SSA). METHODS Global HOPE designed and supports subspecialty training and contingent infrastructure building in SSA in the following disciplines that are critical to pediatric cancer care: pediatric hematology and oncology (PHO), pediatric surgery, pediatric critical care, anatomic and molecular pathology, and pediatric oncology nursing. Key principles underlying the design of each disciplinary program are that it enables the implementation of current best evidence-based practices, primarily uses a problem-based learning approach, and is integrated and accredited by the local health sciences university. Training primarily occurs at an African hub where Global HOPE also supports infrastructure for clinical care and research, in addition to onsite faculty and offsite telemedicine support from the headquarters in Houston, TX. RESULTS The PHO and pediatric surgery fellowship programs based at Makerere University, Kampala, are the most advanced thus far. Twenty pediatricians from 6 African countries have enrolled and 8 have graduated from the 2-year PHO program. One surgeon enrolled in the 3-year pediatric surgery fellowship annually and 6 have graduated since inception. The fellowship programs have directly affected patient outcomes because of evidence-based clinical rigor and enhanced clinical infrastructure. All graduates from the 2 fellowships are currently practicing in SSA. CONCLUSION Formal in situ pediatric subspecialty training is feasible in low- and middle-income countries and carries the critical advantages of infrastructure development, direct patient impact, and is less susceptible to brain drain.

Magnesium, a vasodilator, anti-inflammatory, and pain reliever, could alter the pathophysiology of sickle cell pain crises. We hypothesized that intravenous magnesium would shorten length of stay, decrease opioid use, and improve health-related quality of life (HRQL) for pediatric patients hospitalized with sickle cell pain crises. The Magnesium for Children in Crisis (MAGiC) study was a randomized, double-blind, placebo-controlled trial of intravenous magnesium vs normal saline placebo conducted at 8 sites within the Pediatric Emergency Care Applied Research Network (PECARN). Children 4 to 21 years old with hemoglobin SS or Sβ(0) thalassemia requiring hospitalization for pain were eligible. Children received 40 mg/kg of magnesium or placebo every 8 hours for up to 6 doses plus standard therapy. The primary outcome was length of stay in hours from the time of first study drug infusion, compared using a Van Elteren test. Secondary outcomes included opioid use and HRQL. Of 208 children enrolled, 204 received the study drug (101 magnesium, 103 placebo). Between-group demographics and prerandomization treatment were similar. The median interquartile range (IQR) length of stay was 56.0 (27.0-109.0) hours for magnesium vs 47.0 (24.0-99.0) hours for placebo (P = .24). Magnesium patients received 1.46 mg/kg morphine equivalents vs 1.28 mg/kg for placebo (P = .12). Changes in HRQL before discharge and 1 week after discharge were similar (P > .05 for all comparisons). The addition of intravenous magnesium did not shorten length of stay, reduce opioid use, or improve quality of life in children hospitalized for sickle cell pain crisis. This trial was registered at www.clinicaltrials.gov as #NCT01197417.

Objectives: Chromosomal ploidy is a major risk stratification tool for acute B-cell lymphoblastic leukemia (B-ALL). Low hypodiploidy and near-haploidy are thought to be confined to pediatric B-ALL and associated with a poor prognosis. Doubling of either a low-hypodiploid or a near-haploid clone results in an apparently high-hyperdiploid karyotype, which is often misclassified for risk. Methods: We studied four patients with B-ALL who had chromosome genomic array testing (CGAT), along with fluorescence in situ hybridization and mutation testing. Results: We identified a unique case of adult B-ALL with masked low hypodiploidy (mLH) by genomic duplication, along with a somatic deletion of the IKZF3 gene and a somatic TP53 mutation. Three cases of pediatric B-ALL with mLH, two with TP53 mutations and one untested, were also identified and compared with the adult patient. Conclusions: CGAT was critical in the genotype clarification of these cases through detection of copy-neutral loss of heterozygosity and should be considered performing for B-ALL with apparent hyperdiploidy for accurate prognostic risk stratification and treatment planning.

The high cost, complexity and reliance on electricity, specialized equipment and supplies associated with conventional diagnostic methods limit the scope and sustainability of newborn screening for sickle cell disease (SCD) in sub-Saharan Africa and other resource-limited areas worldwide. Here we describe the development of a simple, low-cost, rapid, equipment- and electricity-free paper-based test capable of detecting sickle hemoglobin (HbS) in newborn blood samples with a limit of detection of 2% HbS. We validated this newborn paper-based test in a cohort of 159 newborns at an obstetric hospital in Cabinda, Angola. Newborn screening results using the paper-based test were compared to conventional isoelectric focusing (IEF). The test detected the presence of HbS with 81.8% sensitivity and 83.3% specificity, and identified SCD newborns with 100.0% sensitivity and 70.7% specificity. The use of the paper-based test in a two-stage newborn screening process could have excluded about 70% of all newborns from expensive confirmatory testing by IEF, without missing any of the SCD newborns in the studied cohort. This study demonstrates the potential utility of the newborn paper-based test for reducing the overall cost of screening newborns for SCD and thus increasing the practicality of universal newborn SCD screening programs in resource-limited settings.

Cumulative Distribution Curve for the Parent Proxy Report PedsQL™ Sickle Cell Disease Total Score. Figure S2. Cumulative Distribution Curve for the Parent Proxy Report PedsQL™ Multidimensional Fatigue Scale Total Score. Figure S3. Cumulative Distribution Curve for the Parent Proxy Report PedsQL™ Generic Core Total Score. Figure S4. Cumulative Distribution Curve for the Parent Proxy Report PedsQL™ Sickle Cell Disease Pain Impact Score. Figure S5. Cumulative Distribution Curve for the Parent Proxy Report PedsQL™ Sickle Cell Disease Pain and Hurt Score. Figure S6. Cumulative Distribution Curve for the Parent Proxy Report PedsQL™ Sickle Cell Disease Pain Management Score. (DOCX 328 kb)

CONSORT PRO PedsQL™ Sickle Cell Disease Module Completion Data. Table S2. CONSORT PRO Outcome Data for PedsQL™ Multi-dimensional Fatigue Module Completion Data. Table S3. CONSORT PRO Outcome Data for PedsQL™ Generic Core Scales Completion Data. Table S4. Parent Proxy Report Effect Size. Table S5. Percentage of patients by parent proxy report with improved HRQL by 1 standard error of measurement or more. Table S6. Mean change in PedsQL™ health-related quality of life parent proxy scores from baseline to 7–10 days post discharge as categorized by child’s perception of pain within the 7–10 days post discharge. (DOCX 41 kb)

Individuals with sickle cell anemia (SCA) exhibit delayed growth trajectories and lower blood pressure (BP) measurements than individuals without SCA. We evaluated factors associated with height, weight, and BP and established reference growth curves and BP tables using data from the Silent Cerebral Infarct Multi-Center Clinical (SIT) Trial (NCT00072761). Quantile regression models were used to determine the percentiles of growth and BP measurements. Multivariable quantile regression was used to test associations of baseline variables with height, weight, and BP measurements. Height and weight measurements were collected from a total of 949 participants with median age of 10.5 years [Interquartile range (IQR) 8.2–12.9] and median follow-up time of 3.2 years (IQR 1.8–4.7, range 0–12.9). Serial BP measurements were collected from a total of 944 and 943 participants, respectively, with median age of 10.6 years (IQR = 8.3–12.9 years), and median follow-up time of 3.3 years (IQR = 1.7–4.8). Multivariable quantile regression analysis revealed that higher hemoglobin measurements at baseline were associated with greater height (P

Silent cerebral infarcts are the most common neurologic injury in children with sickle cell anemia and are associated with the recurrence of an infarct (stroke or silent cerebral infarct). We tested the hypothesis that the incidence of the recurrence of an infarct would be lower among children who underwent regular blood-transfusion therapy than among those who received standard care.In this randomized, single-blind clinical trial, we randomly assigned children with sickle cell anemia to receive regular blood transfusions (transfusion group) or standard care (observation group). Participants were between 5 and 15 years of age, with no history of stroke and with one or more silent cerebral infarcts on magnetic resonance imaging and a neurologic examination showing no abnormalities corresponding to these lesions. The primary end point was the recurrence of an infarct, defined as a stroke or a new or enlarged silent cerebral infarct.A total of 196 children (mean age, 10 years) were randomly assigned to the observation or transfusion group and were followed for a median of 3 years. In the transfusion group, 6 of 99 children (6%) had an end-point event (1 had a stroke, and 5 had new or enlarged silent cerebral infarcts). In the observation group, 14 of 97 children (14%) had an end-point event (7 had strokes, and 7 had new or enlarged silent cerebral infarcts). The incidence of the primary end point in the transfusion and observation groups was 2.0 and 4.8 events, respectively, per 100 years at risk, corresponding to an incidence rate ratio of 0.41 (95% confidence interval, 0.12 to 0.99; P=0.04).Regular blood-transfusion therapy significantly reduced the incidence of the recurrence of cerebral infarct in children with sickle cell anemia. (Funded by the National Institute of Neurological Disorders and Stroke and others; Silent Cerebral Infarct Multi-Center Clinical Trial ClinicalTrials.gov number, NCT00072761, and Current Controlled Trials number, ISRCTN52713285.).

Multiple recent Sickle Cell Disease studies have been terminated due to poor enrollment. We developed methods to overcome past barriers and utilized these to study the efficacy and safety of intravenous magnesium for vaso-occlusive crisis (VOC). We describe the methods of the Intravenous Magnesium in Sickle Vaso-occlusive Crisis (MAGiC) trial and discuss methods used to overcome past barriers. MAGiC was a multi-center randomized double-blind placebo-controlled trial of intravenous magnesium versus normal saline for treatment of VOC. The study was a collaboration between Pediatric Hematologists and Emergency Physicians in the Pediatric Emergency Care Applied Research Network (PECARN). Eligible patients were randomized within 12 hours of receiving intravenous opioids in the Emergency Department (ED) and administered study medication every 8 hours. The primary outcome was hospital length of stay. Associated plasma studies elucidated magnesium's mechanism of action and the pathophysiology of VOC. Health-related quality of life was measured. Site-, protocol-, and patient-related barriers from prior studies were identified and addressed. Limited study staff availability, lack of collaboration with the ED, and difficulty obtaining consent were previously identified barriers. Leveraging PECARN resources, forging close collaborations between Sickle Cell Centers and EDs of participating sites, and approaching eligible patients for prior consent helped overcome these barriers. Participation in the PECARN network and establishment of collaborative arrangements between Sickle Cell Centers and their affiliated EDs are major innovative features of the MAGiC study that allowed improved subject capture. These methods could serve as a model for future studies of VOCs.

Patients on hydroxyurea who achieve maximum tolerated dose (MTD), defined by a target level of mild myelosuppression, may have greater laboratory and clinical benefits than those maintained on a lower dose. MTD is currently determined by gradual dose escalation, a process that often takes six to twelve months. Using data from a previous cohort of pediatric patients escalated to MTD on hydroxyurea, we have developed an equation incorporating baseline serum creatinine, body mass index, and absolute reticulocyte count to predict individualized MTD for patients initiating therapy. The NDEPTH (Novel Dose Escalation to Predict Treatment with Hydroxyurea) study is a prospective, open-label, randomized controlled trial consisting of two treatment arms: a standard arm utilizing a current published dose-escalation protocol for achieving hydroxyurea MTD; and an alternative treatment arm utilizing the dose-prediction equation to determine MTD prior to initiation of treatment. The primary endpoint of the study is time to MTD for each arm. Additional endpoints include analysis of safety and clinical and laboratory response to hydroxyurea therapy We recruited 70 pediatric patients to the study, 68 of whom were randomized equally to the standard and dose-prediction arms of the study. There were no significant differences in baseline characteristics between study participants in the two arms. Twenty-six study participants in the standard arm and 27 in the dose-prediction arm successfully reached MTD. Mean MTD was significantly higher in the dose-prediction arm than the standard arm (27.1 mg/kg vs. 22.6 mg/kg; P In summary, the dose-prediction equation determined actual MTD with a high degree of accuracy and resulted in a significantly higher final hydroxyurea dose for study participants in the dose-prediction arm than that achieved in the standard arm, indicating that young children may be able to tolerate higher hydroxyurea doses than can be achieved by standard dose escalation. The incidence of adverse clinical and laboratory events was similar between the two study arms. Based on these results, we conclude that our dose-prediction method of determining hydroxyurea MTD can be used to safely and rapidly achieve MTD, obviating the delayed MTD and the requirement for frequent clinical and laboratory monitoring associated with standard dose escalation. Table Disclosures George: Global Blood Therapeutics; Pfizer: Consultancy, Honoraria. Fasipe:Novartis: Consultancy, Honoraria; Pfizer and American College of Emergency Physicians: Research Funding. Ware:Bristol Myers Squibb: Other: Research Drug Donation; Addmedica: Other: Research Drug Donation; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Novartis: Other: DSMB; CSL Behring: Membership on an entity's Board of Directors or advisory committees; Nova Laboratories: Membership on an entity's Board of Directors or advisory committees.

The most common form of neurologic injury in sickle cell anemia (SCA) is silent cerebral infarction (SCI). In the Silent Cerebral Infarct Multi-Center Clinical Trial, we sought to identify risk factors associated with SCI. In this cross-sectional study, we evaluated the clinical history and baseline laboratory values and performed magnetic resonance imaging of the brain in participants with SCA (HbSS or HbSβ° thalassemia) between the ages of 5 and 15 years with no history of overt stroke or seizures. Neuroradiology and neurology committees adjudicated the presence of SCI. SCIs were diagnosed in 30.8% (251 of 814) participants who completed all evaluations and had valid data on all prespecified demographic and clinical covariates. The mean age of the participants was 9.1 years, with 413 males (50.7%). In a multivariable logistic regression analysis, lower baseline hemoglobin concentration (P < .001), higher baseline systolic blood pressure (P = .018), and male sex (P = .030) were statistically significantly associated with an increased risk of an SCI. Hemoglobin concentration and systolic blood pressure are risk factors for SCI in children with SCA and may be therapeutic targets for decreasing the risk of SCI. This study is registered at www.clinicaltrials.gov as #NCT00072761.

BACKGROUND: Acute chest syndrome (ACS) is a leading cause of hospitalization and death of children with sickle cell disease (SCD). An evidence-based ACS/SCD guideline was established to standardize care throughout the institution in February 2008. However, by the summer of 2009 use of the guideline was inconsistent, and did not seem to have an impact on length of stay. As a result, an implementation program was developed. OBJECTIVE: This quality-improvement project evaluated the influence of the development and implementation of a clinical practice guideline for children with SCD with ACS or at risk for ACS on clinical outcomes. METHODS: Clinical outcomes of 139 patients with SCD were evaluated before and after the development of the implementation program. Outcomes included average length of stay, number of exchange transfusions, average cost per SCD admission, and documentation of the clinical respiratory score and pulmonary interventions. RESULTS: Average length of stay decreased from 5.8 days before implementation of the guideline to 4.1 days after implementation (P = .033). No patients required an exchange transfusion. Average cost per SCD admission decreased from $30 359 before guideline implementation to $22 368. Documentation of the clinical respiratory score increased from 31.0% before implementation to 75.5%, which is an improvement of 44.5% (P < .001). Documentation of incentive spirometry and positive expiratory pressure increased from 23.3% before implementation to 50.4%, which is an improvement of 27.1% (P < .001). CONCLUSIONS: Implementation of a guideline for children with SCD with ACS or at risk for ACS improved outcomes for patients with SCD.

BACKGROUND Although hydroxyurea is proven effective in treatment of sickle cell anemia (SCA) and is widely prescribed in high-income countries, due to questions about feasibility of treating large numbers of patients in resource-limited health systems, its use is limited in sub-Saharan Africa (SSA), where most children with SCA live. We assessed hematological response and toxicity of hydroxyurea treatment for SCA in Angola. METHODS Retrospective study of children with SCA (not selected for clinical severity) treated on a fixed dose of hydroxyurea for at least 6 months. Because only the 500 mg capsule was available, dose was averaged weekly. We evaluated toxicity events and magnitude of hydroxyurea-induced changes in blood counts and compared patients who received a uniform daily dose to those prescribed intermittent or uneven daily doses. RESULTS Only 13% of 303 patients received a uniform dose of hydroxyurea daily. Dose ranged from 16.5 to 22.8 mg/kg/day. Hydroxyurea increased HGB and mean cell volume values by 0.5 g/dL (P

Background Red cell exchange (RCE) is part of the management of acute chest syndrome (ACS) in patients with sickle cell disease. The study describes the indications and outcome of the procedure. Procedure We retrospectively reviewed 53 episodes of ACS in 44 patients who received RCE from January 2003 to October 2006. Patients were aged between 18 months and 19 years. Results Sixty-two percent of the patients had at least one previous episode of ACS. ACS was diagnosed at presentation in 66%, in the remainder ACS was diagnosed after a median of 2 days. Clinical Respiratory Score (CRS) was assigned retrospectively to assess respiratory distress (0 = no distress, >6 = severe). Median admission CRS of 2, progressed to 4 before RCE and declined to 2 within 24 hr afterwards. Median day of RCE was day 2 (IQR 1–3) and the main indication was worsening respiratory distress. No patient developed venous thrombosis, alloantibodies or other complications from RCE. Median length of hospitalization was 7 days (IQR: 5–9 days). Patients with a platelet count significantly lower than their baseline on admission had an increased risk of mechanical ventilation. Conclusions RCE appears to be a safe and effective treatment for patients with sickle cell disease and ACS. One-third of patients who received RCE for ACS had no respiratory symptoms on admission. Pediatr Blood Cancer 2009;53:1060–1063. © 2009 Wiley-Liss, Inc.

Objective To assess the cost-effectiveness of a pilot newborn screening (NBS) and treatment program for sickle cell anemia (SCA) in Luanda, Angola. Study design In July 2011, a pilot NBS and treatment program was implemented in Luanda, Angola. Infants identified with SCA were enrolled in a specialized SCA clinic in which they received preventive care and sickle cell education. In this analysis, the World Health Organization (WHO) and generalized cost-effectiveness analysis methods were used to estimate gross intervention costs of the NBS and treatment program. To determine healthy life-years (HLYs) gained by screening and treatment, we assumed NBS reduced mortality to that of the Angolan population during the first 5 years based upon WHO and Global Burden of Diseases Study 2010 estimates, but provided no significant survival benefit for children who survive through age 5 years. A secondary sensitivity analysis with more conservative estimates of mortality benefits also was performed. The costs of downstream medical costs, including acute care, were not included. Results Based upon the costs of screening 36 453 infants and treating the 236 infants with SCA followed after NBS in the pilot project, NBS and treatment program is projected to result in the gain of 452-1105 HLYs, depending upon the discounting rate and survival assumptions used. The corresponding estimated cost per HLY gained is $1380-$3565, less than the gross domestic product per capita in Angola. Conclusions These data demonstrate that NBS and treatment for SCA appear to be highly cost-effective across all scenarios for Angola by the WHO criteria.

Purpose: The purpose of this research was to investigate the relationship between glutathione S-transferase (GST) polymorphisms and survival, and chemotherapy-related toxicity in 278 glioma patients. Experimental Design: We determined genetic variants for GSTM1, GSTT1, and GSTP1 enzymes by PCR and restriction fragment length polymorphisms. We conducted Kaplan-Meier and Cox-proportional hazard analyses to examine whether the GST polymorphisms are related to overall survival, and logistic regression analysis to explore whether the GST polymorphisms are associated with toxicity. Results: For patients with anaplastic astrocytoma, anaplastic oligodendroglioma, anaplastic oligoastrocytoma, and anaplastic ependymoma (n = 78), patients with GSTP1*A/*A-M1 null genotype survived longer than did the rest of the group (median survival “not achieved,” and 41 months, respectively; P = 0.06). Among patients treated with nitrosoureas (n = 108), those with GSTP1*A/*A and GSTM1 null genotype were 5.7 times (95% confidence interval, 0.9–37.4) more likely to experience an adverse event secondary to chemotherapy, compared with the others. Conclusions: In patients with anaplastic astrocytoma, anaplastic oligodendroglioma, and anaplastic oligoastrocytoma, combination of germ-line GSTP1*A/*A and GSTM1 null genotype confers a survival advantage. Patients with this genotype also have an increased risk of adverse events secondary to chemotherapy that primarily comprised nitrosourea alkylating agents.

Individuals with sickle cell anemia (SCA) exhibit delayed growth trajectories and lower blood pressure (BP) measurements than individuals without SCA. We evaluated factors associated with height, weight, and BP and established reference growth curves and BP tables using data from the Silent Cerebral Infarct Multi-Center Clinical (SIT) Trial (NCT00072761). Quantile regression models were used to determine the percentiles of growth and BP measurements. Multivariable quantile regression was used to test associations of baseline variables with height, weight, and BP measurements. Height and weight measurements were collected from a total of 949 participants with median age of 10.5 years [Interquartile range (IQR) 8.2-12.9] and median follow-up time of 3.2 years (IQR 1.8-4.7, range 0-12.9). Serial BP measurements were collected from a total of 944 and 943 participants, respectively, with median age of 10.6 years (IQR = 8.3-12.9 years), and median follow-up time of 3.3 years (IQR = 1.7-4.8). Multivariable quantile regression analysis revealed that higher hemoglobin measurements at baseline were associated with greater height (P 0.001), weight (P = 0.000), systolic BP (P 0.001), and diastolic BP (P = 0.003) measurements. We now provide new reference values for height, weight, and BP measurements that are now readily available for medical management.

Five children with malignancies (3 hematologic, 1 medulloblastoma, 1 hepatoblastoma) and one bone marrow transplant patient were treated for tuberculosis over a 30-year period. Three had pulmonary disease, 3 disseminated tuberculosis, and 1 had scrofula. Four of five had positive tuberculin skin tests, cultures were positive in 5/6 children. One child died of disseminated TB after engraftment, and one child had hepatotoxicity likely related to tuberculosis therapy. All cases were potentially preventable had they been screened due to established risk factors of foreign birth (4/6) or parental foreign birth (2/6). All children should be screened for latent tuberculosis before chemotherapy.

The risk of malignancies among persons with neurofibromatosis 1 (NF1) is higher than in the general population, but the excess risk has not been precisely estimated. The effects of gender and inheritance pattern on cancer risk are unclear. Therefore, we conducted a historical cohort study to determine cancer risk factors by contacting 138 Caucasian NF1 patients originally seen at Baylor College of Medicine (BCM) in Houston between 1978 and 1984. A total of 304 patients of all ethnic groups were evaluated at BCM during this period. We successfully located 173 patients, 138 of who were Caucasian. We computed standardized incidence ratios (SIRs) with the age-, gender-, and time period-specific rates from the Connecticut Tumor Registry for 2,094 person-years of observation (median follow-up = 16 years). Eleven incident tumors were reported. Females were at much higher risk of cancer than males (SIR = 5.6, 95% confidence interval (CI) 2.7-10.3 and SIR = 0.6; 95% CI, 0.0-3.0, respectively). We found no elevated cancer risk in unaffected first-degree relatives, regardless of whether the proband had cancer or not (SIR = 1.1 95% CI, 0.6-1.8 and SIR = 1.0, 95% CI, 0.6-1.5, respectively). Our results suggest that malignancy in the proband is not the result of a modifying gene that has a significant impact on general cancer risk.

Summary Background We sought to improve outcome in patients with childhood acute myeloid leukaemia (AML) by applying risk-directed therapy that was based on genetic abnormalities of the leukaemic cells and measurements of minimal residual disease (MRD) done by flow cytometry during treatment. Methods From Oct 13, 2002, to June 19, 2008, 232 patients with de-novo AML (n=206), therapy-related or myelodysplasia-related AML (n=12), or mixed-lineage leukaemia (n=14) were enrolled at eight centres. 230 patients were assigned by block, non-blinded randomisation, stratified by cytogenetic or morphological subtype, to high-dose (18 g/m 2 , n=113) or low-dose (2 g/m 2 , n=117) cytarabine given with daunorubicin and etoposide (ADE; induction 1). The primary aim of the study was to compare the incidence of MRD positivity of the high-dose group and the low-dose group at day 22 of induction 1. Induction 2 consisted of ADE with or without gemtuzumab ozogamicin (GO anti-CD33 monoclonal antibody); consolidation therapy included three additional courses of chemotherapy or haematopoietic stem-cell transplantation (HSCT). Levels of MRD were used to allocate GO and to determine the timing of induction 2. Both MRD and genetic abnormalities at diagnosis were used to determine the final risk classification. Low-risk patients (n=68) received five courses of chemotherapy, whereas high-risk patients (n=79), and standard-risk patients (n=69) with matched sibling donors, were eligible for HSCT (done for 48 high-risk and eight standard-risk patients). All 230 randomised patients were analysed for the primary endpoint. Other analyses were limited to the 216 patients with AML, excluding those with mixed-lineage leukaemia. This trial is closed to accrual and is registered with ClinicalTrials.gov, number NCT00136084. Findings Complete remission was achieved in 80% (173 of 216 patients) after induction 1 and 94% (203 of 216) after induction 2. Induction failures included two deaths from toxic effects and ten cases of resistant leukaemia. The introduction of high-dose versus low-dose cytarabine did not significantly lower the rate of MRD-positivity after induction 1 (34% vs 42%, p=0·17). The 6-month cumulative incidence of grade 3 or higher infection was 79·3% (SE 4·0) for patients in the high-dose group and 75·5% (4·2) for the low-dose group. 3-year event-free survival and overall survival were 63·0% (SE 4·1) and 71·1% (3·8), respectively. 80% (155 of 193) of patients achieved MRD of less than 0·1% after induction 2, and the cumulative incidence of relapse for this group was 17% (SE 3). MRD of 1% or higher after induction 1 was the only significant independent adverse prognostic factor for both event-free (hazard ratio 2·41, 95% CI 1·36–4·26; p=0·003) and overall survival (2·11, 1·09–4·11; p=0·028). Interpretation Our findings suggest that the use of targeted chemotherapy and HSCT, in the context of a comprehensive risk-stratification strategy based on genetic features and MRD findings, can improve outcome in patients with childhood AML. Funding National Institutes of Health and American Lebanese Syrian Associated Charities (ALSAC).

Background: Previous studies have been inconclusive in estimating the risk of different cancer sites among close relatives of glioma patients; however, malignant melanoma has consistently been described. Methods: We obtained family history information from 1,476 glioma patients under age 75 years who registered at M. D. Anderson Cancer Center between June 1992 and June 2006. The number of observed cancers (N = 1,001) among 8,746 first-degree relatives (FDR) was compared with the number expected from age-, sex-, and calendar year–specific rates from the Surveillance, Epidemiology, and End Results Program using standardized incidence ratios (SIR). Results: The overall SIR for any cancer was 1.21 (95% confidence interval, 1.14-1.29). Among FDRs under 45 years the overall SIR was 5.08, and for relatives >45 years the overall SIR was 0.95. The SIRs were significantly elevated for brain tumors (2.14), melanoma (2.02), and sarcoma (3.83). We observed an excess of pancreatic cancer, which was significantly higher only among mothers. Conclusion: We observed an overall 21% increase in cancer among the FDRs of glioma patients including excess cases of brain tumors and melanoma, which could point to similar genetic contributions to these two malignancies. A large international linkage study is under way to examine potential genomic regions important for familial glioma. (Cancer Epidemiol Biomarkers Prev 2007;16(11):2491–5)

Newborn screening for sickle cell disease (SCD) in developing countries is limited by the cost and technical complexity of current screening methodologies and the delayed availability of screening results. We have recently developed a rapid diagnostic test for SCD that can quickly and inexpensively identify blood samples containing hemoglobin S. We hypothesized that our rapid test would be practical for use in a resource-limited setting in Cabinda, Angola, and that screening mothers or neonates for the presence of hemoglobin S in blood samples would be an effective means of identifying neonates at high risk of having sickle cell disease prior to more definitive testing. After informed consent, we collected blood samples heel-stick from neonates and by finger-stick from mothers at the primary obstetric hospital in Cabinda. We then tested these samples by the rapid SCD test and scored them by visual assessment of staining patterns. Neonates were scored as positive (HbS detected) or negative (no HbS detected) and mothers as AA, AS (sickle trait), or SS (sickle cell disease). Neonatal samples were subsequently tested by isoelectric focusing (IEF) electrophoresis to determine exact sickle cell status. In a cohort of 133 mother-neonate pairs, we used rapid testing on maternal samples to categorize neonates as high-risk (mother positive for HbS) or low-risk (mother negative for HbS). The rapid test was highly accurate in identifying neonates who could be excluded from IEF testing, with a negative predictive value of 93% (Figure 1). In a cohort of 95 neonates similarly triaged by rapid testing on neonatal samples, the negative predictive value of the test was 96% (Figure 2). In both cohorts, the one neonate with HbSS disease was successfully triaged into the high-risk group. Maternal screening with the rapid test would have reduced the proportion of neonates requiring confirmatory IEF testing to 19%, while neonatal screening would have reduced this proportion to 26%. These results indicate the potential utility of the rapid diagnostic test as a screening tool prior to more definitive testing. Used in combination with confirmatory IEF, our rapid test could significantly decrease the cost of newborn screening for SCD and increase its clinical utility by permitting more rapid identification of affected infants. Disclosures Piety: Halcyon Biomedical: Patents & Royalties: Mr. Piety is a co-inventor on a utility PCT application, "Paper-based diagnostic test" (PCT/US2012/064856, 11/13/2012), claiming priority benefit of U.S. 61/692,994 (8/24/2012) and U.S. 61/558,009 (11/10/2011). . Shevkoplyas:Halcyon Biomedical: Equity Ownership, Patents & Royalties: Co-inventor on a utility PCT application, "Paper-based diagnostic test" (PCT/US2012/064856, 11/13/2012), claiming priority benefit of U.S. 61/692,994 (8/24/2012) and U.S. 61/558,009 (11/10/2011). Part-owner of Halcyon Biomedical Inc.,.

Abstract 16 With improvements in risk-directed therapy and supportive care, cure rates for children with acute lymphoblastic leukemia are now approaching 90%. In contrast, little progress has been made for children with acute myeloid leukemia (AML). We designed a multicenter treatment protocol for children with newly diagnosed AML that used sequential minimal residual disease (MRD) assessment for risk assignment. Patients (n = 230) with AML were randomized to receive daunorubicin and etoposide plus high-dose cytarabine (HD-ADE, n = 113) or low-dose cytarabine (LD-ADE, n = 117) as Induction I. Induction II consisted of LD-ADE with or without gemtuzumab ozogamicin (GO), depending on the level of MRD after Induction I. The remaining treatment was based on presenting features and MRD levels, and included hematopoietic stem cell transplantation (HSCT) for high-risk patients. The protocol underwent 2 treatment changes. First, LD-ADE + GO was initially given only to patients with MRD more than 25%, but was later extended to patients with MRD more than 1% because the combination was found to be safe and effective at reducing MRD. Of the 30 patients who received LD-ADE + GO, 27 (90%) had a reduction in MRD and 13 (43%) became MRD negative, with a median overall MRD reduction of 98%. CNS-directed therapy initially consisted of intrathecal (IT) cytarabine alone. However, because 3 of the first 33 patients enrolled on AML02 developed CNS relapse, subsequent patients were treated with triple IT therapy consisting of methotrexate, hydrocortisone, and cytarabine. The cumulative incidence of CNS relapse decreased from 9% to 2% after this treatment change (P = 0.004). Of the 212 (92%) evaluable patients, 80% became MRD negative and 95% achieved clinical complete remission (CR) after 2 courses of therapy; overall 3-year event-free survival (EFS) and overall survival (OS) rates were 60% ± 5% and 70% ± 4%, respectively. Patients on the HD-ADE and LD-ADE treatment arms had similar MRD-negative rates after 1 (66% vs. 58%, P = 0.17) and 2 courses of therapy, as well as similar CR, EFS (59% vs. 61%, P = 0.79), and OS rates (68% vs. 73%, P = 0.41). Multipredictor logistic regression modeling indicated that the odds of having detectable MRD after 1 course of therapy was significantly lower for patients with core binding factor (CBF) leukemia [t(8;21) or inv(16)] (P In conclusion, risk-adapted therapy, incorporation of GO, and excellent supportive care contributed to a CR rate of 95%, low mortality, and an overall 3-year OS rate of 70% for children with AML enrolled on AML02. Although this is substantially higher than rates reported in our previous studies, it should be possible to further increase cure rates by additional refinements in risk assignment, as well as by introducing novel agents that can bypass drug resistance. To this end, our current AML08 protocol has incorporated newly discovered molecular predictors, highly sensitive MRD tests, and natural killer cell therapy. Disclosures: No relevant conflicts of interest to declare.

Abstract 262 Introduction: The most common cause of neurological injury in sickle cell anemia is silent cerebral infarcts (SCI). In the Silent Cerebral Infarct Multi-Center Clinical Trial (SIT Trial) cohort, we sought to identify risk factors associated with SCI. Patients and Methods: In this cross-sectional study, we evaluated the clinical history, baseline laboratory values and performed magnetic resonance imaging of the brain. For those children with SCI-like lesions, a pediatric neurologist examined the child and neuroradiology and neurology committees adjudicated the presence of SCI. Children between the ages of 5 and 15 years with hemoglobin SS or S-beta° thalassemia and no history of overt strokes or seizure were evaluated. Results: A total of 542 children were evaluated; 173 (31.9%) had SCI. The mean age of the children was 9.3 years, with 280 males (51.7%). In a multivariate logistic analysis, two covariates were significant: a single systolic blood pressure (SBP) obtained during a baseline well-visit, p = 0.015 and hemoglobin F (Hgb F) level obtained after three years of age, p = 0.038. Higher values of SBP and lower values of Hgb F increased the odds of SCI; Figure. Baseline values of white blood cell count, hemoglobin level, oxygen saturation, reticulocytes, pain, or ACS event rates were not associated with SCI. Conclusion: SBP and Hgb F level are two previously unidentified risk factors for SCI in children with sickle cell disease. Modulation of SBP and Hgb F levels might decrease the risk of SCI. Disclosures: No relevant conflicts of interest to declare.

The multicenter AML02 trial randomly assigns patients to receive high-dose or low-dose cytarabine (A), daunorubicin (D), and etoposide (E) as Induction I; all subsequent therapy is risk-adapted. Pharmacokinetic, pharmacodynamic, and gene expression studies are performed after exposure to high-dose or low-dose cytarabine. Patients with no response (NR, ≥ 25% bone marrow blasts) to Induction I receive low-dose ADE + gemtuzumab ozogamicin (GO) as Induction II, whereas all others receive ADE. Minimal residual disease (MRD) is monitored by flow cytometry and is defined as ≥ 0.1% cells with leukemia-associated immunophenotypes among bone marrow mononuclear cells. Patients who are MRD+ after induction therapy receive GO as a single agent before consolidation chemotherapy or stem cell transplantation. Among the 112 patients enrolled since October 2002, 37 had -7, FAB M6 or M7, FLT3 internal tandem duplication (ITD), or MDS or treatment-related AML and were classified as high-risk (HR); 32 had AML1-ETO, CBFβ-MYH11, or MLL-AF9 (low-risk; LR); the remaining 43 were considered as standard-risk (SR). The rate of complete response (CR