Phase IIa study of dabigatran etexilate in children with venous thrombosis: pharmacokinetics, safety, and tolerability.

Essentials Dabigatran etexilate may provide a new treatment option for pediatric venous thromboembolism. Children aged 1 to < 12 years were given dabigatran etexilate in an open-label, single-arm study. The pharmacokinetic-pharmacodynamic relationship was similar to that seen in adult patients. There were no serious adverse events, bleeding events or recurrent venous thromboembolism. SUMMARY: Background The current standard-of-care treatments for pediatric venous thromboembolism (VTE) have limitations. Dabigatran etexilate (DE), a direct thrombin inhibitor, may offer an alternative therapeutic option. Objectives To assess the pharmacokinetics, pharmacodynamics, safety, and tolerability of a DE oral liquid formulation (OLF) in pediatric patients with VTE. Patients/Methods Patients who had completed planned treatment with low molecular weight heparin or oral anticoagulants for VTE were enrolled in two age groups (2 to < 12 years and 1 to < 2 years), and received a DE OLF based on an age-adjusted and weight-adjusted nomogram. Originally, patients were to receive a DE OLF twice daily for 3 days, but the protocol was amended to a single dose on day 1. The primary endpoints were pharmacokinetics/pharmacodynamics-related: plasma concentrations of DE and its metabolites; activated partial thromboplastin time (APTT), ecarin clotting time (ECT), and dilute thrombin time (dTT); and pharmacokinetic (PK)-pharmacodynamic (PD) correlation. Safety endpoints included incidence rates of bleeding events and all other adverse events (AEs). Results Eighteen patients entered the study and received the DE OLF (an exposure equivalent to a dose of 150 mg twice daily in adults). The projected steady-state dabigatran trough concentrations were largely comparable between pediatric patients and adults. The PK/PD relationship was linear for ECT and dTT, and non-linear for APTT. No serious or severe AEs, bleeding events, or recurrent VTEs were reported. Mild AEs were reported in three patients in the single-dose group (screening period) and in one patient in the multiple-dose group (on-treatment period). Conclusion The current study supports the further evaluation of DE OLFs in pediatric patients with VTE.

Evaluation of a chest radiograph reading and recording system for tuberculosis in a HIV-positive cohort.

AIM: To assess the impact of introducing a chest radiograph reading and recording system (CRRS) with a short training session, on the accuracy and inter-reader variability of tuberculosis (TB) interpretation of chest radiographs (CXRs) by a group of non-expert readers in a human immunodeficiency virus (HIV)-positive cohort. MATERIALS AND METHODS: A set of 139 CXRs was reviewed by a group of eight physicians pre- and post-intervention at two clinics in Shan State, Myanmar, providing HIV/TB diagnosis and treatment services. The results were compared against the consensus of expert radiologists for accuracy. RESULTS: Overall accuracy was similar pre- and post-intervention for most physicians with an average area under the receiver operating characteristic curve difference of 0.02 (95% confidence interval: -0.03, 0.07). The overall agreement among physicians was poor pre- and post-intervention (Fleiss κ=0.35 and κ=0.29 respectively). The assessment of agreement for specific disease patterns associated with active TB in HIV-infected patients showed that for intrinsically subtle findings, the agreement was generally poor but better for the more intrinsically obvious disease patterns: pleural effusion (Cohen's kappa range = 0.37-0.67) and milliary nodular pattern (Cohen's kappa range = 0.25-0.52). CONCLUSION: This study demonstrated limited impact of the introduction of a CRRS on CXR accuracy and agreement amongst non-expert readers. The role in which CXRs are used for TB diagnosis in a HIV-positive cohort in similar clinical contexts should be reviewed.

The development of bone mineral lateralization in the arms.

UNLABELLED: Bone mineral content (BMC) is known to be greater in the dominant arm after the age of 8 years. We studied a group of children and found that BMC sidedness gradually increased up to the age of 6 years and then remained stable into late adolescence. INTRODUCTION: Bone mineral content (BMC) exhibits sidedness in the arms after the age of 8 years, but it is not known whether BMC is greater in the dominant arm from birth or whether lateralization develops in early childhood. To address this, we examined bone mineral status in relation to handedness and age. METHODS: Subjects (N = 158) were children recently initiating glucocorticoids for underlying disease (leukemia 43 %, rheumatic conditions 39 %, nephrotic syndrome 18 %). Handedness was determined by questionnaire and BMC by dual-energy X-ray absorptiometry. RESULTS: Median age was 7.2 years (range, 1.5 to 17.0 years), 49 % was male, and the spine BMD Z-score was -0.9 (SD, 1.3). By linear regression, BMC sidedness in the arms was significantly related to age (r = 0.294, p = 0.0005). Breakpoint analysis revealed two lines with a knot at 6.0 years (95 % CI, 4.5-7.5 years). The formula for the first line was: dominant:nondominant arm BMC ratio = 0.029 × age [in years] + 0.850 (r = 0.323, p = 0.017). The slope of the second line was not different from 0 (p = 0.332), while the slopes for the two lines were significantly different (p = 0.027). CONCLUSIONS: These results show that arm BMC sidedness in this patient group develops up to age 6 years and then remains stable into late adolescence. This temporal profile is consistent with mechanical stimulation of the skeleton in response to asymmetrical muscle use as handedness becomes manifest.

Prevalence of post-thrombotic syndrome following asymptomatic thrombosis in survivors of acute lymphoblastic leukemia.

BACKGROUND: Deep vein thrombosis (DVT) is a complication of treatment of acute lymphoblastic leukemia (ALL) in children but little is known about the long-term outcomes of these DVT. OBJECTIVE: To determine the incidence of post-thrombotic syndrome (PTS) in (i) children with ALL diagnosed with asymptomatic DVT using radiographic testing and (ii) an unselected group of ALL survivors. METHODS: Cross-sectional study in two populations. Group I comprised children in the Prophylactic Antithrombin Replacement in Kids with ALL treated with L-Asparaginase (PARKAA) study diagnosed with DVT by radiographic tests. Group II consisted of non-selected childhood ALL survivors <21 years. PTS was assessed using a standardized scoring sheet. RESULTS: Group I: 13 PARKAA patients (median age 12 years) were assessed, and 7 had PTS (54%; 95% CI, 25-81). All patients had collaterals, three also had increased arm circumference. Group II: 41 patients (median age 13 years) with a history of ALL were enrolled, and 10 had PTS (24%; 95% CI, 11-38). All patients had collaterals; five also had increased arm circumference. CONCLUSION: There is a high incidence of PTS in survivors of childhood ALL with radiographically diagnosed asymptomatic DVT. A significant proportion of ALL survivors develop PTS, indicating previously undiagnosed DVT.

Magnesium absorption using stable isotope tracers in healthy children and children treated for leukemia.

Intestinal magnesium (Mg) absorption was measured in six healthy children (control) and in four children treated for acute lymphoblastic leukemia with the single-isotope fecal recovery technique (SIFRT). The objective of this study was to determine Mg absorption in young children with acute lymphoblastic leukemia using stable isotope tracers. Fractional and absolute absorption levels determined by SIFRT were not significantly different between children with acute lymphoblastic leukemia (fractional absorption: 58.3 +/- 10.6% [mean +/- SEM], absolute absorption: 3.66 +/- 0.71 mg x kg(-1) x d(-1), [0.15 +/- 0.03 mmol x kg(-1) x d(-1)]) and control children (fractional absorption: 61.4 +/- 7.5%, absolute absorption: 5.69 +/- 0.85 mg x kg(-1) x d(-1), [0.23 +/- 0.03 mmol x kg(-1) x d(-1)]). Average Mg absorption in young children (aged 3--8 y) was 60.2 +/- 5.8%. This study describes the first application of the SIFRT to assess Mg absorption in young children and illustrates the feasibility of the SIFRT in this age group to obtain more accurate information on Mg absorption.

Outcome of pediatric thromboembolic disease: a report from the Canadian Childhood Thrombophilia Registry.

The outcome for children with deep vein thrombosis (DVT) and pulmonary embolism (PE) is unknown. An understanding of morbidity and mortality of DVT/PE is crucial to the development of rational treatment protocols. The Canadian Childhood Thrombophilia Registry has followed 405 children aged 1 mo to 18 y with DVT/PE for a mean of 2.86 y (range, 2 wk to 6 y) to assess outcome. The all-cause mortality was 65 of 405 children (16%). Mortality directly attributable to DVT/PE occurred in nine children (2.2%), all of whom had central venous line-associated thrombosis. Morbidity was substantial, with 33 children (8.1%) having recurrent thrombosis, and 50 children (12.4%) having postphlebitic syndrome. Recurrent thrombosis and postphlebitic syndrome were more common in older children, although deaths occurred equally in all age groups. The incidence of recurrent thrombosis and postphlebitic syndrome are likely underestimated because of difficulties in diagnosis, especially in younger children. The significant mortality and morbidity found in our study supports the need for international multicenter randomized clinical trials to determine optimal prophylactic and therapeutic treatment for children with DVT/PE.

Limitation of ankle range of motion in survivors of acute lymphoblastic leukemia: a cross-sectional study.

BACKGROUND: The purpose of this study was to evaluate and determine the factors related to active and passive dorsiflexion range of motion (DF-ROM) in survivors of acute lymphoblastic leukemia (ALL), which is the most obvious impairment of musculoskeletal function in such children. PROCEDURE: The subjects included 54 survivors of ALL treated on Dana-Farber Cancer Institute protocols and 54 comparable healthy children. Bilateral active and passive DF-ROM were measured with the knee extended. RESULTS: The survivors of ALL had significantly less active and passive DF-ROM (6.4 vs. 16.8, 10.5 vs. 18.8 degrees, respectively, P < 0.001) than the comparison children. Weight for age at the time of assessment and change in height during treatment showed significant negative correlations with DF-ROM. Length of time-off treatment was not associated with DF-ROM. CONCLUSIONS: Multiple regression analyses identified the variables of age at diagnosis and gender as significant predictors of both DF-ROM measures following treatment. Children diagnosed at a younger age and females were at greater risk for restricted DF-ROM. Close monitoring and preventative therapy programs for this complication are warranted for children, especially young girls receiving treatment for ALL.

Atrial and venous thrombosis secondary to septic arthritis of the sacroiliac joint in a child with hereditary protein C deficiency.

Septic arthritis and osteomyelitis in children is seldom accompanied by calf vein thrombosis and rarely by atrial thrombosis. We report the case of an 11-year, 5-month-old boy with septic arthritis and osteomyelitis of the sacroiliac region who developed deep venous thrombosis, in addition to life-threatening right atrial thrombosis. After an intensive hematologic investigation, a hereditary protein C deficiency was revealed. The association of venous thrombosis with septic arthritis or osteomyelitis should raise the possibility of the presence of protein C deficiency.

Long-term gross motor performance following treatment for acute lymphoblastic leukemia.

BACKGROUND: The primary purpose of this descriptive study was to determine the long-term effects of cancer treatment in childhood on musculoskeletal function and gross motor skills. PROCEDURE: Musculoskeletal and gross motor function were assessed in a cohort of 36 survivors of acute lymphoblastic leukemia (ALL) seen in a pediatric tertiary care referral centre, compared to 36 age and gender matched comparison subjects. Basic gross motor skills were assessed using dimensions D: standing, and E: walking, running, and jumping of the Gross Motor Function Measure (GMFM). Strength, balance, and running speed and agility were assessed using the Bruininks-Oseretsky Test of Motor Proficiency (BOTMP). Hand grip strength and ankle dorsiflexion range of motion were also measured. Findings in the children with ALL were compared by dependent (paired) t-tests to those in age and gender matched children. RESULTS: The GMFM scores for standing were 98.7% and for walking, running, and jumping were 99% of normal. The mean standard scores for the BOTMP were significantly lower than those of the comparison group: strength 11.5 vs. 19.4, balance 9.4 vs. 15.5, and running speed and agility 9.9 vs. 16.6. The ALL subjects had less hand grip strength 156.3 vs. 190.2, and less ankle dorsiflexion 7.5 vs. 16.1 degrees than the comparison group. The survivors of childhood leukemia were able to perform most basic gross motor functions. However, musculoskeletal impairment was evident and levels of motor proficiency were significantly poorer than those of age and gender matched children. CONCLUSIONS: Programs to promote physical activity and limit disability may improve gross motor function and increase overall quality-of-life in survivors of leukemia in childhood.

Blood lipid profiles in children with acute lymphoblastic leukemia.

BACKGROUND: Abnormal blood lipid profiles have been associated with cancer. The objective of this study was to investigate the frequency and clinical significance of altered lipid profiles in children with acute lymphoblastic leukemia (ALL), the most common form of malignant disease in this age group. METHODS: Fasting blood lipid profiles (cholesterol [C], triglycerides [TG], high density lipoprotein [HDL], low density lipoprotein, very low density lipoprotein, apolipoproteins A1 [apo A1] and B, and lipoprotein a [Lp(a)]) were obtained in 24 children with ALL at diagnosis, 16 children during consolidation therapy with L-asparaginase, and 18 children during maintenance therapy without L-asparaginase. For comparison the authors studied lipid profiles in 15 children previously treated for leukemia, 15 healthy control children, and 17 children with other forms of cancer, both localized and widespread. RESULTS: An altered blood lipid profile was observed at the time of diagnosis of ALL. Statistically significant values included elevated TG (1.82+/-1.23 mmol/L), reduced HDL-C (0.54+/-0.24 mmol/L), and reduced ApoA1 (0.77+/-0.18 g/L) levels. A wide range of Lp(a) levels (0-1990 mg/L) were observed. Significantly reduced HDL-C (0.55+/-0.20 mmol/L) and ApoA1 (0.69+/-0.22 g/L) were observed in children with widespread but not localized solid tumors at diagnosis. C and TG correlated with serum albumin levels. Significant therapy-related changes in lipid profiles were observed in children with ALL during combination therapy with L-asparaginase (extremely elevated TG levels [3.34+/-2.82 mmol/L] and a striking reduction in Lp(a) levels) that were not observed during combination therapy without L-asparaginase or in children during treatment for solid tumors. In this small study there was no relation between these abnormalities and either thromboembolic events or pancreatitis. Blood lipid profiles in children with ALL returned to normal on completion of therapy. CONCLUSIONS: The lipid abnormalities observed at diagnosis in children with widespread cancer (ALL or solid tumors) may reflect altered nutritional states or altered lipid metabolism. Reduced concentrations of Lp(a) and elevated TG levels suggest L-asparaginase specific alterations and may provide insight into the toxicity associated with this drug.

Impact of age and cranial irradiation on radiographic skeletal pathology in children with acute lymphoblastic leukemia.

BACKGROUND: Symptomatic osteopenia is a common form of morbidity in children with acute lymphoblastic leukemia (ALL) before, during, and after treatment. A causal role for corticosteroids has been proposed, but other investigators have suggested that cranial irradiation is an important factor contributing to this disorder. PROCEDURE: In this study of children with ALL, all of whom received steroids, skeletal morbidity was assessed radiographically by an observer who was blinded to the ages of the children, their risk categorization (and related treatment), and the timing of the assessments with respect to the administration of therapy. DISCUSSION: Skeletal morbidity was most prevalent in older subjects who had been given cranial radiotherapy. However, there was no difference in the frequency of fractures in two groups of younger children (< or = 9 years of age), one irradiated and the other not. CONCLUSIONS: It is likely that corticosteroid therapy plays an important part in the pathogenesis of this disorder. The role played by cranial irradiation is much less certain.

Homozygous protein C deficiency: description of a new mutation and successful treatment with low molecular weight heparin.

We present a kindred with a new mutation of the protein C gene, in which the proband had an unusual clinical presentation. The relationship between warfarin induced skin necrosis and level of anticoagulation was investigated. The pharmacokinetics of protein C concentrate was assessed to determine frequency of replacement therapy. The clinical and biochemical efficacy of therapy with low molecular weight heparin (LMWH) was assessed. The effect of long-term LMWH on bone density in the growing child was monitored using whole body densitometry. Warfarin therapy required an INR of greater than 3.5 to avoid skin necrosis. If protein C replacement was to be used, doses of 100 U/kg/day would have been required to maintain protein C levels consistently at or above 0.20 U/ml. While receiving prophylactic therapy with LMWH for almost 3 years, there were no episodes of recurrent thrombosis, no skin necrosis and no bleeding. Biochemical markers of in vivo thrombin generation were suppressed and within the normal range. Bone density continued to increase at the normal rate throughout the treatment period. LMWH is an effective form of long-term therapy for homozygous protein C deficient patients with measurable protein C levels.

Cardiac autonomic dysfunction in survivors of acute lymphoblastic leukemia in childhood.

The purpose of this study was to investigate autonomic regulation of neurocardiac function in survivors of acute lymphoblastic leukemia (ALL) in childhood, through power spectral and time domain analyses of the heart rate variability signal. Studies were conducted on 34 unselected patients and 34 age matched controls. Patients were in remission, off therapy for at least 20 months and from high risk (HR, n=21) and standard risk (SR, n=13) groups as described by Dana-Farber Cancer Institute protocols 87-01 and 91-01. Twenty-nine patients had received cranial irradiation, 7 on a hyperfractionated schedule. Power spectral analysis of the heart rate (PS/HRV) was performed on 30 min heart rate time series and time domain statistics were computed from 24 h Holter recordings. Left ventricular function was assessed by measuring ejection and shortening fractions on echocardiography. All such measures were normal. Analysis of PS/HRV revealed that the supine low frequency: high frequency (LF:HF) area ratio was elevated in patients compared to controls. Changes in the LF and HF power on standing were attenuated in the patients compared to controls. Circadian analysis revealed a depressed diurnal rhythm of heart rate in the patients. Those from the SR group showed greater reduction of the LF power response to orthostatic stress and a reduced circadian rhythm of the heart rate compared to those with HR ALL. Patients from the HR group showed reductions in both HF and LF power responses to orthostasis compared to controls. Elevated supine LF power and depressed circadian variation in the HF power band were evident only in female subjects. Patients who received standard cranial irradiation had higher LF:HF area ratio and diminished LF and HF power responses to orthostatic stress than did subjects in the hyperfractionated group. These findings suggest that the autonomic nervous regulation of the heart is compromised in patients treated for ALL in childhood even when resting echocardiographic measures provide no evidence of cardiac decompensation. The extent of neurocardiac dysfunction is influenced by risk status, gender and schedule of cranial irradiation.

Bone and mineral abnormalities in childhood acute lymphoblastic leukemia: influence of disease, drugs and nutrition.

In children with acute lymphoblastic leukemia (ALL), abnormalities in mineral homeostasis and bone mass were first reported by our group in the late 1980s. Prospective longitudinal cohort studies in 40 consecutive patients receiving treatment according to the Dana-Farber Cancer Institute (DFCI) protocol 87-001 and 16 children receiving DFCI protocol 91-001 afforded us the opportunity to explore various etiologies of the observed abnormalities in mineral and bone metabolism, specifically the leukemic disease process and chemotherapeutic drugs such as steroids and aminoglycoside antibiotics. At diagnosis of ALL, > 70% of children had abnormally low plasma 1,25-dihydroxyvitamin D, 73% had low osteocalcin and 64% had hypercalciuria, indicating an effect of the leukemic process on vitamin D metabolism and bone turnover. During remission induction, treatment with high-dose steroid (prednisone or dexamethasone) resulted in further reduction in plasma osteocalcin and elevated parathyroid hormone levels. During 24 months of chemotherapy-maintained remission, reduction in bone mineral content (BMC), as measured by Z-scores, occurred in 64% of children, most severely affecting those > 11 years of age. A reduction in BMC during the first 6 months had a positive predictive value of 64% for subsequent fracture. By the end of 2 years of therapy, fractures occurred in 39% of children and radiographic evidence of osteopenia was found in 83% of the entire study group. Investigations of the biochemical basis of the bone abnormalities revealed that by 6 months hypomagnesemia developed in 84% of children (of whom 52% were hypermagnesuric) and plasma 1,25-dihydroxyvitamin D remained abnormally low in 70%. Altered magnesium status was attributed to renal wastage of magnesium following cyclical prednisone therapy and treatment with aminoglycoside antibiotics such as amikacin for fever accompanying neutropenia. Dietary intake and absorption of magnesium were normal. In 10 children treated for hypomagnesemia with supplemental magnesium for up to 16-20 weeks, plasma magnesium normalized in only 50% of subjects.

Growth and body composition in response to chemotherapy in children with acute lymphoblastic leukemia.

Severely malnourished children afflicted by acute lymphoblastic leukemia (ALL), particularly in developing countries, have reduced tolerance to chemotherapy and a compromised prospect for survival. We investigated the prevalence and severity of alterations in growth and nutritional status in children with ALL from population-based referral areas in Canada. All children were treated with Dana-Farber Cancer Institute ALL Consortium protocols. First, the relative impact of cranial irradiation (CI) and chemotherapy on growth was studied in 116 children at diagnosis and at 6-month intervals during treatment. We observed a decline in height standard deviation (SD) score in the first year in all children, and a further decline in height SD score during the second year only in the children who received CI. Weight reduction occurred in the first year, but during the second year there was a disproportionate increase in weight compared with height, suggesting that children treated with ALL have a tendency toward obesity. Both chemotherapy and CI contribute to the altered growth observed in children treated for ALL. Second, intestinal functional integrity was assessed in 16 children during post-induction chemotherapy. Nutrient intake was adequate and there was minimal evidence of malabsorption: fat malabsorption occurred in only 1 child (after treatment-related pancreatitis), abnormal D-xylose absorption occurred in 2 children at 6 months of therapy (returning to normal 6 months later) and abnormal lactose absorption occurred in 4 children. Third, weight, height, whole body lean and fat mass measured by dual-energy X-ray absorptiometry and serum albumin were determined at diagnosis and at 6-month intervals throughout therapy in 19 children with ALL. Height SD scores decreased significantly during treatment. Serum albumin was abnormally low in 6/19 at diagnosis and 14/18 during intensive consolidation therapy. The mean change in the ratio of lean mass to total body weight showed a 5% reduction by 6 months of therapy. Body fat increased from a mean of 22% at diagnosis to 28% at completion of therapy. The majority of children treated for ALL thus have significant changes in nutritional status manifested by reductions in growth, alterations in lean and fat body mass and abnormally low serum proteins during intensive therapy.

Altered mineral metabolism and bone mass in children during treatment for acute lymphoblastic leukemia.

Children with acute lymphoblastic leukemia (ALL) often develop bone pain, abnormal gait, and unusual fractures while in remission and receiving continuing chemotherapy. A prospective longitudinal cohort study was undertaken of bone mass and biochemical mineral status in 40 consecutive children (27 male, 13 female, aged 0.3-17.0 years) receiving therapy on the Dana-Farber Cancer Institute protocol 87-01. Radiography, lumbar spine dual-photon absorptiometry, and biochemical measurements of mineral status were performed at diagnosis and at 6-month intervals throughout 24 months of chemotherapy. Eleven patients were not completely evaluated (4 deaths and 7 off study). Radiographic evidence of osteopenia was observed in 10, 64, and 76% at diagnosis, 12 and 24 months, respectively. Fractures occurred in 39% of children during treatment. Reduction in bone mineral content (BMC), as measured by Z scores, occurred in 64% of patients and was most severe in those greater than 11 years of age at diagnosis. Reduction in BMC during the first 6 months of therapy had a positive predictive value of 64%, while an increase in BMC had a negative predictive value of 82% for subsequent fracture. By 6 months of therapy, 31/37 (84%) children were hypomagnesemic, of whom 16 (52%) were hypermagnesuric. Plasma osteocalcin was subnormal at diagnosis in 29/40 (73%) but increased to normal by 6 months of treatment. Vitamin D status was normal throughout, but plasma 1,25-dihydroxyvitamin D remained subnormal in greater than 70% of children. Urinary cross-link N-telopeptide was normal at diagnosis and became elevated in 58% of children by the end of therapy. Suppressed bone mineralization is evident at diagnosis in a minority of children with ALL. Skeletal morbidity and a reduction in bone mineral mass become more prevalent during treatment, with increased bone resorption, perhaps mainly as a consequence of corticosteroid administration.

Cardiorespiratory status after treatment for acute lymphoblastic leukemia.

The use of certain chemotherapeutic agents is associated with dose-related cardiotoxicity and, potentially, with restrictive lung disease. Therefore, we assessed the cardiopulmonary status and exercise capacity of 19 patients (pts; 9M:10F) 1.1 to 7.1 years (mean 4.6 +/- 1.5 years) after successful treatment of acute lymphoblastic leukemia (ALL) with Dana Farber Cancer Institute protocols. As body mass and nutritional status may influence exercise capacity, we also evaluated their anthropometric status and the plasma levels of rapid turnover proteins. Seven pts designated as "standard risk for relapse" (SR) had received low cumulative doses of doxorubicin (50 +/- 21 mg/m2), while twelve pts at "high or very high risk for relapse" (HR/VHR) had received higher doses (349 +/- 16 mg/m2). The evaluations included a questionnaire, anthropometric assessments, echocardiography, pulmonary function studies, exercise testing, and nutritional assays. Patients' data were compared with published normative data or with control values from our laboratories. In addition, we compared SR pt data with HR/VHR pt data. No pt had overt symptoms or signs of cardiorespiratory compromise. The pts had a higher percent of body fat than age-matched healthy controls (29.7 +/- 7.9% vs. 20 +/- 6%; P < 0.001). On echocardiography, cardiac systolic function was within normal limits in all. However, HR/VHR pts had lower left ventricular (LV) shortening fractions than SR pts (P < 0.05). LV filling velocity, indicative of diastolic function (the E/A ratio), was normal in most pts. Pulmonary function studies were normal. Exercise capacity was below predicted in most cases but heart rates at peak exercise and leg muscle function were within normal limits, suggesting a deconditioned state. Plasma levels of rapid turnover proteins were also normal. Despite lack of overt morbidity in our pt population, subtle abnormalities persist in cardiac function while pulmonary function is normal. Longitudinal studies will identify if further abnormalities or overt morbidity develop. In later years, continuing obesity and a sedentary state may contribute to clinically relevant heart disease.

Hypermagnesiuria and hypercalciuria in childhood leukemia: an effect of amikacin therapy.

PURPOSE: The purpose of this study is to assess the effects of amikacin on renal proximal tubular function, and on magnesium (Mg) and calcium (Ca) status in children treated for acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: Eighteen children (11 male/7 female, ages 2-18 years) receiving antileukemic therapy (Dana Farber Cancer Institute protocols 87-001 or 91-001) and admitted for febrile neutropenia to The Children's Hospital at Chedoke-McMaster, Hamilton, Ontario were recruited into this descriptive prospective study. Each child was treated with amikacin (7.5 mg/kg/12 h x 10-14 days) for one or more courses. RESULTS: No patient demonstrated elevations in amikacin trough levels. beta 2-Microglobulinuria, glucosuria, proteinuria, and hyperphosphaturia were absent. Children (50% presenting with hypomagnesemia (< 0.77 mmol/L) had a significant rise in mean urinary Mg:creatinine (0.46 +/- 0.27 versus 0.82 +/- 0.38 mmol, mean +/- SD, p < 0.05) in response to amikacin therapy and the mean Ca:creatinine ratio increased by 95% after 10-14 days of amikacin treatment. Serum Mg and Ca did not change notably after treatment, irrespective of initial Mg status. CONCLUSIONS: Aminoglycoside therapy in children with ALL is not associated with overt nephrotoxicity. A transient renal leak of Mg and Ca does occur. Screening of ALL children for mild hypomagnesemia may help to identify those most at risk of disruption of renal conservation of Mg and possibly Ca.

Fluoride supplementation status, fractures and osteopenia in children with acute lymphoblastic leukemia.

Children with acute lymphoblastic leukemia (ALL) experience fractures on the basis of osteopenia related to chemotherapy administered for the maintenance of remission. It is likely that corticosteroids are the main cause of bone mineral loss in this circumstance. Because fluoride has been used as a therapeutic intervention in osteoporosis, including that induced by corticosteroid therapy, we explored the prospect that children with ALL who received fluoride supplementation (in drinking water or from other sources) may be relatively protected from iatrogenic skeletal morbidity. Children who completed therapy according to the Dana Farber Cancer Institute protocol 87-01 (n=35) were assessed by skeletal radiology and bone densitometry every 6 months from diagnosis. In addition, their families completed a questionnaire relating to fluoride supplementation. There was no correlation between such fluoride supplementation and either the prevalence of fractures or the severity of osteopenia. This outcome may reflect the mainly appendicular location of the fractures in this group of children. These findings, together with a consideration of the risk benefit ratio of fluoride administration to children at large, suggest that such intervention is unlikely to be beneficial in limiting skeletal morbidity during the treatment of ALL in childhood.