There was no overall difference in skeletal toxicity by corticosteroid type; dexamethasone was associated with more infections and, in older children, increased incidence of osteonecrosis and fracture. There was no difference in asparaginase-related toxicity by EC-Asnase dosing method. Dexamethasone and ID EC-Asnase were each associated with superior EFS. Monitoring NSAA during treatment with EC-Asnase may be an effective strategy to improve outcome in pediatric ALL.

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A B S T R A C T PurposeDoxorubicin causes cardiac injury and cardiomyopathy in children with acute lymphoblastic leukemia (ALL). Measuring biomarkers during therapy might help individualize treatment by immediately identifying cardiac injury and cardiomyopathy. Patients and MethodsChildren with high-risk ALL were randomly assigned to receive doxorubicin alone (n ϭ 100; 75 analyzed) or doxorubicin with dexrazoxane (n ϭ 105; 81 analyzed). Echocardiograms and serial serum measurements of cardiac troponin T (cTnT; cardiac injury biomarker), N-terminal pro-brain natriuretic peptide (NT-proBNP; cardiomyopathy biomarker), and high-sensitivity C-reactive protein (hsCRP; inflammatory biomarker) were obtained before, during, and after treatment. ResultscTnT levels were increased in 12% of children in the doxorubicin group and in 13% of the doxorubicin-dexrazoxane group before treatment but in 47% and 13%, respectively, after treatment (P ϭ .005). NT-proBNP levels were increased in 89% of children in the doxorubicin group and in 92% of children in the doxorubicin-dexrazoxane group before treatment but in only 48% and 20%, respectively, after treatment (P ϭ .07). The percentage of children with increased hsCRP levels did not differ between groups at any time. In the first 90 days of treatment, detectable increases in cTnT were associated with abnormally reduced left ventricular (LV) mass and LV end-diastolic posterior wall thickness 4 years later (P Ͻ .01); increases in NT-proBNP were related to an abnormal LV thickness-to-dimension ratio, suggesting LV remodeling, 4 years later (P ϭ .01). Increases in hsCRP were not associated with any echocardiographic variables. ConclusioncTnT and NT-proBNP may hold promise as biomarkers of cardiotoxicity in children with high-risk ALL. Definitive validation studies are required to fully establish their range of clinical utility.

The Dana-Farber Cancer Institute (DFCI) ALL Consortium has been conducting multi-institutional clinical trials in childhood ALL since 1981. The treatment backbone has included 20–30 consecutive weeks of asparaginase during intensification and frequent vincristine/corticosteroid pulses during the continuation phase. Between 1985–2000, 1457 children aged 0–18 years were treated on four consecutive protocols: 85-01 (1985–7), 87-01 (1987–91), 91-01 (1991–5) and 95-01 (1996–2000). The 10-year event-free survival (EFS) ± standard error by protocol was 77.9 ± 2.8% (85-01), 74.2± 2.3 (87-01), 80.8 ± 2.1% (91-01) and 80.5 ± 1.8% (95-01). Approximately 82% of patients treated in the 1980s and 88% treated in the 1990s were long-term survivors. Both EFS and overall survival (OS) rates were significantly higher for patients treated in the 1990s compared with the 1980s (p=0.05 and 0.01, respectively). On the two protocols conducted in the 1990s, EFS was 79–85% for T-ALL patients and 75–78% for adolescents (age 10–18 years). Results of randomized studies revealed that dexrazoxane prevented acute cardiac injury without adversely impacting EFS or OS in high-risk patients and frequently-dosed intrathecal chemotherapy was an effective substitute for cranial radiation in standard-risk patients. Current studies continue to focus on improving efficacy while minimizing acute and late toxicities.

Neuroblastoma survivors have an increased rate of mortality and second malignant neoplasms, relative to the age- and sex-comparable US population, and of chronic health conditions, relative to their siblings, which underscores the need for long-term medical surveillance.

Late complications occur frequently in survivors of advanced stage NB. The majority of these problems are of mild-moderate severity. Long-term follow-up (LFTU) and screening of this population is essential.

Purpose: To determine if osteosarcoma cells express chemokine receptors and if their presence or absence relates to clinical features. Experimental Design: Using fluorescent quantitative real-time PCR, the pattern of 17 chemokine receptors in 3 osteosarcoma cell lines and 68 osteosarcoma patient samples was analyzed.Results: The expression of the chemokine receptors was generally low among the cell lines. In the high-grade osteosarcoma patient samples (n = 47), CXCR4 was the most commonly expressed (63%) and its expression level was inversely correlated to overall survival (P < 0.0001), event-free survival (P < 0.001), and metastasis-free survival (MFS; P = 0.002). There was also a correlation between the expression level of CXCR4 and the presence of metastasis at diagnosis (P = 0.002). CCR7 was expressed in 43% of the samples and its expression level was inversely correlated with overall survival (P = 0.03) and MFS (P = 0.007). CCR10 mRNA expressionlevel was inversely correlated with MFS (P = 0.009). There was no association between the expression of CXCR4, CCR7, and CCR10. Of the 26 samples studied for stromal cell^derived factor-1 expression, 77% expressed it, but there was no correlation with the clinical variables or CXCR4 expression. Multivariate analysis revealed that mRNA expression level of CXCR4 was the only significant variable for overall survival (P = 0.0006), event-free survival (P = 0.004), and MFS (P = 0.025). Conclusions: These data suggest that CXCR4 could be useful as a prognostic factor and as a predictor of potential metastatic development in osteosarcoma. If further studies confirm that it is relevant to metastases in this disease, it could represent a new therapeutic target.Chemokines are small molecules that regulate leukocyte trafficking and homing. Their receptors are seven-transmembrane, G-coupled proteins (1 -3). Recent data suggest that the interactions between chemokines and their receptors are also critical components in the regulation of tumor progression and metastasis in breast cancer and other tumors (4, 5). The chemokine receptor CXCR4 and its ligand stromal cellderived factor-1 (SDF-1) have been shown to mediate organspecific metastasis by creating a chemotactic gradient between the primary tumor site and the metastatic site (4 -6). Prostate and breast cancer cells might use the CXCR4/SDF-1 pathway to localize to bones and develop metastasis (7 -9). Many studies also suggest that the CXCR4/SDF-1 pathway is involved in the metastatic process of rhabdomyosarcoma, neuroblastoma, melanoma, glioblastoma, and colon, lung, pancreatic, ovarian, and thyroid carcinomas (10 -17). In acute lymphoblastic leukemia, high expression of CXCR4 predicts extramedullary organ infiltration and, in acute myeloid leukemia, is a poor prognosis factor (18, 19). Mü ller et al. also found that two other chemokine receptors, CCR10 and CCR7, are highly expressed by melanoma and breast cancer cells, respectively (4). CCR7 and its ligand, CCL21, could have a role in lymph node metastasis in breast ...

Purpose-Vertebral fractures due to osteoporosis are a potential complication of childhood acute lymphoblastic leukemia (ALL). To date, the incidence of vertebral fractures during ALL treatment has not been reported. CIHR Author ManuscriptCIHR Author Manuscript CIHR Author ManuscriptPatient and Methods-We prospectively evaluated 155 children with ALL during the first 12 months of leukemia therapy. Lateral thoracolumbar spine radiographs were obtained at baseline and 12 months. Vertebral bodies were assessed for incident vertebral fractures using the Genant semi-quantitative method, and relevant clinical indices such as spine bone mineral density (BMD), back pain and the presence of vertebral fractures at baseline were analyzed for association with incident vertebral fractures.Results-Of the 155 children, 25 (16%, 95% Confidence Interval (CI) 11% to 23%) had a total of 61 incident vertebral fractures, of which 32 (52%) were moderate or severe. Thirteen of the 25 children with incident vertebral fractures (52%) also had fractures at baseline. Vertebral fractures at baseline increased the odds of an incident fracture at 12 months by an odds ratio of 7.3 (95% CI 2.3 to 23.1, p = 0.001). In addition, for every one standard deviation reduction in spine BMD Zscore at baseline, there was 1.8-fold increased odds of incident vertebral fracture at 12 months (95% CI 1.2 to 2.7, p = 0.006).Conclusion-Children with ALL have a high incidence of vertebral fractures after 12 months of chemotherapy, and the presence of vertebral fractures and reductions in spine BMD Z-scores at baseline are highly associated clinical features.