Compare and contrast: pediatric cancer versus adult malignancies.

Cancer is a leading cause of death in both adults and children, but in terms of absolute numbers, pediatric cancer is a relatively rare disease. The rarity of pediatric cancer is consistent with our current understanding of how adult malignancies form, emphasizing the view of cancer as a genetic disease caused by the accumulation and selection of unrepaired mutations over time. However, considering those children who develop cancer merely as stochastically "unlucky" does not fully explain the underlying aetiology, which is distinct from that observed in adults. Here, we discuss the differences in cancer genetics, distribution, and microenvironment between adult and pediatric cancers and argue that pediatric tumours need to be seen as a distinct subset with their own distinct therapeutic challenges. While in adults, the benefit of any treatment should outweigh mostly short-term complications, potential long-term effects have a much stronger impact in children. In addition, clinical trials must cope with low participant numbers when evaluating novel treatment strategies, which need to address the specific requirements of children.

Coexpression of Multiple ABC-Transporters is Strongly Associated with Treatment Response in Childhood Acute Myeloid Leukemia.

BACKGROUND: To analyze whether expression of ABC-transporters is associated with remission rate and long-term outcome in a prospective clinical trial of childhood acute myeloid leukemia (AML). PROCEDURE: The expression of four ABC-transporter genes (ABCA3 encoding drug transporter ABCA3, ABCB1 encoding multidrug resistance protein 1, ABCC3 encoding multidrug resistance-associated protein 3, and ABCG2 encoding breast cancer resistance protein) was measured by TaqMan real time polymerase chain reaction in pretreatment samples from 112 children with AML. Patients were treated according to multicenter study AML-Berlin, Frankfurt, Munich (BFM) 2004. RESULTS: ABCC3 (P = 0.009) and ABCG2 (P = 0.03) were associated with a lower chance to achieve remission after the first course of chemotherapy. ABCC3 was associated with lower relapse free survival (RFS) (P = 0.02). ABCG2 was expressed at higher levels in subtypes of AML with favorable outcome but within standard- and high-risk patients, it was associated with poor outcome (P = 0.02). A strong association was observed between the number of overexpressed ABC-transporters and the chance to achieve remission (P = 0.01) or the chance of RFS (P < 0.001). CONCLUSIONS: The intensive treatment regimen of AML-BFM 2004 did not readily overcome drug resistance caused by ABC-transporters. Inhibition of ABC-transporters might be particularly useful in patients who express multiple of these genes.

Left Ventricular Strain Analysis During Submaximal Semisupine Bicycle Exercise Stress Echocardiography in Childhood Cancer Survivors.

Background Childhood cancer survivors (CCSs) show relevant cardiac morbidity and mortality throughout life. Early detection is key for optimal support of patients at risk. The aim of this study was to evaluate 2-dimensional speckle-tracking echocardiography strain analysis during semisupine exercise stress in CCSs for detection of subclinical left ventricular dysfunction after cancer treatment. Methods and Results Seventy-seven CCSs ≥1-year postchemotherapy were prospectively examined at rest, low, and submaximal stress level and compared with a cohort of healthy adolescents and young adults (n=50). Global longitudinal strain (GLS), short axis circumferential strain, and corresponding strain rates were analyzed using vendor-independent software. CCSs at median 7.8 years postchemotherapy showed comparable left ventricular GLS, circumferential strain, and strain rate values at all stress stages to healthy controls. Yet, prevalence of abnormal GLS (defined as <2 SD of controls reference) in CCSs was 1.3% at rest, 2.7% at low, and 8.6% at submaximal stress. In CCSs, relative change of circumferential strain from rest to submaximal stress was lower than in healthy controls, median 16.9 (interquartile range [IQR], 3.4; 28.8) % versus 23.3 (IQR, 11.3; 33.3) %, P=0.03, most apparent in the subgroups of CCSs after high-dose anthracycline treatment and cancer diagnosis before the age of 5 years. Conclusions In this prospective 2-dimensional speckle tracking echocardiography strain study, prevalence of abnormal left ventricular GLS increased with stress level reflecting impaired cardiac adaptation to exercise stress in some CCSs. However, relatively early after last chemotherapy, this did not result in significant differences of mean GLS-, circumferential strain-, and strain rate values between CCSs and controls at any stress level.

Prospective validation of a new method of monitoring minimal residual disease in childhood acute myelogenous leukemia.

PURPOSE: This study evaluated the prognostic impact of a novel, simple, and standardized assay for monitoring minimal residual disease (MRD) in pediatric acute myelogenous leukemia (AML). EXPERIMENTAL DESIGN: The expression of seven leukemia-associated genes (WT1, PRAME, CCL23, GAGED2, MSLN, SPAG6, and ST18) was measured by TaqMan Low Density Arrays in 112 patients and 52 healthy controls. Patients were treated according to the multicenter study AML-BFM 2004. Samples were collected prospectively at standard time points. The laboratory that measured MRD was blinded to patient outcome. RESULTS: Relapse-free survival (RFS) was 95% (N = 19; SE = 5%) if expression of all genes was down to normal on day 15, 63% (N = 41; SE = 8%) if expression was normalized on day 28, and 38% (N = 21; SE = 11%) in patients who still showed elevated expression on day 28. The prognostic impact of MRD remained significant (P = 0.002) when patients were stratified for the AML-BFM 2004 risk group. Multivariate analysis identified the MRD risk group and day 28 cytology as the only independent prognostic factors. Patients with a cytologic nonremission on day 28, which was confirmed by MRD, had a dismal prognosis. Only 1 out of 8 patients survived without relapse. CONCLUSIONS: This novel method of monitoring MRD has a strong prognostic impact that is independent from established risk factors in childhood AML.

Transitory dasatinib-resistant states in KIT(mut) t(8;21) acute myeloid leukemia cells correlate with altered KIT expression.

KIT inhibition with dasatinib represents a promising approach to targeted therapy in t(8;21) acute myeloid leukemia (AML) and clinical trials are currently evaluating its clinical relevance. However, data on continuous long-term dasatinib exposure of AML cells are limited and the potential effects on KIT inhibition and dasatinib sensitivity are unexplored. Treatment-related resistance ultimately limits clinical efficacy of tyrosine kinase inhibitors (TKI), which could similarly apply to dasatinib in t(8;21) AML. In this study, we used the dasatinib-sensitive KIT(mut) t(8;21) AML cell line Kasumi-1 to model, in a confined and controllable way, molecular effects upon continuous dasatinib treatment. Long-term dasatinib exposure at clinically relevant levels resulted in markedly decreased drug-sensitivity of KIT(mut) t(8;21) AML cells. Notably, all dasatinib-resistant clones lacked secondary KIT-mutations. Instead, persistent growth correlated with alterations in KIT expression levels-that is, either KIT overexpression with maintained downstream signaling or KIT downregulation with concomitant activation of alternate pathways. Although KIT overexpression was associated with retained receptor activity and STAT3 activation, KIT downregulation correlated with decreased STAT3 levels and increased ERK-signaling. Importantly, brief discontinuation of dasatinib restored dasatinib-sensitivity associated with reversal of signaling signatures similar to treatment-naive, dasatinib-sensitive cells. The observed desensitization of KIT(mut) t(8;21) AML cells upon continuous dasatinib exposure suggests that therapy-related acquisition of resistance could pose significant limitations on therapeutic efficiency. Notably, we identified TKI-resistant states of transient nature that correlate with alterations in KIT expression and can be reversed upon brief inhibitor withdrawal. These findings indicate that discontinuing treatment maintains dasatinib sensitivity in KIT(mut) AML cells.