BCL2L12 improves risk stratification and prediction of BFM-chemotherapy response in childhood acute lymphoblastic leukemia.

Background Risk-adjusted treatment has led to outstanding improvements of the remission and survival rates of childhood acute lymphoblastic leukemia (ALL). Nevertheless, overtreatment-related toxicity and resistance to therapy have not been fully prevented. In the present study, we evaluated for the first time the clinical impact of the apoptosis-related BCL2L12 gene in prognosis and risk stratification of BFM-treated childhood ALL. Methods Bone marrow specimens were obtained from childhood ALL patients upon disease diagnosis and the end-of-induction (EoI; day 33) of the BFM protocol, as well as from control children. Following total RNA extraction and reverse transcription, BCL2L12 expression levels were determined by qPCR. Patients' cytogenetics, immunophenotyping and minimal residual disease (MRD) evaluation were performed according to the international guidelines. Results BCL2L12 expression was significantly increased in childhood ALL and correlated with higher BCL2/BAX expression ratio and favorable disease markers. More importantly, BCL2L12 expression was associated with disease remission, while the reduced BCL2L12 expression was able to predict patients' poor response to BFM therapy, in terms of M2-M3 response and MRD≥0.1% on day 15. The survival analysis confirmed the significantly higher risk of the BFM-treated patients underexpressing BCL2L12 at disease diagnosis for early relapse and worse survival. Lastly, evaluation of BCL2L12 expression clearly strengthened the prognostic value of the established disease prognostic markers, leading to superior prediction of patients' outcome and improved specificity of BFM risk stratification. Conclusions The expression levels of the apoptosis-related BCL2L12 predict response to treatment and survival outcome of childhood ALL patients receiving BFM chemotherapy.

Perinatal role of hepcidin and iron homeostasis in full-term intrauterine growth-restricted infants.

OBJECTIVES: To prospectively investigate iron homeostasis in full-term intrauterine growth-restricted (IUGR) and appropriate-for-gestational-age (AGA) infants at birth, by evaluating cord blood concentrations of hepcidin (a bioactive molecule, principal regulator of iron metabolism, downregulated by hypoxia/iron deficiency and upregulated by inflammation), erythropoietin (EPO, a marker of prolonged fetal hypoxia), soluble transferrin receptor (sTfR, a marker of increased erythropoiesis and tissue iron deficiency), iron, ferritin, and unsaturated iron-binding capacity (UIBC). METHODS: Serum cord blood samples from 47 well-defined IUGR and 104 AGA singleton, full-term infants were analyzed for concentrations of all the aforementioned parameters by enzyme immunoassays and spectrophotometry. RESULTS: Hepcidin concentrations were similar, while EPO concentrations were higher in IUGR cases than in AGA controls (P = 0.047). Cord blood sTfR concentrations were increased in IUGR, compared to AGA infants (P = 0.004), and negatively correlated with their customized centiles and birth weight (r = -0.238, P = 0.003 and r = -0.157, P = 0.050, respectively). Ferritin concentrations were lower in IUGR cases than in AGA controls (P = 0.039). In both groups, no correlations were observed between cord blood hepcidin concentrations and iron status indices. CONCLUSIONS: Cord blood hepcidin concentrations in term IUGRs may remain unaffected, possibly due to a balance between hepcidin downregulation by chronic fetal hypoxia (indicated by higher EPO concentrations) and impaired iron metabolism (indicated by lower ferritin and higher sTfR concentrations) on the one hand, and hepcidin upregulation by the inflammatory state characterizing IUGRs, on the other. Furthermore, our findings may possibly indicate the need for regular follow-up for detection of iron-deficient anemia, not only in preterm but also in full-term IUGR neonates.

Overexpression of BCL2 and BAX following BFM induction therapy predicts ch-ALL patients' poor response to treatment and short-term relapse.

PURPOSE: The identification of childhood acute lymphoblastic leukemia (ch-ALL) patients who are at a higher risk of chemotherapy resistance and relapse is essential for successful treatment decisions, despite the application of novel therapies. The aim of the study is the evaluation of BCL2 and BAX expression for the prognosis of ch-ALL patients treated with Berlin-Frankfurt-Münster (BFM) backbone protocol. METHODS: Bone marrow specimens were obtained at the time of diagnosis and on day 33 following BFM treatment induction from 82 ch-ALL patients, as well as from 63 healthy children. Following extraction, total RNA was reverse transcribed and BCL2 and BAX expression levels were determined by qPCR. RESULTS: BCL2 expression and BCL2/BAX ratio were strongly upregulated in ch-ALL compared to healthy children and were correlated with favorable prognostic disease features. Increased levels of BCL2 and BAX expression were associated with disease remission, as ch-ALL patients with lower expression ran a significantly higher risk of M2-M3 response, positive MRD and poor survival outcome. Moreover, the upregulation of BCL2 and BAX following BFM treatment induction was shown to represent an independent predictor of patients' short-term relapse, which was further confirmed in ch-ALL patients with favorable prognostic markers. CONCLUSIONS: In conclusion, BCL2 and BAX could be effectively used for an enhanced prediction of BFM-treated patients' outcome.

Serum hepcidin: indication of its role as an "acute phase" marker in febrile children.

BACKGROUND: Hepcidin is classified as a type II acute phase protein; its production is a component of the innate immune response to infections. OBJECTIVE: To evaluate the alterations of serum hepcidin in children during and following an acute febrile infection. MATERIALS AND METHODS: 22 children with fever of acute onset (< 6 hours) admitted to the 2nd Department of Pediatrics-University of Athens. Based on clinical and laboratory findings our sample formed two groups: the viral infection group (13 children) and the bacterial infection group (9 children). Hepcidin, ferritin and serum iron measurements were performed in all subjects. RESULTS: Serum hepcidin values did not differ notably between children with viral and bacterial infection, but a significant reduction of hepcidin was noted in both groups post-infection. CONCLUSION: Our study provides clinical pediatric data on the role of hepcidin in the face of an acute infection. In our sample of children, hepcidin was found to rise during the acute infection and fall post-infection.

Cord blood chemerin and obestatin levels in large for gestational age infants.

OBJECTIVE: To investigate possible alterations in cord blood levels of adipokines, chemerin and obestatin (secreted by adipose tissue and associated with later development of insulin resistance/metabolic syndrome), as well as insulin, in large for gestational age (LGA) and appropriate for gestational age (AGA) pregnancies, granted that these groups differ in body fat mass and metabolic/endocrine mechanisms. METHODS: Cord blood chemerin, obestatin, and insulin concentrations were prospectively measured in 40 LGA (9 born from diabetic and 31 from nondiabetic mothers) and 40 AGA singleton full-term infants. RESULTS: Cord blood chemerin concentrations were significantly higher in LGA compared with AGA neonates (b = 38.91, SE 9.29, p < 0.001). In contrast, no significant differences in obestatin concentrations were observed between groups. Insulin levels were significantly elevated as customized centiles increased (b = 0.003, SE = 0.001, p = 0.032). CONCLUSIONS: Higher chemerin concentrations in LGA neonates possibly reflect the increased adipose tissue in this group. Lack of difference between the two groups in circulating levels of obestatin-possibly a sensitive marker of insulin resistance-might be due to development of metabolic disorders later in life.