Maria Moschovi

Early indicators of dysmetabolic syndrome in young survivors of acute lymphoblastic leukemia in childhood as a target for preventing disease.

Purpose To investigate the presence of early indicators of the dysmetabolic syndrome (DS) in young survivors with acute lymphoblastic leukemia (ALL) in childhood. Patients and Methods We enrolled 80 patients with ALL (50 males, median age 13.9 y, median interval since completion of chemotherapy 6.3 y). Sixty-two patients (group A) received chemotherapy only, whereas 18 patients (group B) received chemotherapy and cranial irradiation (18 Gy). Results Frank obesity [25%; confidence interval (CI) 95%, 16.7%-35.6%], increased blood pressure (21%; CI 95%, 13.6%-31.5%), increased serum triglycerides (21%; CI 95%, 13.6%-31.5%), reduced serum high-density lipoprotein cholesterol (12%; CI 95%, 6.7%-21.7%), increased fasting insulin (8%; CI 95%, 3.2%-15.7%), and osteopenia (71%; CI 95%, 60.5%-80.1%) were detected in groups A and B. Reduced IGF-1 (15%; CI 95%, 8.6%-24.6%) and thyroid hormone abnormalities (11%; CI 95%, 5.8%-20.2%) were detected only in group B. In group B, there was a statistically significant increase in the prevalence of obesity (P=0.024), hyperinsulinemia (P=0.004), and the full DS (22%; CI 95%, 8.6%-45.9% vs. 8%; CI 95%, 3.1%-18.0%; P=0.017) compared with group A. Conclusions Young survivors of childhood ALL, especially those treated with cranial irradiation, are at risk for obesity, dyslipidemia, insulin resistance, hypertension, and the full DS early after the completion of therapy.

In vitro fertilization and risk of childhood leukemia in Greece and Sweden.

Cancer risk in children born after in vitro fertilization (IVF) remains largely unknown. We aimed to investigate risk of leukemia and lymphoma following IVF using two nationwide datasets.

Serum lipid alterations in acute lymphoblastic leukemia of childhood.

Epidemiologic studies have indicated a relationship between serum lipids and cancer, and it is possible that lipid abnormalities are involved in the mechanism of oncogenesis. This study was performed to investigate serum lipid alterations in patients with acute lymphoblastic leukemia (ALL) at diagnosis and during remission of the disease. Plasma lipids and lipoproteins were measured at diagnosis, prior to the administration of induction treatment, and every 2 months for the first 12 months of the maintenance phase of chemotherapy in 64 patients with ALL. Nearly all patients demonstrated a predictable pattern of serum lipid alterations that consisted of extremely low levels of high-density lipoprotein cholesterol, elevated triglycerides, and elevated low-density lipoprotein cholesterol. Patients studied again during remission demonstrated a return to normal values, and the difference was statistically significant. The results suggest that at diagnosis of ALL an abnormality in lipid metabolism is present, which is reversed during remission.

Maternal supplementation with folic acid and other vitamins and risk of leukemia in offspring: a Childhood Leukemia International Consortium study.

Background: Maternal prenatal supplementation with folic acid and other vitamins has been inconsistently associated with a reduced risk of childhood acute lymphoblastic leukemia (ALL). Little is known regarding the association with acute myeloid leukemia (AML), a rarer subtype. Methods: We obtained original data on prenatal use of folic acid and vitamins from 12 case-control studies participating in the Childhood Leukemia International Consortium (enrollment period: 1980–2012), including 6,963 cases of ALL, 585 cases of AML, and 11,635 controls. Logistic regression was used to estimate pooled odds ratios (ORs) and 95% confidence intervals (CIs), adjusted for child’s age, sex, ethnicity, parental education, and study center. Results: Maternal supplements taken any time before conception or during pregnancy were associated with a reduced risk of childhood ALL; odds ratios were 0.85 (95% CI = 0.78–0.92) for vitamin use and 0.80 (0.71–0.89) for folic acid use. The reduced risk was more pronounced in children whose parents’ education was below the highest category. The analyses for AML led to somewhat unstable estimates; ORs were 0.92 (0.75–1.14) and 0.68 (0.48–0.96) for prenatal vitamins and folic acid, respectively. There was no strong evidence that risks of either types of leukemia varied by period of supplementation (preconception, pregnancy, or trimester). Conclusions: Our results, based on the largest number of childhood leukemia cases to date, suggest that maternal prenatal use of vitamins and folic acid reduces the risk of both ALL and AML and that the observed association with ALL varied by parental education, a surrogate for lifestyle and sociodemographic characteristics.

Hodgkin's disease in a child with sickle cell disease treated with hydroxyurea.

Hydroxyurea (HU) is an oral drug that ameliorates the clinical course of sickle cell anemia by ¯ increasing the levels of fetal hemoglobin and decreasing the adhesion of red cells to endothelium. Although HU has minimal short-term toxicity, few data are available about the long-term safety and the potential risk for carcinogenesis or leukemogenesis. An 8-year-old child with sickle cell / g 0- thalassemia who received HU treatment for painful crises is described. Six months after the initiation of the HU treatment he developed Hodgkins disease, lymphocyte predominance subtype. Chemotherapy induced a complete remission. After discontinuation of chemotherapy the painful crises recurred and bone marrow transplantation was decided at the age of 12 years. Two years after the bone marrow transplantation, the child is in complete remission without painful crises. Although the authors suggest that the development of Hodgkins disease is a coexisting event, questions arise about the safety of HU treatment in childhood.

Dynamic aberrant NF-κB spurs tumorigenesis: A new model encompassing the microenvironment

Recently it was discovered that a transient activation of transcription factor NF-κB can give cells properties essential for invasiveness and cancer initiating potential. In contrast, most oncogenes to date were characterized on the basis of mutations or by their constitutive overexpression. Study of NF-κB actually leads to a far more dynamic perspective on cancer: tumors caused by diverse oncogenes apparently evolve into cancer after loss of feedback regulation for NF-κB. This event alters the cellular phenotype and the expression of hormonal mediators, modifying signals between diverse cell types in a tissue. The result is a disruption of stem cell hierarchy in the tissue, and pervasive changes in the microenvironment and immune response to the malignant cells.

Maternal smoking during pregnancy and risk for childhood leukemia: A nationwide case–control study in Greece and meta-analysis†

Maternal smoking during pregnancy has been often implicated in the development of childhood leukemia with ambiguous results. Hence, we conducted a meta‐analysis aiming to summarize current evidence and quantify any tentative impact.

Maternal smoking during pregnancy and childhood lymphoma: a meta-analysis.

Results from epidemiological studies exploring the association between childhood lymphoma and maternal smoking during pregnancy have been contradictory. This meta‐analysis included all published cohort (n = 2) and case–control (n = 10) articles; among the latter, the data of the Greek Nationwide Registry for Childhood Hematological Malignancies study were updated to include all recently available cases (‐2008). Odds ratios (ORs), relative risks and hazard ratios were appropriately pooled in three separate analyses concerning non‐Hodgkin lymphoma (NHL, n = 1,072 cases), Hodgkin lymphoma (HL, n = 538 cases) and any lymphoma (n = 1,591 cases), according to data availability in the included studies. An additional metaregression analysis was conducted to explore dose–response relationships. A statistically significant association between maternal smoking (any vs. no) during pregnancy and risk for childhood NHL was observed (OR = 1.22, 95% confidence interval, CI: 1.03–1.45, fixed effects model), whereas the risk for childhood HL was not statistically significant (OR = 0.90, 95% CI: 0.66–1.21, fixed effects model). The analysis on any lymphoma did not reach statistical significance (OR = 1.10, 95% CI = 0.96–1.27, fixed effects model), possibly because of the case‐mix of NHL to HL. No dose–response association was revealed in the metaregression analysis. In conclusion, this meta‐analysis points to a modest increase in the risk for childhood NHL, but not HL, among children born by mothers smoking during pregnancy. Further investigation of dose–response phenomena in the NHL association, however, warrants accumulation of additional data.

Serum Adiponectin As a Predictor of Childhood Non-Hodgkin's Lymphoma: A Nationwide Case-Control Study

PURPOSE To our knowledge, this is the first study exploring the association of childhood non-Hodgkins lymphoma (NHL) with serum adiponectin and leptin levels in a nationwide case-control series. In addition, expression of adiponectin receptors in NHL specimens was assessed, and the association between adipokines and childhood NHL survival and prognosis was examined. PATIENTS AND METHODS We studied 121 incident childhood (0 to 14 years) NHL cases registered in the Nationwide Registry for Childhood Hematological Malignancies (1996 to 2006) and an equal number of matched controls, for whom sociodemographic, lifestyle, prenatal characteristics, and fasting blood serums were collected. Serum adiponectin and leptin levels were determined. Immunohistochemisty for adiponectin receptors expression was performed on commercially available adult NHL specimens (n = 30) and in a subset of childhood NHL cases (n = 6) that were available. Summary statistics, multiple conditional logistic regression analyses, and survival analysis were performed. RESULTS Higher serum adiponectin, but not leptin, levels were independently associated with childhood NHL (odds ratio, 1.82; 95% CI, 1.30 to 2.56), after adjusting for obesity and established risk factors. Higher adiponectin levels at diagnosis were positively associated with relapse and poor survival, but hormone levels did not differ among NHL subtypes. Adiponectin receptors 1 and 2 were present in 90% and 57% of adult samples and in 83% and 100% of childhood NHL samples, respectively. CONCLUSION Elevated serum adiponectin, but not leptin, levels are independently associated with childhood NHL and poor prognosis. Adiponectin receptors are expressed in NHL, suggesting that adiponectin may represent not only a potential clinically significant diagnostic and prognostic marker but also a molecule that may be implicated in NHL pathogenesis.

Genetic variants in immunoregulatory genes and risk for childhood lymphomas

To investigate whether single nucleotide polymorphisms (SNPs) in key cytokine and innate immunity genes influence risk for childhood lymphomas, we genotyped 37 children with Hodgkin’s (HL) and 48 with non‐Hodgkin’s lymphoma (NHL), aged (1 month–14 yr), along with their 85 age‐ and gender‐matched controls suffering from mild medical conditions. Genotypic analysis was performed for 10 SNPs from nine genes with important role in immunoregulatory pathways (IL4, IL4R, IL6, IL10, IL12, IL18, TNFα, IFNγ, CD14). Analysis of SNPs genotypes revealed that the CD14 −159 C>T polymorphism was associated with significantly increased risk for HL regarding both the CC and CT genotypes (ORCC: 5.36; 95% CI, 1.30–22.14; P = 0.02, ORCT: 3.76; 95% CI, 1.00–14.16; P = 0.05). An indicative association between IL18−137 G>C polymorphism with the CC genotype and NHL did not reach, however, statistical significance (ORCC, 3.78; 95% CI, 0.87–16.38; P = 0.08). In conclusion, our findings suggest that genetic variation in the CD14–159 loci may be associated with childhood HL risk; these preliminary findings need to be further confirmed in sizeable multi‐centre studies along with determination of cytokines, which could provide an insight on the biologic basis underlying these findings.