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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. [ABSTRACT FROM AUTHOR]

Background: Several reports point to inverse associations between allergies and ALL; yet, no study has explored this link using both self-reported-data on allergic history and biomarkers of atopic sensitization. Methods: Clinical information for the variables of interest was available for 252 out of 292 cases of childhood (0-14 years) ALL, newly diagnosed across Greece over a 4.5 year period as well as for 294 hospital controls. Allergen-specific-IgEs, as markers of allergic predisposition, against 24 most prevalent respiratory and food allergens, were determined, using an enzyme immunoassay procedure for 199 children with ALL and 113 controls. Cases were compared with controls through frequency distributions and unconditional multiple logistic regression models to estimate odds ratios (ORs) and 95% confidence-intervals (CIs) regarding associations of allergy with childhood ALL. Results: Selfreported- allergic history overall (OR: 0.49, 95%CI: 0.34-0.72) and practically each one of its main components (respiratory, food, any other clinical allergy) were strongly and inversely associated with ALL. Likewise, the serum IgE inverse association was of the same magnitude (OR: 0.43, 95%CI: 0.22-0.84) mainly contributed by food IgE (OR: 0.39, 95%CI: 0.18-0.83). Conclusion: Beyond the already established inverse association of allergic history with childhood ALL, a same magnitude association is evident when serologic markers of allergic predisposition are used as an alternative measure of allergy. Further research with more appropriate study designs is needed to better understand possible associations between prior allergy and childhood ALL risk. [ABSTRACT FROM AUTHOR]

Abstract: An increase of the prevalence of childhood allergic diseases and the incidence of childhood Hodgkin’s (HL) and non-Hodgkin’s lymphoma (NHL) were reported in the late 20th century. Among adults, several studies point to an inverse association with lymphoma; it remains to be confirmed whether allergy is also related to childhood lymphomas and whether the association, if any, is of an aetiologic nature. Between 1996 and 2008, 277 children (aged 0–14years) with HL (N =111) or NHL (N =166) were enrolled in Nationwide Registry for Childhood Hematological Malignancies (NARECHEM), a Greek hospital-based-registry of childhood hematological malignancies. Hospital controls were individually matched to cases on age and sex. Multivariate conditional logistic regression was used to estimate odds ratios (ORs) with 95%confidence intervals (CIs) for associations of allergic diseases and other covariates with childhood HL or NHL risk. Subsequently, we combined our results with those of a French case–control study in a meta-analysis amounting to a total of 330 NHL cases/1478 controls and 239 HL cases/959 controls. After controlling for sociodemographic, perinatal and environmental factors, childhood NHL was less prevalent among children with allergy-associated symptoms overall (OR:0.50, 95%CI:0.27–0.92) or a history of asthma (OR:0.43, 95%CI:0.21–0.88). By contrast, allergy did not seem to be associated with childhood HL risk, although statistical power was limited. Fewer seaside holidays and higher birth weight were also associated with increased childhood NHL risk. The combined OR of the two studies for the association of asthma with NHL risk was: 0.52, 95%CI:0.32–0.84, whereas for HL: 0.86, 95%CI:0.51–1.45. Allergy seems to be strongly and inversely associated with childhood NHL. It remains to be elucidated in future investigations comprising larger populations, focusing on specific disease subtypes and employing more pertinent study-designs, whether this association is genuinely protective. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Rhabdoid tumours (RT) are an aggressive malignancy affecting <2-year-old infants, characterised by biallelic loss-of-function alterations in SWI/SNF-related BAF chromatin remodelling complex subunit B1 (SMARCB1) in nearly all cases. Germline SMARCB1 alterations are found in ~30% of patients and define the RT Predisposition Syndrome type 1 (RTPS1). Uveal melanoma (UVM), the most common primary intraocular cancer in adults, does not harbour SMARCB1 alterations. We report two cases of a previously undescribed intraocular malignancy that shared some features with UVM and RT, but was also distinct from these entities. Both female patients, aged 23 and 14 years, underwent enucleation, and the tumours were subjected to comprehensive genomic, DNA methylation, and transcriptomic profiling. Pathological examination showed large, amelanotic intraocular tumours with epithelioid features, expressing melanocytic markers [S100P, SOX10, Melan-A, PMEL (HMB45), TYR] as seen using immunohistochemistry (IHC), but with little or no melanin production. Both tumours harboured biallelic loss-of-function SMARCB1 alterations, associated with loss of SMARCB1 (BAF47/INI1) expression on IHC. Their genomic profiles were atypical both for UVM and for RT, and no pathogenic variants were found in other genes tested, including those recurrently altered in UVM. In both patients, a germline SMARCB1 variant was found. However, there was no relevant family history of cancer. Transcriptome and methylome profiling suggested that these tumours were distinct from RT, UVM, and skin melanomas. RNAseq confirmed expression of early and late genes related to melanocytic differentiation. The first patient died of metastatic disease 16 months after diagnosis, the second was disease-free 10 months after completion of treatment. In summary, we report two cases of a previously undescribed, aggressive SMARCB1-deficient intraocular malignancy with melanocytic differentiation, which occurs in young patients, is distinct from UVM and RT, and expands the RTPS1 spectrum. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland., (© 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.)

The 5-year overall survival of children and adolescents with osteosarcoma has been in plateau during the last 30 years. The present systematic review (1976-2023) and meta-analysis aimed to explore factors implicated in the prognosis of children and young adults with high-grade osteosarcoma. Original studies including patients ≤30 years and the Nationwide Registry for Childhood Hematological Malignancies and Solid Tumors (NARECHEM-ST) data (2010-2021) referred to children ≤14 years were analysed. Individual participant data (IPD) and summary estimates were used to assess the n-year survival rates, as well as the association of risk factors with overall survival (OS) and event-free survival (EFS). IPD and the n-year survival rates were pooled using Kaplan-Meier and Cox regression models, and random effects models, respectively. Data from 8412 patients, including 46 publications, NARECHEM-ST data, and 277 IPD from 10 studies were analysed. The summary 5-year OS rate was 64% [95% confidence interval (95%CI): 62%-66%, 37 studies, 6661 patients] and the EFS was 52% (95%CI: 49%-56%, 30 studies, 5010 patients). The survival rates generally differed in the pre-specified subgroups. Limb-salvage surgery showed a higher 5-year OS rate (69%) versus amputation (47%). Good responders had higher OS rates at 3 years (94%) and 5 years (81%), compared to poor responders at 3 years (66%), and 5 years (56%). Patients with metastatic disease had a higher risk of death [Hazard Ratio (HR): 3.60, 95%CI: 2.52, 5.15, 11 studies]. Sex did not have an impact on EFS (HR females/males : 0.90, 95%CI: 0.54, 1.48, 3 studies), whereas age>18 years seems to adversely affect EFS (HR 18+/<10 years : 1.36, 95%CI: 1.09, 1.86, 3 studies). Our results summarize the collective experience on prognostic factors of high-grade osteosarcoma among children and young adults. Poor response to neoadjuvant chemotherapy and metastatic disease at diagnosis were confirmed as primary risk factors of poor outcome. International collaboration of osteosarcoma study groups is essential to improve survival., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Stunning advances in treatment modalities implemented in children with hematological malignancies have led to 5-year overall survival rates exceeding 85%. However, this growing population of long-term survivors has raised significant concerns about their fertility status throughout adulthood, while specific treatment- and non-treatment-related factors appear to possibly affect fertility through distinct mechanisms. We aimed to comprehensively review the published literature on the association between treatment-related factors and risk of impaired fertility in childhood hematological cancer survivors. We searched PubMed up to March 2021 to identify eligible studies published during the last two decades. A narrative synthesis of the results was performed, although no meta-analysis was feasible due to the small number of studies and the large heterogeneity of evidence. Five studies on 2020 survivors of childhood leukemia were deemed eligible. The qualitative data synthesis showed significant fertility deficits in survivors treated with cranial radiotherapy and chemotherapy for childhood leukemia. Two studies examined biochemical measures of reduced ovarian reserve, providing some evidence that the levels of anti-Müllerian hormone can be used as a proxy for diminished ovarian reserve. The current findings should facilitate the delivery of age- and gender-appropriate interventions to optimize reproductive outcomes in childhood hematological cancer survivors., (© 2023. The Author(s), under exclusive licence to Hellenic Endocrine Society.)

The prognosis of children with neuroblastoma (NBL) can be dismal with significant variations depending on the stage and biology of the tumor. We assessed the event-free (EFS) and overall (OS) survival using harmonized data from three Southern-Eastern European (SEE) countries. Data for 520 incident NBL cases (2009-2018) were collected from Greece, Slovenia and Russia. Kaplan-Meier curves were fitted, and EFS/OS were derived from Cox proportional models by study variables including the protocol-based risk-group (low/observation, intermediate, high). Over one-third of cases were coded in the high-risk group, of which 23 children (4.4%) received treatment with anti-ganglioside 2 (GD2) mAb. Survival rates were inferior in older (OS 5-year; 1.5-4.9 years: 61%; EFS 5-year; 1.5-4.9 years: 48%) compared to children younger than 1.5 years (OS 5-year; <1.5 years: 91%; EFS 5-year; <1.5 years: 78%). Predictors of poor OS included stage 4 (hazard ratio, HR OS : 18.12, 95% confidence intervals, CI: 3.47-94.54), N-myc amplification (HR OS : 2.16, 95% CI: 1.40-3.34), no surgical excision (HR OS : 3.27, 95% CI: 1.91-5.61) and relapse/progression (HR OS : 5.46, 95% CI: 3.23-9.24). Similar unfavorable EFS was found for the same subsets of patients. By contrast, treatment with anti-GD2 antibody in high-risk patients was associated with decreased risk of death or unfavorable events (HR OS : 0.11, 95% CI: 0.02-0.79; HR EFS : 0.19, 95% CI: 0.07-0.52). Our results confirm the outstanding prognosis of the early NBL stages, especially in children <1.5 years, and the improved outcomes of the anti-GD2 treatment in high-risk patients. Ongoing high-quality clinical cancer registration is needed to ensure comparability of survival across Europe and refine our understanding of the NBL biology., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

IL-23 is an IL-12 cytokine family member with pleiotropic functions that regulates tumour growth in various cancer types, exhibiting both anti-tumorigenic and pro-tumorigenic properties. Preclinical studies have shown a potential anti-leukemic action on childhood B-ALL cells. The study involved 65 children with acute leukemia [59 patients with acute lymphoblastic leukemia (ALL) and 6 patients with acute myeloid leukemia (AML)] and 27 healthy controls. Using an enzyme-linked immunosorbent assay, we aimed to determine the IL-23 levels in the peripheral blood (PB) and bone marrow (BM) of patients at diagnosis and at the end of the induction therapy (EIT). PB IL-23 levels were lower in leukemia patients compared to the healthy controls. In all acute leukemia patients, IL-23 levels were significantly lower at diagnosis both in PB (P = .015) and in BM (P = .037) compared to the PB and BM concentrations at the EIT. The same pattern was present in both subgroups of ALL and AML patients. The high leukemic burden at diagnosis was related with lower IL-23 levels, which were increased with the disease remission. Considering the anti-leukemic potential of this cytokine, the elevation of the IL-23 concentration at the disease remission indicates a beneficial role of IL-23 in paediatric acute leukemia., (© 2021 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Background: Despite overall striking advances in survival of childhood liver tumors, outcomes remain poor for specific patient segments. We aimed to assess overall survival (OS) of this rare disease and evaluate the generalizability of prognostic variables included in international collaborative systems using, for the first time, harmonized clinical data from two geographically different cohorts (Greece and Moscow)., Methods: Data for children (0-14 years) with liver tumors were retrieved from two Southern-Eastern European areas (Greece; 2001-2019 and Moscow; 2012-2019). Kaplan-Meier curves were constructed, and OS values were derived from Cox proportional models controlling for study variables., Results: A total of 171 newly diagnosed cases (54.4% males) were included. The OS 5-year exceeded 80% in patients <5 years, reaching 85% among 133 patients with hepatoblastoma (HBL). By contrast, children with other than HBL histology, especially hepatocellular carcinoma (HCC) had significantly worse prognosis (hazard ratio [HR] HCC : 7.09, 95% confidence intervals [CI]: 2.56-19.65; HR other liver tumors : 5.18; 95%CI: 2.15-12.49). The OS 5-year was poorer (40%-60%) in patients with extensive local, metastatic or relapsed disease. By contrast, a significantly lower risk of death was shown in case of microscopically margin-negative resection (HR: 0.06, 95%CI: 0.02-0.17) and liver transplantation (HR: 0.12, 95% CI: 0.02-0.63) compared to the non- operated group., Conclusions: Outcomes of patients with liver tumors registered in two SEE areas were comparable to those reported by major collaborative trials. Ongoing clinical cancer registration could facilitate comparison of outcomes between different study groups in order to shape state of the art of treatment., (Copyright © 2020. Published by Elsevier Ltd.)

Background: Little is known about the etiology of childhood Wilms tumor (WT) and potentially modifiable maternal risk factors, in particular., Methods: Unpublished data derived from the hospital-based, case-control study of the Greek Nationwide Registry for Childhood Hematological Malignancies and Solid Tumors (NARECHEM-ST) were included in an ad hoc conducted systematic literature review and meta-analyses examining the association between modifiable maternal lifestyle risk factors and WT. Eligible data were meta-analysed in separate strands regarding the associations of WT with (a) maternal folic acid and/or vitamins supplementation, (b) alcohol consumption and (c) smoking during pregnancy. The quality of eligible studies was evaluated using the Newcastle-Ottawa Scale., Results: Effect estimates from 72 cases and 72 age- and sex-matched controls contributed by NARECHEM-ST were meta-analysed together with those of another 17, mainly medium size, studies of ecological, case-control and cohort design. Maternal intake of folic acid and/or other vitamins supplements during pregnancy was inversely associated with WT risk (6 studies, OR: 0.78; 95 %CI: 0.69-0.89, I 2 = 5.4 %); of similar size was the association for folic acid intake alone (4 studies, OR: 0.79; 95 %CI: 0.69-0.91, I 2 = 0.0 %), derived mainly from ecological studies. In the Greek study a positive association (OR: 5.31; 95 %CI: 2.00-14.10) was found for mothers who consumed alcohol only before pregnancy vs. never drinkers whereas in the meta-analysis of the four homogeneous studies examining the effect of alcohol consumption during pregnancy the respective overall result showed an OR: 1.60 (4 studies, 95 %CI: 1.28-2.01, I 2 = 0.0 %). Lastly, no association was seen with maternal smoking during pregnancy (14 studies, OR: 0.93; 95 %CI: 0.80-1.09, I 2 = 0.0 %)., Conclusions: In the largest to-date meta-analysis, there was an inverse association of maternal folic acid or vitamins supplementation with WT risk in the offspring, derived mainly from ecological studies. The association with maternal alcohol consumption found in our study needs to be further explored whereas no association with maternal smoking was detected. Given the proven benefits for other health conditions, recommendations regarding folic acid supplementation as well as smoking and alcohol cessation should apply. The maternal alcohol consumption associations, however, should be further explored given the inherent limitations in the assessment of exposures of the published studies., Competing Interests: Declaration of Competing Interest None, (Copyright © 2020. Published by Elsevier Ltd.)

Background: We explored the association between ionizing radiation (IR) from pre-natal and post-natal radio-diagnostic procedures and brain cancer risk within the MOBI-kids study., Methods: MOBI-kids is an international (Australia, Austria, Canada, France, Germany, Greece, India, Israel, Italy, Japan, Korea, New Zealand, Spain, The Netherlands) case-control study including 899 brain tumor (645 neuroepithelial) cases aged 10-24 years and 1,910 sex-, age-, country-matched controls. Medical radiological history was collected through personal interview. We estimated brain IR dose for each procedure, building a look-up table by age and time period. Lifetime cumulative doses were calculated using 2 and 5 years lags from the diagnostic date. Risk was estimated using conditional logistic regression. Neurological, psychological and genetic conditions were evaluated as potential confounders. The main analyses focused on neuroepithelial tumors., Results: Overall, doses were very low, with a skewed distribution (median 0.02 mGy, maximum 217 mGy). ORs for post-natal exposure were generally below 1. ORs were increased in the highest dose categories both for post and pre-natal exposures: 1.63 (95% CI 0.44-6.00) and 1.55 (0.57-4.23), respectively, based on very small numbers of cases. The change in risk estimates after adjustment for medical conditions was modest., Conclusions: There was little evidence for an association between IR from radio-diagnostic procedures and brain tumor risk in children and adolescents. Though doses were very low, our results suggest a higher risk for pre-natal and early life exposure, in line with current evidence., (© 2020 S. Karger AG, Basel.)

BAFF, APRIL and their receptors regulate the survival, maturation and homeostasis of mature B-cells. Despite the lack of a functional role of BAFF/APRIL system during normal early B-cell development, previous studies indicated a contribution of these molecules in the pathogenesis of B-lineage acute lymphoblastic leukemia (B-ALL). Here, we evaluated the expression of this system in B-ALL and its involvement in spontaneous and drug-induced apoptosis of B-lymphoblasts, taking into consideration the distinct disease subtypes. We found that BAFFR is the most predominant aberrantly expressed receptor in B-ALL and that its expression, along with BCMA and APRIL, positively correlates with the maturation stage of B-lymphoblasts. Moreover, the binding of the E2A-PBX1 chimeric protein to the BAFFR promoter suggests that the transcriptional activator promotes the increase in BAFFR expression observed in about 50% of pre-B-ALL patients carrying the t (1, 19) translocation. BAFF binding to BAFFR led to the processing of NF-κB2 p100 in pre-B ALL cells suggesting that BAFFR can activate the NF-κB2 pathway in pre-B ALL cells. Surprisingly, we found that BAFF treatment promotes the cell death of primary BCR-ABL + BAFFR + pre-B-lymphoblasts in adult B-ALL. It also enhances glucocorticoid-induced apoptosis in the E2A-PBX1 + pre-B-ALL cell line 697. These data suggest that BAFF/BAFFR signaling in B-ALL cells differs from normal B cells and that it may affect the pathogenesis of the disease.

Background: The childhood peak of brain tumors suggests that early-life exposures might have a role in their etiology. Hence, we examined in the Greek National Registry for Childhood Hematological Malignancies and Solid tumors (NARECHEM-ST) whether perinatal and early-life risk factors influence the risk of childhood brain tumors., Methods: In a nationwide case-control study, we included 203 cases (0-14 years) with a diagnosis of brain tumor in NARECHEM-ST (2010-2016) and 406 age-, sex-, and center-matched hospital controls. Information was collected via interviews with the guardians and we analyzed the variables of interest in multivariable conditional logistic regression models., Results: Instrument-assisted delivery was associated with higher (OR: 7.82, 95%CI: 2.18-28.03), whereas caesarean delivery with lower (OR: 0.67, 95%CI: 0.45-0.99) risk of childhood brain tumors, as compared to spontaneous vaginal delivery. Maternal alcohol consumption during pregnancy (OR: 2.35, 95%CI: 1.45-3.81) and history of living in a farm (OR: 4.98, 2.40-10.32) increased the odds of childhood brain tumors. Conversely, higher birth order was associated with lower risk (OR for 2nd vs. 1st child: 0.60, 95%CI: 0.40-0.89 and OR for 3 rd vs. 1 st : 0.34, 95%CI: 0.18-0.63). Birth weight, gestational age, parental age, history of infertility, smoking during pregnancy, allergic diseases, and maternal diseases during pregnancy showed no significant associations., Conclusions: Perinatal and early-life risk factors, and specifically indicators of brain trauma, exposure to toxic agents and immune system maturation, might be involved in the pathogenesis of childhood brain tumors. Larger studies should aim to replicate our findings and examine associations with tumor subtypes., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Despite advances in the management of nephroblastoma (Wilms' tumor, WT), the etiology of the tumor remains obscure. We aimed to compare nephroblastoma incidence rates and time trends among children (0-14 years) in 12 Southern and Eastern European (SEE) countries and the Surveillance, Epidemiology, and End Results Program (SEER), USA, in relation to the human development index (HDI)., Methods: In total 1776 WT cases were recorded in 13 SEE collaborating registries (circa 1990-2016), whereas data on 2260 cases (1990-2012) were extracted from the SEER database. Age-standardized incidence rates (AIRs) were calculated and correlated with HDI, whereas temporal trends were evaluated using Poisson regression and Joinpoint analyses., Results: The overall SEE AIR (9.2/10 6 ) was marginally higher than that of the SEER (8.3/10 6 ), whereas significant differences were noted among the 13 SEE registries which comprised mainly Caucasian populations. A statistically significant temporal increase in incidence was noted only in Belarus. Most cases (∼75%) were diagnosed before the fifth year of life, with rates steadily declining thereafter; median age at diagnosis was similar in SEE countries and SEER. A slight male preponderance in the first year of life (male:female = 1.1) was followed by a female preponderance in the older age groups (male:female = 0.7). Lastly, a statistically significant positive association between higher HDI and increasing nephroblastoma incidence was noted (regression coefficient: +3.25, 95%CI: +1.35, +5.15)., Conclusions: Variations in incidence and time trends across the examined registries, changing male-to-female patterns with advancement in age, and positive associations with the HDI imply a plausible role for environmental and genetic factors in disease etiology, and these need to be explored further., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Childhood (0-14 years) lymphomas, nowadays, present a highly curable malignancy compared with other types of cancer. We used readily available cancer registration data to assess mortality and survival disparities among children residing in Southern-Eastern European (SEE) countries and those in the United States. Average age-standardized mortality rates and time trends of Hodgkin (HL) and non-Hodgkin (NHL; including Burkitt [BL]) lymphomas in 14 SEE cancer registries (1990-2014) and the Surveillance, Epidemiology, and End Results Program (SEER, United States; 1990-2012) were calculated. Survival patterns in a total of 8918 cases distinguishing also BL were assessed through Kaplan-Meier curves and multivariate Cox regression models. Variable, rather decreasing, mortality trends were noted among SEE. Rates were overall higher than that in SEER (1.02/10 6 ), which presented a sizeable (-4.8%, P = .0001) annual change. Additionally, remarkable survival improvements were manifested in SEER (10 years: 96%, 86%, and 90% for HL, NHL, and BL, respectively), whereas diverse, still lower, rates were noted in SEE. Non-HL was associated with a poorer outcome and an amphi-directional age-specific pattern; specifically, prognosis was inferior in children younger than 5 years than in those who are 10 to 14 years old from SEE (hazard ratio 1.58, 95% confidence interval 1.28-1.96) and superior in children who are 5 to 9 years old from SEER/United States (hazard ratio 0.63, 95% confidence interval 0.46-0.88) than in those who are 10 to 14 years old. In conclusion, higher SEE lymphoma mortality rates than those in SEER, but overall decreasing trends, were found. Despite significant survival gains among developed countries, there are still substantial geographic, disease subtype-specific, and age-specific outcome disparities pointing to persisting gaps in the implementation of new treatment modalities and indicating further research needs., (Copyright © 2016 John Wiley & Sons, Ltd.)

Parental alcohol consumption before and during pregnancy has been linked to adverse outcomes in the offspring including leukemogenesis. We, therefore, aimed to systematically assess and quantitatively synthesize published data on the association of paternal consumption during preconception and maternal consumption during pregnancy with leukemia risk in childhood (0-14 years). Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, we searched PubMed (until February 2016) and the reference lists of the relevant studies. Observational studies examining the association between parental alcohol consumption and childhood leukemia were considered eligible. Data extracted from 39 case-control studies (over 16 000 leukemia cases and 30 000 controls) were pooled and summary-effect estimates were calculated. Subgroup analyses were carried out by main acute leukemia type [lymphoblastic or myeloid), cytogenetics/genetic polymorphisms, and specific alcohol beverages. We found a statistically significant dose-response association of any level of maternal alcohol consumption compared with nondrinking during pregnancy exclusively with acute myeloid leukemia (AML) [odds ratio (OR)moderate consumption: 1.64, 95% confidence intervals (CIs): 1.23-2.17 and ORhigh consumption: 2.36, 95% CI: 1.60-3.49]. In contrast, no association of paternal preconception consumption with any leukemia type was noted. In beverage-specific analyses, only a positive association of maternal wine drinking with childhood AML was found, which was more pronounced in analyses including only studies on infant leukemia (ORwine: 2.12, 95% CI: 1.16-3.90). The largest ever meta-analysis shows a sizeable, statistically significant dose-response association of maternal alcohol consumption during index pregnancy with AML risk. Future research exploring the role of genetic polymorphisms is anticipated to shed light on the underlying pathophysiology.

Background: Exploring the effect of maternal and/or childhood diet on offspring leukemogenesis is challenging, given differences in food group categories, their potentially variable impact depending on time window of exposure and the multiple leukemia subtypes. We opted to quantitatively synthesize published data on the association of maternal/child diet with leukemia risk., Methods: Medline was searched until June 30th, 2016 for eligible articles on the association of childhood leukemia with consumption of (i) food groups, excluding alcoholic and non-alcoholic beverages, and (ii) specific dietary supplements before/during index pregnancy and childhood., Results: Eighteen studies of case-control design (N=11,720 cases/18,721 controls) were included, of which nine assessed maternal dietary components, five index child's and four both, mainly focusing on acute lymphoblastic leukemia (ALL). Statistically significant inverse estimates for ALL were found (2 studies, 413 cases, 490 controls) for fruit (OR: 0.81, 95% CI: 0.67, 0.99); vegetables (OR: 0.51, 95% CI: 0.28, 0.94); legumes (OR: 0.76, 95% CI: 0.62, 0.94); fish (OR: 0.27, 95% CI: 0.14, 0.53, among the 0-4year old; 2 studies 215 cases, 215 controls); preconception folic acid supplementation (OR: 0.69, 95%CI: 0.50-0.95; published meta analysis plus 2 studies, 3511 cases, 6816 controls); and use of vitamins during pregnancy (OR: 0.81, 95%CI: 0.74-0.88; published meta analysis plus one study, 5967 cases, 8876 controls). The associations (2 studies) of the remaining food groups and maternal dietary supplements consumption during pregnancy as well as of childhood diet and supplements intake (2-4 studies) were non significant., Conclusions: Maternal consumption of specific food groups comprising"healthy" items of the Mediterranean diet, preconception use of folic acid and intake of vitamins during pregnancy were associated with decreased ALL risk. Further research is needed, however preferably with homogeneous dietary information and data on immunophenotypic/cytogenetic subtypes to also explore the interaction of specific macro- and micronutrients intake with gene polymorphisms., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Pilocytic astrocytomas (PA) comprise the most common childhood central nervous system (CNS) tumor. Exploiting registry-based data from Southern and Eastern Europe (SEE) and SEER, US, we opted to examine incidence, time trends, survival and tentative outcome disparities of childhood PA by sociodemographic and clinical features. Childhood PA were retrieved from 12 SEE registries (N = 552; 1983-2014) and SEER (N = 2723; 1973-2012). Age-standardized incidence rates (ASR) were estimated and survival was examined via Kaplan-Meier and Cox regression analysis. ASR of childhood PA during 1990-2012 in SEE was 4.2/10 6 , doubling in the USA (8.2/10 6 ). Increasing trends, more prominent during earlier registration years, were recorded in both areas (SEE: +4.1 %, USA: +4.6 %, annually). Cerebellum comprised the most common location, apart from infants in whom supratentorial locations prevailed. Age at diagnosis was 1 year earlier in SEE, whereas 10-year survival was 87 % in SEE and 96 % in SEER, improving over time. Significant outcome predictors were age <1 year at diagnosis diagnosis (hazard ratio, HR [95% confidence intervals]: 3.96, [2.28-6.90]), female gender (HR: 1.38, [1.01-1.88]), residence in SEE (HR: 4.07, [2.95-5.61]) and rural areas (HR: 2.23, [1.53-3.27]), whereas non-cerebellar locations were associated with a 9- to 12-fold increase in risk of death. The first comprehensive overview of childhood PA epidemiology showed survival gains but also outcome discrepancies by geographical region and urbanization pointing to healthcare inequalities. The worse prognosis of infants and, possibly, females merits further consideration, as it might point to treatment adjustment needs, whereas expansion of systematic registration will allow interpretation of incidence variations.

Purpose: To describe epidemiologic patterns of childhood (0-14 years) lymphomas in the Southern and Eastern European (SEE) region in comparison with the Surveillance, Epidemiology and End Results (SEER), USA, and explore tentative discrepancies., Methods: Childhood lymphomas were retrieved from 14 SEE registries (n = 4,702) and SEER (n = 4,416), diagnosed during 1990-2014; incidence rates were estimated and time trends were evaluated., Results: Overall age-adjusted incidence rate was higher in SEE (16.9/10 6 ) compared to SEER (13.6/10 6 ), because of a higher incidence of Hodgkin (HL, 7.5/10 6 vs. 5.1/10 6 ) and Burkitt lymphoma (BL, 3.1 vs. 2.3/10 6 ), whereas the incidence of non-Hodgkin lymphoma (NHL) was overall identical (5.9/10 6 vs. 5.8/10 6 ), albeit variable among SEE. Incidence increased with age, except for BL which peaked at 4 years; HL in SEE also showed an early male-specific peak at 4 years. The male preponderance was more pronounced for BL and attenuated with increasing age for HL. Increasing trends were noted in SEER for total lymphomas and NHL, and was marginal for HL, as contrasted to the decreasing HL and NHL trends generally observed in SEE registries, with the exception of increasing HL incidence in Portugal; of note, BL incidence trend followed a male-specific increasing trend in SEE., Conclusions: Registry-based data reveal variable patterns and time trends of childhood lymphomas in SEE and SEER during the last decades, possibly reflecting diverse levels of socioeconomic development of the populations in the respective areas; optimization of registration process may allow further exploration of molecular characteristics of disease subtypes.

The long-term impact of cesarean delivery (CD) on the health of the offspring is being explored methodically. We sought to investigate the effect of birth by (a) prelabor and (b) during-labor CD on the risk of early-onset (≤3 years) acute lymphoblastic leukemia (ALL), specifically of its prevailing precursor B (B-ALL) subtype. A total of 1099 incident cases of ALL (957 B-ALL), 131 of acute myeloid leukemia (AML), and their 1 : 1 age-matched and sex-matched controls, derived from the Nationwide Registry for Childhood Hematological Malignancies (1996-2013), were analyzed using multivariate regression models. A null association was found between prelabor and/or during labor CD and either ALL (B-ALL) or AML in the 0-14 age range. By contrast, birth by CD increased significantly the risk of early-onset ALL [odds ratioCD (ORCD)=1.57, 95% confidence interval (CI): 1.10-2.24] mainly on account of prelabor CD (ORprelaborCD=1.66, 95% CI: 1.13-2.43). The respective figures were even higher for the early-onset precursor B-ALL (ORCD=1.66, 95% CI: 1.15-2.40 and ORprelaborCD=1.79, 95% CI: 1.21-2.66), whereas no association emerged for early-onset AML. Prelabor CD, which deprives exposure of the fetus/infant to the presumably beneficial effect of stress hormones released in both vaginal labor and during labor CD, was associated exclusively with an increased risk of early-onset ALL, particularly the precursor B-ALL subtype. If confirmed, these adverse long-term outcomes of CD may point to re-evaluation of prelabor CD practices and prompt scientific discussion on the best ways to simulate the effects of vaginal delivery, such as a precesarean induction of labor.

Some previous studies have suggested that home pesticide exposure before birth and during a child's early years may increase the risk of childhood leukemia. To further investigate this, we pooled individual level data from 12 case-control studies in the Childhood Leukemia International Consortium. Exposure data were harmonized into compatible formats. Pooled analyses were undertaken using multivariable unconditional logistic regression. The odds ratio (ORs) for acute lymphoblastic leukemia (ALL) associated with any pesticide exposure shortly before conception, during pregnancy and after birth were 1.39 (95% confidence interval [CI]: 1.25, 1.55) (using 2,785 cases and 3,635 controls), 1.43 (95% CI: 1.32, 1.54) (5,055 cases and 7,370 controls) and 1.36 (95% CI: 1.23, 1.51) (4,162 cases and 5,179 controls), respectively. Corresponding ORs for risk of acute myeloid leukemia (AML) were 1.49 (95% CI: 1.02, 2.16) (173 cases and 1,789 controls), 1.55 (95% CI: 1.21, 1.99) (344 cases and 4,666 controls) and 1.08 (95% CI: 0.76, 1.53) (198 cases and 2,655 controls), respectively. There was little difference by type of pesticide used. The relative similarity in ORs between leukemia types, time periods and pesticide types may be explained by similar exposure patterns and effects across the time periods in ALL and AML, participants' exposure to multiple pesticides, or recall bias. Although some recall bias is likely, until a better study design can be found to investigate the associations between home pesticide use and childhood leukemia in an equally large sample, it would appear prudent to limit the use of home pesticides before and during pregnancy, and during childhood., (© 2015 UICC.)

Aim: Childhood central nervous system (CNS) tumour registration and control programs in Southern and Eastern Europe remain thin, despite the lethal nature of the disease. Mortality/survival data were assembled to estimate the burden of malignant CNS tumours, as well as the potential role of sociodemographic survival determinants across 14 cancer registries of this region., Methods: Average age-adjusted mortality rates were calculated, whereas time trends were quantified through Poisson and Joinpoint regressions. Kaplan-Meier curves were derived for the maximum and the more recent (10 and 5 year) registration periods. Multivariate Cox regression models were used to assess demographic and disease-related determinants., Results: Variations in mortality (8-16 per million) and survival (5-year: 35-69%) were substantial among the participating registries; in most registries mortality trend was stable, whereas Bulgaria, having the highest starting rate, experienced decreasing annual mortality (-2.4%, p=0.001). A steep decrease in survival rates was evident before the second year of follow-up. After controlling for diagnostic subgroup, age, gender and diagnostic year, Greece seemed to present higher survival compared with the other contributing registries, although the follow-up period was short. Irrespective of country, however, rural residence was found to impose substantial adverse repercussions on survival (hazard ratio (HR): 1.2, 95% confidence interval (CI): 1.1-1.4)., Conclusion: Cross-country mortality and survival variations possibly reflect suboptimal levels of health care delivery and cancer control in some regions of Southern and Eastern Europe, notwithstanding questionable death certification patterns or follow-up procedures. Continuous childhood cancer registration and linkage with clinical data are prerequisite for the reduction of survival inequalities across Europe., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Aim: Following completion of the first 5-year nationwide childhood (0-14 years) registration in Greece, central nervous system (CNS) tumour incidence rates are compared with those of 12 registries operating in 10 Southern-Eastern European countries., Methods: All CNS tumours, as defined by the International Classification of Childhood Cancer (ICCC-3) and registered in any period between 1983 and 2014 were collected from the collaborating cancer registries. Data were evaluated using standard International Agency for Research on Cancer (IARC) criteria. Crude and age-adjusted incidence rates (AIR) by age/gender/diagnostic subgroup were calculated, whereas time trends were assessed through Poisson and Joinpoint regression models., Results: 6062 CNS tumours were retrieved with non-malignant CNS tumours recorded in eight registries; therefore, the analyses were performed on 5191 malignant tumours. Proportion of death certificate only cases was low and morphologic verification overall high; yet five registries presented >10% unspecified neoplasms. The male/female ratio was 1.3 and incidence decreased gradually with age, apart from Turkey and Ukraine. Overall AIR for malignant tumours was 23/10(6) children, with the highest rates noted in Croatia and Serbia. A statistically significant AIR increase was noted in Bulgaria, whereas significant decreases were noted in Belarus, Croatia, Cyprus and Serbia. Although astrocytomas were overall the most common subgroup (30%) followed by embryonal tumours (26%), the latter was the predominant subgroup in six registries., Conclusion: Childhood cancer registration is expanding in Southern-Eastern Europe. The heterogeneity in registration practices and incidence patterns of CNS tumours necessitates further investigation aiming to provide clues in aetiology and direct investments into surveillance and early tumour detection., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

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.

Purpose: It has been suggested that parental occupational paint exposure around the time of conception or pregnancy increases the risk of childhood leukemia in the offspring., Methods: We obtained individual level data from 13 case-control studies participating in the Childhood Leukemia International Consortium. Occupational data were harmonized to a compatible format. Meta-analyses of study-specific odds ratios (ORs) were undertaken, as well as pooled analyses of individual data using unconditional logistic regression., Results: Using individual data from fathers of 8,185 cases and 14,210 controls, the pooled OR for paternal exposure around conception and risk of acute lymphoblastic leukemia (ALL) was 0.93 [95% confidence interval (CI) 0.76, 1.14]. Analysis of data from 8,156 ALL case mothers and 14,568 control mothers produced a pooled OR of 0.81 (95% CI 0.39, 1.68) for exposure during pregnancy. For acute myeloid leukemia (AML), the pooled ORs for paternal and maternal exposure were 0.96 (95% CI 0.65, 1.41) and 1.31 (95% CI 0.38, 4.47), respectively, based on data from 1,231 case and 11,392 control fathers and 1,329 case and 12,141 control mothers. Heterogeneity among the individual studies ranged from low to modest., Conclusions: Null findings for paternal exposure for both ALL and AML are consistent with previous reports. Despite the large sample size, results for maternal exposure to paints in pregnancy were based on small numbers of exposed. Overall, we found no evidence that parental occupational exposure to paints increases the risk of leukemia in the offspring, but further data on home exposure are needed.

The aim of the present nationwide Greek study is to assess whether survival from acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) is modified by socioeconomic status (SES) and area remoteness. Detailed precoded information derived from a personal interview conducted by specially trained health personnel with the child guardians was available for 883 ALL and 111 AML incident childhood cases registered in the Nationwide Registry for Childhood Hematological Malignancies during the period 1996-2010. Parental socioprofessional category was recorded on the basis of ISCO68 and ISCO88 codes; the exact traveling distance between residence and the treating hospital was ad hoc calculated. Multivariate Cox's proportional hazards models were applied to examine the mutually adjusted associations between survival and potential predictors. Children from a lower parental socioprofessional category experienced 40% worse survival (P=0.02) independent of age, sex, and ALL subtype, whereas those whose parents were married had better outcomes (rate ratio: 0.47, P=0.01). Urbanization of residence at diagnosis or 'residence to treating hospital' distance was not nominally associated with survival from ALL. By contrast, no noteworthy associations implicating SES were found for AML survival, probably because of the burden of the disease and small numbers. Lower SES indicators and a single-parenthood family milieu seem to be independently associated with unfavorable outcomes from childhood ALL. Area remoteness might not be a significant outcome predictor during recent years, following considerable improvements in the motorway infrastructures and care delivery patterns. This study may provide a valuable snapshot capturing the impact of socioeconomic covariates before the burst of the Greek financial crisis.

Purpose: Within Europe, incidence and mortality rates of childhood leukemia and lymphoma are rather heterogeneous. The present study comprising data from five Southern and Eastern European Cancer Registries aims to compare time trends and examine whether sociodemographic variables, clinical parameters, and proxies of efficient care affect survival., Methods: Data spanning 1996-2010 were obtained for a total of 3,041 newly diagnosed childhood leukemia and 1,183 lymphoma cases reported by the Greek Nationwide Registry for Childhood Hematological Malignancies, Bulgarian National Cancer Registry, Moscow Region and Turkey (Antalya and Izmir) Cancer Registries. Poisson modeling for the evaluation of time trends and multivariate Cox regression analysis for the assessment of prognostic factors were performed., Results: The incidence of leukemia was increasing in all cases, with Bulgaria and Greece presenting statistically significant annual changes (+3.5, and +1.7 %, respectively), followed by marginally increasing trends in Izmir and Moscow; by contrast, there was a remarkable, statistically significant, decreasing mortality trend for leukemia. Rates for lymphoma remained flat. Greece experienced almost twofold better survival rates for both leukemia and lymphoma, probably due to its higher socioeconomic status during the study period. Overall, patients with leukemia living in rural areas had a 28 % lower prognosis (RR: 1.28, 95 % CI 1.03-1.59), pointing to effects of remoteness, when the most privileged country (Greece) was excluded from the analysis., Conclusions: The favorable mortality trends highlight the progress in Southern-Eastern European countries along their trajectory to converge with Northern-Western EU counterpart states. Socioeconomic status may act as a multipotent factor underlying the study findings.

Purpose: There is a paucity of findings concerning the role of diet in childhood leukemogenesis, whereas the results are equivocal and the studies heterogeneous with regard to food items examined. This case-control study investigates the association of childhood leukemia with food groups, macronutrient consumption, total energy intake and adherence to Mediterranean diet among children aged 5-14 years in Greece., Methods: A total of 139 consecutive, incident leukemia cases out of which 121 were acute lymphoblastic leukemia were derived from the Nationwide Registry for Childhood Hematological Malignancies along with one : one age- and gender-matched hospital controls. Information on socio-demographic, maternal and child variables and dietary habits was obtained through in-person interviews with the guardians/children. Multiple logistic regression was performed with adjustment for birth weight and possible confounding variables., Results: Higher consumption of added lipids was associated with an increased risk of childhood leukemia, whereas consumption of milk and dairy products with reduced risk. From the macronutrient analysis, a borderline trend linking high protein intake with reduced childhood leukemia risk was observed., Conclusion: Consumption of milk and dairy products in the first year of life may protect against childhood leukemia possibly through vitamin D actions, while added lipids may increase the risk through various mechanisms. These results offer a holistic evaluation of children's nutrition and suggest that dietary habits in the early years of life may contribute to the prevention of childhood leukemia.

Embryonal tumors constitute the most common malignant brain tumor group in children. Experimental results indicate that genes involved in cell cycle and signal transduction are deregulated in medulloblastoma (MB) and atypical teratoid/rhabdoid tumors (AT/RT). The cell cycle is regulated by protein complexes composed of a regulatory subunit called Cyclin and a catalytic domain named Cyclin-dependent kinase (CDK). Cyclins and CDKs are in turn regulated by cyclin-dependent kinase inhibitors (CDKI) which inhibit cell-cycle progression. Cyclins D and Cyclin E are important for the passage of cells through G1 to S phase. P-27, a member of the universal CDKI family, is important in regulating the G1/S transition. Thus, the purpose of this study was to investigate the expression of p-27, Cyclin D3, and Cyclin E, and their possible prognostic significance in pediatric embryonal brain tumors. We retrospectively evaluated 51 children with embryonal tumors that were treated surgically in our institute. All patients had regular follow up examinations. The streptavidin-biotin HRP method was performed on paraffin sections for detection of p-27, Cyclin D3, and Cyclin E. There were 42 cases of MB and nine cases of AT/RT. Cyclin D3 expression was detected in 11/42 MB and 3/9 AT/RT patients. Cyclin E expression was detected in 28/42 MB and 8/9 AT/RT patients. High expression of Ki-67 (>50 %) and p-27 (>50 %) was observed in 23.8-73.8 % of MB patients. Combined high Ki-67 and p-27 expression was observed in 21.4 % cases of MB. In these cases there was expression of Cyclin E in 88.8 % and Cyclin D3 in 22.2 % of MB. No significant correlation was found between Ki-67 and p-27, Cyclin D3, and E. No correlation was found between Cyclin D3, Cyclin E, p-27, and overall survival. Increased p-27 and Cyclin E expression was detected in a substantial number of MB patients and in nearly all AT/RT patients. Further studies on a larger number of patients are needed to clarify a possible correlation of p-27 and Cyclin E with tumor behavior.

Background: 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., Methods: The hospital-based case-control study in Greece derived from the National Registry for Childhood Hematological Malignancies (1996-2008, 814 leukemia and 277 lymphoma incident cases with their 1:1 matched controls). The Swedish case-control study was nested in the Swedish Medical Birth Register (MBR) (1995-2007, 520 leukemia and 71 lymphoma cases with their 5,200 and 710 matched controls) with ascertainment of incident cancer cases in the National Cancer Register. Study-specific and combined odds ratios (OR) were estimated using conditional logistic regression, with adjustment for possible risk factors., Results: Nationwide studies pointed to similar size excess risk of leukemia following IVF, but to a null association between IVF and lymphoma. The proportion of leukemia cases conceived through IVF was 3% in Greece and 2.7% in Sweden; prevalence of IVF in matched controls was 1.8% and 1.6%, respectively. In combined multivariable analyses, the increased risk of leukemia was confined to age below 3.8 years (OR = 2.21; 95% confidence interval, CI: 1.27-3.85) and to acute lymphoblastic leukemia (ALL) (OR = 1.77; 95% CI: 1.06-2.95) with no sufficient evidence of excess risk for other leukemias (OR = 1.34; 95% CI: 0.38-4.69). Following IVF, OR for ALL was 2.58 (95% CI: 1.37-4.84) before age 3.8 and 4.29 (95% CI: 1.49-12.37) before age 2 years., Conclusions: IVF seems to be associated with increased risk of early onset ALL in the offspring., (Copyright © 2011 Wiley Periodicals, Inc.)

Background: 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., Procedure: We retrieved one cohort (553 leukemias compared to 1,440,542 children), 20 case-control studies and also analyzed the updated Greek case-control dataset with unpublished data, yielding in total 11,092 cases and 25,221 controls., Results: Odds ratios reported in the studies included ranged from 0.70 to 2.20 for acute lymphocytic (ALL) and from 0.60 to 2.17 for acute myelocytic leukemia (AML). The combined effect regarding the association of maternal smoking (any vs. no) and leukemia risk was 1.03 for ALL (95% CI = 0.95-1.12, random effects model) and 0.99 for AML (95% CI = 0.90-1.09, fixed effects model). The results remained unchanged when sensitivity analyses were undertaken of studies reporting same maternal smoking periods, those focusing only on childhood leukemia deaths or investigations which did not clearly define AML subtype., Conclusions: The findings of the meta-analysis challenge the limits of traditional epidemiology to provide sound inferences when point estimates of constituent studies range around the null. In particular, this study provides no support to a hypothesis linking maternal smoking during pregnancy with subsequent development of main childhood leukemia subtypes. Further investigations employing molecular and genetic epidemiology, however, might be needed in the hope to reveal even minimal risks pertaining individuals with specific susceptibility to tobacco compounds who sustain high environmental exposures prenatally or postnatally., (Copyright © 2011 Wiley Periodicals, Inc.)

Ewing's sarcoma is a highly malignant neoplasm of bones which accounts for the 10% of primary bone malignancies. Primary Ewing's sarcoma of skull vault is very rare and constitutes 1-6% of all Ewing's sarcomas. We present a case of a primary and a radiation-induced skull Ewing's sarcoma. The symptoms, neuroimaging findings and the treatment for these cases are reviewed. Both children were operated with favorable outcome.

Embryonal tumors constitute the most common malignant brain tumor group in children. Although patient prognosis has been substantially improved over recent decades, identification of prognostic markers would be of obvious significance. In the present study we evaluated the prognostic significance of cyclin A and B1 in correlation with Ki-67 index in pediatric embryonal tumors. We retrospectively evaluated 53 children with embryonic tumors who were treated surgically in our institute. All patients had regular follow-up examinations. The streptavidin-biotin-horseradish peroxidase (HRP) method was performed on paraffin sections for detection of Ki-67/MIB-1, and cyclin A and B1. There were 42 cases of medulloblastoma (MB), 9 cases of atypical teratoid/rhabdoid tumor (AT/RT), and 2 cases of supratentorial primitive neuroectodermal tumor (PNET). In MB patients, Ki-67 index >50% was associated with worse survival (P = 0.003). Cyclin A index >40% was associated with significantly poorer survival (P = 0.023). Patients with cyclin B1 index >15% exhibited a trend towards poorer survival (P = 0.068). On multivariate analysis, only Ki-67 index was identified as a factor with independent prognostic power. In AT/RT and PNET, there was high expression of Ki-67 and variable expression of cyclin A and B1. Apart from Ki-67 index, cyclin A may have a prognostic role. Study of the above indices at diagnosis could alter or intensify treatment methods, so as to improve disease outcome. There is obviously a need for future studies with larger number of patients to confirm our preliminary observations.

Background: The aim of this study was to determine the safety, tolerance and efficacy of linezolid for the treatment of infections from Gram-positive bacteria in immunocompromised children with cancer., Methods: This was a prospective non-comparative unblinded study in the Hematology/Oncology Unit over a two-year period, administering linezolid as monotherapy in children with cancer., Results: Seventeen children received linezolid (30 mg/kgr: 3 i.v. per day). Mean duration of linezolid administration was 12.2 days (range, 6-38 days), while the median age of the evaluable patients was 2.2 years (range, 6 months-11.2 years). Primary diagnosis was acute lymphoblastic leukemia (nine patients), brain tumor (three patients), multi-organ Langerhans cell histiocytosis (two patients), rhabdomyosarcoma, Burkitt's lymphoma and ovarian tumor (one patient each). All patients were in the midst of chemotherapy cycles. Ten out of 17 children had positive blood cultures (methicillin-resistant Staphylococcus aureus, four patients; vancomycin-resistant Enterococcus, three patients; penicillin-resistant Streptococcus pneumoniae, three patients), while seven of the 17 had fever and vancomycin-resistant Enterococcus in stool cultures. All patients were considered clinically cured after the end of the linezolid regimen (100% efficacy). The main adverse events were thrombocytopenia grade 1-3 and anemia grade 2-3 (four and two patients, respectively). Chemotherapy-induced myelotoxicity (six patients) was not worsened during linezolid therapy. No bleeding episodes were presented. Self-limited diarrhea grade 1-2 was presented in four patients (mean duration 2 days). The total adverse event rate was 23.5%; however, there was no premature cessation of linezolid in any patient., Conclusions: Linezolid may be another effective and safe therapy to treat infections from resistant Gram-positive bacteria in immunocompromised children, even in young ages., (© 2010 The Authors. Pediatrics International © 2010 Japan Pediatric Society.)

A 14-months-old girl was admitted to our hospital because of excessive irritability and abnormal eye movements over the last two months. Brain CT and MRI revealed a suprasellar cystic and partially solid mass with calcifications. The laboratory investigation revealed increased serum levels of AFP. These findings were suggestive for a brain germ cell tumor. Therefore, systemic chemotherapy was started. After two courses there was a reduction in the levels of AFP but the tumor size remained unchanged. Subtotal tumor excision was performed that revealed the presence of a craniopharyngioma. One month later there was enlargement of the cystic part of the tumor, while serum AFP was elevated. The child received again systemic chemotherapy and placement of a reservoir into the cystic part of the tumor. Analysis of the intracystic flouid revealed the presence of beta-HCG and AFP. Following that the patient received brachytherapy with intracavity yttrium placement. Three months later repeated MRI showed a decrease in the size of the cystic part, while the solid part remained unchanged. Thus, the solid part was treated by radiosurgery. One year later the patient was stable but with complete loss of vision. These observations support the theory of a germ cell tumor family, in which craniopharyngioma and germ cell tumor present the two sides of the same entity, while between them a wide variety of tumors, with variable type of secretion of AFP and/or beta-HCG, may exist.

This case-control study aims to explore the association of serum adiponectin/leptin with childhood Hodgkin lymphoma (HL). Study participants were 75 children with histologically confirmed HL, registered in the Nationwide Registry for Childhood Haematological Malignancies and 75 age- and gender-matched controls. Multiple conditional logistic regression analyses were performed, adjusting for sociodemographic and lifestyle parameters. Adiponectin levels were consistently higher among cases in all models with ORs >1.25; 95% CIs ranging from 0.9 to 1.8 and P-values from 0.09 to 0.20. By contrast, there was no association of serum leptin with HL. In conclusion, elevated serum adiponectin might be a risk factor for childhood HL., ((c) 2009 Wiley-Liss, Inc.)

Introduction: The aim of the present study is to (a) describe the level of agreement between reports of health-related quality of life (HRQL) obtained from parents and young patients both on- and off-treatment and (b) explore the factors that may affect the level of agreement in the quality of life (QoL) between young patients and parental proxies., Patients and Methods: The study group consisted of 149 young patients (77 children and 72 adolescents) with cancer followed up by an oncology in-patient clinic of a Greek children's hospital with one of their parents (n=298). After parental consent was obtained, data were collected using the Pediatric Quality of Life Inventory (PedsQL) and a sociodemographic data form., Results: The data collection showed that the best agreement was for the physical (ICC=0.82) and the school domains (ICC=0.68), whereas the worst was for the emotional (ICC=0.48) and the social domains (ICC=0.52). In the off-treatment group, the mother's age was a significant predictor of the child-proxy difference on the physical sub-scale (F=9.804, P=0.003). There was a negative relationship between the mother's age and patient proxy difference on the physical sub-scale. In the on-treatment group, the educational level of the father was found to be a significant predictor for the physical (F=4.30, P=0.041), school (F=5.51, P=0.022) and total sub-scales (F=10.41, P=0.002). Parents with basic education tended to have worse agreement with their children's reports on the physical and school sub-scales, while parents with higher education had worse agreement with their children's reports on the total sub-scale., Conclusions: Our findings suggest that the children and adolescents with cancer reported better QoL than their parents. The predictors found to be significant need to be examined extensively by further studies.

Enteroviruses can cause severe manifestations in children with malignancy. Infection-associated hemophagocytic syndrome (IAHS) due to enterovirus is a rare entity in children. Patients with malignancy and IAHS due to enterovirus were retrospectively evaluated at the University of Athens' Hematology-Oncology pediatric unit within a 6-year period (2000-2006). IAHS occurred in three cases among 56 patients with documented enteroviral infection. The diagnosis of IAHS was confirmed by bone marrow aspiration and biopsy. Nested reverse transcriptase-polymerase chain reaction (RT-PCR), sequencing of the amplified alleles, and immunohistochemistry were performed to document the presence of enterovirus. The type of enterovirus was specified by indirect immunofluorescence assay. At the early phase of the disease, patients presented mild, non-specific viral symptoms, persistent unexplained fever, and pancytopenia. At the late phase, patients had more severe manifestations, such as persistent high fever, diarrhea, weight loss, hepatosplenomegaly, and hepatic dysfunction. The therapeutic approach consisted of supportive care, administration of immunoglobulin (400 mg/kg or 2 g/kg), and pleconaril. All patients had fatal outcome; two patients succumbed to multiorgan failure (MOF), while one patient succumbed to ventricular fibrillation. IAHS usually has fulminant course and leads to severe and life-threatening complications, such as liver failure and MOF. IAHS should always be included in the differential diagnosis of viral syndrome or unexplained fever. The therapeutic approach for IAHS should be administered as early as possible, before the progression to irreversible tissue damage. Early therapeutic intervention involving high doses of immunoglobulin might be beneficial for the patient's outcome.

The objective of this study was to quantify improvements in survival due to chemotherapy among children with medulloblastoma treated during the last three decades at a university unit in Greece, compare these gains with figures derived from a specialized unit in the United States and explore the role of extrinsic factors affecting survival. The records of all children with medulloblastoma (n=50) treated at the University Childhood Oncology Unit in Athens, Greece during the period 1973-2003 were reviewed. The role on survival of socio-demographic factors was studied by modeling the data through Cox's proportional-hazards regression, controlling for the mode of treatment (chemotherapy, yes vs. no), whereas survival of children with medulloblastoma treated in Greece was compared with that of 76 children treated in a specialized center in the United States during a respective period. After adjustment for demographic factors, children with medulloblastoma who received adjuvant therapy in Greece had an approximately four times higher instantaneous rate of remaining alive than those who did not (P=0.05). The 5-year survival of children with medulloblastoma treated at specialized medical centers in Greece and the United States was 66 and 63%, respectively. Despite the comparable figure with that of an acceptable standard, however, there was a suggestion (P=0.07) that a rural place of residence in Greece is a poor prognostic indicator. Assuming inherently similar age of occurrence in urban and rural areas, children from rural areas in this study had a more advanced age at diagnosis than those residing in urban Greece (mean age: 7.9 vs. 6.6 years) with a 5-year survival of 57 and 73%, respectively. As expected, incorporation of adjuvant chemotherapy in the treatment of Greek children with medulloblastoma has yielded remarkable improvement in 5-year survival, comparable to that of technologically advanced countries. On the contrary, children residing in rural areas of the country seem to enjoy less favorable prognosis, possibly owing to delays in diagnosis or limited access to optimal treatment facilities.

Desmoplastic small round cell tumor (DSRCT) is a rare neoplasm with aggressive behavior. Usually it presents as a peritoneal mass, although other cases in various locations have been described. Since less than 10 cases of primary DSRCT in the pleura have been described, it is of interest to report a pediatric case arising from the pleura. The diagnosis was confirmed by molecular detection of the EWS/WT-1 fusion gene product. Multidisciplinary treatment with chemotherapy, radiotherapy, and surgical resection resulted in a progression-free survival time above the median survival, suggesting that this conventional approach could prove effective for this rare and very aggressive malignancy., (Copyright (c) 2006 Wiley-Liss, Inc.)

Objectives: The clinical presentation, severity and outcome of enteroviral infections in children with malignancy were studied., Methods: All cases of enteroviral infections in a University Pediatric Hematology-Oncology Unit were assessed, during a 5-year period. RT-PCR, immunohistochemistry and indirect immunofluorescence assay were performed to document the enteroviral infection and the type of virus., Results: Fifty-five children had documented enteroviral infection among 104 patients evaluated for possible enteroviral infection. Severe manifestations occurred in 11/55 (20%) patients, such as encephalitis 5/55, cardiac involvement 3/55 (1/55 myocarditis, 1/55 dilated cardiomyopathy, 1/55 ventricular fibrillation) and infection associated hemophagocytic syndrome 3/55. Children with lymphoid malignancy had increased incidence of enteroviral infections (87%) compared to children with solid tumors (13%). All patients received supportive care, intravenous immunoglobulin (IVIG) (30/55 low dose 400 mg/kg or 25/55 high dose 2 gr/kg) and/or pleconaril (2/55). All patients who received high dose of IVIG developed early negative viral load. However, 4 of them succumbed. Infection related fatality rate was 14.5% (N=8)., Conclusions: Enteroviruses caused more severe and lethal manifestations especially in children with lymphoid malignancy. The administration of high dose of IVIG was beneficial in viremia. Thus, the early therapeutic intervention with high dose of IVIG may improve the outcome.

Purpose: Many risk-directed therapeutic protocols have been proposed in acute lymphoblastic leukemia (ALL). However, the relapse rates remain high. The effectiveness of each protocol depends on how quickly the clearance of blast cells is achieved. In an attempt to improve survival, by minimizing treatment toxicity and relapse rate, different therapeutic protocols were used every 3 yr in our Unit., Patients and Methods: During 1991-2000, 132 children with ALL were diagnosed in our Unit. Modified and intensified NY II and BFM protocols, in three consecutive periods [(Hematology/Oncology Pediatric Department of the University of Athens) HOPDA-91, HOPDA-94, HOPDA-97] were used., Results: At a median follow-up time of 96 months, the 8-year overall survival (OS) was 88% +/- 3%, whereas the event-free survival (EFS) was 85% +/- 3%. There was a significant increase of the 5-year EFS of the high-risk (HR) group through time (65% in HOPDA-91 vs. 80% in HOPDA-97), whereas EFS of the low risk (LR) group in HOPDA-97 was 96%. Five cases relapsed (3.8%), four of which underwent successful bone marrow transplantation. Fifteen children died (13 diagnosed by 1996, two in the last 4 yr)., Conclusion: Modification of the protocols significantly improved survival in both HR and LR groups. The intensified regimen in the LR group did not increase the adverse toxic events, but on the contrary was extremely effective.

Two patients, a 4-year-old boy and a 6-year-old girl who had a 2-year and a 3-year history of idiopathic thrombocytopenic purpura, respectively, were referred to our Department. Both patients had frequent haemorrhagic events. They received i.v. immunoglobulin, corticosteroids, cyclosporine, interferon alpha-2b and azathioprine, but no clinical remission was established. The girl also underwent splenectomy. Anti-CD20 antibody was administered to both patients at a dose of 375 mg/m(2) once weekly for 4 weeks. No side-effects were detected. During the 18-month follow-up period the patients received no other drug and remained in clinical remission. The B lymphocytes remained undetectable in peripheral blood for 3 months and they progressively increased during the following 4 months. Rituximab is a novel, quite effective, safe treatment of chronic refractory idiopathic thrombocytopenic purpura in childhood. More studies and follow up of patients for longer periods are necessary.

We review the clinical courses and outcomes of an outbreak of enteroviral infection that occurred in 5 children with acute lymphoblastic leukemia during a 2-month period in a hematology-oncology unit. Three patients presented with encephalitis and 2 with parotitis. Three of the 5 patients recovered uneventfully and 2 died, 1 of chronic encephalitis and 1 of acute brain stem encephalitis.