Background/Aim:Ewing sarcoma is an aggressive mesenchymal malignancy commonly affecting children and young adolescents. The molecular basis of this neoplasia is well reported with the formation of the EWSR1/FLI1 fusion gene being the most common genetic finding. However, this fusion gene has not been targeted therapeutically nor is being used as a prognostic marker. Its relevance regarding the molecular steps leading to Ewing sarcoma genesis are yet to be defined. The generation of the oncogenic EWSR1/FLI1 fusion gene, can be attributed to the simultaneous introduction of two DNA double-strand breaks (DSBs). The scope of this study is to detect any association between DNA repair deficiency and the clinicopathological aspects of Ewing's sarcoma disease.Patients and Methods:We have conducted an expression analysis of 35 patients diagnosed with Ewing sarcoma concerning the genes involved in non-homologous end joining (NHEJ) and homologous recombination (HR) repair pathways. We have analyzed the expression levels of 6 genes involved in NHEJ (XRCC4, XRCC5, XRCC6, POLλ, POLμ) and 9 genes involved in HR (RAD51, RAD52, RAD54, BRCA1, BRCA2, FANCC, FANCD, DNTM1, BRIT1) using real time PCR. Age, sex, location of primary tumor, tumor size, KI67, mitotic count, invasion of adjacent tissues and treatment were the clinicopathological parameters included in the statistical analysis.Results:Our results show that both these DNA repair pathways are deregulated in Ewing sarcoma. In addition, low expression of the xrcc4 gene has been associated with better overall survival probability (p=0.032).Conclusion:Our results, even though retrospective and in a small number of patients, highlight the importance of DSBs repair and propose a potential therapeutic target for this type of sarcoma.

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, HROS: 18.12, 95% confidence intervals, CI: 3.47-94.54), N-myc amplification (HROS: 2.16, 95% CI: 1.40-3.34), no surgical excision (HROS: 3.27, 95% CI: 1.91-5.61) and relapse/progression (HROS: 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 (HROS: 0.11, 95% CI: 0.02-0.79; HREFS: 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.

The etiology of childhood neuroblastoma remains largely unknown. In this systematic review and meta-analysis, we summarized and quantitatively synthesized published evidence on the association of maternal modifiable lifestyle factors with neuroblastoma risk in the offspring. We searched MEDLINE up to December 31, 2020 for eligible studies assessing the association of maternal smoking, alcohol consumption and nutritional supplementation during pregnancy with childhood (0-14 years) neuroblastoma risk. Random-effects models were run, and summary odds ratios (OR) and 95% confidence intervals (95% CI) on the relevant associations were calculated, including estimates derived from primary data (n = 103 cases and n = 103 controls) of the Nationwide Registry for Childhood Hematological Malignancies and Solid Tumors (NARECHEM-ST) case control study (2009-2017) in Greece. Twenty-one eligible studies amounting 5163 cases participating in both case control and cohort/linkage studies were included in the meta-analysis. Maternal smoking and alcohol consumption were not statistically significantly associated with neuroblastoma risk (summary ORsmoking: 1.08, 95% CI: 0.96-1.22, I-2 =12.0%, n = 17 studies; summary ORalcohol: 1.01, 95% CI: 0.82-1.18, I-2 =0.0%, n = 8 studies). By contrast, maternal vitamin intake during pregnancy was associated with significantly lower neuroblastoma risk (summary OR: 0.57, 95% CI: 0.34-0.95, I-2 =58.9%, n = 4 studies). The results of the largest to-date meta analysis point to an inverse association between vitamin intake during pregnancy and childhood neuroblastoma risk. Future longitudinal studies are needed to confirm and further specify these associations as to guide preventive efforts on modifiable maternal risk factors of childhood neuroblastoma.

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, I2 = 5.4 %); of similar size was the association for folic acid intake alone (4 studies, OR: 0.79; 95 %CI: 0.69-0.91, I2 = 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, I2 = 0.0 %). Lastly, no association was seen with maternal smoking during pregnancy (14 studies, OR: 0.93; 95 %CI: 0.80-1.09, I2 = 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.

Background/Aim: Undifferentiated round cell sarcomas are a heterogeneous group of sarcomas. Identification of BCOR alterations, such as BCOR/CCNB3 and BCOR/MAML3 fusion genes and BCOR ITD has recently contributed in the precise diagnosis of these neoplasms, defining a new entity of the current classification of soft tissue and bone sarcomas. BCOR sarcomas share both morphological and genetic characteristics distinct from Ewing sarcomas. The scope of our study was to retrospectively identify BCOR sarcomas and find the correlations with the clinical outcome of these patients. Patients and Methods: Histopathology and immunohistochemistry of pediatric tumor samples were combined with molecular testing (PCR) and fluorescent in situ hybridization to find BCOR sarcomas. Results: We, herein, present our experience with BCOR sarcomas in a referral center of Greece. Moreover, we report in one case the detection of a variant BCOR/CCNB3 fusion not previously described. Conclusion: We are the first to report a splice variant of BCOR/CCNB3 which reveals the central position of BCOR in the oncogenesis of these tumors, furthermore we highlight the importance of molecular diagnostics in Ewing-like sarcomas and discuss the current treatment options for this rare entity.

Background: Wilms tumour (WT) management represents a success story in pediatric oncology. We aimed to assess, for the first time, the event-free survival (EFS) vs. overall survival (OS) in Southern and Eastern Europe (SEE) using harmonised clinical data collected by childhood cancer registries and to identify respective prognostic factors. Methods: From 1999 to 2017, data for incident WT cases aged 0-14 years from 3 nationwide (Greece, Belarus and Slovenia) and one regional (Greater Poland) SEE registries were collected following common coding. Kaplan-Meier curves were constructed, and EFS vs. OS values were derived from Cox proportional hazard models by study variables. Results: A total of 338 WT cases (45.6% males; median age, 3.19 years; age<5 years, 75%) were included in the analyses. Bilateral were 21 tumours (6.2%). Among the 317 unilateral cases, the majority (93.7%) received International Society of Pediatric Oncology-based protocols; EFS5-year was 85.1%, and OS5-year 91.1%; both outcomes were significantly worse in stage IV patients or in those with high-risk/unfavourable histology. Relapse rate among high-risk/unfavourable histology cases was 2.3 times higher than among low-intermediate risk/favourable histology cases, with respective death rate 5.6 times higher. Both relapse and death rates increased significantly in patients with advanced anatomical stage and high-risk/unfavourable histology. Finally, significantly worse was the outcome in bilateral tumours (OS5-year: 76.3%) vs. unilateral non-metastatic tumours (OS5-year: 94.7%). Conclusions: Our results delineate the potential of high-quality childhood cancer registration entailing clinical data to assess predictors of WT outcome over and beyond those derived from enrolment into clinical trials. Specifically, outcomes among children with WT residing in the four participating SEE countries were comparable with those reported by major cooperative international groups, albeit somehow inferior. Despite the excellent overall prognosis, however, subgroups of patients with advanced or bilateral disease and/or high-risk histology still suffer poor outcomes. (C) 2019 Elsevier Ltd. All rights reserved.

IntroductionIn B-acute lymphoblastic leukemia (B-ALL), the identification of cytogenetic prognostic factors is important for stratifying patients into risk groups and tailoring treatment accordingly. The purpose of this study was to propose flow cytometric (FCM) scoring systems (SSs) for predicting t(12;21)(p13;q22), t(9;22)(q34;q11), t(11q23), and t(1;19)(q23;p13.3) translocations. MethodsWe analyzed retrospectively the FCM immunophenotype of 377 patients with B-ALL with regard to the major cytogenetic findings revealed by interphase fluorescence in situ hybridization (i-FISH). Comparing descriptive data on the expression of each antigen and performing receiver operating characteristic (ROC) analysis, we identified the most reliable predictive markers for each translocation and sought to establish a specific SS for each translocation, based on specific antibody panels. ResultsCD27, CD9, CD66c, CD10, CD25, and CD34 were employed for the prediction of t(12;21), CD25, CD38, CD34, and CD66c for t(9;22), NG2, CD10, CD15, CD34, and CD20 for t(11q23), and CD34, c, CD123, and CD66c for t(1;19). The sensitivity and specificity, respectively, of each predictive score were 89.29% and 96.15% for t(12;21), 75.00% and 88.19% for t(9;22), 84.21% and 99.04% for t(11q23), and 85.71% and 92.71% for t(1;19). ConclusionFour highly specific and significantly sensitive FCM-obtained SSs are proposed for the prediction of the four major translocations observed in patients with B-ALL. Prospective evaluation of the proposed SSs could lead to a better targeted cytogenetic investigation and therefore to more cost-effective laboratory practice.

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 (similar to 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.

Background: Despite recent therapeutic advancements, Wilms tumour (WT) presents remarkable survival variations. We explored mortality and survival patterns for children (0-14 years) with WT in 12 Southern and Eastern European (SEE) countries in comparison with the United States of America (USA). Methods: A total of 3966 WT cases (0-14 years) were registered by a network of SEE childhood cancer registries (N: 1723) during available registration periods circa 1990-2016 and surveillance, epidemiology, and end results program (SEER) (N: 2243; 1990-2012); mortality data were provided by the respective national statistical services. Kaplan-Meier curves and Cox proportional hazards models were used to assess the role of age, sex, year of diagnosis, urbanisation and Human Development Index (HDI) on overall survival (OS). Results: Persisting regional variations shape an overall 78% 5-year OS in the participating SEE countries, lagging behind the USA figure (92%, p=0.001) and also reflected by higher SEE mortality rates. Worth mentioning is the gradually escalating OS in SEE (hazard ratio [HR] 5-year increment: 0.67, 95% confidence interval [CI]: 0.60, 0.75) vs. a non-significant 10% improvement in the SEER data, which had a high starting value. OS differentials [two-fold less favourable among children aged 10-14 years, boys and those living in rural SEE areas (HR: 1.37; CI: 1.10-1.71) or countries with inferior HDI (2-3-fold)] were minimal in the USA. Conclusions: Children with WT residing in SEE countries do not equally enjoy the substantial survival gains, especially for those living in rural areas and in lower HDI countries. Noteworthy are steep and sizeable survival gains in SEE along with the newly presented Greek data pointing to achievable survival goals in SEE despite the financial crisis. (C) 2018 Elsevier Ltd. All rights reserved.

Background The primary objective of our study is to describe the clinical results of children with AML, treated with BFM protocols, in two institutions in Greece.Patients and methods Between January 1997 and December 2011, 84 children with primary and secondary AML were treated with BFM AML 93, 98 and 2004 protocol and were eligible for evaluation.Results Median follow-up for survivors was 86.3 months. The most usual cytogenetic abnormalities t(8; 21), t(15; 17) and Myeloid/Lymphoid (MLL) rearrangement were detected in eight, six, and nine children respectively. Out of the 73 patients with primary AML, three died before completion of first induction. Only one has never responded to chemotherapy and eight patients had M2 or M3 bone marrow after induction and required more than one courses to achieve remission. On the whole, 46/70 (65.7 %) patients are alive, in remission. Out of 24 patients who suffered from relapse, only seven are alive in second remission. The event-free survival in standard and high risk group was 17/21 (80.9 %) and 31/52 (59.6 %), respectively, with the difference being statistically significant.Conclusions The major cause of mortality in children with AML in our institutions was recurrence of disease. Supportive care, molecular features of the disease, and response to therapy are increasingly used to optimize treatment for all patients.

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.

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.

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.

Pediatrics InternationalVolume 52, Issue 3 p. e171-e174 Gastrointestinal presentation of late acute lymphoblastic leukemia relapse Vassilios Papadakis, Corresponding Author Vassilios Papadakis Departments of Pediatric Hematology-Oncology andVassilios Papadakis, MD, PhD, Department of Pediatric Hematology-Oncology, Goudi, Athens 11527, Greece. Email: [email protected]Search for more papers by this authorEleftheria Roma, Eleftheria Roma First Department of Pediatrics, University of Athens andSearch for more papers by this authorKalliopi Stefanaki, Kalliopi Stefanaki Pathology, Agia Sofia Children's Hospital,Search for more papers by this authorIoanna Panagiotou, Ioanna Panagiotou First Department of Pediatrics, University of Athens andSearch for more papers by this authorSofia Papargyri, Sofia Papargyri Departments of Pediatric Hematology-Oncology andSearch for more papers by this authorGeorge Paterakis, George Paterakis Department of Immunology, G. Gennimatas General Hospital, Athens, GreeceSearch for more papers by this authorSofia Polychronopoulou, Sofia Polychronopoulou Departments of Pediatric Hematology-Oncology andSearch for more papers by this author Vassilios Papadakis, Corresponding Author Vassilios Papadakis Departments of Pediatric Hematology-Oncology andVassilios Papadakis, MD, PhD, Department of Pediatric Hematology-Oncology, Goudi, Athens 11527, Greece. Email: [email protected]Search for more papers by this authorEleftheria Roma, Eleftheria Roma First Department of Pediatrics, University of Athens andSearch for more papers by this authorKalliopi Stefanaki, Kalliopi Stefanaki Pathology, Agia Sofia Children's Hospital,Search for more papers by this authorIoanna Panagiotou, Ioanna Panagiotou First Department of Pediatrics, University of Athens andSearch for more papers by this authorSofia Papargyri, Sofia Papargyri Departments of Pediatric Hematology-Oncology andSearch for more papers by this authorGeorge Paterakis, George Paterakis Department of Immunology, G. Gennimatas General Hospital, Athens, GreeceSearch for more papers by this authorSofia Polychronopoulou, Sofia Polychronopoulou Departments of Pediatric Hematology-Oncology andSearch for more papers by this author First published: 14 June 2010 https://doi.org/10.1111/j.1442-200X.2010.03113.xCitations: 5Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Citing Literature Volume52, Issue3June 2010Pages e171-e174 RelatedInformation

PurposeTo our knowledge, this is the first study exploring the association of childhood non-Hodgkin's 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 MethodsWe 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.ResultsHigher 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.ConclusionElevated 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.

Testicular microlithiasis is a relatively uncommon condition in children. It is characterized by the presence of microcalcifications within the testicular parenchyma. Although it is a benign finding, underlying diseases and other conditions must be ruled out because testicular microlithiasis has been found in association with both benign and malignant lesions in the testes and other tissues. We present two brothers with testicular microlithiasis, and highlight the prevalence, natural history, associated malignant conditions and follow-up recommendations of children diagnosed with testicular microlithiasis.