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Development of antimicrobial stewardship programs (ASPs) is strategy for prevention and management of emergence of antimicrobial-resistant organisms. In this study, we systematically reviewed the literature on antimicrobial stewardship interventions in PICUs and analyzed approaches, structure, implementation, and outcomes of the ASPs.PubMed and Scopus databases were systematically searched for studies published from January 1, 2007, to December 31, 2020, reporting interventions on judicious use of antimicrobials in PICUs (last search performed February 28, 2021).Studies that evaluated an intervention in a PICU setting or both in PICU and other settings and reported separate results for PICU were eligible for full-text review. Studies that had implemented stewardship in the entire hospital, including the PICU, but without presenting dedicated PICU data were excluded from the analysis.The strategy of intervention, structure of ASP team, implementation, and outcomes were assessed with a checklist tool for all studies included in the analysis. Risk of bias was assessed with the Cochrane Risk-of-Bias in Nonrandomized studies of Interventions tool.Thirteen articles were found: 11 that applied ASP in PICUs, and two at hospital level. All PICU-dedicated ASPs applied a multimodal intervention combining strategies simultaneously; audit with feedback (6/11) and facility-specific clinical practice guidelines (7/11) were the most common strategies. A multidisciplinary team was formulated in all ASPs except for three biomarker-based interventions. Six of 11 studies included techniques to enhance behavior change and one implemented a behavior-based intervention. Antibiotic consumption was evaluated in all ASPs, cost in three of 11, antibiotic resistance in one of 11, length of hospitalization in six of 11, and mortality in eight of 11. All hospital-wide ASPs used audit with feedback in addition to facility-specific clinical practice guidelines and assessed antimicrobial consumption, expenditures, length of stay, and mortality.The prevalence of ASPs in PICUs is limited, and few programs follow all of the currently available recommendations.

Background There are experimental data demonstrating synergistic in-vitro activity of colistin and daptomycin against extremely drug-resistant (XDR) strains of Acinetobacter baumannii.Aim of this study is the description of a case-series of patients with confirmed XDR A. baumannii bloodstream infection (BSI) receiving an antimicrobial regimen including colistin and daptomycin. Methods Prospective study of patients with BSI caused by XDR A. baumannii from May 2021 to February 2022 in a tertiary level hospital. Demographic, clinical and laboratory data were recorded and evaluated from all patients. BacT Alert system (BiomerieuxR) was used for blood cultures and bacterial identification and susceptibility testing was performed using VITEK® 2. Colistin susceptibility testing (dilution method) were interpreted in accordance to Clinical and Laboratory Standards Institute (CLSI) criteria. Results A total of 16 episodes of XDR A. baumannii were recorded in 16 patients (14 males). Median age was 60 (range 38-85) years. Ten patients (56.2%) were hospitalized in medical wards, and 43.8% in surgery wards. One-third of patients had previously been admitted to the Intensive Care Unit, while all patients had an indwelling central vascular catheter. Fourteen of the 16 XDR strains of A. baumannii were also resistant to colistin. Also, 2 of the 16 strains had a MIC of 2μg/ml for tigecycline, while in the remaining 14 the MIC was > 2μg/ml. All isolates had meropenem MIC >16μg/ml. All patients received a combination of colistin -daptomycin -meropenem -tigecycline. Clinical and laboratory improvement was noted in 15 of the 16 patients within the 14 days of treatment. Fifteen out of the 16 patients showed a microbiological response: the mean duration between the start of treatment and the first negative blood culture was 12 days.Finally, no patient experienced a marked increase in CPK due to daptomycin use. Conclusion The outcome of this case series of patients receiving colistin-daptomycin combination as part of a broader synergistic antimicrobial regimen to treat XDR A. baumannii was satisfactory, with no significant adverse reactions. This potential clinical benefit of the colistin/daptomycin combination should be further evaluated in a larger comparative study. Disclosures All Authors: No reported disclosures.

We assessed event-free (EFS) and overall (OS) survival in 676 incident cases of childhood Hodgkin (HL) and non-Hodgkin (NHL) lymphoma actively registered in Greece (1996-2019). HL-OS5-year was 96% and NHL-OS5-year 85%, whereas HL-EFS5-year was 86% and NHL-EFS5-year was 81%, notably similar to the respective OS rates (HL: 95%, NHL: 85%) in developed countries. For HL, older age at diagnosis, high maternal education and close proximity to treatment centers were linked to remarkably favorable outcomes. By contrast, stage IV patients showed worse OS and EFS. HL patients with low levels of hemoglobin were associated with worse EFS (hazard ratio: 2.81, 95% confidence intervals: 1.09-7.22). OS (76%) and EFS (73%) were poor among high-risk NHL patients and those with increased LDH (71%). The identified predictors of poor disease outcome point to the need for intensification of individualized treatments. Ongoing clinical cancer registration entailing clinical components could contribute to use of state-of-the-art treatments.

Cynara cardunculus (artichoke) is a perennial plant of the Mediterranean basin, known since antiquity as food and for its therapeutic properties. Cynara is a relatively small genus with two cultivated species and one wild one. Recently, successful efforts have been made to cultivate wild cardoon and monetise it as a bioenergy crop. In this study, the seeds of an established Greek cultivar of C. cardunculus, cultivated in the experimental field and used as biofuel, have been researched for their chemical profile and nutritional value. According to the results, six lignans were isolated [arctigenin, arctiin, trachelogenin, tracheloside, cynarinine, and ethylate of trachelogenin (isolated for the first time from a natural source)] as well as the most characteristic metabolites of the genus (linoleic acid, trilinolein, and 3,5-dicaffeoylquinic acid). Moreover, the total phenolic content (31.18 – 54.51 mg gallic acid equivalents/g extract) and antioxidant and enzyme inhibitory activities of the seeds have been evaluated and showed strong antioxidant properties (44.42 – 516.81 mg gallic acid equivalents/g extract) as well as satisfactory bleaching (enzyme tyrosinase, 16.95 – 23.80 mg kojic acid equivalents/g extract), antidiabetic (enzymes a-amylase, a-glucosidase, 0.14 – 1.75 mmol acarbose equivalents/g extract), and protective against neurodegenerative disease (cholinesterase enzymes, 0.49 – 1.22 mg galanthamine equivalents/g extract) activities. The nutritional evaluation of the seeds confirmed them as a rich source of unsaturated fatty acids, dietary fibre (24.1%), and high protein content (19.3%). It is noteworthy that such a neglected bioactive by-product, with essentially high nutritional value, as the studied seeds could be investigated for its value-added applications towards food and food supplements areas.

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

The two crucial cellular insults that take place during cerebral ischemia are the loss of oxygen and loss of glucose, which can both activate a cascade of events leading to neuronal death. In addition, the toxic overactivation of neuronal excitatory receptors, leading to Ca

Ο επαγόμενος από την υποξία παράγοντας HIF-1 είναι ένας ετεροδιμερής μεταγραφικός παράγοντας που ρυθμίζει την προσαρμογή των κυττάρων σε συνθήκες μειωμένης συγκέντρωσης οξυγόνου. Ο HIF-1 αποτελείται από μια αλφα υπομονάδα (HIF-1α), που επάγεται από την υποξία, και μια βήτα υπομονάδα (HIF-1β ή ARNT) η οποία εκφράζεται συνεχώς. Η σταθερότητα του HIF-1α εξαρτάται από τη συγκέντρωση οξυγόνου αλλά η δράση του HIF-1 ρυθμίζεται και από ανεξάρτητους του οξυγόνου μηχανισμούς που δρουν μέσω μετα-μεταφραστικών τροποποιήσεων, όπως είναι η φωσφορυλίωση. Η κινάση ERK φωσφορυλιώνει τον HIF-1α στην επικράτεια ETD και διεγείρει τη δράση του, αναστέλλοντας την έξοδό του από τον πυρήνα. Στο πρώτο μέρος της παρούσας διατριβής εξατάσθηκε η υπόθεση ότι η έκφραση της επικράτειας ETD ή μεταλλαγμένων μορφών της ως ανασυνδυασμένα ανεξάρτητα πολυπεπτίδια, σε κύτταρα που καλλιεργούνται σε συνθήκες υποξίας είναι δυνατόν να εμποδίσει την φωσφορυλίωση και συνεπώς την ενεργοποίηση του ενδογενούς HIF-1α. Πειράματα με διαφορετικούς πλασμιδιακούς φορείς έκφρασης και σε διαφορετικές κυτταρικές σειρές έδειξαν ότι τα πολυπεπτίδια ETD τα οποία περιέχουν τις θέσεις φωσφορυλίωσης της κινάσης ERK (ETD wt, ETD I→A) ή μετάλλαξη που μιμείται την φωσφορυλίωση (ETD S→E) εντοπίστηκαν κυρίως στον πυρήνα, προκάλεσαν την εξαγωγή του HIF-1α στο κυτταρόπλασμα και μείωσαν σημαντικά την μεταγραφική ενεργότητα του HIF-1 στην υποξία. Αντίθετα, το μεταλλαγμένο πολυπεπτίδιο που δεν μπορεί να φωσφορυλιωθεί από την ERK (ETD S→A) εντοπίστηκε στο κυτταρόπλασμα και δεν επηρέασε σημαντικά τον εντοπισμό και τη δραστικότητα του HIF-1α. Σύμφωνα με αυτά τα αποτελέσματα, η επικράτεια ETD μπορεί πράγματι να χρησιμοποιηθεί ως βάση σχεδίασης ειδικών και αποτελεσματικών πεπτιδικών αναστολέων του HIF-1.Στο δεύτερο μέρος μελετήθηκε η επίδραση της κινάσης CK1δ, που φωσφορυλιώνει την επικράτεια PAS του HIF-1α και αναστέλλει τη δράση του, στον σχηματισμό συμπλόκων HIF-1α/ ARNT σε ακέραια ή ζωντανά κύτταρα, χρησιμοποιώντας τις μικροσκοπικές μεθόδους σύνδεση εγγύτητας in situ (in situ PLA) και επαναφορά φθορισμού μετά από φωτολεύκανση (FRAP), αντίστοιχα. Τα αποτελέσματα έδειξαν ότι η φωσφορυλίωση από τη CK1δ εμποδίζει τον ετεροδιμερισμό του HIF-1α με τον ARNT και την δέσμευσή του στη χρωματίνη. Επιπλέον, με πειράματα ανοσοκατακρήμνισης χρωματίνης δείχθηκε ότι η αναστολή της CK1δ ενισχύει την αλληλεπίδραση του HIF-1α με τον υποκινητή του γονιδίου της λιπίνης-1, ενζύμου που συμμετέχει στη σύνθεση τριγλυκεριδίων στην υποξία. Ταυτόχρονα η αναστολή της CK1δ ενίσχυσε τον σχηματισμό λιποσταγονιδίων και τον πολλαπλασιασμό τόσο καρκινικών όσο και πρωτογενών ανθρώπινων κυττάρων σε συνθήκες υποξίας, με εξαρτώμενο από τον HIF-1α και τη λιπίνη-1 τρόπο. Τα αποτελέσματα αυτά αποκαλύπτουν την εμπλοκή της CK1δ στη μεταβολική προσαρμογή των κυττάρων σε συνθήκες υποξίας και αναδεικνύουν νέους τρόπους ρύθμισης του πολλαπλασιασμού των κυττάρων κατά την υποξία.Συνολικά, τα παραπάνω ευρήματα διελευκάνουν περαιτέρω τη ρύθμιση της δράσης του HIF-1 μέσω φωσφορυλίωσης από τις κινάσες ERK1/2 και CK1δ και επιτρέπουν την ανάπτυξη νέων θεραπευτικών προσεγγίσεων σε παθολογικές καταστάσεις όπως ο καρκίνος, όπου είναι απαραίτητη η καταστολή της δράσης του HIF-1α, ή οι ισχαιμικές παθήσεις, όπου, αντίθετα, είναι επιθυμητή η ενίσχυση της λειτουργίας του HIF-1.

Introduction Altered maternal inflammatory responses may play a role in the development of hypertensive disorders of pregnancy like preeclampsia, its more severe early-onset form and intrauterine growth restriction. We evaluated the relation of common allelic variants of Toll-like receptor 4 (TLR4), known to impair the inflammatory response, with the susceptibility to early-onset preeclampsia in Central Greece. Methods We compared the occurrence of TLR4 (Asp299Gly and Thr399Ile) alleles in heterozygous (A/G, C/T) and homozygous (G/G, T/T) states in 84 women with a history of early-onset preeclampsia and 94 age matched controls with a history of only uneventful pregnancies, by direct sequencing. Results Heterozygous TLR4 allelic variants were more common in women with a history of early-onset preeclampsia than in controls (GA for Asp299Gly: 14.3% vs 6.4% (AA), p = 0.053 & CT for Thr399Ile: 16.7% vs. 6.4% (CC), p = 0.019) and a stronger association was obtained when homozygous allelic carriers were also included (GA/GG for Asp299Gly: 16.7% vs. 6.4% (AA), p = 0.03 & TC/TT for Thr399Ile: 19.0% vs. 6.4% (CC), p = 0.01). Discussion We recorded association between common TLR4 gene variants and early-onset preeclampsia. Our findings support the involvement of maternal innate immune system in severe hypertensive disorders of pregnancy and point to the potential value of maternal TLR4 polymorphisms as predictors-risk factors of susceptibility to early-onset preeclampsia in Central Greece.

miRNAs are small non-coding RNA molecules that participate through silencing in post-transcriptional regulation of gene expression. Recent studies have highlighted the importance of microRNAs (miRNAs) as regulators of both the innate and the adaptive immune response. There are emerging data regarding the role of miRNAs in patients with Systemic Lupus Erythematosus (SLE). One of the main stimuli for the induction of miR-21 is hypoxia. Moreover, the expression and function of miR-210 is directly related to the activity of "hypoxia inducible factor-1a" (HIF-1a). The aim of the study is to examine the regulation of miR-21 and mir-210 in patients with SLE based on the hypothesis that cellular hypoxia may have an important role in SLE pathogenesis. Plasma, PBMC and urine samples will be collected from patients with SLE and normal controls. miR expression will be studied with real-time PCR. Functional experiments will examine the effect of miR-21 and miR- 210 on HIFa and ERK1/2 και PI3K/AKT signalling pathways. The study will provide novel data regarding the expression and the role of miR-21 and miR-210 in patients with SLE. The results of the study will contribute to a better understanding of miR network regulation in SLE in order to ultimately identify molecules that can be used in clinical practice as diagnostic or prognostic markers, treatment response markers, or even as potential future therapeutic targets.

Hypoxia is frequently encountered in the microenvironment of solid tumors. Hypoxia-inducible factors (HIFs), the main effectors of cell response to hypoxia, promote cancer cell survival and progression. HIF-1α, the oxygen-regulated subunit of HIF-1, is often correlated with oncogenesis and represents an attractive therapeutic target. We have previously reported that activation HIF-1α by ERK involves modification of two serine residues and masking of a nuclear export signal (NES), all inside a 43-amino acid domain termed ERK Targeted Domain (ETD). Overexpression of ETD variants including wild-type, phospho-mimetic (SE) or NES-less (IA) mutant forms caused HIF-1 inactivation in two hepatocarcinoma cell lines, while a phospho-deficient (SA) form was ineffective and acted as a sequence-specific negative control. To deliver these ETD forms directly into cancer cells, they were fused to the HIV TAT-sequence and produced as cell-permeable peptides. When the TAT-ETD peptides were added to the culture medium of Huh7 cells, they entered the cells and, with the exception of ETD-SA, accumulated inside the nucleus, caused mislocalization of endogenous HIF-1α to the cytoplasm, significant reduction of HIF-1 activity and inhibition of expression of specific HIF-1, but not HIF-2, gene targets under hypoxia. More importantly, transduced nuclear TAT-ETD peptides restricted migration, impaired colony formation and triggered apoptotic cell death of cancer cells grown under hypoxia, while they produced no effects in normoxic cells. These data demonstrate the importance of ERK-mediated activation of HIF-1 for low oxygen adaptation and the applicability of ETD peptide derivatives as sequence-specific HIF-1 and cancer cell growth inhibitors under hypoxia.

Background: Previous studies have shown that children and adolescents with COVID-19 generally have mild disease. Children and adolescents with cancer, however, can have severe disease when infected with respiratory viruses. In this study, we aimed to understand the clinical course and outcomes of SARS-CoV-2 infection in children and adolescents with cancer. Methods: We did a cohort study with data from 131 institutions in 45 countries. We created the Global Registry of COVID-19 in Childhood Cancer to capture de-identified data pertaining to laboratory-confirmed SARS-CoV-2 infections in children and adolescents (

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

The early onset of childhood acute lymphoblastic leukemia (ALL) suggests that critical exposures occurring during pregnancy may increase risk. We investigated the effects of maternal coffee and tea consumption during pregnancy on ALL risk by pooling data from eight case–control studies participating in the Childhood Leukemia International Consortium. Data on maternal coffee intake were available for 2,552 cases and 4,876 controls, and data on tea intake were available for 2,982 cases and 5,367 controls. Coffee and tea intake was categorized into 0, > 0–1, > 1–2, and > 2 cups/day, and covariates were combined and harmonized. Data on genetic variants in NAT2, CYP1A1, and NQO1 were also available in a subset. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression, and linear trends across categories were assessed. No association was seen with ‘any’ maternal coffee consumption during pregnancy, but there was evidence of a positive exposure–response; the pooled OR for > 2 cups/day versus none was 1.27 (95% CI 1.09–1.43), p trend = 0.005. No associations were observed with tea consumption. No interactions were seen between coffee or tea intake and age, maternal smoking or genotype, and there was little or no evidence that associations with coffee or tea differed among cases with and without chromosomal translocations. Despite some limitations, our findings suggest that high coffee intake during pregnancy may increase risk of childhood ALL. Thus, current advice to limit caffeine intake during pregnancy to reduce risk of preterm birth may have additional benefits.

Background Antifungal prophylaxis (AFP) is recommended in at-risk hematology-oncology patients. We evaluated the safety of AFP with voriconazole (VRC) in pediatric hematology/oncology patients. Materials and methods A retrospective study of VRC AFP in children with malignancies hospitalized in all 7 Greek pediatric hematology/oncology centers during 2008 to 2012 was conducted. Patients' demographics, outcome, and adverse event (AE) data were recorded. Results Four hundred twenty-nine VRC AFP courses in 249 patients (median age 6 y, 55% boys) were studied. The most common underlying diseases were acute lymphoblastic leukemia (51%), non Hodgkin lymphoma (8.6%), and acute myeloid leukemia (7.7%). The median number of VRC courses per patient was 1.7, whereas the median VRC dose was 7 mg/kg (range, 5 to 7 mg/kg) every 12 hours. During the last 2 weeks before AFP, 51% of the patients had received corticosteroids, 43% suffered from severe neutropenia, and 17.3% from mucositis. The median duration of VRC AFP was 17 days (range, 1 to 31 d). A single breakthrough fungemia due to Candida glabrata was recorded. Only 1 patient died due to the underlying disease. The most common AEs reported in 70/429 (16.3%) courses with ≥1 AE were elevated liver enzymes (50%), hypokalemia (24.3%), and ophthalmological disorders (14.3%). The median time of AE onset was 5 days (range, 1 to 21 d). Among 70 AEs reported, 38.5%, 48.4%, and 12.8% were of grade I, II, and III, respectively. Conclusions VRC prophylaxis in pediatric hematology/oncology patients appears to be well tolerated.

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.

Evidence for an association of foetal growth with acute myeloid leukaemia (AML) is inconclusive. AML is a rare childhood cancer, relatively more frequent in girls, with distinct features in infancy. In the context of the Childhood Leukemia International Consortium (CLIC), we examined the hypothesis that the association may vary by age, sex and disease subtype using data from 22 studies and a total of 3564 AML cases.Pooled estimates by age, sex and overall for harmonised foetal growth markers in association with AML were calculated using the International Fetal and Newborn Growth Consortium for the 21st Century Project for 17 studies contributing individual-level data; meta-analyses were, thereafter, conducted with estimates provided ad hoc by five more studies because of administrative constraints. Subanalyses by AML subtype were also performed.A nearly 50% increased risk was observed among large-for-gestational-age infant boys (odds ratio [OR]: 1.49, 95% confidence interval [CI]: 1.03-2.14), reduced to 34% in boys aged2 years (OR: 1.34, 95% CI: 1.05-1.71) and 25% in boys aged 0-14 years (OR: 1.25, 95% CI: 1.06-1.46). The association of large for gestational age became stronger in boys with M0/M1subtype (OR: 1.80, 95% CI: 1.15-2.83). Large birth length for gestational age was also positively associated with AML (OR: 1.38, 95% CI: 1.00-1.92) in boys. By contrast, there were null associations in girls, as well as with respect to associations of decelerated foetal growth markers.Accelerated foetal growth was associated with AML, especially in infant boys and those with minimally differentiated leukaemia. Further cytogenetic research would shed light into the underlying mechanisms.

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 OS5-year exceeded 80% in patients 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.

PurposeTo 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. ResultsOverall age-adjusted incidence rate was higher in SEE (16.9/106) compared to SEER (13.6/106), because of a higher incidence of Hodgkin (HL, 7.5/106 vs. 5.1/106) and Burkitt lymphoma (BL, 3.1 vs. 2.3/106), whereas the incidence of non-Hodgkin lymphoma (NHL) was overall identical (5.9/106 vs. 5.8/106), 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.

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 (1.02/106), 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.

Background Transient hyperglycemia (TH) represents an acknowledged adverse event that occurs during treatment in children with acute lymphoblastic leukemia (ALL) and has recently been associated with an increased risk for developing metabolic disturbances in future life. Our aim was to estimate the incidence of TH and to identify risk factors, thus serving as markers for identifying candidates for prevention interventions. Procedure All patients treated with induction treatment for ALL in our department from January 2004 to April 2015 had their data retrieved from medical files and retrospectively analyzed. Results One hundred and two children with ALL treated at our department were identified (49 females and 53 males) with a mean age of 6.03 ± 3.78 years at the time of diagnosis. Sixteen patients developed TH (15.68%). Age at diagnosis >10 years is associated with an 11-fold increase in the risk of developing TH. Additionally, fasting glucose on the eighth day of treatment is an important prognostic factor as fasting glucose >100 mg/dl at that time point is associated with a threefold increase in developing TH during residual treatment period. Conclusions Fasting glucose levels >110 mg/dl on the eighth day of treatment could serve as a trigger for intervention strategies that will prevent the development of TH in pediatric patients treated for ALL. Additional studies are needed to confirm and further extend this preliminary observation.

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.

Objective To systematically review studies and meta-analyze the literature on the association of maternal and/or index child's coffee, tea, and cola consumption with subsequent development of childhood leukemia and its major subtypes. Methods Eligible studies were identified through a detailed algorithm and hand-search of eligible articles' references; thereafter, summary-effect estimates were calculated by leukemia subtype and dose-response meta-analyses were performed. Results Twelve case-control studies, comprising a total of 3649 cases and 5705 controls, were included. High maternal coffee consumption was positively associated with acute lymphoblastic leukemia (ALL; OR: 1.43, 95%CI: 1.22-1.68) and acute myeloid leukemia (AML; OR: 2.52, 95%CI: 1.59-3.57). Any or low to moderate maternal cola consumption was also positively associated with overall leukemia (AL) and ALL, A linear trend between coffee and cola consumption and childhood leukemia was observed in the dose-response analyses. On the contrary, low to moderate tea consumption was inversely associated with AL (OR: 0.85, 95%CI: 0.75-0.97), although the trend was non-significant. A null association between offspring's cola consumption and leukemia was noted. Conclusions Our findings confirm the detrimental association between maternal coffee consumption and childhood leukemia risk and provide indications for a similar role of maternal cola intake. In contrast, an inverse association with tea was found, implying that other micronutrients contained in this beverage could potentially counterbalance the deleterious effects of caffeine. Further research should focus on the intake of specific micronutrients, different types of coffee and tea, specific immunophenotypes of the disease, and the modifying effect of genetic polymorphisms.

Neuroblastoma comprises the most common neoplasm during infancy (first year of life). Our study describes incidence of neuroblastoma in Southern- Eastern Europe (SEE), including - for the first time - the Nationwide Registry for Childhood Hematological Malignancies and Solid Tumors (NARECHEM-ST)/Greece, compared to the US population, while controlling for human development index (HDI). Age-adjusted incidence rates (AIR) were calculated for 1, 859 childhood (0-14 years) neuroblastoma cases, retrieved from 13 collaborating SEE registries (1990-2016), and were compared to those of SEER/US (N = 3, 166 ; 1990-2012) ; temporal trends were assessed using Poisson regression and Joinpoint analyses. The overall AIR was significantly lower in SEE (10.1/million) compared to SEER (11.7 per million) ; the difference was maximum during infancy (43.7 vs. 53.3 per million, respectively), when approximately one-third of cases were diagnosed. Incidence rates of neuroblastoma at ages

Background Despite the putative intrauterine origins of childhood (0–14 years) leukaemia, it is complex to assess the impact of perinatal factors on disease onset. Results on the association of maternal history of fetal loss (miscarriage/stillbirth) with specific disease subtypes in the subsequent offspring are in conflict. We sought to investigate whether miscarriage and stillbirth may have different impacts on the risk of acute lymphoblastic leukaemia (ALL) and of its main immunophenotypes (B-cell and T-cell ALL), as contrasted to acute myeloid leukaemia (AML). Methods One thousand ninety-nine ALL incidents (957 B-ALL) and 131 AML cases along with 1:1 age and gender-matched controls derived from the Nationwide Registry for Childhood Hematological Malignancies and Brain Tumors (1996–2013) were studied. Multivariable regression models were used to assess the roles of previous miscarriage(s) and stillbirth(s) on ALL (overall, B-, T-ALL) and AML, controlling for potential confounders. Results Statistically significant exposure and disease subtype-specific associations of previous miscarriage(s) exclusively with AML [odds ratio (OR) 1.67, 95% confidence interval (CI) 1.00, 2.81] and stillbirth(s) with ALL [OR 4.82, 95% CI 1.63, 14.24] and B-ALL particularly, emerged. Conclusion Differential pathophysiological pathways pertaining to genetic polymorphisms or cytogenetic aberrations are likely to create hostile environments leading either to fetal loss or the development of specific leukaemia subtypes in subsequent offspring, notably distinct associations of maternal miscarriage history confined to AML and stillbirth history confined to ALL (specifically B-ALL). If confirmed and further supported by studies revealing underlying mechanisms, these results may shed light on the divergent leukemogenesis processes.

Despite advancements in the treatment of childhood leukemia, socioeconomic status (SES) may potentially affect disease prognosis. This study aims to evaluate whether SES is associated with survival from childhood leukemia.The US National Cancer Institute Surveillance, Epidemiology and End Results Program (SEER) 1973-2010 data were analyzed; thereafter, results were meta-analyzed along with those from survival (cohort) studies examining the association between SES indices and survival from childhood leukemia (end-of-search date: 31 March 2014). Random-effects models were used to calculate pooled effect estimates (relative risks, RRs); meta-regression was also used.We included 29 studies yielding 28 804 acute lymphoblastic leukemia (ALL), 3208 acute myeloblastic leukemia (AML) and 27 650 'any' leukemia (denoting joint reporting of all subtypes) cases. According to individual-level composite SES indices, children from low SES suffered from nearly twofold higher death rates from ALL (pooled RR: 1.83, 95% confidence interval 1.00-3.34, based on four study arms); likewise, death RRs derived from an array of lower area-level SES indices ranged between 1.17 and 1.33 (based on 11 study arms). Importantly, the survival gap between higher and lower SES seemed wider in the United States, with considerably (by 20%-82%) increased RRs for death from ALL in lower SES. Regarding AML, poorer survival was evident only when area-level SES indices were used. Lastly, remoteness indices were not associated with survival from childhood leukemia.Children with lower SES suffering childhood leukemia do not seem to equally enjoy the impressive recent survival gains. Special health policy strategies and increased awareness of health providers might minimize the effects of socioeconomic disparities.

AIM: Neuroblastoma outcomes vary with disease characteristics, healthcare delivery and socio- economic indicators. We assessed survival patterns and prognostic factors for patients with neuroblastoma in 11 Southern and Eastern European (SEE) countries versus those in the US, including-for the first time-the Nationwide Registry for Childhood Hematological Malignancies and Solid Tumours (NARECHEM-ST)/Greece. METHODS: Overall survival (OS) was calculated in 13 collaborating SEE childhood cancer registries (1829 cases, ∼1990-2016) and Surveillance, Epidemiology, and End Results (SEER), US (3072 cases, 1990-2012) ; Kaplan-Meier curves were used along with multivariable Cox regression models assessing the effect of age, gender, primary tumour site, histology, Human Development Index (HDI) and place of residence (urban/rural) on survival. RESULTS: The 5-year OS rates varied widely among the SEE countries (Ukraine: 45%, Poland: 81%) with the overall SEE rate (59%) being significantly lower than in SEER (77% ; p < 0.001). In the common registration period within SEE (2000-2008), no temporal trend was noted as opposed to a significant increase in SEER. Age >12 months (hazard ratio [HR]: 2.8-4.7 in subsequent age groups), male gender (HR: 1.1), residence in rural areas (HR: 1.3), living in high (HR: 2.2) or medium (HR: 2.4) HDI countries and specific primary tumour location were associated with worse outcome ; conversely, ganglioneuroblastoma subtype (HR: 0.28) was associated with higher survival rate. CONCLUSIONS: Allowing for the disease profile, children with neuroblastoma in SEE, especially those in rural areas and lower HDI countries, fare worse than patients in the US, mainly during the early years after diagnosis ; this may be attributed to presumably modifiable socio-economic and healthcare system performance differentials warranting further research.

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.