TULIPs decorate the three-dimensional genome of PFA ependymoma.

Posterior fossa group A (PFA) ependymoma is a lethal brain cancer diagnosed in infants and young children. The lack of driver events in the PFA linear genome led us to search its 3D genome for characteristic features. Here, we reconstructed 3D genomes from diverse childhood tumor types and uncovered a global topology in PFA that is highly reminiscent of stem and progenitor cells in a variety of human tissues. A remarkable feature exclusively present in PFA are type B ultra long-range interactions in PFAs (TULIPs), regions separated by great distances along the linear genome that interact with each other in the 3D nuclear space with surprising strength. TULIPs occur in all PFA samples and recur at predictable genomic coordinates, and their formation is induced by expression of EZHIP. The universality of TULIPs across PFA samples suggests a conservation of molecular principles that could be exploited therapeutically.

Head-to-head comparison of influenza vaccines in children: a systematic review and meta-analysis.

Although vaccination is considered the most effective weapon against influenza, coverage rates, national vaccination policies, and funding vary largely around the globe. Despite their huge potential for achieving herd immunity, child-focused national vaccination strategies that favor pain-free nasal vaccines are uncommon. CENTRAL, Embase, and MEDLINE were last searched on November 13, 2023. Active-controlled randomized controlled trials comparing the live-attenuated intranasal vaccine with the inactivated intramuscular influenza vaccine in children were included. Event rates of laboratory-confirmed influenza virus infection, all-cause mortality, hospitalization, serious adverse events, adverse events, and financial outcomes were extracted based on the PRISMA 2020 Guideline. PROSPERO: CRD42021285412. Pooled odds ratios (ORs) with 95% confidence intervals (CI) were calculated using the random-effects model when at least three comparable outcomes were available. We found no significant difference between quadrivalent live-attenuated intranasal and trivalent inactivated intramuscular (OR = 1.48; 95% CI 0.49-4.45) or between trivalent live-attenuated intranasal and inactivated intramuscular vaccines (OR = 0.77, CI = 0.44-1.34) regarding their efficacy. However, the subgroup analysis of large, multi-center trials indicated that the trivalent live attenuated intranasal influenza vaccine was superior to the trivalent inactivated intramuscular influenza vaccine (12,154 people, OR = 0.50, CI = 0.28-0.88). Only 23 "vaccine-related serious adverse events" were recorded among 17 833 individuals, with no significant difference between methods. The widespread initiation of pediatric national flu vaccination programs prioritizing the live-attenuated intranasal influenza vaccine would be beneficial. Multi-continent, high-quality studies that include children younger than two years old and those living in subtropical and tropical regions are needed to further enhance our understanding.

Cesarean delivery is associated with lower neonatal mortality among breech pregnancies: a systematic review and meta-analysis of preterm deliveries ≤32 weeks of gestation.

OBJECTIVE: To investigate the association between actual and planned modes of delivery, neonatal mortality, and short-term outcomes among preterm pregnancies ≤32 weeks of gestation. DATA SOURCES: A systematic literature search was conducted in 3 main databases (PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials from inception to November 16, 2022. The protocol was registered in advance in the International Prospective Register of Systematic Reviews (CRD42022377870). STUDY ELIGIBILITY CRITERIA: Eligible studies examined pregnancies ≤32nd gestational week. All infants received active care, and the outcomes were reported separately by different modes of delivery. Singleton and twin pregnancies at vertex and breech presentations were included. Studies that included pregnancies complicated with preeclampsia and abruptio placentae were excluded. Primary outcomes were neonatal mortality and intraventricular hemorrhage. STUDY APPRAISAL AND SYNTHESIS METHODS: Articles were selected by title, abstract, and full text, and disagreements were resolved by consensus. Random effects model-based odds ratios with corresponding 95% confidence intervals were calculated for dichotomous outcomes. Risk Of Bias In Non-randomized Studies - of Interventions-I was used to assess the risk of bias. RESULTS: A total of 19 observational studies were included involving a total of 16,042 preterm infants in this systematic review and meta-analysis. Actual cesarean delivery improves survival (odds ratio, 0.62; 95% confidence interval, 0.42-0.9) and decreases the incidence of intraventricular hemorrhage (odds ratio, 0.70; confidence interval, 0.57-0.85) compared to vaginal delivery. Planned cesarean delivery does not improve the survival of very and extremely preterm infants compared to vaginal delivery (odds ratio, 0.87; 95% confidence interval, 0.53-1.44). Subset analysis found significantly lower odds of death for singleton breech preterm deliveries born by both planned (odds ratio, 0.56; 95% confidence interval, 0.32-0.98) and actual (odds ratio, 0.34; 95% confidence interval, 0.13-0.88) cesarean delivery. CONCLUSION: Cesarean delivery should be the mode of delivery for preterm ≤32 weeks of gestation breech births due to the higher mortality in preterm infants born via vaginal delivery.

Umbilical cord management in newborn resuscitation: a systematic review and meta-analysis.

BACKGROUND: Evidence supporting the benefits of delayed cord clamping is increasing; however, there is no clear recommendation on cord management during newborn resuscitation. This study aimed to investigate the effects of resuscitation initiated with an intact umbilical cord, hypothesizing it is a safe stabilization procedure that improves neonatal outcomes. METHODS: Systematic search was conducted in MEDLINE, Embase, CENTRAL, and Web of Science from inception to March 1, 2024. Eligible articles compared neonatal outcomes in newborns receiving initial stabilization steps before and after cord clamping. RESULTS: Twelve studies met our inclusion criteria, with six RCTs included in the quantitative analysis. No statistically significant differences were found in delivery room parameters, in-hospital mortality, or neonatal outcomes between the examined groups. However, intact cord resuscitation group showed higher SpO2 at 5 min after birth compared to cord clamping prior to resuscitation group (MD 6.67%, 95% CI [-1.16%, 14.50%]). There were no significant differences in early complications of prematurity (NEC ≥ stage 2: RR 2.05, 95% CI [0.34, 12.30], IVH: RR 1.25, 95% CI [0.77, 2.00]). CONCLUSION: Intact cord management during resuscitation appears to be a safe intervention; its effect on early complications of prematurity remains unclear. Further high-quality RCTs with larger patient numbers are urgently needed. IMPACT: Initiating resuscitation with an intact umbilical cord appears to be a safe intervention for newborns. No statistically significant differences were found in delivery room parameters, in-hospital mortality, and neonatal outcomes between the examined groups. The utilization of specialized resuscitation trolleys appears to be promising to reduce the risk of intraventricular hemorrhage in preterm infants. Further high-quality RCTs with larger sample sizes are urgently needed to refine recommendations.

The histologic fetal inflammatory response and neonatal outcomes: systematic review and meta-analysis.

OBJECTIVE: This study aimed to investigate the prognostic role of concomitant histological fetal inflammatory response with chorioamnionitis on neonatal outcomes through a systematic review and meta-analysis of existing literature. DATA SOURCES: The primary search was conducted on October 17, 2021, and it was updated on May 26, 2023, across 4 separate databases (MEDLINE, the Cochrane Central Register of Controlled Trials, Embase, and Scopus) without using any filters. STUDY ELIGIBILITY CRITERIA: Observational studies reporting obstetrical and neonatal outcomes of infant-mother dyads with histological chorioamnionitis and histological fetal inflammatory response vs infant-mother dyads with histological chorioamnionitis alone were eligible. Studies that enrolled only preterm neonates, studies on neonates born before 37 weeks of gestation, or studies on neonates with very low birthweight (birthweight <1500 g) were included. The protocol was registered with the International Prospective Register of Systematic Reviews (registration number: CRD42021283448). METHODS: The records were selected by title, abstract, and full text, and disagreements were resolved by consensus. Random-effect model-based pooled odds ratios with corresponding 95% confidence intervals were calculated for dichotomous outcomes. RESULTS: Overall, 50 studies were identified. A quantitative analysis of 14 outcomes was performed. Subgroup analysis using the mean gestational age of the studies was performed, and a cutoff of 28 weeks of gestation was implemented. Among neonates with lower gestational ages, early-onset sepsis (pooled odds ratio, 2.23; 95% confidence interval, 1.76-2.84) and bronchopulmonary dysplasia (pooled odds ratio, 1.30; 95% confidence interval, 1.02-1.66) were associated with histological fetal inflammatory response. Our analysis showed that preterm neonates with a concomitant histological fetal inflammatory response are more likely to develop intraventricular hemorrhage (pooled odds ratio, 1.54; 95% confidence interval, 1.18-2.02) and retinopathy of prematurity (pooled odds ratio, 1.37; 95% confidence interval, 1.03-1.82). The odds of clinical chorioamnionitis were almost 3-fold higher among infant-mother dyads with histological fetal inflammatory response than among infant-mother dyads with histological chorioamnionitis alone (pooled odds ratio, 2.99; 95% confidence interval, 1.96-4.55). CONCLUSION: This study investigated multiple neonatal outcomes and found association in the case of 4 major morbidities: early-onset sepsis, bronchopulmonary dysplasia, intraventricular hemorrhage, and retinopathy of prematurity.

Superimposed Mosaicism in the Form of Extremely Extended Segmental Plexiform Neurofibroma Caused by a Novel Pathogenic Variant in the NF1 Gene.

Plexiform neurofibromas occurring in approximately 20-50% of all neurofibromatosis type-1 (NF1) cases are histologically benign tumors, but they can be fatal due to compression of vital structures or transformation to malignant sarcomas or malignant peripheral nerve sheath tumors. All sizeable plexiform neurofibromas are thought to result from an early second mutation giving rise to a loss of heterozygosity of the NF1 gene. In this unusual case, a 12-year-old girl presented with a rapidly growing, extremely extensive plexiform neurofibroma with segmental distribution over the entire right arm, extending to the right chest wall and mediastinum, superimposed on classic cutaneous lesions of NF1. After several surgical interventions, the patient was efficiently treated with an oral selective MEK inhibitor, selumetinib, which resulted in a rapid reduction of the tumor volume. Molecular analysis of the NF1 gene revealed a c.2326-2 A>G splice-site mutation in the clinically unaffected skin, peripheral blood sample, and plexiform neurofibroma, which explains the general clinical symptoms. Furthermore, a novel likely pathogenic variant, c.4933dupC (p.Leu1645Profs*7), has been identified exclusively in the girl's plexiform neurofibromas. This second-hit mutation can explain the extremely extensive segmental involvement.

Germline MUTYH mutations and high-grade gliomas: Novel evidence for a potential association.

There is growing body of evidence supporting the role of germline mutations in the pathogenesis of pediatric central nervous system (CNS) tumors, and the widespread use of next-generation sequencing (NGS) panels facilitates their detection. Variants of the MUTYH gene are increasingly recognized as suspected germline background of various extraintestinal malignancies, besides their well-characterized role in the polyposis syndrome associated with biallelic mutations. Using a multigene NGS panel (Illumina TruSight Oncology 500), we detected one H3 G34V- and one H3 K27M-mutant pediatric high-grade diffuse glioma, in association with c.1178G>A (p.G393D) and c.916C>T (p.R306C) MUTYH variants, respectively. Both MUTYH mutations were germline, heterozygous and inherited, according to the subsequent genetic testing of the patients and their first-degree relatives. In the H3 K27M-mutant glioma, amplifications affecting the 4q12 region were also detected, in association with KDR-PDGFRA, KIT-PDGFRA, and KDR-CHIC2 fusions, previously unreported in this entity. Among 47 other CNS tumors of various histological types tested with the same NGS panel in our institution, only one adult glioblastoma harbored MUTYH mutation. Together with a single previous report, our data raises the possibility of an association between germline MUTYH mutations and CNS malignancies, particularly in pediatric histone H3-mutant gliomas.

The Effect of Nutritional Support on the Disease Progression and Survival in Pediatric Patients with Solid Tumors.

Cancer is one of the leading causes of death for children; however, appropriate nutritional status can positively affect survival. The aim of this study was to determine to what extent malnutrition risk screening and intensified nutrition support, provided by a professional team, promoted disease progression and survival in pediatric patients with solid tumors. 145 pediatric cancer patients (average age 6.3 ± 5.6 and 6.7 ± 5.4 years) with solid tumors undergoing chemotherapy participated in the study. Two 3-year periods were studied: 2009-2011 and 2012-2014. Patient characteristics and treatment protocols were identical, but in Period 2, with the foundation of our nutrition support team malnutrition risk screening was made mandatory upon every hospital admission. As a result of intensified nutrition support the time from diagnosis to completion of treatment (802 vs. 512 day, p < 0.001) and the need for antimycotic treatment reduced significantly (47.8% vs. 29.1%, p = 0.036). The total percentage of surviving children was 60.3% and 75.0% in Period 1 and 2 respectively. Decrease in weight-for-height percentile during treatment and central nervous system tumors are significant predictors of a less favorable survival. Malnutrition risk screening and intensified nutrition therapy have positive effects on nutritional status and therefore patient survival in pediatric cancer patients.

Final results of the Choroid Plexus Tumor study CPT-SIOP-2000.

INTRODUCTION: Standards for chemotherapy against choroid plexus tumors (CPT) have not yet been established. METHODS: CPT-SIOP-2000 (NCT00500890) was an international registry for all CPT nesting a chemotherapy randomization for high-risk CPT with Carboplatin/Etoposide/Vincristine (CarbEV) versus Cyclophosphamide/Etoposide/Vincristine (CycEV). Patients older than three years were recommended to receive irradiation: focal fields for non-metastatic CPC, incompletely resected atypical choroid plexus papilloma (APP) or metastatic choroid plexus papilloma (CPP); craniospinal fields for metastatic CPC/APP and non-responsive CPC. High risk was defined as choroid plexus carcinoma (CPC), incompletely resected APP, and all metastatic CPT. From 2000 until 2010, 158 CPT patients from 23 countries were enrolled. RESULTS: For randomized CPC, the 5/10 year progression free survival (PFS) of patients on CarbEV (n = 20) were 62%/47%, respectively, compared to 27%/18%, on CycEV (n = 15), (intention-to-treat, HR 2.6, p = 0.032). Within the registry, histological grading was the most influential prognostic factor: for CPP (n = 55) the 5/10 year overall survival (OS) and the event free survival (EFS) probabilities were 100%/97% and 92%/92%, respectively; for APP (n = 49) 96%/96% and 76%/76%, respectively; and for CPC (n = 54) 65%/51% and 41%/39%, respectively. Without irradiation, 12 out of 33 patients with CPC younger than three years were alive for a median of 8.52 years. Extent of surgery and metastases were not independent prognosticators. CONCLUSIONS: Chemotherapy for Choroid Plexus Carcinoma is feasible and effective. CarbEV is superior to CycEV. A subset of CPC can be cured without irradiation.

Complement-mediated hypersensitivity reactions to an amphotericin B-containing lipid complex (Abelcet) in pediatric patients and anesthetized rats: Benefits of slow infusion.

Intravenous administration of lipid-based nanodrugs can cause hypersensitivity, also known as infusion reactions (IRs), that can be attenuated by slow infusion in adult patients. We studied the role of infusion rate and complement (C) activation in IRs in pediatric patients treated with Abelcet, and also in anesthetized rats. IRs were observed in 6 out of 10 (60%) patients who received Abelcet infusion in 4 h or less, while no patients who received the infusion in 6 h showed C activation or IRs. The rat model indicated an inverse relationship between infusion speed and Abelcet-induced hypotension, taken as an experimental endpoint of IRs, while the rise of C3a in blood, an index of C activation, directly correlated with hypotension. The results suggest that pediatric patients are more prone to produce IRs, and that the optimal infusion time of Abelcet may be much longer than the presently recommended 2 h.

Examining the Vitamin D Status of Children With Solid Tumors.

Objective: Our aims were to compare the vitamin D status of children with and without cancer and to examine the possible correlation between vitamin D levels in children with cancer before initiating treatment and prognosis.Method: We compared the data of 173 children with cancer with those of 569 children without cancer.Results: We measured a significant difference (p = 1.34E-08) between the vitamin D levels of children with cancer before treatment and children without cancer. There was a significant correlation between the initial vitamin D levels of children with cancer and the prognosis (p = 0.016, odds ratio = 51.33) at 5% significance.Conclusions: The average vitamin D level was 19.76% lower in the population with cancer compared with the average of the control group, and we found a correlation between the lower vitamin D levels in children with cancer and the adverse prognosis. We suggest that supplying vitamin D is reasonable and a prospective study of vitamin D in pediatric patients with cancer is recommended.

Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma.

Glioblastoma multiforme (GBM) is a lethal brain tumour in adults and children. However, DNA copy number and gene expression signatures indicate differences between adult and paediatric cases. To explore the genetic events underlying this distinction, we sequenced the exomes of 48 paediatric GBM samples. Somatic mutations in the H3.3-ATRX-DAXX chromatin remodelling pathway were identified in 44% of tumours (21/48). Recurrent mutations in H3F3A, which encodes the replication-independent histone 3 variant H3.3, were observed in 31% of tumours, and led to amino acid substitutions at two critical positions within the histone tail (K27M, G34R/G34V) involved in key regulatory post-translational modifications. Mutations in ATRX (α-thalassaemia/mental retardation syndrome X-linked) and DAXX (death-domain associated protein), encoding two subunits of a chromatin remodelling complex required for H3.3 incorporation at pericentric heterochromatin and telomeres, were identified in 31% of samples overall, and in 100% of tumours harbouring a G34R or G34V H3.3 mutation. Somatic TP53 mutations were identified in 54% of all cases, and in 86% of samples with H3F3A and/or ATRX mutations. Screening of a large cohort of gliomas of various grades and histologies (n = 784) showed H3F3A mutations to be specific to GBM and highly prevalent in children and young adults. Furthermore, the presence of H3F3A/ATRX-DAXX/TP53 mutations was strongly associated with alternative lengthening of telomeres and specific gene expression profiles. This is, to our knowledge, the first report to highlight recurrent mutations in a regulatory histone in humans, and our data suggest that defects of the chromatin architecture underlie paediatric and young adult GBM pathogenesis.

Cognitive deficits and psychopathological symptoms among children with medulloblastoma.

Children with medulloblastoma (MB) are predisposed for negative cognitive sequela, which has been widely identified in this population. The purpose of the present study was to explore cognitive deficits and psychopathological symptoms and analyse their relation among MB survivors. The Wechsler Intelligence Scale for Children and the Mini International Neuropsychiatric Interview (MINI-KID) was administered to 34 MB survivors to measure cognitive functioning and psychopathological symptoms. The MB survivors had lower global IQ (86.41 [79.70-93.13]) compared with the control population mean. We found impaired functioning in all IQ subscales in the MB survivors group, of which processing speed (84.15 [77.71-90.58]) was the most affected. Higher radiation dose and high-dose chemotherapy with stem cell rescue were significantly associated factors for lowered global IQ, while age at diagnosis, sex and time period from diagnosis were not significantly associated. Compulsive disorder, generalised anxiety, separation anxiety and posttraumatic stress disorder were significantly more prevalent in the MB survivor group than a group of 46 control participants. No correlation was found between the cognitive deficits and the psychopathological symptoms. Our results identify that MB survivors suffer from cognitive and psychopathological impairments, and these could exist independently from each other.

[Survival of pediatric patients with Ewing sarcoma treated at Semmelweis University]. / A Semmelweis Egyetemen kezelt Ewing-szarkómás gyermekek kezelési eredményeinek vizsgálata.

The survival of children treated with Ewing sarcoma at Semmelweis University were investigated. Pediatric patients with Ewing sarcoma treated at Semmelweis University from 2001 through 2013 were analyzed in terms of overall survival and clinical factors (age, primary localization and extent of the tumor, time interval from primary complaints to diagnosis). For statistical analysis Kaplan-Meier estimated survival and log rank test were applied. Mean age and follow-up time of the 78 patients were 11.16 and 6.29 years, respectively. In 57% of patients time interval from primary symptoms to diagnosis was less than half year. In 53.8% of the patients the disease was metastatic at primary diagnosis (pulmonary only: 29.5%, any other: 24.3%). 5- and 10-year overall survival of patients were 68.1% and 60.4%, respectively. Among the analyzed factors, the presence of metastasis impaired 5-year overall survival significantly (88.5% for localized disease, 63.5% for pulmonary only and 40.9% for any other metastasis). The survival rate of pediatric patients with Ewing sarcoma treated at Semmelweis University is similar to the result in Western European countries.

Busulfan and melphalan versus carboplatin, etoposide, and melphalan as high-dose chemotherapy for high-risk neuroblastoma (HR-NBL1/SIOPEN): an international, randomised, multi-arm, open-label, phase 3 trial.

BACKGROUND: High-dose chemotherapy with haemopoietic stem-cell rescue improves event-free survival in patients with high-risk neuroblastoma; however, which regimen has the greatest patient benefit has not been established. We aimed to assess event-free survival after high-dose chemotherapy with busulfan and melphalan compared with carboplatin, etoposide, and melphalan. METHODS: We did an international, randomised, multi-arm, open-label, phase 3 cooperative group clinical trial of patients with high-risk neuroblastoma at 128 institutions in 18 countries that included an open-label randomised arm in which high-dose chemotherapy regimens were compared. Patients (age 1-20 years) with neuroblastoma were eligible to be randomly assigned if they had completed a multidrug induction regimen (cisplatin, carboplatin, cyclophosphamide, vincristine, and etoposide with or without topotecan, vincristine, and doxorubicin) and achieved an adequate disease response. Patients were randomly assigned (1:1) to busulfan and melphalan or to carboplatin, etoposide, and melphalan by minimisation, balancing age at diagnosis, stage, MYCN amplification, and national cooperative clinical group between groups. The busulfan and melphalan regimen comprised oral busulfan (150 mg/m2 given on 4 days consecutively in four equal doses); after Nov 8, 2007, intravenous busulfan was given (0·8-1·2 mg/kg per dose for 16 doses according to patient weight). After 24 h, an intravenous melphalan dose (140 mg/m2) was given. Doses of busulfan and melphalan were modified according to bodyweight. The carboplatin, etoposide, and melphalan regimen consisted of carboplatin continuous infusion of area under the plasma concentration-time curve 4·1 mg/mL per min per day for 4 days, etoposide continuous infusion of 338 mg/m2 per day for 4 days, and melphalan 70 mg/m2 per day for 3 days, with doses for all three drugs modified according to bodyweight and glomerular filtration rate. Stem-cell rescue was given after the last dose of high-dose chemotherapy, at least 24 h after melphalan in patients who received busulfan and melphalan and at least 72 h after carboplatin etoposide, and melphalan. All patients received subsequent local radiotherapy to the primary tumour site followed by maintenance therapy. The primary endpoint was 3-year event-free survival, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01704716, and EudraCT, number 2006-001489-17. FINDINGS: Between June 24, 2002, and Oct 8, 2010, 1347 patients were enrolled and 676 were eligible for random allocation, 598 (88%) of whom were randomly assigned: 296 to busulfan and melphalan and 302 to carboplatin, etoposide, and melphalan. Median follow-up was 7·2 years (IQR 5·3-9·2). At 3 years, 146 of 296 patients in the busulfan and melphalan group and 188 of 302 in the carboplatin, etoposide, and melphalan group had an event; 3-year event-free survival was 50% (95% CI 45-56) versus 38% (32-43; p=0·0005). Nine patients in the busulfan and melphalan group and 11 in the carboplatin, etoposide, and melphalan group had died without relapse by 5 years. Severe life-threatening toxicities occurred in 13 (4%) patients who received busulfan and melphalan and 29 (10%) who received carboplatin, etoposide, and melphalan. The most frequent grade 3-4 adverse events were general condition (74 [26%] of 281 in the busulfan and melphalan group vs 103 [38%] of 270 in the carboplatin, etoposide, and melphalan group), infection (55 [19%] of 283 vs 74 [27%] of 271), and stomatitis (138 [49%] of 284 vs 162 [59%] of 273); 60 (22%) of 267 patients in the busulfan and melphalan group had Bearman grades 1-3 veno-occlusive disease versus 21 (9%) of 239 in the carboplatin, etoposide, and melphalan group. INTERPRETATION: Busulfan and melphalan improved event-free survival in children with high-risk neuroblastoma with an adequate response to induction treatment and caused fewer severe adverse events than did carboplatin, etoposide, and melphalan. Busulfan and melphalan should thus be considered standard high-dose chemotherapy and ongoing randomised studies will continue to aim to optimise treatment for high-risk neuroblastoma. FUNDING: European Commission 5th Framework Grant and the St Anna Kinderkrebsforschung.

Development of the SIOPE DIPG network, registry and imaging repository: a collaborative effort to optimize research into a rare and lethal disease.

Diffuse intrinsic pontine glioma (DIPG) is a rare and deadly childhood malignancy. After 40 years of mostly single-center, often non-randomized trials with variable patient inclusions, there has been no improvement in survival. It is therefore time for international collaboration in DIPG research, to provide new hope for children, parents and medical professionals fighting DIPG. In a first step towards collaboration, in 2011, a network of biologists and clinicians working in the field of DIPG was established within the European Society for Paediatric Oncology (SIOPE) Brain Tumour Group: the SIOPE DIPG Network. By bringing together biomedical professionals and parents as patient representatives, several collaborative DIPG-related projects have been realized. With help from experts in the fields of information technology, and legal advisors, an international, web-based comprehensive database was developed, The SIOPE DIPG Registry and Imaging Repository, to centrally collect data of DIPG patients. As for April 2016, clinical data as well as MR-scans of 694 patients have been entered into the SIOPE DIPG Registry/Imaging Repository. The median progression free survival is 6.0 months (95% Confidence Interval (CI) 5.6-6.4 months) and the median overall survival is 11.0 months (95% CI 10.5-11.5 months). At two and five years post-diagnosis, 10 and 2% of patients are alive, respectively. The establishment of the SIOPE DIPG Network and SIOPE DIPG Registry means a paradigm shift towards collaborative research into DIPG. This is seen as an essential first step towards understanding the disease, improving care and (ultimately) cure for children with DIPG.

Evaluation of the good tumor response of embryonal tumor with abundant neuropil and true rosettes (ETANTR).

The embryonal tumor with abundant neuropil and true rosettes is a rare and highly malignant variant of embryonal brain tumors. It usually affects infants and young children under the age of 4 years and exhibits a very aggressive course with a dismal prognosis. For the 68 cases reported to date the mean age at diagnosis was 25.42 months (range 3-57 months). Survival data are available for 48 children (including our case): the median overall survival is 13.0 months, though 6 (9%) of the children have had a relative long survival (>30 months). The aggressive combined treatment, involving primary surgical tumor removal, adjuvant polychemotherapy, including high-dose chemotherapy with stem cell transplantation, radiotherapy and radiochemotherapy, might play an important role in the longer survival. We have performed a literature review and we present here a multimodal-treated case of a 2- year-old girl with a long survival, who was reoperated when recurrence occurred. The residual tumor demonstrated a good response to temozolomide radiochemotherapy (craniospinal axis + boost) and followed by maintenance temozolomide. The described complex aggressive treatment option might be considered for future cases of this tumor entity.

Molecular subgroups of atypical teratoid rhabdoid tumours in children: an integrated genomic and clinicopathological analysis.

BACKGROUND: Rhabdoid brain tumours, also called atypical teratoid rhabdoid tumours, are lethal childhood cancers with characteristic genetic alterations of SMARCB1/hSNF5. Lack of biological understanding of the substantial clinical heterogeneity of these tumours restricts therapeutic advances. We integrated genomic and clinicopathological analyses of a cohort of patients with atypical teratoid rhabdoid tumours to find out the molecular basis for clinical heterogeneity in these tumours. METHODS: We obtained 259 rhabdoid tumours from 37 international institutions and assessed transcriptional profiles in 43 primary tumours and copy number profiles in 38 primary tumours to discover molecular subgroups of atypical teratoid rhabdoid tumours. We used gene and pathway enrichment analyses to discover group-specific molecular markers and did immunohistochemical analyses on 125 primary tumours to evaluate clinicopathological significance of molecular subgroup and ASCL1-NOTCH signalling. FINDINGS: Transcriptional analyses identified two atypical teratoid rhabdoid tumour subgroups with differential enrichment of genetic pathways, and distinct clinicopathological and survival features. Expression of ASCL1, a regulator of NOTCH signalling, correlated with supratentorial location (p=0·004) and superior 5-year overall survival (35%, 95% CI 13-57, and 20%, 6-34, for ASCL1-positive and ASCL1-negative tumours, respectively; p=0·033) in 70 patients who received multimodal treatment. ASCL1 expression also correlated with superior 5-year overall survival (34%, 7-61, and 9%, 0-21, for ASCL1-positive and ASCL1-negative tumours, respectively; p=0·001) in 39 patients who received only chemotherapy without radiation. Cox hazard ratios for overall survival in patients with differential ASCL1 enrichment treated with chemotherapy with or without radiation were 2·02 (95% CI 1·04-3·85; p=0·038) and 3·98 (1·71-9·26; p=0·001). Integrated analyses of molecular subgroupings with clinical prognostic factors showed three distinct clinical risk groups of tumours with different therapeutic outcomes. INTERPRETATION: An integration of clinical risk factors and tumour molecular groups can be used to identify patients who are likely to have improved long-term radiation-free survival and might help therapeutic stratification of patients with atypical teratoid rhabdoid tumours. FUNDING: C17 Research Network, Genome Canada, b.r.a.i.n.child, Mitchell Duckman, Tal Doron and Suri Boon foundations.

Clinical significance of CYP2C9-status guided valproic acid therapy in children.

OBJECTIVES: Valproic acid (VPA)-induced adverse effects, which are sometimes serious in children, can be associated with alterations in VPA metabolism. VPA-evoked toxicity is attributed to both the parent compound and its unsaturated metabolites, primarily formed by the cytochrome P450 (CYP)2C9 enzyme. Thus, patients' CYP2C9-status may account for the predisposition to adverse reactions, and testing CYP2C9-status may contribute to the improvement and rationalization of VPA therapy in children. METHODS: In the CYPtest group, children's CYP2C9-status was screened before initiating antiepileptic therapy. CYP2C9-status was estimated by the identification of defective CYP2C9 allelic variants (CYP2C9*2, CYP2C9*3) and current CYP2C9 expression in patients' leukocytes, which reflects hepatic CYP2C9 activities. When the results of CYP2C9 genotyping and CYP2C9 expression were combined, the patients' VPA-metabolizing capacity was predicted, and VPA dosing was adjusted to the patients' CYP2C9-status. Clinical and biochemical parameters, such as VPA serum levels, blood cell counts, liver function parameters, and adverse effects in patients of CYPtest group were compared with those of the control group treated with VPA according to conventional clinical practice. RESULTS: CYP2C9-guided treatment significantly reduced VPA misdosing and consequently decreased the ratio of patients out of the range of target VPA blood concentrations. In the CYPtest group of children who received CYP2C9-status adapted dose, serum alkaline phosphatase (ALP) level and the ratio of patients with abnormal ALP levels were substantially lower than in the control group. The incidence of serious side effects, notably hyperammonemia, was reduced in the CYPtest group; however, some other side effects, such as weight changes and somnolence, could not be avoided. SIGNIFICANCE: The knowledge of pediatric patients' CYP2C9-status can contribute to the optimization of VPA dosing and to the avoidance of misdosing-induced side effects.