Noise suppression of proton magnetic resonance spectroscopy improves paediatric brain tumour classification.

Proton magnetic resonance spectroscopy (1H-MRS) is increasingly used for clinical brain tumour diagnosis, but suffers from limited spectral quality. This retrospective and comparative study aims at improving paediatric brain tumour classification by performing noise suppression on clinical 1H-MRS. Eighty-three/forty-two children with either an ependymoma (ages 4.6 ± 5.3/9.3 ± 5.4), a medulloblastoma (ages 6.9 ± 3.5/6.5 ± 4.4), or a pilocytic astrocytoma (8.0 ± 3.6/6.3 ± 5.0), recruited from four centres across England, were scanned with 1.5T/3T short-echo-time point-resolved spectroscopy. The acquired raw 1H-MRS was quantified by using Totally Automatic Robust Quantitation in NMR (TARQUIN), assessed by experienced spectroscopists, and processed with adaptive wavelet noise suppression (AWNS). Metabolite concentrations were extracted as features, selected based on multiclass receiver operating characteristics, and finally used for identifying brain tumour types with supervised machine learning. The minority class was oversampled through the synthetic minority oversampling technique for comparison purposes. Post-noise-suppression 1H-MRS showed significantly elevated signal-to-noise ratios (P < .05, Wilcoxon signed-rank test), stable full width at half-maximum (P > .05, Wilcoxon signed-rank test), and significantly higher classification accuracy (P < .05, Wilcoxon signed-rank test). Specifically, the cross-validated overall and balanced classification accuracies can be improved from 81% to 88% overall and 76% to 86% balanced for the 1.5T cohort, whilst for the 3T cohort they can be improved from 62% to 76% overall and 46% to 56%, by applying Naïve Bayes on the oversampled 1H-MRS. The study shows that fitting-based signal-to-noise ratios of clinical 1H-MRS can be significantly improved by using AWNS with insignificantly altered line width, and the post-noise-suppression 1H-MRS may have better diagnostic performance for paediatric brain tumours.

Characterisation of paediatric brain tumours by their MRS metabolite profiles.

1H-magnetic resonance spectroscopy (MRS) has the potential to improve the noninvasive diagnostic accuracy for paediatric brain tumours. However, studies analysing large, comprehensive, multicentre datasets are lacking, hindering translation to widespread clinical practice. Single-voxel MRS (point-resolved single-voxel spectroscopy sequence, 1.5 T: echo time [TE] 23-37 ms/135-144 ms, repetition time [TR] 1500 ms; 3 T: TE 37-41 ms/135-144 ms, TR 2000 ms) was performed from 2003 to 2012 during routine magnetic resonance imaging for a suspected brain tumour on 340 children from five hospitals with 464 spectra being available for analysis and 281 meeting quality control. Mean spectra were generated for 13 tumour types. Mann-Whitney U-tests and Kruskal-Wallis tests were used to compare mean metabolite concentrations. Receiver operator characteristic curves were used to determine the potential for individual metabolites to discriminate between specific tumour types. Principal component analysis followed by linear discriminant analysis was used to construct a classifier to discriminate the three main central nervous system tumour types in paediatrics. Mean concentrations of metabolites were shown to differ significantly between tumour types. Large variability existed across each tumour type, but individual metabolites were able to aid discrimination between some tumour types of importance. Complete metabolite profiles were found to be strongly characteristic of tumour type and, when combined with the machine learning methods, demonstrated a diagnostic accuracy of 93% for distinguishing between the three main tumour groups (medulloblastoma, pilocytic astrocytoma and ependymoma). The accuracy of this approach was similar even when data of marginal quality were included, greatly reducing the proportion of MRS excluded for poor quality. Children's brain tumours are strongly characterised by MRS metabolite profiles readily acquired during routine clinical practice, and this information can be used to support noninvasive diagnosis. This study provides both key evidence and an important resource for the future use of MRS in the diagnosis of children's brain tumours.

Transatlantic progress in measurement of cognitive outcomes in paediatric oncology trials.

The importance of measuring quality of survival within paediatric oncology trials is increasingly recognised. However, capturing neuropsychological outcomes and other aspects of quality of survival in the context of large or multinational trials can be challenging. We provide examples of protocols designed to address this challenge recently employed in clinical trials in the USA and Europe. We discuss their respective strengths and challenges, obstacles encountered and future opportunities for transatlantic collaboration.

National advisory panels for childhood cancer in the United Kingdom: An evaluation of current practice and a best practice statement for the future.

BACKGROUND: National advisory panels (NAPs) have been established for the care of children and young people (CYP) with cancer in the United Kingdom since 2011, with an increase in panel number in recent years. Their practice has not previously been reviewed; therefore, we sought to evaluate the role, practice and impact of six selected NAPs offering expertise in ependymoma, histiocytosis, leukaemia, neuroblastoma, renal tumours and sarcoma. PROCEDURE: This service evaluation used mixed methodology, including review of NAP documentation, semi-structured interviews with the NAP chairs and an analysis of the cases referred for discussion. RESULTS: Total 1110 referrals were analysed. Results demonstrated the significant scope and amount of work undertaken by the NAPs, largely testament to the commitment of the panel members. Specific roles fulfilled have been highlighted, and NAP recommendations have been shown to influence clinical decision-making and be implemented in the majority of cases. Despite widespread good practice, areas to address have been identified; these include clarity regarding NAP membership, consistency in recommendations, the consideration of holistic information to promote personalised management and the exploration of wider multidisciplinary team roles. CONCLUSIONS: In the context of increasing demand and the escalating number of NAPs, it is timely to consider how service improvement can be facilitated. Best practice guidelines have been formulated as a product of this study, to promote a sustainable and effective model for NAPs. Review and benchmarking national panel performance against these guidelines will drive high standards of care going forward and they should be embedded as standard practice.

Evaluating the efficacy and safety of single-agent etoposide intra-CSF chemotherapy in children and young people with relapsed/refractory central nervous system tumours.

PURPOSE: The aim of the project was to evaluate intra-CSF etoposide administration in a palliative setting for children and young people with relapsed/refractory central nervous system (CNS) tumours, with the primary endpoints being overall survival and progression-free survival time. A safety endpoint was to assess the side effect profile and complications of intra-CSF etoposide. METHODS: Thirty-five patients under the age of 30 years (median age: 5.33 years) were enrolled onto the project. The cross-centre study was a service evaluation, with a data collection spreadsheet designed in Nottingham and completed by both Nottingham and Oxford centres. Data was analysed using SPSS, assessing the overall survival and progression-free survival times, as well as the 6-month and 1-year survival rates. RESULTS: The median overall survival and progression-free survival times were 10.97 and 5.91 months, respectively. The 6-month and 1-year overall survival rates were 67% and 48%, and the progression-free survival rates were 50% and 22%. Age at the start of intra-CSF therapy was significantly associated with overall survival (P = 0.046), with the 6 + age group having improved overall survival. Treatment type was significantly associated with overall survival (P = 0.012), with etoposide intra-CSF treatment being associated with improved overall survival. Treatment duration was significantly associated with both overall survival (P < 0.001) and progression-free survival (P < 0.001). CONCLUSION: Intra-CSF etoposide treatment has shown to increase both overall and progression-free survival significantly, whilst having few side effects and maintaining a good quality of life for patients, reflecting it as a beneficial therapy in the palliative setting.

A common polymorphism in the 5' UTR of ERCC5 creates an upstream ORF that confers resistance to platinum-based chemotherapy.

We show that a common polymorphic variant in the ERCC5 5' untranslated region (UTR) generates an upstream ORF (uORF) that affects both the background expression of this protein and its ability to be synthesized following exposure to agents that cause bulky adduct DNA damage. Individuals that harbor uORF1 have a marked resistance to platinum-based agents, illustrated by the significantly reduced progression-free survival of pediatric ependymoma patients treated with such compounds. Importantly, inhibition of DNA-PKcs restores sensitivity to platinum-based compounds by preventing uORF1-dependent ERCC5 expression. Our data support a model in which a heritable 5' noncoding mRNA element influences individuals' responses to platinum-based chemotherapy.

Response assessment in paediatric intracranial ependymoma: recommendations from the Response Assessment in Pediatric Neuro-Oncology (RAPNO) working group.

Response criteria for paediatric intracranial ependymoma vary historically and across different international cooperative groups. The Response Assessment in the Pediatric Neuro-Oncology (RAPNO) working group, consisting of an international panel of paediatric and adult neuro-oncologists, neuro-radiologists, radiation oncologists, and neurosurgeons, was established to address both the issues and the unique challenges in assessing the response in children with CNS tumours. We established a subcommittee to develop response assessment criteria for paediatric ependymoma. Current practice and literature were reviewed to identify major challenges in assessing the response of paediatric ependymoma to clinical trial therapy. For areas in which data were scarce or unavailable, consensus was reached through an iterative process. RAPNO response assessment recommendations include assessing disease response on the basis of changes in tumour volume, and using event-free survival as a study endpoint for patients entering clinical trials without bulky disease. Our recommendations for response assessment include the use of brain and spine MRI, cerebral spinal fluid cytology, neurological examination, and steroid use. Baseline postoperative imaging to assess for residual tumour should be obtained 24-48 h after surgery. Our consensus recommendations and response definitions should be prospectively validated in clinical trials.

Meta-Analysis of Apparent Diffusion Coefficient in Pediatric Medulloblastoma, Ependymoma, and Pilocytic Astrocytoma.

BACKGROUND: Medulloblastoma, ependymoma, and pilocytic astrocytoma are common pediatric posterior fossa tumors. These tumors show overlapping characteristics on conventional MRI scans, making diagnosis difficult. PURPOSE: To investigate whether apparent diffusion coefficient (ADC) values differ between tumor types and to identify optimum cut-off values to accurately classify the tumors using different performance metrics. STUDY TYPE: Systematic review and meta-analysis. SUBJECTS: Seven studies reporting ADC in pediatric posterior fossa tumors (115 medulloblastoma, 68 ependymoma, and 86 pilocytic astrocytoma) were included following PubMed and ScienceDirect searches. SEQUENCE AND FIELD STRENGTH: Diffusion weighted imaging (DWI) was performed on 1.5 and 3 T across multiple institution and vendors. ASSESSMENT: The combined mean and standard deviation of ADC were calculated for each tumor type using a random-effects model, and the effect size was calculated using Hedge's g. STATISTICAL TESTS: Sensitivity/specificity, weighted classification accuracy, balanced classification accuracy. A P value < 0.05 was considered statistically significant, and a Hedge's g value of >1.2 was considered to represent a large difference. RESULTS: The mean (± standard deviation) ADCs of medulloblastoma, ependymoma, and pilocytic astrocytoma were 0.76 ± 0.16, 1.10 ± 0.10, and 1.49 ± 0.16 mm2 /sec × 10-3 . To maximize sensitivity and specificity using the mean ADC, the cut-off was found to be 0.96 mm2 /sec × 10-3 for medulloblastoma and ependymoma and 1.26 mm2 /sec × 10-3 for ependymoma and pilocytic astrocytoma. The meta-analysis showed significantly different ADC distributions for the three posterior fossa tumors. The cut-off values changed markedly (up to 7%) based on the performance metric used and the prevalence of the tumor types. DATA CONCLUSION: There were significant differences in ADC between tumor types. However, it should be noted that only summary statistics from each study were analyzed and there were differences in how regions of interest were defined between studies. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 3.

Dynamic susceptibility-contrast magnetic resonance imaging with contrast agent leakage correction aids in predicting grade in pediatric brain tumours: a multicenter study.

BACKGROUND: Relative cerebral blood volume (rCBV) measured using dynamic susceptibility-contrast MRI can differentiate between low- and high-grade pediatric brain tumors. Multicenter studies are required for translation into clinical practice. OBJECTIVE: We compared leakage-corrected dynamic susceptibility-contrast MRI perfusion parameters acquired at multiple centers in low- and high-grade pediatric brain tumors. MATERIALS AND METHODS: Eighty-five pediatric patients underwent pre-treatment dynamic susceptibility-contrast MRI scans at four centers. MRI protocols were variable. We analyzed data using the Boxerman leakage-correction method producing pixel-by-pixel estimates of leakage-uncorrected (rCBVuncorr) and corrected (rCBVcorr) relative cerebral blood volume, and the leakage parameter, K2. Histological diagnoses were obtained. Tumors were classified by high-grade tumor. We compared whole-tumor median perfusion parameters between low- and high-grade tumors and across tumor types. RESULTS: Forty tumors were classified as low grade, 45 as high grade. Mean whole-tumor median rCBVuncorr was higher in high-grade tumors than low-grade tumors (mean ± standard deviation [SD] = 2.37±2.61 vs. -0.14±5.55; P<0.01). Average median rCBV increased following leakage correction (2.54±1.63 vs. 1.68±1.36; P=0.010), remaining higher in high-grade tumors than low grade-tumors. Low-grade tumors, particularly pilocytic astrocytomas, showed T1-dominant leakage effects; high-grade tumors showed T2*-dominance (mean K2=0.017±0.049 vs. 0.002±0.017). Parameters varied with tumor type but not center. Median rCBVuncorr was higher (mean = 1.49 vs. 0.49; P=0.015) and K2 lower (mean = 0.005 vs. 0.016; P=0.013) in children who received a pre-bolus of contrast agent compared to those who did not. Leakage correction removed the difference. CONCLUSION: Dynamic susceptibility-contrast MRI acquired at multiple centers helped distinguish between children's brain tumors. Relative cerebral blood volume was significantly higher in high-grade compared to low-grade tumors and differed among common tumor types. Vessel leakage correction is required to provide accurate rCBV, particularly in low-grade enhancing tumors.

Genome-Wide Expression and Anti-Proliferative Effects of Electric Field Therapy on Pediatric and Adult Brain Tumors.

The lack of treatment options for high-grade brain tumors has led to searches for alternative therapeutic modalities. Electrical field therapy is one such area. The Optune™ system is an FDA-approved novel device that delivers continuous alternating electric fields (tumor treating fields-TTFields) to the patient for the treatment of primary and recurrent Glioblastoma multiforme (GBM). Various mechanisms have been proposed to explain the effects of TTFields and other electrical therapies. Here, we present the first study of genome-wide expression of electrotherapy (delivered via TTFields or Deep Brain Stimulation (DBS)) on brain tumor cell lines. The effects of electric fields were assessed through gene expression arrays and combinational effects with chemotherapies. We observed that both DBS and TTFields significantly affected brain tumor cell line viability, with DBS promoting G0-phase accumulation and TTFields promoting G2-phase accumulation. Both treatments may be used to augment the efficacy of chemotherapy in vitro. Genome-wide expression assessment demonstrated significant overlap between the different electrical treatments, suggesting novel interactions with mitochondrial functioning and promoting endoplasmic reticulum stress. We demonstrate the in vitro efficacy of electric fields against adult and pediatric high-grade brain tumors and elucidate potential mechanisms of action for future study.

Severity of COVID-19 in children with cancer: Report from the United Kingdom Paediatric Coronavirus Cancer Monitoring Project.

BACKGROUND: Children with cancer are frequently immunocompromised. While children are generally thought to be at less risk of severe SARS-CoV-2 infection than adults, comprehensive population-based evidence for the risk in children with cancer is unavailable. We aimed to produce evidence of the incidence and outcomes from SARS-CoV-2 in children with cancer attending all hospitals treating this population across the UK. METHODS: Retrospective and prospective observational study of all children in the UK under 16 diagnosed with cancer through data collection from all hospitals providing cancer care to this population. Eligible patients tested positive for SARS-CoV-2 on reverse transcription polymerase chain reaction (RT-PCR). The primary end-point was death, discharge or end of active care for COVID-19 for those remaining in hospital. RESULTS: Between 12 March 2020 and 31 July 2020, 54 cases were identified: 15 (28%) were asymptomatic, 34 (63%) had mild infections and 5 (10%) moderate, severe or critical infections. No patients died and only three patients required intensive care support due to COVID-19. Estimated incidence of hospital identified SARS-CoV-2 infection in children with cancer under 16 was 3%. CONCLUSIONS: Children with cancer with SARS-CoV-2 infection do not appear at increased risk of severe infection compared to the general paediatric population. This is reassuring and supports the continued delivery of standard treatment.

Sequential Orbitrap Secondary Ion Mass Spectrometry and Liquid Extraction Surface Analysis-Tandem Mass Spectrometry-Based Metabolomics for Prediction of Brain Tumor Relapse from Sample-Limited Primary Tissue Archives.

We present here a novel surface mass spectrometry strategy to perform untargeted metabolite profiling of formalin-fixed paraffin-embedded pediatric ependymoma archives. Sequential Orbitrap secondary ion mass spectrometry (3D OrbiSIMS) and liquid extraction surface analysis-tandem mass spectrometry (LESA-MS/MS) permitted the detection of 887 metabolites (163 chemical classes) from pediatric ependymoma tumor tissue microarrays (diameter: <1 mm; thickness: 4 µm). From these 163 classes, 60 classes were detected with both techniques, whilst LESA-MS/MS and 3D OrbiSIMS individually allowed the detection of another 83 and 20 unique metabolite classes, respectively. Through data fusion and multivariate analysis, we were able to identify key metabolites and corresponding pathways predictive of tumor relapse, which were retrospectively confirmed by gene expression analysis with publicly available data. Altogether, this sequential mass spectrometry strategy has shown to be a versatile tool to perform high-throughput metabolite profiling on sample-limited tissue archives.

Recurrent fusions in PLAGL1 define a distinct subset of pediatric-type supratentorial neuroepithelial tumors.

Ependymomas encompass a heterogeneous group of central nervous system (CNS) neoplasms that occur along the entire neuroaxis. In recent years, extensive (epi-)genomic profiling efforts have identified several molecular groups of ependymoma that are characterized by distinct molecular alterations and/or patterns. Based on unsupervised visualization of a large cohort of genome-wide DNA methylation data, we identified a highly distinct group of pediatric-type tumors (n = 40) forming a cluster separate from all established CNS tumor types, of which a high proportion were histopathologically diagnosed as ependymoma. RNA sequencing revealed recurrent fusions involving the pleomorphic adenoma gene-like 1 (PLAGL1) gene in 19 of 20 of the samples analyzed, with the most common fusion being EWSR1:PLAGL1 (n = 13). Five tumors showed a PLAGL1:FOXO1 fusion and one a PLAGL1:EP300 fusion. High transcript levels of PLAGL1 were noted in these tumors, with concurrent overexpression of the imprinted genes H19 and IGF2, which are regulated by PLAGL1. Histopathological review of cases with sufficient material (n = 16) demonstrated a broad morphological spectrum of tumors with predominant ependymoma-like features. Immunohistochemically, tumors were GFAP positive and OLIG2- and SOX10 negative. In 3/16 of the cases, a dot-like positivity for EMA was detected. All tumors in our series were located in the supratentorial compartment. Median age of the patients at the time of diagnosis was 6.2 years. Median progression-free survival was 35 months (for 11 patients with data available). In summary, our findings suggest the existence of a novel group of supratentorial neuroepithelial tumors that are characterized by recurrent PLAGL1 fusions and enriched for pediatric patients.

Germline mutations and somatic inactivation of TRIM28 in Wilms tumour.

Wilms tumour is a childhood tumour that arises as a consequence of somatic and rare germline mutations, the characterisation of which has refined our understanding of nephrogenesis and carcinogenesis. Here we report that germline loss of function mutations in TRIM28 predispose children to Wilms tumour. Loss of function of this transcriptional co-repressor, which has a role in nephrogenesis, has not previously been associated with cancer. Inactivation of TRIM28, either germline or somatic, occurred through inactivating mutations, loss of heterozygosity or epigenetic silencing. TRIM28-mutated tumours had a monomorphic epithelial histology that is uncommon for Wilms tumour. Critically, these tumours were negative for TRIM28 immunohistochemical staining whereas the epithelial component in normal tissue and other Wilms tumours stained positively. These data, together with a characteristic gene expression profile, suggest that inactivation of TRIM28 provides the molecular basis for defining a previously described subtype of Wilms tumour, that has early age of onset and excellent prognosis.

Pineoblastoma segregates into molecular sub-groups with distinct clinico-pathologic features: a Rare Brain Tumor Consortium registry study.

Pineoblastomas (PBs) are rare, aggressive pediatric brain tumors of the pineal gland with modest overall survival despite intensive therapy. We sought to define the clinical and molecular spectra of PB to inform new treatment approaches for this orphan cancer. Tumor, blood, and clinical data from 91 patients with PB or supratentorial primitive neuroectodermal tumor (sPNETs/CNS-PNETs), and 2 pineal parenchymal tumors of intermediate differentiation (PPTIDs) were collected from 29 centres in the Rare Brain Tumor Consortium. We used global DNA methylation profiling to define a core group of PB from 72/93 cases, which were delineated into five molecular sub-groups. Copy number, whole exome and targeted sequencing, and miRNA expression analyses were used to evaluate the clinico-pathologic significance of each sub-group. Tumors designated as group 1 and 2 almost exclusively exhibited deleterious homozygous loss-of-function alterations in miRNA biogenesis genes (DICER1, DROSHA, and DGCR8) in 62 and 100% of group 1 and 2 tumors, respectively. Recurrent alterations of the oncogenic MYC-miR-17/92-RB1 pathway were observed in the RB and MYC sub-group, respectively, characterized by RB1 loss with gain of miR-17/92, and recurrent gain or amplification of MYC. PB sub-groups exhibited distinct clinical features: group 1-3 arose in older children (median ages 5.2-14.0 years) and had intermediate to excellent survival (5-year OS of 68.0-100%), while Group RB and MYC PB patients were much younger (median age 1.3-1.4 years) with dismal survival (5-year OS 37.5% and 28.6%, respectively). We identified age < 3 years at diagnosis, metastatic disease, omission of upfront radiation, and chr 16q loss as significant negative prognostic factors across all PBs. Our findings demonstrate that PB exhibits substantial molecular heterogeneity with sub-group-associated clinical phenotypes and survival. In addition to revealing novel biology and therapeutics, molecular sub-grouping of PB can be exploited to reduce treatment intensity for patients with favorable biology tumors.

Switching from linear to macrocyclic gadolinium-based contrast agents halts the relative T1 -Weighted signal increase in deep gray matter of children with brain tumors: A retrospective study.

BACKGROUND: Studies have shown signal intensity (SI) changes in the brains of children exposed to repeated doses of a gadolinium-based contrast agent (GBCA). HYPOTHESIS: The trajectory of changes in relative dentate nucleus (DN) and globus pallidus (GP) SI in children receiving multiple doses of GBCA will alter when switched from linear to macrocyclic agents. STUDY TYPE: Retrospective longitudinal. POPULATION: Thirty-five children, age range 0.5-17.0 years, undergoing brain tumor follow-up between 2006 and 2017. FIELD STRENGTH/SEQUENCE: Unenhanced T1 WI, serial scans at both 1.5T and 3T. ASSESSMENT: Regions of interest were drawn on DN, GP, and SIs normalized to middle cerebellar peduncle (DN/MCP) and cerebral white matter (GP/CWM), respectively. A change in SI ratios as a function of dose (slope gradient) calculated according to the type of contrast agent received: linear only, macrocyclic only, or switchover from linear to macrocyclic. For the latter, gradients were compared before and after switchover. The effect of anticancer treatment on slope gradient was tested. STATISTICAL TESTS: One-sample t-test or Mann-Whitney U-test for slope gradients differing from zero. Independent samples t-tests to compare slope gradient groups. Paired sample t-tests to compare slope gradients before and after switchover. RESULTS: A significant (P < 0.05) increase in SI ratio was observed following multiple doses of linear but not macrocyclic agents: mean percentage increase per dose in SI was 0.063% vs. -0.034% for DN/MCP, and 0.078% vs. 0.004% for GP/CWM ratios. A significant (P < 0.05) change of SI trajectory in the DN/MCP ratio was demonstrated when switching from a linear to macrocyclic agent. There was no difference in SI trajectory between patients who had anticancer therapies and those who did not, DN/MCP P = 0.740; GP/BWM P = 0.694. DATA CONCLUSION: Switching from linear to macrocyclic gadolinium-based contrast agents seems to halt the relative T1 signal increase in deep gray matter in children. Anticancer treatments appeared to have no impact on the trajectory of T1 SI. LEVEL OF EVIDENCE: 4 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2020;51:288-295.

A retrospective analysis of recurrent pediatric ependymoma reveals extremely poor survival and ineffectiveness of current treatments across central nervous system locations and molecular subgroups.

BACKGROUND: Relapse occurs in 50% of pediatric ependymoma cases and has poor prognosis. Few studies have investigated the clinical progress of relapsed disease, and treatment lacks a standardized approach. METHODS AND MATERIALS: We analyzed 302 pediatric ependymoma cases. Tumor, demographic, and treatment variables were investigated for association with relapse risk, time to recurrence, and survival after relapse. DNA methylation profiling was performed for 135/302 cases, and predominant subgroups were EPN_PFA (n = 95) and EPN_RELA (n = 24). Chromosome 1q status was ascertained for 185/302 cases by fluorescent in-situ hybridization (FISH), multiplex ligation-dependent probe amplification (MLPA), and DNA methylation profiles. RESULTS: Sixty-two percent of cases relapsed, with a median of two recurrences with no difference between posterior fossa and supratentorial locations (66% vs 55% relapse rate). One hundred seventeen (38%) cases relapsed within two years and five (2%) beyond 10 years. The late relapses were clinically heterogeneous. Tumor grade and treatment affected risk and time to relapse variably across subgroups. After relapse, surgery and irradiation delayed disease progression with a minimal impact on survival across the entire cohort. In the EPN_PFA and EPN_RELA groups, 1q gain was independently associated with relapse risk (subhazard ratio [SHR] 4.307, P = 0.027 and SHR 1.982, P = 0.010, respectively) while EPN_PFA had increased relapse risk compared with EPN_RELA (SHR = 0.394, P = 0.018). CONCLUSIONS: Recurrent pediatric ependymoma is an aggressive disease with poor outcomes, for which current treatments are inadequate. We report that chromosome 1q gain increases relapse risk in common molecular subgroups in children but a deeper understanding of the underlying biology at relapse and novel therapeutic approaches are urgently needed.

Neurocognitive, academic and functional outcomes in survivors of infant ependymoma (UKCCSG CNS 9204).

PURPOSE: This is the first UK multi-centre case-controlled study with follow-up in excess of 10 years to report the neurocognitive, academic and psychological outcomes of individuals diagnosed with a brain tumour in early childhood. Children enrolled into the UKCCSG CNS 9204 trial, diagnosed with intracranial ependymoma when aged ≤ 36 months old, who received a primary chemotherapy strategy to defer or avoid radiotherapy, were recruited. METHODS: Outcomes of those who relapsed and subsequently received radiotherapy (n = 13) were compared to those enrolled who did not relapse (n = 16), age-matched controls-diagnosed with solid non-central nervous system (SN-CNS; n = 15) tumours or low-grade posterior fossa pilocytic astrocytoma (PFPA; n = 15), and normative data. Analyses compared nine neurocognitive outcomes as primary measures with quality of survival as secondary measures. RESULTS: Relapsed ependymoma participants performed significantly worse than their non-relapsed counterparts on measures of Full Scale IQ, Perceptual Reasoning, Word Reading and Numerical Operations. The relapsed ependymoma group performed significantly worse than SN-CNS controls on all primary measures, whereas non-relapsing participants only differed significantly from SN-CNS controls on measures of Processing Speed and General Memory. Relapsed ependymoma participants fared worse than all groups on measures of quality of survival. CONCLUSIONS: The relapsed irradiated ependymoma group demonstrated the most significantly impaired neurocognitive outcomes at long-term follow-up. Non-relapsing participants demonstrated better outcomes than those who relapsed. Results tentatively suggest avoiding radiotherapy helped preserve neurocognitive and learning outcomes of individuals diagnosed with ependymoma when aged ≤ 36 months old. Prospective neurocognitive surveillance is required. Recommendations for clinical and research practice are provided.

Application of pattern recognition techniques for classification of pediatric brain tumors by in vivo 3T 1 H-MR spectroscopy-A multi-center study.

PURPOSE: 3T magnetic resonance scanners have boosted clinical application of 1 H-MR spectroscopy (MRS) by offering an improved signal-to-noise ratio and increased spectral resolution, thereby identifying more metabolites and extending the range of metabolic information. Spectroscopic data from clinical 1.5T MR scanners has been shown to discriminate between pediatric brain tumors by applying machine learning techniques to further aid diagnosis. The purpose of this multi-center study was to investigate the discriminative potential of metabolite profiles obtained from 3T scanners in classifying pediatric brain tumors. METHODS: A total of 41 pediatric patients with brain tumors (17 medulloblastomas, 20 pilocytic astrocytomas, and 4 ependymomas) were scanned across four different hospitals. Raw spectroscopy data were processed using TARQUIN. Borderline synthetic minority oversampling technique was used to correct for the data skewness. Different classifiers were trained using linear discriminative analysis, support vector machine, and random forest techniques. RESULTS: Support vector machine had the highest balanced accuracy for discriminating the three tumor types. The balanced accuracy achieved was higher than the balanced accuracy previously reported for similar multi-center dataset from 1.5T magnets with echo time 20 to 32 ms alone. CONCLUSION: This study showed that 3T MRS can detect key differences in metabolite profiles for the main types of childhood tumors. Magn Reson Med 79:2359-2366, 2018. © 2017 International Society for Magnetic Resonance in Medicine.