bluuebunny/crossref_metadata_2025_split huggingface dataset:
NFB-18. IMMUNE FUNCTION IN CHILDREN TREATED WITH TRAMETINIB
Authors: Moukhaiber Perla , Samolej Anna , Somsri Palita , McCowage Geoffrey 
Published: December 2020

Abstract

BACKGROUND
Trametinib (Tr) has been applied in the treatment of children with various tumor types, often for prolonged periods. Little is known regarding immune function (IF) following prolonged Tr in this age group.

OBJECTIVE
Describe laboratory measures of IF in children on Tr.

METHOD
Patients receiving Tr had low grade glioma with BRAF anomalies (6), or neurofibromatosis-1 (16) with glioma or plexiform neurofibroma. IF was evaluated using leukocyte/lymphocyte counts, immunoglobulin levels, and antibody titres.

RESULTS
22 patients received Tr. 2 also received Dabrafenib. Median age at Tr initiation of Tr was 7.75 years. As of June 2020, 7 patients have had IFT; results are pending on 15. Median duration of Tr therapy at time of IF was 3.5 years (0.8 – 4). In these 7 patients, median white cell count was 6.9 x 10^9/L (4.1 – 12.6), neutrophils 4.2 x 10^9/L (1.8 – 6.8) and lymphocytes 3.2 x 10^9/L (1.4 – 7). IgG levels, B cells and CD8 cytotoxic T cells were normal across 7/7 patients:medians 9.47 g/L (8.62 – 17), 0.51 x 10^9/L (0.2 – 1.26) and 0.58 x 10^9/L (0.25 – 2.03) respectively. CD3 and CD4 T cells: median 2.08 x 10^9/L (0.67 – 4.62) and 1.34 x 10^9/L (0.35 – 2.31), borderline low in 1 heavily pre-treated patient. An adequate immune response was present in all 4 vaccine antigens tested in 5/5 patients.

CONCLUSION
IF appears relatively intact, relevant for immunisation and infection precautions in children on Tr. Data on the complete cohort will be presented.
NURS-10. IMPROVEMENTS IN A BEHAVIORAL TRAINING AND PHARMACOLOGICAL ANXIOLYSIS ALGORITHM FOR INCREASED COMPLIANCE IN PEDIATRIC PATIENTS IN PREPARATION FOR RADIATION THERAPY: A RETROSPECTIVE ANALYSIS
Authors: Tran Judy , Holt Jennifer , Crump Danielle , Shea Anita , Whetzel Lin , Lattimore Andrea , Carson Rebecca , Anderson Roberta 
Published: December 2020

Abstract

BACKGROUND
In the pediatric population, the probability of compliance with radiation involves multifactorial elements. Younger pediatric patients often require anesthesia to ensure accurate delivery of radiotherapy. The purpose of this analysis was to refine our algorithm in pediatric patients to better identify children who would benefit from behavioral training and/or anxiolyxis intervention with the goal of minimizing anesthesia use.

METHOD
Retrospective data was collected from electronic medical records from 150 pediatric oncology patients &lt;18 years old, treated with photon and proton radiation at our center from August 2016 to December 2019. We identified potential socio-developmental treatment factors thought to impact behavioral compliance and categorized risk factors based on an algorithm to determine risk for noncompliance with radiotherapy.

RESULTS
Six categories demonstrated statistical significance (p&lt;0.05) in their influence on behavioral compliance during radiotherapy: age category (specifically age &lt;7: Odds ratio [OR] 3.0, 95% Confidence Interval [CI] 1.0, 9.1), need for sedation with prior imaging studies (p&lt;0.001), parental premonition of requiring anesthesia for successful treatment (p&lt;0.001), duration of treatment, primary language (p&lt;0.001), and use of total body irradiation (OR 3.1, 95% CI 1.1, 9.3).

CONCLUSION
Identification of pre-radiation risk factors allowed for better recognition of patients at risk for treatment non-compliance and for requiring daily sedation. Future studies should focus on implementing the algorithm prospectively in an effort to identify and direct early intervention with behavioral training and/or anxiolytics to minimize the need for sedation.
PATH-01. MOLECULAR PROFILING OF PAEDIATRIC CENTRAL NERVOUS SYSTEM TUMOURS IN AUSTRALASIA – AN UPDATE ON THE AIM BRAIN AND MNP2.0 PROJECTS
Authors: Algar Elizabeth , Christine White , Kinross Kathryn , Buntine Molly , Jones David , Pfister Stefan , Strong Robyn , Gottardo Nicholas , Hansford Jordan 
Published: December 2020

Abstract
The Access to Innovative Molecular Profiling for Paediatric Brain Cancers (AIM BRAIN) project is a trial testing the feasibility of clinical implementation of diagnostic methylation and molecular profiling for central nervous system (CNS) tumours in Australia and New Zealand. AIM BRAIN builds on an existing study, MNP2.0, and allows cross-validation of results derived from identical samples in separate laboratories in Melbourne, Australia, and DKFZ, Heidelberg, Germany. Parallel methylation profiling (Illumina 850K EPIC array) from co-enrolled cases has revealed excellent concordance between laboratories with 50/51 cases (98%) yielding identical classification using the DKFZ Molecular Neuropathology 2.0 Classifier v11b4. 77/91 (85%) of AIM BRAIN cases classified concordantly by methylation array when compared to their diagnostic histopathology. Of these 77 cases, 16 had classifications below a threshold of 0.90, however still classified correctly. In 14 discordant cases either the histopathology was not well defined, not represented on the classifier, or a very low classification score was obtained. Molecular profiling through MNP2.0 identified 49/167 (29.3%) tumours with gene fusions including BRAF-KIAA1549 (n=29), RELA-C1lorf95 (n=5) and 15 rare or novel fusions. BRAF-KIAA1549 was almost exclusively associated with pilocytic astrocytoma (28/29) and RELA-C1lorf95 with ependymoma. Six pathogenic germline mutations were identified in TP53 (n=2), BRCA1, NF1, LZTR1 and ATM. The incidence of germline predisposition was low (4%) and sex biased towards females (5F:1M), (p&lt;0.08). Our findings confirm methylation profiling as a robust platform for classifying CNS tumours with potential to reveal new CNS tumour entities when combined with molecular profiling.
PATH-04. AN ENHANCED AI-DRIVEN PLATFORM FOR PRECISION MOLECULAR BRAIN TUMOR DIANOSTICS
Authors: Sill Martin , Sahm Felix , Schrimpf Daniel , Capper David , Pfister Stefan M , von Deimling Andreas , Jones David T W 
Published: December 2020

Abstract
Tumors of the CNS represent one of the most complex groups of human cancer, with a vast number of different entities occurring across a spectrum of ages and anatomic locations. This heterogeneity makes accurate diagnosis challenging, with the current gold standard relying on multiple subjective elements. We recently proposed a classification algorithm based on tumor DNA methylation profiling as an objective way to assign samples to over 80 distinct molecular classes. Here we present a substantial update to our machine learning-based algorithm, with more than 170 molecular classes now being represented amongst the 5,915 samples in our reference cohort. These new classes include further subclassification of known groups such as medulloblastoma and ependymoma, as well as multiple new molecular entities described here for the first time. A further improvement is the introduction of a more rationally layered output, making use of ‘families’ of closely-related molecular classes to improve the compatibility with the current WHO classification of CNS tumors. This approach is designed to increase the clinical relevance of the primary output, while also retaining the full information content from the random forest-driven classification. Benchmarking our new algorithm by cross-validation and on an independent validation cohort indicates a retention of the excellent accuracy of diagnosis (error-rate &lt; 4%), with a significant improvement in the proportion of confidently classifiable tumors compared with our previous tool. We believe that this approach, freely accessible through an online web portal, has the potential to enhance diagnostic precision and thereby support clinical care for brain tumor patients.
PATH-14. GENETIC SUSCEPTIBILITY AND OUTCOMES OF PEDIATRIC, ADOLESCENT AND YOUNG ADULT IDH-MUTANT ASTROCYTOMAS
Authors: Bornhorst Miriam , Nobre Liana , Zapotocky Michal , Barseghyan Hayk , Goecks Jeremy , Boue Daniel , Tabori Uri , Hawkins Cynthia , Bouffet Eric , MacDonald Tobey , Schniederjan Matthew , Bronischer Alberto , Orr Brent , Solomon David , Mueller Sabine , Opocher Enrico , Vortmeyer Alexander , Marks Asher , Koschmann Carl , Leung Denise Leung , Mody Rajen , Hwang Eugene , Bhattacharya Surajit , Vilain Eric , Turner Joyce , Kilburn Lindsay , Rood Brian , Packer Roger , Nazarian Javad , Ho Cheng-Ying 
Published: December 2020

Abstract

INTRODUCTION
Previously thought to be rare, recent case series have shown that IDH mutations in young patients are more common than previously described. In this study, we analyzed IDH-mutant tumors to determine clinical significance of these mutations in children, adolescents and young adults.

METHODS
Through this multi-institution study (10 institutions), we collected 64 IDH1/2-mutant infiltrating astrocytoma specimens from 58 patients aged 4–26 (M:F, 0.4:0.6). Specimens included 46 low-grade (LGG) and 18 high-grade (HGG) astrocytomas. Tumor sequencing data (n=45), germline sequencing data (n=37) and outcome data (n=40) was analyzed.

RESULTS
Similar to adults, most sequenced tumors had a co-mutation in the TP53 gene, while ATRX mutations were less common and primarily seen in HGGs. Approximately 60% (n=21) of patients with germline data available had a mutation in a cancer predisposition gene. Mismatch repair (MMR) mutations were most common (n=12; MSH6 n=9), followed by TP53mutations (n=7). All patients with MMR gene mutations had HGGs and poor progression free (PFS=10% at 2 years, mean TTP=9 months) and overall (OS &lt;30% at 2 years) survival. Despite an OS of 90% at 5 years, many LGG patients had tumor progression/recurrence requiring additional treatment (PFS= 80% at 2 yrs, 40% at 5 yrs, mean TTP=3.5 years). Four LGG tumors (2 with TP53+ATRXloss, 2 with TP53 loss+1p19q co-deletion) underwent malignant transformation.

CONCLUSION
IDH-mutant tumors in pediatric patients are strongly associated with cancer predisposition and increased risk for progression/recurrence or malignant transformation. Routine screening for IDH1/2 mutations in children with grade 2–4 astrocytomas could greatly impact patient management.
PATH-20. METHYLATION ARRAY PROFILING OF PEDIATRIC BRAIN TUMORS; SINGLE CENTRE EXPERIENCE
Authors: Zapotocky Michal , Vicha Ales , Krskova Lenka , Zamecnik Josef , Stolova Lucie , Misove Adela , Vanova Katerina , Koblizek Miroslav , Ramaswamy Vijay , Jones David , Sumerauer David 
Published: December 2020

Abstract

BACKGROUND
Significant heterogeneity of pediatric brain tumors poses major challenge on diagnostics. Therefore, we aimed to evaluate feasibility of methylation array in the diagnostic process.

METHODS
Methylation array (Infinium MethylationEPIC, Illumina) was performed on DNA extracted from fresh frozen tissue from prospective newly diagnosed and selected retrospective patients. Results from Heidelberg classifier (www.molecularneuropathology.org) were compared to the histological diagnosis and further genetic testing was performed to establish integrated morphological/molecular diagnosis.

RESULTS
Within years 2018–2019, we performed methylation array profiling of 102 samples consisting mainly of ependymoma, medulloblastoma high-grade and low-grade glioma. High calibrated score (&gt;0.9) was achieved in 62 patients (61%). In 46 cases (74%) with score &gt;0.9, the histological diagnosis matched the methylation class (MC). In the remaining cases (16) that were classified by histopathology mainly as ependymomas, the methylation profiles were classified as novel molecular entities (HGNET_BCOR, HGNET_MN1, etc.) or different tumor type. In 40 cases (39%) with the score &lt;0.9, six were found to have high normal tissue content. Nine cases had no match in the classifier and 25 were assigned MC with score 0.3 to 0.89. In 20 out of 34 cases with low score, the molecular diagnosis could be confirmed based on copy number variants inferred from the methylation array or using additional testing for gene fusions and mutations.

CONCLUSIONS
Our experience on the first 100+ cases demonstrated that methylation array could be integral part of diagnostic process in order to establish integrated morphological and molecular diagnosis of pediatric brain tumors.
PATH-22. COMPARISON OF SUPERVISED CLASSIFICATION METHODS FOR CENTRAL NERVOUS SYSTEM TUMORS BASED ON DNA-METHYLATION
Authors: Orr Brent , Breuer Alex , Lin Tong , Tran Quynh , Suh Edward , Pounds Stanley 
Published: December 2020

Abstract
Classification of brain tumors using methylation profiling is an important diagnostic advance, reducing subjectivity and improving interpretability of clinical outcome data. Despite the recognized value of methylation profiling in the clinical laboratory, the performance characteristics of different supervised classification models has not been directly compared. We developed 3 methods using methylation profiles to classify CNS tumors: an exact bootstrap k-nearest neighbor (kNN), a multi-layer perceptron neural net (NN), and a random forest classifier (RF). We trained these methods on the publicly available CNS tumor reference cohort (GSE90496) with 2,801 profiles and 91 classes. We evaluated the performance of these methods by leave-out-25% cross-validation. The relative performance of these methods were evaluated in terms of accuracy, precision, and recall for class or class family. The kNN, RF, and NN classifier had an estimate error rate of 10.74%, 4.01%, and 1.89%, respectively for class prediction and an error rate for family prediction of 5.97%, 0.90%, and 0.6%, respectively. At perfect recall for class assignment, the RF and kNN had a precision of 0.96 and 0.89 while the NN reached 0.98. For family assignment, the precision for the three classifiers was almost 1.0 with recall of nearly 0.8. At the recall rate of 1.0, the precision dropped to 0.94, 0.991 and 0.994 for kNN, RF, and NN, respectively. Overall, the NN showed improved performance metrics compared to the kNN and RF in CNS tumor classification for both class and class family assignment.
PATH-25. GENOME-WIDE METHYLATION ANALYSIS CAN SEGREGATE RADIATION-INDUCED GLIOBLASTOMA FROM LATE RECURRENCE OF MEDULLOBLATOMAS
Authors: Hiraki Takamasa , Fukuoka Kohei , Matsushita Yuko , Hibiya Yuko , Honda Satoko , Mori Makiko , Arakawa Yuki , Ichimura Koichi , Kobayashi Masao , Tanami Yutaka , Nakazawa Atsuko , Kurihara Jun , Koh Katsuyoshi 
Published: December 2020

Abstract
It could be difficult to diagnose recurrent medulloblastoma with conventional diagnostic tools because other lesions mimic relapse of the tumor from both a morphological and radiological standpoint, particularly when it happens late. We report two medulloblastoma cases, both of which seemed to develop late-recurrence more than 5 years from the initial surgery. Genome-wide methylation analysis revealed that one of the recurrent tumors was in fact a radiation-induced glioblastoma. The first patient was a 6-year-old female patient who developed a posterior fossa tumor. The pathological diagnosis was medulloblastoma with focal desmoplasia. She was in complete remission for 9 years after the treatment but developed an intradural lesion in her thoracic spine. The lesion was biopsied and pathologically confirmed as recurrence of the tumor. The second patient was a female patient who developed non-metastatic medulloblastoma at the age of 10. She suffered local recurrence 5 years after the diagnosis. Biopsy was performed, and the pathological diagnosis was relapse of the tumor. We performed unsupervised hierarchical clustering of the methylation data from our cases and reference data. In contrast to consistency of methylation profiling and copy number abnormalities between primary and recurrent tumors of case 1, the analysis revealed that the recurrent tumor of case 2 was distinct from medulloblastomas and clustered with “IDH-wild type glioblastomas”, which suggested that the recurrent tumor was radiation-induced glioblastoma. This report highlights the clinical utility of molecular genetic/epigenetic approach to confirm diagnosis of brain tumor recurrence.
PATH-28. MOLECULAR DIAGNOSIS FOR CENTRAL DIAGNOSIS OF BRAIN TUMORS FROM 2016 TO 2019— A REPORT FROM THE JAPAN CHILDREN’S CANCER GROUP (JCCG)
Authors: Nakano Yoshiko , Hirato Junko , Yoshioka Takako , Nobusawa Sumihito , Shoufuda Tomoko , Kitahara Mai , Fukuoka Kohei , Yamasaki Kai , Sakamoto Hiroaki , Nishikawa Ryo , Hara Junichi , Kanemura Yonehiro , Ichimura Koichi 
Published: December 2020

Abstract

INTRODUCTION
Since 2016, the Japan Children’s Cancer Group (JCCG) has established a nationwide network that prospectively provides pathological review and molecular analysis.

METHODS
Patients who were diagnosed with brain tumors between ages 0 and 29 were eligible. The central office at National Center for Child Health and Development served as a hub for the hospitals involved and institutions conducting pathological and molecular analysis, and managed the patients’ clinical information and tumor samples. Histopathology of all cases were centrally reviewed. Routine non-NGS based analyses were conducted based on histological diagnosis and included pyrosequencing for glioma-associated hot spot mutations and PFA/PFB classification for ependymoma, RT-PCR for RELA fusion and BRAF fusion, and nanostring for subgrouping medulloblastoma. In selected cases, methylation analysis, RNA sequencing and exon sequencing of 93 genes were performed in selected cases.

RESULTS
In total, 985 cases were registered to this study in four years. Frozen samples were collected from approximately 80% of cases. The number increased from 152 in 2016 to 326 in 2019. They includes glioma (n=268), medulloblastoma (n=161), ependymoma (n=103), germ cell tumor (n=93), ATRT (n=29) and others. In 55 % of the glioma cases, at least one abnormality was detected by the routine analysis. The detailed analysis for atypical cases identified targetable alternations. DISCUSSION: This nationwide central diagnostic system has now been well established. Current issues and future prospective of the system will be discussed.
PATH-30. EXOSOMES AS A SOURCE OF PLASMA ctDNA TO IDENTIFY POINT MUTATIONS IN PEDIATRIC GLIOMA PATIENTS
Authors: Nobre Liana , Carreiro Isabel Porto , Camacho Aline Helen da Silva , Reis Rafaela , Chimelli Leila , Zalcberg Ilana , Ferman Sima , Ferman Sima , Mor Barbara Monte 
Published: December 2020

Abstract
Surgery consists in the mainstay of treatment in most gliomas, but in many cases, a resection is not feasible. Liquid biopsy is an ideal tool providing a minimally invasive method through plasma or CSF sampling to assess cell-free tumor DNA (ctDNA). Here we explore the feasibility of detecting DNA in plasma exosomes (exoDNA) extracted from glioma patients and further investigate its use in identifying molecular alterations. Exosomes were isolated from 2ml of plasma from 24 patients (13 LGG, 8 HGG, 3 DIPG) and fully characterized by nanoparticle tracking analysis and transmission electron microscopy. DNA was extracted from 13 samples (exoDNA) so far. Five patients had confirmed point mutations in the primary tumor (3BRAFV600E; 1FGFR1N546K; 1H3.3), additionally, 3 samples were collected from clinically diagnosed DIPG patients to inquire H3K27M mutations. DNA was extracted successfully from all exosome samples; a pre-amplification step was needed and direct sequencing was carried out for BRAFV600E. FGFR1N546K and H3K27M mutations were sought in patients with positive tumors. Wildtype BRAF fragment was identified in 12/13samples (1 patient failed sequencing). However, none of the five tumor positive patients nor the DIPG patients had mutations detected at the exo-DNA level. There is growing evidence that CSF may be the ideal source of ctDNA in brain tumor patients, therefore although we could not detect mutations in plasma DNA we are currently analyzing CSF exoDNA and cell-free DNA to evaluate if this proves a successful strategy and weather exoDNA is more representative of the tumor content.
QOL-04. INFLUENCE OF FAMILY, SCHOOL, AND HOSPITAL SYSTEMS IN SUPPORTING SURVIVORS OF PEDIATRIC BRAIN TUMORS WITH NEUROCOGNITIVE LATE EFFECTS
Authors: Moscato Emily , Gies Lisa , Miley Aimee , Salloum Ralph , Wade Shari 
Published: December 2020

Abstract

OBJECTIVE
Pediatric brain tumor survivors (PBTS) are at risk for developing neurocognitive late effects that may interfere with academic and adaptive functioning. To mitigate the potential impact, some PBTS may implement strategies independently, while others may rely on system-level support from family, school, or hospital systems. Given the limited knowledge on survivor and family perspectives of these supports, we conducted a mixed-methods study involving PBTS and their caregivers to examine the influence of family, educational, and hospital supports, and identify areas of unmet need. PARTICIPANTS AND

METHODS
PBTS (N=56,Mage=18.12,range=10–25) completed questionnaires on academic accommodations. Medical chart reviews provided diagnosis and treatment information. A subset of families, who did not significantly differ from the larger sample on demographics, completed qualitative interviews (N=25). Three coders identified themes separately for parents and survivors and reached consensus (kappa’s &gt; .78) using thematic content analysis.

RESULTS
Families emphasized the role of family support, including providing individualized help, setting up a structured learning environment, and suggesting metacognitive strategies. Parents also emphasized how they have adjusted their expectations. At school, 53% reported an individualized education plan. Formal accommodations (e.g., modified coursework, small group instruction, extra time) were helpful, yet some noted barriers, including embarrassment and lack of follow-through. Survivors emphasized the value of informal accommodations. Families described unmet needs related to connecting with other survivors, navigating community and educational resources, and transitioning to adulthood.

CONCLUSIONS
PBTS seem to rely on systems-level supports to mitigate neurocognitive effects. Future work should strengthen communication between systems and adult transition services.
QOL-11. COMPARISON OF TREATMENT BURDEN RATING SCALES ON NEUROCOGNITIVE OUTCOMES IN A MIXED SAMPLE OF PEDIATRIC BRAIN TUMOR SURVIVORS
Authors: Baig Muhammad , Olsthoorn Ineke , Yang Grace , Zaky Wafik , Stavinoha Peter 
Published: December 2020

Abstract

BACKGROUND
Predicting neurocognitive outcomes in pediatric brain tumor (PBT) patients is challenging. Rarity of PBT makes inclusion of detailed risk factors (e.g., treatment modality, intensity, individual complications) difficult when sample sizes are small. The Neurological Predictor Scale (NPS) summarizes complications and treatment factors associated with neurocognitive risks and has modest validation. Recently, the Pediatric Neuro-Oncology Rating of Treatment Intensity (PNORTI) was developed to evaluate the impact of treatment intensity on psychosocial outcomes but has not been compared to neurocognitive outcomes. This study compared the NPS and PNORTI in terms of relationship to neurocognitive outcomes known to be at risk in PBT survivors.

METHODS
88 PBT survivors’ neuropsychological outcomes were retrospectively analyzed in relation to the NPS and PNORTI. Variables of interest included IQ, working memory, and processing speed.

RESULTS
NPS associated with lower IQ (rs=-.476, p=.001), lower working memory (rs=-.323, p=.010), and lower processing speed (rs=-.389, p=.007) in patients diagnosed at a younger age, but only processing speed for children diagnosed after age 7 years (rs=-.262, p=.036). PNORTI was not correlated with neurocognitive variables for either group.

CONCLUSION
NPS has value in predicting neurocognitive outcomes, though much more in a younger age at diagnosis group compared to older patients. The PNORTI did not demonstrate predictive value for these neurocognitive domains in our sample. Given the potential clinical and research value of a summary rating of treatment burden relating to long-term outcome, future research should include relationship to psychosocial outcomes and quality of life.