bluuebunny/crossref_metadata_2025 huggingface dataset:
MBRS-66. COST-EFFECTIVE METHOD TO INCORPORATE MOLECULAR CLASSIFICATION OF MEDULLOBLASTOMA INTO A LATIN-AMERICAN CLINICAL TRIAL
Authors: Epelman Sidnei , Sakamoto Luis Henrique , Real Juliana Monte , Ramaswamy Vijay , Pereira Gregorio , Aguiar Simone dos Santos , Queiroz Flavia Caldeira
Published: December 2020

BACKGROUND

It is now widely accepted that medulloblastoma actually comprises four distinct molecular subgroups, requiring specific treatment strategies. Implementing routine subgrouping in a time and cost effective manner is a major challenge in Latin America, particularly the development of molecular informed clinical trials. Herein we describe the feasibility of reliable and rapid molecular stratification using a qPCR method integrated with immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH – c-myc, monosomy 6) from heterogeneously fixed, low-quality FFPE samples across Latin America.

RESULTS

Fifty-four FFPE samples were classified according to histologic and molecular criteria. Classic medulloblastoma was found in 53.7%, desmoplastic/extensive nodularity in 24.1%, NOS in 16,7% and anaplastic in 5,6%. IHC markers classified patients in three groups (WNT, SHH and non-WNT/non-SHH) in 98% of cases. PCR-based method confirmed results from IHC in 81,5%. Additionally, we were able to detect WNT activation in 2 patients, previously classified as SHH. For both cases, the presence of monosomy 6 further confirmed WNT subgroup. Integration of these three techniques resulted in the following frequencies: WNT (13.0%), SHH (38.9%), group 3 (9.3%), group 4 (20.3%) and non-WNT/non-SHH (18.5%). From 40 patients with clinical information available, 3-year overall survival (n=40) for low, intermediate and high-risk groups were 100%, 60% and 20%, respectively (p<0.05), based only in molecular criteria, which confirmed the prognostic importance of this method.

CONCLUSIONS

At an estimated cost of $220 per patient, we are able to implement central molecular diagnosis for the incorporation into a prospective clinical trial protocol in Latin America.
MBRS-68. SINGLE NUCLEUS RNA-SEQUENCING DECIPHERS INTRATUMORAL HETEROGENEITY IN MEDULLOBLASTOMA WITH EXTENSIVE NODULARITY (MBEN)
Authors: Ghasemi David N , Okonechnikov Konstantin , Malm Jan-Philipp , Lappalainen Kati , Bauer Katharina , Liberio Michelle S , Giese Laura , Maass Kendra K , Kool Marcel , Jones David T W , von Deimling Andreas , Pfister Stefan M , Korshunov Andrey , Pajtler Kristian W
Published: December 2020

Medulloblastoma (MB) with extensive nodularity (MBEN) represent a rare subtype of cerebellar tumors of infancy which comprise two histologically distinct components, nodular reticulin-free zones and inter-nodular reticulin-rich regions. We applied single nucleus RNA-sequencing (snRNA-seq) using the 10X Genomics and the SMARTseq V2 protocols, bulk RNA-sequencing, DNA-methylation profiling and DNA-panel sequencing to ten histologically confirmed MBEN specimens. All tumors were classified as sonic hedgehog (SHH) MB based on DNA methylation. Somatic mutations within the SHH-pathway were detected in seven samples (3x SUFU, 2x PTCH1, 2x SMO) by DNA panel sequencing. The combined snRNAseq approach resulted in data on ~30.000 single cells. Several non-malignant cell types were identified, e.g. endothelial cells, astrocytes, and microglia. Amongst malignant cell populations SHH-pathway activation and mitotic activity differed revealing actively cycling embryonic stem (ES) cell-like and more differentiated neuronal-like cell types. In addition, distinct histological components of these tumours were subjected to bulk RNA sequencing following microdissection. This approach was repeated for DNA methylation profiling in an independent paraffin embedded MBEN cohort. However, these analyses did not reveal significant transcriptomic differences or differential methylation patterns between the two histological components. In summary, snRNA-seq identified a strongly proliferating, ES-like subset of cells in MBEN, which might represent the driving cell population in these malignancies, while direct analyses of nodular and inter-nodular regions did not reveal any significant differences. These findings suggest that both components originate from the same cell of origin but represent different cellular developmental stages.
MBRS-71. ATAXIA TELANGIECTASIA AND RAD3-RELATED PROTEIN ATTENUATES DNA DAMAGE AND IS A THERAPEUTIC TARGET IN Myc-DRIVEN MEDULLOBLASTOMA
Authors: Abdel-Hafiz Ahmed , Madhavan Krishna , Balakrishnan Ilango , Pierce Angela , Wang Dong , Danis Etienne , Serkova Natalie , Venkataraman Sujatha , Vibhakar Rajeev
Published: December 2020

Group 3 medulloblastoma tumors (Myc-MB), and particularly the 3γ subtype, have the worst prognosis and show a 5-year overall survival of less than 40%. Group 3 tumors are often accompanied by Myc amplification and have a higher rate of metastatic disease and relapse. Unfortunately, therapeutic strategies to target Mychave remained elusive. Further, the relapse of the MB has been linked to DNA replication stress. Ataxia telangiectasia and Rad3-related protein (ATR) senses persistent DNA damage, which arises due to replication stress, and activates damage checkpoints, thereby leading to increased cell survival. ATR is highly expressed in MB and is thought to contribute to undisturbed DNA replication to protect genomic integrity. Yet, the exact underlying mechanisms involving ATR are still unclear in MB. Inhibition of ATR (ATRi) using the ATR inhibitor, AZD6738, suppressed clonogenicity and cell self-renewal in Myc-MB. ATRi in Myc-MB cell lines downregulated Chk1 and upregulated P21. ATRi also induced cell cycle arrest and increased apoptosis in Myc-MB cell lines. Further, mice with orthotopic xenografts treated with ATR inhibitor survived significantly longer than control mice. High-throughput drug screening showed ATRi to be synergistic with chemotherapeutic agents including gemcitabine, cisplatin and topotecan. The treatment of Myc-MB cells with ATR inhibitor in combination with gemcitabine and with radiation increased in expression of DNA damage markers. These findings emphasize the role of ATR in alleviating DNA replication stress and that its inhibition is critical to the treatment of Myc-MB.
MBRS-72. MiR-212 FUNCTIONS AS A TUMOR SUPPRESSOR GENE IN GROUP 3 MEDULLOBLASTOMA VIA TARGETING NUCLEAR FACTOR I/B (NFIB)
Authors: Perumal Naveenkumar , Kanchan Ranjana , Atri Pranita , Venkata Ramakanth , Thapa Ishwor , Nasser Mohd , Batra Surinder , Mahapatra Sidharth
Published: December 2020

Medulloblastoma (MB), the most frequent malignant pediatric brain tumor is divided into four primary subgroups, i.e. wingless-type (WNT), sonic hedgehog (SHH), group 3, and group 4. Haploinsufficiency of chromosome 17p13.3 and c-myc amplification distinguish high-risk group 3 tumors and are associated with rapid recurrence and early mortality. We sought to identify the role of miR-212, which resides on chromosome 17p13.3, in the pathophysiology of group 3 medulloblastoma. RNA expression analyses revealed dramatically reduced levels of miR-212 in group 3 tumors and cell lines mainly through epigenetic silencing via histone modification (deacetylation). Restoring in vitro expression reduced tumor cell proliferation with decreased p-AKT and p-ERK levels, colony formation, migration and invasion in group 3 MB. Interestingly, a shift in differential c-myc phosphorylation (from serine-62 to threonine-58) was noted, resulting in reduced total c-myc levels, concurrent with elevated cellular apoptosis. In turn, pro-apoptotic binding partners of c-myc, i.e. Bin-1 and P19ARF, were upregulated in these cells. A dual luciferase assay confirmed direct targeting of miR-212 to NFIB, a nuclear transcription factor implicated in metastasis and recurrence. Concurrently, increased expression of NFIB was confirmed in group 3 MB tumors with poor survival in high NFIB-expressing patients. Transient NFIB silencing in vitro reduced tumor cell proliferation, migration and invasion, and medullosphere formation along with a reduction in stem cell markers (Nanog, Oct4, Sox2, CD133) and the multi-drug resistance maker, ABCG2. Taken together, these results substantiate the tumor suppressive role of miR-212 in group 3 medulloblastomas and provide a potential new therapeutic target, NFIB.
MBRS-73. AN EXPLORATORY ANALYSIS LOOKING AT THE ASSOCIATION OF GERMLINE CODING MUTATIONS WITH IMPAIRED DEVELOPMENT AND ADAPTIVE BEHAVIOR FUNCTION IN PEDIATRIC MEDULLOBLASTOMA PATIENTS TREATED ON HEAD START 4
Authors: Fleming Jessica L , Sells Blake E , Bell Erica H , McElroy Joseph P , Webb Amy , Zhao Yue , Graham Richard T , Guo Yingshi , Liu Tom , Timmers Cynthia , Dhall Girish , Sands Stephen , Finlay Jonathan , Chakravarti Arnab
Published: December 2020

Children with brain tumors often carry germline mutations known to contribute to tumorigenesis and treatment response; however, little is known about how these mutations impact developmental and behavioral outcomes. As the molecular mechanisms governing cancerous and normal tissues expand, we hypothesize that specific germline variants may impact baseline neurocognitive function and/or treatment-induced toxicities. In this pilot study, ten children on the Head Start 4 (HS4) clinical trial diagnosed with medulloblastoma were assessed for baseline adaptive functioning using the Adaptive Behavior Assessment System Third Edition (ABAS-III) and germline whole-exome sequencing was performed. After filtering for high impact variants, Welch’s T-tests were used to identify mutations associated with lower ABAS-III General Adaptive Composite (GAC) scores, reflecting developmental and adaptive behavior delays compared with peers their age. We found twenty genes with alterations associated with lower scores with p-values less than 0.05. Genes found to be significant included LAMC1 (p=0.04) and KRTAP1-1 (p=0.045), which encode members of the laminin and keratin family respectively and are involved in extracellular matrix adhesion. Mutations in PITX1, a known suppressor of RAS, were also associated with lower ABAS-III GAC scores (p=0.007). We hypothesize that additional analyses of HS4 patients will reveal alterations in cell-to-cell communication and signal transduction pathways, common molecular perturbations in tumors that would likely impact central nervous system function. Validation studies are essential to improve our understanding of the functional impact of germline variants on both tumor and regular tissue biology, allowing for novel strategies to circumvent these delays.
MODL-03. ADAPTING PALBOCICLIB FOR MEDULLOBLASTOMA THERAPY BY IMPROVING DRUG DELIVERY AND ADDRESSING RESISTANCE
Authors: Dismuke Taylor , Gershon Timothy
Published: December 2020

CDK4/6 inhibition may be a promising therapy for medulloblastoma. All medulloblastoma subgroups show D-cyclin/CDK4/RB pathway activity, suggesting broad potential for efficacy. To address drug delivery and systemic toxicity limitations, we developed a nanoparticle formulation of CDK 4/6 inhibitor, palbociclib, in poly (2-oxazoline) micelles (POx-palbo). POx-palbo showed reduced systemic toxicity in transgenic mice engineered to develop medulloblastoma, allowing for higher dosing. Pharmacodynamic studies showed POx-palbo suppressed RB phosphorylation acutely and after 24hrs, the effect diminished. This inhibition produced a longer lasting suppression of SHH pathway activity, demonstrated by Gli-luc reporter tumor mice. Importantly, POx-palbo therapy, administered daily, reduced tumor growth and improved the survival of mice with medulloblastoma. While POx-palbo was clearly effective as a single agent, all mice treated with POx-palbo eventually developed progressive disease, as resistant populations of tumors cells emerged. To understand the mechanisms of resistance, we compared tumors early and late in the course of therapy. We found that after 5 days of treatment, palbociclib altered cell cycle progression to produce an extended period of S-phase and that the fractions of cell expressing the stem cell marker Olig2 were markedly increased. Based on these data, we propose that tumors respond to the initial suppressive effect of palbociclib by increasing the pool of Olig2+ stem cells, that these cells show discernably different cell cycle kinetics and are resistant to CDK4/6 inhibition. Combining POx-palbo with additional therapies that target Olig2+ stem cells, by disrupting their prolonged S-phase, or by disrupting Olig2 function, may lead to newly effective medulloblastoma treatment.
MODL-06. PRECLINICAL EFFICACY OF THE IMIPRIDONE ONC-206 AGAINST MEDULLOBLASTOMA
Authors: Malhotra Anshu , Liu Jingbo , Zhang Hongying , Ma Minhui , Vega Jose Velazquez , Schniederjan Matthew , Prabhu Varun , Allen Joshua , MacDonald Tobey
Published: December 2020

Treatment for medulloblastoma (MB) is typically ineffective for MYC amplified or metastatic SHH, Group 3 and 4 subgroups. Promising preclinical and clinical results have been obtained in brain cancers treated with ONC-201, a selective antagonist of DRD2, a G-protein coupled receptor that regulates prosurvival pathways. Herein, we report the activity of ONC-201 and ONC-206, which has increased non-competitive antagonism of DRD2, against MB. We treated three different MB cell types representative of SHH- and Group 3-like cells, with varied levels of DRD2 expression, and consistently observed increased cell death in a dose-dependent manner at lower doses of ONC-206 compared to ONC-201. We also evaluated ClpP as an additional drug target in MB. ClpP is a mitochondrial protease that has been shown to directly bind and be activated by ONC 201, and is highly expressed at the protein level across pediatric MB, malignant glioma and ATRT, but not normal brain. We observed that similar to ONC-201, ONC-206 treatment of MB cells induces the restoration of mitochondrial membrane potential to the non-proliferative state, degradation of the mitochondrial substrate SDHB, reduction in survivin and elevation in ATF4 (integrated stress response). Importantly, ONC-206 treatment induced significant cell death of patient-derived SHH, WNT, and Group 3 tumors ex vivo and Group 4 cells in vitro, while having no observable toxicity in normal brain. Efficacy studies of ONC-206 against MB in vivo will be reported in preparation for a planned Phase I study of ONC-206 in children with malignant brain tumors.
MODL-14. SMALL MOLECULE TARGETING OF ONCOGENIC FGF2-FGFR SIGNALING IN BRAIN TUMORS
Authors: Kumar Karthiga Santhana , Brunner Cyrill , Schuster Matthias , Zerbe Oliver , Grotzer Michael , Schneider Gisbert , Baumgartner Martin
Published: December 2020

FGF2, the ligand of FGF receptors (FGFRs), is expressed in the developing and adult brain. FGF2-FGFR1 signaling causes the induction and maintenance of cancer stem cells through ERK-dependent up-regulation of ZEB1 and Olig2 in glioblastoma. In SHH medulloblastoma, Olig2 triggers tumor initiation from GCPs, maintains quiescent stem-like cells during the disease and contributes to tumor outgrowth at recurrence. We found that FGF2-FGFR signaling causes increased growth and tissue invasion through the FGFR adaptor protein FRS2 in SHH and group-3 medulloblastoma 1. Thus, targeting of FGFR-FRS2 signaling could abrogate brain tumor growth and spread by repressing tumor-promoting functions that are induced by microenvironmental FGF2. Using virtual screening combined with functional validation, we identified protein-protein interaction inhibitors (F2i) that bind FRS2 and abrogate FGFR signaling to the MAP-ERK pathway. Consistent with the requirement of FRS2 for pro-invasive signaling downstream of FGFR1 in medulloblastoma, F2i also efficiently block FGF2-induced migration and invasion in medulloblastoma-derived cells. Selected F2i display excellent binding kinetics with a similar Kd as the natural ligand domain of FGFR and cause steric alterations in the targeted protein domain. On-target activity was confirmed by thermal proteome profiling. Neither in silico screening nor empirical testing revealed significant off-target activity of the compounds. No toxicity of F2i was observed in cell-based models with confirmed functional activity on invasion and MAPK activation. Thus, we identified novel, low molecular weight pharmacological protein-protein interaction inhibitors with an excellent potential to specifically block FGFR functions relevant for brain tumor progression. 1. Santhana Kumar et al., CellReports23, 3798–3812.e8 (2018).
MODL-19. DIPG HARBOUR ALTERATIONS TARGETABLE BY MEK INHIBITORS, WITH ACQUIRED RESISTANCE MECHANISMS OVERCOME BY COMBINATORIAL UP- OR DOWN-STREAM INHIBITION
Authors: Izquierdo Elisa , Carvalho Diana , Mackay Alan , Temelso Sara , Boult Jessica K R , Molinari Valeria , Stubbs Mark , Depani Sarita , O’Hare Patricia , Robinson Simon P , Hubank Michael , Hargrave Darren , Jones Chris
Published: December 2020

The survival of children with DIPG remains dismal, with new treatments desperately needed. In the era of precision medicine, targeted therapies represent an exciting treatment opportunity, yet resistance can rapidly emerge, playing an important role in treatment failure. In a prospective biopsy-stratified clinical trial (BIOMEDE), we combined detailed molecular profiling (methylation BeadArray, exome, RNAseq, phospho-proteomics) linked to drug screening in newly-established patient-derived models of DIPG in vitro and in vivo. We identified a high degree of in vitro sensitivity to the MEK inhibitor trametinib (GI50 16-50nM) in samples which harboured genetic alterations targeting the MAPK pathway, including the non-canonical BRAF_G469V mutation, and those affecting PIK3R1. Treatment of PDX models and the patient with trametinib at relapse, however, failed to elicit a significant response. We generated trametinib-resistant clones (62-188-fold, GI50 2.4–5.2µM) in the BRAF_G469V model through continuous drug exposure, and identified acquired mutations in MEK1/2 (MEK1_K57N, MEK1_I141S and MEK2_I115N) with sustained pathway up-regulation. These cells showed the hallmarks of mesenchymal transition, with overexpression of key proteins involved in invasion/migration, such as collagen-family proteins, integrins, MMPs and AHNAK2, amongst others. Resistant clones were conversely sensitive to the upstream receptor tyrosine kinase inhibitor dasatinib (GI50 36-93nM), and combinations of trametinib with dasatinib and the downstream ERK inhibitor ulixertinib showed synergistic effects in vitro. These data highlight the MAPK pathway as a therapeutic target in DIPG, and show the importance of parallel resistance modelling and rational combinatorial treatments likely to be required for meaningful clinical translation.
MODL-23. DNA METHYLATION AND COPY NUMBER VARIATION PROFILE FOR CHARACTERIZATION OF PEDIATRIC BRAIN TUMOR PRIMARY CELL LINES
Authors: Pedace Lucia , Vinci Maria , Pizzi Simone , Pericoli Giulia , Catanzaro Giuseppina , Abballe Luana , Del Bufalo Francesca , Caruana Ignazio , Camassei Francesca Diomedi , Rossi Sabrina , Giangaspero Felice , Ferretti Elisabetta , Ciolfi Andrea , Tartaglia Marco , Locatelli Franco , Mastronuzzi Angela , Miele Evelina
Published: December 2020

BACKGROUND

In vitro models of pediatric brain tumors (pBT) are instrumental for both understanding the oncogenic molecular mechanisms and identifying/testing new therapeutic strategies. DNA methylation (DM) is a stable epigenetic modification recently used to classify tumors. We aim to apply DM and Copy Number Variation (CNV) profiling to characterize pBT primary cell lines and tumors.

METHODS

We included 36 pBT tissues from different histology (13 LGG, 9 DIPG, 9 HGG, 3 MB, and 2 Ependymomas), paired to their derived primary cultures. Cultures were established in two-dimensional (2D) or three-dimensional (3D) condition, as stem-cell or in serum-supplemented medium. For 9 cultures, both early (P2-P3) and long-term passages (>P4) were considered. Samples were analyzed for DM and CNV profiles using Illumina EPIC arrays and data compared with those of the brain tumor classifier.

RESULTS

At early passages all cells retained the same DM and genetic patterns of original tumors, with no differences related to 2D/3D methods or presence of serum in media. Primary cell lines analyzed at > P4 and cultured in serum diverged from the primary tumor.

CONCLUSIONS

DM profiles and CNV are useful tools to detect the recapitulation of pBT-derived primary cell-lines from the original tumor. Whatever subgroups tested, results suggest that in vitro models should be passaged as little as possible to retain the epigenetic and genetic alterations of the tumors and thus to be considered relevant for basic and translational biology. Ongoing experiments are aimed to determine how stable DM and CNV are in other conditions/tumor subgroups.
NFB-04. EXAMINING DIFFUSION, ARTERIAL SPIN-LABELED PERFUSION, AND VOLUMETRIC CHANGES IN THE NEUROFIBROMATOSIS TYPE 1 BRAIN USING AN ATLAS-BASED, MULTI-PARAMETRIC APPROACH
Authors: Tam Lydia , Ng Nathan , Moon Peter , Zheng Jimmy , McKenna Emily , Forkert Nils , Campen Cynthia , Yeom Kristen
Published: December 2020

BACKGROUND

Neurofibromatosis Type 1 (NF1) is a multisystem disorder with wide ranging clinical implications. Patients may present with macrocephaly, stroke, and cognitive deficits, all of which may impede normal neural development. We applied atlas-based, multi-parametric MRI analysis of regional brain to evaluate diffusion, arterial spin-labeled (ASL) perfusion, and volumetric changes in children with NF1.

METHODS

Children evaluated for NF1 from 2009 to 2018 at Stanford University (n=78) were retrospectively reviewed and compared to healthy controls (n=100). All patients underwent diffusion-weighted (DWI) magnetic resonance imaging at 3T, and children with brain tumors were excluded. Using atlas-based DWI analyses, we assessed volume, median apparent diffusion coefficient (ADC), and cerebral blood flow in the cerebral cortex, thalamus, caudate, putamen, globus pallidus, hippocampus, amygdala, nucleus accumbens, brain stem, and cerebral white matter. We also measured volume of the lateral ventricles. Multivariate analysis of covariance was used to test for differences between controls and NF1 patients, controlling for gender and age at time of imaging.

RESULTS

Comparing NF1 to controls, we detected increased volume and decreased ASL cerebral blood flow in white matter and all subcortical and cortical structures except for brainstem volume. Median ADC was also increased in the thalamus, pallidum, hippocampus, and brainstem.

CONCLUSIONS

Using a multi-parametric approach, we demonstrate quantitative measures of microstructural and physiologic changes of the NF1 brain. Atlas-based, quantitative MRI brain signatures may serve as biomarkers of neural development and further provide insight into associated cognitive dysfunction or risks for vasculopathy-related strokes in children with NF1.
NFB-11. WHITE MATTER DIFFERENCES IN CHILDREN WITH NF1 COMPARED TO CONTROLS
Authors: Bruckert Lisa , Travis Katie , McKenna Emily , Yeom Kristen , Campen Cynthia
Published: December 2020

INTRODUCTION

Neurofibromatosis type 1 (NF1) is a genetic condition in which children develop learning challenges and glioma. White matter tracts (WMT) are implicated in these cognitive functions, while oligodendroglial precursor cells are implicated in both gliomagenesis and white-matter development. Specific WMTs have not been well characterized in NF1.

METHODS

Twenty NF1 patients aged 1.4–17.6 years (M = 9.5 years, 24 male) and 20 age-and-sex-matched controls underwent dMRI at 3T (25 directions, b=1000 s/mm2). Automated segmentation of WMTs extracted fractional anisotropy (FA) and mean diffusivity (MD) of 18 major WMTs. Covariance analysis examined the effect of group (NF1/controls) on FA/MD after controlling for intracranial volume. Regression analyses for WMTs determined the interaction of FA/MD with age for NF1 patients compared to controls. Significance was set at p<0.05 after correcting for multiple comparisons using false discovery rate.

RESULTS

Compared to controls, children with NF1 had significantly decreased FA in 8 and increased MD in 12/18 tracts. Differences held after controlling for intracranial volume. The interaction between group and age accounted for a significant proportion of the variance in FA in 9 and in MD in 16/18 tracts. FA and MD differences between children with NF1 and controls were greater at younger than older ages.

CONCLUSION

Microstructural differences were observed in WMTs in children with NF1 compared to controls. These differences were not explained by intracranial volume and were most pronounced in younger children with NF1 compared to controls. These findings have implications for understanding neurocognitive deficits and gliomagenesis observed in children with NF1.
NFB-14. PSYCHOSOCIAL OUTCOMES IN CHILDREN WITH NEUROFIBROMATOSIS TYPE 1 AND PLEXIFORM NEUROFIBROMAS
Authors: Damodharan Sudarshawn , Mission Paige , Puccetti Diane
Published: December 2020

OBJECTIVE

This case series seeks to examine neurocognitive outcomes, social-emotional functioning, and family burden in young children diagnosed with Neurofibromatosis, type 1 (NF1) with early growing plexiform neurofibromas (PNFs).

BACKGROUND

Neurofibromatosis, type 1 (NF1) is a common predisposing chronic disease arising in early childhood, with an incidence of approximately 1:3000. Though NF1 displays a wide range of phenotypic variability, the primary feature of the disease is peripheral nerve sheath tumors called neurofibromas. Less is well known regarding the broader neurocognitive and social-emotional profile in presentations with more complex tumor growths, namely PNFs, which are present in at least half of the NF1-affected population.

METHODS

Participants with NF1 and PNFs (n=2) aged 6-7years completed comprehensive neuropsychological evaluations and parents completed measures of quality of life, social-emotional/behavioral functioning of child, parental stress, family adaptability, and family cohesion.

RESULTS

Outcomes suggest broad neurocognitive dysfunction (e.g., executive functioning deficits, attention problems, visual-motor delays, and poor motor coordination), social-emotional challenges (e.g., symptoms of anxiety and depression, and poor social skills), and familial distress.

CONCLUSIONS

Findings indicate the value of early and frequent monitoring of children with PNFs in medical systems and multi-disciplinary teams, and the importance of early intervention for both children and families.
NURS-03. DEVELOPMENT OF A PATIENT-HELD TREATMENT SUMMARY FOR PAEDIATRIC CNS TUMOUR PATIENTS
Authors: McAndrew Rachel , Wilkie Bernadine , Brougham Mark , Phillips Jo
Published: December 2020

BACKGROUND

Following the Scottish Government Cancer Plan 2012–15(1) ‘End of Treatment’ summaries for paediatric oncology patients treated in SE Scotland have been successfully implemented. However, it became evident that the particular needs of patients with CNS tumours were not adequately captured on the standardised documentation.

METHODS

In view of these difficulties an alternative document was prepared specifically for this patient cohort by the multi-disciplinary team, including Nurse Specialists, Paediatric Neuro-oncology and Neuro-psychology. This was designed to be a flexible, fluid summary to be used for all such patients regardless of tumour grade or treatment modality and included those undergoing surveillance only. OUTCOMES: The document is primarily completed by the Neuro-Oncology Nurse Specialist alongside the patient and family, usually following initial treatment and is used alongside their holistic needs assessment. The document is circulated to all involved professionals, including Primary Care, and a copy is retained by the patient. This then provides a concise source of information detailing diagnosis and treatment, any specific ongoing sequelae and details of red flag symptoms to alert patients and health professionals to the potential of relapse or other associated significant health problems. These treatment summaries are currently being piloted and have been well received thus far. They will be formally audited in due course with the aim to use nationally throughout Scotland in future.
NURS-07. STAFF EDUCATION THROUGH NURSING AND PHARMACY COLLABORATION
Authors: Hancock Lauren , Pittman Whitney
Published: December 2020

Even within the focused field of pediatric oncology, there are healthcare providers who lack education regarding the specialized population of children with brain tumors. In order to improve staff knowledge of pediatric neuro-oncology, nursing and pharmacy developed a collaborative Lunch and Learn program to provide additional education. An eight week brain tumor curriculum was developed, and informal sessions grouped by diagnosis were held over lunch between the neuro-oncology nursing team (nurse practitioners and nurse coordinator) and a clinical pharmacy resident. A nurse practitioner provided academic literature and the pharmacy resident did further research and developed an outline for discussion. During these sessions, nursing was able to contribute academic knowledge and clinical experience, while pharmacy presented an overview of each tumor and provided education about medications. After each session, the pharmacy resident presented the information from the Lunch and Learn to all staff oncology pharmacists, which then increased their working knowledge of neuro-oncology as a whole, helping them feel better able to manage this population within their scope of practice. Because this innovative collaboration was so successful in heightening knowledge and awareness of the care and management of pediatric neuro-oncology patients for all those involved, the team now has future plans to utilize a similar model to provide neuro-oncology education to clinic and inpatient RNs.
NURS-08. A CASE REPORT OF RARE AND PROFOUND ANTEROGRADE AMNESIA IN A PAEDIATRIC SURVIVOR OF A BIFOCAL NON GERMINOMATOUS GERM CELL TUMOUR AND DIABETES INSIPIDUS
Authors: Bland Elizabeth
Published: December 2020

We present the case of a 12yo female who presented to the emergency department with increasing agitation, confusion, fluctuating GCS, hydrocephalus, and deranged electrolytes. MRI revealed tumour in pineal region and filling the third ventricle. Biopsy and tumour markers confirmed the diagnosis of bifocal Non Germinomatous Germ Cell Tumour (NGGCT). The diagnosis was complicated with the secondary diagnoses of diabetes insipidus and profound permanent anterograde amnesia. Whilst DI is common in NGGT in pineal region, anterograde amnesia is a very rare condition in paediatrics. Thus there is paucity of literature available to the clinicians to know how much improvement to expect or how to target rehabilitation whilst undergoing curative therapy, chemotherapy and craniospinal irradiation; however the importance of a consistent and coordinated nursing and allied health team approach with structure and errorless learning must be initiated from the beginning if independence is to be achieved.
NURS-09. INTRODUCTION OF A WELLNESS PROGRAM FOR PEDIATRIC NEURO-ONCOLOGY PROVIDERS
Authors: Waters Kaaren , Morgan Helene , Rangan Kasey , Bira Kim , Davidson Tom , Robison Nathan , Margol Ashley
Published: December 2020

INTRODUCTION

Pediatric oncology providers have unique and rewarding careers. The medical and psychosocial complexity of caring for pediatric oncology patients and their family units is simultaneously inspiring and challenging. In addition, the complex demands of the healthcare system can lead to chronic stress, burnout, and disruption to the healthcare professional’s individual well-being. Time constraints, lack of resources, and limited access to wellness interventions serve as barriers for providers to address adaptive coping within themselves. Identifying gaps to achieving wellness and implementing interventions may lead to improved equanimity for pediatric oncology providers in their personal lives as well as their medical practice.

METHODS

An interdisciplinary team of nurse practitioners and physicians in a large pediatric neuro-oncology program at an academic institution completed anonymized wellness self-assessments regarding the areas of emotional, environmental, intellectual, occupational, physical, social, spiritual, coping, and professional role wellness. The results were analyzed and barriers to provider health and well-being were identified. Tailored and regularly scheduled wellness interventions were implemented for the study participants addressing the identified wellness barriers. Participants will each complete post-intervention wellness self-assessments to evaluate the effectiveness of the program.

CONCLUSION

The introduction of a provider wellness program exemplifies a feasible approach to identify barriers and evaluate efficacy of wellness interventions in achieving multi-factorial provider wellness. Secondary aims include dissemination of findings, with the intention of cultivating improvement in provider quality of life throughout the healthcare profession, and the ultimate goal of improving care to patients and families.
NURS-11. MARIJUANA, HEMP, AND THE CHILD WITH CANCER: PATIENT, PARENT, AND CLINICIAN EDUCATION
Authors: Hemenway Molly
Published: December 2020

Many pediatric oncology patients report medical marijuana (MMJ) and hemp-based CBD use. Eleven states and Washington, DC have legalized marijuana for recreational use for adults greater than 21. Medical marijuana is legalized in 33 states. Additionally, due to the bipartisan Farm Bill passed in December of 2018, hemp is federally legal. Marijuana has medical legalization in 23 countries worldwide. Clinical trials in adults have examined MMJ for cancer-related symptoms. New research is emerging on MMJ in anticancer therapy, MMJ receptors on tumor cells, and the potential role for MMJ as an immunomodulator. Few pediatric oncology studies have evaluated MMJ. We describe the initial findings of a prospective observational study of MMJ on the quality of life (QOL) in pediatric brain tumor patients. Specific aims included (1) MMJ’s association with symptoms (nausea, anxiety, pain, fatigue, and cognitive problems) and (2) MMJ’s impact on family dynamics. The legality of hemp plus the increasing use of MMJ raises concerns with pharmacological interactions with CBD and the medications routinely administered to children with cancer. Nurses are the frontline for discussions with patients about MMJ and must be aware of the emerging field of MMJ in pediatric cancer. Additionally, nurses can influence patient care protocols and processes for alternative therapy administration enabling an open dialogue between providers, parents, and patients regarding treatments, symptoms, adverse effects, and drug interactions. Education about how to have conversations about important facets to cover and consider is crucial to patient safety and increased quality of life.
OTHR-02. MULTIMODALITY TREATMENT FOR CHILDREN WITH CENTRAL NERVOUS SYSTEM (CNS) TUMOR IN OUR INSTITUTE
Authors: Sasano Mari , Sumi Koichiro , Moro Nobuhiro , Oshima Hideki , Hirai Maiko , Yagasaki Hiroshi , Yoshino Atsuo
Published: December 2020

BACKGROUND

The brain tumor has a highest mortality rate among childhood malignant tumors. Development of peripheral blood stem cell transplant combined chemotherapy and radiation therapy improved the survival rate of patients with pediatric brain tumor drastically late years. Because of its complicated treatment plan, neurosurgeons cannot readily manage these aggressive therapies which require minute whole body control including prevention of lethal infection due to bone marrow suppression. Even if such treatment is effective and patient survives, the aftereffects may reduce patient’s QOL.

PURPOSE

We report outcomes of the patients with CNS tumor after multimodality treatment. In addition, we introduce the activity contents by the in-hospital children brain tumor multi-disciplinary medical treatment team organized in March 2016.

METHODS

We retrospectively reviewed 29 patients (under 15 years old) diagnosed as CNS tumors with total of 43 tumor surgeries between January 2001 and December 2019.

RESULTS

The histopathological diagnoses were 7 germ cell tumor, 7 astrocytic tumor, 4 ependymal tumor, 4 medulloblastoma, 2 craniopharyngioma, 2 AT/RT and 3 others. The mean age at first surgery was 7.4 y.o. (range: 0.3–14.8). Both chemotherapy and radiation therapy were performed in 22 cases out of 29. There were 15 survivors (11 ambulant, 3 W/C, 1 bedridden), 12 deaths, 2 lost follow-ups. Mean follow-up period was 66 months (range: 1–206).

CONCLUSION

To improve outcomes, we hold on a regular basis of team meeting, discuss treatment plan, and share information. Recently, we also care issues of the patients, such as fertility and palliative medicine.
OTHR-07. CHRONIC ENCEPHALOPATHY DUE TO METHOTREXATE NEUROTOXICITY AS A RARE COMPLICATION IN A CHILD WITH LEUKEMIA: A CASE REPORT
Authors: Rafli Achmad , Adiprabowo Srisadono Fauzi , Rahmartani Ludi Dhyani , Handryastuti Setyo
Published: December 2020

Methotrexate (MTX) is an essential component of chemotherapy for childhood acute lymphoblastic leukemia (ALL). Both intravenous (IV) and most commonly intrathecal (IT) routes of MTX have been complicated in acute, subacute, and chronic neurotoxicity syndromes. A 9-year-old girl had been diagnosed with standard risk ALL since 2011 with first chemotherapy protocol was Indonesian protocol standard risk ALL 2006 and remission in 2012. On July 2015, patient was diagnosed as relapse ALL and underwent Indonesian protocol high risk ALL 2013. The last chemotherapy protocol of patient was Indonesian protocol high risk ALL 2013 maintenance phase 89th weeks with total dosage of MTX was 336 mg (IT), 6000 mg/m2 (IV), and 2500 mg/m2 orally. Her presenting symptom was progressive decrease of consciousness since 3 months before hospital admission. First brain computed tomography (CT-Scan) and magnetic resonance imaging (MRI) revealed brain atrophy. One month later she had abnormality in behavior and functional ability with second brain CT-Scan revealed brain atrophy and lacunar infarct in left pons. This case can be in accordance with chronic encephalopathy due to MTX. It is important to recognize early complications taking the form of subclinical or symptomatic CNS damage (e.g. headache, dizziness, tremor, ataxia, aphasia, dysarthria, emotional instabilities, seizures, hemiparesis, encephalopathy) that can occur in the course of chemotherapy especially MTX. Determination of the cause of encephalopathy is associated with considerable difficulty despite the use of various diagnostic methods and also treatment of MTX neurotoxicity is mainly supportive and recovery is usually complete. Keywords: imaging, methotrexate, neurotoxicity, leukemia
OTHR-14. DIENCEPHALIC SYNDROME SECONDARY TO PITUITARY STALK THICKENING
Authors: Almeida Carlos , Mançano Bruna Minniti , Eugui Gilda D’Agostino , Matsushita Marcus , Alvarenga Gabrielle , Lourenço Lucas Dias
Published: December 2020

BACKGROUND

Diencephalic syndrome (DS) is a rare condition associated with neoplastic lesions of the sellar-suprasellar region, whose pathophysiological mechanisms are still unclear. DS occurs in <10% of hypothalamic gliomas and has also been described in suprasellar germinomas, craniopharyngiomas, epidermoid cysts, rarely with non-suprasellar lesions such as brainstem gliomas. DS has not been associated with isolated pituitary stalk thickening. Isolated pituitary stalk thickening (IPST) presents a diagnostic challenge, ranging from benign (craniopharyngioma) to malignant lesions (germinoma, metastasis, histiocytoses of the Langerhans group). The coexistence of diabetes insipidus (DI) with anterior pituitary dysfunction and IPST implies more risk to harbor neoplasia. CASE REPORT: A 6-year old girl presented with DI and inadequate weight gain (despite regular caloric intake) and preservation of linear growth. Neurological examination showed no abnormalities. However, physical examination revealed a malnourished patient (both weight-for-age value and body-mass-index below the third percentile). Blood tests and negative IgA anti-endomysial antibodies excluded malabsorption as a cause of her malnutrition; endocrine work-up excluded thyroid dysfunction, growth hormone deficiency, and adrenal insufficiency. Magnetic resonance imaging (MRI) showed thickening of the pituitary stalk with a transverse diameter of 7 mm. The patient underwent a biopsy through a supraorbital eyebrow approach. Histopathological examination revealed lymphocytic hypophysitis, with tissue markers all negative for germinoma. The girl is currently under follow up with serial MRI every three months.

CONCLUSION

DS should be considered as a differential diagnosis in any child with failure to thrive, and imaging studies should be performed even if there are no additional neurological symptoms.
OTHR-16. CONCURRENT USE OF APREPITANT AND IFOSFAMIDE IN PEDIATRIC CANCER PATIENTS
Authors: Winzent Shelby , Dahl Nathan , Hemenway Molly , Lovria Rachel , Dorris Kathleen
Published: December 2020

BACKGROUND

Aprepitant, a selective neurokinin-1 receptor antagonist, is commonly used for prevention of chemotherapy-induced nausea and vomiting. Its use with ifosfamide is controversial due to the putative risk of potentiating neurotoxicity via inhibition of cytochrome P450 3A4 (CYP3A4). The current literature examining this interaction is inconclusive, and little data exists in pediatrics. We seek to describe a single-institution experience with concurrent aprepitant and ifosfamide administration.

METHODS

A retrospective review of patients treated with ifosfamide and aprepitant from 2009–2018 was conducted. Data collected included demographics, tumor type, number of days of concurrent therapy, dosing, and documented of neurotoxicity.

RESULTS

Twenty patients aged 7–21 years (median 17 years) were identified. Diagnoses included thirteen sarcomas and seven CNS tumors (6 germ cell tumors; 1 intracranial sarcoma). Five patients received high dose ifosfamide (>2,000mg/m2/day). The number of concurrent ifosfamide and aprepitant doses ranged from 2–18 (median, 8.5). Only one patient (5%) developed ifosfamide-induced neurotoxicity: a 7-year-old female with a nongerminomatous germ cell tumor who presented with seizures and somnolence. She received methylene blue and returned to her neurologic baseline. She completed her ifosfamide course without incident. She was the only patient to require weight-based aprepitant dosing and to receive the liquid formulation.

CONCLUSIONS

Aprepitant should be used with caution when administered concurrently with ifosfamide due to the risk of neurotoxicity. However, the incidence of neurotoxicity in this retrospective pediatric cohort was low. This interaction may be more significant in younger patients due to age-related differences in hepatic metabolism, but further study is required.
PATH-03. HIGH-GRADE NEUROEPITHELIAL TUMOR SHOWING BCOR IMMUNOPOSITIVITY WITHOUT EXON 15 INTERNAL TANDEM DUPLICATIONS IN A FIVE-YEAR-OLD BOY: A CASE REPORT
Authors: Wakita Shogo , Matsutani Tomoo , Watanabe Yosuke , Hirono Seiichiro , Higuchi Yoshinori , Iwadate Yasuo , Ikeda Zyunichiro , Yokoo Hideaki
Published: December 2020

Recent DNA methylation profiling clarified several rare entities of pediatric CNS tumors from institutionally-diagnosed primitive neuroectodermal tumors (PNETs). One of which is CNS high-grade neuroepithelial tumor with BCOR alteration (CNS HGNET-BCOR), and it carries in-frame internal tandem duplications (ITD) of the BCL6 corepressor (BCOR) in exon 15. In the report, we describe a case of immunohistologically-diagnosed CNS HGNET-BCOR, which lacks exon 15 ITD of BCOR. A five-year-old boy visited a local hospital complaining uncontrolled vomiting for two months, and magnetic resonance imaging (MRI) showed a large well-circumscribed mass in his left cerebellum with ventricular dilatation. He referred to our hospital, and an additional MRI revealed diffuse and weak enhancement of gadolinium and low ADC values in mass. Immediately, he underwent total removal of the tumor and ventricular drainage, and his consciousness recovered soon after surgery. The tumor presented high BCOR expression by IHC, but target PCR did not identify exon 15 ITD of BCOR. As the previously-reported clinical and imaging features of CNS HGNET-BCOR resembled our case, we clinically diagnosed it as a similar phenotype of CNS HGNET-BCOR without exon 15 ITD. He received 60 Gy of extended-local irradiation with concomitant temozolomide and discharged without any neurological deficits. Since BCOR alterations, including ITD, gene fusions, and mutations, play an oncogenic role in several cancers, the present case might harbor another gene aberration of BCOR.
PATH-06. IMAGE-BASED MACHINE LEARNING CLASSIFIER FOR PEDIATRIC POSTERIOR FOSSA TUMOR HISTOPATHOLOGY
Authors: Tam Lydia , Bala Wasif , Lavezo Jonathan , Lummus Seth , Vogel Hannes , Yeom Kristen
Published: December 2020

BACKGROUND

Pediatric posterior fossa (PF) tumors can include astrocytomas, ependymomas, and medulloblastomas, all of which demonstrate unique histopathology. Whole slide image analyses can be time consuming and difficult. Therefore, we used machine learning to create a screenshot-based histopathology image classifier that can distinguish between types of pediatric PF tumors.

METHODS

We took 179 histopathology slides from Stanford University, dated from 2008–2019: 87 astrocytomas, 42 ependymomas, and 50 medulloblastomas, per pathology report. Each slide was viewed under a microscope at 20x. Then, a screenshot was taken of the region of interest representative of principal slide pathology, confirmed by a trained neuropathologist. These screenshots were used to train Resnet-18 models pre-trained on the ImageNet dataset and modified to predict three classes. Various models with different hyperparameters were trained using a random hyperparameter search method. Trained models were evaluated using 5-fold cross-validation, assigning 20% of the dataset for validation with each evaluation. Qualitative analysis of model performance was assessed by creating Class Activation Map (CAM) representations of image predictions.

RESULTS

The top performing Resnet-18 model achieved a cross-validation F1 of 0.967 on categorizing screenshots of tumor pathology into three types. Qualitative analysis using CAMs indicated the model was able to identify salient distinguishing features of each tumor type.

CONCLUSIONS

We present a PF lesion classifier capable of distinguishing between astrocytomas, ependymomas, and medulloblastomas based on a histopathology screenshot. Given its ease of use, this tool has potential as an educational tool in an academic setting.