bluuebunny/crossref_metadata_2025 huggingface dataset:
MEDB-77. Metastasic medulloblastoma: radiological features and its correlation with molecular subgroups and dissemination pattern
Authors: Bellón Marina Caballero , Moreno Marta Pérez-Somarriba , Lavarino Cinzia , Lopez Vicente Santa-María , Martinez Ofelia Cruz , Lopez Jordi Muchart , La Madrid Andrés Morales
Published: June 2022

Medulloblastoma (MB) is the most frequent malignant childhood brain tumor. Four molecular subgroups have been described (WNT, SHH, group3, group4), which are associated with a different biological profile, prognosis, specific MRI characteristics and patterns of metastatic dissemination. We aimed to determine the imaging features of the metastatic MB and its molecular subgroup and their outcomes. Retrospective single-center analytic-observational study conducted from January 2004-January 2022 in a tertiary-care center. Pediatric patients with metastatic medulloblastoma at disease onset were included. We collected epidemiological and clinical characteristics, treatment received, and outcomes. The molecular subgroup was determined by its methylation profile. MRI were reviewed by the neuroradiologist. Sixty-three patients were diagnosed, 17 (26.9%) were metastatic. The median age at diagnosis was 5.1 years (range 2.1-17.5 years), 58.8% were male. According to histopathologic classification, fifteen patients (93.8%) were classic,1 (6.3%) desmoplastic. Molecular subgroup analysis showed 2 WNT (12.5%), 1 SHH (6.3%), 3 (18.8%) group 3 (G3) and 5 (31.2%) group 4 (G4). Four patients (25%) were classified as G3/G4 and 1 (6.3%) as mixed. Five patients (29.4%) were M2 and 12 patients (70.6%) were M3 according to Chang staging system. The location in the cerebellar hemispheres was only observed in SHH patient while G3 tumors presented homogeneous contrast enhancement. All WNT, G3 and G4 were located in IV ventricle. We found no association between molecular subgroup and metastatic site (intracranial vs spinal, Fisher test, p=0.45). All patients presented with metastasis in the third ventricular infundibular recess were G4. Four patients died, all of them were G3 or G3/G4. Our results supported the literature previously reported. According to the MRI imaging features, the molecular medulloblastoma subgroups could be suggested. The presence of metastasis in the infundibular recess suggested MB group 4. However, the dissemination pattern could not be associated with any subgroup in our series.
MEDB-79. MYC-driven upregulation of thede novo serine and glycine pathway is a novel therapeutic target for Group 3 MYC-amplified Medulloblastoma
Authors: Adiamah Magretta , Lindsey Janet C , Burté Florence , Kohe Sarah , Morcavallo Alaide , Blair Helen , Hill Rebecca M , Singh Mankaran , Crosier Stephen , Zhang Tong , Maddocks Oliver , Peet Andrew , Chesler Louis , Hickson Ian , Maxwell Ross , Clifford Steven C
Published: June 2022

Despite advances in the molecular sub-classification and risk-stratification of medulloblastoma (MB), a subset of tumours remain refractory to current multimodal therapies. Group 3 (MBGroup3) patients represent around 25% of MBs, and amplification and elevated expression of MYC in this group correlates with dismal clinical outcomes. Since direct targeting of MYC remains elusive, understanding and exploiting metabolic dependencies in MYC-amplified MBGroup3 may reveal novel therapeutic opportunities. We engineered three independent regulable MYC-amplified MBGroup3 cell-based models, each harbouring doxycycline-inducible anti-MYC shRNAs (two independent species) or a non-silencing shRNA control. In all three models, MYC knockdown (KD) revealed persistent MYC-dependent cancer phenotypes, reduction in proliferation and cell cycle progression. We utilised 1H high-resolution magic angle spectroscopy (HRMAS) and stable isotope-resolved metabolomics to assess changes in intracellular metabolites and pathway dynamics when MYC expression was modulated. Profiling revealed consistent MYC-dependent changes in metabolite concentrations across models. Notably, glycine was consistently accumulated following MYC KD suggesting altered pathway dynamics. 13C-glucose tracing further revealed a reduction in glucose-derived serine and glycine (de novo synthesis) following MYC KD which was attributable to lower expression of PHGDH, the rate-limiting enzyme of this pathway. Furthermore, in human primary tumours, elevated expression of PHGDH was associated with MYC amplification and poorer survival outcomes. MYC expressing cells showed greater sensitivity to pharmacological inhibition of PHGDH compared to MYC KD (MBGroup3) and MBSHH subgroup cell lines in vitro. Critically, targeting PHGDH in vivo, using MYC-dependent xenografts and genetically engineered mouse models, consistently slowed tumour progression and increased survival. In summary, metabolic profiling has uncovered MYC-dependent metabolic alterations and revealed the de novo serine/glycine synthesis pathway as a novel and clinically relevant therapeutic target in MYC-amplified MBGroup3. Together, these findings reveal metabolic vulnerabilities of MYC-amplified MBGroup3 which represent novel therapeutic opportunities for this poor-prognosis disease group.
MEDB-82. Exploring cell-cell communication networks in medulloblastoma using single-cell genomics
Authors: Gabler Lisa , Gojo Johannes , Smith Kyle S , Bihannic Laure , Filbin Mariella G , Northcott Paul A , Berger Walter , Hovestadt Volker
Published: June 2022

Medulloblastoma is a high-risk embryonal brain tumor arising in the cerebellum. Genomic profiling has revealed a striking molecular heterogeneity between medulloblastoma patients, yet treatment regimens are mostly uniform. Many children with medulloblastoma die from their disease and surviving patients often face severe long-term side effects, highlighting an urgent need for more effective treatment options. We and others have recently identified pronounced intra-tumoral heterogeneity and defined cellular hierarchies within medulloblastoma tumors. The functional role of these cellular hierarchies remains unknown. We now hypothesize the existence of an inter-cellular communication network that is maintained by receptor/ligand interactions. To test our hypothesis, we use our medulloblastoma single-cell RNA sequencing dataset of 25 patients, as well as bulk RNA sequencing, DNA methylation array, and genome sequencing data across molecular subtypes. Single-cell RNA sequencing data are analyzed to dissect cell compartments characterized by high expression of potentially oncogenic receptors and their respective ligands. Consequently, cell type-specific roles in auto- or paracrine signal transduction within the cellular community are explored. We further investigate downstream oncogenic signaling pathways by approximating transcription factor activity and explore genetic and epigenetic activation mechanisms by matched genome sequencing and DNA methylation profiling, respectively. Our findings will be applied to deconvolute bulk RNA sequencing data, thus identifying therapeutically relevant signaling networks in larger cohorts of medulloblastoma patients. Eventually, candidate targets will be validated on patient-derived cell models and xenografts by overexpression and inhibition studies. Together, here we aim at identifying tumor-driving receptor/ligand interactions in medulloblastoma, with the goal to define targets susceptible to precision oncology approaches.
MEDB-87. Transcriptome-driven drug repurposing in group 3 medulloblastoma
Authors: Doss David , Kanchan Ranjana , Perumal Naveenkumar , Batra Surinder , Mahapatra Sidharth
Published: June 2022

Across the molecular spectrum of medulloblastoma (MB), group 3 (G3) tumors are the most aggressive with <50% five-year survival, the lowest of all MB subgroups. G3 MB tumors are characterized by frequent metastases at diagnosis, unique methylation profiles, MYC amplification, and i17q, but these unique molecular features have yet to be exploited for therapeutic purposes despite their contribution to the disease process. As such, we sought to address this gap in survivorship by identifying FDA-approved compounds with the potential to inhibit cellular processes critical to G3 MB tumor proliferation and metastasis, aiming to exploit the unique molecular pathogenesis of G3 tumors. Guided by analysis of RNA-sequencing data from locally obtained, patient-derived MB samples against the LINCS chemical perturbagens database, we identified nortriptyline (NT), a tricyclic antidepressant, as a candidate MB therapeutic due to: 1) its ability to revert the transcriptomic signature of G3 MB to a normal cerebellum-like state and 2) its ability to cross the blood-brain barrier. We first identified the IC50 of NT in D425 and HDMB03 cells as 28μM and 20μM, respectively. Then, we observed that NT increased apoptosis of HDMB03 cells 3-fold by flow cytometry and confirmed our observations with Western blotting of apoptotic markers. Additionally, NT treatment resulted in abrogation of colony formation, impairment of wound healing, and inhibition of cell migration and invasion in vitro in HDMB03 cells. In all, transcriptome-driven drug repurposing holds great promise, as identifying novel uses for compounds with a known safety profile can deliver effective treatments into the hands of both patients and physicians in an expedited manner when compared to traditional means.
MEDB-89. Elucidation of the Oncogenic role of Nuclear Factor I/B (NFIB) in group 3 medulloblastoma
Authors: Perumal Naveenkumar , Kanchan Ranjana , Doss David , Thapa Ishwor , Nasser Mohd W , Batra Surinder , Mahapatra Sidharth
Published: June 2022

Amongst the 4 subgroups of medulloblastoma (MB), tumors falling into group 3 are the most aggressive and associated with increased incidence of aberrations on chromosome 17p, c-Myc amplification, metastases at diagnosis, and rapid tumor relapse. Thus, patients with group 3 tumors suffer the worst prognosis with a 5-year survival rate of <50%. We have prior identified a novel tumor-suppressive microRNA, miR-212, silenced on chromosome 17p and its deregulated oncoprotein target, Nuclear Factor I/B (NFIB). Here, we sought to identify the role of NFIB in group 3 MB pathophysiology. NFIB is a transcription factor that regulates chromosomal gene accessibility and expression of pro-metastatic genes in various cancers. Transcriptomic interrogation of group 3 tumors revealed deregulated expression of NFIB. Kaplan-Meier survival analysis confirmed poorer survival in NFIB high-expressing patients. Using inducible silencing of NFIB in a classic group 3 MB cell line, HDMB03, we observed downregulation of key driver genes (49 genes, Log2 fold change < -0.5, p < 0.001) associated with group 3 MB pathogenesis by RNA sequencing. NFIB expression knockdown (NFIBKD) further reduced tumor cell growth and aggressiveness, as evidenced by reduced proliferation, colony formation, migration, and invasion. NFIBKD also affected group 3 MB stemness, with attenuation of medullospheres and a reduction in stem cell markers (Nanog, Oct4, Sox2, CD133). Moreover, NFIBKD destabilized c-Myc phosphorylation at serine-62, resulting in reduced total c-Myc levels and subsequent cellular apoptosis. Concurrently, NFIBKD decreased the expression of upstream activators of c-Myc such as p-Akt and p-Erk. Taken together, these results validate the oncogenic role of NFIB in group 3 medulloblastomas and provide a potential new therapeutic target.
NFB-05. A family-centered neurocutaneous syndrome clinic in the age of targeted therapies
Authors: Marks Asher , Antaya Richard , Balsamo Lyn , Cardinale Kathleen , Cheron Rebecca , Frumberg David , Gentile Victoria , Habib Larissa , Puthenpura Vidya , Zhang Hui
Published: June 2022

On April 10, 2020, the FDA approved selumetinib for the treatment of pediatric patients 2 years of age and older with neurofibromatosis type 1 who have symptomatic, inoperable plexiform neurofibromas. This, combined with the 2016 EXIST-3 data showing the efficacy of adjunctive everolimus in the treatment of tuberous sclerosis associated seizures, have resulted in the re-imagining of the treatment of these neurocutaneous syndromes and subsequently, the multidisciplinary clinics in which they are treated. In early 2021, this reshaping resulted in the launch of a unique, family-centered clinic at Yale New Haven Children’s Hospital serving children and young adults up to 30 years of age in the management of NF1, NF2, tuberous sclerosis and schwannomatosis. Here we present the clinical reasoning and benefit of a multidisciplinary, family-centered clinic that manages to combine on-site, real-time access to neuro-oncology, neurology, psychology, dermatology, orthopedics, genetics, and ophthalmology. We will describe how the collaboration of these specialists is essential for providing high-quality, easy-access care to patients and families with the above noted syndromes – particularly with the advent of effective, readily available targeted therapies that carry their own side effects requiring further subspecialty consultation. Furthermore, we will describe previous and ongoing challenges to the creation of such a clinic and offer solutions based on our experience.
NFB-12. Effect of trametinib on leg length discrepancy in a child with NF1 related plexiform neurofibroma
Authors: Pradeep Celia , Abouassaly Marcel , Assis Zarina , Finkbeiner Melanie , Lafay-Cousin Lucie
Published: June 2022

INTRODUCTION: Plexiform neurofibroma(PN) is a challenging benign tumor. Recently, MEK inhibitors (MEKi) showed encouraging tumor response. We report the observed effect of Trametinib on leg length discrepancy (LLD) in a child with NF1. CASE DESCRIPTION: A 4 year old girl with sporadic NF1, developed progressive bilateral L1-L5 paraspinal PN extending to the left thigh resulting in hypertrophy of left leg and associated with LLD. At 33 months of age, length difference of 2.8 cm between both femurs was described on scanogram with a projected LLD of at 6.1- 6.2 cm LLD at bone maturity using the multiplier method, a common method of predicting LLD. At 36 months of age, treatment with Trametinib was initiated for her large PN. Ten months into therapy, parents reported impression of decrease swelling of her left thigh enlargement. MRI evaluation showed stable measurement of PN using the RECIST criteria. Repeat measurement on scanogram at 46 months of age disclosed a stable difference of 2.8 cm between both femurs, with a LLD projected at 5.2-5.3 cm at maturity by multiplier method. Bone age at study entry and at 11 months into therapy (Greulich-Pyle) was reported normal for chronologic age. DISCUSSION/CONCLUSION: LLD has not been commonly described in association with NF1 related PN. Given the PN involved mainly the left thigh in our patient, it is reasonable to suggest common underlying mechanism for the PN and faster growth of her left femur. Although with limited time point’s measurements, the early observation of stabilization of the LLD, 10 months into Trametinib therapy suggesting a final discrepancy in femurs length less than initially predicted, is encouraging. Further evaluation at completion of treatment and on follow-up are needed. Larger case series will be useful to explore this unexpected and possible clinical effect of MEKi in NF1 children.
NFB-20. Pre-clinical models of Mismatch Repair Deficient Gliomas
Authors: Putnam Ethan , Yadavilli Sridevi , Dawood Adam , Mizoguchi Sean , Subramaniam Bavani , Bornhorst Miriam , Nazarian Javad
Published: June 2022

INTRODUCTION: Lynch syndrome and Biallelic Mismatch Repair Deficiency (BMMRD) are hereditary tumor predisposition syndromes, resulting from one or two (respectively) germline alterations in DNA mis-match repair (MMR) genes. Currently, there are few treatments for mismatch repair deficient (MMRD) gliomas, in part due to a lack of suitable pre-clinical models for drug testing. The purpose of this study is to develop and characterize pre-clinical models of MMRD gliomas. METHODS: Primary cells were developed from patients diagnosed with MMRD gliomas and characterized through immunofluorescence staining (IF) for different cell type markers, western blot assays, and genome and transcriptome analysis. Murine models were generated through intracranial injection of mCherry-luciferase reporter expressing primary cells, and mice were monitored for evidence of engraftment and clinical symptoms. Drug screening on the cell lines was performed to identify potential therapeutic agents for in-vivo testing. RESULTS: The cell lines had similar characteristics as the primary glial tumors by IF staining and genome and transcriptome analysis. Adult NSG mice developed tumors around three weeks after intercranial transplantation of the tumor cells. These tumors closely resembled the primary patient tumors on histology. Preliminary drug testing on the cell lines showed efficacy of ONC201, ONC206, and RM006 against MMRD gliomas with IC50 concentrations of 1.77 μM, 185 nM, and 699 nM respectively. CONCLUSION: The generation of pre-clinical MMRD glioma models can lead to improved understanding of tumorigenesis, allowing for the identification of targetable molecules, and supporting novel treatment development.
QOL-03. Beyond Survival: Clinical Rehabilitation and Functional Optimization Pearls for the Neuro-Oncologist
Authors: Rosenberg Nathan
Published: June 2022

Over the past decades, major advances in treatment for pediatric brain tumors have led to higher survival rates. Management including surgical resection, chemotherapy and radiation have led to prolonged survival though each comes with potential deleterious impact upon a child's level of function. While function-sparing treatments continue to be developed and utilized each year, the standard of care for many conditions leaves our patients with the potential for worsening function. The areas of mobility, activities of daily living, cognition, communication and swallow are all potentially impacted. Rehabilitation medicine specialists focus on detecting impairments, addressing them with practical interventions and improving the function our shared patients. Unfortunately, there is a worldwide scarcity of rehabilitation medicine physicians and the role of improving function often falls into the hands of the neuro-oncologist. A number of practical clinical assessments and interventions utilized by rehabilitation medicine specialists can be translated to the toolbox of the neuro-oncoligst. The aim of this presentation is to provide the neuro-oncologist with further abilities to enhance function with interventions that typically require low time investment. Topics covered will include the following: 1. What is spasticity, when is it necessary to treat and how is it treated? 2. Leg braces -- who needs them, who doesn't and what are the goals? 3. What physical exam signs can be utilized to detect peripheral neuropathy early and inform further treatment decisions with agents such as Vincristine. 4. What aspects of a gait assessment are high yield in detecting concern for clinical progression? The goal of this talk is high yield and low time investment.. It is unfortunately not applicable for a poster presentation. A minimum amount of time would be 15 minutes. If less time is available for the this presentation, a photo/video-based, rapid-fire format (similar to Tik-Tok content) could be utilized.
QOL-05. Cardiorespiratory fitness and health-related quality of life amongst survivors of childhood central nervous system tumours.
Authors: Keating Rachael , Curry Sarah , Hussey Juliette
Published: June 2022

INTRODUCTION: Due to recent advancements in surgical techniques, imaging and adjuvant therapies, survival rates for children with central nervous system (CNS) tumours have improved. Research priorities have now shifted to focus on late-effects and quality of survivorship amongst childhood CNS tumour survivors. Our study aimed to assess levels of cardiorespiratory fitness and health-related quality of life (HRQoL) amongst survivors of childhood CNS tumours. A secondary aim was to investigate potential relationships between cardiorespiratory fitness and HRQoL. METHODS: Participants were recruited from the National Children’s Cancer Service in CHI Crumlin. Inclusion criteria included: diagnosis of a primary CNS tumour, aged between 6-17 years, between 3 months and 5 years post completion of oncology treatment, independent mobility, deemed clinically appropriate to participate by treating oncologist. Cardiorespiratory fitness was assessed using the six-minute walk test. HRQoL was assessed with the PedsQL Generic Core Scales, Version 4.0, both self-report and parent proxy report forms were used. RESULTS: 20 participants (n=9 male) were recruited with a mean age of 12.34 (SD = 3.46) years. Mean time since completion of oncology treatment was 2.31 (SD = 1.38) years. Mean 6-minute walk distance (6MWD) was 482.75 (SD = 50.04) metres, equating to the 5.55th (SD = 6.83th) percentile overall. 6MWD was significantly reduced compared to predicted 6MWD (t = -12.52, p <.001, 95% CI [-163.52, -116.68]). Parent proxy-reported HRQoL was significantly reduced compared to healthy population norms (t = -5.82, p <0.001, 95% CI [-25.76, -12.17]). A strong positive correlation exists between 6MWD and both parent-proxy (Pearson’s r = 0.533, p = 0.015) and child-reported HRQoL (r = 0.580, p = 0.007). CONCLUSION: Survivors of childhood CNS tumours present with impaired levels of cardiorespiratory fitness and HRQoL compared to healthy population norms. Higher levels of cardiorespiratory fitness are associated with higher levels of HRQoL.
QOL-09. SyMon-SAYS: A symptom monitoring and reporting program for children with cancer
Authors: Lai Jin-Shei , Jensen Sally , Urban Megan , Goldman Stewart , Lenzen Alicia
Published: June 2022

Unrelieved symptom burden due to cancer treatments can lead to poor psychosocial functioning and decreased health-related quality of life (HRQOL) for patients and their families. Barriers at the patient, healthcare provider and system levels can contribute to poor symptom management. Funded by the US National Cancer Institute, we have developed the Symptom Monitoring & Systematic Assessment and Reporting System in Young Survivors (SyMon-SAYS) program. SyMon-SAYS is a technology-based program with the potential to minimize symptom management barriers by routinely collecting and interpreting patient-reported outcomes in pediatric oncology ambulatory settings in a manner that is efficient, actionable by clinicians, supports engagement of patients and families with their health and care, and improves clinical processes and outcomes. This is a single institution modified waitlist control 16-week randomized trial of 200 children (ages 8-17) with cancer and their parents/guardians. Participants in the intervention phase will complete a symptom checklist weekly via the electronic health record patient portal. Scores exceeding a pre-defined threshold will trigger an alert to the treatment team, which will review the report and take appropriate actions. Participants will complete a separate battery of questionnaires assessing HRQOL at baseline and weeks 8 and 16. The recruitment is in progress. As of today, we have recruited 57 patients/parents. 29 completed 16-week study (15 intervention & 14 wait-list). Preliminary results showed SyMon-SAYS system was easy (92%) and convenient (85%) to use. Parents were satisfied (74.1%) with the SyMon-SAYS program. Comparing to the waitlist control, intervention group parents reported significantly less concerns on not having enough time to discuss their child’s symptoms with treating clinicians (p=0.0022), and disagreed that it is not necessary to treat their child’s symptoms as they will go away (p=0.04). We anticipate completing the recruitment by the end of 2023.
QOL-11. Comparison of Neuropsychological Functioning in Pediatric Posterior Fossa Tumor Survivors: Medulloblastoma, Low-Grade Astrocytoma, and Healthy Controls
Authors: Levitch Cara , Holland Alice Ann , Bledsoe Jesse , Kim Soo Young , Barnett Marie , Ramjan Sameera , Sands Stephen
Published: June 2022

BACKGROUND: Neuropsychological comparison of medulloblastoma (MB) and cerebellar low-grade astrocytoma (LGA) survivors to controls can clarify treatment-related neurocognitive late effects. While both brain tumor groups undergo surgery to the posterior fossa, children with MB additionally receive craniospinal irradiation with boost and chemotherapy. This study provides an updated comparison of neuropsychological functioning in these two groups and examines effects of demographic risk factors upon outcomes. PROCEDURE: Forty-two children (16 MB, 9 LGA, 17 controls) completed measures of intellectual functioning, verbal learning/memory, visual-motor integration, and fine motor functioning. The effects of age at diagnosis, time since diagnosis, gender, fatigue, and social status on neuropsychological functioning were examined. RESULTS: MB survivors demonstrated the worst neurocognitive late effects, but they were less severe and extensive than in prior studies. LGA survivors’ mean scores were below normative expectations in working memory, processing speed, and fine motor functioning. Additionally, parents of LGA survivors reported the most difficulty with behavior and cognitive regulation compared to healthy controls and medulloblastoma survivors. In this overall sample, processing speed difficulties were independent of fine motor functioning and fatigue. Higher parental education was associated with better intellectual functioning, working memory, delayed recall, and visual-motor integration. Neuropsychological function was not associated with gender, age at diagnosis, or time since diagnosis. CONCLUSION: The results support that contemporary treatment approaches with craniospinal irradiation plus boost and chemotherapy confer the greatest risk for late effects, while surgical resection is associated with subtle but important neurocognitive difficulties. Ultimately, this study furthers our understanding of factors impacting neuropsychological function in pediatric MB and LGA survivors and contributes to empirical support for close monitoring and targeted interventions into survivorship.
QOL-14. Long term neurocognitive and psychosocial outcomes among adolescents and young adults survivors of paediatric brain tumour.
Authors: Profio Sonia Di , De Giuseppe Sara , Robotti Sabrina , Uccello Miriana , Crocco Marco , Verrico Antonio , Piccolo Gianluca , Satragno Camilla , Milanaccio Claudia , Venturino Cristina , Garrè Maria Luisa
Published: June 2022

PURPOSE: The aim of the study was to describe neurocognitive and psychological outcomes among adolescents and young adults (AYA) survivors of paediatric brain tumour (BT). METHODS: neurocognitive and psychological assessment of 45 AYA (M = 30; F = 15), treated for paediatric BT at our institution between 1978 and 2018, were retrospectively collected. Survivors received psychological and neurocognitive assessment at a mean age of 21.4 years (range 15.11-39.4) after a median of 120 months from diagnosis. The assessment was carried out using the following self-report questionnaires: Beck Depression Inventory, State-Trait Anxiety Inventory, Body Uneasiness Test, Multidimensional Fatigue Inventory, European Organization for the Research and Treatment of Cancer Quality of LifeQuestionnaire. Neurocognitive evaluation was carried out using Wechsler Adult Intelligence Scale. RESULTS: 18/45 survivors had received a diagnosis of germ cell tumor, 12 of low grades glioma, 10 of embryonal tumor, 3 of high-grade glioma, 2 of meninges and mesenchymal tumor. Thirty-four patients received neurosurgery, 34 patients chemotherapy, 44 patients cranial radiotherapy. Fatigue was reported in 56% of the patients, 15% of them also showed low level of QoL. The psychological assessment showed clinical levels of anxiety in 56% of AYA, depression in 41% and body image problems in 29%. Neurocognitive assessment showed that 73% has an average tIQ (tIQ ≥ 80). CONCLUSIONS: The psychological evaluation showed that 77% of our cohort had at least one clinically significant distress symptom as fatigue, depressive symptoms, anxiety and body image problems, compared to 23% who did not report any problem. Further analysis is needed to identify any possible psychopathological risk factors. It is essential to provide an accurate and comprehensive assessment and effective psychological support to these patients, to help them better manage the late effects of cancer and therapies at different levels: physical, psychological and neurocognitive.
QOL-22. Neurocognitive performance in survivors of pediatric brain tumors with neurocutaneous syndromes
Authors: Tonning Olsson Ingrid
Published: June 2022

BACKGROUND: Pediatric brain tumors (PBT) in children with neurocutaneous syndromes are typically low-grade and survival rates are close to 100%. Neurocutaneous syndromes are associated with neurocognitive and behavioral problems, and a diagnosis of brain tumor adds to the total neurocognitive burden. The aim of this study was to describe neurocognitive performance in survivors of PBT with a neurocutaneous syndrome and to find associated factors. METHOD: Neurocognitive data (verbal and non-verbal reasoning, cognitive processing speed, working memory, and executive function) on 20 survivors of brain tumors with neurocutaneous syndromes were collected from medical logs. Results were converted to z-scores (m=0, sd=1) using age-adjusted national norms. Generalized linear models were built to find factors associated with neurocognitive performance. Most survivors had received several assessments and all assessments were added to the model together with time since diagnosis at assessment. RESULTS: Seventeen of the survivors (85%) had undergone 1-3 assessments and 3 survivors had undergone 4-5 assessments. Six survivors (30%) had a diagnosis of intellectual disability, and neurocognitive scores were low at all assessment points: average z-score across all datapoints(sd): verbal reasoning -1.1(1.2); non-verbal reasoning -1.2(0.9); working memory -1.9(0.7); cognitive processing speed -1.0 (1.0); executive function -0.6 (1.0)). Factors associated with worse neurocognitive performance were young age at brain tumor diagnosis, larger tumors, epilepsy, and longer time span between diagnosis and assessment. CONCLUSIONS: Survivors of PBT with neurocutaneous syndromes are at risk for neurocognitive deficits that might worsen over time. These survivors need personalized neurocognitive follow-up. When examining neurocognitive performance and associated factors in survivors of PBT special consideration needs to be taken to survivors with neurocutaneous syndrome since these survivors receive limited cancer treatment and still have neurocognitive deficits.
QOL-23. Expanded protocols for hearing loss related cisplatin-based therapy in childhood cancer patients.
Authors: Grosnik Amy , Graham Richard T , Pillay-Smiley Natasha , de Blank Peter , Hummel Trent , Mochizuki Aaron , Raskin Scott , Windmill Ian
Published: June 2022

BACKGROUND: Most children who require cisplatin chemotherapy incur hearing loss. The basal end of the cochlea, corresponding to high frequency sound perception, is typically affected first, with progression along the basilar membrane and to lower frequencies over time. Typical audiologic protocols for children are often restricted to the speech frequencies (500-4000Hz). However, reliable responses to higher frequencies can be obtained using specialized electrophysiologic measures or adapted behavioral test procedures, which may lead to earlier identification of hearing loss during ototoxicity monitoring. METHODS: Auditory Brainstem Response (ABR) and behavioral threshold assessments were completed for patients during cisplatin treatment at Cincinnati Children’s Hospital between 2017 and 2021. High frequency ABR protocols were established to include 6000 and 8000 Hz and behavioral testing protocols were expanded to include frequencies 8000 through 16000 Hz. Hearing loss was defined as >20 dB eHL at any frequency. The typical and high frequency protocols were compared to determine if higher frequency measurement provides a more sensitive means to detect the onset of hearing loss. RESULTS: One-hundred and fifty-three patients receiving cisplatin were assessed audiometrically. For patients who required ABR evaluations, 38% were identified with hearing loss when using the typical test protocol, where 79% of the patients were identified with hearing loss when using the high frequency protocol. For patients who were able to complete behavioral audiometric evaluations, 42% were identified with hearing loss with the typical protocol while 84% were identified with the high frequency protocol. CONCLUSIONS: The addition of higher frequencies to audiologic evaluation protocols for both ABR and behavioral audiometry significantly increases sensitivity to detect hearing loss during ototoxicity monitoring of cisplatin treatment and is a feasible strategy in pediatric cancer patients. Audiologically, the increased sensitivity to detect hearing loss may lead to earlier intervention regarding hearing and communication for the patient/family.
QOL-24. Evaluating the diagnostic validity & predictive value of the Cerebellar Cognitive Affective Syndrome (CCAS) in pediatric posterior fossa tumour patients
Authors: Hoffmann-Lamplmair Doris , Leiss Ulrike , Peyrl Andreas , Slavc Irene , Czech Thomas , Gram Alexandra , Pletschko Thomas
Published: June 2022

OBJECTIVE: The present study aimed to examine the extent of deficits associated with the Cerebellar Cognitive Affective Syndrome (CCAS) in patients treated for paediatric posterior fossa tumours (PFT). Furthermore, we wanted to assess its diagnostic validity and predictive value for late sequelae. METHOD: Neuropsychological test data from 56 PFT patients treated at our pediatric neuro-onocology unit (mean age at treatment: seven years; mean age at first neuropsychological examination: nine years) were examined for severity of deficits in the CCAS core domains of executive functions, verbal functions, visuospatial abilities and emotions/behaviour. Patients with CCAS (n=20) were compared to two control groups without the syndrome (PFT patients treated either surgically (n=18) or surgically followed by radio/chemotherapy (n=18)) in terms of long-term neuropsychological and educational outcomes (mean age: 14 years). We also examined risk factors for CCAS development. RESULTS: The results showed mild to severe impairment in at least one CCAS domain in 55 out of 56 patients. Complete CCAS was diagnosed in 35.7% of cases. Seven years after tumour diagnosis, information processing, logical thinking, verbal functions, visuospatial skills and executive functions were more impaired in CCAS patients than in controls. They also needed more special educational support. Information processing speed was equally poor in CCAS patients and in controls treated with chemotherapy/radiotherapy. A significant association was found between risk factors and deficits in information processing speed, but not with the occurrence of CCAS. CONCLUSION: Deficits in the central CCAS features are common in PFT patients, but in varying degrees, suggesting that it is a continuous syndrome rather than a dichotomous one. However, it is problematic that domains such as information processing speed are not included in the diagnosis. External criteria regarding everyday life should be considered in future studies.
QOL-27. Sociocultural variables have a major impact on participation in patients treated for pediatric posterior fossa tumors
Authors: Hoffmann-Lamplmair Doris , Gram Alexandra , Krottendorfer Kerstin , Peyrl Andreas , Leiss Ulrike , Czech Thomas , Slavc Irene , Pletschko Thomas
Published: June 2022

OBJECTIVE: This study investigates the extent of participation barriers in patients with pediatric posterior fossa tumors (PFTs) at long-term follow-up. While most studies focus on pathobiological variables that promote the occurrence of adverse late effects, the present analysis aims to investigate the importance of environmental variables. METHOD: Ten years after tumor diagnosis, 42 patients (mean age: 17 years) treated at our pediatric neuro-oncology unit were assessed for school and social difficulties using a questionnaire developed within the framework of this study. Participation barriers were assumed if patients and/or their parents reported difficulties at school or with peers. The children and adolescents were classified into groups with adequate and limited participation. Potential pathobiological (treatment type, hydrocephalus, tumor recurrence, gender, age at diagnosis, seizures, cerebellar mutism) and environmental risk factors (parental and maternal education, siblings, primary language, discrepancies between personal and environmental values, regular physical activity, private housing) were identified and examined to see if the participation groups differed in the amount of risk factors. RESULTS: Almost a decade after treatment, two thirds of the patients had school and/or social difficulties. Not only pathobiological risk factors (type of treatment, hydrocephalus, tumor recurrence, cerebellar mutism and seizures), but also environmental factors (low maternal education level, siblings, a main language other than German, discrepancies between social and personal values, and irregular physical activity) were associated with limited participation. These variables discriminated significantly between patients with and without participation barriers. CONCLUSION: Participation barriers in patients treated for pediatric PFT are frequent. In addition to pathobiological variables, environmental risk factors also play an important role in limiting school and social participation. This underlines the fact that a sole consideration of pathobiology is not sufficient when examining risk factors for the occurrence of late effects. The adoption of biopsychosocial perspectives in future studies is inevitable.
NURS-02. Incorporating Nurses and Advanced Practice Providers into Clinical Trial Consortiums; results of a multi-institutional survey from the Pacific Pediatric Neuro-Oncology Consortium (PNOC)
Authors: Raber Shannon , Hoffman Carly , Kline Cassie , Prados Michael , Mueller Sabine , Meyer Ashley
Published: June 2022

BACKGROUND: Incorporation of nurses and advanced practice providers (APPs) creates an opportunity to enhance the work of clinical trial consortia in providing care to children with central nervous system tumors enrolled on clinical trials. Within PNOC, nurses and APPs led an effort to engage nurse scientists in collaborative work. A formalized APP and nursing committee confirmed multi-institutional interest for this effort via a widely distributed, electronic survey. OBJECTIVES: The primary aim was to assess the need for a nursing and APP committee by surveying nurses, APPs, physicians, and CRCs across academic institutions within US and international sites. A secondary aim was to explore educational needs of nurses and APPs and establish resources to augment clinical trial protocol initiation and compliance. METHODS: A de-identified, electronic Qualtrics survey was distributed to all PNOC member institutions in Fall 2021. Participants were divided into 3 groups: physicians, nurses or APPs, and CRCs. RESULTS: A total of 68 participants from 20 different institutions completed surveys. All groups confirmed support for a formalized nursing and APP committee within PNOC. Nurses requested education on targeted therapies, specific study protocols, general neuro-oncology information, and late effects. Barriers for nurse participation included lack of dedicated time (50%) and travel funding for conferences (39%). The surveys elicited physicians overwhelmingly identified key needs for APP or nursing involvement in standardizing protocolized care across institutions (100%), education for patients and staff (95%), and protocol development (89%). CONCLUSIONS: Based on multi-institutional survey results, a nursing and APP working group has been established within PNOC. In response to the needs-based survey, the working group provides a quarterly nursing newsletter, offers education sessions and mentorship opportunities, and participates in multi-disciplinary, disease-specific working groups. Future efforts will review the impact of this committee on protocol development and compliance and overall clinical care of pediatric neuro-oncology patients.
OTHR-05. Visual impairment in children with a newly diagnosed brain tumor: a Dutch prospective nationwide cohort study
Authors: Nuijts Myrthe , Stegeman Inge , Seeters Tom , Bennebroek Carlien , Naus Nicole , Porro Giorgio , van Egmond-Ebbeling Michelle , Imhof Saskia , van Meeteren Antoinette Schouten-
Published: June 2022

PURPOSE: Visual impairment is a serious adverse effect in children with a brain tumor. To date, visual impairment is often underestimated and unrecognized, while early detection of visual impairment is important to potentially preserve the visual function. Our aim was to assess the prevalence and type of abnormal ophthalmological findings in an unselected cohort of children with a newly diagnosed brain tumor and to identify potential oncological and clinical risk factors. PATIENTS AND METHODS: In this prospective nationwide cohort study, we included children, aged 0-18 years, with a newly diagnosed brain tumor in the Netherlands between May 2019 and August 2021. A comprehensive ophthalmological examination (including orthoptic evaluation, visual acuity, visual fields and funduscopy) was performed at diagnosis. Multivariable logistic regression analyses were performed to estimate the odds ratio (OR) and 95% confidence interval (CI) of the risk factors. RESULTS: In total, 170 children were included (43.5% female; median age [interquartile range], 8.3 [3.9 – 13.0] years; 48.2% infratentorial tumors, 31.2% midline tumors and 20.6% cerebral hemispheres tumors). Overall, 101 children (59.4%) presented with visual symptoms at diagnosis. The most common findings on ophthalmological examination were papilledema (52.4%), gaze deficits (33.5%), visual field defects (28.1%), nystagmus (24.8%), strabismus (19.9%) and decreased visual acuity (8.6%). The risk of papilledema was associated with older age in years (OR 1.2, 95% CI 1.1 – 1.3) and hydrocephalus (OR 14.8, 95% CI 5.4 – 40.0). Visual field defects were detected more frequently in children with a tumor located in the cerebral hemisphere (OR 4.5, 95% CI 1.3 – 15.3) or midline (OR 7.0, 95% CI 2.2 – 21.9). CONCLUSIONS: More than 50% of the children had abnormal ophthalmological findings at brain tumor diagnosis. These findings emphasize the necessity of standardized ophthalmological surveillance and the importance of awareness of health care providers of ophthalmological abnormalities in this patient group.
OTHR-06. Knowledge gap among health care providers in childhood central nervous system tumors: Result from an international multicenter survey
Authors: Rajagopal Revathi , Moreira Daniel C , Faughnan Lane , Wang Huiqi , Naqvi Sameen , Devidas Meenakshi , Qaddoumi Ibrahim
Published: June 2022

BACKGROUND: Central nervous system (CNS) tumors in children are associated with a longer delay in diagnosis. One of the contributing factors is the lack of awareness regarding childhood CNS tumors presentation among health care providers. To evaluate the knowledge gap among health care providers, we conducted a cross-sectional survey that was distributed globally. METHODS: The survey was disseminated to health care practitioners via electronic mail in November 2018 and it was closed in March 2020. The participants were asked to complete a pre-test survey, requested to view a CNS tumor education seminar, and subsequently complete a post-test survey. The survey had nine questions focusing on CNS tumor symptoms, pre-diagnosis symptom interval (PSI), and imaging indication. The knowledge gap was evaluated with pre-test and post-test scores. RESULTS: 889 pre-test and 392 post-test responses were received. The majority of the respondents were from Asia, with a percentage of 73.1% and 87.5% in pre-test and post-test respectively. For the pre-test, the median score for accurate answers was 40.0% (range:13.1-92.9%). Interestingly, a high rate of correctness was achieved in the post-test with a median score of 77.1% (14.9-98.2%). In the pre-test, only 18.7% of the participants responded precisely that Cushing’s triad is a less common symptom and just 15.0% recognized that older children >10 years old are at risk for late diagnosis. Surprisingly, 21.9% falsely reported that patients with malignant tumors experience the longest PSI, and 54.5% of the respondents wrongly selected medulloblastoma as the commonest CNS tumor. Overall, the pre-test scores among pediatricians and professionals with >10 years of experience did not demonstrate improved knowledge when compared to other specialties. CONCLUSIONS: The survey analysis showed a significant knowledge gap regarding childhood CNS tumors among health care providers. Therefore, raising professional awareness is very important and can be achieved through targeted educational strategies.
OTHR-09. The prevalence and complex management of MEK inhibitor induced cutaneous side effects
Authors: Meyer Ashley , Ogle Andrea , Shatara Margaret , Cantor Evan , Cluster Andrew , McHugh Michele , Beck Mary , Reiners Stephanie , Coughlin Carrie , Abdelbaki Mohamed , Brossier Nicole
Published: June 2022

BACKGROUND: Cutaneous side effects commonly occur with MEK inhibitor (MEKi) therapy and can be challenging to manage. METHODS: A retrospective chart review was performed on sixteen pediatric patients treated with MEKi therapy for at least three months. These patients were diagnosed with either a brain tumor, plexiform neurofibroma, Langerhans Cell Histiocytosis, or Parkes Weber Syndrome (PWS). OBJECTIVES: To describe cutaneous side effects from MEKi therapy, compare the side effect profiles of patients treated for different diagnoses, and compare the side effect profiles between different MEKi agents. RESULTS: The most prevalent cutaneous toxicities for all eligible patients were acneiform rash (81%, most common), paronychia (50%, second most common), hair changes and xerosis. Mean number of cutaneous skin toxicities were 3.2 (trametinib group: 3.4, selumetinib group: 2.8). Only one patient, treated with trametinib for PWS, did not experience a cutaneous side effect. The average number of interventions (new medication or over-the-counter product) recommended to prevent or treat cutaneous-related toxicities was 6.8 per person, the majority of those were for acne and paronychia. Over 75% of the interventions were topical. Of those who experienced an acneiform rash, the average number of recommended interventions were 3.1. Sixty two percent of these patients developed acne within the first cycle; average time to development was 2.6 months into therapy. Most exhibited improvement overtime following intervention. Those patients who experienced paronychia were treated with a mean of 3.1 interventions – 37.5% developed paronychia within the first cycle of therapy; average time to development was 3.9 months into therapy. CONCLUSIONS: Cutaneous side effects are common, occur early in therapy, and require multiple interventions. The number and complexity of these interventions may further complicate the overall management of cutaneous side effects given that the responsibility of the administration falls on the patient. This differs from traditional chemotherapy regimens.