bluuebunny/crossref_metadata_2025 huggingface dataset:
OTHR-15. Papillary tumor of the pineal region: case series of this rare pediatric entity
Authors: Shatara Margaret , Cantor Evan , Meyer Ashley , Ogle Andrea , Green Tammy , Beck Mary , McHugh Michele , Brossier Nicole , Cluster Andrew , Rubin Joshua , Mian Ali , Dahiya Sonika , Perkins Stephanie , Abdelbaki Mohamed S , Strahle Jennifer , Limbrick David , McEvoy Sean D
Published: June 2022

BACKGROUND: The optimal management of pediatric papillary tumors of the pineal region (PTPR) is not yet established. We report three cases, as an addition to the existing literature. PATIENT 1: A 22-month-old female presented with progressive ataxia and incoordination, found to have an enhancing solid and cystic mass centered within the pineal region, with associated obstructive hydrocephalus. Tumor biopsy revealed PTPR, prompting a subsequent subtotal resection. No adjuvant therapy was recommended. Patient has remained without evidence of disease progression for 92 months, since resection. PATIENT 2: An 8-year-old female presented with progressive headaches and new-onset generalized seizures, found to have a heterogeneously enhancing pineal lesion, with associated obstructive hydrocephalus. Following a biopsy demonstrating PTPR, patient underwent subtotal resection of the tumor. A second resection was completed 6 months later followed by focal irradiation. Targeted next-generation sequencing (NGS) demonstrated two non-targetable genomic alterations (CREBBP and MLL2). The patient remains without tumor recurrence, now 37 months, since irradiation. PATIENT 3: A 7-year-old male with Autism spectrum disorder presented with new-onset focal complex seizures. A brain MRI showed a heterogeneously enhancing lesion in the region of the pineal gland, with associated obstructive hydrocephalus. A tumor biopsy revealed PTPR, prompting a subsequent gross total resection (GTR). NGS demonstrated no reportable genomic alterations. Methylome profiling classified the tumor as PTPR, group B. Post-operative imaging with no residual tumor and he has remained without tumor progression, now eight months, since resection. CONCLUSION: PTPR are extremely rare in the pediatric setting, and were initially introduced in the WHO 2007 classification as grade II-III pineal gland tumors with distinct morphologic and immunohistochemical features. GTR is the mainstay of treatment but post-surgical management remains controversial. The clinical course is characterized by frequent local recurrence, hence, adjuvant chemotherapy and/or irradiation may be necessary upon disease progression.
OTHR-23. Development of a cerebrospinal fluid liquid biopsy platform in pediatric patients with central nervous system tumors
Authors: O’Halloran Katrina , Ostrow Dejerianne , Christodoulou Eirini , Bootwalla Moiz , Yellapantula Venkata , Chapman Nicholas , Chiarelli Peter , Chu Jason , Krieger Mark , Gai Xiaowu , Biegel Jaclyn
Published: June 2022

Pediatric central nervous system (CNS) tumors carry high morbidity and mortality. The advent of targeted agents is aiming to change that through individualized, less invasive, and real-time molecular profiling. We successfully developed a cerebrospinal fluid (CSF) liquid biopsy (LB) platform combining low-pass whole genome sequencing (WGS) and targeted mutation and gene fusion analysis of cell-free (cf) DNA. WGS libraries were constructed with the xGen Prism DNA Library Prep Kit using 5ng of input cfDNA and paired-end sequenced (Illumina NextSeq 500) for an average 0.5x coverage across the genome. Copy number (CN) profiles were analyzed using the ichorCNA R package and compared with CN abnormalities of the primary tumors detected with CytoScanHD or Oncoscan arrays. Selected cases were analyzed for mutations or gene fusions using a custom glioma hybrid capture-based panel (Twist Bioscience) sequenced to 500-1000x across targeted regions. Mutations identified in LBs were compared with primary tumor OncoKids NGS panel results. CSF LBs from 44 tumor cases and 15 non-tumor controls were analyzed. Sixteen primary tumors had copy number changes, 10 had cfDNA detected in the LB across various primary tumor diagnoses (AT/RT, diffuse midline glioma, ependymoma, high-grade glioma, medulloblastoma, pilocytic astrocytoma). Four primary tumors had sequence alterations from the custom panel, two with detectable cfDNA (diffuse midline glioma H3K27M variant allele frequency (VAF) 49% and low-grade glioma BRAFV600E VAF 1.7%). Three patients had TP53 variants detected, all ultimately germline. Controls were negative across WGS and hybrid gene capture. Tumor DNA is detectable by both WGS and hybrid gene capture. Various histologic subtypes are detectable including embryonal and glioneuronal. CSF seems more enriched for cfDNA in high grade versus low grade tumors. These data suggest that NGS-based LB assays may be used to monitor pediatric patients with a variety of CNS tumors, from diagnosis through treatment and recurrence.
OTHR-31. The molecular profile of secondary meningiomas in survivors of childhood non-central nervous system (CNS) cancers
Authors: Corriveau-Bourque Catherine , Wong Derek , van Landeghem Frank , Snuderl Matija , Spavor Maria , Yip Stephen , Eisenstat David
Published: June 2022

INTRODUCTION: Secondary meningiomas are a late effect in children who received cranial irradiation, frequently with a long latency. The molecular genetic profile of primary meningiomas is well studied; however, few studies describe the genomic landscape of radiation-induced meningiomas (RIM). METHODS: Patients followed at the Stollery Children’s Hospital (Edmonton, Canada) with a history of non-CNS malignancies who received cranial irradiation and then developed meningiomas between 1971 and 2013 were identified. Whole exome sequencing (WES), RNA sequencing as well as DNA methylation profiling were performed for patients with available tumor tissue and germline DNA. RESULTS: Of 96 patients who received cranial irradiation for non-CNS tumors, 16 (16.7%) developed symptomatic meningiomas. This patient cohort is unique; all 16 patients identified received 2000-2400 cGy of cranial irradiation, suggesting a threshold dose. 9/16 (56%) had WHO Grade 2 meningiomas or greater and 7/16 (44%) of meningiomas infiltrated other tissues. Post-surgical recurrences occurred in 43%. Patients experienced considerable morbidities directly attributable to the meningiomas or their treatment. 14 patients had samples suitable for further analysis. NF2 mutations were identified in 50% (8; 4 DNA,4 fusion). Other meningioma related genes with mutations identified in other cohorts were not identified. Copy number alternations were noted in all 16 patients in chromosomes 1p and 22q. 850k methylation analysis with PCA as well as UMAP and tSNE did not demonstrate clustering. Ongoing additional studies include examining tumor mutation burden and the radiation mutational profile. CONCLUSIONS: This study examined the RIM in a cohort of patients having received similar doses of radiation for their childhood cancer. There is increased risk of radiation-induced meningioma in survivors of non-CNS cancers given ≥ 2000 cGy during childhood. To date, our findings are consistent with previously described primary and RIM mutations. Enhanced knowledge in secondary meningiomas is crucial for accurate patient counselling, prognostication, and treatment.
OTHR-33. INTRODUCTION OF A MULTIDICIPLINARY NEURO ONCOLOGY LONG TERM FOLLOW UP CLINIC
Authors: Dahl Christine , Farrell Nicola , Blount Nicola , Mould ryan , Simcox Angela , Malcolm Charlotte , Freeman Anita , King Vicky , Bell Daniel , Michalski Antony , Gan Hoong-Wei
Published: June 2022

INTRODUCTION: The number of children and young people (CYP) surviving brain tumours is increasing annually with a doubling of 5-year survival over the last 40 years. More than two-thirds of these survivors suffer multiple long-term co-morbidities (“late effects”) from their tumour and/ or treatment(s) necessitating lifelong multiprofessional follow-up. This results in multiple appointments and increases the burden of care on patients. Method/Project description To establish a collaborative multidisciplinary “one stop shop” long-term follow-up clinic for CYP >5 years from the end of neuro-oncological treatment to the reduce the need for multiple hospital appointments and to provide holistic assessment and care.The first clinic began in January 2020 as a collaboration between the departments of neuro-oncology, endocrinology, neuropsychology, psychology, physiotherapy and occupational therapy. RESULTS: We have audited the last 60 patients seen in clinic in 2 years and the services they required both in and out of clinic are noted below: Endocrinology – 58 patients Educational help and formal neuropsychology (44 and 39 respectively) There are significant emotional problems in the group and 32 saw clinical psychology and 13 were referred to CAMHS. Physical function issues – 31 saw both physiotherapy and occupational therapy. 10 required referral to orthopaedics Neurology and neurosurgery (13 and 11 respectively) Visual impairment – 33 saw ophthalmology Hearing problems – 17 saw audiology Other organ dysfunction – 4 saw cardiology and 3 urology. We have some feedback data on patient and parent satisfaction with the clinic which shows 92% (13 of 14) families preferred to be seen in the MDT setting rather than by separate clinicians. DISCUSSION: Few models of similar multidisciplinary neuro-oncology long-term follow-up clinics exist in the UK with a lack of streamlined funding, despite recognition from families and professionals about their utility.
OTHR-34. Identifying mechanisms of microglia-tumor cell interactions in retinoblastoma
Authors: Pohlmann Anike , Gerling Teresa , Walter Carolin , Melcher Viktoria , de Faria Flavia W , Disch Alina , Kanber Deniz , Wöstefeld Julia , Steenpass Laura , Lohmann Dietmar , Ryl Tatsiana , Riedel Nicole , Ketteler Petra , Schönberger Stefan , Ting Saskia , Bedzhov Ivan , Kiefer Tobias , Lever Mael , Schlüter Sabrina , Biewald Eva , Bechrakis Nikolaos , Albert Thomas K , Kerl Kornelius
Published: June 2022

BACKGROUND: Treatment-related long-term sequelae and chemotherapy resistance diminish the success of retinoblastoma (RB) treatment. To unravel the mechanisms leading to tumor progression and resistance we examined the intratumoral cellular heterogeneity of RB and its interactions with cells of the tumor microenvironment (TME). METHODS: We used single-cell RNA (scRNA-seq) and ATAC sequencing (scATAC-seq) as well as spatial transcriptomics to analyze and compare RB samples from patients with or without previous chemotherapy (chemo-treated vs. naïve). In addition, we developed a 3D model by injection of RB and TME cells into retinal organoids, which mimics the heterogeneous surrounding of the tumor in a spatially and functionally organized manner. RESULTS: ScRNA-seq revealed a high intratumoral heterogeneity of tumor cells representing distinct developmental stages from progenitors to more differentiated photoreceptor cells. The predominant cell type in the TME was M2-activated microglia (MG). M2-MG exerted multiple receptor-ligand interactions with RB tumor cells which were not found in non-diseased retinas. These tumor-specific cellular interactions regulate multiple signaling pathways (e. g. VEGF-, WNT-, BMP-, PGF- signaling) known to be involved in RB progression. By comparing chemo-treated and chemo-naïve RB samples we were able to identify treatment-resistant and -sensitive subpopulations of tumor cells. Finally, data from our RB-retina in vitro model highlighted the impact of RB cells on gene expression programs of normal retinal cells. CONCLUSION: In summary, we deciphered the intratumoral heterogeneity of RB, uncovered an intricate network of microglia-tumor cell interactions that connects numerous important signaling pathways, and further identified chemotherapy-resistant/sensitive tumor cell populations. The latter observation could prove to be very helpful in the development of novel therapeutic approaches in the treatment of RB.
OTHR-37. Pediatrics Cutaneous Reactions in Patient Treated with the Mitogen-Activated Protein Kinase Extracellular Signal-Regulated Kinase Inhibitor Trametinib
Authors: Gluck Mirit , Ben-amitai Dan , Friedland Rivka , Toledano Helen
Published: June 2022

OBJECTIVE: To describe the cutaneous adverse effects (AE) to MAPK Extracellular Signal-Regulated Kinase (MEK) Inhibitor Trametinib in the pediatric population. METHODS: This was a retrospective single-center study. Included were all pediatric patients, treated with trametinib, for an oncologic indication. All patients were evaluated by a pediatric dermatologist, prior to, and during treatment, with documentation of cutaneous findings. RESULT: Twenty patients were enrolled in the study. All patients received treatment with trametinib, of which 6 received a combination of trametinib and dabrafenib (BRAF inhibitor). Out of twenty patients, 18 patients (90%) presented with at least one cutaneous AE. Xerosis and pruritic eczematous changes were the most common (15 patients, 75%), which, in most cases, were tolerable and responded well to the use of emollients and topical corticosteroids. Eleven patients (55%) presented with paronychia which was treated with topical combined corticosteroids antifungals and antibiotics, all with good response. Six patients (30%) presented with acneiform eruption, treated with topical antibiotic, benzoyl peroxide and tretinoin, mostly with good response. Six patients (30%) presented with irreversible hair heterochromia. Reaction grades were reported for cutaneous reactions, most of them were Grade I or II. Only 2 patients reported to have grade III and IV cutaneous reactions: exfoliative dermatitis and erythema multiforme, respectively. Out of 6 patients that received combined treatment of trametinib and dabrafenib one patient had no cutaneous adverse reaction, and one had panniculitis (which was related to dabrafenib). The rest presented relatively mild AE. DISCUSSION: Cutaneous AEs are very common in children and adolescents treated with trametinib, and in most cases are classified as mild. Nevertheless, as this treatment is usually chronic, it is important to inform the patients and their guardians of the potential cutaneous toxicities prior to treatment initiation, and to refer them to a dermatologist for proper management.
OTHR-38. The development of patient-derived models of pediatric brain tumors
Authors: Messiaen Julie , Derweduwe Marleen , Claeys Annelies , Solie Lien , Sciot Raf , Bempt Isabelle Vanden , Devleeschouwer Steven , Van Calenbergh Frank , De Vloo Philippe , Depreitere Bart , Jacobs Sandra , De Smet Frederik
Published: June 2022

Brain tumors are still a major cause of morbidity and mortality in children, despite extensive research. An individualized therapy is warranted to combat the heterogeneity present in these tumors. Therefore, this study aims at developing patient-derived models from both low- and high-grade tumors. As such, the heterogeneity in these tumors can be further characterized and treatment sensitivities can be studied. All pediatric patients diagnosed with a brain tumor at the University Hospitals Leuven and receiving surgical intervention were included after informed consent. If sufficient tumoral material was available, a fresh tumor sample was collected during surgery. The sample was processed into dissociated cells, which were grown in culture in order to develop a patient-derived cell line (PDCL). Biomarker expression using a qPCR array was performed if growth beyond passage 3 was achieved. Established PDCLs were subsequently subjected to genomic and transcriptional profiling and cytotoxicity assays were performed to determine therapeutic sensitivities. Patient-derived xenografts (PDX) are developped in selected cases. 70 patients were included prospectively up until January 2022 and tumoral material was available for 50 of them. In total, 10 PDCLs could be generated (3 high-grade, 7 low-grade tumors), while 9 early cultures (3 high-grade, 6 low-grade) are still being expanded. qPCR and sequencing analysis confirm preservation of driving mutations. The high level of growth failures of the PDCLs can be explained by the high proportion of lower grade tumors included. One PDX model was generated. In conclusion, novel patient-derived models from pediatric brain tumors have been generated, which recapitulate the characteristics of the original tumor. The models are a valuable tool to study these tumors and the responses to different treatments. Further on, we will continue with the development of these models and the study of their therapeutic sensitivities. This will help further improving the understanding of these tumors.
PATH-06. Molecular subgrouping of medulloblastoma via low-depth whole genome bisulfite sequencing
Authors: Thompson Dean , Castle Jemma , Hicks Debbie , Schwalbe Ed , Clifford Steve
Published: June 2022

INTRODUCTION: International consensus recognises four molecular subgroups of medulloblastoma, each with distinct molecular features and clinical outcomes. Assigning molecular subgroup is typically achieved via the Illumina DNA methylation microarray. Given the rapidly-expanding WGS capacity in healthcare institutions, there is an unmet need to develop platform-independent, sequence-based subgrouping assays. Whole genome bisulfite sequencing (WGBS) enables the assessment of genome-wide methylation status at single-base resolution. To date, its routine application for subgroup assignment has been limited, due to high economic cost and sample input requirements. Currently, no optimised pipeline exists that is tailored to handle samples sequenced at low-pass (i.e., <10x depth). METHODOLOGY: Two datasets were utilised; 36 newly sequenced low-depth (10x) and 42 publicly available high-depth (30x) WGBS medulloblastoma samples (n=34), alongside cerebellar control samples (n=8), all with matched DNA methylation microarray data. We applied imputation to low-pass WGBS data, assessed inter-platform correlation and identified molecular subgroups by directly integrating WGBS sample data with pre-existing array-trained models. We developed machine learning WGBS-based classifiers and compared performance against microarray. We optimised reference-free aneuploidy detection with low-pass WGBS and assessed concordance with microarray-derived aneuploidy calls. RESULTS: We optimised a pipeline for processing, QC, and analysis of low-pass WGBS data, suitable for routine molecular subgrouping and reference-free aneuploidy assessment that achieves 96% sensitivity compared to microarray approaches. A pilot study of the suitability of FFPE was promising, and we demonstrate that WGBS data can be integrated into existing array-trained models with high assignment probabilities. Also, WGBS-derived classifier performance measures exceeded microarray-derived classifiers. CONCLUSION: We describe a platform-independent WGBS assay for molecular subgrouping of medulloblastoma. It performs equivalently to array-based methods at increasingly comparable cost ($400 vs $580) and provides a proof-of-concept for routine clinical adoption using standard WGS technology. Finally, the full methylome enabled elucidation of additional biological heterogeneity that has hitherto been inaccessible.
PATH-09. Liquid biopsy of cerebrospinal fluid enables detecting and monitoring ofMYC/MYCN amplification in pediatric CNS malignancies
Authors: Stepien Natalia , Haberler Christine , Furtner-Srajer Julia , Dorfer Christian , Czech Thomas , Lötsch-Gojo Daniela , Mayr Lisa , Baumgartner Alicia , Azizi Amedeo A , Peyrl Andreas , Slavc Irene , Müllauer Leonhard , Madlener Sibylle , Gojo Johannes
Published: June 2022

In the era of precision oncology, rapid molecular profiling as well as continuous monitoring of response to treatment or relapse are of increasing importance. We investigated digital droplet (dd)PCR for cerebrospinal fluid (CSF) derived cell-free (cf)DNA detection as a new method for rapid diagnosing of MYC/MYCN amplification in CNS malignancies - a patient collective with a dismal prognosis. Wet lab validated ddPCR probes for MYC were first investigated in D425 cells, a human medulloblastoma cell line with confirmed MYC amplification. Results of the methylation array of patients with stored CSF/serum samples (-80°C) were screened for patients with MYC/MYCN amplification. Five patients with medulloblastoma (group 3/4) and MYC-amplification and one patient with a diffuse glioma and MYCN-amplification were included in this study. ddPCR was performed on cfDNA isolated from CSF or serum. MYC amplification was detected by ddPCR in 28/33 (85%) CSF samples, with 4/5 negative samples being from one patient, and only one sample showing an unsuccessful analysis. MYC amplification was detectable in all longitudinal samples in 4/5 patients. 1/1 sample from the patient with MYCN amplific ation was positive in ddPCR. We were not able to detect MYC amplification in serum samples. Importantly, a turn-around time of only six hours from sample thawing/acquisition to result generation was easily achievable. Concluding, detection of MYC/MYCN-amplification in CSF by ddPCR is feasible in the clinical setting and allows for a rapid molecular diagnosis. MYC-amplification was constantly detectable in 4/5 patients with longitudinal CSF samples, which is in-line with the tumor burden our patients suffered from. Interestingly, the detectability in the patient’s serum was low, presumably due to the lower percentage of cell-free tumor (ct)DNA in serum when compared to CSF. Our results render ddPCR as a promising tool for bed-side molecular diagnosis and disease monitoring.
PATH-11. Detection of genetic and epigenetic alterations in Liquid Biopsies from pediatric brain tumor patients
Authors: Fischer Tom T , Maaß Kendra K , Puranachot Pitithat , Finster Agnes M E , Mieskolainen Markus , Schad Paulina S , Sill Martin , Rosing Fabian , Wedig Tatjana , Schwarz Nathalie , Iser Florian , Meyer Jochen , Sahm Felix , Brors Benedikt , Haapasalo Hannu , Pfister Stefan M , Haapasalo Joonas , Pajtler Kristian W , Nordfors Kristiina
Published: June 2022

BACKGROUND: Liquid biopsies (LBs) hold great promise as a non-invasive method for tumor detection and disease monitoring. Their application in pediatric neuro-oncology patients has been challenging due to the blood-brain barrier limiting the amount of circulating tumor DNA (ctDNA) and low volumes of cerebrospinal fluid (CSF) and serum samples. Here, we assessed the feasibility of LBs in a pediatric brain tumor cohort (n=12 patients) by adapting pre-analytical protocols to low cell-free DNA (cfDNA) input and bioinformatic pipelines for genome-wide analyses. METHODS: Genomic DNA isolated from tumor tissues, including medulloblastoma (n=6), ependymoma (n=4), low-grade glioma (n=1), and choroid plexus papilloma (n=1), and cfDNA isolated from matched CSF and serum samples were subjected to low-coverage whole genome sequencing (lcWGS) and the EPIC DNA methylation array. For methylation analyses, samples were prepared using both traditional bisulfite- and recently developed enzymatic-based methylation conversion. Molecular tumor (sub)type predictions were performed using the Heidelberg Brain Tumor Classifier. RESULTS: lcWGS revealed tumor-specific copy number variations (CNVs) in both CSF and serum samples. The detection rate of tumor-specific CNVs (median 92% vs. 23%) and the ctDNA fraction (median 31% vs. 1.5%) were higher in CSF vs. serum samples. Bisulfite-converted as well as enzymatically converted tumor DNA and cfDNA samples could be readily analyzed using the Heidelberg Classifier. In comparison to bisulfite-based conversion, enzymatic-based conversion improved the quality of methylation analyses for minimal input cfDNA samples. CONCLUSIONS: Our results highlight the feasibility of liquid biopsies from both CSF and serum in brain tumor patients. In contrast to CNV-based tumor detection from serum samples, ctDNA analysis from CSF allowed a more comprehensive genetic and epigenetic profiling which is expected to assist in less-invasive tumor classification, identification of drug targets, or the investigation of tumor evolution. Altogether, this study provides the rationale for further implementation of LBs in pediatric neuro-oncology.
LINC-04. Optic pathway gliomas in children: an 18-year experience in a middle-income country
Authors: Ramirez-Melo Jorge , Moreira Daniel , Orozco-Alvarado Ana , Sánchez-Zubieta Fernando , del Campo Regina Navarro-Martín
Published: June 2022

BACKGROUND: Optic pathway gliomas (OPGs) have favorable survival outcomes, but can have significant morbidity, from the tumor or from its treatment. This retrospective study sought to describe the clinical presentation and outcomes of children with OPGs at a tertiary center in a middle-income country. METHODS: Patients younger than 18 years diagnosed with OPGs between 2002-2020 at the Hospital Civil de Guadalajara in Mexico, were included. Survival analyses and logistic regression were used to determine risk factors for progression. RESULTS: Thirty patients were identified with a median age of six years. Common clinical characteristics at presentation included: visual accuracy impairment (40%), headache (23.3%), nystagmus (20%), endocrine disturbances (16.6%), and diencephalic syndrome (13%). Neurofibromatosis-1 was present in 23.3% of the patients. Eight patients underwent resection at diagnosis, 7 of them had secondary complications. One died during surgery due to catecholamine-resistant shock, and the other developed neuro-infection and died due to septic shock after surgery. Five children developed neurological or endocrine sequelae. Fifteen total patients received chemotherapy as their first line treatment. The 5-year progression-free survival was 77.9±10% and overall survival was 89.5±5%. Patients who received chemotherapy or targeted therapy as the first line of treatment had higher PFS compared to those who received other therapies (p=0.03). The patients who received surgery as first-line treatment had a 3.1 times greater risk of achieving a Lansky/Karnofsky score of fewer than 90 points 6 months after diagnosis (p=0.006). Ten patients had pre- and post-treatment ophthalmologic assessment, either visual acuity or visual evoqued potentials. Five had no changes and 5 showed improvement after treatment. CONCLUSIONS: These results show inferior outcomes compared to high-income countries, influenced importantly due to morbidity after surgical resection. These data can be used to prospectively optimize treatment at our institute and other middle-income countries through a multidisciplinary neuro-oncology team.
LINC-05. Successful response to bevacizumab/irinotecan/temozolomide in a progressive choroid plexus carcinoma: A case report
Authors: del Campo Regina Navarro-Martin , Pozos-Ochoa Ivan , Bañuelos-Gallo David , Sanchez-Zubieta Fernando , Orozco-Alvarado Ana L
Published: June 2022

Choroid plexus carcinomas (CPC) are a rare type of aggressive pediatric brain tumors with poor survival rates, and no standard curative therapy after relapse. We report the case of a 1-year-oldmale, with a right lateral ventricular CPC and disseminated leptomeningeal disease. First line therapy was an initial surgery aborted due to hemorrhage and a second near total resection. After the second surgery six cycles of ICE regimen were applied. The MRI after primary therapy showed progression with a new lesion located on the optic pathway and leptomeningeal disease. At this point a second line therapy consisting of Bebacizumab 10 mg/kg and Irinotecan 125 mg/kg every 2 weeks and Temozolamide 150 mg/m2 every 4 weeks was given. He received up to 24 cycles. His imaging demonstrated 80% primary tumor reduction and improvement of leptomeningeal disease. This treatment gave him the time to turn 3 years old to receive 3D conformational craniospinal radiotherapy as follows: spine 24Gy, overdose 27 Gy to tumor bed and cranial for a total dose 51 Gy. The patient is now 19 months from the end of treatment with stable disease. He is clinically well, with good performance status (Lansky 100%) and attending school. The relevance to present this case is to highlight a safe and effective treatment for a relapsed CPC since there is not a curative therapy for these children.
LINC-08. Neuro-Oncology tumor board – one-year experience of international collaboration
Authors: Shatara Margaret , Cantor Evan , Meyer Ashley , Ogle Andrea , Hofmann Kimberly , Green Tammy , Beck Mary , McHugh Michele , Brossier Nicole , Cluster Andrew , Mian Ali , Dahiya Sonika , Abdelaziz Zeyad M , Fadel Shady , Mobark Nahla , AlHarbi Musa , AlJaouni Soad , Aljunaid Abrar , Said Waleed , El-ayadi Moatasem , Mahmoud Madeha , Al-Battashi Abeer , Chabchoub Imène , Khalifa Nisreen , Dengler Nora , Driever Pablo Hernáiz , Del Río Nicolás Rojas , Dembowska-Bagińska Bozenna , Perek-Polnik Marta , Skoczeń Szymon , Dholaria Hetal , Nagabushan Sumanth , Oliveira Milena , Hirbe Angela C , Armstrong Amy E , Limbrick David , Gutmann David H , Abdelbaki Mohamed S
Published: June 2022

BACKGROUND: The management of childhood central nervous system (CNS) tumors is complex and often faces numerous challenges in low- and middle- income countries (LMICs), including delayed diagnosis and limited treatment resources. Twinning initiatives between LMICs with high- income countries are feasible and proven to be highly effective at exchanging skills and expertise to improve diagnosis, treatment and care for children with brain tumors. METHODS: A monthly multidisciplinary international pediatric neuro-oncology tumor board via zoom videoconferencing was established in January 2021. This effort is a collaboration between Washington University School of Medicine, in St. Louis, Missouri, USA and nine international sites. Given the significant contributions of this international effort, it has since grown to include 20 institutions and cancer centers from 12 countries in the Middle East, Europe, Australia and South America. RESULTS: As of January 2022, we have held 11 tumor boards, 35 cases were reviewed, and have had 320 experts attend from several specialties – neuro-oncology, neurology, neurosurgery, neuroradiology and neuropathology. A multidisciplinary team of physicians reviewed each case and recommendations were given accordingly. We also started a quarterly neurofibromatosis (NF) meeting focused to leverage the expertise of dedicated specialists in the NF center. Two NF-focused meetings took place since establishing the program, and total of five cases were discussed. CONCLUSION: Virtual videoconferencing promotes a multi-disciplinary approach for the management of pediatric CNS tumors, and it allows access for medical expertise. We anticipate the current initiative will also provide a platform for future international research collaborations and deliver the optimal medical care for neuro-oncology patients globally. Multiple potential collaborative projects are currently underway.
LINC-16. Factors Associated with Delayed Diagnosis Among Filipino Pediatric Brain Tumor Patients: A Retrospective Review
Authors: Orduña Patricia , Lubaton-Sacro Cheryl Anne
Published: June 2022

BACKGROUND: Delayed diagnosis is observed greatest among pediatric brain tumors compared to other childhood malignancies. Several factors have been found to influence delay. OBJECTIVE: To determine delayed diagnosis measured by the prediagnostic symptomatic interval (PSI) among Filipino pediatric brain tumor patients and identify associated factors. METHODS: Data was collected retrospectively on pediatric brain tumor patients of Philippine General Hospital from 2015-2019. PSI was calculated. Demographic and clinical data were presented using descriptive statistics. Bivariate and linear regression analyses were used to determine factors. RESULTS: The median overall PSI was 80.5days. The median interval from symptom onset to first physician consult was 22days. The median interval from first consult to subspecialty referral was 23.5days. Majority presented with 2 symptoms at onset (42.3%) and during first physician consult (36.2%). Upon subspecialist referral, 52% have ≥4 symptoms. Most patients (68.4%) consulted with a pediatrician. Most were diagnosed with another condition prior to brain tumor diagnosis. Longer PSI was significantly associated with older age (p=0.005), tumor location (p=0.009), tumor grade (p<0.001), and more physicians consulted prior to subspecialist referral (p=0.001). Significant predictors of delayed diagnosis were supratentorial tumors (4-month delay, p=0.014), and those presenting with seizures (11-month delay, p=0.002), poor school performance (1-year delay, p=0.008), behavioral changes (1.3-year delay, p=0.033), and secondary amenorrhea (3-year delay, p=0.021). Predictors of earlier brain tumor diagnosis include posterior fossa tumors (p=0.041), malignant tumors (p=0.002), and vomiting (p=0.020). CONCLUSION: Delayed diagnosis among Filipino brain tumor patients is associated with age, tumor characteristics and symptoms that are uncommon in this condition. This emphasizes the need for first contact physicians to be aware about these symptoms, and keep a diagnosis of brain tumor as a differential. This, coupled with a detailed history, accurate neurologic examination and early subspecialist referral may lead to earlier diagnosis and treatment for pediatric brain tumor patients.
LINC-17. A single center retrospective analysis of pediatric intracranial choroid plexus carcinoma in Beijing
Authors: Li Miao , Sun Yanling , Du Shuxu , Zhang Jin , Wu Wanshui , Sun Liming
Published: June 2022

Objective: To explore the clinical characteristics and outcome in children with intracranial choroid plexus carcinoma in Beijing. Methods: We retrospectively analyzed 13 children with pathologically confirmed diagnosis of choroid plexus carcinoma between January 2017 and December 2021. They were treated with surgical resection followed by adjuvant therapies. Results: Male/female ratio=0.625(5:8). The median age at diagnosis was 1.2 years (range, 6 months to 9.8 years) with 9 cases < 3 years of age. Gross total resection was achieved in 12 cases (92.3%), and subtotal resection in 1 case. Seven patients received only adjuvant chemotherapy according to CPT-SIOP-2009 protocol, and 6 patients underwent radiotherapy with combined chemotherapy. Six patients developed a recurrence, and 4 cases died at last follow-up. Among 9 patients alive, 7 cases attained CR, 1 PR and 1 SD.The 5-year progression-free survival (PFS) and overall survival (OS) were (64.8±14.3) % and (68.4 ± 13.1) %, respectively. The survival of children treated under both irradiation and chemotherapy were higher than chemotherapy only (P<0.05). The cases < 3 years of age had worse survival than those ≥3 years (P<0.05), and the 4 cases died were all younger than 3 years old. Conclusions: Choroid plexus carcinoma is a rare and malignant brain tumor, and affects mainly younger children in our center. Surgical resection is the mainstream treatment. Adjuvant radiotherapy with combined chemotherapy and patients older than 3 years old tend to have better survival. Keywords: Choroid plexus carcinoma; Therapy; Survival.
LINC-19. Epidemiological Profile And Management Trends in Pediatric Brain Tumour Patients – 15 Year Experience From a Tertiary Neuro-Oncology Centre In South Asia
Authors: Singh Vikas , Pathiyal Rajesh , Shetty Prakash , Sridhar Epari , Chinnaswamy Girish , Gupta Tejpal , Moiyadi Aliasgar
Published: June 2022

INTRODUCTION: Brain tumour in pediatric age group are the most common solid tumour. Commonly occurring tumours include astrocytomas, medulloblastoma and ependymoma. Astrocytoma and medulloblastoma are common in Europe as compared to the Asian countries. AIM: To study the epidemiological profile and trends in management of pediatric brain tumor patients treated at a tertiary Neuro-oncology center. MATERIALS AND METHODS: This a retrospective audit of a prospectively maintained neurosurgical database from January 2007 to December 2021. All pediatric cases (< 18 years) operated by the neurosurgical oncology unit during the study period were included for analysis. CSF diversions and non oncologic surgical procedures were excluded. Demography, referral pattern, surgical and pathological variables of these patients was analyzed from the database and electronic medical records. Patients with missing data were excluded from analysis. RESULTS: 668 patients underwent oncologic surgical procedures. There was a male preponderance (60%) and 35% of children were in the age group of 5-11 years. Hospital received maximum referral from the parent city and state (46%) followed by north india (21%). Supratentorial tumours (52 %) were seen more commonly as compared to infratentorial tumours (39 %). Astrocytoma (31 %) and embryonal tumours( 25 %) were the common histological types. On subset analysis, both astrocytic (70%) and embryonal tumours (57%) were more common in children more than five years. Intraoperative neuromonitoring, intraoperative ultrasound and navigation were used during the surgical procedures as necessary. CONCLUSION: This study is one of the largest single institution analysis of pediatric brain tumours demonstrating trends in the demographic, surgical and pathological variables over 15 years and the observed pattern is similar to published literature from Indian subcontinent.
LINC-23. Factors influencing outcomes of older children with Medulloblastoma over 15 years in Peru, a resource limited setting
Authors: Diaz-Coronado Rosdali , Reinecke James B , Stanek Joseph R , Finlay Jonathan L , Hernandez-Broncano Eddy , Chavez-Paredes Sharon , Miranda-Tunque Yesenia , Heredia-Zelaya Adela , Casavilca-Zambrano Sandro , Garcia-Corrochano Pamela , Ojeda-Medina Luis , Orrego-Puelles Enrique , Torres-Malca Ebert , Sernaque-Quintana Raymundo , Quispe-Valverde William , Garcia-Leon Juan , Osorio Diana S
Published: June 2022

BACKGROUND: Medulloblastoma is the most common malignant brain tumor in children. While survival has improved in high-income countries (HIC), the outcomes for patients in low-middle-income countries (LMIC) are unclear. Therefore, we sought to determine the survival of children with Medulloblastoma at the Instituto Nacional de Enfermedades Neoplasicas (INEN) between 1997 and 2013 in Peru. METHODS: Between 1997-2013, data from 103 children older than three years with Medulloblastoma were analyzed. Fourteen patients were excluded. The patients were split into two distinct cohorts, 1997 – 2008 and 2009 – 2013, corresponding with chemotherapy regimen changes. Event-free (EFS) and overall survival (OS) were calculated using the Kaplan-Meier method, while prognostic factors were determined by univariate analysis (log-rank test). RESULTS: Eighty-nine patients were included; median age was 8.1 years (range: 3-13.9 years). The five-year OS was 62% (95% CI: 53 – 74%) while EFS was 57% (95% CI: 48 – 69%). The variables adversely affecting survival were anaplastic histology [compared to desmoplastic; OS: HR=3.4, p=0.03], metastasis [OS: HR=3.5, p=0.01; EFS: HR=4.3, p=0.004], delay in radiation therapy of 31-60 days [compared to ≤30 days; EFS: HR=2.1, p=0.04], and treatment 2009 – 2013 cohort[OS: HR=2.2, p=0.02; EFS: HR=2.0; p=0.03]. CONCLUSIONS: Outcomes for Medulloblastoma at INEN were low compared with HIC. Anaplastic sub-type, metastasis at diagnosis, delay in radiation therapy, and treatment in the period 2009 - 2013 negatively affected the outcomes in our study. Multidisciplinary teamwork, timely delivery of treatment and partnerships with loco-regional groups and colleagues in HIC is likely beneficial.
MODL-04. Drug screening in Disorders with Abnormal DNA Damage Response/Repair (DADDR) andin vivo validation
Authors: Kolodziejczak Anna , Selt Florian , Peterziel Heike , Jamaladdin Nora , Mack Norman , Maass Kendra , Kool Marcel , Herold-Mende Christel , El Damaty Ahmed , Oehme Ina , Jones David T W , Witt Olaf , Pajtler Kristian W , Kratz Christian , Pfister Stefan M , Milde Till
Published: June 2022

INTRODUCTION: Disorders with Abnormal DNA Damage Response/Repair (DADDRs) are inherited conditions caused by constitutional mutations of DNA damage response and repair genes and are characterized by an increased cancer risk. Furthermore, affected individuals also show an elevated risk of secondary neoplasms as well as excessive toxicity, poor therapy response and increased mortality when treated with standard radiation and chemotherapy regimens. The main aim of this project is to screen for potential novel chemotherapeutic approaches for these cancer entities, and to employ faithful PDX models for in vivo validation. METHODS: In vitro drug screening was performed using a custom library composed of 345 compounds targeting 61 different proteins. For two specific DADDRs, Li-Fraumeni syndrome (LFS) and Constitutional Mismatch Repair Deficiency (CMMRD), two cancerous (glioblastoma and medulloblastoma) and one non-cancerous cell lines were selected to model each of these conditions. Performance of each drug was assessed based on its efficacy (sensitivity score) and genotoxicity (micronucleus assay). For DADDR PDX model establishment tumor material from DADDR patients is currently being injected orthotopically (brain tumors) or subcutaneously (non-brain tumors) into NSG mice. Following engraftment and expansion, the PDX models will be characterized molecularly and compared with original patient material. RESULTS AND OUTLOOK: In vitro screening revealed n=26 drugs that fulfilled the following criteria: a) favorable toxicity in cancerous cell lines compared to non-cancerous cell lines, b) little to no genotoxic effect in non-cancerous cell lines. These characteristics qualify them as potentially suitable candidates for novel therapeutic approaches specifically for DADDR patients. The hits included inhibitors of ATM/ATR, CHK1/CHK2, DHFR, mTOR and PI3K, as well as microtubule-associated compounds. Combination testing and further validation of these hits using disease-specific in vitro and in vivo PDX models is ongoing.
MODL-21. Multi-omics investigation of medulloblastoma resistant models reveals functional association between intracellular regulatory networks and drug susceptibility
Authors: Mariotto Elena , Rampazzo Elena , Bortolozzi Roberta , Rruga Fatlum , Manfreda Lorenzo , Marchioro Chiara , Bresolin Silvia , Viola Giampietro , Persano Luca
Published: June 2022

Medulloblastoma (MB) is the most common malignant brain tumor of childhood. Despite high-dose radio/chemotherapy treatment, 15-30% of patients still display a high risk of tumor recurrence. In this context, the characterization of innovative cellular models resembling therapy-induced drug resistance represents an unprecedented opportunity for selecting relevant therapies for chemotherapy-refractory patients. In order to unveil the molecular mechanisms sustaining chemotherapy resistance in MB, we setup in vitro models of MB drug resistance by exposing Patient-Derived MB (PD-MB) cells to a combination of the commonly used chemotherapeutics for pediatric MB treatment. Integration of multi-omics data, including transcriptional, proteomic and kinase activation profiling, disclosed that drug resistant PD-MB cells are characterized by a significant deregulation of several cancer-related pathways converging to metabolism of xenobiotics, adaptation of the biochemical processes sustaining energetic metabolic demand, cell proliferation and survival, protein homeostasis, RNA processing and modification, and immune response. Moreover, this intriguing regulatory network was functionally associated to the response of drug-resistant MB cells to a large library of compounds through a semi-automated High-Throughput drug Screening (HTS) workflow, suggesting the antimetabolite class of drugs as relevant therapeutics displaying high selectivity and efficacy against resistant MB models, together with a significant synergistic action when combined with standard chemotherapeutic agents. Collectively, our results suggest that drug-resistant MB cells are subjected to a peculiar adaptation of multiple intracellular processes during adaptation to chemotherapy, which protects them from the toxic environment but, at the same time, provides targetable vulnerabilities for therapeutic purposes.
MODL-23. The identification and validation of plasma membrane proteins as potential therapeutic targets for histone H3 mutant paediatric high-grade gliomas.
Authors: Snary Anya , Pickering James , Rahman Ruman , Grundy Richard , Haque Farhana , Layfield Robert
Published: June 2022

Paediatric high grade gliomas (pHGG) are the leading cause of cancer-related death in children. Histone H3.3 mutations are an important hallmark of pHGG, but their underlying oncogenic mechanisms are incompletely understood. Towards identifying molecular effectors that may be therapeutically effective, we employed proteomic profiling and determined plasma membrane proteins of the surfactome that are differentially expressed on the surface of H3.3 mutant (G34R, G34V) compared to H3.3-wildtype human glioma cells in culture. Profiling of plasma membrane-enriched fractions identified 34 membrane proteins exclusively detected from H3 G34V mutant cells compared to H3 wild-type cells, and 10 membrane proteins exclusively detected from H3 G34R mutant cells, with 39 membrane proteins shared between both H3 G34R/V genotypes. One of these shared membrane proteins, GLUT1 (glucose transporter), has very recently been reported to be over-expressed and linked to tumour phenotypes in mouse glioma cells manipulated to carry the most common DIPG-associated H3.3-K27M mutation [Miya et al. Neuro-Oncology Advances 2021]. Here, we explore the functional significance of GLUT1 differential expression in H3.3 mutant (G34R, G34V) human glioma cells. Collective observations support a model where different H3.3 mutations converge on changes in GLUT1 expression and reinforce GLUT1 as a potential therapeutic target in paediatric high-grade gliomas.
MODL-26. Development of humanized immune system, posterior fossa A ependymoma patient-derived xenograft model
Authors: Griesinger Andrea , Lang Julie , Donson Andrew , Grimaldo Enrique , Pierce Angela , Knox Aaron , Steiner Jenna , Serkova Natalie , Ritzmann Timothy , Grundy Richard , Foreman Nicholas
Published: June 2022

Cellular interactions between tumor and immune cells are critical in ependymoma biology. We have shown distinct immunobiology phenotypes by ependymoma molecular subgroups, with PFA2 developing an anti-tumor immune phenotype and in contrast PFA1 tumor immune cells being pro-tumor. We recently established two fully characterized pediatric PFA1 intracranial xenograft models in NSG mice. These models, while critical for advancing PFA studies, lack the ability to make lymphocytes. To address this we have established a humanized orthotopic model of PFA1 ependymoma that are grafted to produce functional human lymphocytes. To do this, CD34+ human umbilical cord blood was injected into the cranial facial vein of newborn, irradiation immunodepleted, BRGS mice. Human immune chimerism was determined at 10 weeks by flow cytometry of peripheral blood. Next, we injected existing PDX model MAF-928_XF cells into the 4th ventricle at 12 weeks age and tumors were monitored by MRI. Initial scanning found the tumors were delayed in developing, consistent with other humanized solid tumor mouse models. Mice were euthanized between 32-34 weeks age and necropsies were performed to isolate brain, lymph nodes, blood and spleen. Human chimerism was detectable, by flow cytometry, in spleen, lymph nodes and blood, and most cells were T-cells. Human T-cells were detectable in all tumors, in proportions consistent with human disease (0.05-0.5% of CD45+). Tumors also had 35-50% mouse myeloid infiltration. Tumors were MHC I negative and MHC II positive, and PD-L1 low. Histology was consistent with human ependymoma. We are using spatial proteomics to determine cellular location and phenotype of infiltrating immune cells. Initial studies indicate this model will be usable for modeling the critical tumor-immune interactions and pre-clinically testing the next therapies in PFA ependymoma and can be easily adapted to other pediatric brain tumors in which immune factors have a critical role.