CNS Tumors In Children Research Articles

RONC-17. Feasibility of proton therapy with and without simultaneous chemotherapy in CNS malignancies of children and adolescents

Abstract BACKGROUND: Proton therapy (PT) is a valuable alternative to photon radiotherapy in treatment of CNS tumors in children and adolescents. The aim of this study was to investigate the feasibility of recent treatment strategies with a particular focus on the acute toxicity of a simultaneous radiotherapy and chemotherapy (sRCT). PATIENTS AND METHODS: We investigated 199 patients (116 male, 83 female, median age 7.4 years) who received in total 200 cycles of PT (60.5% at new diagnosis, 39.5% at relapse) from September 2013 to February 2017. Entities included ependymomas (34%), medulloblastomas (16%), low grade gliomas (13%), ATRTs (12%), craniopharyngiomas (9%), germ cell tumors (6%), and other entities (10%). SRCT was administered in 52 (26%) treatment cycles. The target tumor was predominantly localized infratentorial (53%), supratentorial (23.5%) and supra-/intrasellar (18%). 38 patients received additional CSI and 8 patients a boost to metastases. Data were collected retrospectively based on patient records. Toxicity was documented according to CTCAE version 4.03. RESULTS: Severe adverse events (SAE ≥ grade 3) occurred in 33.5% of all patients, in particular in form of hematotoxicity (64.1%) and infections (26.8%). In-patient treatment for unexpected SAEs was necessary in 33 patients (16.5%). In the group treated with sRCT 15 out of 52 (28.8%) patients couldn’t receive the recommended dose or time schedule of planned chemotherapy due to SAEs. Comparing the SAE frequency in both groups, the children who have been treated with sRCT had a significantly higher risk of SAEs than the patients who have received proton therapy only (63.5% vs. 23.0%, p=0.001). CONCLUSIONS: PT and concomitant chemotherapy are feasible, but require an interdisciplinary team with continuous out-/inpatient management of patients, as the risk of toxicity is significantly increased. Risk-adapted adjustment of simultaneous chemotherapy is necessary to reduce relevant interruptions of radiotherapy. Funded by the German Childhood Cancer Foundation

DIPG-47. TSO500ctDNA sequencing reveals oncogenic mutations and copy number variations in the liquid biome of children with diffuse midline glioma

BACKGROUND: Molecular profiling of childhood CNS tumors is critical for diagnosis and clinical management, yet tissue access is restricted due to sensitive neuroanatomical locations. Moreover, CNS tumors including diffuse midline glioma (DMG) exhibit mutational heterogeneity and clonal evolution, which cannot be captured by upfront diagnostic biopsy alone. To address the lack of tumor visibility, and tprovide opportunity for longitudinal sampling, we validated and optimized a commercially available deep sequencing platform for analysis of circulating tumor DNA (TSO500ctDNATM). METHODS: In a proof-of-concept study, we defined the sensitivity, specificity, and clinical relevance of our novel ctDNA platform via analysis of paired tissue, CSF, and blood from children with DMG (n=10). Paired samples were assessed for concordance and sequencing results were compared to digital droplet PCR (ddPCR) detection of prognostic H3K27M mutation. RESULTS: DMG associated mutations in genes including H3-3A, H3C2, TP53, and ACVR1 were detected in ctDNA, including in CSF samples with low (<5ng) starting DNA input. Of 9 H3K27M mutations identified in tumor, 8 were present in CSF and 3 in plasma/serum, for a positive percent agreement with tumor results of 89% and 33%, respectively. Among CSF samples, H3.3K27M was detected in 6/6 cases, and H3.1K27M in 2/3 cases, with variant allele frequencies comparable to ddPCR results. CNVs including PDGFRA, KIT, and MDM4 gains were detected in CSF and paired tumor. Low frequency events including ACVR1, PIK3CA activating mutations and KRAS amplification were detected in CSF but absent from paired tumor, indicating tissue heterogeneity. Strategies to optimize ctDNA detection, including optimization of ctDNA isolation and adjustment of library QC metrics, were identified. CONCLUSION: Targeted ctDNA deep sequencing is feasible, can inform on clinically relevant tumor mutation and CNV profiling, and provides an opportunity for longitudinal monitoring of tumor genomic evolution in the liquid biome of children with CNS tumors.

LGG-44. Multi-omic analysis reveals integrated signalling networks in paediatric low-grade glioma

Paediatric low-grade gliomas (pLGGs) are the most common type of childhood CNS tumours. Our study included pilocytic astrocytomas (PAs; KIAA1549:BRAF), glioneuronal tumours (GNTs; BRAFV600E) and location-matched controls. We initially performed kinase substrate enrichment analysis (KSEA) to infer differential kinase activity, which allowed us to identify altered signalling networks in the two tumour types. Here we report the integration of these kinase signalling networks together with total proteomics, transcription factor enrichment analysis (TFEA) and transcriptomics (coding and non-coding). Total proteomic profiling confirmed an increase in proteins involved in cell cycle, inflammatory response and signal transduction in PAs, whilst there was an increase in proteins promoting cell growth, immune response and inflammation in GNTs. TFEA was performed using the DoRothEA database to identify master transcriptional regulators. We observed significant activation of transcription factors (TFs) that are direct targets of MAPK signalling in both tumour types. Notable differences include the higher activation of NF-kB/STAT TFs in PAs and the increased activation of RFX1/2 in GNTs. Next, we constructed kinase-TF networks and identified multiple kinases targeting STAT3 in PAs and STAT1/3 in GNTs. Pathway analysis of RNA-Sequencing data showed enrichment of NF-kB in both tumours and repression of E2F target genes (PA) and reduced expression of MYC target genes (GNT). We developed a BRAF-OIS signature and found 23 genes commonly enriched in both tumour types, highlighting shared senescence-associated targets. MicroRNA profiling identified upregulation of microRNAs that target MAPK and NF-kB signalling networks, and many down-regulated microRNAs with tumour suppressive roles. Finally, we identified several lncRNAs known to be differentially expressed in glioma and, whilst their mechanism(s) of action are varied, they are thought to act with other well-established regulators to fine-tune cellular processes. Taken together, we present a comprehensive signalling network as a framework for studying pLGGs.

Our Experience Of Pediatric Brain Tumour In Medan: Demographic Study In Adam Malik General Hospital 2019-2020

Abstract&#x0D; Introduction: Primary brain and central nervous system tumors are the most prevalent and frequent neoplasm in children and adolescents aged 0 to 19 years. Brain and CNS tumors are the second leading cause of cancer-related deaths in children and adolescents aged 0 to 19 years old. Previous studies in several countries have reported the incidence rate of primary brain and CNS tumors in children and adolescent, ranged from 1.08 to 5.57 per 100,000 population. The incidence of brain tumor in pediatric patients has increased in the past decades, due to innovations in the imaging studies and the increase of benign form diagnoses. The highest occurrence of pediatric brain tumor is in the United States. Based on the study by Rictherova et al. in 2018, according to the age groups, the highest incidence is in adolescents aging 15-19 years with 6.38 per 100,000 children, followed by children aging under 1 year with 6.2 per 100,000 children.&#x0D; Method: A total of 58 patients were reported in this study. Data was collected from medical bank data of Neurosurgical Department of Faculty of Medicine of North Sumatera in Indonesia. The variables that we collected were as follows: gender, tumor diagnosis, Glasgow-Coma Scale (GCS) score on admission, and age group. We classified age group into &lt;1 year, 2-4 years, 5-9 years, 10-14 years, and 15-19 years old. The data was computed using the SPSS 25th edition.&#x0D; Result: Out of 58 diagnosis, boys were the predominance frequency with a total of 69% and girls were 31%. most patients had medulloblastoma (27.6%) followed by glioma (24.1%), craniopharyngioma (8.6%), and meningioma (8.6%). Other types of tumor, namely cerebral abscess, cerebromalacia, choroid plexus papilloma, craniopharyngioma, ependymoma, neurofibromatosis 1, soft tissue tumor, were accounted for 1.7%, respectively&#x0D; Discussion: Primary brain and central nervous system tumors are the most prevalent and frequent neoplasm in children and adolescents aged 0 to 19 years. Brain and CNS tumors are the second leading cause of cancer-related deaths in children and adolescents aged 0 to 19 years old. In our study, from a total of 58 patients, most of the patients (69%) were boys with a frequency of 40. Girls were only accounted for 18 (31%). A study by Stiller et al. in 2019 regarding incidence of childhood CNS tumors in Britain also reported similar result, with 2275 boys and 1891 girls out of 4166 tumor patients. The most common diagnosis was medulloblastoma (27.6%), in line with the study by Stiller et al. and Suresh et al. The most common age group with brain tumor was 10-14 years old (34.5%).&#x0D; Conclusion: Based on our study, from the total of 58 patients, most of the patients were boys (69%). The most common tumor diagnosis in our study was medulloblastoma (27.6%) followed by glioma (24.1%). The results in our study had been in line with other literatures. However, the age group distribution was not in line with other literatures as our study reported the age group of 10-14 years old having the highest percentage of brain tumors. Overall, this study had reported the demographic result of pediatric brain tumor in Adam Malik General Hospital from 2019-2020.

NECESSITY FOR A CUSTOMIZED NGS PANEL FOR ACCURATE DIAGNOSIS AND TARGETED THERAPIES IN PEDIATRIC GLIAL TUMORS

Pediatric glial tumors comprise wide range pathologies which may mimic histomorphological features of each other's but generally have very diverse disease course. WHO Classification of Tumors of Central Nervous System (2016 and 2021) points to the necessity of investigating several molecular alterations for integrated pathological diagnosis of childhood CNS tumors. This makes customized next-generation sequencing (NGS) a powerful tool for the diagnosis of childhood CNS tumors. Acıbadem Molecular Pathology Brain Tumor NGS Panel was designed according to targeted deep RNA and DNA sequencing. RNA and DNA were isolated from paraffin blocks containing more than 50% tumor in 45 cases with childhood CNS tumors. Miniseq Sequencıng System, Illumına and Archer Analysıs Ver 6.0.3.2 platforms were used. Fusions (translocations), mutations, and DNA copy number changes in 81 genes were screened for the most common molecular alterations in CNS tumors. Fourty-five childhood CNS tumors were evaluated with NGS results. Among these there were 19 pilocytic astrocytomas, 1 case of high grade astrocytoma with piloid features, 4 diffuse leptomeningeal glioneuronal tumors, 1 pleomorphic xanthoastrocytoma, 4 pediatric diffuse glial tumors, 1 infantile hemispheric astrocytoma, 1 astroblastoma, 12 diffuse midline glioma. Sixteen of these tumors were able to be diagnosed based on these molecular findings. Thirty-four cases received targeted therapies. The customized NGS panel, as a single molecular workflow is very helpful and supportive in diagnosis for CNS childhood tumors. Since the number of driver mutations are few in childhood tumors, detection of the driver molecular alteration is guiding the medical treatment startegy in terms of targeted regimens.

Natural and cryptic peptides dominate the immunopeptidome of atypical teratoid rhabdoid tumors

BackgroundAtypical teratoid/rhabdoid tumors (AT/RT) are highly aggressive CNS tumors of infancy and early childhood. Hallmark is the surprisingly simple genome with inactivating mutations or deletions in the SMARCB1 gene as...

OMIC-07. FEASIBILITY AND UTILITY OF EPIGENOMIC PROFILING FOR CHILDHOOD CNS TUMORS IN HONG KONG

Genome-wide DNA methylation profiling has emerged as an important diagnostic tool that complements histopathology for CNS tumors in children and adults. Literature describing its application in Asian countries is nonetheless limited. Herein, we report the feasibility and utility of adopting such platform for children diagnosed with CNS tumors in Hong Kong. A multi-institutional cohort (n=94, 97% of Chinese ethnicity) with CNS embryonal or high grade neuroepithelial tumors (HGNET) diagnosed in Hong Kong from 1996–2020 was assembled based on tissue availability. DNA was extracted from FFPE tumor material (median 301ng, range 13-1000ng), bisulfite converted and profiled with the Infinium Methylation EPIC BeadChip kit. Raw data were analyzed on the German Cancer Research Center MNP 2.0 classifier and through unsupervised dimensionality-reduction analysis (t-SNE) referencing a published CNS tumor reference dataset (GSE90496). The radio-histologic diagnosis included medulloblastoma (n=65), ATRT (n=9), pineal parenchymal tumors (n=7), ETMR (n=5), CNS-PNET (n=4) and other embryonal tumors/HGNETs (n=4). Methylation class could be assigned based on results from MNP 2.0 (calibrated score ≥ 0.9) in 62 patients (66%, including 2 clustering with control) and t-SNE in 22 (23%), while no-match was encountered in 10 (11%). Methylation-based analysis allowed confirmation of diagnosis and assignment of molecular subgroup in 64 patients (68%), confirmation of histologic diagnosis alone in 5 (5%) and resulted in revision/reassignment of diagnosis in 13 (14%). Among medulloblastoma samples that were assigned molecular tumor classes (n=57), 8 clustered with WNT-activated medulloblastoma, 13 with SHH-activated medulloblastoma, 10 with Group 3 medulloblastoma, 21 with Group 4 medulloblastoma, and 5 with non-medulloblastoma entities (high-grade gliomas=3, ETMR=1, ATRT=1). In conclusion, epigenomic profiling allowed refinement of disease classification for pediatric CNS tumors. Availability of such methodology in Asia sets the stage for international collaborations in molecularly-driven trials.

Identifying individuals with primary central nervous system tumors at risk for hereditary cancer syndromes using the Utah Population Database.

10532 Background: CNS tumors are the most common solid tumors and the deadliest cancers in children. Approximately 10% of children with a CNS tumor harbor a hereditary cancer syndrome (HCS), but many will not be tested for a HCS. The Utah Population Database (UPDB) contains comprehensive cancer registry data for Utah families and can determine multigenerational cancer pedigrees across an archive of 5.8 million individuals. Early identification of HCSs results in improved cancer surveillance and outcomes, reducing the impact of CNS tumors in children. We hypothesize that the UPDB can identify children and families with HCSs not previously identified. Methods: We queried the UPDB for individuals ages 0-39 diagnosed with a primary CNS tumor (malignant and benign) between 1966-2017 and generated cancer pedigrees of 3 generations or more for probands, extending to at least third-degree relatives. Specialized software calculated a familial standardized incidence ratio (FSIR) to determine families with excess clustering of CNS tumors. Clinical cancer genetics experts reviewed pedigrees to confirm patterns of HCS. Results: We identified 4,634 CNS tumors in 4,550 individuals, of whom 2,233 (49%) reside in high-quality pedigrees containing ≥2 grandparents, at least 1 from both maternal and paternal sides. To identify families with excess clustering of CNS tumors, we selected pedigrees with an FSIR P&lt; 0.05 and ≥2 affected patients, resulting in 161 high-risk families with a mean of 170 (median 96) relatives per pedigree of 3-6 generations. Among these 161 families, there were 2,017 unique relatives (first-third degree) of CNS probands with 2,355 tumors (any site), for a per pedigree average of 14.7 tumors in 12.5 relatives. Review of the 10 highest risk pedigrees indicated that 4 meet HCS criteria, including Li-Fraumeni (n = 2), von Hippel-Lindau (n = 1), and rhabdoid tumor predisposition (n = 1). Conclusions: The UPDB can produce multigenerational cancer pedigrees that identify individuals and families at risk of harboring a HCS who warrant germline testing. These findings should encourage clinicians to perform thorough family history screening and to always consider workup for associated HCSs.

Single institution experience in re-irradiation of biopsy-proven diffuse intrinsic pontine gliomas.

Diffuse intrinsic pontine glioma (DIPG) is the leading cause of death from CNS tumors in children. Multiple clinical trials have failed to show any benefit from systemic therapy in DIPG, and radiation therapy (RT) alone remains the standard of care. Re-irradiation (rRT) for symptomatic relief is an option at disease progression. However, published data on treatment details and outcomes are limited. The objective of this study was to review and report our institutional experience with re-irradiation of patients with biopsy-proven DIPG. We identified a cohort of pediatric patients with biopsy-proven DIPG with clinical disease progression after initial radiotherapy who received a second course of radiotherapy at our institution. We reviewed patient and treatment characteristics and outcomes. Between January 2014 and July 2018, we identified five patients with progressive DIPG who received re-irradiation. Re-irradiation was well tolerated with no serious adverse events reported and all patients experiencing stable to improved neurologic function during treatment. Median survival from completion of re-irradiation was 116 days (range 62 to 159 days). Median overall survival from time of diagnosis was 16.3 months (range 13.0 to 18.0 months), which is longer than the historical average of less than 12 months. In patients with available postmortem neuropathology, common findings were Wallerian degeneration and necrosis. In our experience, re-irradiation is safe and feasible for patients with DIPG with symptomatic disease progression following initial radiotherapy treatment.

European Society for Paediatric Oncology (SIOPE) MRI guidelines for imaging patients with central nervous system tumours.

Standardisation of imaging acquisition is essential in facilitating multicentre studies related to childhood CNS tumours. It is important to ensure that theimaging protocol can be adopted by centres with varying imaging capabilities without compromising image quality. An imaging protocol has been developed by the Brain Tumour Imaging Working Group of the European Society for Paediatric Oncology (SIOPE) based onconsensus among its members, which consists of neuroradiologists, imaging scientists and paediatric neuro-oncologists. This protocol has been developed tofacilitate SIOPE led studies and regularly reviewed by the imaging working group. The protocol consists of essential MRI sequences with imaging parameters for 1.5 and 3 Tesla MRI scanners and a set of optional sequences that can beused in appropriate clinical settings. The protocol also provides guidelines for early post-operative imaging and surveillance imaging. The complementaryuse of multimodal advanced MRI including diffusion tensor imaging (DTI), MR spectroscopy and perfusion imaging is encouraged, and optional guidance isprovided in this publication. The SIOPE brain tumour imaging protocol will enable consistent imaging across multiple centres involved in paediatric CNS tumour studies.

Diagnostic accuracy and clinical impact of [18F]FET PET in childhood CNS tumors.

Central nervous system (CNS) tumors cause the highest death rates among childhood cancers, and survivors frequently have severe late effects. Magnetic resonance imaging (MRI) is the imaging modality of choice, but its specificity can be challenged by treatment-induced signal changes. In adults, O-(2-[18F]fluoroethyl)-l-tyrosine ([18F]FET) PET can assist in interpreting MRI findings. We assessed the clinical impact and diagnostic accuracy of adding [18F]FET PET to MRI in children with CNS tumors. A total of 169 [18F]FET PET scans were performed in 97 prospectively and consecutively included patients with known or suspected childhood CNS tumors. Scans were performed at primary diagnosis, before or after treatment, or at relapse. Adding [18F]FET PET to MRI impacted clinical management in 8% [95% confidence interval (CI): 4%-13%] of all scans (n = 151) and in 33% [CI: 17%-53%] of scans deemed clinically indicated due to difficult decision making on MRI alone (n = 30). Using pathology or follow-up as reference standard, the addition of [18F]FET PET increased specificity (1.00 [0.82-1.00] vs 0.48 [0.30-0.70], P = .0001) and accuracy (0.91 [CI: 0.87-0.96] vs 0.81 [CI: 0.75-0.89], P = .04) in 83 treated lesions and accuracy in 58 untreated lesions (0.96 [CI: 0.91-1.00] vs 0.90 [CI: 0.82-0.92], P < .001). Further, in a subset of patients (n = 15) [18F]FET uptake correlated positively with genomic proliferation index. The addition of [18F]FET PET to MRI helped discriminate tumor from non-tumor lesions in the largest consecutive cohort of pediatric CNS tumor patients presented to date.

A CORRELATION OF CLINICOPATHOLOGICAL AND RADIOLOGICAL FINDINGS OF CENTRAL NERVES SYSTEM TUMOURS

The annual incidence of tumors of the central nervous system ranges from 10 to 17 per 100,000 persons for intracranial tumors and 1 to 2 per 100,000 persons for intraspinal tumors. Tumors of the CNS account for nearly 20% of all cancers of childhood. Seventy percent of childhood CNS tumors arise in the posterior fossa; a comparable number of tumors in adults arise within the cerebral hemispheres above the tentorium

Outcomes after first relapse of childhood intracranial ependymoma.

Ependymoma is the third most common malignant CNS tumor in children. Despite multimodal therapy, prognosis of relapsed ependymoma remains poor. Approaches to therapy for relapsed ependymoma are varied. We present a single-institution retrospective review of the outcomes after first relapse of intracranial ependymoma in children. We performed a retrospective, IRB-approved chart review of patients with recurrent intracranial ependymoma treated at Dana-Farber/Boston Children's Cancer and Blood Disorders Center from 1990 to 2019. Thirty-four patients with relapsed intracranial ependymoma were identified. At initial diagnosis, 11 patients had supratentorial disease, 22 with posterior fossa disease and one with metastatic disease. Median time-to-first relapse was 14.9months from initial diagnosis (range 1.4-52.5). Seven patients had metastatic disease at first relapse. Gross total resection (GTR) was associated with improved 5-year progression-free survival (PFS) relative to subtotal resection (STR) and no surgery (p=.005). Localized disease at relapse was associated with improved 5-year overall survival (OS) when compared to metastatic disease (p=.02). Irradiation at first relapse seemed to delay progression but was not associated with statistically prolonged PFS or OS. Tumor location, histology, and chromosomal 1q status did not impact outcome at first relapse, although available molecular data were limited making definitive conclusions difficult. Median time-to-second relapse was 10months (range 0.7-124). Five-year PFS and OS after first relapse were 19.9% and 45.1%, respectively. Median PFS and OS were 10.0 and 52.5months after first relapse, respectively. Relapsed intracranial ependymoma has a poor prognosis despite multimodal therapy. Novel therapeutic strategies are desperately needed for this disease.

Lin28A/let-7 oncogenic circuit is a potential therapeutic target in neurocutaneous melanosis-associated CNS tumors in children.

Lin28A/let-7 oncogenic circuit is a potential therapeutic target in neurocutaneous melanosis-associated CNS tumors in children.

DDEL-14. SAFETY OF INTERVENTRICULAR METHOTREXATE ADMINISTRATION FOLLOWING RADIATION IN PEDIATRIC PATIENTS WITH MALIGNANT BRAIN TUMORS

BACKGROUNDMethotrexate has been used for intrathecal administration in leukemia as well as embryonal CNS tumors in children. Concerns about neurologic side effects including leukoencephalopathy, demyelination, and seizures have limited the use of methotrexate following exposure to focal radiation.OBJECTIVETo evaluate and determine safety of Intraventricular administration of Methotrexate in pediatric patients with recurrent malignant brain tumors along with systemic Topotecan and Cyclophosphamide after exposure to prior radiation therapy. DESIGN/METHOD: Patients with recurrent cerebellar embryonal tumors after standard treatment that included radiation were enrolled on this IRB approved phase 2 study. An Ommaya reservoir was inserted in the lateral ventricle and used to administer 4 daily doses of methotrexate (2 mg/dose) along with (Topotecan [0.75mg/m2/day] and Cyclophosphamide [250 mg/m2/day]). A neurological evaluation was performed at baseline and daily during the intraventricular administration of the Methotrexate, this evaluation was repeated prior to each subsequent cycle and at completion of the protocol.RESULTSThree patients (age range 3–20) received 2–3 cycles of intra-Ommaya Methotrexate and Topotecan/Cyclophosphamide. No MRI demyelination or white matter changes were seen after completion of the intraventricular Methotrexate therapy. None of the patients enrolled on this trial had adverse effects related to the therapy regimen received. Clinical neurological status was unchanged during the entire course of the treatment and upon completion of the scheduled therapy.CONCLUSIONIntraventricular administration of daily low dose Methotrexate is well tolerated in children with recurrent embryonal CNS tumors who had prior exposure to radiation.

GCT-73. EXPRESSION PROFILING OF INTRACRANIAL GERM CELL TUMORS REVEALS UPREGULATION OF RAS THROUGH mRNA-microRNA SIGNALING PATHWAY

Intracranial germ cell tumors (IGCTs) account for 3% of CNS tumors in children in the U.S. and 11% in Japan and East Asian countries. IGCTs are separated into two distinct subtypes based on histology: germinomas and non-germinomatous germ cell tumors (NGGCTs). The deep central location of IGCTs makes surgical resection and therefore molecular subtype classification difficult, and previous gene expression studies are limited. We performed mRNA expression profiling (Human Genome U133 Plus 2.0) and microRNA expression profiling (ABI TaqMan) with 36 and 49 IGCTs, respectively. Sample stratification using non-negative matrix factorization clustering of gene expression revealed two distinct subgroups that delineated germinomas from NGGCTs. Employing stepwise model building in each data set separately, we were able to separate these groups using only mRNA probes for the LIN28B and L1TD1 genes, and two microRNA, microRNA-26a and microRNA-373. MicroRNA26a suppresses the LIN28B gene and is down-regulated in germinoma. LIN28B directly binds and suppresses the let-7 microRNA family, which suppress the KRAS oncogene, previously found to be mutated in ~19% of IGCTs. L1TD1 is required for human stem cell renewal and directly interacts with LIN28B for its RNA binding function. LIN28B and L1TD1 are both known to be upregulated in other systemic germ cell tumors, but this has not yet been documented in IGCTs. In conclusion, these results show that intracranial germinomas have similar gene expression compared to systemic seminoma, and suggest a mechanism by which activation of LIN28B and L1TD1 downregulates the let-7 microRNA and subsequently upregulates KRAS.

SWK-08. DELAYED DIAGNOSIS OF CENTRAL NERVOUS SYSTEM (CNS) TUMORS IN CHILDREN: PERSPECTIVE FROM THE FRONTLINE

Delayed diagnosis of CNS tumors in children is well documented, partially due to challenges in recognizing rare diagnoses. Our objective was to describe Canadian family physicians’ attitudes and confidence in diagnosing and managing pediatric CNS tumors. A standardized questionnaire was administered at a Canadian national family physicians’ conference. Items were based on observations from our institutional study of prediagnostic symptomatic interval in pediatric CNS tumors. 449 surveys were completed. 302/443 (68%) physicians practice in cities. 153/447 (34%) report encountering parents that inquire about their children having brain tumors. 261/449 (58%) have not managed a pediatric brain tumor. 153/447 (34%) report they are not confident, 255/447 (57%) somewhat confident and 39/447 (9%) confident in managing a suspected brain tumor in a stable child. 259/447 (58%) would refer directly to a hospital/specialist. The reported median time for suspicion of a brain tumor was 8–14 days for children with vomiting and/or headache and 1 day for children with seizure and/or ataxia. 410/447 (97%) report not knowing any guidelines to help with management. 235/447 (53%) suggested barriers they experience to include 52/235 (22%) wait times for imaging/specialists, 37/235 (16%) geographical location of the child, 27/235 (12%) knowledge, 25/235 (11%) access to imaging/specialist, and 15/235 (6%) patient-related factors or system barriers, and 8/235 (3%) specialist attitudes. 68/235 (29%) identified no barriers in their practice. This study provides insight into family physicians’ perceived challenges and barriers in diagnosing and managing new suspected pediatric CNS tumors. Educational effort and overcoming systemic perceived barriers may increase physicians’ confidence.

EPEN-35. PERITONEAL CARCINOMATOSIS OF ANAPLASTIC EPENDYMOMA: FIRST REPORTED CASE

Peritoneal Carcinomatosis of anaplastic ependymoma is not a previously reported entity. The authors report on a child with multiple successfully treated brain and spine disease occurrences who subsequently develops carcinomatosis of the abdomen and no evidence of CNS recurrence. Ependymoma accounts for up to 10% of childhood CNS tumors diagnosed in the United States with a median age of 51–71 months. Typical locations are based on age. Disease is typically treated with surgical resection followed by radiation. The role of chemotherapy has not been proven but currently being examined with open clinical trials. We will describe patient’s presentations, clinical treatment and recurrence with subsequent treatment and outcome at time of meeting.

LGG-57. SIGNALLING MECHANISMS IN PAEDIATRIC LOW-GRADE GLIOMA

Paediatric low-grade gliomas (pLGGs) constitute the largest group of childhood CNS tumours. They often cause significant disability and morbidity, despite their indolent growth and the good survival rate of patients. The most common genetic alterations in these tumours, KIAA1549:BRAF fusion and BRAFV600E mutation, lead to abnormal activation of MAPK signalling. The central role of this pathway in pLGG development is emphasized by the occasional presence of other MAPK-activating alterations such as RTK mutations. It is not known how these different aberrations can induce the variety of clinical phenotypes seen in pLGG. Here, we compared pilocytic astrocytomas (PAs) containing the KIAA1549:BRAF fusion with glioneuronal tumours (GNTs) containing the BRAFV600E mutation, to identify differentially activated downstream targets of the MAPK pathway. Liquid chromatography tandem mass spectrometry (LC-MS/MS) was used as a multi-proteomic approach. Kinase Set Enrichment Analysis (KSEA) using PhosphositePlus and NetworkIN was used to determine relative enrichment of kinase activity in the tumours compared to healthy control brain tissue. Significant similarities and differences were found in the two tumour types. For example, more robust MAPK activation was found in the GNTs than in PAs. However, while PI3K/AKT1/mTOR signalling was active in both PAs and GNTs, there was statistically higher activation in the PAs. In both tumour types, there was significant reduction in casein kinase 2 activity, which likely affects nuclear translocation of ERK and, in turn, alters the range of its phosphorylated substrates. We will present these data together with transcriptomics to further characterise the downstream targets of these genetic alterations.

NCOG-73. EFFECT OF TIME TO DIAGNOSIS IN CHILDREN WITH MALIGNANT CENTRAL NERVOUS SYSTEM TUMORS ON SURVIVAL OUTCOMES AND DISEASE-ASSOCIATED MORBIDITY: AN INSTITUTIONAL COHORT STUDY

Abstract OBJECTIVE To determine the impact of time to diagnosis on disease related morbidity and mortality. METHODS This is a retrospective review of all diagnoses of malignant CNS tumors in children presenting to BC Children’s Hospital (BCCH) from 2000-2019. Analyses were conducted to assess the relationship between time to diagnosis and overall survival as well as long-term morbidity; stratified by tumor type, age and presence of metastatic disease. RESULTS From 2000-2019, there were 116 children diagnosed with malignant CNS tumors at BCCH (mean age 9.5 years, 67% male). Tumors included medulloblastoma (27, 23.3%), ependymoma (14, 12.1%), high grade gliomas (19, 16.4%), CNS germ cell tumors (40, 34.4%), and other embryonal CNS tumors (16, 13.8%). Median time to diagnosis from first symptom onset was 63 days (IQR 26.5 – 237.5 days). 18% had metastatic disease. Within this cohort, 3-year EFS was 57%, and 5-year overall survival was 78.4%. 64% of patients were alive with no evidence of disease at median follow up from treatment completion of 4.31 years (IQR 1.77 – 6.15 years). Long-term morbidity included panhypopituitarism (20.7%), vision loss(22.4%), hearing loss(30.2%), learning disability(17.2%) and cognitive impairment (19.8%). In a cox proportional hazards model, overall survival was associated with time to diagnosis(estimate 0.0271;SE=1.6500;p=0.028), high grade glioma(estimate 8.3200; SE=0.6650; p=0.001), age at diagnosis(estimate 0.8590; SE=0.0532; p=0.004), relapse (estimate 4.9600; SE=0.6100; p=0.009) and metastatic disease (estimate 9.1700; SE=0.5660; p&amp;lt; 0.001). Vision loss was also significantly correlated with time to diagnosis (estimate 0.542; SE=0.2940; p=0.038). CONCLUSION Median time to diagnosis is associated with overall survival and long-term morbidity in pediatric patients treated for malignant CNS tumors. These data highlight that knowledge translation to the public, primary care and emergency room professionals should be a priority in order to promote early connection with medical care and mitigate morbidity and mortality in those with pediatric CNS tumors.