bluuebunny/crossref_metadata_2025 huggingface dataset:
EPCT-08. ACTIVITY OF LAROTRECTINIB IN PEDIATRIC TROPOMYOSIN RECEPTOR KINASE (TRK) FUSION CANCER PATIENTS WITH PRIMARY CENTRAL NERVOUS SYSTEM (CNS) TUMORS
Authors: Goto Hiroaki , Geoerger Birgit , DuBois Steven G , Grilley-Olson Juneko E , van Tilburg Cornelis M , Schulte Johannes , Kang Hyoung Jin , Tahara Makoto , Boni Valentina , Perreault Sebastien , Capra Michael , Reeves John A , Brega Nicoletta , Childs Barrett H , Laetsch Theodore W , Ziegler David S , Doz François
Published: December 2020

BACKGROUND

TRK fusions are oncogenic drivers in a variety of tumors, many involving the CNS. Larotrectinib, a selective FDA- and EMA-approved TRK inhibitor, demonstrated a 79% objective response rate (ORR) and a 35.2-month median duration of response (DoR) in adult and pediatric patients with various non-CNS solid tumors harboring NTRK gene fusions. We report the clinical activity of larotrectinib in pediatric patients with primary TRK fusion CNS tumors.

METHODS

Patients aged <18 years with primary CNS tumors harboring an NTRK gene fusion detected by local molecular testing who were treated with larotrectinib in two clinical trials (NCT02637687, NCT02576431) were identified. Larotrectinib was administered until disease progression, withdrawal, or unacceptable toxicity. Disease status was investigator assessed (RANO).

RESULTS

As of February 2019, 14 pediatric patients with primary TRK fusion CNS tumors were identified. Gene fusions involved NTRK2 (n=10), NTRK1 (n=2), and NTRK3 (n=2). Median age was 7.0 years (range 1.3–16.7). ORR was 45% (95% CI 17–77%) among 11 evaluable patients. Two patients had complete responses (pending confirmation), three had confirmed partial responses, and six had stable disease. 24-week disease control rate was 73%. DoR ranged from 2.6+ to 5.5+ months and progression-free survival ranged from 0.03+ to 13.9+ months. Duration of treatment ranged from 0.03+ to 16.6+ months. Treatment-emergent adverse events were mainly grade 1–2.

CONCLUSIONS

Larotrectinib resulted in objective responses and durable disease control in pediatric patients with primary TRK fusion CNS tumors. These results support expanded testing for NTRK gene fusions in patients with CNS tumors.
EPCT-18. PHASE 0/I STUDY OF GM-CSF AND INTRATHECAL TRASTUZUMAB IN CHILDREN WITH RECURRENT POSTERIOR FOSSA EPENDYMOMA
Authors: Dorris Kathleen , Widener Melissa , Amani Vladimir , Donson Andrew , Schissel Debra , Carson Jessica , Mettetal Ashley , Ramirez Dominique , Gustafson Daniel , Hankinson Todd , Handler Michael , Macy Margaret , Foreman Nicholas
Published: December 2020

BACKGROUND

Posterior fossa ependymoma (PF EPN) is a pediatric central nervous system malignancy that has a poor outcome to standard therapeutic approaches. The majority of PF EPN tumors have increased HER2 expression. Trastuzumab is a monoclonal antibody that targets HER2, and sargramostim (GM-CSF) stimulates hematopoietic progenitor cell proliferation. The combination of trastuzumab and GM-CSF has been shown to trigger antibody-dependent cell cytotoxicity in vitro in PF EPN cell lines.

METHODS

Children aged 1–21 years with relapsed PF EPN and no ventriculoperitoneal shunt or CSF obstruction are eligible for the Phase 0/I institutional trial at Children’s Hospital Colorado. Stratum 1 involves IT trastuzumab and subcutaneous (subQ) GM-CSF prior to standard-of-care surgical resection. Stratum 2 involves a 3 + 3 phase I design with serial IT trastuzumab doses, each preceded by three days of GM-CSF, to establish the MTD for IT trastuzumab.

RESULTS

Trastuzumab was detected in a sufficient number of tumors after presurgical IT delivery in Stratum 1 to open Stratum 2. Four patients (75% female) have been enrolled in Stratum 2 at trastuzumab Dose Level 1. Median age at enrollment is 9.8 years (range, 3.5–20.2 years). Preliminary CSF pharmacokinetic analysis demonstrated detectable trastuzumab up to 14 days after IT doses. No dose-limiting toxicities have occurred. Two patients progressed on therapy (median, 4 cycles). One patient is progression-free at 18 months off therapy. One patient remains on study therapy.

CONCLUSIONS

IT trastuzumab penetrates PF EPN tumor tissue. Stratum 2 remains open to accrual at Dose Level 2.
EPEN-09. IMPACT OF MOLECULAR SUBGROUP ON OUTCOME FOR INFANTS <12 MONTHS WITH INTRACRANIAL EPENDYMOMA - GERMAN EXPERIENCE FROM HIT2000, INTERIM-2000-REGISTRY AND I-HIT-MED REGISTRY
Authors: Obrecht Denise , Mynarek Martin , von Hoff Katja , Witt Hendrik , Pajtler Kristian W , Juhnke B Ole , Warmuth-Metz Monika , Bison Brigitte , Kortmann Rolf-Dieter , Timmermann Beate , Pfister Stefan M , Sahm Felix , Sturm Dominik , von Deimling Andreas , Schüller Ulrich , Pietsch Torsten , Benesch Martin , Gerber Nicolas U , Rutkowski Stefan
Published: December 2020

BACKGROUND

For infant ependymoma (EP), decision for radiotherapy during first-line therapy is a dilemma. We analyzed therapy outcomes of EP patients younger than 12 months at diagnosis according to molecular subgroup.

PATIENTS AND METHODS

Between 2001 and 2017, 30 patients with histological diagnosis of intracranial EP <12 months at diagnosis with DNA-methylation profiling available were registered in HIT-MED-studies/-registries.

RESULTS

In 3/30, DNA methylation-based CNS tumor classification suggested a diagnosis other than EP or could not be assigned to a reference class. Of the remaining 27 tumors, 16 were classified as PF-A, 8 as RELA-fusion positive and 3 as YAP-fusion positive. Median age at diagnosis was 0.73 (0.30–0.99) years. After a median follow-up time of 5.36 (0.20–12.90) years, 59.3% experienced progressive disease (PD). 5y-PFS and -OS for the whole cohort were 38.2% and 73.1%. RELA- and YAP-fusion positive EP had significantly better OS than PF-A (5y-OS for PF-A: 55.9%; RELA 100%; YAP 100%; p=0.023). PFS was not significantly different. All but one patient with relapsed PF-A died despite multimodal salvage strategies. In contrast, patients with relapsing RELA- and YAP-fusion positive EP (n=5), survived with a combination of re-surgery and first or second local radiotherapy.

CONCLUSION

In this cohort of infants <12 months, patients with PF-A had a significantly inferior OS compared to patients with RELA- and YAP-fusion positive EP. Salvage therapy was ineffective for patients with PF-A, whereas patients with can RELA- and YAP-fusion positive EP can be long-term survivors after PD. Therefore, subgroups-specific therapy should be discussed.
EPEN-14. GENERATION OF A C11orf95-RELA FUSION TARGETING ANTIBODY AS A DIAGNOSTIC TOOL FOR SUPRATENTORIAL EPENDYMOMA
Authors: Ruff Lisa , Chan Denice Y , Jenkinson Lesley , Haynes Stuart , Austin Mark , Holt Sarah , Groves Maria , Gilbertson Richard J
Published: December 2020

Ependymomas account for 10% of paediatric brain tumours and arise in the ventricular walls of the central nervous system. Ependymomas were previously classified as one tumour type and all patients received similar treatment. However, recent genomic studies have identified nine different molecular subgroups of the disease, including one supratentorial subtype characterized by a novel fusion gene C11ORF95-RELA. When introduced into neural stem cells, this fusion is a potent driver of tumorigenesis and its presence in patient samples has previously also been shown to negatively correlate with overall survival. Accurate diagnosis of this subgroup is currently limited to sophisticated approaches such as break-apart FISH or RNA sequencing. Here, we report the generation of a C11ORF95-RELA Fusion-specific antibody that can be used for routine immunohistochemistry (IHC). Candidate antibodies were first selected using phage display and favourable leads were subjected to affinity maturation using ribosome display after a screening process involving immunoblotting and IHC. Further IHC-based screening of affinity-matured candidates using fusion-positive and -negative mouse tissue as well as human fusion-negative ependymoma tumour tissue produced one lead antibody. The antibody detects fusion-specific nuclear staining pattern on fusion-positive tissue and does not react with fusion-negative tissues. This candidate antibody is currently being tested on human fusion-positive ependymoma tissue. This accurate diagnostic tool holds great promise to transform the management of patients with supratentorial ependymoma.
EPEN-37. TREATMENT OUTCOME OF RECURRENT EPENDYMOMA IN CHILDREN IN NORTHERN EGYPT
Authors: Fadel Shady , Abdelaziz Zeyad , Kerim Amr Abdel , Abbassy Mahmoud , Samy Samer , Elsaba Basma
Published: December 2020

INTRODUCTION

1/3 of Ependymoma patients will develop recurrence with only 25% are long term survivors. Treatment is usually between surgery, radiotherapy or combinations.

PATIENTS AND METHODS

Retrospective review of children with recurrent Ependymoma in northwest of Egypt between 2005 and 2019 in Alexandria School of medicine records.

RESULTS

27 patients were identified 19 of them after 2010. The median age is 9.7 years (1.5–19), with 16 males and 11 females. Pathology were 11 grade II Ependymoma and 16 anaplastic Ependymoma. 16 had gross residual disease after 1st surgery and 22 received radiotherapy initially at median dose of 53.5 Gy, 4 patients received suboptimal radiotherapy. The initial site was14 supratentorial tumors and 13 infratentorial. Median time to recurrence is 27.6 months(3–84), and recurrences were 17 local and 9 CSF disseminated, and one patient had recurrence at the scar with lung metastasis. At a median follow up of 56.6 months 14(51.8%) are still alive. Treatment was surgery only in 6(4 alive) radiotherapy alone in 2(1alive), combined in 15(9 alive) and 4 patients received neither. The best outcome were in patients with late local relapse treated with complete resection and CSI after 2010. Radiotherapy dose was between 54 to 57.3 Gy and one patient developed reirradiation injury at brain stem. 5 of the 14 living patients is having toxicity in form of hearing aids (4) and low TSH(1).

CONCLUSION

Aggressive treatment of recurrent Ependymoma with surgery and radiotherapy is feasible and about half of the patients are salvageable.
EPEN-38. EZH2 INHIBITORY PROTEIN (EZHIP/Cxorf67) EXPRESSION IS HIGHLY CONCORDANT WITH H3K27me3 LOSS AND IS A PROMISING SURROGATE MARKER FOR POSTERIOR FOSSA TYPE A EPENDYMOMAS
Authors: Nambirajan Aruna , Rajeshwari Madhu , Boorgula Meher , Doddamani Ramesh , Singh Manmohan , Garg Ajay , Suri Vaishali , Sarkar Chitra , Sharma Mehar
Published: December 2020

BACKGROUND

Gene expression and DNA methylation have identified 2 distinct clinicopathological subgroups among the WHO Grade II/III posterior fossa (PF) ependymomas (EPN), of which the PF-A molecular subgroup associates with poor outcome.

OBJECTIVE

To analyse the utility of immunohistochemistry for H3K27me3, Tenascin C, EZHIP (Cxorf67), EZH2 and fluorescence-in-situ-hybridisation for chromosome 1q21 locus gain in the prognostic stratification of PF-EPNs.

METHODS

All PF Grade II/III tumors were retrieved (2009–2019). Immunohistochemistry for H3K27me3, H3K27M-mutation-specific antibody, EZH2, EZHIP, Tenascin-C and fluorescence in-situ hybridisation for 1q21 locus was performed and compared with outcome.

RESULTS

71 PF-EPNs were included. H3K27me3 loss (PF-A) was seen in 65% (46/71) of cases, of which majority were positive for EZHIP (73%, 24/33) and Tenascin C (65%, 28/43). Minority showed chromosome 1q gain (19%, 8/42). An EZHIP negative PF-A tumor was immunopositive for H3K27M-mutant staining, while all others were negative. PF-A EPNs occurred at a median age of 4.5 years (range 1–53), were predominantly grade III (Grade III:II – 1.6:1), and 50% (10/20) of patients on follow-up experienced tumor progression. EPNs with retained H3K27me3 (PF-B) did not show EZHIP expression (0/20) or 1q gain; however, tenascin C expression was seen in 47% (8/25) of them. They occurred predominantly in adults, showed Grade II preponderance and only 2/11 patients on follow-up experienced progression. EZH2 expression did not correlate with H3K27me3 loss but positively correlated with EZHIP expression (p=0.015).

CONCLUSION

H3K27me3 is a reliable surrogate for prognostic classification of PF-EPNs. EZHIP expression is highly concordant with H3K27me3 loss and is a valuable adjunct.
EPEN-50. THE MANAGEMENT AND TREATMENT OF PEDIATRIC SPINAL CORD EPENDYMOMA: RESULTS FROM A COLLABORATIVE INTERNATIONAL MULTI-INSTITUTIONAL REVIEW
Authors: Lucas John , Kumirova Ella , Tsang Derek , Vinitsky Anna , Chiang Jason , Hazrati Lili-Naz , Lane Shelby , Agbahiwe Harold , Upadhyay Santhosh , Tinkle Christopher , Konovalov Dmitry , El-Ayadi Moatasem , Maher Eslam , Emtsova Victoria , Nechesnyuk Alexey , Sarhan Nasim , Loginova Anna , Hsu Chih-Yang , Ladra Matthew , Terezakis Stephanie , Boop Frederick , Klimo Paul , Ahmed Soha , Laperriere Normand , Ramaswamy Vijay , Merchant Thomas
Published: December 2020

PURPOSE

Pediatric Spinal cord ependymoma (SCE) is rare, and the management is often heterogeneous across centers. We evaluated the impact of clinical, pathologic, and treatment-related factors on outcomes in a multi-institutional, international cohort.

METHODS

SCE patients age <21 years were reviewed across 5 institutions. We utilized nonparametric descriptive statistics, survival, and recursive partitioning analysis (RPA) to examine patient, tumor, histopathologic and treatment characteristics, failure pattern, and cause of death.

RESULTS

125 patients were identified, 18 (14.4%) with metastases. Initial surgery was GTR, and STR in 44, 56% of patients respectively. Histology was grade 1, 2, and 3 in 55, 17.7 and 23.2% respectively. 55 patients with initial GTR were observed (52.7%) or irradiated (43.6%); 60 patients had STR and were observed (40%) or irradiated (60%). The 7-year event-free (EFS) and overall survival (OS) was 60% (95% CI 51.5–71.4) and 79% (95% CI 71.1–87.8) respectively. STR and metastasis increased the hazard for death [HR 1.87, 95% CI 1.02–3.57, p=0.05 (vs. GTR)] and [HR 2.28, 95% CI 1.1–5.2, p=0.048 (vs. localized)] respectively. Across 43 failures, local failure predominated (48.8%). Distant and combined failure occurred in 30.2 and 13.9% respectively. Adjuvant RT offered a 20% absolute improvement (vs. observation) in EFS at 5 years regardless of extent of resection. RPA identified thoracic (vs. non-thoracic), grade (1 & 3 vs. 2), STR (vs. GTR) and metastases as determinants of inferior EFS.

CONCLUSIONS

Tumor and treatment-related factors are predictive of EFS. OS is favorable despite diverse schema and frequent distant failures.
EPID-03. COMPARISON OF SURVIVAL IN ADULT AND PEDIATRIC PATIENTS WITH MEDULLOBLASTOMA: A 2018 SEER BASED ANALYSIS
Authors: Moisander-Joyce Hanna M , Sinha Anoushka , Fernandez-Ledon Shannon , Lee Davon T , Hatano Satoki , Kahn Justine , Garvin James H , Zacharoulis Stergios , Gartrell-Corrado Robyn D
Published: December 2020

Medulloblastoma (MB) is the most common high-grade primary brain malignancy in children and accounts for 1% of adult brain tumors. Previous studies have compared survival in pediatric and adult MB from the National Cancer Institute Surveillance Epidemiology and End Results (SEER) database finding no difference. However, diagnostic subgroup analyses are limited. We examined survival in children (age 0–19) and adults (20–79) coded as MB in the 2018 SEER database (2000–2016), using Kaplan Meier analysis, log-rank test and Cox proportional hazard ratios (HR) with 95% confidence intervals (CI).). MB in SEER-18 is defined as ICD-O-3 histology codes 9470–9474 (n=1,728). ICD 9473, supratentorial PNET (sPNET, n=97) is biologically distinct so was analyzed separately. 5-year survival for MB, excluding sPNET, was similar in children (n = 1,091, 75.3%) and adults (n= 488, 79.1%) (HR=0.97, CI: 0.79 – 1.17, p=0.50). Subtype analyses showed no survival difference comparing adults and children with desmoplastic nodular MB (n=222, p=0.09), large cell MB (n=73, p=0.46), or MB NOS (n=1330, p=0.10). In contrast, children with sPNET had improved survival (n=65, 72.3%) compared to adults (n=29, 51.7%) (HR = 2.0, CI: 1.10 – 3.92; p=0.02,). In conclusion, 2018 SEER data for MB continue to show no survival difference between adults and children, suggesting adult patients could appropriately be entered on pediatric MB treatment protocols. Further analyses of the 2018 data are ongoing adjusting for sex, race, and treatment. Comparison of adults and children with MB and sPNET will be re-evaluated using the new 2016 World Health Organization classification.
EPID-05. EVALUATION OF THE INCIDENCE OF CENTRAL NERVOUS SYSTEM TUMORS IN A CHILDHOOD CANCER TREATMENT CENTER AND THE CREATION OF A SPECIFIC GROUP
Authors: Azambuja Alessandra , Barreto Juliana , Cristofani Lilian Maria , Sanders Felipe , Baraldi Helena , Weltman Eduardo , Lucato Leandro , Paes Vitor , Frassetto Fernando , Petitto Carlo , Rosemberg Sergio , Matushita Hamilton , Odone Vicente
Published: December 2020

Central Nervous System Tumors (CNST) are the main solid neoplasm of childhood, representing 20% diagnosis. Based on this information, a search was carried out at a reference treatment center for childhood cancer in the state of Sao Paulo, belonging to University of Sao Paulo- ITACI/HCFMUSP, and at between 2017 and 2019, 352 new patients, 116 of which were neoplasm of CNS (32.9%). Aiming at an incidence of new cases, in 2019, an institutional group was created, with a team composed of Pediatric Oncologists, Neurosurgeons, Radiologists, Radiotherapists and Pathologists. In this first year, 31,8% of the 132 new patients were diagnosed with CNS tumor. According to WHO 2016, 15 patients were classified as a group that includes Diffuse Astrocytomas, Oligodendrioglial Tumors and Other Astrocytic Tumors. Among the other patients, 14.2% were Medulloblastomas, 4.7% Embryonic Tumors and 2.3% ART / RT. Patients diagnosed with diffuse brainstem glioma accounted for 11.9% of the total. The institution had a diagnosis of Angiocentric Glioma, Craniopharyngioma, Plexiform Neurofibroma and Anaplastic Ependymoma. Neuronal-glial tumors accounted for 9.5% of cases. Choroid plexus tumors represents 5%. Among them, 4.72% had metastatic tumors: Neuroblastoma and Ewing’s Sarcoma. Of the total of 42 patients, there were 5 deaths, 4 due to disease progression and one due to clinical complications. With the group, the discussions were carried out, allowing us to analyze that the presence of the Radiotherapy, Neurosurgery and Pathology team from the first moment, optimized the beginning of treatment and increased the patients’ survival.
EPID-07. A GLOBAL PERSPECTIVE ON THE BURDEN OF PEDIATRIC CENTRAL NERVOUS SYSTEM TUMORS
Authors: Moreira Daniel , Qaddoumi Ibrahim , Bhakta Nickhill , Gajjar Amar , Rodriguez-Galindo Carlos
Published: December 2020

Although approximately 90% of pediatric cancer cases exist in low- and middle-income countries, the magnitude of the global burden of pediatric central nervous system (CNS) tumors remains poorly quantified. METHODS: Data from International Incidence of Childhood Cancer-3 and CONCORD-3, which include observed incidence and survival from population-based cancer registries (PBCR), and from GLOBOCAN 2018 and Global Burden of Disease 2016, which produce burden estimates from observed and modelled data, were used to analyze epidemiologic characteristics and correlations for CNS tumors globally. Data from The World Bank were used for national macroeconomic variables. RESULTS: The majority of countries are not covered by PBCR, with information on incidence and survival available for 37% and 27% of countries, respectively. Survival data is not available for any low-income country. The incidence of CNS tumors varies markedly, from 0.4 to 49 x106 person-years, the greatest variability in pediatric cancer subgroups. Modelled data suggests that approximately 40,000 incident cases and 19,000 deaths occur from CNS tumors worldwide. When country-level data are segregated based on World Bank groups, a difference in incidence and survival exists (p<0.05). A higher national health expenditure correlates with both an increased incidence and survival of CNS tumors, while the inverse is true for under-5 mortality (p<0.05). CONCLUSIONS: Scarce facts are available, but this analysis establishes a link between national income and epidemiologic parameters for CNS tumors. In this context, carefully designed initiatives, focusing on a health-systems approach are critical to meet the global challenge of pediatric CNS tumors.
EPID-09. THE INCIDENCE OF PRIMARY BRAIN TUMORS IN CHILDREN IN JAPAN BASED ON 2016 NATIONAL CANCER REGISTRY IN JAPAN
Authors: Watanabe Yuko , Narita Yoshitaka , Kayama Takamasa
Published: December 2020

The national cancer registries began in January 2016 and the actual number of cancer patients in 2016 including primary brain tumors in Japan was released as a preliminary report in January 2019. According to the report, 667 incidence of pediatric brain tumors were reported in aged 0–14 years (boy: 382; girl: 285), of them 537 patients underwent surgery, chemotherapy, or radiation therapy (diagnosis: 516, undiagnosed: 21), and 130 patients were followed up without any treatments. The breakdown of tumor types was 279 Neuroepithelial tumors, 73 Embryonal tumors (61 Medulloblastomas), and 63 Germ Cell Tumors (GCTs). The crude rate per 100,000 population in 2016 was 4.23 for all pediatric brain tumors, 1.77 for Neuroepithelial tumor, 0.39 for Medulloblastoma, and 0.40 for GCTs. In comparison, the United States CBTRUS2019 (2012–2016) reported that the age-adjusted incidence rates per 100,000 population in the United States was 5.74 for all pediatric brain tumors, 4.15 for Neuroepithelial tumors, 0.48 for Medulloblastoma, and 0.22 for GCTs. The age-adjusted incidence in Japan based on the US population in 2000 was 4.21 for all pediatric brain tumors, Neuroepithelial tumor 1.77, Medulloblastoma 0.39, and GCTs 0.39, suggesting that the incidence of Neuroepithelial tumor and Medulloblastoma is lower whereas that of GCTs is approximately twice comparing to the US. By taking advantage of the national cancer registry data, which was publicly opened to researchers in 2019, we report the incidence of primary brain tumors and its comparison worldwide based on the re-classification criteria of primary brain tumors including benign tumor.
EPID-10. EPIDEMIOLOGY STUDY OF UNCOMMON CHILDHOOD BRAIN TUMOURS IN ASIAN CHILDREN
Authors: Chan Godfrey Chi-Fung , Liu Anthony Pak-Yin , Shing Matthew Ming-Kong , Ku Dennis Tak-Noi
Published: December 2020

Our local registry identified 656 brain tumours from Jan 1999 to Dec 2018, (incidence: 29.8/yr/million). Other from Glioma, Medulloblastoma/PNET, Germ Cell tumours, Ependymoma, the remaining rarer tumours accounted for 18% (n=118). The 7 more common groups are: craniopharyngioma(n=28); ATRT(n=18); choroid plexus papilloma/CA(n=12); Ganglioglioma(n=11); ETMR(n=7); DNET(n=7); meningioma(n=6). Their respective incidences are 1.27; 0.81; 0.55; 0.5; 0.32; 0.32 0.27/yr/million. For craniopharyngioma, M:F=15:13 and median age was 7.4yrs (2mons-16.5yrs). 12/28 children had surgery alone and 13/28 had focal RT post-surgery with better outcome. 3 underwent intra-cystic interferon-beta also stable. For ATRT, M:F=7:8 and median age was 2.3yrs (4mos-14.2yrs). 2 had metastatic disease and 7/18 patients remained alive. For choroid plexus tumours, there were 7 papilloma, 2 atypia and 3 carcinoma. M:F=5:6 and median age was 1.5yrs (4mos-14yrs). All papilloma, 1/2 atypia and 1/3 carcinoma survived. For ganglioglioma, M:F=7:4 with median age of 5.5yrs (5mos-13.2yrs). They commonly presented with seizure and only one died (brainstem primary). The ETMR includes ependymoblastoma and medulloepithelioma, they had quite different clinical characteristics and outcome. 6/7 DNET had convulsion and M:F=6:1. Median age was 11.5yrs (2.66-14yrs). They all survived even if incompletely resected. For meningioma, 1/6 had germline mutation of NF-2 gene. M:F=3:3 and onset was >8yrs except the NF-2 patient. All survived but the NF-2 had multiple recurrences. 4 patients developed secondary meningioma due to irradiation but they were >18yrs so excluded. In summary, rarer forms of childhood brain tumours only accounted for <20% of all brain tumours and they had diverse presenting features and outcome.
EPID-16. INTEGRATION OF EHR AND CANCER REGISTRY DATA TO CONSTRUCT A PEDIATRIC NEURO-ONCOLOGY SURVIVORSHIP COHORT AND IMPROVE LONG-TERM FOLLOW-UP CARE
Authors: Noyd David , Howell Claire , Oeffinger Kevin , Landi Daniel , Schroeder Kristin
Published: December 2020

BACKGROUND

Pediatric neuro-oncology (PNO) survivors suffer long-term physical and neurocognitive morbidity. Comprehensive care addressing late effects of brain tumors and treatment in these patients is important. Clinical guidelines offer a framework for evaluating late effects, yet lack of extended follow-up is a significant barrier. The electronic health record (EHR) allows novel and impactful opportunities to construct, maintain, and leverage survivorship cohorts for health care delivery and as a platform for research.

METHODS

This survivorship cohort includes all PNO cases ≤18-years-old reported to the state-mandated cancer registry by our institution. Data mining of the EHR for exposures, demographic, and clinical data identified patients with lack of extended follow-up (>1000 days since last visit). Explanatory variables included age, race/ethnicity, and language. Primary outcome included date of last clinic visit.

RESULTS

Between January 1, 2013 and December 31, 2018, there were 324 PNO patients reported to our institutional registry with ongoing analysis to identify the specific survivorship cohort. Thirty patients died with an overall mortality of 9.3%. Two-hundred-and-sixteen patients were seen in PNO clinic, of which 18.5%% (n=40) did not receive extended follow-up. Patients without extended follow-up were an average of 3.5 years older up (p<0.01); however, there was no significant difference in preferred language (p=0.97) or race/ethnicity (p=0.57).

CONCLUSION

Integration of EHR and cancer registry data represents a feasible, timely, and novel approach to construct a PNO survivorship cohort to identify and re-engage patients without extended follow-up. Future applications include analysis of exposures and complications during therapy on late effects outcomes.
EPID-18. TRENDS IN INCIDENCE AND SURVIVAL OF MALIGNANT PEDIATRIC CENTRAL NERVOUS SYSTEM TUMORS IN THE NETHERLANDS
Authors: Hoogendijk Raoull , van der Lugt Jasper , van Vuurden Dannis , Hoving Eelco , Kremer Leontien , Wesseling Pieter , Karim-Kos Henrike
Published: December 2020

BACKGROUND

Variation in survival of pediatric central nervous system (CNS) tumors is large between countries. Within Europe, the Netherlands had one of the worst reported survival rates of malignant CNS (mCNS) tumors during 2000–2007.

METHODS

Using the Netherlands Cancer Registry, we evaluated trends in incidence and survival of pediatric mCNS tumors (behavior /3, 5th digit in the morphology code) diagnosed between 1990–2017.

RESULTS

839 newly-diagnosed mCNS tumor patients <18 years were registered between 1990–2017. Incidence of mCNS tumors remained stable (average incidence rate, 21.6 per million person-years). However, an increased incidence of malignant gliomas, NOS was found (Estimated Annual Percentage Change (EAPC) 11.6% p<0.001). This appears to be related to a registration shift between 1990–1999 and 2000–2009 as brainstem tumors increased (+25%, n=79) for astrocytomas and other gliomas but decreased (-31%, n=32) for unspecified intracranial and intraspinal neoplasms. Overall, 5-year observed survival (5Y-OS) of mCNS tumors increased from 51% in 1990–1999 to 61% in 2010–2017 (P-for-trend<0.001). This increase was not constant over time, as 5Y-OS for the period 2000–2009 was 47%. The only significant decrease in survival was found for malignant astrocytomas and other gliomas with a 5Y-OS of 56% in 1990–1999 decreasing to 48% in 2010–2017 (P-for-trend<0.001).

CONCLUSION

Between 1990–2017 incidence of mCNS tumors in the Netherlands remained stable and survival increased. However, a decrease in survival was seen for malignant astrocytomas and other gliomas, which is partially explained by the registration shift of brainstem tumors. The impact of this shift on survival for all mCNS tumors is subject to further research.
ETMR-03. THE ROLE OF FOXR2 IN PEDIATRIC BRAIN CANCER
Authors: Schmitt-Hoffner Felix , van Rijn Sjoerd , Hübner Jens-Martin , Lambo Sander , Mauermann Monika , Mack Norman , Schwalm Benjamin , Pfister Stefan , Kool Marcel
Published: December 2020

Forkhead Box R2 (FOXR2) is a transcription factor of the Forkhead Box family that has been correlated with tumorigenesis, aberrant cell growth or tumor progression. Expression of FOXR2 in pediatric brain tumors is, besides in subsets of medullo-, pineo- and glioblastoma, primarily present in CNS neuroblastoma with FOXR2 activation (CNS NB-FOXR2), a novel entity that we in 2016 identified from the former class of primitive neuroectodermal tumors of the central nervous system (CNS-PNET). Analyzing CNS-NB-FOXR2 tumors we found that FOXR2 mRNA is expressed in an anti-correlative manner compared to the proto-oncogenes MYC and MYCN. With immunoprecipitation analyses we show that FOXR2 binds to MYC and MYCN and is thereby stabilizing these proteins. These observations on the interaction and the anti-correlative manner suggest that FOXR2 and MYC(N) may drive tumor formation in a molecularly similar fashion. To investigate this further we stably expressed FOXR2, MYCN and MYC and a combination of FOXR2 with MYC(N) in human neural stem cells (hNSC) and injected these in the striatum of NSG mice. We could show that hNSC itself do not from a tumor, whereas the expression of FOXR2 and/or MYC(N) in hNSC results in tumorigenesis. Tumors expressing both, FOXR2 and MYC(N) were growing faster than tumors with FOXR2 alone. In addition, tumors are currently being analyzed by ChIP-sequencing for FOXR2, MYC, and MYCN, to better understand the mechanisms how FOXR2 drives tumor formation compared to its interaction partners MYC and MYCN.
ETMR-10. EARLY FOCAL RADIOTHERAPY AND TEMOZOLOMIDE FOLLOWING COMPLETE RESECTION APPEAR SUPERIOR TO INTENSIVE CHEMOTHERAPY AND DELAYED RADIOTHERAPY IN CHILDREN WITH EMBRYONAL TUMORS WITH MULTILAYERED ROSETTES (ETMR)
Authors: Mayr Lisa , Gojo Johannes , Peyrl Andreas , Azizi Amedeo , Dieckmann Karin , Haberler Christine , Czech Thomas , Slavc Irene
Published: December 2020

BACKGROUND

Embryonal tumor with multilayered rosettes (ETMR) is a rare, aggressive embryonal central nervous system tumor characterized by LIN28A expression and alterations in the C19MC locus. ETMRs predominantly occur in young children, have a dismal prognosis, and no definitive treatment guidelines have been established. We report on our experience in nine consecutive patients.

METHODS

Between 2006 and 2017, nine patients were diagnosed with ETMR. Median age was 25 months (5–38), seven were treated for primary diagnosis, two referred with progressing tumors, seven diagnosed prospectively, two retrospectively, five were located supratentorially, three pineal, one in the brainstem.

RESULTS

Seven patients had a gross total resection, one a partial resection and one a biopsy at initial diagnosis, followed by second resections at progression. Six patients were treated with intensive chemotherapy regimens including high-dose chemotherapy in three patients and all recurred after a median of 6 months (range 2–11) and all except one patient who died after high-dose chemotherapy, succumbed to their disease after a median of 13 months (range 7–28). Two patients were treated with gross total tumor resection, early focal radiotherapy and concomitant temozolomide followed by temozolomide and intrathecal therapy for one year and both are in continuous complete remission 51 and 46 months after diagnosis.

CONCLUSION

Gross total resection followed by early focal radiotherapy, temozolomide, and intrathecal chemotherapy seem to be superior to intensive chemotherapy including high-dose chemotherapy. Steady progression was observed in both patients with initial biopsy and PR only despite intensive therapy. Radiotherapy at recurrence/progression was not successful.
ETMR-12. EMBRYONAL TUMOR WITH MULTILAYERED ROSETTES: A SINGLE CENTER EXPERIENCE
Authors: Yoshimura Sodai , Sugawa Masahiro , Fukuoka Kohei , Mori Makiko , Arakawa Yuki , Kobayashi Masao , Tanami Yutaka , Nakazawa Atsuko , Koh Katsuyoshi , Kurihara Jun
Published: December 2020

BACKGROUND

Embryonal tumor with multilayered rosettes (ETMR) is a rare, highly malignant tumor of the central nervous system and is usually diagnosed in children aged <2 years. Currently, because no defined treatment strategy has been reported, treatment regimens are often extrapolated from other embryonal tumors. Therefore, data collection of ETMR cases is important for further understanding EMTR. Here, we present our experience with four patients with ETMR.

MATERIAL AND METHODS

Patients with a pathological diagnosis of ETMR from 1999 to 2016 at Saitama Children’s Medical Center were included. Their clinical data were retrospectively analyzed.

RESULTS

This study included four cases of ETMR (one male and three females). The mean age at diagnosis was 29.5 (range, 15–37) months. Presenting symptoms included seizure, hemiparesis, vomiting, and headache. The mean maximal tumor diameter was 42.5 mm. The tumor locations included frontal lobe, temporal lobe, occipital lobe, cerebellum, and brainstem. Gross total resection was achieved in two cases. Fluorescence in situ hybridization analysis demonstrated amplification of 19q13.42 chromosome region in all cases, and diffuse positive expression was observed in the immunohistochemical staining for LIN28A. Systemic postoperative chemotherapy was administered to all patients. Three patients received intrathecal therapy and three were irradiated. The mean overall survival and progression-free survival were 45.3 and 42 months, respectively. Two patients who underwent gross total resection are alive without recurrence.

CONCLUSION

Complete surgical resection may be an important prognostic factor in patients with ETMR. Further prospective studies are needed to confirm these results.
ETMR-15. USE OF HIGH-DOSE CHEMOTHERAPY FOR TWO CHILDREN WITH EMBRYONAL TUMOR WITH MULTILAYERED ROSETTES
Authors: Kusano Shimpei , Fujimura Junya , Fujiwara Megumi , Yaguchi Akinori , Ishibashi Takeshi , Tomita Osamu , Tamaichi Hiroyuki , Kondo Akihide , Shimizu Toshiaki
Published: December 2020

Embryonal tumor with multilayered rosettes (ETMR) is new entity defined in the 4th revised edition of the WHO classification of tumors of the central nervous system. Although radical resection, radiotherapy, and multiagent chemotherapy are considered to be necessary for ETMR, the efficacy of chemotherapy for ETMR in Japan has not been established. Here, we report different clinical courses for two children with localized ETMR treated with the St. Jude medulloblastoma-96 (SJMB96) regimen, which consists of four cycles of high-dose chemotherapy with autologous peripheral blood stem cell transplantation. For both children, the diagnosis of ETMR, C19MC-altered was confirmed after gross total tumor resection. Multiagent chemotherapy was administered following cranio-spinal irradiation with local boost. One month after completion of the treatment, one patient experienced local recurrence but has been in remission for over 2 years after tumor resection and stereotactic irradiation with a CyberKnife and treatment every three weeks with bevacizumab. The other patient also experienced local recurrence after the third cycle of chemotherapy and several times thereafter. Although she again underwent tumor resection and local irradiation, her tumor grew larger and invaded. Because her prognosis was very poor, her parents choose only palliative care. Based on our experience, we believe that continuous chemotherapy at conventional doses is preferred over intensive-dose chemotherapy such as SJMB96. However, the number of reports on chemotherapy for ETMR is still small, and a prospective multicenter trial is needed to establish effective chemotherapy for ETMR.
GCT-15. INTEGRATED CLINICAL, HISTOPATHOLOGICAL, AND MOLECULAR DATA ANALYSIS OF 190 CENTRAL NERVOUS SYSTEM GERM CELL TUMORS FROM THE IGCT CONSORTIUM
Authors: Takami Hirokazu , Ichimura Koichi , Fukuoka Kohei , Mukasa Akitake , Saito Nobuhito , Narita Yoshitaka , Shibui Soichiro , Nakazato Yoichi , Nishikawa Ryo , Matsutani Masao
Published: December 2020

BACKGROUND

We integrated clinical, histopathological, and molecular data of central nervous system germ cell tumors to provide insights into their management.

METHODS

Data from the Intracranial Germ Cell Tumor Genome Analysis Consortium were reviewed. A total of 190 cases were classified as primary GCTs based on central pathological reviews.

RESULTS

All but one of the cases that were bifocal (neurohypophysis and pineal glands) and cases with multiple lesions including neurohypophysis or pineal gland were germinomas (34 of 35). Age was significantly higher in patients with germinoma than other histologies. Comparison between tumor marker and histopathological diagnoses showed that 18.2% of histopathologically diagnosed germinomas were marker-positive and 6.1% of non-germinomatous GCTs were marker-negative, suggesting a limitation in the utility of markers or histopathology alone using small specimens for diagnosis. Comparison between local and central histopathological diagnoses revealed a discordance of 12.7%. Discordance was significantly less frequent in biopsy cases, implying difficulty in detecting all histopathological components of heterogeneous GCTs. Germinomas at the typical sites (neurohypophysis or pineal gland) showed a better PFS than those at atypical sites (p=0.03). A molecular-clinical association study revealed frequent MAPK pathway mutations in males (51.4 vs 14.3 %, p=0.007), and PI3K/mTOR pathway mutations in basal ganglia cases (p=0.004). Basal ganglia cases also had frequent chromosomal losses. Some chromosomal aberrations (2q, 8q gain, 5q, 9p/q, 13q, 15q loss) showed potential prognostic significance.

CONCLUSIONS

These in-depth findings of this study regarding the clinical and molecular heterogeneity will increase our understanding of the pathogenesis of this enigmatic tumor.
GCT-45. YOLK SAC TUMOR IN THE CEREBELLAR VERMIS - A CASE REPORT
Authors: Otake Saori , Matsutani Tomoo , Watanabe Yousuke , Numata Osamu , Ando Ryo , Ochiai Hidemasa , Junichiro Ikeda , Iwadate Yasuo
Published: December 2020

Yolk sac tumor (YST) is a non-germinomatous malignant germ cell tumor in a young child. It usually arises along a midline axis, mostly pineal region or suprasellar compartment, and it is exceedingly rare to locate in a cerebellar vermis. In the present report, we describe a case of a pure YST located in the cerebellar vermis and review the previous literature. A three-year-old boy visited a local clinic for gait disturbance and frequent vomiting. Gadolinium-enhanced magnetic resonance imaging (MRI) showed a homogeneously-enhanced mass with a cystic component in his cerebellar vermis, and it resulted in hydrocephalus. By its location and his age, our pre-operative diagnosis was a medulloblastoma, and we performed a total resection of the tumor with ventricular drainage. Unexpectedly, the histological investigation revealed it to be a YST. We confirmed that the serum levels of α-fetoprotein (AFP) had elevated at 3176.4 ng/ml in his preserved sample, obtained before the surgery, and it was consistent with the pathological diagnosis. He is receiving chemotherapy consisting of ifosfamide, cisplatin, and etoposide, followed by radiation therapy. In this case, pre-operative MRI revealed that the tumor did not grow into the IVth ventricle in spite of midline location, which was not typical for medulloblastoma. Of note, serum AFP levels had increased, and they might contribute to a precise pre-operative diagnosis and be able to propose an alternative treatment plan, such as neoadjuvant chemotherapy to reduce surgical risk. As a conclusion, a YST should be considered even if it locates in a cerebellar vermis.
GCT-48. OUTCOME OF CNS MALIGNANT NON-GERMINOMATOUS GERM CELL TUMORS (GCT) WITH AFP > 1000 ng/ml AT DIAGNOSIS TREATED ACCORDING TO SIOP CNS GCT 96
Authors: Calaminus Gabriele , Frappaz Didier , Kortmann Rolf-Dieter , Ajithkumar Thankamma , Pietsch Torsten , Vasiljevic Alexandre , Ricardi Umberto , Faure-Conter Cecile , Timmermann Beate , Alapetite Claire , Murray Matthew J , Garre Maria Luisa , Nicholson James C
Published: December 2020

Analysis of CNS MMGCT with AFP >1000 ng/ml (serum and/or CSF) at diagnosis, treated on trial in SIOP-CNS-GCT-96, revealed an inferior prognosis (32% 5-year progression-free survival) compared with AFP <1000 ng/ml (76%). As this patient group is small, to evaluate a bigger cohort, we revisited all patients treated according to SIOP-CNS-GCT-96, who were registered in the database until July 2015. Between October 1996 and July 2015, 373 patients with CNS MMGCT were registered. 48 patients (13%) presented with an AFP >1000 ng/ml at diagnosis. 41 patients were evaluable with a median observation time of 2.4 years; 6/41 received chemotherapy alone. Primary site, histological components (if available), metastatic status and outcome were evaluated. Primary site was pineal in 29/41, suprasellar in 6/41, bifocal 1/41 and other in 5/41 patients. 10/41 patients were metastatic at diagnosis. Four to five courses of standard PEI and radiotherapy (RT) or 2 standard and two intensified PEI (as for SIOP CNS GCT II) were administered in 32 patients. Two received less then 4x PEI and RT, 6 patients <6 years were treated with PEI (either standard or intensified) alone. 16/34 patients with PEI and RT are alive in CR; 2/6 patients without RT survived. Overall, 18/40 (45%) survived. 10–15% of CNS MGGCT are high-risk patients by diagnostic AFP, with the pineal as the main tumour site. Outcome of <50% survival is unsatisfactory. Further research, international cooperation and common data analysis is needed to identify additional risk factors and develop alternative treatment strategies.
GCT-53. CASE OF INTRACRANIAL GROWING TERATOMA SYNDROME WITH DIFFICULTY IN TIMING OF RESECTION
Authors: Yoshitake Hidenobu , Nakamura Hideo , Hamamoto Yuta , Otsu Yusuke , Kikuchi Jin , Koga Motohisa , Kajiwara Soushou , Nagata Yui , Matsumoto Yoshihisa , Hashikawa Takuro , Sakai Hideki , Komaki Satoru , Takeshige Nobuyuki , Miyagi Naohisa , Nakagawa Setsuko , Takahashi Kenji , Sugita Yasuo , Morioka Motohiro
Published: December 2020

BACKGROUND

Intracranial Growing teratoma syndrome(iGTS) is a phenomenon in which a tumor with a teratoma component grows during treatment, and its pathological tissue is often a mature teratoma. Here we report a case of iGTS in which the timing of surgery was determined by tumor markers and changes in tumor size on MRI images. CASE-REPORT: 11-year-old boy with a short stature. He developed a headache and we found a pineal gland tumor on MRI. Due to obstructive hydrocephalus, an endoscopic third ventriculostomy and biopsy were performed. The pathological diagnosis was mature teratoma, but AFP was elevated at 104.2 ng/mL. Considering NGGCT, we started chemoradiation immediately. Despite the declining AFP, it gradually increased, at which point we suspected iGTS. Resection was considered, but at some point tumor growth had stopped, so radiation therapy and a second course of ICE therapy preceded the resection. Thereafter, the tumor was completely removed, and a third course of ICE therapy was performed.

DISCUSSION

The onset mechanism of iGTS has not been elucidated, and its prediction is difficult. Early resection of the tumor is required, but discontinuation of radiation therapy and side effects of chemotherapy also need to be considered. In our case, resection was performed after normalization of AFP and recovery of myelosuppression. The patient followed an uneventful course, but the timing of resection was controversial.

CONCLUSION

We experienced a case of iGTS in NGGCT, a mixed tumor with mature teratoma. The optimal timing of the resection was discussed and literature was reviewed.
GCT-55. INTRACRANIAL GERMINOMA ORIGINATING FROM ATYPICAL LOCATION WITH SUBCLINICAL ADH INSUFFICIENCY
Authors: Kuranari Yuki , Miwa Tomoru , Kono Maya , Kanazawa Tokunori , Yoshida Kazunari
Published: December 2020

INTRODUCTION

Intracranial germinomas are rare tumors which usually develop in the midline structures and affect in 90% of cases the pineal gland and suprasellar regions. Sometimes they involve basal ganglia, septum pellucidum, and other regions. We report a very unusual presentation of an intracranial germinoma originating from the lateral ventricle.

METHODS

A 10-year-old boy presented with a 1-year history of polydipsia and polyuria. During the hypertonic saline test, a low ADH was detected and established the diagnosis of subclinical ADH insufficiency. MRI showed a heterogeneously enhancing periventricular lesion in the lateral ventricle, but no other abnormal findings, including hypophyseal stalk. Initially, the correlation of imaging findings and clinical symptoms were not clear. With suspected subependymoma, tumor removal was performed by small craniotomy. Since the intra-operative pathological diagnosis was germinoma, we performed only partial removal of the tumor. After establishing the histological diagnosis of germinoma, the patient received chemotherapy using carboplatin and etoposide, followed by radiation therapy. MRI showed no recurrence for five years after treatment. RESULTS/

CONCLUSION

Our case presents two atypical features. First, intracranial germinoma originating from the lateral ventricle is quite rare. Though the cases with intracranial germinoma originating from septum pellucidum and corpus callosum have been reported, this case is even different. Second, imaging findings did not match clinical symptoms. The cause of subclinical ADH deficiency may be the occult hypophyseal germinoma. In conclusion, we report a 10-year-old case with a very unusual presentation of an intracranial germinoma originating from the lateral ventricle.
GCT-72. ANALYSIS OF microRNA EXPRESSION PROFILE OF INTRACRANIAL GERM CELL TUMORS: A PROMISING TOOL FOR DIFFERENTIAL DIAGNOSIS
Authors: Nakano Yoshiko , Satomi Kaishi , Takami Hirokazu , Nishikawa Ryo , Yamasaki Fumiyuki , Taketoshi Maehara , Saito Nobuhito , Kanemura Yonehiro , Sakamoto Hiroaki , Ochiya Takahiro , Ichimura Koichi
Published: December 2020

INTRODUCTION

One of the major limitations of pathological diagnosis for intracranial germ cell tumors (iGCTs) is tumor heterogeneity, which cannot be evaluated using limited amount of tumor tissues. In this study, we performed comprehensive analysis of microRNA (miRNA) of iGCTs to identify miRNAs profile to help determine tumor diagnosis.

METHODS

RNA was extracted from frozen samples of 16 germinoma and 14 NGGCTs. Five non-iGCT pediatric brain tumor tissues were used as control. miRNA expression analysis was performed using a 3D-Gene Human miRNA Oligo Chip ver.22 (Toray Industries, Inc) which was designed to detect 2565 miRNAs. The miRNA expression profile was analyzed using t-SNE dimensionality reduction and weighted average difference method (WAD).

RESULTS

Different histological subtypes of the iGCTs and control samples were clustered into distinct classes. Furthermore, we found that the germinoma, NGGCTs and control samples may be readily distinguished by expression patterns of miR-200 and miR-371a-3p: a high expression of miR-200 was observed in the NGGCTs, whereas a high expression of miR-371a-3p was observed in all cases of germinoma and some of NGGCTs. Neither of miR-200 nor miR371-3p was highly expressed in control samples.

CONCLUSION

Our data indicated that germ cell tumor and other pediatric brain tumors, and also germinoma and NGGCT can be distinguished by expression patterns of 2 micro RNA, miR-200 and miR-371a-3p. These 2 microRNA may serve as a useful tool for supporting the pathological diagnosis of iGCTs.