bluuebunny/crossref_metadata_2025_split huggingface dataset:
EPEN-33. PHARMACOGENOMICS REVEALS SYNERGISTIC INHIBITION OF ERBB2 AND PI3K SIGNALING AS A THERAPEUTIC STRATEGY FOR EPENDYMOMA
Authors: Pauck David , Paisana Eunice , Cascão Rita , Sarikaya-Seiwert Sevgi , Marquardt Viktoria , Picard Daniel , Bartl Jasmin , Blümel Lena , Maue Mara , Dimitriadis Christian , Taban Kübra , Fischer Ute , Steiger Hans Jakob , Faria Cláudia , Reifenberger Guido , Borkhardt Arndt , Beez Thomas , Remke Marc 
Published: December 2020

Abstract
Subgroups of ependymoma, especially RELA fusion-positive and posterior fossa type A tumors, are associated with poor prognosis. Curative therapeutic strategies have not yet been identified. We set up a high-throughput drug screening (HTS) pipeline to evaluate clinically established compounds (n=196) in primary ependymoma cultures (n=12). As culturing ependymoma is challenging, assay miniaturization to 1536-well microplates emerged as a key feature to process HTS despite smallest cell numbers. DNA methylation profiling showed that entity and subgroup affiliation from primary diagnosis was maintained in primary cultures, as assessed through molecular neuropathology 2.0 based classification (MNP 2.0, Capper, D. et al., Nature, 2018). A comparison of HTS data of ependymoma and other pediatric brain tumor models (n=48) revealed a remarkable chemoresistance in vitro. However, we identified Neratinib, an irreversible ERBB2 inhibitor, as the most prominent candidate which was preferentially active in a subset of the investigated ependymoma cultures (n=5). Combinatory treatment with Copanlisib, a PI3K inhibitor, was able to overcome resistance to single agent treatment using Neratinib in established cell lines of ependymoma (n=3) and 2/4 primary cultures for which combinatory treatment could be tested. Finally, we validated efficacy of Neratinib combined with Copanlisib in mice bearing ependymoma xenografts which revealed significantly reduced tumor size compared to vehicle-treated animals. In summary, our study demonstrates that HTS may reveal targeted therapies for pediatric brain tumors. Specifically, we found a synergistic interaction of Neratinib and Copanlisib for treatment of ependymoma, thereby providing a novel therapeutic approach in an otherwise largely chemoresistant entity.
EPEN-35. PERITONEAL CARCINOMATOSIS OF ANAPLASTIC EPENDYMOMA: FIRST REPORTED CASE
Authors: Schwartz Jonathan , Weinmann Dena , Guerin Julia , Eckel Laurence , Gesina Keating , Daniels David 
Published: December 2020

Abstract
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.
EPEN-49. RESPONSE OF RECURRENT EPENDYMOMA TO MEMMAT BASED METRONOMIC ANTIANGIOGENIC COMBINATION THERAPY UTILIZING TAPERED BEVACIZUMAB AND MAINTENANCE THERAPY WITH CELECOXIB AND FENOFIBRATE
Authors: Gillan Eileen 
Published: December 2020

Abstract
Recurrent ependymomas have a dismal prognosis (2 year survival rates 29% OS and 23% EFS) and are relatively resistant to conventional chemotherapy. We previously reported five relapsed ependymoma patients treated with a MEMMAT based metronomic antiangiogenic combination therapy. All patients are currently alive, including four patients who were multiply relapsed with at least three recurrences. These four patients received between 44–52 weeks of therapy with minimal toxicity. Three had recurrent disease within an average of 44 months (median 42 months) after discontinuation of therapy. One patient who received the following tapering bevacizumab schedule: q3 weeks x 3, q4 weeks x 4 and q5 weeks x 5 followed by maintenance therapy with fenofibrate and celecoxib is in complete remission 12 months post treatment. This regimen was well tolerated with good quality of life in this patient population. Our results suggest that the chosen anti-angiogenic drug combination prolonged the time to progression in these multiply relapsed patients and thus may be particularly beneficial for patients with recurrent ependymoma. Tapered bevacizumab and maintenance therapy with celecoxib and fenofibrate may be modifications worth further investigation for prolonged disease free survival in relapsed ependymoma patients.
EPEN-52. METABOLIC REGULATION OF THE EPIGENOME DRIVES LETHAL INFANTILE EPENDYMOMA
Authors: Kumar Sachin , Michealraj Antony , Kim Leo , Rich Jeremy , Taylor Michael 
Published: December 2020

Abstract
PFA ependymomas are a lethal glial malignancy of the hindbrain found in infants and toddlers. Lacking any highly recurrent somatic mutations, PFAs have been proposed to be a largely epigenetically driven entity, defined by hypomethylation at the histone 3 lysine 27 residue. Unfortunately, an almost complete lack of model systems has limited the discovery of novel PFA therapies. In this study, we have identified that the PFA hypoxic microenvironment controls the availability of specific metabolites, resulting in diminished H3K27 trimethylation and increased H3K27 acetylation in vitro and in vivo. Unique to PFA cells, transient exposure to ambient oxygen results in irreversible cellular toxicity. Furthermore, perturbation of key metabolic pathways is sufficient to inhibit growth of PFA primary cultures in vitro. Although PFA tumors exhibit a low basal level of H3K27me3, inhibition of H3K27 methylation paradoxically demonstrates significant and specific activity against PFA. Thus, we propose a “Goldilocks Model” of metabolic-epigenetic regulation in PFA ependymoma, whereby increased or decreased H3K27 trimethylation results in cell death. Mapping of PFA ependymoma tumours suggests a cell of origin arising in the first trimester of human development where there is a known hypoxic microenvironment. Therefore, targeting metabolism and/or the epigenome presents a unique opportunity for rational therapy for infants with PFA ependymoma.
EPEN-54. ACNS0831, PHASE III RANDOMIZED TRIAL OF POST-RADIATION CHEMOTHERAPY IN PATIENTS WITH NEWLY DIAGNOSED EPENDYMOMA AGES 1 TO 21 YEARS
Authors: Smith Amy , Onar-Thomas Arzu , Ellison David , Owens-Pickle Emily , Wu Shengjie , Leary Sarah E S , Fouladi Maryam , Merchant Thomas , Gajjar Amar , Foreman Nicholas 
Published: December 2020

Abstract

PURPOSE
The primary objective of this study is to determine the EFS and OS of children with gross total and near totally resected ependymoma (EPN) treated with post-operative focal radiation therapy (RT) followed by randomization to either RT alone or RT + 4 cycles of maintenance chemotherapy with vincristine, cisplatin, cyclophosphamide and etoposide. Secondary objectives include estimating the EFS and OS of children not randomized, evaluation of neurobehavioral and quality of life (QoL) endpoints, and EPN biomarkers.

RESULTS
479 patients enrolled, 451 were eligible. Of 325 eligible randomized patients, 161 were randomized to RT alone and 164 to RT + maintenance chemotherapy. Age range (1–21 years, median 4.9 years). The planned primary analysis was based on intent-to-treat, irrespective of actual treatment received. Based on the data available as of 12/31/2019, estimated 3-year EFS in the RT + maintenance chemotherapy vs. RT arms were 78% vs. 72%, respectively, which did not meet statistical criteria to establish the benefit of maintenance chemotherapy post RT (1-sided log-rank p-value=0.074). Due to significant noncompliance (30.5% in the RT + maintenance vs 4.3% in the RT arm), a planned secondary “as treated” analysis was performed. With median follow-up of 42.6 months among patients without events, the 3 year EFS estimates for patients who received any chemotherapy (n=114) vs. those who received RT only (n=196) were 80% vs. 71%, respectively (1-sided p-value = 0.0121).

CONCLUSION
Early results in this randomized trial suggest that there may be some EPN patients who benefit from maintenance chemotherapy. Genomic analyses are ongoing.
EPID-04. MORBIDITY IN PAEDIATRIC BRAIN TUMOURS: 17 YEARS’ EXPERIENCE IN A TERTIARY NEUROSURGICAL UNIT
Authors: Goh Chun Peng , Nga Vincent Diong Weng , Ho Cindy Wei Li 
Published: December 2020

Abstract
The treatment of paediatric brain tumours has shown significant improvement over the last 2 decades. The aim of our study is to evaluate the prevalence of various effects among this population within our institution. 102 patients diagnosed with a brain tumour at the age of 0–18 years between 2002 and 2018 were identified within a single paediatric institution. Data was collected retrospectively based on electronic medical records. Medulloblastoma (20.6%) was the most common subtype followed by pilocytic astrocytoma (18.6%) and craniopharyngioma (11.8%). Overall, the 5-years survival rate was approximately 77%. Endocrine dysfunction was reported in 36% of the population, mainly due to tumour located in suprasellar region and irradiation causing progressive pituitary dysfunction. Neurological disorders such as epilepsy, weakness, cranial nerves palsy, visual and hearing impairment were present in 46% of the population. Importantly, 20.4% of patients who received chemotherapy had some degree of sensorineural hearing loss. 16% of the population suffered from impaired neurocognition which is likely an underestimation as screening could not be performed on all patients. Other significant complications are infections (12%) and ventriculoperitoneal shunt dysfunction (7%). Most of these effects can be attributed to direct injury to the developing brain caused by the tumour or related to its treatment during surgical excision and the long term side effects of chemotherapy and radiation therapy. Morbidities in various domains can pose significant challenges to survivors of paediatric brain tumours. Active screening and surveillance of these effects can help improve the health outcomes of survivors of paediatric brain tumours.
EPID-11. ESTABLISHING A BASELINE TIME-FRAME FOR SYMPTOM ONSET TO DEFINITIVE DIAGNOSIS FOR CHILDREN WITH NEWLY-DIAGNOSED CNS TUMORS: AN EXPANDED, MULTI-INSTITUTIONAL COLLABORATIVE STUDY
Authors: Eccles Eamon , Han Yan , Liu Hao , Walker David , Rush Sarah , Finlay Jonathan , Coven Scott 
Published: December 2020

Abstract

BACKGROUND
We have previously documented the presence of diagnostic delays in children with central nervous system (CNS) tumors in the United States. This study serves to expand and validate the previously established baseline from symptom onset to definitive diagnosis in children with newly-diagnosed CNS tumors. DESIGN: The medical records of children with newly-diagnosed CNS tumors were retrospectively reviewed from January 2004 to December 2017 at Nationwide Children’s Hospital, Akron Children’s Hospital and Riley Hospital for Children at IU Health. Records were reviewed for age, gender, tumor type, presenting symptoms, number of healthcare visits prior to diagnosis, time interval (in months) from onset of symptoms to definitive diagnosis and any associated genetic syndromes.

RESULTS
Of the 768 patients with newly-diagnosed CNS tumors, the median time interval from symptom onset to definitive diagnosis was 40.5 days while the mean symptom interval was 144 days (range &lt; 1 to 5,475 days). The median age of diagnosis was 7 years, with a male predominance (57%). This expanded cohort continues to reveal that pediatric brain tumor patients most often seek care at the primary care level, although many patients were seen in various multiple subspecialty clinics prior to diagnosis.

CONCLUSIONS
This multi-institutional cohort study updates our previously documented single state time interval and provides a consistent Midwest “benchmark” to improve awareness for children with brain tumors through the adaptation of the UK ‘HeadSmart,’ now renamed ‘BrainFirst.’ Additionally, future work could include a prospective registry to better examine potential risk factors for delays in diagnosis.
EPID-17. A SINGLE INSTITUTE EXPERIENCE IN THE REGISTRATION STUDY OF PEDIATRIC SOLID TUMOR IN JAPAN CHILDREN’S CANCER GROUP
Authors: Furukawa Keiko , Mineharu Yohei , Arakawa Yoshiki 
Published: December 2020

Abstract
A larger scale prospective registration study has been conducted nationwide in Japan since 2011, called as “registration study in pediatric solid tumor”, in Japan Children’s Cancer Group (JCCG). In this study, clinical data and surgical specimen are collected into the National Center for Child Health. Kyoto University Hospital has participated in this study since IRB approval in 2011. We reviewed our registered patients to the registration study and assessed the current status. 40 patients with pediatric brain tumors participated in this study from 2011 to 2020. There were 13 intracranial germ cell tumors, 9 medulloblastomas, 6 gliomas in 4 diffuse midline gliomas, 4 pilocytic astrocytoma, and 4 other types of tumor. The informed consent was obtained from 36 patients by pediatricians and 3 patients by neurosurgeons. Twenty-five surgical specimens were collected for central review. The reasons of no surgical specimens were nonsurgical management in 6 patients and no enough FFPE sample in 3 patients. There was no discrepancy between central review and institutional diagnosis. The status of clinical data entry was complete in 13 patients and uncomplete in 9 patients. These registration data including pathological diagnosis, molecular diagnosis, treatment, clinical information in patients with pediatric brain tumor are very important to realize current status. To conduct this study certainly, the collaboration among pediatrician, neurosurgeon, and supporting staff should be needed in collecting specimens and clinical data.
ETMR-04. EMBRYONAL TUMOR WITH MULTILAYERED ROSETTES: THE MD ANDERSON CANCER CENTER EXPERIENCE
Authors: Gupta Sumit , Ragoonanan Dristhi , Itzep Nelda , Sandberg David , Fuller Greg , Ketonen Leena , Meador Heather , Zaky Wafik , Khatua Soumen 
Published: December 2020

Abstract

BACKGROUND
Embryonal Tumor with Multilayered Rosettes (ETMR) are rare tumors that are molecularly diagnosed by C19MC amplification. Rarity of this tumor has precluded profiling uniform therapeutic strategy.

METHODS
Retrospective review after institutional approval, identified 10 pediatric case of ETMR, treated at MD Anderson Cancer Center during the period of 2005 to 2019.

RESULTS
Median age of at diagnosis was 4.6 years. Tumor sites include frontal or parietal lobes (3), spine (3) and posterior fossa involving the brainstem (4). All patients received a combination of chemotherapy and radiation. 4 patients had metastasis at the presentation. 9 patients received focal radiation but only 6 of them received Craniospinal irradiation (CSI). Average dose of radiation was 50 Gy. Surgical resection was performed in all cases except the brainstem tumors. 7 children had recurrence including all the patients with metastasis at diagnosis (median time: 9.4 months), 1 passed away secondary to hemorrhage in brainstem and data was not available for 2 patients. 5/6 patients who received CSI had recurrence.

CONCLUSIONS
To-date no well-defined treatment regimens exists for these neoplasms, resulting in poor overall survival. Preclinical drug screen have shown the efficacy of topotecan, actinomycin D, and volasertib as potential new therapeutic candidates, though this has not translated successfully into the clinical arena. Given the limited success with current conventional therapeutic methods, molecular interrogation in addition to histopathological diagnosis are essential upfront, as it could provide clues to targeted therapy. Defining molecularly-based treatment with less toxicities and increased survival are warranted.
ETMR-09. THE ROLE OF RADIATION FOR EMBRYONAL TUMOR WITH MULTILAYERED ROSETTES
Authors: Kondo Akihide , Suzuki Mario , Fujimura Junya 
Published: December 2020

Abstract

BACKGROUND
Embryonal tumor with multilayered rosettes (ETMR) is a challenging tumor. The prognosis of the patients suffering from this tumor is extremely poor. We have survival cases of more than 12 months. However, the status of illness is different. In order to clarify the cause of this difference, we reviewed our treatments in this study. TREATMENT COURSE: We have two cases. Both have relapsed after the same chemotherapy after the same radiation therapy. After the recurrence we used protocols that were included extended resection, second radiation therapy with bevacizumab.

METHODS
We compared molecular biological evaluations for the initial and recurrent tumors. The resection rate at the time of second removal and the intensity of radiation therapy intensity were compared.

RESULTS
We succeeded to remove the tumors with the confirmation of intraoperative MRI. No apparent differences could be seen in molecular biological characters of tumors before and after treatment. There was a difference between the period until radiation therapy and the irradiation methods.

CONCLUSIONS
This tumor is untreatable only by resection. We need the second radiation therapy with bevacizumab. It was presumed that tumor should be irradiated quickly with appropriate irradiation field and dose.
ETMR-13. NFI GENES IN ETMR TUMORIGENESIS AND NEURODEVELOPMENT
Authors: Bunt Jens , Lambo Sander , Lim Jonathan , Mauermann Monika , Pfister Stefan , Richards Linda , Kool Marcel 
Published: December 2020

Abstract
Embryonal tumors with multilayered rosettes (ETMRs) are aggressive pediatric embryonal brain tumors with a universally poor prognosis. These tumors are commonly characterized by amplification of C19MC, but other miRNA-related aberrations, such as DICER mutations or MIR17HG amplifications, are also observed. Nevertheless, it remains unknown how these aberrations are driving the tumorigenesis. We applied miRNA target prediction to investigate the downstream targets shared by these aberrations affecting normal brain development and tumorigenesis. The nuclear factor one (NFI) family of transcription factors were found to be top candidates shared by both miRNA clusters. These genes are expressed at very low levels in ETMRs, in contrast to other brain tumors. During normal brain development these genes are expressed in radial glial progenitors and are required for the transition of proliferation to differentiation. Since radial glial progenitors are the potential cell-of-origin of ETMRs, we hypothesize that downregulation of NFI is required for the proliferative, undifferentiated state of ETMRs. Indeed, mouse models with deletion of an Nfi family member display sustained proliferation and delayed differentiation of radial glial progenitors during development. This leads into brain overgrowth, which has also been observed in humans with intellectual disabilities caused by NFI haploinsufficiency. When multiple Nfi family members are simultaneously targeted in mice, the progenitors are retained and both neurogenesis and gliogenesis are inhibited, resulting in a neuropathology similar to that of human ETMR tumors. Hence, downregulation of NFI genes resulting from miRNA aberrations could contribute to the developmental state and possibly tumorigenesis of ETMRs.
ETMR-18. TARGETING Lin28 IN ETMR WITH ODC1 INHIBITOR DFMO
Authors: Goodyke Austin , Kelly Shannon , Zagorski Joseph , VanSickle Elizabeth , Maser Tyler , Sortwell Caryl , Kemp Christopher , Nagulapally Abhinav , Dykema Karl , Saulnier-Sholler Giselle 
Published: December 2020

Abstract
Embryonal tumor with multilayered rosettes (ETMR), is an aggressive brain tumor primarily occurring in young patients (&lt;4 years of age) and characterized by C19MC amplification and Lin28 overexpression. These genetic hallmarks have been shown to participate in driving ETMR in a C19MC-Lin28-MYCN circuit. Reducing Lin28 disrupts this circuit and reduces cell viability in ETMR models. Investigation of therapeutic agents targeting this pathway is required to provide new treatment options for this deadly disease. We present data showing the effect of DFMO (α-difluoromethylornithine) in ETMR, an ODC1 inhibitor known to reduce Lin28 in neuroblastoma. DFMO treatment of the ETMR cell line BT-183 resulted in a significant reduction of intracellular Lin28 protein levels (P&lt;0.05) as indicated by flow cytometry. In concert with this reduction in Lin28, there was a as significant reduction in viable cells (P&lt;0.05), and the number of CD133+ cells were reduced 2-fold (P&lt;0.05). High throughput drug testing of BT-183 identified a number of additional therapeutic agents with potential therapeutic efficacy for ETMR and combining these with cytostatic agent DFMO demonstrated the potential use of these drugs in combination. These in vitro data were complemented by testing of DFMO in an in vivo stereotaxic xenograft ETMR model, with inhibition of tumor burden monitored by bioluminescent imaging of the tumors. Together this work shows that Lin28 targeting agents such as DFMO merit further examination and integrating these types of agents into treatment strategies for ETMR may lead to better outcomes.
GCT-03. TREATMENT OUTCOMES, PHYSICAL DEVELOPMENT AND QUALITY OF LIFE OF PATIENTS WITH BIFOCAL GERM CELL TUMOURS
Authors: Li Bo 
Published: December 2020

Abstract

BACKGROUND
The optimal radiation field in patients with bifocal germ cell tumours(GCTs) is controversial, especially in non-metastatic cases. Accordingly, we analysed the survival, growth, and health-related quality of life (HRQOL) data of patients with bifocal GCTs.

METHODS
The data of 87 patients diagnosed with bifocal GCTs at our hospital during the last 10 years were collected. The WHO AnthroPlus software—used to monitor the growth of persons aged 5–19 years—was employed to calculate the Z-score of height (ZSOH) at diagnosis and the last follow-up. The absolute change in the ZSOH was defined as |ZSOH last follow-up - ZSOH diagnosis|. The Pediatric Quality of Life Inventory 4.0 was used to evaluate HRQOL.

RESULTS
The median follow-up was 49 months (range,6–134 months). Among 49 patients with non-metastatic germinoma, those receiving cranial spinal irradiation(CSI; n=12) or whole-brain radiotherapy (WBRT; n=34) had comparable disease-free survival (DFS;p=0.54), but better DFS than those receiving focal radiotherapy(n=3;p=0.016). Furthermore, among 17 patients with non-metastatic non-germinomatous GCTs, DFS was not significantly different between those treated with CSI(n=4) and those receiving WBRT(n=13;p=0.11). Twenty-nine patients had paired ZSOH data at both diagnosis and the last follow-up. Patients receiving CSI(p=0.026) or &gt;40Gy(p=0.048) experienced a significant decline of absolute change in the ZSOH. HRQOL analysis(n=35) did not reveal difference between patients receiving CSI and those not receiving CSI.

CONCLUSIONS
Given the comparable DFS and HRQOL but negative impact on growth, CSI could be spared, especially in patients with non-metastatic bifocal germinoma.