Intracranial Ependymoma Research Articles

Response assessment in pediatric neurooncology (RAPNO) criteria revisited: a practical navigation guide for neuroradiologists.

The Response Assessment in Pediatric Neuro-Oncology (RAPNO) Working Group is an international, collaborative network of experts dedicated to pediatric central nervous system (CNS) tumors that was created in 2011. Since then, six RAPNO articles with imaging guidelines for response assessment in diverse pediatric tumor subgroups have been published, namely: 1) medulloblastomas and leptomeningeal seeding tumors (2018), 2) pediatric high-grade gliomas (2020), 3) pediatric low-grade gliomas (2020), 4) diffuse intrinsic pontine gliomas (2020), 5) pediatric intracranial ependymomas (2022) and 6) pediatric craniopharyngiomas (2023). The purpose of this article is to review all current available RAPNO criteria using a systematized and comparative approach centered on the role of neuroradiologists and supported by neuroimaging examples. Special emphasis will be placed on clarification of core concepts as well as practical adoption aspects of the RAPNO guidelines, namely how and when to image the brain and/or the spine; how to interpret the imaging findings; which other clinical, therapeutic and laboratory variables to consider; and finally how to apply the information to attribute the final appropriate response assessment classification.

Radiotherapy dosing in intracranial ependymoma using the national cancer database.

To determine the dose-dependent effect of adjuvant radiotherapy on survival for pediatric intracranial ependymomas and explore patient and disease characteristics that experience survival benefit from higher doses. Data was accessed from the National Cancer Database. Inclusion criteria was comprised of a diagnosis of non-metastatic intracranial ependymoma, World Health Organization (WHO) grade 2 or 3, surgical resection, adjuvant radiotherapy between 4500-6300cGy, and non-missing survivorship data. Crude and adjusted Cox proportional hazard ratios (HRs) were calculated to estimate the associations of patient, tumor, and treatment characteristics with overall survival (OS). Kaplan-Meier (KM) estimations were used to visualize survival curves for dosing for the general cohort and by subgroups (age, resection extent, and grade). Of the 1154 patients who met inclusion criteria, 405 received ≤ 5400cGy and 749 received > 5400cGy. We found no difference in OS crude (0.95, 95% CI 0.72-1.06) or adjusted (0.88, 95% CI 0.46-1.69) HR for those receiving ≤ 5400cGy. KM curves showed no difference in OS for dosing for the general cohort based on age, surgical extent, and grade. However, there was better OS in those with WHO grade 2 tumors compared to grade 3 regardless of dose received. There was no difference in OS between patients who received ≤ 5400cGy compared to > 5400cGy. We found improved OS in those with grade 2 tumors compared to grade 3, however there was no difference in OS based on dose received by tumor grade, age, or resection extent. Limitations in data available prevent exploring other outcomes or toxicity.

Systematic Review and Meta-Analysis of Adjuvant Radiation Dose for Pediatric Patients (≤22 years) with Nonmetastatic Intracranial Ependymomas

Ependymomas are the third most common brain tumors in children. Standard of care is surgery followed by adjuvant radiotherapy. Controversy in the literature still exists over optimal radiotherapy dose. We completed a systematic review and meta-analysis to determine the optimal dose for local control (LC), event-free survival (EFS), and overall survival (OS) in pediatric patients. We searched MEDLINE (PubMed), Cochrane Database of Systematic Reviews, and Web of Science through January 2024. We included cohort studies that compared adjuvant radiotherapy of ≤54Gy to >54Gy in pediatric patients (≤22 years) with non-metastatic intracranial ependymomas. We assessed study quality using the Newcastle-Ottawa Quality Assessment Scale of Cohort Studies. We pooled studies using a random effects meta-analysis for hazard ratios (HR), 95% confidence intervals (CI), and assessed statistical heterogeneity via I2. When HRs were unavailable, we transformed risks using established methods. We narratively summarized qualitative outcomes. Seven studies met our inclusion criteria, covering a combined 1321 patients. Studies included a range of doses from 45-66.6Gy. Compared with >54Gy, we found no difference in LC for those receiving ≤54Gy (HR=0.83, 95% CI 0.56-1.24, I2=49.1%), in EFS (HR=1.02, 95% CI 0.95-1.09, I2=0.00%), and OS (HR=0.99, 95% CI 0.82-1.20, I2=37.5%). Two studies reported on subtotal resection by radiotherapy dose, neither study reporting statistical differences in LC, EFS, or OS, though the number of patients was small (n≤30). Five studies reported on late effects, with brainstem radionecrosis, radiation-induced vasculopathy, and secondary tumors being the most frequent. Overall study quality was high, though lower scores were consistently seen in comparability of cohorts. No studies reported on molecular subgroups. We found no difference in LC, EFS, or OS for those treated with ≤54Gy compared to >54Gy. There was insufficient data to complete a subgroup meta-analysis on radiotherapy dosing based on extent of resection or molecular subgroups.

EPEN-30. PROTON THERAPY FOR PEDIATRIC INTRACRANIAL EPENDYMOMA: A SYSTEMATIC REVIEW, META-ANALYSIS AND META-REGRESSION

Abstract BACKGROUND Pediatric intracranial ependymoma (IE) represents a challenging subset of tumors necessitating tailored therapeutic strategies. Conventional treatments, including surgery and conventional radiation therapy, have shown limitations in achieving optimal outcomes, particularly in preserving neurocognitive function and mitigating long-term sequelae. Proton therapy (PT) has emerged with its ability to offer precise tumor targeting with reduced irradiation of healthy surrounding tissues. METHODS A systematic search was conducted using the electronic databases PubMed, CENTRAL, and EMBASE from inception through February 2024 following the PRISMA statement. Statistical analysis was conducted using R (R Foundation for Statistical Computing; Vienna, Austria) with the packages ‘meta’ and ‘metafor’. The random effects model of proportions was estimated using the generalized linear mixed-effects model (GLMM) method. RESULTS A total of 7 studies were included comprising 943 patients, with a mean age of 4 years, 543 boys (57.58%) and a mean dose of 56.94 Gy. The local control (LC) rate at 3 years was 83% (95% CI = 0.80 to 0.86, p=0.65) and a 5-year rate was 81% (95% CI = 0.72 to 0.89, p=0.35). Progression-free survival (PFS) was 75% at 3 years (95% CI = 0.68 to 0.82, p=0.17) and 71% at 5 years (95% CI = 0.56 to 0.87, p=0.07). Overall survival (OS) rates were notably high, with 93% at 3 years (95% CI = 0.89 to 0.97, p=0.11) and 85% at 5 years (95% CI = 0.83 to 0.87, p=0.96). Meta-regression analysis revealed that total dose significantly influenced 3-year OS (p=0.04), indicating a dose-dependent effect on survival rates. CONCLUSIONS This meta-analysis supports the effectiveness of PT through the outcomes LC, PFS and OS in pediatric IE. The significant correlation between total dose and 3-year OS underscores the importance of dose optimization in treatment planning. These findings highlight the importance of PT in pediatric neuro-oncology management, offering evidence-based guidance for enhancing therapeutic strategies and patient outcomes.

EPEN-29. IS THE OUTCOME OF SUPRATENTORIAL EPENDYMOMA WITH ZFTA FUSION REALLY POOR?

Abstract BACKGROUND Survival of children with intracranial ependymoma is known to depend, in part, on the molecular group of the tumor. Previous studies have linked both PFA and ZFTA molecular group ependymomas to poor outcomes. As part of an unplanned analysis from ACNS0831, we explored outcomes for ZFTA supratentorial (ST) and PFA ependymomas. METHODS Patients were stratified by location, grade and extent of resection. Grade 2, ST tumors with no evidence of disease were observed only, N=37. All other patients were randomized to RT versus RT + maintenance chemotherapy or non-randomly assigned to RT + M if residual disease. A planned “as treated” analysis was performed by actual treatment received for randomized patients, excluding those who did not receive RT. Molecular groups were compared using two-sided log-rank tests stratified by study arms for all and randomized patients. Molecular characterization was achieved in 161/166 (97%) ST and 282/283(99.6%) PF. Among ST, 94% were classified ZFTA and 6% YAP1. Homozygous CDKN2A deletion was detected in 16 tumors, all ZFTA and WHO grade 3. Among posterior fossa ependymomas, 88% were classified as PFA and 12% as PFB. RESULTS There was no statistical difference in outcome according to treatment. Across all study arms, 5-year EFS was 69.6%+4.3 for ZFTA vs. 52.9%+3.4 for PFA (p=0.028). For the randomized cohort, 5-year EFS was 72.1+4.8 for ZFTA vs. 60.1+3.9 for PFA (p=0.076). For the randomized cohort with initial GTR/NTR, 5-year EFS was 74.1+5.1 for ZFTA patients vs. 61.0+4.2 for PFA patients (p=0.045). The 5-year EFS was 66.7+12.2 for ZFTA patients with CDKN2A deletion vs. 69.3+4.7 for ZFTA patients without CDKN2A deletion (p=0.232) CONCLUSION Children with ST ZFTA ependymomas have a significantly better outcome than those with PFA tumors. Homozygous deletion of CDKN2A was present in 12% of ST ependymomas but was not an indicator of poor outcome.

EPEN-20. LEVERAGING ABERRANT EXTRACELLULAR VESICLE SIGNALING FOR TARGETED DRUG REPURPOSING IN PEDIATRIC EPENDYMOMA

Abstract Increasing evidence highlights the diverse functions of extracellular vesicles (EVs) as intercellular messengers in all facets of cancer progression, pointing towards a potential new avenue in cancer treatment. Limited understanding of tumor-specific deregulations and lack of suitable drug compounds have hampered clinical translation of targeted interference with EV signaling. The most aggressive types of intracranial ependymoma (EPN) in children and adults are resistant to chemotherapy. Despite enormous diagnostic advancements in classification and stratification, EPN lack recurrent effective molecular targets precluding access of affected patients to precision-based oncology therapeutics. Here, we characterized the proteome of ninety-five EPN and five matching healthy control brain tissue samples. Employing a mulit-omic data integration approach, we identified EVs as an excessively augmented pathway on the functional level. Isolation and molecular characterization of EPN EVs combined with single cell sequencing analysis, and ultra-high content imaging unraveled perivascular mesenchymal cell populations as predominant EV originators. Targeting EV pathways through chemical inhibition of sphingomyelinases (SMPD1, SMPD2, SMPD3) including re-purposed FDA approved compounds revealed growth inhibition, reduced invasion capacity in vitro and significant survival probability in vivo. Transcriptomic analysis and scanning electron microscopy delineated transition of mesenchymal-to neuroepithelial subpopulations in cells and patient-derived xenograft (PDX) models of EPN upon reduction of EV release. This study showcases the inhibition of EV signaling as a promising therapeutic strategy against mesenchymal tumor persister cells, which are the suspected origins of repeated EPN relapses. Our study provides a framework to leverage cell state-specific vulnerabilities and drug repurposing to attack the most aggressive cell populations in cancers with unfavorable prognosis.

EPEN-05. SURGERY FOR CHILDHOOD EPENDYMOMA: THE EPENDYMOMA MULTIDISCIPLINARY ADVISORY GROUP (EMAG) CLINICAL TRIAL EXPERIENCE

Abstract INTRODUCTION The National Ependymoma Multidisciplinary Advisory Group (EMAG) is the central review mechanism for the SIOP Ependymoma II clinical trial in the UK. EMAG is a multiprofessional group which meets weekly to support decision making. We report detailed surgical outcomes for children with confirmed intracranial ependymoma, discussed through EMAG between January 2020 and November 2022. METHODS Data was collected on resection status, surgical outcomes, reasons for not achieving Gross Total Resection (GTR), number of surgeries and adjuvant therapies. Data was analysed descriptively. RESULTS After first surgery, GTR or near total resection (NTR) rate was 69/105 (66%) rising to 83/105 (79%) following repeated surgeries. 17 patients underwent second-look surgery prior to further therapy, whilst 9 underwent second-look surgery after chemotherapy but before radiotherapy. Eight (17%) posterior fossa (PF) surgeries were not completed due to factors including patient instability and tumour attachments. Most post-operative problems were seen in PF tumours with 26/60 (43%) bulbar palsy, 13/60 (22%) focal weakness and 12/60 (20%) cerebellar mutism. Incomplete PF resections were associated with increased bulbar palsy risk (p=0.02, Chi-Square test). 73% of PF patients required hydrocephalus management with external ventricular drainage, endoscopic third ventriculostomy (ETV) or shunt. Longer term hydrocephalus management with ETV or shunt was required in 29% and was more common in those with subtotal resection (R3-RX, 8/16, 50%) compared to GTR or NTR (R0-R2, 9/43, 21%, p=0.03). 27/60 (45%) received post-op NG feeding and 2/60 (3%) needed tracheostomies. Second surgery was associated with lower complication rates. DISCUSSION Our National MDT approach supports collaborative surgical decision making without a need for centralisation of the surgery itself. There was no evidence of increased complication rates compared to historical trials despite a more aggressive surgical approach. We argue for continued centralisation of EPN evaluation to support optimal care for children with this devastating disease.

Differentiating Low-Grade from High-Grade Intracranial Ependymomas: Comparison of Dynamic Contrast-Enhanced MRI and Diffusion-Weighted Imaging.

The aim of this study was to determine the diagnostic value of fractional plasma volume derived from dynamic contrast-enhanced perfusion MR imaging versus ADC, obtained from DWI in differentiating between grade 2 (low-grade) and grade 3 (high-grade) intracranial ependymomas. A hospital database was created for the period from January 2013 through June 2022, including patients with histologically-proved ependymoma diagnosis with available dynamic contrast-enhanced MR imaging. Both dynamic contrast-enhanced perfusion and DWI were performed on each patient using 1.5T and 3T scanners. Fractional plasma volume maps and ADC maps were calculated. ROIs were defined by a senior neuroradiologist manually by including the enhancing tumor on every section and conforming a VOI to obtain the maximum value of fractional plasma volume (Vpmax) and the minimum value of ADC (ADCmin). A Mann-Whitney U test at a significance level of corrected P = .01 was used to evaluate the differences. Additionally, receiver operating characteristic curve analysis was applied to assess the sensitivity and specificity of Vpmax and ADCmin values. A total of 20 patients with ependymomas (10 grade 2 tumors and 10 grade 3 tumors) were included. Vpmax values for grade 3 ependymomas were significantly higher (P < .002) than those for grade 2. ADCmin values were overall lower in high-grade lesions. However, no statistically significant differences were found (P = .12114). As a dynamic contrast-enhanced perfusion MR imaging metric, fractional plasma volume can be used as an indicator to differentiate grade 2 and grade 3 ependymomas. Dynamic contrast-enhanced perfusion MR imaging plays an important role with high diagnostic value in differentiating low- and high-grade ependymoma.

Treatment Outcomes of Patients with Ependymoma Receiving Radiotherapy: A Single Institution Experience

Introduction: This study explored the failure pattern and clinical outcomes in patients with ependymoma undergoing radiotherapy. Methods: Between January 2004 and June 2022, we included 32 patients with ependymoma who underwent radiotherapy as part of the multimodality treatment at our institution. Of these, 27 (84.4%) underwent adjuvant radiotherapy, four received radiotherapy after local recurrence, and one received definitive CyberKnife radiotherapy (21 Gy in three fractions). The median prescribed dose was 54 Gy in patients who received conventional radiotherapy. We analyzed the local progression-free survival (LPFS), distant metastasis-free survival (DMFS), progression-free survival (PFS), overall survival (OS), and potential prognostic factors. Results: The median age was 29.8 years. Approximately 28.1% were pediatric patients. Fifteen tumors (46.9%) were World Health Organization (WHO) grade II, 10 (31.3%) were WHO grade III, and seven (22.8%) were WHO grade I. Among them, 15 patients (46.9%) had posterior fossa tumors, 10 (31.3%) had supratentorial tumors, and seven (22.8%) had spinal tumors. Of the 31 patients who underwent upfront surgical resection, 19 (61.3%) underwent gross total resection or near-total resection. Seventeen of 19 patients with first failures (89.5%) had isolated local recurrences. Of the 19 patients with disease progression, 11 (57.9%) were disease free or had stable disease after salvage therapy, and five (26.3%) had disease-related mortality. Most of the first local recurrences after radiotherapy occurred infield (13 of 16, 81.3%). The 5-year LPFS, DMFS, PFS, and OS rates were 48.5%, 89.6%, 45.1%, and 88.4%, respectively, at a median follow-up of 6.25 years. Subtotal resection was associated with poorer LPFS and PFS in patients with intracranial ependymoma (hazard ratio = 3.69, p = 0.018, for LPFS; hazard ratio = 3.20, p = 0.029, for PFS). Conclusion: Incorporating radiotherapy into multimodal treatment has led to favorable outcomes in patients with ependymoma, and the extent of resection is a prognostic factor for the local control of intracranial ependymoma.

Consensus guidelines for the management of intracranial ependymoma for low- and middle-income countries.

This paper presents comprehensive consensus guidelines for the management of intracranial ependymoma, neoplasms arising from ependymal cells in the central nervous system's ventricular system, in low- and middleincome countries (LMICs). Acknowledging the distinct epidemiological patterns of ependymomas, notably their higher incidence in paediatric patients, and variable survival rates, these guidelines emphasize tailored management approaches for different age groups. An expert panel, comprising specialists in neuro-oncology, convened to address gaps in diagnosis and management within LMICs, considering the varying clinical presentation based on tumour size and location. Emphasizing surgical intervention as the cornerstone of treatment, the guidelines also address challenges such as intraoperative bleeding and tumour location impacting complete resection. The role of molecular subgrouping in stratifying treatment and predicting prognosis is highlighted, alongside a careful consideration of radiotherapy timing, dose, and volume based on risk factors. Chemotherapy's role, especially in paediatric cases, is explored. The paper synthesizes current research and expert opinions, including the need for standardisation, genetic testing, and exploration of less invasive treatment modalities, to address the unique healthcare infrastructure challenges in LMICs. The guidelines also emphasize multidisciplinary teams, aiming to bridge the care gap between high-income countries and LMICs, and improve survival rates and quality of life for patients with intracranial ependymoma. This article serves as a valuable resource for clinicians, researchers, and policymakers in Pakistan and beyond, facilitating the development of evidence-based strategies in diverse healthcare settings.

Whole-tumor histogram analysis of postcontrast T1-weighted and apparent diffusion coefficient in predicting the grade and proliferative activity of adult intracranial ependymomas.

To investigate the value of histogram analysis of postcontrast T1-weighted (T1C) and apparent diffusion coefficient (ADC) images in predicting the grade and proliferative activity of adult intracranial ependymomas. Forty-seven adult intracranial ependymomas were enrolled and underwent histogram parameters extraction (including minimum, maximum, mean, 1st percentile (Perc.01), Perc.05, Perc.10, Perc.25, Perc.50, Perc.75, Perc.90, Perc.95, Perc.99, standard deviation (SD), variance, coefficient of variation (CV), skewness, kurtosis, and entropy of T1C and ADC) using FireVoxel software. Differences in histogram parameters between grade 2 and grade 3 adult intracranial ependymomas were compared. Receiver operating characteristic curves and logistic regression analyses were conducted to evaluate the diagnostic performance. Spearman's correlation analysis was used to evaluate the relationship between histogram parameters and Ki-67 proliferation index. Grade 3 intracranial ependymomas group showed significantly higher Perc.95, Perc.99, SD, variance, CV, and entropy of T1C; lower minimum, mean, Perc.01, Perc.05, Perc.10, Perc.25, Perc.50 of ADC; and higher CV and entropy of ADC than grade 2 intracranial ependymomas group (all p < 0.05). Entropy (T1C) and Perc.10 (ADC) had a higher diagnostic performance with AUCs of 0.805 and 0.827 among the histogram parameters of T1C and ADC, respectively. The diagnostic performance was improved by combining entropy (T1C) and Perc.10 (ADC), with an AUC of 0.857. Significant correlations were observed between significant histogram parameters of T1C (r = 0.296-0.417, p = 0.001-0.044) and ADC (r = -0.428-0.395, p = 0.003-0.038). Whole-tumor histogram analysis of T1C and ADC may be a promising approach for predicting the grade and proliferative activity of adult intracranial ependymomas.

Brainstem toxicity after proton or photon therapy in children and young adults with localized intracranial ependymoma: A French retrospective study

Background and purposeEpendymoma is the third most frequent childhood braintumor. Standard treatment is surgery followed by radiation therapy including proton therapy (PBT). Retrospective studies have reported higher rates of brainstem injury after PBT than after photon therapy (XRT). We report a national multicenter study of the incidence of brainstem injury after XRT versus PBT, and their correlations with dosimetric data. Material and methodsWe included all patients aged < 25 years who were treated with PBT or XRT for intracranial ependymoma at five French pediatric oncology reference centers between 2007 and 2020. We reviewed pre-irradiation MRI, follow-up MRIs over the 12 months post-treatment and clinical data. ResultsOf the 83 patients, 42 were treated with PBT, 37 with XRT, and 4 with both (median dose: 59.4 Gy, range: 53‑60). No new or progressive symptomatic brainstem injury was found. Four patients presented asymptomatic radiographic changes (punctiform brainstem enhancement and FLAIR hypersignal), with median onset at 3.5 months (range: 3.0‑9.4) after radiation therapy, and median offset at 7.6 months (range: 3.7‑7.9). Two had been treated with PBT, one with XRT, and one with mixed XRT-PBT. Prescribed doses were 59.4, 55.8, 59.4 and 54 Gy. ConclusionAsymptomatic radiographic changes occurred in 4.8% of patients with ependymoma in a large national series. There was no correlation with dose or technique. No symptomatic brainstem injury was identified.

What Do We Know about Grade 3 Intracranial Ependymoma in Adults?

To investigate the long-term results of treatment for adults with primary grade 3 (G3) intracranial ependymoma and to identify the factors related to survival. A retrospective analysis of all consecutive patients (pts) older than 18 years old treated due to primary G3 intracranial ependymoma (EP) in years 1996-2018 was performed. Progression-free survival (PFS) and overall survival (OS) were calculated with Kaplan-Maier method. Log rank test and Cox regression model were used in univariate (UVA) and multivariate analysis (MVA). The group consisted of 41 pts (14 female, 27 male) with median age of 36 years (range 18-65). Infra- and supratentorial location was observed in 12 (29%) and 29 (71%) of cases, respectively. Most of the pts (93%) were in good performance status (ECOG 0 or 1). In 3 cases dissemination along craniospinal axis was diagnosed initially. All had surgery as primary treatment with R0, R1, R2 resection in 15, 9 and 15 cases, respectively. In 2pts no information regarding resection range was available. Adjuvant radiotherapy (RT) was performed in 38 pts (93%). Five patients received palliative RT and 33 radical irradiation. In 2 pts chemotherapy (CT) was administered (5%). In 3 cases no information regarding postoperative treatment was available. Among those who had RT: craniospinal irradiation was performed in 29 pts (median total dose, TD 36 Gy) with local boost (median TD 55.8 Gy, range 32.4 - 60 Gy) and 9 had local treatment (median TD 54 Gy, range 20 - 60 Gy). Median follow-up (FU) was 12.2 years. During that time 30 pts died, and 5- and 10-year overall survival (OS) was 39% and 26%. Local failure and metastases during the FU were diagnosed in 22 and 15 pts, respectively. Two- and 5-year PFS was 37% and 24%, respectively. In UVA younger age (p = 0.0001), infratentorial location of the tumor (p = 0.001) and adjuvant radical RT (p = 0.025) with high TD (p = 0.0433) positively impacted OS. In MVA only younger age (p = 0.01) confirmed positive impact on OS, however trend for better OS was observed in those who received higher RT TD (p = 0.08). Neither local nor distant recurrence had impact on OS. Younger age (p = 0.0026), infratentorial location of the tumor (p = 0.0011), extent of resection (p = 0.067), RT TD (p = 0.0396) and radical RT (p = 0.002) impacted positively PFS in UVA. In MVA younger age (p = 0.0009), extent of the resection (p = 0.00006) and radical RT (p = 0.027) confirmed positive impact on PFS. The outcome of adult patients with cranial G3 ependymoma is poor. Better survival (both OS and PFS) is observed in younger patients. Extent of surgical resection and adjuvant RT strongly impact PFS. In our analysis neither local nor distant recurrence impacted OS.

Respective Roles of Surgery, Chemotherapy, and Radiation Therapy for Recurrent Pediatric and Adolescent Ependymoma: A National Multicentric Study

Half of the children and adolescents treated for intracranial ependymoma experience recurrences that are not managed in a standardized manner. This study aimed to retrospectively evaluate recurrence treatments. We assessed overall survival (OS) and progression-free survival (PFS) after a first relapse in a population of patients from the Pediatric Ependymoma Photons Protons and Imaging study (PEPPI study) who were treated with surgery and radiation therapy in French Society of Childhood Cancer reference centers between 2000 and 2013. Data were analyzed using the Cox model as well as a landmark analysis at 4 months that accounted for the guarantee-time bias. The median follow-up of the whole population of 202 patients was 105.1 months, with a 10-year OS of 68.2% and PFS of 45.5%. Among the 100 relapse cases, 68.0% were local relapses, 20.0% were metastatic, and 12.0% were combined (local and metastatic). Relapses were treated by surgery (n = 79) and/or reirradiation (n = 52) and/or chemotherapy (n = 22). The median follow-up after relapse was 77.8 months. The OS and PFS at 5 years were 43.1% and 16.2%, respectively. After surgery or radiation therapy of the first relapse, OS and PFS were more favorable, whereas treatments that included chemotherapy with or without focal treatment were associated with worse OS and PFS. In the multivariate analysis, stereotactic hypofractionated reirradiation after surgery was associated with a significantly better outcome (OS, P = .030; PFS, P = .008) and chemotherapy with a worse outcome (OS, P = .028; PFS, P = .033). This analysis of relapse treatments within the PEPPI study determined that irrespective of whether the relapse was localized or metastatic, treatments that included surgery and/or reirradiation had better outcomes.

Difference in presentation of pediatric and adult ependymoma: An NCDB analysis.

e14055 Background: Ependymomas originate from ependymal cells and account for 6.2% of primary brain tumors in the pediatric population. Adult and pediatric ependymomas are identical in histology, but present in different sites, with intracranial ependymomas seen in children and spinal ependymomas more frequent in adults. The unique presentation of ependymoma in children warrants exploration separate from adults; however, there is currently limited data providing a baseline understanding of pediatric ependymoma and those that it impacts. The National Cancer Database (NCDB) was analyzed to identify common presentations and demographic characteristics of ependymoma in children. Methods: Patients aged 18 and younger with a diagnosis of Ependymoma (ICD 9391-9394) were identified utilizing the National Cancer Database (NCDB) from 2004 – 2020 for a retrospective cohort analysis (N = 2,098). Demographic factors such as age, sex, race, ethnicity, primary site, insurance status, and surgical procedure were analyzed by descriptive statistics. Additionally, identical NCDB data was identified for patients over 18 years old for use as a comparison factor (N = 8,227). Results: A total of 2,098 pediatric patients were identified with an average age of diagnosis of 7.0 years (SD = 5.609, range = ( &lt; 1) - 18 years) with a higher percentage being male (55.9%) than female (44.1%). The vast majority of cases of pediatric ependymoma originate in the brain (91.2%), followed by occurrences on the spinal cord and cranial nerves (8.8%). This differs from ependymoma in adults where only 44.8% of cases occur in the brain and 55.2% occur in the spinal cord. Of the 2,098 pediatric patients identified, they were histologically identified as either Ependymoma, NOS (51.5%), or Anaplastic Ependymoma (47.5%). Comparatively, Anaplastic Ependymoma makes up only 9.7% of ependymomas in adult populations. Additionally, the majority of patients were Non-Hispanic (76.3%) and white (76.9%). Most patients were privately insured (58.0%) followed by those insured by Medicaid (33.1%). Pediatric ependymoma is primarily treated with surgical resection (95.7%). Conclusions: Compared to adult occurrences, pediatric cases of ependymoma are not only unique in the site that they affect but also in histology, with a higher proportion of anaplastic ependymoma. This NCDB analysis is the first to specifically analyze pediatric ependymoma and fills a gap in our understanding of how this cancer presents in children. The majority of ependymoma patients are non-Hispanic and White with a primary site occurring in the brain rather than in the spinal cord, consistent with literature. These findings emphasize the importance of a deeper understanding of the nature of this disorder. Future research should further explore the impact of demographic and socioeconomic factors on the treatments utilized, and overall survival of pediatric patients with ependymoma.

Pediatric Intracranial Ependymoma - Recommendations for First-Line Treatment from the German HIT-MED study group

Biological subtypes of ependymoma (EPN) have been introduced by the recent WHO classification and appear to have great impact on the clinical course, but have not yet found their way into clinical risk stratification. Further, the overall unfavorable prognosis underlines the fact that current therapeutic strategies need further evaluation for improvement. To date, there is no international consensus regarding first-line treatment for children with intracranial EPN. Extent of resection is known to be the most important clinical risk factor, leading to the consensus that consequent evaluation for re-surgery of postoperative residual tumor needs to have highest priority. Furthermore, efficacy of local irradiation is unquestioned and recommended for patients aged>1 year. In contrast, efficacy of chemotherapy is still under discussion. The European trial SIOP Ependymoma II aims at evaluating efficacy of different chemotherapy elements, leading to the recommendation to include German patients. The BIOMECA study, as biological accompanying study, aims at identifying new prognostic parameters. These results might help to develop targeted therapies for unfavorable biological subtypes. For patient who are not qualified for inclusion into the interventional strata, the HIT-MED Guidance 5.2 provides specific recommendations. This article is meant as an overview of national guidelines regarding diagnostics and treatment as well as of treatment according to the SIOP Ependymoma II trial protocol.

MO-0552 Adult intracranial ependymoma - the role of DNA methylation in radiotherapeutic treatment decisions

MO-0552 Adult intracranial ependymoma - the role of DNA methylation in radiotherapeutic treatment decisions

Identification of HDAC4 as a potential therapeutic target and prognostic biomarker for ZFTA-fused ependymomas.

Members of the HDAC family are predictive biomarkers and regulate the tumorigenesis in several cancers. However, the role of these genes in the biology of intracranial ependymomas (EPNs) remains unexplored. Here, an analysis of eighteen HDACs genes in an EPN transcriptomic dataset, revealed significantly higher levels of HDAC4 in supratentorial ZFTA fusion (ST-ZFTA) compared with ST-YAP1 fusion and posterior fossa EPNs, while HDAC7 and SIRT2 were downregulated in ST-ZFTA. HDAC4 was also overexpressed in ST-ZFTA as measured by single-cell RNA-Seq, quantitative real time-polymerase chain reaction, and immunohistochemistry. Survival analyses showed a significantly worse outcome for EPNs with higher HDAC4 and SIRT1 mRNA levels. Ontology enrichment analysis showed an HDAC4-high signature consistent with viral processes while collagen-containing extracellular matrix and cell-cell junction were enriched in those with an HDAC4-low signature. Immune gene analysis demonstrated a correlation between HDAC4 expression and low levels of NK resting cells. Several small molecules compounds targeting HDAC4 and ABCG2, were predicted by in silico analysis to be effective against HDAC4-high ZFTA. Our results provide novel insights into the biology of the HDAC family in intracranial ependymomas and reveal HDAC4 as a prognostic marker and potential therapeutic target in ST-ZFTA.

Application of Drug Testing Platforms in Circulating Tumor Cells and Validation of a Patient-Derived Xenograft Mouse Model in Patient with Primary Intracranial Ependymomas with Extraneural Metastases

Primary intracranial ependymoma is a challenging tumor to treat despite the availability of multidisciplinary therapeutic modalities, including surgical resection, radiotherapy, and adjuvant chemotherapy. After the completion of initial treatment, when resistant tumor cells recur, salvage therapy needs to be carried out with a more precise strategy. Circulating tumor cells (CTCs) have specifically been detected and validated for patients with primary or recurrent diffused glioma. The CTC drug screening platform can be used to perform a mini-invasive liquid biopsy for potential drug selection. The validation of potential drugs in a patient-derived xenograft (PDX) mouse model based on the same patient can serve as a preclinical testing platform. Here, we present the application of a drug testing model in a six-year-old girl with primary ependymoma on the posterior fossa, type A (EPN-PFA). She suffered from tumor recurrence with intracranial and spinal seeding at 2 years after her first operation and extraneural metastases in the pleura, lung, mediastinum, and distant femoral bone at 4 years after initial treatment. The CTC screening platform results showed that everolimus and entrectinib could be used to decrease CTC viability. The therapeutic efficacy of these two therapeutic agents has also been validated in a PDX mouse model from the same patient, and the results showed that these two therapeutic agents significantly decreased tumor growth. After precise drug screening and the combination of focal radiation on the femoral bone with everolimus chemotherapy, the whole-body bone scan showed significant shrinkage of the metastatic tumor on the right femoral bone. This novel approach can combine liquid biopsy, CTC drug testing platforms, and PDX model validation to achieve precision medicine in rare and challenging tumors with extraneural metastases.

Why haven't we solved intracranial pediatric ependymoma? Current questions and barriers to treatment advances.

Pediatric intracranial ependymoma has seen a recent exponential expansion of biological findings, rapidly dividing the diagnosis into several subgroups, each with specific molecular and clinical characteristics. While such subdivision may complicate clinical conclusions from historical trials, this knowledge also provides an opportunity for interrogating the major clinical and biological questions preventing near-term translation into effective therapy for children with ependymoma. In this article, we briefly review some of the most critical clinical questions facing both patient management and the construct of future trials in childhood ependymoma, as well as explore some of the current barriers to efficient translation of preclinical discovery to the clinic.