Posterior Fossa Ependymoma Research Articles

H3K27me3 Loss in Central Nervous System Tumors: Diagnostic, Prognostic, and Therapeutic Implications.

Central nervous system (CNS) tumors represent a formidable clinical challenge due to their molecular complexity and varied prognostic outcomes. This review delves into the pivotal role of the epigenetic marker H3K27me3 in the development and treatment of CNS tumors. H3K27me3, specifically the trimethylation of lysine 27 on the histone H3 protein, plays a crucial role in regulating gene expression and maintaining chromatin architecture (e.g., in X-chromosome inactivation). Notably, a reduction in H3K27me3 levels, frequently tied to mutations in the H3 gene family such as H3F3A and HIST1H3B, is evident in diverse brain tumor variants, including the diffuse midline glioma characterized by the H3K27M mutation and certain pediatric high-grade gliomas. The loss of H3K27me3 has been linked to more aggressive behavior in meningiomas, with the trimethylation loss associated with significantly shorter recurrence-free survival (RFS) among grade 2 meningiomas, albeit not within grade 1 tumors. Pediatric posterior fossa ependymomas characterized by a lowered H3K27me3 and DNA hypomethylation exhibit poor prognosis, underscoring the prognostic significance of these epigenetic alterations in CNS tumors. Comprehending the role of H3K27me3 in CNS tumors is vital for advancing diagnostic tools and therapeutic interventions, with the goal of enhancing patient outcomes and quality of life. This review underscores the importance of ongoing investigations into H3K27me to refine and optimize management strategies for CNS tumors, paving the way for improved personalized medicine practices in oncology.

Unlocking the Door for Precision Medicine in Rare Conditions: Structural and Functional Consequences of Missense ACVR1 Variants.

Rare diseases and conditions have thus far received relatively less attention in the field of precision/personalized medicine than common chronic diseases. There is a dire need for orphan drug discovery and therapeutics in ways that are informed by the precision/personalized medicine scholarship. Moreover, people with rare conditions, when considered collectively across diseases worldwide, impact many communities. In this overarching context, Activin A Receptor Type 1 (ACVR1) is a transmembrane kinase from the transforming growth factor-β superfamily and plays a critical role in modulating the bone morphogenetic protein signaling. Missense variants of the ACVR1 gene result in modifications in structure and function and, by extension, abnormalities and have been predominantly linked with two rare conditions: fibrodysplasia ossificans progressiva and diffuse intrinsic pontine glioma. We report here an extensive bioinformatic analyses assessing the pool of 50,951 variants and forecast seven highly destabilizing mutations (R206H, G356D, R258S, G328W, G328E, R375P, and R202I) that can significantly alter the structure and function of the native protein. Protein-protein interaction and ConSurf analyses revealed the crucial interactions and localization of highly deleterious mutations in highly conserved domains that may impact the binding and functioning of the protein. cBioPortal, CanSAR Black, and existing literature affirmed the association of these destabilizing mutations with posterior fossa ependymoma, uterine corpus carcinoma, and pediatric brain cancer. The current findings suggest these deleterious nonsynonymous single nucleotide polymorphisms as potential candidates for future functional annotations and validations associated with rare conditions, further aiding the development of precision medicine in rare diseases.

Posterior Fossa Ependymoma in a Child with Extensive Chondro-Osseous Metaplasia Occurring at Cerebellopontine Angle and Masquerading as a Vestibular Schwannoma: An Exceptionally Rare Clinicopathological Manifestation with Review of Literature.

Ependymoma occurring at the cerebellopontine (CP) angle is an extremely uncommon sight and poses diagnostic and management dilemmas to neurosurgeons, radiologists, and neuropathologists alike. Moreover, the presence of extensive chondro-osseous metaplastic elements in ependymomas is an exceptionally infrequent histopathological manifestation. However, due to the seldom-seen nature of this histomorphological feature, there is no definite consensus regarding its etiopathogenesis and clinical consequences, and there is an extreme scarcity of literature elucidating its clinicopathological spectrum and prognostic significance. Herein, we illustrate an intriguing clinical tale of a 7-year-old male child with posterior fossa ependymoma, central nervous system (CNS) World Health Organization (WHO) grade 3, arising at the right CP angle and masquerading as a vestibular schwannoma, which in itself is a rare presentation, and additionally, exhibiting extensive chondro-osseous metaplasia, which is a very uncommon histomorphological observation. To the best of the authors' knowledge and after a comprehensive literature search, the coexistence of these two rare observations has merely been described once in international literature. This case sheds light on and highlights the importance of keeping ependymoma as a possible differential while coming across CP angle space-occupying lesions. They should be diligently distinguished from schwannomas and other masqueraders that typically occur at this site, as they have diverse management and follow-up protocols, with varying prognostic outcomes for the patients. Moreover, this case also unravels and details the clinicopathological characteristics of a scarcely described feature of chondro-osseous metaplasia in ependymomas.

Arterial Spin-Labeling Perfusion Lightbulb Sign: An Imaging Biomarker of Pediatric Posterior Fossa Hemangioblastoma.

Hemangioblastoma is a rare vascular tumor that occurs within the central nervous system in children. Differentiating hemangioblastoma from other posterior fossa tumors can be challenging on imaging, and preoperative diagnosis can change the neurosurgical approach. We hypothesize that a "lightbulb sign" on the arterial spin-labeling (ASL) sequence (diffuse homogeneous intense hyperperfusion within the solid component of the tumor) will provide additional imaging finding to differentiate hemangioblastoma from other posterior fossa tumors. In this retrospective comparative observational study, we only included pathology-proved cases of hemangioblastoma, while the control group consisted of other randomly selected pathology-proved posterior fossa tumors from January 2022 to January 2024. Two blinded neuroradiologists analyzed all applicable MRI sequences, including ASL sequence if available. ASL was analyzed for the lightbulb sign. Disagreements between the radiologists were resolved by a third pediatric neuroradiologist. χ2 and Fisher exact test were used to analyze the data. Ninety-five patients were enrolled in the study; 57 (60%) were boys. The median age at diagnosis was 8 years old (interquartile range: 3-14). Of the enrolled patients, 8 had hemangioblastoma, and 87 had other posterior fossa tumors, including medulloblastoma (n = 31), pilocytic astrocytoma (n = 23), posterior fossa ependymoma type A (n = 16), and other tumors (n = 17). The comparison of hemangioblastoma versus nonhemangioblastoma showed that peripheral edema (P = .02) and T2-flow void (P = .02) favor hemangioblastoma, whereas reduced diffusion (low ADC) (P = .002) and ventricular system extension (P = .001) favor nonhemangioblastoma tumors. Forty-two cases also had ASL perfusion sequences. While high perfusion favors hemangioblastoma (P = .03), the lightbulb sign shows a complete distinction because all the ASL series of hemangioblastoma cases (n = 4) showed the lightbulb sign, whereas none of the nonhemangioblastoma cases (n = 38) showed the sign (P < .001). Lightbulb-like intense and homogeneous hyperperfusion patterns on ASL are helpful in diagnosing posterior fossa hemangioblastoma in children.

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.

RADT-04. ASSESSMENT OF CLINICAL AND NEUROLOGICAL ALTERATIONS BEFORE RADIATION THERAPY IN CHILDREN WITH MALIGNANT BRAIN TUMORS

Abstract BACKGROUND Young patients with malignant brain tumors show neurocognitive alterations as both consequences of the tumor and of treatments received. A prospective study of longitudinal radiation damages after focal RT was activated in 2017. We present the first analysis correlating tumor localization, symptoms, neurological/endocrinological impairments, surgery/ies if adopted, and cognitive assessments at the time of enrollment. METHODS Sixty-six children eligible for focal RT were enrolled and underwent a neurocognitive assessment based on standardized tests (“impaired”/“non-impaired”). The database included demographical, clinical and pathological variables. The latter, together with MRI morphological scans, were used to define different kind of damage scores. The pattern of associations between clinical variables and damage scores was investigated. RESULTS Patients median age was 8 years; the most frequent tumor was Ependymoma (41%) and Posterior Fossa (29%) was the prevalent tumor site. All but 5 children (with Germ Cell Tumors), had undergone surgery and 32 had undergone chemotherapy before irradiation and evaluations. Ad-hoc scores of neurological deficits and endocrine alterations were created to characterize each patient. Moreover, structural abnormalities were quantified in a score for each cortical/subcortical region. Patients with posterior fossa Ependymomas and infratentorial tumors showed higher neurological damage scores. Endocrine alterations were more serious in supratentorial tumors, specifically in patients with Craniopharyngioma and Germ Cell tumors of the sellar region and ventricular system. Deficit scores were not associated to the presence of hydrocephalus and surgery, unlike endocrine alteration scores. The median number of child’s structural damaged areas was equal to 2 (IQR: 2-3). Tumor sites of patients with an impaired or non-impaired full-scale IQ or visual-perception index, was found to be different. CONCLUSIONS The analysis of baseline evaluations highlights damages preexisting to irradiations and generated by multiple factors. In light of these findings, damages over time could be better investigated by distinguishing multiple generating factors.

EPEN-13. PRE-IRRADIATION CHEMOTHERAPY EXPERIENCE FOR PEDIATRIC EPENDYMOMA POLISH PROTOCOL

Abstract BACKGROUND Pediatric ependymomas are aggressive central nervous system malignancies arising from the ependymal linings of ventricles and spinal canal. Despite better understanding of tumor biology ependymomas remain therapeutic challenge in pediatric neurooncology. The role of chemotherapy remains controversial. Herein, we describe the outcomes of patients treated at the largest center in Poland who underwent surgery, pre-irradiation chemotherapy and irradiation regardless of extent of surgical resection. METHODS This retrospective review includes pediatric patients with ependymoma treated according to national protocol at the Children’s Memorial Health Institute. We reviewed histology, disease extent, treatment, and report on overall survival (OS) and progression free survival rates (PFS). Descriptive statistics were analyzed using SPSS software. RESULTS Forty-nine patients were included (median age: 84 months). Most patients (96%) had cranial ependymomas (43% supratentorial and 57% posterior fossa lesions). Disseminated disease was found in 16% of cases. Complete resection was achieved in 43%. All patients received pre-irradiation chemotherapy; 6.1% had progressive disease and 41% achieved complete response (CR). All patients, except one, underwent irradiation (67% focal, 2% focal/ventricular, 29% craniospinal, and 2% whole brain). Thirty-five percent of patients relapsed. Five-year PFS and OS were 69% and 80% respectively. Comparing posterior fossa to supratentorial lesions, there was no difference in response after surgery and pre-irradiation chemotherapy (CR 37% versus 50% (p=0.51)) or irradiation (CR 42% versus 55% (p=0.37)). However, relapse was more likely in posterior fossa ependymomas (OR 0.30 IQR (0.70, 1.29), p=0.03) with lower 5-year PFS (56% versus 85%, p=0.03) and 10-year PFS (52% versus 85%, p=0.02). The benefit of chemotherapy was marked in patients with Grade 3 (5-year OS 82% versus 69%) CONCLUSIONS We describe a large cohort of pediatric ependymoma patients who received pre-irradiation chemotherapy. This strategy did not negatively impact the incidence of progression before irradiation.

IMG-22. ASL PERFUSION LIGHTBULB SIGN: A POTENTIAL PATHOGNOMONIC FEATURE OF PEDIATRIC POSTERIOR FOSSA HEMANGIOBLASTOMA

Abstract INTRODUCTION Hemangioblastoma is a rare vascular tumor which occurs within the central nervous system in children. Differentiating hemangioblastoma from other posterior fossa tumors can be challenging on imaging and preoperative diagnosis can change neurosurgical approach. We hypothesize a ‘lightbulb sign’ (diffuse homogenous intense hyperperfusion within solid component of tumor) will help differentiate hemangioblastoma from other posterior fossa tumors. METHODS In this retrospective case-control study, we only included pathology-proven cases of hemangioblastoma, while the control group consisted of other randomly selected pathology-proven posterior fossa tumors from January 2022 to January 2024. Two blinded neuroradiologists analyzed all applicable MRI sequences. Their perfusion analysis also included the “lightbulb sign” as an extra criterion. Disagreements between the radiologists were confirmed by a third pediatric neuroradiologist. Chi-square and Fisher’s exact test were used to analyze the data. RESULTS 95 patients were enrolled in the study, 57(60%) were male. The median age at diagnosis was 8 (IQR: 3-14). Out of the enrolled patients, 8 had hemangioblastoma, and 87 had other posterior fossa tumors, including medulloblastoma (n=31), pilocytic astrocytoma (n=23), posterior fossa ependymoma type A (n=16), and other tumors (n=17). The comparison of hemangioblastoma vs non-hemangioblastoma showed that peripheral edema (p=0.020, OR=1.8) and T2 flow void (p=0.021, OR=1.7) favors hemangioblastoma, whereas reduced diffusion (low ADC) (p=0.002, OR=2.3) and ventricular system extension (p=0.001, OR=2.4) favors non-hemangioblastoma tumors. 42 cases also had perfusion studies. While high perfusion favors hemangioblastoma (p=0.021, OR=2.9), the lightbulb sign shows a complete distinction since all the ASL series of hemangioblastoma cases (n=4) showed the lightbulb sign, whereas none of the non-hemangioblastoma cases (n=38) showed the sign (p&amp;lt;0.001). CONCLUSION Lightbulb-like intense and homogenous hyperperfusion pattern on ASL allows differentiation of hemangioblastoma from other posterior fossa tumors in children.

EPEN-28. NOVEL TARGET IDENTIFICATION IN RECURRENT POSTERIOR FOSSA EPENDYMOMA GROUP A

Abstract BACKGROUND Posterior fossa ependymoma group A (PF-EPN-A) are an aggressive subgroup of ependymal tumors which occur predominantly in infants and possess a poor prognosis. Treatment is limited to surgical resection and adjuvant radiation with no approved chemotherapies or targeted therapies available. Despite treatment efforts, nearly half of all PF-EPN-A cases will experience tumor recurrence within a decade of initial diagnosis. Our current understanding of relapse is limited to clinical risk stratification based on subtotal resection of the primary tumor, male sex and specific chromosomal copy number aberrations. In an effort to overcome the shortcomings of current literature on PF-EPN-A recurrence, we present a concerted effort to investigate the biology of both recurrent human tissue specimens and patient-derived cell models to identify novel drivers of recurrence. METHODS Utilizing a multi-omics approach, we have conducted transcriptomic (bulk RNA-Seq), proteomic and phosphoproteomic (LC-MS/MS) analyses in order to identify molecular pathways that are enriched in recurrent disease as compared to primaries. We have also performed genome-wide CRISPR essentiality screens to further pinpoint essential genes and pathways with therapeutic potential. RESULTS Through the comparison of primary and recurrent PF-EPN-A samples, we have identified both previously implicated and novel genes and pathways in recurrent disease. Our multi-omic analyses identified the upregulation of genes involved in DNA repair, DNA damage response and cell cycle pathways in recurrent PF-EPN-A. CONCLUSIONS Our combined approach has enabled the identification of novel targets with therapeutic potential in the treatment of recurrent PF-EPN-A. The identified targets will be validated using a combination of drug screening and knockdown approaches in vitro. Top candidates will be further validated in vivo with established recurrent xenograft mouse models. PF-EPN-A is an aggressive disease with limited treatment options and the identification of novel targets with potential therapeutic utility will allow us to better treat this patient population.

EPEN-26. DRUG SCREENING IN PATIENT-DERIVED MODELS OF POSTERIOR FOSSA A EPENDYMOMA REVEALS NOVEL PHARMACOLOGICAL VULNERABILITIES

Abstract Ependymoma (EPN) is the third most common malignant intracranial pediatric brain tumor. The most common and aggressive EPN subgroup, posterior fossa ependymoma group A (PFA-EPN), occurs predominantly in younger children and has a 5-year progression free survival of only 33%. Despite progress in the molecular characterization and subtyping of EPN, the standard treatment remains surgery with adjuvant radiation therapy. There is currently no approved role for chemotherapy in PFA-EPN. As such, identifying novel therapies for PFA-EPN is an important unmet medical need. To define therapeutic sensitivities for PFA-EPN, we performed a drug screen on three patient-derived PFA-EPN cell lines. We found that PFA-EPN cell lines were sensitive to several clinically relevant drugs, most notably those targeting epigenetic regulators. This is of a particular interest as a common molecular feature of PFA-EPN is the global reduction of the repressive post-translational histone modification H3K27me3 due to transcriptional EZHIP overexpression or H3 K27M mutations. To further characterize our PFA-EPN cell lines, we performed optical genome mapping analysis, revealing previously undescribed structural variants affecting genes encoding proteins responsible for signaling and transcription. One PFA-EPN sample that showed profound sensitivity to EGFR inhibitors, also had a duplication of a genomic region containing the EGFR ligand encoding genes, AREG, BTC, EREG, and EPGN. We are currently working to validate these results in larger cohorts of PFA-EPN models. Collectively, these findings provide new clues on drugs, signaling and putative therapeutic targets in these rare yet aggressive tumors.

Commentary: Impact of Molecular Subgroups on Prognosis and Survival Outcomes in Posterior Fossa Ependymomas: A Retrospective Study of 412 Cases.

Commentary: Impact of Molecular Subgroups on Prognosis and Survival Outcomes in Posterior Fossa Ependymomas: A Retrospective Study of 412 Cases.

Impact of Molecular Subgroups on Prognosis and Survival Outcomes in Posterior Fossa Ependymomas: A Retrospective Study of 412 Cases.

Posterior fossa ependymomas (PFEs) are rare brain tumors classified as PF-EPN-A (PFA) and PF-EPN-B (PFB) subgroups. The study aimed to evaluate the prognosis and survival outcomes in PFEs, with a focus on the impact of molecular subgroups. A retrospective study was conducted on 412 patients with PFEs. Kaplan-Meier survival analyses were conducted to evaluate the overall survival (OS) and progression-free survival. Cox regression analyses were conducted to assess the prognostic factors. A nomogram was developed to predict the OS rates of PFEs. The study revealed significant differences between PFA and PFB in patient and tumor characteristics. PFAs were associated with poorer OS (hazard ratios [HR] 3.252, 95% CI 1.777-5.950, P < .001) and progression-free survival (HR 4.144, 95% CI 2.869-5.985, P < .001). World Health Organization grade 3 was associated with poorer OS (HR 2.389, 95% CI 1.236-4.617, P = .010). As for treatment patterns, gross total resection followed by radiotherapy or the combination of radiotherapy and chemotherapy yielded the most favorable OS for PFA ( P = .025 for both), whereas gross total resection followed by radiotherapy rather than observation showed improved OS for PFB ( P = .046). The nomogram demonstrated a high degree of accuracy and discrimination capacity for the prediction of OS rates for up to 10 years. In addition, 6 cases of PFA (3.51%) with H3K27M mutations were identified. PFAs demonstrate worse prognosis and survival outcomes compared with PFBs. Both PFAs and PFBs necessitate maximal resection followed by intensive adjuvant therapies in long-term effects.

Abstract 5106: Pharmacological targeting of LSD1 prolongs animal survival times in patient derived orthotopic xenograft models of posterior fossa ependymoma in combination with fractionated radiation

Abstract Background: Posterior Fossa Group A Ependymoma (PFA EPN) constitute one of the most aggressive and highly recurrent molecular subtypes of childhood Ependymomas. We recently performed a comprehensive genome-wide DNA methylation analysis in recurrent pediatric EPN tumors from patients that were followed up for over 13 years. Integrative analysis between tumor DNA methylation and histone modification identified LSD1 as a druggable driver of PFA EPN recurrence. In this study, we examined the therapeutic efficacy of our newly developed LSD1 inhibitor SYC-836 in PDOX models of recurrent PFA EPN. Methodology: To determine the in vitro anti-tumor activities of SYC-836, paired PFA EPN xenograft cell cultures (monolayer and 3D neurospheres) were treated with SYC-836 at 8 concentrations (0.02-25 µM) and examined for changes of cell proliferation every 3-4 days through day 14. To validate the drug’s in vivo efficacy, two established posterior fossa EPN PDOX models, ICb-4423EPN and ICb-2002EPN, were utilized. Forty 8-week old SCID mice of both genders received intra-cerebellar tumor cell implantation and were divided into 4 treatment groups (n=10 per group): 1) control, 2) radiation (2 Gy/day x 5 days), 3) SYC-836 (15 mg/kg, daily intra-peritoneal injection for 28 days), and 4) combination (radiation + SYC-836). Animal survival times were analyzed using log-rank analysis. Changes in LSD1 protein expression and histone lysine methylation were examined through western hybridization. Results: SYC-836 strongly suppressed PFA EPN cell growth in vitro, in both, a time- and dose-dependent manner. While there was no survival benefit with either SYC-836 only (P=0.186) or XRT only (P=0.205); combining SYC-836 with XRT significantly (P=0.04) prolonged the median survival time of ICb-4423EPN, from 46 days in the untreated group to 59 days; and in ICb-2002EPN, even more prominent, from 136 days to 180 days (P=0.007). SYC-836 was well tolerated in mice with no loss of body weight or other toxicities. Changes in LSD1 protein expression and H3K4me2 were detected through western hybridization during and after SYC-836 treatment. Conclusion: Our data support LSD1 as a druggable driver of PFA recurrence and highlights strong anti-tumor activities of SYC-836 in combination with radiation, a standard therapy of pediatric EPN. SYC-836 may have a role in the clinical setting by either reducing radiation dosages or be an adjuvant agent to other chemotherapy drugs in our treatment approach for ependymoma. Citation Format: Milagros M. Suarez Palacios, Sibo Zhao, Huiyuan Zhang, Lin Qi, Holly Lindsay, Mari Kogiso, Frank Braun, Adekunle M. Adesina, Yuchen Du, Yongcheng Song, Xiao-Nan Li. Pharmacological targeting of LSD1 prolongs animal survival times in patient derived orthotopic xenograft models of posterior fossa ependymoma in combination with fractionated radiation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5106.

Implications of DNA Methylation Classification in Diagnosing Ependymoma

BackgroundEpendymoma is a central nervous system tumor that arises from the ependymal cells of the brain's ventricles and spinal cord. The histopathology of ependymomas is indistinguishable regardless of the site of origin, and the prognosis varies. Recent studies have revealed that the development site and prognosis reflect the genetic background. In this study, we used genome-wide DNA methylation array analysis to investigate the epigenetic background of ependymomas from different locations treated at our hospital. MethodsFour cases of posterior fossa ependymomas and 11 cases of spinal ependymomas were analyzed. ResultsDNA methylation profiling using the DKFZ methylation classifier showed that the methylation diagnoses of the two cases differed from the histopathological diagnoses, and two cases could not be classified. Tumor that spread from the brain to the spinal cord was molecularly distinguishable from other primary spinal tumors. ConclusionsAlthough adding DNA methylation classification to conventional diagnostic methods may be helpful, the diagnosis in some cases remains undetermined. This may affect decision-making regarding treatment strategies and follow-up. Further investigations are required to improve the diagnostic accuracy of these tumors.

Lateral-type posterior fossa ependymomas in pediatric population

BackgroundLateral-type posterior fossa ependymomas are a well-defined subtype of tumours both clinically and pathologically, with a poor prognosis. Their incidence is low and surgical management is challenging. The objective of the present work is to review our series of lateral-tye posterior fossa ependymomas and compare our results with those of previous series. MethodsAmong 30 cases of ependymoma operated in our paediatric department in the last ten years, we identified seven cases of lateral-type posterior fossa ependymomas. We then performed a retrospective, descriptive study. ResultsMean age of our patients was 3.75 years. 6 cases presented with hydrocephalus. Mean tumour volume at diagnosis was 61 cc. A complete resection was achieved in six cases and a near-total resection in one patient. 5 patients transiently required a gastrostomy and a tracheostomy. Mean follow-up was 58 months. One case progressed along this period and eventually died. 4 cases of hydrocephalus required a ventriculoperitoneal CSF shunt and two were managed with a third ventriculostomy. At last follow-up 4 patients carried a normal life and two displayed a mild restriction according to Lansky´s scale. ConclusionsThe aim of surgical treatment in lateral-type posterior fossa ependymomas is complete resection. Neurological deficits associated to lower cranial nerve dysfunction are common but transient. Deeper genetic characterization of these tumours may identify risk factors that guide stratification of adjuvant therapies.

Feasibility and antitumour activity of the FGFR inhibitor erdafitnib in three paediatric CNS tumour patients.

Alterations of the fibroblast growth factor (FGF) signalling pathway are increasingly recognized as frequent oncogenic drivers of paediatric brain tumours. We report on three patients treated with the selective FGFR1-4 inhibitor erdafitinib. Two patients were diagnosed with a posterior fossa ependymoma group A (PFA EPN) and one with a low-grade glioma (LGG), harbouring FGFR3/FGFR1 overexpression and an FGFR1 internal tandem duplication (ITD), respectively. While both EPN patients did not respond to erdafitinib treatment, the FGFR1-ITD-harbouring tumour showed a significant decrease in tumour volume and contrast enhancement throughout treatment. The tumour remained stable 6months after treatment discontinuation.

Complications following resection of primary and recurrent pediatric posterior fossa ependymoma.

Extent of resection (EOR) is the most important modifiable prognostic variable for pediatric patients with posterior fossa ependymoma. An understanding of primary and recurrent ependymoma complications is essential to inform clinical decision-making for providers, patients, and families. In this study, the authors characterize postsurgical complications following resection of primary and recurrent pediatric posterior fossa ependymoma in a molecularly defined cohort. The authors conducted a 20-year retrospective single-center review of pediatric patients undergoing resection of posterior fossa ependymoma at the Hospital for Sick Children in Toronto, Canada. Complications were dichotomized into major and minor groups; EOR was compared across complication categories. The association between complication occurrence with length of stay (LOS) and mortality was also assessed using multivariable regressions. There were 60 patients with primary resection included, 41 (68%) of whom were alive at the time of data collection. Gross-total resection was achieved in 33 (58%) of 57 patients at primary resection. There were no 30-day mortality events following primary and recurrent ependymoma resection. Following primary resection, 6 patients (10%) had posterior fossa syndrome (PFS) and 36 (60%) developed cranial neuropathies, 56% of which recovered within 1 year. One patient (1.7%) required a tracheostomy and 9 patients (15%) required gastrostomy tubes. There were 14 ventriculoperitoneal shunts (23%) inserted for postoperative hydrocephalus. Among recurrent cases, there were 48 recurrent resections performed in 24 patients. Complications included new cranial neuropathy in 10 patients (21%), of which 5 neuropathies resolved within 1 year. There were no cases of PFS following resection of recurrent ependymoma. Gastrostomy tube insertion was required in 3 patients (6.3%), and 1 patient (2.0%) required a tracheostomy. Given the differences in the location of tumor recurrence, a direct comparison between primary and recurrent resection complications was not feasible. Following multivariate analysis adjusting for sex, age, molecular status, and EOR, occurrence of major complications was found to be associated with prolonged LOS but not mortality. These results detail the spectrum of postsurgical morbidity following primary and recurrent posterior fossa ependymoma resection. The crude complication rate following resection of infratentorial recurrent ependymoma was lower than that of primary ependymoma, although a statistical comparison revealed no significant differences between the groups. These results should serve to inform providers of the morbidity profile following surgical management of posterior fossa ependymoma and inform perioperative counseling of patients and their families.

Spinal ependymoma in adults: from molecular advances to new treatment perspectives

Ependymomas are rare glial tumors with clinical and biological heterogeneity, categorized into supratentorial ependymoma, posterior fossa ependymoma, and spinal cord ependymoma, according to anatomical localization. Spinal ependymoma comprises four different types: spinal ependymoma, spinal ependymoma MYCN-amplified, myxopapillary ependymoma, and subependymoma. The clinical onset largely depends on the spinal location of the tumor. Both non-specific and specific sensory and/or motor symptoms can be present. Owing to diverse features and the low incidence of spinal ependymomas, most of the current clinical management is derived from small retrospective studies, particularly in adults. Treatment involves primarily surgical resection, aiming at maximal safe resection. The use of radiotherapy remains controversial and the optimal dose has not been established; it is usually considered after subtotal resection for WHO grade 2 ependymoma and for WHO grade 3 ependymoma regardless of the extent of resection. There are limited systemic treatments available, with limited durable results and modest improvement in progression-free survival. Thus, chemotherapy is usually reserved for recurrent cases where resection and/or radiation is not feasible. Recently, a combination of temozolomide and lapatinib has shown modest results with a median progression-free survival (PFS) of 7.8 months in recurrent spinal ependymomas. Other studies have explored the use of temozolomide, platinum compounds, etoposide, and bevacizumab, but standard treatment options have not yet been defined. New treatment options with targeted treatments and immunotherapy are being investigated. Neurological and supportive care are crucial, even in the early stages. Post-surgical rehabilitation can improve the consequences of surgery and maintain a good quality of life, especially in young patients with long life expectancy. Here, we focus on the diagnosis and treatment recommendations for adults with spinal ependymoma, and discuss recent molecular advances and new treatment perspectives.

DISP-09. HISTOPATHOLOGIC AND MOLECULAR PROFILE OF GLIOMAS: A 9-YEAR RETROSPECTIVE STUDY OF CASES DIAGNOSED IN LAGOS NIGERIA

Abstract BACKGROUND The diagnosis and management of patients with brain tumors currently uses WHO defined morphologic and molecular features. However, neuro-oncology practice in low resource settings relies on histomorphology. This study aims to reclassify glioma cases diagnosed in the Department of Anatomic and Molecular Pathology Lagos University Teaching Hospital using the 2021 WHO classification. METHODS Fifty-six cases of glioma diagnosed between 2013 to 2021 were evaluated. Morphologic diagnosis was reassessed. Five-micron sections were obtained for immunohistochemistry (IHC), and genetic testing (DNA and RNA); after manual macrodissection for tumor enrichment using 10μm sections. IHC for IDH1-R132H, ATRX, BRAFV600E, P53,Ki67, and H3K27M and OncoScan chromosomal microarray analysis were performed. NGS mutation/fusion analysis and EPIC methylation array profiling are in progress. RESULTS Of 56 cases evaluated, median age was 22 years (range=1-60 years); 71% were males. The initial morphologic diagnosis include 21 pilocytic astrocytoma, 11 glioblastoma, 9 ependymoma, 7 diffuse astrocytoma, 3 anaplastic astrocytoma, 2 high-grade gliomas, 1 oligodendroglioma, 1 diffuse midline glioma, and 1 pleomorphic xanthoastrocytoma (PXA). Histomorphologic re-evaluation revealed discordant diagnosis in 29% (16/56) of cases. Of the 56 cases, 73% (41/56) had usable DNA yield and 38% (21/56) had DNA yield of ≥ 750ng. Chromosomal microarray analysis was completed for 50% (28/56) cases. The revised 2021 WHO diagnosis were: 5 glioblastoma, IDH-wildtype, 5 pilocytic astrocytoma, 4 glioma NEC, 3 posterior fossa ependymoma, group B, 3 PXAs, 3 astrocytoma, IDH-mutant, 2 pediatric low-grade glioma, 2 supratentorial ependymoma, ZFTA fusion-positive, 1 posterior fossa ependymoma, group A. In 71% (20/28) of cases, diagnosis was revised using the 2021 WHO criteria. CONCLUSION Most cases had usable DNA yield. Overall, hsitologic re-evaluation and molecular testing based on the 2021 WHO classification guidelines refined the diagnosis in 48% (27/56) of cases.

PATH-46. A NOVEL POT1-TPD PRESENTATION: A GERMLINE POT1 MUTATION DISCOVERED IN A PATIENT WITH NEWLY DIAGNOSED POSTERIOR FOSSA EPENDYMOMA

Abstract INTRODUCTION POT1 tumor predisposition (POT1-TPD) is an autosomal dominant disorder characterized by increased lifetime malignancy risk. Melanoma, angiosarcoma and chronic lymphocytic leukemia are the most frequently reported malignancies. Other related cancers include gliomas. Protection of telomeres protein 1 is part of the shelterin protein complex to maintain/protect telomeres. Proposed mechanisms for oncogenesis with POT1 loss of function include telomere elongation and DNA damage response causing genomic instability. Ependymomas are a heterogeneous group comprising 12% of pediatric brain tumors and are locally aggressive with frequent recurrence. CASE PRESENTATION A healthy 3-year-old male presented with worsening vertigo, headaches, and emesis. Radiographic studies demonstrated a midline posterior fossa mass in the fourth ventricle. Following a gross total resection, pathology demonstrated a posterior fossa ependymoma, group A. Next generation sequencing (NGS) using our institution’s clinically validated panel, “CinCSeq”, demonstrated a POT1 splice site variant (c.1164-1G &amp;gt;A; variant allele frequency 46%). Paired germline testing via the molecular characterization initiative confirmed this variant as a heterozygote in the patient. Genetic testing confirmed a germline mutation in his mother who has a history of multiple nevi. He completed treatment with focal proton radiotherapy with no evidence of disease recurrence to date. DISCUSSION To our knowledge, this represents the first documented pediatric ependymoma with a familial, germline POT1 mutation. Somatic POT1 mutational frequency as determined by NGS in 60,000 solid tumors occurs at a rate of 2.94%. 45/60,000 were ependymomas with 1 non-benign POT1 mutation. Alterations of telomere maintenance have been reported in infratentorial ependymomas through increased human telomerase reverse transcriptase (hTERT) expression. This case sheds light on potential new mechanisms/predispositions for ependymoma development and the expanding phenotype of POT1-TPD. We recognize the POT1 mutation may have been discovered incidentally in this case. Further research into an association between POT1 and ependymomas is needed to advance our understanding.