Anaplastic Ependymoma Research Articles

PATH-34. IT NEVER RAINS BUT IT POURS - DIAGNOSING ANAPLASTIC PLEOMORPHIC XANTHASTROCYTOMA TWICE IN A FORTNIGHT - OUR EXPERIENCE IN A RESOURCE CONSTRAINED SETTING

Abstract Grade 3 Pleomorphic Xanthastrocytoma is a rare tumour (less than 1% of all astrocytic glial neoplasms). Present most commonly with seizures. Surgery and Radiation remain the mainstay of treatment with no clear role for traditional systemic chemotherapies; BRAF inhibitors show some benefit. We report two cases who were diagnosed within a month of each other - one was initially diagnosed in 2017- presented with altered smell, headache and diplopia. Found to have a well-defined lobulated heterogeneously enhancing suprasellar parasellar lesion. After Gross Total Resection, was diagnosed from various centers as Anaplastic Ependymoma WHO Grade III; Gllioblastoma WHO Grade IV; Anaplastic Pleomorphic Xanthastrocytoma WHO Grade III. Based on immunohistochemistry, was considered Anaplastic Ependymoma WHO Grade III. Spine screening was negative; received adjuvant Radiation 60Gy in 30 fractions. After a disease free interval of 6 years, developed a recurrence at the post op site. He underwent repeat decompression and the histopathology showed Grade 3 Pleomorphic Xanthastrocytoma. Immunohistochemistry- OLIG2: diffuse positive; R132H p.IDH1: negative; ATRX: intact nuclear expression; Mismatch repair proteins (MSH2, MSH6, MLH1, PMS2); intact nuclear expression; MIB-1 labelling index: 10-12%; H3 p.K27M: negative; GFAP: variable positivity; Podoplanin and p53 shows focal positivity; EMA, CD 34 are negative. He competed Reirradiation in January 2024. He is asymptomatic and on follow up. The second case -15 year old boy presented with episodes of absence seizures. Imaging showed a predominantly extraaxial lesion at tentorial apex. He underwent decompression and histopathology showed Grade 3 Pleomorphic Xanthastrocytoma. Immunohistochemistry - cells positive for S100 and variably positive for GFAP, OLIG2 and vimentin; ATRX: Retained expression, IDH1p.R132H, EMA, Synaptophysin, Neu N: Negative, p53: Focally positive, CD34: Positive in few tumour cells, Ki-67: 14-16 %.V600 mutation detected in the BRAF gene. Had Adjuvant RT 60 Gy in 30 fractions -completed in March 2024. MRI at 1 month - no significant change in overall tumour burden compared to post operative MRI. Was offered Dabrafenib with Trametinib.

Transcranial motor-evoked potentials disappear with pons transection.

Motor-evoked potential (MEP) monitoring by transcranial electrical stimulation (TES) is important for intraoperative motor function assessment in neurosurgery; however, false-negative results sometimes occur, and these findings should be interpreted with caution. Herein, we report an interesting MEP change resulting from a pons transection. The patient was a boy aged 5years and 2months. He underwent multiple craniotomies for cerebellar anaplastic ependymoma and was already paralyzed in the right upper and lower limbs. Therefore, we decided to remove the recurrent lesion from the left anterior pons. MEPs were recorded on both the right and left sides after the start of surgery but disappeared 1h 30min after the start of surgery in the TES on the operative side, even when the stimulation intensity was increased. The contralateral TES consistently recorded stable MEPs throughout the surgery. The tumor was completely resected on imaging. Immediately postoperatively, the patient experienced flaccid paralysis on the right side of the body, which recovered to preoperative levels over time. A transcranial MEP cannot be derived if the corticospinal tract is transected at the pons. Transcranial MEP findings may accurately reflect the corticospinal tract function if the injury is caudal to the pons.

AB094. Association of body mass index with grading and survival of glioma patients.

Glioma is the second most common type of brain tumor, representing 24% of all brain tumor cases. The role of body mass index (BMI) on glioma remains unclear, with conflicting findings regarding the association between higher BMI and the risk of developing certain brain tumors. Glioblastoma, an aggressive and malignant form of glioma with limited treatment options and a poor prognosis, has been linked to BMI in some studies, suggesting that individuals with higher BMIs may have an elevated risk of glioblastoma development. However, a comprehensive understanding of the mechanisms underlying this relationship and its extent is still needed. The study aimed to investigate the correlation between BMI and the grading and survival of glioma patients. A retrospective cross-sectional analysis was conducted on 117 histologically confirmed glioma patients at Dr. Sardjito General Hospital in Yogyakarta, Indonesia. Clinical data were collected from medical records. BMI was calculated by measuring weights (kg) and dividing it by squared heights (m2). The statistical analysis focused on assessing the association between BMI, tumor grade, and patient survival. Among 117 glioma patients, glioblastoma was the most prevalent tumor type (48.7%; n=57/117), followed by diffuse astrocytoma (22%; n=26/117). The remaining cases included anaplastic ependymoma, anaplastic oligodendroglioma, and pilocytic astrocytoma. Most patients were male (61%), with an average age of 47.5 years, age ranges between 20 and 79 years. The majority had grade IV of World Health Organization (WHO) classification (58%, n=68/117), while only two patients were classified as grade I. The average BMI was 23.5 kg/m2, indicating overweight status for the Asian population, with more than half of the patients being overweight or obese (54%, n=63/117). Additionally, ten patients were underweight. There was a trend of higher BMI being associated with higher grading and survival. However, no significant association between BMI and tumor grade (P=0.23) or survival (P=0.26) was found. Although no significant associations were found between BMI, tumor grade, and survival in glioma patients, further studies are warranted. The high prevalence of overweight and obesity among patients should be further investigated to provide valuable insights for patient management and care.

METB-11. HOW METHYLATION PROFILING HELPS IN DIAGNOSING AND TREATING PEDIATRIC BRAIN TUMORS IN INDONESIA

Abstract BACKGROUNDS Pediatric brain tumors (PBT) exhibit extensive heterogeneity, impacting treatment outcomes. While traditionally classified based on histopathological features, recent WHO classifications have integrated DNA methylation array profiling amongst other molecular characteristics, which improves diagnostic accuracy and thus treatment decisions. However, access to this technology is limited in low- and middle-income countries (LMICs) like Indonesia. As part of the MNP Outreach Consortium, we aimed to introduce methylation profiling in Indonesia to aid in diagnosing and stratifying PBT patients. METHODS In 2023, we conducted a case series involving seven challenging PBT cases from Cipto Mangunkusumo National General Hospital, re-assessing them with methylation profiling. RESULTS Through collaboration with the Institute of Neuropathology Heidelberg and the DKFZ, our centre adopted a discerning approach to re-evaluate histopathological samples from complex cases. This endeavour yielded notable results, reaffirming four initial diagnoses and altering three others Amongst the findings, one case initially diagnosed as anaplastic ependymoma, CNS WHO grade 3, was reclassified as a supratentorial ependymoma with YAP1 fusion gene, based on methylation class. Noteworthy within this latter group, one case initially categorized as low-grade pilocytic astrocytoma was reclassified as high-grade diffuse midline glioma, H3 K27 altered. Moreover identifying the copy number plot could indicate a KIAA1549::BRAF fusion to reclassify a case from diffuse pediatric glioma WHO grade 2 to pilocytic astrocytoma WHO grade 1. The recurrent pigmented neuroectodermal tumor of infancy (MNTI) was reclassified as Medulloblastoma, non-WNT/non-SHH, group 3 subtype II on methylation profiling, highlighting molecular similarities and potential treatment insights. These findings offer insights into genetic mechanisms and guide treatment strategies. CONCLUSION Accurate diagnosis, facilitated by advanced molecular profiling, enhances prognostication and enables personalized treatment plans, even in LMICs. This underscores the importance of expanding access to advanced diagnostic technologies in resource-limited settings.

BIOM-02. DISSECTING CDK4/6 INHIBITOR RESISTANCE MECHANISMS IN RECURRENT PEDIATRIC BRAIN TUMORS WITH LONGITUDINAL CSF LIQUID BIOPSIES FROM THE SJDAWN CLINICAL TRIAL

Abstract BACKGROUND SJDAWN (NCT03434262) is a St. Jude Children’s Research Hospital phase 1 trial that assessed the safety and benefit of CDK4/6 inhibitor-based therapy in patients with relapsed CNS tumors. To capture tumor evolution dynamics and arising resistance mechanisms in response to treatment, 143 longitudinal CSF samples were collected from 34/68 (50%) patients for cell-free DNA (cfDNA) analysis. METHODS cfDNA was extracted from CSF liquid biopsies and analyzed using a novel methylation-based platform that integrates copy number, tumor classification, and deconvolution of methylation signatures into normal vs. disease fractions. Samples with measurable residual disease (MRD) were further characterized by deep whole-genome sequencing to discover mutation-driven resistance mechanisms. When available, pre- and post-SJDAWN tumor tissues were processed for single-nucleus multi-omics to track tumor evolution at single-cell resolution. RESULTS In the context of CDK4/6 inhibitor-based therapy, longitudinal cfDNA assessment revealed treatment-induced selection for subclones with focal amplification of positive cell cycle regulators CDK6, CCND2, and MYCN. Emergence of these resistance mechanisms notably preceded disease progression on MRI and CSF cytology by up to 6 months. Of the 68 patients enrolled on SJDAWN, 4 patients (3 Group 3/4, subtype III medulloblastomas and 1 anaplastic ependymoma) achieved >2-year progression-free survival. Interestingly, serial cfDNA profiling of 1 long-term survivor (Group 3/4, subtype III medulloblastoma) exhibited undetectable MRD status for >1.5 years prior to reemergence, suggesting tumor senescence by CDK4/6 inhibition may impede circulating tumor DNA (ctDNA) release kinetics. CSF liquid biopsies were further evaluated in comparison to matched tumor tissues, and changes in CSF-specific subclones were observed in response to treatment. CONCLUSIONS In addition to early MRD detection, liquid biopsies capture tumor evolution dynamics and can inform developing resistance mechanisms. Focal amplification of CDK6, CCND2, and MYCN facilitates CDK4/6 inhibitor resistance. In responders, treatment-induced senescence may inhibit ctDNA release kinetics.

OTHR-01. ALK-DRIVEN INFANT-TYPE HEMISPHERIC HIGH-GRADE GLIOMA AND CNS HISTIOCYTOSIS SUCCESSFULLY TREATED WITH A SECOND GENERATION ALK-INHIBITOR: MOLECULAR CHARACTERIZATION SAVES THE DAY

Abstract BACKGROUND Molecular characterization of brain tumors (BT) is increasingly becoming essential for diagnosing and managing central nervous system (CNS) tumors. Infant BT is a particular category of pediatric CNS tumors that poses a challenge to the neuro-oncologist. METHODS Here, we present two distinctive cases where molecular characterization significantly influenced diagnosis, management, and outcome. RESULTS The first case is a 2-year-old boy presented with generalized seizures. MRI of the brain showed multiple dural-based tumors. Biopsy was consistent with ALK-positive histiocytosis (KIF5B-ALK fusion). Additional lesions were detected in the right kidney and left femoral head. Despite three months of LCH-based therapy, the tumor progressed. Chemotherapy was halted, and treatment with alectinib was initiated. Follow-up MRIs after 3 and 6 months showed marked regression and a complete resolution of the lesions, respectively. The second case is a 12-month-old boy who exhibited developmental regression and increased head circumference over the past three months. MRI revealed a large complex right ventricle mass measuring 8.6x7.2x8 cm. Subtotal resection was complicated by severe intracranial bleeding, requiring prolonged intensive care stay. The initial pathological diagnosis was anaplastic ependymoma. He received two cycles of neoadjuvant chemotherapy followed by a second look surgery, which failed to achieve a gross total resection. Molecular testing by this time identified an ALK-CCDC85A fusion, altering the diagnosis to infant-type hemispheric glioma. He was started on alectinib. MRI after 3 and 6 months showed a favorable response with an overall improvement in his cognitive function. Both patients tolerated alectinib well, remaining on therapy for 6 and 12 months, respectively. No toxicities were reported. CONCLUSION These cases illustrate the transformative role of molecular characterization in managing infants with CNS tumors, highlighting its potential as a game-changer in pediatric neuro-oncology.

ETMR-27. ANTI-ANGIOGENIC METRONOMIC THERAPY OF RARE TUMOURS OF THE CENTRAL NERVOUS SYSTEM

Abstract BACKGROUND Improvement of molecular diagnostics has led to significant changes in the categorization of paediatric brain tumours, unveiling novel tumour entities in the latest 2021 WHO classification of central nervous system (CNS) tumours (5th edition), particularly within the group of rare tumours of the CNS (encompassing rare embryonal and sarcomatous tumours (REST) and gliomas). However, treatment recommendations are currently based on small patient cohorts lacking standardized protocols, with even more limited options for progressive or relapsed disease. METHODS Patients from specialized European oncologic centres diagnosed or reclassified as REST receiving anti-angiogenic therapy after relapse (Medulloblastoma European Multitarget Metronomic Anti-Angiogenic Trial - MEMMAT) will be analysed. RESULTS So far, 14 patients from Austria, Czech Republic, Denmark and France were identified, with molecularly reclassified 4 CNS tumours with BCOR/BCORL1 alteration (CNS BCOR/BCORL1), 4 CNS astroblastomas, MN1-altered (ABM_MN1), 3 embryonal tumours with multi-layered rosettes (ETMR) and 1 DICER1-mutated intracranial sarcoma (CNS DICER1) as well as 2 primitive neuroectodermal tumours (PNETs, reclassification ongoing). Initial histological classifications ranged from ependymoma group 3, ETMR, malignant peripheral nerve sheath tumour (MPNST) to EGFR-positive glioblastoma. In 2 cases categorization was unclear with either anaplastic ependymoma, plexus carcinoma or ETMR. 10 patients received standard MEMMAT protocol (biweekly intravenous Bevacizumab with oral drugs: Celebrex, Thalidomide, Fenofibrate, Cyclophosphamide/Etoposide alternating and intrathecal Etoposide and Cytarabine). In 4 cases therapy was modified with an individualized metronomic treatment regimen. CONCLUSION Therapy at initial diagnosis, duration of relapse-treatment, clinical as well as radiological response, overall survival, progression-free survival and molecular hallmarks will be presented.

ETMR-32. SUPRATENTORIAL NEUROEPITHELIAL TUMOR WITH PLAGL1 FUSION: A CASE REPORT

Abstract BACKGROUND Supratentorial neuroepithelial tumor with PLAGL1 fusion has emerged as a novel subgroup within pediatric brain tumors. Despite its recent identification, critical aspects such as optimal clinical characteristics and management strategies remain elusive. This case report aims to contribute essential insights to the growing body of literature surrounding this enigmatic tumor entity, providing a detailed exploration of its clinical presentation and histopathological features. METHODS A retrospective chart review was conducted, and relevant data were analyzed. RESULTS An 11-year-old female presented with a two-week history of headaches, vomiting, lethargy, and decreased oral intake. Neuroimaging revealed a left frontal lesion with conspicuous mass effect and midline shift, prompting urgent craniotomy due to sudden onset altered mental status. Histopathological analysis revealed a hypercellular glial neoplasm characterized by perivascular pseudorosettes, scattered microcalcifications, microcysts, and areas of necrosis. Immunohistochemical staining revealed GFAP positivity in a substantial subset of tumor cells, rare dot-like positivity for EMA, and diffuse membranous and focal dot-like positivity for D240. Olig2 was mostly negative, indicating the absence of Oligodendrocyte lineage differentiation. The tumor exhibited an elevated Ki-67 proliferation index (approximately 20-30%). Fluorescence in situ hybridization (FISH) studies were negative for RELA, YAP1, and C19MC rearrangements. Targeted next-generation sequencing unveiled an EWSR1-PLAG1 fusion and methylation profiling classified the tumor as “Neuroepithelial tumors, PLAG1-fused” with high confidence. Given the morphological resemblance to anaplastic ependymoma, the therapeutic recommendation included focal irradiation (54 Gy) with proton therapy. The patient, now 12 months post-therapy, is showing favorable clinical outcomes. CONCLUSION This case report underscores the clinical and histopathological intricacies of supratentorial neuroepithelial tumors with PLAGL1 fusion. The identification of EWSR1-PLAG1 fusion and associated molecular alterations informs diagnostic considerations and treatment strategies for this novel entity, emphasizing the importance of continued research to enhance our understanding of its clinical behavior and optimal management approaches.

Single-cell RNA sequencing of anaplastic ependymoma and H3K27M-mutant diffuse midline glioma.

Anaplastic ependymoma and H3K27M-mutant diffuse midline glioma are two common subtypes of brain tumors with poor long-term prognosis. The present study analyzed and compared the differences in cell types between two tumors by single-cell RNA sequencing (scRNA-seq) technology. ScRNA-seq was performed to profile cells from cancer tissue from anaplastic ependymoma patient and H3K27M-mutant diffuse midline glioma patient. Cell clustering, marker gene identification, cell type annotation, copy number variation analysis and function analysis of differentially expressed genes were then performed. A total of 11,219 cells were obtained from anaplastic ependymoma and H3K27M mutant diffuse midline glioma, and these cells categorized into 12 distinct clusters. Each cell cluster could be characterized with specific cell markers to indicate cellular heterogeneity. Five cell types were annotated in each sample, including astrocyte, oligodendrocytes, microglial cell, neural progenitor cell and immune cell. The cluster types and proportion of cell types were not consistent between the two brain tumors. Functional analyses suggest that these cell clusters are involved in tumor-associated pathways, with slight differences in the cells of origin between the two tumors. In addition, cell communication analysis showed that the NRG3-ERBB4 pair is a key Ligand-receptor pair for anaplastic ependymoma, while in H3K27M-mutant diffuse midline glioma it is the PTN-PTPRZ1 pair that establishes contact with other cells. There was intratumor heterogeneity in anaplastic ependymoma and H3K27M mutant diffuse midline glioma, and that the subtype differences may be due to differences in the origin of the cells.

10154-PEDT-6 RETROSPECTIVE STUDY OF 12 PEDIATRIC EPENDYMOMAS TREATED AT OUR HOSPITAL

Abstract Ependymoma is an important disease in pediatric brain tumors, but reports with a large number of cases are scarce. In this study, we investigated the clinical course of 12 cases of ependymoma in children treated at our hospital.The median age was 2.5 years (0-15 years), and 10 had posterior fossa and 2 had supratentorial onset. Surgery was performed in all cases, and total resection was achieved in 9 cases (75%). Five cases were diagnosed as ependymoma, Grade II, and seven cases were diagnosed as anaplastic ependymoma, Grade III, according to the WHO revised 4th edition. Adjuvant therapy was administered in 8 patients, 6 with radiotherapy and 2 with combination chemotherapy and radiotherapy. Recurrence was seen in 6 cases, 4 of which were local recurrences and 2 of which were dissemination. The 2-year and 5-year progression-free survival rates were both 60%, and the 2-year and 5-year survival rates were 100% and 66.6%. Progression-free survival/overall survival analysis was performed, and the above results were considered to be equivalent to the published data of 27 cases (Peralia et al. Cell 2022). Progression-free survival tended to be favorable in patients with complete resection (HR = 0.18, 95% CI: 0.025-1.28) and patients with supratentorial disease (HR = 0.18, 95% CI: 0.030-1.11). No difference was seen by WHO grade (HR = 1.022, 95% CI: 0.20-5.24). Our cohort also yielded the same results regarding prognostic factors as previously reported, and WHO grade did not correlate with prognosis. The WHO 5th edition classification adopts molecular diagnosis and further subclassifies ependymoma. Since molecular diagnostics require advanced analytical techniques, there is a problem that it is difficult to put them into practical use, but surrogate markers that can be applied clinically have also been reported. This time, we will reclassify pediatric ependymoma using surrogate markers and compare it with the old classification.

Multifocal thoracic intradural extramedullary anaplastic ependymoma: case report and review of the literature

BackgroundEpendymomas are neuroectodermal tumors that grow from the ependymal cells of the ventricles or the central canal of the spinal cord. When the ependymoma is anaplastic, extramedullary, intradural and multifocal, it is a very rare anatomical entity, same as case described by us.Case presentationA 44-year-old man had been admitted to our hospital for progressive paralysis of both legs over the past 5 weeks. Contrast-enhanced MRI showed intradural extramedullary tumor at T11 with cord compression and an other more little tumor at T6 level, also intradural and extramedullary. The largest lesion was completely removed by laminectomy. Histology documented an anaplastic ependymoma. Contrast-enhanced brain and spinal MRI showed the results of the previous surgery.ConclusionMultifocal intradural extramedullary anaplastic ependymomas are very rare entity. Surgery is the main treatment that can improve prognosis, while radiotherapy is useful, after surgery, in the treatment of residues, recurrences, anaplastic transformations, metastases and multifocal lesions.

ANGI-10. METRONOMIC 5 DRUG ANTI-ANGIOGENESIS THERAPY FOR RECURRENT EPENDYMOMA

Abstract Low dose continuous (metronomic) anti-angiogenesis therapy is a treatment regimen currently under investigation for chemo-refractory tumors to target tumor vasculature. This effect has been shown to improve survival in primary brain tumors such as medulloblastoma. The Dana Farber Antiangiogenic Chemotherapy Phase II Trial and MEMMAT trial are investigations into outcomes of metronomic anti-angiogenesis therapy for children with recurrent ependymoma, among other primary brain tumors. We retrospectively report 9 pediatric patients diagnosed between the ages of 1 and 8 with surgery and radiation refractory posterior fossa ependymoma that were treated with 5 drug metronomic anti-angiogenesis therapy including celecoxib, thalidomide, fenofibrate, and alternating low dose etoposide and cyclophosphamide. For one patient, we added bevacizumab every other week. 7 patients had anaplastic presentation of ependymoma. All patients either had gross total resection or multiple subtotal resections. Tumor markers include GFAP, S100, EMA, OLIG 2, CD99, and Ki-67. Side effects were primarily hematologic but also included muscle pain, constipation, and dizziness, however treatment was tolerated well overall. The primary reason for stopping treatment early was progression of disease, no patients stopped therapy for side effects. There was no change in response to therapy based on tumor markers found. 2-year survival was 78% and 2-year progression free survival was 56%. 3/9 patients have no recurrent disease, two of these patients had anaplastic ependymoma and 1 presented with metastatic disease to the spine. We show improved outcomes with a minimal side effect profile for metronomic anti-angiogenesis therapy in pediatric patients with recurrent ependymoma refractory to surgical and radiation therapy.

Association of early surgery and absence of ataxia with full recovery after spinal intramedullary ependymoma resection.

Spinal intramedullary ependymomas (IEs) represent a well-defined tumor entity usually warranting resection. Factors that determine full long-term neurological recovery after resection are seldomly reported on in larger clinical series. In this study, the authors aimed to highlight the neurological outcome of patients with IEs after resection, with a focus on full neurological recovery, and to explore possible risk factors for the absence of neurological amelioration to an optimal function after surgical treatment. A single-center retrospective analysis of all patients undergoing surgery for IEs between 2007 and 2021 was performed. Data collection included patient demographics, symptoms, clinical findings, histopathological diagnosis, surgical procedures, complications, and neurological outcome. Patients harboring a favorable outcome (modified McCormick Scale [mMS] grade of I) were compared with patients with a less favorable outcome (mMS grade ≥ II) at the final follow-up. In total, 72 patients with a histologically diagnosed IE were included. IEs in those patients (41 males, 31 females; median age 51 [IQR 40-59] years) mostly occurred in the cervical (n = 40, 56%) or thoracic (n = 23, 32%) spine. Upon admission, motor deficits or gait deficits (mMS grade ≥ II) were present in 29 patients (40%), with a median mMS grade of II (IQR I-II). Gross-total resection was achieved in 60 patients (90%), and the rate of surgical complications was 7%. Histopathologically, 67 tumors (93%) were classified as WHO grade 2 ependymomas, 3 (4%) as WHO grade 1 subependymomas, and 2 (3%) as WHO grade 3 anaplastic ependymomas. After a mean follow-up of 863 ± 479 days, 37 patients (51%) had a fully preserved neurological function and 62 patients (86%) demonstrated an mMS grade of I or II. Comparison of favorable with unfavorable outcomes revealed an association of early surgery (within a year after symptom onset), the absence of ataxia or gait disorders, and a low mMS grade with full neurological recovery at the final follow-up. A subgroup of patients (n = 15, 21%) had nonresolving deterioration at the final follow-up, with no significant differences in relevant variables compared with the rest of the cohort. The data presented solidify the role of early surgery in the management of spinal IEs, especially in patients with mild neurological deficits. Furthermore, the presence of gait disturbance or ataxia confers a higher risk of incomplete long-term recovery after spinal ependymoma resection. Because a distinct subgroup of patients had nonresolving deterioration, even when presenting with an uneventful history, further analyses into this subgroup of patients are required.

Supratentorial extra-axial anaplastic ependymoma: a rare case report.

Ependymomas are central nervous system tumors arising from the ependymal lining of the ventricle and spinal cord. Supratentorial extra-axial ependymomas are very rare, most commonly affecting the pediatric population and rarely in adults. The authors report a case of a 71-year-old female with a headache and blurred vision. An MRI scan revealed a lesion at the parafalcine region of the occipital lobe. A parieto-occipital craniotomy was performed. When the dura was opened during the operation, the extra-axially located, well-circumscribed, dirty yellow-white tumor dissected from the surrounding tissue was excised entirely by microdissection. Histopathological examination revealed supratentorial extra-axial anaplastic ependymoma. The patient received postoperative radiation therapy (54 Gray over 30 fractions). No recurrence of the tumor was observed during the 4-year follow-up. Supratentorial ependymomas at the extra-axial region are uncommon; extra-axial anaplastic ependymoma and meningiomas have similar radiological findings, such as a dural tail, subarachnoid plane, and diffuse enhancement after contrast injection. This close similarity might cause misdiagnoses. Total surgical resection was followed by adjuvant radiotherapy and close follow-up in the gold standard of the treatment. The authors report a rare case of anaplastic ependymomas located at the extra-axial region. Anaplastic tumors are prone to recurrence despite total resection and radiation therapy; hence, a close follow-up is warranted.

An In-Depth Analysis of Ependymoma: Neuropathological Insights, Therapeutic Strategies, and Prognostic Implications in Intracranial Ependymal Tumors

Ependymomas are primary central nervous system (CNS) neoplasms arising from ependymal cells lining the ventricular system and spinal cord. They represent a heterogeneous group of tumors with distinct histological and molecular subtypes, making their diagnosis, management, and prognosis a complex and evolving challenge in the field of neuro-oncology. This comprehensive review delves into the intricate landscape of ependymomas, elucidating their pathogenesis, classification, and molecular underpinnings. Histologically, they can manifest as myxopapillary, subependymoma, and anaplastic ependymomas, each carrying distinct clinical implications and therapeutic strategies. Moreover, recent advancements in molecular profiling have unveiled significant genetic alterations such as amplifications in RELA, YAP1, and C11orf95-MAML2 fusion, which have profound implications for prognosis and therapeutic decision-making. We explore the intricacies of clinical management, encompassing surgical resection, radiation therapy, and chemotherapy regimens tailored to the tumor's location, grade, and molecular profile. Despite their location within the CNS, ependymomas are notorious for their diverse clinical presentations, including headache, neurological deficits, and intracranial hypertension, necessitating multidisciplinary care and vigilant surveillance. Additionally, this article investigates the latest developments in targeted therapies, immunotherapeutic approaches, and ongoing clinical trials in an attempt to provide a glimpse into the future of ependymoma treatment, as precision medicine begins to play a more significant role in guiding therapeutic decisions. Furthermore, the abstract examines the critical issue of ependymoma prognosis, emphasizing the importance of integrating histopathological and molecular data in order to stratify patients into risk categories more accurately. The role of genetic markers, such as chromosome 1q gain and chromosome 6q loss, in predicting outcomes is thoroughly explored. In summary, this article aims to offer a comprehensive perspective on ependymomas, from their cellular origins to the latest breakthroughs in their management, offering insights into their clinical course, and underscoring the critical role of multidisciplinary collaboration in advancing the understanding and treatment of these complex intracranial tumors.

Dorsal cervical approach for recurrent intradural anaplastic ependymoma.

The video demonstrates an operative approach to a recurrent cervical anaplastic ependymoma. MYCN-amplified anaplastic ependymomas are locally aggressive, recurrent, and have a high risk of iatrogenic injury. In this case, the patient presented with local, aggressive tumor expansion, arachnoid adhesions, and pial invasion ventral to the spinal cord. Subcapsular decompression minimized cord retraction from a dorsal approach. Removal of the tumor capsule was guided by bipolar stimulation paired with neuromonitoring. Local gross-total resection was achieved, and the patient had a postoperative improvement in his neurological deficits and myelopathy.

P10.01.A A PATIENT-DERIVEDEX VIVO ORGANOID MODEL ALLOWS EVALUATION OF TUMOR TREATING FIELDS (TTFIELDS) EFFECTS ON GLIOBLASTOMA, ANAPLASTIC EPENDYMOMA AND OLIGODENDROGLIOMA SAMPLES

Abstract BACKGROUND The use of TTFields, which are alternating electric fields of low intensity (1-3 V/cm) and intermediate frequency (100-500 kHz), has shown its clinical efficacy in the treatment of newly diagnosed glioblastoma (GBM) patients at 200 kHz. Nevertheless, more knowledge is required for the prediction of individual tumors’ responsiveness to treatment. Recently, we developed patient-derived three-dimensional GBM tissue culture models to screen patient tumors for TTFields treatment susceptibility. Here, we extended these models to brain tumors beyond GBM, namely anaplastic ependymoma (AE) and oligodendroglioma. We cultured tumor-organoids as microtumors on murine organotypic hippocampal slice cultures (OHSCs) and subjected them to TTFields at 200 kHz. MATERIAL AND METHODS We prepared OHSCs by slicing the brains of mice 5-8 days postpartum to a thickness of 350 µm using a vibratome and culturing them for 14 days. We obtained organoids from freshly resected tumor tissue from three GBM, one AE, and one oligodendroglioma patient, each. The organoids were cultured for 14 days as well and then stained with carboxyfluorescein succinimidyl ester. Next, we placed the organoids onto the OHSCs and administered TTFields at 200 kHz and 1.5 V/cm for 72 h using the inovitro™ laboratory research system. We quantified microtumor growth by fluorescence imaging. RESULTS The three tumor entities, in particular organoids from GBM, AE and oligodendroglioma, grew as microtumors after being placed onto OHSCs. TTFields treatment at 200 kHz led to significantly decreased microtumor size of the three analysed GBM samples as well as the AE sample. However, the oligodendroglioma microtumor size was not significantly reduced. CONCLUSION Based on clinical experience, we expected that TTFields lead to a reduction in microtumor size. However, to our knowledge, we were the first to apply TTFields to patient-derived AE and oligodendroglioma samples. The lack of TTFields-effects on the latter might be due to different inter-patient sensitivity or suboptimal TTFields frequency. Nevertheless, our work is proof of principle that an organoid-based patient-derived 3D tissue culture model could be used to evaluate effects of TTFields on different brain tumor entities.

P04.02.A CEREBELLAR GLIOMA WITH BRAF ACTIVATION: A MOLECULARY DISTINCT GLIOMA SUBGROUP WITH MAPK ACTIVATION

Abstract BACKGROUND Rendering the correct tumor diagnosis is key to optimise cancer therapies and to orient patients and relatives regarding prognosis and general understanding of the disease. With the rising impact of molecular diagnostics more molecular profiles of tumors are being generated and assembled in central institutes. With this critical data assembly in world-wide repositories such as www.molecularneuropathology.org, new tumor groups with differing prognosis and driver alterations can be discerned. MATERIAL AND METHODS By analysing the epigenetic profiles from over 125.000 CNS tumor samples a distinct group of cases was identified (n=24). The samples in this group did not match an established reference methylation class in the Heidelberg brain tumor classifier (version 12.5). In a first analysis with the clinical data external suppliers have provided, these tumors are located in the cerebellum and typically in children (mean age = 9 years). RESULTS The variable histology ranged from low grade glial/glioneuronal appearances such as pilocytic astrocytoma (n= 12), ganglioglioma (n= 4), gangliocytoma (n= 1) to ependymoma (n= 2) and anaplastic ependymoma (n=1). For some cases just a descriptive histopathological diagnosis could be rendered (n= 6). A prominent feature in radiology and histology were micro- and macrocalifications (n =5). From 24 cases, 17 tumors (89% of all analysed tumors) harboured a BRAF V600E mutation. One case revealed a PRKAR2B:BRAF fusion. 6 cases could not be analysed because no remaining tumor material was available. While clinical follow-up data collection is still maturing, relapses were reported in 2 patients, and stable disease was reported in 12 cases. For 10 cases no follow up data is available, yet. CONCLUSION We found an epigenetically distinct group of childhood brain tumors located in the posterior fossa with an enrichment of BRAF V600E mutations. Clinical follow-up is yet to be evaluated, but recurrence was observed in a proportion of patients with available follow-up.

P11.85.B LONG-TERM OUTCOME AFTER INCOMPLETE RESECTION OF INTRAMEDULLARY GRADE II EPENDYMOMAS WITHOUT ADJUVANT RADIOTHERAPY

Abstract BACKGROUND Ependymomas are the most frequent intramedullary tumors in adults. While gross total resection is the aim of surgery, tumor infiltration might limit resection. In case of subtotal removal, the adjuvant management remains unclear. The aim of our study was to assess the need for adjuvant radiotherapy after incomplete resection of grade II intramedullary ependymomas (IME-II). MATERIAL AND METHODS We retrospectively reviewed all cases of IME-II operated in a single tertiary neurosurgical center from 2009 to 2018. Patients with anaplastic or myxopapillary ependymomas, and patients with a follow-up of less than 3 years were excluded. RESULTS We included 46 patients: 19 (41.3%) had gross total resection, 21 (45.7%) had subtotal resection and 6 (13%) had partial resection. None of the patients underwent adjuvant radiotherapy. Over a median follow-up of 79 months (range = 36-186), 7 patients presented a radiological tumor progression with a mean delay of 50.9 months (range =18-85), of which 2 were symptomatic (4.3%). Progression-free survival (PFS) was 90.1% at 5 years and 76.8% at 10 years. Extent of resection was the only significant risk factor for secondary tumor progression (p=0.012). 4 of the 7 patients with recurring IME-II were treated: 3 patients had a second surgery, leading to 2 GTR and 1STR, followed by radiotherapy in one case, and 1 patient underwent radiotherapy alone. CONCLUSION In this study, the rate of symptomatic progression and retreatment after incomplete resection of IME-II without adjuvant radiotherapy was low, supporting a conservative approach in such cases.

Ependymoma in WHO Classification of Tumours 5th Edition

Ependymoma is a rare central nervous system tumor that occurs in all age groups and is one of the most common childhood malignant brain tumors. Until the 3rd edition of the WHO Classification of Brain Tumours, ependymoma was classified based solely on histologic findings, but advances in molecular analysis led to the incorporation of molecular information into the diagnosis of ependymoma for the first time in the 2016 WHO Classification, 4th edition. However, the low correlation between tumor grade and survival prognosis remained a problem. Unlike other malignant brain tumors, ependymoma is genetically and epigenetically characterized with few identified point mutations. Methylation profiling was found to classify ependymoma into distinct subgroups, and the 2021 WHO Classification, 5th Edition, adopted new classifications by histologic findings, genetic alterations, methylation patterns, and anatomic location. This new classification includes 10 diagnostic entities: 1)supratentorial subependymoma; 2)supratentorial ependymoma, ZFTA-fusion positive; 3)supratentorial ependymoma, YAP1-fusion positive; 4)posterior fossa subependymoma; 5)posterior fossa group A ependymoma; 6)posterior fossa group B ependymoma; 7)spinal subependymoma; 8)spinal ependymoma; 9)spinal myxopapillary ependymoma; and 10)spinal ependymoma, MYCN-amplified. The previously accepted term "anaplastic ependymoma" was dropped. As with other CNS tumors, a new classification was introduced based on an integrated diagnosis that incorporates histologic and molecular diagnosis. In this article, we summarize the molecular classification of ependymoma in the WHO Classification of Brain Tumours, 5th edition.