TULIPs decorate the three-dimensional genome of PFA ependymoma.

Posterior fossa group A (PFA) ependymoma is a lethal brain cancer diagnosed in infants and young children. The lack of driver events in the PFA linear genome led us to search its 3D genome for characteristic features. Here, we reconstructed 3D genomes from diverse childhood tumor types and uncovered a global topology in PFA that is highly reminiscent of stem and progenitor cells in a variety of human tissues. A remarkable feature exclusively present in PFA are type B ultra long-range interactions in PFAs (TULIPs), regions separated by great distances along the linear genome that interact with each other in the 3D nuclear space with surprising strength. TULIPs occur in all PFA samples and recur at predictable genomic coordinates, and their formation is induced by expression of EZHIP. The universality of TULIPs across PFA samples suggests a conservation of molecular principles that could be exploited therapeutically.

Metabolic Regulation of the Epigenome Drives Lethal Infantile Ependymoma.

Posterior fossa A (PFA) ependymomas are lethal malignancies of the hindbrain in infants and toddlers. Lacking highly recurrent somatic mutations, PFA ependymomas are proposed to be epigenetically driven tumors for which model systems are lacking. Here we demonstrate that PFA ependymomas are maintained under hypoxia, associated with restricted availability of specific metabolites to diminish histone methylation, and increase histone demethylation and acetylation at histone 3 lysine 27 (H3K27). PFA ependymomas initiate from a cell lineage in the first trimester of human development that resides in restricted oxygen. Unlike other ependymomas, transient exposure of PFA cells to ambient oxygen induces irreversible cellular toxicity. PFA tumors exhibit a low basal level of H3K27me3, and, paradoxically, inhibition of H3K27 methylation specifically disrupts PFA tumor growth. Targeting metabolism and/or the epigenome presents a unique opportunity for rational therapy for infants with PFA ependymoma.

Histone serotonylation regulates ependymoma tumorigenesis.

Bidirectional communication between tumours and neurons has emerged as a key facet of the tumour microenvironment that drives malignancy1,2. Another hallmark feature of cancer is epigenomic dysregulation, in which alterations in gene expression influence cell states and interactions with the tumour microenvironment3. Ependymoma (EPN) is a paediatric brain tumour that relies on epigenomic remodelling to engender malignancy4,5; however, how these epigenetic mechanisms intersect with extrinsic neuronal signalling during EPN tumour progression is unknown. Here we show that the activity of serotonergic neurons regulates EPN tumorigenesis, and that serotonin itself also serves as an activating modification on histones. We found that inhibiting histone serotonylation blocks EPN tumorigenesis and regulates the expression of a core set of developmental transcription factors. High-throughput, in vivo screening of these transcription factors revealed that ETV5 promotes EPN tumorigenesis and functions by enhancing repressive chromatin states. Neuropeptide Y (NPY) is one of the genes repressed by ETV5, and its overexpression suppresses EPN tumour progression and tumour-associated network hyperactivity through synaptic remodelling. Collectively, this study identifies histone serotonylation as a key driver of EPN tumorigenesis, and also reveals how neuronal signalling, neuro-epigenomics and developmental programs are intertwined to drive malignancy in brain cancer.

Understanding the Deadly Silence of Posterior Fossa A Ependymoma.

In a breakthrough study in a recent issue of Cell, Michealraj et al. (2020) demonstrate that posterior fossa A ependymoma, a lethal pediatric brain tumor with a silent genome, is dependent upon metabolic changes associated with hypoxia that drive the tumor's characteristic epigenetic dysregulation.

Sox9 directs divergent epigenomic states in brain tumor subtypes.

Epigenetic dysregulation is a universal feature of cancer that results in altered patterns of gene expression that drive malignancy. Brain tumors exhibit subtype-specific epigenetic alterations; however, the molecular mechanisms responsible for these diverse epigenetic states remain unclear. Here, we show that the developmental transcription factor Sox9 differentially regulates epigenomic states in high-grade glioma (HGG) and ependymoma (EPN). Using our autochthonous mouse models, we found that Sox9 suppresses HGG growth and expands associated H3K27ac states, while promoting ZFTA-RELA (ZRFUS) EPN growth and diminishing H3K27ac states. These contrasting roles for Sox9 correspond with protein interactions with histone deacetylating complexes in HGG and an association with the ZRFUS oncofusion in EPN. Mechanistic studies revealed extensive Sox9 and ZRFUS promoter co-occupancy, indicating functional synergy in promoting EPN tumorigenesis. Together, our studies demonstrate how epigenomic states are differentially regulated in distinct subtypes of brain tumors, while revealing divergent roles for Sox9 in HGG and EPN tumorigenesis.

Molecular characteristics and improved survival prediction in a cohort of 2023 ependymomas.

The diagnosis of ependymoma has moved from a purely histopathological review with limited prognostic value to an integrated diagnosis, relying heavily on molecular information. However, as the integrated approach is still novel and some molecular ependymoma subtypes are quite rare, few studies have correlated integrated pathology and clinical outcome, often focusing on small series of single molecular types. We collected data from 2023 ependymomas as classified by DNA methylation profiling, consisting of 1736 previously published and 287 unpublished methylation profiles. Methylation data and clinical information were correlated, and an integrated model was developed to predict progression-free survival. Patients with EPN-PFA, EPN-ZFTA, and EPN-MYCN tumors showed the worst outcome with 10-year overall survival rates of 56%, 62%, and 32%, respectively. EPN-PFA harbored chromosome 1q gains and/or 6q losses as markers for worse survival. In supratentorial EPN-ZFTA, a combined loss of CDKN2A and B indicated worse survival, whereas a single loss did not. Twelve out of 200 EPN-ZFTA (6%) were located in the posterior fossa, and these tumors relapsed or progressed even earlier than supratentorial tumors with a combined loss of CDKN2A/B. Patients with MPE and PF-SE, generally regarded as non-aggressive tumors, only had a 10-year progression-free survival of 59% and 65%, respectively. For the prediction of the 5-year progression-free survival, Kaplan-Meier estimators based on the molecular subtype, a Support Vector Machine based on methylation, and an integrated model based on clinical factors, CNV data, and predicted methylation scores achieved balanced accuracies of 66%, 68%, and 73%, respectively. Excluding samples with low prediction scores resulted in balanced accuracies of over 80%. In sum, our large-scale analysis of ependymomas provides robust information about molecular features and their clinical meaning. Our data are particularly relevant for rare and hardly explored tumor subtypes and seemingly benign variants that display higher recurrence rates than previously believed.

Transcriptomic and epigenetic dissection of spinal ependymoma (SP-EPN) identifies clinically relevant subtypes enriched for tumors with and without NF2 mutation.

Ependymomas encompass multiple clinically relevant tumor types based on localization and molecular profiles. Tumors of the methylation class "spinal ependymoma" (SP-EPN) represent the most common intramedullary neoplasms in children and adults. However, their developmental origin is ill-defined, molecular data are scarce, and the potential heterogeneity within SP-EPN remains unexplored. The only known recurrent genetic events in SP-EPN are loss of chromosome 22q and NF2 mutations, but neither types and frequency of these alterations nor their clinical relevance have been described in a large, epigenetically defined series. Transcriptomic (n = 72), epigenetic (n = 225), genetic (n = 134), and clinical data (n = 112) were integrated for a detailed molecular overview on SP-EPN. Additionally, we mapped SP-EPN transcriptomes to developmental atlases of the developing and adult spinal cord to uncover potential developmental origins of these tumors. The integration of transcriptomic ependymoma data with single-cell atlases of the spinal cord revealed that SP-EPN display the highest similarities to mature adult ependymal cells. Unsupervised hierarchical clustering of transcriptomic data together with integrated analysis of methylation profiles identified two molecular SP-EPN subtypes. Subtype A tumors primarily carried previously known germline or sporadic NF2 mutations together with 22q loss (bi-allelic NF2 loss), resulting in decreased NF2 expression. Furthermore, they more often presented as multilocular disease and demonstrated a significantly reduced progression-free survival as compared to SP-EP subtype B. In contrast, subtype B predominantly contained samples without NF2 mutation detected in sequencing together with 22q loss (monoallelic NF2 loss). These tumors showed regular NF2 expression but more extensive global copy number alterations. Based on integrated molecular profiling of a large multi-center cohort, we identified two distinct SP-EPN subtypes with important implications for genetic counseling, patient surveillance, and drug development priorities.

Clinically relevant molecular hallmarks of PFA ependymomas display intratumoral heterogeneity and correlate with tumor morphology.

Posterior fossa type A (PF-EPN-A, PFA) ependymoma are aggressive tumors that mainly affect children and have a poor prognosis. Histopathology shows significant intratumoral heterogeneity, ranging from loose tissue to often sharply demarcated, extremely cell-dense tumor areas. To determine molecular differences in morphologically different areas and to understand their clinical significance, we analyzed 113 PF-EPN-A samples, including 40 corresponding relapse samples. Cell-dense areas ranged from 0 to 100% of the tumor area and displayed a higher proportion of proliferating tumor cells (p < 0.01). Clinically, cell density was associated with poor progression-free and overall survival (pPFS = 0.0026, pOS < 0.01). Molecularly, tumor areas with low and high cell density showed diverging DNA methylation profiles regarding their similarity to distinct previously discovered PF-EPN-A subtypes in 9/21 cases. Prognostically relevant chromosomal changes at 1q and 6q showed spatial heterogeneity within single tumors and were significantly enriched in cell-dense tumor areas as shown by single-cell RNA (scRNA)-sequencing as well as copy number profiling and fluorescence in situ hybridization (FISH) analyses of different tumor areas. Finally, spatial transcriptomics revealed cell-dense areas of different tumors to be more similar than various different areas of the same tumor. High-density areas distinctly overexpressed genes encoding histone proteins, WNT5A, TGFB1, or IGF2. Relapsing tumors displayed a higher proportion of cell-dense areas (p = 0.036), a change in PF-EPN-A methylation subtypes (13/32 patients), and novel chromosome 1q gains and 6q losses (12/32 cases) compared to corresponding primary tumors. Our data suggest that PF-EPN-A ependymomas habor a previously unrecognized intratumoral heterogeneity with clinical implications, which has to be accounted for when selecting diagnostic material, inter alia, by histological evaluation of the proportion of cell-dense areas.

Convolutional neural network-based magnetic resonance image differentiation of filum terminale ependymomas from schwannomas.

PURPOSE: Preoperative diagnosis of filum terminale ependymomas (FTEs) versus schwannomas is difficult but essential for surgical planning and prognostic assessment. With the advancement of deep-learning approaches based on convolutional neural networks (CNNs), the aim of this study was to determine whether CNN-based interpretation of magnetic resonance (MR) images of these two tumours could be achieved. METHODS: Contrast-enhanced MRI data from 50 patients with primary FTE and 50 schwannomas in the lumbosacral spinal canal were retrospectively collected and used as training and internal validation datasets. The diagnostic accuracy of MRI was determined by consistency with postoperative histopathological examination. T1-weighted (T1-WI), T2-weighted (T2-WI) and contrast-enhanced T1-weighted (CE-T1) MR images of the sagittal plane containing the tumour mass were selected for analysis. For each sequence, patient MRI data were randomly allocated to 5 groups that further underwent fivefold cross-validation to evaluate the diagnostic efficacy of the CNN models. An additional 34 pairs of cases were used as an external test dataset to validate the CNN classifiers. RESULTS: After comparing multiple backbone CNN models, we developed a diagnostic system using Inception-v3. In the external test dataset, the per-examination combined sensitivities were 0.78 (0.71-0.84, 95% CI) based on T1-weighted images, 0.79 (0.72-0.84, 95% CI) for T2-weighted images, 0.88 (0.83-0.92, 95% CI) for CE-T1 images, and 0.88 (0.83-0.92, 95% CI) for all weighted images. The combined specificities were 0.72 based on T1-WI (0.66-0.78, 95% CI), 0.84 (0.78-0.89, 95% CI) based on T2-WI, 0.74 (0.67-0.80, 95% CI) for CE-T1, and 0.81 (0.76-0.86, 95% CI) for all weighted images. After all three MRI modalities were merged, the receiver operating characteristic (ROC) curve was calculated, and the area under the curve (AUC) was 0.93, with an accuracy of 0.87. CONCLUSIONS: CNN based MRI analysis has the potential to accurately differentiate ependymomas from schwannomas in the lumbar segment.

Clinical presentation and extent of resection impacts progression-free survival in spinal ependymomas.

PURPOSE: Primary treatment of spinal ependymomas involves surgical resection, however recurrence ranges between 50 and 70%. While the association of survival outcomes with lesion extent of resection (EOR) has been studied, existing analyses are limited by small samples and archaic data resulting in an inhomogeneous population. We investigated the relationship between EOR and survival outcomes, chiefly overall survival (OS) and progression-free survival (PFS), in a large contemporary cohort of spinal ependymoma patients. METHODS: Adult patients diagnosed with a spinal ependymoma from 2006 to 2021 were identified from an institutional registry. Patients undergoing primary surgical resection at our institution, ≥ 1 routine follow-up MRI, and pathologic diagnosis of ependymoma were included. Records were reviewed for demographic information, EOR, lesion characteristics, and pre-/post-operative neurologic symptoms. EOR was divided into 2 classifications: gross total resection (GTR) and subtotal resection (STR). Log-rank test was used to compare OS and PFS between patient groups. RESULTS: Sixty-nine patients satisfied inclusion criteria, with 79.7% benefitting from GTR. The population was 56.2% male with average age of 45.7 years, and median follow-up duration of 58 months. Cox multivariate model demonstrated significant improvement in PFS when a GTR was attained (p <.001). Independently ambulatory patients prior to surgery had superior PFS (p <.001) and OS (p =.05). In univariate analyses, patients with a syrinx had improved PFS (p =.03) and were more likely to benefit from GTR (p =.01). Alternatively, OS was not affected by EOR (p =.78). CONCLUSIONS: In this large, contemporary series of adult spinal ependymoma patients, we demonstrated improvements in PFS when GTR was achieved.

Imaging features to distinguish posterior fossa ependymoma subgroups.

OBJECTIVES: Posterior fossa ependymoma group A (EPN_PFA) and group B (EPN_PFB) can be distinguished by their DNA methylation and give rise to different prognoses. We compared the MRI characteristics of EPN_PFA and EPN_PFB at presentation. METHODS: Preoperative imaging of 68 patients with posterior fossa ependymoma from two centers was reviewed by three independent readers, blinded for histomolecular grouping. Location, tumor extension, tumor volume, hydrocephalus, calcifications, tissue component, enhancement or diffusion signal, and histopathological data (cellular density, calcifications, necrosis, mitoses, vascularization, and microvascular proliferation) were compared between the groups. Categorical data were compared between groups using Fisher's exact tests, and quantitative data using Mann-Whitney tests. We performed a Benjamini-Hochberg correction of the p values to account for multiple tests. RESULTS: Fifty-six patients were categorized as EPN_PFA and 12 as EPN_PFB, with median ages of 2 and 20 years, respectively (p = 0.0008). The median EPN_PFA tumoral volume was larger (57 vs 29 cm3, p = 0.003), with more pronounced hydrocephalus (p = 0.002). EPN_PFA showed an exclusive central position within the 4th ventricle in 61% of patients vs 92% for EPN_PFB (p = 0.01). Intratumor calcifications were found in 93% of EPN_PFA vs 40% of EPN_PFB (p = 0.001). Invasion of the posterior fossa foramina was mostly found for EPN_PFA, particularly the foramina of Luschka (p = 0.0008). EPN_PFA showed whole and homogeneous tumor enhancement in 5% vs 75% of EPN_PFB (p = 0.0008). All mainly cystic tumors were EPN_PFB (p = 0.002). The minimal and maximal relative ADC was slightly lower in EPN_PFA (p = 0.02 and p = 0.01, respectively). CONCLUSION: Morphological characteristics from imaging differ between posterior fossa ependymoma subtypes and may help to distinguish them preoperatively. CLINICAL RELEVANCE STATEMENT: This study provides a tool to differentiate between group A and group B ependymomas, which will ultimately allow the therapeutic strategy to be adapted in the early stages of patient management. KEY POINTS: • Posterior fossa ependymoma subtypes often have different imaging characteristics. • Posterior fossa ependymomas group A are commonly median or lateral tissular calcified masses, with incomplete enhancement, affecting young children and responsible for pronounced hydrocephalus and invasion of the posterior fossa foramina. • Posterior fossa ependymomas group B are commonly median non-calcified masses of adolescents and adults, predominantly cystic, and minimally invasive, with total and homogeneous enhancement.

The medical and functional burden of surviving childhood ependymoma: A population-based study in Ontario, Canada.

BACKGROUND: Few studies have characterized the burden of late effects among childhood ependymoma survivors. To address this gap, we examined these sequelae using real-world health services data in a population-based ependymoma survivor cohort. METHODS: All individuals younger than 18 years diagnosed with an ependymoma in Ontario, Canada between 1987 and 2015 who had survived at least 5 years from their latest pediatric cancer event (index date) were matched 1:5 with population controls. Following linkage with provincial health services data, the cumulative incidences of multiple medical and functional outcomes between survivors and controls were compared. RESULTS: Among 96 survivors, 77.1% had been irradiated and 9.4% had received cisplatin. At 10 years post-index, survivors were at significantly higher risk of all-cause mortality (7.1%, 95% confidence interval [CI]: 1.0-13.3 vs. 0.3%, 95% CI: 0.0-1.0; p = .0002), non-obstetric hospitalization (45.1%, 95% CI: 32.6-56.7 vs. 10.6%, 95% CI: 7.6-14.1; p < .0001), stroke (6.5%, 95% CI: 2.3-13.7 vs. 0%; p < .0001), severe hearing loss requiring an amplification device (7.5%, 95% CI: 2.7-15.7 vs. 0%; p < .0001), receiving homecare service (27.6%, 95% CI: 18.5-37.5 vs. 7.7%, 95% CI: 5.3-10.7; p < .0001), and submitting a disability support prescription claim (24.0%, 95% CI: 14.8-34.3 vs. 5.4%, 95% CI: 3.5-7.8; p < .0001) compared to controls. CONCLUSIONS: Pediatric ependymoma survivors are highly vulnerable to severe late sequelae, including death, stroke, severe hearing loss, and disability. Urgent efforts are needed to improve risk-stratification approaches that mitigate exposure to toxic therapies for children with lower risk disease. Interventions to prevent or decrease the risk of developing late sequelae are critical to optimizing survivor long-term health.

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

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

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

PURPOSE: 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. METHODS: 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. RESULTS: 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). CONCLUSION: Whole-tumor histogram analysis of T1C and ADC may be a promising approach for predicting the grade and proliferative activity of adult intracranial ependymomas.

When a dermatopathologist encounters the ultra-rare: A case series of superficial soft tissue/cutaneous myxopapillary ependymomas.

Myxopapillary ependymoma (MPE) is an uncommon variant of ependymoma, almost exclusively seen in conus medullaris or filum terminale. MPE can be diagnostically challenging, especially when arising extra-axially. Here we report 5 cases of superficial soft tissue/cutaneous MPE, identified across three tertiary institutions. All patients were female and three of them (3/5, 60%) were children (median age 11 years, range 6-58 years). The tumors presented as slow-growing masses of the sacrococcygeal subcutaneous soft tissues, occasionally identified after minor trauma and clinically favored to be pilonidal sinuses. Imaging showed no neuraxis connection. Macroscopically, tumors were well-circumscribed, lobulated, and solid and microscopically they exhibited typical histopathology of MPE, at least focally. Two of the tumors (2/5, 40%) showed predominantly solid or trabecular architecture with greater cellular pleomorphism, scattered giant cells, and increased mitotic activity. All tumors (5/5, 100%) showed strong diffuse immunohistochemical expression of GFAP. One tumor clustered at the category "ependymoma, myxopapillary" by methylome analysis. Two patients (2/5, 40%) had local recurrence at 8 and 30 months after the initial surgery. No patients developed metastases during the follow-up period (median 60 months, range 6-116 months). Since a subset of extra-axial MPEs behaves more aggressively, timely and accurate diagnosis is of paramount importance.

Therapeutic targeting of ependymoma as informed by oncogenic enhancer profiling.

Genomic sequencing has driven precision-based oncology therapy; however, the genetic drivers of many malignancies remain unknown or non-targetable, so alternative approaches to the identification of therapeutic leads are necessary. Ependymomas are chemotherapy-resistant brain tumours, which, despite genomic sequencing, lack effective molecular targets. Intracranial ependymomas are segregated on the basis of anatomical location (supratentorial region or posterior fossa) and further divided into distinct molecular subgroups that reflect differences in the age of onset, gender predominance and response to therapy. The most common and aggressive subgroup, posterior fossa ependymoma group A (PF-EPN-A), occurs in young children and appears to lack recurrent somatic mutations. Conversely, posterior fossa ependymoma group B (PF-EPN-B) tumours display frequent large-scale copy number gains and losses but have favourable clinical outcomes. More than 70% of supratentorial ependymomas are defined by highly recurrent gene fusions in the NF-κB subunit gene RELA (ST-EPN-RELA), and a smaller number involve fusion of the gene encoding the transcriptional activator YAP1 (ST-EPN-YAP1). Subependymomas, a distinct histologic variant, can also be found within the supratetorial and posterior fossa compartments, and account for the majority of tumours in the molecular subgroups ST-EPN-SE and PF-EPN-SE. Here we describe mapping of active chromatin landscapes in 42 primary ependymomas in two non-overlapping primary ependymoma cohorts, with the goal of identifying essential super-enhancer-associated genes on which tumour cells depend. Enhancer regions revealed putative oncogenes, molecular targets and pathways; inhibition of these targets with small molecule inhibitors or short hairpin RNA diminished the proliferation of patient-derived neurospheres and increased survival in mouse models of ependymomas. Through profiling of transcriptional enhancers, our study provides a framework for target and drug discovery in other cancers that lack known genetic drivers and are therefore difficult to treat.

Recurrence Patterns and Surveillance Imaging in Pediatric Brain Tumor Survivors.

Surveillance magnetic resonance imaging (MRI) is routinely used to detect recurrence in pediatric central nervous system (CNS) tumors. The frequency of neuroimaging surveillance varies without a standardized approach. A single-institutional retrospective cohort study evaluated the frequency of recurrences. This study included 476 patients with the majority diagnosed with low-grade glioma (LGG) (n=138, 29%), high-grade glioma (HGG) (n=77, 16%), ependymoma (n=70, 15%), or medulloblastoma (n=61, 13%). LGG, HGG, and ependymoma patients more commonly had multiply recurrent disease ( P =0.08), with ependymoma patients demonstrating ≥2 relapses in 47% of cases. Recurrent disease was identified by imaging more often than clinical symptoms (65% vs. 32%; P =<0.01). Patients diagnosed with meningioma demonstrated the longest mean time to first relapse (74.7 mo) whereas those with atypical teratoid rhabdoid tumor and choroid plexus carcinoma tended to have the shortest time to relapse (8.9 and 9 mo, respectively). Overall, 22 patients sustained first relapse >10 years from initial diagnosis. With a higher tendency toward detection of tumor recurrence/progression on MRI surveillance in comparison to clinical progression, surveillance imaging is necessary in routine follow up of pediatric CNS tumor survivors. With some relapses >10 years from initial diagnosis, imaging beyond this time point may be useful in particular tumor types. While the study is limited in outcome analysis, earlier detection of recurrence would lead to earlier initiation of treatment and implementation of salvage treatment regimens which can impact survival and quality of life.

Strong OLIG2 expression in supratentorial ependymoma, ZFTA fusion-positive: A potential diagnostic pitfall.

Ependymomas (EPN) are central nervous system neoplasms that exhibit an ependymal phenotype. In particular, supratentorial EPN (ST-EPN) must be differentiated from more aggressive entities such as glioblastoma, IDH-wildtype. This task is frequently addressed with the use of immunohistochemistry coupled with clinical presentation and morphological features. Here we describe the case of a young adult presenting with migraine-like symptoms and a temporoinsular-based expansile mass that was first diagnosed as a GBM, mostly based on strong and diffuse oligodendrocyte transcription factor 2 (OLIG2) expression. Molecular characterization revealed a ZFTA::RELA fusion, supporting the diagnosis of ST-EPN, ZFTA fusion-positive. OLIG2 expression is rarely reported in tumors other than GBM and oligodendrocyte-lineage committed neoplasms. The patient was treated with radiotherapy and temozolomide after surgery and was alive and well at follow-up. This report illustrates the need to assess immunostains within a broader clinical, morphological and molecular context to avoid premature exclusion of important differential diagnoses.

Ependymoma from Benign to Highly Aggressive Diseases: A Review.

Ependymomas comprise biologically distinct tumor types with respect to age distribution, (epi)genetics, localization, and prognosis. Multimodal risk-stratification, including histopathological and molecular features, is essential in these biologically defined tumor types. Gross total resection (GTR), achieved with intraoperative monitoring and neuronavigation, and if necessary, second-look surgery, is the most effective treatment. Adjuvant radiation therapy is mandatory in high-risk tumors and in case of residual tumor. There is yet growing evidence that some ependymal tumors may be cured by surgery alone. To date, the role of chemotherapy is unclear and subject of current studies.Even though standard therapy can achieve reasonable survival rates for the majority of ependymoma patients, long-term follow-up still reveals a high probability of relapse in certain biological entities.With increasing knowledge of biologically distinct tumor types, risk-adapted adjuvant therapy gains importance. Beyond initial tumor control, and avoidance of therapy-induced morbidity for low-risk patients, intensified treatment for high-risk patients comprises another challenge. With identification of specific risk features regarding molecular alterations, targeted therapy may represent an option for individualized treatment modalities in the future.

Supratentorial and Infratentorial Ependymoma.

Ependymomas are the third most common intracranial tumor in children, presenting in both the supratentorial and infratentorial compartments. They may present in infants, young children, and adolescents with symptoms depending on size, location, and the age of the patient. The ideal imaging for evaluation and treatment is MRI. This is crucial for preoperative evaluation and planning, as well as postoperative assessment and evaluating the efficacy of treatment. Essentially without exception, aggressive surgery aimed at complete resection is the initial and most important factor in the long-term outcome of all these children. Histopathologic diagnosis for intracranial pediatric ependymoma has been narrowed to grade II and grade III, no longer characterized as classic and anaplastic. Subsequent conformal photon or proton beam irradiation is an established post-surgical therapy, with solid evidence that it benefits survival and offers lower toxicity to the normal brain of the young child. Although chemotherapeutic treatment has not been generally impactful, immunotherapeutic interventions may be on the horizon. Updated molecular subgrouping of ependymoma is changing the post-resection approach of these tumors with regard to both treatment and outcome. Excluding spinal ependymoma and subependymoma, there are four subtypes that are defined by genetic characteristics, two found in the supratentorial compartment, ST-EPN-YAP1 and ST-EPN-ZFTA, and two in the posterior fossa, PF-EPN-A and PF-EPN-B. Younger children harboring ZFTA fusion-positive supratentorial and type A posterior fossa tumors, regardless of histology, tend toward the poorest outcomes. On the contrary, older children with supratentorial YAP1 fusion-positive ependymomas and type B posterior fossa tumors may survive with surgery alone. The paradigm shift regarding the behavior of the various childhood ependymoma subtypes will hopefully lead to targeted, individualized therapies and improved outcomes.