Common molecular features of H3K27M DMGs and PFA ependymomas map to hindbrain developmental pathways.

Globally decreased histone 3, lysine 27 tri-methylation (H3K27me3) is a hallmark of H3K27-altered diffuse midline gliomas (DMGs) and group-A posterior fossa ependymomas (PFAs). H3K27-altered DMGs are largely characterized by lysine-to-methionine mutations in histone 3 at position 27 (H3K27M). Most PFAs overexpress EZH inhibitory protein (EZHIP), which possesses a region of similarity to the mutant H3K27M. Both H3K27M and EZHIP inhibit the function of the polycomb repressive complex 2 (PRC2) responsible for H3K27me3 deposition. These tumors often arise in neighboring regions of the brainstem and posterior fossa. In rare cases PFAs harbor H3K27M mutations, and DMGs overexpress EZHIP. These findings together raise the possibility that certain cell populations in the developing hindbrain/posterior fossa are especially sensitive to modulation of H3K27me3 states. We identified shared molecular features by comparing genomic, bulk transcriptomic, chromatin-based profiles, and single-cell RNA-sequencing (scRNA-seq) data from the two tumor classes. Our approach demonstrated that 1q gain, a key biomarker in PFAs, is prognostic in H3.1K27M, but not H3.3K27M gliomas. Conversely, Activin A Receptor Type 1 (ACVR1), which is associated with mutations in H3.1K27M gliomas, is overexpressed in a subset of PFAs with poor outcome. Despite diffuse H3K27me3 reduction, previous work shows that both tumors maintain genomic H3K27me3 deposition at select sites. We demonstrate heterogeneity in shared patterns of residual H3K27me3 for both tumors that largely segregated with inferred anatomic tumor origins and progenitor populations of tumor cells. In contrast, analysis of genes linked to H3K27 acetylation (H3K27ac)-marked enhancers showed higher expression in astrocytic-like tumor cells. Finally, common H3K27me3-marked genes mapped closely to expression patterns in the human developing hindbrain. Overall, our data demonstrate developmentally relevant molecular similarities between PFAs and H3K27M DMGs and support the overall hypothesis that deregulated mechanisms of hindbrain development are central to the biology of both tumors.

Patterns of Extraneural Metastases in Children With Ependymoma.

Ependymomas account for 10% of all malignant pediatric central nervous system tumors. Standard therapy includes maximal safe surgical resection, followed by focal radiation. Despite the aggressive therapy, progression-free survival is poor. Most ependymoma relapses occur locally at the original tumor site. Extraneural presentations of ependymoma are extremely rare, and no standard of care treatment exists. We present a single-institution case series of 3 patients who experienced extraneural relapses of supratentorial ependymoma and describe their treatment and outcome. These cases of extraneural relapse highlight the possible modes of extraneural spread, including hematogenous, lymphatic, and microscopic seeding through surgical drains and shunts. In addition, they illustrate the increase in histologic grade and mutational burden that may occur at the time of relapse. These cases illustrate the role of aggressive, individualized treatment interventions using a combination of surgery, radiation, and chemotherapy.

Assessment of Social Vulnerability in Pediatric Head and Neck Cancer Care and Prognosis in the United States.

Importance: Prior investigations in social determinants of health (SDoH) in pediatric head and neck cancer (HNC) have only considered a narrow scope of HNCs, SDoH, and geography while lacking inquiry into the interrelational association of SDoH with disparities in clinical pediatric HNC. Objectives: To evaluate the association of SDoH with disparities in HNC among children and adolescents and to assess which specific aspects of SDoH are most associated with disparities in dynamic and regional sociodemographic contexts. Design, Setting, and Participants: This retrospective cohort study included data about patients (aged ≤19 years) with pediatric HNC who were diagnosed from 1975 to 2017 from the Surveillance, Epidemiology, and End Results Program (SEER) database. Data were analyzed from October 2021 to October 2022. Exposures: Overall social vulnerability and its subcomponent contributions from 15 SDoH variables, grouped into socioeconomic status (SES; poverty, unemployment, income level, and high school diploma status), minority and language status (ML; minoritized racial and ethnic group and proficiency with English), household composition (HH; household members aged ≥65 and ≤17 years, disability status, single-parent status), and housing and transportation (HT; multiunit structure, mobile homes, crowding, no vehicle, group quarters). These were ranked and scored across all US counties. Main Outcomes and Measures: Regression trends were performed in continuous measures of surveillance and survival period and in discrete measures of advanced staging and surgery receipt. Results: A total of 37 043 patients (20 729 [55.9%] aged 10-19 years; 18 603 [50.2%] male patients; 22 430 [60.6%] White patients) with 30 different HNCs in SEER had significant relative decreases in the surveillance period, ranging from 23.9% for malignant melanomas (mean [SD] duration, lowest vs highest vulnerability: 170 [128] months to 129 [88] months) to 41.9% for non-Hodgkin lymphomas (mean [SD] duration, lowest vs highest vulnerability: 216 [142] months vs 127 [94] months). SES followed by ML and HT vulnerabilities were associated with these overall trends per relative-difference magnitudes (eg, SES for ependymomas and choroid plexus tumors: mean [SD] duration, lowest vs highest vulnerability: 114 [113] months vs 86 [84] months; P < .001). Differences in mean survival time were observed with increasing social vulnerability, ranging from 11.3% for ependymomas and choroid plexus tumors (mean [SD] survival, lowest vs highest vulnerability: 46 [46] months to 41 [48] months; P = .43) to 61.4% for gliomas not otherwise specified (NOS) (mean [SD] survival, lowest vs highest vulnerability: 44 [84] months to 17 [28] months; P < .001), with ML vulnerability followed by SES, HH, and HT being significantly associated with decreased survival (eg, ML for gliomas NOS: mean [SD] survival, lowest vs highest vulnerability: 42 [84] months vs 19 [35] months; P < .001). Increased odds of advanced staging with non-Hodgkin lymphoma (OR, 1.21; 95% CI, 1.02-1.45) and retinoblastomas (OR, 1.31; 95% CI, 1.14-1.50) and decreased odds of surgery receipt for melanomas (OR, 0.79; 95% CI, 0.69-0.91) and rhabdomyosarcomas (OR, 0.90; 95% CI, 0.83-0.98) were associated with increasing overall social vulnerability. Conclusions and Relevance: In this cohort study of patients with pediatric HNC, significant decreases in receipt of care and survival time were observed with increasing SDoH vulnerability.

Nuclear condensates of YAP fusion proteins alter transcription to drive ependymoma tumourigenesis.

Nuclear localization of HIPPO-YAP fusion proteins has been implicated in supratentorial ependymoma development. Here, unexpectedly, we find that liquid-liquid phase separation, rather than nuclear localization, of recurrent patient-derived YAP fusions, YAP-MAMLD1 and C11ORF95-YAP, underlies ependymoma tumourigenesis from neural progenitor cells. Mutagenesis and chimaera assays demonstrate that an intrinsically disordered region promotes oligomerization of the YAP fusions into nuclear, puncta-like, membrane-less condensates. Oligomerization and nuclear condensates induced by YAP fusion with a coiled-coil domain of transcriptional activator GCN4 also promote ependymoma formation. YAP-MAMLD1 concentrates transcription factors and co-activators, including BRD4, MED1 and TEAD, in condensates while excluding transcriptional repressive PRC2, and induces long-range enhancer-promoter interactions that promote transcription and oncogenic programmes. Blocking condensate-mediated transcriptional co-activator activity inhibits tumourigenesis, indicating a critical role of liquid phase separation for YAP fusion oncogenic activity in ependymoma. YAP fusions containing the intrinsically disordered region features are common in human tumours, suggesting that nuclear condensates could be targeted to treat YAP-fusion-induced cancers.

Outcomes following management of relapsed pediatric posterior fossa ependymoma in the molecular era.

PURPOSE: The overall survival and prognostic factors for children with multiply recurrent posterior fossa ependymoma are not well understood. We aimed to assess prognostic factors associated with survival for relapsed pediatric posterior fossa ependymoma. METHODS: An institutional database was queried for children with a primary diagnosis of posterior fossa ependymoma from 2000 to 2019. Kaplan-Meier survival analysis and Cox-proportional hazard regression were used to assess the relationship between treatment factors and overall survival. RESULTS: There were 60 patients identified; molecular subtype was available for 56, of which 49 (87.5%) were PF-A and 7 (12.5%) were PF-B. Relapse occurred in 29 patients (48%) at a mean time of 24 months following primary resection. Median 50% survival was 12.3 years for all patients and 3.3 years following diagnosis of first relapsed disease. GTR was associated with significantly improved survival following primary resection (HR 0.373, 95% CI 0.14-0.96). Presence of recurrent disease was significantly associated with worse survival (p < 0.0001). At recurrent disease diagnosis, disseminated disease was a negative prognostic factor (HR 11.0 95% CI 2.7-44) while GTR at first relapse was associated with improved survival HR 0.215 (95% CI: 0.048-0.96, p = 0.044). Beyond first relapse, the impact of GTR was not significant on survival, though surgery compared to no surgery was favorable with HR 0.155 (95% CI: 0.04-0.59). CONCLUSIONS: Disseminated disease at recurrence and extent of resection for first relapsed disease were important prognostic factors. Surgery compared to no surgery was associated with improved survival for the multiply recurrent ependymoma cohort.

Differentiating between adult intracranial medulloblastoma and ependymoma using MRI.

AIM: To investigate the value of routine magnetic resonance imaging (MRI) examination combined with diffusion-weighted imaging (DWI) in the differential diagnosis of adult intracranial medulloblastomas and ependymomas. MATERIALS AND METHODS: MRI images of 18 medulloblastomas and 18 ependymomas in adult patients were analysed retrospectively, and the differences in MRI features of lesions and apparent diffusion coefficient (ADC) of solid lesions between the two groups were recorded. Independent sample t-tests and χ2 tests were used to analyse the differences in MRI signs and maximum ADC (ADCmax), minimum ADC (ADCmin), and mean ADC (ADCmean) values between the two groups. The receiver operating characteristic (ROC) curve was used to determine the differential diagnostic efficacy and optimal threshold for each ADC value. RESULTS: Age, tumour location, and tumour enhancement were significantly different between adult medulloblastoma and ependymoma (p<0.05). The ADCmax (0.69 ± 0.11 versus 1.04 ± 0.20 × 10-3 mm2/s, p<0.001), ADCmin (0.57 ± 0.12 versus 0.96 ± 0.21 × 10-3 mm2/s, p<0.001), and ADCmean (0.62 ± 0.11 versus 1.00 ± 0.20 × 10-3 mm2/s, p<0.001) values were significantly lower in adult medulloblastoma than in ependymoma. The areas under the ROC curves of ADCmax, ADCmin, and ADCmean were 0.951, 0.957, and 0.966, respectively. The optimal ADCmean threshold was 0.75 × 10-3 mm2/s, with a sensitivity of 88.9% and a specificity of 88.9%. CONCLUSION: Routine MRI examination combined with DWI helps differentiate between intracranial infratentorial medulloblastoma and ependymoma in adults.

MYB/MYBL1::QKI fusion-positive diffuse glioma.

The MYB/MYBL1::QKI fusion induces the protooncogene, MYB, and deletes the tumor suppressor gene, QKI. MYB/MYBL1::QKI rearrangement was previously reported only in angiocentric glioma (AG) and diffuse low-grade glioma. This report compares 2 tumors containing the MYB/MYBL1::QKI fusion: a diffuse pediatric-type high-grade glioma (DPedHGG) in an 11-year-old boy and an AG in a 46-year-old woman. We used immunohistochemistry, next-generation sequencing, and methylation profiling to characterize each tumor and compare our findings to the literature on AG and tumors with the MYB/MYBL1::QKI rearrangement. Both tumors were astrocytic with angiocentric patterns. The MYB::QKI fusion-positive DPedHGG, which recurred once, was accompanied by TP53 mutation and amplification of CDK6 and KRAS, suggesting malignant transformation secondary to additional genetic aberrations. The second case was the adult AG with MYBL1::QKI fusion, which mimicked ependymoma based on histopathology and its dot- and ring-like epithelial membrane antigen positivity. Combined with a literature review, our results suggest that MYB/MYBL1 alterations are not limited to low-grade gliomas, including AG. AG is most common in the cerebra of children and adolescents but exceptional cases occur in adults and the acquisition of additional genetic mutations may contribute to high-grade glioma. These cases further demonstrate that molecular characteristics, morphologic features, and clinical context are essential for diagnosis.

Infantile metastatic ependymoma with a novel molecular profile and favorable outcome to intensive chemotherapy without irradiation: Case-based review.

Ependymal tumors are the third most common brain tumor under 14 years old. Even though metastatic disease is a rare event, it affects mostly young children and carries an adverse prognosis. The factors associated with dissemination and the best treatment approach have not yet been established and there is limited published data on how to manage metastatic disease, especially in patients under 3 years of age. We provide a review of the literature on clinical characteristics and radiation-sparing treatments for metastatic ependymoma in children under 3 years of age treated. The majority (73%) of the identified cases were above 12 months old and had the PF as the primary site at diagnosis. Chemotherapy-based approaches, in different regimens, were used with radiation reserved for progression or relapse. The prognosis varied among the studies, with an average of 50%-58% overall survival. This study also describes the case of a 7-month-old boy with metastatic posterior fossa (PF) ependymoma, for whom we identified a novel SPECC1L-RAF1 gene fusion using a patient-centric comprehensive molecular profiling protocol. The patient was successfully treated with intensive induction chemotherapy followed by high-dose chemotherapy and autologous hematopoietic progenitor cell rescue (AuHSCR). Currently, the patient is in continuous remission 5 years after his diagnosis, without radiation therapy. The understanding of the available therapeutic approaches may assist physicians in their management of such patients. This report also opens the perspective of newly identified molecular alterations in metastatic ependymomas that might drive more chemo-sensitive tumors.

Ependymomas.

Ependymal neoplasms are a heterogenous group of neoplasms arising from the progenitors of the cells lining the ventricular system and the spinal central canal. During the last few years, significant novel data concerning oncogenesis, molecular characteristics and clinical correlations of these tumours have been collected, with a strong relevance for their pathological classification. The recently published 5th edition of WHO Classification of Central Nervous System Tumours integrates this novel knowledge and represents a substantial update compared to the previous edition. Concerning supratentorial ependymomas, the previous RELA fusion-positive ependymoma has been renamed into ZFTA fusion-positive and the novel YAP1 fusion-positive ependymoma subtype has been added. Posterior fossa ependymomas should now be allocated either to the Type A or Type B subtypes based on molecular profiling or using the H3 K27me3 immunohistochemical surrogate. Regarding spinal ependymomas, a novel subtype has been added based on a distinctive molecular trait, presence of MYCN amplification, and on the unfavourable outcome. Finally, myxopapillary ependymoma is now classified as a grade 2 tumour in accordance with its overall prognosis which mirrors that of conventional spinal ependymomas. The aim of this review is to present these changes and summarize the current diagnostic framework of ependymal tumours, according to the most recent updates.

[Pediatric Posterior Fossa Tumors].

Posterior fossa tumors tend to entail obstructive hydrocephalus, and urges initiating prompt treatment. Prevalent pathologies include medulloblastoma, ependymoma, pilocytic astrocytoma, and atypical teratoid/rhabdoid tumor(AT/RT). In most cases, maximal safe resection is related to better prognosis. In some cases of ependymoma and AT/RT with high vascularity, second-look surgery with neoadjuvant chemotherapy is effective. The treatment strategy should be tailored according to each tumor.

Detection of multidrug-resistant Acinetobacter baumannii by metagenomic next-generation sequencing in central nervous system infection after neurosurgery: A case report.

Background: Central nervous system (CNS) infection is one of the most serious complications after neurosurgery. Traditional clinical methods are difficult to diagnose the pathogen of intracranial infection. Due to recent advances in genomic approaches, especially sequencing technologies, metagenomic next-generation sequencing (mNGS) has been applied in many research and clinical settings. Case presentation: Here, we report a case of CNS infection with Acinetobacter baumannii in a 15-year-old woman, who previously underwent surgery for recurrence of ependymoma in the fourth ventricle. On the eleventh postoperative day, the patient had a high fever and leukocytosis in the cerebrospinal fluid (CSF). mNGS using CSF rapidly and accurately identified the causative pathogen as A. baumannii with carbapenem resistance genes blaOXA-23 and blaOXA-51, which were confirmed by subsequent culture and susceptibility tests within 5 days. During the disease, mNGS, culture, and drug susceptibility testing were continued to monitor changes in pathogenic bacteria and adjust medication. At present, there are no case reports on to the use of mNGS for detecting pathogens in postoperative infection with ependymoma and guide medication. Conclusion: mNGS has great advantages in pathogen identification and even pathogen resistance prediction. Multiple mNGS examinations during the course of the disease play an important role in the dynamic monitoring of pathogens.

Epigenetic Alterations of Repeated Relapses in Patient-matched Childhood Ependymomas.

Recurrence is frequent in pediatric ependymoma (EPN). Our longitudinal integrated analysis of 30 patient-matched repeated relapses (3.67 ± 1.76 times) over 13 years (5.8 ± 3.8) reveals stable molecular subtypes (RELA and PFA) and convergent DNA methylation reprogramming during serial relapses accompanied by increased orthotopic patient derived xenograft (PDX) (13/27) formation in the late recurrences. A set of differentially methylated CpGs (DMCs) and DNA methylation regions (DMRs) are found to persist in primary and relapse tumors (potential driver DMCs) and are acquired exclusively in the relapses (potential booster DMCs). Integrating with RNAseq reveals differentially expressed genes regulated by potential driver DMRs (CACNA1H, SLC12A7, RARA in RELA and HSPB8, GMPR, ITGB4 in PFA) and potential booster DMRs (PLEKHG1 in RELA and NOTCH, EPHA2, SUFU, FOXJ1 in PFA tumors). DMCs predicators of relapse are also identified in the primary tumors. This study provides a high-resolution epigenetic roadmap of serial EPN relapses and 13 orthotopic PDX models to facilitate biological and preclinical studies.

Ubiquitin Proteasome Gene Signatures in Ependymoma Molecular Subtypes.

The ubiquitin proteasome system (UPS) is critically important for cellular homeostasis and affects virtually all key functions in normal and neoplastic cells. Currently, a comprehensive review of the role of the UPS in ependymoma (EPN) brain tumors is lacking but may provide valuable new information on cellular networks specific to different EPN subtypes and reveal future therapeutic targets. We have reviewed publicly available EPN gene transcription datasets encoding components of the UPS pathway. Reactome analysis of these data revealed genes and pathways that were able to distinguish different EPN subtypes with high significance. We identified differential transcription of several genes encoding ubiquitin E2 conjugases associated with EPN subtypes. The expression of the E2 conjugase genes UBE2C, UBE2S, and UBE2I was elevated in the ST_EPN_RELA subtype. The UBE2C and UBE2S enzymes are associated with the ubiquitin ligase anaphase promoting complex (APC/c), which regulates the degradation of substrates associated with cell cycle progression, whereas UBE2I is a Sumo-conjugating enzyme. Additionally, elevated in ST_EPN_RELA were genes for the E3 ligase and histone deacetylase HDAC4 and the F-box cullin ring ligase adaptor FBX031. Cluster analysis demonstrated several genes encoding E3 ligases and their substrate adaptors as EPN subtype specific genetic markers. The most significant Reactome Pathways associated with differentially expressed genes for E3 ligases and their adaptors included antigen presentation, neddylation, sumoylation, and the APC/c complex. Our analysis provides several UPS associated factors that may be attractive markers and future therapeutic targets for the subtype-specific treatment of EPN patients.