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.

Development of Chromosome 1q+ Specific Treatment for Highest Risk Pediatric Posterior Fossa Ependymoma.

PURPOSE: There are no effective treatment strategies for children with highest-risk posterior fossa group A ependymoma (PFA). Chromosome 1q gains (1q+) are present in approximately 25% of newly diagnosed PFA tumors, and this number doubles at recurrence. Seventy percent of children with chromosome 1q+ PFA will die because of the tumor, highlighting the urgent need to develop new therapeutic strategies for this population. EXPERIMENTAL DESIGN: In this study, we utilize 1q+ PFA in vitro and in vivo models to test the efficacy of combination radiation and chemotherapy in a preclinical setting. RESULTS: 5-fluorouracil (5FU) enhances radiotherapy in 1q+ PFA cell lines. Specifically, 5FU increases p53 activity mediated by the extra copy of UCK2 located on chromosome 1q in 1q+ PFA. Experimental downregulation of UCK2 resulted in decreased 5FU sensitivity in 1q+ PFA cells. In in vitro studies, a combination of 5FU, retinoid tretinoin (ATRA), and radiation provided the greatest reduction in cellular proliferation and greatest increase in markers of apoptosis in 1q+ PFA cell lines compared with other treatment arms. Similarly, in vivo experiments demonstrated significant enhancement of survival in mice treated with combination radiation and 5FU and ATRA. CONCLUSIONS: These results are the first to identify a chromosome 1q+ specific therapy approach in 1q+ PFA. Existing phase I studies have already established single-agent pediatric safety and dosages of 5FU and ATRA, allowing for expedited clinical application as phase II trials for children with high-risk PFA.

Association Between Urbanicity and Outcomes Among Patients with Spinal Cord Ependymomas in the United States.

BACKGROUND: Spinal cord ependymomas (SCEs) represent the most common intramedullary spinal cord tumors among adults. Research shows that access to neurosurgical care and patient outcomes can be greatly influenced by patient location. This study investigates the association between the outcomes of patients with SCE in metropolitan and nonmetropolitan areas. METHODS: Cases of SCE between 2004 and 2019 were identified within the Central Brain Tumor Registry of the United States, a combined dataset including the Centers for Disease Control and Prevention's National Program of Cancer Registries and National Cancer Institute's Surveillance, Epidemiology, and End Results Program data. Multivariable logistic regression models were constructed to evaluate the association between urbanicity and SCE treatment, adjusted for age at diagnosis, sex, race and ethnicity. Survival data was available from 42 National Program of Cancer Registries (excluding Kansas and Minnesota, for which county data are unavailable), and Cox proportional hazard models were used to understand the effect of surgical treatment, county urbanicity, age at diagnosis, and the interaction effect between age at diagnosis and surgery, on the survival time of patients. RESULTS: Overall, 7577 patients were identified, with 6454 (85%) residing in metropolitan and 1223 (15%) in nonmetropolitan counties. Metropolitan and nonmetropolitan counties had different age, sex, and race/ethnicity compositions; however, demographics were not associated with differences in the type of surgery received when stratified by urbanicity. Irrespective of metropolitan status, individuals who were American Indian/Alaska Native non-Hispanic and Hispanic (all races) were associated with reduced odds of receiving surgery. Individuals who were Black non-Hispanic and Hispanic were associated with increased odds of receiving comprehensive treatment. Diagnosis of SCE at later ages was linked with elevated mortality (hazard ratio = 4.85, P < 0.001). Gross total resection was associated with reduced risk of death (hazard ratio = 0.37, P = 0.004), and age did not interact with gross total resection to influence risk of death. CONCLUSIONS: The relationship between patients' residential location and access to neurosurgical care is critical to ensuring equitable distribution of care. This study represents an important step in delineating areas of existing disparities.

Intracranial ependymoma in an adult patient with multiple primary malignancies.

The incidence of multiple primary malignancies (MPM) is increasing, and therefore, it has become highly important for clinicians to consider the concept of MPM when treating oncology patients. In this case report, we follow the clinical course of a patient diagnosed with a new intracranial lesion, an ependymoma, on a background of MPM. We explore the barriers implicating the delay in her diagnosis, dissect the challenges in managing her disease and emphasise the importance of social determinants in optimising her care.

Tumors of Choroid Plexus and Other Ventricular Tumors.

Tumors arising inside the ventricular system are rare but represent a difficult diagnostic and therapeutic challenge. They usually are diagnosed when reaching a big volume and tend to affect young children. There is a wide broad of differential diagnoses with significant variability in anatomical aspects and tumor type. Differential diagnosis in tumor type includes choroid plexus tumors (papillomas and carcinomas), ependymomas, subependymomas, subependymal giant cell astrocytomas (SEGAs), central neurocytomas, meningiomas, and metastases. Choroid plexus tumors, ependymomas of the posterior fossa, and SEGAs are more likely to appear in childhood, whereas subependymomas, central neurocytomas, intraventricular meningiomas, and metastases are more frequent in adults. This chapter is predominantly focused on choroid plexus tumors and radiological and histological differential diagnosis. Treatment is discussed in the light of the modern acquisition in genetics and epigenetics of brain tumors.

Latest classification of ependymoma in the molecular era and advances in its treatment: a review.

Ependymoma is a rare central nervous system (CNS) tumour occurring in all age groups and is one of the most common paediatric malignant brain tumours. Unlike other malignant brain tumours, ependymomas have few identified point mutations and genetic and epigenetic features. With advances in molecular understanding, the latest 2021 World Health Organization (WHO) classification of CNS tumours divided ependymomas into 10 diagnostic categories based on the histology, molecular information and location; this accurately reflected the prognosis and biology of this tumour. Although maximal surgical resection followed by radiotherapy is considered the standard treatment method, and chemotherapy is considered ineffective, the validation of the role of these treatment modalities continues. Although the rarity and long-term clinical course of ependymoma make designing and conducting prospective clinical trials challenging, knowledge is steadily accumulating and progress is being made. Much of the clinical knowledge obtained from clinical trials to date was based on the previous histology-based WHO classifications, and the addition of new molecular information may lead to more complex treatment strategies. Therefore, this review presents the latest findings on the molecular classification of ependymomas and advances in its treatment.

[Pediatric Intracranial Ependymoma - Recommendations for First-Line Treatment from the German HIT-MED study group]. / Kinder und Jugendliche mit intrakraniellem Ependymom ­ Empfehlungen der HIT-MED-Studiengruppe der GPOH zur Erstlinientherapie.

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

Recent Advancements in Ependymoma: Challenges and Therapeutic Opportunities.

BACKGROUND: Ependymoma is one of the most common malignant pediatric brain tumors and can be difficult to treat. Over the last decade, much progress has been made in the understanding of the underlying molecular drivers within this group of tumors, but clinical outcomes remain unchanged. SUMMARY: Here, we review the most recent molecular advances in pediatric ependymoma, evaluate results of recent clinical trials and discuss the ongoing challenges in the field and questions that remain. KEY MESSAGES: The field of ependymoma has vastly changed over the last several decades with ten distinct molecular subgroups now described, but much progress needs to be made in developing new therapeutic strategies and targets.

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

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

Adult intracranial ependymoma-relevance of DNA methylation profiling for diagnosis, prognosis, and treatment.

BACKGROUND: A methylation-based classification of ependymoma has recently found broad application. However, the diagnostic advantage and implications for treatment decisions remain unclear. Here, we retrospectively evaluate the impact of surgery and radiotherapy on outcome after molecular reclassification of adult intracranial ependymomas. METHODS: Tumors diagnosed as intracranial ependymomas from 170 adult patients collected from 8 diagnostic institutions were subjected to DNA methylation profiling. Molecular classes, patient characteristics, and treatment were correlated with progression-free survival (PFS). RESULTS: The classifier indicated an ependymal tumor in 73.5%, a different tumor entity in 10.6%, and non-classifiable tumors in 15.9% of cases, respectively. The most prevalent molecular classes were posterior fossa ependymoma group B (EPN-PFB, 32.9%), posterior fossa subependymoma (PF-SE, 25.9%), and supratentorial ZFTA fusion-positive ependymoma (EPN-ZFTA, 11.2%). With a median follow-up of 60.0 months, the 5- and 10-year-PFS rates were 64.5% and 41.8% for EPN-PFB, 67.4% and 45.2% for PF-SE, and 60.3% and 60.3% for EPN-ZFTA. In EPN-PFB, but not in other molecular classes, gross total resection (GTR) (P = .009) and postoperative radiotherapy (P = .007) were significantly associated with improved PFS in multivariable analysis. Histological tumor grading (WHO 2 vs. 3) was not a predictor of the prognosis within molecularly defined ependymoma classes. CONCLUSIONS: DNA methylation profiling improves diagnostic accuracy and risk stratification in adult intracranial ependymoma. The molecular class of PF-SE is unexpectedly prevalent among adult tumors with ependymoma histology and relapsed as frequently as EPN-PFB, despite the supposed benign nature. GTR and radiotherapy may represent key factors in determining the outcome of EPN-PFB patients.

Spatial transcriptomic analysis delineates epithelial and mesenchymal subpopulations and transition stages in childhood ependymoma.

BACKGROUND: The diverse cellular constituents of childhood brain tumor ependymoma, recently revealed by single cell RNA-sequencing, may underly therapeutic resistance. Here we use spatial transcriptomics to further advance our understanding of the tumor microenvironment, mapping cellular subpopulations to the tumor architecture of ependymoma posterior fossa subgroup A (PFA), the commonest and most deadly childhood ependymoma variant. METHODS: Spatial transcriptomics data from intact PFA sections was deconvoluted to resolve the histological arrangement of neoplastic and non-neoplastic cell types. Key findings were validated using immunohistochemistry, in vitro functional assays and outcome analysis in clinically-annotated PFA bulk transcriptomic data. RESULTS: PFA are comprised of epithelial and mesenchymal histological zones containing a diversity of cellular states, each zone including co-existing and spatially distinct undifferentiated progenitor-like cells; a quiescent mesenchymal zone population, and a second highly mitotic progenitor population that is restricted to hypercellular epithelial zones and that is more abundant in progressive tumors. We show that myeloid cell interaction is the leading cause of mesenchymal transition in PFA, occurring in zones spatially distinct from hypoxia-induced mesenchymal transition, and these distinct EMT-initiating processes were replicated using in vitro models of PFA. CONCLUSIONS: These insights demonstrate the utility of spatial transcriptomics to advance our understanding of ependymoma biology, revealing a clearer picture of the cellular constituents of PFA, their interactions and influence on tumor progression.

Novel nomograms predicting overall and cancer-specific survival of malignant ependymoma patients: a population-based study.

BACKGROUND: Malignant ependymomas are rare cancerous tumors that are associated with increased morbidity and mortality in the affected patients. Lately, there has been a lot of controversy about the correct way to manage and predict the survival outcome of these patients. We aim in this retrospective cohort study to develop novel nomograms that can better predict the overall survival (OS) and cancer-specific survival (CSS) of these patients. METHODS: This is a retrospective cohort study that was conducted through the Surveillance, Epidemiology, and End Results databases (SEER) between 1998 and 2016. Patients were excluded if they had an unknown diagnosis, unknown cause of death or those with survival duration less than a month. We used penalized regression models with the highest time-dependent area under the ROC curve (AUC) and most stable calibrations to construct the nomograms. By searching the SEER database and applying the eligibility criteria, we identified 3391 patients for the final analysis. RESULTS: Nine penalized regression models were developed of which two models including adaptive elastic-net was selected for both OS and CSS. The model incorporated age, sex, year of diagnosis, site, race, radiation, chemotherapy, surgery, and type for the construction of nomograms. We aimed in this population-based cohort study to develop novel prediction tools that can help physicians estimate the survival of malignant ependymoma patients and provide better care. CONCLUSIONS: Our nomograms appear to have high accuracy and applicability, which we hope that can predict the survival and improve the treatment and prognosis of these patients.

Response assessment in paediatric intracranial ependymoma: recommendations from the Response Assessment in Pediatric Neuro-Oncology (RAPNO) working group.

Response criteria for paediatric intracranial ependymoma vary historically and across different international cooperative groups. The Response Assessment in the Pediatric Neuro-Oncology (RAPNO) working group, consisting of an international panel of paediatric and adult neuro-oncologists, neuro-radiologists, radiation oncologists, and neurosurgeons, was established to address both the issues and the unique challenges in assessing the response in children with CNS tumours. We established a subcommittee to develop response assessment criteria for paediatric ependymoma. Current practice and literature were reviewed to identify major challenges in assessing the response of paediatric ependymoma to clinical trial therapy. For areas in which data were scarce or unavailable, consensus was reached through an iterative process. RAPNO response assessment recommendations include assessing disease response on the basis of changes in tumour volume, and using event-free survival as a study endpoint for patients entering clinical trials without bulky disease. Our recommendations for response assessment include the use of brain and spine MRI, cerebral spinal fluid cytology, neurological examination, and steroid use. Baseline postoperative imaging to assess for residual tumour should be obtained 24-48 h after surgery. Our consensus recommendations and response definitions should be prospectively validated in clinical trials.

Prognostic Factors and Histopathological Features of Pediatric Intracranial Ependymomas: Nationwide Brain Tumor Registry-based Study of Japan.

To assess the clinicopathological features and prognostic factors of pediatric intracranial ependymomas and to explore the current diagnostic practice, we analyzed clinical data from the Brain Tumor Registry of Japan (BTRJ). Data of fifty children under 18 years of age diagnosed with intracranial ependymoma were extracted from the BTRJ database. Cases were reviewed for overall survival (OS) and progression-free survival (PFS), with attention to gender, preoperative Karnofsky performance status score, location of the tumor, the extent of resection, World Health Organization (WHO) histopathological grading, and adjuvant therapy. The median age at diagnosis was 6.1 years, ranging from 7 months to 17.6 years. Based on the WHO histopathological grading, 27 patients were classified under grade 2 (54%) and 23 patients were classified under grade 3 (46%). Gross total resection (GTR) was achieved in 30 patients (60%). The median follow-up time was 65 months. Five-year PFS and OS were 47.2 ± 7.3% and 73.3 ± 6.7%, respectively. GTR was associated with longer OS (P = 0.02). The histopathological grading was not an independent prognostic factor for the OS. Mitosis and microvascular proliferation were higher among patients with grade 3 than in those with grade 2, which aided in deciding the WHO grade. This nationwide study revealed the characteristics and outcomes of patients with childhood ependymomas. GTR was the factor most consistently associated with improved survival. In contrast, the histopathological grading in this cohort was not a significant prognostic factor. More reproducible and practical criteria for the diagnosis of intracranial ependymomas should be further pursued in future studies.

Ependymoma: Evaluation and Management Updates.

PURPOSE OF REVIEW: To review state of art and relevant advances in the molecular genetics and management of ependymomas of children and adults. RECENT FINDINGS: Ependymomas may occur either in the brain or in the spinal cord. Compared with intracranial ependymomas, spinal ependymomas are less frequent and exhibit a better prognosis. The new WHO classification of CNS tumors of 2021 has subdivided ependymomas into different histomolecular subgroups with different outcome. The majority of studies have shown a major impact of extent of resection; thus, a complete resection must be performed, whenever possible, at first surgery or at reoperation. Conformal radiotherapy is recommended for grade 3 or incompletely resected grade II tumors. Proton therapy is increasingly employed especially in children to reduce the risk of neurocognitive and endocrine sequelae. Craniospinal irradiation is reserved for metastatic disease. Chemotherapy is not useful as primary treatment and is commonly employed as salvage treatment for patients failing surgery and radiotherapy. Standard treatments are still the mainstay of treatment: the discovery of new druggable pathways will hopefully increase the therapeutic armamentarium in the near future.

SIOP Ependymoma I: Final results, long-term follow-up, and molecular analysis of the trial cohort-A BIOMECA Consortium Study.

BACKGROUND: SIOP Ependymoma I was a non-randomised trial assessing event free and overall survival (EFS/OS) of non-metastatic intracranial ependymoma in children aged 3-21 years treated with a staged management strategy. A further aim was to assess the response rate (RR) of subtotally resected (STR) ependymoma to vincristine, etoposide, and cyclophosphamide (VEC). We report final results with 12-year follow-up and post hoc analyses of recently described biomarkers. METHODS: Seventy-four participants were eligible. Children with gross total resection (GTR) received radiotherapy, whilst those with STR received VEC before radiotherapy. DNA methylation, 1q, hTERT, ReLA, Tenascin-C, H3K27me3, and pAKT status were evaluated. RESULTS: Five- and ten-year EFS was 49.5% and 46.7%, OS was 69.3% and 60.5%. GTR was achieved in 33/74 (44.6%) and associated with improved EFS (P = .003, HR = 2.6, 95% confidence interval (CI) 1.4-5.1). Grade 3 tumours were associated with worse OS (P = .005, HR = 2.8, 95%CI 1.3-5.8). 1q gain and hTERT expression were associated with poorer EFS (P = .003, HR = 2.70, 95%CI 1.49-6.10 and P = .014, HR = 5.8, 95%CI 1.2-28) and H3K27me3 loss with worse OS (P = .003, HR = 4.6, 95%CI 1.5-13.2). Methylation profiles showed expected patterns. 12 participants with STR did not receive chemotherapy; a protocol violation. However, best chemotherapy RR was 65.5% (19/29, 95%CI 45.7-82.1), exceeding the prespecified 45%. CONCLUSIONS: Participants with totally resected ependymoma had the best outcomes. RR of STR to VEC exceeded the pre-specified efficacy criterion. However, cases of inaccurate stratification highlighted the need for rapid central review. 1q gain, H3K27me3 loss, and hTERT expression were all associated with poorer survival outcomes.

The biology of ependymomas and emerging novel therapies.

Ependymomas are rare central nervous system tumours that can arise in the brain's supratentorial region or posterior fossa, or in the spinal cord. In 1924, Percival Bailey published the first comprehensive study of ependymomas. Since then, and especially over the past 10 years, our understanding of ependymomas has grown exponentially. In this Review, we discuss the evolution in knowledge regarding ependymoma subgroups and the resultant clinical implications. We also discuss key oncogenic and tumour suppressor signalling pathways that regulate tumour growth, the role of epigenetic dysregulation in the biology of ependymomas, and the various biological features of ependymoma tumorigenesis, including cell immortalization, stem cell-like properties, the tumour microenvironment and metastasis. We further review the limitations of current therapies such as relapse, radiation-induced cognitive deficits and chemotherapy resistance. Finally, we highlight next-generation therapies that are actively being explored, including tyrosine kinase inhibitors, telomerase inhibitors, anti-angiogenesis agents and immunotherapy.

Ongoing Response in a Multiply Relapsed Metastatic Posterior Fossa Ependymoma A After Vorinostat and Concomitant Irradiation.

Posterior fossa ependymomas A confer the worst prognosis among all subtypes. They demonstrate distinct epigenetic changes, which can be targeted with epigenetic modifiers like histone deacetylase inhibitors (Vorinostat). We describe a 3-year-old male diagnosed with a posterior fossa ependymoma who had a number of recurrences requiring multimodal therapy. Molecular analysis demonstrated a BCL-6 corepressor mutation, and methylation profiling matched with posterior fossa ependymomas A. He received craniospinal irradiation and focal boost with Vorinostat. Serial imaging after irradiation revealed a progressively decreasing tumor burden with nearly complete resolution of disease at 15 months. Histone deacetylase inhibitors demonstrate promise in treatment of carefully selected cases of ependymoma.