Re-evaluating surgery and re-irradiation for locally recurrent pediatric ependymoma – a multi-institutional study

Background The goal of this study was to evaluate extent of surgical resection, and timing and volume of re-irradiation, on survival for children with locally recurrent ependymoma. Methods Children with locally recurrent ependymoma treated with a second course of fractionated radiotherapy (RT2) from six North American cancer centres were reviewed. The index time was from the start of RT2 unless otherwise stated. Results 35 patients were included in the study. The median doses for first radiation (RT1) and RT2 were 55.8 and 54 Gy, respectively. Median follow-up time was 5.6 years. Median overall survival (OS) for all patients from RT2 was 65 months. Gross total resection (GTR) was performed in 46% and 66% of patients prior to RT1 and RT2, respectively. GTR prior to RT2 was independently associated with improved progression free survival (PFS) for all patients (HR 0.41, p = 0.04), with an OS benefit (HR 0.26, p = 0.03) for infratentorial tumours. Median PFS was superior with craniospinal irradiation (CSI) RT2 (not reached) compared to focal RT2 (56.9 months; log-rank p = 0.03). All distant failures (except one) occurred after focal RT2. Local failures after focal RT2 were predominantly in patients with less than GTR pre-RT2. Conclusions Patients with locally recurrent pediatric ependymoma should be considered for re-treatment with repeat maximal safe resection (ideally GTR) and CSI re-irradiation, with careful discussion of the potential side effects of these treatments.

Ependymoma Presenting as a ­Rim-Enhancing Lesion in the Brainstem

<b><i>Introduction:</i></b> The posterior fossa is the most common intracranial location for pediatric ependymoma. While ependymoma usually arises from the ventricular lining of the fourth ventricle as a solid mass, it rarely originates from the brainstem. Grade II ependymomas also infrequently appear as a cavitary ring-enhancing lesion. <b><i>Case Presentation:</i></b> We describe a case of a 6-year-old boy with an ependymoma arising within the medulla with imaging features of a thick-walled rim-enhancing cavitary lesion. A stereotactic biopsy was obtained which confirmed a grade II ependymoma. The patient received focal proton beam radiation therapy and is doing well with no concerns for disease progression at 28 months after diagnosis. <b><i>Conclusion:</i></b> Posterior fossa ependymomas typically arise from ependymal cells within the fourth ventricle or foramina of Luschka. They rarely invade or arise within the brainstem parenchyma. Our case had atypical imaging findings in addition to the atypical tumor location. The lesion was described as a thick-walled rim-enhancing focal cystic necrotic lesion centered within the medulla with surrounding nonenhancing expansile infiltrative changes. Ring-enhancing lesions can be seen in patients with anaplastic ependymoma, but is not commonly reported in grade II ependymomas. In summary, this report highlights a unique case of a posterior fossa ependymoma in a pediatric patient arising in an atypical brainstem location as well as having unique imaging features.

Pediatric ependymoma: an overview of a complex disease

Pediatric ependymomas comprise biologically distinct tumor entities with different (epi)genetics, age distribution and localization, as well as a different prognosis. Regarding risk stratification within these biologically defined entities, histopathological features still seem to be relevant. The mainstay of treatment is gross total resection (GTR) if possible, achieved with intraoperative monitoring and neuronavigation—and if necessary second surgery—followed by adjuvant radiation therapy. However, there is growing evidence that some ependymal tumors may be cured by surgery alone, while others relapse despite adjuvant treatment. To date, the role of chemotherapy is not clear. Current therapy achieves reasonable survival rates for the majority of ependymoma patients. The next challenge is to go beyond initial tumor control and use risk-adapted therapy to reduce secondary effect and therapy-induced morbidity for low-risk patients and to intensify treatment for high-risk patients. With identification of specific alterations, targeted therapy may represent an option for individualized treatment modalities in the future.

Targeted Therapy with Sirolimus and Nivolumab in a Child with Refractory Multifocal Anaplastic Ependymoma

Pediatric ependymoma (EPN) is the third most common central nervous system (CNS) tumor, with 90% arising intracranially. Management typically involves maximal surgical resection and radiotherapy, but patients’ outcome is poor. Moreover, there are only a few therapeutical options available for recurrent or refractory disease. In this report, we present the case of a 7-year-old girl with relapsed refractory multifocal grade III EPN who failed conventional treatments and experienced a stable and durable response to the immune checkpoint inhibitor (ICPI) nivolumab in association with the mammalian target of rapamycin (m-TOR) inhibitor sirolimus. This experimental therapy was targeted on immune phenotypical analyses of the patient’s last relapse tumor sample, and this procedure should be routinely done to find new possible therapeutical approaches in recurrent solid tumors.

The BET Inhibitor OTX015 Exhibits In Vitro and In Vivo Antitumor Activity in Pediatric Ependymoma Stem Cell Models

Childhood ependymomas are heterogenous chemoresistant neoplasms arising from aberrant stem-like cells. Epigenome deregulation plays a pivotal role in ependymoma pathogenesis, suggesting that epigenetic modifiers hold therapeutic promise against this disease. Bromodomain and extraterminal domain (BET) proteins are epigenome readers of acetylated signals in histones and coactivators for oncogenic and stemness-related transcriptional networks, including MYC/MYCN (Proto-Oncogene, BHLH Transcritpion Factor)-regulated genes. We explored BET inhibition as an anticancer strategy in a panel of pediatric patient-derived ependymoma stem cell models by OTX015-mediated suppression of BET/acetylated histone binding. We found that ependymoma tissues and lines express BET proteins and their targets MYC and MYCN. In vitro, OTX015 reduced cell proliferation by inducing G0/G1-phase accumulation and apoptosis at clinically tolerable doses. Mechanistically, inhibitory p21 and p27 increased in a p53-independent manner, whereas the proliferative driver, phospho-signal transducer and activator of transcription 3 (STAT3), decreased. Upregulation of apoptosis-related proteins and survivin downregulation were correlated with cell line drug sensitivity. Minor alterations of MYC/MYCN expression were reported. In vivo, OTX015 significantly improved survival in 2/3 orthotopic ependymoma models. BET proteins represent promising targets for pharmaceutical intervention with OTX015 against ependymoma. The identification of predictive determinants of sensitivity may help identify ependymoma molecular subsets more likely to benefit from BET inhibitor therapies.