Tumor-treating fields (TTFields) are alternating electric fields applied continuously to the brain by attaching two-pair arrays on the scalp. Although TTFields therapy has demonstrated efficacy against supratentorial glioblastoma (GBM) in adults, its safety and efficacy in children have not been confirmed. Despite differences in the genetic etiology of the adult and pediatric forms of GBM, both have certain clinical behaviors in common, allowing us to test TTFields therapy in pediatric GBM. Recently, several, pediatric case-series using TTFields therapy have been published, and a few, prospective, pediatric studies are ongoing. Because GBMs are extremely rare in pediatric patients, where they comprise a wide variety of genetic subtypes, these pediatric studies are feasibility studies targeting various types of malignant brain tumor. Although they are important for confirming the safety and feasibility of TTFields therapy in the pediatric population, confirming its efficacy against each type of pediatric brain tumor, including the GBM, is difficult. Our clinical research team, therefore, planned an investigator-initiated clinical trial targeting pediatric supratentorial GBMs (as in adults) with the aim of expanding regulatory approval of TTFields therapy for pediatric GBM treatment based on safety and exploratory efficacy data in combination with the accumulated evidence on adult GBMs.

The Bacillus Calmette-Guérin (BCG) vaccine is widely used worldwide. Intracranial manifestation as an adverse event of BCG is extremely rare. A previously healthy 16-month-old boy was referred to our hospital for eye contact difficulties and progressive gait disturbance lasting two months. He was inoculated with BCG at seven months of age. Brain magnetic resonance imaging (MRI) revealed hydrocephalus with widespread and disseminated enhancement lesions with thickening of the third ventricle floor, and brain tissue pathologically showed non-caseous granulomatous inflammation. Immunosuppressive therapies were initiated because of a provisional diagnosis of neurosarcoidosis. Three months later, a positive polymerase chain reaction (PCR) result for the Mycobacterium tuberculosis complex was obtained. Eventually, M. bovis (BCG Tokyo 172 strain) was identified in the cerebrospinal fluid (CSF) and shunt tube culture. The prolonged use of antituberculosis drugs and multiple shunt replacement surgeries were needed for recovery. There was no evidence of immunodeficiency. Unfortunately, he had severe neurological sequelae of bilateral blindness and neurodevelopmental delay. Our purpose in this report was to highlight the potential for intracranial manifestations of adverse reactions related to BCG vaccination. We propose that the CSF PCR assay of Mycobacterium tuberculosis (MTB) complex should be applied repeatedly in children suspected of intractable neurosarcoidosis, with a history of BCG vaccination.

Background/Objectives: Although Tumor-Treating Fields (TTFields) therapy is an established treatment modality for adult glioblastoma, clinical data on its efficacy in pediatric brain tumors are extremely scarce. The present study aimed to evaluate the safety of TTFields therapy for pediatric diffuse high-grade glioma (HGG) and to conduct an exploratory analysis of its efficacy. Methods: A prespecified, interim analysis was performed to determine whether the study should be continued on the basis of safety and feasibility data on the first three patients. The target population was children aged 5 to 17 years with newly diagnosed, supratentorial HGG or its first recurrence following frontline therapy. After completion of initial, local treatment for the tumor (surgical removal and/or radiotherapy), all patients received TTFields therapy using Optune^TM for 28 days per course for up to 26 courses until disease progression. Results: The interim analysis, which was completed in October 2022, included three female patients aged 14, 17, and 9 years. All had a histological grade 4 tumor, two of which were radiation-induced, secondary HGG. No serious, treatment-related toxicities or device-related issues were observed. All three patients were able to continue using the device for 75% or more of the time in accordance with the protocol, suggesting that the treatment was feasible. The MRI findings of two patients indicated that the treatment has a potential antitumor effect. Based on these results, the study was resumed and is currently being continued at multiple centers. Conclusions: The initial results of the prespecified, interim analysis demonstrated that TTFields therapy was safe and feasible for children with HGG. This study was funded by the Japan Agency for Medical Research and Development (AMED) and was registered with the Japan Registry of Clinical Trials (jRCTs032200423).

Among intracranial embryonal tumors, genetic/epigenetic analysis can help unveil the molecular background. Herein, we report a case of a cerebellar pontine angular embryonic tumor complicated by Cowden syndrome in an infant. The tumor radiologically lacked evidence of interaction with the cerebellum and appeared to show continuity with the pons. Pathological appearance was similar to that of a medulloblastoma with extensive nodularity. DNA methylation analysis indicated that the tumor was a “medulloblastoma, sonic hedgehog-activated” with a substantial confidence. Although the diagnosis deviated from the definition of medulloblastoma, clinical, pathological and molecular data suggested that it was an “ectopic” medulloblastoma.

Embryonal tumor with multilayered rosettes (ETMR) is a rare, highly malignant tumor of the central nervous system and is usually diagnosed in children aged <2 years. Currently, because no defined treatment strategy has been reported, treatment regimens are often extrapolated from other embryonal tumors. Therefore, data collection of ETMR cases is important for further understanding EMTR. Here, we present our experience with four patients with ETMR. Patients with a pathological diagnosis of ETMR from 1999 to 2016 at Saitama Children’s Medical Center were included. Their clinical data were retrospectively analyzed. This study included four cases of ETMR (one male and three females). The mean age at diagnosis was 29.5 (range, 15–37) months. Presenting symptoms included seizure, hemiparesis, vomiting, and headache. The mean maximal tumor diameter was 42.5 mm. The tumor locations included frontal lobe, temporal lobe, occipital lobe, cerebellum, and brainstem. Gross total resection was achieved in two cases. Fluorescence in situ hybridization analysis demonstrated amplification of 19q13.42 chromosome region in all cases, and diffuse positive expression was observed in the immunohistochemical staining for LIN28A. Systemic postoperative chemotherapy was administered to all patients. Three patients received intrathecal therapy and three were irradiated. The mean overall survival and progression-free survival were 45.3 and 42 months, respectively. Two patients who underwent gross total resection are alive without recurrence. Complete surgical resection may be an important prognostic factor in patients with ETMR. Further prospective studies are needed to confirm these results.