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Background We integrated clinical, histopathological, and molecular data of central nervous system germ cell tumors to provide insights into their management. Methods Data from the Intracranial Germ Cell Tumor Genome Analysis (iGCT) Consortium were reviewed. A total of 190 cases were classified as primary germ cell tumors (GCTs) based on central pathological reviews. Results All but one of the cases that were bifocal (neurohypophysis and pineal glands) and cases with multiple lesions including neurohypophysis or pineal gland were germinomas (34 of 35). Age was significantly higher in patients with germinoma than other histologies. Comparison between tumor marker and histopathological diagnoses showed that 18.2% of histopathologically diagnosed germinomas were marker positive and 6.1% of non-germinomatous GCTs were marker negative, suggesting a limitation in the utility of markers or histopathology alone using small specimens for diagnosis. Comparison between local and central histopathological diagnoses revealed a discordance of 12.7%. Discordance was significantly less frequent in biopsy cases, implying difficulty in detecting all histopathological components of heterogeneous GCTs. Germinomas at the typical sites (neurohypophysis or pineal gland) showed a better progression-free survival than those at atypical sites (P = 0.03). A molecular clinical association study revealed frequent mitogen-activated protein kinase (MAPK) pathway mutations in males (51.4% vs 14.3%, P = 0.007), and phosphatidylinositol-3 kinase/mammalian target of rapamycin (PI3K/mTOR) pathway mutations in basal ganglia cases (P = 0.004). Basal ganglia cases also had frequent chromosomal losses. Some chromosomal aberrations (2q, 8q gain, 5q, 9p/q, 13q, 15q loss) showed potential prognostic significance. Conclusions The in-depth findings of this study regarding clinical and molecular heterogeneity will increase our understanding of the pathogenesis of this enigmatic tumor.

Chordoma is an uncommon bone tumor arising from notochordal remnant, which accounts for 1–4% of all bone malignancies. It commonly occurs along the cranial-spinal axis, and skull base is one of most frequent sites, representing 35–49% of all chordoma cases. Surgical resection is widely accepted as the first choice of treatment. There are only limited number of reports about pediatric chordoma cases, and its biological behavior including genetic backgrounds were largely unknown. Here, we present a 5 year-old girl with a large aggressive skull base chordoma of 6 cm in maximum diameter, which eventually had multiple systemic metastasis. We initially tried chemotherapy based on the protocol for the osteosarcoma, but in vain. Because the tumor was highly vascularized on angiography, after embolization of the feeding arteries and bilateral internal maxillary arteries, endoscopic endonasal surgery was performed. The tumor was sufficiently removed, achieving effective mass reduction, and the residual tumors involving the lower cranial nerves and craniocervial junction were additionally treated with Gamma Knife radiosurgery. However, one month later, it showed systemic metastasis to bilateral cervical lymph nodes and lung. We tried chemotherapy with nivolmab and imatinib for this patient, whereas they showed the partial effect. The genetic analysis revealed somatic TP53 c.569C>T, (p.P190L) mutation in chordoma specimen. In the past literature, we found only one study of the adult chordoma cases, in which majority of the patients had somatic TP53 mutation (p.P72R). Further investigation with large number of the cases is essential to clarify the molecular biology of pediatric chordomas.

INTRODUCTION Recently endo- and exoscopic surgeries have been gradually performed in neurosurgery. To improve the accuracy and safety of our endoscopic procedures, we are currently trialing 4K or 8K systems. Here we report our experience of endo- and exoscopic procedures for pediatric neurosurgery. METHODS We retrospectively identified 22 patients (15 males, 7 females; mean age, 9.2 years) who underwent surgery for sellar lesions and intraventricular or intraparenchymal lesions with an endo- or exoscopic procedure at our institute between 2010 and 2020. We used a full HD endoscope system (Storz) and an organic electroluminescence (EL) monitor (Sony), and a 4K system (Sony and Olympus). VITOM 3D (Storz) was used as the exoscope. Videoscope (Olympus) was used as a flexible scope for intraventricular tumors. RESULTS We performed surgical procedures as 11 biopsies, 6 third ventriculostomies, 5 resections, and 3 fenestrations. The full HD system with organic EL monitor presented high color contrast. We could easily distinguish between tumor microstructure and the normal structure with the 4K system comparing to full HD. Moreover, electronic zoom function enabled us to discriminate tumor boundaries without having to move the endoscope closer. As a result, we could delineate the surgical working space. VITOM 3D was simple to sharpen the focus on the wider surgical field, similar to the application of an operating microscope. CONCLUSION In pediatric neurosurgery, an endo- or exoscope enables clear visual recognition of a boundary between tumor and normal area.

INTRODUCTION: Anti-VEGF therapies such as bevacizumab have been shown to attenuate VEGF-mediated angiogenesis, to decrease vascular permeability, and to inhibit tumor growth in malignant glioma. Conversely, bevacizumab has also been reported to induce invasive proliferation. Oncolytic viral therapy is considered to be a promising treatment modality for malignant glioma. Previous studies indicate that RAMBO (rapid anti angiogenesis mediated by oncolytic virus), a vasculostatin-expressing Herpes simplex virus (HSV)-1-derived oncolytic virus, has potent anti tumor activity against malignant glioma. In this study, the effects of RAMBO on bevacizumab-induced invasive changes in glioma were evaluated. MATERIALS AND METHODS: RAMBO is composed of the cDNA encoding for human vasculostatin (Vstat120), driven by the HSV-1 IE4/5 promotor, within the backbone of an attenuated HSV-1 virus (HSVQ). Experiments were conducted using the human malignant glioma cell lines U373 and U87deltaEGFR, and Vstat120 expression in the supernatant was assessed by western blotting. The effect of the combination of RAMBO with bevacizumab was assessed by cytotoxicity assays, scratch wound assays, and Matrigel invasion assays. RESULTS: Vasculostatin was detected in cell lysates and secreted CM at 14 hours after infection with RAMBO. The cytotoxicity assay demonstrated that bevacizumab did not increase the cytotoxicity of RAMBO against glioma cells. Conversely, in the scratch wound assay, RAMBO CM significantly reduced both the number of migrating cells and the rate of migration compared with saline used as control. Furthermore, the number and the rate of migrating cells induced by bevacizumab treatment was reduced by RAMBO CM. In the Matrigel invasion assays, the number of invasive cells induced by bevacizumab was reduced by RAMBO CM. CONCLUSIONS: These results demonstrated that RAMBO suppressed bevacizumab-induced glioma invasion, which may lead to a promising approach for the treatment of malignant glioma.

BACKGROUND: Despite advances in multimodal therapy, patients with malignant glioma have a dismal prognosis. Aberrant angiogenesis and diffuse glioma cell invasion are major obstacles for effective treatment. Therefore, investigation of angiogenesis and invasion is essential for the development of a curative therapy. We established animal models that histologically mimic two invasive and angiogenic phenotypes of glioma, ie, angiogenesis-dependent invasion (J3T-1) and angiogenesis-independent invasion (J3T-2). In our previous study, comparative proteomic analysis showed that annexin A2 was more highly expressed in J3T-1 than in J3T-2. In this study, the function of annexin A2 in malignant glioma in relation to angiogenesis and invasion was investigated using these animal models. METHODS: Annexin A2-downregulated J3T-1 cells (J3T-1shA) and annexin A2-upregulated J3T-2 cells (J3T-2A) were generated by gene transfection. Quantitative reverse transcription polymerase chain reaction (QRT-PCR) and immunohistochemical staining of annexin A2 and vascular endothelial growth factor (VEGF) were performed on cultured cells. J3T-1, J3T-1shA, J3T-2, and J3T-2A brain tumors were established in athymic rats. Brain sections were evaluated histopathologically. Human glioblastoma specimens were stained for annexin A2, VEGF, and platelet-derived growth factor (PDGF). RESULTS: QRT-PCR and immunohistochemical staining of cultured cells revealed that expression of VEGF was upregulated in accordance with the expression of annexin A2 in J3T-1 and J3T-2A cells. J3T-1 tumors showed remarkable angiogenic activity and invasion around neovasculature, whereas J3T-1shA tumors, including J3T-2 tumors, showed no angiogenic activity, but diffuse single-cell infiltration of tumor cells into normal parenchyma. J3T-2A tumors were highly angiogenic and showed angiogenesis-dependent invasion. Human glioblastoma specimens revealed that annexin A2 was positive in clusters of tumor cells around dilated vessels (25/30 cases). The intensity of VEGF and PDGF staining corresponded to the expression of annexin A2 (correlation coefficients: annexin A2/VEGF: R = 0.73, P < 0.05; annexin A2/PDGF: R = 0.37, P < 0.05). CONCLUSIONS: Our results revealed that the phenotype of glioma invasion is closely related to angiogenesis, and annexin A2 is one of the factors that regulates angiogenesis and invasion phenotype of malignant glioma. SECONDARY CATEGORY: Neuropathology & Tumor Biomarkers.