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Purpose: Non-germinomatous germ cell tumors (NGGCTs) are rare pediatric conditions. This multicenter study using Asian multinational patient data investigated treatment outcomes and prognostic factors for NGGCTs., Methods: Medical records of 251 patients with NGGCTs treated from 1995 to 2015 were retrospectively analyzed from participating centers in Asian countries (Korea, Taiwan, Singapore, and Japan)., Results: The median follow up was 8.5 years (95% CI 7.8-9.9). In the total cohort, 5-year event-free survival (EFS) and overall survival (OS) rates were 78.2% and 85.4%, respectively. In 17.9% of the patients, diagnosis was determined by tumor markers alone (alpha-fetoprotein ≥ 10 ng/mL (Korea) or > 25 ng/mL (Taiwan and Singapore), and/or β-human chorionic gonadotropin (β-hCG) ≥ 50 mIU/mL). Patients with immature teratomas and mature teratomas comprised 12.0% and 8.4%, respectively. The 5-year EFS rate was higher in patients with histologically confirmed germinoma with elevated β-hCG (n = 28) than those in patients with malignant NGGCTs (n = 127). Among malignant NGGCTs, patients with choriocarcinoma showed the highest 5-year OS of 87.6%, while yolk sac tumors showed the lowest OS (68.8%). For malignant NGGCT subgroups, an increase in serum β-hCG levels by 100 mIU/mL was identified as a significant prognostic factor associated with the EFS and OS., Conclusion: Our result shows excellent survival outcomes of overall CNS NGGCT. However, treatment outcome varied widely across the histopathologic subgroup of NGGCT. Hence, this study suggests the necessity for accurate diagnosis by surgical biopsy and further optimization of diagnosis and treatment according to the histopathology of NGGCTs. Future clinical trials should be designed for individualized treatments for different NGGCTs subsets., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: This multinational study was conducted to report clinical presentations and treatment strategies in patients with intracranial germinomas across selected Asian centers, including failure patterns, risk factors, and outcomes., Methods: A retrospective data collection and analysis of these patients, treated between 1995 and 2015 from eight healthcare institutions across four countries was undertaken., Results: From the results, 418 patients were analyzed, with a median follow-up of 8.9 years; 79.9% of the patients were M0, and 87.6% had β-human chorionic gonadotropin values <50 mIU/mL. The 5/10-year overall survival (OS) and recurrence-free survival (RFS) rates were 97.2%/96.2% and 89.9%/86.9%, respectively. RFS was predicted by the radiotherapy (RT) field, with focal RT having the worst outcome, whereas chemotherapy usage had no impact on survival. Among patients who received chemotherapy, response to chemotherapy did not predict survival outcomes. In M0 patients, primary basal ganglia tumors predicted a worse RFS. In patients with bifocal tumors, an extended field RT was associated with better outcomes. In multivariable analysis, only RT fields were associated with RFS. In relapsed patients, salvage rates were high at 85.7%. Additionally, patients who received salvage RT had a better outcome (91.6% vs. 66.7%)., Conclusions: Survival outcomes of patients with germinoma were excellent. Thus, the focus of treatment for intracranial germinoma should be on survivorship. Further studies are warranted to find the optimal intensity and volume of radiation, including the role of chemotherapy in the survival of patients with intracranial germinomas, considering age, primary tumor location, and extent of disease., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: We investigated optimal management for intracranial germinoma, including target volume and dose of radiation therapy (RT) and the combination of RT and chemotherapy (CTx)., Methods and Materials: We retrospectively evaluated 213 patients with intracranial germinoma treated between 1971 and 2017. Treatment policies changed as diagnostic techniques and clinical experience improved. In the 1980s, trial RT and tumor marker study were performed, and craniospinal irradiation was performed to treat patients with presumed germinoma. CTx was introduced in 1991, and RT volume was reduced in patients showing a complete response. In 2012, the policy was changed to a "reduced volume/dose RT alone" approach, involving a smaller target volume (the whole ventricle/whole brain for localized disease) without CTx. RT doses were gradually reduced to 36 Gy for primary tumors and 18 Gy for neuraxis., Results: The median age was 16 years. In total, 118 and 95 patients had pathologically proven and presumed germinoma, respectively, and 151 and 62 patients had localized and multifocal or metastatic diseases, respectively. With a median follow-up of 141 months, the 10-year disease-free and overall survival rates were 91.6% and 95.6%, respectively. Recurrence rates were similar for patients receiving RT-only (9 of 137, 6.6%) and those receiving CTx + RT (4 of 73, 5.5%); all patients receiving CTx-only experienced recurrences (3 of 3, 100%). Rates were the highest in the focal RT group (10 of 29, 34.5%) but were relatively low in the whole ventricle/whole brain RT (3 of 51, 5.9%) and craniospinal irradiation groups (0 of 130, 0%). Infield failure occurred in 3 patients. Fourteen patients died of recurrence (n = 4), secondary malignancy (n = 4), CTx-related toxicity (n = 2), and others (n = 4). Among the 33 patients who received "reduced volume/dose RT alone" treatment, 2 (6.1%) experienced recurrence in the spinal cord and biopsy tract, respectively., Conclusions: The additional benefit of CTx in the treatment of intracranial germinoma seems minimal. An RT-only approach with reduced target volume and dose seems reasonable., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: To assess the efficacy of upfront chemotherapy followed by response-adapted reduced-dose/reduced-volume radiotherapy (RT) for intracranial germinoma., Materials and Methods: Ninety-one patients from five institutions were registered in the KSPNO G051/G081 Protocol. Germinomas were classified as solitary or multiple/disseminated diseases, and upfront chemotherapy was administered. For all patients with multiple or disseminated disease, and patients with partial response after chemotherapy, 19.5-24 Gy of craniospinal irradiation plus 10.8-19.8 Gy of tumor bed boost were planned. For patients with complete response (CR), reduced-dose RT (30.6 Gy) was planned, along with a reduced field for solitary lesions., Results: The median patient age was 14 (range, 3-30) years. Sixty-five patients (71.4%) had a solitary lesion. The median follow-up duration was 67.9 (range, 6.6-119.3) months. Recurrence was not observed in 32 patients in the protocol compliant group. Four patients (4.4%) in the protocol non-compliant group experienced relapse after CR and one patient died of the disease. The 5-year and 7-year overall survival rates were 98.8% and 98.8%, while the corresponding event-free survival rates were 96.6% and 93.8%, respectively. All three patients with basal ganglia germinomas who were treated with local RT experienced recurrence outside the RT field. Among the 23 patients with pineal or suprasellar lesions who received whole-ventricle RT, there was no recurrence., Conclusions: Currently used upfront chemotherapy followed by reduced-dose, reduced-volume RT appears acceptable, when whole-ventricle RT for pineal or suprasellar tumors and, at minimum, whole-brain RT for basal ganglia/thalamus lesions are applied., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objective: Low-grade epilepsy-associated tumors (LEATs) are associated with childhood seizures that are typically drug-resistant, necessitating surgical interventions. In this study, we aimed to investigate the efficacy of surgical intervention in children with LEATs and to identify factors associated with seizure and cognitive outcomes., Methods: We reviewed 58 children less than 18 years of age who underwent epilepsy surgery due to histopathologically confirmed LEATs and had a minimum postoperative follow-up duration of 24 months., Results: Of the 58 patients who were followed for a median duration of 5.6 (IQR 3.2 to 10.0) years, 51 (87.9%) were seizure-free after surgery. In univariate analysis, shorter epilepsy duration, fewer antiepileptic drugs at time of surgery, gross total resection, and unilobar tumor involvement were associated with seizure freedom. In multivariate analysis, gross total resection was independently associated with seizure freedom. The preoperative and postoperative full-scale intelligence quotient (FSIQ) scores were 78.9 ± 27.1 and 80.9 ± 28.7, respectively. In univariate analysis, younger age at seizure onset, longer epilepsy duration, more antiepileptic drugs at time of surgery, multilobar tumor involvement, and presence of generalized epileptic discharges were associated with lower preoperative FSIQ. In multivariate analysis, longer epilepsy duration was independently associated with lower preoperative FSIQ scores. Postoperative FSIQ scores were significantly influenced by preoperative FSIQ scores., Conclusions: Epilepsy surgery for LEATs in children resulted in excellent seizure outcome. Gross total resection was the only independent factor associated with favorable seizure outcome. Preoperative and postoperative cognitive abilities were significantly influenced by epilepsy duration, so early surgical intervention should be considered., (Copyright © 2018. Published by Elsevier Inc.)

Pediatric brain tumors are highly associated with epileptic seizures 1 . However, their epileptogenic mechanisms remain unclear. Here, we show that the oncogenic BRAF somatic mutation p.Val600Glu (V600E) in developing neurons underlies intrinsic epileptogenicity in ganglioglioma, one of the leading causes of intractable epilepsy 2 . To do so, we developed a mouse model harboring the BRAF V600E somatic mutation during early brain development to reflect the most frequent mutation, as well as the origin and timing thereof. Therein, the BRAF V600E mutation arising in progenitor cells during brain development led to the acquisition of intrinsic epileptogenic properties in neuronal lineage cells, whereas tumorigenic properties were attributed to high proliferation of glial lineage cells. RNA sequencing analysis of patient brain tissues with the mutation revealed that BRAF V600E -induced epileptogenesis is mediated by RE1-silencing transcription factor (REST), which is a regulator of ion channels and neurotransmitter receptors associated with epilepsy. Moreover, we found that seizures in mice were significantly alleviated by an FDA-approved BRAF V600E inhibitor, vemurafenib, as well as various genetic inhibitions of Rest. Accordingly, this study provides direct evidence of a BRAF somatic mutation contributing to the intrinsic epileptogenicity in pediatric brain tumors and suggests that BRAF and REST could be treatment targets for intractable epilepsy.

Despite great advances in understanding of molecular pathogenesis and achievement of a high cure rate in medulloblastoma, recurrent medulloblastomas are still dismal. Additionally, misidentification of secondary malignancies due to histological ambiguity leads to misdiagnosis and eventually to inappropriate treatment. Nevertheless, the genomic characteristics of recurrent medulloblastomas are poorly understood, largely due to a lack of matched primary and recurrent tumor tissues. We performed a genomic analysis of recurrent tumors from 17 pediatric medulloblastoma patients. Whole transcriptome sequencing revealed that a subset of recurrent tumors initially diagnosed as locally recurrent medulloblastomas are secondary glioblastomas after radiotherapy, showing high similarity to the non-G-CIMP proneural subtype of glioblastoma. Further analysis, including whole exome sequencing, revealed missense mutations or complex gene fusion events in PDGFRA with augmented expression in the secondary glioblastomas after radiotherapy, implicating PDGFRA as a putative driver in the development of secondary glioblastomas after treatment exposure. This result provides insight into the possible application of PDGFRA-targeted therapy in these second malignancies. Furthermore, genomic alterations of TP53 including 17p loss or germline/somatic mutations were also found in most of the secondary glioblastomas after radiotherapy, indicating a crucial role of TP53 alteration in the process. On the other hand, analysis of recurrent medulloblastomas revealed that the most prevalent alterations are the loss of 17p region including TP53 and gain of 7q region containing EZH2 which already exist in primary tumors. The 7q gain events are frequently accompanied by high expression levels of EZH2 in both primary and recurrent medulloblastomas, which provides a clue to a new therapeutic target to prevent recurrence. Considering the fact that it is often challenging to differentiate between recurrent medulloblastomas and secondary glioblastomas after radiotherapy, our findings have major clinical implications both for correct diagnosis and for potential therapeutic interventions in these devastating diseases.

Leucine-rich glioma inactivated 3 (LGI3) is a secreted protein in vertebrates, which belongs to the LGI family. In our previous study, LGI3 was found to be expressed in brain, adipose tissues and the skin, where it functions as a multifunctional cytokine. In the present study, we used bioinformatic tools to perform data mining, phylogenetics and prognostic association analysis to investigate the prognostic role of LGI3 in cancers. The sequences of LGI3 orthologues were analyzed from various species, and it was found that LGI3 was highly conserved in mammals and that the subsets of amino acid residues were phylogenetically coevolved in four major clusters. Single nucleotide polymorphisms (SNPs) of the human LGI3 gene included 228 functionally relevant variants (missense, nonsense and frameshift) in a total of 1,042 SNPs. Four missense SNPs had a global minor allele frequency ≥0.001. Somatic mutations in cancer with functional relevance were found in various types of cancer, including uterine, stomach and lung cancer. In addition, five amino acid residues with cancer mutations were shown to be coevolved in the vertebrate phylogeny, suggesting their importance in protein dysfunctions in cancer. One conserved amino acid and three SNPs were found to be mutated in stomach cancer and melanoma. Analysis of expression microarray data demonstrated that the expression of LGI3 was significantly associated with the prognosis of brain, colorectal and lung cancer. Taken together, these results suggested that the genetic variations and expression levels of LGI3 have potential value in cancer prognosis.

Background: Atypical teratoid/rhabdoid tumor (ATRT) is a rare malignant pediatric brain tumor with a dismal prognosis. We evaluated the efficacy of multimodal therapy in children with ATRT., Procedure: Nine children diagnosed with cranial ATRT, who received multimodal therapy between 2005 and 2014, including surgical resection followed by radiotherapy (RT), systemic chemotherapy (CT), and high-dose chemotherapy/stem cell transplantation (HDCT/SCT), were analyzed retrospectively. The median age at diagnosis was 32 months. Initial treatment included surgery in eight patients (88%), CT in all (100%), RT in eight (88%), and HDCT/SCT in seven (78%)., Results: The median follow-up period for survivors was 21 months. The 2-year progression-free rate was 66.7%. Two patients had progression 4 and 17 months after diagnosis. One received multimodal treatment, including surgery and upfront CT with delayed RT; the other underwent surgery and upfront CT without RT. The 2-year event-free survival and overall survival rates were 46.7% and 62.2%, respectively. Hematologic toxicity of grade 3 or more was observed in six patients treated with HDCT/SCT and two who underwent craniospinal irradiation. Deaths were attributed to progressive disease (n = 2) and treatment-related toxicity (n = 2) from sepsis and acute respiratory failure after CT and HDCT/SCT., Conclusions: Maximal safe resection in conjunction with upfront RT is a reasonable multimodal treatment in patients with ATRT for prolonging progression-free survival. Further research may help determine the optimal parameters for reducing treatment toxicity, such as intensity of HDCT/SCT and the RT field., (© 2017 Wiley Periodicals, Inc.)

The term "long-term epilepsy-associated tumor (LEAT)" encompasses brain lesions associated with drug-resistant epilepsy over a long duration (≥2 years). Notably, some LEATs do not fit into any of the classifications of the World Health Organization (WHO). Herein, we report a LEAT that occurred in the left amygdala of a 16-year-old patient with intractable epilepsy. Histological examination of the resected amygdala revealed diffusely infiltrating tumor cells in the cortex. Perineuronal satellitosis and perivascular aggregation of tumor cells were apparent, along with mild nuclear enlargement and cytologic atypia. Tumor cells were positive for oligodendrocyte transcription factor 2 and neuronal markers including NeuN, neurofilaments, and synaptophysin, but were negative for CD34 and nestin. The most intriguing finding was intranuclear filaments, which appeared as rod- or needle-like shapes under high-power view. Ancillary ultrastructural analysis revealed thin filamentous intranuclear structures in tumor cells. Based on the glioneuronal nature of these cells as well as the infiltrative growth pattern, a diagnosis of LEAT was rendered that was deemed WHO grade I to II; however, the clinicopathological implications of the intranuclear inclusions remain unknown. The patient is currently alive and well without seizures.

The present study analyzed outcomes of surgery followed by concomitant chemoradiotherapy (CCRT) with temozolomide (TMZ) in patients with newly diagnosed glioblastoma (GBM) at a single institution. Outcomes were retrospectively reviewed in 252 consecutive patients with newly diagnosed GBM who underwent surgery followed by CCRT with TMZ at the authors' institution between 2005 and 2013. At initial operation, 126 (50.0%), 55 (21.8%), 45 (17.9%), and 26 (10.3%) patients underwent gross total resection (GTR), subtotal resection, partial resection (PR), and biopsy, respectively. Their median overall survival (OS) was 20.8 months (95% confidence interval [CI] 17.7-23.9 months) and their median progression-free survival was 12.7 months (95% CI 11.2-14.2 months). The O-methylguanine-DNA methyltransferase (MGMT) promoter was methylated in 78 (34.1%) of the 229 patients assayed, and an isocitrate dehydrogenase 1 mutation was detected in 7 (6.6%) of the 106 patients analyzed. Univariate analyses showed that patient age, involvement of eloquent areas, involvement of the subventricular zone, presence of leptomeningeal seeding, Karnofsky Performance Status, extent of resection (EOR), MGMT promoter methylation, and presence of an oligodendroglioma component were prognostic of OS. Multivariate analysis showed that age, involvement of eloquent areas, presence of leptomeningeal seeding, EOR, and MGMT promoter methylation were significantly predictive of survival. OS in patients with GBM who undergo surgery followed by CCRT with TMZ is enhanced by complete resection. Other factors significantly prognostic of OS include that age, involvement of eloquent areas, presence of leptomeningeal seeding, and MGMT promoter methylation.

The existence of tumorspheres (TSs) might confer treatment resistance to pineoblastoma (PB). The existence of PB TSs with cellular immortalization potential has not yet been reported. We developed a procedure for isolating TSs from recurrent PB (rPB) and tested whether their properties made them suitable for use as a patient-derived xenograft (PDX). Immunocytochemical staining, RT-PCR and quantitative real-time PCR showed that, among stemness proteins, CD133, musashi and podoplanin were expressed at elevated levels in rPB TSs, but nestin was not. rPB TSs cultured under neuro-glial differentiation conditions expressed TUBB3, but not GFAP, MBP or NeuN. Unlike glioblastoma TSs, rPB TSs showed no clear evidence of invasion in 3D invasion assay or increased expression of genes associated with epithelial-mesenchymal transition. An orthotopic xenograft showed that tumor xenografts replicated the histopathological features of the patient tumor and expressed similar genome profiles, as determined by short tandem repeat genotyping. These data demonstrate the isolation and the characterization of rPB TSs for the first time. Using an orthotopic xenograft, we showed that rPB TSs could replicate the patient tumor, demonstrating their potential as a PDX for precision medicine.

The authors describe a series of 15 intracranial germ cell tumors (IGCTs) excluding mature teratomas; 3 cases in children younger than 3 years of age who were treated at 3 different international institutions over the course of 20 years, and 12 from a PubMed search. These tumors, with possible in utero origins, often occur in atypical locations. The clinical behavior differed significantly from these tumors' counterparts in older children. In this young age group germinoma is highly aggressive, whereas nongerminomatous germ cell tumors may be cured without radiotherapy. Ongoing genomic studies reveal insights to attain an understanding of the biology of these tumors. New treatment strategies are needed to improve outcomes for IGCTs in this age group, particularly for germinomas.

Purpose: It has been reported that cancer stem cells (CSCs) can be isolated from primitive neuroectodermal tumor (PNET) specimens. Moreover, mesenchymal stem-like cells (MSLCs) have been isolated from Korean glioma specimens. Here, we tested whether tumor spheres and MSLCs can be simultaneously isolated from a single PNET specimen, a question that has not been addressed., Methods: We isolated single-cell suspensions from PNET specimens, then cultured these cells using methods for MSLCs or CSCs. Cultured cells were analyzed for surface markers of CSCs using immunocytochemistry and for surface markers of bone marrow-derived mesenchymal stem cells (BM-MSCs) using fluorescence-activated cell sorting (FACS). Tumor spheres were exposed to neural differentiation conditions, and MSLCs were exposed to mesenchymal differentiation conditions. Possible locations of MSLCs within PNET specimens were determined by immunofluorescence analysis of tumor sections., Results: Cells similar to tumor spheres and MSLCs were independently isolated from one of two PNET specimens. Spheroid cells, termed PNET spheres, were positive for CD133 and nestin, and negative for musashi and podoplanin. PNET spheres were capable of differentiation into immature neural cells and astrocytes, but not oligodendrocytes or mature neural cells. FACS analysis revealed that adherent cells isolated from the same PNET specimen, termed PNET-MSLCs, had surface markers similar to BM-MSCs. These cells were capable of mesenchymal differentiation. Immunofluorescence labeling indicated that some CD105(+) cells might be closely related to endothelial cells and pericytes., Conclusion: We showed that both tumor spheres and MSLCs can be isolated from the same PNET specimen. PNET-MSLCs occupied a niche in the vicinity of the vasculature and could be a source of stroma for PNETs.

Purpose: We describe our institution's experience with seven patients who developed second brain tumors following cranial irradiation., Methods: The median age at first irradiation was 8 years (range, 3-20 years). Initial diagnoses were two cases of germinoma, one non-germinomatous germ cell tumor (NGGCT), three cases of medulloblastoma, and one pineal gland tumor (pathology undetermined). All patients received craniospinal irradiation followed by local boost and the median dose to the initial tumor area was 54.0 Gy (range, 49.8-60.6 Gy). Four patients (two medulloblastomas, one germinoma, and one NGGCT) received chemotherapy., Results: Second brain tumors were diagnosed a median of 114 months (range, 64-203) after initial radiation. Pathologic diagnoses were one glioblastoma, two cases of anaplastic astrocytoma, one medulloblastoma, one low-grade glioma, one high-grade glial tumor, and one atypical meningioma. Five patients underwent surgical resection with subsequent radiotherapy. One anaplastic astrocytoma patient received chemotherapy only following stereotactic biopsy. The meningioma patient was alive 32 months after total resection and radiosurgery for subsequent recurrences. Six patients died within 18 months and most deaths were due to disease progression., Conclusions: Most patients diagnosed with second brain tumors had received high-dose, large-volume radiotherapy with chemotherapy at a young age. Further studies are required to determine the relationship between radiotherapy/chemotherapy and the development of secondary brain tumors.

We analyzed the treatment outcomes of intracranial ependymomas in Korean children aged <18 years. Data for 96 patients were collected from five hospitals. Survival rates were calculated using the Kaplan-Meier method. Log-rank tests for univariate analyses and Cox regression model for multivariate analysis were conducted to identify prognostic factors for survival. The median age of the patients was 4 years (range, 0.3-17.9 years). The median follow-up was 55 months (range, 2-343 months). Age <3 years was an important factor for selecting adjuvant therapy after surgery. Among children aged <3 and ≥ 3 years, adjuvant radiotherapy (RT) was applied to 55 and 84 %, respectively, and adjuvant chemotherapy to 52 and 10 %, respectively. The 5 year local progression-free survival (LPFS), disease-free survival (DFS), and overall survival (OS) rates were 54, 52, and 79 %, respectively. Gross total resection was the most significant prognostic factor for all survival endpoints. Age ≥ 3 years and RT were significant prognostic factors for superior LPFS and DFS. However, the significance of age was lost in multivariate analysis for DFS. LPFS, DFS, and OS were superior in patients who started RT within 44 days after surgery (the median time) than in patients who started RT later in the patients aged ≥ 3 years. Postoperative RT was a strong prognostic factor for intracranial ependymomas. Our results suggest that early use of RT is an essential component of treatment, and should be considered in young children.

Purpose: It was presented that mesenchymal stem cells (MSCs) can be isolated from western glioma specimens. However, whether MSCs exist in glioma specimens of different ethnicities is unknown. To verify the existence of MSCs in an independent cohort, we undertook studies to isolate MSCs from a group of Korean patients. We hypothesized that cells resembling MSCs that were deemed mesenchymal stemlike cells (MSLCs) exist in an independent cohort of Korean gliomas., Methods: We cultured fresh glioma specimens using the protocols used for culturing MSCs. The cultured cells were analyzed with fluorescence-activated cell sorting (FACS) for surface markers associated with MSCs. Cultured cells were exposed to mesenchymal differentiation conditions. To presume possible locations of MSLCs in the glioma, sections of glioma were analyzed by immunofluorescent labeling for CD105, CD31, and NG2., Results: From nine of 31 glioma specimens, we isolated cells resembling MSCs, which were deemed Korean glioma stroma MSLCs (KGS-MSLCs). KGS-MSLCs were spindle shaped and adherent to plastic. KGS-MSLCs had similar surface markers to MSCs (CD105(+), CD90(+), CD73(+), and CD45(-)). KGS-MSLCs were capable of mesenchymal differentiation and might be located around endothelial cells, pericytes, and in a disorganized perivascular area inside glioma stroma., Conclusions: We found that cells resembling MSCs indeed exist in an independent cohort of glioma patients, as presented in western populations. We could presume that the possible location of KGS-MSLCs was in perivascular area or in glioma stroma that was a disorganized vascular niche. It might be possible that KGS-MSLCs could be one of constituent of stroma of glioma microenvironment.

Object: This prospective randomized clinical study will address the efficacy of radiation (RT)-alone and combined with pre-RT chemotherapy (CTX) treatments and propose the novel standard treatment strategy for intracranial primary pure germinoma., Materials and Methods: Between 2005 and 2008, there were 54 patients diagnosed with intracranial primary pure germinomas in a single institute. Twenty-eight patients were enrolled. The mean age of the patients was 16.2 years (range 6-31 years). There were 19 men and 9 women (men/women ratio = 2.1:1). There were 21 patients with solitary tumors and 7 with multiple tumors. These patients were randomized as RT-only treatment group (11 solitary and 3 multiple tumors) and combined (10 solitary and 4 multiple tumors, neo-adjuvant CTX followed by response-adapted RT) treatment group. The follow-up period for RT only group has a median of 58 months (mean 58.2 months, range 41-82 months), and for combine therapy group, the median was 68.5 months (mean 67.8 months, range 41-88 months). All 14 patients in the RT-only group showed complete response (CR) and no recurrence. Eleven patients in the combined group had CR and three patients had partial response after neo-adjuvant CTX. All patients responded to RT as CR without recurrence. At the time of analysis, all 28 patients were alive without evidence of disease., Conclusion: Neo-adjuvant CTX for localized germinomas seems to be unnecessary as a method to reduce radiation dose in our RT protocol. However, the effective control of multifocal or disseminated germinoma can be achieved by neo-adjuvant CTX followed by response-adapted reduced dose RT.

Purpose: The existence of cancer stem cells (CSCs) in glioblastoma has been proposed. However, the unknown knowledge that is yet to be revealed is the presence of glioma CSCs (gCSCs) in correlation to each WHO grades of glioma. We approached this study with a hypothesis that specimens from high-grade gliomas would have higher isolation rate of gCSCs in comparison to those of lower-grade gliomas., Methods: The glioma specimens were obtained from patients and underwent gliomasphere assay. The gliomaspheres were chosen to be analyzed with immunocytochemisty for surface markers. Then the selected gliomaspheres were exposed to neural differentiation conditions. Lastly, we made mouse orthotopic glioma models to examine the capacity of gliomagenesis., Results: The gliomaspheres were formed in WHO grade IV (13 of 21) and III (two of nine) gliomas. Among them, WHO grade IV (11 of 13) and III (two of two) gliomaspheres showed similar surface markers to gCSCs and were capable of neural differentiation. Lastly, among the chosen cells, 10 of 11 WHO grade IV and two of two WHO grade III gliomaspheres were capable of gliomagenesis. Thus, overall, the rates of existence of gCSCs were more prominent in high-grade gliomas: 47.6% (10 of 21) in WHO grade IV gliomas and 22.2% (two of nine) in WHO grade III gliomas, whereas WHO grade II and I gliomas showed virtually no gCSCs., Conclusions: This trend of stage-by-stage increase of gCSCs in gliomas showed statistical significance by chi-square test linear-by-linear association. We prove that the rates of existence of gCSCs increase proportionally as the WHO grades of gliomas rise.

Purpose: Currently, the interaction between the niche and glioma cancer stem cells (gCSCs) is gaining attention. However, there are few studies concerned with the effects of repeated exposure to a new microenvironment on gCSCs characteristics. In this study, serial in vivo subtransplantation was performed to create a new microenvironment. We evaluated and compared the biological characteristics of gCSCs after serial in vivo subtransplantation., Methods: We cultured gCSCs from human glioma specimens according to cultured gliomasphere methods. The isolated gCSCs were termed zero-generation gCSCs (G0-gCSCs). By subsequent serial subtransplantation, we obtained first-generation gCSCs (G1-gCSCs) and second-generation gCSCs (G2-gCSCs). We evaluated and compared the biological characteristics of G0-gCSCs, G1-gCSCs, and G2-gCSCs. The in vitro characteristics included the morphology, surface marker profiles, and neural differentiation capacity and the in vivo characteristics was the survival of mice xenografts. Additionally, brain sections were analyzed using PCNA, TUNEL, and CD31 staining., Results: We observed no significant differences in the in vitro characteristics of G0-gCSCs, G1-gCSCs, and G2-gCSCs. However, the survival time of mice glioma xenografts was significantly decreased upon serial subtransplantation. In addition, immunohistochemical analyses showed that the number of TUNEL(+) cells was significantly decreased while the number of CD31(+) cells was significantly increased with serial in vivo subtransplantation., Conclusions: There were significant in vivo biological changes in gCSCs upon serial in vivo subtransplantation, which were shorter xenograft survival, increased angiogenesis, and decreased apoptosis. This study suggests that the repeated exposure to new microenvironments may affect the biological changes in gCSCs in vivo.

Purpose: To evaluate whether a multimodal approach including craniospinal irradiation (CSI) improves treatment outcome in nongerminomatous germ cell tumor (NGGCT) patients., Methods and Materials: We reviewed the records of 32 patients with NGGCTs. Fourteen patients belonged to the intermediate prognosis group (immature teratoma, teratoma with malignant transformation, and mixed tumors mainly composed of germinoma or teratoma), and 18 patients belonged to the poor prognosis group (other highly malignant tumors). Patients with pure germinoma or mature teratoma were excluded from this study. Nineteen patients were treated with a combination of surgery, chemotherapy, and radiotherapy (RT); 9 patients received chemotherapy plus RT; 3 patients received surgery plus RT; and 1 patient received RT alone. Twenty-seven patients received CSI with a median of 36 Gy (range, 20-41 Gy) plus focal boost of 18-30.6 Gy, and 5 patients received whole-brain RT (WBRT) (20-36 Gy) or focal RT (50.4-54 Gy). The rate of total and subtotal resection was 71.9%. The median follow-up for surviving patients was 121 months., Results: Treatment failed in 7 patients. Three of the 5 patients who received focal RT or WBRT had local failure. Four cerebrospinal fluid (CSF) failures occurred after CSI. No failure occurred in the intermediate prognosis group. Ten-year recurrence-free survival (RFS) and overall survival (OS) for all patients were 77.6% and 74.6%, respectively. Ten-year RFS for the intermediate and poor prognosis groups were 100% and 61.1%, respectively (p = 0.012). OS for the two groups were 85.1% and 66.7%, respectively (p = 0.215). Tumor histology and CSI were significant prognostic factors for RFS, and CSI was significantly associated with OS., Conclusions: A multimodal approach was effective for treating NGGCTs. CSI should be considered for patients with poor prognostic histology., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: We analyzed the usefulness of initial or recurrent treatment of temozolomide (TMZ) in pediatric high-grade gliomas (HGGs)., Methods: Between 2002 and 2010, we performed surgery on 35 patients with 17 glioblastomas, 14 anaplastic astrocytomas, 3 anaplastic oligodendrogliomas, and 1 anaplastic oligoastrocytoma. The male-to-female ratio was 21:14, and the median age was 13 years (range, 3-18 years). The mean follow-up period was 15.9 (± 1.8) months. As the TMZ treatment, 22 patients received the initial treatment and 13 patients at recurrence. We analyzed the prognostic significance of TMZ treatment, tumor location, extent of removal, pathology, and recurrence pattern., Results: The median progression-free survival (PFS) and overall survival (OS) were 9.7 (± 1.4) and 17.8 (± 2.5) months, respectively. Based on univariate analysis, the median PFS was 9.9 (± 1.6) months in the tumors located in the cerebral hemisphere and 5.6 (± 1.3) months in the diencephalon (p = 0.03). Median PFS was 12.5 (± 1.7) months in the initial treatment and 6.8 (±0.8) months in the recurrent treatment (p = 0.03). The median OS was 14.9 (± 2.3) months in glioblastomas and 24.4 (± 4.1) months in tumors with an anaplastic pathology (p = 0.01). The median OS was 12.1 (± 3.7) months in patients with cerebrospinal fluid (CSF) dissemination and 18.2 (± 2.9) months in patients without CSF dissemination (p = 0.02). Grades 3 and 4 treatment-related toxicity occurred in 7.7-9 % of the patients., Conclusions: Initial or recurrent TMZ treatment in pediatric HGGs was safe and tolerable. Initial treatment showed improved PFS compared to recurrent treatment, and both showed similar OS.

Various diseases should be considered when evaluating a suprasellar mass. Diabetes insipidus has been reported as the primary manifestation in a patient with Langerhans cell histiocytosis involving the hypothalamopituitary axis (HPA) and can be helpful for the diagnosis. The use of endoscopic biopsy for suprasellar masses has increased. However, as it is difficult to make a diagnosis with endoscopic biopsy because of the many artifacts, pathologists must be careful. Langerhans cell histiocytosis involving the HPA as solitary lesions is rare. We report the eighth case that provides neurologists, radiologists, and pathologists with various implications.

Background: We evaluated the reliability and validity of the Pediatric Functional Assessment of Cancer Therapy-Childhood Brain Tumor Survivor version 2.0 (pedsFACT-BrS; patient version for grade school children aged 7-12 years)., Methods: After translating and cross-culturally adapting it into Korean, the psychometric properties of the pedsFACT-BrS were evaluated in 148 childhood brain tumor survivors (mean age, 9.67 years). Pre-testing was performed in 25 patients., Results: The pedsFACT-BrS showed good symptom coverage and overall user comprehension. Internal consistency was acceptable, with Cronbach's α coefficients ranging from 0.70 to 0.92. The pedsFACT-BrS also demonstrated good convergent and divergent validities when correlated with the Revised Children's Manifest Anxiety Scale and Kovacs' Children's Depression Scale. The pedsFACT-BrS showed good known-group validity and effectively differentiated between clinically distinct patient groups (patient vs. control groups, and among patients having different Karnofsky scores), but offered only partial discrimination of physical well-being (PWB) scores when patients were grouped by treatment type., Conclusions: Our results indicate that this instrument is reliable and valid and can be used to evaluate the quality of life of Korean childhood brain tumor survivors.

Unlabelled: Potentially harmful effects of irradiation on the developing central nervous system have been well documented. We report 2 pediatric patients with moyamoya syndrome developed after irradiation., Case: A 3-year-old girl had received 4,860 cGy of postoperative radiation for optic pathway glioma. Cerebral angiography 7 months after completion of the radiation therapy revealed progressive cerebral arterial occlusive disease, involving the internal carotid artery on either side of the circle of Willis, with abnormal netlike vessels. Another 5-year-old girl had received 3,600 cGy of postoperative radiation on the cerebrum for a medulloblastoma. Two years later, she was diagnosed with moyamoya syndrome and treated with indirect revascularization. She died due to further progressive obstruction of the right M1 and A1 on the unoperated hemisphere, in spite of well-developed collateral circulation from the superficial temporal artery and middle meningeal artery on the operated left hemisphere. We suggest that radiation therapy with portals typically including carotid siphon may particularly cause vascular damage, regardless of the tumor pathology and lead to radiation-induced moyamoya syndrome. The prognosis may be poorer in case of poor collateral flow and rapid progression. The radiation therapy may cause fatal vascular damage so it should be taken into consideration when a treatment plan is being formulated for young patients., (Copyright © 2011 S. Karger AG, Basel.)

We evaluated the reliability and validity of the Pediatric Functional Assessment of Cancer Therapy-Childhood Brain Tumor Survivor Questionnaire (pedsFACT-BrS, Version 2). This was specifically directed to patients aged 13 years and older (adolescents). The pedsFACT-BrS was translated and cross-culturally adapted into Korean, following standard Functional Assessment of Chronic Illness Therapy methodology. The psychometric properties of the pedsFACT-BrS in adolescents were evaluated in 161 brain tumor (BT) patients (mean age=15.53 years). Pretesting was performed in 30 patients, and the results indicated good symptom coverage and overall comprehensibility. In validating the pedsFACT-BrS for adolescents, we found high internal consistency, with Cronbach's α coefficients ranging from 0.76 to 0.91. The pedsFACT-BrS for adolescents also demonstrated good convergent and divergent validities when correlated with the Revised Children's Manifest Anxiety Scale and the Kovacs' Children's Depression Inventory. The pedsFACT-BrS for adolescents showed good clinical validity and effectively differentiated between clinically distinct patient groups according to Karnofsky score, type of treatment, and treatment on/off status. This reliable and valid instrument can now be used to properly evaluate the quality of life of Korean adolescent BT patients., (Copyright © 2010 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved.)

Background: This study investigated the agreement between self-reports from pediatric brain tumor patients and proxy reports from their parents regarding the patients' quality of life (QOL), as assessed using a brain tumor-specific QOL assessment tool, the Pediatric Functional Assessment of Cancer Therapy-Childhood Brain Tumor Survivors (pedsFACT-BrS) questionnaire. The authors expected moderate correlation and similar mean scores between patient and parent reports., Methods: The pedsFACT-BrS for those aged 7 to 18 years was completed by 351 brain tumor patients (166 children and 185 adolescents), and the parent proxy reports were completed by 351 mother proxies and 37 father proxies. Statistical analyses, including the Pearson product-moment correlation coefficient, intraclass correlation, and comparison of group means, were used to compare the 33 items shared by all 4 versions of the pedsFACT-BrS., Results: The correlation between reports completed by pediatric patients and their parent proxies was significant (P=.59-.84), whereas that between the reports of adolescent patients and their parent proxies was slightly weaker (P=.47-.78). The patient and parent proxy reports showed moderate-to-good agreement and yielded similar mean scores in both the child and adolescent brain tumor patient groups; the sole exception was a difference in emotional well-being scores., Conclusions: The results indicate that proper use of the pedsFACT-BrS for patients and their parent proxies can provide clinicians with valid information about the overall QOL of child and adolescent brain tumor patients, including both their general health and their brain tumor-specific well-being., (Copyright (c) 2010 American Cancer Society.)

Purpose: Until recently, postoperative adjuvant treatment for intracranial teratomas has remained controversial because of the rarity of the tumors and the heterogeneity of histologic types. To define optimal therapy modalities, we retrospectively analyzed the treatment of patients with intracranial teratomas., Methods: Between 1979 and 2007, 31 patients with intracranial teratomas were treated at our institution. The median age of the 31 patients was 14.8 years. The median follow-up time was 72.7 months (range 11 approximately 291 months). Perioperative radiochemotherapy was done in 19 patients. Proper chemotherapy regimens were followed, such as PE (cisplatin and VP-16), PVB (cisplatin, VP-16, and bleomycin), ICE (carboplatin, VP-16, and ifosfamide), and NGGCT (etoposide, carboplatin, bleomycin, and cyclophosphamide with mesna)., Results: Eight patients experienced recurrence, and a second operation was carried out in six patients. Fifteen patients survived for more than 5 years without recurrence, irrespective of having received adjuvant therapies. The 5-year survival rate of the 31 patients was 74%., Conclusion: Treatment of intracranial teratomas is very difficult because of the heterogeneity of the tumor cells from totipotent origins. Accurate histological diagnosis of teratoma subtypes is the most important factor for adequate treatment, and proper therapeutic protocols are needed to cure teratomas.

Purpose: To determine the optimal radiotherapy (RT) dose and volume for treatment of intracranial germinoma., Materials and Methods: Eighty-one intracranial germinoma patients (33 pathologically-verified; 48 presumed by radiosensitivity testing) treated with RT alone between 1971 and 2002 were analyzed. The RT volume varied from focal (13) to whole brain (8), or to the entire neuraxis (60). All the cases after 1982 received craniospinal irradiation (CSI). Radiation dose was reduced gradually during the study period from 59 to 39.3 Gy for primary tumors, and from 34.2 to 19.5 Gy for the neuraxis. The median follow-up time was 120 months (48-260 months)., Results: Five- and ten-year relapse-free survival rates were 98.8% and 94.1%, respectively. All the recurrences occurred in the patients who received local (4/13) or whole brain RT (1/8). None of the patients who received CSI suffered from a recurrence. Forty-six patients received 45 Gy or less to the primary site and 22 patients received less than 20 Gy to the spinal axis., Conclusion: Low-dose CSI-based RT should remain the standard treatment for intracranial germinoma. The RT dose can be reduced to 39.3 Gy for primary tumor sites and to 19.5 Gy for the spinal axis.

Objective: Cavernous malformations (CMs) are vascular malformations affecting any part of the central nervous system. CMs in the pediatric age group are known to be different from those of adults both in origin and clinical characteristics. In this paper, we report our experience in managing CMs in pediatric patients., Materials and Methods: Between January 1994 and December 2006, 33 patients younger than 20 years of age with intracranial CMs were treated with microsurgery or radiosurgery. We retrospectively reviewed the presentation and treatment of these 33 patients (18 boys and 15 girls; average age 11.6 years)., Results: The most common symptom at presentation was seizure (19 children, 57.6%). The most common type of CM, classified on the basis of magnetic resonance imaging, was type II (18, 54.5%). The supratentorial compartment was the most frequent location (27, 71.8%), and only six CMs (18.2%) were observed in the infratentorial compartment. Microsurgery was performed on 25 patients (75.8%), and radiosurgery was performed on eight patients (24.2%). The overall post-treatment results were positive. Only two children (6.1%) had persistent presurgical neurological signs, although the treatment ameliorated them. No progression of the preoperative neurological signs or onset of new neurological deficits was seen in any of the patients. In our patient group, the microsurgical removal of CMs resulted in the prevention of recurrent hemorrhage and the control of seizure disorders in all cases., Conclusions: Our results suggest that pediatric patients with symptomatic CMs should be treated surgically because of the risk of recurrent hemorrhaging and the general benefits of CM removal.

Object: A radiation dose of 40-50 Gy is able to produce a cure rate of more than 90% in intracranial pure germinoma. However, many attempts have been made to reduce the dose and volume of radiation without compromising the disease control rate because of the toxicity of irradiation. This retrospective study is intended to provide the physician with an appropriate therapeutic strategy., Materials and Methods: We reviewed a series of 10 recurrent germinomas among 117 germinomas diagnosed histologically or clinically between 1979 and 2002. These patients involved underwent three different treatment modalities; radiation alone (N = 71), chemotherapy alone (N = 9), and combined therapy (N = 37). The 10-year overall and relapse-free survival rates were 97 and 93% in the radiation alone group, 89 and 67% in the chemotherapy alone group, and 92 and 92% in the combined therapy group, respectively. As expected, both radiation therapy and combined therapy were effective in controlling the disease. Tumor recurrence was closely related to the volume of radiation but not to the dose of radiation. If the tumor bed and craniospinal axis were fully covered, the radiation dose might be reduced. Chemotherapy alone showed earlier recurrence and a higher tumor recurrence rate. In the case of combined therapy, chemotherapy was useful in reducing the radiation dose but revealed some toxicity (death of two patients)., Conclusions: The investigation of a possible further dose reduction seems worthwhile. Radiation therapy alone with a dose of less than 40 Gy should be compared with ongoing chemotherapeutic protocols combined with low-dose irradiation.

Objective and Importance: We report the extremely rare occurrence of a second germ-cell tumor at a different site and with different histological types long after total resolution of a pineal germinoma., Clinical Presentation: A 21-year-old man who presented with headache and diplopia was admitted to our hospital. Neuroradiological studies revealed a tumor in the pineal region. The tumor was biopsied with endoscope, and third ventriculostomy was performed. Histologically, the tumor proved to be a germinoma. The patient received 3 cycles of combination chemotherapy consisting of carboplatin and etoposide with radiotherapy. The tumor was totally resolute. Twelve months later, he was readmitted with headache and diplopia. Neuroradiological studies showed a tumor in the right temporal lobe., Intervention: The second tumor was totally removed. Histologically, the tumor proved to be a mixed germ-cell tumor, which consisted a yolk-sac tumor and a germinoma. After the second course of chemotherapy, magnetic resonance image studies revealed no evidence of the tumor., Conclusion: The second tumor was considered to be a metachronous neoplasm rather than a recurrence of the original mixed germ-cell tumor, which consisted a yolk-sac tumor and a germinoma.

Septins are a highly conserved subfamily of GTPases that play an important role in the process of cytokinesis. To increase our understanding of the expression and localization of the different mammalian septins in human brain tumors, we used antibodies against septins 2, 3, 4, 5, 6, 7, 9, and 11 in immunofluorescence and Western blot analyses of astrocytomas and medulloblastomas. We then characterized the expression and subcellular distribution of the SEPT2 protein in aphidicolin-synchronized U373 MG astrocytoma cells by immunofluorescence and fluorescence-activated cell sorter analysis. To determine the role of SEPT2 in astrocytoma cytokinesis, we inducibly expressed a dominant-negative (DN) SEPT2 mutant in U373 MG astrocytoma cells. We show variable levels and expression patterns of the different septins in brain tissue, brain tumor specimens, and human brain tumor cell lines. SEPT2 was abundantly expressed in all brain tumor samples and cell lines studied. SEPT3 was expressed in medulloblastoma specimens and cell lines, but not in astrocytoma specimens or cell lines. SEPT2 expression was cell cycle-related, with maximal levels in G2-M. Immunocytochemical analysis showed endogenous levels of the different septins within the perinuclear and peripheral cytoplasmic regions. In mitosis, SEPT2 was concentrated at the cleavage furrow. By immunocytochemistry and flow cytometry, we show that a DN SEPT2 mutant inhibits the completion of cell division and results in the accumulation of multinucleated cells. These results suggest that septins are variably expressed in human brain tumors. Stable expression of the DN SEPT2 mutant leads to a G2-M cell cycle block in astrocytoma cells.

Case Report: A 17-month-old infant girl was admitted with complex partial seizures and right side hemiparesis. Five days after the last seizure, MR signal changes were observed in the left hemisphere with a cavernous hemangioma in the middle temporal gyrus. However, these MR signal changes had normalized 11 days after the last seizure, except for the cavernous hemangioma. The scalp EEG findings revealed that the epileptic focus was on the mid-temporal gyrus. The patient underwent lesionectomy only. Two months after this operation the MR showed no signal abnormality. Throughout a 12-month follow-up after surgery the patient remained seizure free., Discussion: MR signal changes in seizure patients do not always indicate the structural region concerned, but can be transient signal changes. They may be due to the propagation of epileptic discharge along the association fiber from the seizure focus. However, transient signal changes after seizure must be followed up to allow exclusion of a tumor and other diseases.

We previously showed that the expression of p16(ink4a) (p16), in conjunction with retinoic acid (RA) treatment in the p16-deficient astrocytoma cell line, U343 MG-A, induced a potent cell cycle arrest in G(1) associated with changes in morphology. In this study, we investigated the effects of p16 expression and RA treatment on the expression and distribution of actin, glial fibrillary acidic protein (GFAP), and vimentin within the U343 MG-A astrocytoma cytoskeleton. Changes in expression and location of the small GTPase, rhoA, were also examined after p16 expression and RA treatment. We showed that p16 expression and RA treatment led to an increase in the expression of GFAP, as well as its reorganization but that it did not significantly affect actin or vimentin expression. p16 induction in combination with RA treatment resulted in a decreased expression and activation of rhoA as determined by immunocytochemistry and Western blot analysis of soluble and insoluble fractions of cell lysates. Endogenous levels of rhoA expression varied among samples in a panel of astrocytoma cell lines as determined by Western blot analysis. Introduction of a dominant active rhoA mutant into p16-induced, RA-treated U343 MG-A astrocytoma cells was associated with the loss of long astrocytic processes and stellate morphology. These data are among the first to report the pattern of rhoA expression in human astrocytoma cell lines. They furthermore suggest that the stellate cell phenotype observed in U343 MG-A astrocytoma cells after cyclin-dependent kinase inhibitor (CKI) induction and RA treatment is accompanied by an inhibition and inactivation of rhoA in this cell system., (Copyright 2002 Wiley-Liss, Inc.)