Existence of glioma stroma mesenchymal stemlike cells in Korean glioma specimens

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.     

Isolation of glioma cancer stem cells in relation to histological grades in glioma specimens

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.     

Changes in the biological characteristics of glioma cancer stem cells after serial in vivo subtransplantation

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.     

Isolation of tumor spheres and mesenchymal stem-like cells from a single primitive neuroectodermal tumor specimen

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.     

Fractionated stereotactic radiotherapy using Novalis for confined intra-orbital optic nerve glioma in pediatric patient

Introduction

Optic gliomas are the most common tumors in the optic pathways during childhood. Among them, about 10 % are located within intra-orbital cavity. However, the optimal management for intra-orbital optic nerve gliomas remains controversial. An 11-year-old male complained about progressive decline of vision in his right eye. Brain MRI revealed a fusiform enlargement of right optic nerve within intra-orbital cavity.

Materials and methods

A presumptive diagnosis of optic nerve glioma was made. Therefore, we performed fractionated stereotactic radiotherapy (FSRT) using Novalis.

Discussion

Five years after FSRT treatment, follow-up MRI revealed size reduction of tumor and visual acuity improvement without radiation-related complications.     

Inhibition of phosphorylated STAT3 by cucurbitacin I enhances chemoradiosensitivity in medulloblastoma-derived cancer stem cells

Introduction

CD133 (PROM1) is a potential marker for cancer stem cells (CSCs), including those found in brain tumors. Recently, medulloblastoma (MB)-derived CD133-positive cells were found to have CSC-like properties and were proposed to be important contributors to tumorigenicity, cancer progression, and chemoradioresistance. However, the biomolecular pathways and therapeutic targets specific to MB-derived CSCs remain unresolved.

Materials and methods

In the present study, we isolated CD133⁺ cells from MB cell lines and determined that they showed increased tumorigenicity, radioresistance, and higher expression of both embryonic stem cell-related and drug resistance-related genes compared to CD133^? cells. Bioinformatics analysis suggested that the STAT3 pathway might be important in MB and CD133⁺ cells. To evaluate the effects of inhibiting the STAT3 pathway, MB-derived CD133^+/? cells were treated with the potent STAT3 inhibitor, cucurbitacin I. Treatment with cucurbitacin I significantly suppressed the CSC-like properties and stemness gene signature of MB-derived CD133⁺ cells. Furthermore, cucurbitacin I treatment increased the apoptotic sensitivity of MB-derived CD133⁺ cells to radiation and chemotherapeutic drugs. Notably, cucurbitacin I demonstrated synergistic effects with ionizing radiation to inhibit tumorigenicity in MB-CD133⁺-inoculated mice.

Results

These results indicate that the STAT3 pathway plays a key role in mediating CSC properties in MB-derived CD133⁺ cells. Targeting STAT3 with cucurbitacin I may therefore represent a novel therapeutic approach for treating malignant brain tumors.     

Initial bradykinin triggers calcium-induced calcium release in C6 glioma cells and its significance

Objective

To investigate the underlying mechanism for the selective modulation of the permeability of blood-tumor barrier (BTB) by small dose of bradykinin (BK).

Methods

C6 glioma cells were treated with BK, and changes of intracellular nitric oxide (NO) and intracellular calcium level were measured with fluorescent spectrophotometer.

Results

The initial application of BK easily triggered extracellular calcium influx, which resulted in intracellular calcium store release in C6 glioma cells. The above mechanism was also named ryanodine mediated calcium induced calcium release (CICR). We also detected a long-lasting intracellular NO elevation in C6 glioma cells upon BK treatment. Further study showed that ryanodine mediated CICR contributed greatly to the secondary NO elevation induced by BK treatment.

Conclusion

These results suggested that BK triggered CICR in C6 glioma cells and the associated NO generation might be the underlying mechanism for the selective modulation of BTB permeability by BK.     

Brain stem tumors in children and adolescents: single institutional experience

Purpose

Pediatric brain stem tumors (BsT) are a heterogeneous group of diseases. Our aim was to analyze our experience to find out prognostic factors.

Method

A retrospective study with BsT patients was performed. Imaging characteristics, extension of surgery, pathology, and adjuvant therapy were analyzed and correlated with overall survival (OS) and progression-free survival (PFS) as outcome measures.

Result

Since 1980 to 2010, we analyzed 65 BsT patients, 41 of them girls (63 %), median age of 8 years (range 13.9?months to 17.6 years). Twenty-two patients (33.8 %) had diffuse intrinsic pontine gliomas (DIPG) and 43 (66.2 %) presented with focal BsT. Histology was available in 42 patients; the most frequent is low-grade glioma in 24/42 patients (57 %). DIPG’s histology (obtained usually at necropsy) confirmed five high-grade gliomas. After median follow-up of 49.3 months (0.5–175 months), 20/22 DIPG patients have died (90.9 %), while 27/43 with focal tumors were alive (62.8 %). Variables related to outcome were histology (better for low-grade glioma (LGG) OS p?<?0.001), surgery (better if operated OS p?<?0.001), and adjuvant therapy (worse if given, PFS p?=?0.001, OS p?=?0.024). The outcome for DIPG was dismal, median OS/EFS of 14.2/9.4 months, significantly worse than focal BsT (p?=?0.000), while OS/EFS was 122.8/87.2 months for focal intrinsic, 88.2/47.1 months for exophytic, and 124.4/54 months for cervico–medullary tumors: no differences were found among them, except the histology (OS p?<?0.001 for low-grade vs high-grade tumors).

Conclusion

BsT in children comprised two different groups: diffuse (DIPG) and focal gliomas. The DIPGs continue having a dismal prognosis, needing new approaches, while focal tumors including LGG have better prognosis.     

Celecoxib enhances radiosensitivity in medulloblastoma-derived CD133-positive cells

Objects

Cyclooxygenase-2 (COX-2), the enzyme that converts arachidonic acid to prostaglandins, is overexpressed in a variety of tumors, including medulloblastoma (MB). CD133, a transmembrane glycoprotein, has been suggested as a marker for cancer stem cells in brain tumors. The aim of the present study was to investigate the role of celecoxib, a selective COX-2 inhibitor, in enhancing the effects of ionizing radiotherapy (IR) on medulloblastoma-derived CD133-positive cells (MB-CD133⁺).

Materials and methods

MB-CD133⁺ were isolated from two medulloblastoma cell lines (Daoy and UW228). Then, they were treated with celecoxib in different concentrations, and cell viability was assessed. The assays of cell survival, soft agar, radiosensitivity, colony formation, and apoptotic activity in MB-CD133⁺ treated with celecoxib alone, radiation alone, or celecoxib combined with radiation were further evaluated.

Results

MB-CD133⁺ showed the self-renew ability to form sphere bodies in vitro and regenerate tumors in vivo. The levels of COX-2 mRNA and protein in MB-CD133⁺ were significantly higher than those in MB-CD133^?. The treatment of 30 μM celecoxib could effectively inhibit the abilities of cell proliferation and colony formation and increase IR-induced apoptosis in treated MB-CD133⁺. Furthermore, in vivo study demonstrated that celecoxib significantly enhanced radiosensitivity in MB-CD133⁺-transplanted grafts. Notably, xenotransplantation analysis demonstrated that the treatment of celecoxib could further suppress the expressions of angiogenic and stemnness-related genes in treated MB-CD133⁺ grafts of SCID mice.

Conclusions

Celecoxib presents the potential of radiosensitizing effect in MB-derived cancer stem cells. Therefore, it should be warranted in future trials to enhance the radiotherapeutic effects in MB patients.     

Combination Therapy for Gliomas Using Temozolomide and Interferon-Beta Secreting Human Bone Marrow Derived Mesenchymal Stem Cells

Objective

Malignant gliomas are the most common primary tumors of the central nervous system and the prognosis of patients with gliomas is poor. The combination of interferon-bata (IFN-β) and temozolomide (TMZ) has shown significant additive antitumor effects in human glioma xenograft models. Considering that the poor survival of patients with human malignant gliomas relates partly to the inability to deliver therapeutic agents to the tumor, the tropism of human bone marrow-derived mesenchymal stem cells (MSC) for malignant gliomas can be exploited to therapeutic advantages. We investigated the combination effects of TMZ and MSCs that secrete IFN-β on gliomas.

Methods

We engineered human MSCs to secret mouse IFN-β (MSC-IFN-β) via adenoviral transduction and confirmed their secretory capacity using enzyme-linked immunosorbent assays. In vitro and in vivo experiments were performed to determine the effects of the combined TMZ and MSC-IFN-β treatment.

Results

In vitro, the combination of MSC-IFN-β and TMZ showed significantly enhanced antitumor effects in GL26 mouse glioma cells. In vivo, the combined MSC-IFN-β and TMZ therapy significantly reduced the tumor size and improved the survival rates compared to each treatment alone.

Conclusion

These results suggest that MSCs can be used as an effective delivery vehicle so that the combination of MSC-IFN-β and TMZ could be considered as a new option for the treatment of malignant gliomas.     

Formation of new lymphatic vessels in glioma: An immunohistochemical analysis

We investigated the distribution and formation of new lymphatic vessels in gliomas. Specimens from seven glioma cases were analyzed by immunohistochemical staining for CD34, lymphatic endothelial hyaluronic acid receptor 1 (LYVE-1), prospero-related homeobox 1 (Prox1), nestin, and hypoxia-inducible factor 1α (HIF-1α). Three types of vessels were observed in glioma specimens: LYVE-1⁺ lymphatic vessels, CD34⁺ blood vessels, and LYVE-1⁺/CD34⁺ blood vessels. Prox1⁺/LYVE-1⁺ cells were distributed in some lymphatic vessels as well as among vascular endothelial cells and glioma cells. Nestin⁺ cells were scattered throughout the gliomas, and some lymphatic cells also expressed nestin. HIF-1α⁺ Prox1⁺ cells were widely distributed within the glioma specimens. The present immunohistochemical analysis revealed upregulation of Prox1 and HIF-1α in some glioma tissues as well as the differentiation of nestin⁺ tumor stem cells into LYVE-1⁺ lymphatic vessels.     

Harvey Cushing��s early experience with pediatric gliomas

Purpose

Diagnosing and operating pediatric patients with intracranial lesions posed a greater diagnostic challenge for physicians during the early twentieth century. At the time, an intracranial neoplasm was indistinctively diagnosed as a glioma, encompassing a broad category of brain tumor pathologies. The treatment and surgical interventions followed for children diagnosed with gliomas is not well-described in the literature from this time.

Methods

Following IRB approval, and through the courtesy of the Alan Mason Chesney Archives, we reviewed the Johns Hopkins Hospital surgical files from 1896?C1912. Patients 18?years or younger, who underwent surgical intervention by Cushing for suspected intracranial tumors, were selected.

Results

Of the eight pediatric cases diagnosed with gliomas by Cushing, four cases were later diagnosed as medulloblastomas by Dr. Cushing in 1925. Of the remaining four pediatric cases, one was diagnosed as a brainstem glioma and another as a ventricular glioma. We describe the remaining two cases.

Conclusion

These examples illustrate Cushing??s approach to treating brain tumors diagnosed as gliomas in pediatric patients, focusing on an initial decompression and followed by a thorough surgical exploration for tumor. Furthermore, these cases demonstrate Cushing??s early attempts to manage such lesions in children and highlight the challenges faced in diagnosing and localizing intracranial lesions within this group of patients.     

Transcerebellar biopsy of diffuse pontine gliomas in children: a technical note

Introduction

The need for a surgical biopsy for diffuse pontine glioma (DPG) is increasing, and a safer and less invasive procedure is required.

Methods

We describe a transcerebellar stereotactic biopsy procedure that can be safely performed in young children. Four pediatric patients with DPG underwent transcerebellar stereotactic biopsies.

Results

All of the patients were diagnosed with gliomas, and one patient had a transient numbness of the lip margin after the procedure.

Discussion

Transcerebellar stereotactic biopsy is a relatively safe way to obtain a tissue diagnosis for children with DPG.     

Endoscopic third ventriculostomy for hydrocephalus in brainstem glioma: a case series

Object

A brainstem glioma is an incurable brain tumor that can be complicated by hydrocephalus. A ventriculoperitoneal (VP) shunt is generally performed for the control of hydrocephalus. This study aimed to reveal the safety and efficacy of an endoscopic third ventriculostomy (ETV) for hydrocephalus in brainstem gliomas.

Methods

Six patients who had pontine glioma with hydrocephalus underwent an ETV between May 2010 and November 2015. In all the cases, there were one or more symptoms of hydrocephalus (headache, nausea, vomiting, or lethargy). Retrospective review of these patients was performed using the medical records and neuroimagings.

Result

The ETV was performed safely and there were no intraoperative complications in all patients. The mean follow-up period was 12.3 months. An immediate symptomatic relief of hydrocephalus and an adequate control of symptoms were achieved without a VP shunt in all patients.

Conclusions

The ETV is considered to be an effective and safe procedure for the treatment of hydrocephalus in brainstem gliomas. Determining the ventriculostomy site according to the preoperative MRI in each case is considered to be important for the safe procedure.

     

Suprasellar pilocytic astrocytoma: one national centre’s experience

Introduction

Pilocytic astrocytomas in the supratentorial compartment make up 20 % of all brain tumours in children with only 5 % of these arising in the suprasellar region. Optic pathway gliomas or suprasellar gliomas are often seen in neurofibromatosis type 1 (NF1) patients. Given their location, suprasellar pilocytic astrocytomas are challenging to manage surgically with high morbidity rates from surgical resection. We assess our cohort of patients with suprasellar pilocytic astrocytoma and document our experience.

Method

A retrospective review of patients diagnosed with suprasellar glioma between 2000–October 2012. We included patients diagnosed with optic pathway glioma based on radiological features (with or without biopsy) and those who had a biopsy confirming pilocytic astrocytoma.

Results

Fifty-three patients included (sporadic tumours 24 and NF1 related 29). Fifteen sporadic and four NF1 patients were biopsied. Twelve sporadic and 13 NF1 patients were initially treated with chemotherapy while only 1 patient had radiotherapy initially. Progression was noted in 58 % of the sporadic group and 24 % of the NF1 group. The only significant factor for progression was NF1 status (p?=?0.026).

Conclusion

Management should be guided by individual patient circumstance. In our cohort, chemotherapy did not significantly improve progression free survival; however, NF1 status significantly correlated with the decreased progression.     

The top cited articles on glioma stem cells in Web of Science

BACKGROUND: Glioma is the most common intracranial tumor and has a poor patient prognosis. The presence of brain tumor stem cells was gradually being understood and recognized, which might be beneficial for the treatment of glioma. OBJECTIVE: To use bibliometric indexes to track study focuses on glioma stem cell, and to investigate the relationships among geographic origin, impact factors, and highly cited articles indexed in Web of Science. METHODS: A list of citation classics for glioma stem cells was generated by searching the database of Web of Science-Expanded using the terms "glioma stem cell" or "glioma, stem cell’" or "brain tumor stem cell". The top 63 cited research articles which were cited more than 100 times were retrieved by reading the abstract or full text if needed. Each eligible article was reviewed for basic information on subject categories, country of origin, journals, authors, and source of journals. Inclusive criteria: (1) articles in the field of glioma stem cells which was cited more than 100 times; (2) fundamental research on humans or animals, clinical trials and case reports; (3) research article; (4) year of publication: 1899-2012; and (5) citation database: Science Citation Index-Expanded. Exclusive criteria: (1) articles needing to be manually searched or accessed only by telephone; (2) unpublished articles; and (3) reviews, conference proceedings, as well as corrected papers. RESULTS: Of 2 040 articles published, the 63 top-cited articles were published between 1992 and 2010. The number of citations ranged from 100 to 1 754, with a mean of 280 citations per article. These citation classics came from nineteen countries, of which 46 articles came from the United States. Duke University and University of California, San Francisco led the list of classics with seven papers each. The 63 top-cited articles were published in 28 journals, predominantly Cancer Research and Cancer Cell, followed by Cell Stem Cell and Nature. CONCLUSION: Our bibliometric analysis provides a historical perspective on the progress of glioma stem cell research. Articles originating from outstanding institutions of the United States and published in high-impact journals are most likely to be cited.     

Primary gliomatosis cerebri involving gray matter in pediatrics: a distinct entity? A multicenter study of 14 cases

Background and purpose

Gliomatosis cerebri (GC) is a rare neoplasm including a variety of tumors, with extremely variable evolution and heterogeneity of prognosis. It may appear either de novo or after a focal glioma, involve predominantly the white or the gray matter, and concern either pediatric or adult patients. We focused on primary GC involving exclusively gray matter in a pediatric population in order better to define the presentation and outcome of this disease.

Patients and methods

We reviewed the databases of seven Departments of Pediatric Oncology to identify pediatric cases of GC between 1990 and 2007. Patients were included if they demonstrated a diffuse infiltrative process involving gray matter in magnetic resonance imaging (MRI) and histological tissue analyses, confirming a proliferative glial disorder.

Results

Fourteen patients with a median age of 8 years were identified. Epilepsy was the main presenting symptom. Brain MRI showed a lesion of the temporal and insular cerebral cortex associated with tumoral infiltration of the thalami and the basal ganglia. Histological examination confirmed the diagnosis of high-grade glioma. Prognosis was always very gloomy in the short term, with a median survival of less than a year.

Conclusion

This rare entity, whose prognosis is appalling whatever the treatment proposed, should be clearly identified within the heterogeneous group of GC in the same way as diffuse intrinsic pontine gliomas have been identified among brain stem tumors. Systematic biopsies appear essential to permit the molecular studies which will assist in guiding the choice of future targeted treatments.     

Cavernous malformation of the optic pathway mimicking optic glioma: a case report

Purpose

Optic pathway cavernous malformations (CMs) are extremely rare, accounting for less than 1 % of all intracranial CMs. We report a case of optic pathway CM mimicking optic glioma because the initial magnetic resonance (MR) images did not disclose hemorrhagic findings such as popcorn-like lesion or hemosiderin ring.

Methods

A 20-year-old woman presented with subacute left visual acuity loss and visual field defect and was referred to our hospital. Initial MR imaging findings were suggestive of optic glioma. Second MR imaging demonstrated hemorrhagic findings, but the hemorrhage was considered to be intratumoral hemorrhage from left optic pilocytic astrocytoma. She underwent radiochemotherapy and intravenous administration of corticosteroids but her symptoms deteriorated. Third and fourth MR imaging revealed enlargement of the hematoma. Therefore, the radiation therapy was interrupted at a delivered dose of 16.2 Gy, and craniotomy was performed to preserve residual right visual field. The lesion was totally removed and the histological diagnosis was CM. Her right visual field was preserved, but not improved.

Results

The present case and previous cases suggest that optic pathway CMs sometimes do not initially manifest with signs of hemorrhage, so CMs should be included in the differential diagnosis of optic pathway lesions.

Conclusions

Histological confirmation with preparation for total resection should be considered for rapidly progressive cases even if the neuroimaging findings are compatible with optic glioma.     

IDH1 mutations are common in malignant gliomas arising in adolescents: a report from the Children��s Oncology Group

Purpose

Recent studies have demonstrated a high frequency of IDH mutations in adult ??secondary?? malignant gliomas arising from preexisting lower grade lesions, often in young adults, but not in ??primary?? gliomas. Because pediatric malignant gliomas share some molecular features with adult secondary gliomas, we questioned whether a subset of these tumors also exhibited IDH mutations.

Experimental design

We examined the frequency of IDH mutations, using real-time polymerase chain reaction and sequencing analysis, in a cohort of 43 pediatric primary malignant gliomas treated on the Children??s Oncology Group ACNS0423 study. The relationship between IDH mutations and other molecular and clinical factors, and outcome, was evaluated.

Results

IDH1 mutations were observed in 7 of 43 (16.3%) tumors; no IDH2 mutations were observed. A striking age association was apparent in that mutations were noted in 7 of 20 tumors (35%) from children ??14?years, but in 0 of 23 (0%) younger children (p?=?0.0024). No association was observed with clinical factors other than age. One-year event-free survival was 86?±?15% in the IDH-mutated group versus 64?±?8% in the non-mutated group (p?=?0.03, one-sided logrank test). One-year overall survival was 100% in patients with mutations versus 81?±?6.7% in those without mutations (p?=?0.035, one-sided logrank test).

Conclusions

IDH1 mutations are common in malignant gliomas in older children, suggesting that a subset of these lesions may be biologically similar to malignant gliomas arising in younger adults and may be associated with a more favorable prognosis.