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Purpose: The KNOG-1101 study showed improved 2-year PFS with temozolomide during and after radiotherapy compared to radiotherapy alone for patients with anaplastic gliomas. This trial investigates the effect of concurrent and adjuvant temozolomide on health-related quality of life (HRQoL)., Materials and Methods: In this randomized, open-label, phase II trial, 90 patients with World Health Organization grade III glioma were enrolled across multiple centers in South Korea between March 2012 to February 2015 and followed up through 2017. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire 30 (EORTC QLQ-C30) and 20-item EORTC QLQ-Brain Neoplasm (QLQ-BN20) were used to compare HRQoL between patients assigned to concurrent chemoradiotherapy with temozolomide followed by 6 cycles of adjuvant temozolomide (arm A) and radiotherapy (RT) alone (arm B)., Results: Of the 90 patients in the study, 84 patients (93.3%) completed the baseline HRQoL questionnaire. Emotional functioning, fatigue, nausea and vomiting, dyspnea, constipation, appetite loss, diarrhea, seizures, itchy skin, drowsiness, hair loss, and bladder control were not affected by the addition of temozolomide. All other items did not differ significantly between arm A and arm B throughout treatment. Global health status particularly stayed consistent at the end of adjuvant temozolomide (p=0.47) and at the end of RT (p=0.33)., Conclusion: The addition of concurrent and adjuvant temozolomide did not show negative influence on HRQoL with improvement of progression-free survival for patients with anaplastic gliomas. The absence of systematic and clinically relevant changes in HRQoL suggests that an overall long-term net clinical benefit exists for concurrent and adjuvant temozolomide.

Introduction: A mixed germ cell tumor with a teratoma component can become enlarged following chemotherapy, and such an event is diagnosed as growing teratoma syndrome. Removing large, hypervascular tumors including a tumor encased by developed vasculatures from the pineal region is challenging during a single operation., Case Report: A 15-year-old male underwent chemotherapy for mixed germ cell tumors according to the KSPNO G082 protocol. This case of a mixed germ cell tumor with growing teratoma syndrome was recognized very early during chemotherapy. The tumor was completely removed during the staged operations. First, the anteriorly located tumor on the third ventricle was removed via the transcallosal interforniceal approach, and 1 month later, the occipital transtentorial approach was used for the pineal tumor with decreased vascularity., Conclusion: Performing staged operations could be recommended for large hypervascular pineal tumors, which can be safely removed during the second operation once vascularity has decreased., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: An open-label single-arm phase 2 study was conducted to evaluate the role of levetiracetam as a sensitizer of concurrent chemoradiotherapy (CCRT) for patients with newly diagnosed glioblastoma. This study aimed to determine the survival benefit of levetiracetam in conjunction with the standard treatment for glioblastoma., Methods: Major eligibility requirements included histologically proven glioblastoma in the supratentorial region, patients 18 years or older, and Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. Levetiracetam was given at 1,000-2,000 mg daily in two divided doses during CCRT and adjuvant chemotherapy thereafter. The primary and the secondary endpoints were 6-month progression-free survival (6mo-PFS) and 24-month overall survival (24mo-OS), respectively. Outcomes of the study group were compared to those of an external control group., Results: Between July 2016 and January 2019, 76 patients were enrolled, and 73 patients were included in the final analysis. The primary and secondary outcomes were improved in the study population compared to the external control (6mo-PFS, 84.9% vs. 72.3%, p = 0.038; 24mo-OS, 58.0% vs. 39.9%, p = 0.018), but the differences were less prominent in a propensity score-matched analysis (6mo-PFS, 88.0% vs. 76.9%, p = 0.071; 24mo-OS, 57.1% vs. 38.8%, p = 0.054). In exploratory subgroup analyses, some results suggested that patients with ages under 65 years or unmethylated MGMT promoter might have a greater survival benefit from the use of levetiracetam., Conclusions: The use of levetiracetam during CCRT in patients with newly diagnosed glioblastoma may result in improved outcomes, but further investigations are warranted., (© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

The promising immunotherapy effects of a multiple antigenic peptide on glioblastoma (GBM) in a previous study encourage the use of adjuvants to enhance its therapeutic efficacy. Among adjuvants, pan HLA-DR-binding epitope (PADRE) and anti-programmed cell death protein 1 (anti-PD1) have potentially been tested for cancer immunotherapy. Therefore, here we evaluated the ability of PADRE and anti-PD1 to enhance the function of the branched multipeptide against GBM. The potential utility of tumor-associated antigens (ErbB-2 and WT-1) targeting GBM with HLA-A24 was confirmed and a branched multipeptide was constructed from these antigens. The effects of the branched multipeptide and PADRE on immunophenotyping and polarized Th cytokine production in dendritic cells were clarified. The expression of PD1 on T cells and PDL1 on GBM cells was also investigated. The interferon-γ enzyme-linked immunospot and lactate dehydrogenase release assays were performed to determine the function of GBM peptide antigen-specific cytotoxic T cells against GBM cells. Overall, this study showed that both ErbB-2 and WT-1 are potential candidates for branched multipeptide construction. The branched multipeptide and PADRE enhanced the expression of major histocompatibility complex and co-stimulatory molecules and the production of polarized Th1 cytokines in dendritic cells. The increase in the number of interferon-γ+ effector T cells was consistent with the increase in the percentage specific lysis of GBM target cells by GBM peptide antigen-specific cytotoxic T cells in the presence of the branched multipeptide, PADRE, and anti-PD1. Our study suggests the combination of branched multipeptide and adjuvants such as PADRE and anti-PD1 can potentially enhance the effects of immunotherapy for GBM treatment., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

In malignant gliomas, invasive phenotype and cancer stemness promoting resurgence of residual tumor cells render treatment very difficult. Hence, identification of epithelial-mesenchymal transition (EMT) factors associated with invasion and stemness of glioma cells is critical. To address the issue, we investigated several EMT factors in hypermotile U87MG and U251 cells, orthotopic mouse glioma model, and human glioma samples. Of several EMT markers, SLUG expression was notably increased at the invasive fronts of gliomas, both in mouse tumor grafts and human glioma samples. The biological role played by SLUG was investigated using a colony-forming assay after chemotherapy and irradiation, and by employing a neurosphere culture assay. The effect of SLUG on glioma progression was examined in our patient cohort and samples, and compared to large public data from the REMBRANDT and TCGA. Genetic upregulation of SLUG was associated with increased levels of stemness factors and enhanced resistance to radiation and temozolomide. In our cohort, patients exhibiting lower-level SLUG expression evidenced longer progression-free survival (P = 0.042). Also, in the REMBRANDT dataset, a group in which SLUG was downregulated exhibited a significant survival benefit (P < 0.001). Although paired glioblastoma samples from our patients did not show a significant increase of SLUG expression, increased mRNA levels of SLUG were found in recurrent glioblastoma from TCGA (P = 0.052), and in temozolomide-treated glioma cells and mouse tumor grafts. SLUG may contribute to glioma progression by controlling invasion at infiltrating margins, associated with increased stemness and therapeutic resistance.

Background: Although 11C-methionine positron emission tomography (MET-PET) images can be fused with magnetic resonance (MR) images using planning software for gamma knife radiosurgery (GKR), the stereotactic information has limited value in patients with recurrent malignant brain tumor due to the difference in imaging protocols between MET-PET and MR images. The aim of this study was to evaluate the clinical application of MR imaging (MRI)-deformed MET-PET images in GKR using a deformable registration tool., Methods: We examined the enhanced MR stereotactic images, MET-PET and MRI-deformed MET-PET images without stereotactic information for 12 newly developed metastatic brain tumors. MET-PET and MRI-deformed MET-PET images were co-registered with the MR stereotactic images using radiosurgery planning software. Visual analysis was performed to determine whether the MET-PET and MR images matched better after using the deformable registration tool. In addition, the matching volume between MR and MET-PET images was compared before and after applying this tool. The matching volume was calculated as the metabolic tumor volume on the MET-PET images, including the MR-enhanced volume. The matching percentage was calculated as the matching volume divided by the MR-enhanced volume, multiplied by 100., Results: Visual analysis revealed that the MRI-deformed MET-PET images provided the same axial plane as that of the MR images, with the same window level, enabling easy identification of the tumor with the radiosurgery planning software. The mean matching percentage of the MET-PET/MR fusion images was 61.1% (range 24.7-94.7) and that of the MRI-deformed MET-PET/MR fusion images was 63.4% (range 20.8-94.3). No significant difference was found in the matching percentage between the two types of fusion images (p = 0.754)., Conclusions: The MRI-deformed MET-PET images enable utilization of the functional information when planning a treatment in GKR without significant volume change., (© 2019 S. Karger AG, Basel.)

Introduction: Optimal treatment strategies for low-grade glioma (LGG) remain controversial. We analyzed treatment outcomes and evaluated prognostic factors of adult LGG patients in Korea., Methods: We reviewed the medical records of 555 patients diagnosed with WHO grade II LGG (astrocytoma 37.8%, oligoastrocytoma 15.3%, and oligodendroglioma 46.8%) at 14 institutions between 2000 and 2010. Primary and secondary endpoints were progression-free survival (PFS) and overall survival (OS). Propensity-score matching (PSM) analyses were performed to correct imbalances in patient/tumor characteristics among adjuvant treatment groups., Results: The median follow-up time was 83.4 months, and the 5-year PFS and OS rates were 52.2% and 83.0%, respectively. Male, older age, poorer performance status, multiple lobe involvement, and astrocytoma histology were associated with poorer survival. Among the treatment factors, gross total resection (GTR) was associated with better PFS and OS, and adjuvant chemotherapy with improved PFS. Interestingly, adjuvant radiotherapy (RT) did not improve PFS; rather, it was related with poorer OS. Regarding patient/tumor characteristics, the RT group had poorer characteristics than the non-RT group. After PSM, we detected a tendency for improved PFS in the matched RT group, and no significant difference in OS compared with the matched non-RT group., Conclusions: The achievement of GTR is important to improve survival in LGG patients. Adjuvant chemotherapy may enhance PFS, but adjuvant RT did not improve survival outcomes. After PSM, we observed potential impacts of adjuvant RT on PFS. Our results may reflect real-world practice and consequently may help to optimize treatment strategies for LGG.

Glioma is one of the most devastating and refractory cancers. The main factors underlying therapeutic failure include extremely invasive characteristics and lack of effective methods for drug delivery. Attenuated Salmonella strains presented a high concentration of tumor targets in various types of cancer models, suggesting a role as potential vectors for drug delivery. In this study, we genetically engineered an attenuated strain of Salmonella as an anti-invasive vector for the targeted delivery and expression of tissue inhibitor of metalloproteinases 2 (TIMP-2) in an orthotopic nude mouse model of glioma. The bioluminescence signals related to tumor size significantly declined in the TIMP-2-expressing Salmonella (SLpTIMP-2)-treated group compared with the control group. Compared with the control group with a survival rate of an average of 33 days, the SLpTIMP-2 group showed an extended survival rate by nearly 60% and lasted an average period of 53 days with TIMP-2 induction. These results indicated the promising therapeutic potential of S. typhimurium for targeted delivery and secretion of TIMP-2 in glioma., (Copyright © 2018. Published by Elsevier B.V.)

We investigated the diagnostic and prognostic significance of metabolic parameters from 11 C-methionine (MET) positron emission tomography (PET) in patients with malignant glioma. The MET-PET was examined in 42 patients who had been previously treated with adjuvant treatment for malignant glioma. Both ratios of maximal MET uptake of the tumors to those of the contralateral normal gray matter (T/N ratio) and metabolic tumor volume (MTV) were estimated in each lesion. The diagnostic performance for recurrence was investigated in all enrolled patients. A definitive diagnosis was done with pathologic confirmation or clinical follow-up. Among recurrent patients, we evaluated the prognostic value of metabolic parameters (T/N ratio and MTV) as well as clinical factors. Among 42 patients, 35 patients were revealed with recurrence. Both T/N ratios (p = 0.009) and MTV (p = 0.001) exhibited statistical significance to differentiate between recurrence and post-treatment radiation effect. A T/N ratio of 1.43 provided the best sensitivity and specificity for recurrence (91.4 and 100 %, respectively), and a MTV of 6.72 cm 3 provided the best sensitivity and specificity (77.1 % and 100 %, respectively). To evaluate the prognostic impact, different cutoffs of MTV were examined in patients with recurrent tumor and a threshold of 60 cm 3 was determined as a best cutoff value to separate the patients in two prognostic groups. Univariate analysis revealed improved overall survival (OS) for patients with Karnofsky performance scale (KPS) score ≥70 (p < 0.001) or MTV <60 cm 3 (p = 0.049). Multivariate analysis showed that patients with KPS score ≥70 (p < 0.001; hazard ratio = 0.104; 95 % CI, 0.029-0.371) or MTV < 60 cm 3 (p = 0.031; hazard ratio = 0.288; 95 % CI, 0.093-0.895) were significantly associated with a longer OS. However, T/N ratio was not correlated with patients' outcome. Metabolic parameters had the diagnostic value to differentiate recurrence from post-treatment radiation effect. Compared with T/N ratio, MTV was an independent significant prognostic factor with KPS score in patients with recurrent tumor. Our study had a potential to manage these patients according to prognostic information using MET-PET.

Background: Even with great advances in surgery and improved clinical outcome, morbidity and mortality are still high for large-volume intracranial meningiomas (MNGs). Recently, Gamma Knife radiosurgery (GKS) has proven to be a safe and effective treatment for many patients with intracranial MNGs. However, single-session GKS may increase the risk of radiation-induced toxicity for large MNGs. Recently, fractionated GKS (FGKS) has been performed for an increasing number of patients with surgically high-risk and large intracranial tumors. In this study, we report our results on the efficacy and safety of FGKS for large MNGs., Methods: The authors performed a retrospective review of 70 patients who underwent GKS for large-volume (>10 cm 3 ) intracranial MNGs between 2004 and 2015, with a minimum follow-up of 12 months. The authors classified these patients into 2 groups of single-session GKS, FGKS. The patients were followed by clinical examination and serial imaging with magnetic resonance imaging., Results: In the single-session GKS group (42 patients), the median tumor volume was 15.2 cm 3 (range 10.3-48.3 cm 3 ); the median prescription dose was 12 Gy (range 8-14 Gy), and the median follow-up duration was 57.8 months (range 14.5-128.4 months). In the FGKS group (28 patients), the median tumor volume was 21 cm 3 (range 10.2-54.7 cm 3 ), and the median prescription was 7.5 Gy in 2 fractions (range 5-8 Gy), 6 Gy in 3 fractions (range 5-6.5 Gy), and 4.5 Gy in 4 fractions. The median follow-up duration for the FGKS group was 50 months (range 12.5-90.6 months). The overall 5-year tumor control rate was 92.9% in the FGKS group and 88.1% in the single-session GKS group. Fourteen (33.3%) symptomatic complications after single-session GKS were noted, including 5 cases of hemiparesis, 4 of seizure, 3 of peritumoral edema, and 2 of hydrocephalus. Two (7.1%) symptomatic complications after FGKS were noted, including 2 cases of hemiparesis. The FGKS group had higher progression-free survival (PFS) rate at 5 years (92.9% vs. 88.1%), but the differences did not reach statistical significance (P = 0.389). The patients in the FGKS group, however, experienced a lower complication rate compared with patients with a single-session GKS group (P = 0.017, hazard ratio, 5.7:1)., Conclusion: When the large-volume (>10 cm 3 ) intracranial MNGs are expected to have high morbidity after microsurgery and for patients that have a poor medical status for surgery, FGKS can be considered an alternative with good tumor control and lower complications rates compared with single-session GKS (P = 0.017)., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: The purpose of this study was to investigate the feasibility and survival benefits of combined treatment with radiotherapy and adjuvant temozolomide (TMZ) in a Korean sample., Materials and Methods: A total of 750 Korean patients with histologically confirmed glioblastoma multiforme, who received concurrent chemoradiotherapy with TMZ (CCRT) and adjuvant TMZ from January 2006 until June 2011, were analyzed retrospectively., Results: After the first operation, a gross total resection (GTR), subtotal resection (STR), partial resection (PR), biopsy alone were achieved in 388 (51.7%), 159 (21.2%), 96 (12.8%), and 107 (14.3%) patients, respectively. The methylation status of O 6 -methylguanine-DNA methyltransferase (MGMT) was reviewed retrospectively in 217 patients. The median follow-up period was 16.3 months and the median overall survival (OS) was 17.5 months. The actuarial survival rates at the 1-, 3-, and 5-year OS were 72.1%, 21.0%, and 9.0%, respectively. The median progression-free survival (PFS) was 10.1 months, and the actuarial PFS at 1-, 3-, and 5-year PFS were 42.2%, 13.0%, and 7.8%, respectively. The patients who received GTR showed a significantly longer OS and PFS than those who received STR, PR, or biopsy alone, regardless of the methylation status of the MGMT promoter. Patients with a methylated MGMT promoter also showed a significantly longer OS and PFS than those with an unmethylated MGMT promoter. Patients who received more than six cycles of adjuvant TMZ had a longer OS and PFS than those who received six or fewer cycles. Hematologic toxicity of grade 3 or 4 was observed in 8.4% of patients during the CCRT period and in 10.2% during the adjuvant TMZ period., Conclusion: Patients treated with CCRT followed by adjuvant TMZ had more favorable survival rates and tolerable toxicity than those who did not undergo this treatment., Competing Interests: relevant to this article was not reported.

We investigated the use of cytotoxic T-lymphocyte (CTL) epitopes in peptide immunotherapy for glioblastoma. Three peptides (ERBB2, BIRC5 and CD99) were selected based on their peptide-T2 cell binding affinities and combined in a multipeptide cocktail or a branched multipeptide synthesized with mini-polyethylene glycol spacers. Dendritic cells (DCs) pulsed with the multipeptide cocktail or branched multipeptide were compared based on their immunophenotype and cytokine secretion. FACS analysis of alpha-type 1 polarized dendritic cells (αDC1s) revealed that both groups highly expressed CD80, CD83 and CD86, indicating that both treatments efficiently generated mature αDC1s with the expected phenotype. Production of IL-12p70, IL-12p40 and IL-10 also increased upon αDC1 maturation in both groups. CTLs stimulated by either αDC1 group ("DC-CTLs") included numerous IFN-γ-secreting cells against T2 cells loaded with the corresponding multipeptides. Large numbers of IFN-γ-secreting cells were observed when human glioblastoma cell lines and primary cells were treated with multipeptide-pulsed DC-CTLs. Both multipeptide-pulsed DC-CTL groups exhibited cytotoxic activity of 40-60% against the U251 cell line and 60-80% against primary cells. Branched multipeptide from ERBB2, BIRC5 and CD99 stably bound with T2 cells, and its cytotoxicity toward target cells was similar to that of the multipeptide cocktail. Thus, branched multipeptides could be promising candidates for immunotherapeutic glioblastoma treatment., Competing Interests: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

Purpose: Pilocytic astrocytoma (PA) is a World Health Organization grade I neoplasm that generally follows a benign course. However, in some patients, PA exhibits an aggressive clinical course. Here, we examined the clinical course of pediatric and adult PAs with progression at a single institution., Methods: Between 1995 and 2013, 39 patients with PA were treated. Nineteen were pediatric patients (mean age, 12 years; range, 1-17 years) with a male-to-female patient ratio of 10:9, while 20 were adults (mean age, 36.4 years; range, 19-65 years) with a male-to-female ratio of 9:11. We analyzed and compared tumor location, extent of tumor resection, adjuvant treatment, and clinical course in all patients., Results: In the 19 pediatric patients, tumors were located in the cerebellar vermis, cerebellar hemisphere, optic pathways plus hypothalamus, hypothalamus, brainstem, and the temporal lobe in 6 (31.6%), 5 (26.3%), 3 (15.8%), 2 (10.5%), and 2 (10.5%) patients and 1 (5.3%) patient, respectively. The mass was totally, subtotally, or partially resected in 11 (57.9%), 2 (10.5%), and 4 (21.1%) patients, respectively; biopsies were performed in 2 (10.5%) patients. Immediate postoperative adjuvant treatment was carried out in 6 patients. Tumor progression was detected in 3 patients at 3.0, 4.6, and 5.2 years after treatment, respectively, without significant symptoms. In the 20 adult patients, tumors were located in the cerebellar hemisphere, cerebellar vermis, hypothalamus, brainstem, cerebral hemisphere, and lateral ventricle in 5 (25%), 4 (20%), 3 (15%), 3 (15%), 3 (15%), and 2 (10%) patients, respectively. The mass was totally, subtotally, or partially resected in 11 (55%) and 6 (30%) patients and 1 (5%) patient, respectively; biopsies were performed in 2 patients. Immediate adjuvant treatment was carried out in 2 patients. Progression was detected in 3 patients at 0.3, 0.9, and 2.5 years after treatment, respectively, with progressive neurologic symptoms. There was one case of disease-related mortality during follow-up among the adult patients., Conclusion: Most of the PA cases evaluated in this study were benign. However, tumor progression in adult PAs followed a more aggressive clinical course than those in pediatric PAs.

Objective: Radiotherapy (RT) has been advocated for gliomatosis cerebri (GC) to delay tumor progression. However, patients with GC may experience poor performance status without recurrence after RT. Herein, we reviewed the responses of patients with GC treated with RT., Materials and Methods: Seventeen patients with diffuse radiologic infiltration of more than two cerebral lobes and diagnosed as having grade II (N=12) or III (N=5) glioma were treated with a mean radiation dose of 51.8 Gy (range, 42-59.4 Gy). The mean radiation volume to a mean marginal dose of 42.8 Gy (range, 36-45 Gy) was 693.4 cc (range, 316.5-1279.6 cc), which was 45.3% of the mean whole brain volume. We reviewed the clinical prognostic factors related to progression-free survival (PFS) and overall survival (OS) in all patients and described characteristics of patients with poor performance (Eastern Cooperative Oncology Group performance scale 3-4) without recurrence., Results: In all patients, the median PFS was 12.3 months, and oligodendroglial pathology (p=0.002) and non-enhanced tumor (p=0.002) were associated with an improved PFS. The median OS was 39.3 months, and young age and adjuvant chemotherapy were associated with improved OS (p=0.022 and 0.002, respectively). Based on multivariate analysis, adjuvant chemotherapy was significantly associated with a longer OS (p=0.012; hazard ratio=0.099; 95% CI, 0.016-0.596). Five patients (29.4%) showed poor performance without recurrence. The median age of these 5 patients was 65 years (range, 60-75 years). The mean radiation volume to a mean marginal dose of 41 Gy (range, 36-45 Gy) was 539.9 cc (range, 255.5-983.1 cc). The pathologic diagnosis was grade II glioma in 2 patients and grade III in 3 patients. The median OS was 10.0 months (range, 8.2-45.9 months)., Conclusions: Some GC patients, especially the elderly, might have a poor performance status without recurrence after RT of a larger radiation field., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: Gamma knife radiosurgery (GKRS) has been increasingly employed for the treatment of elderly patients with brain metastases, mainly due to its demonstrated effectiveness and low complication rate. However, only a few studies have investigated the prognostic factors that influence the survival of elderly patients after GKRS. The purpose of this study was to identify a scoring system that is able to predict the survival of elderly patients undergoing GKRS using data obtained at the time of diagnosis for brain metastases., Methods: Between 2004 and 2011, death was confirmed in 147 patients aged 70 years and older who had been treated with GKRS for brain metastases. Median age at the time of GKRS was 75.7 years (range, 70-86 years). The median tumor volume was 5.1 cm(3) (range, 0.05-59.9 cm(3)). The median marginal prescription dose was 21.4 Gy (range, 14-25 Gy)., Results: The median survival was 167 days. Overall survival rates at 6 months and 1 year were 60.4% and 29.4%, respectively. Among the patient characteristics pertaining to systemic cancer and brain metastasis for which data were obtained preoperatively, a multivariate analysis showed that low Karnofsky performance status (KPS ≤ 80, P = 0.047) and the presence of extracranial metastases (P = 0.014) detected at the time of brain metastasis diagnosis were independent prognostic factors for short survival. A high score index for radiosurgery (SIR score ≥ 4, P = 0.024) and a high graded prognostic assessment (GPA score ≥ 2, P = 0.004) were associated with longer survival. A multivariate analysis of the important characteristics of systemic cancer, and the scoring system evaluating survival duration showed that a low GPA score was the most powerful independent factor for predicting short survival (hazard ratio 1.756, 95% confidence interval 1.252-2.456, P = 0.001)., Conclusions: GKRS is a safe approach to treat brain metastases in patients age 70 years and older. In this group, our study identified GPA score at the time of GKRS as a powerful prognostic factor for survival.

Background: We report a case of progressive multiple cavernous angiomas., Patient and Method: A 16-year-old boy presented with a 2-month history of headache and dizziness. Six years earlier, he underwent surgery for cerebellar medulloblastoma and subsequent chemoradiotherapy according to the M-051 protocol of the Korean Society of Pediatric Neuro-Oncology. Follow-up brain magnetic resonance imaging (MRI) revealed a tiny hemorrhage on the cerebellum 3 months after 23.4-Gy craniospinal and 32.4-Gy boost radiotherapy., Result: The multiple hemorrhagic lesions had progressively developed on the whole brain without any symptoms for 6 years. On admission, MRI revealed a 1.5-cm enlarged mass with subacute hemorrhage on the right frontal area. The mass was totally removed and diagnosed as cavernous angioma. However, 5 months later, the patient complained of a headache. MRI revealed 1.4- and 0.7-cm enlarged masses on the left frontal and right temporal areas with internal hemorrhage, respectively. The left frontal mass was totally removed, and the histopathological finding was suggestive of cavernous angioma., Conclusion: This case showed early-developed multiple hemorrhagic lesions after radiotherapy, which had been progressive and were associated with some symptomatic cavernous angiomas. Pediatric patients with brain radiotherapy should undergo radiological check-up to identify vascular lesions, especially symptomatic patients., (© 2015 S. Karger AG, Basel.)

Objective: The median survival of leptomeningeal metastases is short despite therapy and is sometime associated with hydrocephalus. We investigated the prognostic significance of surgically treated hydrocephalus in leptomeningeal metastases., Materials and Methods: Between December 2005 and November 2012, 1343 patients had brain metastases from systemic solid tumors. Of these, 71 patients (5.3%) experienced leptomeningeal metastases from 45 lung cancers, 14 breast cancers, 4 gastric cancers and 8 other cancers. The mean age was 60 years (range 37-89). The clinical symptoms presented in the cerebral hemisphere and cerebellum in 58 patients, cranial nerve in 7 patients and spinal cord and nerves in 6 patients. Twenty-nine (40.8%) patients were Radiation Therapy Oncology Group recursive partitioning analysis (RTOG-RPA) class II and 42 (59.2%) were class III. Hydrocephalus was associated in 18 (25.4%) patients and 7 patients underwent ventriculoperioneal shunt. The primary cancer, clinical symptoms, RTOG-RPA class, surgically treated hydrocephalus and systemic chemotherapy were analyzed as the prognostic factors for overall survival., Results: The overall incidence of leptomeningeal seeding was 5.0% of the brain metastases. The median duration of leptomeningeal metastases from first brain metastasis was 4.0 months and 24 (33.8%) patients showed leptomeningeal metastases as the first form of brain metastasis. The median overall survival (OS) was 2.1 months. Based on the univariate and multivariate analyses, RTOG-RPA class II patients, treatment of leptomeningeal metastases (such as radiotherapy or intrathecal chemotherapy) and systemic chemotherapy improved OS with statistical significance. Surgically untreated hydrocephalus (median OS, 1.7 months) showed poor OS compared with surgically treated hydrocephalus (median OS, 5.7 months) and no hydrocephalus (median OS, 2.3 months) without statistical significance., Conclusions: The leptomeningeal metastases were often associated with hydrocephalus and the surgical treatment was helpful in limited patients. The prognosis was related with RTOG-RPA class and treatment of local and systemic treatment., (Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved.)

We present to our knowledge the first patient with histopathologically proven brain metastasis from extramammary Paget's disease (EMPD) and discuss the effect of brain radiation therapy for this condition. A 68-year-old man presented to our hospital with headache and gait disturbance. Brain MRI showed multiple enhancing mass lesions, and two large cystic lesions in the left cerebellum. The patient had been diagnosed with scrotal Paget's disease 3 months previously but no further management had been performed due to his refusal. The patient underwent stereotactic aspiration and biopsy of the two large cystic lesions. A histopathological examination revealed that the tumor was a metastatic adenocarcinoma. Immunohistochemical staining revealed that the tumor cells were strongly positive for cytokeratin 7 and moderately positive for carcinoembryonic antigen and gross cystic disease fluid protein 15. These findings were similar to those of his scrotal skin lesions and were consistent with metastatic EMPD. The patient underwent brain radiation therapy with a total radiation dose of 30 Gy in 10 fractions. The patient improved neurologically so as to be self-ambulatory, and a mild improvement in the metastatic tumors was found on follow-up MRI. We had planned systemic chemotherapy, but the patient died of acute respiratory failure 2 months after radiation therapy., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: Surgical removal is the first choice of treatment for large cystic brain metastases. However, some patients cannot undergo surgical resection due to their general condition and/or the tumor location., Aims: In this study, we investigated the feasibility and safety of stereotactic cyst aspiration and gamma knife radiosurgery (GKR) as an alternative treatment for these lesions and followed the volumetric changes in cystic and solid portions., Methods: Between February 2005 and March 2012, a total of 24 patients underwent GKR after cyst aspiration for 29 cystic metastatic brain tumors. The median age was 60 years (range, 18-81). The number of male patients was 18 and that of female patients 6. Most of the patients were in class II (87.5%) based on the data of the Radiation Therapy Oncology Group using recursive partitioning analysis. We analyzed the changes in tumor volume, the local control rate, intracranial progression-free survival (PFS) and overall survival (OS)., Results: Before aspiration, the mean total tumor volume was 32.7 cm(3) (range, 12.1-103.3) and cystic volume was 18.6 cm(3) (range, 8-72.3). The mean duration of cyst drainage was 1 day (range, 1-2). The mean amount of aspiration was 16.8 cm(3) (range, 6-67.4). After aspiration, the total mean volume was 12.4 cm(3) (range, 3.7-38.1) and cystic volume was 2.0 cm(3) (range, 0.1-9.5). The nature of the cyst was serous in 18, serous and hemorrhagic in 3, and serous and necrotic in 8. The median prescription dose was 16 Gy (range, 14-20). There was no treatment-related complication. The local control rate was 58.6% (17/29). The median survival to local recurrence was 6.0 (±1.42) months. During the follow-up period, an Ommaya reservoir was placed in 3 patients. Insertion of an Ommaya reservoir and whole-brain radiotherapy (WBRT) or GKR were done in 2 patients, WBRT in 2, GKR in 1 and operation in 1. The median intracranial PFS and OS after intracranial metastasis was 5.2 (±0.42) and 6.8 (±0.38) months., Conclusions: Cyst aspiration and GKR were feasible and safe but not very efficient, which could be an alternative option for large cystic metastases in patients who could not expect longer survival time., (2014 S. Karger AG, Basel.)

Background: The incidence of brain metastasis from hepatocellular carcinoma (HCC) is expected to increase as a result of prolonged survival due to the recent advances in HCC treatment. However, there is no definite treatment strategy for brain metastasis from HCC mainly due to its rarity and dismal prognosis. To provide helpful recommendations in treatment of brain metastasis from HCC, the authors aimed to identify prognostic factors that influence survival rates with a review of the recently published data., Methods: Thirty-three cases of brain metastasis, whose incidence was 0.65%, were selected from a total of 5015 HCC patients and reviewed retrospectively in terms of clinical and radiological features., Results: Median overall survival time after diagnosis of brain metastasis was 10.4 weeks (95% confidence interval [CI], 5.1-15.7 weeks) with 1-, 6- and 12-month survival rates, of 79%, 24% and 6%, respectively. Median survival of the patients treated with surgical resection or surgical resection followed by whole-brain radiation therapy (WBRT) (25.3 weeks; range, 15.8-34.8 weeks) was longer than that of the patients treated with gamma knife surgery (GKS), WBRT, or GKS followed by WBRT (10.4 weeks; range, 7.5-13.3 weeks) as well as that of patients treated with only steroids (1 week; range, 0.0-3.3 weeks) (p<0.001). Child-Pugh's classification A group had a longer median survival time than Child-Pugh's classification B or C group (14.4 weeks vs 8.4 weeks, p=0.038). RPA class I & II group had also a longer median survival time than RPA class III group did (13.4 weeks vs 2.4 weeks, p=0.001). Surgical resection (hazard ratio [HR] 0.23, 95% CI 0.08-0.66, p=0.006) and good liver function at the time of brain metastasis (HR 0.25, 95% CI 0.09-0.69, p=0.007) were found to be the powerful prognostic factors for favorable survival in the multivariate analysis. In addition, presence of intratumoral hemorrhage was a statistically significant prognostic factor for survival., Conclusion: Although HCC patients with brain metastasis showed a very dismal prognosis, surgical intervention was shown to lead to relative prolongation of the survival time, especially in those with preserved hepatic function.

The aim of this study was to investigate the clinical outcomes after gamma knife surgery (GKS) or surgery as the first treatment for brain metastases in colorectal cancer (CRC). Of the 4350 patients diagnosed with CRC at our institution identified from 1987 to 2009, 27 patients who underwent GKS (GKS group) and 11 who underwent surgery (surgery group) were included. The oncologic outcomes were compared between the two groups. Local control was significantly better in the surgery group than in the GKS group (90% versus [vs.] 71.4%, respectively; p=0.006). The rate of symptom relief after 3 months was significantly higher in the surgery group than in the GKS group (72.7 vs.18.5%, respectively; p=0.005). The median survival after GKS was 5.6 months and surgery was 16.2 months. In multivariate analysis, controlled primary tumor (p=0.038) and solitary metastasis (p=0.028) were correlated with prolonged overall survival, whereas surgery (p=0.034) was associated with longer local control. Surgery for brain metastasis from CRC is more advantageous in local control and neurologic symptom palliation than GSK. In multivariate analysis, overall survival was associated with controlled primary tumor and solitary metastasis., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

For elderly patients with glioblastoma multiforme (GBM), radiotherapy plus concomitant and adjuvant temozolomide has resulted in longer survival. We investigated patient performance status, treatment-related toxicity and overall survival (OS) following treatment. Twenty patients aged 70years or older with a newly diagnosed GBM were treated with radiotherapy (60Gy in 16 patients and 40Gy in four patients) plus concomitant and adjuvant temozolomide. We assessed age, the extent of tumor removal, and initial performance status as possible prognostic factors for OS and good performance status following treatment. The median OS was 11.8months (95% confidence interval [CI], 8.7-14.8). The median time for patients to reach an Eastern Cooperative Oncology Group (ECOG) performance status grade 2 was 3.0months (95% CI, 2.4-3.5), and the time to ECOG performance status grade 3 was 5.8months (95% CI, 1.6-9.9). World Health Organization grade III or grade IV toxicity was observed in four patients (20%), leucopenia and thrombocytopenia was noted in two patients, and major infection occurred in two patients. Univariate analysis showed a significantly longer OS (p=0.003) and a longer time with good performance status for gross total removal (GTR) (p=0.003). An initial good performance status was related to a good performance status during and after treatment (p=0.003). Based on multivariate analysis, GTR was significantly associated with a longer OS (hazard ratio [HR]=0.236; 95% CI, 0.060-0.922, p=0.038) and a good performance status (HR=0.124; 95% CI, 0.022-0.693, p=0.017). During and after treatment, elderly patients with GBM frequently exhibited an early deterioration of performance status. Therefore, in light of a rapidly fatal illness, elderly patients should be treated to preserve and respect their quality of life., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Anaplastic astrocytoma (AA) sometimes shows a rapid poor course like glioblastoma. In this study, we investigated the prognosis of AA with radiologic necrosis which is the representative radiologic finding of glioblastoma. From 1995 to 2010, we operated on 26 patients who were confirmed to have AA. The male:female ratio was 13:13, and the median age was 47.23 years. The mean follow-up period was 3 years. We analyzed the prognostic significance of radiologic necrosis with age, sex, KPS, tumour location, radiologic findings, extent of removal and radiation therapy oncology group recursive partitioning analysis (RTOG-RPA) classification. The median progression-free survival (PFS) was 0.5 (± 0.17) years and the median overall survival (OS) was 1.6 (± 0.40) years. In univariate analysis, the clinical variables of younger age (p = 0.030) and RTOG-RPA class III (p = 0.043) correlated with longer PFS, and KPS (p = 0.038), radiologic necrosis (p = 0.013) and the extent of removal (p = 0.041) correlated with OS. The median OS was 1.0 (± 0.21) year in AA with radiologic necrosis compared to AA without radiologic necrosis, which showed 2.1 (± 0.29) years median OS. On multivariate analysis, there was no statistically significant prognostic factor. However, Cox's regression model revealed that gross total removal was associated with a longer OS (hazard ratio = 0.136; 95% CI, 0.018 to 1.046; p = 0.055) compared to partial removal or biopsy. Gross total resection was associated with good prognosis, and AA with radiologic necrosis had poor prognosis like glioblastoma.

Purpose: Glioblastomas are the most malignant tumors of central nervous system neoplasms and are well known for their biological heterogeneity. Contrary to the putative hypothesis of purely glial differentiation in glioblastomas, they often demonstrate immunopositivity for neuronal markers. However, the significance of their neuronal marker expression is still controversial. To evaluate the prognostic implication of neuronal expression in glioblastoma, this study investigated the expression of neuronal markers in a large series of glioblastoma patients in terms of patient survival rate., Methods: Expression of synaptophysin, neurofilament protein, and NeuN was explored using immunohistochemistry in 88 cases of glioblastoma. Clinicopathological variables as well as patients' survival data were compared according to the immunopositivity of cases., Results: Sixty-one of the 88 tumors (69.3 %) were positive for at least one neuronal marker. Synaptophysin positivity was observed in 43 cases (48.9 %). Neurofilament protein and NeuN were positive in 38 (43.2 %) and 42 cases (47.7 %), respectively. There was no statistically significant difference in overall survival and progression-free survival in association with neuronal marker expression. However, gross total removal or combined radiotherapy and chemotherapy significantly prolonged survival (P=0.041 and 0.044). Cox's proportional hazard model revealed that NeuN expression was the independent prognostic factors in progression-free survival (P=0.012)., Conclusions: Although the correlation of neuronal marker expression and clinical outcome in glioblastoma is of considerable interest, the presented data support the limited prognostic value of neuronal marker expression in glioblastoma.

Metallothionein 1E (MT1E) has been found to be highly expressed in motile cell lines. We investigated whether MT1E actually modulates the migration and invasion of human glioma cell lines and the types of factors that have an effect on MT1E. RNA differential display was performed using Genefishing™ technology in the human glioma cell lines U343MG-A, U87MG and U87MG-10'; the results were validated by RT-PCR and northern blot analysis, in order to detect possible genetic changes as the determining factors for migration ability in malignant glioma. MT1E was identified in U87MG, a highly motile cell line. The migration and invasion abilities of human glioma cell lines, and MT1E transfectants were investigated using simple scratch testing and Matrigel invasion assays. Morphological and cytoskeletal (actin, vimentin) changes were documented by light and confocal microscopy. The expression of MT1E in four glioma cell lines was assessed by RT-PCR and western blotting. In addition, the effects of MT1E on the activity of the NF-κB p50/p65 transcription factor, MMP-2 and -9 were examined by western blotting and zymography. The endogenous MT1E expression in the human glioma cell lines was statistically correlated with their migratory abilities and invasion. The U87-MT-AS cells became more round and had decreased stress fibers, compared with the U87MG cells. Endogenous MT1E expression in the four human glioma cell lines was directly correlated with migration. Two antisense MT1E-transfected cell lines showed decreased NF-κB p50 translocation into the nucleus, which led to decreased activity of MMP-9 in conditioned media. It may be postulated that MT1E can enhance the migration and invasion of human glioma cells by inducing MMP-9 inactivation via the upregulation of NF-κB p50.

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.

To obtain more representative biopsy specimens in glioblastoma, we performed multiple stereotactic biopsies of active tumor and necrosis. We investigated their pathologic differences of diagnosis and also examined the pathologic features that varied with 11C-methionine uptake on PET. From December 2009 to October 2010, we performed stereotactic biopsies in 12 patients with radiologically heterogeneous, ring-enhanced lesions. We biopsied the MR enhanced lesions for active tumor and the MR non-enhanced lesions for necrosis and analyzed differences of pathologic diagnoses between them. As correlating factors of the degree of 11C-methionine uptake (T/N ratio), the pathologic findings, including cell density, Ki‑67 LI, microvessel density, number of endothelial proliferations, the immunopositivity for L-amino acid transporter 1 (LAT1) were analyzed. The final diagnosis of each specimen was glio-blastoma. The diagnostic failure rate was 33.3% (4/12 patients) when we selected only active tumors and 40% (4/10 patients) when we selected necrotic lesions. The T/N ratio showed a statistical correlation with cell density depending on the degree of necrosis and LAT1 immunopositivity (P=0.002 and 0.032). LAT1 was localized in the tumor cells, vascular endothelium, and the vicinity of endothelial proliferation. Multiple stereotactic biopsies of active tumor and necrosis could provide the diagnostic yield in glioblastoma. The 11C-methionine uptake mostly reflected cell densities depending on the degree of necrosis.

This study was designed to determine the incidence and prognostic value of various populations of tumour-infiltrating T cells in glioblastomas. We also evaluated the difference in T-cell populations after conventional treatment. Sixty-seven patients with glioblastomas underwent surgery between 2003 and April 2009. Immunohistochemical staining was performed for CD3, CD4, CD8 and FoxP3, and the average number and percentage of positive cells were calculated. In eight patients, the average number of subpopulations was compared between the specimens obtained during the first and second operations. Age, gender, Karnofsky performance status, Radiation Therapy Oncology Group-recursive partitioning analysis (RTOG-RPA) classes, extent of removal, treatment modality, O-6-methylguanine-DNA methyltransferase (MGMT) methylation status and immunopositivity for CD4, CD8 and FoxP3 were analyzed as prognostic factors. There was an average of 12.8 ± 1.8 CD31 T cells, 1.5 ± 0.5 CD41 T cells, 6.8 ± 1.3 CD81 T cells and 0.6 ± 0.2 FoxP3 cells. The percentage of positive T-cell subpopulations was 89.6%, 22.4%, 77.6% and 34.3% for CD3, CD4, CD8 and FoxP3, respectively. In eight patients, there was no difference in the subpopulations between the first and second operations. The median progression-free survival was 7.0 months (95% CI, 5.2-8.9 months) and the overall survival was 14.8 months (95% CI, 11-18.7 months). Univariate analysis showed a statistically significant difference in progression-free survival for CD8 (p = 0.02) and overall survival for RTOG-RPA classes (p = 0.003), the extent of removal (p = 0.01) and MGMT promoter methylation status (p = 0.005). Based on multivariate analysis, RTOG-RPA classes were significantly associated with longer overall survival. The intratumoural immune response occurred frequently in glioblastomas and there was a consistent response, even after conventional treatment. There was a statistically significant difference in progression-free survival for CD81 T cells in immunologically privileged central nervous system.

Objective: Low-grade gliomas (LGGs) are infiltrative tumors characterized by slow growth. However, during early period, LGGs can progress and transform into a malignant pathology. We analyzed the prognostic factors for progression and malignant transformation in LGGs., Materials and Methods: From 2000 to 2009, we operated on 86 patients: 42 oligodendrogliomas, 12 oligoastrocytomas, and 32 astrocytomas. The male:female ratio was 47:39, and the median age was 41 (±17.4) years. The mean follow-up period was 4.25 (±2.8) years. We analyzed the prognostic factors for progression-free survival (PFS), overall survival (OS), and malignant transformation, considering age, sex, KPS, clinical presentation, tumor location, radiologic pattern, extent of removal, pathologic subtype, and adjuvant treatment., Results: In univariate analysis, non-eloquent location, gross total removal, and oligodendroglial pathology statistically correlated with improved PFS and OS. In multivariate analysis, gross total removal correlated with longer PFS (p=0.043), and gemistocytic astrocytoma had a poor PFS (p=0.004). Younger age and non-eloquent area showed an improved OS (p=0.002 and 0.041), and astrocytic pathology showed a poor OS (p=0.01). Malignant transformation was pathologically diagnosed in 13 out of 86 patients (15%). Gemistocytic astrocytoma correlated independently with malignant transformation (p=0.022)., Conclusion: In LGGs, extent of removal associated with tumor progression. The pathology of astrocytoma, especially gemistocytic astrocytoma, was an independent prognostic factor for recurrence and malignant transformation., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Glioblastoma is one of the most frequent primary brain tumors and is characterized by aggressive clinical behavior and biologic heterogeneity. To evaluate the prognostic implication of cancer stem cell markers in glioblastoma, the expression of these markers was investigated in a large series of glioblastoma patients in relation to the survival rate. This series includes 88 cases of glioblastoma that were diagnosed at the Chonnam University Hwasun Hospital from 2004 to 2009. The expression of newly established stem cell markers (nestin, CD133 and CD15) was detected using immunohistochemical analysis. The presence of immunopositive tumor cells was evaluated and interpreted in comparison with the patients' survival data. The expression of nestin was high in 60 cases (68.2%). CD133 and CD15 were positive in 52 cases (59.1%) and 40 cases (45.5%), respectively. No statistically significant difference in patient survival according to stem cell marker expression was observed (P > 0.05). However, gross total resection or combined radiation therapy and chemotherapy significantly prolonged survival (P = 0.04 and P = 0.04). Cox's proportional hazards model showed that the gross total resection and combined radiation therapy and chemotherapy were independent prognostic factors. Although the correlation of stem cell marker expression with clinical outcome in glioma is of considerable interest, the data do not support their prognostic value in glioblastoma. Identification of the key cells in the glioblastoma population in the context of clinical outcomes will provide insight into the mechanism of brain tumorigenesis and will be of paramount importance in determining therapeutically appropriate targets., (© 2011 Japanese Society of Neuropathology.)

Nogo-A belongs to the reticulon protein family and is expressed in the inner and outer loops of myelin sheaths of oligodendrocytes. We analyzed the patterns of Nogo-A expression in human gliomas in an effort to identify a useful marker for the characterization of oligodendroglial tumors. We determined the expression of Nogo-A in a panel of 58 astrocytic and oligodendroglial tumors using immunohistochemistry and compared the expression of Nogo-A with Olig-2, a recently identified marker for oligodendrogliomas. To localize Nogo-A expression, immunofluorescent staining was performed using other glial markers (MAP-2 and GFAP). We also confirmed the overexpression of the Nogo-A protein in 53 astrocytic and oligodendroglial tumors using Western blot analysis. Based on immunohistochemical analysis, Nogo-A and Olig-2 had specificity in the detection of oligodendroglial tumors from astrocytic tumors (P=0.001). The level of Nogo-A staining was highly correlated with Olig-2 (P=0.001). The sensitivity and specificity of Nogo-A for oligodendroglial tumors was 86.9% and 57.1%, respectively. Nogo-A expression overlapped that of other oligodendroglial markers, but with different patterns of expression. Western blot analysis revealed that Nogo-A is predominantly expressed in 85.7% of oligodendroglioma cells and 93.7% of anaplastic oligodendroglioma cells. Like other oligodendroglial markers, Nogo-A is highly expressed in oligodendroglial tumors; however, it does not serve as a definite marker specific for oligodendroglial tumors., (© 2010 Japanese Society of Neuropathology.)

Background: Celecoxib, a cyclo-oxygenase (COX)-2 inhibitor, has been reported to mediate growth inhibitory effects and to induce apoptosis in various cancer cell lines. In this study, we examined the potential effects of celecoxib on glioma cell proliferation, migration, and inhibition of COX-2 expression in vitro., Methods: Celecoxib was incorporated into poly DL-lactide-co-glycolide (PLGA) nanoparticles for antitumor drug delivery., Results: PLGA nanoparticles incorporating celecoxib had spherical shapes and their particle sizes were in the range of 50-200 nm. Drug-loading efficiency was not significantly changed according to the solvent used, except for acetone. Celecoxib was released from the PLGA nanoparticles for more than 2 days, and the higher the drug content, the longer the duration of drug release. PLGA nanoparticles incorporating celecoxib showed cytotoxicity against U87MG tumor cells similar to that of celecoxib administered alone. Furthermore, celecoxib did not affect the degree of migration of U87MG cells. PLGA nanoparticles incorporating celecoxib showed dose-dependent cytotoxicity similar to that of celecoxib alone in C6 rat glioma cells. Western blot assay of the C6 cells showed that neither celecoxib alone nor PLGA nanoparticles incorporating celecoxib affected COX-2 expression., Conclusion: PLGA nanoparticles incorporating celecoxib had antitumor activity similar to that of celecoxib alone, even though these particles did not affect the degree of migration or COX-2 expression in the tumor cells.

The aim of this study was to evaluate variations of O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation and protein expression after adjuvant treatment in glioblastoma patients. Sixteen patients with a glioblastoma underwent 34 microsurgeries including 18 re-operations. After surgery, patients underwent follow-up with radiotherapy and chemotherapy (temozolomide, ACNU and cisplatin) between 2000 and 2008. To investigate MGMT methylation and MGMT expression, methylation-specific PCR (MSP) and immunohistochemical staining (IHC) were performed. The methylation status of the MGMT promoter was altered in five (27.8%) of 18 re-operation specimens. In four specimens, the MGMT promoter was found to be methylated after primary surgery, but was found to be unmethylated on post-treatment samples. MGMT protein expression was altered in 15 (83.3%) of 18 cases. Fifteen specimens showed higher levels of protein expression as compared to previous samples and three samples demonstrated a similar expression pattern. After irradiation and exposure to steroid and temozolomide 6 and 24 h later, a methylated MGMT promoter and negative protein expression were seen in U343 glioblastoma cell lines which have methylated promoter and negative protein expression. Variations in MGMT promoter methylation and protein expression can occur after treatment. We suggest that changes of MGMT promoter methylation and protein expression might not be related to a direct effect of irradiation and exposure to steroid and temozolomide.

Objective: The aim of this study was to evaluate the correlation and prognostic significance of MGMT promoter methylation and protein expression in patients with glioblastoma., Methods: Eighty-three patients with glioblastoma underwent surgery followed by radiotherapy and temozolomide chemotherapy between October 2000 and June 2008. To investigate the correlation between MGMT methylation and MGMT expression, methylation-specific polymerase chain reaction (MSP) and immunohistochemical staining was performed. To analyze the correlation between MGMT methylation and MGMT expression according to location, biopsies were obtained from 37 different sites within the tumors in 12 patients. Age, sex, Karnofsky Performance Scale status, extent of removal, chemotherapeutic methods, and MGMT promoter methylation and protein expression were analyzed as prognostic factors., Results: The total median survival was 15.8 months (range, 12.6-19.1 months). The results of MSP were the same at various sites in 12 patients. A correlation between MSP and immunohistochemical staining was observed in 50% of the patients. In 73 patients, negative MGMT expression was detected in 70.5% of 44 patients with MGMT promoter methylation, and positive expression was observed in 55.2% of the 29 patients with unmethylated promoters. Multivariate analysis revealed that the extent of removal (P = 0.001) and the combination of MGMT promoter methylation and negative MGMT expression (median survival, 20.06 months; P = 0.006) were significantly associated with longer survival., Conclusion: We report the feasibility of using MSP combined with immunohistochemical staining as a prognostic factor. The results of the present study suggest that MGMT promoter methylation in combination with negative MGMT expression might be a good prognostic factor in patients with glioblastoma.

Background: Hemorrhage at presentation in primary CNS lymphoma is extremely rare and only 2 studies have reported it. We experienced a case of hemorrhage in primary CNS lymphoma, but the feature was different from those in the 2 studies mentioned. We report a case of primary CNS lymphoma presenting as an acute massive ICH causing catastrophic mental deterioration, along with immunohistochemical profiles., Case Description: A 49-year-old woman was admitted with sudden deterioration of mental status. Immediate CT scan showed a massive ICH in the left frontal lobe with perilesional edema and midline shifting. Emergency operation was performed and the hematoma was removed gross totally, including the abnormal lesions distinguished from adjacent normal brain. The histopathologic diagnosis was non-Hodgkin lymphoma, diffuse, large, B cell type with acute hemorrhage, and immunohistochemistry results showed high VEGF immunoreactivity and intermediate CD34 immunoreactivity., Conclusion: Primary CNS lymphoma can present as an acute massive ICH, and immunohistochemistry in the present study strengthened the suggestion that VEGF activity is related to the hemorrhage in primary CNS lymphoma.

Object: Galectin-1 is highly expressed in motile cell lines. The authors investigated whether galectin-1 actually modulates the migration and invasion of human glioblastoma multiforme (GBM) cell lines, and whether its expression with respect to invasion and prognosis is attributable to certain glioma subgroups., Methods: In the human GBM cell lines U343MG-A, U87MG, and U87MG-10', the RNA differential display was evaluated using Genefishing technology. The results were validated by reverse transcription polymerase chain reaction and Northern blot analysis to detect possible genetic changes as the determining factors for the motility of the malignant glioma. The migration and invasion abilities were investigated in human GBM cell lines and galectin-1 transfectant using an in vitro brain slice invasion model and a simple scratch technique. The morphological and cytoskeletal (such as the development of actin and vimentin) changes were examined under light and confocal microscopy. Galectin-1 expression was assessed on immunohistochemical tests and Western blot analysis., Results: Endogenous galectin-1 expression in the human GBM cell lines was statistically correlated with migratory abilities and invasiveness. The U87-G-AS cells became more round than the U87MG cells and lacked lamellipodia. On immunohistochemical staining, galectin-1 expression was increased in higher-grade glioma subgroups (p = 0.027)., Conclusions: Diffuse gliomas demonstrated higher expression levels than pilocytic astrocytoma in the Western blot. Galectin-1 appears to modulate migration and invasion in human glioma cell lines and may play a role in tumor progression and invasiveness in human gliomas.

This paper reports the first case in which an intracranial dermoid cyst that underwent traumatic rupture was treated surgically and discusses the importance of the preoperative radiological identification and management of the rupture. For adequate management of a ruptured intracranial dermoid cyst, in addition to early surgery, we emphasize the importance of expeditious identification of the rupture with MRI, including an additional fat-suppression sequence, and prompt management of the accompanying chemical meningitis with intravenous steroid therapy beginning from the pre-operative period.

Although several types of brain tumors are commonly associated with cyst formation, the pathogenesis of tumor-associated cysts (TAC) is unknown. We investigated the matrix metalloproteinase (MMP) expression of cyst fluids to elucidate the pathogenesis of TAC in brain tumors. We also examined the relationship between the severity of peritumoral edema and the expression of intracystic MMP. We collected 40 cyst fluid samples from 34 patients with TAC and studied the expression of MMP-2 and -9 in the cyst fluid using gelatin zymography. Radiological studies were used to estimate the severity of the peritumoral edema and to determine the presence of TAC. Although gelatin zymography of the cyst fluid showed high levels of MMPs, there was no correlation between the expression of MMPs in the cyst fluid and that in the tumor tissue. The level of MMP expression in the cyst fluid did not reflect the pathologic grade of the individual tumors. However, the total and activated MMP-9 levels were significantly associated with the severity of the peritumoral edema (p<0.05). These results suggest that MMPs may be partly involved in the pathogenesis of TAC and peritumoral edema in brain tumors.

A 54-year-old man and a 63-year-old woman presented with glioblastoma manifesting as seizure and headache, respectively. Magnetic resonance imaging of the two patients revealed hypointense area on T(1)-weighted imaging, and hyperintense area on T(2)-weighted and diffusion-weighted imaging, with no enhancement after gadolinium administration. Both patients underwent conservative therapy under diagnoses of non-neoplastic cerebral lesion. Six months later, they suffered aggravated symptoms and new neurological deficits. Follow-up magnetic resonance imaging revealed hypointense area on diffusion-weighted imaging and ring enhancement on T(1)-weighted imaging with gadolinium at the site of the previously detected lesions. The tumors showed growth pattern of superficial origin. The large enhanced masses were totally removed through craniotomy under neuronavigator guidance. The histological diagnoses were glioblastoma. Glioblastoma may mimic non-neoplastic conditions on neuroimaging in the early stages. Close follow up of such patients is essential.

The most characteristic feature of a malignant astrocytoma is its early and extensive infiltration into adjacent parenchymal structures. We focused on detecting the possible expression changes as the determining factors for malignant astrocytoma's motile ability. We confirmed that four of 39 genes showed different expression on DD-PCR by RT-PCR and Northern blot analysis. These findings suggest that the genes identified may be important for determining high motility in astrocytoma cell lines. These findings may help us understand the molecular invasion mechanism in astrocytomas.

A 50-year-old woman presented with a rare chordoid glioma manifesting as an approximately 4-year history of decreased cognitive function and recent decreased visual acuity. Magnetic resonance imaging showed a 4.5 x 3.5 cm multilobulated strongly enhanced mass in the suprasellar cistern and third ventricle associated with hydrocephalus. The tumor was subtotally removed via a transcallosal approach. Histological examination showed chordoid glioma. Two months later, ventriculoperitoneal shunting was performed for hydrocephalus. The tumor and hydrocephalus recurred after 3 months. She died after 4 months because of deepened mentality and combined pneumonia. This very short duration before recurrence suggests that neuroimaging follow up may be necessary in patients with subtotally removed choroid glioma.

We report a case of extranodal marginal zone B-cell lymphoma (MZL) mimicking meningioma in a lateral ventricle and suggest its possible pathogenesis. The patient was a 63-year-old male with seizure attack. MRI showed a 3.5x1.7 cm sized homogeneously enhancing mass in the trigon of the right lateral ventricle, possibly arising from the choroid plexus. The provisional diagnosis was meningioma or metastasis. In the surgical findings, the mass was attached to the choroid plexus and totally removed. Pathologic examination revealed a monotonous population of medium-sized mononuclear lymphoma cells associated with meningothelial whorl formation and neoplastic cells which invaded the meningothelial cells. The tumor was immunopositive for CD79a, CD20, CD43 and bcl-2. We suggest that intracranial extranodal marginal zone B-cell lymphomas might mimic meningiomas, because of their relation with the arachnoid cells and that meningothelial cells serve as a substitute for the mucosal surface in intracranial MALT lymphomas.

A new era of neurosurgery has recently been unveiled with the advent of image-guided surgery. The use of neuronavigation is beginning to have a significant impact on a variety of intracranial procedures. Herein, we report our clinical experience using a neuronavigation system with different surgical applications and techniques for a variety of brain tumors. We used the BrainLab VectorVision neuronavigation system, which is a frameless and image-guided system. We operated on 420 cases having various types of brain tumor with the help of this system. The mean target localizing accuracy and mean volume were 1.15 mm and 30.8 mL (0.2-216.4 mL), respectively. We utilized this system to effectively make bone flaps, to detect critically located, deep-seated, subcortical, skull-base and skull bone tumors, and to operate on intraparenchymal lesions with grossly unclear margins, such as gliomas. We also performed tumor biopsy using the combination of a conventional stereotactic biopsy instrument and an endoscope. The application of the neuronavigation system not only revealed benefits for operative planning, appreciation of anatomy, lesion location and the safety of surgery, but also greatly enhanced surgical confidence.

Background: Intratumoral hemorrhage, as one of the cerebrovascular complications in various tumor-related conditions, occurs mainly in malignant brain tumors. Recent studies have shown that the overexpression of vascular endothelial growth factor (VEGF) and metalloproteinase (MMP) may play a role for the loss of vascular integrity and the subsequent hemorrhage in several instances, in addition to their well-known properties in tumor development and metastasis., Methods: To investigate the potential role of VEGF and MMP in hemorrhagic complication of metastatic brain tumor, we estimated the expression of VEGF, MMP-2 & -9 by immunohistochemical studies in pathological specimens of metastatic brain tumors obtained from 16 patients, 7 in hemorrhagic and 9 in non-hemorrhagic group. We also examined the expression of collagen type IV, CD34, Factor VIII in order to evaluate the status of tumor vasculature., Results: Patients in hemorrhagic group showed a higher VEGF expression with neovascularization than those in non-hemorrhagic group. The basement membranes of newly formed vessels were disrupted in cases with high expression in both MMP-2 and -9. These results indicate that rapid growing nascent blood vessels, responding vigorously to VEGF, are concentrated around the hemorrhagic tumors. Besides, these results suggest a possibility that the basement membranes of these nascent vessels could be disrupted proteolytically by MMP., Conclusion: We conclude that overexpression of VEGF and MMP may play a role in metastatic brain tumor-associated hemorrhage. Presumably, the underlying pathophysiological mechanisms are through rapid growth and breakdown of vessels around the tumors caused by overexpression of VEGF and MMP of tumor cells.

Background: Recent developments in magnetic resonance (MR) technology now enable the use of MR venography, providing 3-dimensional (3D) images of intracranial venous structures. The purpose of this study was to assess the usefulness of 3D contrast-enhanced MR venography (CE MRV) in the evaluation of intracranial venous system for surgical planning of brain tumors., Methods: Forty patients underwent 3D CE MRV, as well as 25 patients, 2-dimensional (2D) time-of-flight (TOF) MR venography in axial and sagittal planes; and 10 patients, digital subtraction angiography. We determined the number of visualized sinuses and cortical veins. Degree of visualization of the intracranial venous system on 3D CE MRV was compared with that of 2D TOF MR venography and digital subtraction angiography as a standard. We also assessed the value of 3D CE MRV in the investigation of sinus occlusion or localization of cortical draining veins preoperatively., Results: Superficial cortical veins and the dural sinus were better visualized on 3D CE MRV than on 2D TOF MR venography. Both MR venographic techniques visualized superior sagittal sinus, lateral sinus, sigmoid sinus, straight sinus, and internal cerebral vein and provided more detailed information by showing obstructed sinuses in brain tumors. Only 3D CE MRV showed superficial cortical draining veins. However, it was difficult to accurately evaluate the presence of cortical collateral venous drainage., Conclusion: Although we do not yet advocate MR venography to replace conventional angiography as the imaging standard for brain tumors, 3D CE MRV can be regarded as a valuable diagnostic method just in evaluating the status of major sinuses and localization of the cortical draining veins.

We have applied the neuronavigation system to endoscopic biopsy and third ventriculostomy in the management of patients with a pineal tumor with hydrocephalus. With the guidance of neuronavigation, the two optimal sites of burr hole and trajectories were planned preoperatively, and the advancing endoscopic device was monitored in real time during the procedure. In our five patients, the diameters of the tumors were 2-3 cm, and the mean systemic accuracy of registration with neuronavigation was 1.2 mm. The biopsy and third ventriculostomy were performed successfully via the respective optimal burr hole and the trajectory determined using preoperative neuronavigation. There were no procedure-related complications, and none of the patients needed another procedure for CSF diversion during the follow-up periods. We present our technique which includes the application of the neuronavigation system to the biopsy and third ventriculostomy in pineal tumor with associated hydrocephalus. This technique can be performed using a simple rigid endoscope via the determined optimal entries and trajectories. The optimal preoperative planning and the intraoperative guidance by neuronavigation are thought to be able to give more chances to minimize the brain injury related to movements or deviation of endoscopic device.