• Journal of Korean Neurosurgical Society
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• v.61 no.4
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• pp.516-524
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• 2018

Objective : This study aims to determine whether gamma knife radiosurgery (GKR) improves survival in patients with recurrent high-grade gliomas. Methods : Twenty nine patients with recurrent high-grade glioma underwent 38 GKR. The male-to-female ratio was 10 : 19, and the median age was 53.8 years (range, 20-75). GKR was performed in 11 cases of recurrent anaplastic oligodendrogliomas, five anaplastic astrocytomas, and 22 glioblastomas. The median prescription dose was 16 Gy (range, 10-24), and the median target volume was 7.0 mL (range, 1.1-15.7). Of the 29 patients, 13 (44.8%) received concurrent chemotherapy. We retrospectively analyzed the progression-free survival (PFS) and overall survival (OS) after GKR depending on the Eastern Cooperative Oncology Group (ECOG) performance status (PS), pathology, concurrent chemotherapy, radiation dose, and target tumor volume. Results : Starting from when the patients underwent GKR, the median PFS and OS were 5.0 months (range, 1.1-28.1) and 13.0 months (range, 1.1-75.1), respectively. On univariate analysis, the median PFS was significantly long in patients with anaplastic oligodendroglioma, ECOG PS 1, and target tumor volume less than 10 mL (p<0.05). Meanwhile, on multivariate analysis, patients with ECOG PS 1 and target tumor volume less than 10 mL showed improved PFS (p=0.043 and p=0.007, respectively). The median OS was significantly increased in patients with ECOG PS 1 and tumor volume less than 10 mL on univariate and multivariate analyses (p<0.05). Conclusion : GKR could be an additional treatment option in recurrent high-grade glioma, particularly in patients with good PS and limited tumor volume.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.22
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• pp.9805-9812
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• 2014

Radixin, a member of the ERM (ezrin-radixin-moesin) family, plays important roles in cell motility, invasion and tumor progression. It is expressed in a variety of normal and neoplastic cells, including many types of epithelial and lymphoid examples. However, its function in glioblastomas remains elusive. Thus, in this study, radixin gene expression was first examined in the glioblastoma cells, then suppressed with a lentivirus-mediated short-hairpin RNA (shRNA) method.We found that there were high levels of radixin expression in glioblastoma U251cells. Radixin shRNA caused down-regulation of radixin gene expression and when radixin-silenced cells were implanted into nude mice, tumor growth was significantly inhibited as compared to blank control cells or nonsense shRNA cells. In addition, microvessel density in the tumors was significantly reduced. Thrombospondin-1 (TSP-1) and E-cadherin were up-regulated in radixin- suppressed glioblastoma U251 cells. In contrast, MMP9 was down-regulated. Taken together, our findings suggest that radixin is involved in GBM cell migration and invasion, and implicate TSP-1, E-cadherin and MMP9 as metastasis-inducing factors.

• Journal of Korean Neurosurgical Society
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• v.43 no.4
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• pp.190-193
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• 2008

Objective : Cancer-testis (CT) genes are considered promising candidates for immunotherapeutic approaches. The aim of this study was to investigate which CT genes should be targeted in immunotherapy for brain tumors. Methods : We investigated the expression of 6 CT genes (MAGE-E1, SOX-6, SCP-1, SSX-2, SSX-4, and HOMTES-85) using reverse-transcription polymerase chain reaction in 26 meningiomas and 32 other various brain tumor specimens, obtained from the patients during tumor surgery from 2000 to 2005. Results : The most frequently expressed CT genes of meningiomas were MAGE-E1, which were found in 22/26 (85%) meningioma samples, followed by SOX-6 (9/26 or 35%). Glioblastomas were most frequently expressed SOX-6 (6/7 or 86%), MAGE-E1 (5/7 or 71%), followed by SSX-2 (2/7 or 29%) and SCP-1 (1/7 or 14%). However, 4 astrocytomas, 3 anaplastic astrocytomas, and 3 oligodendroglial tumors only expressed MAGE-E1 and SOX-6. Schwannomas also expressed SOX-6 (5/6 or 83%), MAGE-E1 (4/6 or 67%), and SCP-1 (2/6 or 33%). Conclusion : The data presented here suggest that MAGE-E1 and SOX-6 genes are expressed in a high percentage of human central nervous system tumors, which implies the CT genes could be the potential targets of immunotherapy for human central nervous system tumors.

• Journal of Korean Neurosurgical Society
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• v.52 no.2
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• pp.92-97
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• 2012

Objective : This study was performed to determine the safety and outcome of concurrent chemoradiotherapy (CCRT) and adjuvant chemotherapy with temozolomide for Korean patients with a newly diagnosed glioblastoma. Methods : Patients were recruited from four institutions between 2004 and 2007. The patients received fractionated focal irradiation in daily fractions of 2 Gy given 5 days per week for 6 weeks and daily temozolomide, followed by 6 cycles of adjuvant temozolomide. The primary endpoint was overall survival (OS) and the secondary endpoints were progression-free survival (PFS), response, and safety. Results : A total of 103 patients were enrolled in this study. Ninety-six patients (93%) completed the CCRT and 54 patients (52%) received 6 cycles of adjuvant temozolomide. The response rate was 73% (53/73) and the tumor control rate was 92% (67/73). Of the 96 patients who completed the CCRT, the median OS was 18.0 months and the 1- and 2-year OS rates were 74 and 38%, respectively. The median PFS was 10.0 months and the 1- and 2-year PFS rates were 33 and 16%, respectively. The only significant prognostic factor of survival was the extent of surgical resection (p<0.05). CCRT resulted in grade 3 or 4 hematologic toxic effects in 8% of patients. No opportunistic infections were noted. Conclusion : This study is the first prospective multi-institutional report of CCRT and adjuvant chemotherapy with temozolomide for patients with a newly diagnosed glioblastoma in Korea. The current protocol may prolong the survival of Korean patients with a glioblastoma and may be tolerable in terms of toxicity.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.7
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• pp.2883-2887
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• 2015

Background: The calcium-binding S100A4 protein is involved in epithelial to mesenchymal transition, oncogenic transformation, angiogenesis, cytoskeletal integrity, mobility and metastasis of cancer cells. This study aimed to clarify the roles of S100A4 in genesis and progression of glioma. Materials and Methods: S100A4 expression was examined by real-time RT-CPR and Western blot in glioma and paired normal brain tissue (n=69), and compared with clinicopathological parameters of tumors. In addition, glioma U251 cells transfected with an S100A4-expressing plasmid were examined for proliferation by MTT, apoptosis by Annexin V-FITC, and migration and invasion with Transwell chambers. Results: Increased S100A4 mRNA expression was found in gliomas, compared with paired non-tumor tissue (p<0.001). Gradual elevation of overexpression of S100A4 was observed with increasing glioma grade (p<0.001). Astrocytoma showed lower S100A4 mRNA expression than oligodendrogliomas, with glioblastomas having highest values (p<0.001). Similar results were obtained for S100A4 protein, a positive link being found between mRNA and protein expression in gliomas (p<0.001). There was higher growth, lower apoptosis, stronger migration and invasion of S100A4 transfectants than control and mock transfected cells (p<0.001). Conclusions: These findings indicate that up-regulated S100A4 expression is positively linked to pathogenesis, progression and histogenesis of glioma by modulating proliferation, apoptosis, migration and invasion.

• Asian Pacific Journal of Cancer Prevention
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• v.17 no.9
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• pp.4205-4208
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• 2016

Background: The aim of this study was to analyse the expression of EGFR in newly diagnosed and recurrent glioblastoma multiforme (GBM). Materials and Methods: Our study included a total of 48 paired samples collected from 24 patients diagnosed with GBM. The intensity of EGFR cytoplasmatic staining was scored on a scale of 1-3+ (weak, intermediate or strong). Results: We found EGFR overexpression in 23 patients (96%) with newly diagnosed GBM, while all recurrent tumours overexpressed EGFR. Ten recurrent tumours (42%) had a lower expression than their new counterpart 13 tumours (54%) had a similar expression, and only one case (2%) had increased expression on recurrence. The expression of EGFR in newly diagnosed GBM was significantly correlated with EGFR expression in recurrent tumour (p = 0.036). In addition, new GBMs with strong EGFR expression had a mean relapse-free interval of 11.5 months (p=0.017). A benefit of combined therapy was observed in the radiotherapy-plus-chemotherapy group where the average time was 11 months (p=0.011), as compared with surgery/radiotherapy alone (average time 6.8 months). Conclusions: The present data show that EGFR is overexpressed in paired GBMs. The discrepancies of EGFR expression between the primary tumour and the recurrence suggest heterogeneity of GBMs but also unity at relapse.

• Journal of Korean Neurosurgical Society
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• v.63 no.4
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• pp.444-454
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• 2020

Objective : Glioblastoma multiforme (GBM) is the most aggressive for of brain tumor and treatment often fails due to the invasion of tumor cells into neighboring healthy brain tissues. Activation of the Janus kinase-signal transducer and activator of transcription (JAK/STAT) signaling pathway is essential for normal cellular function including angiogenesis, and has been proposed to have a pivotal role in glioma invasion. This study aimed to determine the dose-dependent effects of ruxolitinib, an inhibitor of JAK, on the interferon (IFN)-I/IFN-α/IFN-β receptor/STAT and IFN-γ/IFN-γ receptor/STAT1 axes of the IFN-receptor-dependent JAK/STAT signaling pathway in glioblastoma invasion and tumorigenesis in U87 glioblastoma tumor spheroids. Methods : We administered three different doses of ruxolitinib (50, 100, and 200 nM) to human U87 glioblastoma spheroids and analyzed the gene expression profiles of IFNs receptors from the JAK/STAT pathway. To evaluate activation of this pathway, we quantified the phosphorylation of JAK and STAT proteins using Western blotting. Results : Quantitative real-time polymerase chain reaction analysis demonstrated that ruxolitinib led to upregulated of the IFN-α and IFN-γ while no change on the hypoxia-inducible factor-1α and vascular endothelial growth factor expression levels. Additionally, we showed that ruxolitinib inhibited phosphorylation of JAK/STAT proteins. The inhibition of IFNs dependent JAK/STAT signaling by ruxolitinib leads to decreases of the U87 cells invasiveness and tumorigenesis. We demonstrate that ruxolitinib may inhibit glioma invasion and tumorigenesis through inhibition of the IFN-induced JAK/STAT signaling pathway. Conclusion : Collectively, our results revealed that ruxolitinib may have therapeutic potential in glioblastomas, possibly by JAK/STAT signaling triggered by IFN-α and IFN-γ.

• BMB Reports
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• v.55 no.12
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• pp.615-620
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• 2022

The murine leukemia virus-based semi-retroviral replicating vectors (MuLV-based sRRV) had been developed to improve safety and transgene capacity for cancer gene therapy. However, despite the apparent advantages of the sRRV, improvements in the in vivo transduction efficiency are still required to deliver therapeutic genes efficiently for clinical use. In this study, we established a gibbon ape leukemia virus (GaLV) envelope-pseudotyped semi-replication-competent retrovirus vector system (spRRV) which is composed of two transcomplementing replication-defective retroviral vectors termed MuLV-Gag-Pol and GaLV-Env. We found that the spRRV shows considerable improvement in efficiencies of gene transfer and spreading in both human glioblastoma cells and pre-established human glioblastoma mouse model compared with an sRRV system. When treated with ganciclovir after intratumoral injection of each vector system into pre-established U-87 MG glioblastomas, the group of mice injected with spRRV expressing the herpes simplex virus type 1-thymidine kinase (HSV1-tk) gene showed a survival rate of 100% for more than 150 days, but all control groups of mice (HSV1-tk/PBS-treated and GFP/GCV-treated groups) died within 45 days after tumor injection. In conclusion, these findings sug-gest that intratumoral delivery of the HSV1-tk gene by the spRRV system is worthy of development in clinical trials for the treatment of malignant solid tumors.

• Journal of Korean Neurosurgical Society
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• v.63 no.1
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• pp.119-135
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• 2020

Objective : To investigate the epidemiology of newly-diagnosed, histologically-confirmed (NDHC) central nervous system (CNS) tumours and its changes over a 21-year period in a regional hospital in Hong Kong. Methods : This is a single-institute retrospective descriptive study of patients undergoing surgery for CNS tumours in a regional hospital of Hong Kong in the period from January 1996 to December 2016. The histological definition of CNS tumours was according to the World Health Organization classification, while the site definition for case ascertainment of CNS tumours was as set out by the Central Brain Tumour Registry of the United States. Patients of any age, who had NDHC CNS tumours, either primary or secondary, were included. The following parameters of the patients were retrieved : age at diagnosis, gender, tumour location, and histological diagnosis. Population data were obtained from sources provided by the Government of Hong Kong. The incident rate, estimated by the annual number of cases per 100000 population, for each histology grouping was calculated. Statistical analyses, both including and excluding brain metastases, were performed. Statistical analysis was performed with Microsoft Excel, 2016 (Microsoft, Redmond, WA, USA). Results : Among the 2134 cases of NDHC CNS tumours, there were 1936 cases of intracranial tumours and 198 cases of spinal tumours. The annual number of cases per 100000 population of combined primary intracranial and spinal CNS tumours was 3.6 in 1996, and 11.1 in 2016. Comparing the 5-year average annual number of cases per 100000 population of primary CNS tumours from the period 1996-2000 to 2011-2015, there was an 88% increase, which represent an increase in the absolute number of cases by 4.52 cases/100000 population. This increase was mainly contributed by benign histologies. In the aforementioned periods, meningiomas increased by 1.45 cases/100000 population; schwannomas by 1.05 cases/100000 population, and pituitary adenomas by 0.91 cases/100000 population. While gliomas had a fluctuating 5-year average annual number of cases per 100000 population, it only had an absolute increase of 0.51 cases/100000 population between the 2 periods, which was mainly accounted for by the change in glioblastomas. Conclusion : This retrospective study of CNS tumour epidemiology revealed increasing trends in the incidences of several common CNS tumour histologies in Hong Kong, which agrees with the findings in large-scale studies in Korea and the United States. It is important for different geographic locations to establish their own CNS tumour registry with well-defined and structured data collection and analysis system to meet the international standards.

• Molecules and Cells
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• v.40 no.4
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• pp.254-261
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• 2017

Glioblastomas (GBM) are very difficult to treat and their aggressiveness is one of the main reasons for this as well as for the frequent recurrences. MicroRNAs post-transcriptionally regulate their target genes through interaction between their seed sequence and 3'UTR of the target mRNAs. We previously reported that miR-296-3p is regulated by neurofibromatosis 2 (NF2) and enhances the invasiveness of GBM cells via SOCS2/STAT3. In this study, we investigated whether miR-296-5p, which originates from the same precursor miRNA as miR-296-3p, can increase the invasiveness of GBM cells. It was observed that miR-296-5p potentiated the invasion of various GBM cells including LN229, T98G, and U87MG. Through bioinformatics approaches, two genes were identified as miR-296-5p targets: caspase-8 (CASP8) and nerve growth factor receptor (NGFR). From results obtained from Ago2 immunoprecipitation and luciferase assays, we found that miR-296-5p downregulates CASP8 and NGFR through direct interaction between seed sequence of the miRNA and 3'UTR of the target mRNA. Knockdown of CASP8 or NGFR also increased the invasive ability of GBM cells, indicating that CASP8 and NGFR are involved in potentiation of invasiveness by miR-296-5p. Consistent with our findings, CASP8 was downregulated in brain metastatic lung cancer cells, which have a high level of miR-296-5p, compared to parental cells, suggesting that miR-296-5p may be generally associated with the acquisition of invasiveness. Collectively, our results implicate miR-296-5p as a potential cause of invasiveness in cancer and suggest it as a promising therapeutic target for GBM.