• Journal of Korean Neurosurgical Society
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• 제57권5호
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• pp.323-328
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• 2015

Objective : Malignant gliomas are the most common primary tumors of the central nervous system and the prognosis of patients with gliomas is poor. The combination of interferon-bata (IFN-${\beta}$) and temozolomide (TMZ) has shown significant additive antitumor effects in human glioma xenograft models. Considering that the poor survival of patients with human malignant gliomas relates partly to the inability to deliver therapeutic agents to the tumor, the tropism of human bone marrow-derived mesenchymal stem cells (MSC) for malignant gliomas can be exploited to therapeutic advantages. We investigated the combination effects of TMZ and MSCs that secrete IFN-${\beta}$ on gliomas. Methods : We engineered human MSCs to secret mouse IFN-${\beta}$ (MSC-IFN-${\beta}$) via adenoviral transduction and confirmed their secretory capacity using enzyme-linked immunosorbent assays. In vitro and in vivo experiments were performed to determine the effects of the combined TMZ and MSC-IFN-${\beta}$ treatment. Results : In vitro, the combination of MSC-IFN-${\beta}$ and TMZ showed significantly enhanced antitumor effects in GL26 mouse glioma cells. In vivo, the combined MSC-IFN-${\beta}$ and TMZ therapy significantly reduced the tumor size and improved the survival rates compared to each treatment alone. Conclusion : These results suggest that MSCs can be used as an effective delivery vehicle so that the combination of MSC-IFN-${\beta}$ and TMZ could be considered as a new option for the treatment of malignant gliomas.

• Journal of Korean Neurosurgical Society
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• 제30권7호
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• pp.855-860
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• 2001

Introduction : It has been reported that the survival of low-grade glioma patients depends upon the time of malignant transformation. The authors presents the clinical analysis of histologically proven trasformed gliomas. Materials and Method : A total 92 patients who were consecutively treated and histologically confirmed hemispheric low-grade gliomas between 1980 and 1998 were analyzed and followed. All cases meet the criteria of WHO glioma classification of grade II. Results : The mean follow-up period was 73 months. Twenty two among 92 cases(24%) were histologically proven to be transformed into malignant ones. The mean time to transformation was 56 months. The 5-year and 10-year survival rates of the transformed group were 66% and 30% respectively and significantly different from the survival rates of the non-transformed group(p=0.0018). Among clinical factors at presentation, the initial tumor volume had a tendency to be larger in the transformed group than that of the non-transformed group and became significant when it was divided into more than $30cm^3$ or not(p=0.02). Among therapeutic factors, the extent of removal had no influence on the rate of malignant transformation. But postoperative radiation therapy were more frequently given to the pre-transformed group than the non-transformed group and the frequency was significantly different(p=0.02). Conclusions : The authors had found that the initial tumor volume and radiation therapy could be clinical prognostic factors for the malignant transformation of low-grade gliomas.

• Journal of Korean Neurosurgical Society
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• 제38권1호
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• pp.47-53
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• 2005

Objective : Anti-malaria drugs may modulate tumor resistance to chemotherapeutic agents, but it has not been proven effective in the treatment of malignant gliomas. The aim of this study was to determine whether adequate pre-clinical data on co-administration of chemotherapeutic agents with anti-malaria drugs on malignant cell lines could be obtained that would warrant its further potential consideration for use in a clinical trial for malignant gliomas. Methods : Two malignant glioma cell lines [U87MG, T98G] were treated with chemotherapeutic agents alone or with anti-malaria drugs. Cells were incubated with drugs for 4 days. Following the 4-day incubation, drug sensitivity assays were performed using 3-[4,5-dimethyl-2-thiazol-2-yl] 2,5-diphenyltetrazolium bromide [MTT] assay following optimization of experimental conditions for each cell lines and cell viability was calculated. Results : In all of four chemotherapeutic agents[doxorubicin. vincrisitne, nimustine, and cisplatin], the cell viability was found to be markedly decreased when hydroxychloroquine was co-administered on both U87MG and T98G cell lines. The two way analysis of variance[ANOVA] yielded a statistically significant two-sided p-value of 0.0033[doxorubicin], 0.0005[vincrisitne], 0.0007[nimustine], and 0.0003[cisplatin] on U87MG cell lines and 0.0006[doxorubicin], 0.0421[vincrisitne], 0.0317[nimustine], and 0.0001[cisplatin] on T98G cell lines, respectively. However, treatment with chloroquine and primaquine did not induce a decrease in cell viability on both U87MG and T98G cell lines. Conclusion : Our data support further consideration of the use of hydroxychloroquine prior to systemic chemotherapy to maximize its tumoricidal effect for patients with malignant gliomas.

• Journal of Korean Neurosurgical Society
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• 제49권6호
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• pp.334-338
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• 2011

Objective : The incidence of leptomeningeal dissemination from malignant glioma is rare, so the clinical features of this are not well documented yet We attempted to determine the clinical features of leptomeningeal dissemination from malignant gliomas. Methods : We retrospectively analyzed 11 cases of leptomeningeal dissemination of malignant glioma, who were treated at our institution between 2006 and 2009. We investigated the clinical features of these patients by considering the following factors : tumor locations, the events of ventricular opening during surgery and the cerebrospinal fluid (CSF) profiles, including the cytology. Results : The group was composed of 9 males and 2 females. The histological diagnosis of their initial intracranial tumors were 4 primary glioblastoma, 3 anaplastic astrocytoma, 1 anaplastic oligoastrocytoma, 2 ganglioglioma and 1 pleomorphic xanthoastrocyotma with anaplastic features. The mean age of the patients at the time of the initial presentation was $42.8{\pm}10.3$ years. The mean time between surgery and the diagnosis of spinal dissemination was $12.3{\pm}7.9$ (3-28) months. The mean overall survival after dissemination was $2.7{\pm}1.3$ months. All our patients revealed a history of surgical opening of the ventricles. Elevated protein in the CSF was reported for eight patients who had their CSF profiles checked. Conclusion : We propose that in the malignant gliomas, the surgical opening of ventricles can cause the spinal leptomeningeal dissemination and the elevated protein content of CSF may be a candidate marker of leptomeningeal dissemination.

• Journal of Korean Neurosurgical Society
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• 제50권5호
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• pp.426-433
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• 2011

Objective : The Histoculture Drug Response Assay (HDRA), which measures chemosensitivity using minced tumor tissue on drug-soaked gelfoam, has been expected to overcome the limitations of in vitro chemosensitivity test in part. We analyzed interim results of HDRA in malignant gliomas to see if the test can deserve further clinical trials. Methods : Thirty-three patients with malignant gliomas were operated and their tumor samples were examined for the chemosensitivity to 10 chosen drugs by HDRA. The most sensitive chemotherapy regimen among those pre-established was chosen based on the number of sensitive drugs or total inhibition rate (IR) of the regimen. The response was evaluated by 3 month magnetic resonance image. Results : Among 13 patients who underwent total resection of the tumor, 12 showed no evidence of disease and one patient revealed progression. The response rate in 20 patients with residual tumors was 55% (3 complete and 8 partial responses). HDRA sensitivity at the cut-off value of more than one sensitive drug in the applied regimen showed a sensitivity of 100%, specificity of 60% and predictability of 70%. Another cut-off value of >80% of total IR revealed a sensitivity of 100%, specificity of 69%, and predictability of 80%. For 12 newly diagnosed glioblastoma patients, median progression-free survival of the HDRA sensitive group was 21 months, while that of the non-sensitive group was 6 months ($p$=0.07). Conclusion : HDRA for malignant glioma was inferred as a feasible method to predict the chemotherapy response. We are encouraged to launch phase 2 clinical trial with chemosensitivity on HDRA.

• Journal of Korean Neurosurgical Society
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• 제30권2호
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• pp.137-143
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• 2001

Objective : Telomerase, a ribonucleoprotein adds telomere repeats to the ends of telomeres to compensate for the progressive loss. A favorable prognosis associated with low or no telomerase activity in some tumors, and cells transfected with antisense human telomerase lost telomeric repeats and die. We studied about the relationship between telomerase activity and apoptosis in the human brain tumors. Material and Methods : Between July 1998 and December 1999, 62 patients with brain tumors underwent surgery and their surgical specimens were obtained. Telomerase activity was investigated by telomeric repeats amplification protocol(TRAP) assay. Apoptosis was also evaluated by DNA fragmentation analysis. Differences and correlation in data were analyzed using Mann-Whitney test and Wilcoxon-signed rank test. Results : Expression rate of telomerase activity and apoptosis were 80% and 30% in malignant gliomas, 33% and 0% in low grade gliomas, 63% and 38% in meningiomas, 67% and 33% in pituitary adenomas, 33% and 33% in metastatic tumors, 67% and 17% in acoustic neurinomas, 100% and 100% in pineoblastomas, 100% and 0% in the hemangioblastoma, respectively. There was no significant difference of telomerase activity and apoptosis between histological types. But a significant difference was noted in the expression of telomerase activity between malignant gliomas and low grade gliomas(p = 0.022). Brain tumors with telomerase activity expressed the lower rate of apoptosis. A significant correlation was also found between telomerase activity and absence of apoptosis in the human brain tumors(p = 0.005). Conclusions : Our data suggests that telomerase may protect from apoptosis of the human brain tumors and also may play an important role in the biological malignancy of the gliomas.

• Journal of Korean Neurosurgical Society
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• 제40권4호
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• pp.217-226
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• 2006

Malignant gliomas are the most common type of primary brain tumor and are in great need of novel therapeutic approaches. Advances in treatment have been very modest, significant improvement in survival has been lacking for many decades, and prognosis remains dismal. Despite "gross total" surgical resections and currently available radio-chemotherapy, malignant gliomas inevitably recur due to reservoirs of notoriously invasive tumor cells that infiltrate adjacent and non-adjacent areas of normal brain parenchyma. In principle, the immune system is uniquely qualified to recognize and target these infiltrative pockets of tumors cells, which have generally eluded conventional treatment approaches, In the span of the last 10 years, our understanding of the cancer-immune system relationship has increased exponentially; and yet we are only beginning to tease apart the intricacies of the central nervous system and immune cell interactions. This article reviews the complex associations of the immune system with brain tumors. We provide an overview of currently available treatment options for malignant gliomas, existing gaps in our knowledge of brain tumor immunology, and strategies that might be exploited for improved design of "custom immunotherapeutics." We will also examine major new immunotherapy approaches that are being actively investigated to treat patients with malignant glioma, and identify some current and future research priorities in this area.

• Asian Pacific Journal of Cancer Prevention
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• 제13권11호
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• pp.5725-5728
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• 2012

Growing evidence shows that deregulation of the circadian clock plays an important role in the development of malignant tumors, including gliomas. However, the molecular mechanisms of gene chnages controlling circadian rhythm in glioma cells have not been explored. Using real time polymerase chain reaction and immunohistochemistry techniques, we examined the expression of two important clock genes, cry1 and cry2, in 69 gliomas. In this study, out of 69 gliomas, 38 were cry1-positive, and 51 were cry2-positive. The expression levels of cry1 and cry2 in glioma cells were significantly different from the surrounding non-glioma cells (P<0.01). The difference in the expression rate of cry1 and cry 2 in high-grade (grade III and IV) and low-grade (grade 1 and II) gliomas was non-significant (P>0.05) but there was a difference in the intensity of immunoactivity for cry 2 between high-grade gliomas and low-grade gliomas (r=-0.384, P=0.021). In this study, we found that the expression of cry1 and cry2 in glioma cells was much lower than in the surrounding non-glioma cells. Therefore, we suggest that disturbances in cry1 and cry2 expression may result in the disruption of the control of normal circadian rhythm, thus benefiting the survival of glioma cells. Differential expression of circadian clock genes in glioma and non-glioma cells may provide a molecular basis for the chemotherapy of gliomas.

• Journal of Korean Neurosurgical Society
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• 제44권4호
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• pp.222-227
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• 2008

Objective : Malignant gliomas are the most common primary cerebral neoplasms in adults. Despite multimodality treatments, the prognosis for patients with malignant glioma remains poor. However, recently, the effectiveness of concomitant chemoradiotherapy (CCRT) with temozolomide (TMZ) has been reported. We report for the first time preliminary results of the treatment with CCRT of newly diagnosed malignant gliomas in Korean people. Methods : Thirty-two patients over the age of 17 years with newly diagnosed and histologically confirmed high-grade gliomas (HGG), from June 2004 to August 2007 were the subjects of this study. There were 17 men and 15 women, with a median age of 53.5 years (range, 17-74). Pathologically, glioblastoma, anaplastic astrocytoma, anaplastic oligodendroglioma, and gliomatosis cerebri had been diagnosed in eighteen, eight, four, and two patients, respectively. These 32 patients were treated with CCRT with TMZ. Results : The median follow-up period was 12.5 months (range 3-48). At the time of this analysis, 13 patients died and three patients had been lost to follow-up. There was no mortality caused by drug toxicity. The median progression-free survival (PFS) of these patients was 9.0 months, and the six-month PFS rate was 72.4%. The median overall survival (OS) was 26 months, and the one-year OS rate was 83.6%. The 18 patients with glioblastoma were analyzed separately from the other patients with HGG, and the median OS was 18 months, and the one-year OS rates were 81.8%. The median PFS was seven months, and the six-month PFS rate was 75.0%. Conclusion : Our results are consistent with many other reports, confirming that CCRT with TMZ achieves good clinical outcomes in the treatment of HGG. Therefore, we suggest that CCRT with TMZ as adjuvant chemotherapy be considered as a standard therapy for patients with HGG.

• Journal of Korean Neurosurgical Society
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• 제59권1호
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• pp.44-51
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• 2016

Objective : Malignant gliomas with neuronal marker expression (MGwNM) are rare and poorly characterized. Increasingly diverse types of MGwNM have been described and these reported cases underscore the dilemmas in the classification and diagnosis of those tumors. The aim of this study is to provide additional insights into MGwNM and present the clinicopathological features of 18 patients. Methods : We reviewed the medical records of 18 patients diagnosed as MGwNM at our institute between January 2006 and December 2012. Macroscopic total resection was performed in 11 patients (61%). We evaluated the methylation status of $O^6$-methylguanine-DNA methyltransferase (MGMT) and expression of isocitrate dehydrogenase 1 (IDH-1) in all cases, and deletions of 1p and 19q in available cases. Results : The estimated median overall survival was 21.2 months. The median progression-free survival was 6.3 months. Six patients (33%) had MGMT methylation but IDH1 mutation was found in only one patient (6%). Gene analysis for 1p19q performed in nine patients revealed no deletion in six, 19q deletion only in two, and 1p deletion only in one. The extent of resection was significantly correlated with progression free survival on both univariate analysis and multivariate analysis (p=0.002 and p=0.013, respectively). Conclusion : In this study, the overall survival of MGwNM was not superior to glioblastoma. The extent of resection has a significant prognostic impact on progression-free survival. Further studies of the prognostic factors related to chemo-radio therapy, similar to studies with glioblastoma, are mandatory to improve survival.