• Radiation Oncology Journal
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• v.23 no.4
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• pp.211-216
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• 2005

Purpose: It has been reported that all-trans retinoic acid (ATRA) can inhibit glioma growing in vitro. However, clinical trials with ATRA alone in gliomas revealed modest results. ATRA has been shown to increase radiosensitivity in other tumor types, so combining radiation and ATRA would be one of alternatives to increase therapeutic efficacy in malignant gliomas. Thus, we intended to know the role of catalase, which is induced by ATRA, for radiosensitivity if radiation-reduced reactive oxygen species (ROS) is removed by catalase, the effect of radiation will be reduced. Materials and Methods: A rat glioma cell line (36B10) was used for this study. The change of catalase activity and radiosensitivity by ATRA, with or without 3-amino-1, 2, 4-triazole (ATZ), a chemical inhibitor of catalase were measured. Catalase activity was measured by the decomposition of $H_2O_2$ spectrophotometrically Radiosensitivity was measured with clonogenic assay. Also ROS was measured using a 2, 7-dichlorofluorescein diacetate spectrophotometrically. Results: When 36B10 cells were exposed to 10, 25 and $50{\mu}M$ of ATRA for 48 h, the expression of catalase activity were increased with increasing concentration and incubation time of ATRA. Catalase activity was decreased with increasing the concentration of AT (1, $10{\mu}M$) dose-dependently. ROS was increased with ATRA and it was augmented with the combination of ATRA and radiation. ATZ decreased ROS production and increased cell survival in combination of ATRA and radiation despite the reduction of catalase. Conclusion: The increase of ROS is one of the reasons for the increased radiosensitivity in combination with ATRA. The catalase that is induced by ATRA doesn't decrease ROS production and radiosensitivity.

• Journal of Korean Neurosurgical Society
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• v.30 no.11
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• pp.1263-1270
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• 2001

Objective : To analyze the radiosurgical results of intracranial meningiomas after Gamma Knife radiosurgery (GKS) and to assess the possible factors related to the outcome and complications in treating meningiomas. Patients and Methods : We retrospectively reviewed the clinical and radiological data in 179 patients(194 lesions) treated with GKS for intracranial meningiomas between May 1992 and October 2000. Radiosurgical responses were categorized as shrinkage, stasis and enlargement, and we defined the shrunken and static group as a radio-logical control. A Cox proportional hazards model was used to evaluate the correlation between the radiosurgical outcomes and various factors such as location and size of tumor, age and gender of patients, relation to venous sinus, pre-GKS degree of edema, treatment modality, radiosurgical parameters, and pathologic findings. Results : Patients were grouped into skull base meningiomas(57.7%), non-skull base tumor including convexity, parasagittal, and falx meningiomas(37.1%), and others(5.2%) according to the location of tumors. The mean maximum dose and the margin dose of tumor was 30.0Gy(19-45Gy) and 15.1Gy(9.5-24.5Gy), respectively. The mean volume of the tumors was 9.4cc(0.003-45.0cc). The radiologic control rate was 97.1%. The radiation induced imaging change with or without neurologic deficit was the most common complication(23.6%). There were seen mostly in convexity, parasagittal, and falx meningiomas which were deeply embedded in cortex. Conclusion : GKS for intracranial meningioma seems to be safe and effective treatments. However, GKS should be considered very cautiously in non-skull base tumor such as convexity, parasagittal, or falx meningiomas with regards to patient's age and general condition, size and location of tumor, pattern of embedding into cortex, presenting symptoms and patient's preference.

• Journal of Korean Neurosurgical Society
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• v.30 no.3
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• pp.334-341
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• 2001

Objective : We have currently changed treatment strategies to methotrexate(MTX)-based preirradiation chemotherapy with subsequent planned radiation for the initial therapy of primary central nervous system lymphoma (PCNSL). The aim of this study was to evaluate the results of treating PCNSL with chemotherapy plus radiotherapy (CRT) or radiotherapy(RT) alone. Method and Material : This study involved 10 females and 3 males patients with a mean age of 54.2 years. All patients underwent surgery, open(8 cases) or stereotactic biopsy(5 cases) for histological diagnosis. Eleven tumors were diffuse large B-cell lymphomas. Tumor volume change in the follow-up images and survival time were evaluated in patients treated with CRT and RT alone. In the beginning, two patients received ProMACE-Cytabom chemotherapeutic regimen, but did not complete the course and died of progressive tumor 8 and 9 months after diagnosis, respectively. One patient died at 6 months before chemotherapy. These three were excluded from the survival analysis. Five patients(RT group) completed full courses of cranial irradiation with or without boost. For the current combined modality treatment, high-dose MTXbased chemotherapy(systemic and intrathecal MTX, IV vincristine, and oral procarbazine) followed by whole brain irrdiation to 45Gy to tumor was introduced in 5 patients of CRT group. Result : A complete response was achieved in three of five who received RT only and in all of five who received CRT. All patients in CRT groups are in disease free status at a mean 23 months following therapy. The RT group patients refused any additional salvage therapy at tumor relapse and survived at mean 20 months from diagnosis. The Karnofsky performance status improved in eight of ten patients with treatment. The treatment toxicity included leukoencephalopathy in RT group and severe leukopenia, transient hepatitis, avascular necrosis of femoral head, hearing loss, and amenorrhea in CRT group, respectively. Conclusion : The combined modality therapy of MTX-based chemotherapy plus radiotherapy for PCNSL may enhance tumor response and improve patient survival. The patients who received CRT should be carefully followed up because of the higher risk of treatment-induced late neurotoxicity.

• The Journal of Korean Society for Radiation Therapy
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• v.24 no.2
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• pp.95-106
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• 2012

Purpose: The objective of this study was to investigate the usefulness of an IMRT treatment plan according to whether there was a shell-type pseudo target during radiation therapy for patients in Stage III or IV of non-small cell lung cancer (NSCLC). Materials and Methods: After setting an IMRT (Intensity-Modulated Radiation Therapy, IMRT) plan for when there was a shell-type pseudo target (SPT) and when there was none (WSPT) with 22 patients in Stage III or IV of NSCLC, the investigator analyzed dose-volume histograms (DVHs) and made assessment with dosimetric comparisons such as homogeneity index (HI) inside the tumor target, conformity index (CI) of the tumor target, spinal cord maximum dose, Esophagus $V_{50%}$, mean lung dose (MLD), and $V_{40%}$, $V_{30%}$, $V_{20%}$, $V_{10%}$, $V_{5%}$. Results: The mean CI of WSPT and SPT was $1.22{\pm}0.04$ and $1.16{\pm}0.032$ ($.000^*$), respectively, and the mean HI of WSPT and SPT was $1.06{\pm}0.015$ and $1.07{\pm}0.014$ ($.000^*$), respectively. In SPT, the mean of each CI difference decreased by $-5.16{\pm}2.54%$, while HI increased by average $0.81{\pm}0.47%$. Esophagus $V_{50%}$ recorded $14.54{\pm}12.01%$ (WSPT) and $12.14{\pm}11.09%$ ($.000^*$, SPT) with the mean of SPT differences dropping by $-26.37{\pm}25.05%$. Mean spinal cord maximum dose was $3,898.44{\pm}1,075.0$ cGy (WSPT) and $3,810.8{\pm}1,134.9$ cGy ($.004^*$, SPT) with SPT dropping by average $-3.36{\pm}5.81%$. As for lung $V_{X%}$, the mean of $V_{5%}$ and $V_{10%}$ differences was $-1.62{\pm}2.29%$ ($.006^*$) and $-1.98{\pm}5.02%$ ($.005^*$), respectively with SPT making a decrease. The mean of V20%, V30%, and V40% differences was $-3.51{\pm}3.07%$ ($.000^*$), $-4.84{\pm}6.01%$ ($.000^*$), and $-6.16{\pm}8.46%$ ($.001^*$), respectively, with SPT making a decrease with statistical significance. In MLD assessment, SPT also dropped by average $-2.83{\pm}2.41%$ ($.000^*$). Those results show that SPT allows for mean 169 cGy (Max: 547 cGy, Min: 6.4 cGy) prescription dose. Conclusion: An IMRT treatment plan with SPT during radiation therapy for patients in Stage III or IV of NSCLC will help to reduce the risk of lung toxicity and radiation-induced pneumonia by cutting down radiation doses entering the normal lung, reduce the local control failure rate during radiation therapy due to increasing prescription doses to a certain degree, and increase treatment effects.

• Biomolecules & Therapeutics
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• v.21 no.1
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• pp.29-34
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• 2013

The tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the tumor necrosis factor family of cytokines. TRAIL selectively induces apoptotic cell death in various tumors and cancer cells, but it has little or no toxicity in normal cells. Agonism of TRAIL receptors has been considered to be a valuable cancer-therapeutic strategy. However, more than 85% of primary tumors are resistant to TRAIL, emphasizing the importance of investigating how to overcome TRAIL resistance. In this report, we have found that nemadipine-A, a cell-permeable L-type calcium channel inhibitor, sensitizes TRAIL-resistant cancer cells to this ligand. Combination treatments using TRAIL with nemadipine-A synergistically induced both the caspase cascade and apoptotic cell death, which were blocked by a pan caspase inhibitor (zVAD) but not by autophagy or a necrosis inhibitor. We further found that nemadipine-A, either alone or in combination with TRAIL, notably reduced the expression of survivin, an inhibitor of the apoptosis protein (IAP) family of proteins. Depletion of survivin by small RNA interference (siRNA) resulted in increased cell death and caspase activation by TRAIL treatment. These results suggest that nemadipine-A potentiates TRAIL-induced apoptosis by down-regulation of survivin expression in TRAIL resistant cells. Thus, combination of TRAIL with nemadipine-A may serve a new therapeutic scheme for the treatment of TRAIL resistant cancer cells, suggesting that a detailed study of this combination would be useful.

• Proceedings of the Korean Society of Medical Physics Conference
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• 2005.04a
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• pp.59-63
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• 2005

Respiration motion causes movement of internal structures in the thorax and abdomen, making accurate delivery of radiation therapy to tumors in those areas a challenge. Accounting for such motion during treatment, therefore, has the potential to reduce margins drawn around the clinical target volume (CTV), resulting in a lower dose to normal tissues (e.g., lung and liver) and thus a lower risk of treatment induced complications. Among the techniques that explicitly account for intrafraction motion are breath-hold, respiration gating, and 4D or tumor-tracking techniques. Respiration gating methods periodically turn the beam on when the patient's respiration signal is in a certain part of the respiratory cycle (generally end-inhale or end-exhale). These techniques require acquisition of some form of respiration motion signal (infrared reflective markers, spirometry, strain gauge, thermistor, video tracking of chest outlines and fluoroscopic tracking of implanted markers are some of the techniques employed to date), which is assumed to be correlated with internal anatomy motion. In preliminary study for the respiratory gating radiation therapy, we performed to measurement of this respiration motion signal. In order to measure the respiratory motion signals of patient, respiration measurement system (RMS) was composed with three sensor (spirometer, thermistor, and belt transducer), 4 channel data acquisition system and mobile computer. For two patients, we performed to evaluation of respiratory cycle and shape with RMS. We observed under this system that respiratory cycle is generally periodic but asymmetric, with the majority of time spent. As expected, RMS traced patient's respiration each other well and be easily handled for application.

• Journal of Ginseng Research
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• v.36 no.1
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• pp.86-92
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• 2012

The glioblastoma multiforme (GBM) is the most common malignant brain tumor in adults. Despite combination treatments of radiation and chemotherapy, the survival periods are very short. Therefore, this study was conducted to assess the potential of ginsenoside $F_2$ (F2) to treat GBM. In in vitro experiments with glioblastoma cells U373MG, F2 showed the cytotoxic effect with $IC_{50}$ of 50 ${\mu}g/mL$ through apoptosis, confirmed by DNA condensation and fragmentation. The cell population of cell cycle sub-G1 as indicative of apoptosis was also increased. In xenograft model in SD rats, F2 at dosage of 35 mg/kg weight was intravenously injected every two days. This reduced the tumor growth in magnetic resonance imaging images. The immunohistochemistry revealed that the anticancer activity might be mediated through inhibition of proliferation judged by Ki67 and apoptosis induced by activation of caspase-3 and -8. And the lowered expression of CD31 showed the reduction in blood vessel densities. The expression of matrix metalloproteinase-9 for invasion of cancer was also inhibited. The cell populations with cancer stem cell markers of CD133 and nestin were reduced. The results of this study suggested that F2 could be a new potential chemotherapeutic drug for GBM treatment by inhibiting the growth and invasion of cancer.

• Radiation Oncology Journal
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• v.26 no.2
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• pp.104-112
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• 2008

Purpose: To assess the toxicity and tumor response induced by $DCVac/IR^{(R)}$ dendritic cell(DC) immunotherapy combined with irradiation for refractory colorectal cancer patients with multiple liver metastases. Materials and Methods: Between May 2004 and November 2006, applicants from a pool of refractory colorectal cancer patients with multiple liver metastases were enrolled. The patients were registered after having signed the informed consent form, which had been approved by the Institutional Review Board from the Dong-A University and Busan National University Hospital. DCs were obtained from peripheral blood of each patient, and then cultured in vitro. A total of $6{\times}10^6$ DCs were packed into a vial($DCVac/IR^{(R)}$, 0.5 ml) at the convenience of each patient's schedule. On the day before and on the day of each vaccination, each patient received a 4 Gy radiation dose to the target tumor. On the day of vaccination, the indicated dose of autologous DCs was injected into the irradiated tumor using ultrasound-guided needle injection procedures. A total of four vaccinations were scheduled at three 2-week intervals and one 4 week interval at the Dong-A University and Busan National University Hospital. If the tumor status was deemed to be stable or responding to therapy, an additional vaccination dose or two was approved at 4 week intervals beyond the fourth immunization. A tolerance test for DCs was conducted by injecting a range of doses($3{\times}10^6\;to\;12{\times}10^6$ DCs) after the 3rd injection. Moreover, the maximal tolerable dose was applied to additional patients. Treatment safety was evaluated in all patients who had at least one injection. Treatment feasibility was evaluated by the 10th week by assessing the response of patients having at least 4 injections. For systemic toxicities, the evaluation was performed using the National Cancer Institute Common Toxicity Criteria, whereas adverse effects were recorded using common WHO toxicity criteria. Results: Of the 24 registered patients, 22 received the DCs injections. Moreover, of the 14 patients that applied for the tolerance test, only 11 patients completed it because 3 patients withdrew their testing agreement. A grade 3 or more side effect, which was possibly related to the DC injection, did not occur in additional patients. The $12{\times}10^6$ DC injection was identified as the maximum tolerable dose, and was then injected in an additional 8 patients. Patients tolerated the injection fairly well, with no fatal side effects. In order to assess the feasibility of DC immunotherapy, the response was evaluated in other hepatic lesions outside of the targeted hepatic lesion. The response evaluation was performed in 15 of the 17 patients who received at least 4 injections. Stable and progressive disease was found in 4 and 11 patients, respectively. Conclusion: The DC-based immunotherapy and radiotherapy is theoretically synergistic for the local control and systemic control. The $DCVac/IR^{(R)}$ immunotherapy combined with irradiation was tolerable and safe in the evaluated cases of refractory colorectal cancer with multiple liver metastases. Future work should include well designed a phase II clinical trials.

• Radiation Oncology Journal
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• v.19 no.2
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• pp.181-189
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• 2001

Purpose : Changes in the balance between MMP and TIMP can have a profound effect on the composition in the extracellular matrix (ECM) and affect various cellular functions including adhesion, migration, differentiation of cells, and fibrosis and invasion and metastasis of cancer cells. Radiation therapy is a popular treatment modality for benign and malignant tumor, but the study for radiation effect on MMP and TIMP is scarce. In the current study, we have examined the expression of TIMP in fibrosis-prone (C57BL/6) mice after radiation. Methods and Materials : Adult female mice of $10\~12$ weeks were used. The whole body were irradiated using a Varian CL-4/100 with 2 and 10 Gy. Immunohistochemical staining was peformed according to Avidin Biotin complex method and evaluated by observing high power field. For TIMP-1, TIMP-2 antibodies, reactivity was assessed in the parenchymal cell and in the stromal cell. The scale of staining was assessed by combining the quantitative and qualiative intensity of staining. Results : TIMP-1 immunoreactivity did not change in lung. But, in liver, TIMP-1 immunoreactivity was localized in cytoplasm of hepatocyte and Kupffer cell. in kidney, TIMP-1 immunoreactivity was localized in cytoplasm of some tubular cell. Temporal variations were not seen. Dose-response relationship was not seen except kidney. TIMP-2 immunoreactivity in lung was a score (++) at 0 Gy and elevated to a score (+++) at 2 Gy. TIMP-2 immunoreactivity was a score (++) in liver at 0 Gy. TIMP-2 immunoreactivity was localized in cytoplasm of hepatocyte and Kupffer cell as same as patterns of TIMP-1 immunoreactivity. The TIMP-2 immunoreactivity in liver was elevated to (+++) at 2 Gy. Immunoreactivity to TIMP-2 in kidney was a score (+++) at 0 Gy and was not changed at 10 Gy. The score of TIMP-2 immunoreactivity was reduced to (++) at 2 Gy. TIMP-2 immunoreactivity was confined to tubules in kidney. Temporal variation of TIMP-2 immunoreactivity was irregular. Dose-response relationship of TIMP-2 immunoreactivity was not seen. Conclusions : Differences between intensity of expression of TIMP-1 and TIMP-2 in each organ was present. Expression of TIMP was localized to specific cell in each organ. Irradiation increased TIMP-1 immunoreactivity in the liver and the kidney. Irradiation increased TIMP-2 immunoreactivity in the lung. But, in the liver and the kidney, TIMP-2 expression to radiation was irregular. Temporal variation of TIMP-2 immunoreactivity was irregular. Dose-response relationship of TIHP-2 immunoreactivity was not seen. In the future, we expect that the study of immunohistochemical staining of longer period of postirradiation and quantitative analysis using western blotting and northern blotting could define the role of TIMP in the radiation induced tissue fibrosis.

• Journal of Life Science
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• v.26 no.2
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• pp.212-219
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• 2016

Glioblastoma multiforme is the most common and most aggressive type of primary brain tumor in humans. Despite intensive treatment, including surgery, radiation, and chemotherapy, most patients die of the disease. Although the anti-cancer activity of resveratrol has been demonstrated in various cancer cell types, its underlying mechanism in glioma cells is not fully elucidated. The present study was undertaken to investigate the effect of resveratrol on cell viability and to determine the molecular mechanism in A172 human glioma cells. Resveratrol caused the generation of reactive oxygen species (ROS), and resveratrol-induced cell death was prevented by antioxidants (N-acetylcysteine and catalase), suggesting that an oxidative mechanism is responsible for resveratrol-induced cell death. Resveratrol-induced phosphorylation of extracellular signal-regulated kinase (ERK), p38 kinase, and c-Jun N-terminal kinase (JNK), and resveratrol-induced cell death were prevented by inhibitors of these kinases. Resveratrol-induced activation of caspase-3 and cell death were prevented by the caspase inhibitors. ERK activation and caspase-3 activation induced by resveratrol was blocked by N-acetylcysteine. Taken together, these results suggest that resveratrol causes a caspase-dependent cell death via activation of ERK, p38, and JNK, mediated by ROS generation, in human glioma cells.