• Journal of the Korean Society of Radiology
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• v.81 no.3
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• pp.688-700
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• 2020

Purpose To compare the incidence, survival rate, and CT findings of acute exacerbation (AE) of idiopathic pulmonary fibrosis (IPF) between patients with and without lung cancer. Materials and Methods From June 2004 to July 2018, 89 consecutive patients diagnosed with IPF were included. Among them, 26 patients had IPF with lung cancer (IPF-LCA), and 63 patients had IPF alone. The clinical characteristics and CT findings associated with IPF, lung cancer, and AE were reviewed. Surgery and chemotherapy were performed for 6 and 23 cases of lung cancer, respectively, as the first- or second-line anticancer treatment. The overall survival, CT findings, disease-free period before AE, and duration from the onset of AE to death were compared. Results The incidence of AE was 61.5% in the IPF-LCA group and 58.7% in the IPF group (p = 0.806). The mean overall survival in the IPF-LCA and IPF groups were 16.8 and 83.0 months, respectively (p < 0.001). The mean durations from the start of the lung cancer treatment to the onset of AE were 16.0 and 4.6 months in cases of surgical treatment and chemotherapy, respectively. In comparison of death from AE, the survival rate was significantly lower in the IPF-LCA group than in the IPF group (p = 0.008). In the CT findings associated with AE, the IPF-LCA group tended to have a peribronchial (p < 0.001) or asymmetric distribution (p = 0.016). Conclusion In patients with IPF who develop lung cancer, the rate of death from AE is higher than that in patients with IPF alone. They tend to have unusual CT patterns associated with AE, such as a peribronchial or asymmetric distribution.

• Asia pacific journal of information systems
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• v.19 no.3
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• pp.69-98
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• 2009

We investigated what factors motivate gamers to participate in a guild and why they continue to be engaged as members of the guild. We find that, based on the result of focus group interviews with MMORPG gamers, social support and self-esteem factors play important roles. Considering both prior research and the focus group interviews we have conducted, we define social support and character control as independent variables. Character identity, guild identity, and self-esteem are proposed as mediating variables while guild flow and game loyalty as dependent variables. Accordingly, we develop the research model and hypotheses, and verify them empirically. Based on our experiences of playing the WoW game, we proposed a research model and conducted focus-group interviews (FGIs). FGIs involve formulating a hypothesis and then collecting some relevant data. FGIs were conducted face-to-face with students of C University in Korea. We formulated structured interview schedules, and the questions were based on our research variables and personal experiences. The questions for the interviews encompassed the following areas: (a) the demographic characteristics of the focus group; (b) the number of years for which respondents had played online games; (c) the motive for starting a game; (d) the number of game-characters assumed by each gamer; (e) the type of game played; and (f) other issues such as the reasons for involvement in the play, the willingness to reuse the game in case new versions were released, etc. On average, it took two hours to interview each of three groups. A primary set of FGIs was conducted with three groups on the premise that there would be some differences caused by character race (Horde vs. Alliance) or by playable server (Normal vs. Combat). With respect to the manner of playing, we found that guild members shared information, felt a sense of belonging, and played computer games for quite a long time through the guild; however, they did not undergo these experiences when playing alone. Gamers who belonged to a specific guild helped other players without expecting compensation for that, freely shared information about the game, gave away items for free, and more generous with other members who made mistakes. The guild members were aware of the existence other members and experienced a sense of belonging through interactions with, and evaluations from, other players. It was clear that social support was shown within the guild and that it played an important role as a major research variable. Based on the results of the first FGIs, a second set of in-depth FGIs was carried out with a focus on the psychology of the individual within the guild and the social community of the guild. The second set of FGIs also focused on the guild's offline meetings. Gamers, over all, recognize the necessity of joining a community, not only off-line but also online world of the guild. They admit that the guild is important for them to easily and conveniently enjoy playing online computer games. The active behavior and positive attitudes of existing guild members can motivate new members of the guild to adapt themselves to the guild environment. They then adopt the same behaviors and attitudes of established guild members. In this manner, the new members of the guild strengthen the bonds with other gamers while feeling a sense of belonging, and developing social identity, thereby. It was discovered that the interaction among guild members and the social support encouraged new gamers to quickly develop a sense of social identity and increase their self-esteem. The guild seemed to play the role of socializing gamers. Sometimes, even in the real world, the guild members helped one another; therefore, the features of the guild also spilled over to the offline environment. We intend to use self-esteem, which was found through the second set of FGIs, as an important research variable. To collect data, an online survey was designed with a questionnaire to be completed by WoW gamers, who belong to a guild. The survey was registered on the best three domestic game-sites: 'WoW playforum,' 'WoW gamemeca,' and 'Wow invent.' The selected items to be measured in the questionnaire were decided based on prior research and data from FGIs. To verify the content of the questionnaire, we carried out a pilot test with the same participants to point out ambiguous questions as a way to ensure maximum accuracy of the survey result. A total of 244 responses were analyzed from the 250 completed questionnaires. The SEM analysis was used to test goodness-of-fit of the model. As a result, we found important results as follows: First, according to the statistics, social support had statistically significant impacts on character control, character identity, guild identity and self-esteem. Second, character control had significant effects on character identity, guild identity and self-esteem. Third, character identity shows its clear impact on self-esteem and game loyalty. Fourth, guild identity affected self-esteem, guild flow and game loyalty. Fifth, self-esteem had a positive influence on the guild flow. These days, the number of virtual community is rising along with its significance largely because of the nature of the online games. Accordingly, this study is designed to clarify the psychological relationship between gamers within the guild that has been generally established by gamers to play online games together. This study focuses on the relationships in which social support influences guild flow or game loyalty through character control, character identity, guild identity, and self-esteem, which are present within a guild in the MMORPG game environment. The study results are as follows. First, the effects of social support on character control, character identity, guild identity and self-esteem are proven to be statistically significant. It was found that character control improves character identity, guild identity and self-esteem. Among the seven variables, social support, which is derived from FGIs, plays an important role in this study. With the active support of other guild members, gamers can improve their ability to develop good characters and to control them. Second, character identity has a positive effect on self-esteem and game loyalty, while guild identity has a significant effect on self-esteem, guild flow and game loyalty. Self-esteem affects guild flow. It was found that the higher the character and guild identities become, the greater the self-esteem is established. Contrary to the findings of prior research, our study results indicate that the relationship between character identity and guild flow is not significant. Rather, it was found that character identity directly affects game players' loyalty. Even though the character identity had no direct effect on increasing guild flow, it has indirectly affected guild flow through self-esteem. The significant relationship between self-esteem and guild flow indicates that gamers achieve flow, i.e., a feeling of pleasure and excitement through social support. Several important implications of this study should be noted. First, both qualitative and quantitative methods were used to conduct this study. Through FGIs, it was observed that both social support and self-esteem are important variables. Second, because guilds had been rarely studied, this research is expected to play an important role in the online community. Third, according to the result, six hypotheses (H1, H5, H6, H7, H8, and H11) setup based on FGIs, were statistically significant; thus, we can suggest the corresponding relationships among the variables as a guideline for follow-up research. Our research is significant as it has following implications: first, the social support of the guild members is important when establishing character control, character identity, guildidentity and self-esteem. It is also a major variable that affects guild flow and game loyalty. Second, character control when improved by social support shows notable influence on the development of character identity, guild identity and self-esteem. Third, character identity and guild identity are major factors to help establish gamers' own self-esteem. Fourth, character identity affects guild flow through self-esteem and game loyalty. The gamers usually express themselves through characters; the higher character identity is, the more loyalty a gamer has. Fifth, guild identity, established within the guild, has clear effects on self-esteem, guild flow and game loyalty. Sixth, qualitative and quantitative methods are employed to conduct this study. Based on the results of focus group interviews and SEM analysis, we find that the social support by guild members and psychological factors are significant in strengthening the flow of guild and loyalty to the game. As such, game developers should provide some extra functions for guild community, through which gamers can play online games in collaboration with one another. Also, we suggest that positive self-esteem which is built up through social support can help gamers achieve higher level of flow and satisfaction, which will consequently contribute to minimizing the possibility for the players to develop negative attitude toward the guild they belong to.

• Tuberculosis and Respiratory Diseases
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• v.56 no.1
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• pp.51-66
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• 2004

Objectives : The matrix metalloproteinases (MMPs) that participate in the extracellular matrix metabolism play a important role in the progression of pulmonary fibrosis. The effects of the MMPs are regulated by several factors including Th-1 cytokines, $interferon-{\gamma}$ ($IFN-{\gamma}$). Up to now, $IFN-{\gamma}$ is known to inhibit pulmonary fibrosis, but little is known regarding the exact effect of $IFN-{\gamma}$ on the regulation of the MMPs. This study investigated the effects of $interferon-{\gamma}$ on the pulmonary fibrosis and the expression of the lung MMP-2,-9, TIMP-1,-2, and Th-2 cytokines in aa rat model of bleomycin induced pulmonary fibrosis. Materials and methods : Male, specific pathogen-free Sprague-Dawley rats were subjected to an intratracheal bleomycin instillation. The rats were randomized to a saline control, a bleomycin treated, and a bleomycin+$IFN-{\gamma}$ treated group. The bleomycin+$IFN-{\gamma}$ treated group was subjected to an intramuscular injection of $IFN-{\gamma}$ for 14 days. At 3, 7, 14, and 28 days after the bleomycin instillation, the rats were sacrificed and the lungs were harvested. In order to evaluate the effects of the $IFN-{\gamma}$ on lung fibrosis and inflammation, the lung hydroxyproline content, inflammation and fibrosis score were measured. Western blotting, zymography and reverse zymography were performed at 3, 7, 14, 28 days after bleomycin instillation in order to evaluate the MMP-2,-9, and TIMP-1,-2 expression level. ELISA was performed to determine the IL-4 and IL-13 level in a lung homogenate. Results : 1. 7 days after bleomycin instillation, inflammatory changes were more severe in the bleomycin+$IFN-{\gamma}$ group than the bleomycin group (bleomycin group : bleomycin+$IFN-{\gamma}$ group=$2.08{\pm}0.15:2.74{\pm}0.29$, P<0.05), but 28 days after bleomycin instillation, lung fibrosis was significantly reduced as a result of the $IFN-{\gamma}$ treatment (bleomycin group : bleomycin+$IFN-{\gamma}$ group=$3.94{\pm}0.43:2.64{\pm}0.13$, P<0.05). 2. 28 days after bleomycin instillation, the lung hydroxyproline content was significantly reduced as a result of $IFN-{\gamma}$ treatment (bleomycin group : bleomycin+$IFN-{\gamma}$ group=$294.04{\pm}31.73{\mu}g/g:194.92{\pm}15.51{\mu}g/g$, P<0.05). 3. Western blotting showed that the MMP-2 level was increased as a result of the bleomycin instillation and highest in the 14 days after bleomycin instillation. 4. In zymography, the active forms of MMP-2 were significantly increased as a result of the $IFN-{\gamma}$ treatment 3 days after the bleomycin instillation, bleomycin+$IFN-{\gamma}$ group (bleomycin group : bleomycin+$IFN-{\gamma}$ group=$209.63{\pm}7.60%:407.66{\pm}85.34%$, P<0.05), but 14 days after the bleomycin instillation, the active forms of MMP-2 were significantly reduced as a result of the $IFN-{\gamma}$ treatment (bleomycin group : bleomycin+$IFN-{\gamma}$ group=$159.36{\pm}20.93%:97.23{\pm}12.50%$, P<0.05). 5. The IL-4 levels were lower in the bleomycin and bleomycin+$IFN-{\gamma}$ groups but this was not significant, and the IL-13 levels showed no difference between the experiment groups. Conclusion : The author found that lung inflammation was increased in the early period but the pulmonary fibrosis was inhibited in the late stage as a result of $IFN-{\gamma}$. The inhibition of pulmonary fibrosis by $IFN-{\gamma}$ appeared to be associated with the inhibition of MMP-2 activation by $IFN-{\gamma}$. Further studies on the mechanism of the regulation of MMP-2 activation and the effects of MMP-2 activation on pulmonary fibrosis is warranted in the future.

• Journal of Chest Surgery
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• v.37 no.3
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• pp.201-209
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• 2004

Extracorporeal life support (ECLS) system is a device for respiratory and/or heart failure treatment, and there have been many trials for development and clinical application in the world. Currently, a non-pulsatile blood pump is a standard for ECLS system. Although a pulsatile blood pump is advantageous in physiologic aspects, high pressure generated in the circuits and resultant blood cell trauma remain major concerns which make one reluctant to use a pulsatile blood pump in artificial lung circuits containing a membrane oxygenator. The study was designed to evaluate the hypothesis that placement of a pressure-relieving compliance chamber between a pulsatile pump and a membrane oxygenator might reduce the above mentioned side effects while providing physiologic pulsatile blood flow. The study was performed in a canine model of oleic acid induced acute lung injury (N=16). The animals were divided into three groups according to the type of pump used and the presence of the compliance chamber, In group 1, a non-pulsatile centrifugal pump was used as a control (n=6). In group 2 (n=4), a single-pulsatile pump was used. In group 3 (n=6), a single-pulsatile pump equipped with a compliance chamber was used. The experimental model was a partial bypass between the right atrium and the aorta at a pump flow of 1.8∼2 L/min for 2 hours. The observed parameters were focused on hemodynamic changes, intra-circuit pressure, laboratory studies for blood profile, and the effect on blood cell trauma. In hemodynamics, the pulsatile group II & III generated higher arterial pulse pressure (47$\pm$ 10 and 41 $\pm$ 9 mmHg) than the nonpulsatile group 1 (17 $\pm$ 7 mmHg, p<0.001). The intra-circuit pressure at membrane oxygenator were 222 $\pm$ 8 mmHg in group 1, 739 $\pm$ 35 mmHg in group 2, and 470 $\pm$ 17 mmHg in group 3 (p<0.001). At 2 hour bypass, arterial oxygen partial pressures were significantly higher in the pulsatile group 2 & 3 than in the non-pulsatile group 1 (77 $\pm$ 41 mmHg in group 1, 96 $\pm$ 48 mmHg in group 2, and 97 $\pm$ 25 mmHg in group 3: p<0.05). The levels of plasma free hemoglobin which was an indicator of blood cell trauma were lowest in group 1, highest in group 2, and significantly decreased in group 3 (55.7 $\pm$ 43.3, 162.8 $\pm$ 113.6, 82.5 $\pm$ 25.1 mg%, respectively; p<0.05). Other laboratory findings for blood profile were not different. The above results imply that the pulsatile blood pump is beneficial in oxygenation while deleterious in the aspects to high pressure generation in the circuits and blood cell trauma. However, when a pressure-relieving compliance chamber is applied between the pulsatile pump and a membrane oxygenator, it can significantly reduce the high circuit pressure and result in low blood cell trauma.

• Radiation Oncology Journal
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• v.20 no.1
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• pp.53-61
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• 2002

Purpose : To determine the optimal scheme of postoperative chemoradiotherapy in rectal cancer by comparing survival, Patterns of failure, toxicities in early and late radiotherapy groups using a Phase III randomized prospective clinical trial. Materials and Methods : From January 1996 to March 1999, 307 patients with curatively resected AJCC stage II and III rectal cancer were assigned randomly to an 'early (151 patients, arm 1)' or a 'late (156 patients, arm II)' and were administered combined chemotherapy (5-FU $375\;mg/m^2/day$, leucovorin $20\;mg/m^2$, IV bolus daily, for 3 days with RT, 5 days without RT, 8 cycles with 4 weeks interval) and radiation therapy (whole pelvis with 45 Gy/25 fractions/5 weeks). Patients of arm I received radiation therapy from day 1 of the first cycle of chemotherapy and those of arm II from day 57 with a third cycle of chemotherapy. The median follow-up period of living patients was 40 months. Results : Of the 307 patients enrolled, fifty patients did not receive scheduled radiation therapy or chemotherapy. The overall survival rate and disease free survival rate at 5 years were $78.3\%\;and\;68.7\%$ in arm I, and $78.4\%\;and\;67.5\%$ in arm II. The local recurrence rate was $6.6\%\;and\;6.4\%$ (p=0.46) in arms I and II, respectively, no significant difference was observed between the distant metastasis rates of the two arms ($23.8\%\;and\;29.5\%$, p=0.16). During radiation therapy, grade 3 diarrhea or more, by the NCI common toxicity criteria, was observed in $63.0\%\;and\;58.2\%$ of the respective arms (p=N.S.), but most were controlled with supportive care. Hematologic toxicity (leukopenia) greater than RTOG grade 2 was found in only $1.3\%\;and\;2.6\%$ of patients in each respective arm. Conclusion : There was no significant difference in survival, patterns of failure or toxicities between the early and late radiation therapy arms. Postoperative adjuvant chemoradiation was found to be a relatively safe treatment but higher compliance is needed.

• Tuberculosis and Respiratory Diseases
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• v.49 no.1
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• pp.37-48
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• 2000

Backgrounds : The pathophysiology of chronic airflow obstruction, such as bronchial asthma, is characterized by mucus hypersecretion, goblet cell hyperplasia(GCH), smooth muscle hypertrophy, and inflammatory cells infiltration. In fatal asthma patients, one distinct findings is mucus hypersecretion due to GCH. However, the mechanisms of GCH in these hypersecretory diseases remain still unknown. In this study, a rat model was rapidly induced with GCH by instillation of $TiO_2$, intratracheally. We intend to confirm GCH and association of concomitant inflammatory cells infiltration and to observe the effect of potent antiinflammatory agent, that is dexamethasone, on GCH with inflammatory cells. Methods : Twenty-one 8-weeks-old male Sprague-Dawley rats were divided into three groups. Endotoxinfree water was instilled intratracheally in group 1(control) ; $TiO_2$, was instilled in the group 2 ; and dexamethasone was injected intraperitoneally to group 3 before $TiO_2$ instillation. After 120 hours, all rats were sacrificed, and trachea, bronchi, and lungs were resected respectively. These tissues were made as paraffin blocks and stained as PAS for goblet cells and Luna stain for eosinophils. We calculated the ratio of goblet cell to respiratory epithelium and number of infiltrated eosinophils from each tissue. Results : (1) Fraction of goblet cells was significantly increased in group 2 than in group 1 in the trachea and in the main bronchus. (10.19$\pm$11.33% vs 4.09$\pm$8.28%, p<0.01 and 34.09$\pm$23.91% vs 3.61$\pm$4.84%, p<0.01, respectively). (2) Eosinophils were significantly increased in the airway of group 2 than that of group 1. (5.43$\pm$3.84% vs 0.17$\pm$0.47 in trachea and 47.71$\pm$16.91 vs 2.71$\pm$1.96 in main bronchi). (3) There was a positive correlation between goblet cells and eosinophils(r=0.719, p=0.001). (4) There was significant difference in the decrease of goblet cells after dexamethasone injection between group 2 and group 3 (p<0.01). Also, infiltration of eosinophils was suppressed by dexamethasone. Conclusion : We made an animal model of $TiO_2$-induced goblet cell hyperplasia. GCH was observed mainly in the main bronchi with concomitant eosinophilic infiltration. Both goblet cell hyperplasia and eosinophilic infiltration were suppressed by dexamethasone. This animal model may serve as a useful tool in understanding of the mechanism of GCH in chronic airway diseases.

• Journal of Yeungnam Medical Science
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• v.17 no.1
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• pp.21-30
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• 2000

Background: The purpose of the present study was to investigate the effect of exercise on the activities of antioxidant enzymes, super oxide dismutase(SOD), glutathione peroxidase(GPX) and catalase(CAT) of skeletal muscle(gastrocnemius) and liver in streptozotocin(STZ) induced diabetic rats. The malondialdehyde(MDA) concentration was also measured as an index of lipid poroxidation of tho tissues by exercise-induced oxidative stresses in diabetic rats. Material and Methods: Male Sprague-Dawley rats were randomly divided into control and STZ-induced diabetic rats. The STZ in citrate buffer solution was injected twice at S days intervals intraperitoneally(50, 70 mg/kg respectively). On the 28th day after the first STZ injection, the diabetic animals were randomly divided into pre- and post-exercise groups, The exercise was introduced to the rats of post-exercise group by treadmill running until exhaution with moderate intensity ($V_{O2max}$: 50-70%) of exercise. The duration of average running time was 2 hours and 19 minutes. Results: The blood glucose concentration was increased(p<0.001) and plasma insulin concentration was decreased(p<0.001) in the diabetic rats. The glycogen concentration in the muscle and liver was decreased by exhaustive exercise in the diabetic rats(p<0.001), In the skeletal muscle, the activities of GPX was increased(p<0.05) and the activities of SOD and CAT were not changed in the diabetic rats compare to those of the control rats. The activities of GPX was not changed by exercise but the activities of SOD(p<0.01) and CAT(p<0.01) were decreased by exercise in the diabetic rats, The concentration of MDA was not changed by exercise in diabetic rats, and the values of pre-exercise and post-exercise diabetic rats were not different from the value those of control rats, In the liver, the activities of SOD was decreased(p<0.01), and the activities of GPX and CAT were not changed in diabetic rats compared to the values of control rats, The activities of SOD, GPX and CAT were not changed by exercise in diabetic rats but the activity of SOD seemed to decrease slightly, The MDA concentration was increased in the diabetic rats compared to the values of control rats(p<0.001), but there was no change of MDA concentration by exercise in diabetic rats, Conclusions: In summary, exhaustive physical exercise did not seem to impose oxidative stress on the skeletal muscle because of due to oxygen free radicals, regardless of the decrease in SOD and CAT in the diabetic rats, In liver tissue, the tissue damage by oxidative stress was observed in diabetic rats but the additional tissue damage by exhaustive physical exercise was not observed.

• Radiation Oncology Journal
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• v.27 no.4
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• pp.181-188
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• 2009

Purpose: The aim of this study was to evaluate the results of postoperative radiotherapy in a case of perihilar cholagiocarcinoma by analyzing overall survival rate, patterns of failure, prognostic factors for overall survival, and toxicity. Materials and Methods: Between January 1998 and March 2008, 38 patients with perihilar cholangiocarcinoma underwent a surgical resection and adjuvant radiotherapy. The median patient age was 59 years (range, 28 to 72 years), which included 23 men and 15 women. The extent of surgery was complete resection in 9 patients, microscopically positive margins in 25 patients, and a subtotal resection in 4 patients. The tumor bed and regional lymphatics initially received 45 Gy or 50 Gy, but was subsequently boosted to a total dose of 59.4 Gy or 60 Gy in incompletely resected patients. The median radiotherapy dose was 59.4 Gy. Concurrent chemotherapy was administered in 30 patients. The median follow-up period was 14 months (range, 6 to 45 months). Results: The 3-year overall survival and 3-year progression free survival rates were 30% and 8%, respectively. The median survival time was 28 months. A multivariate analysis showed that differentiation was the only significant factor for overall survival. The 3-year overall survival was 34% in R0 patients and 20% in R1 patients. No statistically significant differences in survival were found between the 2 groups (p=0.3067). The first site of failure was local in 18 patients (47%). No patient experienced grade 3 or higher acute toxicity and duodenal bleeding developed in 2 patients. Conclusion: Our results suggest that adjuvant RT might be a significant factor in patients with a positive margin following a radical resection. However, there was still a high locoregional recurrence rate following surgery and postoperative radiotherapy. Further study is necessary to enhance the effect of the adjuvant radiotherapy.

• Radiation Oncology Journal
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• v.14 no.3
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• pp.221-228
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• 1996

Purpose : We tried to evaluate the clinical characteristics, the treatment methods, the results of treatments, and the Patterns of failure in ovarian dysgerminoma retrospectively According to the results we would like to suggest the proper management guideline of stage la ovarian dysgerminoma patients who want to maintain fertility. Materials and Methods : Between 1975 and 1990, 34 patients with ovarian dysgerminoma were treated at the Yonsei University Hospital. The case records of these patients have been reviewed for presenting symptoms, treatment methods, local control and survival following treatment. Excluded from analysis were five patients with mixed ovarian germ cell tumors and gonadoblastomas (46,XY) Treatment results of the twenty nine patients were analysed by each treatment modality. Twenty one patients were treated with surgery and postoperative adjuvant radiotherapy (group 2). The other eight patients were treated with operation alone (group 2). The median age of twenty-nine patients was 23 years with a range of 8 to 39 years. Presenting symptoms were abdominal mass (20) pelvic discomfort or pain (5) et al. Radiotherapy was performed by 10MV LINAC or Co-60 teletherapy unit. The total radiation dose of the whole abdomen was 20-25 Gy/3weeks, 1-1.5 Gy/fraction with a boost to the whole pelvis 10-15 Gy/l-2weeks 1.8-2.0 Gy/fraction. Advanced stage disease (stage II or stage III) patients received prophylactic mediastinal and supraclavicular irradiation to a dose of 16-26 Gy. Median duration of follow-up of living patients was 80 months (range 13-201 months). Results : All of the twenty one patients of group 1 were alive without disease ($100\%$). Among the eight patients who were not treated with radiotherapy (group 2), six patients developed local recurrence. Four Patients referred with recurrent disease were treated with salvage radiotherapy. Three of four patients were salvaged and one Patient who had recurrent intra-abdominal disease died of progressed carcinomatosis at 11 months after salvage radiotherapy. The other two patients with recurrence were salvaged with chemotherapy (1 patient) or re-operation (1 Patient). Twenty eight patients remained alive without disease at last follow up, so the 5 year local control rate and 5 year overall survival rate for all groups were $96.6\%$ (28/29), respectively. Among thirteen patients with stage la unilateral tumors seven patients were treated with postoperative radiotherapy and the other six patients were treated with unilateral salpingo-oophorectomy alone. Five patients who did not received radiotherapy developed local failure but all of the recurrent ovarian dysgerminomas were salvaged with radiotherapy, chemotherapy or re-operation. So all the 13 patients with stage la ovarian dysgerminoma were free of disease from 20-201 months (median 80 months). Conclusion : The authors consider external irradiation to be an effective treatment as a complement to surgery in ovarian dysgerminoma. For those patients with disease presenting in stage la tumors who wish to maintain fertility, unilateral salpingo-oophorectomy alone may be curative and spare ovarian function considering excellent salvage rate of recurrent ovarian dysgerminoma in present study.

• 한국균학회소식:학술대회논문집
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• 2016.05a
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• pp.19-20
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• 2016

Sesquiterpenoids are defined as $C_{15}$ compounds derived from farnesyl pyrophosphate (FPP), and their complex structures are found in the tissue of many diverse plants (Degenhardt et al. 2009). FPP's long chain length and additional double bond enables its conversion to a huge range of mono-, di-, and tri-cyclic structures. A number of cyclic sesquiterpenes with alcohol, aldehyde, and ketone derivatives have key biological and medicinal properties (Fraga 1999). Fungi, such as the wood-rotting Polyporus brumalis, are excellent sources of pharmaceutically interesting natural products such as sesquiterpenoids. In this study, we investigated the biosynthesis of P. brumalis sesquiterpenoids on modified medium. Fungal suspensions of 11 white rot species were inoculated in modified medium containing $C_6H_{12}O_6$, $C_4H_{12}N_2O_6$, $KH_2PO_4$, $MgSO_4$, and $CaCl_2$ for 20 days. Cultivation was stopped by solvent extraction via separation of the mycelium. The metabolites were identified as follows: propionic acid (1), mevalonic acid lactone (2), ${\beta}$-eudesmane (3), and ${\beta}$-eudesmol (4), respectively (Figure 1). The main peaks of ${\beta}$-eudesmane and ${\beta}$-eudesmol, which were indicative of sesquiterpene structures, were consistently detected for 5, 7, 12, and 15 days These results demonstrated the existence of terpene metabolism in the mycelium of P. brumalis. Polyporus spp. are known to generate flavor components such as methyl 2,4-dihydroxy-3,6-dimethyl benzoate; 2-hydroxy-4-methoxy-6-methyl benzoic acid; 3-hydroxy-5-methyl phenol; and 3-methoxy-2,5-dimethyl phenol in submerged cultures (Hoffmann and Esser 1978). Drimanes of sesquiterpenes were reported as metabolites from P. arcularius and shown to exhibit antimicrobial activity against Gram-positive bacteria such as Staphylococcus aureus (Fleck et al. 1996). The main metabolites of P. brumalis, ${\beta}$-Eudesmol and ${\beta}$-eudesmane, were categorized as eudesmane-type sesquiterpene structures. The eudesmane skeleton could be biosynthesized from FPP-derived IPP, and approximately 1,000 structures have been identified in plants as essential oils. The biosynthesis of eudesmol from P. brumalis may thus be an important tool for the production of useful natural compounds as presumed from its identified potent bioactivity in plants. Essential oils comprising eudesmane-type sesquiterpenoids have been previously and extensively researched (Wu et al. 2006). ${\beta}$-Eudesmol is a well-known and important eudesmane alcohol with an anticholinergic effect in the vascular endothelium (Tsuneki et al. 2005). Additionally, recent studies demonstrated that ${\beta}$-eudesmol acts as a channel blocker for nicotinic acetylcholine receptors at the neuromuscular junction, and it can inhibit angiogenesis in vitro and in vivo by blocking the mitogen-activated protein kinase (MAPK) signaling pathway (Seo et al. 2011). Variation of nutrients was conducted to determine an optimum condition for the biosynthesis of sesquiterpenes by P. brumalis. Genes encoding terpene synthases, which are crucial to the terpene synthesis pathway, generally respond to environmental factors such as pH, temperature, and available nutrients (Hoffmeister and Keller 2007, Yu and Keller 2005). Calvo et al. described the effect of major nutrients, carbon and nitrogen, on the synthesis of secondary metabolites (Calvo et al. 2002). P. brumalis did not prefer to synthesize sesquiterpenes under all growth conditions. Results of differences in metabolites observed in P. brumalis grown in PDB and modified medium highlighted the potential effect inorganic sources such as $C_4H_{12}N_2O_6$, $KH_2PO_4$, $MgSO_4$, and $CaCl_2$ on sesquiterpene synthesis. ${\beta}$-eudesmol was apparent during cultivation except for when P. brumalis was grown on $MgSO_4$-free medium. These results demonstrated that $MgSO_4$ can specifically control the biosynthesis of ${\beta}$-eudesmol. Magnesium has been reported as a cofactor that binds to sesquiterpene synthase (Agger et al. 2008). Specifically, the $Mg^{2+}$ ions bind to two conserved metal-binding motifs. These metal ions complex to the substrate pyrophosphate, thereby promoting the ionization of the leaving groups of FPP and resulting in the generation of a highly reactive allylic cation. Effect of magnesium source on the sesquiterpene biosynthesis was also identified via analysis of the concentration of total carbohydrates. Our current study offered further insight that fungal sesquiterpene biosynthesis can be controlled by nutrients. To profile the metabolites of P. brumalis, the cultures were extracted based on the growth curve. Despite metabolites produced during mycelia growth, there was difficulty in detecting significant changes in metabolite production, especially those at low concentrations. These compounds may be of interest in understanding their synthetic mechanisms in P. brumalis. The synthesis of terpene compounds began during the growth phase at day 9. Sesquiterpene synthesis occurred after growth was complete. At day 9, drimenol, farnesol, and mevalonic lactone (or mevalonic acid lactone) were identified. Mevalonic acid lactone is the precursor of the mevalonic pathway, and particularly, it is a precursor for a number of biologically important lipids, including cholesterol hormones (Buckley et al. 2002). Farnesol is the precursor of sesquiterpenoids. Drimenol compounds, bi-cyclic-sesquiterpene alcohols, can be synthesized from trans-trans farnesol via cyclization and rearrangement (Polovinka et al. 1994). They have also been identified in the basidiomycota Lentinus lepideus as secondary metabolites. After 12 days in the growth phase, ${\beta}$-elemene caryophyllene, ${\delta}$-cadiene, and eudesmane were detected with ${\beta}$-eudesmol. The data showed the synthesis of sesquiterpene hydrocarbons with bi-cyclic structures. These compounds can be synthesized from FPP by cyclization. Cyclic terpenoids are synthesized through the formation of a carbon skeleton from linear precursors by terpene cyclase, which is followed by chemical modification by oxidation, reduction, methylation, etc. Sesquiterpene cyclase is a key branch-point enzyme that catalyzes the complex intermolecular cyclization of the linear prenyl diphosphate into cyclic hydrocarbons (Toyomasu et al. 2007). After 20 days in stationary phase, the oxygenated structures eudesmol, elemol, and caryophyllene oxide were detected. Thus, after growth, sesquiterpenes were identified. Per these results, we showed that terpene metabolism in wood-rotting fungi occurs in the stationary phase. We also showed that such metabolism can be controlled by magnesium supplementation in the growth medium. In conclusion, we identified P. brumalis as a wood-rotting fungus that can produce sesquiterpenes. To mechanistically understand eudesmane-type sesquiterpene biosynthesis in P. brumalis, further research into the genes regulating the dynamics of such biosynthesis is warranted.