醫學碩士學位請求論文 부비동내시경수술후비용종의경구용스테로이드복용효과 Oral steroid effect in nasal polyposis after endoscopic sinus surgery 2006 년 8 월 仁荷大學校大學院 醫學科 ( 이비인후과학전공 ) 崔淨晳 1
醫學碩士學位請求論文 부비동내시경수술후비용종의경구용스테로이드복용효과 Oral steroid effect in nasal polyposis after endoscopic sinus surgery 2006 년 8 월 指導敎授김영모이論文을碩士學位論文으로提出함. 仁荷大學校大學院醫學科 ( 이비인후과학전공 ) 崔淨晳 2
이論文을崔淨晳의碩士學位論文으로認定함. 2006 년 8 월 主審 副審 委員 3
국문요약 목적 : 부비동내시경수술을시행한비용종증을동반한만성부비동염환자 에게술후일정기간국소용, 경구용스테로이드투여후환자의증상과비 용종의재발여부를정기적으로관찰하여그효과를알아보고자하였다. 방법 : 비용종을동반한만성부비동염환자 12예를실험군, 10예를대조군으로하여동일술자가부비동내시경수술을시행한후, 실험군에는술후경구용스테로이드 (Methylprednisolone, 5 mg/kg) 를 10일간분할투여한후국소용스테로이드분무제 (triamcinolone, 110 mcg/side/day) 를적어도 2달간투여하였고, 대조군은술후국소용스테로이드분무제만을투여하면서환자가호소하는증상 ( 코막힘, 전비루, 후비루, 두통, 후각저하 ) 과비용종의재발여부를전향적으로관찰하였다. 술전비용종상태는 Gaskin의방법에의해, 부비동의상태는 Harvard system에의해분류되었고, 추적관찰은술후 2주, 1개월, 2개월, 3개월, 6개월, 12개월에하였다. 결과 : 실험군과대조군모두에서수술직후부터추적관찰기간동안중등도이상의증상호전을보였으나두군간의통계학적인차이는없었다. 추적관찰기간동안두군모두에서경도의점막의폴립양변화 (Polypoid mucosal change) 소견을보였고대조군이실험군보다첫한달간점막비후소견이심하였다. 결론 : 비용종환자의부비동내시경수술후국소적, 경구용스테로이드의 4
병합요법이국소적스테로이드단독요법에비해단기간의증상호전과비용 종의재발방지에더효과적이지않았다. 중심단어 : 비용종, 경구용스테로이드 5
Abstract Background and Objectives : The object of this study was to evaluate the effect of topical and oral steroids after endoscopic sinus surgery in chronic paranasal sinusitis patients with nasal polyposis, by observing the nasal symptoms and the recurrence of polyposis in a stated period. Material and Method : 22 cases of chronic paranasal sinusitis patients with nasal polyposis were selected. All 22 cases underwent endoscopic sinus surgery by the same surgeon. 12 cases out of 22 study group received 10 days of oral steroid treatment and topical nasal steroid 110 mcg/side/day spray at least for 2 month after surgery. The control group received only the topical nasal steroid spray during the same period. All patients were surveyed by there nasal symptoms (nasal obstruction, anterior rhinorrhea, posterior rhinorrhea, headache, anosmia or hypospnea) and investigated for the polyposis recurrence. Preoperative nasal polyposis conditions were classified by Gaskin method, and the paranasal sinusitis states by Harvard System. The follow-up was done 14 days, 1 month, 2 months, 3 months, 6 months and 12 months after endoscopic sinus surgery. 6
Result : Both the study group and the control group showed symptomatic relief below average, but there was no statistical differences. The two groups showed only mild mucosal changes and no recurrence of nasal polyposis. But interestingly, the study group showed less polypoid mucosal changes in the maxillary sinus in the first month of follow-up. Conclusion : Topical and oral use of steroid in patients with nasal polyposis after endoscopic sinus surgery showed no effect over the topical use of steroid alone, in the matter of short term relief of symptoms and recurrence of nasal polyposis. Further studies, for long term follow-up are necessary in the future. KEY WORDS:nasal polyp, oral steroid 7
목차 서론 1 대상및방법 3 1. 환자대상 3 2. 진단과병기, 배제기준 4 3. 연구방법 6 4. 통계학적분석 9 결과 10 1. 주관적증상의개선 10 2. 비용종의재발 14 3. 술전비용종, 부비동염점수와재발과의연관성 17 고찰 20 결론 23 참고문헌 24 감사의글 26 8
List of figure Fig. 1. Identification of polyp recurrence 7 Fig. 2. Polyp staging 8 Fig. 3. Comparison of pre-operative mean symptom score 11 Fig. 4. The change of nasal obstruction 12 Fig. 5. The change of anterior rhinorrhea 12 Fig. 6. The change of posterior rhinorrhea 13 Fig. 7. The change of headache 13 Fig. 8. The change of hyposmia 14 Fig. 9. Sinusitis grade and recurrence 18 Fig. 10. Polyp stage and recurrence 19 9
서론 비용종에대한치료에대해서는수십년간많은이견이있어왔다. 1)2)3)4)5) 이는수술적치료와약물적치료로나눌수있고대부분두가지방법을병행하여치료를하고있으며특히수술후사용하는약물적치료로서스테로이드의사용은비용종을줄이는데효과적이라고보고되고있다. 7) 비용종환자에서의비강내점막스테로이드치료는전신적부작용을최소화하면서임상적호전을나타내며비용종의크기를감소시키고부비동내시경수술후재발을방지하는데효과가있음이밝혀져있다. 3)4)6) 국소용스테로이드에대한효과로 Hartwig 등은부비동내시경수술후비용종의재발의빈도를줄일수있다고하였고 9) Kanai 등은국소용스테로이드자체만으로도코와관련된증상을개선시킬수있다고하였으며 10) Mygind 등은비용종환자에있어서후각저하에대한어느정도의개선효과가있다고하였다. 7) 경구용스테로이드에대해서 Ballantyne 등은비용종을줄이는효과가있으나여러부작용등으로무조건적인사용은추천되지않는다고하였고 8), Lildholdt 등은단기간의경구스테로이드사용이수술적인비용종 절제술과같은효과를가진다고보고하였다. 11) 또한 Mygind 등은심각한 비용종을가지고있는환자에있어서수술적치료와경구용스테로이드 사용을동시에시행하는것이효과가있다고보고하였다. 7) 술자에따라 차이는있으나일반적으로부비동환자의비내시경수술후국소분무형스테로이드를사용하다가술후상태가악화되는경우경구스테로이드를추가하여사용하는데이에대한장기적인연구결과는알려진것이거의없는실정이다. 이에저자들은비용종을가진환자에있어서부비동내시경 10
수술후국소분무형스테로이드만을사용한환자군과국소분무형스테로이드와단기간의경구용스테로이드를함께사용한환자군을비교하여증상의개선정도와재발의빈도에대하여알아봄으로써술후경구용스테로이드의투여가수술효과에미치는영향을알아보고자하였다. 11
대상및방법 환자대상 2003년 3월부터 2005년 2월까지인하대병원이비인후과를방문하여부비동내시경수술을받은, 증상이있었던 22명의비용종환자를대상으로하였다. 이들은무작위에의해두군이나누어졌으며모두한사람의술자에의해수술을받았다. 이중 12명은실험군으로부비동내시경수술후국소분무형스테로이드와단기간의경구용스테로이드를함께사용하였고 10명은대조군으로부비동내시경수술후국소분무형스테로이드만으로치료하였다. 두군모두에서스테로이드를사용할수없는금기증을가진환자는없었다. 두군간의남녀성비는 14:8로남자가많았으며평균나이는 35.7세였으며평균추적관찰기간은 14.7개월이었다. 대상환자의 23% 에서과거부비동내시경수술을받은과거력이있었다 (Tab. 1.). 대상환자모두에서술전스테로이드를복용한경우는없었고두군간의성비, 나이, 추적관찰기간, 질병의정도, 과거력등에서통계학적차이는없었다 (P>0.05). 12
Table 1. Clinical data of the 22 patients Case group (n=12) Control group (n=10) Total (n=22) M : F 9 : 3 5 : 5 14 : 8 Mean age (years) 42.8±16.9 27.1±17.8 35.7±18.7 Mean follow-up (months) 17.2±5.4 12.5±6.7 14.7±5.9 Mean disease extent S3.8, P2.7 S3.7, P2.9 S3.8, P2.8 Previous sinus surgery history 4 (33%) 1(10%) 5 (23%) Allergy (positive skin test or MAST) 1 (8%) 1 (10%) 2 (9%) Asthma or aspirin intolerance 2 (17%) 2 (20%) 4 (18%) S : sinusitis stage P : polyp stage MAST : Multiple Allergen Simultaneous Test There were no statistical differences in sex, age, mean follow-up period, severity of disease, and past history in case and control group preoperatively. 진단과병기, 배제기준 비용종의진단기준으로 Stammberger(1997) 의정의에의해내시경검사상양측비강에비용종이있는경우와 Zinreich(1994) 의정의에의한 OMU CT(Ostiomeatal Unit Computed Tomography) 상사골동부위 (Ethmoid area) 에양측모두혼탁한소견이보일때로정의하였다. 비용종의병기 (stage) 는부비동염병기 (Sinusitis stage) 의경우 Harvard system을적용하였고 12) (Tab. 2.) 비용종병기 (Polyp stage) 의경우 13
Gaskins stage의기준을적용하였다 13) (Tab. 3.). 술전경구용스테로이드를복용하였거나, 진균성부비동염인경우, 반전성유두종, 편측성부비동염의경우, 첫방문시에비용종점수가 1-2점, 부비동염의점수가 1-2점인경우는제외하였다. Table 2. Sinusitis Staging Staging system proposed by Gillklich and Metson (Harvard System) Stage 0 Stage I Stage II Stage III Stage IV Normal (<2cm mucosal thickening on any sinus wall) All unilateral disease or anatomic abnormality Bilateral disease limited to ethmoidal or maxillary sinuses Bilateral disease with involvement of at least one spenoidal or frontal sinus Pansinusitis Table 3. Polyp Staging Staging system proposed by Gaskins Stage 0 Stage I No polyps No polyps or polyps localized to <10% of sinus space Stage II Polyp involvement of 10~50% of the nasal & sinus cavity Stage III Polyposis filling > 50% of the nasal and sinus cavities Stage IV Inverting papilloma or other potentially malignant nasal or sinus neoplasm 14
연구방법 스테로이드의치료는국소분무형스테로이드의경우는 Triamcinolone을 110 mcg/side/day로적어도 2개월간분무하였고경구용스테로이드의경우에있어서는 Methylprednisolone(4 mg) 을총용량 300 mg 사용하였고첫 5일간은 50 mg/day, 나머지 5일간은점진적인감량을시행하였다. 추적관찰은술후 2주, 1개월, 2개월, 3개월, 6개월, 12개월로하였으며각방문시한조사자에의하여모든환자의증상변화를파악하고비내시경검사를통하여비용종의재발유무를확인하고이를사진촬영하여연속적인비교를시행하였다 (Fig. 1.)(Tab. 4.). 비용종의재발은술후내시경검사를통하여이루어졌고재발의위치는상악동 (Maxillary sinus antrum), 사골동 (Ethmoid sinus), 전두함요 (Frontal recess) 로나누어기술하였고재발의정도는재발이없는경우 0, 점막의폴립양변화 (Polypoid mucosal change) 의경우 1, 비용종이 25% 이하이면서정상점막이보이는경우 2, 비용종이 50% 이하의경우 3, 비용종이 50% 이상의경우를 4로하였다 (Fig. 2.). 15
Fig. 1. Identification of polyp recurrence The follow-up period is defined as preoperative and postoperative 2 weeks, 1, 2, 3, 6, and 12 months. We checked the recurrences of polyp by endoscopy and took photos of it in each visit. 16
0 : No recurrence 1+ : Polypoid mucosal change 2+ : Polyp <25%, but visible normal mucosa 3+ : Polyp <50% 4+ : Polyp >50% Fig. 2. Polyp staging The degree of recurrence is as follows : 0 as no recurrences, 1 as Polypoid mucosal change, 2 as less than 25% polyp and normal mucosa, 3 as less than 50% polyp, and 4 as more than 50% polyp. 17
Table 4. Symptom score Pre & Post-Operative questionnaires 없음 (0) 조금있음 (1) 조금심함 (2) 심함 (3) 1. Nasal obstruction 2. Anterior rhinorrhea 3. Posterior rhinorrhea 4. Headache 5. Sense of smell We got patients' data such as nasal obstruction, anterior rhinorrhea, posterior rhinorrhea, headache, and hyposmia by questionnaire in preoperative and postoperative follow-up. 통계학적분석 통계학적인분석방법으로는 Prism (version 3.02) 을이용하여 Wilcoxon signed rank test 와 Fisher exact test 를시행하였고평균과표준편차로 결과을나타내었고유의수준은 0.05 로검정하였다. 18
결과 주관적증상의개선 두군모두술전평가한 5가지주관적인증상중코막힘을가장심하게호소하였다. 이외에두군간의증상에대한통계학적차이는없었다 (P>0.05)(Fig. 3.). 치료후외래추적기간동안증상의변화를보면코막힘, 전비루, 후비루, 두통, 후각저하의모든증상이양군모두에서치료전에비해현저한증상호전을보였으나두군간의통계학적인차이는없었다 (Fig. 4-8.). 후각저하의경우다른증상보다술후호전양상이두드러지지는않았다. 19
symptom score Fig. 3. Comparison of pre-operative mean symptom score This is the table comparing the symptom score of nasal obstruction (case 2.58±0.21, control 2.60±0.32), anterior rhinorrhea (case 1.75±0.19, control 1.10±0.71), postnasal drip (case 1.42±0.32, control 1.70±0.19), headache (case 0.58±0.32, control 0.80±0.34), and hyposmia (case 2.58±0.20, control 2.30±0.34) between the patient and control group. The nasal obstruction is most common in both groups. There was no statistically significant difference of symptom score between two groups (P>0.05) (mean ± standard deviation). 20
symptom score 3.50 3.00 2.50 case control 2.00 1.50 1.00 0.50 0.00 preop POD#14d POD#1m POD#2m POD#3m POD#6m POD#12m POD#18m Fig. 4. The change of nasal obstruction This figure is showing the change of nasal obstruction symptom between the two groups pre and postoperatively. Both group showed marked symptom relief, but there was no statistically significant difference between two groups (P=0.84). symptom score 2.00 1.80 1.60 1.40 1.20 1.00 0.80 0.60 0.40 0.20 0.00 preop POD#14d POD#1m POD#2m POD#3m POD#6m POD#12m POD#18m Fig. 5. The change of anterior rhinorrhea This figure is showing the change of anterior rhinorrhea symptom between the two groups pre and postoperatively. Both group showed marked symptom relief, but there was no statistically significant difference between two groups (P=1.0). 21
symptom score 2.00 1.80 1.60 1.40 1.20 1.00 0.80 0.60 0.40 0.20 0.00 preop POD#14d POD#1m POD#2m POD#3m POD#6m POD#12m POD#18m Fig. 6. The change of posterior rhinorrhea This figure is showing the change of posterior rhinorrhea symptom between the two groups pre and postoperatively. Both group showed marked symptom relief, but there was no statistically significant difference between two groups (P=0.16). symptom score 1.20 1.00 0.80 0.60 0.40 0.20 0.00 preop POD#14d POD#1m POD#2m POD#3m POD#6m POD#12m POD#18m Fig. 7. The change of headache This figure is showing the change of headache symptom between the two groups pre and postoperatively. Both group showed marked symptom relief, but there was no statistically significant difference between two groups (P=0.16). 22
symptom score 3.00 2.50 2.00 1.50 1.00 0.50 0.00 preop POD#14d POD#1m POD#2m POD#3m POD#6m POD#12m POD#18m Fig. 8. The change of hyposmia This figure is showing the change of hyposmia symptom between the two groups pre and postoperatively. Sense of smell showed less symptomatic relief compared to other symptoms in both group, but there was no statistically significant difference between two groups (P=0.22). 비용종의재발 외래추적기간동안상악동 (Maxillary sinus antrum) 에재발한경우가전사골동 (Frontoethmoid) 에재발한경우보다많은경향을보였으나두군간의통계학적인차이는없었다 (P>0.05)(Tab. 5.). 대조군의경우비용종의재발양상이실험군의재발양상보다술후초기에많은것처럼보이나통계학적인의의는없었다 (P>0.05)(Tab. 6. and 7.). 23
Table 5. Comparison of recurrence of nasal polyp Case (n=12) Control (n=10) Antrum Frontoethmoid 1+ 6 6 2+ 1-3+ - - 4+ - - 1+ 5 7 2+ 3-3+ - - 4+ - - There were more recurrences in maxillary sinus antrum than in frontoethmoid in both groups during the follow-up period. There was no difference in recurrence between the case and control group (P=0.92). 24
Table 6. Post-operative polypoid mucosal change (Case group) This table is showing the trend in recurrences of nasal polyp in case group according to period and location during the follow-up period. 25
Table 7 Post-operative polypoid mucosal change (Control group) This table is showing the trend in recurrences of nasal polyp in control group according to period and location during the follow-up period. The control group showed more recurrences than the case group in one month after operation. However, it was not statistically significant (P=0.44). 술전비용종, 부비동염점수와재발과의연관성 술전비용종과부비동염점수가높을수록재발이많은양상을보이기는 하였으나점수차에따른두군간의통계학적인차이는없었다 (Fig. 9. and 10.). 26
No. of patient 7 6 5 case control 4 3 2 1 0 Sinusitis G3 Sinusitis G4 Fig. 9. Sinusitis grade and recurrence Comparing the recurrence tendency between the case and control group, we found that there were more recurrences in group with higher pre-operative sinusitis score, but that was statistically not significant (P=1.0). Sinusitis G3 (case 1.0±0.0, control 0.67±0.58), Sinusitis G4 (case 0.60±0.52, control 0.43±0.53) (mean±standard deviation) 27
No. of patient 6 5 4 case control 3 2 1 0 Polyp S2 Polyp S3 Fig. 10. Polyp stage and recurrence Comparing the recurrence tendency between the patient and control group, we found that there were more recurrences in group with higher pre-operative nasal polyp score, but that was statistically not significant (P=0.96). Polyp S2 (case 0.75±0.50, control 0.00±0.00), Polyp S3 (case 0.63±0.52, control 0.44±0.53)(mean±standard deviation) 28
고찰 본연구는연구계획에서부터자료의정리에이르기까지한조사자에의해이루어졌다. 치료에대한효과는대부분의비용종을가진환자가호소하는주된증상을내용으로하였다. 스테로이드는염증과관련된사이토카인 (cytokine) 이나중간물질 (mediator) 등을차단하여항염증작용을나타나게함으로써삼출액 (exudate), 부종 (edema), 화학적주성 (chemotaxis) 을줄여줌으로서비용종을억제한다고알려져있다. 14) 아직경구용스테로이드의비용종에대한전향적환자대조군연구 (prospective case-control trial study) 는어느연구기관에서도진행되지않고있다. 경구용스테로이드는지난 20년간비용종에있어서널리사용되어져왔고이는비점막의부종을줄여주며통증을줄여준다. 경구용스테로이드의단기간사용이비용종절제술과같은효과를가진다는보고도 있으나 11) 단기간만유용하다는단점이있다. 본연구에서도경구용 스테로이드를사용하지않은군이사용한군보다초기점막의폴립양변화의경향이많았고시간이지나면서두군간의점막차이가없었는데이는이러한경향을반영하는것으로생각된다. 한편, 국소분무형스테로이드의비용종에대한효과는많이입증되어있다. 현재까지국소분무형스테로이드는환자의주관적인증상인코막힘, 비루, 재채기, 비강의공기흐름을좋게한다고알려져있다. 16) 비용종에서대개의경우치료방침은경구용스테로이드복용후국소분무형스테로이드로효과를이어간다. 그이유는치료의초기에비용종의크기가크면국소분무형스테로이드가비용종사이로들어가지못하여 29
고르게분포되지못하여치료에의미있게반응하지못하므로경구용스테로이드로비용종의크기를먼저줄인후국소분무형스테로이드를사용하게된다. 이것이단독으로쓰는국소분무형스테로이드치료의실패요인이되기도한다. 부비동내시경수술후에는비용종이제거되므로국소분무형스테로이드가고르게분포될수있다. 하지만국소분무형스테로이드에대한효과의연구도수주간의연구만있고장기간관찰이없는실정이다. 이번연구에서환자의주관적인증상변화가실험군과대조군모두에서좋아졌지만두군간의차이가없었던것은단순히생각해보면국소분무형스테로이드가모두사용되어경구용스테로이드의효과가국소분무형스테로이드효과에가려그차이가없었을가능성을생각할수있다. 이를수술적치료와연관지어생각해보면경구용스테로이드는비용종절제술과같은효과를가지는데이미부비동비내시경수술을통하여대부분의비용종이제거되었기때문에술후국소분무형스테로이드가비점막내로골고루분무되어탁월한수술적치료의효과로인해경구용스테로이드의효과가드러나지않았을가능성도생각해볼수있다. 후각저하의경우에있어서는두군모두에서다른주관적인증상변화의개선이덜두드러졌다. 이는연구대상집단이심한비용종을가진환자로서후열 (olfactory cleft) 주변까지도비용종으로점막의변화을일으켰기때문이라고생각하며부비동수술이후열까지취기물질 (odorant) 이도달할수있도록기계적인폐쇄를해결했을지라도변화된점막이정상후각점막으로돌아오기까지는상당한시간을필요로하기때문에다른주관적증상처럼술후바로개선되지않았을것이라고생각된다. 한편재발의경향을살펴보면추적관찰초기에대조군이실험군에비해 30
재발이많은경향을보였는데이는경구용스테로이드의효과가술후초기에만비용종의재발을줄이는데기여하지않았을까하는추측도해볼수있다. 경구용스테로이드는술후에바로복용하였기때문에이에대한효과가추적관찰초기에만있을수있으며만약그이후에도경구용스테로이드의복용이있었다면재발경향의차이가있었을가능성도배제할수는없다. 하지만이는추측일뿐이고무분별한경구용스테로이드의복용이다른전신적인문제를야기하지않는다는보장이없으므로무조건적인경구용스테로이드의사용은그결과가확실하지않은이상절제되어야하는것이타당하다고본다. 두군간의증상변화와재발에차이가나지않는다른요인을생각해보면두군간의사이토카인 (cytokine) 의다양성에대한고려를생각해볼수있으며, 다른요인으로는비용종과부비동염이비교적심했던환자가많았다는점을들수있다. 스테로이드의치료는이차적인손상에우선하여염증반응을줄이기위하여초기질환에사용되어지는것이최근의추세이므로경구용스테로이드의효과는비용종과부비동염이경한환자에게더효과적일수있기때문이다. 17) 좀더나은연구가되기위해서는많은환자를대상으로하여다양한정도의비용종과부비동염을가진환자를오랜기간동안추적관찰하는것이필요하고환자의상태에따라군을세분화하여연구를하는것도의미있을것으로생각된다. 31
결론 부비동내시경수술후스테로이드의사용은비용종환자에있어서환자의주관적인증상을현저하게개선시키는효과가있다. 그러나국소분무형스테로이드와경구용스테로이드를같이사용한환자군과국소분무형스테로이드만을사용한환자군의치료효과를비교하면주관적인증상의경감에서큰차이가없었다. 비용종의재발에있어서도술전비용종, 부비동염의점수가높을수록재발이높았지만통계학적의의는없었다. 만성부비동염의환자에있어서내시경부비동수술후경구용스테로이드의일반적인사용은자제하여야할것으로사료된다. 중심단어 : 비용종, 스테로이드 32
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감사의글 뜨거운햇살과무더운날씨가새삼여름임을실감나게합니다. 곧장마가 온다고하니더위도한풀꺽이려나봅니다. 그러나, 석사논문을끝낸제마 음은이미여름을지나시원한가을하늘을향해날아갑니다. 사실석사학위를받는과정이그리어려운일은아니지만학사를마치고 석사학위를받기까지많은분들이제주위에서도와주시지않았더라면이 런감사의글을쓰기는어려웠을겁니다. 무엇보다도이비인후과의과장님이자본연구의과정을계획하고세심한지도를해두신장태영교수님, 이비인후과의주임교수님이자지도교수님이신김영모교수님, 연구과정마다끝없는관심으로돌봐주신최윤석교수님께진심으로감사드립니다. 더불어배움의길목에서늘다정한조언을해주신김규성교수님, 김재원교수님, 최호석교수님께도감사의말씀을드립니다. 언제나그렇듯물심양면으로도와주신부모님께새삼감사드리며아울러석사과정을수료할수있도록배려해준이비인후과동기이하전공의선생님들에게도감사를드립니다. 이번석사과정과졸업을계기로다시한번제자신이성숙해지는기회로삼아더노력하는사람이되겠습니다. 2006 년 6 월 29 일 최정석 35