Diagnosis and Treatment of Primary Mediastinal Tumors and Cysts -Forty-two years report in a University Hospital-

Background : The diagnostic and therapeutic approaches to mediastinal tumors and cysts have changed over the past three decades. This report summarizes our forty-two years of experience with these tumors. Materials and Methods : This study retrospectively reviewed 479 patients with primary mediastinal tumors and cysts that were diagnosed and managed over the past 17-year period (1985～2002) and compared them to the report of the previous 25-year result (1960～1985) in Yonsei University College of Medicine, Severance Hospital in Seoul, Korea. Results : During the 17 years, there were 479 cases of pathologically proven mediastinal tumors and cysts. Thymoma (38.2%) was the most common mediastinal tumor and has increased noticeably during recent years. The gender ratio showed a male predominance (1.3:1) and the age distributions were even over all the age groups. The most common sites of the tumor and the proportion(28.6%) of malignant tumors were the same as that previously reported. A diagnosis of a tumor in asymptomatic patients was possible in 174 cases (36.3%), which was higher that reported previously. 　The diagnostic yield of a fine needle aspiration biopsy was 68.6% in the total tumors and 80.9% in the malignant tumors. A surgical resection was the most frequently chosen treatment modality and was performed in 405 cases (84.6%). The complete resection rate was 91.1%, which is higher than the previous result of 78.8%. Conclusion : These results showed that the prevalence of mediastinal tumors and cysts, particularly thymoma, increased. A fine needle aspiration biopsy was a valuable preoperative differential diagnostic method for malignant tumors. The surgical and complete resection rate increased remarkably possibly due to the better applicable chest CT scans, the more frequent health check-up provided by the regular health promotion program for all people as a health insurance policy, and the improved diagnostic techniques in the pathologic, radiological, and clinical fields.ope

Effects of the mutation of the p53 tumor suppressor gene and the K-ras gene on clinical manifestation in non-small cell lung cancer

의학과/박사[한글] 암이 발생하기 위해서는 단 한번의 유전자 변화로 되는 것이 아니라 여러 단계에서의 변화들이 동반되어야 하는데 비소세포폐암의 유전자 이상중p53 유전자 돌연변이가 가장 높은 빈도를 보이고 ras 유전자 돌연변이가 그 다음의 빈도를 보인다. p53 유전자 돌연변이의 대부분은 아미노산 치환을 유발하는 missense 돌연변이로써, 비세포폐암에서는 다른 종류의 암에 비하여 돌연변이의 위치와 속성이 상당히 다양한 특징을 보이며 염기전환과 염기이행이 모두 관찰된다. 사람에서 확인된 ras 유잔자중 폐암은 거의 대부분 K-ras 유전자의 변화이다. K-rras 유전자의 12번째 위치에 존재하는 g1ycine이 다른 아미노산으로 대치되면 ras 유전자가 활성화되는데 폐선암의 K-ras 유전자 돌연변이는 대부분 G → T 염기전환을 보인다. 그러나 이 두 유전자의 돌연변이가 비소세포폐암의 임상양상과 예후에 미치는 영향에 대해서는 아직도 논란의 여지가 많으며 또한 두 유전자간의 상호관계에 대한 보고도 미미한 실정이다. 따라서 본 연구에서는 병기 Ⅰ기부터 Ⅲ기까지의 비소세포폐암으르 진단받고 근치적 절제술을 시행받은 후 합병증없이 1개월이상 생쫀하면서 추적관찰중인 환자들을 대상으로, 절제된 폐암의 원발병소조직을 이용해서 면역조직화학 염색법, 그리고 PCR-SSCP 분석 및 염기서열확인법 등으로p53 유전자 및 K-ras 유전자의 구조적 변이 유무를 검색하고 분석하여 다음과 같은 결과를 얻었다. 1. p53 면역조직화학염색상 P53 핵단백질의 과발현은 25.9%에서 관찰되었고 편평상퍼암에서 유의하게 높은 빈도를 보였으나(p=0.01634) 병기와 생존분석상 유의한 차이가 없었다. PCR-SSCP 분석결과 p53 유전자의 이동변위는 29.1%에서 확인되었으나 세포형, 병기, 생존분석상유의한 차이가 없었다. 염기서열확인법상 p53 유전자의 돌연변이는 37.9%에서 확인되었다. 돌연변이의 위치는 여러 codon에 분산되어 있었고 다양한 양상을 보였으며 염기이행형(54.6%)이 염기전환형(36.3%)보다 많았다. 염기서열확인법에 의한 돌연변이 역시 세포형, 병기, 생존 분석상 유의한 차이가 없었다. 2. K-ras 유전자의 돌연변이는 24.1%에서 확인되었는데 모두 codon 12에서만 관찰되었고 G → A 염기이행형이 78.6%로, G → T 염기전환형의 21.4%보다 많았다. K-ras 유전자 돌연변이가 확인된 군과 없는 군간에 흡연력이나 세포형, 병기에 따라서 유의한 차이가 없었으나 K-ras 유전자 돌연변이군에서 예후가 유의하게 불량하였다(생존기간 p=0.0391, 무병생존기간 p=0.0318). 3. p53 유전자 돌연변이 및 K-ras 유전자 돌연변이의 여부에 따라 분류한 경우 각 군간에 세포형과 병기에 따른 유의한 차이는 없었다. 그러나 생존기간은 p53 유전자의 돌연변이 없이 K-ras 유전자의 돌연변이만 동반한 경우가 유의하게 가장 짧았고(p=0.0021), 무병생존기간 역시 동일한 양상을 보였다(p = 0.0166). 4. 예후에 영향을 미칠 수 있는 인자들을 Cox's multivariate regression test로 분석한 결과 병기(p=0.0267)와 K-ras 유전자의 돌연변이 여부(p=0.0493)만이 예후에 유의한 예측 인자임을 확인하였다. 병기별로 K-ras 유전자의 돌연변이 여부에 따른 생존분석 결과 Ⅲ기에서 K-ras 유전자 돌연변이군의 생존 기간이 유의하게 짧은 양상을 보여(p=0.0085) K-ras 유전자돌연변이 자체가 병기와는 독립적인 유의한 예후인자로 생각되었다. 이상의 결과에서 p53 유전자 돌연변이 여부는 비소세포폐암 환자의 예후와 무관하였으나 K-ras 유전자의 돌연변이는 불량한 예후 인자로써 작용함을 알 수 있었다. 비소세포폐암의 임상 양상과 예후에서 p53 유전자 돌연변이와 K-ras 유전자 돌연변이는 서로 독립적으로 작용함을 확인할 수 있었다. 따라서 비소세포폐암 환자에서 K-ras 유전자의 돌연변이가 동반된 경우 불량한 예후의 개선을 위하여 유전자 치료 같은 적극적인 치료법의 개발이 필요할 것으로 생각된다. [영문] A multistep process of gene alterations is required for tumor formation. p53 gene mutation is the most frequent and K-ras gene mutation places second in the gene abnormalities of non-small cell lung cancer(NSCLC ). The phosphoprotein p53 is a tumor suppressor gene. When compared to other types of tumors, the locations and nature of p53 gene mutation are very diverse and both transversion and transition are found in NSCLC. Members of the mammalian ras family, H-ras, K-ras, N-ras, can be con-verted into active oncogenes by specific alterations, at which point mutations occurring in eithercodon 12, 13 or 61 are most common. The effect by the mutations of the p53 and ras genes on clinical manifestation is still highly controversial. Little is known about the interaction between them in NSCLC. The present study was designed to investigate the effect by the mutations of the p53 tumor suppressor gene and K-ras oncogene on clinical manifestation, and the interaction between the mutations of two genes in the Korean NSCLC. Fifty-eight patients were enrolled in this study who had been diagnosed as having NSCLC from stage Ⅰ to stave Ⅲ. They all had been alive for more than one month without any complication after curative resection. The paraffin-embedded lung tissues after resection were used to investigate the p53 expression by iinmunohistochemical staining, the mutations of the p53 and K-ras genes by polymerase chain reaction-sin히e strand conformation polymorphism(PCR-SSCP) and nucleotide sequencing. The results obtained were as follows: 1. p53 protein was overexpressed in 25.9% by immunohistochemical staining. Overexpression was significantly mare frequent in epidermoid carcinoma(p = 0.001634). But there was no significant diference between the overexpression group and the negative expression group according to stage and survival. By PCR-SSCP analysis, the mobility shift of the p53 gene was found in 29.1%.There was no significant difference between the groups with and without mobility shift according to cell type, stage and survival. By nucleotide sequencing, p53 gene mutation was 37.9%. The locations of mutation were dispersed among numerous codons and the modes of mutation were also diverse. There was also no significant difference between the groups with and without mutation according to cell type, stage and survival. 2. K-ras gene mutation was 24.1% and only in codon 12 by nucleotide sequencing. Although there was no significant difference between the groups with and without mutation according to cell type or stage, K-ras gene mutation carried a significantly worse prognosis in NSCLC (overall survival, p=0.0391; disease-free survival, p= 0.0318). 3. When the patients were divided into 4 groups according to p53 gene mutation and K-ras gene mutation, there was also no significant difference among any group according to cell type or stave. The Prognosis became worse if K-ras gene mutation accompanied(overall survival, p=0.0021; disease-free survival, p= 0.0166). 4. Only the stage(p= 0.0267) and K-ras gene mutation(p = 0.0493) were significant prognostic factors by Cox's multivariate regression test. An analysis in stage Ⅲ showed the significantly shorter survival period in the patients with K-ras gene mutation. K-ras gene mutation, therefore, was confirmed as the independently significant prognostic factor, separately from stage. In conclusion, p53 gene mutation had no clinical or prognostic significance because of scattered locations and diverse modes of mutation in contrast to K-ras gene mutation, which had a significantly negative effect on the prognosis of NSCLC. p53 and K-ras gene mutations were apparently independent genetic alterations which played different roles in the clinical manifestation and prognosis of NSCLC. For the Patients of NSCLC accompanied by K-ras gene mutation, development of active therapeutic method such as gene therapy will be needed to overcome the poor prognosis.restrictio

(A) study on clinical appicability of dyspnea index and the 6-minute walking test in patients complaining of dyspnea

의학과/석사[한글] 호흡곤란은 임상적으로 중요한 증상이며 여러 가지 요소들의 복합적인 상호작용에 의해 유발된다. 환자들이 호소하는 호흡곤란의 정도를 좀 더 정확히 평가하기 위하여 정신물리학적 방법과 임상적 척도법이 사용되는데 전자는 기술적인 문제나 소모시간 등 몇가지 제한 요소때문에 임상적으로 적응하기에는 어렵다. 임상적 척도법은 예민하고 생리학적 검사에 보완적인 정보를 제공할 뿐 아니라 치료 효과의 평가에 유용한 것으로 보고되어 왔다. 걷기 검사는 호흡기 질환 환자들의 일상 생활에서의 생리적 운동요구량을 잘 반영하며 재현성이 높고 약물 치료의 효과 판정에 유용하다. 본 연구에서는 호흡곤란을 주소로 내원한 39명의 환자들을 대상으로 치료 전후에 각각, MBS (Modified Borg Scale Dyspnea Index)와 BDI(Baseline Dyspnea Index)를 이용한 호흡곤란 지수의 측정, 6분걷기 검사와 폐기능 검사, 동맥혈가스 검사를 시행하여 호흡곤란 지수와 6분걷기 검사가 임상적으로 유용한지 여부와 각 검사간의 상관관계에 대하여 연구하였다. 1. 전체 환자군에서 치료전에 비해 치료후에 PaCO^^2외의 모든 검사치가 유의하게 호전되었고, 치료전에서 MBS, BDl, 걷기 검사는 FEV^^1과 유의한 상관관계를 보였으며 치료후에서는 MBS와 걷기 검사에서 FEV^^1과 유의한 상관관계를 보였다. 2. 만성 폐쇄성 폐질환 환자군에서 치료전에 비해 치료후에 MBS, BDI, 걷기검사값과 FVC값이 유의하게 호전되었고, 치료전에서 걷기 검사는 FEV^^1, FVC, PaO^^2와, 치료후에서 BOI는 PaO^^2, PaCO^^2와, 그리고 걷기 검사는 FEV^^1, FVC, PaO^^2, PaC0^^2와 유의하게 상관관계가 있었다. 3. 기관지 천식 환자군에서 치료전에 비해 치료후에 MMFR와 PaCO^^2를 제외하고 모든 검사치가 유의한 호전을 보였다. 걷기 검사와 MMFR은 치료 전후와 변화치 모두에서 유의한 상관관계를 보였으며, 치료후에서 MBS, BDl는 FEV^^1와 유의한 상관 관계를 보였다. 4. MBS와 BDI간에는 치료 전과 후에서, 그리고 BDI와 걷기 검사간에는 치료후에 유의한 상관관계가 있었다. 이상의 경과에서 호흡곤란 지수와 걷기 검사는 치료 효과의 평가에 유용하였고 특히 만성 폐쇄성 폐질환 환자에서는 가장 예민하여 폐기능 검사에 보완적인 수단으로 유용함을 알 수 있었다. 호흡곤란 지수, 특히 MBS는 전체 환자의 치료 전과 후에서 FEV^^1(% Predi cted)과 유의한 상관관계를 보였다. 걷기 검사는 만성 폐쇄성 폐질환 환자군에서는 치료전과 후에서 FEV^^1, FVC, PaO^^2와, 기관지 천식 환자군에서는 MMFR과 유의한 상관관계를 보였다. [영문] Dyspnea or pathologic breathlessness is frequent one of the patient's major complaint. As a symptom it probably depends on a complex interplay of pathophysiologic, psychologic, experiential and other factors. Both psychophysical methods and clinical scales have been used to assess breathlessness, Several factors including technical aspects and time-requirement limit the clinical application of evaluation in patients by psychophysical methods. Clinical scales can give sensitive and complementary information on physiologic measurements and they have proved very useful in testing the efficacy of a variety of physiologic and pharmacologic treatments for patients with chronic lung diseases. The walking teat can Measure a patient's ability to undertake the physiologically demanding activities of day-to-day life, and it has proved to be highly reproducible and very useful to evaluate the efficacy of pharmacologic treatment. Dyspnea indices( Modified Borg Scale Dyspnea Index, Basel me Dyspnea Index) and the distance patients could walk in 6 minutes in 39 patients who visited our hospital because of dyspnea were measured before and after treatment. Pulmonary function test and arterial blood gas studies were done in the same manner. Through the above method, I examined the clinical usefulness of the dyspnea index, the talking test, and the correlation between each test. 1. In all patients all test values following treatment improved significantly except PaCO^^2. The pretreatment values of MBS, BDl, the walking test and the posttreatment values of MBS, the talking test showed significants correlations with values of FEV^^1. 2. In patients with COPD, the values of MBS, BDI, the walking test and FVC improved significantly. The pretreatment values of the walking test had significant correlation with those of FEV^^1, FVC and PaO^^2. In the posttreatment values of BDI with those of PaO^^2, PaCO^^2, there was a significant correlation and the result of the walking test was similar with FEV^^1, FVC, PaO^^2, PaCO^^2. 3. In patients with bronchial asthma, all test values except MMFR and PaCO^^2 shored significant improvement. The values of the walking test and MMFR showed a significant correlation in the pretreatment, posttreatment and changed values between pretreatment and posttreatment values. The posttreatment valves of MBS and BDI correlated significantly with that of FEV^^1. 4. We could find a significant correlation between MBS and BOI in pretreatment and posttreatment values, between BDI and the walking test in posttreatment values. In conclusion, dyspnea index and the walking test were proven useful for evaluation of treatment efficacy, and especially inpatients with COPD, they were the most sensitive. They were valuable as supplementary measures to physiologic tests. Significant correlations were observed among the dyspnea indices, especially MBS and FEV^^1 in all patients. The walking test had significant correlations with FEV^^1, FVC, PaO^^2 in patients with COPD and with MMFR in patients with bronchial asthma.restrictio