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1 DOI: /trd ISSN: (Print)/ (Online) Tuberc Respir Dis 2009;66: CopyrightC2009. The Korean Academy of Tuberculosis and Respiratory Diseases. All rights reserved. Original Article 원발성폐암에서혈장과립구자극인자의암표지자로서의역할과의의 원광대학교의과대학 1 내과학교실, 2 병리학교실, 3 방사선종양학교실, 4 영상의학교실, 5 임상병리학교실, 6 굿셀라이프, 7 원광대학교의과대학흉부외과학교실송정섭 1, 김소영 1, 조향정 2, 이강규 3, 신정현 1, 신성남 1, 김동 1, 박성훈 4, 이영진 5, 고창보 6, 이미경 7, 최순호 7, 정종훈 1, 박정현 1, 김휘정 1, 김학렬 1, 정은택 1, 양세훈 1 The Role and Significance of Biomarker for Plasma G-CSF in Patients with Primary Lung Cancer Jung Sub Song, M.D. 1, So Young Kim, M.D. 1, Hyang Jeong Jo, M.D. 2, Kang Kyoo Lee, M.D. 3, Jeong Hyun Shin, M.D. 1, Seong Nam Shin, M.D. 1, Dong Kim, M.D. 1, Seong Hoon Park, M.D. 4, Young Jin Lee, M.D. 5, Chang Bo Ko, Ph.D. 6, Mi Kung Lee, M.D. 7, Soon Ho Choi, M.D. 7, Jong Hoon Jeong, M.D. 1, Jung Hyun Park, M.D. 1, Hui Jung Kim, M.D. 1, Hak Ryul Kim, M.D. 1, Eun Taik Jeong, M.D. 1, Sei Hoon Yang, M.D. 1 Departments of 1 Internal Medicine, 2 Pathology, 3 Therapeutic Radiology & Oncology, 4 Radiology, 5 Clinical Pathology, Wonkwang University College of Medicine, Iksan, 6 Good Cell Life, Inc., Seoul, 7 Department of Thoracic Surgery, Wonkwang University College of Medicine, Iksan, Korea Background: Biomarkers for cancer have several potential clinical uses, including the following: early cancer detection, monitoring for recurrence prognostication, and risk stratification. However, no biomarker has been shown to have adequate sensitivity and specificity. Many investigators have tried to validate biomarkers for the early detection and recurrence of lung cancer. To evaluate plasma G-CSF as such a biomarker, protein levels were measured and were found to correlate with the clinicopathological features of primary lung tumors. Methods: Between December 2006 and May 2008, 100 patients with histologically-validated primary lung cancer were enrolled into this study. To serve as controls, 127 healthy volunteers were enrolled into this study. Plasma G-CSF levels were measured in lung cancer patients using the sandwich ELISA system (R & D inc.) prior to treatment. Results: The mean plasma G-CSF levels were 12.2±0.3 pg/ml and 46.0±3.8 pg/ml (mean±se) in the normal and in the cancer groups, respectively. In addition, plasma G-CSF levels were higher in patients with early lung cancer than in healthy volunteers (p<.001). Plasma G-CSF levels were higher in patients who were under 65 years old or smokers. Within the cancer group, plasma G-CSF levels were higher in patients with non small cell lung cancer than in patients with small cell lung cancer (p<.05). Overall, plasma G-CSF levels were shown to increase dependent upon the type of lung cancer diagnsosed. In the order from highest to lowest, the levels of plasma G-CSF tended to decrease in the following order: large cell carcinoma, squamous cell carcinoma, adenocarcinoma, and bronchioloalveolar carcinoma. Plasma G-CSF levels tended to be higher in patients with advanced TNM stage than in localized TNM stage (I, II<III, IV). Increased levels were also seen in patients with distant metastasis in the order of bone, adrenal gland involvement. Conclusion: Plasma G-CSF level were significantly increased in patients with lung cancer, and in especially advanced TNM stage. These results suggest that plasma G-CSF can be used to support the diagnostic process of lung cancer staging and as an indicator of metastasis. Key Words: Biological markers, Lung neoplasms, Granulocyte colony-stimulating factor, Metastasis 본연구는 2007 년도원광대학교교내연구비지원에의해이루어졌음. Address for correspondence: Sei Hoon Yang, M.D. Department of Internal Medicine, Wonkwang University Hospital, 344-2, Shinyong-dong, Iksan , Korea Phone: , Fax: yshpul@wonkwang.ac.kr Received: Jan. 21, 2009 Accepted: Jun. 22, 2009 서론폐암은전세계적으로매년모든암환자의 12.4% 에해당하는 13,500,000명이새로진단된다. 또한폐암은악성 444

2 Tuberculosis and Respiratory Diseases Vol. 66. No. 6, Jun 종양과관련된사망원인의 17.8% 로주된사망원인이된다 1. 폐암예후는비소세포폐암의경우병기에따른 5년생존율이 4병기 0% 에서수술이가능한 1병기 50% 까지다양하게나타난다. 소세포암의경우제한병기는평균생존기간이 10 18개월, 확장병기는 7 12개월로예후가나쁘다 2,3. 따라서폐암조기진단을위해객담도말세포검사, 저용량전산화단층촬영, 형광기관지내시경등많은방법이시도되고있다. 하지만아직까지는폐암에대한조기진단법이정립되어있지않은실정이다. 암표지자는악성종양세포에서혈액으로분비되는다양한호르몬, 단백질, 효소, 항원등을의미한다. 암표지자는악성종양선별검사, 예후예측, 치료효과분석, 재발조기발견등을시행할수있어여러악성종양에서임상적으로이용하고있다 4. 하지만아직까지높은유병률과사망률을가진폐암에서는이상적인암표지자가존재하지않는다. 최근에 CYFRA 21-1, tissue polypeptide specific antigen (TPS), neuron specific enolase (NSE), 편평세포암항원그리고 carcinoembryonic antigen (CEA) 등이암표지자로연구되고있다. 하지만가장민감도가높다고알려진 CYFRA 21-1 마저도비소세포폐암에서 65.5% 로보고하고있다. 따라서아직까지폐암에서진단, 예후그리고치료후재발판정에보편적으로사용되어지는암표지자는밝혀져있지않다 5-8. 최근에암표지자로서 granulocyte- colony stimulating factor (G-CSF) 는악성종양의진행과더불어조혈전구세포의분화증식을유발하는성장인자이다 악성종양은 G-CSF mrna 발현으로결합부위에영향을주며, 높은농도의 G-CSF 는비혈액암에서도암의활동성과연관이있음이보고되었다 12,13. 최근 Mroczko 등 14 은대장직장암에서혈청내 macrophage-colony stimulating factor (M-CSF) 증가는병의진행, 림프절전이와관련이있고나쁜예후를갖는다고보고하였다. 특히, 악성중피종, 폐암, 췌장암, 유방암환자에서혈청내에 G-CSF 가증가하는경우가보고된바가있으며, 또한악성중피종과폐암환자에서 G-CSF 의증가는병의급속한악화와연관이있을것이라보고된바가있다 15,16. 이에본연구에서는혈장 G-CSF 가종양의진행에대하여아직까지확실하게보고된바가없어, 원발성폐암으로진단받은환자의혈장내 G-CSF 를측정하여정상인과비교하고, G-CSF 가폐암의진행및조직학적형태에따른차이가있는지를알아보고자하였다. 대상및방법 1. 대상 2006년 12월부터 2008년 5월까지본병원에서조직학적으로원발성폐암으로확진된 100 명의환자와건강검진에서이상소견이없는 127명의정상인을대조군으로하였다. 후향적조사를하였으며, 환자와보호자에게사전동의서를취득하였고, 본병원임상시험위원회 (IRB) 승인을받았다. 대조군과폐암환자의연령에따른비교는연령차이가너무커서시행하지못했다. 2. 방법폐암환자와정상인혈장에존재하는 G-CSF 농도는 Sandwich ELISA (R & D Inc., Minneapolis, MN, USA) 법으로 protocol 에따라작성한표준곡선으로계산하였다. Sandwich ELISA는캡쳐항체가코팅되어있는키트를사용해혈액을키트에떨어트린후다시효소부착항체를처리하여발색과정을통해항원농도를측정한다. 1) Receiver operator characteristic (ROC) curve: 혈장 G-CSF 검사가폐암의선별검사로서타당성이있는지알기위해민감도 (sensitivity) 와특이도 (specificity) 를이용한 ROC curve를확인하였다. 2) 통계학적방법 : 통계학적방법은 SPSS 12.0 프로그램 (SPSS Inc., Chicago, IL, USA) 을이용하였다. 각군간의비교는독립표본 T 검정과일원배치분산분석을사용하였다. 정상인과폐암환자, 나이, 성별, 원격전이유무에따른혈장 G-CSF 비교는독립표본 T 검정을실시하였다. 또한흡연력, 조직병리, TNM 병기, 전이부위에따른혈장 G-CSF 비교는일원배치분산분석을사용하였다. 결과 1. 정상인및폐암환자의특성정상인과폐암환자의평균연령은 47세, 69세였고, 양쪽모두남녀비는남자가높았다. 비흡연자 ( 평생 100 개비이하흡연 ) 및과거에흡연 ( 최소 1년이상금연 ) 한경우보다현재흡연하고있는경우가많았다. 조직병리학적분류 (WHO classification, 1999) 는비소세포폐암이소세포폐암보다많았으며, 비소세포폐암중편평상피암와선암이많았다. 비소세포폐암에서 T병기와 N병기가증가할수록예의수는증가하였으며, 원격전이는 M0 49예, M1 51예였고, TNM병기는 4기가제일많았다. 소세포폐암에 445

3 JS Song et al: G-CSF on lung cancer 서는확장병기가많았다 (Table 1). 원격전이부위는골 26 예, 부신 10예, 간 7예, 뇌 9예, 기타 15예였다. 2. 정상인및원발성폐암환자에서혈장 G-CSF 농도폐암환자와정상인의혈장 G-CSF 농도는각각 45.98± 3.8 pg/ml (mean±se), 12.23±0.3 pg/ml으로, 정상인에비해폐암환자에게혈장농도는유의하게증가하였다 (p<0.0001). 또한 1병기비소세포폐암, 제한병기소세포폐암, 정상인의혈장 G-CSF 농도를비교하면각각 23.95± 8.3 pg/ml, 23.79±6.3 pg/ml, 12.23±0.3 pg/ml로정상인의농도보다두배정도증가하였다 (p<0.0001). 3. 폐암환자의성별, 나이및흡연력에따른혈장 G-CSF 농도 성별에따른농도는남자에게높았고, 65세를기준으로한연령에의한농도차이는 65세미만에서높았다. 흡연력에따른혈장농도는흡연력이있는경우높게측정되었으나이모두통계적유의성은없었다 (Table 2). Table 1. Demographics of lung cancer patients Age (mean, range) 69 (37 87) Sex (male:female) 79:21 Smoking (no.) Nonsmoker 21 Ex-smoker 32 Current smoker 47 Histology (no.) NSCLC 85 Squamous cell carcinoma 39 Adenocarcinoma 33 Large cell carcinoma 5 Bronchioloalveolar carcinoma 2 Others 6 SCLC 15 Tumor T1 7 T2 14 T3 6 T4 58 Lymph node N0 11 N1 5 N2 27 N3 42 Metastasis M0 49 M1 51 Stage NSCLC Stage1 4 Stage2 2 Stage3 38 Stage4 41 SCLC Limited 5 Extensive 10 NSCLC: non-small cell lung cancer; SCLC: small cell lung cancer. 4. 조직병리학적분류에따른혈장 G-CSF 농도 조직병리학적분류에따른혈장농도는비소세포폐암 47.95±4.4 pg/ml, 소세포폐암 34.80±3.8 pg/ml으로유의성있게비소세포폐암에서높았다 (p<0.05) (Table 3). Table 2. of gender, age, smoking Gender Female 43.08±5.1 Male 46.75±4.6 Age ±3.4 < ±11.2 Smoking Nonsmoker 41.58±5.1 Ex-smoker 42.12±4.2 Current smoker 50.58±7.2 p=ns. Table 3. of histologic types Histologic type SCLC 34.80±3.8 NSCLC 47.95±4.4* Large cell carcinoma 56.56±10.9 Squamous cell carcinoma 51.77±8.3 Adenocarcinoma 40.08±3.2 Bronchioloalveolar carcinomal 28.56±11.0 NSCLC: non-small cell lung cancer; SCLC: small cell lung cancer. *p<

4 Table 4. of the lung cancer stage Tuberculosis and Respiratory Diseases Vol. 66. No. 6, Jun Stage NSCLC I 23.95±8.3* II 33.10±2.1 III 40.10±5.3 IV 58.30±7.3 SCLC Limited 23.79±6.3 Extensive 40.31±4.0 NSCLC: non-small cell lung cancer; SCLC: small cell lung cancer. *p=ns, p= Table 5. of metastasis Figure 1. Receiver operator characteristic (ROC) curve for plasma G-CSF concentration. There were ROC curve for plasma G-CSF of lung cancer and normal person. When plasma G-CSF's cut-off value was 21 pg/ml, we determinated sensitivity was 90%, and specificity was 99%. Metastasis M0 36.8±4.3* M1 54.8±6.0 Multiple metastasis 66.1±16.8 Single metastasis 49.6±4.1 Bone 53.2±6.0 Adrenal gland 43.0±14.3 Brain 38.3±2.8 Others 46.1±7.4 Metastasis with bone 60.8±10.7 Metastasis without bone 48.5±5.0 *p<0.05, p=ns, p=ns. 비소세포폐암에서는대세포폐암, 편평상피암, 선암, 세기관지폐포암순으로농도는감소하였으나통계적유의성은없었다. 5. TNM 병기에따른혈장 G-CSF 농도 TNM 병기에따른비소세포폐암의혈장농도는병기가진행할수록증가하는경향을보이나, 통계적유의성은없었다. 소세포폐암에서도마찬가지로제한병기 23.79±6.3 pg/ml, 확장병기 40.31±4.0 pg/ml로확장병기에서통계적유의성에근접하게혈장농도가높았다 (p=0.062) (Table 4). 6. 원격전이유무에따른혈장 G-CSF 농도원격전이에따른혈장농도는원격전이 (+) 36.8±4.3 pg/ml, 원격전이 (-) 54.8±6.0 pg/ml 로유의하게원격전이 (+) 시증가하였다 (p<0.05). 단일전이와다발성전이를비교시, 단일전이 49.6±4.1 pg/ml, 다발성전이 66.1±16.8 pg/ml 로다발성전이에서증가하는경향을보였다. 단일전이중에서는골, 부신, 뇌순으로골전이시에혈장농도가증가하였다. 또한골전이와골이외전이로비교시, 골전이가있는경우가증가하는양상보였다 (Table 5). 7. 원발성폐암환자에서민감도와특이도혈장 G-CSF 농도 21 pg/ml 을양성값 (cut-off point) 으로정하였을때민감도와특이도는각각 90% 와 99% 였다 (Figure 1). 고찰현재폐암은남녀모두에서암사망 1위를차지하고있을정도로예후가불량한암으로알려져있다. 폐암조기진단을위한많은시도가이루어지고있으나, 아직까지조기진단을위한유용한방법은정립되지못하고있다. Post-genomic era ( 게놈프로젝트 ) 이후에는영상이나세 447

5 JS Song et al: G-CSF on lung cancer 포검사와함께, 폐암에서분비되는특이항원을이용한혈액학적선별검사및진단을위한종양표지자에대한연구가활발히이루어지고있다. 지금까지폐암의종양표지자로알려진것은편평세포암항원, CYFRA 21-1, tissue polypeptide specific antigen (TPS), neuron specific enolase (NSE) 그리고 carcinoembryonic antigen (CEA) 등이있으며, 이들에대한폐암진단및예후예측, 치료효과등에대한연구가많이이루어졌다 8, 하지만 NSE 와 CEA 는특이도가부족하고, 암이외의상황에서도증가하는양상을보이고, 편평세포암항원은민감도가 33 61% 정도로낮게보고되어졌다 21. 또한 CYFRA 21-1 역시좀더폐암과연관성이있으나, 역시민감도에서 56 68% 정도로낮게측정되었다 22. 위에서언급한암표지자외에혈장 G-CSF 는폐암을포함한고형암세포에서증가한다고알려져있어암표지자가능성을제시하고있다. 혈장내 G-CSF 가비혈액암에서증가하는이유는암세포가 G-CSF 전령RNA 와결합부위의활성을증가시키는것으로보고되어진바는있으나아직정확한기전은알려져있지않다 9, 혈장내 G-CSF는대장, 직장암환자에게증가하는경향을보인다. 그리고대장, 직장암의병기와도연관이있는것으로보고되어졌다. 또한악성중피종을가진환자에게도예후와연관성이있을것으로알려져있다 15,23,24. 폐암과혈장 G-CSF 와의연관성은 Asano 등 25 의보고에의하면실험용쥐에인간의폐암조직을이식한경우, 쥐에서혈장 G-CSF 가증가된다고보고하였다. Watari 등 26 의보고에의하면건강한성인과여러질병을가진환자를대상으로혈장내 G-CSF 농도를측정한결과정상인에게는거의 30 pg/ml 이내로측정되어졌으나, 폐암을가진환자는 pg/ml 로높게측정된바있다. 본연구에서는정상인과폐암환자에서혈장 G-CSF 농도를확인하고, 암병기진행에있어예측인자로서의의가있는지확인하고자하였다. 혈장 G-CSF 농도는앞선보고들과같이본연구에서도정상인보다폐암환자에게유의하게증가하였다. 더욱이 1병기비소세포폐암과정상인에서농도비교시, 두배가량폐암에서통계적으로유의하게증가하는결과보였다. 따라서낮은병기의폐암환자에서도혈장 G-CSF 가진단에도움이될수있을것으로사료된다. Mroczko 등 23 에따르면비소세포폐암에서혈청 G-CSF 농도가상승하여이는암표지자로서의의가있을것으로보고하였다. 본연구에서도암표지자로서의의를확인하 는민감도와특이도는각각 90% 와 99% 로매우높게측정되었다. 하지만폐암에서만특징적으로의의가있는지알기위해서는다른암또는염증성질환과의비교가필요하며, 앞으로더욱연구해야할제한점이다. 본연구에서조직학적으로는소세포폐암보다는비소세포폐암인경우에혈장내 G-CSF 가증가하였다. 비소세포폐암중에서는세기관지폐포암, 선암, 편평상피암, 대세포암순으로증가하는경향을보였다. 이결과는 Hasegawa 등 27 이보고한대세포폐암에서혈장 G-CSF 농도가많이증가한다는보고와일치하며, Tsuruta 등 28 이보고한편평상피세포암과혈장 G-CSF 가연관성이있다는보고와는차이가있었다. 본연구에서비소세포폐암병기에따른혈장 G-CSF 농도는병기가진행할수록혈장내 G-CSF 가증가하였다. 그리고소세포폐암에서도역시제한기보다확장기에증가하는경향을보여, 수술후또는항암요법및방사선요법후추적검사상에서폐암의진행여부를혈장에서 G-CSF 를측정함으로써예측할수있으리라사료된다. 또한단일전이보다는다발성전이에서증가하는양상을보여또한폐암전이여부를판단하는데도유용하게사용될수있으리라사료된다. 결론적으로폐암환자에게혈중 G-CSF 농도측정은폐암의진행성여부판단에도유용할것으로사료된다. 또한진행된폐암에서 G-CSF 농도의증가양상은예후와도연관성이있을것으로추론되며, 추후에이와관련된연구가이루어져야할것으로사료된다. 요약연구배경 : 폐암은진단당시에완치할수있는확률이적어예후가불량한종양으로알려져있어, 폐암진행을예측할수있는암표지자 (tumor marker) 의발굴이필요한실정이다. 그러나폐암에서아직까지특이적인항원이없고현재까지알려진많은종양관련항원들의민감도가떨어지기때문에보편화되지못하고있다. 본연구에서는원발성폐암환자에서혈장 G-CSF 를측정하고암의진행및예후와관련이있는지알아보고자하였다. 방법 : 원발성폐암으로진단된 100명환자와건강검진에서이상소견이없는 127명정상인을대상으로하였다. 결과 : 정상인에서혈장 G-CSF 농도는 12.2±3.6 pg/ ml (mean±sd), 폐암환자에서는 46.0±38.0 pg/ml였다 (p<0.001). 비소세포폐암에서 G-CSF 농도는유의하게 448

6 Tuberculosis and Respiratory Diseases Vol. 66. No. 6, Jun 소세포폐암보다높았으며 (p<0.05), 비소세포폐암중대세포폐암이가장높았고, 편평세포암, 선암, 세기관지폐포암순이었다. G-CSF 농도는국소형보다는진행형비소세포폐암에서증가하는경향을보였다. 또한타장기로의전이가있을때유의하게증가하였으며 (p<0.05), 다발성전이에서는뇌, 부신, 골전이순으로혈청 G-CSF 농도가증가하는경향이었다. 결론 : 혈장 G-CSF 농도는폐암이진행한경우, 특히타장기로의전이가있을때유의하게증가하였다. 그러므로진행형폐암의추적관찰에이용할수있으리라사료된다. 참고문헌 1. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, CA Cancer J Clin 2005;55: Mountain CF. A new international staging system for lung cancer. Chest 1986;89:225S-33S. 3. Albain KS, Crowley JJ, Livingston RB. Long-term survival and toxicity in small cell lung cancer. Expanded Southwest Oncology Group experience. Chest 1991;99: Cooper DL. Tumor markers. In: Goldman L, Bennett JC, editors. Cecil textbook of medicine. 21st ed. Philadelphia: W.B. Saunders company; p Müller LC, Gasser R, Huber H, Klingler A, Salzer GM. Neuron-specific enolase (NSE) in small-cell lung cancer: longitudinal tumors marker evaluation. Lung Cancer 1992;8: Akoun GM, Scarna HM, Milleron BJ, Bénichou MP, Herman DP. Serum neuron-specific enolase: a marker for disease extent and response to therapy for smallcell lung cancer. Chest 1985;87: Bonomi P, Gale M, Rowland K, Taylor SG 4th, Purl S, Reddy S, et al. Pre-treatment prognostic factors in stage III non-small cell lung cancer patients receiving combined modality treatment. Int J Radiat Oncol Biol Phys 1991;20: Karnak D, Ulubay G, Kayacan O, Beder S, Ibis E, Oflaz G. Evaluation of Cyfra 21-1: a potential tumor marker for non-small cell lung carcinomas. Lung 2001;179: McDermott RS, Deneux L, Mosseri V, Védrenne J, Clough K, Fourquet A, et al. Circulating macrophage colony stimulating factor as a marker of tumor progression. Eur Cytokine Netw 2002;13: Miyagawa K, Chiba S, Shibuya K, Piao YF, Matsuki S, Yokota J, et al. Frequent expression of receptors for granulocyte-macrophage colony-stimulating factor on human nonhematopoietic tumor cell lines. J Cell Physiol 1990;143: Turner AM, Zsebo KM, Martin F, Jacobsen FW, Bennett LG, Broudy VC. Nonhematopoietic tumor cell lines express stem cell factor and display c-kit receptors. Blood 1992;80: Tani K, Ozawa K, Ogura H, Shimane M, Shirafuji N, Tsuruta T, et al. Expression of granulocyte and granulocyte macrophage colony-stimulating factors by human non-hematopoietic tumor cells. Growth Factors 1990;3: Yee LD, Liu L. The constitutive production of colony stimulating factor 1 by invasive human breast cancer cells. Anticancer Res 2000;20: Mroczko B, Groblewska M, Wereszczyńska-Siemiatkowska U, Okulczyk B, Kedra B, Laszewicz W, et al. Serum macrophage-colony stimulating factor levels in colorectal cancer patients correlate with lymph node metastasis and poor prognosis. Clin Chim Acta 2007; 380: Usami N, Uchiyama M, Kawaguchi K, Yasuda A, Ito S, Yokoi K. Granulocyte colony-stimulating factor-producing malignant pleural mesothelioma. J Thorac Oncol 2007;2: Kobashi Y, Okimoto N, sakamoto K. Squamous cell carcinoma of the lung producing granulocyte colonystimulating factor and resembling a malignant pleural mesothelioma. Intern Med 2004;43: Buccheri G, Ferrigno D. Lung tumor markers of cytokeratin origin: an overview. Lung Cancer 2001;34 Suppl 2:S Body JJ, Sculier JP, Raymakers N, Paesmans M, Ravez P, Libert P, et al. Evaluation of squamous cell carcinoma antigen as a new marker for lung cancer. Cancer 1990;65: Buccheri G, Ferrigno D. Usefulness of tissue polypeptide antigen in staging, monitoring, and prognosis of lung cancer. Chest 1988;93: Sculier JP, Body JJ, Jacobowitz D, Fruhling J. Value of CEA determination in biological fluids and tissues. Eur J Cancer Clin Oncol 1987;23: Mino N, Iio A, Hamamoto K. Availability of tumor-antigen 4 as a marker of squamous cell carcinoma of the lung and other organs. Cancer 1988;62: Wieskopf B, Demangeat C, Purohit A, Stenger R, Gries P, Kreisman H, et al. Cyfra 21-1 as a biologic marker 449

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Jkbcs016(92-97).hwp Expression of bcl-2 and Apoptosis and Its Relationship to Clinicopathological Prognostic Factors in Breast Cancer - A Study with Long Term Follow-up correlated with the survival rate.(journal of Korean