請用此 Handle URI 來引用此文件:
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/58255
完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 張逸良(Yih-Leong Chang) | |
dc.contributor.author | Mong-Wei Lin | en |
dc.contributor.author | 林孟暐 | zh_TW |
dc.date.accessioned | 2021-06-16T08:09:30Z | - |
dc.date.available | 2014-10-09 | |
dc.date.copyright | 2014-10-09 | |
dc.date.issued | 2014 | |
dc.date.submitted | 2014-05-01 | |
dc.identifier.citation | References
1. Hoffman PC, Mauer AM, Vokes EE. Lung cancer. Lancet. 2000;355:479-85. 2. Yoshimi I, Ohshima A, Ajiki W, et al. A comparison of trends in the incidence rate of lung cancer by histological type in the Osaka Cancer Registry, Japan and in the surveillance, epidemiology and end results program, USA. Jpn J Clin Oncol. 2003;33:98-104. 3. Shigematsu H, Lin L, Takahashi T, et al. Clinical and Biological Features Associated With Epidermal Growth Factor Receptor Gene Mutations in Lung Cancers. J Natl Cancer Inst. 2005;97:339-46. 4. Olayioye MA, Neve RM, Lane HA, Hynes NE. The ErbB signaling network: receptor heterodimerization in development & cancer. EMBO J. 2000;19:3159-67. 5. Chang YL, Wu CT, Lin SC, et al. Clonality and prognostic implications of p53 and epidermal growth factor receptor somatic aberrations in multiple primary lung cancers. Clin Cancer Res. 2007;13:52-8. 6. Marks JL, Broderick S, Zhou Q, et al. Prognostic and therapeutic implications of EGFR and KRAS mutations in resected lung adenocarcinoma. J Thorac Oncol. 2008;3:111-6. 7. Kobayashi N, Toyooka S, Ichimura K, et al. Non-BAC component but not epidermal growth factor receptor gene mutation is associated with poor outcomes in small adenocarcinoma of the lung. J Thorac Oncol. 2008;3:704-10. 8. Sugio K, Uramoto H, Ono K, et al. Mutations within the tyrosine kinase domain of EGFR gene specifically occur in lung adenocarcinoma patients with a low exposure of tobacco smoking. Br J Cancer. 2006;94:896-903. 9. Mitsudomi T, Steinberg SM, Nau MM, et al. p53 gene mutations in non-small-cell lung cancer cell lines and their correlation with the presence of ras mutations and clinical features. Oncogene. 1992;7:171-80. 10. Finlay CA, Hinds PW, Levine AJ. The p53 proto-oncogene can act as a suppressor of transformation. Cell. 1989;57:1083-93. 11. Kosaka T, Yatabe Y, Onozato R, et al. Prognostic implication of EGFR, KRAS, and TP53 gene mutations in a large cohort of Japanese patients with surgically treated lung adenocarcinoma. J Thorac Oncol. 2009;4:22-9. 12. Mitsudomi T, Hamajima N, Ogawa M, Takahashi T. Prognostic significance of p53 alterations in patients with non-small cell lung cancer: a meta-analysis. Clin Cancer Res. 2000;6:4055-63. 13. Kozower BD, Larner JM, Detterbeck FC, Jones DR; American College of Chest Physicians. Special treatment issues in lung cancer. ACCP evidence-based clinical practice guidelines (3rd edition). Chest. 2013;143:e369s-e399s. 14. Detterbeck FC, Mazzone PJ, Naidich DP, Bach PB; American College of Chest Physicians. Screening for lung cancer: ACCP evidence-based clinical practice guidelines (3rd edition). Chest. 2013;143:e78s-e92s. 15. Ebright MI , Zakowski MF , Martin J , et al. Clinical pattern and pathologic stage but not histologic features predict outcome for bronchioloalveolar carcinoma. Ann Thorac Surg. 2002;74:1640-6. 16. Mun M, Kohno T. Efficacy of thoracoscopic resection for multifocal bronchioloalveolar carcinoma showing pure ground-glass opacities of 20 mm or less in diameter. J Thorac Cardiovasc Surg. 2007;134:877-82. 17. Roberts PF, Straznicka M, Lara PN, Lau DH, Follette DM, Gandara DR, Benfield JR. Resection of multifocal non-small cell lung cancer when the bronchioloalveolar subtype is involved. J Thorac Cardiovasc Surg. 2003;126:1597-602. 18. Nakata M, Sawada S, Yamashita M, Saeki H, Kurita A, Takashima S, Tanemoto K. Surgical treatments for multiple primary adenocarcinoma of the lung. Ann Thorac Surg. 2004;78:1194-9. 19. Carretta A, Ciriaco P, Melloni G, et al. Surgical treatment of multiple primary adenocarcinomas of the lung. Thorac Cardiovasc Surg. 2009;57:30-4. 20. Kim HK, Choi YS, Kim J, Shim YM, Lee KS, Kim K. Management of multiple pure ground-glass opacity lesions in patients with bronchioloalveolar carcinoma. J Thorac Oncol. 2010;5:206-10. 21. Casali C, Rossi G, Marchioni A, et al. A single institution-based retrospective study of surgically treated bronchoioloalveolar adenocarcinoma of the lung: clinicopathologic analysis, molecular features, and possible pitfalls in routine practice. J Thorac Oncol. 2010;5:830-6. 22. Mitsudomi T, Yatabe Y, Koshikawa T, et al. Mutations of the P53 tumor suppressor gene as clonal marker for multiple primary lung cancers. J Thorac Cardiovasc Surg. 1997;114:354-60. 23. Matsuzoa D, Hideshima T, Ohshima K, Kawahara K, Shirakusa T, Kimura A. Discrimination of double primary lung cancer from intrapulmonary metastasis by P53 gene mutation. Br J Cancer. 1999;79:1549-52. 24. Van Rens MT, Eijken EJ, Elbers JR, Lammers JW, Tilanus MG, Slootweg PJ. P53 mutation analysis for definite diagnosis of multiple primary lung carcinoma. Cancer. 2002;94:188-96. 25. Tang X, Shigematsu H, Bekele BN, et al. EGFR tyrosine kinase domain mutations are detected in histologically normal respiratory epithelium in lung cancer patients. Cancer Res. 2005;65:7568-72. 26. American Joint Committee on Cancer. Lung. In: Edge S, Byrd DR, Compton CC, Fritz AG, Greene FI, Trotti, III A, editors. AJCC Cancer Staging Manual. 7th ed. New York: Springer; 2010:253-70. 27. Travis WD, Brambilla E, Muller-Hermelink HK, et al. Pathology and Genetics. Tumours of the Lung, Pleura, Thymus and Heart. Lyon, France: IARC Press, 2004. 28. Linardou H, Dahabreh IJ, Kanaloupiti D, et al. Assessment of somatic k-RAS mutations as a mechanism associated with resistance to EGFR-targeted agents: a systemic review and meta-analysis of studies in advanced non-small-cell lung cancer and metastatic colorectal cancer. Lancet Oncol. 2008;9:962-72. 29. Sidransky D, Mikkelsen T, Schwechheimer K, Rosenblum ML, Cavanee W, Vogelstein B. Clonal expansion of P53 mutant cells is associated with brain tumour progression. Nature. 1992;355:846-7. 30. Sobue T, Moriyama N, Kaneko M, et al. Screening for lung cancer with low-dose helical computed tomography: anti-lung cancer association project. J Clin Oncol. 2002;20:911-20. 31. Lee YC, Chang YL, Luh SP, et al. Significance of P53 and Rb protein expression in surgically treated non-small cell lung cancers. Ann Thorac Surg. 1999;68:343-8. 32. Chang YL, Wu CT, Shih JY, Lee YC. Comparison of p53 and Epidermal Growth Factor Receptor Gene Status Between Primary Tumors and Lymph Node Metastases in Non-Small Cell Lung Cancers. Ann Surg Oncol. 2011;18:543-50. 33. Chung KP, Huang YT, Chang YL, et al. Clinical significance of thyroid transcription factor-1 in advanced lung adenocarcinoma under epidermal growth factor receptor tyrosine kinase inhibitor treatment. Chest. 2012;141:420-8. 34. Chiba I, Takahashi T, Nau MM, et al. Mutations in the p53 gene are frequent in primary, resected non-small cell lung cancer. Lung Cancer Study Group. Oncogene. 1990;5:1603-10. 35. Kawasaki M, Noguchi M, Morikawa A, et al. Nuclear p53 accumulation by small-sized adenocarcinomas of the lung. Pathol Int. 1996;46:486-90. 36. Chang YL, Wu CT, Shih JY, Lee YC. Roles of Fhit and p53 in Taiwanese surgically treated non-small-cell lung cancers. Br J Cancer. 2003;89:320-6. 37. Harris CC. p53 tumor suppressor gene: from the basic research laboratory to the clinic - an abridged historical perspective. Carcinogenesis. 1996;17:1187-98. 38. Chang YL, Lin MW, Shih JY, et al. The significance of visceral pleural surface invasion in 321 cases of non-small cell lung cancers with pleural retraction. Ann Surg Oncol. 2012;19:3057-64. 39. Beyreuther H. Multipicate von carcinomen bei einem fall von sog: ‘Schnee- berger’ lungenkrebs mit tuberculose. Virchows Arch Pathol Anat. 1924;250:230-6. 40. Ferguson MK, DeMeester TR, DesLauriers J, Little AG, Piraux M, Golomb H. Diagnosis and management of synchronous lung cancers. J Thorac Cardiovasc Surg. 1985;89:378-85. 41. Chang YL, Wu CT, Lee YC. Surgical treatment of synchronous multiple primary lung cancers: Experience of 92 patients. J Thorac Cardiovasc Surg. 2007;134:630-7. 42. Nelson MA, Wymer J, Clements JrN. Detection of K-ras gene mutations in non-neoplastic lung tissue and lung cancers. Cancer Lett. 1996;103:115-21. 43. Goldstraw P. Staging Manual in Thoracic Oncology. Denver: IASLC, 2009;85-89. 44. Yoo SB, Chung JH, Lee HJ, Lee CT, Jheon S, Sung SW. Epidermal growth factor receptor mutation and p53 overexpression during the multistage progression of small adenocarcinoma of the lung. J Thorac Oncol. 2010;5:964-9. 45. Malumbres M, Barbacid M. RAS oncogenes: the first 30 years. Nat Rev Cancer. 2003;3:459-65. 46. Bos JL. Ras oncogenes in human cancer: a review. Cancer Res. 1989;49:4682-9. 47. Sugio K, Ishida T, Yokoyama H, Inoue T, Sugimachi K, Sasazuki T. Ras gene mutations as a prognostic marker in adenocarcinoma of the human lung without lymph node metastasis. Cancer Res. 1992;52:2903-6. 48. Nakamura H, Haruki T, Adachi Y, Fujioka S, Miwa K, Taniguchi Y. Smoking affects prognosis after lung cancer surgery. Surg Today. 2008;38:227-31. 49. Sobue T, Suzuki T, Fujimoto I, Doi O, Tateishi R, Sato T. Prognostic factors for surgically treated lung adenocarcinoma patients, with special reference to smoking habit. Jpn J Cancer Res. 1991;82:33-9. 50. Okumura T, Asamura H, Suzuki K, Kondo H, Tsuchiya R. Intrapulmonary metastasis of non-small cell lung cancer: a prognostic assessment. J Thorac Cardiovasc Surg. 2001;122:24-8. 51. Martini N, Melamed MR. Multiple primary lung cancers. J Thorac Cardiovasc Surg. 1975;70:606-12. | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/58255 | - |
dc.description.abstract | 近幾年來,由於低輻射劑量電腦斷層檢查的普及,臨床上越來越常見到小型肺腺癌病例。這些病患過去因為沒有症狀,往往無法被早期發現。小型肺腺癌包括兩種形態:單一肺腺癌,以及同時多發性肺腺癌。關於這兩類肺腺癌的基因特性,臨床病理特徵,以及與手術治療後預後的相關性等方面,目前仍未有詳細研究。
本研究收納了172位小型單一肺腺癌,及64位小型同時多發性肺腺癌病例。這些病患的肺腺癌腫瘤各別大小均 ≤ 2公分,且均經過手術完全切除。本研究採用石蠟包埋檢體,進行EGFR,p53及KRAS基因定序分析,並將基因分析結果與臨床病理特性,病患預後等相關因子進行統計分析。 在小型單一肺腺癌的病患中,EGFR跟p53基因突變的比率分別為60.5% (104/172)及20.9% (36/172)。EGFR基因突變與腫瘤大小(>1公分)有關聯,而p53基因突變與腫瘤大小(>1公分)及中等度腫瘤分化(moderately differentiated)有相關。這一組病患中,有163位屬肺癌分期第一期,就這些第一期病患進行無病存活率分析(Disease-free survival),發現四個疾病復發因子:p53 基因突變 (p = 0.039),腫瘤肋膜表層侵犯(visceral pleural surface invasion, PL2; p = 0.001),癌症胚胎抗原異常(carcinoembryonic antigen; p < 0.001),以及中等度腫瘤分化(moderately differentiation; p = 0.002)。共有30位病患有疾病復發的情形,在其中23位腫瘤有EGFR基因突變的病患中,有接受標靶藥物治療的病患五年存活率比僅接受傳統化學治療的病患要好,五年存活率分別各為71.1%與44.4%。 本研究納入的64位小型同時多發性肺腺癌病患,其五年無病存活率(disease-free survival)與總存活率(overall survival)分別為86.1%及95.8%,與第一期肺腺癌存活率相近。這組病人的腫瘤基因分析,EGFR,p53與KRAS基因突變比率分別為64.1% (41/64),12.5% (8/64)及6.3% (4/64)。利用EGFR/p53/KRAS這三個基因突變進行克隆性分析(clonality assessment),其中14位病患屬於同源性(same clonality),30位病患屬於異源性(different clonality),這些研究結果可進一步支持”field cancerization”理論。多變數無病存活率分析發現兩個與腫瘤復發相關的因子:淋巴結轉移(p = 0.003)與抽煙 (p = 0.011)。手術方式(lobar or sublobar resection),克隆性分析結果(clonality),以及腫瘤位置與腫瘤復發均無統計上的顯著相關性。 因此,總結來說,在小型單一肺腺癌病例,p53基因突變與腫瘤復發有顯著關聯,可當作IB期病患是否要接受手術後化學治療的一個參考因子。對於腫瘤復發的病患來說,若EGFR基因有突變,可採用標靶藥物治療,以得到較好的存活率。對於小型同時多發性肺腺癌病患,無論是腫瘤位置或是以EGFR/p53/KRAS基因突變進行克隆性分析的結果如何,對每一個病灶採用肺節切除(segmentectomy)或是肺楔狀切除(wedge resection)進行完整的腫瘤切除後,可以達到很好的長期無病存活率。淋巴結轉移是腫瘤復發的危險因子,因此,病患若手術後發現有淋巴結轉移的情形,應考慮給予術後化學治療。 | zh_TW |
dc.description.abstract | As a result of improved lung cancer detection in asymptomatic patients, small solitary and synchronous multiple adenocarcinomas are found more frequently than in the past. However, the genetic profile, treatment, and prognosis of these two kinds of patients remain unclear. For treatment decisions and prognostic applications, we evaluated the correlation of epidermal growth factor receptor (EGFR)/p53 mutations with clinicopathologic characteristics and tumor relapse in 172 surgically resected solitary lung adenocarcinomas ≤ 2 cm in maximal dimension. We also evaluated the presence of EGFR, p53, and KRAS somatic mutations in 64 synchronous multiple lung adenocarcinomas ≤ 2 cm in maximal dimension. Mutational analysis was performed on DNA extracted from paraffin-embedded tumors.
EGFR and p53 mutations were identified in 104 (104/172, 60.5%) and 36 (36/172, 20.9%) small solitary lung adenocarcinomas, respectively. EGFR/p53 mutations were associated with tumor size > 1cm, whereas p53 mutations were frequently observed in moderately differentiated tumors. Disease-free survival analysis showed that p53 mutation (p = 0.039), visceral pleural surface invasion (p = 0.001), carcinoembryonic antigen (p < 0.001), and tumor differentiation (p = 0.002) were significantly correlated with tumor relapse in patients with stage I disease. The 5-year survival rate was higher in relapsed patients with EGFR-mutated tumors who were treated with tyrosine kinase inhibitor (TKI) than in those who were not treated with TKI (71.1% versus 44.4%). The 5-year disease-free survival of the 64 small synchronous multiple lung adenocarcinoma patients was 86.1%, and the overall survival of these patients was 95.8%. EGFR, p53, and KRAS mutations were detected in 41 (41/64, 64.1%), 8 (8/64, 12.5%), and 4 (4/64, 6.3%) patients, respectively. The high frequency of genetic mutations resulted in high discrimination rate of tumor clonality (68.8%; 44/64) in the study group. Fourteen (14/64, 31.8%) patients were assessed as having the same clonality, whereas 30 (30/64, 68.2%) patients had different clonality, which further supported the concept of field cancerization. Multivariate analysis showed lymph node metastasis (p = 0.003) and smoking (p = 0.011) were significantly correlated with tumor relapse. Surgical method, clonality and tumor location were not correlated with tumor relapse in small synchronous multiple lung adenocarcinomas. In small solitary lung adenocarcinoma patients, p53 mutation was significantly correlated with tumor progression, and our findings may provide a rationale for the selective use of adjuvant chemotherapy in stage IB lung adenocarcinoma patients with p53 mutations. EGFR mutation was a predictor of EGFR TKI response in relapsed patients. On the other hands, no matter whether the small synchronous multiple lung adenocarcinomas are different or same clonal, sublobar resection of each lesion can achieve long-term disease-free survival and is the treatment of choice. Patients with lymph node metastasis are at risk of relapse and adjuvant chemotherapy is indicated. | en |
dc.description.provenance | Made available in DSpace on 2021-06-16T08:09:30Z (GMT). No. of bitstreams: 1 ntu-103-D99444002-1.pdf: 13018593 bytes, checksum: 5c0bf057576881acc7137cd0428315b8 (MD5) Previous issue date: 2014 | en |
dc.description.tableofcontents | 目錄
論文口試委員審定書………………………………………………………………………… I 誌謝…………………………………………………………………………………………… II 中文摘要……………………………………………………………………………………… III 英文摘要……………………………………………………………………………………… V Chapter 1 Introduction…………………………………………………………………. 1 Chapter 2 Materials and Methods……………………………………………………. 4 2.1 Study Population of Small Solitary Lung Adenocarcinomas………………… 4 2.2 Study Population of Small Synchronous Multiple Lung Adenocarcinomas………………………………………………………………………. 5 2.3 Mutational Analysis of EGFR, p53 and KRAS…………………………………… 6 2.4 Statistical Analysis…………………………………………………………………… 7 Chapter 3 Results………………………………………………………………………… 8 3.1 Patient Characteristics in Small Solitary Lung Adenocarcinomas…………. 8 3.2 EGFR and p53 Mutation Patterns in Small Solitary Lung Adenocarcinomas………………………………………………………………………. 8 3.3 Correlations of Genetic Mutations with Clinicopathologic Features in Small Solitary Lung Adenocarcinomas…………………………………………….. 9 3.4 Disease-free Survival Analysis in Stage I and IA Adenocarcinomas…………………………………………………………………….. 10 3.5 EGFR TKI Treatment after Initial Relapse in Small Solitary Lung Adenocarcinomas…………………………………………………………………….. 11 3.6 Patient Characteristics in Small Synchronous Multiple Lung Adenocarcinomas………………………………………………….…………………. 11 3.7 Correlation of Genetic Mutations with Clinicopathologic Features and Clonality Assessment in Small Synchronous Multiple Lung Adenocarcinomas…………………………………………………………………….. 12 3.8 Clonality Analysis Using Mutations in EGFR/p53/ KRAS in Small Synchronous Multiple Lung Adenocarcinomas………………………………… 13 3.9 Correlation Between Clinicopathologic Features and Disease-free Survival in Small Synchronous Multiple Lung Adenocarcinomas…………… 14 Chapter 4 Discussion………………………………………………………………….. 15 4.1 Small Solitary Lung Adenocarcinoma………………………………………….. 15 4.2 Small Synchronous Multiple Lung Adenocarcinomas………………………. 18 Chapter 5 Conclusions………………………………………………………………... 23 References…………………………………………………………………………………. 25 圖目錄 圖一:CT image and sequencing chromatogram of EGFR/p53 mutation in a small moderately differentiated adenocarcinoma (case 62) …………………… 31 圖二:Kaplan-Meier survival curves in 163 surgically resected stage I lung adenocarcinomas ≤ 2 cm in maximal dimension………………………………… 32 圖三:Correlation of EGFR mutation with TKI treatment response in 30 patients with tumor relapse…………………………………………………………… 33 圖四:Representative results of CT imaging, histological type, and sequencing chromatogram………………………………………………………………………. 34 圖五:Kaplan-Meier survival curves in synchronous multiple lung adenocarcinomatous tumors ≤ 2 cm in maximal dimension………………….. 36 圖六:Algorism of postoperative management in surgical resected node-negative lung adenocarcinomas ≤ 2 cm in maximal dimension………………. 37 圖七:Algorism of management in synchronous multiple lung adenocarcinomas ≤ 2 cm in maximal dimension………………………………… 38 表目錄 表一:Clinicopathologic Characteristics of Patients with Small Solitary Adenocarcinoma…………………………………………………………………………. 39 表二:Mutations Detected in EGFR Genes in Patients with Small Solitary Adenocarcinoma…………………………………………………………………………. 41 表三:Mutations Detected in p53 Genes in Patients with Small Solitary Adenocarcinoma…………………………………………………………………………. 43 表四:The Association between Genetic Mutations and Clinicopathologic Characteristics in Small Solitary Lung Adenocarcinomas……………………….. 45 表五:Clinicopathologic Characteristics of Patients with Two Different Classical EGFR Mutations in Small Solitary Lung Adenocarcinomas……………………… 47 表六:Disease-free Survival Analysis for Relapse in Patients with Pathologic Stage I and IA Small Adenocarcinoma……………………………………………… 49 表七:Clinicopathologic Characteristics of Patients with Small Synchronous Multiple Lung Adenocarcinomas……………………………………………………….51 表八:Frequency of p53, EGFR and KRAS Mutation in relation to Clinical Variables and Pathologic Characteristics in Small Synchronous Multiple Lung Adenocarcinomas………………………………………………………………………... 54 表九:Clinicopathologic Characteristics of Patients with Same Clonality and Different Clonality between Tumors in Small Synchronous Multiple Lung Adenocarcinomas... …………………………………………………………………….. 56 表十:Univariate Survival Analysis of Clinicopathologic Features in Patients with Small Synchronous Multiple Lung Adenocarcinomas……………………… 58 表十一:Multivariate Survival Analysis of Clinicopathologic Features in Patients with Small Synchronous Multiple Lung Adenocarcinomas……………………… 60 | |
dc.language.iso | en | |
dc.title | 小型單發性及同時多發性肺腺癌之臨床病理、基因表現與手術治療預後的相關性 | zh_TW |
dc.title | Clinicopathology and Genetic Profile of Small Solitary and Synchronous Multiple Lung Adenocarcinomas: Implication for Surgical Treatment | en |
dc.type | Thesis | |
dc.date.schoolyear | 102-2 | |
dc.description.degree | 博士 | |
dc.contributor.oralexamcommittee | 楊泮池(Pan-Chyr Yang),陳志毅(Chih-Yi Chen),施金元(Jin-Yuan Shih),吳振都(Chen-Tu Wu) | |
dc.subject.keyword | 早期肺癌,肺腺癌,同時多發性肺癌,epidermal growth factor receptor,KRAS,p53, | zh_TW |
dc.subject.keyword | early stage lung cancer,epidermal growth factor receptor,KRAS,lung adenocarcinoma,p53,synchronous multiple lung cancers, | en |
dc.relation.page | 60 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2014-05-01 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 病理學研究所 | zh_TW |
顯示於系所單位: | 病理學科所 |
文件中的檔案:
檔案 | 大小 | 格式 | |
---|---|---|---|
ntu-103-1.pdf 目前未授權公開取用 | 12.71 MB | Adobe PDF |
系統中的文件,除了特別指名其著作權條款之外,均受到著作權保護,並且保留所有的權利。