Lung fibrosis caused by Gefitinib therapy for lung cancer with EGFR mutation

• Project/Area Number: 24590438
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Human pathology
• Research Institution: Japanese Foundation for Cancer Research (2013-2014); National Defense Medical College (2012)
• Principal Investigator: MATSUBARA Osamu 公益財団法人がん研究会, その他部局等, 研究員 (40107248)
• Co-Investigator(Kenkyū-buntansha): ISHIKAWA Yuichi がん研究所, 病理部, 部長 (80222975)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2013: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2012: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000)
• Keywords: 肺線維症 / 間質性肺炎 / 病理発生機序 / EGFR変異肺癌

Outline of Final Research Achievements

Gefitinib therapy is very effective for lung cancer with epithelial growth factor receptor (EGFR) mutation, but it sometimes causes interstitial pneumonia/lung fibrosis. The important pathohistology shows destruction of alveolar structures, activation of fibroblastic foci and an increase of myofibroblasts. We studied pathological materials of video-assisted thoracoscopic surgery (VATS) lung biopsy, using 20 cases including 5 Gefitinib therapy cases and 10 controls to examine molecular mechanism of activation.　Immunohistochemically myofobroblasts were positive for a-SMA, vimentin, desmin　and regenerated pneumocytes were positive for TGF-b and CTGF. Pneumocytes revealed apoptosis. Myofibroblasts are thought to appear by epithelial mesenchymal transformation (EMT). Proteome analysis showed the difference of protein expression of some proteins, such as annexin A3, plastin-2, Hsp 27 and Hsp 70. We now have examined again to confirm the results.

Research Products

• [Journal Article] The clinicopathological features associated with skip N2 metastases in patients with clinical stage IA non-small-cell lung cancer (2015)
  • Author(s): Gorai A, Sakao Y, Kuroda H, Uehara H, Mun M, Ishikawa Y, Nakagawa K, Masuda M, Okumura S
  • Journal Title: Eur J Cardiothorac Surg Volume: 47(4) Pages: 653-8
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] SEVERAL TOPICS OF PULMONARY VASCULITIS AND PULMONARY HEMORRHAGE SYNDROMES (2014)
  • Author(s): Matsubara O
  • Journal Title: Pathology Volume: Suppl 2
  • Peer Reviewed
• [Journal Article] Community-acquired lobar pneumonia caused by Pseudomonas aeruginosa infection in Japan: a case report with histological and immunohistochemical examination (2014)
  • Author(s): Takajo D, Iwaya K, Katsurada Y, Miyai K, Takasu A, Matsubara O, Sakamoto T, Tamai S, Tsuda H
  • Journal Title: Pathol Int Volume: 64(5) Pages: 224-30
  • Peer Reviewed / Open Access
• [Journal Article] The expression and clinical significance of connective tissue growth factor in advanced head and neck squamous cell cancer (2014)
  • Author(s): Kikuchi R, Kikuchi Y, Tsuda H, Maekawa H, Kozaki K, Imoto I, Tamai S, Shiotani A, Iwaya K, Sakamoto M, Sekiya T, Matsubara O
  • Journal Title: Hum Cell Volume: 27(3) Pages: 121-8
  • Peer Reviewed / Open Access
• [Journal Article] Pleuroparenchymal fibroelastosis as a series of airway complications associated with chronic graft-versus-host disease following allogeneic bone marrow transplantation (2014)
  • Author(s): Fujikura Y, Kanoh S, Kouzaki Y, Hara Y, Matsubara O, Kawana A
  • Journal Title: Intern Med Volume: 53(1) Pages: 43-6
  • NAID: 130003383776
  • Peer Reviewed / Open Access
• [Journal Article] Wide local extension and higher proliferation indices are characteristic features of symptomatic lobular neoplasias (LNs) and LNs with an early invasive component (2014)
  • Author(s): Katsurada Y, Yoshida M, Maeshima AM, Ikeda K, Shibata T, Kinoshita T, Matsubara O, Tsuda H
  • Journal Title: Histopathology Volume: 64(7 Pages: 994-1003
  • Peer Reviewed / Open Access
• [Journal Article] Fatty acid synthase overexpression in adult testicular germ cell tumors: potential role in the progression of non-seminomatous germ cell tumors (2014)
  • Author(s): Miyai K, Iwaya K, Asano T, Tamai S, Matsubara O, Tsuda H
  • Journal Title: Virchows Arch Volume: 464(2) Pages: 221-8
  • Peer Reviewed / Open Access
• [Journal Article] A Novel Mechanism of EML4-ALK Rearrangement Mediated by Chromothripsis in a Patient-Derived Cell Line (2014)
  • Author(s): Kodama T, Motoi N, Ninomiya H, Sakamoto H, Kitada K, Tsukaguchi T, Satoh Y, Nomura K, Nagano H, Ishii N, Terui Y, Hatake K, Ishikawa Y
  • Journal Title: J Thorac Oncol Volume: 9(11) Pages: 1638-46
  • Peer Reviewed / Open Access
• [Journal Article] Combined effects of asbestos and cigarette smoke on the development of lung adenocarcinoma: different carcinogens may cause different genomic changes (2014)
  • Author(s): Inamura K, Ninomiya H, Nomura K, Tsuchiya E, Satoh Y, Okumura S, Nakagawa K, Takata A, Kohyama N, Ishikawa Y
  • Journal Title: Oncol Rep Volume: 32(2) Pages: 475-82
  • Peer Reviewed / Open Access
• [Journal Article] A pilot study of adjuvant chemotherapy with irinotecan and cisplatin for completely resected high-grade pulmonary neuroendocrine carcinoma (large cell neuroendocrine carcinoma and small cell lung cancer) (2014)
  • Author(s): Kenmotsu H, Niho S, Ito T, Ishikawa Y, Noguchi M, Tada H, Sekine I, Watanabe S, Yoshimura M, Yamamoto N, Oshita F, Kubota K, Nagai K
  • Journal Title: Lung Cancer Volume: 84(3) Issue: 3 Pages: 254-8
  • DOI: 10.1016/j.lungcan.2014.03.007
  • Peer Reviewed / Open Access
• [Journal Article] Long noncoding RNA HOTAIR is relevant to cellular proliferation, invasiveness, and clinical relapse in small-cell lung cancer. (2014)
  • Author(s): Ono, H., Motoi, N., Nagano, H et al.
  • Journal Title: Cancer Medicine Volume: 3 MAR Issue: 3 Pages: 1-11
  • DOI: 10.1002/cam4.220
  • Peer Reviewed / Open Access
• [Journal Article] Reproducibility of histopathological diagnosis in poorly differentiated NSCLC: an international multiobserver study (2014)
  • Author(s): Thunnissen E, Noguchi M, Aisner S, Beasley MB, Brambilla E, Chirieac LR, Chung JH, Dacic S, Geisinger KR, Hirsch FR, Ishikawa Y, Kerr KM, Lantejoul S, Matsuno Y, Minami Y, Moreira AL, Pelosi G, Petersen I, Roggli V, Travis WD, Wistuba I, Yatabe Y, Dziadziuszko R, Witte B, Tsao MS, Nicholson AG
  • Journal Title: J Thorac Oncol Volume: 9(9) Pages: 1354-62
  • Peer Reviewed / Open Access
• [Journal Article] A subset of small cell lung cancer with low neuroendocrine expression and good prognosis: a comparison study of surgical and inoperable cases with biopsy. (2014)
  • Author(s): Hamanaka, W, Motoi, N, Ishikawa, S., et al.
  • Journal Title: Human Pathology Volume: 45 Issue: 5 Pages: 1045-1056
  • DOI: 10.1016/j.humpath.2014.01.001
  • Peer Reviewed / Open Access
• [Journal Article] Pulmonary tumor thrombotic microangiopathy with circulatory failure treated with imatinib (2014)
  • Author(s): Ogawa A, Yamadori I, Matsubara O, Matsubara H
  • Journal Title: Intern Med Volume: 52(17) Pages: 1927-30
  • NAID: 130003365790
  • Peer Reviewed / Open Access
• [Journal Article] Pleuroparenchymal fibroelastosis as a series of airway complications associated with chronic graft-versus-host disease following allogeneic bone marrow transplantation. (2014)
  • Author(s): Fujikura Y, Kanoh S, Kouzaki Y, Hara Y, Matsubara O, Kawana A.
  • Journal Title: Intern Med Volume: 53(1) Pages: 43-46
  • NAID: 130003383776
  • Peer Reviewed
• [Journal Article] Wide local extension and higher proliferation indices are characteristic features of symptomatic lobular neoplasias (LNs) and LNs with an early invasive component. (2014)
  • Author(s): Katsurada Y, Yoshida M, Maeshima AM, Ikeda K, Shibata T, Kinoshita T, Matsubara O, Tsuda H.
  • Journal Title: Histopathology Volume: 64(7) Issue: 7 Pages: 994-1003
  • DOI: 10.1111/his.12356
  • Peer Reviewed
• [Journal Article] Fatty acid synthase overexpression in adult testicular germ cell tumors: potential role in the progression of non-seminomatous germ cell tumors. (2014)
  • Author(s): Miyai K, Iwaya K, Asano T, Tamai S, Matsubara O, Tsuda H.
  • Journal Title: Virchows Arch Volume: 464(2) Issue: 2 Pages: 221-228
  • DOI: 10.1007/s00428-013-1525-y
  • Peer Reviewed
• [Journal Article] Pulmonary tumor thrombotic microangiopathy with circulatory failure treated with imatinib. (2013)
  • Author(s): Ogawa A, Yamadori I, Matsubara O, Matsubara H
  • Journal Title: Intern Med Volume: 52(17) Pages: 1927-1930
  • NAID: 130003365790
  • Peer Reviewed
• [Journal Article] Allelotyping analysis suggesting a consecutive progression from intratubular germ cell neoplasia to seminoma and then to embryonal carcinoma of the adult testis. (2013)
  • Author(s): Miyai K, Yamamoto S, Iwaya K, Asano T, Tamai S, Tsuda H, Matsubara O.
  • Journal Title: 6. Hum Pathol Volume: 44(10) Pages: 2312-2322
  • Peer Reviewed
• [Journal Article] DJ-1 protein expression as a predictor of pathological complete remission after neoadjuvant chemotherapy in breast cancer patients. (2013)
  • Author(s): Kawate T, Iwaya K, Kikuchi R, Kaise H, Oda M, Sato E, Hiroi S, Matsubara O, Kohno N.
  • Journal Title: Breast Cancer Res Treat Volume: 139(1) Issue: 1 Pages: 51-59
  • DOI: 10.1007/s10549-013-2523-0
  • Peer Reviewed
• [Journal Article] A simple immunohistochemical panel comprising 2 conventional markers, Ki67 and p53, is a powerful tool for predicting patient outcome in luminal-type breast cancer. (2013)
  • Author(s): Kobayashi T, Iwaya K, Moriya T, Yamasaki T, Tsuda H, Yamamoto J, Matsubara O.
  • Journal Title: BMC Clin Pathol Volume: 13 Issue: 1 Pages: 5-16
  • DOI: 10.1186/1472-6890-13-5
  • Peer Reviewed
• [Journal Article] Diagnosis of Lung Cancer in Small Biopsies and Cytology: Implications of the 2011 International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society Classification (2013)
  • Author(s): Travis WD, Brambilla E, Noguchi M, Nicholson AG, Geisinger K, Yatabe Y, Ishikawa Y, et al.
  • Journal Title: Arch Pathol Lab Med. Volume: 137 Pages: 668-684
  • Peer Reviewed
• [Journal Article] Altered expression of p27(Kip1) -interacting cell-cycle regulators in the adult testicular germ cell tumors: potential role in tumor development and histological progression. (2012)
  • Author(s): Miyai K, Yamamoto S, Iwaya K, Asano T, Tamai S, Tsuda H, Matsubara O.
  • Journal Title: APMIS. Volume: 120 Issue: 11 Pages: 890-900
  • DOI: 10.1111/j.1600-0463.2012.02919.x
  • Peer Reviewed
• [Journal Article] Deficiency of interleukin-1 receptor antagonist promotes spontaneous femoral artery aneurysm formation in mice. (2012)
  • Author(s): Isoda K, Kitagaki M, Niida T, Kondo H, Matsubara O, Kikuchi M, Ohsuzu F, Adachi T.
  • Journal Title: Am J Pathol Volume: 180 Issue: 3 Pages: 1254-1263
  • DOI: 10.1016/j.ajpath.2011.11.028
  • Peer Reviewed
• [Journal Article] Loss of ARID1A protein expression occurs as an early event in ovarian clear-cell carcinoma development and frequently coexists with PIK3CA mutations. (2012)
  • Author(s): Yamamoto S, Tsuda H, Takano M, Tamai S, Matsubara O.
  • Journal Title: Mod Pathol. Volume: 25 Issue: 4 Pages: 615-624
  • DOI: 10.1038/modpathol.2011.189
  • Peer Reviewed
• [Journal Article] Distinct histopathology of acute onset or abrupt exacerbation of hypersensitivity pneumonitis. (2012)
  • Author(s): Hariri LP, Mino-Kenudson M, Shea B, Digumarthy S, Onozato M, Yagi Y, Fraire AE, Matsubara O, Mark EJ.
  • Journal Title: Hum Pathol. Volume: 43 Issue: 5 Pages: 660-608
  • DOI: 10.1016/j.humpath.2011.06.001
  • Peer Reviewed
• [Journal Article] RET, ROS1, and ALK fusions in lung cancer (2012)
  • Author(s): Takeuchi K, et al
  • Journal Title: Nature Medicine Volume: (In press) Issue: 3 Pages: 378-381
  • DOI: 10.1038/nm.2658
  • Peer Reviewed
• [Presentation] Adenocarcinoma in situ of the lung (2015)
  • Author(s): Matsubara O
  • Organizer: 10th Asia Pacific IAP Congress
  • Place of Presentation: Brisbane, Australia
  • Year and Date: 2015-06-04 – 2015-06-07
  • Invited
• [Presentation] Several topics of lung pathology (2015)
  • Author(s): Matsubara O
  • Organizer: 3rd Pacific Pathology Workshop
  • Place of Presentation: Suva, Fiji
  • Year and Date: 2015-05-08 – 2015-05-09
  • Invited
• [Presentation] Pathological role of fibroblastic foci and bronchiolar epithelial proliferation in IPF/UIP (2015)
  • Author(s): Matsubara O
  • Organizer: 104th US and Canadian Academy of Pathology
  • Place of Presentation: Boston, USA
  • Year and Date: 2015-03-22 – 2015-03-27
• [Presentation] Pulmonary neuroendocrine tumors (2014)
  • Author(s): Matsubara O
  • Organizer: 9th Asia Pacific Society for Molecular Immunohistology
  • Place of Presentation: Cebu, Phillipines
  • Year and Date: 2014-11-27 – 2014-11-28
  • Invited
• [Presentation] Pathology of pulmonary vasculitis (2014)
  • Author(s): Matsubara O
  • Organizer: International Congress of IAP
  • Place of Presentation: Bangkok, Thailand
  • Year and Date: 2014-10-05 – 2014-10-10
  • Invited
• [Presentation] Pulmonary Adenocarcinoma In Situ Is Not Simply A Precursor Of Invasive Tumor: Evidence By Status Of Smoking, Driver Mutations And Receptor Tyrosine Kinase Pathway Activation. (2014)
  • Author(s): Seijiro Sato, Noriko Motoi, Sakae Okumura, Osamu Matsubara, Masanori Tsuchida, Yuichi Ishikawa
  • Organizer: United States and Canadian Academy of Pathology (USCAP) 2014年Annual Meeting
  • Place of Presentation: San Diego, USA
• [Presentation] Blastomatoid Carcinosarcoma of the Lung: A Clinicopathological and Immunohistochemical Analysis of 13 Cases. (2014)
  • Author(s): Masaki Suzuki, Satoshi Ota, Yoshiaki Inayama, Osamu Matsubara, Eugene J. Mark, Yukio Nakatani
  • Organizer: United States and Canadian Academy of Pathology (USCAP) 2014年Annual Meeting
  • Place of Presentation: San Diego, USA
• [Presentation] SEVERAL TOPICS OF PULMONARY VASCULAR DISEASES (2013)
  • Author(s): O. Matsubara
  • Organizer: The 8th Asian Pacific Society of Molecular Immunohistochemistry Annual Meeting
  • Place of Presentation: Bangkok, Thailand
  • Invited
• [Presentation] Neuroendocrine Tumors of the Lung, molecular aspects and comparison with other organs (2013)
  • Author(s): O. Matsubara
  • Organizer: The 8th Aisa Pacific IAP Congress
  • Place of Presentation: Busan, Korea
  • Invited
• [Presentation] 多彩な肺の血管炎の病理Various forms of pulmonary vasculitides (2013)
  • Author(s): 松原修
  • Organizer: 第102回日本病理学会総会
  • Place of Presentation: 札幌
  • Invited
• [Presentation] Epithelial-mesenchymal transition (EMT) in active fibroblastic foci in IPF/UIP (2013)
  • Author(s): Matsubara O, Miyai K, Ishikawa Y, Nakatani Y, Mark EJ
  • Organizer: The 102nd Annual Meeting of the United States and Canadian Academy of Pathology
  • Place of Presentation: Baltimore, U.S.A.
• [Presentation] Pathology of pulmonary neuroendocrine tumor (2012)
  • Author(s): Matsubara O.
  • Organizer: The 7th Annual Scientific Meeting of the Asia Pacific Society for Molecular Immunohistology
  • Place of Presentation: Bali, Indonesia
  • Invited
• [Presentation] Predictive and therapeutic biomarkers in lung cancers. (2012)
  • Author(s): Matsubara O.
  • Organizer: The 29th International Congress of the International Acaademy of Pathology
  • Place of Presentation: Cape Town, South Africa
  • Invited
• [Book] 20 HHV-8 related lung neoplastic and nonneoplastic diseases. In: Fraire AE et al.ed. Viruses and the LUng (2014)
  • Author(s): Matsubara O, Mark EJ
  • Publisher: Springer
• [Book] Chapter 19 Pulmonary vasculitis and pulmonary hemorrhage syndromes. In: P. Hasleton and D.B. Flieder, ed. Spencer’s pathology of the Lung, sixth edition. (2013)
  • Author(s): Eugene J Mark and Osamu Matsubara
  • Publisher: Cambridge University Press, Cambridge
• [Book] Chapter 20 HHV-8-related Lung Neoplastic and Nonneoplastic Diseases. In: A.E. Fraire et al., ed. Viruses and the Lung. (2013)
  • Author(s): Osamu Matsubara and Eugene J Mark
  • Publisher: Springer, Heidelberg
• [Book] hapter 26 Molecular biology and pathology of lung cancer: Genotype-morphology correlation. In: Tan D, Lynch H ed. Principles of Molecular Diagnosis and Personalized Cancer Medicine (2013)
  • Author(s): Ishikawa Y, Matsubara O.
  • Publisher: Lippincott Williams & Wilkins
• [Book] Chapter 18. Pulmonary vasculitis and pulmonary hemorrhage syndromes. In: Hasleton P, Flieder D ed., The 6th edition Spencer’s Pathology of the Lung, (2013)
  • Author(s): Mark EJ, Smith RN, Niles JL, Sharma A, Matsubara O.
  • Publisher: Cambridge University Press
• [Book] 8. 肺の炎症性偽腫瘍（inflammatory pseudotumor）と炎症性筋線維芽細胞性腫瘍（Inflammatory myofibroblastic tumor) -疾患概念、臨床病理像、治療法、In: Annual Review 呼吸器2013 (2013)
  • Author(s): 松原修、菊池良子、河手敬彦、岩屋啓一、石川雄一、中谷行雄
  • Publisher: 中外医学社