Research and Our Work

研究・実績

基礎研究

１．研究の背景

肺癌は喫煙が主な原因とされていますが、日本の肺癌患者は男性の約40％、女性の約80%が非喫煙者となっています。非喫煙者肺腺癌の50-60%に上皮性成長因子受容体（epidermal growth factor receptor: EGFR）遺伝子変異が認められ、この遺伝子は肺癌の発癌とその進展に関与しており、それらに対してゲフィチニブなどのEGFRチロシンキナーゼ阻害剤（TKI）の有用性が示されています。しかしながら、その奏効期間は平均約1年で耐性となるため新たな治療法の開発が望まれています。我々は、EGFR遺伝子改変マウスを開発し、その進展にはEGFR下流のJAK2/STAT3やAKT/mTOR経路の活性化、および血管新生が関与していることをこれまで報告してきました。

以下にこれまでの研究内容の一部を紹介いたします。

２．目的

活性型EGFR遺伝子変異肺癌細胞株、異種移植モデル、およびEGFR遺伝子改変マウスにおける、各種分子標的薬剤とシグナル伝達機構を解析し、EGFR-TKI耐性解除に関する研究を行っている。

３．対象と方法

1) EGFR遺伝子変異細胞株

EGFR-TKIの耐性株は、PC-9（EGFR変異 exon 19欠失）を親株として当科で樹立された4つの耐性株RPC-9（T790M）、PC-9/Van-R（T790M + MET増幅 + HGF増幅）、PC-9/ER3（JAK2/STAT3発現増強）およびPC-9/GR（SRC発現増強）を用いる。薬剤はJAK2/STAT3阻害剤（JSI-124、AZD1480）、EGFRとVEGFRの両阻害剤（バンデタニブ）、第2世代EGFR-TKI（アファチニブ）、SRC阻害剤（ダサチニブ）、mTOR阻害剤（エベロリムス）などの各種阻害薬を用いて薬剤耐性の克服について検討した。

2) 異種移植モデル

BALB/cAJcl-nu雄5週齢のヌードマウスを2週間予備飼育した後、各腫瘍細胞株を2 x 106個ずつ皮下投与し、異種移植モデルを作製する。約2週間後より腫瘍が確認されるので、腫瘍が0.05cm3になったところで、3群に分け、プラセボ、各種薬剤（低用量と高用量）を投与する。飼育中、腫瘍径の測定を行い、6週間観察する。2週毎に各群2匹ずつsacrificeを行う。組織をホルマリン固定しパラフィン包埋を行い、検体の連続切片を作成しHE染色および免疫組織染色とWestern blottingで蛋白発現を確認する。

3) 遺伝子改変マウス

exon 19欠失とexon 21 L858Rの2系統のEGFR遺伝子改変マウスを用いて、各種薬剤を投与し発癌抑制効果を検討する。マウス3週齢各系統をコントロール群と薬剤投与群とする。1週毎に各群のマウスの体重測定を行い、全身状態を観察する。10週後（15週齢）にsacrificeし、表面から肺腫瘍数と腫瘍サイズを測定する。腫瘍組織はホルマリン固定パラフィン包埋として保存し、EGFR関連蛋白および新生血管の解析を行う。

４．研究成果

ROR1を標的としたOsimertinib併用によるEGFR変異陽性細胞への治療効果

ROR1を阻害することにより活性型EGFR変異（PC-9）、各EGFR-TKI耐性株（RPC-9, PC9/ER3, PC9/GR）ともに有意な成長阻害効果を認めた。ROR1阻害により細胞形態はやや凝集を認めた。

Flow cytometryにてsiROR曝露後72時間でアポトーシスを評価すると、早期と後期いずれのアポトーシスも増加していた。Caspase3, PARPの増加も認めた。ROR1阻害によりアポトーシスによる細胞死が誘導されていると考えられた。

またROR1阻害による遺伝子発現をマイクロアレイにて網羅的に検討した結果、75の遺伝子が有意に発現低下していた。そのうち6つの遺伝子（TGF-β2, AXL, CDH2, PARP1, PEG10, TYMS）に着目し更に検討を進めている。

また、ROR1阻害とOsimertinibの併用効果の検討において、活性型変異を有するPC-9、EGFR-TKI耐性株であるRPC-9と PC9/GRにおいて有意な相乗効果を認めた。

EGFR遺伝子変異陽性細胞の耐性克服においてROR1阻害との併用が治療戦略のひとつとなりうる可能性が示唆された。

Reference
Nakagawa N, Miyake N, Ochi N, Yamane H, Takeyama M, Nagasaki Y, et al. Targeting ROR1 in combination with osimertinib in EGFR mutant lung cancer cells. Exp Cell Res 2021;409:112940.

JAK2活性化によるEGFR-TKI獲得耐性

PC-9/ER3では、非受容型チロシンリン酸化酵素であるJAK2の活性化が認められ、エルロチニブによりリン酸化EGFRは抑制されたものの、EGFR下流シグナルのAKTは不活化されなかった。JAK2阻害剤であるJSI-124とエルロチニブの併用によりPC-9/ER3のJAK2並びにAKTの活性化が抑制され、エルロチニブに対する感受性の回復が得られた（右図上）。

siRNAでJAK2を抑制することでも同様の知見を得た。また、マウスの異種移植モデルを用いてJSI-124とエルロチニブ併用によりPC-9/ER3の有意な腫瘍縮小効果も示した（右図下）。

これらの結果は、JAK2の活性化がエルロチニブの獲得耐性に部分的に関与していることが示唆された。

Reference
Daijiro Harada, Nagio Takigawa, Nobuaki Ochi, Katsuyuki Kiura, et al. JAK2-related pathway induces acquired erlotinib resistance in lung cancer cells harboring an　epidermal growth factor receptor activating mutation. Cancer Science 103, 1795-1802, 2012.

PTEN欠失EGFR遺伝子変異肺がんにおけるバンデタニブの有効性

PTEN欠失のEGFR遺伝子変異を有する肺癌細胞株を用いた異種移植モデルではゲフィチニブと比較してバンデタニブで明らかな腫瘍抑制効果を認めた（図）。EGFR遺伝子変異を有するPTEN欠失肺癌細胞株においてバンデタニブは有用であることが示唆された。

Reference
Hiromasa Takeda, Nagio Takigawa, Nobuaki Ochi, Katsuyuki Kiura, et al. Vandetanib is effective in EGFR-mutant lung cancer cells with PTEN deficiency. Experimental Cell Research 319, 417-423, 2013.

EGFR-TKI耐性に対するEGFR-TKIと血管新生阻害薬併用効果

exon 19欠失EGFR遺伝子改変マウスに対して、アファチニブとゲフィチニブをそれぞれ4週間投与したところ、アファチニブ投与群において腫瘍は少ない傾向にあった。病理組織像ではゲフィチニブ投与群で明らかな結節腫瘍の残存が認められた。生存期間を比較したところ、アファチニブはゲフィチニブよりも生存期間を有意に延長した（右図上）。

EGFR-TKI耐性細胞株の異種移植モデルでは、アファチニブとベバシズマブの併用投与は、各単剤投与よりも強い抗腫瘍効果を示した（右図下）。

アファチニブはゲフィチニブよりも有用であり、耐性に対してもベバシズマブとの併用が有用であることが示唆された。

Reference
Takashi Ninomiya, Nagio Takigawa, Nobuaki Ochi, Katsuyuki Kiura, et al. Afatinib prolongs survival compared with gefitinib in an epidermal growth factor receptor-driven lung cancer model. Mol Cancer Ther 12:589-597, 2013.

AZD1480のEGFR遺伝子変異陽性細胞に対する治療効果

AZD1480はゲフィチニブ感受性および耐性細胞株に同等の効果を示した。ゼノグラフトモデルにおいてAZD1480は、血管新生を抑制し腫瘍縮小効果を呈した。遺伝子改変マウスにAZD1480を投与したところ、1 mm以上の肺の腫瘍数（0.37 ± 0.18）は、対照群（2.25 ± 0.53）に比し有意に減少した。さらに、マウスの生存期間中央値も、投与群（217日）が対照群（106日）に比し有意に延長した（図）。AZD1480は、活性型EGFR遺伝子変異を有する肺癌に対して効果が期待できることが示唆された。

Reference
Toshi Murakami, Nagio Takigawa, Nobuaki Ochi, Katsuyuki Kiura, et al. Effect of AZD1480 in an epidermal growth factor receptor-driven lung cancer model. Lung Cancer 83: 30-36. 2014.

SRCを介したERK再活性化によるEGFR-TKI耐性メカニズム

PC9-GRではゲフィチニブによりEGFRシグナル経路が一旦は抑制されたが、SRCによるERK再活性化が誘導された。ダサチニブとの併用により、PC9-GR はin vitro（図上）でもin vivo（図下）でもゲフィチニブへの感受性が回復した。以上より、SRCを介したERK再活性化が新たなゲフィチニブ獲得耐性機序に関与している可能性が示唆され、ゲフィチニブとSRC阻害剤の併用がこの耐性克服に有効であると考えられた。

Reference
Nobuaki Ochi, Nagio Takigawa, Katsuyuki Kiura, et al. Src mediates ERK reactivation in gefitinib resistance in non-small cell lung cancer. Exp Cell Res 322: 168-177, 2014.

活性型EGFR遺伝子変異陽性肺がんに対するエベロリムスの有効性

エベロリムスに対する感受性は、EGFR遺伝子変異の有無に関わらずほぼ同等であった。L858R変異を有するEGFR遺伝子改変マウスに5週齢から20週齢までエベロリムスを投与したところ、肺表面の腫瘍数は有意に抑制された。さらにエベロリムスを長期継続投与することにより、有意な生存期間の延長が認められた（図）。

エベロリムスはin vitroではアポトーシスとオートファジーを誘導していた。しかしながら、EGFR遺伝子改変マウスにおいてはアポトーシスおよびオートファジーは確認されず、血管新生が抑制されていた。エベロリムスは血管新生を抑制することにより、活性型EGFR遺伝子変異を有する肺癌への有効性が示唆された。

Reference
Masayuki Yasugi, Nagio Takigawa, Nobuaki Ochi, Katsuyuki Kiura, et al. Everolimus prolonged survival in transgenic mice with EGFR-driven lung tumors. Exp Cell Res 326: 201-209, 2014.

臨床研究

免疫チェックポイント阻害薬の治療効果に対する抗生剤治療の影響

免疫チェックポイント阻害薬（ICI）は様々な癌腫における必須の治療手段となっているが、近年、ICI治療に対する抗生剤の負の影響がいくつも報告されている。その確定的な部分は未だ不明確であるが、PD-L1発現レベルとの関連について検討した。

531症例を対象とした後ろ向き検討により、抗生剤使用群でOSが有意に短縮していた。一方でPFSは短縮傾向を認めたが有意ではなかった。PD-L1発現量が明らかな265症例に絞った解析でも同様の結果であった。

多変量解析では、良好な全身状態（PS2未満）、PD-L1高発現（50%以上）、ドライバー遺伝子変異陰性が有意に良好なPFSと関連していた。OSではPSとPD-L1高発現との関連が有意であった。

ICI治療前後の抗生剤使用とPD-L1発現レベルの関連について検討した。PD-L1高発現群において、抗生剤の使用によりPFS, OSともにより有意に短縮を認めた。

Reference
Ochi N, Ichihara E, Takigawa N, Harada D, Inoue K, Shibayama T, et al. The effects of antibiotics on the efficacy of immune checkpoint inhibitors in patients with non-small-cell lung cancer differ based on PD-L1 expression. Eur J Cancer 2021;149:73–81.

悪性リンパ腫における薬剤性間質性肺炎のバイオマーカーについての検討

悪性リンパ腫患者における薬剤性肺障害の診断的バイオマーカーとしてのKL-6とTARC/CCL17の有用性について比較検討した。悪性リンパ腫症例のうち２２．２％の症例で薬剤性肺障害を発症していた。すべての症例で治療中止とステロイド治療により速やかに改善が得られていた。

KL-6とTARC/CCL17の感度はほぼ同程度であったが、KL-6の平均血中濃度は肺障害発症前と比較して有意に上昇していた。

薬剤性肺障害は初回のリツキシマブ併用CHOP-likeレジメンで多く認めた。

TARC/CCL17とKL-6はpredictive biomarkerとしては同程度と考えられたが、KL-6のほうがより特異的であった。

Reference
Yamane H, Ochi N, Nagasaki Y, Yamagishi T, Honda Y, Nakagawa N, et al. Drug-induced interstitial lung disease in the treatment of malignant lymphoma as a potential diagnostic marker: a comparison of serum Krebs von Lungen-6 and thymus and activation-regulated chemokine/CC chemokine ligand 17. Ther Clin Risk Manag 2018;14:1457–1465.

業績一覧

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Yamane H, Monobe Y, Tanikawa T, Ochi N, Honda Y, Kawamoto H, et al. Herpetic esophagitis following bendamustine-containing regimen. Ther Clin Risk Manag 2016;12:883–886.
Oda N, Hotta K, Yoshioka H, Kudo K, Ichihara E, Kato Y, et al. Potential influence of being overweight on the development of hepatic dysfunction in Japanese patients with EGFR-mutated non-small cell lung cancer undergoing gefitinib monotherapy: the Okayama Lung Cancer Study Group experience. Cancer Chemother Pharmacol 2016;78:941–947.
Ochi N, Yamane H, Honda Y, Takigawa N. Dropped Head Syndrome Following Mantle Radiation Therapy. Intern Med 2016;55:421–422.
Ochi N, Kawamoto H, Monobe Y, Takigawa N. Cytomegalovirus Colitis in a Lung Cancer Patient. Intern Med 2016;55:2313–2314.
Ochi N, Isozaki H, Takeyama M, Singer JW, Yamane H, Honda Y, et al. Synergistic effect of pacritinib with erlotinib on JAK2-mediated resistance in epidermal gowth factor receptor mutation-positive non-small cell lung Cancer. Exp Cell Res 2016;344:194–200.
Nagasaki Y, Yamane H, Ochi N, Honda Y, Takigawa N. High Uptake of FDG Along a Biliary Stent. Clin Nucl Med 2016;41:890–891.
Minami D, Takigawa N, Watanabe H, Ninomiya T, Kubo T, Ohashi K, et al. Safety and discomfort during bronchoscopy performed under sedation with fentanyl and midazolam: a prospective study. Jpn J Clin Oncol 2016;46:871–874.
Minami D, Takigawa N, Oda N, Ninomiya T, Kubo T, Ohashi K, et al. Endobronchial ultrasound-guided transbronchial needle aspiration of hilar and mediastinal lymph nodes detected on 18F-fluorodeoxyglucose positron emission tomography/computed tomography. Jpn J Clin Oncol 2016;46:529–533.
Kudo K, Hotta K, Bessho A, Nogami N, Kozuki T, Kuyama S, et al. Development of a skin rash within the first week and the therapeutic effect in afatinib monotherapy for EGFR-mutant non-small cell lung cancer (NSCLC): Okayama Lung Cancer Study Group experience. Cancer Chemother Pharmacol 2016;77:1005–1009.
Kubo T, Fujiwara K, Hotta K, Okada T, Kuyama S, Harita S, et al. A phase II study of topotecan and cisplatin with sequential thoracic radiotherapy in elderly patients with small-cell lung cancer: Okayama Lung Cancer Study Group 0102. Cancer Chemother Pharmacol 2016;78:769–774.
Klionsky DJ, Abdelmohsen K, Abe A, Abedin MJ, Abeliovich H, Acevedo Arozena A, et al. Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 2016;12:1–222.
Isozaki H, Ichihara E, Takigawa N, Ohashi K, Ochi N, Yasugi M, et al. Non-Small Cell Lung Cancer Cells Acquire Resistance to the ALK Inhibitor Alectinib by Activating Alternative Receptor Tyrosine Kinases. Cancer Res 2016;76:1506–1516.
Isozaki H, Hotta K, Ichihara E, Takigawa N, Ohashi K, Kubo T, et al. Protocol Design for the Bench to Bed Trial in Alectinib-Refractory Non-Small-Cell Lung Cancer Patients Harboring the EML4-ALK Fusion Gene (ALRIGHT/OLCSG1405). Clin Lung Cancer 2016;17:602–605.
Hotta K, Sasaki J, Saeki S, Takigawa N, Katsui K, Takayama K, et al. Gefitinib Combined With Standard Chemoradiotherapy in EGFR-Mutant Locally Advanced Non-Small-Cell Lung Cancer: The LOGIK0902/OLCSG0905 Intergroup Study Protocol. Clin Lung Cancer 2016;17:75–79.
Fukazawa T, Guo M, Ishida N, Yamatsuji T, Takaoka M, Yokota E, et al. SOX2 suppresses CDKN1A to sustain growth of lung squamous cell carcinoma. Sci Rep 2016;6:20113.
Yamane H, Ochi N, Yamagishi T, Takigawa N, Maeda Y. Progressive paraplegia caused by recurrence of mantle-cell lymphoma with atypical spinal magnetic resonance imaging features. J Cancer Res Ther 2015;11:1036.
Yamane H, Ochi N, Yamagishi T, Honda Y, Takeyama M, Takigawa N. Circulating thymus and activation-regulated chemokine/CC chemokine ligand 17 is a strong candidate diagnostic marker for interstitial lung disease in patients with malignant tumors: a result from a pilot study. Ther Clin Risk Manag 2015;11:949–959.
Yamane H, Ochi N, Honda Y, Takigawa N. PET Superscan Caused by Lung Cancer. Intern Med 2015;54:2951.
Yamane H, Isozaki H, Takeyama M, Ochi N, Kudo K, Honda Y, et al. Programmed cell death protein 1 and programmed death-ligand 1 are expressed on the surface of some small-cell lung cancer lines. Am J Cancer Res 2015;5:1553–1557.
Yamane H, Fukuda N, Nishino K, Yoshida K, Ochi N, Yamagishi T, et al. Non-occlusive mesenteric ischemia after splenic metastasectomy for small-cell lung cancer. Intern Med 2015;54:743–747.
Yamagishi T, Ochi N, Yamane H, Kuribayashi F, Takigawa N. A 60-year-old asymptomatic woman with pulmonary lesions and cervical lymphadenopathy. Chest 2015;147:e48–e51.
Nogami N, Takigawa N, Hotta K, Segawa Y, Kato Y, Kozuki T, et al. A phase II study of cisplatin plus S-1 with concurrent thoracic radiotherapy for locally advanced non-small-cell lung cancer: the Okayama Lung Cancer Study Group Trial 0501. Lung Cancer 2015;87:141–147.
Minami D, Takigawa N, Morichika D, Kubo T, Ohashi K, Sato A, et al. Endobronchial ultrasound-guided transbronchial biopsy with or without a guide sheath for diagnosis of lung cancer. Respir Investig 2015;53:93–97.
Minami D, Takigawa N, Kato Y, Kudo K, Isozaki H, Hashida S, et al. Downregulation of TBXAS1 in an iron-induced malignant mesothelioma model. Cancer Sci 2015;106:1296–1302.
Isozaki H, Takigawa N, Kiura K. Mechanisms of Acquired Resistance to ALK Inhibitors and the Rationale for Treating ALK-positive Lung Cancer. Cancers (Basel) 2015;7:763–783.
Isoda R, Yamane H, Nezuo S, Monobe Y, Ochi N, Honda Y, et al. Successful palliation for an aged patient with primary pericardial mesothelioma. World J Surg Oncol 2015;13:273.
Ishida N, Fukazawa T, Maeda Y, Yamatsuji T, Kato K, Matsumoto K, et al. A novel PI3K inhibitor iMDK suppresses non-small cell lung Cancer cooperatively with A MEK inhibitor. Exp Cell Res 2015;335:197–206.
Ichihara E, Hotta K, Nogami N, Kuyama S, Kishino D, Fujii M, et al. Phase II trial of gefitinib in combination with bevacizumab as first-line therapy for advanced non-small cell lung cancer with activating EGFR gene mutations: the Okayama Lung Cancer Study Group Trial 1001. J Thorac Oncol 2015;10:486–491.
Hotta K, Ninomiya K, Takigawa N, Tanimoto M, Kiura K. Reappraisal of short-term low-volume hydration in cisplatin-based chemotherapy; hoping for it as a public domain. Jpn J Clin Oncol 2015;45:603–604.
Hotta K, Kato Y, Leighl N, Takigawa N, Gaafar RM, Kayatani H, et al. Magnitude of the benefit of progression-free survival as a potential surrogate marker in phase 3 trials assessing targeted agents in molecularly selected patients with advanced non-small cell lung cancer: systematic review. PLoS One 2015;10:e0121211.
Yasugi M, Takigawa N, Ochi N, Ohashi K, Harada D, Ninomiya T, et al. Everolimus prolonged survival in transgenic mice with EGFR-driven lung tumors. Exp Cell Res 2014;326:201–209.
Yamane H, Ochi N, Yamagishi T, Takigawa N. Guidelines for long-term steroid therapy in end-of-life palliative care. J Clin Oncol 2014;32:607–608.
Yamane H, Ochi N, Yamagishi T, Takigawa N. Fibrin sheath following pleurodesis. BMJ Case Rep 2014;2014:bcr2013203047.
Yamane H, Ochi N, Isozaki H, Yamagishi T, Honda Y, Takigawa N. Skin involvement in diffuse large B-cell lymphoma detected using positron emission tomography. Thorac Cancer 2014;5:581–582.
Yamamoto H, Higasa K, Sakaguchi M, Shien K, Soh J, Ichimura K, et al. Novel germline mutation in the transmembrane domain of HER2 in familial lung adenocarcinomas. J Natl Cancer Inst 2014;106:djt338.
Yamagishi T, Shimizu K, Ochi N, Yamane H, Irei I, Sadahira Y, et al. Histological comparison between preoperative and surgical specimens of non-small cell lung cancer for distinguishing between “squamous” and “non-squamous” cell carcinoma. Diagn Pathol 2014;9:103.
Yamagishi T, Ochi N, Yamane H, Takigawa N. Neurogenic pulmonary edema after subarachnoid hemorrhage. J Emerg Med 2014;46:683–684.
Yamagishi T, Ochi N, Yamane H, Hasebe S, Takigawa N. Epiphora in lung cancer patients receiving docetaxel: a case series. BMC Res Notes 2014;7:322.
Wada H, Isobe M, Kakimi K, Mizote Y, Eikawa S, Sato E, et al. Vaccination with NY-ESO-1 overlapping peptides mixed with Picibanil OK-432 and montanide ISA-51 in patients with cancers expressing the NY-ESO-1 antigen. J Immunother 2014;37:84–92.
Ochi N, Yamane H, Hotta K, Fujii H, Isozaki H, Honda Y, et al. Cisplatin-induced hyponatremia in malignancy: comparison between brand-name and generic formulation. Drug Des Devel Ther 2014;8:2401–2408.
Ochi N, Takigawa N, Harada D, Yasugi M, Ichihara E, Hotta K, et al. Src mediates ERK reactivation in gefitinib resistance in non-small cell lung cancer. Exp Cell Res 2014;322:168–177.
Ochi N, Goto D, Yamane H, Yamagishi T, Honda Y, Monobe Y, et al. Obstructive jaundice caused by intraductal metastasis of lung adenocarcinoma. Onco Targets Ther 2014;7:1847–1850.
Murakami T, Takigawa N, Ninomiya T, Ochi N, Yasugi M, Honda Y, et al. Effect of AZD1480 in an epidermal growth factor receptor-driven lung cancer model. Lung Cancer 2014;83:30–36.
Minami D, Takigawa N, Inoue H, Hotta K, Tanimoto M, Kiura K. Rapid on-site evaluation with BIOEVALUATOR(®) during endobronchial ultrasound-guided transbronchial needle aspiration for diagnosing pulmonary and mediastinal diseases. Ann Thorac Med 2014;9:14–17.
Kojima K, Kato K, Fukazawa T, Morita I, Takigawa N, Monobe Y, et al. A case of autoimmune pulmonary alveolar proteinosis appearing as a localized ground-glass opacity. Jpn J Radiol 2014;32:657–660.
Isozaki H, Yasugi M, Takigawa N, Hotta K, Ichihara E, Taniguchi A, et al. A new human lung adenocarcinoma cell line harboring the EML4-ALK fusion gene. Jpn J Clin Oncol 2014;44:963–968.
Hotta K, Kiura K, Tabata M, Takigawa N, Tanimoto M, Ueoka H. A survey of Japanese thoracic oncologists’ perception of diagnostic and treatment strategies for EGFR mutant or EML4-ALK fusion non-small cell lung cancer. Chest 2014;146:e222–e225.
Harada D, Takigawa N, Kiura K. The Role of STAT3 in Non-Small Cell Lung Cancer. Cancers (Basel) 2014;6:708–722.
Aoe K, Takigawa N, Hotta K, Maeda T, Kishino D, Nogami N, et al. A phase II study of S-1 chemotherapy with concurrent thoracic radiotherapy in elderly patients with locally advanced non-small-cell lung cancer: the Okayama Lung Cancer Study Group Trial 0801. Eur J Cancer 2014;50:2783–2790.
Yamane H, Takigawa N. Thickened colon wall in follicular lymphoma. Int J Hematol 2013;97:549–550.
Yamane H, Ochi N, Yasugi M, Tabayashi T, Yamagishi T, Monobe Y, et al. Docetaxel for non-small-cell lung cancer harboring the activated EGFR mutation with T790M at initial presentation. Onco Targets Ther 2013;6:155–160.
Ochi N, Yamane H, Yamagishi T, Monobe Y, Takigawa N. Methotrexate-induced lymphoproliferative disease: Epstein-Barr virus-associated lymphomatoid granulomatosis. J Clin Oncol 2013;31:e348-350.
Minami D, Takigawa N, Hayakawa H, Mizuta M, Kudo K, Uchida K, et al. Usefulness of endobronchial ultrasound-guided transbronchial needle aspiration in distinguishing sarcoidosis from recurrent cancer in patients with lymphadenopathy after surgery. Jpn J Clin Oncol 2013;43:1110–1114.
Ichihara E, Hotta K, Takigawa N, Kudo K, Kato Y, Honda Y, et al. Impact of physical size on gefitinib efficacy in patients with non-small cell lung cancer harboring EGFR mutations. Lung Cancer 2013;81:435–439.
Hao H, Maeda Y, Fukazawa T, Yamatsuji T, Takaoka M, Bao X-H, et al. Inhibition of the growth factor MDK/midkine by a novel small molecule compound to treat non-small cell lung cancer. PLoS One 2013;8:e71093.
Yamane H, Ochi N, Tabayashi T, Takigawa N. Stewart-Treves syndrome after cervical cancer. Intern Med 2012;51:513.
Yamane H, Ochi N, Tabayashi T, Lu L, Yamagishi T, Monobe Y, et al. Elevated coagulation factor VIII plasma activity in a patient with lymphangiosarcoma. Intern Med 2012;51:3213–3215.
Ochi N, Yasugi M, Yamane H, Tabayashi T, Kawanaka N, Okimoto N, et al. Spontaneous expectoration of tumor tissue in a patient with adenocarcinoma of the lung. Respir Care 2012;57:1521–1523.
Ochi N, Yasugi M, Takigawa N. Asymptomatic double aortic arch with compressed oesophagus in an adult. BMJ Case Rep 2012;2012:bcr1220115315.
Yamane H, Ohsawa M, Shiote Y, Umemura S, Suwaki T, Shirakawa A, et al. Cavitary pulmonary involvement of diffuse large B-cell lymphoma transformed from extra nodal marginal zone B-cell lymphoma MALT type. Clin J Gastroenterol 2011;4:401–406.
Takigawa N, Kiura K, Kishimoto T. Medical treatment of mesothelioma: anything new? Curr Oncol Rep 2011;13:265–271.