研究者詳細 - 槇本　剛

論文 - 槇本　剛

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Efficacy of amivantamab, a bi-specific antibody targeting EGFR and MET, in ALK-rearranged non-small-cell lung cancer cell lines. 国際誌

Tatsuya Nishi, Ayako Morita, Naofumi Hara, Go Makimoto, Kiichiro Ninomiya, Masanori Fujii, Kammei Rai, Kadoaki Ohashi, Katsuyuki Hotta, Masahiro Tabata, Yosuke Togashi, Yoshinobu Maeda, Eiki Ichihara

Lung cancer (Amsterdam, Netherlands) 201 108415 - 108415 2025年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) are highly effective in treating ALK-rearranged non-small-cell lung cancer (NSCLC). However, at least 40% of patients develop acquired resistance during treatment. Adaptive or acquired resistance to ALK TKIs could be mediated through epidermal growth factor receptor (EGFR) and mesenchymal-epithelial transition factor (MET) signaling. Sixteen percent of acquired resistance cases are linked to bypass signaling. METHODS: In this study, we evaluated the effects of amivantamab, a bi-specific antibody targeting both EGFR and MET, on ALK-rearranged NSCLC cells. We investigated the effect of amivantamab on the ALK-rearranged NSCLC cell lines H3122, ABC-19, and ABC-11. RESULTS: Combining alectinib with amivantamab resulted in greater inhibition of cell growth inhibition in H3122 and ABC-19 cells compared to alectinib alone, but not in ABC-11 cells. EGFR TKI erlotinib showed similar efficacy in H3122 and ABC-19 cells, whereas MET TKI tepotinib was ineffective in both, suggesting that the efficacy of amivantamab is through EGFR inhibition. Unlike H3122 and ABC-19 cells, ABC-11 cells were resistant to EGFR/MET signaling inhibition. Interestingly, amivantamab enhanced alectinib efficacy against ABC-11 cells in the presence of peripheral blood mononuclear cells (PBMCs), despite showing no effect alone without PBMCs, suggesting action through non-signal inhibitory mechanisms. Finally, we treated alectinib-resistant cellswith alectinib, with or without amivantamab, and found that amivantamab restored the sensitivity of these cells to alectinib. CONCLUSION: The bi-specific antibody amivantamab, which targets EGFR and MET, enhanced the efficacy of alectinib through both signal and non-signal inhibitory mechanisms in ALK-rearranged NSCLC cells.

DOI： 10.1016/j.lungcan.2025.108415

A Prompt Diagnosis and Treatment of a Case of Nuclear Protein of the Testis Carcinoma Characterized by a Bronchial Lesion and High Serum Alpha-fetoprotein Level Following Genomic Testing.

Hiroaki Matsuura, Go Makimoto, Naohiro Oda, Kiichiro Ninomiya, Hisao Higo, Masanori Fujii, Kammei Rai, Eiki Ichihara, Kadoaki Ohashi, Katsuyuki Hotta, Masahiro Tabata, Yoshinobu Maeda

Internal medicine (Tokyo, Japan) 63 ( 19 ) 2655 - 2660 2024年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

Nuclear protein of the testis carcinoma (NUTC) is a rare and aggressive malignancy. We herein report a case of NUTC in the lung characterized by a bronchial lesion and elevated alpha-fetoprotein levels. A 35-year-old Japanese man presented to our institution with suspected advanced lung cancer based on a histological examination. Subsequently, next-generation sequencing (NGS) yielded a positive BRD4-NUTM1 fusion. In addition, positive NUT immunostaining of the lung biopsy specimen confirmed NUTC in the lungs. Systemic chemotherapy and radiotherapy showed a temporary response, with decreased serum alpha-fetoprotein levels. We highlight this case of a prompt diagnosis by NGS of NUTC in a young individual with a rapidly progressing tumor.

DOI： 10.2169/internalmedicine.2938-23

MET遺伝子増幅を認め、カプマチニブが著効した原発不明癌の1例

槇本剛, 田中孝明, 住井遼平, 表梨華, 二宮貴一朗, 安藤弥生, 前田嘉信, 田端雅弘

日本癌治療学会学術集会抄録集 62回 ICCJ3 - 3 2024年10月

A Case of Single-lung Transplant in a Patient with Mycobacterium avium Pulmonary Disease Successfully Treated with Amikacin Liposome Inhalation Suspension.

Taichi Ozeki, Hisao Higo, Hiroki Omori, Shunta Mori, Shin Tanaka, Go Makimoto, Kiichiro Ninomiya, Akihiko Taniguchi, Masanori Fujii, Kentaro Miyoshi, Kammei Rai, Eiki Ichihara, Kadoaki Ohashi, Seiichiro Sugimoto, Katsuyuki Hotta, Masahiro Tabata, Shinichi Toyooka, Yoshinobu Maeda, Nobuaki Miyahara

Internal medicine (Tokyo, Japan) 2024年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

A 55-year-old man presented to our hospital with idiopathic pulmonary fibrosis (IPF). He was registered with the Japan Organ Transplant Network the following year due to disease progression. Treatment with clarithromycin, ethambutol, and rifampicin for complications of Mycobacterium avium pulmonary disease was initiated, but sputum conversion could not be achieved. The administration of an amikacin liposome inhalation suspension (ALIS) resulted in sputum conversion, and single-lung transplantation was performed. ALIS therapy was continued after lung transplantation, and no M. avium disease was observed for 15 months. ALIS may cause M. avium pulmonary disease with additional indications for lung transplantation.

DOI： 10.2169/internalmedicine.3854-24

Response to Imatinib in a Patient With Gastric Adenocarcinoma With KIT Q556_K558 In-Frame Deletion: A Case Report. 国際誌

Kiichiro Ninomiya, Daisuke Ennishi, Kunio Okamoto, Midori Ando, Satoko Nakamura, Shuta Tomida, Yoshiyuki Ayada, Go Makimoto, Eiki Ichihara, Natsuko Okita, Shinichi Toyooka, Yoshinobu Maeda, Masahiro Tabata

JCO precision oncology 8 e2400228 2024年9月

A randomized, open-label phase II study on the preventive effect of goshajinkigan against peripheral neuropathy induced by paclitaxel-containing chemotherapy: The OLCSG2101 study protocol. 国際誌

Naoki Nakamura, Go Makimoto, Takaaki Tanaka, Yuka Kato, Isao Oze, Toshiyuki Kozuki, Toshihide Yokoyama, Hirohisa Ichikawa, Shoichi Kuyama, Naofumi Hara, Yoshinobu Maeda, Katsuyuki Hotta

Respiratory investigation 62 ( 5 ) 897 - 900 2024年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Paclitaxel (PTX) is an essential cytotoxic anticancer agent and a standard treatment regimen component for various malignant tumors, including advanced unresectable non-small cell lung cancer, thymic cancer, and primary unknown cancers. However, chemotherapy-induced peripheral neuropathy (CIPN) caused by PTX is a significant adverse event that may lead to chemotherapy discontinuation and deterioration of the quality of life (QOL). Although treatment modalities such as goshajinkigan (GJG), pregabalin, and duloxetine are empirically utilized for CIPN, there is no established evidence for an agent as a preventive measure. We designed a randomized phase II trial (OLCSG2101) to investigate whether prophylactic GJG administration can prevent the onset of CIPN induced by PTX. METHODS: This study was designed as a two-arm, prospective, randomized, multicenter phase II trial. The patients will be randomly assigned to either the GJG prophylaxis arm (Arm A) or the GJG non-prophylaxis arm (Arm B), using cancer type (lung cancer or not) and age (<70 years or not) as adjustment factors. A total of 66 patients (33 in each arm) will be enrolled. DISCUSSION: The results of this study may contribute to better management of CIPN, which can enable the continuation of chemotherapy and maintenance of the patient's QOL. ETHICS AND DISSEMINATION: Ethical approval was obtained from the certified review board of Okayama University (approval no. CRB21-005) on September 28, 2021. Results will be published in peer-reviewed journals and presented at national and international conferences. TRIAL REGISTRATION: Japan Registry of Clinical Trials (registration number jRCTs061210047).

DOI： 10.1016/j.resinv.2024.07.017

Two Cases of Cytomegalovirus Colitis During the Treatment of Immune Checkpoint Inhibitor-Associated Colitis. 国際誌

Masaya Iwamuro, Takehiro Tanaka, Go Makimoto, Eiki Ichihara, Sakiko Hiraoka

Cureus 16 ( 6 ) e63308 2024年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

Herein, we outlined two case reports of patients who developed cytomegalovirus colitis following the initiation of corticosteroid therapy for colitis as a result of immune-related adverse events (irAEs). For both patients, endoscopic findings were similar to those observed for patients with irAE colitis but were devoid of the characteristic features associated with cytomegalovirus colitis, including punched-out ulcers. Given the therapeutic disparities between these two conditions, it is imperative to distinguish between these conditions in clinical practice. When addressing exacerbations or refractory manifestations of irAE-associated colitis, clinicians should remain vigilant with regard to the potential for cytomegalovirus infection, even in the absence of punched-out ulcers in the colorectum.

DOI： 10.7759/cureus.63308

Concomitant osimertinib and antituberculosis therapy in an elderly patient with EGFR-mutated lung cancer and pulmonary tuberculosis: A case report. 国際誌

Hiroaki Matsuura, Hisao Higo, Tadahiro Kuribayashi, Akihiko Tamaoki, Takamasa Nakasuka, Mari Uno, Go Makimoto, Kiichiro Ninomiya, Masanori Fujii, Kammei Rai, Eiki Ichihara, Katsuyuki Hotta, Nobuaki Miyahara, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura, Kadoaki Ohashi

Thoracic cancer 15 ( 17 ) 1390 - 1394 2024年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

The concurrent incidence of lung cancer and tuberculosis is expected to escalate due to the projected growth in the older population. Combination therapy with osimertinib and antituberculosis drugs has not been well-established. We report a case of successful treatment involving the concomitant administration of osimertinib and antituberculosis drugs in an older patient, an 89-year-old female, diagnosed with epidermal growth factor receptor (EGFR)-mutant lung cancer and pulmonary tuberculosis. Accumulating evidence is warranted to develop an optimal treatment strategy for patients with lung cancer and tuberculosis.

DOI： 10.1111/1759-7714.15324

肝切除後の難治性気管支胆汁瘻に対してEndobronchial Watanabe Spigotの挿入が感染制御に有効であった1例

宇野真梨, 槇本剛, 藤智和, 大森洋樹, 肥後寿夫, 本倉優美, 田中孝明, 森俊太, 大西桐子, 二宮貴一朗, 頼冠名, 市原英基, 田端雅弘, 宮原信明, 堀田勝幸, 大橋圭明

気管支学 46 ( Suppl. ) S337 - S337 2024年5月

Effectiveness and safety of primary prophylaxis with G-CSF for lung cancer: a systematic review and meta-analysis to develop clinical practice guidelines for the use of G-CSF 2022

Eiki Ichihara, Nobuaki Ochi, Go Makimoto, Kenichiro Kudo, Daijiro Harada, Yukinori Ozaki, Hiroshi Nishio, Kenji Tsuchihashi, Yuji Miura, Makoto Endo, Shingo Yano, Dai Maruyama, Tetsuhiro Yoshinami, Nobuyuki Susumu, Munetaka Takekuma, Takashi Motohashi, Mamoru Ito, Eishi Baba, Keita Uchino, Takahiro Kimura, Yutaro Kamiyama, Shinji Nakao, Shinobu Tamura, Hitomi Nishimoto, Yasuhisa Kato, Atsushi Sato, Toshimi Takano, Toshio Kubo

International Journal of Clinical Oncology 29 ( 4 ) 355 - 362 2024年2月

Protracted coronavirus disease 2019 after chimeric antigen receptor-T cell therapy successfully treated with sequential multidrug therapy. 国際誌

Masahiro Yamashita, Hisao Higo, Nobuharu Fujii, Chiaki Matsumoto, Go Makimoto, Kiichiro Ninomiya, Masanori Fujii, Kammei Rai, Eiki Ichihara, Kadoaki Ohashi, Katsuyuki Hotta, Masahiro Tabata, Yoshinobu Maeda, Nobuaki Miyahara

Respiratory medicine case reports 51 102104 - 102104 2024年

記述言語：英語掲載種別：研究論文（学術雑誌）

A 56-year-old woman who received CD19 chimeric antigen receptor-T cell therapy for refractory diffuse large B-cell lymphoma developed severe coronavirus disease 2019 (COVID-19) and was treated with nirmatrelvir/ritonavir in April 2022. However, she experienced persistent fatigue and cough and fever in June. Computed tomography revealed bilateral ground-glass opacities (GGO), and the patient was treated with corticosteroids for organizing pneumonia after COVID-19. Partial improvement was observed, but new GGO appeared despite corticosteroid therapy. Genome analysis of severe acute respiratory syndrome coronavirus 2 detected Omicron variant BA.1.1.2, which was prevalent at the time of initial infection. The patient was diagnosed with protracted COVID-19 and was treated with remdesivir, molnupiravir, nirmatrelvir/ritonavir, and tixagevimab/cilgavimab. These treatments appeared to contribute to the improvement of protracted COVID-19.

DOI： 10.1016/j.rmcr.2024.102104

[Survival Mechanisms of Drug Tolerant Persister Cancer Cells against Targeted Anticancer Drugs].

Masataka Taoka, Go Makimoto, Kadoaki Ohashi

Gan to kagaku ryoho. Cancer & chemotherapy 50 ( 12 ) 1239 - 1245 2023年12月

記述言語：日本語掲載種別：研究論文（学術雑誌）

Persister cells constitute a subset of cancer cells that exhibit resistance to anticancer therapies. They evade anticancer drug-induced cell death by slowing down the cell cycle and transiently adapting to the drugs through multiple pathways. Subsequently, these persister cells function as reservoirs, leading cancer cells towards diverse and irreversible mechanisms of drug resistance. The causes of treatment resistance in persister cells have been reported to be primarily epigenetic changes, rather than irreversible genetic mutations. Acquisition of stem-like features, epithelial-to-mesenchymal transition, alterations in survival and apoptosis signaling, changes in metabolism, variations in the tumor microenvironment, and acquisition of immune escape mechanisms are reported to be involved in the survival of persister cells. Although various therapeutic interventions have been explored for each of these aspects, few have been clinically applied. In this article, we place a particular emphasis on EGFR lung cancer and persister cells. We discuss the reasons why EGFR tyrosine kinase inhibitors fail to achieve curative outcomes and consider the biological characteristics of persister cells. We also review an overview of potential therapeutic strategies to overcome persister cell-induced resistance.

扁平上皮癌転化を来したEGFR変異肺腺癌に対してサルベージ手術を施行した1例

藤井龍之介, 諏澤憲, 柳光剛志, 田中真, 橋本好平, 枝園和彦, 三好健太郎, 山本寛斉, 岡崎幹生, 杉本誠一郎, 豊岡伸一, 槇本剛

肺癌 63 ( 7 ) 1005 - 1005 2023年12月

扁平上皮癌転化を来したEGFR変異肺腺癌に対してサルベージ手術を施行した1例

藤井龍之介, 諏澤憲, 柳光剛志, 田中真, 橋本好平, 枝園和彦, 三好健太郎, 山本寛斉, 岡崎幹生, 杉本誠一郎, 豊岡伸一, 槇本剛

肺癌 63 ( 7 ) 1005 - 1005 2023年12月

CDK4/6 signaling attenuates the effect of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in EGFR-mutant non-small cell lung cancer. 国際誌

Naofumi Hara, Eiki Ichihara, Hirohisa Kano, Chihiro Ando, Ayako Morita, Tatsuya Nishi, Sachi Okawa, Takamasa Nakasuka, Atsuko Hirabae, Masaya Abe, Noboru Asada, Kiichiro Ninomiya, Go Makimoto, Masanori Fujii, Toshio Kubo, Kadoaki Ohashi, Katsuyuki Hotta, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura

Translational lung cancer research 12 ( 10 ) 2098 - 2112 2023年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Epidermal growth factor receptor (EGFR) mutations, such as exon 19 deletion and exon 21 L858R, are driver oncogenes of non-small cell lung cancer (NSCLC), with EGFR tyrosine kinase inhibitors (TKIs) being effective against EGFR-mutant NSCLC. However, the efficacy of EGFR-TKIs is transient and eventually leads to acquired resistance. Herein, we focused on the significance of cell cycle factors as a mechanism to attenuate the effect of EGFR-TKIs in EGFR-mutant NSCLC before the emergence of acquired resistance. METHODS: Using several EGFR-mutant cell lines, we investigated the significance of cell cycle factors to attenuate the effect of EGFR-TKIs in EGFR-mutant NSCLC. RESULTS: In several EGFR-mutant cell lines, certain cancer cells continued to proliferate without EGFR signaling, and the cell cycle regulator retinoblastoma protein (RB) was not completely dephosphorylated. Further inhibition of phosphorylated RB with cyclin-dependent kinase (CDK) 4/6 inhibitors, combined with the EGFR-TKI osimertinib, enhanced G0/G1 cell cycle accumulation and growth inhibition of the EGFR-mutant NSCLC in both in vitro and in vivo models. Furthermore, residual RB phosphorylation without EGFR signaling was maintained by extracellular signal-regulated kinase (ERK) signaling, and the ERK inhibition pathway showed further RB dephosphorylation. CONCLUSIONS: Our study demonstrated that the CDK4/6-RB signal axis, maintained by the MAPK pathway, attenuates the efficacy of EGFR-TKIs in EGFR-mutant NSCLC, and targeting CDK4/6 enhances this efficacy. Thus, combining CDK4/6 inhibitors and EGFR-TKI could be a novel treatment strategy for TKI-naïve EGFR-mutant NSCLC.

DOI： 10.21037/tlcr-23-99

Severe Cytokine Release Syndrome and Immune Effector Cell-associated Neurotoxicity Syndrome in a Man Receiving Immune Checkpoint Inhibitors for Lung Cancer: A Case Report.

Takaaki Tanaka, Masataka Taoka, Go Makimoto, Kiichiro Ninomiya, Hisao Higo, Masanori Fujii, Eiki Ichihara, Kadoaki Ohashi, Katsuyuki Hotta, Masahiro Tabata, Yoshinobu Maeda

Internal medicine (Tokyo, Japan) 2023年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

A 55-year-old man with stage IV lung adenocarcinoma was treated with cisplatin, pemetrexed, nivolumab, and ipilimumab. Approximately 100 days after treatment initiation, he became disoriented and presented to the emergency department with a high fever. Blood tests revealed liver and kidney dysfunctions. Subsequently, the patient developed generalized convulsions that required intensive care. He was clinically diagnosed with cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Organ damage was gradually controlled with immunosuppressive drugs, including steroids, and the patient was discharged. Successful treatment is rare in patients with CRS, including ICANS, during immune checkpoint inhibitor treatment for solid tumors.

DOI： 10.2169/internalmedicine.2429-23

Efficacy of gilteritinib in comparison with alectinib for the treatment of ALK-rearranged non-small cell lung cancer. 国際誌

Chihiro Ando, Eiki Ichihara, Tatsuya Nishi, Ayako Morita, Naofumi Hara, Kenji Takada, Takamasa Nakasuka, Hiromi Watanabe, Hirohisa Kano, Kazuya Nishii, Go Makimoto, Takumi Kondo, Kiichiro Ninomiya, Masanori Fujii, Toshio Kubo, Kadoaki Ohashi, Ken-Ichi Matsuoka, Katsuyuki Hotta, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura

Cancer science 2023年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

Gilteritinib is a multitarget tyrosine kinase inhibitor (TKI), approved for the treatment of FLT3-mutant acute myeloid leukemia, with a broad range of activity against several tyrosine kinases including anaplastic lymphoma kinase (ALK). This study investigated the efficacy of gilteritinib against ALK-rearranged non-small cell lung cancers (NSCLC). To this end, we assessed the effects of gilteritinib on cell proliferation, apoptosis, and acquired resistance responses in several ALK-rearranged NSCLC cell lines and mouse xenograft tumor models and compared its efficacy to alectinib, a standard ALK inhibitor. Gilteritinib was significantly more potent than alectinib, as it inhibited cell proliferation at a lower dose, with complete attenuation of growth observed in several ALK-rearranged NSCLC cell lines and no development of drug tolerance. Immunoblotting showed that gilteritinib strongly suppressed phosphorylated ALK and its downstream effectors, as well as mesenchymal-epithelial transition factor (MET) signaling. By comparison, MET signaling was enhanced in alectinib-treated cells. Furthermore, gilteritinib was found to more effectively abolish growth of ALK-rearranged NSCLC xenograft tumors, many of which completely receded. Interleukin-15 (IL-15) mRNA levels were elevated in gilteritinib-treated cells, together with a concomitant increase in the infiltration of tumors by natural killer (NK) cells, as assessed by immunohistochemistry. This suggests that IL-15 production along with NK cell infiltration may constitute components of the gilteritinib-mediated antitumor responses in ALK-rearranged NSCLCs. In conclusion, gilteritinib demonstrated significantly improved antitumor efficacy compared with alectinib against ALK-rearranged NSCLC cells, which can warrant its candidacy for use in anticancer regimens, after further examination in clinical trial settings.

DOI： 10.1111/cas.15958

PD-1 blockade augments CD8+ T cell dependent antitumor immunity triggered by Ad-SGE-REIC in Egfr-mutant lung cancer. 国際誌

Takamasa Nakasuka, Kadoaki Ohashi, Kazuya Nishii, Atsuko Hirabae, Sachi Okawa, Nahoko Tomonobu, Kenji Takada, Chihiro Ando, Hiromi Watanabe, Go Makimoto, Kiichiro Ninomiya, Masanori Fujii, Toshio Kubo, Eiki Ichihara, Katsuyuki Hotta, Masahiro Tabata, Hiromi Kumon, Yoshinobu Maeda, Katsuyuki Kiura

Lung cancer (Amsterdam, Netherlands) 178 1 - 10 2023年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

OBJECTIVES: No immunotherapeutic protocol has yet been established in never-smoking patients with lung cancer harboring driver oncogenic mutations, such as epidermal growth factor receptor (EGFR) mutations. The immunostimulatory effect of Ad-REIC, a genetically engineered adenovirus vector expressing a tumor suppressor gene, reduced expression in immortalized cells (REIC), has been investigated in clinical trials for various solid tumors. However, the immunostimulatory effect of the Ad-REIC in EGFR-mutant lung cancer with a non-inflamed tumor microenvironment (TME) has not been explored. MATERIALS AND METHODS: We used a syngeneic mouse model developed by transplanting Egfr-mutant lung cancer cells into single or double flanks of C57BL/6J mice. Ad-SGE-REIC, a 2nd-generation vector with an enhancer sequence, was injected only into the tumors from one flank, and its antitumor effects were assessed. Tumor-infiltrating cells were evaluated using immunohistochemistry or flow cytometry. The synergistic effects of Ad-SGE-REIC and PD-1 blockade were also examined. RESULTS: Injection of Ad-SGE-REIC into one side of the tumor induced not only a local antitumor effect but also a bystander abscopal effect in the non-injected tumor, located on the other flank. The number of PD-1+CD8+ T cells increased in both injected and non-injected tumors. PD-1 blockade augmented the local and abscopal antitumor effects of Ad-SGE-REIC by increasing the number of CD8+ T cells in the TME of Egfr-mutant tumors. Depletion of CD8+ cells reverted the antitumor effect, suggesting they contribute to antitumor immunity. CONCLUSION: Ad-SGE-REIC induced systemic antitumor immunity by modifying the TME status from non-inflamed to inflamed, with infiltration of CD8+ T cells. Additionally, in Egfr-mutant lung cancer, this effect was enhanced by PD-1 blockade. These findings pave the way to establish a novel combined immunotherapy strategy with Ad-SGE-REIC and anti-PD-1 antibody for lung cancer with a non-inflamed TME.

DOI： 10.1016/j.lungcan.2023.01.018

肺膿瘍を合併し急速な増大を認めたが,迅速に診断しテポチニブが奏効したMET陽性肺癌の1例

目瀬優衣, 槇本剛, 藤井昌学, 市原英基, 大橋圭明, 木浦勝行, 久保寿夫, 田端雅弘, 二宮貴一朗, 堀田勝幸

肺癌 63 ( 1 ) 68 - 69 2023年2月

COVID-19 Vaccine-Associated Lymphadenopathy Mimicking Regrowth of Axillary Lymph Node Metastasis of Lung Adenocarcinoma.

Taku Noumi, Hiromi Watanabe, Kiichiro Ninomiya, Kadoaki Ohashi, Eiki Ichihara, Toshio Kubo, Go Makimoto, Yuka Kato, Masanori Fujii, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Hotta, Katsuyuki Kiura

Acta medica Okayama 76 ( 5 ) 593 - 596 2022年10月

記述言語：英語

We encountered a woman with re-enlarged axillary lymph nodes during a computed tomography (CT) scan for surveillance of lung adenocarcinoma with axillary lymph node metastasis at the initial diagnosis that had shrunk with standard chemotherapy. We first suspected cancer recurrence and considered a change in the chemotherapeutic regimen. However, after careful history taking regarding the timing of her Coronavirus Disease 2019 (COVID-19) vaccination, and subsequent careful, close follow-up, radiological shrinkage suggested a strictly benign cause. Especially in lung cancer with a medical history of axillary lymph node involvement, cliniciansshould be aware that vaccine-associated lymphadenopathy can mimic cancer recurrence and sometimesprompt serious misjudgment regarding a current treatment course and strategy.

DOI： 10.18926/AMO/64041

CD8+ T-cell responses are boosted by dual PD-1/VEGFR2 blockade after EGFR inhibition in Egfr-mutant lung cancer. 国際誌

Kazuya Nishii, Kadoaki Ohashi, Shuta Tomida, Takamasa Nakasuka, Atsuko Hirabae, Sachi Okawa, Jun Nishimura, Hisao Higo, Hiromi Watanabe, Hirohisa Kano, Chihiro Ando, Go Makimoto, Kiichiro Ninomiya, Yuka Kato, Toshio Kubo, Eiki Ichihara, Katsuyuki Hotta, Masahiro Tabata, Shinichi Toyooka, Heiichiro Udono, Yoshinobu Maeda, Katsuyuki Kiura

Cancer immunology research 10 ( 9 ) 1111 - 1126 2022年7月

記述言語：英語掲載種別：研究論文（学術雑誌）

Epidermal growth factor receptor (EGFR) is the most frequently mutated driver oncogene in non-smoking-related, non-small-cell lung cancer (NSCLC). EGFR-mutant NSCLC has a non-inflamed tumor microenvironment (TME), with low infiltration by CD8+ T cells and, thus, immune checkpoint inhibitors, such as anti-programmed cell death-1 (anti-PD-1) have weak anti-tumor effects. Here, we showed that CD8+ T-cell responses were induced by an EGFR-tyrosine kinase inhibitor (TKI) in syngeneic Egfr-mutant NSCLC tumors, which was further pronounced by sequential dual blockade of PD-1 and vascular endothelial growth factor receptor 2 (VEGFR2). However, simultaneous triple blockade had no such effect. PD-1/VEGFR2 dual blockade did not exert tumor-inhibitory effects without pre-treatment with the EGFR-TKI, suggesting that treatment schedule is crucial for efficacy of the dual blockade therapy. Pre-treatment with EGFR-TKI increased the CD8+ T-cell/regulatory T-cell (Treg) ratio, while also increasing expression of immunosuppressive chemokines and chemokine receptors, as well as increasing the number of M2-like macrophages, in the TME. Discontinuing EGFR-TKI treatment reversed the transient increase of immunosuppressive factors in the TME. The subsequent PD-1/VEGFR2 inhibition maintained increased numbers of infiltrating CD8+ T cells and CD11c+ dendritic cells. Depletion of CD8+ T cells in vivo abolished tumor growth inhibition by EGFR-TKI alone and the sequential triple therapy, suggesting that EGFR inhibition is a prerequisite for the induction of CD8+ T-cell responses. Our findings could aid in developing an alternative immunotherapy strategy in patients with cancers that have driver mutations and a non-inflamed TME.

DOI： 10.1158/2326-6066.CIR-21-0751

大量喀血に対して気管支動脈塞栓術と気管支充填術が奏効したALK陽性肺癌の1例

藤岡佑輔, 田岡征高, 槇本剛, 栗林忠弘, 松浦宏昌, 下西惇, 二宮貴一朗, 肥後寿夫, 久保寿夫, 大橋圭明, 堀田勝幸, 宮原信明, 田端雅弘, 木浦勝行

気管支学 44 ( Suppl. ) S307 - S307 2022年5月

First and repeat rebiopsy for detecting EGFR T790M mutation in non-small-cell lung cancer: CS-Lung-003 prospective observational registry study. 国際誌

Kenichiro Kudo, Kazuya Nishii, Go Makimoto, Nobuhisa Ishikawa, Yukari Tsubata, Masahiro Kodani, Nobukazu Fujimoto, Masahiro Yamasaki, Tetsuya Kubota, Nagio Takigawa, Kazunori Fujitaka, Nobuhiro Kanaji, Takuo Shibayama, Junko Itano, Chihiro Ando, Katsuyuki Hotta, Katsuyuki Kiura

Journal of cancer research and clinical oncology 148 ( 8 ) 1869 - 1877 2022年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

PURPOSE: Osimertinib is still essential for the treatment of epidermal growth factor receptor (EGFR)-T790M-positive non-small-cell lung cancer (NSCLC) even in a relapsed setting, which suggests the importance of rebiopsy. The clinical value of repeat rebiopsy in patients with NSCLC who are T790M-negative on a first rebiopsy remains unclear. In this study, we examined the status of the first rebiopsy and evaluated the frequency of repeat rebiopsy of T790M-negative tumors detected by the first rebiopsy. METHODS: We reviewed 144 patients with NSCLC with major EGFR mutations, but not T790M, who received first- or second-generation EGFR tyrosine kinase inhibitors (TKIs), registered in the prospective, umbrella-type lung cancer patient registry (CS-Lung-003). RESULTS: Overall, 63 patients (44%) underwent the first rebiopsy. In the first rebiopsy, 51 (81%) and 12 (19%) of 63 underwent histological/cytological rebiopsy and liquid biopsy with the blood sampling, respectively. In the repeat rebiopsy, 23 (85%) and 4 (15%) of 27 underwent histological/cytological rebiopsy and liquid biopsy, respectively. The most frequently rebiopsied site was a pulmonary lesion (n = 24, 38.7%). Overall, 29 (46.0%) of 63 patients harbored the T790M mutation. Interestingly, a high detection rate of cancer cells did not necessarily indicate a high detection rate of the T790M mutation (p < 0.01). Among 34 patients with T790M-negative tumors confirmed on the first rebiopsy, 20 (58.8%) underwent repeat rebiopsies following interval therapy, revealing that seven (36.8%) had T790M-positive tumors. Osimertinib yielded median progression-free survival of 11.8 and 16.2 months in patients with the 790M mutation detected by the first rebiopsy and repeat rebiopsy, respectively. CONCLUSION: In our prospective cohort, the T790M mutation was detected in 46% of patients who underwent the first rebiopsy. Repeat rebiopsy may increase the ability to detect the T790M mutation positivity rate.

DOI： 10.1007/s00432-021-03893-z

がん遺伝子パネル検査を行った胸腺がん5例の検討

久保寿夫, 二宮貴一朗, 槇本剛, 加藤有加, 藤井昌学, 市原英基, 大橋圭明, 堀田勝幸, 田端雅弘, 前田嘉信, 木浦勝行

日本呼吸器学会誌 11 ( 増刊 ) 279 - 279 2022年4月

Identification of targetable kinases in idiopathic pulmonary fibrosis. 国際誌

Hisao Higo, Kadoaki Ohashi, Shuta Tomida, Sachi Okawa, Hiromasa Yamamoto, Seiichiro Sugimoto, Satoru Senoo, Go Makimoto, Kiichiro Ninomiya, Takamasa Nakasuka, Kazuya Nishii, Akihiko Taniguchi, Toshio Kubo, Eiki Ichihara, Katsuyuki Hotta, Nobuaki Miyahara, Yoshinobu Maeda, Shinichi Toyooka, Katsuyuki Kiura

Respiratory research 23 ( 1 ) 20 - 20 2022年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Tyrosine kinase activation plays an important role in the progression of pulmonary fibrosis. In this study, we analyzed the expression of 612 kinase-coding and cancer-related genes using next-generation sequencing to identify potential therapeutic targets for idiopathic pulmonary fibrosis (IPF). METHODS: Thirteen samples from five patients with IPF (Cases 1-5) and eight samples from four patients without IPF (control) were included in this study. Six of the thirteen samples were obtained from different lung segments of a single patient who underwent bilateral pneumonectomy. Gene expression analysis of IPF lung tissue samples (n = 13) and control samples (n = 8) was performed using SureSelect RNA Human Kinome Kit. The expression of the selected genes was further confirmed at the protein level by immunohistochemistry (IHC). RESULTS: Gene expression analysis revealed a correlation between the gene expression signatures and the degree of fibrosis, as assessed by Ashcroft score. In addition, the expression analysis indicated a stronger heterogeneity among the IPF lung samples than among the control lung samples. In the integrated analysis of the 21 samples, DCLK1 and STK33 were found to be upregulated in IPF lung samples compared to control lung samples. However, the top most upregulated genes were distinct in individual cases. DCLK1, PDK4, and ERBB4 were upregulated in IPF case 1, whereas STK33, PIM2, and SYK were upregulated in IPF case 2. IHC revealed that these proteins were expressed in the epithelial layer of the fibrotic lesions. CONCLUSIONS: We performed a comprehensive kinase expression analysis to explore the potential therapeutic targets for IPF. We found that DCLK1 and STK33 may serve as potential candidate targets for molecular targeted therapy of IPF. In addition, PDK4, ERBB4, PIM2, and SYK might also serve as personalized therapeutic targets of IPF. Additional large-scale studies are warranted to develop personalized therapies for patients with IPF.

DOI： 10.1186/s12931-022-01940-y

Massive hemoptysis in a post-operative patient with recurrent lung cancer successfully treated by the combination therapy of Endobronchial Watanabe Spigot and bronchial artery embolization 国際誌

Masataka Taoka, Go Makimoto, Noriyuki Umakoshi, Kiichiro Ninomiya, Hisao Higo, Yuka Kato, Masanori Fujii, Toshio Kubo, Eiki Ichihara, Kadoaki Ohashi, Katsuyuki Hotta, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura

Respiratory Medicine Case Reports 38 101669 - 101669 2022年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Elsevier BV

A 76-year-old woman who was treated with lorlatinib for postoperative recurrent anaplastic lymphoma kinase-positive lung adenocarcinoma visited our hospital with massive hemoptysis. Chest computed tomography showed massive bleeding from the right upper lobe; however, the cause of bleeding was unclear. After bronchial artery embolization (BAE), bronchial occlusion was performed using an Endobronchial Watanabe Spigot (EWS) that was easily placed because BAE had reduced the bleeding volume. Treatment with BAE alone was inadequate; however, additional therapy with EWS after BAE successfully controlled the massive hemoptysis, especially in this patient who underwent lobectomy to prevent respiratory dysfunction.

DOI： 10.1016/j.rmcr.2022.101669

Successful and Prompt Treatment with Tepotinib for Lung Adenocarcinoma Harboring MET Exon 14 Skipping Mutation Combined with Lung Abscess Formation: A Case Report. 国際誌

Go Makimoto, Atsushi Shimonishi, Kadoaki Ohashi, Kiichiro Ninomiya, Hisao Higo, Yuka Kato, Masanori Fujii, Toshio Kubo, Eiki Ichihara, Katsuyuki Hotta, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura

Case reports in oncology 15 ( 2 ) 494 - 498 2022年

記述言語：英語

Tepotinib, the novel MET-tyrosine kinase inhibitor, shows an antitumor effect for patients with non-small-cell lung cancer (NSCLC) harboring MET exon 14 skipping mutation. In January 2022, the AmoyDx® Pan Lung Cancer polymerase chain reaction Panel (AmoyDx® panel), which had a shorter turnaround time than the conventional test, was launched in Japan as a tepotinib companion test. We report a patient with an advanced MET-mutant NSCLC promptly diagnosed using the AmoyDx® panel and successfully treated with tepotinib. Although the patient's performance status (PS) worsened due to the rapid tumor progression and lung abscess formation, the tumor shrank immediately after tepotinib treatment with marked PS improvement.

DOI： 10.1159/000524326

Dasatinib-induced massive left chylothorax in a patient with chronic myeloid leukemia. 国際誌

Go Makimoto, Mahito Misawa, Yoshinobu Maeda, Katsuyuki Kiura

Respiratory medicine case reports 37 101662 - 101662 2022年

記述言語：英語

Dasatinib, an effective second-generation tyrosine kinase inhibitor, is used to treat breakpoint cluster region-Ableson-positive chronic myeloid leukemia or Philadelphia chromosome-positive acute lymphocytic leukemia. One common adverse event associated with dasatinib use is fluid retention, including pleural effusion. Chylothorax, however, is a rare adverse event. Although the precise mechanism of dasatinib-induced chylothorax is unclear, almost all cases involve right or bilateral chylothorax, and mostly occur within 5 years of dasatinib initiation. Here, we report a rare case of a patient with dasatinib-induced massive left chylothorax 10 years after dasatinib initiation, which improved after dasatinib termination and a switch to bosutinib.

DOI： 10.1016/j.rmcr.2022.101662

Carboplatin, pemetrexed, and pembrolizumab was effective for primary salivary gland-type lung adenocarcinoma diagnosed due to esophageal stricture: A case report

Keita Kawakado, Tomoki Tamura, Masamoto Nakanishi, Go Makimoto, Yumiko Sato, Shoichi Kuyama

Thoracic Cancer 12 ( 18 ) 2513 - 2516 2021年9月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：John Wiley and Sons Inc

Primary salivary gland-type tumors of the lung are rare, accounting for &lt
1% of all lung tumors. There are few reports on chemotherapy for the treatment of primary salivary gland-type tumors of the lung. The patient in this report was a 71-year-old woman who presented with a chief complaint of dysphagia. Upper gastrointestinal endoscopy revealed an esophageal stricture, but biopsy showed no malignancy. Chest computed tomography (CT) showed carcinomatous lymphangiomatosis and a nodule in the right lung. Bronchoscopy showed a rough mucous membrane of the central bronchi, while biopsy showed adenocarcinoma. The patient was diagnosed with bronchogenic adenocarcinoma and received carboplatin, pemetrexed, and pembrolizumab, which alleviated the esophageal stricture and cancerous lymphangiopathy. However, the adenocarcinoma progressed, and she subsequently received several rounds of chemotherapy. One year after diagnosis, the patient died, and pathological autopsy revealed primary salivary gland-type tumors of the lung.

DOI： 10.1111/1759-7714.14100

Triple therapy with osimertinib, bevacizumab and cetuximab in EGFR-mutant lung cancer with HIF-1α/TGF-α expression. 国際誌

Kazuya Nishii, Kadoaki Ohashi, Hiromi Watanabe, Go Makimoto, Takamasa Nakasuka, Hisao Higo, Kiichiro Ninomiya, Yuka Kato, Toshio Kubo, Kammei Rai, Eiki Ichihara, Katsuyuki Hotta, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura

Oncology letters 22 ( 3 ) 639 - 639 2021年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

Osimertinib, a third generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, is the standard treatment for patients with lung cancer harboring EGFR T790M; however, acquired resistance is inevitable due to genetic and epigenetic changes in cancer cells. In addition, a recent randomized clinical trial revealed that the combination of osimertinib and bevacizumab failed to exhibit superior progression-free survival compared with osimertinib alone. The present study aimed to investigate the effect of triple therapy with osimertinib, bevacizumab and cetuximab in xenograft tumors with different initial tumor volumes (conventional model, 200 mm3 and large model, 500 mm3). The results demonstrated that osimertinib significantly inhibited tumor growth in both the conventional and large models; however, maximum tumor regression was attenuated in the large model in which hypoxia-inducible factor-1α (HIF-1α) and transforming growth factor-α (TGF-α) expression levels increased. Although the combination of osimertinib and bevacizumab exerted a greater inhibitory effect on tumor growth compared with osimertinib in the conventional model, the effect of this combination therapy was attenuated in the large model. TGF-α attenuated sensitivity to osimertinib in vitro; however, this negative effect was counteracted by the combination of osimertinib and cetuximab, but not osimertinib and bevacizumab. In the large xenograft tumor model, the triple therapy induced the greatest inhibitory effect on tumor growth compared with osimertinib alone and its combination with bevacizumab. Clinical trials of the triple therapy are required for patients with lung cancer with EGFR mutations and HIF-1α/TGF-α.

DOI： 10.3892/ol.2021.12900

Triple therapy with osimertinib, bevacizumab and cetuximab in EGFR-mutant lung cancer with HIF-1 alpha/TGF-alpha expression

Kazuya Nishii, Kadoaki Ohashi, Hiromi Watanabe, Go Makimoto, Takamasa Nakasuka, Hisao Higo, Kiichiro Ninomiya, Yuka Kato, Toshio Kubo, Kammei Rai, Eiki Ichihara, Katsuyuki Hotta, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura

ONCOLOGY LETTERS 22 ( 3 ) 2021年9月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：SPANDIDOS PUBL LTD

Osimertinib, a third generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, is the standard treatment for patients with lung cancer harboring EGFR T790M; however, acquired resistance is inevitable due to genetic and epigenetic changes in cancer cells. In addition, a recent randomized clinical trial revealed that the combination of osimertinib and bevacizumab failed to exhibit superior progression-free survival compared with osimertinib alone. The present study aimed to investigate the effect of triple therapy with osimertinib, bevacizumab and cetuximab in xenograft tumors with different initial tumor volumes (conventional model, 200 mm(3) and large model, 500 mm(3)). The results demonstrated that osimertinib significantly inhibited tumor growth in both the conventional and large models; however, maximum tumor regression was attenuated in the large model in which hypoxia-inducible factor-1 alpha (HIF-1 alpha) and transforming growth factor-alpha (TGF-alpha) expression levels increased. Although the combination of osimertinib and bevacizumab exerted a greater inhibitory effect on tumor growth compared with osimertinib in the conventional model, the effect of this combination therapy was attenuated in the large model. TGF-alpha attenuated sensitivity to osimertinib in vitro; however, this negative effect was counteracted by the combination of osimertinib and cetuximab, but not osimertinib and bevacizumab. In the large xenograft tumor model, the triple therapy induced the greatest inhibitory effect on tumor growth compared with osimertinib alone and its combination with bevacizumab. Clinical trials of the triple therapy are required for patients with lung cancer with EGFR mutations and HIF-1 alpha/TGF-alpha.

DOI： 10.3892/ol.2021.12900

Retrobulbar Optic Neuritis Induced by Pembrolizumab in a Patient with Lung Adenocarcinoma.

Keita Kawakado, Tomoki Tamura, Masamoto Nakanishi, Go Makimoto, Shoichi Kuyama

Internal medicine (Tokyo, Japan) 2021年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

Pembrolizumab is a monoclonal antibody with anti-tumor effects. Only a few reports have previously described retrobulbar optic neuritis induced by pembrolizumab. We herein report the case of a 64 -year-old man with advanced lung adenocarcinoma who received cisplatin, pemetrexed, and pembrolizumab combination therapy for six months. Following treatment, a visual field test showed a left central scotoma. Imaging studies showed left optic neuritis without brain metastasis. Blood tests showed an elevated serum creatinine level. He was diagnosed with retrobulbar optic neuritis and pembrolizumab-induced renal failure. After receiving corticosteroid treatment, his renal function rapidly improved. The optic neuritis improved somewhat, but it was not adequately resolved.

DOI： 10.2169/internalmedicine.7425-21

Heerfordt's Syndrome Associated with Trigeminal Nerve Palsy and Reversed Halo Sign.

Go Makimoto, Keita Kawakado, Masamoto Nakanishi, Tomoki Tamura, Minori Noda, Satoko Makimoto, Yumiko Sato, Shoichi Kuyama

Internal medicine (Tokyo, Japan) 60 ( 11 ) 1747 - 1752 2021年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

Heerfordt's syndrome is a rare subtype of sarcoidosis and features a combination of facial palsy, parotid swelling, and uveitis, associated with a low-grade fever. Cases with two of three symptoms are called "incomplete Heerfordt's syndrome." Heerfordt's syndrome involving other cranial nerve symptoms is relatively rare. We herein report a case of incomplete Heerfordt's syndrome presenting with trigeminal nerve palsy and a reversed halo sign, a rare manifestation of pulmonary sarcoidosis. The histological diagnosis following a biopsy of the parotid gland and endobronchial ultrasound-guided trans-bronchial needle aspiration of the mediastinal lymph nodes was sarcoidosis. The symptoms and lung lesions improved after corticosteroid therapy.

DOI： 10.2169/internalmedicine.6176-20

Limited effect of afatinib in a non-small cell lung cancer patient harboring an epidermal growth factor receptor K860I missense mutation: A case report. 国際誌

Tomoki Tamura, Keita Kawakado, Go Makimoto, Masamoto Nakanishi, Shoichi Kuyama

Thoracic cancer 12 ( 11 ) 1770 - 1774 2021年6月

記述言語：英語

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are key drugs in the treatment of non-small cell lung cancer (NSCLC) patients with EGFR mutations; however, first-generation EGFR-TKIs, such as gefitinib and erlotinib, are not effective in patients with uncommon EGFR mutations. In contrast, efficacy of afatinib has been reported in some types of uncommon EGFR mutation such as G710X, L861Q. The effect of afatinib in NSCLC patients with the EGFR K860I mutation has been shown in vitro, but its clinical efficacy has not been demonstrated. Here, we report the experience of afatinib administration in an NSCLC patient with an EGFR K860I mutation. A 69-year-old woman presented with right hemiplegia and dysarthria. Multiple brain and lung tumors were observed. She underwent craniotomy and was diagnosed with lung adenocarcinoma. After stereotactic brain radiation therapy, cisplatin, pemetrexed, and bevacizumab combination therapy was initiated. Unfortunately, she was unable to continue chemotherapy as she had an intestinal perforation after two cycles. After five months, recurrence of multiple brain metastases and an increase in primary lung cancer were confirmed. Next-generation sequencing (NGS) was performed in a clinical trial, and an EGFR K860I mutation was detected in her tumor. Afatinib was administered and the primary lung tumor shrank, but multiple brain metastases were exacerbated. After irradiation of the brain, afatinib administration was continued. In conclusion, afatinib may show an effect in NSCLC patients with the EGFR K860I mutation, but its efficacy is limited.

DOI： 10.1111/1759-7714.13941

A novel osimertinib-resistant human lung adenocarcinoma cell line harbouring mutant EGFR and activated IGF1R. 国際誌

Go Makimoto, Kiichiro Ninomiya, Toshio Kubo, Ryota Sunami, Yuka Kato, Eiki Ichihara, Kadoaki Ohashi, Kammei Rai, Katsuyuki Hotta, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura

Japanese journal of clinical oncology 51 ( 6 ) 956 - 965 2021年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

OBJECTIVE: A third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), osimertinib, is the standard treatment for patients with non-small cell lung cancer harbouring mutant EGFR. Unfortunately, these patients inevitably acquire resistance to EGFR-TKI therapies, including osimertinib. However, the mechanism associated with this resistance remains unclear. METHODS: A 63-year-old Japanese female with lung adenocarcinoma underwent right upper lobectomy (pT1bN2M0 pStage IIIA, EGFR Ex21 L858R). She manifested post-operative tumour recurrence with multiple lung metastases 8 months later and began gefitinib treatment. The lung lesions re-grew 15 months later, and EGFR T790M mutation was detected in the lung metastasis re-biopsy. She was administered osimertinib; however, it relapsed with pleural effusion 16 months later. We isolated cells from the osimertinib-resistant pleural effusion to establish a novel cell line, ABC-31. RESULTS: Although the EGFR L858R mutation was detected in ABC-31 cells, the T790M mutation was lost. ABC-31 cells were resistant to EGFR-TKIs, including osimertinib. Phospho-receptor tyrosine kinase array revealed activation of the insulin-like growth factor 1 receptor (IGF1R), whereas overexpression of the IGF1R ligand, IGF2, induced IGF1R activation in ABC-31 cells. Combination therapy using EGFR-TKIs and IGF1R inhibitor acted synergistically in vitro. She was re-administered osimertinib since EGFR-TKIs and IGF1R inhibitor combination therapy was impossible in clinical practice. This had a slight and short-lived effect. CONCLUSIONS: Taken together, we have successfully established a new osimertinib-resistant lung adenocarcinoma cell line with activated IGF1R. These ABC-31 cells will help develop novel therapeutic strategies for patients with lung adenocarcinoma resistant to specific treatment via IGF1R activation.

DOI： 10.1093/jjco/hyab048

Effect of Prophylactic Anti-emetics on Opioid-induced Nausea and Vomiting: A Retrospective Observational Cohort Study

Tomoki Tamura, Keita Kawakado, G. O. Makimoto, Masamoto Nakanishi, Shoichi Kuyama

IN VIVO 35 ( 3 ) 1737 - 1742 2021年5月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：INT INST ANTICANCER RESEARCH

Background: The guidelines on pharmacotherapy for cancer-related pain advocate active measures against the adverse effects of opioids to increase adherence to medication. However, preventative therapy for the management of nausea and vomiting has not been specified. This study aimed to verify the effects of prophylactic anti emetics in preventing opioid-induced nausea and vomiting. Patients and Methods: We conducted a retrospective analysis of cases at our hospital in which oral opioids or patches were initiated for the management of pain due to malignant tumours from January 2017 to September 2019. Results: Strong opioids were initiated for 349 patients; of these, data for 298 patients were analysed. A total of 193 patients were on anti-emetic prophylaxis. We found that the group that did not receive anti-emetic prophylaxis was significantly more likely to be prescribed an additional anti emetic. Conclusion: Prophylactic administration of anti emetics at the time of initiating opioid analgesics may reduce gastrointestinal toxicity.

DOI： 10.21873/invivo.12432

VEGFR2 blockade augments the effects of tyrosine kinase inhibitors by inhibiting angiogenesis and oncogenic signaling in oncogene-driven non-small-cell lung cancers. 国際誌

Hiromi Watanabe, Eiki Ichihara, Hiroe Kayatani, Go Makimoto, Kiichiro Ninomiya, Kazuya Nishii, Hisao Higo, Chihiro Ando, Sachi Okawa, Takamasa Nakasuka, Hirohisa Kano, Naofumi Hara, Atsuko Hirabae, Yuka Kato, Takashi Ninomiya, Toshio Kubo, Kammei Rai, Kadoaki Ohashi, Katsuyuki Hotta, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura

Cancer science 112 ( 5 ) 1853 - 1864 2021年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

Molecular agents targeting the epidermal growth factor receptor (EGFR)-, anaplastic lymphoma kinase (ALK)- or c-ros oncogene 1 (ROS1) alterations have revolutionized the treatment of oncogene-driven non-small-cell lung cancer (NSCLC). However, the emergence of acquired resistance remains a significant challenge, limiting the wider clinical success of these molecular targeted therapies. In this study, we investigated the efficacy of various molecular targeted agents, including erlotinib, alectinib, and crizotinib, combined with anti-vascular endothelial growth factor receptor (VEGFR) 2 therapy. The combination of VEGFR2 blockade with molecular targeted agents enhanced the anti-tumor effects of these agents in xenograft mouse models of EGFR-, ALK-, or ROS1-altered NSCLC. The numbers of CD31-positive blood vessels were significantly lower in the tumors of mice treated with an anti-VEGFR2 antibody combined with molecular targeted agents compared with in those of mice treated with molecular targeted agents alone, implying the antiangiogenic effects of VEGFR2 blockade. Additionally, the combination therapies exerted more potent antiproliferative effects in vitro in EGFR-, ALK-, or ROS1-altered NSCLC cells, implying that VEGFR2 inhibition also has direct anti-tumor effects on cancer cells. Furthermore, VEGFR2 expression was induced following exposure to molecular targeted agents, implying the importance of VEGFR2 signaling in NSCLC patients undergoing molecular targeted therapy. In conclusion, VEGFR2 inhibition enhanced the anti-tumor effects of molecular targeted agents in various oncogene-driven NSCLC models, not only by inhibiting tumor angiogenesis but also by exerting direct antiproliferative effects on cancer cells. Hence, combination therapy with anti-VEGFR2 antibodies and molecular targeted agents could serve as a promising treatment strategy for oncogene-driven NSCLC.

DOI： 10.1111/cas.14801

Randomized study comparing mannitol with furosemide for the prevention of cisplatin-induced renal toxicity in non-small cell lung cancer: The OLCSG1406 trial. 国際誌

Go Makimoto, Katsuyuki Hotta, Isao Oze, Kiichiro Ninomiya, Masamoto Nakanishi, Naofumi Hara, Hirohisa Kano, Hiromi Watanabe, Yusuke Hata, Kazuya Nishii, Takamasa Nakasuka, Junko Itano, Takashi Ninomiya, Toshio Kubo, Kadoaki Ohashi, Eiki Ichihara, Daisuke Minami, Akiko Sato, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura

Asia-Pacific journal of clinical oncology 17 ( 1 ) 101 - 108 2021年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

AIM: Evidence is lacking on the best standard method for forced diuresis to prevent cisplatin-induced nephrotoxicity. We compared the cisplatin-induced nephrotoxicity prevention effect of furosemide or mannitol in patients with advanced non-small cell lung cancer. METHODS: Patients with advanced non-small cell lung cancer suitable to receive cisplatin-containing regimen were randomly assigned to receive furosemide or mannitol with appropriate hydration. The primary endpoint was the proportion of ≥ grade 1 serum creatinine elevation in the first cycle. RESULTS: The trial was terminated early with 44 (22 per arm) of the planned 66 patients because of slow accrual. Patients' characteristics were well balanced with median baseline creatinine clearance of 98.0 and 95.1 mL/min in the furosemide and mannitol arms, respectively. In the first cycle, two (9%) and four (18%) patients developed grade 1 creatinine elevation (P = .66), respectively, despite no ≥ grade 2 toxicity. The median times to develop the worst creatinine score were 10 and 8 days, respectively. For all cycles, median times to recover to grade 0 were 56 and 20 days, respectively. The furosemide arm was characterized by relatively high urine output after cisplatin administration (900 vs 550 mL/h), low frequency of unplanned additional hydration (14% vs 32%), and high incidence of hyponatremia (18% and 5%) compared with the mannitol arm. Both arms showed similar progression-free survival and overall survival. CONCLUSION: The preventive effect of the two forced diuretics on cisplatin-induced nephrotoxicity was not significantly different. However, the two diuretics have some distinct types of clinical presentations.

DOI： 10.1111/ajco.13423

Successful Treatment with Lorlatinib after the Development of Alectinib-Induced Liver Damage in ALK-Positive Non-Small-Cell Lung Cancer: A Case Report

Go Makimoto, Keita Kawakado, Masamoto Nakanishi, Tomoki Tamura, Shoichi Kuyama

CASE REPORTS IN ONCOLOGY 14 ( 1 ) 197 - 201 2021年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：KARGER

Alectinib is a key drug for treating anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC). Alectinib-induced hepatotoxicity is less common than that through other ALK inhibitors, such as crizotinib or ceritinib. Herein, we describe a case of ALK-positive adenocarcinoma successfully treated with lorlatinib after developing alectinib-induced hepatotoxicity. A 57-year-old Japanese man received alectinib as first-line therapy for ALK-positive NSCLC. After 79 days, alectinib was discontinued because of hepatotoxicity and later restarted at 150 mg/day, inducing hepatotoxicity again after 64 days. Switching to lorlatinib treatment (continued for >4 months) caused no severe adverse effects. Hence, lorlatinib may be useful for patients experiencing alectinib-induced hepatotoxicity.

DOI： 10.1159/000513624

Successful corticosteroid treatment of necrotizing sarcoid granulomatosis associated with tracheal lesion recurred after a surgical lung biopsy. 国際誌

Go Makimoto, Keita Kawakado, Masamoto Nakanishi, Tomoki Tamura, Yumiko Sato, Shoichi Kuyama

Respiratory medicine case reports 33 101402 - 101402 2021年

記述言語：英語

Necrotizing sarcoid granulomatosis (NSG) is a rare disease that presents with nodular lung lesions and necrosis. The pathology is consistent with sarcoidosis, but the necrosis can lead to a diagnosis of tuberculosis. Herein, we report a rare case of NSG that recurred four years after the initial diagnosis was made by surgical lung biopsy. A 51-year-old woman was initially referred to our hospital for the evaluation of multiple lung nodules. The pathological evaluation of a lung biopsy showed granulomas with necrosis and the infiltration of lymphocytes; thus, she was diagnosed with NSG. The lung nodules gradually improved after the diagnosis and we continued to follow her even though she did not require treatment. Four years after her initial diagnosis, she complained of back pain. Upon evaluation, we found that multiple lung nodules had recurred. Bronchoscopy also revealed a tracheal polypoid lesion, which showed granulomas with necrosis pathologically. Therefore, we diagnosed her with the recurrence of NSG. After the corticosteroid therapy, multiple lung nodules drastically improved. NSG patients should be carefully followed-up over several years, even if they do not require treatment.

DOI： 10.1016/j.rmcr.2021.101402

Successful transcatheter arterial embolization of asymptomatic aneurysm associated with left inferior phrenic artery-to-left pulmonary artery fistula: A case report. 国際誌

Keita Kawakado, Takayuki Yabuki, Tatsuya Nishi, Masamoto Nakanishi, Go Makimoto, Tomoki Tamura, Shoichi Kuyama

Respiratory medicine case reports 33 101444 - 101444 2021年

記述言語：英語

Cases of inferior phrenic artery-to-pulmonary artery fistulas and those complicated by massive hemoptysis have been rarely reported. A 38-year-old man presented to our hospital with a chief complaint of coughing. Computed tomography (CT) revealed a nodule in the left lower lobe, and contrast-enhanced CT showed inflow of contrast medium into the nodule. CT angiography detected an aneurysm associated with a left inferior phrenic artery-to-left pulmonary artery fistula. Transcatheter arterial embolization (TAE) was performed to prevent hemoptysis. Hemoptysis did not occur during the 2-year follow-up. We report a rare case of asymptomatic aneurysm associated with a left inferior phrenic artery-to-left pulmonary artery fistula, which was successfully treated using TAE to prevent hemoptysis.

DOI： 10.1016/j.rmcr.2021.101444

Detection of epidermal growth factor receptor mutations in exhaled breath condensate using droplet digital polymerase chain reaction. 国際誌

Kazuya Nishii, Kadoaki Ohashi, Tomoki Tamura, Kiichiro Ninomiya, Takehiro Matsubara, Satoru Senoo, Hirohisa Kano, Hiromi Watanabe, Naohiro Oda, Go Makimoto, Hisao Higo, Yuka Kato, Takashi Ninomiya, Toshio Kubo, Hiromasa Yamamoto, Shuta Tomida, Katsuyuki Hotta, Masahiro Tabata, Shinichi Toyooka, Yoshinobu Maeda, Katsuyuki Kiura

Oncology letters 20 ( 6 ) 393 - 393 2020年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

The detection of certain oncogenic driver mutations, including those of epidermal growth factor receptor (EGFR), is essential for determining treatment strategies for advanced non-small cell lung cancer (NSCLC). The current study assessed the feasibility of testing exhaled breath condensate (EBC) for EGFR mutations by droplet digital PCR (ddPCR). Samples were collected from 12 patients with NSCLC harboring EGFR mutations that were admitted to Okayama University Hospital between June 1, 2014 and December 31, 2017. A total of 21 EBC samples were collected using the RTube™ method and EGFR mutations (L858R, exon 19 deletions or T790M) were assessed through ddPCR analysis (EBC-ddPCR). A total of 3 healthy volunteer samples were also tested to determine a threshold value for each mutation. Various patient characteristics were determined, including sex (3 males and 9 females), age (range 54-81 years; median, 66 years), smoking history (10 had never smoked; 2 were former smokers), histology (12 patients exhibited adenocarcinoma), clinical stage (9 patients were stage IV; 3 exhibited post-operative recurrence) and EGFR mutation type (4 had L858R; 8 had exon 19 deletions; 8 had T790M). EBC-ddPCR demonstrated positive droplets in 8 of the 12 patients. The sensitivity and specificity of each mutation was as follows: 27.3 and 80.0% for EGFR L858R, 30.0 and 90.9% for EGFR Ex19del, and 22.2 and 100% for EGFR T790M. EBC-ddPCR analysis of EGFR mutations exhibited modest sensitivity and acceptable specificity. EBC-ddPCR is a minimally invasive and replicable procedure and may be a complementary method for EGFR testing in patients where blood or tissue sampling proves difficult.

DOI： 10.3892/ol.2020.12256

Beneficial effect of erlotinib and trastuzumab emtansine combination in lung tumors harboring EGFR mutations. 国際誌

Hiroe Kayatani, Kadoaki Ohashi, Kiichiro Ninomiya, Go Makimoto, Kazuya Nishii, Hisao Higo, Hiromi Watanabe, Hirohisa Kano, Yuka Kato, Takashi Ninomiya, Toshio Kubo, Kammei Rai, Eiki Ichihara, Katsuyuki Hotta, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura

Biochemical and biophysical research communications 532 ( 3 ) 341 - 346 2020年11月

記述言語：英語掲載種別：研究論文（学術雑誌）

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) is the standard therapy for non-small cell lung cancer (NSCLC) harboring EGFR mutations, but the resistance is inevitable. The drug-tolerant persister cancer cells are thought to be involved in the resistance. We recently reported that HER2 expression had a negative impact on time-to-treatment-failure in patients with EGFR mutant NSCLC. In this study, we hypothesized that HER2 might be a potential target for alternative combination therapy in NSCLC harboring EGFR mutations. In vitro study showed that the level of HER2 expression had no correlation with the sensitivity to EGFR-TKI, erlotinib but showed some correlation with HER2-inhibitor, ado-trastuzumab emtansine (T-DM1) in multiple EGFR-mutant lung cancer cell lines. In addition, HER2 expression was increased in persister cancer cells in 11-18 cell line harboring EGFR L858R or HCC827 cell line harboring EGFR exon 19 deletion after the exposure to erlotinib in vitro and in vivo. The combination of erlotinib and T-DM1 showed a superior inhibitory effect on cell proliferation compared with those of the erlotinib or T-DM1 alone in either 11-18 or HCC827 cells in vitro. The combination therapy also induced a significantly greater inhibitory effect on tumor growth in xenograft model in mice transplanted with either 11-18 or HCC827 cells compared with erlotinib alone or T-DM1 alone. No body weight loss was observed in these mice. These results suggested that the combination therapy with EGFR-TKI and T-DM1 might be a potentially promising strategy for treating lung cancer harboring EGFR mutations.

DOI： 10.1016/j.bbrc.2020.07.055

Anaplastic Lymphoma Kinase Fusion: A Review of Therapeutic Drugs and Treatment Strategies.

Go Makimoto, Kadoaki Ohashi, Yoshinobu Maeda, Katsuyuki Kiura

Acta medica Okayama 74 ( 5 ) 371 - 379 2020年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

The prognosis of advanced non-small cell lung cancer (NSCLC) patients has improved in recent decades, especially for patients with an oncogenic driver mutation. Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) are effective for patients with the echinoderm microtubule-associated protein-like 4-ALK fusion gene. Several ALK-TKIs have been established: the first-generation ALK-TKI, crizotinib; second-generation ALK-TKIs, alectinib and ceritinib; and third-generation ALK-TKI, lorlatinib. Some ALK-TKIs are effective for tumors that are resistant to other ALK-TKIs; however, as is known in epidermal growth factor receptormutant lung cancer, tumor resistance is inevitable. ALK-positive NSCLCs acquire resistance via various mechanisms, making it a heterogeneous disease. Therefore, it is necessary to develop next-generation treatment strategies, such as the use of next-generation ALK-TKIs for secondary mutations, or combination therapies with ALK-TKIs and other TKIs. In this review, we summarize the development and use of ALK-TKIs, prior pivotal clinical trials, and resistance mechanisms.

DOI： 10.18926/AMO/60796

Successful Desensitization Treatment with Osimertinib after the Development of Osimertinib-induced Urticaria in a Patient Undergoing Treatment for Non-small Cell Lung Cancer Harboring the EGFR T790M Mutation.

Go Makimoto, Tatsuya Nishi, Keita Kawakado, Tomoka Nishimura, Tomoki Tamura, Kenichiro Kudo, Shoichi Kuyama

Internal medicine (Tokyo, Japan) 59 ( 17 ) 2161 - 2164 2020年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

Some patients discontinue receiving osimertinib for non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) Thr790Met (T790M) mutation due to adverse its effects. We report a case of successful desensitization therapy after osimertinib-induced urticaria. An 85-year-old Japanese woman received osimertinib as third-line therapy for NSCLC with the EGFR T790M mutation. After two days, she developed urticaria of the lower extremities. We started osimertinib desensitization therapy at 0.1 mg/day, which was gradually increased to 40 mg/day. She continued osimertinib for >12 months without adverse effects. Desensitization therapy with osimertinib could be useful for patients experiencing osimertinib-induced urticaria.

DOI： 10.2169/internalmedicine.4429-20

Dramatic Response of Brain Metastasis from EGFR-mutation-positive NSCLC to Dacomitinib.

Kenichiro Kudo, Keita Kawakado, Tomoka Kawajiri, Tatsuya Nishi, Go Makimoto, Tomoki Tamura, Shoichi Kuyama, Mitsune Tanimoto

Internal medicine (Tokyo, Japan) 59 ( 14 ) 1739 - 1740 2020年7月

記述言語：英語掲載種別：研究論文（学術雑誌）

The central nervous system efficacy of dacomitinib, a key agent used in the treatment of epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC), is unclear. We herein present our experience in the use of dacomitinib for the treatment of multiple brain metastatic lesions from EGFR-mutation-positive NSCLC in an elderly patient. This case report demonstrates that dacomitinib can be an essential treatment option for patients with brain metastases.

DOI： 10.2169/internalmedicine.4449-20

Successful Re-administration of Osimertinib in Osimertinib-induced Interstitial Lung Disease with an Organizing Pneumonia Pattern: A Case Report and Literature Review.

Junko Itano, Hisao Higo, Kadoaki Ohashi, Go Makimoto, Kazuya Nishii, Katsuyuki Hotta, Nobuaki Miyahara, Yoshinobu Maeda, Katsuyuki Kiura

Internal medicine (Tokyo, Japan) 59 ( 6 ) 823 - 828 2020年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

Osimertinib is the standard therapy for epidermal-growth-factor-receptor (EGFR)-mutant lung cancers. We herein report a case of osimertinib-induced interstitial lung disease (OsiILD) with an organizing pneumonia (OP) pattern and provide a literature-based review. Six months after osimertinib administration, a 75-year-old woman with right pleural carcinomatosis developed ILD with an OP pattern. After salvage chemotherapy, osimertinib with corticosteroid was successfully re-administered. A literature review suggested that 1) OsiILD with an OP pattern was rare but should be recognized, and 2) re-administration of osimertinib in OsiILD was successful in select patients. A criterion that determines whether a patient would benefit from re-administration is warranted.

DOI： 10.2169/internalmedicine.3689-19

Patients' preferences and perceptions of lung cancer treatment decision making: results from Okayama lung cancer study group trial 1406. 国際誌

Go Makimoto, Katsuyuki Hotta, Isao Oze, Kiichiro Ninomiya, Masamoto Nakanishi, Naofumi Hara, Hirohisa Kano, Hiromi Watanabe, Yusuke Hata, Kazuya Nishii, Takamasa Nakasuka, Junko Itano, Takashi Ninomiya, Toshio Kubo, Kadoaki Ohashi, Eiki Ichihara, Daisuke Minami, Akiko Sato, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura

Acta oncologica (Stockholm, Sweden) 59 ( 3 ) 324 - 328 2020年3月

Rapid Acquisition of Alectinib Resistance in ALK-Positive Lung Cancer With High Tumor Mutation Burden. 国際誌

Go Makimoto, Kadoaki Ohashi, Shuta Tomida, Kazuya Nishii, Takehiro Matsubara, Hiroe Kayatani, Hisao Higo, Kiichiro Ninomiya, Akiko Sato, Hiromi Watanabe, Hirohisa Kano, Takashi Ninomiya, Toshio Kubo, Kammei Rai, Eiki Ichihara, Katsuyuki Hotta, Masahiro Tabata, Shinichi Toyooka, Minoru Takata, Yoshinobu Maeda, Katsuyuki Kiura

Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 14 ( 11 ) 2009 - 2018 2019年11月

記述言語：英語掲載種別：研究論文（学術雑誌）

INTRODUCTION: The highly selective ALK receptor tyrosine kinase (ALK) inhibitor alectinib is standard therapy for ALK-positive lung cancers; however, some tumors quickly develop resistance. Here, we investigated the mechanism associated with rapid acquisition of resistance using clinical samples. METHODS: Autopsied samples were obtained from lung, liver, and renal tumors from a 51-year-old male patient with advanced ALK-positive lung cancer who had acquired resistance to alectinib in only 3 months. We established an alectinib-resistant cell line (ABC-14) from pleural effusion and an alectinib/crizotinib-resistant cell line (ABC-17) and patient-derived xenograft (PDX) model from liver tumors. Additionally, we performed next-generation sequencing, direct DNA sequencing, and quantitative real-time reverse transcription polymerase chain reaction. RESULTS: ABC-14 cells harbored no ALK mutations and were sensitive to crizotinib while also exhibiting MNNG HOS transforming gene (MET) gene amplification and amphiregulin overexpression. Additionally, combined treatment with crizotinib/erlotinib inhibited cell growth. ABC-17 and PDX tumors harbored ALK G1202R, and PDX tumors metastasized to multiple organs in vivo, whereas the third-generation ALK-inhibitor, lorlatinib, diminished tumor growth in vitro and in vivo. Next-generation sequencing indicated high tumor mutation burden and heterogeneous tumor evolution. The autopsied lung tumors harbored ALK G1202R (c. 3604 G>A) and the right renal metastasis harbored ALK G1202R (c. 3604 G>C); the mutation thus comprised different codon changes. CONCLUSIONS: High tumor mutation burden and heterogeneous tumor evolution might be responsible for rapid acquisition of alectinib resistance. Timely lorlatinib administration or combined therapy with an ALK inhibitor and other receptor tyrosine-kinase inhibitors might constitute a potent strategy.

DOI： 10.1016/j.jtho.2019.07.017

腫瘍免疫と微小環境遺伝子改変EGFR変異肺癌マウスモデルの腫瘍免疫回避経路の検討

西井和也, 大橋圭明, 槇本剛, 渡邉洋美, 狩野裕久, 原尚史, 中須賀崇匡, 安東千裕, 二宮貴一朗, 加藤有加, 二宮崇, 久保寿夫, 頼冠名, 市原英基, 堀田勝幸, 田端雅弘, 鵜殿平一郎, 木浦勝行

肺癌 59 ( 6 ) 567 - 567 2019年11月

臨床的疑問より発した研究-Reverse translational research High tumor mutation burdenのALK陽性肺癌におけるアレクチニブ早期耐性について

槇本剛, 大橋圭明, 冨田秀太, 二宮貴一朗, 久保寿夫, 頼冠名, 市原英基, 堀田勝幸, 田端雅弘, 豊岡伸一, 木浦勝行

肺癌 59 ( 6 ) 571 - 571 2019年11月

A Long-term Response to Nivolumab in a Case of PD-L1-negative Lung Adenocarcinoma with an EGFR Mutation and Surrounding PD-L1-positive Tumor-associated Macrophages.

Hiromi Watanabe, Kadoaki Ohashi, Kazuya Nishii, Keisuke Seike, Go Makimoto, Katsuyuki Hotta, Yoshinobu Maeda, Katsuyuki Kiura

Internal medicine (Tokyo, Japan) 58 ( 20 ) 3033 - 3037 2019年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

Anti-programmed cell death 1 (PD-1) antibodies have poor efficacy in epidermal growth factor receptor (EGFR)-mutated lung cancer. We herein report a 72-year-old man with programmed cell death-ligand 1 (PD-L1)-negative lung adenocarcinoma harboring an EGFR mutation that responded to nivolumab for more than 2 years. A pathological examination revealed infiltration of CD8-positive lymphocytes and macrophages expressing CD68, CD206, and PD-L1 into the PD-L1-negative tumor; CD206 expression is a marker of immunosuppressive tumor-associated macrophages (TAMs). The presence of PD-L1-positive TAMs in the tumor environment might be a predictor of a positive response to anti-PD-1 antibodies.

DOI： 10.2169/internalmedicine.2875-19

EGFR-TKI acquired resistance in lung cancers harboring EGFR mutations in immunocompetent C57BL/6J mice. 国際誌

Hisao Higo, Kadoaki Ohashi, Go Makimoto, Kazuya Nishii, Kenichiro Kudo, Hiroe Kayatani, Hiromi Watanabe, Hirohisa Kano, Kiichiro Ninomiya, Katsuyuki Hotta, Yoshinobu Maeda, Katsuyuki Kiura

Lung cancer (Amsterdam, Netherlands) 136 86 - 93 2019年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

OBJECTIVES: Lung cancers harboring epidermal growth factor receptor (EGFR) mutations inevitably develop resistance to EGFR tyrosine-kinase inhibitors (EGFR-TKIs). Therefore, we sought to establish clinically relevant lung-cancer mouse models to achieve deep remission of cancers. MATERIALS AND METHODS: We previously established two transgenic lung-cancer mouse models harboring human EGFR exon 21 L858R substitution (hLR) and mouse Egfr exon 19 deletion (mDEL) in the C57BL/6 J background. Lung tumors from these two transgenic mouse strains were transplanted subcutaneously into BALB/c-nunu mice or C57BL/6 J mice. RESULTS: The transplanted tumors developed the ability to grow on the subcutaneous tissue, peritoneum, or lung of C57BL/6 J mice. While hLR tumors could grow only in C57BL/6 J mice carrying the transgene, mDEL tumors could grow in wild-type C57BL/6 J mice. The tumors maintained EGFR-dependency, and, thus, the EGFR-TKI gefitinib inhibited tumor growth; however, similar to human lung cancers, hLR and mDEL tumors acquired resistance in 60 and 200 days, respectively, following gefitinib administration. Secondary EGFR T790 M mutation in hLR tumors and secondary Egfr T792I mutation in mDEL tumors developed; however, no MET activation was detected. Accordingly, the third-generation EGFR-TKI osimertinib effectively inhibited gefitinib-resistant tumors in vivo. Furthermore, gefitinib-resistant tumors developed resistance to osimertinib in 100 days. CONCLUSION: These syngeneic lung-cancer mouse models harboring EGFR mutations are suitable for studying the drug-resistance mechanisms and the role of the tumor microenvironment. Further investigation with these mouse models is warranted for developing next-generation treatment strategies for lung cancer.

DOI： 10.1016/j.lungcan.2019.08.019

SHP2阻害薬によるクリゾチニブのROS1陽性肺癌細胞阻害効果の増強(SHP2 inhibitor enhanced the effects of crizotinib in ROS1 rearranged lung cancer cell lines)

狩野裕久, 市原英基, 原尚史, 渡邉洋美, 西井和也, 槇本剛, 二宮貴一朗, 久保寿夫, 頼冠名, 大橋圭明, 前田嘉信, 木浦勝行

日本癌学会総会記事 78回 E - 3031 2019年9月

Primary Resistance to Alectinib Was Lost after Bevacizumab Combined Chemotherapy in ALK-Rearranged Lung Adenocarcinoma. 国際誌

Takamasa Nakasuka, Eiki Ichihara, Go Makimoto, Yoshinobu Maeda, Katsuyuki Kiura

Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 14 ( 8 ) e168-e169 2019年8月

Recent trends in the treatment of unresectable stage III non-small-cell lung cancer. 国際誌

Go Makimoto, Katsuyuki Hotta, Katsuyuki Kiura

Respiratory investigation 57 ( 4 ) 330 - 336 2019年7月

記述言語：英語掲載種別：研究論文（学術雑誌）

Approximately 20-25% of non-small-cell lung cancer (NSCLC) is diagnosed when the disease has progressed to clinical stage III. At this stage, and even if the cancer is considered unresectable, the treatment strategy should aim to achieve a cure. At the time of the initial diagnosis, it is necessary for medical oncologists to devise the best treatment strategy for each patient by composing a multidisciplinary treatment team including thoracic surgeons and radiation oncologists. In this review, we summarize prior pivotal clinical trials in unresectable clinical stage III NSCLC. Furthermore, we review very recent clinical trials evaluating the efficacy of immune checkpoint inhibitors in the treatment of NSCLC.

DOI： 10.1016/j.resinv.2019.03.004

Beneficial Effect of Osimertinib Readministration in Non-small-cell Lung Cancer Harboring an Epidermal Growth Factor Receptor (EGFR) Mutation with a History of Acquired Resistance to Osimertinib.

Go Makimoto, Kadoaki Ohashi, Satoru Senoo, Katsuyuki Hotta, Yoshinobu Maeda, Katsuyuki Kiura

Internal medicine (Tokyo, Japan) 58 ( 11 ) 1625 - 1627 2019年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

We herein report a case of the beneficial effect of osimertinib readministration in non-small-cell lung cancer (NSCLC) harboring an epidermal growth factor receptor (EGFR) mutation. A 69-year-old non-smoking woman was diagnosed with advanced NSCLC harboring an EGFR exon19 deletion and T790M. She was treated with osimertinib for two years but eventually acquired resistance. After 1.5 years of salvage chemotherapies, osimertinib was re-administered. She has been effectively and safely treated with osimertinib readministration for over 10 months. A prospective study is warranted to evaluate the efficacy and safety of osimertinib readministration in NSCLC with EGFR mutations.

DOI： 10.2169/internalmedicine.2152-18

Successful Treatment of Metastatic Urothelial Carcinoma after Accurate Diagnosis by Immunohistochemistry.

Go Makimoto, Hisakazu Nishimori, Reiko Kondo, Hiroyuki Yanai, Morito Sugimoto, Naohiro Oda, Toshio Kubo, Katsuyuki Hotta, Masahiro Tabata, Katsuyuki Kiura, Yoshinobu Maeda

Acta medica Okayama 73 ( 3 ) 279 - 284 2019年6月

記述言語：英語

Urothelial carcinoma usually presents with hematuria, but cases of multiple lymphadenopathy with elevated S-pancreas-1 antigen (SPan-1) levels have not been reported. A 62-year-old Japanese man with lymphadenopathies was diagnosed with an adenocarcinoma of unknown origin and transferred to our hospital for further diagnosis. Serum carbohydrate antigen 19-9 and SPan-1 levels were extremely elevated. Uroplakin III immunostaining was positive in the inguinal lymph node, and cystoscopy revealed the presence of invasive urothelial carcinoma. Treatment with cisplatin and gemcitabine promoted a complete metabolic response for > 4 years. The detection of uroplakin III and serum SPan-1 might help diagnose urothelial carcinoma.

DOI： 10.18926/AMO/56873

Chemoradiotherapy for locally advanced lung cancer patients with interstitial lung abnormalities. 国際誌

Hisao Higo, Toshio Kubo, Satoko Makimoto, Go Makimoto, Hiroki Ihara, Yoshihisa Masaoka, Takashi Ninomiya, Eiki Ichihara, Kadoaki Ohashi, Akiko Sato, Katsuyuki Hotta, Masahiro Tabata, Nagio Takigawa, Yoshinobu Maeda, Katsuyuki Kiura

Japanese journal of clinical oncology 49 ( 5 ) 458 - 464 2019年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

INTRODUCTION: Although chemoradiotherapy for locally advanced lung cancer has the potential for cure, treatment is avoided in patients with interstitial lung disease because of the risk for severe radiation pneumonitis. Interstitial lung abnormalities (ILA) can be evaluated using high-resolution computed tomography (HRCT) to assess interstitial changes. In this study, we retrospectively examined the feasibility and efficacy of chemoradiotherapy for locally advanced lung cancer patients with ILA. METHODS: Patients who underwent chemoradiotherapy for locally advanced lung cancer at Okayama University Hospital between 2012 and 2015 were reviewed retrospectively. HRCT prior to treatment was evaluated by one pulmonologist and two radiologists using a sequential reading method. RESULTS: Of the 77 patients enrolled in this study, ILA was present in 25 (32.5%) and indeterminate ILA in 24 patients; 28 patients did not have ILA. Desaturation at rest (SpO2 < 95%) and honeycombing on HRCT were not observed in ILA patients. Only one patient with ILA had a low vital capacity (%VC < 80%). Severe radiation pneumonitis (≥Grade 2) occurred in 36.0% of the patients with ILA, but it was controllable; Grade 4 or 5 was not observed. Multivariate analysis showed that >25% of the lung volume receiving >20 Gy was risk factors of severe radiation pneumonitis, but ILA was not. The 2-year survival rates of patients with and without ILA were 56.8% and 74.1%, respectively, but the difference was not significant (P = 0.33). CONCLUSIONS: Chemoradiotherapy was feasible and effective in some patient population with ILA without desaturation, low VC and honeycombing on HRCT.

DOI： 10.1093/jjco/hyz016

Rapid and Long-term Response of Pulmonary Pleomorphic Carcinoma to Nivolumab.

Satoru Senoo, Takashi Ninomiya, Go Makimoto, Kazuya Nishii, Hirohisa Kano, Hiromi Watanabe, Yusuke Hata, Toshio Kubo, Takehiro Tanaka, Katsuyuki Hotta, Yoshinobu Maeda, Katsuyuki Kiura

Internal medicine (Tokyo, Japan) 58 ( 7 ) 985 - 989 2019年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

Pulmonary pleomorphic carcinoma (PPC) is a rare very aggressive subtype of non-small cell lung cancer. We herein report a case of PPC that showed a rapid response to nivolumab. The patient, whose multiple tumors had progressed very aggressively, was treated with nivolumab, an anti-programmed cell death-1 (PD-1) antibody. The tumors dramatically shrank after one cycle of nivolumab. The tumors were positive for programmed cell death ligand 1 (PD-L1). An immunohistochemical analysis revealed numerous PD-1+, CD68+ and CD206+ macrophages. This PD-1 antibody may be a good treatment option, especially in tumors that express PD-L1 and which show PD-1+ macrophage infiltration.

DOI： 10.2169/internalmedicine.0890-18

Long-term spontaneous remission with active surveillance in IgG4-related pleuritis: A case report and literature review. 国際誌

Go Makimoto, Kadoaki Ohashi, Kohei Taniguchi, Junichi Soh, Akihiko Taniguchi, Nobuaki Miyahara, Shinichi Toyooka, Tadashi Yoshino, Yoshinobu Maeda, Katsuyuki Kiura

Respiratory medicine case reports 28 100938 - 100938 2019年

記述言語：英語

Pleural effusion is a relatively rare feature of IgG4-related disease (IgG4-RD). Here, we report a case of a 72-year-old woman who presented with pleural effusion. Although the pleural adenosine deaminase level was increased, surgical biopsy of the pleura and left inguinal lymph node indicated that the effusion was due to IgG4-RD. Active surveillance was initiated because serum IgG4 and pleural effusion naturally decreased and then completely disappeared. The patient has shown no recurrence for >4 years. This case suggests that pleural biopsy can be used to distinguish IgG4-RD from tuberculosis; moreover, some cases with pleural effusion could improve without treatment.

DOI： 10.1016/j.rmcr.2019.100938

Combined effect of cabozantinib and gefitinib in crizotinib-resistant lung tumors harboring ROS1 fusions. 国際誌

Yuka Kato, Kiichiro Ninomiya, Kadoaki Ohashi, Shuta Tomida, Go Makimoto, Hiromi Watanabe, Kenichiro Kudo, Shingo Matsumoto, Shigeki Umemura, Koichi Goto, Eiki Ichihara, Takashi Ninomiya, Toshio Kubo, Akiko Sato, Katsuyuki Hotta, Masahiro Tabata, Shinichi Toyooka, Yoshinobu Maeda, Katsuyuki Kiura

Cancer science 109 ( 10 ) 3149 - 3158 2018年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

The ROS1 tyrosine kinase inhibitor (TKI) crizotinib has shown dramatic effects in patients with non-small cell lung cancer (NSCLC) harboring ROS1 fusion genes. However, patients inevitably develop resistance to this agent. Therefore, a new treatment strategy is required for lung tumors with ROS1 fusion genes. In the present study, lung cancer cell lines, HCC78 harboring SLC34A2-ROS1 and ABC-20 harboring CD74-ROS1, were used as cell line-based resistance models. Crizotinib-resistant HCC78R cells were established from HCC78. We comprehensively screened the resistant cells using a phosphor-receptor tyrosine kinase array and RNA sequence analysis by next-generation sequencing. HCC78R cells showed upregulation of HB-EGF and activation of epidermal growth factor receptor (EGFR) phosphorylation and the EGFR signaling pathway. Recombinant HB-EGF or EGF rendered HCC78 cells or ABC-20 cells resistant to crizotinib. RNA sequence analysis by next-generation sequencing revealed the upregulation of AXL in HCC78R cells. HCC78R cells showed marked sensitivity to EGFR-TKI or anti-EGFR antibody treatment in vitro. Combinations of an AXL inhibitor, cabozantinib or gilteritinib, and an EGFR-TKI were more effective against HCC78R cells than monotherapy with an EGFR-TKI or AXL inhibitor. The combination of cabozantinib and gefitinib effectively inhibited the growth of HCC78R tumors in an in vivo xenograft model of NOG mice. The results of this study indicated that HB-EGF/EGFR and AXL play roles in crizotinib resistance in lung cancers harboring ROS1 fusions. The combination of cabozantinib and EGFR-TKI may represent a useful alternative treatment strategy for patients with advanced NSCLC harboring ROS1 fusion genes.

DOI： 10.1111/cas.13752

EMT化を示すAlectinib耐性後の患者由来新規ALK肺癌細胞株の樹立とその耐性化の克服

槇本剛, 大橋圭明, 佐藤晃子, 渡邉洋美, 二宮貴一朗, 二宮崇, 頼冠名, 久保寿夫, 市原英基, 片山英樹, 堀田勝幸, 田端雅弘, 豊岡伸一, 前田嘉信, 木浦勝行

肺癌 58 ( 6 ) 599 - 599 2018年10月

デジタルPCR法による呼気濃縮液を用いたEGFR遺伝子診断法の検討

西井和也, 大橋圭明, 田村朋季, 妹尾賢, 狩野裕久, 渡邉洋美, 小田尚廣, 槇本剛, 肥後寿夫, 二宮貴一朗, 加藤有加, 南大輔, 二宮崇, 久保寿夫, 堀田勝幸, 田端雅弘, 冨田秀太, 豊岡伸一, 前田嘉信, 木浦勝行

肺癌 58 ( 6 ) 597 - 597 2018年10月

Randomized Phase II Study Comparing Mannitol with Furosemide for the Prevention of Renal Toxicity Induced by Cisplatin-based Chemotherapy with Short-term Low-volume Hydration in Advanced Non-small Cell Lung Cancer: The OLCSG1406 Study Protocol.

Go Makimoto, Eiki Ichihara, Katsuyuki Hotta, Kiichiro Ninomiya, Isao Oze, Daisuke Minami, Takashi Ninomiya, Toshio Kubo, Kadoaki Ohashi, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura

Acta medica Okayama 72 ( 3 ) 319 - 323 2018年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

Although cisplatin-based chemotherapy shows a survival advantage compared to carboplatin for treating advanced non-small cell lung cancer, high-volume hydration and a long infusion time are necessary to avoid nephrotoxicity, and cisplatin-based chemotherapy has been difficult to administer in outpatient settings. A low-volume hydration method using mannitol or furosemide as forced diuresis was recently introduced, but there are no clear conclusions regarding which agent should be used. We describe our ongoing randomized phase II trial (the OLCSG1406 Study) evaluating the efficacy of forced diuresis. This study will clarify whether mannitol or furosemide is more suitable in cisplatin-based chemotherapy with low-volume hydration.

DOI： 10.18926/AMO/56080

Second primary cancer in survivors of locally advanced non-small cell lung cancer treated with concurrent chemoradiation followed by surgery. 国際誌

Go Makimoto, Toshio Kubo, Isao Oze, Kadoaki Ohashi, Katsuyuki Hotta, Masahiro Tabata, Junichi Soh, Shinichi Toyooka, Kuniaki Katsui, Nagio Takigawa, Mitsune Tanimoto, Katsuyuki Kiura

Japanese journal of clinical oncology 48 ( 3 ) 287 - 290 2018年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

The standard treatment for patients with locally advanced non-small-cell lung cancer (LA-NSCLC) is chemoradiotherapy (CRT), but surgical resection following induction CRT can extend overall survival in a select population. However, patients who survive longer are at risk of developing a second primary cancer (SPC). This is the first report to determine the incidence of SPC in survivors with LA-NSCLC after trimodal therapy. Between October 1997 and October 2013, 112 Stage III NSCLC patients underwent trimodal therapy in our hospital. The 5-year overall survival rate was 71.8%. SPC developed in 10 of the 112 patients 0.60-15.0 (median 5.49) years after initiating CRT. The observed incidence of SPC was 1.8 per 100 patient-years. Although trimodal therapy can prolong patient survival, the estimated incidence of SPC does not increase. A large prospective study with a longer follow-up time is required to determine the effects of trimodal therapy, including the development of SPC.

DOI： 10.1093/jjco/hyy003

MET or NRAS amplification is an acquired resistance mechanism to the third-generation EGFR inhibitor naquotinib. 国際誌

Kiichiro Ninomiya, Kadoaki Ohashi, Go Makimoto, Shuta Tomida, Hisao Higo, Hiroe Kayatani, Takashi Ninomiya, Toshio Kubo, Eiki Ichihara, Katsuyuki Hotta, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura

Scientific reports 8 ( 1 ) 1955 - 1955 2018年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

As a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), osimeritnib is the standard treatment for patients with non-small cell lung cancer harboring the EGFR T790M mutation; however, acquired resistance inevitably develops. Therefore, a next-generation treatment strategy is warranted in the osimertinib era. We investigated the mechanism of resistance to a novel EGFR-TKI, naquotinib, with the goal of developing a novel treatment strategy. We established multiple naquotinib-resistant cell lines or osimertinib-resistant cells, two of which were derived from EGFR-TKI-naïve cells; the others were derived from gefitinib- or afatinib-resistant cells harboring EGFR T790M. We comprehensively analyzed the RNA kinome sequence, but no universal gene alterations were detected in naquotinib-resistant cells. Neuroblastoma RAS viral oncogene homolog (NRAS) amplification was detected in naquotinib-resistant cells derived from gefitinib-resistant cells. The combination therapy of MEK inhibitors and naquotinib exhibited a highly beneficial effect in resistant cells with NRAS amplification, but the combination of MEK inhibitors and osimertinib had limited effects on naquotinib-resistant cells. Moreover, the combination of MEK inhibitors and naquotinib inhibited the growth of osimertinib-resistant cells, while the combination of MEK inhibitors and osimertinib had little effect on osimertinib-resistant cells. Clinical assessment of this novel combination (MEK inhibitors and naquotinib) is worth considering in osimertinib-resistant lung tumors.

DOI： 10.1038/s41598-018-20326-z

Potential influence of interleukin-6 on the therapeutic effect of gefitinib in patients with advanced non-small cell lung cancer harbouring EGFR mutations. 国際誌

Tomoki Tamura, Yuka Kato, Kadoaki Ohashi, Kiichiro Ninomiya, Go Makimoto, Hiroko Gotoda, Toshio Kubo, Eiki Ichihara, Takehiro Tanaka, Koichi Ichimura, Yoshinobu Maeda, Katsuyuki Hotta, Katsuyuki Kiura

Biochemical and biophysical research communications 495 ( 1 ) 360 - 367 2018年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

Although epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are a key therapy used for patients with EGFR-mutant non-small cell lung cancer (NSCLC), some of whom do not respond well to its therapy. Cytokine including IL-6 secreted by tumour cells is postulated as a potential mechanism for the primary resistance or low sensitivity to EGFR-TKIs. Fifty-two patients with advanced EGFR-mutant NSCLC who had received gefitinib were assessed retrospectively. The protein expression of IL-6 in the tumour cells was assessed by immunostaining and judged as positive if ≥ 50 of 100 tumour cells stained positively. Of the 52 patients, 24 (46%) and 28 (54%) were defined as IL-6-postitive (group P) and IL-6-negative (group N), respectively. Group P had worse progression-free survival (PFS) than that of group N, which was retained in the multivariate analysis (hazard ratio: 2.39; 95 %CI: 1.00-5.68; p < 0.05). By contrast, the PFS after platinum-based chemotherapy did not differ between groups P and N (p = 0.47). In cell line-based model, the impact of IL-6 on the effect of EGFR-TKIs was assessed. The combination of EGFR-TKI and anti-IL-6 antibody moderately improved the sensitivity of EGFR-TKI in lung cancer cell with EGFR mutation. Interestingly, suppression of EGFR with EGFR-TKI accelerated the activation of STAT3 induced by IL-6. Taken together, tumour IL-6 levels might indicate a subpopulation of EGFR-mutant NSCLC that benefits less from gefitinib monotherapy.

DOI： 10.1016/j.bbrc.2017.10.175

Triplet therapy with afatinib, cetuximab, and bevacizumab induces deep remission in lung cancer cells harboring EGFR T790M in vivo. 国際誌

Kenichiro Kudo, Kadoaki Ohashi, Go Makimoto, Hisao Higo, Yuka Kato, Hiroe Kayatani, Yasuko Kurata, Yoichiro Takami, Daisuke Minami, Takashi Ninomiya, Toshio Kubo, Eiki Ichihara, Akiko Sato, Katsuyuki Hotta, Tadashi Yoshino, Mitsune Tanimoto, Katsuyuki Kiura

Molecular oncology 11 ( 6 ) 670 - 681 2017年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have changed the treatment strategy for EGFR-mutant lung cancers; however, resistance usually occurs due to a secondary mutation, T790M, in EGFR. Combination therapy using afatinib and cetuximab has had good results in lung tumors harboring EGFRT790M mutations in clinical trials. The effect of bevacizumab, an antivascular endothelial growth factor (VEGF) antibody, combined with EGFR-TKIs has also been investigated. We hypothesized that the dose of afatinib and cetuximab could be reduced by combination with bevacizumab and that the triplet therapy may result in better tumor inhibition with tolerable toxicity. Using a xenograft mouse model with H1975-harboring EGFRL858R+T790M and RPC-9-harboring EGFR19DEL+T790M , we tested the efficacy of the triplet therapy with a modified dose of afatinib, cetuximab, and bevacizumab, and compared this therapy to single and double therapies. Triplet therapy with afatinib, cetuximab, and bevacizumab induced pathological complete remission in xenograft tumors with H1975 and RPC-9 cells versus tumors treated with single or double therapies. We saw no body weight loss in the mice. The triple therapy induced a significant reduction in CD31-positive vascular endothelial cells and increased cleaved caspase-3-positive cells in the tumors. This suggests that one mechanism underlying the deep remission could be suppression of neovascularization and induction of apoptosis by intensive inhibition of driver oncoproteins and VEGF. These results highlight the potential of afatinib, cetuximab, and bevacizumab to induce deep remission in tumors harboring EGFRT790M mutations. Therefore, clinical trials of this combination therapy are warranted.

DOI： 10.1002/1878-0261.12063

腫瘍疫学・基礎 EGFR変異を有する肺癌細胞株における第三世代EGFR-TKI耐性機序の検討

二宮貴一朗, 大橋圭明, 槇本剛, 肥後寿夫, 萱谷紘枝, 田村朋季, 二宮崇, 久保寿夫, 市原英基, 佐藤晃子, 堀田勝幸, 谷本光音, 木浦勝行

日本呼吸器学会誌 6 ( 増刊 ) 142 - 142 2017年3月

同時化学放射線療法後の手術により治療した局所進行性NSCLCの生存者における第二原発性癌(Second primary cancer in survivors of locally advanced NSCLC treated with concurrent chemoradiation followed by surgery)

Makimoto Go, Kubo Toshio, Oze Isao, Ohashi Kadoaki, Hotta Katsuyuki, Takigawa Nagio, Toyooka Shinichi, Katsui Kuniaki, Tanimoto Mitsune, Kiura Katsuyuki

日本呼吸器学会誌 6 ( 増刊 ) 345 - 345 2017年3月

Heerfordt's Syndrome Associated with a High Fever and Elevation of TNF-α.

Go Makimoto, Nobuaki Miyahara, Mao Yoshikawa, Akihiko Taniguchi, Arihiko Kanehiro, Mitsune Tanimoto, Katsuyuki Kiura

Acta medica Okayama 70 ( 4 ) 273 - 7 2016年8月

記述言語：英語

Heerfordt's syndrome is a rare manifestation of sarcoidosis and is defined as a combination of facial palsy, parotid swelling, and uveitis, associated with a low-grade fever. We report a case of Heerfordt's syndrome presenting with a high fever and increased serum tumor necrosis factor alpha (TNF-α) levels. The patient had facial palsy, parotid swelling, uveitis, and swelling of the right supraclavicular and hilar lymph nodes. Corticosteroid therapy was initiated, and her symptoms soon resolved completely, in tandem with a decrease in TNF-α serum levels.

ボリュームアナライザーSYNAPSE VINCENTを用いたガイドシース併用気管支腔内超音波断層法の肺癌診断への導入効果

南大輔, 瀧川奈義夫, 槇本剛, 狩野裕久, 秦雄介, 渡邊洋美, 中西将元, 二宮崇, 久保寿夫, 大橋圭明, 堀田勝幸, 宮原信明, 金廣有彦, 田端雅弘, 谷本光音, 木浦勝行

気管支学 38 ( 2 ) 153 - 153 2016年3月

PET-CTで縦隔・肺門リンパ節陽性肺癌に対するEBUS-TBNAの有用性

南大輔, 瀧川奈義夫, 槇本剛, 狩野裕久, 秦雄介, 渡邉洋美, 中西将元, 加藤有加, 二宮崇, 久保寿夫, 大橋圭明, 堀田勝幸, 宮原信明, 金廣有彦, 田端雅弘, 谷本光音, 木浦勝行

日本呼吸器学会誌 5 ( 増刊 ) 187 - 187 2016年3月

放射線化学療法後に外科手術を行った局所進行非小細胞肺癌症例の長期フォローアップ解析

槇本剛, 久保寿夫, 南大輔, 大橋圭明, 堀田勝幸, 田端雅弘, 豊岡伸一, 勝井邦彰, 谷本光音, 木浦勝行

日本内科学会雑誌 105 ( Suppl. ) 192 - 192 2016年2月

肺類上皮血管内皮腫の1例

田中晶平, 小田尚廣, 佐藤晃子, 宮原信明, 狩野裕久, 中西将元, 秦雄介, 槇本剛, 久保寿夫, 大橋圭明, 二宮崇, 堀田勝幸, 金廣有彦, 田端雅弘, 谷本光音, 木浦勝行, 牧佑歩, 宗淳一, 豊岡伸一, 三好新一郎

肺癌 55 ( 7 ) 1127 - 1127 2015年12月

III期肺腺癌に対する化学療法併用根治的外科切除から15年後に発症した放射線誘発軟部肉腫の1例

中野靖浩, 豊田容輔, 大橋圭明, 小田尚廣, 槇本剛, 久保寿夫, 木浦勝行, 谷本光音, 山口隆廣, 柳井広之

肺癌 55 ( 7 ) 1128 - 1128 2015年12月

薬疹、薬剤性肺炎を治療経過で認めた胸腺癌にnab-paclitaxel単剤療法が有用であった1例

河合三津保, 南大輔, 槇本剛, 中西将元, 小田尚廣, 豊田容輔, 肥後寿夫, 二宮崇, 久保寿夫, 大橋圭明, 佐藤晃子, 堀田勝幸, 宮原信明, 金廣有彦, 田端雅弘, 谷本光音, 木浦勝行

肺癌 55 ( 7 ) 1126 - 1126 2015年12月

当院呼吸器内科おけるペグフィルグラスチムの使用経験

渡邉洋美, 久保寿夫, 中西将元, 槇本剛, 秦雄介, 狩野裕久, 加藤有加, 南大輔, 二宮崇, 大橋圭明, 堀田勝幸, 田端雅弘, 谷本光音, 木浦勝行

肺癌 55 ( 5 ) 711 - 711 2015年10月

当院における進行非小細胞肺癌患者に対するrebiopsyの検討

狩野裕久, 久保寿夫, 南大輔, 中西将元, 槇本剛, 秦雄介, 渡邉洋美, 加藤有加, 二宮崇, 大橋圭明, 堀田勝幸, 田端雅弘, 谷本光音, 木浦勝行

肺癌 55 ( 5 ) 457 - 457 2015年10月

PET-CTにて縦隔・肺門リンパ節転移陽性の肺癌症例における超音波気管支鏡ガイド下針生検の有用性

南大輔, 瀧川奈義夫, 小田尚廣, 槇本剛, 二宮貴一朗, 豊田容輔, 肥後寿夫, 久保寿夫, 大橋圭明, 佐藤晃子, 堀田勝幸, 宮原信明, 金廣有彦, 田端雅弘, 谷本光音, 木浦勝行

気管支学 37 ( 3 ) 345 - 345 2015年5月

経気管支肺生検にて悪性リンパ腫と確定診断された4例

小田尚廣, 南大輔, 瀧川奈義夫, 槙本剛, 二宮貴一郎, 豊田容輔, 肥後寿夫, 久保寿夫, 大橋圭明, 佐藤晃子, 堀田勝幸, 宮原信明, 金廣有彦, 田端雅弘, 谷本光音, 木浦勝行

気管支学 37 ( 3 ) 350 - 350 2015年5月

腎移植後の免疫抑制療法に合併した肺クリプトコッカス症の診断にEBUS-GSが有用であった1例

槇本剛, 南大輔, 宮原信明, 久保寿夫, 大橋圭明, 佐藤晃子, 堀田勝幸, 金廣有彦, 田端雅弘, 谷本光音, 木浦勝行

気管支学 37 ( 3 ) 345 - 345 2015年5月

気管支鏡検査における迅速細胞診の進歩と問題点 BIOEVALUATORを用いた迅速細胞診断を併用した超音波気管支鏡ガイド下針生検の有用性

南大輔, 瀧川奈義夫, 槇本剛, 小田尚廣, 豊田容輔, 二宮貴一朗, 肥後寿夫, 久保寿夫, 大橋圭明, 佐藤晃子, 堀田勝幸, 宮原信明, 金廣有彦, 田端雅弘, 谷本光音, 木浦勝行

気管支学 37 ( Suppl. ) S151 - S151 2015年5月

PET-CTにて縦隔、肺門リンパ節転移偽陽性の肺癌症例における超音波気管支鏡ガイド下針生検の有用性

南大輔, 瀧川奈義夫, 小田尚廣, 槇本剛, 二宮貴一朗, 豊田容輔, 肥後寿夫, 久保寿夫, 大橋圭明, 佐藤晃子, 堀田勝幸, 宮原信明, 金廣有彦, 田端雅弘, 谷本光音, 木浦勝行

気管支学 37 ( Suppl. ) S193 - S193 2015年5月

ガイドシース併用気管支腔内超音波断層法による経気管支肺生検で確定診断された悪性リンパ腫の2例

肥後寿夫, 南大輔, 小田尚廣, 豊田容輔, 二宮貴一朗, 槇本剛, 谷口暁彦, 久保寿夫, 大橋圭明, 佐藤晃子, 堀田勝幸, 宮原信明, 田端雅弘, 金廣有彦, 谷本光音, 木浦勝行

気管支学 37 ( Suppl. ) S287 - S287 2015年5月

BIOEVALUATORを用いた迅速細胞診断を併用したEBUS-TBNAの有用性

槇本剛, 南大輔, 瀧川奈義夫, 二宮貴一朗, 小田尚廣, 豊田容輔, 肥後寿夫, 久保寿夫, 大橋圭明, 佐藤晃子, 堀田勝幸, 宮原信明, 金廣有彦, 田端雅弘, 谷本光音, 木浦勝行

日本呼吸器学会誌 4 ( 増刊 ) 216 - 216 2015年3月

ガイドシース併用気管支腔内超音波断層法の肺癌診断への導入効果

南大輔, 瀧川奈義夫, 二宮貴一朗, 小田尚廣, 豊田容輔, 槙本剛, 肥後寿夫, 久保寿夫, 大橋圭明, 佐藤晃子, 堀田勝幸, 宮原信明, 金廣有彦, 田端雅弘, 谷本光音, 木浦勝行

肺癌 54 ( 5 ) 534 - 534 2014年10月

ACTH産生胸腺神経内分泌腫瘍に合併したニューモシスチス肺炎の1例

枝木久典, 南大輔, 二宮貴一朗, 小田尚廣, 豊田容輔, 槇本剛, 肥後寿夫, 久保寿夫, 大橋圭明, 佐藤晃子, 堀田勝幸, 宮原信明, 金廣有彦, 田端雅弘, 谷本光音, 木浦勝行, 小松原基志, 稲垣兼一

肺癌 54 ( 4 ) 260 - 260 2014年8月

Phrenic nerve paralysis as the initial presentation in pleural sarcomatoid mesothelioma. 国際誌

Go Makimoto, Keiichi Fujiwara, Nobukazu Fujimoto, Ichiro Yamadori, Toshio Sato, Takumi Kishimoto

Case reports in oncology 7 ( 2 ) 389 - 92 2014年5月

記述言語：英語

A 74-year-old man was referred to our hospital because of persistent cough. A chest radiograph revealed an elevation of the right diaphragm. Computed tomography (CT) images revealed a small nodule localized on the right mediastinum. Five months later, the nodule had grown and was diagnosed as malignant pleural mesothelioma (MPM) by a CT-guided needle biopsy. The patient underwent combined chemotherapy, but the disease progressed rapidly and he passed away. On autopsy, microscopic findings and immunohistological examinations supported the diagnosis of sarcomatoid mesothelioma. Therefore, we diagnosed this rare case as localized sarcomatoid MPM showing phrenic nerve paralysis as an initial presentation.

DOI： 10.1159/000363760

nab-Paclitaxel in Combination with Carboplatin for a Previously Treated Thymic Carcinoma. 国際誌

Go Makimoto, Keiichi Fujiwara, Hiromi Watanabe, Nobuhisa Kameyama, Mizuho Matsushita, Kammei Rai, Ken Sato, Toshiro Yonei, Toshio Sato, Takuo Shibayama

Case reports in oncology 7 ( 1 ) 14 - 7 2014年1月

記述言語：英語

We present the case of a 40-year-old man with previously treated thymic carcinoma, complaining of gradually worsening back pain. Computed tomography scans of the chest showed multiple pleural disseminated nodules with a pleural effusion in the right thorax. The patient was treated with carboplatin on day 1 plus nab-paclitaxel on day 1 and 8 in cycles repeated every 4 weeks. Objective tumor shrinkage was observed after 4 cycles of this regimen. In addition, the elevated serum cytokeratin 19 fragment level decreased, and the patient's back pain was relieved without any analgesics. Although he experienced grade 4 neutropenia and granulocyte colony-stimulating factor (G-CSF) injection, the severity of thrombocytopenia and nonhematological toxicities such as reversible neuropathy did not exceed grade 1 during the treatment. To our knowledge, this is the first report to demonstrate the efficacy of combination chemotherapy consisting of carboplatin and nab-paclitaxel against thymic carcinoma. This case report suggests that nab-paclitaxel in combination with carboplatin can be a favorable chemotherapy regimen for advanced thymic carcinoma.

DOI： 10.1159/000357938

Diffuse parenchymal pulmonary amyloidosis showing an objective response to bortezomib-based chemotherapy.

Hisao Higo, Keiichi Fujiwara, Hiromi Watanabe, Go Makimoto, Nobuhisa Kameyama, Mizuho Matsushita, Kammei Rai, Ken Sato, Tomoko Inomata, Kazutaka Sunami, Takuo Shibayama

Internal medicine (Tokyo, Japan) 53 ( 16 ) 1809 - 12 2014年

記述言語：英語掲載種別：研究論文（学術雑誌）

A 77-year-old woman was admitted because of bilateral hand numbness and dyspnea on exertion. Her serum IgG was increased, and a bone marrow aspiration analysis supported a diagnosis of multiple myeloma. Additionally, computed tomography scans of the chest showed bilateral ground glass attenuations, linear opacities, and consolidations. Transbronchial lung biopsy revealed Congo Red-positive amorphous eosinophilic deposits. She was therefore diagnosed with diffuse parenchymal pulmonary amyloidosis accompanied by multiple myeloma. Following combination chemotherapy including bortezomib, her serum monoclonal protein levels were normalized, and pulmonary function and oxygenation improved.

Two cases of possible neuro-Sweet disease with meningoencephalitis as the initial manifestation. 国際誌

Go Makimoto, Yasuhiro Manabe, Chizuru Yamakawa, Daiki Fujii, Yasuko Ikeda-Sakai, Hisashi Narai, Nobuhiko Omori, Koji Abe

Neurology international 4 ( 1 ) e5 2012年1月

記述言語：英語

We report 2 cases that were considered to be neuro-Sweet disease. They initially manifested with meningoencephalitis and no skin lesions, and rapidly improved with corticosteroid therapy. In both cases, patients complained of meningitic symptoms such as fever and headache, and HLA-B54 and -Cw1 turned out to be positive over the clinical course. Cerebrospinal fluid analysis showed increased levels of lymphocytes and protein. In case #1, fluid-attenuated inversion recovery (FLAIR), magnetic resonance imaging (MRI) and diffusion-weighted images (DWI) showed high-intensity signals in the right dorsal medulla oblongata, bilateral dorsal midbrain, and left thalamus. In case #2, FLAIR and DWI showed high-intensity signals in the bilateral cerebellar cortex and left caudate nucleus. Symptoms and MRI images were markedly improved in both cases after corticosteroid pulse therapy. According to published diagnostic criteria, these 2 cases were considered possible neuro-Sweet disease. These cases suggest that the combination of meningoencephalitis and HLA specificity is important to consider the possibility of neuro-Sweet disease, even without skin lesions.

DOI： 10.4081/ni.2012.e5

Bilateral Pleural Effusions as an Initial Presentation in Primary Sjögren's Syndrome. 国際誌

Go Makimoto, Michiko Asano, Nobukazu Fujimoto, Yasuko Fuchimoto, Katsuichiro Ono, Shinji Ozaki, Koji Taguchi, Takumi Kishimoto

Case reports in rheumatology 2012 640353 - 640353 2012年

記述言語：英語掲載種別：研究論文（学術雑誌）

Sjögren's syndrome (SS) is a systemic autoimmune disease characterized by sicca symptoms. Interstitial pulmonary fibrosis and tracheobronchial sicca are the most common symptoms of pulmonary involvement in primary SjS, and they are rarely accompanied by serositis such as pleuritis or pericarditis. We report a case of SS presenting initially with bilateral pleural effusions. A 63-year old man was admitted to our hospital with a one-month history of cough, dyspnea, and right chest pain. Chest-computed tomography revealed bilateral pleural effusions. Serum anti-SS-A antibody titer was 1 : 256. Ophthalmological examination revealed a positive Schirmer test. Lip biopsy showed atrophy and plasmacytic infiltration of the salivary gland. Corticosteroid treatment was initiated. Pleural effusions were almost completely resolved by day 30. The patient has not experienced any recurrence.

DOI： 10.1155/2012/640353

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