Faculty Profiles - HOTTA Katsuyuki

Papers - HOTTA Katsuyuki

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osimertinibが誘導する抗腫瘍免疫はM2マクロファージの抑制により増強される

大川祥, 大橋圭明, 西井和也, 中須賀崇匡, 平生敦子, 高田健二, 西村淳, 栗林忠弘, 安東千裕, 西達也, 森田絢子, 槇本剛, 二宮貴一朗, 藤井昌学, 市原英基, 堀田勝幸, 田端雅弘, 前田嘉信, 木浦勝行

肺癌 62 ( 6 ) 657 - 657 2022.11

CD8陽性細胞抵抗性Egfr肺癌に対するSTING agonistによる抗腫瘍免疫の誘導

西村淳, 大橋圭明, 栗林忠弘, 森田絢子, 西達也, 大川祥, 高田健二, 安東千裕, 中須賀崇匡, 西井和也, 平生敦子, 二宮貴一朗, 槇本剛, 藤井昌学, 市原英基, 堀田勝幸, 田端雅弘, 前田嘉信, 木浦勝行

肺癌 62 ( 6 ) 754 - 754 2022.11

EGFR変異陽性肺癌に対するAd-SGE-REICと抗PD-1抗体併用による抗腫瘍免疫賦活効果

中須賀崇匡, 大橋圭明, 西井和也, 平生敦子, 大川祥, 高田健二, 西村淳, 栗林忠弘, 安東千裕, 西達也, 森田絢子, 槇本剛, 二宮貴一朗, 藤井昌学, 市原英基, 堀田勝幸, 田端雅弘, 前田嘉信, 木浦勝行

肺癌 62 ( 6 ) 715 - 715 2022.11

EGFR阻害が誘導するEgfr肺癌に対する抗腫瘍免疫を逐次的VEGFR-2/PD-1阻害が増強する

西井和也, 大橋圭明, 冨田秀太, 中須賀崇匡, 平生敦子, 大川祥, 西村淳, 安東千裕, 槇本剛, 二宮貴一朗, 加藤有加, 久保寿夫, 市原英基, 堀田勝幸, 田端雅弘, 豊岡伸一, 鵜殿平一郎, 前田嘉信, 木浦勝行

肺癌 62 ( 6 ) 657 - 657 2022.11

More than one-third of advanced non-small-cell lung cancer patients do not receive immunochemotherapy due to intolerance. International journal

Chihiro Ando, Eiki Ichihara, Toshihide Yokoyama, Koji Inoue, Tomoki Tamura, Keiichi Fujiwara, Naohiro Oda, Hirohisa Kano, Daizo Kishino, Kazuhiko Watanabe, Masaaki Inoue, Nobuaki Ochi, Fumie Onishi, Hirohisa Ichikawa, Hiroshi Kobe, Sayaka Tachibana, Katsuyuki Hotta, Yoshinobu Maeda, Katsuyuki Kiura

Journal of cancer research and clinical oncology 2022.10

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Combination therapy with immune checkpoint inhibitors (ICIs) and chemotherapy (ICI + chemotherapy) has become the standard first line treatment for driver oncogene-negative advanced non-small-cell lung cancer (NSCLC). However, it may be more toxic compared to monotherapy, which limits its use. Moreover, the feasibility of the combination therapy in clinical practice remains unknown. METHODS: We conducted a cohort study to determine the implementation rate of ICI + chemotherapy in clinical practice. We retrospectively reviewed clinical data from advanced NSCLC patients who received systemic therapy at 13 institutions between December 2018 and December 2020. RESULTS: After excluding 154 patients with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) gene alterations, a total of 919 NSCLC patients were included. Among them, 442 were treated with ICI + chemotherapy (48%), whereas 477 were treated with other therapies (52%). Among these 477 patients, 340 did not receive ICI + chemotherapy because of intolerance (71%); thus, more than one-third of the advanced NSCLC patients do not benefit from the combination therapy due to intolerance. Among the 659 NSCLC patients for whom PD-L1 was < 50% or unknown, only 342 received the ICI + chemotherapy combination (52%) even though it is considered preferable to either therapy alone; the remaining 318 patients were treated with other therapies (48%). Among the 318 patients who did not receive ICI + chemotherapy, 274 were intolerant to it (86%). CONCLUSION: Our results revealed that a substantial proportion of advanced NSCLC patients did not benefit from ICI + chemotherapy due to intolerance. As treatments for NSCLC are moving toward combinations for greater efficacy, their feasibility in clinical practice must be taken into consideration.

DOI： 10.1007/s00432-022-04415-1

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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 2022.10

Language：English

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

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Fulminant Myocarditis for Non-small-cell Carcinoma of the Lung with Nivolumab and Ipilimumab Plus Chemotherapy: A Case Report. Reviewed

Tomoka Nishimura, Kiichiro Ninomiya, Mitsutaka Nakashima, Satoshi Akagi, Tadahiro Kuribayashi, Hisao Higo, Katsuyuki Hotta, Yoshinobu Maeda, Hiroshi Ito, Katsuyuki Kiura

Internal medicine (Tokyo, Japan) 62 ( 9 ) 1319 - 1322 2022.9

Language：English Publishing type：Research paper (scientific journal)

A 59-year-old man with a high level of antinuclear antibody received nivolumab and ipilimumab plus chemotherapy for lung cancer. Two weeks after the second course, he was admitted with a fever and severe fatigue. Laboratory studies showed elevated markers of myocardial damage, and a myocardial biopsy showed inflammatory cell infiltration, damaged myocardial fibers. Myocarditis was diagnosed as an immune-related adverse event (irAE), and high-dose corticosteroids were initiated. However, his cardiac function rapidly worsened, and he died on the fifth day after admission. There is no established treatment strategy for fulminant myocarditis as an irAE, and the further exploration of viable treatment strategies is required.

DOI： 10.2169/internalmedicine.0505-22

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

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 2022.7

Language：English Publishing type：Research paper (scientific journal)

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

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Pembrolizumab in advanced NSCLC patients with poor performance status and high PD-L1 expression: OLCSG 1801.

Shinobu Hosokawa, Eiki Ichihara, Daijiro Harada, Shoichi Kuyama, Koji Inoue, Kenichi Gemba, Hirohisa Ichikawa, Yuka Kato, Naohiro Oda, Isao Oze, Tomoki Tamura, Toshiyuki Kozuki, Takahiro Umeno, Toshio Kubo, Katsuyuki Hotta, Akihiro Bessho, Yoshinobu Maeda, Katsuyuki Kiura

International journal of clinical oncology 27 ( 7 ) 1139 - 1144 2022.7

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: The role of pembrolizumab in the treatment of poor performance status (PS) patients remains unclear. PATIENTS AND METHODS: We conducted a phase II trial to investigate the efficacy and safety of pembrolizumab as first-line therapy for non-small-cell lung cancer (NSCLC) patients with PSs of 2-3 and programmed cell death ligand 1 (PD-L1) expression ≥ 50%. The primary endpoint of this study was the objective response rate (ORR). RESULTS: Fourteen patients treated at eight institutions were enrolled. Most patients had PS 2 (12/14; 86%) and others had PS 3 (2/14; 14%). The ORR was 57.1% (95% confidence interval 28.9-82.3%), which met the primary endpoint. The median progression-free survival (PFS) and 1-year PFS rates were 5.8 months and 20.0%, respectively. At the time of data cut-off, one patient had received treatment for more than 1 year; another patient had received treatment for more than 2 years. Nine patients had improved PS with treatment (Wilcoxon signed-rank test, p = 0.003). Two patients had immune-related adverse events ≥ grade 3: grades 5 and 3 elevation in alanine and aspartate aminotransferases. Two PS 3-stage patients were diagnosed with clinically progressive disease prior to initial computed tomography; both died within 2 months. CONCLUSION: Pembrolizumab was effective for the treatment of NSCLC patients with a poor PS and PD-L1 level ≥ 50%. However, given the poor outcomes of the PS 3 patients, the drug is not indicated for such patients. Adverse events, including liver dysfunction, should be carefully monitored. REGISTRATION ID: UMIN000030955.

DOI： 10.1007/s10147-022-02164-2

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Three doses of mRNA COVID‐19 vaccine protects from SARS‐CoV‐2 infections in Japan International journal

Katsuyuki Hotta, Etsuji Suzuki, Eiki Ichihara, Katsuyuki Kiura

Journal of Internal Medicine 292 ( 4 ) 687 - 689 2022.6

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 2022.5

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

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 2022.4

Language：English Publishing type：Research paper (scientific journal)

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

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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 2022.4

Identification of targetable kinases in idiopathic pulmonary fibrosis. International journal

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 2022.2

Language：English Publishing type：Research paper (scientific journal)

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

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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. International journal

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

Language：English

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

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

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

Language：English

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

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複視・有痛性筋痙攣を有し急速に歩行困難を来たした胸腺腫に伴う傍腫瘍性神経症候群の1例

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

肺癌 61 ( 7 ) 1010 - 1010 2021.12

Significance of PD-L1 expression in the cytological samples of non-small cell lung cancer patients treated with immune checkpoint inhibitors. International journal

Naofumi Hara, Eiki Ichihara, Daijiro Harada, Koji Inoue, Keiichi Fujiwara, Shinobu Hosokawa, Daizo Kishino, Kawai Haruyuki, Nobuaki Ochi, Naohiro Oda, Katsuyuki Hotta, Yoshinobu Maeda, Katsuyuki Kiura

Journal of cancer research and clinical oncology 147 ( 12 ) 3749 - 3755 2021.12

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER

OBJECTIVES: The programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) in tumor tissue samples is an established clinical biomarker for non-small cell lung cancer (NSCLC). However, the significance of PD-L1 expression in other types of samples has not been fully investigated. PATIENTS AND METHODS: We conducted a multicenter retrospective cohort study of advanced NSCLC patients who received ICI treatment during the clinical course and investigated the effects of ICIs according to PD-L1 expression in cytology samples, including cell block and endobronchial ultrasound-guided (EBUS) transbronchial needle aspiration (TBNA) samples. RESULTS: A total of 264 patients were included in this study: PD-L1 expression was determined in cell block or TBNA specimens in 55 patients, and in tissue samples in 209 patients. Among the former patients, the median progression-free survival (PFS) of those with a TPS for PD-L1 ≥ 50% was significantly longer compared to that of those with a TPS < 50% (6.5 vs. 1.9 months, respectively, p = 0.008). When the cutoff value was set at 1%, the median PFS was 4.2 months in patients with a TPS ≥ 1% and 1.5 months in patients with a TPS < 1% (p < 0.001). CONCLUSION: PD-L1 expression determined using cytology specimens predicts the efficacy of ICIs.

DOI： 10.1007/s00432-021-03615-5

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免疫チェックポイント阻害薬投与後に筋炎合併筋無力症様症状を呈した3症例

久保寿夫, 加藤有加, 二宮貴一朗, 槇本剛, 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

肺癌 61 ( 6 ) 701 - 701 2021.10

Marginal Zone Lymphoma and Lung Adenocarcinoma with an EGFR Exon 19 E746-S752del Mutation in a Patient with IgG4-related Disease

Sachi Okawa, Kammei Rai, Nobuharu Fujii, Yuka Gion, Kiichiro Ninomiya, Yuka Kato, Akihiko Taniguchi, Toshio Kubo, Eiki Ichihara, Kadoaki Ohashi, Nobuaki Miyahara, Katsuyuki Hotta, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura

Internal Medicine 60 ( 17 ) 2831 - 2837 2021.9

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Papers - HOTTA Katsuyuki