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Benralizumab treatment in an elderly patient with eosinophilic esophagitis resulted in remission: a case report. 査読有り

Ishii A, Shibata T, Tsunoda Y, Kayukawa T, Kobayashi M, Orinaka M, Miyamatsu S, Ryuge Y, Asano S, Tanaka I

BMC geriatrics 24 巻 ( 1 ) 頁： 92 2024年1月

担当区分：筆頭著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：BMC Geriatrics

Background: Interleukin-5 (IL-5) has recently been shown to play a crucial role in eosinophil-mediated diseases, implying that an IL-5 receptor alpha chain (IL-5Rα) antibody (benralizumab) can be effective against eosinophilic esophagitis (EoE). Here, we present a case in which benralizumab significantly improved the symptoms and signs of an elderly Asian woman with EoE who had inadequate response to existing treatments. Case presentation A 73-year-old woman with an 8-year history of bronchial asthma (BA) and a 7-year history of dysphagia presented to our hospital with worsening dysphagia, vomiting, chest pain, and difficulty in eating. Blood biochemical findings revealed an increase in the eosinophil fraction of white blood cells (42.2%), and a conventional chest computed tomography scan revealed esophageal wall thickening. An upper gastrointestinal endoscopy revealed mucosal edema as well as multiple esophageal rings, and esophageal biopsy specimens showed an eosinophilic infiltrate of more than 15 cells/ high power field. Based on these findings, she was diagnosed as EoE complicated by BA. We firstly administrated 20 mg/day of prednisolone, rabeprazole sodium and liquid budesonide oral suspension for 5 months; however, they were ineffective and her dysphagia worsened over time. Then, benralizumab treatment in combination with these drugs was started. Her dysphagia completely disappeared 2 weeks after starting benralizumab, and an upper endoscopy showed that the clinical findings had completely disappeared after another 6 weeks. Benralizumab was then given to her for 41 months, and her symptoms remained in remission. In addition, she had no EoE recurrence for more than 12 months after discontinuing benralizumab. Conclusions: Benralizumab in combination with other multiple drugs significantly improved the symptoms and examination findings of an elderly patients with EoE. Furthermore, she experienced no recurrence even after discontinuing benralizumab withdrawal, suggesting that benralizumab could be an appropriate therapeutic option for EoE.

DOI： 10.1186/s12877-024-04683-1

Metabolic barriers in non-small cell lung cancer with LKB1 and/or KEAP1 mutations for immunotherapeutic strategies. 査読有り

Tanaka I, Koyama J, Itoigawa H, Hayai S, Morise M

Frontiers in oncology 13 巻頁： 1249237 2023年

担当区分：筆頭著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Frontiers in Oncology

Currently, immune checkpoint inhibitors (ICIs) are widely considered the standard initial treatment for advanced non-small cell lung cancer (NSCLC) when there are no targetable driver oncogenic alternations. NSCLC tumors that have two alterations in tumor suppressor genes, such as liver kinase B1 (LKB1) and/or Kelch-like ECH-associated protein 1 (KEAP1), have been found to exhibit reduced responsiveness to these therapeutic strategies, as revealed by multiomics analyses identifying immunosuppressed phenotypes. Recent advancements in various biological approaches have gradually unveiled the molecular mechanisms underlying intrinsic reprogrammed metabolism in tumor cells, which contribute to the evasion of immune responses by the tumor. Notably, metabolic alterations in glycolysis and glutaminolysis have a significant impact on tumor aggressiveness and the remodeling of the tumor microenvironment. Since glucose and glutamine are essential for the proliferation and activation of effector T cells, heightened consumption of these nutrients by tumor cells results in immunosuppression and resistance to ICI therapies. This review provides a comprehensive summary of the clinical efficacies of current therapeutic strategies against NSCLC harboring LKB1 and/or KEAP1 mutations, along with the metabolic alterations in glycolysis and glutaminolysis observed in these cancer cells. Furthermore, ongoing trials targeting these metabolic alterations are discussed as potential approaches to overcome the extremely poor prognosis associated with this type of cancer.

DOI： 10.3389/fonc.2023.1249237

Clinical efficacy of osimertinib in EGFR-mutant non-small cell lung cancer with distant metastasis 査読有り

Gen S., Tanaka I., Morise M., Koyama J., Kodama Y., Matsui A., Miyazawa A., Hase T., Hibino Y., Yokoyama T., Kimura T., Yoshida N., Sato M., Hashimoto N.

BMC Cancer 22 巻 ( 1 ) 2022年12月

担当区分：筆頭著者,　責任著者記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：BMC Cancer

Background: Osimertinib—the third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI)—has been widely used as a first-line treatment for patients with metastatic EGFR-mutant non-small cell lung cancer (NSCLC). Osimertinib demonstrated central nervous system activity in patients with brain metastasis; however, its efficacy against other distant metastatic organs, including bone and liver, remains unclear. Therefore, we retrospectively analyzed the clinical efficacy of osimertinib in these patients in comparison to other EGFR-TKIs. Methods: Clinical data of patients with advanced NSCLC receiving gefitinib/erlotinib (n = 183), afatinib (n = 55), or osimertinib (n = 150) at five medical institutions were retrospectively assessed for progression-free survival (PFS), overall survival (OS), and best overall response rate (ORR). Results: In univariate and multivariate analyses, most distant metastases, including the brain and bone, were unrelated to the therapeutic efficacy of osimertinib, although liver metastasis and L858R mutation were independently associated with shorter PFS. PFS and OS in patients with liver metastases were significantly shorter than those in patients without liver metastases (PFS: 7.4 vs. 19.7 months, OS: 12.1 months vs. not reached, respectively). Osimertinib provided significantly longer PFS in patients with brain or bone metastasis and exon 19 deletion than the other EGFR-TKIs. The PFS of patients with liver metastases was not significantly different among the three EGFR-TKI groups. Furthermore, the ORR of osimertinib in patients with liver metastases was significantly attenuated, and the effectiveness was similar to 1st- or 2nd -generation EGFR-TKIs. Conclusion: Osimertinib provided better clinical benefits than 1st- and 2nd-generation EGFR-TKIs for patients with EGFR-mutant NSCLC, particularly those with brain or bone metastases and exon 19 deletion; however, its efficacy against liver metastasis was remarkably attenuated. New therapeutic developments for patients with EGFR-mutant NSCLC with liver metastases are needed.

DOI： 10.1186/s12885-022-09741-8

SRGN-Triggered Aggressive and Immunosuppressive Phenotype in a Subset of TTF-1-Negative Lung Adenocarcinomas. 査読有り国際共著

Tanaka I, Dayde D, Tai MC, Mori H, Solis LM, Tripathi SC, Fahrmann JF, Unver N, Parhy G, Jain R, Parra ER, Murakami Y, Aguilar-Bonavides C, Mino B, Celiktas M, Dhillon D, Casabar JP, Nakatochi M, Stingo F, Baladandayuthapani V, Wang H, Katayama H, Dennison JB, Lorenzi PL, Do KA, Fujimoto J, Behrens C, Ostrin EJ, Rodriguez-Canales J, Hase T, Fukui T, Kajino T, Kato S, Yatabe Y, Hosoda W, Kawaguchi K, Yokoi K, Chen-Yoshikawa TF, Hasegawa Y, Gazdar AF, Wistuba II, Hanash S, Taguchi A

Journal of the National Cancer Institute 2022年2月

Current immunotherapeutic strategies targeting the PD-1/PD-L1 axis in non-small cell lung cancer with oncogenic driver mutations 査読有り

Tanaka I., Morise M.

International Journal of Molecular Sciences 23 巻 ( 1 ) 2022年1月

担当区分：筆頭著者,　責任著者記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：International Journal of Molecular Sciences

Treatment strategies targeting programed cell death 1 (PD-1) or its ligand, PD-L1, have been developed as immunotherapy against tumor progression for various cancer types including non-small cell lung cancer (NSCLC). The recent pivotal clinical trials of immune-checkpoint inhibiters (ICIs) combined with cytotoxic chemotherapy have reshaped therapeutic strategies and established various first-line standard treatments. The therapeutic effects of ICIs in these clinical trials were analyzed according to PD-L1 tumor proportion scores or tumor mutational burden; however, these indicators are insufficient to predict the clinical outcome. Consequently, molecular biological approaches, including multi-omics analyses, have addressed other mechanisms of cancer immune escape and have revealed an association of NSCLC containing specific driver mutations with distinct immune phenotypes. NSCLC has been characterized by driver mutation-defined molecular subsets and the effect of driver mutations on the regulatory mechanism of PD-L1 expression on the tumor itself. In this review, we summarize the results of recent clinical trials of ICIs in advanced NSCLC and the association between driver alterations and distinct immune phenotypes. We further discuss the current clinical issues with a future perspective for the role of precision medicine in NSCLC.

DOI： 10.3390/ijms23010245

The current issues and future perspective of artificial intelligence for developing new treatment strategy in non-small cell lung cancer: harmonization of molecular cancer biology and artificial intelligence 招待有り査読有り

Tanaka Ichidai, Furukawa Taiki, Morise Masahiro

CANCER CELL INTERNATIONAL 21 巻 ( 1 ) 頁： 454 2021年8月

担当区分：筆頭著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Cancer Cell International

Comprehensive analysis of omics data, such as genome, transcriptome, proteome, metabolome, and interactome, is a crucial technique for elucidating the complex mechanism of cancer onset and progression. Recently, a variety of new findings have been reported based on multi-omics analysis in combination with various clinical information. However, integrated analysis of multi-omics data is extremely labor intensive, making the development of new analysis technology indispensable. Artificial intelligence (AI), which has been under development in recent years, is quickly becoming an effective approach to reduce the labor involved in analyzing large amounts of complex data and to obtain valuable information that is often overlooked in manual analysis and experiments. The use of AI, such as machine learning approaches and deep learning systems, allows for the efficient analysis of massive omics data combined with accurate clinical information and can lead to comprehensive predictive models that will be desirable for further developing individual treatment strategies of immunotherapy and molecular target therapy. Here, we aim to review the potential of AI in the integrated analysis of omics data and clinical information with a special focus on recent advances in the discovery of new biomarkers and the future direction of personalized medicine in non-small lung cancer.

DOI： 10.1186/s12935-021-02165-7

Oxytocin receptor is a promising therapeutic target of malignant mesothelioma 査読有り

Cancer Sci. 2021年7月

Efficacies of programmed cell death 1 ligand 1 blockade in non-small cell lung cancer patients with acquired resistance to prior programmed cell death 1 inhibitor and development of diabetic ketoacidosis caused by two different etiologies: a retrospective case series. 査読有り国際共著

Ishi A, Tanaka I, Iwama S, Sakakibara T, Mastui T, Kobayashi T, Hase T, Morise M, Sato M, Arima H, Hashimoto N

Endocrine journal 68 巻 ( 5 ) 頁： 613 - 620 2021年5月

担当区分：責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：一般社団法人日本内分泌学会

<p>The programmed cell death 1 (PD-1)/programmed cell death 1 ligand 1 (PD-L1) axis is vital for immune resistance during tumor development, while PD-L1 inhibitors can also inhibit the PD-L1/B7-1 (CD80) interaction, indicating one of the molecular differences between PD-1 and PD-L1 inhibitors. However, the clinical benefits of PD-L1 inhibitors in patients previously treated with PD-1 inhibitors remain unknown. In this study, we retrospectively analyzed the clinical data of eight patients with non-small cell lung cancer who received the PD-L1 inhibitor atezolizumab and previously treated with the PD-1 inhibitor nivolumab. The median progression-free survival was 2.1 months (1.8–18.7 months), and 4 of 8 patients achieved at least stable disease. In two of these patients, atezolizumab treatment resulted in longer progression-free survival (PFS) compared with that of nivolumab. Conversely, one patient exhibited grade 4 diabetic ketoacidosis (DKA) within 2 weeks after the initial administration of atezolizumab. Another patient had developed type 1 diabetes mellitus (T1DM) during the prior nivolumab treatment and then developed DKA due to an infection after the initiation of atezolizumab. Both of them had high-risk human leukocyte antigen-DR/DQ types relevant to T1DM. These results demonstrate the potential efficacy of PD-L1 inhibitors to some tumors that have acquired resistance to PD-1 inhibitors and suggest that appropriate managements are required for not only a newly onset of T1DM but also blood glucose control after the development of T1DM during a reiteration of the PD-1/PD-L1 blockade.</p>

DOI： 10.1507/endocrj.EJ20-0769

Potential Benefits of Bevacizumab Combined With Platinum-Based Chemotherapy in Advanced Non-Small-Cell Lung Cancer Patients With EGFR Mutation 査読有り国際共著国際誌

Tanaka Ichidai, Morise Masahiro, Miyazawa Ayako, Kodama Yuta, Tamiya Yutaro, Gen Soei, Matsui Akira, Hase Tetsunari, Hashimoto Naozumi, Sato Mitsuo, Hasegawa Yoshinori

CLINICAL LUNG CANCER 21 巻 ( 3 ) 頁： 273 - + 2020年5月

Potential for afatinib as an optimal treatment for advanced non-small cell lung carcinoma in patients with uncommon EGFR mutations 査読有り国際誌

Tanaka Ichidai, Morise Masahiro, Kodama Yuta, Matsui Akira, Ozawa Naoya, Ozone Sachiko, Goto Daiki, Miyazawa Ayako, Hase Tetsunari, Hashimoto Naozumi, Sato Mitsuo, Hasegawa Yoshinori

LUNG CANCER 127 巻頁： 169 - 171 2019年1月

The Subunit eIF2 ss of Translation- Initiation Factor EIF2 Is a Potential Therapeutic Target for Non-Small Cell Lung Cancer 査読有り国際共著

Tanaka Ichidai, Sato Mitsuo,Goto Daiki, Kato Toshio, Kakumu Tomohiko, Miyazawa Ayako, Yogo Naoyuki, Hase Tetsunari, Morise Masahiro, Sekido Yoshitaka, Kondo Masashi, Hasegawa Yoshinori

CANCER SCIENCE 109 巻頁： 1181-1181 2018年12月

Aberrant tryptophan catabolism marked by high kynureninase expression contributes to immunosuppression and poor outcome in lung adenocarcinoma 査読有り国際共著

Ostrin Edwin J., Fahrmann Johannes F., Tanaka Ichidai, Celiktas Muge, Aguilar Clemente, Aguilar Mitzi, Dennison Jennifer B., Murage Eunice, Tripathi Satyendra C., Delgado Oliver, Wang Hong, Rodriguez-Canales Jaime, Behrens Carmen, Wistuba Ignacio I., Taguchi Ayumu, Hanash Samir M.

CANCER RESEARCH 78 巻 ( 13 ) 2018年7月

A phase II trial of Ifosfamide combination with recommended supportive therapy for recurrent SCLC in second-line and heavily treated setting 査読有り国際共著国際誌

Tanaka Ichidai, Kawada Kenji, Morise Masahiro, Hase Tetsunari, Hayashi Hiroaki, Sokai Akihiko, Fukatsu Asuki, Kondo Masashi, Nomura Fumio, Hasegawa Yoshinori

CANCER CHEMOTHERAPY AND PHARMACOLOGY 81 巻 ( 2 ) 頁： 339 - 345 2018年2月

Role of CPS1 in Cell Growth, Metabolism, and Prognosis in LKB1-Inactivated Lung Adenocarcinoma 査読有り国際共著国際誌

Celiktas Muge, Tanaka Ichidai, Tripathi Satyendra Chandra, Fahrmann Johannes F., Aguilar-Bonavides Clemente, Villalobos Pamela, Delgado Oliver, Dhillon Dilsher, Dennison Jennifer B., Ostrin Edwin J., Wang Hong, Behrens Carmen, Do Kim-Anh, Gazdar Adi F., Hanash Samir M., Taguchi Ayumu

JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE 109 巻 ( 3 ) 頁： 1 - 9 2017年3月

LIM-domain protein AJUBA suppresses malignant mesothelioma cell proliferation via Hippo signaling cascade 査読有り国際誌

Tanaka I., Osada H., Fujii M., Fukatsu A., Hida T., Horio Y., Kondo Y., Sato A., Hasegawa Y., Tsujimura T., Sekido Y.

ONCOGENE 34 巻 ( 1 ) 頁： 73 - 83 2015年1月

Circulating microRNA Panel for Prediction of Recurrence and Survival in Early-Stage Lung Adenocarcinoma 査読有り

Tai, MC; Bantis, LE; Parhy, G; Kato, T; Tanaka, I; Chow, CW; Fujimoto, J; Behrens, C; Hase, T; Kawaguchi, K; Fahrmann, JF; Ostrin, EJ; Yokoi, K; Chen-Yoshikawa, TF; Hasegawa, Y; Hanash, SM; Wistuba, II; Taguchi, A

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES 25 巻 ( 4 ) 2024年2月

担当区分：筆頭著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：International Journal of Molecular Sciences

Early-stage lung adenocarcinoma (LUAD) patients remain at substantial risk for recurrence and disease-related death, highlighting the unmet need of biomarkers for the assessment and identification of those in an early stage who would likely benefit from adjuvant chemotherapy. To identify circulating miRNAs useful for predicting recurrence in early-stage LUAD, we performed miRNA microarray analysis with pools of pretreatment plasma samples from patients with stage I LUAD who developed recurrence or remained recurrence-free during the follow-up period. Subsequent validation in 85 patients with stage I LUAD resulted in the development of a circulating miRNA panel comprising miR-23a-3p, miR-320c, and miR-125b-5p and yielding an area under the curve (AUC) of 0.776 in predicting recurrence. Furthermore, the three-miRNA panel yielded an AUC of 0.804, with a sensitivity of 45.8% at 95% specificity in the independent test set of 57 stage I and II LUAD patients. The miRNA panel score was a significant and independent factor for predicting disease-free survival (p < 0.001, hazard ratio [HR] = 1.64, 95% confidence interval [CI] = 1.51–4.22) and overall survival (p = 0.001, HR = 1.51, 95% CI = 1.17–1.94). This circulating miRNA panel is a useful noninvasive tool to stratify early-stage LUAD patients and determine an appropriate treatment plan with maximal efficacy.

DOI： 10.3390/ijms25042331

The oncogenic role of LGR6 overexpression induced by aberrant Wnt/β-catenin signaling in lung cancer. 査読有り

Sunaga N, Kaira K, Shimizu K, Tanaka I, Miura Y, Nakazawa S, Ohtaki Y, Kawabata-Iwakawa R, Sato M, Girard L, Minna JD, Hisada T

Thoracic cancer 15 巻 ( 2 ) 頁： 131 - 141 2024年1月

担当区分：筆頭著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Thoracic Cancer

Background: Molecular abnormalities in the Wnt/β-catenin pathway confer malignant phenotypes in lung cancer. Previously, we identified the association of leucine-rich repeat-containing G protein-coupled receptor 6 (LGR6) with oncogenic Wnt signaling, and its downregulation upon β-catenin knockdown in non-small cell lung cancer (NSCLC) cells carrying CTNNB1 mutations. The aim of this study was to explore the mechanisms underlying this association and the accompanying phenotypes. Methods: LGR6 expression in lung cancer cell lines and surgical specimens was analyzed using quantitative RT-PCR and immunohistochemistry. Cell growth was assessed using colony formation assay. Additionally, mRNA sequencing was performed to compare the expression profiles of cells subjected to different treatments. Results: LGR6 was overexpressed in small cell lung cancer (SCLC) and NSCLC cell lines, including the CTNNB1-mutated NSCLC cell lines HCC15 and A427. In both cell lines, LGR6 knockdown inhibited cell growth. LGR6 expression was upregulated in spheroids compared to adherent cultures of A427 cells, suggesting that LGR6 participates in the acquisition of cancer stem cell properties. Immunohistochemical analysis of lung cancer specimens revealed that the LGR6 protein was predominantly overexpressed in SCLCs, large cell neuroendocrine carcinomas, and lung adenocarcinomas, wherein LGR6 overexpression was associated with vascular invasion, the wild-type EGFR genotype, and an unfavorable prognosis. Integrated mRNA sequencing analysis of HCC15 and A427 cells with or without LGR6 knockdown revealed LGR6-related pathways and genes associated with cancer development and stemness properties. Conclusions: Our findings highlight the oncogenic roles of LGR6 overexpression induced by aberrant Wnt/β-catenin signaling in lung cancer.

DOI： 10.1111/1759-7714.15169

Inhalation adherence for asthma and COPD improved during the COVID-19 pandemic: a questionnaire survey at a university hospital in Japan. 査読有り

Fukutani E, Wakahara K, Nakamura S, Yokoi E, Yoshimi A, Miyazaki M, Nakamura M, Shindo Y, Sakamoto K, Okachi S, Tanaka I, Hamajima N, Noda Y, Hashimoto N, Ishii M

The Journal of asthma : official journal of the Association for the Care of Asthma 60 巻 ( 11 ) 頁： 2002 - 2013 2023年11月

担当区分：筆頭著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of Asthma

Background: Good adherence to an inhaled medication protocol is necessary for the management of asthma and chronic obstructive pulmonary disease (COPD), and several interventions to improve adherence have been reported. However, the impact of patient life changes and psychological aspects on treatment motivation is obscure. Here, we investigated changes in inhaler adherence during the COVID-19 pandemic and how lifestyle and psychological changes affected it. Methods: Seven-hundred sixteen adult patients with asthma and COPD who had visited Nagoya University Hospital between 2015 and 2020 were selected. Among them, 311 patients had received instruction at a pharmacist-managed clinic (PMC). We distributed one-time cross-sectional questionnaires from January 12 to March 31, 2021. The questionnaire covered the status of hospital visits, inhalation adherence before and during the COVID-19 pandemic, lifestyles, medical conditions, and psychological stress. The Adherence Starts with Knowledge-12 (ASK-12) was used to assess adherence barriers. Results: Four-hundred thirty-three patients answered the questionnaire. Inhalation adherence was significantly improved in both diseases during the COVID-19 pandemic. The most common reason for improved adherence was fear of infection. Patients with improved adherence were more likely to believe that controller inhalers could prevent COVID-19 from becoming more severe. Improved adherence was more common in patients with asthma, those not receiving counseling at PMC, and those with poor baseline adherence. Conclusions: Inhalation adherence for asthma and COPD improved in the COVID-19 pandemic. The patients seemed to realize the necessity and benefits of the medication more strongly than before the pandemic, which motivated them to improve adherence.

DOI： 10.1080/02770903.2023.2209173

Silencing of GRHL2 induces epithelial‑to‑mesenchymal transition in lung cancer cell lines with different effects on proliferation and clonogenic growth. 査読有り

Kawabe N, Matsuoka K, Komeda K, Muraki N, Takaba M, Togami Y, Ito Y, Yamada M, Sunaga N, Girard L, Minna JD, Cai L, Xie Y, Tanaka I, Morise M, Sato M

Oncology letters 26 巻 ( 3 ) 頁： 391 2023年9月

担当区分：筆頭著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Oncology Letters

Grainyhead-like 2 (GRHL2) is a transcription factor that suppresses epithelial-to-mesenchymal transition (EMT). It has been previously shown that GRHL2 can confer both oncogenic and tumor-suppressive roles in human cancers, including breast, pancreatic and colorectal cancers. However, its role in lung cancer remains elusive. In the present study, a meta-analysis of multiple gene expression datasets with clinical data revealed that GRHL2 expression was increased in lung cancer compared with that in the normal tissues. Copy number analysis of GRHL2, performed using datasets of whole exome sequencing involving 151 lung cancer cell lines, revealed frequent amplifications, suggesting that the increased GRHL2 expression may have resulted from gene amplification. A survival meta-analysis of GRHL2 using The Cancer Genome Atlas (TCGA) dataset showed no association of GRHL2 expression with overall survival. GRHL2 expression was found to be associated with EMT status in lung cancer in TCGA dataset and lung cancer cell lines. GRHL2 knockdown induced partial EMT in the hTERT/Cdk4-immortalized normal lung epithelial cell line HBEC4KT without affecting proliferation measured by CCK-8 assays. In addition, GRHL2 silencing caused three lung cancer cell lines, H1975, H2009 and H441, to undergo partial EMT. However, the proliferative effects differed significantly. GRHL2 silencing promoted proliferation but not colony formation in H1975 cells whilst suppressing colony formation without affecting proliferation in H2009 cells, but it did not affect proliferation in H441 cells. These results suggest cell type-dependent effects of GRHL2 knockdown. Downstream, GRHL2 silencing enhanced the phosphorylation of AKT and ERK, assessed by western blotting with phospho-specific antibodies, in HBEC4KT, H1975 and H2009 cell lines but not in the H441 cell line. By contrast, transient GRHL2 overexpression did not affect A549 cell proliferation, which lack detectable endogenous expression of the GRHL2 protein. However, GRHL2 overexpression did suppress E-cadherin expression in A549 cells. These results suggested that GRHL2 does not only function as a tumor suppressor of EMT but can also behave as an oncogene depending on the lung cancer cell-type context.

DOI： 10.3892/ol.2023.13977

Non-invasive early prediction of immune checkpoint inhibitor efficacy in non-small-cell lung cancer patients using on-treatment serum CRP and NLR. 査読有り

Matsuzawa R, Morise M, Kinoshita F, Tanaka I, Koyama J, Kimura T, Kondoh Y, Tanaka T, Shima K, Hase T, Wakahara K, Ishii M, Hashimoto N

Journal of cancer research and clinical oncology 2022年8月

担当区分：筆頭著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of Cancer Research and Clinical Oncology

Purpose: We determined the clinical relevance of early C-reactive protein (CRP) and neutrophil–lymphocyte ratio (NLR) change in blood as surrogate markers of pro-tumor inflammation (PTI) for predicting clinical outcome of programmed cell death (PD)-1/programmed cell death ligand (PD-L) 1 inhibitor treatment in non-small-cell lung carcinoma (NSCLC). Methods: We retrospectively reviewed NSCLC patients treated with anti-PD-1 or PD-L1 inhibitors. Early CRP change was defined as the ratio of 6 weeks CRP to baseline CRP, and early NLR change was defined as that of the 6 weeks NLR to baseline NLR. PTI index was determined by combinatorial evaluation of early CRP change and early NLR change, PTI index low: both of these were low, intermediate: either of these was low, high; both of these were high. Results: The study included 217 patients. Early CRP change and early NLR change were both associated with PFS and OS. The combinatorial evaluation using these two markers enabled the clear stratification of PFS and OS. The median PFS in patient with PTI index low was 13.9 months, while the median PFS in those with PTI index high was 2.5 months (p < 0.01, log-rank test). The median OS in patients with PTI index low was not reached; the median OS in those with PTI index high was only 15.4 months (p < 0.01, log-rank test). Conclusions: The combinatorial early CRP change and early NLR change as PTI biomarkers have clinical potential in identifying NSCLC patients who can achieve a durable response and long-term survival using PD-1/PD-L1 inhibitors.

DOI： 10.1007/s00432-022-04300-x

Resistance to mutant KRAS<sup>V12</sup>-induced senescence in an hTERT/Cdk4-immortalized normal human bronchial epithelial cell line 査読有り

Muraki N., Yamada M., Doki H., Nakai R., Komeda K., Goto D., Kawabe N., Matsuoka K., Matsushima M., Kawabe T., Tanaka I., Morise M., Shay J.W., Minna J.D., Sato M.

Experimental Cell Research 414 巻 ( 1 ) 2022年5月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Experimental Cell Research

Mutant KRAS, the most frequently occurring (∼30%) driver oncogene in lung adenocarcinoma, induces normal epithelial cells to undergo senescence. This phenomenon, called “oncogene-induced senescence (OIS)”, prevents mutant KRAS-induced malignant transformation. We have previously reported that mutant KRASV12 induces OIS in a subset of normal human bronchial epithelial cell line immortalized with hTERT and Cdk4. Understanding the mechanism and efficacy of this important cancer prevention mechanism is a key knowledge gap. Therefore, this study investigates mutant KRASV12-induced OIS in upregulated telomerase combined with the p16/RB pathway inactivation in normal bronchial epithelial cells. The normal (non-transformed and non-tumorigenic) human bronchial epithelial cell line HBEC3 (also called “HBEC3KT”), immortalized with hTERT (“T”) and Cdk4 (“K”), was used in this study. HBEC3 that expressed mutant KRASV12 in a doxycycline-regulated manner was established (designated as HBEC3-RIN2). Controlled induction of mutant KRASV12 expression induced partial epithelial-to-mesenchymal transition in HBEC3-RIN2 cells, which was associated with upregulated expression of ZEB1 and SNAIL. Mutant KRASV12 caused the majority of HBEC3-RIN2 to undergo morphological changes; suggestive of senescence, which was associated with enhanced autophagic flux. Upon mutant KRASV12 expression, only a small HBEC3-RIN2 cell subset underwent senescence, as assessed by a senescence-associated β-galactosidase staining (SA-βG) method. Furthermore, mutant KRASV12 enhanced cell growth, evaluated by colorimetric proliferation assay, and liquid and soft agar colony formation assays, partially through increased phosphorylated AKT and ERK expression but did not affect cell division, or cell cycle status. Intriguingly, mutant KRASV12 reduced p53 protein expression but increased p21 protein expression by prolonging its half-life. These results indicate that an hTERT/Cdk4 -immortalized normal bronchial epithelial cell line is partially resistant to mutant KRASV12-induced senescence. This suggests that OIS does not efficiently suppress KRASV12-induced transformation in the context of the simultaneous occurrence of telomerase upregulation and inactivation of the p16/Rb pathway.

DOI： 10.1016/j.yexcr.2022.113053

Mutational Activation of the NRF2 Pathway Upregulates Kynureninase Resulting in Tumor Immunosuppression and Poor Outcome in Lung Adenocarcinoma 査読有り

Fahrmann Johannes F., Tanaka Ichidai, Irajizad Ehsan, Mao Xiangying, Dennison Jennifer B., Murage Eunice, Casabar Julian, Mayo Jeffrey, Peng Qian, Celiktas Muge, Vykoukal Jody V., Park Soyoung, Taguchi Ayumu, Delgado Oliver, Tripathi Satyendra C., Katayama Hiroyuki, Soto Luisa Maren Solis, Rodriguez-Canales Jaime, Behrens Carmen, Wistuba Ignacio, Hanash Samir, Ostrin Edwin J.

CANCERS 14 巻 ( 10 ) 2022年5月

担当区分：筆頭著者,　責任著者記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Cancers

Activation of the NRF2 pathway through gain-of-function mutations or loss-of-function of its suppressor KEAP1 is a frequent finding in lung cancer. NRF2 activation has been reported to alter the tumor microenvironment. Here, we demonstrated that NRF2 alters tryptophan metabolism through the kynurenine pathway that is associated with a tumor-promoting, immune suppressed microenvironment. Specifically, proteomic profiles of 47 lung adenocarcinoma (LUAD) cell lines (11 KEAP1 mutant and 36 KEAP1 wild-type) revealed the tryptophan-kynurenine enzyme kynureninase (KYNU) as a top overexpressed protein associated with activated NRF2. The siRNA-mediated knockdown of NFE2L2, the gene encoding for NRF2, or activation of the NRF2 pathway through siRNA-mediated knockdown of KEAP1 or via chemical induction with the NRF2-activator CDDO-Me confirmed that NRF2 is a regulator of KYNU expression in LUAD. Metabolomic analyses confirmed KYNU to be enzymatically functional. Analysis of multiple independent gene expression datasets of LUAD, as well as a LUAD tumor microarray demonstrated that elevated KYNU was associated with immunosuppression, including potent induction of T-regulatory cells, increased levels of PD1 and PD-L1, and resulted in poorer survival. Our findings indicate a novel mechanism of NRF2 tumoral immunosuppression through upregulation of KYNU.

DOI： 10.3390/cancers14102543

Amelanotic Malignant Melanoma with a BRAF V600E Mutation Mimicking Primary Lung Cancer. 査読有り

Matsuzawa R, Morise M, Tanaka I, Hayai S, Tamiya Y, Koyama J, Hase T, Wakahara K, Deoksu K, Shimoyama Y, Hashimoto N

Internal medicine (Tokyo, Japan) 2021年8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：一般社団法人日本内科学会

<p>Amelanotic melanoma is a rare type of melanoma that shows little or no melanin pigmentation. When tumor lesions are not detected in cutaneous sites, the presence of melanin is the hallmark sign of malignant melanoma. We herein report a case of amelanotic melanoma with a <i>BRAF V600E</i> mutation mimicking primary lung cancer that was finally diagnosed on an autopsy. The current case suggests important caveats for the differential diagnosis of patients with <i>BRAF V600E</i> mutation-positive poorly differentiated lung tumors. In terms of the pathological diagnosis, routine immunohistochemical staining may be useful, especially in patients with a poorly differentiated lung tumor without TTF-1 expression. </p>

DOI： 10.2169/internalmedicine.6657-20

Is area under the curve the best parameter for carboplatin induced emetic risk stratification? 査読有り

Ozone S., Ichikawa K., Morise M., Matsui A., Kinoshita F., Matsuzawa R., Koyama J., Tanaka I., Hashimoto N.

Nagoya Journal of Medical Science 83 巻 ( 4 ) 頁： 773 - 785 2021年

担当区分：筆頭著者,　責任著者記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Nagoya Journal of Medical Science

Carboplatin (CBDCA)-induced emetic risk is currently classified on the basis of CBDCA-area under the curve (CBDCA-AUC). We investigated the utility of three CBDCA dosage parameters for predicting emesis by CBDCA. Patients with thoracic cancer treated with CBDCA were included. The endpoints were complete response (CR) and total control (TC). CR was defined as no vomiting and no use of rescue medication during the overall assessment period, whereas TC was defined as no vomiting, nausea, nor use of rescue medication during the overall assessment period. The parameters of CBDCA were defined as follows: (1) CBDCA-AUC; (2) CBDCA/body surface area (BSA): the administered dose of CBDCA per body surface area (mg/m2); and (3) total CBDCA/body: the total administered dose of CBDCA (mg). Eighty-five patients were evaluated. The median CBDCA/BSA but not CBDCA-AUC was higher in patients with non-CR compared to those with CR. Receiver operating characteristic curve analysis revealed that the AUC of CBDCA/BSA for predicting non-CR was higher than that of CBDCA-AUC. CBDCA/BSA shows greater potential for predicting CBDCA-induced emetic risk compared with CBDCA-AUC, which is the parameter in current antiemetic guidelines.

DOI： 10.18999/nagjms.83.4.773

Primary Prophylaxis Indication for Docetaxel Induced Febrile Neutropenia in Elderly Patients with Non-Small Cell Lung Cancer 査読有り国際誌

Matsui Akira, Morise Masahiro, Tanaka Ichidai, Ozone Sachiko, Matsuzawa Reiko, Koyama Junji, Hase Tetsunari, Hashimoto Naozumi, Sato Mitsuo, Hasegawa Yoshinori

CANCER INVESTIGATION 38 巻 ( 7 ) 頁： 424 - 430 2020年8月

Plasma-Derived Extracellular Vesicles Convey Protein Signatures That Reflect Pathophysiology in Lung and Pancreatic Adenocarcinomas 査読有り国際共著国際誌

Fahrmann Johannes F., Mao Xiangying, Irajizad Ehsan, Katayama Hiroyuki, Capello Michela, Tanaka Ichidai, Kato Taketo, Wistuba Ignacio I., Maitra Anirban, Ostrin Edwin J., Hanash Samir M., Vykoukal Jody

CANCERS 12 巻 ( 5 ) 2020年5月

UHRF1, a Regulator of Methylation, as a Diagnostic and Prognostic Marker for Lung Cancer 査読有り

Goto D., Komeda K., Uwatoko N., Nakashima M., Koike M., Kawai K., Kodama Y., Miyazawa A., Tanaka I., Hase T., Morise M., Hasegawa Y., Kawabe T., Sato M.

Cancer Investigation 38 巻 ( 4 ) 頁： 240 - 249 2020年4月

担当区分：筆頭著者,　責任著者記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Cancer Investigation

We evaluated the value of UHRF1, a regulator of methylation, as a biomarker for lung cancer. UHRF1 is expressed at higher levels in both lung adenocarcinoma (AD) and squamous cell carcinoma (SQ); however, a meta-analysis showed that UHRF1 expression is correlated with worse survival in patients with AD but not in those with SQ. UHRF1 knockdown suppressed the growth of lung cancer cell lines through G1 cell cycle arrest in some cell lines. These results suggest that UHRF1 may server as a diagnostic marker for AD and SQ and as a prognostic marker for AD in lung cancer.

DOI： 10.1080/07357907.2020.1747483

Impact of Combined Evaluation Using Tumor Volume and Metastatic Nodal Extent in Stage III NSCLC Treated with CRT 査読有り国際誌

Tamiya Y., Morise M., Matsuzawa R., Tanaka I., Okada T., Iwano S., Hase T., Hashimoto N., Sato M., Itoh Y., Hasegawa Y.

JOURNAL OF THORACIC ONCOLOGY 14 巻 ( 10 ) 頁： S909 - S910 2019年10月

UHRF1 as a Potential Therapeutic Target for KRAS Mutated Non-Small Cell Lung Cancer 査読有り国際誌

Goto D., Kizuki M., Uwatoko N., Kawai K., Koike M., Nakashima M., Miyazawa A., Tanaka I., Hase T., Morise M., Hasegawa Y., Minna J., Sato M.

JOURNAL OF THORACIC ONCOLOGY 14 巻 ( 10 ) 頁： S692 - S692 2019年10月

Impact of Combined Evaluation Using Tumor Volume and Metastatic Nodal Extent in Stage III NSCLC Treated with CRT 査読有り国際誌

Tamiya Y, Morise M, Matsuzawa R, Tanaka I, Okada T, Iwano S, Hase T, Hashimoto N, Sato M, Itoh Y, Hasegawa Y

JOURNAL OF THORACIC ONCOLOGY 14 巻 ( 10 ) 頁： S909 - S910 2019年10月

CADM1 associates with Hippo pathway core kinases; membranous co-expression of CADM1 and LATS2 in lung tumors predicts good prognosis 査読有り国際誌

Ito Takeshi, Nakamura Atsuko, Tanaka Ichidai, Tsuboi Yumi, Morikawa Teppei, Nakajima Jun, Takai Daiya, Fukayama Masashi, Sekido Yoshitaka, Niki Toshiro, Matsubara Daisuke, Murakami Yoshinori

CANCER SCIENCE 110 巻 ( 7 ) 頁： 2284 - 2295 2019年7月

Mechanobiology of Lung Cancer Cells: Regulation of PD-L1 Expression by Matrix Stiffness

Miyazawa A., Ito S., Asano S., Tanaka I., Sato M., Kondo M., Hasegawa Y.

JOURNAL OF THORACIC ONCOLOGY 13 巻 ( 10 ) 頁： S518-S518 2018年10月

eIF2 beta, A Subunit of Translation-Initiation Factor EIF2, as a Potential Therapeutic Target for Non-Small Cell Lung Cancer

Goto D., Tanaka I., Sato M., Kato T., Miyazawa A., Hase T., Morise M., Sekido Y., Girard L., Minna J., Byers L., Heymach J., Coombes K., Kondo M., Hasegawa Y.

JOURNAL OF THORACIC ONCOLOGY 13 巻 ( 10 ) 頁： S516 - S517 2018年10月

eIF2 beta, a subunit of translation-initiation factor EIF2, is a potential therapeutic target for non-small cell lung cancer 査読有り国際誌

Tanaka Ichidai, Sato Mitsuo, Kato Toshio, Goto Daiki, Kakumu Tomohiko, Miyazawa Ayako, Yogo Naoyuki, Hase Tetsunari, Morise Masahiro, Sekido Yoshitaka, Girard Luc, Minna John D., Byers Lauren A., Heymach John V., Coombes Kevin R., Kondo Masashi, Hasegawa Yoshinori

CANCER SCIENCE 109 巻 ( 6 ) 頁： 1843 - 1852 2018年6月

Regulation of PD-L1 expression by matrix stiffness in lung cancer cells 査読有り国際誌

Miyazawa Ayako, Ito Satoru, Asano Shuichi, Tanaka Ichidai, Sato Mitsuo, Kondo Masashi, Hasegawa Yoshinori

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 495 巻 ( 3 ) 頁： 2344 - 2349 2018年1月

An EGFR-mutated Lung Adenocarcinoma Undergoing Squamous Cell Carcinoma Transformation Exhibited a Durable Response to Afatinib 査読有り国際誌

Sato Mitsuo, Matsui Akira, Shimoyama Yoshie, Omote Norihito, Morise Masahiro, Hase Tetsunari, Tanaka Ichidai, Suzuki Kojiro, Hasegawa Yoshinori

INTERNAL MEDICINE 57 巻 ( 23 ) 頁： 3429 - 3432 2018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：一般社団法人日本内科学会

<p>Squamous cell carcinoma (SCC) transformation has been identified as a mechanism of resistance to first-generation epidermal growth factor receptor tyrosine kinase inhibitors (<i>EGFR</i>-TKIs), gefitinib or erlotinib, in <i>EGFR</i>-mutated lung cancer. However, whether second- or third-generation TKIs can overcome resistance due to SCC transformation remains unclear. We herein report an <i>EGFR</i>-mutated lung adenocarcinoma undergoing transformation into SCC that exhibited a durable response to afatinib, which is a second-generation irreversible <i>EGFR</i>-TKI. We suggest that afatinib can be considered as a treatment option for <i>EGFR</i>-mutated tumor undergoing SCC transformation, particularly in the absence of a <i>T790M</i> mutation. </p>

DOI： 10.2169/internalmedicine.0999-18

A phase II trial of Ifosfamide combination with recommended supportive therapy for recurrent SCLC in second-line and heavily treated setting 査読有り

Ichidai Tanaka Kenji Kawada Masahiro Morise Tetsunari Hase Hiroaki Hayashi Akihiko Sokai Asuki Fukatsu Masashi Kondo Fumio Nomura Yoshinori Hasegawa

Cancer Chemotherapy and Pharmacology 2017年12月

Plasma-derived extracellular vesicle proteins as a source of biomarkers for lung adenocarcinoma 査読有り国際共著国際誌

Vykoukal Jody, Sun Nan, Aguilar-Bonavides Clemente, Katayama Hiroyuki, Tanaka Ichidai, Fahrmann Johannes F., Capello Michela, Fujimoto Junya, Aguilar Mitzi, Wistuba Ignacio I., Taguchi Ayumu, Ostrin Edwin J., Hanash Samir M.

ONCOTARGET 8 巻 ( 56 ) 頁： 95466 - 95480 2017年11月

Predictive and Prognostic Molecular Biomarkers for Response to Neoadjuvant Chemoradiation in Rectal Cancer 査読有り国際誌

Dayde Delphine, Tanaka Ichidai, Jain Rekha, Tai Mei Chee, Taguchi Ayumu

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES 18 巻 ( 3 ) 2017年3月

【特集】呼吸器科医に役立つ最先端のメカノバイオロジー研究　2）各論：3．肺癌・悪性中皮腫のメカノバイオロジーとYAP/TAZの役割査読有り

田中一大

呼吸臨床 1 巻 ( 2 ) 2017年

担当区分：筆頭著者,　責任著者記述言語：日本語掲載種別：論文集(書籍)内論文出版者・発行元：COSMIC

生体を構成する細胞は，さまざまな物理的刺激（メカニカルストレス）に応答して，増殖・分化・形態形成を制御する。近年，物理的刺激が感知された後の応答分子として，Hippoシグナル経路およびその標的因子である転写共役因子YAP/TAZが同定された。Hippoシグナル経路・YAP/TAZは，発生過程で臓器サイズを決定する重要な役割を担う一方で，腫瘍の悪性化にも深く関連している。肺癌においては，YAP/TAZが細胞外基質の硬度に応答して細胞増殖に寄与している可能性が高い。それに対し，悪性中皮腫においてはHippoシグナル経路の破綻が基軸となり，YAPの恒常的活性化を引き起こしている。YAP/TAZの活性化は，細胞外基質の再構築にも関与し腫瘍進展を促進している。

DOI： 10.24557/kokyurinsho.1.e00020

Loss of YAP1 defines neuroendocrine differentiation of lung tumors 査読有り国際誌

Ito Takeshi, Matsubara Daisuke, Tanaka Ichidai, Makiya Kanae, Tanei Zen-ichi, Kumagai Yuki, Shiu Shu-Jen, Nakaoka Hiroki J., Ishikawa Shumpei, Isagawa Takayuki, Morikawa Teppei, Shinozaki-Ushiku Aya, Goto Yasushi, Nakano Tomoyuki, Tsuchiya Takehiro, Tsubochi Hiroyoshi, Komura Daisuke, Aburatani Hiroyuki, Dobashi Yoh, Nakajima Jun, Endo Shunsuke, Fukayama Masashi, Sekido Yoshitaka, Niki Toshiro, Murakami Yoshinori

CANCER SCIENCE 107 巻 ( 10 ) 頁： 1527 - 1538 2016年10月

Activation of Yes-Associated Protein in Low-Grade Meningiomas Is Regulated by Merlin, Cell Density, and Extracellular Matrix Stiffness 査読有り国際誌

Tanahashi Kuniaki, Natsume Atsushi, Ohka Fumiharu, Motomura Kazuya, Alim Adiljan, Tanaka Ichidai, Senga Takeshi, Harada Ichiro, Fukuyama Ryuichi, Sumiyoshi Naoyuki, Sekido Yoshitaka, Wakabayashi Toshihiko

JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY 74 巻 ( 7 ) 頁： 704 - 709 2015年7月

RASSF3 downregulation increases malignant phenotypes of non-small cell lung cancer 査読有り国際誌

Fukatsu Asuki, Ishiguro Futoshi, Tanaka Ichidai, Kudo Takumi, Nakagawa Kentaro, Shinjo Keiko, Kondo Yutaka, Fujii Makiko, Hasegawa Yoshinori, Tomizawa Kenji, Mitsudomi Tetsuya, Osada Hirotaka, Hata Yutaka, Sekido Yoshitaka

LUNG CANCER 83 巻 ( 1 ) 頁： 23 - 29 2014年1月

DYSREGULATION OF HIPPO TUMOR-SUPPRESSIVE PATHWAY IN MALIGNANT MESOTHELIOMA 査読有り国際誌

Sekido Yoshitaka, Tanaka Ichidai, Fujii Makiko, Osada Hirotaka

JOURNAL OF THORACIC ONCOLOGY 8 巻頁： S1045 - S1046 2013年11月

YAP induces malignant mesothelioma cell proliferation by upregulating transcription of cell cycle-promoting genes 査読有り国際誌

Mizuno T., Murakami H., Fujii M., Ishiguro F., Tanaka I., Kondo Y., Akatsuka S., Toyokuni S., Yokoi K., Osada H., Sekido Y.

ONCOGENE 31 巻 ( 49 ) 頁： 5117 - 5122 2012年12月

Convergent signaling in the regulation of connective tissue growth factor in malignant mesothelioma TGF beta signaling and defects in the Hippo signaling cascade 査読有り国際誌

Fujii Makiko, Nakanishi Hayao, Toyoda Takeshi, Tanaka Ichidai, Kondo Yutaka, Osada Hirotaka, Sekido Yoshitaka

CELL CYCLE 11 巻 ( 18 ) 頁： 3373 - 3379 2012年9月

Interstitial Pneumonia and Nodular Regenerative Hyperplasia of the Liver as Initial Manifestations of Polyarteritis Nodosa 査読有り国際誌

Tanaka Ichidai, Imaizumi Kazuyoshi, Hashimoto Izumi, Asai Naoya, Yokoi Toyoharu, Matsuno Tadakatsu, Hasegawa Yoshinori

INTERNAL MEDICINE 51 巻 ( 6 ) 頁： 635 - 638 2012年

担当区分：筆頭著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：一般社団法人日本内科学会

A 65-year-old man was admitted to our hospital because of progressive dyspnea. A laboratory examination and high-resolution computed tomography (HRCT) revealed that he had interstitial pneumonia (IP) with liver dysfunction. Myeloperoxidase-ANCA (MPO-ANCA) was negative. Although his respiratory condition had become stable after initiation of steroid therapy, liver dysfunction had worsened with progressive portal hypertension. He died of hepatic insufficiency about three years after the first medical examination.<br> Autopsy showed that he had vasculitis of medium and small blood vessels of the spleen, lungs, and liver. The final diagnosis was classical polyarteritis nodosa (PAN). Microscopically, non-specific interstitial pneumonia was identified in the autopsied lung. The pathological findings of the liver were consistent with nodular regenerative hyperplasia (NRH). We report a case of PAN with IP and NRH preceding findings of systemic vasculitis.<br>

DOI： 10.2169/internalmedicine.51.5638

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