Researcher Database

Eiki Kikuchi
Hokkaido University Hospital Internal Medicine
Lecturer

Researcher Profile and Settings

Affiliation

  • Hokkaido University Hospital Internal Medicine

Job Title

  • Lecturer

Degree

  • M.D., Ph.D.(Hokkaido University)

Research funding number

  • 60463741

Researcher ID

  • M-9688-2014

J-Global ID

Research Interests

  • DNA repair   Cell cycle   Epigenetics   Chemotherapy   Lung Cancer   

Research Areas

  • Life sciences / Molecular biology
  • Life sciences / Hematology and oncology
  • Life sciences / Respiratory medicine

Academic & Professional Experience

  • 2020/07 - Today Hokkaido University Hokkaido University Hospital Lecturer
  • 2014/02 - 2020/06 Hokkaido University University Hospital Assistant professor
  • 2011/01 - 2014/01 Dana Farber Cancer Institute Medical Oncology Research fellow
  • 2007/07 - 2010/12 Hokkaido Univ. Hospital Assistant professor

Education

  • 2002/04 - 2007/03  Hokkaido Univ.  Graduate School of Medicine
  • 1991/04 - 1997/03  Hokkaido Univ.  School of Medicine

Research Activities

Published Papers

  • Tetsuaki Shoji, Eiki Kikuchi, Junko Kikuchi, Yuta Takashima, Megumi Furuta, Hirofumi Takahashi, Kosuke Tsuji, Makie Maeda, Ichiro Kinoshita, Hirotoshi Dosaka-Akita, Jun Sakakibara-Konishi, Satoshi Konno
    Cancer chemotherapy and pharmacology 85 (5) 843 - 853 2020/05 [Refereed][Not invited]
     
    PURPOSE: We evaluated the expression of proteasome subunits to assess whether the proteasome could be a therapeutic target in cisplatin-resistant lung cancer cells. METHODS: Cisplatin-resistant (CR) variants were established from three non-small cell lung cancer (NSCLC) cell lines (A549, H1299, and H1975) and two small cell lung cancer (SCLC) cell lines (SBC3 and SBC5). The expression of proteasome subunits, the sensitivity to immunoproteasome inhibitors, and 20S proteasomal proteolytic activity were examined in the CR variants of the lung cancer cell lines. RESULTS: All five CR cell lines highly expressed one or both of the immunoproteasome subunit genes, PSMB8 and PSMB9, while no clear trend was observed in the expression of constitutive proteasome subunits. The CR cells expressed significantly higher levels of PSMB8 and PSMB9 proteins, as well. The CR variants of the H1299 and SBC3 cell lines were more sensitive to immunoproteasome inhibitors, and had significantly more proteasomal proteolytic activity than their parental counterparts. CONCLUSIONS: The immunoproteasome may be an effective therapeutic target in a subset of CR lung cancers. Proteasomal proteolytic activity may be a predictive marker for the efficacy of immunoproteasome inhibitors in cisplatin-resistant SCLC and NSCLC.
  • Yuta Takashima, Eiki Kikuchi, Junko Kikuchi, Motofumi Suzuki, Hajime Kikuchi, Makie Maeda, Tetsuaki Shoji, Megumi Furuta, Ichiro Kinoshita, Hirotoshi Dosaka-Akita, Jun Sakakibara-Konishi, Satoshi Konno
    International journal of cancer 146 (4) 1114 - 1124 2020/02/15 [Refereed][Not invited]
     
    Bromodomain and extraterminal domain (BET) inhibitors are broadly active against distinct types of cancer, including nonsmall cell lung cancer (NSCLC). Previous studies have addressed the effect of BET-inhibiting drugs on the expression of oncogenes such as c-Myc, but DNA damage repair pathways have also been reported to be involved in the efficacy of these drugs. AZD1775, an inhibitor of the G2-M cell cycle checkpoint kinase WEE1, induces DNA damage by promoting premature mitotic entry. Thus, we hypothesized that BET inhibition would increase AZD1775-induced cytotoxicity by impairing DNA damage repair. Here, we demonstrate that combined inhibition of BET and WEE1 synergistically suppresses NSCLC growth both in vitro and in vivo. Two BET inhibitors, JQ1 and AZD5153, increased and prolonged AZD1775-induced DNA double-strand breaks (DSBs) and concomitantly repressed genes related to nonhomologous end joining (NHEJ), including XRCC4 and SHLD1. Furthermore, pharmaceutical inhibition of BET or knockdown of the BET protein BRD4 markedly diminished NHEJ activity, and the BET-inhibitor treatment also repressed myelin transcription factor 1 (MYT1) expression and promoted mitotic entry with subsequent mitotic catastrophe when combined with WEE1 inhibition. Our findings reveal that BET proteins, predominantly BRD4, play an essential role in DSB repair through the NHEJ pathway, and further suggest that combined inhibition of BET and WEE1 could serve as a novel therapeutic strategy for NSCLC.
  • Jun Sakakibara-Konishi, Mineyoshi Sato, Michiko Takimoto Sato, Kohei Kasahara, Masahiro Onozawa, Hidenori Mizugaki, Eiki Kikuchi, Hajime Asahina, Naofumi Shinagawa, Satoshi Konno
    Respiratory medicine case reports 31 101170 - 101170 2020 [Refereed][Not invited]
     
    Malignant pleural mesothelioma (MPM) is a rare and highly aggressive tumor. Nivolumab showed durable antitumor effect in patients with recurrent MPM and was approved for those patients in Japan in 2018. Immune related adverse event (irAE) is occurred in various organs and is suggestive to be related to better outcome of nivolumab. Frequency of hematological irAE is low and there are few reports about hematological irAE and association between irAE and outcome of nivolumab in patients with MPM. We present a case of recurrent MPM who responded to nivolumab treatment and experienced nivolumab-induced immune thrombocytopenia (ITP). Although high dose dexamethasone was administered and platelet count increased transiently, re-administration of dexamethasone was required to maintain normal count of platelet. The careful and intensive management of ITP treatment is necessary in cases who show no response or relapse to initial glucocorticoids treatment. This is the first report about nivolumab-induced ITP and association with response to nivolumab in MPM.
  • Hajime Asahina, Satoshi Oizumi, Kei Takamura, Toshiyuki Harada, Masao Harada, Hiroshi Yokouchi, Kenya Kanazawa, Yuka Fujita, Tetsuya Kojima, Fumiko Sugaya, Hisashi Tanaka, Ryoichi Honda, Eiki Kikuchi, Tomoo Ikari, Takahiro Ogi, Kaoruko Shimizu, Masaru Suzuki, Satoshi Konno, Hirotoshi Dosaka-Akita, Hiroshi Isobe, Masaharu Nishimura
    Lung cancer (Amsterdam, Netherlands) 138 65 - 71 2019/12 [Refereed][Not invited]
     
    OBJECTIVES: Patients with concomitant advanced non-small cell lung cancer (NSCLC) and interstitial lung disease (ILD) are excluded from most clinical chemotherapy trials because of the high risk of exacerbating the latter condition. This study prospectively investigated the efficacy and safety of albumin-bound paclitaxel (nab-paclitaxel) in combination with carboplatin in patients with both advanced NSCLC and ILD. PATIENTS AND METHODS: The enrolled patients had treatment-naïve, advanced NSCLC with ILD. Patients received 100 mg/m2nab-paclitaxel weekly and carboplatin at an area under the concentration-time curve of 6 once every 3 weeks for 4-6 cycles. The primary endpoint was the overall response rate (ORR); secondary endpoints included toxicity, progression-free survival (PFS), and overall survival (OS). RESULTS: Thirty-six patients were enrolled between April 2014 and September 2017. Sixteen patients (44.4%) had adenocarcinoma, 15 (41.7%) had squamous cell carcinoma (Sq), and 5 (13.9%) had non-small cell carcinoma. The median number of cycles administered were 4 (range: 1-6). The ORR was 55.6% (95% confidence interval [CI]: 39.6-70.5). The median PFS and OS were 5.3 months (95% CI: 3.9-8.2) and 15.4 months (95% CI: 9.4-18.7), respectively. A greater proportion of patients with Sq experienced improvements than did those with non-Sq: ORRs, 66.7% (95% CI: 41.7-84.8) vs. 47.6% (95% CI: 28.3-67.6) (P = 0.254); median PFS, 8.2 months (95% CI: 4.0-10.2) vs. 4.1 months (95% CI: 3.3-5.4) (HR, 0.60 [95% CI, 0.30-1.20]; P = 0.15); and median OS, 16.8 months (95% CI: 9.8-not reached) vs. 11.9 months (95% CI: 7.3-17.4) (HR, 0.56 [95% CI, 0.24-1.28]; P = 0.17). Two patients (5.6%) experienced grade ≥2 pneumonitis and 1 patient (2.8%) died. CONCLUSION: Weekly nab-paclitaxel combined with carboplatin showed favorable efficacy with acceptable toxicity in patients with both advanced NSCLC and ILD.
  • Jeffrey H Becker, Yandi Gao, Margaret Soucheray, Ines Pulido, Eiki Kikuchi, María L Rodríguez, Rutu Gandhi, Aranzazu Lafuente-Sanchis, Miguel Aupí, Javier Alcácer Fernández-Coronado, Paloma Martín-Martorell, Antonio Cremades, José M Galbis-Caravajal, Javier Alcácer, Camilla L Christensen, Patricia Simms, Ashley Hess, Hajime Asahina, Michael P Kahle, Fatima Al-Shahrour, Jeffrey A Borgia, Agustín Lahoz, Amelia Insa, Oscar Juan, Pasi A Jänne, Kwok-Kin Wong, Julian Carretero, Takeshi Shimamura
    Cancer research 79 (17) 4439 - 4452 2019/09/01 [Refereed][Not invited]
     
    Although EGFR mutant-selective tyrosine kinase inhibitors (TKI) are clinically effective, acquired resistance can occur by reactivating ERK. We show using in vitro models of acquired EGFR TKI resistance with a mesenchymal phenotype that CXCR7, an atypical G protein-coupled receptor, activates the MAPK-ERK pathway via β-arrestin. Depletion of CXCR7 inhibited the MAPK pathway, significantly attenuated EGFR TKI resistance, and resulted in mesenchymal-to-epithelial transition. CXCR7 overexpression was essential in reactivation of ERK1/2 for the generation of EGFR TKI-resistant persister cells. Many patients with non-small cell lung cancer (NSCLC) harboring an EGFR kinase domain mutation, who progressed on EGFR inhibitors, demonstrated increased CXCR7 expression. These data suggest that CXCR7 inhibition could considerably delay and prevent the emergence of acquired EGFR TKI resistance in EGFR-mutant NSCLC. SIGNIFICANCE: Increased expression of the chemokine receptor CXCR7 constitutes a mechanism of resistance to EGFR TKI in patients with non-small cell lung cancer through reactivation of ERK signaling.
  • Tomoo Ikari, Jun Sakakibara-Konishi, Gaku Yamamoto, Hidenori Kitai, Hidenori Mizugaki, Hajime Asahina, Eiki Kikuchi, Naofumi Shinagawa
    Clinical lung cancer 20 (4) e531-e533  2019/07 [Refereed][Not invited]
  • Gaku Yamamoto, Jun Sakakibara-Konishi, Tomoo Ikari, Hidenori Kitai, Hidenori Mizugaki, Hajime Asahina, Eiki Kikuchi, Naofumi Shinagawa
    Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 14 (5) e97-e99  2019/05 [Refereed][Not invited]
  • Megumi Furuta, Hajime Kikuchi, Tetsuaki Shoji, Yuta Takashima, Eiki Kikuchi, Junko Kikuchi, Ichiro Kinoshita, Hirotoshi Dosaka-Akita, Jun Sakakibara-Konishi
    Cancer science 110 (5) 1599 - 1608 1347-9032 2019/05 [Refereed][Not invited]
     
    Delta-like protein 3 (DLL3) is a ligand of Notch signaling, which mediates cell-fate decisions and is tumor-suppressive or oncogenic depending on the cellular context. Previous studies show that DLL3 is highly expressed in small cell lung cancer (SCLC) but not in normal lung tissue, suggesting that DLL3 might be associated with neuroendocrine tumorigenesis. However, its role in SCLC remains unclear. To investigate the role of DLL3 in tumorigenesis in SCLC, we performed loss-of-function and gain-of-function assays using SCLC cell lines. In vitro analysis of cell migration and invasion by transwell assay showed that DLL3 knockdown reduced migration and invasion of SCLC cells, whereas DLL3 overexpression increased these activities. In addition, DLL3 positively regulated SNAI1 expression and knockdown of SNAI1 attenuated the migration and invasion ability of SCLC cells. Moreover, upregulated DLL3 expression induced subcutaneous tumor growth in mouse models. These results indicate that DLL3 promoted tumor growth, migration and invasion in an SCLC model by modulating SNAI1/Snail.
  • 当院におけるFFPE検体、細胞診検体を用いたROS1融合遺伝子の検査成功率の検証
    北井 秀典, 榊原 純, 高橋 宏典, 國崎 守, 庄司 哲明, 高島 雄太, 古田 恵, 水柿 秀紀, 朝比奈 肇, 菊地 英毅, 品川 尚文, 畑中 佳奈子, 畑中 豊, 松野 吉宏, 大井 優子
    肺癌 (NPO)日本肺癌学会 59 (1) 112 - 112 0386-9628 2019/02 [Refereed][Not invited]
  • Hajime Kikuchi, Jun Sakakibara-Konishi, Megumi Furuta, Eiki Kikuchi, Junko Kikuchi, Satoshi Oizumi, Yasuhiro Hida, Kichizo Kaga, Ichiro Kinoshita, Hirotoshi Dosaka-Akita, Masaharu Nishimura
    Oncotarget 9 (50) 29379 - 29391 2018/06/29 [Refereed][Not invited]
     
    Some reports suggest that Numb is a potential tumor suppressor. However, its role in non-small cell lung cancer remains unclear. Non-small cell lung cancer comprises two major histological subtypes, adenocarcinoma and squamous cell carcinoma. To investigate the role of Numb in tumorigenesis of lung adenocarcinoma and squamous cell carcinoma, we firstly performed loss-of-function and gain-of-function assays. Moreover, Numb expression was investigated in surgically resected lung adenocarcinoma and squamous cell carcinoma tissues by immunohistochemistry and correlations with prognosis were analyzed. Numb suppressed the proliferation, migration, and invasion of adenocarcinoma cells and inhibited Notch signaling and epithelial-mesenchymal transition in vitro. Numb overexpression also inhibited subcutaneous adenocarcinoma tumor growth. In contrast, Numb promoted the proliferation, migration, and invasion of squamous cell carcinoma cells, but did not induce any consistent changes in Notch signaling. High Numb expression was associated with favorable prognosis in patients with lung adenocarcinoma, but not in those with squamous cell carcinoma. Collectively, our data demonstrate that Numb plays distinct roles in lung adenocarcinoma and squamous cell carcinoma. In lung adenocarcinoma, Numb impairs tumor growth and inhibits the Notch pathway and epithelial-mesenchymal transition, whereas in lung squamous cell carcinoma it may promote proliferation.
  • Tetsuaki Shoji, Hidenori Mizugaki, Yasuyuki Ikezawa, Megumi Furuta, Yuta Takashima, Hajime Kikuchi, Houman Goudarzi, Hajime Asahina, Junko Kikuchi, Eiki Kikuchi, Jun Sakakibara-Konishi, Naofumi Shinagawa, Ichizo Tsujino, Masaharu Nishimura
    Internal medicine (Tokyo, Japan) 57 (12) 1769 - 1772 0918-2918 2018/06/15 [Refereed][Not invited]
     
    This report describes the case of a 66-year-old man with non-small cell lung cancer and venous thromboembolism (VTE). Unfractionated heparin (UFH) was initially used to control VTE before chemotherapy. However, switching UFH to warfarin or edoxaban, a novel oral anticoagulant (NOAC), failed. Chemotherapy was then administered to control the tumor which was thought to have been the main cause of VTE, which had been treated by UFH. After tumor shrinkage was achieved by chemotherapy, we were able to successfully switch from UFH to edoxaban. Controlling the tumor size and activity enabled the use of edoxaban as maintenance therapy for VTE.
  • Jun Sakakibara-Konishi, Yasuyuki Ikezawa, Satoshi Oizumi, Junko Kikuchi, Eiki Kikuchi, Hidenori Mizugaki, Ichiro Kinoshita, Hirotoshi Dosaka-Akita, Masaharu Nishimura
    International journal of clinical oncology 22 (2) 257 - 268 1341-9625 2017/04 [Refereed][Not invited]
     
    BACKGROUND: Inhibition of Notch by γ-secretase inhibitor (GSI) has been shown to have an antitumor effect in Notch-expressing non-small cell lung cancer (NSCLC) and to induce apoptosis through modulation of Bcl-2 family proteins. In particular, Bim, a BH3-only member of the Bcl-2 family of proteins, has an important role in the induction of apoptosis in NSCLC when cells are treated with GSI. ABT-737, a BH3-only mimetic, targets the pro-survival Bcl-2 family and also induces apoptosis. METHODS: The Notch-expressing NSCLC cell lines H460, A549, H1793, and HCC2429 were used. The combined antitumor effect of GSI and ABT-737 was evaluated using the MTT proliferation assay in vitro and in xenograft mouse models. The expression of the Notch pathway and Bcl-2 family was analyzed using Western blotting analysis when cells were treated with a single drug treatment or a combination treatment. RESULTS: GSI XX or ABT-737 alone inhibited cell proliferation in a dose-dependent manner, and combination drug treatment showed a synergistic antitumor effect in vitro. In vivo, this drug combination significantly suppressed tumor proliferation compared to the single drug treatment. Phospho-Bcl-2 was downregulated and Bax was upregulated by both the single and combination drug treatments. Bim was induced by a single drug treatment and was enhanced by combination treatment. Combination treatment-induced apoptosis was decreased by Bim inhibition, suggesting that the antitumor effect of the drug combination was dependent on Bim. CONCLUSION: Based on our data, we propose that the combination treatment is a promising strategy for NSCLC therapy.
  • Yutaka Takeuchi, Naofumi Shinagawa, Eiki Kikuchi, Yoshihiro Matsuno, Yasuhiro Hida, Kichizo Kaga, Satoshi Oizumi, Masaharu Nishimura
    Respiratory investigation 54 (6) 473 - 478 2212-5345 2016/11 [Refereed][Not invited]
     
    BACKGROUND: Recent studies have shown differential response to chemotherapy among the subtypes of non-small cell lung carcinoma (NSCLC). Therefore, to accurately differentiate between the types of lung cancer is of paramount importance. Transbronchial biopsy using endobronchial ultrasonography with a guide sheath (EBUS-GS) is a promising method for the diagnosis of NSCLC. The purpose of this study was to evaluate the consistency between the types of lung cancer histologically diagnosed by bronchial biopsy or cytologically by EBUS-GS, and the final diagnosis of the resected specimen. METHODS: A retrospective analysis was performed on 203 patients having primary lung cancers diagnosed by EBUS-GS, who subsequently underwent curative pulmonary resection at the Hokkaido University Hospital between July 2003 and December 2011. In the present study, non-small cell carcinoma was defined as non-squamous cell carcinoma, and squamous cell carcinoma (Sq) was excluded. RESULTS: Of the 40 cases diagnosed as Sq by EBUS-GS, 37 cases were diagnosed as Sq, and 3 cases were diagnosed as non-Sq after surgical resection. Of the 159 cases diagnosed as non-Sq by EBUS-GS, 151 cases were diagnosed as non-Sq, 6 as Sq, and 2 as small cell carcinoma after surgical resection. These results showed that the positive predictive value of EBUS-GS in the diagnosis of Sq was 93%, and its positive predictive value in diagnosing non-Sq was 95%. CONCLUSIONS: The pathological subtyping of NSCLC using small tissue and cytology samples obtained by EBUS-GS appears to effectively distinguish between Sq and non-Sq and is therefore considered useful in making a treatment decision.
  • Haikuo Zhang, Jun Qi, Jaime M Reyes, Lewyn Li, Prakash K Rao, Fugen Li, Charles Y Lin, Jennifer A Perry, Matthew A Lawlor, Alexander Federation, Thomas De Raedt, Yvonne Y Li, Yan Liu, Melissa A Duarte, Yanxi Zhang, Grit S Herter-Sprie, Eiki Kikuchi, Julian Carretero, Charles M Perou, Jacob B Reibel, Joshiawa Paulk, Roderick T Bronson, Hideo Watanabe, Christine Fillmore Brainson, Carla F Kim, Peter S Hammerman, Myles Brown, Karen Cichowski, Henry Long, James E Bradner, Kwok-Kin Wong
    Cancer discovery 6 (9) 1006 - 21 2159-8274 2016/09 [Refereed][Not invited]
     
    UNLABELLED: As a master regulator of chromatin function, the lysine methyltransferase EZH2 orchestrates transcriptional silencing of developmental gene networks. Overexpression of EZH2 is commonly observed in human epithelial cancers, such as non-small cell lung carcinoma (NSCLC), yet definitive demonstration of malignant transformation by deregulated EZH2 remains elusive. Here, we demonstrate the causal role of EZH2 overexpression in NSCLC with new genetically engineered mouse models of lung adenocarcinoma. Deregulated EZH2 silences normal developmental pathways, leading to epigenetic transformation independent of canonical growth factor pathway activation. As such, tumors feature a transcriptional program distinct from KRAS- and EGFR-mutant mouse lung cancers, but shared with human lung adenocarcinomas exhibiting high EZH2 expression. To target EZH2-dependent cancers, we developed a potent open-source EZH2 inhibitor, JQEZ5, that promoted the regression of EZH2-driven tumors in vivo, confirming oncogenic addiction to EZH2 in established tumors and providing the rationale for epigenetic therapy in a subset of lung cancer. SIGNIFICANCE: EZH2 overexpression induces murine lung cancers that are similar to human NSCLC with high EZH2 expression and low levels of phosphorylated AKT and ERK, implicating biomarkers for EZH2 inhibitor sensitivity. Our EZH2 inhibitor, JQEZ5, promotes regression of these tumors, revealing a potential role for anti-EZH2 therapy in lung cancer. Cancer Discov; 6(9); 1006-21. ©2016 AACR.See related commentary by Frankel et al., p. 949This article is highlighted in the In This Issue feature, p. 932.
  • Margaret Soucheray, Marzia Capelletti, Inés Pulido, Yanan Kuang, Cloud P Paweletz, Jeffrey H Becker, Eiki Kikuchi, Chunxiao Xu, Tarun B Patel, Fatima Al-Shahrour, Julián Carretero, Kwok-Kin Wong, Pasi A Jänne, Geoffrey I Shapiro, Takeshi Shimamura
    Cancer research 75 (20) 4372 - 83 0008-5472 2015/10/15 [Refereed][Not invited]
     
    Non-small cell lung cancers (NSCLC) that have developed resistance to EGF receptor (EGFR) tyrosine kinase inhibitor (TKI), including gefitinib and erlotinib, are clinically linked to an epithelial-to-mesenchymal transition (EMT) phenotype. Here, we examined whether modulating EMT maintains the responsiveness of EGFR-mutated NSCLCs to EGFR TKI therapy. Using human NSCLC cell lines harboring mutated EGFR and a transgenic mouse model of lung cancer driven by mutant EGFR (EGFR-Del19-T790M), we demonstrate that EGFR inhibition induces TGFβ secretion followed by SMAD pathway activation, an event that promotes EMT. Chronic exposure of EGFR-mutated NSCLC cells to TGFβ was sufficient to induce EMT and resistance to EGFR TKI treatment. Furthermore, NSCLC HCC4006 cells with acquired resistance to gefitinib were characterized by a mesenchymal phenotype and displayed a higher prevalence of the EGFR T790M mutated allele. Notably, combined inhibition of EGFR and the TGFβ receptor in HCC4006 cells prevented EMT but was not sufficient to prevent acquired gefitinib resistance because of an increased emergence of the EGFR T790M allele compared with cells treated with gefitinib alone. Conversely, another independent NSCLC cell line, PC9, reproducibly developed EGFR T790M mutations as the primary mechanism underlying EGFR TKI resistance, even though the prevalence of the mutant allele was lower than that in HCC4006 cells. Thus, our findings underscore heterogeneity within NSCLC cells lines harboring EGFR kinase domain mutations that give rise to divergent resistance mechanisms in response to treatment and anticipate the complexity of EMT suppression as a therapeutic strategy.
  • Akriti Kharbanda, Hasan Rajabi, Caining Jin, Jeremy Tchaicha, Eiki Kikuchi, Kwok-Kin Wong, Donald Kufe
    Clinical cancer research : an official journal of the American Association for Cancer Research 20 (21) 5423 - 34 1078-0432 2014/11/01 [Refereed][Not invited]
     
    PURPOSE: Non-small cell lung cancers (NSCLC) that express EGF receptor with activating mutations frequently develop resistance to EGFR kinase inhibitors. The mucin 1 (MUC1) heterodimeric protein is aberrantly overexpressed in NSCLC cells and confers a poor prognosis; however, the functional involvement of MUC1 in mutant EGFR signaling is not known. EXPERIMENTAL DESIGN: Targeting the oncogenic MUC1 C-terminal subunit (MUC1-C) in NSCLC cells harboring mutant EGFR was studied for effects on signaling, growth, clonogenic survival, and tumorigenicity. RESULTS: Stable silencing of MUC1-C in H1975/EGFR(L858R/T790M) cells resulted in downregulation of AKT signaling and inhibition of growth, colony formation, and tumorigenicity. Similar findings were obtained when MUC1-C was silenced in gefitinib-resistant PC9GR cells expressing EGFR(delE746_A750/T790M). The results further show that expression of a MUC1-C(CQC → AQA) mutant, which blocks MUC1-C homodimerization, suppresses EGFR(T790M), AKT and MEK → ERK activation, colony formation, and tumorigenicity. In concert with these results, treatment of H1975 and PC9GR cells with GO-203, a cell-penetrating peptide that blocks MUC1-C homodimerization, resulted in inhibition of EGFR, AKT, and MEK → ERK signaling and in loss of survival. Combination studies of GO-203 and afatinib, an irreversible inhibitor of EGFR, further demonstrate that these agents are synergistic in inhibiting growth of NSCLC cells harboring the activating EGFR(T790M) or EGFR(delE746-A750) mutants. CONCLUSIONS: These findings indicate that targeting MUC1-C inhibits mutant EGFR signaling and survival, and thus represents a potential approach alone and in combination for the treatment of NSCLCs resistant to EGFR kinase inhibitors.
  • Jeremy H Tchaicha, Esra A Akbay, Abigail Altabef, Oliver R Mikse, Eiki Kikuchi, Kevin Rhee, Rachel G Liao, Roderick T Bronson, Lynette M Sholl, Matthew Meyerson, Peter S Hammerman, Kwok-Kin Wong
    Cancer research 74 (17) 4676 - 84 0008-5472 2014/09/01 [Refereed][Not invited]
     
    Somatic mutations in FGFR2 are present in 4% to 5% of patients diagnosed with non-small cell lung cancer (NSCLC). Amplification and mutations in FGFR genes have been identified in patients with NSCLCs, and clinical trials are testing the efficacy of anti-FGFR therapies. FGFR2 and other FGFR kinase family gene alterations have been found in both lung squamous cell carcinoma and lung adenocarcinoma, although mouse models of FGFR-driven lung cancers have not been reported. Here, we generated a genetically engineered mouse model (GEMM) of NSCLC driven by a kinase domain mutation in FGFR2. Combined with p53 ablation, primary grade 3/4 adenocarcinoma was induced in the lung epithelial compartment exhibiting locally invasive and pleiotropic tendencies largely made up of multinucleated cells. Tumors were acutely sensitive to pan-FGFR inhibition. This is the first FGFR2-driven lung cancer GEMM, which can be applied across different cancer indications in a preclinical setting.
  • Hidenori Mizugaki, Jun Sakakibara-Konishi, Junko Kikuchi, Jun Moriya, Kanako C Hatanaka, Eiki Kikuchi, Ichiro Kinoshita, Satoshi Oizumi, Hirotoshi Dosaka-Akita, Yoshihiro Matsuno, Masaharu Nishimura
    International journal of clinical oncology 19 (2) 254 - 9 1341-9625 2014/04 [Refereed][Not invited]
     
    BACKGROUND: CD133 is a membrane glycoprotein containing five transmembrane loops. Previous reports suggest that a CD133-positive subpopulation of multipotent cells with extensive proliferative and self-renewal characteristics has biological features of a cancer stem cell. In addition, the presence of CD133-positive cells was associated with a significantly poorer prognosis for some solid tumors, compared to those with CD133-negative cells. However, the clinicopathological significance of CD133 in non-small cell lung cancer (NSCLC) remains controversial. METHODS: We conducted immunohistochemical assessment of 161 NSCLCs surgically resected at Hokkaido University Hospital between 1982 and 1994 to evaluate correlations between CD133 expression and various clinicopathological features. RESULTS: CD133 expression was significantly correlated with pathological stages (pStages) II, III, and IV for the various NSCLC types analyzed and was an independent factor for unfavorable prognosis in this population (hazard ratio = 3.157, P = 0.015). CONCLUSION: CD133 expression was correlated with pStage and was predictive of unfavorable prognosis in patients with pStages II, III, and IV NSCLC. These results suggest the possibility of using CD133 as a novel prognostic marker in these patients.
  • Esra A Akbay, Javid Moslehi, Camilla L Christensen, Supriya Saha, Jeremy H Tchaicha, Shakti H Ramkissoon, Kelly M Stewart, Julian Carretero, Eiki Kikuchi, Haikuo Zhang, Travis J Cohoon, Stuart Murray, Wei Liu, Kazumasa Uno, Sudeshna Fisch, Kristen Jones, Sushma Gurumurthy, Camelia Gliser, Sung Choe, Marie Keenan, Jaekyoung Son, Illana Stanley, Julie A Losman, Robert Padera, Roderick T Bronson, John M Asara, Omar Abdel-Wahab, Philip C Amrein, Amir T Fathi, Nika N Danial, Alec C Kimmelman, Andrew L Kung, Keith L Ligon, Katharine E Yen, William G Kaelin Jr, Nabeel Bardeesy, Kwok-Kin Wong
    Genes & development 28 (5) 479 - 90 0890-9369 2014/03/01 [Refereed][Not invited]
     
    Mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) have been discovered in several cancer types and cause the neurometabolic syndrome D2-hydroxyglutaric aciduria (D2HGA). The mutant enzymes exhibit neomorphic activity resulting in production of D2-hydroxyglutaric acid (D-2HG). To study the pathophysiological consequences of the accumulation of D-2HG, we generated transgenic mice with conditionally activated IDH2(R140Q) and IDH2(R172K) alleles. Global induction of mutant IDH2 expression in adults resulted in dilated cardiomyopathy, white matter abnormalities throughout the central nervous system (CNS), and muscular dystrophy. Embryonic activation of mutant IDH2 resulted in more pronounced phenotypes, including runting, hydrocephalus, and shortened life span, recapitulating the abnormalities observed in D2HGA patients. The diseased hearts exhibited mitochondrial damage and glycogen accumulation with a concordant up-regulation of genes involved in glycogen biosynthesis. Notably, mild cardiac hypertrophy was also observed in nude mice implanted with IDH2(R140Q)-expressing xenografts, suggesting that 2HG may potentially act in a paracrine fashion. Finally, we show that silencing of IDH2(R140Q) in mice with an inducible transgene restores heart function by lowering 2HG levels. Together, these findings indicate that inhibitors of mutant IDH2 may be beneficial in the treatment of D2HGA and suggest that 2HG produced by IDH mutant tumors has the potential to provoke a paraneoplastic condition.
  • K. Ikawa, E. Kikuchi, J. Kikuchi, M. Nishimura, H. Derendorf, N. Morikawa
    Journal of Clinical Pharmacy and Therapeutics 39 (4) 411 - 417 1365-2710 2014 [Refereed][Not invited]
     
    What is known and objective Clinical pharmacokinetic profiles of clarithromycin and telithromycin in bronchopulmonary sites have not been fully characterized. This study aimed to describe in more detail the pharmacokinetics of the two macrolides in epithelial lining fluid (ELF) of human bronchi and to evaluate their pharmacodynamic target attainment at this site. Methods Previously reported drug concentration data for serum and ELF were simultaneously fitted to a three-compartment pharmacokinetic model using nonmem program. The model parameter estimates were used for site-specific pharmacodynamic simulation. Results and discussion Population mean parameters for clarithromycin were as follows: distribution volumes of central, peripheral and ELF compartments (V1/F, V2/F and V3/F) = 204·7, 168·9 and 67·1 L clearance (CL/F) = 34·4 L/h absorption rate constant (Ka) = 0·680 1/h transfer rate constants connecting compartments (K12, K21, K 13 and K31 = 0·0193, 0·434, 0·667 and 0·260 1/h, respectively). Mean parameters for telithromycin were as follows: V1/F, V2/F and V3/F = 370·3, 290·3 and 213·8 L CL/F = 89·5 L/h Ka = 0·740 1/h K12, K21, K13 and K 31 = 0·0026, 1·044, 0·758 and 0·158 1/h, respectively. Using these parameters, the mean ELF/serum ratio in the area under drug concentration-time curve (AUC) was 7·80 for clarithromycin and 8·05 for telithromycin. Clarithromycin achieved a ≥ 90% probability of attaining a pharmacodynamic target [AUC/minimum inhibitory concentration (MIC) = 100] in ELF against bacterial isolates for which MICs were ≤0·5 and ≤1 mg/L for twice-daily doses of 250 and 500 mg, respectively. For telithromycin, once-daily doses of 600 and 800 mg achieved a ≥90% probability in ELF against Streptococcus pneumoniae, Staphylococcus aureus and Moraxella catarrhalis isolates but not Haemophilus influenzae isolates. What is new and conclusion These results should provide a better understanding of the bronchial pharmacokinetics of clarithromycin and telithromycin, while also providing useful information about their dosages for respiratory tract infections based on site-specific pharmacodynamic evaluation. Further studies in a large number of patients are needed to confirm our findings and clarify their therapeutic implications. This article should provide a better understanding of the bronchial pharmacokinetics of clarithromycin and telithromycin, while also providing useful information about their dosages for respiratory tract infections based on site-specific pharmacodynamic evaluation. Further studies in a large number of patients are needed to confirm our findings and clarify their therapeutic implications. © 2014 John Wiley & Sons Ltd.
  • Takeshi Shimamura, Zhao Chen, Margaret Soucheray, Julian Carretero, Eiki Kikuchi, Jeremy H Tchaicha, Yandi Gao, Katherine A Cheng, Travis J Cohoon, Jun Qi, Esra Akbay, Alec C Kimmelman, Andrew L Kung, James E Bradner, Kwok-Kin Wong
    Clinical cancer research : an official journal of the American Association for Cancer Research 19 (22) 6183 - 92 1078-0432 2013/11/15 [Refereed][Not invited]
     
    PURPOSE: Amplification of MYC is one of the most common genetic alterations in lung cancer, contributing to a myriad of phenotypes associated with growth, invasion, and drug resistance. Murine genetics has established both the centrality of somatic alterations of Kras in lung cancer, as well as the dependency of mutant Kras tumors on MYC function. Unfortunately, drug-like small-molecule inhibitors of KRAS and MYC have yet to be realized. The recent discovery, in hematologic malignancies, that bromodomain and extra-terminal (BET) bromodomain inhibition impairs MYC expression and MYC transcriptional function established the rationale of targeting KRAS-driven non-small cell lung cancer (NSCLC) with BET inhibition. EXPERIMENTAL DESIGN: We performed functional assays to evaluate the effects of JQ1 in genetically defined NSCLC cell lines harboring KRAS and/or LKB1 mutations. Furthermore, we evaluated JQ1 in transgenic mouse lung cancer models expressing mutant kras or concurrent mutant kras and lkb1. Effects of bromodomain inhibition on transcriptional pathways were explored and validated by expression analysis. RESULTS: Although JQ1 is broadly active in NSCLC cells, activity of JQ1 in mutant KRAS NSCLC is abrogated by concurrent alteration or genetic knockdown of LKB1. In sensitive NSCLC models, JQ1 treatment results in the coordinate downregulation of the MYC-dependent transcriptional program. We found that JQ1 treatment produces significant tumor regression in mutant kras mice. As predicted, tumors from mutant kras and lkb1 mice did not respond to JQ1. CONCLUSION: Bromodomain inhibition comprises a promising therapeutic strategy for KRAS-mutant NSCLC with wild-type LKB1, via inhibition of MYC function. Clinical studies of BET bromodomain inhibitors in aggressive NSCLC will be actively pursued. Clin Cancer Res; 19(22); 6183-92. ©2013 AACR.
  • Toshiyuki Harada, Satoshi Oizumi, Kenichiro Ito, Kei Takamura, Eiki Kikuchi, Tomoya Kuda, Shunichi Sugawara, Aya Suzuki, Makoto Maemondo, Yuka Fujita, Ichiro Kinoshita, Akira Inoue, Fumihiro Hommura, Yutaka Katsuura, Hirotoshi Dosaka-Akita, Hiroshi Isobe, Masaharu Nishimura
    The oncologist 18 (4) 439 - 45 1083-7159 2013 [Refereed][Not invited]
     
    Amrubicin, a third-generation synthetic anthracycline agent, has favorable clinical activity and acceptable toxicity for the treatment of patients with non-small cell lung cancer (NSCLC) and small cell lung cancer. We conducted this study to evaluate the efficacy and safety of amrubicin for advanced NSCLC patients as a third- or fourth-line therapy. Eligible patients had recurrent or refractory advanced NSCLC after second- or third-line therapy. Patients received amrubicin, 35 mg/m(2) i.v. on days 1-3 every 3 weeks. The primary endpoint was the disease control rate (DCR). Secondary endpoints were the overall survival (OS) time, progression-free survival (PFS) time, response rate, and toxicity profile. Of the 41 patients enrolled, 26 received amrubicin as a third-line and 15 received it as a fourth-line therapy. The median number of treatment cycles was two (range, 1-9). Objective responses were complete response (n = 0), partial response (n = 4), stable disease (n = 21), progressive disease (n = 15), and not evaluable (n = 1), resulting in a DCR of 61.0% (95% confidence interval, 46.0%-75.9%). The overall response rate was 9.8% (95% confidence interval, 0.6%-18.8%). The median PFS interval was 3.0 months, median OS time was 12.6 months, and 1-year survival rate was 53.7%. Grade 3 or 4 hematological toxicities were neutropenia (68%), anemia (12%), thrombocytopenia (12%), and febrile neutropenia (17%). Nonhematological toxicities were mild and reversible. No treatment-related deaths were observed. Amrubicin showed significant clinical activity with manageable toxicities as a third- or fourth-line therapy for patients with advanced NSCLC. This study provides relevant data for routine practice and future prospective trials evaluating third- or fourth-line treatment strategies for patients with advanced NSCLC.
  • Junko Kikuchi, Taichi Takashina, Ichiro Kinoshita, Eiki Kikuchi, Yasushi Shimizu, Jun Sakakibara-Konishi, Satoshi Oizumi, Victor E Marquez, Masaharu Nishimura, Hirotoshi Dosaka-Akita
    Lung cancer (Amsterdam, Netherlands) 78 (2) 138 - 43 0169-5002 2012/11 [Refereed][Not invited]
     
    EZH2 (enhancer of zeste homolog 2) is the catalytic subunit of PRC2 (polycomb repressive complex 2), which mediates histone methyltransferase activity and functions as transcriptional repressor involved in gene silencing. EZH2 is involved in malignant transformation and biological aggressiveness of several human malignancies. We previously demonstrated that non-small cell lung cancers (NSCLCs) also overexpress EZH2 and that high expression of EZH2 correlates with poor prognosis. Growing evidence indicates that EZH2 may be an appropriate therapeutic target in malignancies, including NSCLCs. Recently, an S-adenosyl-l-homocysteine hydrolase inhibitor, 3-Deazaneplanocin A (DZNep), has been shown to deplete and inhibit EZH2. The aim of this study was to determine the effect of DZNep in NSCLC cells. Knockdown of EZH2 by small-interfering RNA (siRNA) resulted in decreased growth of four NSCLC cell lines. MTT assays demonstrated that DZNep treatment resulted in dose-dependent inhibition of proliferation in the NSCLC cell lines with a half maximal inhibitory concentration (IC50) ranging from 0.08 to 0.24 μM. Immortalized but non-cancerous bronchial epithelial and fibroblast cell lines were less sensitive to DZNep than the NSCLC cell lines. Soft agarose assays demonstrated that anchorage-independent growth was also reduced in all three NSCLC cell lines that were evaluated using this assay. Flow cytometry analysis demonstrated that DZNep induced apoptosis and G1 cell cycle arrest in NSCLC cells, which was partially associated with cyclin A decrease and p27(Kip1) accumulation. DZNep depleted cellular levels of EZH2 and inhibited the associated histone H3 lysine 27 trimethylation. These results indicated that an epigenetic therapy that pharmacologically targets EZH2 via DZNep may constitute a novel approach to treatment of NSCLCs.
  • Jun Sakakibara-Konishi, Satoshi Oizumi, Junko Kikuchi, Eiki Kikuchi, Hidenori Mizugaki, Ichiro Kinoshita, Hirotoshi Dosaka-Akita, Masaharu Nishimura
    BMC cancer 12 286 - 286 2012/07/12 [Refereed][Not invited]
     
    BACKGROUND: The BH3-only members of the Bcl-2 protein family have been proposed to play a key role in the control of apoptosis and in the initiation of the apoptotic pathways. In this study, we evaluated the expression of Bim, Noxa, and Puma in non-small cell lung cancer (NSCLC). METHODS: A total of 135 surgically resected NSCLCs were immunohistochemically assessed for Bim, Noxa, and Puma expression. The immunoscores were determined, and then its correlation with either the clinicopathological variables or the survival outcomes were analyzed. RESULTS: Immunohistochemical reactivity for Bim, Noxa, and Puma was detected in the cytoplasm of the tumor cells. Bim expression was associated with several clinicopathological factors, including sex (p < 0.001), smoking habit (p = 0.03), pathological histology (p = 0.001), pathological T stage (p = 0.03), pathological disease stage (p = 0.02), and differentiation of tumor (p < 0.001). Multivariate logistic regression analysis showed a significant correlation between low Bim expression and squamous cell carcinoma (p = 0.04), in addition to a correlation between high Bim expression and well differentiated tumors (p = 0.02). Analysis of cellular biological expression demonstrated a link between low Bim expression and high Ki67. While Noxa expression was also shown to be correlated with both smoking habit (p = 0.02) and the pathological histology (p = 0.03), there was no strong association observed between the expression and the clinical features when they were examined by a multivariate logistic regression analysis. No correlations were noted between Puma expression and any of the variables. Our analyses also indicated that the expression levels of the BH3-only proteins were not pertinent to the survival outcome. CONCLUSIONS: The current analyses demonstrated that Bim expression in the NSCLCs was associated with both squamous cell carcinoma histology and tumor proliferation.
  • Lu Xu, Eiki Kikuchi, Chunxiao Xu, Hiromichi Ebi, Dalia Ercan, Katherine A. Cheng, Robert Padera, Jeffrey A. Engelman, Pasi A. Jaenne, Geoffrey I. Shapiro, Takeshi Shimamura, Kwok-Kin Wong
    CANCER RESEARCH 72 (13) 3302 - 3311 0008-5472 2012/07 [Refereed][Not invited]
     
    Tyrosine kinase inhibitors (TKI) that target the EGF receptor (EGFR) are effective in most non-small cell lung carcinoma (NSCLC) patients whose tumors harbor activating EGFR kinase domain mutations. Unfortunately, acquired resistance eventually emerges in these chronically treated cancers. Two of the most common mechanisms of acquired resistance to TKIs seen clinically are the acquisition of a secondary "gatekeeper" T790M EGFR mutation that increases the affinity of mutant EGFR for ATP and activation of MET to offset the loss of EGFR signaling. Although up to one-third of patient tumors resistant to reversible EGFR TKIs harbor concurrent T790M mutation and MET amplification, potential therapies for these tumors have not been modeled in vivo. In this study, we developed a preclinical platform to evaluate potential therapies by generating transgenic mouse lung cancer models expressing EGFR-mutant Del19-T790M or L858R-T790M, each with concurrent MET overexpression. We found that monotherapy targeting EGFR or MET alone did not produce significant tumor regression. In contrast, combination therapies targeting EGFR and MET simultaneously were highly efficacious against EGFR TKI-resistant tumors codriven by Del19-T790M or L858R-T790M and MET. Our findings therefore provide an in vivo model of intrinsic resistance to reversible TKIs and offer preclinical proof-of-principle that combination targeting of EGFR and MET may benefit patients with NSCLC. Cancer Res; 72(13); 3302-11. (C) 2012 AACR.
  • H. Mizugaki, J. Sakakibara-Konishi, Y. Ikezawa, J. Kikuchi, E. Kikuchi, S. Oizumi, T. P. Dang, M. Nishimura
    BRITISH JOURNAL OF CANCER 106 (12) 1953 - 1959 0007-0920 2012/06 [Refereed][Not invited]
     
    BACKGROUND: Notch receptor has an important role in both development and cancer. We previously reported that inhibition of the Notch3 by gamma-secretase inhibitor (GSI) induces apoptosis and suppresses tumour proliferation in non-small-cell lung cancer. Although radiation is reported to induce Notch activation, little is known about the relationship between radiation and Notch pathway. METHODS: We examined the effect of combining GSI and radiation at different dosing in three Notch expressing lung cancer cell lines. The cytotoxic effect of GSI and radiation was evaluated using MTT assay and clonogenic assay in vitro and xenograft models. Expressions of Notch pathway, mitogen-activated protein kinase (MAPK) pathway and Bcl-2 family proteins were investigated using western blot analysis. RESULTS: We discovered that the antitumour effect of combining GSI and radiation was dependent on treatment schedule. gamma-Secretase inhibitor administration after radiation had the greatest growth inhibition of lung cancer in vitro and in vivo. We showed that the combination induced apoptosis of lung cancer cell lines through the regulation of MAPK and Bcl-2 family proteins. Furthermore, activation of Notch after radiation was ameliorated by GSI administration, suggesting that treatment with GSI prevents Notch-induced radiation resistance. CONCLUSION: Notch has an important role in lung cancer. Treatment with GSI after radiation can significantly enhance radiation-mediated tumour cytotoxicity. British Journal of Cancer (2012) 106, 1953-1959. doi:10.1038/bjc.2012.178 www.bjcancer.com Published online 17 May 2012 (C) 2012 Cancer Research UK
  • Naofumi Shinagawa, Kosuke Nakano, Hajime Asahina, Eiki Kikuchi, Tomoo Ito, Yoshihiro Matsuno, Satoshi Oizumi, Yasuyuki Nasuhara, Masaharu Nishimura
    ANNALS OF THORACIC SURGERY 93 (3) 951 - 957 0003-4975 2012/03 [Refereed][Not invited]
     
    Background. For appropriate treatment, such as the selection of antibiotics or initiation of steroid therapy, correctly diagnosing benign pulmonary diseases located at the periphery is vital. This study assessed the usefulness of bronchoscopy using endobronchial ultrasonography with a guide sheath (EBUS-GS) in the diagnosis of benign pulmonary diseases, especially those presenting peripheral nodular lesions. Methods. We retrospectively reviewed 159 patients with 171 peripheral pulmonary lesions (PPLs) that were subsequently diagnosed as benign diseases. To examine the role of bronchoscopy with EBUS-GS, the contribution of bronchoscopy was classified into 4 categories. We also retrospectively reviewed 24 patients with 25 PPLs that were subsequently diagnosed as benign diseases by bronchoscopy without EBUS-GS (historical control). Results. The ultimate diagnosis of 171 PPLs included 45 cases of mycobacteriosis, 45 cases of bronchiolitis obliterans organizing pneumonia/chronic organized pneumonia (BOOP), 23 cases of bacterial pneumonia, 13 abscesses, 11 cases of sarcoidosis, and 34 other benign diseases. Among them, a definitive diagnosis was obtained by bronchoscopy with EBUS-GS in 99 lesions (58%). Lesions in which the probe was positioned within the lesion had a higher diagnostic yield (64%) than did lesions in which the probe was positioned adjacent to the lesion (52%) or outside the lesion (20%; P = 0.01). The diagnostic yield of bronchoscopy with EBUS-GS was higher compared with that of the historical control (58% versus 28%; P = 0.04). Conclusions. Bronchoscopy using EBUS-GS is a reasonable option as a diagnostic procedure for PPLs, even if they are suspected to be benign in nature. (Ann Thorac Surg 2012;93:951-7) (C) 2012 by The Society of Thoracic Surgeons
  • Noriyuki Yamada, Satoshi Oizumi, Hajime Asahina, Naofumi Shinagawa, Eiki Kikuchi, Junko Kikuchi, Jun Sakakibara-Konishi, Tomoaki Tanaka, Kunihiko Kobayashi, Koichi Hagiwara, Masaharu Nishimura
    ONCOLOGY 82 (6) 341 - 346 0030-2414 2012 [Refereed][Not invited]
     
    Objectives: Cytological examination of samples obtained by bronchoscopy is a useful method for establishing the diagnosis of non-small cell lung cancer (NSCLC). However, the utility of a highly sensitive method for the detection of epidermal growth factor receptor (EGFR) mutation in the cytological specimens has not been fully evaluated. Methods: We retrospectively examined the efficacy of the peptide nucleic acid-locked nucleic acid polymerase chain reaction (PNA-LNA PCR) clamp method for detecting EGFR mutations in 122 bronchoscopic cytological specimens from NSCLC patients. Results: Overall, 41 specimens (33.6%) were positive for EGFR mutation. Twenty-nine (39.7%) of 73 specimens obtained by using endobronchial ultrasonography with a guide sheath, 7 (33.3%) of 21 specimens obtained under direct vision by using a conventional bronchoscope, 4 (36.4%) of 11 specimens obtained by using an ultrathin bronchoscope, and 1 (5.9%) of 17 specimens obtained by endobronchial ultrasound-guided transbronchial needle aspiration were positive for EGFR mutation. Furthermore, among 22 resected NSCLC cases, the EGFR mutation status obtained from bronchoscopic materials was consistent with the status obtained from surgical samples, with the exception of 1 case. Conclusion: The detection of EGFR mutation by subjecting bronchoscopic cytological specimens to a PNA-LNA PCR clamp assay proves useful. Copyright (C) 2012 S. Karger AG, Basel
  • Junko Kikuchi, Ichiro Kinoshita, Yasushi Shimizu, Eiki Kikuchi, Kayoko Takeda, Hiroyuki Aburatani, Satoshi Oizumi, Jun Konishi, Kichizo Kaga, Yoshihiro Matsuno, Michael J. Birrer, Masaharu Nishimura, Hirotoshi Dosaka-Akita
    LUNG CANCER 72 (2) 229 - 237 0169-5002 2011/05 [Refereed][Not invited]
     
    Background: Minichromosome maintenance (MCM) proteins 2-7 form a complex essential for the initiation of DNA replication. In the process to screen expression changes related to growth suppression of non-small cell lung cancer (NSCLC) cells by a cJun dominant-negative mutant, we found that reduced expression of MCM4 was correlated with this growth suppression. Method: We determined the relevance of MCM4 in proliferation of NSCLC by downregulating its expression with small-interfering RNA in three NSCLC cell lines. We then immunohistochemically analyzed MCM4 expression in 156 surgically resected NSCLCs to correlate clinicopathologic characteristics. Results: MCM4 downregulation reduced proliferation in two cell lines. MCM4 expression was higher in cancer cells than in adjacent normal bronchial epithelial cells (p < 0.001). High MCM4 expression was correlated with male gender, heavy smoking, poorer differentiation and non-adenocarcinoma histology (p < 0.001, respectively). High MCM4 expression was also correlated with proliferation markers, Ki-67 and cyclin E expression (p < 0.001, respectively). MCM4 expression was not associated with survival. Conclusion: MCM4 may play an essential role in the proliferation of some NSCLC cells. Taken together with higher expression in NSCLCs and its correlation with clinicopathologic characteristics such as non-adenocarcinoma histology. MCM4 may have potential as a therapeutic target in certain population with NSCLCs. (C) 2010 Elsevier Ireland Ltd. All rights reserved.
  • Kenji Akie, Satoshi Oizumi, Shigeaki Ogura, Naofumi Shinagawa, Eiki Kikuchi, Shinichi Fukumoto, Masao Harada, Ichiro Kinoshita, Tetsuya Kojima, Toshiyuki Harada, Yuka Fujita, Yoshinobu Ohsaki, Hirotoshi Dosaka-Akita, Hiroshi Isobe, Masaharu Nishimura
    ONCOLOGY 81 (2) 84 - 90 0030-2414 2011 [Refereed][Not invited]
     
    Objective: Platinum-free regimens can represent an alternative for advanced non-small cell lung cancer (NSCLC) if similar efficacy is provided with better tolerability. This study evaluated the efficacy and safety of combined irinotecan and S-1 for chemotherapy-naive advanced NSCLC. Methods: Chemotherapy consisted of 4-week cycles of intravenous irinotecan (100 mg/m(2), days 1 and 15) and oral S-1 (80 mg/m(2), days 1-14). The primary endpoint was response rate, while secondary endpoints were overall survival, progression-free survival (PFS), and safety. Results: A total of 112 cycles was administered to 40 patients (median 3 cycles; range 1-6 cycles). Twelve patients showed partial response and 17 patients had stable disease, representing a response rate of 30% and a disease control rate of 72.5%. Median survival time and median PFS were 16.1 and 4.8 months, respectively. Hematological toxicities of grade 3 or 4 were neutropenia (32.5%) and anemia (5.0%). The most common nonhematological toxicities of grade 3 or 4 included diarrhea (15.0%) and anorexia (17.5%). Patients homo-or heterozygous for UGTA1A*6 tended to show a higher incidence of grade 3 diarrhea (p = 0.055). Conclusion: The combination of irinotecan and S-1 offers good efficacy and tolerability for previously untreated advanced NSCLC. Copyright (C) 2011 S. Karger AG, Basel
  • Noriyuki Yamada, Satoshi Oizumi, Eiki Kikuchi, Naofumi Shinagawa, Jun Konishi-Sakakibara, Atsushi Ishimine, Keisuke Aoe, Kenichi Gemba, Takumi Kishimoto, Toshihiko Torigoe, Masaharu Nishimura
    CANCER IMMUNOLOGY IMMUNOTHERAPY 59 (10) 1543 - 1549 0340-7004 2010/10 [Refereed][Not invited]
     
    Defects in human leukocyte antigen (HLA) class I expression may allow tumor cells to escape immune recognition. T cell infiltration is associated with a good prognosis in many cancers. However, the role of HLA class I expression and tumor-infiltrating lymphocytes (TILs) in malignant pleural mesothelioma (MPM) has not been fully analyzed. In the present study, we investigated the immune profiles and conducted outcome analyses of MPM patients. HLA class I expression and TILs (CD4(+), CD8(+), and NK cells) were detected by immunohistochemistry in a series of 44 MPM cases. To detect HLA class I expression, specimens were stained with the anti-pan HLA class I monoclonal antibody EMR8-5. The expression of HLA class I was positive in all patients. There was no case that showed negative HLA class I expression. The density of CD4(+) and CD8(+) TILs were strongly correlated (R = 0.76, p < 0.001). A high density of CD8(+) TILs was a significantly better prognostic factor for the survival of patients with extrapleural pneumonectomy (p < 0.05). Multivariate analysis revealed that a high density of CD8(+) TILs is an independent prognostic factor for patients who underwent extrapleural pneumonectomy. The presence of intratumoral CD8(+) T cells was correlated with an improved clinical outcome, raising the possibility that CD8(+) T cells might play a pivotal role in the antitumor immune response against MPMs. Thus, the stimulation of CD8(+) lymphocytes might be an efficacious immunotherapy for MPM patients.
  • Junko Kikuchi, Ichiro Kinoshita, Yasushi Shimizu, Eiki Kikuchi, Jun Konishi, Satoshi Oizumi, Kichizo Kaga, Yoshihiro Matsuno, Masaharu Nishimura, Hirotoshi Dosaka-Akita
    CANCER 116 (12) 3015 - 3024 0008-543X 2010/06 [Refereed][Not invited]
     
    BACKGROUND: The polycomb group genes Bmi1 polycomb ring finger oncogene (Bmi1) and enhancer of zeste homolog 2 (EZH2) function as transcriptional repressors involved in gene silencing and in the malignant transformation and biologic aggressiveness of several human carcinomas. In the current study, the authors evaluated Bmi1 and EZH2 protein expression in specimens of human nonsmall cell lung cancer (NSCLC). METHODS: The authors conducted an immunohistochemical assessment of 157 surgically resected NSCLCs to evaluate the correlation between Bmi1 and EZH2 expression and various features, including clinical, clinicopathologic, and biologic characteristics. RESULTS: Normal bronchial epithelia revealed abundant expression of Bmi1 and sporadic expression of EZH2. Patients who had high EZH2 expression in tumor cells had a poorer prognosis than patients who had low EZH2 expression in tumor cells all pathologic stages of NSCLC (P=.001) and in pathologic stage I NSCLC (P=.006). Multivariate analysis revealed that high EZH2 expression was a independent, unfavorable prognostic factor in patients with pathologic stage I disease (P=.048). High EZH2 expression was correlated significantly with nonadenocarcinoma histology (P=.001), moderate and poor differentiation (P=.001), advanced pathologic tumor classification (P=.02), and high Ki-67 and cyclin E labeling indices (P<.001). Bmi1 expression, in contrast, was not a significant prognostic factor and was not correlated with any clinicopathologic factors other than early pathologic tumor classification. CONCLUSIONS: Bmi1 and EZH2 had characteristic and distinctive expression in NSCLCs. High EZH2 expression was correlated with tumor aggressiveness and may provide a novel prognostic marker for NSCLCs. Cancer 2010;116:3015-24. (C) 2010 American Cancer Society.
  • Hidenori Mizugaki, Naofumi Shinagawa, Kakuko Kanegae, Noriyuki Yamada, Hajime Asahina, Eiki Kikuchi, Satoshi Oizumi, Nagara Tamaki, Masaharu Nishimura
    LUNG CANCER 68 (2) 211 - 215 0169-5002 2010/05 [Refereed][Not invited]
     
    To evaluate the combination of transbronchial biopsy (TBB) using endobronchial ultrasonography with a guide sheath (EBUS-GS) and positron emission tomography with fluorodeoxyglucose (FDG-PET) for the diagnosis of small peripheral pulmonary lesions (PPLs) <= 30 mm in mean diameter. A total of 74 PPLs (69.2%) were diagnosed by TBB using EBUS-GS with X-ray fluoroscopy. Diagnostic yield by FDG-PET was 78.5% for the 107 PPLs examined. Diagnostic yield with the combination of TBB using EBUS-GS and FDG-PET (90.7%) was significantly higher compared with that for each procedure alone. A significant increment in diagnostic yield with this combination was seen for PPLs >20 mm and <= 30 mm and for malignant lesions. Combination of TBB using EBUS-GS and FDG-PET is useful for the diagnosis of small PPLs. (C) 2009 Elsevier Ireland Ltd. All rights reserved.
  • Satoshi Konno, Satoshi Oizumi, Naofumi Shinagawa, Eiki Kikuchi, Jun Konishi, Kenichiro Ito, Nobuyuki Hizawa, Akihiro Takiyama, Shinya Tanaka, Masaharu Nishimura
    INTERNAL MEDICINE 49 (8) 771 - 775 0918-2918 2010 [Refereed][Not invited]
     
    Primary mediastinal liposarcoma was observed in a 73-year-old man. Because of tight adhesions to adjacent tissues, neither complete resection nor surgical debulking of the tumor was possible. A T-tube was inserted into the patient's trachea for severe dyspnea, and he was treated with radiotherapy and an oral peroxisome proliferator-activated receptor-gamma agonist. The patient died 6 years after the initial diagnosis. Autopsy revealed liposarcoma composed of 3 subtypes in the primary tumor: well-differentiated, dedifferentiated, and round cell components. Round cell and dedifferentiated liposarcomas were predominantly observed in the metastatic nodules.
  • Tetsuya Inoue, Shinichi Shimizu, Rikiya Onimaru, Atsuya Takeda, Hiroshi Onishi, Yasushi Nagata, Tomoki Kimura, Katsuyuki Karasawa, Takuro Arimoto, Masato Hareyama, Elki Kikuchi, Hiroki Shirato
    INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS 75 (3) 683 - 687 0360-3016 2009/11 [Refereed][Not invited]
     
    Purpose: Image-guided biopsy occasionally fails to diagnose small lung lesions, which are highly suggestive of primary lung cancer. The aim of the present study was to evaluate the outcome of stereotactic body radiotherapy (SBRT) for small lung lesions that were clinically diagnosed as primary lung cancer without pathologic confirmation. Methods and Materials: A total of 115 patients were treated with SBRT in 12 institutions. Tumor size ranged from 5 to 45 mm in diameter, with a median of 20 mm. Results: The 3-year and 5-year overall survival rates for patients with a tumor size <= 20 mm in diameter (it = 58) were both 89.8%, compared with 60.7% and 53.1% for patients with tumors >20 mm (n = 57) (p < 0.0005), respectively. Local progression occurred in 2 patients (3.4%) with a tumor size <= 20 mm and in 3 patients (5.3%) with tumors >20 mm. Among the patients with a tumor size <= 20 mm, Grade 2 pulmonary complications were observed in 2 (3.4%), but no Grade 3 to 5 toxicity was observed. In patients with a tumor size >20 mm, Grades 2, 3, and 5 toxicity were observed in 5 patients (8.8%), 3 patients (5.3%), and 1 patient (1.8%), respectively. Conclusion: In patients with a tumor <= 20 mm in diameter, SBRT was reasonably safe in this retrospective study. The clinical implications of the high local control rate depend on the accuracy of clinical/radiologic diagnosis for small lung lesions and are to be carefully evaluated in a prospective study. (C) 2009 Elsevier Inc.
  • Naofumi Shinagawa, Noriyuki Yamada, Hajime Asahina, Eiki Kikuchi, Satoshi Oizumi, Noriaki Kurimoto, Masaharu Nishimura
    Journal of Bronchology and Interventional Pulmonology 16 (4) 261 - 265 1944-6586 2009/10 [Refereed][Not invited]
     
    BACKGROUND AND OBJECTIVES: Transbronchial biopsy (TBB) using endobronchial ultrasonography with a guide sheath (EBUS-GS) is a promising technique for small peripheral pulmonary lesions (PPLs), but is not a real-time procedure. We attempted to examine the practicality of TBB under real-time EBUS guidance for PPLs. METHODS: We performed TBB under real-time EBUS and x-ray fluoroscopic guidance using flexible bronchoscopy with 2 working channels for PPLs (mean diameter,> 30 mm). RESULTS: Between January 2007 and May 2007, we recruited 6 patients for this trial. On computed tomography images, the mean±SD diameter of the lesions was 37.4±4.5 mm (range: 32.0 to 45.0 mm). All lesions were detected by EBUS and could eventually be diagnosed. However, an image of the biopsy forceps or brush was obtained on real-time EBUS in only 4 cases. The other 2 cases involved technical limitations in inserting both the EBUS probe and biopsy forceps simultaneously into the lesion. Unfortunately, even in the 4 cases in which biopsy forceps images could be obtained on real-time EBUS, we could not recognize the position of the tip of the forceps on EBUS images, because the EBUS images of the tip of the forceps and the body of forceps were very similar. CONCLUSIONS: Our attempt to perform TBB under real-time EBUS guidance for PPLs was successful in 4 of 6 patients. There were some technical limitations using flexible bronchoscopy with 2 working channels. Improvement of instruments will be necessary for future trials of TBB under real-time EBUS guidance. Copyright © 2009 by Lippincott Williams & Wilkins.
  • Eiki Kikuchi, Junko Kikuchi, Yasuyuki Nasuhara, Satoshi Oizumi, Akitoshi Ishizaka, Masaharu Nishimura
    ANTIMICROBIAL AGENTS AND CHEMOTHERAPY 53 (7) 2799 - 2803 0066-4804 2009/07 [Refereed][Not invited]
     
    The time above the MIC (T>MIC) is the pharmacokinetic/pharmacodynamic (PK/PD) parameter that correlates with the therapeutic efficacy of beta-lactam antibiotics. A prolonged infusion can provide plasma drug concentrations that remain above the MIC for a long period. The objective of this study was to compare the PK/PD parameters in bronchial epithelial lining fluid (ELF) of biapenem given as 0.5-h and 3-h infusions by using bronchoscopic microsampling (BMS). Six healthy adult volunteers received 0.5-h and 3-h infusions of 0.3 g of biapenem with a washout interval. BMS was performed repeatedly from 0.5 to 24 h after biapenem administration in order to determine the pharmacokinetics in bronchial ELF. The subjects received intravenous biapenem with the same regimens again and then underwent bronchoalveolar lavage (BAL) at the end of infusion in order to determine the concentration of the drug in alveolar ELF. The percentages (means +/- standard deviations) of T>MIC in bronchial ELF at MICs from 0.25 to 4 mu g/ml ranged from zero to 34.6% +/- 5.2% after the 0.5-h infusion and from 5.1% +/- 5.6% to 52.2% +/- 17.0% after the 3-h infusion. The percentage of T>MIC in bronchial ELF after the 3-h infusion tended to be higher than that after the 0.5-h infusion. The concentrations of the drug in alveolar ELF after 0.5-h and 3-h infusions were 3.5 +/- 1.2 mu g/ml and 1.3 +/- 0.3 mu g/ml, respectively. The present results support the use of prolonged infusions of beta-lactam antibiotics and may provide critical information for successful treatment of lower respiratory tract infections based on PK/PD parameters in bronchial ELF.
  • Inoue T, Shimizu S, Onimaru R, Takeda A, Onishi H, Nagata Y, Kimura T, Karasawa K, Arimoto T, Hareyama M, Kikuchi E, Shirato H
    Int J Radiat Oncol Biol Phys 75 (3) 683 - 7 1879-355X 2009 [Refereed][Not invited]
  • Prolonged survival of patients with lung adenocarcinoma expressing XAGE-1b and HLA class I antigens
    Eiki Kikuchi, Koichi Yamazaki, Eiichi Nakayama, Shuichiro Sato, Akiko Uenaka, Noriyuki Yamada, Satoshi Oizumi, Hirotoshi Dosaka-Akita, Masaharu Nishimura
    Cancer Immunity 8 13  1424-9634 2008/08/28 [Refereed][Not invited]
     
    XAGE-1b is a cancer/testis antigen that has been shown to be expressed at a significant frequency and to be immunogenic in nonsmall cell lung cancer (NSCLC). In the present study, we investigated correlations between XAGE-1b expression and NSCLC patient survival. XAGE-1b expression was examined immunohistochemically using USO9-13, an anti-XAGE-1b monoclonal antibody, in 121 NSCLCs (83 adenocarcinomas and 38 other histological types). XAGE-1b expression was observed in 27 (32.5%) adenocarcinoma specimens. In the other histological types, positive staining was observed in only 1 specimen. HLA class I expression in these samples was assessed previously. XAGE-1b expression had no correlation with overall survival. However, both XAGE-1b and HLA class I expression correlated with prolonged survival (P = 0.019). Moreover, expression of XAGE-1b combined with down-regulated HLA class I expression correlated with poor survival (P = 0.01). The density of cancer nest-infiltrating CD8+ Tcells in tumors expressing both XAGE-1b and HLA class I was higher than that in other groups. The findings suggest that XAGE-1b and HLA class I expression elicited a CD8+ T-cell response against minimal residual disease after surgery and resulted in prolonged survival of NSCLC patients. Copyright © 2008 by Eiki Kikuchi.
  • Eiki Kikuchi, Koichi Yamazaki, Junko Kikuchi, Naoki Hasegawa, Satoru Hashimoto, Akitoshi Ishizaka, Masaharu Nishimura
    RESPIROLOGY 13 (2) 221 - 226 1323-7799 2008/03 [Refereed][Not invited]
     
    Background and objective: BAL is an established technique for measuring antibiotic concentrations in the epithelial lining fluid (ELF) of the bronchiolar-alveolar regions. However, the results may not reflect concentrations in bronchial regions. Bronchoscopic microsampling (BMS) is a technique for repeated sampling of bronchial ELF. The objective of the present study was to determine the time versus concentration profile of clarithromycin and its active metabolite, 14-hydroxy-clarithromycin, in bronchial ELF, as determined by BMS. Methods: BMS was performed at 1, 2, 3, 5 and 10 h after a single oral administration of 200 mg clarithromycin in five healthy volunteers. BAL was performed 3 h after administration to determine clarithromycin concentrations in alveolar ELF and alveolar macrophages (AM). Results: The maximum concentration (C-max) of clarithromycin was 0.36 +/- 0.07 mg/L in serum and 1.44 +/- 0.49 mg/L in bronchial ELF (P < 0.01). C-max for 14-hydroxy-clarithromycin was 0.34 +/- 0.13 mg/L in serum and 0.68 +/- 0.34 mg/L in bronchial ELF. The area under the concentration-time curve from 0 to 10 h (AUC(0-10)) for clarithromycin was 2.10 +/- 0.49 mg.h/L for serum and 7.37 +/- 2.07 mg.h/L for bronchial ELF (P < 0.01). The concentrations of clarithromycin in alveolar ELF and AM, 3 h after oral administration, were 4.84 +/- 3.39 mg/L and 10.7 +/- 8.7 mg/L, respectively. Conclusions: A single oral dose of clarithromycin produces a significantly higher C-max and AUC(0-10) for clarithromycin in bronchial ELF than in serum, and higher concentrations in alveolar ELF and AM than in serum. BMS might be useful for measuring the pharmacokinetic profile of clarithromycin in bronchial ELF.
  • Naofumi Shinagawa, Koichi Yamazaki, Yasuaki Tamura, Akihito Imai, Eiki Kikuchi, Hiroshi Yokouchi, Fumihiro Hommura, Satoshi Oizumi, Masaharu Nishimura
    CANCER IMMUNOLOGY IMMUNOTHERAPY 57 (2) 165 - 174 0340-7004 2008/02 [Refereed][Not invited]
     
    Background and purpose Immunization with heat shock proteins, gp96, elicits specific protective immunity against parent tumors. However, it is marginally effective as a therapeutic tool against established tumors. In the present study, we evaluated the efficacy and mechanism of immunotherapy with bone marrow-derived dendritic cells (DCs) pulsed with tumor-derived gp96 against murine lung cancer. Methods Mice were transplanted subcutaneously with ovalbumin (OVA)-transfected Lewis Lung Cancer (LLC-OVA) cells and immunized with gp96 derived from LLC-OVA, DCs, or DCs pulsed with gp96 derived from LLC-OVA. Results The antitumor effect was significantly enhanced in the mice immunized with DCs pulsed with gp96 derived from LLC-OVA, compared to mice immunized with gp96 or DCs (P < 0.05). The antitumor effect was significantly dependent on natural killer (NK) cells and CD8(+) cells and partially dependent on CD4(+) cells. Analysis by laser confocal microscopy demonstrated that gp96 was shown on the cell surface at 15 min, and after 30 min internalized in the endosomes and not in the endoplasmic reticulum or lysosomes. OVA-specific(+) CD8(+) cells were more readily recruited into the draining lymph nodes and higher CD8(+) cytotoxic T cell activity against LLC-OVA was observed in splenocytes from mice immunized with DCs pulsed with gp96 derived from LLC-OVA. Re-challenge of the surviving mice with LLC-OVA tumors after the initial tumor inoculation showed dramatic retardation in tumor growth. Conclusion In conclusion, immunotherapy of DCs pulsed with tumor-derived gp96 against murine lung cancer is effective through immune response of CD8(+) cytotoxic T lymphocytes and NK cells.
  • Hiroshi Yokouchi, Koichi Yamazaki, Kenji Chamoto, Eiki Kikuchi, Naofumi Shinagawa, Satoshi Oizumi, Fumihiro Hommura, Takashi Nishimura, Masaharu Nishimura
    CANCER SCIENCE 99 (2) 361 - 367 1347-9032 2008/02 [Refereed][Not invited]
     
    The therapeutic effect of agonistic anti-OX40 (CD134) monoclonal antibody (mAb) in combination with radiotherapy was evaluated in a murine lung cancer model. After intradermal transplantation of ovalbumin (OVA)-transfected Lewis lung carcinoma, C57BL/6 mice were irradiated locally with a single dose of 20 Gy in combination with an intratumoral injection of anti-OX40 mAb at 50 mu g on day 4 after transplantation, which is when the major axis of the inoculated tumor reached a diameter of 7-9 mm. On days 8, 11, and 14, the tumor-bearing mice were further treated with the same dose of anti-OX40 mAb. Anti-OX40 mAb in combination with radiotherapy prolonged survival and provided greater efficacy than either single treatment against well-established tumors. An in vivo depletion study suggested that therapeutic immunity was mainly CD8(+) T-cell dependent. OX40(+)CD8(+) T cells were augmented in draining lymph nodes obtained from irradiated mice compared with those from non-irradiated mice. OVA-major histocompatibility complex tetramer(+) CD8(+) T cells had been strongly recruited to the draining lymph nodes obtained from mice treated with anti-OX40 mAb in combination with radiotherapy, and strong antigen-specific cytotoxicity was confirmed by a Cr-51-release assay. Moreover, a tumor-rechallenge model indicated that this combination therapy induced durable tumor immunity. Thus, anti-OX40 mAb in combination with radiotherapy may potentially help the management of patients with lung cancer.
  • Eiki Kikuchi, Koichi Yamazaki, Toshihiko Torigoe, Yasushi Cho, Masaki Miyamoto, Satoshi Oizumi, Fumihiro Hommura, Hirotoshi Dosaka-Akita, Masaharu Nishimura
    CANCER SCIENCE 98 (9) 1424 - 1430 1347-9032 2007/09 [Refereed][Not invited]
     
    Human leukocyte antigen (HLA) class I displays a repertoire of endogenously processed peptides to CD8(+) T lymphocytes. The present study assessed correlations between HLA class I expression, clinicopathologic factors, and tumor-infiltrating immune cells in human non-small cell lung cancers (NSCLC). Expression of HLA class I was assessed in 161 resected primary NSCLC by immunohistochemistry using EMR8-5, a novel monoclonal anti-pan HLA class I heavy chain antibody. Expression of HLA class I was classified into three categories: strongly positive, weakly positive, or negative. Tumor-infiltrating CD8(+) lymphocytes and CD56(+) natural killer cells within cancer nests and stroma were also counted. Expression of HLA class I was strongly positive in 50 tumors, weakly positive in 57 tumors, and negative in 54 tumors. Down-regulation of HLA class I was significantly correlated with male sex, history of smoking, non-adenocarcinoma histology, and moderate-/low-grade differentiation. The density of cancer nest-infiltrating CD8(+) cells in HLA class I-negative tumors was significantly decreased compared to that in HLA class I strongly positive tumors (P < 0.01). Kaplan-Meier analysis revealed a significant favorable influence on overall survival for patients displaying tumors with strongly positive expression of HLA class I (P < 0.01). Multivariate analysis revealed down-regulation of HLA class I as an independent factor of poor prognosis in pathological stage I patients, but not in late-stage patients. These results suggest that down-regulation of HLA class I expression in NSCLC is a marker of poor prognosis, and this may play a critical role in immune surveillance of patients with NSCLC.
  • Noriyuki Yamada, Koichi Yamazaki, Noriaki Kurimoto, Hajime Asahina, Eiki Kikuchi, Naofumi Shinagawa, Satoshi Oizumi, Masaharu Nishimura
    CHEST 132 (2) 603 - 608 0012-3692 2007/08 [Refereed][Not invited]
     
    Study objectives: To evaluate factors predicting the diagnostic yield of transbronchial biopsy (TBB) using endobronchial ultrasonography with a guide sheath (EBUS-GS) in small peripheral pulmonary lesions (PPLs) 5 30 mm in mean diameter. Design: Retrospective analysis. Patients and methods: One hundred fifty-five consecutive patients with 158 small PPLs underwent TBB using EBUS-GS. Results: A definitive diagnosis was established by TBB using EBUS-GS in 106 PPLs (67%). The diagnostic yield of PPLs :5 15 mm in mean diameter (40%) was significantly lower than that of PPLs > 15 mm and :5 30 mm in mean diameter (76%; p < 0.001). PPLs in which the probe was positioned within the PPL on the endobronchial ultrasonography (EBUS) image had a higher diagnostic yield (83%) than PPLs in which the probe was positioned adjacent to the PPL (61 %) or outside the PPL (4%; p < 0.001). There were no significant differences in diagnostic yield for underlying disease, location, CT scan bronchus sign, operator, or type of EBUS probe. In the multivariate analysis, only the position of the probe (within or adjacent to the PPL when judged against outside the PPL) was determined to be a significant factor predicting diagnostic yield. On the other hand, a pathologic diagnosis was established with the first, second, third, fourth, and fifth biopsy specimens in 65%, 80%, 87%, 91%, and 97% of PPLs, respectively. Conclusions: The position of the probe (ie, within or adjacent to the PPL) is a significant factor in predicting the diagnostic yield of TBB using EBUS-GS for small PPLs; the optimum number of biopsy specimens is at least five.
  • Motoko Yoshikawa, Noriaki Sukoh, Koichi Yamazaki, Kenya Kanazawa, Shin-ichi Fukumoto, Masao Harada, Eiki Kikuchi, Mitsuru Munakata, Masaharu Nishimura, Hiroshi Isobe
    CHEST 131 (6) 1788 - 1793 0012-3692 2007/06 [Refereed][Not invited]
     
    Study objectives: We evaluated the feasibility and efficacy of transbronchial biopsy (TBB) and bronchial brushing by endobronchial ultrasonography (EBUS) with a guide sheath (GS) as a guide for diagnosing peripheral pulmonary lesions (PPLs) without radiographic fluoroscopy. Patients: One hundred twenty-one patients with 123 PPLs (mean diameter, 31.0 mm) whose bronchoscopic findings were normal. Methods: An EBUS-GS was inserted and advanced to the PPL without fluoroscopy. Once we obtained the EBUS image, the probe was withdrawn and the GS was left in place. TBB and/or bronchial brushing were performed via the GS. When an EBUS image could not be obtained, we changed to the bronchoscopic examination under fluoroscopy. Results: Seventy-six of 123 PPLs (61.8%) were diagnosed by EBUS-GS guidance without fluoroscopy. The diagnostic yield for PPLs > 20 min in diameter (75.6%) was significantly higher than that for those > 20 min in diameter (29.7%; p < 0.01). The PPLs located in the middle lobe and the lingular segment had significantly higher diagnostic yields (p < 0.05). When the bronchus leading to the PPL was identified on the CT scan, the yield was 79.2%. Moreover, the solid lesions had a higher diagnostic yield (67.0%) compared with nonsolid lesions (35.0%; p < 0.05). Multivariate analysis revealed that the diameter and the location of the PPL were independent predictors of diagnostic sensitivity by EBUS-GS-guided bronchoscopy (p < 0.05). Conclusions: EBUS-GS-guided bronchoscopy without the use of radiographic fluoroscopy is effective for diagnosing PPLs. The diameter, location, and CT scan appearance of the PPLs, and the identification of the bronchus leading to the PPLs were valuable as factors related to a higher diagnostic sensitivity with this procedure.
  • Naofumi Shinagawa, Koichi Yamazaki, Yuya Onodera, Hajime Asahina, Eiki Kikuchi, Fumihiro Asano, Kazuo Miyasaka, Masaharu Nishimura
    CHEST 131 (2) 549 - 553 0012-3692 2007/02 [Refereed][Not invited]
     
    Background: We investigated factors related to the diagnostic sensitivity of CT-guided transbronchial biopsy (TBB) using an ultrathin bronchoscope and virtual bronchoscopy (VB) navigation for small peripheral pulmonary lesions. Method: We have performed this procedure on 83 patients with 85 small peripheral pulmonary lesions (< 20 mm in diameter). We analyzed the relationship between the diagnostic sensitivity and the location of the lesions, the bronchial generation to which an ultrathin bronchoscope was inserted, and the lesion-bronchial and lesion-pulmonary arterial relationships on high-resolution CT. Results: Fifty-six of the 85 lesions (66%) were diagnosed following CT-guided TBB using an ultrathin bronchoscope with VB navigation. The lesions located in the left superior segment of the lower lobe (S-6) had a significantly low diagnostic sensitivity compared to other locations (p < 0.01). When an ultrathin bronchoscope could be inserted to the fifth or greater bronchial generation, the yield was above the average diagnostic sensitivity of 66%. Moreover, not only the patients with the presence of a bronchus leading directly to a lesion (CT-bronchus sign), but also the patients with the presence of a pulmonary artery leading to a lesion (CT-artery sign), had high diagnostic sensitivity (p < 0.01). Multivariate analysis revealed that the location of lesion was an independent predictor of diagnostic sensitivity (p < 0.05). Conclusions: The location of the lesion, the bronchial generation to which an ultrathin bronchoscope was inserted, and the presence of a bronchus as well as a pulmonary artery leading to the lesion were valuable for predicting successful CT-guided TBB using an ultrathin bronchoscope with VB navigation.
  • Junko Kikuchi, Koichi Yamazaki, Eiki Kikuchi, Akitoshi Ishizaka, Masaharu Nishimura
    PULMONARY PHARMACOLOGY & THERAPEUTICS 20 (5) 549 - 555 1094-5539 2007 [Refereed][Not invited]
     
    Objectives: Bronchoscopic microsampling (BMS) is a new technique for repeated sampling of bronchial epithelial lining fluid (ELF) to obtain the pharmacokinetic profile of drugs. We analyzed the time versus concentration profiles of telithromycin in bronchial ELF obtained by BMS and compared these finding to those in plasma and alveolar ELF obtained by bronchoalveolar lavage (BAL). Methods: Bronchial ELF samples were obtained from five healthy Subjects using BMS probe at 0, 2, 3, 4, 6, 10 and 24 h after single or multiple oral doses of 600 mg of telithromycin. Alveolar ELF was also obtained by BAL 3 h after single or multiple oral doses of 600 mg of telithromycin. Results: The areas under the concentration-time curve from 0 to 24h (AUC0-24) of telithromycin in plasma and bronchial ELF were 2.86 +/- 0.60 and 19.5 +/- 10.4 mg h/l after single treatment and 3.60 +/- 0.49 and 42.2 +/- 22.7 mg h/l after multiple treatments, respectively. Single and multiple oral doses of telithromycin produced significantly (p < 0.05) higher AUC0-24 in bronchial ELF compared to those in plasma. While concentrations in bronchial ELF obtained by BMS were significantly lower than those in alveolar ELF obtained by BAL, they tended to be higher than those in plasma after multiple administration. The telithromycin concentrations obtained by BMS method were very consistent in bronchial ELF at different bronchi at one time point and at the same bronchus at different time points. Conclusions: Using the BMS technique, we could describe the pharmacokinetics of telithromycin in bronchial ELF. Furthermore, BMS was reasonably validated and reconfirmed to be a feasible and reliable method for measuring antimicrobial concentrations in bronchial ELF. (c) 2006 Elsevier Ltd. All rights reserved.
  • Junko Kikuchi, Koichi Yamazaki, Eiki Kikuchi, Akitoshi Ishizaka, Masaharu Nishimura
    CLINICAL THERAPEUTICS 29 (1) 123 - 130 0149-2918 2007/01 [Refereed][Not invited]
     
    Background: Bronchoalveolar lavage (BAL) is an established technique for measuring antibiotic concentrations in the epithelial lining fluid (ELF) of the bronchiolar and alveolar regions; however, the results may not reflect concentrations in bronchial regions. Bronchoscopic microsampling (BMS) is a technique that makes it possible to obtain multiple samples from bronchial ELF. Objective: BMS and BAL were used to analyze the pharmacokinetics of gatifloxacin in bronchial ELF from healthy young adult subjects and adult patients with chronic bronchitis. Methods: Bronchial ELF samples were obtained by BMS at 1, 2, 3, 4, 6, 10, and 24 hours after administration of a single oral dose of gatifloxacin 200 mg in healthy young adult (aged 20-25 years) subjects, and at 1, 2, 4, and 10 hours after a single dose in patients with chronic bronchitis (aged >= 20 years). At least I month after the initial BMS, alveolar (BAL) and bronchial (BMS) ELF samples were obtained from another group of healthy subjects 2 hours after administration of a single oral dose of gatifloxacin 200 mg for comparison of gatifloxacin concentrations in samples obtained by the 2 techniques. Results: Bronchial ELF samples were obtained from 8 healthy subjects and 5 patients with chronic bronchitis; alveolar ELF samples were obtained from a separate group of 5 healthy subjects. For the healthy subjects, the mean (SD) AUC(0-24) in serum and bronchial ELF, corrected for mg/kg doses, was 4.6 (1.1) and 7.6 (3.5) mg (.) h/L, respectively. In the patients with chronin serum and bronchial ELF, ic bronchitis, the AUC(0-10) corrected for mg/kg doses, was 3.9 (0.8) and 4.1 (1.5) mg (.) h/L. The C-max. in serum and bronchial ELF, corrected for mg/kg doses, was 0.6 (0.2) and 1.4 (0.8) mg/L in healthy subjects and 0.7 (0.2) and 0.7 (0.2) mg/L in patients with chronic bronchitis. In healthy subjects, the C-max and AUC(0-24) were significantly higher in bronchial ELF than in serum (both, P < 0.05). Gatifloxacin concentrations were significantly lower in bronchial ELF obtained by BMS than in alveolar ELF obtained by BAL (P < 0.05). Conclusions: Based on the findings of this study in small numbers of healthy young adult volunteers and patients with chronic bronchitis, BMS appears to be a promising method for measuring drug concentrations and determining the pharmacokinetic profile of gatifloxacin in bronchial ELF. Additional studies are needed to correlate measured concentrations obtained by BMS with clinical and/or microbiologic outcomes in larger populations.
  • Eiki Kikuchi, Ichiro Kinoshita, Koichi Yamazaki, Tomoo Itoh, Tadamichi Shimizu, Hiroshi Shimizu, Masaharu Nishimura
    RESPIROLOGY 11 (6) 826 - 829 1323-7799 2006/11 [Refereed][Not invited]
     
    A 39-year-old Japanese woman presented with a swollen right hand and a right-sided pneumothorax. Chest CT revealed bilateral multiple pulmonary thin-walled cysts measuring <= 1 cm in diameter and small nodules. An initial skin biopsy led to a misdiagnosis of metastatic adenocarcinoma, as tumour cells were positive for cytokeratin, epithelial membrane antigen, carcinoembryonic antigen and cancer antigen 125. However, chemotherapy proved ineffective, and the skin biopsy was repeated. A final diagnosis of epithelioid sarcoma (ES) was made. Open lung biopsy showed that the pulmonary nodules represented metastases of ES. Although the pulmonary cyst walls did not contain tumour cells, bronchiolar wall adjacent to the cysts had been infiltrated by tumour cells. These findings suggested that pulmonary cysts, a rare form of pulmonary metastases from soft tissue sarcomas, had developed through a ball-valve effect of metastatic tumour in small airways. However, presence of cancer antigen 125 hindered obtaining a correct diagnosis of ES.
  • Evaluation of an auto-guidance system for bronchoscope insertion
    F. Asano, Y. Matsuno, T. Ichihara, A. Tsuzuku, T. Suzuki, H. Asahina, E. Kikuchi, N. Shinagawa, K. Yamazaki, T. Ishida, H. Moriya, M. Shimizu
    PROCEEDINGS OF THE 14TH WORLD CONGRESS FOR BRONCHOLOGY(WCB)/14TH WORLD CONGRESS FOR BRONCHOESOPHAGOLOGY (WCBE) 37 - + 2006 [Refereed][Not invited]
     
    Using an Auto-Guidance System for Bronchoscope Insertion by virtual bronchoscopic navigation, when the lesion is set as a target, the bronchus is isolated by automatic adjustment of the threshold, then, the route to the target is searched, and virtual images are obtained. We performed transbronchial biopsy (TBB) using the system in combination with a thin bronchoscope and endobronchial ultrasonography using a thin guide sheath (thin GS-EBUS) for diagnosing twenty-three pulmonary peripheral lesions. Virtual images to a median of the 5th generation bronchus could be obtained. In all patients, the branching patterns on virtual images were the same as those on actual images. Twenty-one lesions could be visualized by EBUS, and biopsy confirmed 15 pulmonary cancerous lesions and 4 inflammatory lesions.
  • H Asahina, K Yamazaki, Y Onodera, E Kikuchi, N Shinagawa, F Asano, M Nishimura
    CHEST 128 (3) 1761 - 1765 0012-3692 2005/09 [Refereed][Not invited]
     
    Study objectives: We evaluated the feasibility, safety, and efficacy of transbronchial biopsy (TBB) using endobronchial ultrasonography with a guide sheath (EBUS-GS) and virtual bronchoscopy (VB) navigation for small peripheral pulmonary lesions <= 30 mm in diameter. Design: Pilot study. Setting: A national university hospital. Patients: We performed TBB using EBUS-GS with VB navigation for 29 patients with 30 small peripheral pulmonary lesions (average diameter, 18.6 mm) between January 1, 2004, and August 31,2004. Interventions: VB images were reconstructed from helical CT data. TBB was then performed using EBUS-GS with VB navigation. Results: In all patients, TBB was performed safely with no complications. Bronchi seen on VB imaging were highly consistent with the actual structures confirmed using fiberoptic bronchoscopy. Following VB navigation, the endobronchial ultrasonography (EBUS) probe was inserted into third- to sixth-generation bronchi. Twenty-four lesions (80%) were visualized on EBUS images. Average durations of the initial EBUS examination of lesions, first biopsy, and the total procedure were 9.56 min, 11.99 min, and 25.72 min, respectively. Nineteen lesions (63.3%) were diagnosed from histopathologic or cytologic examination. Diagnostic sensitivities were 44.4% (8 of 18) for lesions < 20 mm in mean diameter and 91.7% (11 of 12) for lesions 20 to 30 mm in mean diameter. Conclusions: In summary, TBB using EBUS-GS with VB navigation was safely performed and was effective in diagnosing small peripheral pulmonary lesions.
  • Analysis of the response and toxicity to gefitinib of non-small cell lung cancer
    J Konishi, K Yamazaki, Kinoshita, I, H Isobe, S Ogura, S Sekine, T Ishida, R Takashima, M Nakadate, S Nishikawa, T Hattori, H Asahina, M Imura, E Kikuchi, J Kikuchi, N Shinagawa, H Yokouchi, M Munakata, H Dosaka-Akita, M Nishimura
    ANTICANCER RESEARCH 25 (1B) 435 - 441 0250-7005 2005/01 [Refereed][Not invited]
     
    Background: Gefitinib is an oral agent that inhibits the tyrosine kinase of epidermal growth factor receptor (EGFR), which had antitumor activity in patients with previously treated non-small cell lung cancer (NSCLC). We analyzed the efficacy, toxicity and overall survival time of gefitinib treatment in patients with NSCLC. Patients and Methods: One hundred and twenty-two patients with NSCLC, who received gefitinib between 2002 and 2004 in our institutes, were evaluated retrospectively. Results: The objective response rate was 24.6%. The variables identified as significant in univariate analysis included gender and smoking habit. The median overall survival time was 14.4 months. Significant variables associated with improved survival included good performance status (PS), female, adenocarcinoma and never smoked status, while never smoked status and good PS were independent prognostic factors in multivariate analysis. Four patients (3.3%) developed interstitial pneumonitis associated with gefitinib. Conclusion: Gefitinib showed favorable antitumor activity in females, never smokers and adenocarcinoma.
  • E Kikuchi, K Yamazaki, N Sukoh, J Kikuchi, H Asahina, M Imura, Y Onodera, N Kurimoto, Kinoshita, I, M Nishimura
    EUROPEAN RESPIRATORY JOURNAL 24 (4) 533 - 537 0903-1936 2004/10 [Refereed][Not invited]
     
    The usefulness of endobronchial ultrasonography (EBUS) with guide-sheath (GS) as a guide for transbronchial biopsy (TBB) for diagnosing peripheral pulmonary lesions (PPL)s and for improving diagnostic accuracy was evaluated in this study. EBUS-GS-guided TBB was performed in 24 patients with 24 PPLs of less than or equal to30 mm in diameter (average diameter=18.4 mm). A 20-MHz radial-type ultrasound probe, covered with GS was inserted via a working bronchoscope channel and advanced to the PPL in order to produce an EBUS image. The probe with the GS was confirmed to reach the lesion by EBUS imaging and X-ray fluoroscopy. When the lesion was not identified on the EBUS image, the probe was removed and a curette was used to lead the GS to the lesion. After localising the lesion, the probe was removed, and TBB and bronchial brushing were performed via the GS. Nineteen peripheral lesions (79.2%) were visualised by EBUS. All patients whose PPLs were visible on EBUS images subsequently underwent an EBUS-GS-guided diagnostic procedure. A total of 14 lesions (58.3%) were diagnosed. Even when restricted to PPLs <20 mm in diameter, the diagnostic sensitivity was 53%. In conclusion, endobronchial ultrasonography with guide sheath-guided transbronchial biopsy was feasible and effective for diagnosing peripheral pulmonary lesions.
  • J Kikuchi, K Yamazaki, Kinoshita, I, H Asahina, M Imura, E Kikuchi, J Konishi, N Shinagawa, H Oki, H Dosaka-Akita, M Nishimura
    JAPANESE JOURNAL OF CLINICAL ONCOLOGY 34 (9) 505 - 509 0368-2811 2004/09 [Refereed][Not invited]
     
    Objective: This study was designed to determine the maximum tolerated dose of paclitaxel administered weekly in combination with carboplatin and to assess its dose limiting toxicity and preliminary activity in patients with previously untreated, advanced non-small-cell lung cancer. Methods: Carboplatin was administered at a fixed dose that maintained an area under the curve of 6. Paclitaxel was given over 1 h once a week for 3 weeks starting at 60 mg/m(2) and escalated in 10 mg/m(2) increments. Results: Twenty-one patients were treated with six dose levels (60, 70, 80, 90, 100, 110 mg/m(2)) of paclitaxel. The dose limiting toxicity was infection and the maximum tolerated dose was 110 mg/m(2). Nine of 21 (42.9%) patients demonstrated a therapeutic response. Conclusion: Weekly paclitaxel and carboplatin were well tolerated. Based on our results, 100 mg/m(2) of paclitaxel for 3 weeks of a 4-week cycle, in combination with carboplatin, was recommended for a phase II study.
  • CT-guided transbronchial biopsy using an ultrathin bronchoscope with virtual bronchoscopic navigation
    N Shinagawa, K Yamazaki, Y Onodera, K Miyasaka, E Kikuchi, H Dosaka-Akita, M Nishimura
    CHEST 125 (3) 1138 - 1143 0012-3692 2004/03 [Refereed][Not invited]
     
    Study objectives: We evaluated the feasibility, safety, and efficacy of CT-guided transbronchial biopsy (TBB) using an ultrathin bronchoscope with navigation by virtual bronchoscopy (VB) for small peripheral pulmonary lesions of < 20 mm in diameter. Design: A pilot study. Setting: A national university hospital. Patients: We performed CT-guided TBB after VB navigation for 25 patients with 26 small peripheral pulmonary lesions (average diameter, 13.2 mm) between June 1, 2001, and October 31, 2002. Of the 26 lesions, 10 were in the right upper lobe, 2 were in the right middle lobe, 6 were in the right lower lobe, and 8 were in the left upper lobe. Nineteen lesions were not detected on chest radiographs. Interventions: VB images were reconstructed from helical CT scans. CT-guided TBB was performed using an ultrathin bronchoscope after studying the VB image. Results: CT-guided TBB was performed safely without any complications for all patients. The bronchi seen under VB imaging were highly consistent with the actual bronchi confirmed using an ultrathin bronchoscope. The ultrathin bronchoscope was inserted between the fifth and eighth generation bronchi. The average durations of the initial scan, the first biopsy, and the total examination were 5.46, 12.96, and 29.27 min, respectively. Seventeen lesions (65.4%) were diagnosed from pathology examinations (primary lung cancers, 13; atypical adenomatous hyperplasia, 1; metastatic cancer, 1; sarcoidosis, 1; and nontuberculous mycobacteriosis, 1). Diagnoses were not obtained for the remaining lesions due to an insufficient number of specimens (six specimens) or to the inability to reach the lesions even using the ultrathin bronchoscope (three specimens). Conclusions: In summary, CT-guided TBB using an ultrathin bronchoscope with VB navigation was safely performed and was effective for diagnosing small peripheral pulmonary lesions.
  • Desmoplastic malignant mesothelioma of the pleura: Autopsy reveals asbestos exposure
    R Ishikawa, H Kikuchi, ML Jin, M Fujita, T Itoh, H Sawa, K Nagashima
    PATHOLOGY INTERNATIONAL 53 (6) 401 - 406 1320-5463 2003/06 [Refereed][Not invited]
     
    Desmoplastic mesothelioma is a rare subtype of diffuse malignant mesothelioma, and is often difficult to distinguish from reactive pleural fibrosis because of associated extensive collagen fibrosis. An 82-year-old woman with a severe cough was revealed to have pleural effusion and diffuse pleural thickening on the right side. Antibiotics were ineffective, and a compression fracture of the ninth and tenth thoracic vertebral bodies was recognized on X-ray. Autopsy revealed a diffuse pleural thickening with hyalinized collagen tissue in the central part of the pleura. However, the peripheral part of the fibrous tissue was composed of spindle and polygonal cell proliferation that were immunohistochemically positive for antibodies against cytokeratin and vimentin. In addition, the ninth and tenth thoracic spines were infiltrated by similar cells. The condition was diagnosed as desmoplastic mesothelioma with bone metastases. Asbestos bodies were detected in the thickened pleura and fibrosed alveolar septa, and it was suggested retrospectively that the patient had been exposed to asbestos. Thus, autopsy analyses of fibrous pleurisy are necessary to detect a desmoplastic variant of mesothelioma of the pleura and its association with asbestos exposure.

MISC

Awards & Honors

  • 2008 第21回日本内科学会奨励賞
     ヒト非小細胞肺癌におけるHLA class I 発現の臨床的意義と腫瘍内浸潤免疫細胞 
    受賞者: 菊地英毅

Research Grants & Projects

  • Development of A Noninvasive Electrical Conductivity Measurement System for Lung Tumors
    Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2017/04 -2020/03 
    Author : Tha KhinKhin, 杉森 博行, 菊地 英毅, 真鍋 徳子
     
    導電率は各構造物が持つ物理特性であり、組織・疾患間で異なる。導電率情報を非侵襲的に取得できれば、疾患の非侵襲的診断の補助が期待される。本研究は、肺腫瘤における非侵襲的導電率イメージングの確立に挑戦することを目的としている。 平成30年度では、(1)肺MRIによる非侵襲的導電率イメージング撮像パラメータの最適化と(2)臨床試験を予定した。 (1)肺MRIによる非侵襲的導電率イメージング撮像パラメータの最適化について、下記臨床研究で得られた結果を基に撮像パラメータ・解析アルゴリズムの改良・最適化を行った。撮像パラメータでは、特に撮像断面やダイナミックスキャン回数に着目した。異なる断面間での導電率の一致率やダイナミックスキャン回数の導電率への影響について検討し、得られた結果をもとに改良・最適化を行った。解析アルゴリズムの改良では、病変のセグメンテーションの精度の導電率への影響について検討し、セグメンテーションアルゴリズムの改良を行った。これらの最適化を行うことで、アーチファクトの少ない高解像度画像を提供できることを目指している。 (2)臨床試験については、患者ボランティアをリクルートし、本研究に同意した肺腫瘍患者の肺EPT撮像を行い、データ収集をしている状況である。現時点で、12人のEPT撮像を終えている。必要な症例数に到達する次第、MRIを用いた導電率画像は様々な疾患の鑑別診断、腫瘍の悪性度評価、病変と周囲正常組織の区別に有用かについて検討する。
  • Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2015/04 -2018/03 
    Author : Kikuchi Eiki
     
    Cell culture was performed using a total of 80 specimens of 77 cases of bronchial brushing specimen, 2 cases of pleural effusion and 1 autopsy lung, and cell culture and passage were possible in 53 of them (66.3%). Most of the cells that could not be cultured were due to bacterial contamination, probably by bacteria from lower respiratory tract. The EGFR and human KRAS gene sequence showed that all of the 53 cultured cells have human genes, and the KRAS mutation was observed in one of 8 cases.

Educational Activities

Teaching Experience

  • 医学総論
    開講年度 : 2018
    課程区分 : 博士後期課程
    開講学部 : 医学研究科
  • Master's Thesis Research in Medical Sciences
    開講年度 : 2018
    課程区分 : 修士課程
    開講学部 : 医学院
    キーワード : 炎症性肺疾患、免疫性肺疾患、腫瘍性肺疾患、感染性肺疾患、肺循環系疾患、がんプロフェッショナル inflammatory lung disease, immune-mediated lung disease, neoplastic lung disease, infectious lung disease, pulmonary circulation diseases, cancer professional
  • Basic Principles of Medicine
    開講年度 : 2018
    課程区分 : 修士課程
    開講学部 : 医学院
    キーワード : 炎症性肺疾患、免疫性肺疾患、腫瘍性肺疾患、感染性肺疾患、肺循環系疾患、がんプロフェッショナル inflammatory lung disease, immune-mediated lung disease, neoplastic lung disease, infectious lung disease, pulmonary circulation diseases, cancer professional
  • Dissertation Research in Clinical Medicine
    開講年度 : 2018
    課程区分 : 博士後期課程
    開講学部 : 医学院
    キーワード : 炎症性肺疾患、免疫性肺疾患、腫瘍性肺疾患、感染性肺疾患、肺循環系疾患、がんプロフェッショナル inflammatory lung disease, immune-mediated lung disease, neoplastic lung disease, infectious lung disease, pulmonary circulation diseases, cancer professional
  • Dissertation Research in Medical Sciences
    開講年度 : 2018
    課程区分 : 博士後期課程
    開講学部 : 医学院
    キーワード : 炎症性肺疾患、免疫性肺疾患、腫瘍性肺疾患、感染性肺疾患、肺循環系疾患、がんプロフェッショナル inflammatory lung disease, immune-mediated lung disease, neoplastic lung disease, infectious lung disease, pulmonary circulation diseases, cancer professional
  • Principles of Medicine
    開講年度 : 2018
    課程区分 : 博士後期課程
    開講学部 : 医学院
    キーワード : 炎症性肺疾患、免疫性肺疾患、腫瘍性肺疾患、感染性肺疾患、肺循環系疾患、がんプロフェッショナル inflammatory lung disease, immune-mediated lung disease, neoplastic lung disease, infectious lung disease, pulmonary circulation diseases, cancer professional


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