Researcher Database

Hajime Asahina
Hokkaido University Hospital Internal Medicine
Assistant Professor

Researcher Profile and Settings


  • Hokkaido University Hospital Internal Medicine

Job Title

  • Assistant Professor

Research funding number

  • 90374298

J-Global ID

Research Areas

  • Life sciences / Respiratory medicine

Academic & Professional Experience

  • 2012 Hokkaido University

Research Activities

Published Papers

  • Kitajima S, Asahina H, Chen T, Guo S, Quiceno LG, Cavanaugh JD, Merlino AA, Tange S, Terai H, Kim JW, Wang X, Zhou S, Xu M, Wang S, Zhu Z, Thai TC, Takahashi C, Wang Y, Neve R, Stinson S, Tamayo P, Watanabe H, Kirschmeier PT, Wong KK, Barbie DA
    Cancer cell 34 (3) 439 - 452.e6 1535-6108 2018/09 [Refereed][Not invited]
  • Takashina T, Asahina H, Oizumi S, Yamada N, Harada M, Takamura K, Yokouchi H, Harada T, Honjo O, Ogi T, Morikawa N, Kinoshita I, Honda R, Nakano K, Kanazawa K, Amano T, Dosaka-Akita H, Isobe H, Nishimura M, Hokkaido Lung, Cancer Clinical, Study Group
    International journal of clinical oncology 1341-9625 2018/07 [Refereed][Not invited]
  • 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.
  • Yasuyuki Ikezawa, Hajime Asahina, Satoshi Oizumi, Masahiro Watanabe, Kei Takamura, Yasutaka Kawai, Noriyuki Yamada, Toshiyuki Harada, Ichiro Kinoshita, Yuka Fujita, Eisaku Miyauchi, Takahiro Ogi, Toraji Amano, Megumi Furuta, Jun Sakakibara-Konishi, Hiroshi Nishihara, Hirotoshi Dosaka-Akita, Hiroshi Isobe, Masaharu Nishimura
    CANCER CHEMOTHERAPY AND PHARMACOLOGY 80 (5) 955 - 963 0344-5704 2017/11 [Refereed][Not invited]
    A high proportion of patients with wild-type EGFR non-small cell lung cancer (NSCLC) receive third-line therapy and beyond, with no prospective randomized trials addressing the issue. This study aimed to select the most suitable regimen as a third- or fourth-line therapy for wild-type EGFR NSCLC. This multicenter, randomized phase II study in Japan included patients with recurrent or advanced NSCLC with wild-type or unknown EGFR, who progressed after two or three previous chemotherapies. The patients were randomly assigned to erlotinib (150 mg/day, days 1-21) or S-1 (80-120 mg/day, days 1-14) every 3 weeks until disease progression or unacceptable toxicity. The primary endpoint was disease control rate (DCR). The secondary endpoints included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), toxicity, and quality of life (QOL). From 2011 to 2016, 37 patients were randomly assigned to receive erlotinib (E arm, n = 19) and S-1 (S arm, n = 18). This study was terminated prematurely because of poor patient accrual. DCR/ORR were 42.1%/15.8% in the E arm and 66.7%/16.7% in the S arm. Median PFS/OS were 1.6 months/8.0 months in the E arm and 3.3 months/12.2 months in the S arm. In both groups, the most commonly reported grade 3-4 toxicities were fatigue, anorexia, and nausea. One grade 5 pneumonitis occurred in the S arm. No significant difference was seen in QOL. S-1 as a third- or fourth-line therapy for wild-type EGFR NSCLC showed numerically better clinical outcomes than erlotinib. UMIN000005308.
  • Hiroshi Nokihara, Noboru Yamamoto, Yasuhide Yamada, Kazunori Honda, Hajime Asahina, Yosuke Tamura, Rebecca R. Hozak, Ling Gao, Kazumi Suzukawa, Sotaro Enatsu, Tomohide Tamura
    JAPANESE JOURNAL OF CLINICAL ONCOLOGY 47 (4) 298 - 305 0368-2811 2017/04 [Refereed][Not invited]
    Objective: Ramucirumab is a recombinant human immunoglobulin G1 monoclonal antibody targeting the vascular endothelial growth factor receptor-2. The aim of this phase 1 study was to evaluate the safety and tolerability of ramucirumab monotherapy in Japanese patients with advanced solid tumors.Methods: Patients with solid tumors who had not responded to standard therapy or for whom no standard therapy was available received escalating doses of ramucirumab, administered once every 2 (Q2W) or 3 (Q3W) weeks. The primary objective was to establish the safety and pharmacokinetic profiles of ramucirumab. Secondary and exploratory objectives included assessment of immunogenicity and antitumor activity. NCT01005355.Results: Fifteen patients were treated with ramucirumab at a dose of 6 mg/kg Q2W (N = 3), 8 mg/ kg Q2W (N = 6) or 10 mg/kg Q3W (N = 6). There were no dose-limiting toxicities and the maximum tolerated dose was not reached. The most common ramucirumab-related adverse events were headache, pyrexia, hypertension and increased aspartate aminotransferase. Following single-dose administration of ramucirumab, there appeared to be a dose-proportional increase in maximum observed drug concentration but not in area under the curve. Treatment-emergent anti-ramucirumab antibodies were not detected in any patient.Conclusions: Ramucirumab monotherapy was well tolerated and feasible at the doses and schedules used in this study population of Japanese patients with advanced solid tumors.
  • Yosuke Tamura, Hiroshi Nokihara, Kazunori Honda, Yuko Tanabe, Hajime Asahina, Yasuhide Yamada, Sotaro Enatsu, Raffael Kurek, Noboru Yamamoto, Tomohide Tamura
    CANCER CHEMOTHERAPY AND PHARMACOLOGY 78 (5) 995 - 1002 0344-5704 2016/11 [Refereed][Not invited]
    To establish the safety and pharmacokinetic profile of necitumumab in Japanese patients with advanced solid tumors not responsive to standard therapy or for which no standard therapy was available.In this phase I study, patients aged aeyen20 years with advanced solid tumors, and an Eastern Cooperative Oncology Group performance statuses of 0-1 were enrolled in a 3 + 3 design, with dose-escalation based on dose-limiting toxicity (DLT). Planned dose levels were: cohort 1: 600 mg IV, days 1 and 8, every 3 weeks; cohort 2: 800 mg IV, day 1, every 2 weeks; and cohort 3: 800 mg IV, days 1 and 8, every 3 weeks. After the first 6-week cycle, patients with an objective response or stable disease could continue to receive necitumumab (same dose and schedule) until disease progression or other withdrawal criteria were met. Safety, antitumor activity, and pharmacokinetics were assessed.Fourteen of 15 enrolled patients received all scheduled infusions in cycle 1 (median cycles: N = 2, range 1-4). No DLTs were observed. The most common treatment-emergent adverse events were headache (73 %), dry skin (67 %), pruritus (60 %), and rash (53 %), mostly grade 1/2. All patients achieved serum trough concentrations > 40 A mu g/mL, a level associated with antitumor activity in preclinical models. No patients had an objective response; stable disease was seen in 67 % of patients.Necitumumab can be safety administered to Japanese patients at dose levels established in Western patients: 800 mg every 2 weeks, or on days 1 and 8 of a 3-week cycle.
  • Shohei Koyama, Esra A. Akbay, Yvonne Y. Li, Amir R. Aref, Ferdinandos Skoulidis, Grit S. Herter-Sprie, Kevin A. Buczkowski, Yan Liu, Mark M. Awad, Warren L. Denning, Lixia Diao, Jing Wang, Edwin R. Parra-Cuentas, Ignacio I. Wistuba, Margaret Soucheray, Tran Thai, Hajime Asahina, Shunsuke Kitajima, Abigail Altabef, Jillian D. Cavanaugh, Kevin Rhee, Peng Gao, Haikuo Zhang, Peter E. Fecci, Takeshi Shimamura, Matthew D. Hellmann, John V. Heymach, F. Stephen Hodi, Gordon J. Freeman, David A. Barbie, Glenn Dranoff, Peter S. Hammerman, Kwok-Kin Wong
    CANCER RESEARCH 76 (5) 999 - 1008 0008-5472 2016/03 [Refereed][Not invited]
    STK11/LKB1 is among the most commonly inactivated tumor suppressors in non-small cell lung cancer (NSCLC), especially in tumors harboring KRAS mutations. Many oncogenes promote immune escape, undermining the effectiveness of immunotherapies, but it is unclear whether the inactivation of tumor suppressor genes, such as STK11/LKB1, exerts similar effects. In this study, we investigated the consequences of STK11/LKB1 loss on the immune microenvironment in a mouse model of KRAS-driven NSCLC. Genetic ablation of STK11/LKB1 resulted in accumulation of neutrophils with T-cell-suppressive effects, along with a corresponding increase in the expression of T-cell exhaustion markers and tumor-promoting cytokines. The number of tumor-infiltrating lymphocytes was also reduced in LKB1-deficient mouse and human tumors. Furthermore, STK11/LKB1-inactivating mutations were associated with reduced expression of PD-1 ligand PD-L1 in mouse and patient tumors as well as in tumor-derived cell lines. Consistent with these results, PD-1-targeting antibodies were ineffective against Lkb1-deficient tumors. In contrast, treating Lkb1-deficient mice with an IL6-neutralizing antibody or a neutrophil-depleting antibody yielded therapeutic benefits associated with reduced neutrophil accumulation and proinflammatory cytokine expression. Our findings illustrate how tumor suppressor mutations can modulate the immune milieu of the tumor microenvironment, and they offer specific implications for addressing STK11/LKB1-mutated tumors with PD-1-targeting antibody therapies. (C)2016 AACR.
  • Shohei Koyama, Esra A. Akbay, Yvonne Y. Li, Grit S. Herter-Sprie, Kevin A. Buczkowski, William G. Richards, Leena Gandhi, Amanda J. Redig, Scott J. Rodig, Hajime Asahina, Robert E. Jones, Meghana M. Kulkarni, Mari Kuraguchi, Sangeetha Palakurthi, Peter E. Fecci, Bruce E. Johnson, Pasi A. Janne, Jeffrey A. Engelman, Sidharta P. Gangadharan, Daniel B. Costa, Gordon J. Freeman, Raphael Bueno, F. Stephen Hodi, Glenn Dranoff, Kwok-Kin Wong, Peter S. Hammerman
    NATURE COMMUNICATIONS 7 10501  2041-1723 2016/02 [Refereed][Not invited]
    Despite compelling antitumour activity of antibodies targeting the programmed death 1 (PD-1): programmed death ligand 1 (PD-L1) immune checkpoint in lung cancer, resistance to these therapies has increasingly been observed. In this study, to elucidate mechanisms of adaptive resistance, we analyse the tumour immune microenvironment in the context of anti-PD-1 therapy in two fully immunocompetent mouse models of lung adenocarcinoma. In tumours progressing following response to anti-PD-1 therapy, we observe upregulation of alternative immune checkpoints, notably T-cell immunoglobulin mucin-3 (TIM-3), in PD-1 antibody bound T cells and demonstrate a survival advantage with addition of a TIM-3 blocking antibody following failure of PD-1 blockade. Two patients who developed adaptive resistance to anti-PD-1 treatment also show a similar TIM-3 upregulation in blocking antibody-bound T cells at treatment failure. These data suggest that upregulation of TIM-3 and other immune checkpoints may be targetable biomarkers associated with adaptive resistance to PD-1 blockade.
  • Chunxiao Xu, Kevin A. Buczkowski, Yanxi Zhang, Hajime Asahina, Ellen M. Beauchamp, Hideki Terai, Yvonne Y. Li, Matthew Meyerson, Kwok-kin Wong, Peter S. Hammerman
    MOLECULAR CANCER THERAPEUTICS 14 (10) 2382 - 2389 1535-7163 2015/10 [Refereed][Not invited]
    Genetically engineered mouse models of lung cancer have demonstrated an important role in understanding the function of novel lung cancer oncogenes and tumor-suppressor genes identified in genomic studies of human lung cancer. Furthermore, these models are important platforms for preclinical therapeutic studies. Here, we generated a mouse model of lung adenocarcinoma driven by mutation of the discoidin domain receptor 2 (DDR2) gene combined with loss of TP53. DDR2(L63V); TP53(L/L) mice developed poorly differentiated lung adenocarcinomas in all transgenic animals analyzed with a latency of 40 to 50 weeks and a median survival of 67.5 weeks. Mice expressing wild-type DDR2 with combined TP53 loss did not form lung cancers. DDR2(L63V); TP53(L/L) tumors displayed robust expression of DDR2 and immunohistochemical markers of lung adenocarcinoma comparable with previously generated models, though also displayed concomitant expression of the squamous cell markers p63 and SOX2. Tumor-derived cell lines were not solely DDR2 dependent and displayed upregulation of and partial dependence on MYCN. Combined treatment with the multitargeted DDR2 inhibitor dasatinib and BET inhibitor JQ1 inhibited tumor growth in vitro and in vivo. Together, these results suggest that DDR2 mutation can drive lung cancer initiation in vivo and provide a novel mouse model for lung cancer therapeutics studies. (C) 2015 AACR.
  • Shinji Nakamichi, Hiroshi Nokihara, Noboru Yamamoto, Yasuhide Yamada, Yutaka Fujiwara, Yosuke Tamura, Hiroshi Wakui, Kazunori Honda, Hidenori Mizugaki, Satoru Kitazono, Yuko Tanabe, Hajime Asahina, Naoya Yamazaki, Shigenobu Suzuki, Mieko Matsuoka, Yoshitaka Ogita, Tomohide Tamura
    INVESTIGATIONAL NEW DRUGS 33 (3) 641 - 651 0167-6997 2015/06 [Refereed][Not invited]
    RO4987655 is an oral and selective inhibitor of MEK, a key enzyme of the mitogen-activated protein kinase (MAPK) signaling pathway. This phase I dose-escalation study of RO4987655 in Japanese patients with advanced solid tumors aimed to determine maximum tolerated dose (MTD) and to evaluate safety, pharmacokinetics (PK), pharmacodynamics (PD), and anti-tumor activity. Patients received a single dose of RO4987655 (1, 2, 4, 5, or 6.5 mg) followed by continuous once-daily dosing (1, 2, or 4 mg QD) or twice-daily dosing (4, 5, or 6.5 mg BID) in 28-day cycles. A 3 + 3 dose-escalation design was used. PD was evaluated by pERK inhibition in peripheral blood mononuclear cells (PBMCs). In dose-escalation, 25 patients were enrolled. After the MTD was determined, a further six patients were administered the MTD for further confirmation of safety. MTD was determined as 8 mg/day (4 mg BID) due to a total of four dose-limiting toxicities (DLTs) of grade 3 creatine phosphokinase (CPK) elevation (2 DLTs each in 10 mg/day and 13 mg/day). Most commonly related adverse events included dermatitis acneiform, CPK elevation, and eye disorders. Plasma concentration of RO4987655 appeared to increase in a dose-proportional manner with a plasma half-life of 4.32 to 21.1 h. Following multiple dose administration, a steady-state condition was reached by Cycle 1 Day 8. The inhibitory effects of RO4987655 on pERK in PBMCs increased in a dose-dependent manner. One esophageal cancer patient had confirmed partial response and seven patients showed progression-free survival for longer than 16 weeks. The MTD of RO4987655 for Japanese patients was determined as 8 mg/day (4 mg BID). RO4987655 was tolerated up to the MTD with a favorable PK/PD profile in Japanese patients with advanced solid tumors.
  • Akira Inoue, Shunichi Sugawara, Masao Harada, Kunihiko Kobayashi, Toshiyuki Kozuki, Shoichi Kuyama, Makoto Maemondo, Hajime Asahina, Akiko Hisamoto, Taku Nakagawa, Katsuyuki Hotta, Toshihiro Nukiwa
    JOURNAL OF THORACIC ONCOLOGY 9 (12) 1805 - 1809 1556-0864 2014/12 [Refereed][Not invited]
    Background: There has been no standard chemotherapy for advanced or recurrent thymic malignancies including thymic carcinoma (TC) and invasive thymoma (IT), though platinum and anthracycline have been reported as effective agents for the treatment of these diseases. The objective of this study was to evaluate the efficacy and safety of the combination of amrubicin (AMR), a new anthracycline agent, and carboplatin (CBDCA) in patients with advanced thymic malignancies. Methods: Patients with histologically confirmed thymic malignancies received AMR (35 mg/m(2), days 1-3) and CBDCA (area under the curve 4.0, day 1) every 3 weeks. Patients who had received previous chemotherapy were treated with a reduced dose of AMR (30 mg/m2). The primary end point was objective response rate (ORR), and secondary endpoints were progression-free survival, overall survival, and toxicity profile. Results: From December 2008 to October 2012, 51 patients (33 TC and 18 IT) were enrolled. The median number of treatment cycles was four in each group. The ORR and progression-free survival were 30% (95% confidence interval, 14-46) and 7.6 months in the TC group, and 17% (95% confidence interval, 0-34) and 7.6 months in the IT group, respectively. The ORR of TC patients without previous chemotherapy (n = 19) was 42%. Although grade 3 or 4 hematological toxicities were common including neutropenia (82%) and febrile neutropenia (22%), these were transient and manageable. Nonhematological toxicities were moderate and no treatment-related death was observed. Conclusions: The combination of AMR with CBDCA was active for TC with acceptable toxicity, although it was not effective for IT. Further investigation of this regimen for advanced TC is warranted.
  • Yosuke Kawashima, Akira Inoue, Shunichi Sugawara, Satoshi Oizumi, Makoto Maemondo, Koichi Okudera, Toshiro Suzuki, Kazuhiro Usui, Masao Harada, Naoto Morikawa, Yukihiro Hasegawa, Ryota Saito, Osamu Ishimoto, Tomohiro Sakakibara, Hajime Asahina, Toshihiro Nukiwa
    Respiratory Investigation 52 (3) 190 - 194 2212-5353 2014 [Refereed][Not invited]
    Background: Amrubicin (AMR), a new anthracycline agent, has shown promising results for advanced small-cell lung cancer (SCLC), although the efficacy of AMR alone against refractory relapsed SCLC is insufficient. This study was conducted to evaluate the safety and efficacy of the combination of AMR and carboplatin (CBDCA) in patients with refractory relapsed SCLC. Methods: Patients with advanced SCLC who relapsed within 90 days after the completion of first-line chemotherapy received AMR (30mg/m2, days 1-3) and CBDCA (area under the curve 4.0mgmL-1min-1, day 1) every 3 weeks. The primary endpoint of this study was the overall response rate (ORR), and the secondary endpoints were progression-free survival (PFS), overall survival, and the toxicity profile. Assuming that an ORR of 45% in eligible patients would indicate potential usefulness and an ORR of 20% would be the lower limit of interest, with α=0.10 and β=0.10, at least 24 patients were required. Results: Among 29 eligible patients, the ORR was 34% (90% confidence interval, 20-48). The median PFS was 3.5 months, whereas the median survival time was 7.3 months. The most common grade 3-4 toxicity was neutropenia (79%), although only one patient (3%) suffered from febrile neutropenia. Non-hematological toxicities were of moderate severity and no treatment-related death was observed. Conclusions: This is the first prospective study of AMR combined with CBDCA for refractory relapsed SCLC, which was effective and well tolerated. However, further investigation of this regimen is warranted. © 2014 The Japanese Respiratory Society.
  • Kazunori Honda, Noboru Yamamoto, Hiroshi Nokihara, Yosuke Tamura, Hajime Asahina, Yasuhide Yamada, Shigenobu Suzuki, Naoya Yamazaki, Yoshitaka Ogita, Tomohide Tamura
    CANCER CHEMOTHERAPY AND PHARMACOLOGY 72 (3) 577 - 584 0344-5704 2013/09 [Refereed][Not invited]
    RO5126766, a highly selective dual Raf and MEK inhibitor, is a first-in-class tandem mitogen-activated protein kinase signaling pathway inhibitor. The objectives of this phase I study were to determine maximum-tolerated dose (MTD) and to evaluate safety, pharmacokinetics (PK), pharmacodynamics (PD), and anti-tumor activity of RO5126766 in Japanese patients with advanced solid tumors.Patients received a single oral dose of RO5126766 (0.8, 1.2, 1.8, or 2.25 mg) followed by continuous once-daily dosing at the same dosage in 28-day cycles. A 3 + 3 dose-escalation design was used. PD was evaluated by pMEK and pERK inhibition in peripheral blood mononuclear cells (PBMCs).A total of 12 patients were enrolled in cohorts of 0.8, 1.2, 1.8, and 2.25 mg/day. In the dose range tested, no dose-limiting toxicity was observed, and therefore, MTD was not defined. Main adverse events included acneiform dermatitis, creatine phosphokinase elevation, and ocular disorders. The plasma exposure of RO5126766 appeared to increase in a dose-proportional manner with a long plasma half-life (t (1/2)) of 45.8-93.7 h. Following multiple dose administration, a steady-state condition was reached by Cycle 1 Day 8 (240 h). The inhibitory effects of RO5126766 on both pERK and pMEK in PBMCs increased in a dose-dependent manner. Five out of 12 patients achieved stable diseases, including a melanoma case with over 20 % shrinkage.RO5126766 has a manageable safety profile up to 2.25 mg/day once daily with a favorable PK/PD profile in Japanese patients with advanced solid tumors.
  • Hajime Asahina, Hiroshi Nokihara, Noboru Yamamoto, Yasuhide Yamada, Yosuke Tamura, Kazunori Honda, Yoshitaka Seki, Yuko Tanabe, Hitoshi Shimada, Xiaojin Shi, Tomohide Tamura
    INVESTIGATIONAL NEW DRUGS 31 (3) 677 - 684 0167-6997 2013/06 [Refereed][Not invited]
    Background This is the first phase I, dose-finding study of AZD8055, a first-in-class dual mTORC1/2 inhibitor, in Japanese patients with advanced solid tumors. Patients and methods Patients received a single oral dose of AZD8055, followed by twice-daily (BID) dosing. The starting dose was 10 mg with dose escalations in subsequent cohorts to a maximum of 90 mg BID or a non-tolerated dose. Results Seventeen patients were dosed: 10 mg (n = 3), 40 mg (n = 4), 60 mg (n = 3), 90 mg (n = 7). In the 90 mg cohort, one dose limiting toxicity (n = 1) of increased aspartate aminotransferase and increased alanine aminotransferase was observed in the 90 mg BID cohort (n = 1). Four patients, all in the 90 mg BID cohort, experienced a serious adverse event considered to be related to AZD8055: increased alanine aminotransferase (n = 3), increased aspartate aminotransferase (n = 3), increased gamma-glutamyltransferase (n = 2). The 90 mg BID dose was considered as tolerated in Japanese patients but higher doses were not investigated as this dose was also the maximum tolerated dose in Western patients. AZD8055 was rapidly absorbed with greater-than-proportional increases in exposure with increasing dose. No responses were reported, but two patients had stable disease. Mean pAKT and p4EBP1 levels decreased in most cohorts. Conclusion The tolerability and pharmacokinetic profiles of AZD8055 in Japanese patients were similar to those reported in Western patients.
  • Yasushi Goto, Ikuo Sekine, Maki Tanioka, Takashi Shibata, Chiharu Tanai, Hajime Asahina, Hiroshi Nokihara, Noboru Yamamoto, Hideo Kunitoh, Yuichiro Ohe, Hironori Kikkawa, Emiko Ohki, Tomohide Tamura
    INVESTIGATIONAL NEW DRUGS 30 (4) 1548 - 1556 0167-6997 2012/08 [Refereed][Not invited]
    Objectives The insulin-like growth factor (IGF) signaling pathway has been implicated in the pathogenesis of numerous tumor types, including non-small cell lung cancer (NSCLC). Figitumumab is a fully human IgG2 monoclonal antibody against IGF-1 receptor (IGF-1R). Methods This phase I, open-label, dose-escalation study ( NCT00603538) assessed the safety and tolerability of figitumumab (6, 10 and 20 mg/kg) in combination with carboplatin (area under the curve: 6 mg center dot min/mL) and paclitaxel (200 mg/m(2)) in Japanese patients (N = 19) with chemotherapy-na < ve, advanced NSCLC. Treatments were administered intravenously on day 1 of a 21-day cycle for four to six cycles. Pharmacokinetics, biomarkers, and antitumor activity were also evaluated. Results Figitumumab in combination with carboplatin and paclitaxel was well tolerated at doses up to 20 mg/kg; no dose-limiting toxicities were observed at this dose level. When given in combination, figitumumab plasma exposure increased in an approximately dose-proportional manner. The approximate 2-fold accumulation following repeated administration supported the 21-day regimen as appropriate for figitumumab administration. Serum total IGF-1 and IGF binding protein-3 concentrations increased following figitumumab dosing, but a clear dose-dependent relationship was not demonstrated. Seven of 18 evaluable patients experienced a partial response. Conclusions Figitumumab 20 mg/kg in combination with carboplatin and paclitaxel was well tolerated in chemotherapy-na < ve Japanese patients with NSCLC. Further analysis of biomarker data is necessary for the development of figitumumab therapy.
  • Hajime Asahina, Yosuke Tamura, Hiroshi Nokihara, Noboru Yamamoto, Yoshitaka Seki, Takashi Shibata, Yasushi Goto, Maki Tanioka, Yasuhide Yamada, Andrew Coates, Yi-Lin Chiu, Xiaohui Li, Rajendra Pradhan, Peter J. Ansell, Evelyn M. McKeegan, Mark D. McKee, Dawn M. Carlson, Tomohide Tamura
    CANCER CHEMOTHERAPY AND PHARMACOLOGY 69 (6) 1477 - 1486 0344-5704 2012/06 [Refereed][Not invited]
    This phase 1 study assessed the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of linifanib in Japanese patients with advanced solid tumors.Patients were assigned to one of four sequential cohorts (0.05, 0.10, 0.20, or 0.25 mg/kg) of oral, once-daily linifanib on a 21-day cycle. Adverse events (AEs) were assessed per common terminology criteria for adverse events v3.0; tumor responses were assessed by response evaluation criteria in solid tumors.Eighteen patients were enrolled. Eleven (61%) received a parts per thousand yen3 prior therapies. Dose-limiting toxicities were Grade 3 ALT increase (0.10 mg/kg linifanib) and Grade 1 T-wave inversion (0.25 mg/kg linifanib) requiring dose interruption for > 7 days and discontinuation on day 29. The most common linifanib-related AE was hypertension. Other significant treatment-related AEs included proteinuria, fatigue, and palmar-plantar erythrodysaesthesia. Linifanib pharmacokinetics were dose-proportional across 0.10-0.25 mg/kg. Two patients (11.1%) had confirmed partial responses, 12 had a best response of stable disease (11 had stable disease for a parts per thousand yen12 weeks), and four patients were not evaluable due to incomplete data. Four patients (lung cancer, breast cancer, thymic cancer, sarcoma) have continued linifanib for a parts per thousand yen48 weeks (range, 48-96+ weeks).Linifanib was well tolerated with promising preliminary clinical activity in Japanese patients. Later-phase global studies examining linifanib efficacy will include Japanese patients.
  • Yoshinori Makino, Noboru Yamamoto, Hitoshi Sato, Reiko Ando, Yasushi Goto, Chiharu Tanai, Hajime Asahina, Hiroshi Nokihara, Ikuo Sekine, Hideo Kunitoh, Yuichiro Ohe, Erika Sugiyama, Nobuaki Yokote, Tomohide Tamura, Hiroshi Yamamoto
    CANCER CHEMOTHERAPY AND PHARMACOLOGY 69 (4) 861 - 869 0344-5704 2012/04 [Refereed][Not invited]
    Purpose The pharmacokinetic (PK)-pharmacodynamic (PD) relationship of amrubicin and its active metabolite, amrubicinol, has only been evaluated using trough levels of these agents since the full PK profiles not yet been clarified so far. This study was performed to analyze the full PK profiles of amrubicin and amrubicinol and to evaluate their toxicity-PK relationships in Japanese patients. Methods Amrubicin (35-40 mg/m(2)) was administered to 21 lung cancer patients on days 1-3 every 3-4 weeks. Fourteen blood samples were obtained per patient over the course of 3 administration days. The plasma concentrations of amrubicin and amrubicinol were quantitated by HPLC, and the relationships between PK parameters of these compounds and hematological toxicities were evaluated. Results The overall PK profiles of amrubicin and amrubicinol were well characterized using a 3-compartment model and a 1-compartment model with a first-order metabolic process, respectively. The major toxicities were hematological. The clearance of amrubicinol was significantly correlated with grade 4 neutropenia (P = 0.01). The percentage decreases in the neutrophil count, hemoglobin level and platelet count were well correlated with the amrubicinol AUC. Conclusion The pharmacokinetic profiles of amrubicin and amrubicinol were clarified, and the subsequent PK-PD analyses indicate that the clearance of amrubicinol is the major determinant of neutropenia.
  • Yoshitaka Seki, Noboru Yamamoto, Yosuke Tamura, Yasushi Goto, Takashi Shibata, Maki Tanioka, Hajime Asahina, Hiroshi Nokihara, Yasuhide Yamada, Takashi Shimamoto, Kazuo Noguchi, Tomohide Tamura
    CANCER CHEMOTHERAPY AND PHARMACOLOGY 69 (4) 1099 - 1105 0344-5704 2012/04 [Refereed][Not invited]
    Purpose Ridaforolimus is a non-prodrug mTOR inhibitor. The safety, pharmacokinetics (PK), and antitumor activity of oral ridaforolimus were assessed in Japanese patients with refractory solid tumors.Methods Ridaforolimus (20 or 40 mg) was administered as a single dose on Day 1, followed by once daily dosing Wve times a week for a 3-week cycle beginning on Day 8. Full PK sampling was performed on Days 1 and 26.Results Thirteen patients (7 at 20 mg and 6 at 40 mg) were enrolled. The median treatment duration was 82 days. The most common drug-related adverse events were stomatitis, hypertriglyceridemia, and proteinuria. Two patients had dose-limiting toxicities (grade 3 stomatitis at 20 mg, and grade 3 anorexia and vomiting at 40 mg). Four patients had grade 1 interstitial pneumonitis. Ridaforolimus in the whole blood was rapidly absorbed and slowly eliminated with a half-life of approximately 56-58 h after a single dose. Two patients (with non-small cell lung cancer and angiosarcoma, respectively) achieved a partial response, and Wve patients (one with thymic cancer and four with soft tissue sarcomas) had a stable disease for, >= 16 weeks.Conclusions Ridaforolimus was well tolerated up to a dose of 40 mg in Japanese patients. Preliminary evidence of antitumor activity was observed for patients with solid tumors. Further investigation at this dose is warranted.
  • Noboru Yamamoto, Hiroshi Nokihara, Yasuhide Yamada, Yasushi Goto, Maki Tanioka, Takashi Shibata, Kazuhiko Yamada, Hajime Asahina, Toshio Kawata, Xiaojin Shi, Tomohide Tamura
    CANCER SCIENCE 103 (3) 504 - 509 1347-9032 2012/03 [Refereed][Not invited]
    Olaparib (AZD2281) is an orally active Poly(ADP-ribose) polymerase (PARP) inhibitor with favorable antitumor activity in advanced ovarian and breast cancers with BRCA1/2 mutations in Western (USA and European) studies. This Phase I dose-finding study evaluated the tolerability, pharmacokinetics, PARP inhibitory activity, and antitumor activity of olaparib in Japanese patients with solid tumors. Olaparib was administered as a single-dose on day 1, followed by twice-daily dosing for 28 days from 48 h after a single dose. Doses were escalated from 100 mg b.i.d. in successive cohorts, up to a maximum of 400 mg b.i.d. The present study enrolled 12 patients (n = 3, 3, and 6 in 100, 200 and 400-mg b.i.d. levels, respectively). The most common adverse events were nausea, increased blood creatinine, decreased hematocrit, leukopenia and lymphopenia; dose-limiting toxicities were not observed up to and including the 400-mg b.i.d. dose level. Following twice-daily dosing, olaparib showed no marked increase in exposure at steady state over that expected from the single-dose pharmacokinetics. PARP-1 inhibition was observed from the 100-mg b.i.d. dose level in peripheral blood mononuclear cells from 6 h post-dose on day 1 during the multiple-dosing period. A patient with metastatic breast cancer (100 mg b.i.d.) had a partial response for 13 months and four patients (two each in the 200 and 400-mg b.i.d. levels) had stable disease >8 weeks. Olaparib was well tolerated up to the 400-mg b.i.d. dose in Japanese patients with solid tumors. Preliminary evidence of antitumor activity was observed. (Cancer Sci 2012; 103: 504509)
  • 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
  • Hajime Asahina, Ikuo Sekine, Hidehito Horinouchi, Hiroshi Nokihara, Noboru Yamamoto, Kaoru Kubota, Tomohide Tamura
    CLINICAL LUNG CANCER 13 (1) 39 - 43 1525-7304 2012/01 [Refereed][Not invited]
    The efficacy of third-line chemotherapy for advanced non-small-cell lung cancer (NSCLC) remains unknown. The clinical outcome of 599 patients with advanced NSCLC who received first-line chemotherapy was evaluated. Thirty-eight percent of these patients could receive third-line chemotherapy, demonstrating the objective response rate of 17%. Randomized controlled trials of third-line treatment in patients with advanced NSCLC are warranted. Background: The efficacy of third-line and further-line chemotherapy for advanced non-small-cell lung cancer (NSCLC) remains unknown. Patients and Methods: We evaluated the clinical outcome of third-and fourth-line chemotherapy for the treatment of advanced NSCLC in consecutive patients who received first-line chemotherapy at our institute between July 2002 and June 2006. From a hospital-based registry, the following data were extracted: (a) patient characteristics, (b) type of chemotherapeutic agents, and (c) objective response and survival data. Results: A total of 599 patients were included in this analysis. Overall, 69.3%, 38.4%, 17.7%, and 6.0% of the patients received second-, third-, fourth-, and fifth-line chemotherapy, respectively. Significant differences in age (P<.0001), performance status at the start of first-line chemotherapy (P<.0001), and histology (P=.0175) were observed between patients who received third-line chemotherapy and those who did not. Docetaxel, gefitinib, and S-1 were the most frequently used regimens for third-or fourth-line chemotherapy. Five percent of the patients had participated in phase I trials of investigational new drugs. The objective response rates and disease control rates of third-and fourth-line chemotherapy were 17.0% and 34.4% and 11.3% and 24.5%, respectively. The median survival times (95% confidence interval [CI]) from the start of first-, second-, third-, and fourth-line chemotherapy until death were 15.3 months (95% CI, 13.8-16.5 months), 12.8 months (95% CI, 10.7-14.5 months), 12.0 months (95% CI, 9.3-14.2 months), and 9.9 months (95% CI, 8.6-12.0 months), respectively. Conclusion: As many as 38% of patients with advanced NSCLC who received first-line chemotherapy could receive third-line chemotherapy. This result emphasizes the need for randomized controlled trials of third-line treatment in patients with advanced NSCLC.
  • 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
  • Ikuo Sekine, Kaoru Kubota, Yosuke Tamura, Hajime Asahina, Kazuhiko Yamada, Hidehito Horinouchi, Hiroshi Nokihara, Noboru Yamamoto, Tomohide Tamura
    CANCER SCIENCE 102 (1) 162 - 165 1347-9032 2011/01 [Refereed][Not invited]
    To compare the incidence and degree of renal toxicity associated with innovator and generic cisplatin formulations, increase in the serum creatinine (CRN) levels (mg/dL) and incidence of grade 2-3 CRN elevation during the first and all cycles of chemotherapy were retrospectively evaluated in patients treated with innovator (group 1, n = 296) and generic (group 2, n = 321) cisplatin formulations. There were no differences in the sex, age, performance status or number of chemotherapy cycles between groups 1 and 2. The median increases in CRN levels during the first cycle were 0.20 mg/dL regardless of the sex or group. There was no difference in the incidence of grade 2-3 CRN elevation between groups 1 and 2 among female or male patients. The median increases in CRN levels during all cycles were 0.2 (0-1.0) and 0.3 (0-1.8) in the female patients of groups 1 and 2, respectively (P = 0.68), and 0.3 (0-2.1) and 0.5 (0-3.6) in the male patients of groups 1 and 2, respectively (P < 0.001). Grade 2-3 CRN elevation was observed in 18.1% and 24.7% of the female patients in groups 1 and 2, respectively (P = 0.33), and 9.4% and 20.9% of the male patients in groups 1 and 2, respectively (P < 0.001). Renal toxicity was slightly more severe in patients treated with the generic cisplatin formulation than in those treated with the innovator formulation, especially among the male patients. (Cancer Sci 2011; 102: 162-165).
  • 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.
  • Hajime Asahina, Satoshi Oizumi, Akira Inoue, Ichiro Kinoshita, Takashi Ishida, Yuka Fujita, Noriaki Sukoh, Masao Harada, Makoto Maemondo, Yasuo Saijo, Hirotoshi Dosaka-Akita, Hiroshi Isobe, Toshihiro Nukiwa, Masaharu Nishimura
    ONCOLOGY 79 (5-6) 423 - 429 0030-2414 2010 [Refereed][Not invited]
    Objective: Salvage treatment for acquired resistance to gefitinib has yet to be developed. We conducted the first prospective phase II study of gefitinib readministration in previous gefitinib responders. Methods: Gefitinib (250 mg/day) was readministered to patients with advanced/metastatic non-small cell lung cancer who had achieved objective response to initial gefitinib and subsequently received cytotoxic chemotherapy after disease progression with initial gefitinib. The primary endpoint was the objective response rate with gefitinib readministration. Secondary endpoints were disease control rate, progression-free survival (PFS), overall survival (OS), quality of life, and toxicity. Changes in lung cancer-related symptoms were evaluated using the seven-item lung cancer subscale of the questionnaire. Results: Sixteen patients were enrolled between February 2005 and January 2008. Most had received >= 3 regimens of chemotherapy. Response and disease-control rates for all patients were 0 and 44%. Median PFS and OS were 2.5 and 14.7 months, respectively. Four of 7 patients with stable disease experienced a long duration (>= 6 months) of disease control without severe toxicity. Symptom improvement was observed in 2 of 12 patients (17%) for whom quality of life was evaluable. Conclusion: Gefitinib represents a useful therapeutic option for selected previous gefitinib responders. Copyright (C) 2011 S. Karger AG, Basel
  • 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.
  • Satoshi Morita, Isamu Okamoto, Kunihiko Kobayashi, Koichi Yamazaki, Hajime Asahina, Akira Inoue, Koichi Hagiwara, Noriaki Sunaga, Noriko Yanagitani, Toyoaki Hida, Kimihide Yoshida, Tomonori Hirashima, Kosei Yasumoto, Kenji Sugio, Tetsuya Mitsudomi, Masahiro Fukuoka, Toshihiro Nukiwa
    CLINICAL CANCER RESEARCH 15 (13) 4493 - 4498 1078-0432 2009/07 [Refereed][Not invited]
    Purpose: Somatic mutations of the epidermal growth factor receptor (EGFR) gene are associated with an increased response to gefitinib in patients with non-small cell lung cancer. We have examined the impact of gefitinib on progression-free survival and overall survival in patients with EGFR mutation - positive non - small cell lung cancer. Experimental Design: We searched for all clinical trials that prospectively evaluated the efficacy of gefitinib for advanced non - small cell lung cancer with EGFR mutations in Japan. We did a combined analysis based on individual patient data from the identified trials. Results: Seven eligible trials were identified fora total of 148 non - small cell lung cancer patients with EGFR mutations. The overall response rate to gefitinib was 76.4% [95% confidence interval (95% CI), 69.5-83.2]. The median progression-free survival and overall survival were 9.7 months (95% CI, 8.2-11.1) and 24.3 months (95% CI, 19.8-28.2), respectively. Good performance status and chemotherapy-naive status were significantly associated with a longer progression-free survival or overall survival. Of the 148 patients, 87 received gefitinib as a first-line therapy, whereas 61 received systemic chemotherapy before gefitinib treatment. The median progression-free survival after the start of first-line therapy was significantly longer in the gefitinib-first group than in the chemotherapy-first group (10.7 versus 6.0 months; P < 0.001), whereas no significant difference in median overall survival was apparent between the two groups (27.7 versus 25.7 months; P = 0.782). Conclusions: Gefitinib monotherapy confers substantial clinical benefit in terms of progression-free survival and overall survival in non-small cell lung cancer patients with EGFR mutations. Randomized trials comparing chemotherapy with gefitinib as a first-line treatment are warranted in such patients.
  • Masaru Suzuki, Hajime Asahina, Jun Konishi, Koichi Yamazaki, Masaharu Nishimura
    INTERNAL MEDICINE 47 (6) 533 - 536 0918-2918 2008 [Refereed][Not invited]
    Gefitinib, the epidermal growth factor receptor tyrosine kinase inhibitor, is effective for patients with non-small cell lung cancer. However, a serious adverse effect, interstitial lung disease ILD), has been reported. The re-administration of gefitinib might be considered when there is no other choice of treatment and a therapeutic effect can be expected; however, there is no published data on the safety of restarting gefitinib after its discontinuation in cases suspected of having gefitinib-induced ILD. We report a case with recurrent gefitinib-induced ILD, which suggests that re-administration of gefitinib should be considered cautiously in patients who have previously developed gefitinib-induced ILD.
  • Naofumi Shinagawa, Koichi Yamazaki, Hajime Asahina, Jun Agata, Takayuki Ltoh, Masaharu Nishimura
    LUNG CANCER 58 (3) 422 - 424 0169-5002 2007/12 [Refereed][Not invited]
    Gefitinib is mainly metabolized by the liver and its excretion is mostly in bile excrements. However, the feasibility of gefitinib in patients with chronic renal failure undergoing hemodialysis has not, so far, been reported. A 58-year-old woman with chronic renal failure due to polycystic kidney disease, undergoing hemodialysis, experienced diplopia due to meningitis carcinomatosa by lung adenocarcinoma. Sequencing analysis of her tumor tissue revealed deletion of 15 nuclectides in E746-A750 of exon 19. She started daily administration of 250 mg gefitinib with hemodialysis three times a week. Her pharmacokinetic pattern after gefitinib administration was similar to those in patients with normal renal function and 88.7% of gefitinib was kept in the plasma through hemodialysis. Her symptoms and signs of meningitis carcinomatosa on brain magnetic resonance images improved. Thirteen months later, the meningitis got worse again and she stopped gefitinib administration. During gefitinib administration, there were no signs of adverse events. In summary, gefitinib is not eliminated by hemodialysis and was safety administered to a patient with non-small cell lung cancer and chronic renal failure who was undergoing hemodialysis. (c) 2007 Elsevier Ireland Ltd. All rights reserved.
  • 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.
  • Hiroshi Yokouchi, Koichi Yamazaki, Ichiro Kinoshita, Jun Konishi, Hajime Asahina, Noriaki Sukoh, Masao Harada, Kenji Akie, Shigeaki Ogura, Takashi Ishida, Mitsuru Munakata, Hirotoshi Dosaka-Akita, Hiroshi Isobe, Masaharu Nishimura
    BMC CANCER 7 51  1471-2407 2007/03 [Refereed][Not invited]
    Background: Gefitinib, an oral agent of epidermal growth factor receptor tyrosine kinase inhibitor, has a certain efficacy against non-small cell lung cancer (NSCLC). Several predictive factors of gefitinib sensitivity have been well described. However, few studies have investigated the clinical features of gefitinib-responders. In the present study, we analyzed the response and disease progression of primary and metastatic lesions to gefitinib in responders and the results of gefitinib readministration following temporary cessation of gefitinib upon progression of initial gefitinib treatment and other treatments. Method: We retrospectively evaluated the clinical courses of 27 NSCLC patients who received gefitinib and achieved either a complete or partial response. Results: The best-response rate and disease-control rate against the initial chemotherapy for the gefitinib-responders were 27.3% and 77.3%, respectively. Favorable efficacy was observed in the primary lesion and metastases to the lung, liver and brain, while there was no obvious effect on bone metastasis. The primary lesion and intrapulmonary metastasis were the sites of major recurrence. Median progression-free survival was 13.8 months, median duration of gefitinib treatment was 17.0 months and median overall survival was 29.2 months. Some of the patients who experienced disease progression after responding to gefitinib were again sensitive to readministration of gefitinib following temporary cessation of gefitinib and other treatments. Conclusion: Patients may still be expected to have prolonged survival if they once responded to gefitinib and then underwent various subsequent treatments followed by readministration of gefitinib. These findings might provide valuable information for the management of gefitinib-responders.
  • 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.
  • Hajime Asahina, Koichi Yamazaki, Ichiro Kinoshita, Hiroshi Yokouchi, Hirotoshi Dosaka-Akita, Masaharu Nishimura
    LUNG CANCER 54 (3) 419 - 422 0169-5002 2006/12 [Refereed][Not invited]
    Mutations in the tyrosine kinase (TK) domain of the epidermal growth factor receptor (EGFR) are associated with clinical responsiveness to EGFR-tyrosine kinase inhibitors (EGFR-TKIs) in patients with non-small cell, lung cancers (NSCLCs). However, certain rare EGFR mutations including S7681 are reported to confer less in vitro sensitivity to gefitinib, an EGFR-TKI, than major mutations such as exon 19 deletions and L858R and even the wild-type counterpart. Here, we report the first case of adenocarcinoma of the lung in which the patient had rare mutations S7681 and V769L and was treated with gefitinib. Disease progressed during 6 weeks of treatment. This case suggests that in vitro sensitivity to gefitinib correlates with distinct clinical responsiveness to gefitinib in various types of EGFR mutations. (C) 2006 Elsevier Ireland Ltd. All rights reserved.
  • H. Asahina, K. Yamazaki, I. Kinoshita, N. Sukoh, M. Harada, H. Yokouchi, T. Ishida, S. Ogura, T. Kojima, Y. Okamoto, Y. Fujita, H. Dosaka-Akita, H. Isobe, M. Nishimura
    BRITISH JOURNAL OF CANCER 95 (8) 998 - 1004 0007-0920 2006/10 [Refereed][Not invited]
    Retrospective analysis has shown that activating mutations in exons 18-21 of the epidermal growth factor receptor ( EGFR) gene are a predictor of response to gefitinib. We conducted a phase II trial to evaluate the efficacy and safety of gefitinib as first-line therapy for advanced non-small cell lung cancer (NSCLC) with EGFR mutations. Patients with stage IIIB or IV chemotherapy- naive NSCLC with EGFR mutation were treated with 250 mg gefitinib daily. For mutational analysis, DNA was extracted from paraffin-embedded tissues and EGFR mutations were analysed by direct sequence of PCR products. Twenty (24%) of the 82 patients analysed had EGFR mutations ( deletions in or near E746-A750, n = 16; L858R, n 4). Sixteen patients were enrolled and treated with gefitinib. Twelve patients had objective response and response rate was 75% (95% CI, 48-93%). After a median follow-up of 12.7 months ( range, 3.1-16.8 months), 10 patients demonstrated disease progression, with median progression-free survival of 8.9 months ( 95% CI, 6.7-11.1 months). The median overall survival time has not yet been reached. Most of the toxicities were mild. This study showed that gefitinib is very active and well tolerated as first-line therapy for advanced NSCLC with EGFR mutations.
  • Hiroshi Yokouchi, Koichi Yamazaki, Hajime Asahina, Masahiko Shigemura, Takanori Moriyama, Kazuo Takaoka, Jun Moriya, Tomoo Itoh, Ichiro Kinoshita, Hirotoshi Dosaka-Akita, Yutaka Tsutsumi, Masaharu Nishimura
    ANTICANCER RESEARCH 26 (4B) 2821 - 2827 0250-7005 2006/07 [Refereed][Not invited]
    Background: Few studies have successfully established an amylase-producing lung cancer cell line or have examined its cytological, biochemical and biological features. Patients and Methods: Cancer cells, isolated from pleural effusion using a gradient method, were cultivated. Results: Amylase production from the newly established cell line was confirmed by positive staining for a-amylase and increased amylase levels in the culture supernatant. Electron microscopy revealed zymogen granule-like structures. Sialylation of salivary-type amylase was confirmed directly from the cell line by examining the neuraminidase sensitivity and amylase elution profile under high-performance liquid chromatography. Neither EGFR or KRAS mutation were found. Conclusion: This cell line offers a useful tool for analyzing the pathogenesis and pathophysiology of amylase-producing lung cancers. Moreover, it might be useful for probing the metastasis and invasiveness of lung cancer cells and for developing an early diagnostic method based on sialylated salivary-amylase production.
  • 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.
  • 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.
  • Tanaka A, Osawa H, Yamauchi A, Asahina H, Kikuchi H, Ogura S, Yamamoto K, Ikeda H, Koshiba R
    Kyobu geka. The Japanese journal of thoracic surgery 55 (11) 971 - 975 0021-5252 2002/10 [Refereed][Not invited]


Educational Activities

Teaching Experience

  • 医学総論
    開講年度 : 2019
    課程区分 : 博士後期課程
    開講学部 : 医学研究科
  • 全科臨床実習
    開講年度 : 2019
    課程区分 : 学士課程
    開講学部 : 医学部

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