Nagio Takigawa

Kawasaki Saiwai Hospital, Kawasaki, Fukuoka, Japan

Are you Nagio Takigawa?

Claim your profile

Publications (240)792.58 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Whether bevacizumab enhances the effect of the epidermal growth factor receptor (EGFR) inhibitor gefitinib on EGFR mutant non-small cell lung cancers (NSCLCs) remains unknown. We conducted a phase II trial to investigate the efficacy and safety of gefitinib when combined with bevacizumab as first-line therapy in patients with advanced NSCLC harboring EGFR gene mutations. In this trial, 42 patients with a performance status of 0 to 2 received gefitinib (250 mg/d) and bevacizumab (15 mg/kg, every 3 weeks). The primary end point of this study was the 1-year progression-free survival (PFS) rate. We assumed that a 1-year PFS rate of 55% would indicate potential usefulness and that a 1-year PFS rate of 40% would constitute the lower limit of interest. Forty-two patients were enrolled in the study with a median age of 73 (range 42-86) years. Activating EGFR gene mutations included exon 19 deletion (57%) and L858R point mutations in exon 21 (38%). The objective response rate was 73.8% and included two complete responses. The 1-year PFS rate and median PFS time were 56.7% (95% confidence interval [CI] 39.9-70.5) and 14.4 months (95% CI 10.1-19.2), respectively. The median PFS differed significantly between EGFR exon 19 deletion and the L858R point mutation (18.0 versus 9.4 months, respectively; p = 0.006). The median overall survival had not yet been reached. Severe adverse events included grade 3 skin rash (15%), hypertension (17%), aspartate transaminase/alanine aminotransferase elevation (17%), proteinuria (7%), intracranial hemorrhage (2%), and grade 4 perforation of the digestive tract (2%). There were no treatment-related deaths. Gefitinib in combination with bevacizumab as first-line therapy seems to be a favorable and well-tolerated treatment for patients with advanced NSCLC with activating EGFR gene mutations, especially those with EGFR exon 19 deletion mutations, although the primary end point was not met because the lower limit of the CI was less than 40%.
    Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 03/2015; 10(3):486-91. DOI:10.1097/JTO.0000000000000434 · 4.55 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: A 60-year-old asymptomatic woman was referred to our hospital because of an abnormal chest roentgenogram during a routine medical checkup. The patient had no history of memorable infectious diseases, except a liver abscess caused by Serratia marcescens at age 46 years. Her son was diagnosed with chronic granulomatous disease at the age of 1 year. She had never smoked cigarettes and drank only occasionally.
    Chest 02/2015; 147(2):e48-51. DOI:10.1378/chest.14-1215 · 7.13 Impact Factor
  • Chest 12/2014; 146(6):e222-5. DOI:10.1378/chest.14-2055 · 7.13 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Although cisplatin-based chemotherapy combined with thoracic irradiation (TRT) is a standard treatment for unresectable, locally advanced non-small cell lung cancer (NSCLC), this treatment outcome has remained unsatisfactory. We had previously conducted a phase I trial of cisplatin plus S-1, an oral 5-fluorouracil derivative, and TRT, which were safe and effective.Methods In this phase II trial, 48 patients with stage III NSCLC received cisplatin (40 mg/m2 on days 1, 8, 29 and 36) and S-1 (80 mg/m2 on days 1–14 and 29–42) and TRT (60 Gy). The primary endpoint was the response rate.ResultsA partial response was observed in 37 patients (77%; 95% confidence interval: 63–88%). At a median follow up of 54 months, the median progression-free survival and median survival time were 9.3 and 31.3 months, respectively. No difference in efficacy was observed when the patients were stratified by histology. Toxicities were generally mild except for grade 3 or worse febrile neutropenia and pneumonitis of 8% and 4%, respectively. No patient developed severe esophagitis. At the time of this analysis, 35 (73%) of the 48 patients recurred; 15 (31%) showed distant metastasis, 17 (35%) had loco-regional disease, and 2 (4%) showed both loco-regional disease and distant metastasis.Conclusions This chemoradiotherapy regimen yielded a relatively favorable efficacy with mild toxicities in patients with locally advanced NSCLC.
    Lung Cancer 11/2014; 87(2). DOI:10.1016/j.lungcan.2014.11.001 · 3.74 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Objective: The echinoderm microtubule associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) fusion gene was identified in patients with non-small cell lung cancer. To the best of our knowledge, there are only three cell lines harboring the EML4-ALK fusion gene, which have contributed to the development of therapeutic strategies. Therefore, we tried to establish a new lung cancer cell line harboring EML4-ALK. Methods: A 61-year-old Japanese female presented with chest discomfort. She was diagnosed with left lung adenocarcinoma with T4N3M1 Stage IV. Although she was treated with chemotherapy, her disease progressed with massive pleural effusion. Because the EML4-ALK rearrangement was found in a biopsied specimen using fluorescence in situ hybridization, she was treated with crizotinib. She did well for 3 months. Results: Tumor cells were obtained from the malignant pleural effusion before treatment with crizotinib. Cells continued to proliferate substantially for several weeks. The cell line was designated ABC-11. The EML4-ALK fusion protein and genes were identified in ABC-11 cells using fluorescence in situ hybridization and immunohistochemistry, respectively. ABC-11 cells were sensitive to crizotinib and next-generation ALK inhibitors (ceritinib and AP26113), as determined by a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Phosphorylated ALK protein and its downstream signaling were suppressed by treatment with crizotinib in western blotting. Furthermore, we could transplant ABC-11 cells subcutaneously into BALB/c nu/nu mice. Conclusions: We successfully established a new lung adenocarcinoma cell line harboring the EML4-ALK fusion gene. This cell line could contribute to future research of EML4-ALK-positive lung cancer both in vivo and in vitro.
    Japanese Journal of Clinical Oncology 08/2014; 44(10). DOI:10.1093/jjco/hyu110 · 1.75 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background: Although thoracic irradiation (TRT) is a standard treatment for elderly patients with locally advanced non-small-cell lung cancer (LA-NSCLC), treatment outcomes are poor. We previously reported a phase I trial combining S-1, an oral 5-fluorouracil derivative, and thoracic radiation, which yielded safe and effective outcomes. Methods: In this phase II trial, 30 patients aged 76 years or older with LA-NSCLC received S-1 (80 mg/m(2) on days 1-14 and 29-42) and TRT (60 Gy). The primary end-point was the response rate. Results: The median age and pre-treatment Charlson score were 79 years and 1, respectively. The mean proportions of the actual doses of S-1 and TRT delivered relative to the planned doses were 95% and 98%, respectively. Partial responses were observed in 19 patients (63%; 95% confidence interval: 45-82%), which did not attain the end-point. At a median follow-up time of 23.7 months, the median progression-free survival and median survival times were 13.0 months and 27.9 months, respectively. No difference in efficacy was observed upon stratification by tumour histology. Toxicities were generally mild, except for grade 3 or greater febrile neutropenia and pneumonitis in 7% and 10% of patients, respectively. No patient developed severe oesophagitis. Conclusions: Although the primary end-point was not met, concurrent S-1 chemotherapy and radiotherapy yielded favourable survival data. Also, the combined treatment was well-tolerated in elderly patients with LA-NSCLC. (c) 2014 Elsevier Ltd. All rights reserved.
    European journal of cancer (Oxford, England: 1990) 08/2014; 50(16). DOI:10.1016/j.ejca.2014.07.024 · 4.12 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Pulmonary alveolar proteinosis (PAP) is a rare diffuse lung disease caused by abnormal intra-alveolar surfactant accumulation; it commonly appears as a "crazy-paving" pattern on high-resolution computed tomography. Here, we report a rare case of autoimmune PAP appearing as localized ground-glass opacity. An 82-year-old woman underwent chest computed tomography (CT) at another facility for cough, and a 2-cm localized ground-glass opacity was detected at the bottom of the right upper lung lobe. When she presented for follow-up at our hospital 6 months later, she was asymptomatic. The CT examinations performed at that point and 2 months thereafter did not reveal any changes. However, a CT examination performed after 5 months revealed slight increases in size and concentration. Adenocarcinoma in situ or minimally invasive adenocarcinoma was suspected. Incomplete lobulation between the upper and middle lobes of the right lung was detected, and video-assisted thoracoscopic lobectomy of the upper lobe and partial resection of the middle lobe of the right lung were performed. Histological examination revealed alveoli and terminal bronchioles filled with eosinophilic proteinaceous material positive for periodic acid-Schiff stain. The histopathological diagnosis was PAP and positive serum anti-GM-CSF antibody findings confirmed autoimmune PAP.
    Japanese journal of radiology 08/2014; DOI:10.1007/s11604-014-0348-3 · 0.74 Impact Factor
  • Source
    Daijiro Harada, Nagio Takigawa, Katsuyuki Kiura
    [Show abstract] [Hide abstract]
    ABSTRACT: Persistent phosphorylation of signal transducer and activator of transcription 3 (STAT3) has been demonstrated in 22%~65% of non-small cell lung cancers (NSCLC). STAT3 activation is mediated by receptor tyrosine kinases, such as epidermal growth factor receptor (EGFR) and MET, cytokine receptors, such as IL-6, and non-receptor kinases, such as Src. Overexpression of total or phosphorylated STAT3 in resected NSCLC leads to poor prognosis. In a preclinical study, overexpression of STAT3 was correlated with chemoresistance and radioresistance in NSCLC cells. Here, we review the role of STAT3 and the mechanisms of treatment resistance in malignant diseases, especially NSCLC. As STAT3 is a critical mediator of the oncogenic effects of EGFR mutations, we discuss STAT3 pathways in EGFR-mutated NSCLC, referring to mechanisms of EGFR tyrosine kinase inhibitor resistance.
    06/2014; 6(2):708-22. DOI:10.3390/cancers6020708
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Docetaxel is a key antineoplastic drug for treatment of non-small cell lung cancer. Ocular adverse events of docetaxel include epiphora (excess tearing) and conjunctivitis. Epiphora has been reported to be associated with canalicular and nasolacrimal duct stenosis, but it is not necessarily caused by lacrimal duct obstruction.
    BMC Research Notes 05/2014; 7(1):322. DOI:10.1186/1756-0500-7-322
  • [Show abstract] [Hide abstract]
    ABSTRACT: Non-small cell lung cancers (NSCLCs) are frequently heterogeneous and in approximately 70% of cases, NSCLCs are diagnosed and staged by small biopsies or cytology rather than by examination of surgically resected specimens. Thus, in most patients, the diagnosis is established based on examination of preoperative specimens alone. Recently, classification of NSCLC into pathologic subtypes has been shown to be important for selecting the appropriate systemic therapy, from both the point of view of treatment efficacy and prevention of toxicity.
    Diagnostic Pathology 05/2014; 9(1):103. DOI:10.1186/1746-1596-9-103 · 2.41 Impact Factor
    This article is viewable in ResearchGate's enriched format
  • [Show abstract] [Hide abstract]
    ABSTRACT: Everolimus is an orally administered mTOR inhibitor. The effect, and mechanism of action, of everolimus on lung cancers with an epidermal growth factor receptor (EGFR) mutation remain unclear. Four gefitinib-sensitive and -resistant cell lines were used in the present work. Growth inhibition was determined using the MTT assay. Transgenic mice carrying the EGFR L858R mutation were treated with everolimus (10mg/kg/day), or vehicle alone, from 5 to 20 weeks of age, and were then sacrificed. To evaluate the efficacy of everolimus in prolonging survival, everolimus (10mg/kg/day) or vehicle was administered from 5 weeks of age. The four cell lines were similarly sensitive to everolimus. Expression of phosphorylated (p) mTOR and pS6 were suppressed upon treatment with everolimus in vitro, whereas the pAKT level increased. The numbers of lung tumors with a long axis exceeding 1mm in the everolimus-treated and control groups were 1.9±0.9 and 9.4±3.2 (t-test, p<0.001), respectively. pS6 was suppressed during everolimus treatment. Although apoptosis and autophagy were not induced in everolimus-treated EGFR transgenic mice, angiogenesis was suppressed. The median survival time in the everolimus-treated group (58.0 weeks) was significantly longer than that in the control group (31.2 weeks) (logrank test, p<0.001). These findings suggest that everolimus had an indirect effect on tumor formation by inhibiting angiogenesis and might be effective to treat lung tumors induced by an activating EGFR gene mutation.
    Experimental Cell Research 04/2014; DOI:10.1016/j.yexcr.2014.04.012 · 3.37 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Early administration of both epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) monotherapy and cytotoxic chemotherapy is crucial for non-small cell lung cancer (NSCLC) patients harboring EGFR mutations. We investigated the effect of first-line administration of these therapies on subsequent therapy in NSCLC patients. This study enrolled 63 consecutive patients with advanced EGFR-mutant NSCLC and good performance status (PS) and who underwent first-line EGFR-TKI therapy or standard cytotoxic chemotherapy and then had progressive disease, from 2007 to 2011. The ability of each patient to receive the other therapy after first-line treatment failure was assessed. In the first-line setting, 23 and 40 patients received EGFR-TKI therapy and cytotoxic chemotherapy, respectively. At relapse, the EGFR-TKI therapy group showed more frequent PS deterioration (p = 0.042) and greater likelihood of symptomatic central nervous system (CNS) relapse (p = 0.093) compared with the cytotoxic chemotherapy group. Nine (39 %) of 23 patients initially receiving EGFR-TKI therapy could not receive standard cytotoxic therapy after progression mainly due to symptomatic CNS relapse. Only one (3 %) of 40 initially treated with cytotoxic chemotherapy failed to receive subsequent EGFR-TKI therapy (p < 0.001). Multivariate analysis revealed a correlation between the first-line therapy and the failure to switch to the other therapy after disease progression (OR 48.605, p = 0.005). In this study, patients who could not receive both EGFR-TKI therapy and cytotoxic chemotherapy in the early-line setting were included more in the first-line EGFR-TKI group, suggesting a potential risk associated with missing the timing of administration of subsequent therapy. Further investigation is warranted to detect their pretreatment clinical or molecular characteristics for development of a new treatment strategy specific for such subpopulation.
    Cancer Chemotherapy and Pharmacology 03/2014; DOI:10.1007/s00280-014-2425-9 · 2.80 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Rapid on-site evaluation (ROSE) is used widely during endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA). BIOEVALUATOR(®) is a device used for determining whether the tissues obtained by EBUS-TBNA are appropriate for a pathological diagnosis. This study describes our experience with ROSE using BIOEVALUATOR(®) during EBUS-TBNA for diagnosing pulmonary and mediastinal diseases. We retrospectively evaluated the results of 35 patients who underwent EBUS-TBNA with BIOEVALUATOR(®) between December 2011 and February 2013. For the diagnosis, the tissue areas were appearing white and red through BIOEVALUATOR(®) are considered to be appropriate and inappropriate, respectively. We examined their medical records to obtain information concerning the examination of BIOEVALUATOR(®) results of the patient's materials (white/red), the diagnosis yield, site and size of lymph nodes and number of needle passes. The median longest diameter of 40 lymph nodes (21 #7, 13 #4R, 4 #4L and 2 #11) from 35 patients was 27.9 (range 12.4-50.6) mm and the median number of needle passes was 2 (range 1-5). The definitive diagnosis was made by EBUS-TBNA in 28 of 35 patients, by thoracotomy in one patient and BIOEVALUATOR(®) results were white and lymphocytes were seen in the rest six patients. The BIOEVALUATOR(®) results of other patients without accurate diagnosis were left indefinitive. Finally, the six patients were judged as having benign lymphadenopathy because the lymph node size on computed tomography decreased or remained stable after for at least 8 months. Checking aspirated samples using BIOEVALUATOR(®) appears useful for determining their adequacy for pathological diagnosis.
    Annals of Thoracic Medicine 03/2014; 9(1):14-7. DOI:10.4103/1817-1737.124415 · 1.34 Impact Factor
    This article is viewable in ResearchGate's enriched format
  • Source
    Journal of Emergency Medicine 02/2014; 46(5). DOI:10.1016/j.jemermed.2013.11.094 · 1.18 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: We conducted a clinical trial of an NY-ESO-1 cancer vaccine using 4 synthetic overlapping long peptides (OLP; peptides #1, 79-108; #2, 100-129; #3, 121-150; and #4, 142-173) that include a highly immunogenic region of the NY-ESO-1 molecule. Nine patients were immunized with 0.25 mg each of three 30-mer and a 32-mer long NY-ESO-1 OLP mixed with 0.2 KE Picibanil OK-432 and 1.25 mL Montanide ISA-51. The primary endpoints of this study were safety and NY-ESO-1 immune responses. Five to 18 injections of the NY-ESO-1 OLP vaccine were well tolerated. Vaccine-related adverse events observed were fever and injection site reaction (grade 1 and 2). Two patients showed stable disease after vaccination. An NY-ESO-1-specific humoral immune response was observed in all patients and an antibody against peptide #3 (121-150) was detected firstly and strongly after vaccination. NY-ESO-1 CD4 and CD8 T-cell responses were elicited in these patients and their epitopes were identified. Using a multifunctional cytokine assay, the number of single or double cytokine-producing cells was increased in NY-ESO-1-specific CD4 and CD8 T cells after vaccination. Multiple cytokine-producing cells were observed in PD-1 (-) and PD-1 (+) CD4 T cells. In conclusion, our study indicated that the NY-ESO-1 OLP vaccine mixed with Picibanil OK-432 and Montanide ISA-51 was well tolerated and elicited NY-ESO-1-specific humoral and CD4 and CD8 T-cell responses in immunized patients.
    Journal of Immunotherapy 02/2014; 37(2):84-92. DOI:10.1097/CJI.0000000000000017 · 3.35 Impact Factor
  • Source
    Case Reports 01/2014; 2014. DOI:10.1136/bcr-2013-203047
  • Source
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: To study epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) resistance mechanisms, we established a novel gefitinib-resistant lung cancer cell line derived from an EGFR-mutant non-small cell lung cancer cell line (PC-9) pretreated with 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (designated PC9-GR). We found that gefitinib substantially suppressed the EGFR signaling pathway, whereas ERK was reactivated after several hours in PC9-GR but not in PC-9. The combination of gefitinib with ERK inhibition (by U0126) restored gefitinib susceptibility in PC9-GR, but PI3K-Akt inhibition with LY294002 did not. Although the levels of phosphorylated Src were up-regulated simultaneously with ERK reactivation, neither ERK suppression using U0126 nor an ERK-specific siRNA induced Src phosphorylation. Furthermore, dual inhibition of EGFR and Src restored gefitinib sensitivity in PC9-GR in vitro and in vivo. In conclusion, our results indicate that Src-mediated ERK reactivation may play a role in a novel gefitinib resistance mechanism, and that the combined use of gefitinib with a Src inhibitor may be a potent strategy to overcome this resistance.
    Experimental Cell Research 01/2014; DOI:10.1016/j.yexcr.2014.01.007 · 3.37 Impact Factor
  • Source
    Journal of Clinical Oncology 01/2014; 32(6). DOI:10.1200/JCO.2013.53.2226 · 17.88 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Obstructive jaundice caused by metastases to the porta hepatis is often observed in patients with various advanced cancers; however, metastasis of lung cancer to the common bile duct with subsequent development of jaundice is rare. A 75-year-old female with lung adenocarcinoma harboring epidermal growth factor receptor (EGFR) mutation (15-bp in-frame deletion in exon 19 and T790M in exon 20) developed obstructive jaundice during therapy. Obstruction of the common bile duct caused by an intraductal tumor was identified by computed tomography, endoscopic retrograde cholangiopancreatography, and endoscopic ultrasonography. Although primary cholangiocarcinoma was highly suspected according to the imaging findings, immunohistochemical evaluation of the intraductal tumor demonstrated thyroid transcription factor-1 positive adenocarcinoma. Furthermore, peptide nucleic acid-locked nucleic acid polymerase chain reaction clamp analysis showed that the tumor contained the same EGFR mutation as that in the primary lung cancer. Thus, we confirmed intraductal metastasis from a lung adenocarcinoma. To our knowledge, this is the second report of obstructive jaundice caused by intraductal metastasis of lung cancer.
    OncoTargets and Therapy 01/2014; 7:1847-50. DOI:10.2147/OTT.S68757 · 1.34 Impact Factor

Publication Stats

2k Citations
792.58 Total Impact Points

Institutions

  • 2011–2014
    • Kawasaki Saiwai Hospital
      Kawasaki, Fukuoka, Japan
  • 2007–2014
    • Kawasaki Medical University
      • Department of General Internal Medicine 4
      Kurasiki, Okayama, Japan
  • 2001–2014
    • Okayama University
      • Department of Allergy and Respiratory Medicine
      Okayama, Okayama, Japan
  • 1996–2012
    • Shikoku Cancer Center
      Matuyama, Ehime, Japan
  • 2010
    • Aichi Cancer Center
      Ōsaka, Ōsaka, Japan
    • National Hospital Organization Yamaguchi-Ube Medical Center
      Ubi, Yamaguchi, Japan
  • 2009
    • Kurashiki Central Hospital
      Kurasiki, Okayama, Japan
  • 2004–2007
    • Minami Okayama Medical Center
      Okayama, Okayama, Japan