Nagio Takigawa

Kawasaki Saiwai Hospital, Kawasaki, Fukuoka, Japan

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Publications (214)618.7 Total impact

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    ABSTRACT: 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.
    Japanese Journal of Clinical Oncology 08/2014; · 1.90 Impact Factor
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    ABSTRACT: 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.
    European journal of cancer (Oxford, England: 1990) 08/2014; · 4.12 Impact Factor
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    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; · 0.73 Impact Factor
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    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.
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    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.
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    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; · 3.56 Impact Factor
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    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; · 2.80 Impact Factor
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    Journal of Emergency Medicine 02/2014; · 1.33 Impact Factor
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    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; · 3.56 Impact Factor
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    Journal of Clinical Oncology 01/2014; · 18.04 Impact Factor
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    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 01/2014; 37(2):84-92.
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    Case Reports 01/2014; 2014.
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    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. · 2.07 Impact Factor
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    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 01/2014; 9(1):14-7. · 1.12 Impact Factor
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    Daijiro Harada, Nagio Takigawa, Katsuyuki Kiura
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    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.
    Cancers. 01/2014; 6(2):708-22.
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    ABSTRACT: We encountered a family of Japanese descent in which multiple members developed lung cancer. Using whole-exome sequencing, we identified a novel germline mutation in the transmembrane domain of the human epidermal growth factor receptor 2 (HER2) gene (G660D). A novel somatic mutation (V659E) was also detected in the transmembrane domain of HER2 in one of 253 sporadic lung adenocarcinomas. Because the transmembrane domain of HER2 is considered to be responsible for the dimerization and subsequent activation of the HER family and downstream signaling pathways, we performed functional analyses of these HER2 mutants. Mutant HER2 G660D and V659E proteins were more stable than wild-type protein. Both the G660D and V659E mutants activated Akt. In addition, they activated p38, which is thought to promote cell proliferation in lung adenocarcinoma. Our findings strongly suggest that mutations in the transmembrane domain of HER2 may be oncogenic, causing hereditary and sporadic lung adenocarcinomas.
    CancerSpectrum Knowledge Environment 12/2013; · 14.07 Impact Factor
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    ABSTRACT: STAT3 plays a vital role in inducing and maintaining a pro-carcinogenic inflammatory microenvironment and is reported to be a critical mediator of the oncogenic effects of EGFR mutations. STAT3 activation is mediated through JAK family kinases. We investigated the effect of the JAK1/2 inhibitor AZD1480 on lung tumors induced by an activating EGFR mutation. Three EGFR tyrosine kinase inhibitor-resistant cell lines (RPC-9, PC-9/Van-R and PC-9/ER3) established from PC-9 harboring an EGFR exon19 deletion mutation were used. Growth inhibition was measured using an MTT assay. Effects of AZD1480 were also evaluated in the xenograft model and in the EGFR transgenic mice model. Protein expressions were assessed by immunoblotting and immunohistochemistry. Group differences were compared using Student's t-test. To evaluate the efficacy of AZD1480 on survival, AZD1480 or vehicle was administered orally from 7 weeks of age of the transgenic mice. Overall survival curves were calculated using the Kaplan-Meier method. The sensitivities of resistant and parent cells to AZD1480 were similar in vitro. AZD1480 (30 or 50mg/kg/day, per os) reduced angiogenesis and revealed significant tumor regression in a mouse xenograft model. Subsequently, the transgenic mice were treated with AZD1480 (30mg/kg/day) or vehicle alone. The numbers of lung tumors (long axis exceeding 1mm) in the AZD1480-treated group and control group were 0.37±0.18 and 2.25±0.53 (p<0.001), respectively. AZD1480 treatment suppressed pSTAT3, pJAK1, pJAK2 and angiogenesis. The median survival time in the AZD1480-treated group (217 days) was significantly greater than that in the control group (106 days) (log-rank test, p<0.0001). AZD1480 may be effective against lung tumors driven by an activating EGFR mutation.
    Lung cancer (Amsterdam, Netherlands) 10/2013; · 3.14 Impact Factor
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    ABSTRACT: Cisplatin can induce severe renal toxicity. However, the degree and pattern of hydration that is most efficient at preventing it have scarcely been formally evaluated. We here performed a prospective feasibility study of cisplatin-based chemotherapy with short-term low-volume hydration in advanced lung cancer. Chemo-naïve patients with advanced lung cancer and reserving renal function who were suitable for cisplatin use (≥60 mg/m(2) on Day 1) were eligible for this study. Two-and-a-half-liter hydration within ∼4.5 h was investigated. The primary end point was the proportion of patients who underwent cisplatin-based chemotherapy without any Grade 2 or more renal toxicity in the first cycle. A total of 46 patients were registered, all of whom were evaluable for renal toxicity. The median baseline creatinine score was 0.70 mg/dl and the median cisplatin dose on Day 1 was 80 mg/m(2). In the first cycle, none of the patients developed Grade 2 or more creatinine toxicity, which met the primary endpoint. Four patients (9%) had Grade 1 toxicity, with a median worst creatinine score of 1.19 mg/dl, but it disappeared rapidly. Creatinine toxicity was influenced by several clinical factors, including the performance status. Ten patients (22%) needed extra hydration during the first cycle, mainly due to gastrointestinal toxicity. However, all 10 were able to undergo further cycles of treatment. Thirty-two (86%) of the 37 patients who were assumed to be able to undergo further treatment at our institute received it in an outpatient setting. This study demonstrated prospectively the feasibility of short-term low-volume hydration.
    Japanese Journal of Clinical Oncology 09/2013; · 1.90 Impact Factor
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    ABSTRACT: Non-small cell lung cancers (NSCLCs) with epidermal growth factor receptor (EGFR) mutations are sensitive to EGFR tyrosine kinase inhibitors (TKIs); however, unlike cytotoxic agents, it is generally accepted that minimal doses of drugs inhibiting target molecules are sufficient when molecular-targeted agents, including EGFR-TKIs, are administered. Thus, any utility of higher doses remains unclear. We compared low-dose (15 mg/kg) gefitinib therapy with high-dose (50 mg/kg) therapy using an EGFR-mutated lung cancer xenograft model. Both gefitinib doses induced tumor shrinkage, but tumors regrew in the low-dose group within 1 month, whereas tumors in the high-dose group did not. Neither the T790M mutation nor MET amplification was apparent in regrown tumors. We also compared outcomes after administration of two doses of gefitinib (5 and 25 mg/kg) in a transgenic EGFR-mutated lung cancer mouse model. In line with the results obtained using the xenograft model, both gefitinib doses completely inhibited tumor growth, but tumors treated with the lower dose of gefitinib developed earlier drug resistance. In conclusion, administration of a low gefitinib dose caused tumors to become drug-resistant prior to acquisition of the T790M mutation or MET amplification in EGFR-mutated models of lung cancer. This suggests that it is important to optimize the EGFR-TKI dose for treatment of EGFR mutation-associated lung cancer. Gefitinib may need to be administered at a dose greater than the minimum required for inhibition of target molecules. This article is protected by copyright. All rights reserved.
    Cancer Science 09/2013; · 3.48 Impact Factor

Publication Stats

1k Citations
618.70 Total Impact Points


  • 2011–2014
    • Kawasaki Saiwai Hospital
      Kawasaki, Fukuoka, Japan
  • 2012
    • National Cancer Center, Japan
      Edo, Tōkyō, Japan
  • 1996–2012
    • Shikoku Cancer Center
      Matuyama, Ehime, Japan
  • 2002–2011
    • Okayama University
      • Department of Allergy and Respiratory Medicine
      Okayama, Okayama, Japan
  • 2010
    • National Hospital Organization Yamaguchi-Ube Medical Center
      Ubi, Yamaguchi, Japan
  • 2009
    • Miki Sanyo Hospital
      Kōbe, Hyōgo, Japan
    • Kurashiki Central Hospital
      Kurasiki, Okayama, Japan
  • 2004–2007
    • Minami Okayama Medical Center
      Okayama, Okayama, Japan
  • 2006
    • National Hospital Organization Sagamihara Hospital
      Sagamihara, Kanagawa, Japan