Faculty Profiles - ICHIHARA Eiki

Role of survival post-progression in phase III trials of systemic chemotherapy in advanced non-small-cell lung cancer: a systematic review. International journal

Katsuyuki Hotta, Katsuyuki Kiura, Yoshiro Fujiwara, Nagio Takigawa, Akiko Hisamoto, Eiki Ichihara, Masahiro Tabata, Mitsune Tanimoto

PloS one 6 ( 11 ) e26646 2011

Language：English Publishing type：Research paper (scientific journal) Publisher：PUBLIC LIBRARY SCIENCE

BACKGROUND: In advanced non-small-cell lung cancer (NSCLC), with the increasing number of active compounds available in salvage settings, survival after progression to first-line chemotherapy seems to have improved. A literature survey was conducted to examine whether survival post-progression (SPP) has improved over the years and to what degree SPP correlates with overall survival (OS). METHODS AND FINDINGS: Median progression-free survival (MPFS) time and median survival time (MST) were extracted in phase III trials of first-line chemotherapy for advanced NSCLC. SPP was pragmatically defined as the time interval of MST minus MPFS. The relationship between MPFS and MST was modeled in a linear function. We used the coefficient of determination (r(2)) to assess the correlation between them. Seventy trials with 145 chemotherapy arms were identified. Overall, median SPP was 4.7 months, and a steady improvement in SPP was observed over the 20 years (9.414-day increase per year; p<0.001) in parallel to the increase in MST (11.253-day increase per year; p<0.001); MPFS improved little (1.863-day increase per year). Overall, a stronger association was observed between MST and SPP (r(2) = 0.8917) than MST and MPFS time (r(2) = 0.2563), suggesting SPP and MPFS could account for 89% and 25% of the variation in MST, respectively. The association between MST and SPP became closer over the years (r(2) = 0.4428, 0.7242, and 0.9081 in 1988-1994, 1995-2001, and 2002-2007, respectively). CONCLUSIONS: SPP has become more closely associated with OS, potentially because of intensive post-study treatments. Even in advanced NSCLC, a PFS advantage is unlikely to be associated with an OS advantage any longer due to this increasing impact of SPP on OS, and that the prolongation of SPP might limit the original role of OS for assessing true efficacy derived from early-line chemotherapy in future clinical trials.

DOI： 10.1371/journal.pone.0026646

異種移植モデルにおいて高用量ゲフィチニブは肝細胞成長因子(HGF)誘発性のゲフィチニブ耐性を克服する(High-dose gefitinib overcomes the gefitinib resistance induced by hepatocyte growth factor (HGF) in a xenograft model)

Early palliative care in non-small-cell lung cancer. International journal

Eiki Ichihara, Junji Matsuoka, Katsuyuki Kiura

The New England journal of medicine 363 ( 23 ) 2263; author reply 2264-5 - 2263 2010.12

Kashihara Hiromi, Ichihara Eiki, Takata Saburo, Ohashi Kadoaki, Kubo Toshio, Takeda Hiromasa, Fujii Masanori, Takigawa Nagio, Tanimoto Mitsune, Kiura Katsuyuki

日本呼吸器学会雑誌 48 ( 増刊 ) 407 - 407 2010.3

Chemopreventive effects of gefitinib on nonsmoking-related lung tumorigenesis in activating epidermal growth factor receptor transgenic mice. International journal

Kadoaki Ohashi, Nagio Takigawa, Masahiro Osawa, Eiki Ichihara, Hiromasa Takeda, Toshio Kubo, Seiki Hirano, Tadashi Yoshino, Minoru Takata, Mitsune Tanimoto, Katsuyuki Kiura

Cancer research 69 ( 17 ) 7088 - 95 2009.9

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER ASSOC CANCER RESEARCH

Twenty-five percent of all lung cancer cases are not attributable to smoking. Epidermal growth factor receptor (EGFR) mutations, which are involved in approximately 50% of nonsmoker lung cancer, are positively correlated with responsiveness to gefitinib, and inversely correlated with smoking history. Activating EGFR mutations play a critical role in the carcinogenesis of nonsmoking-related lung cancer. To investigate the chemopreventive effects of gefitinib on nonsmoking-related lung cancer, we generated transgenic mice expressing EGFR L858R in type II pneumocytes constitutively using the surfactant protein-C promoter. The transgenic mice invariably developed atypical adenomatous hyperplasia at age 4 weeks and multifocal adenocarcinoma of varying sizes at age 7 weeks. Notably, the expression levels of phosphorylated and total ErbB2, ErbB3, and thyroid transcription factor-1 were elevated in the transgenic mice compared with wild-type controls at age 3 weeks. Administration of gefitinib to 3-week-old transgenic mice for 1 week before carcinogenesis reduced the amount of phosphorylated EGFR in the lungs of the mice to the baseline level. Gefitinib (5 mg/kg/d; n = 5, 5, and 15) or vehicle (n = 5, 5, and 15) was administered to transgenic mice from age 3 to 8, 13, and 18 weeks, respectively. The numbers of lung tumors in the control and gefitinib-treated groups were 1.75, 5.8, 10.2, and 0 (P < 0.05), respectively. No fatal toxic events occurred in either group, and gefitinib inhibited tumorigenesis completely in this mouse model. These results suggest the utility of molecular targeted chemoprevention against nonsmoking-related lung cancer.

DOI： 10.1158/0008-5472.CAN-08-4205

Effects of vandetanib on lung adenocarcinoma cells harboring epidermal growth factor receptor T790M mutation in vivo. International journal

Eiki Ichihara, Kadoaki Ohashi, Nagio Takigawa, Masahiro Osawa, Atsuko Ogino, Mitsune Tanimoto, Katsuyuki Kiura

Cancer research 69 ( 12 ) 5091 - 8 2009.6

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER ASSOC CANCER RESEARCH

Vandetanib is a novel multitarget tyrosine kinase inhibitor (TKI) that inhibits vascular endothelial growth factor receptor-2 (VEGFR-2), with additional inhibition of epidermal growth factor receptor (EGFR) and rearranged during transfection receptor signaling, which has shown promising results in clinical trials for advanced non-small cell lung cancer. However, the mechanisms of acquired resistance to vandetanib remain unclear. Therefore, we established in vitro vandetanib-resistant PC-9/VanR cells from PC-9, a vandetanib-sensitive lung adenocarcinoma cell line, by chronic exposure to this agent. PC-9/VanR cells were 50-fold more resistant to vandetanib than PC-9 cells in vitro. Compared with PC-9 cells, PC-9/VanR cells showed emergence of an EGFR T790M mutation, moderately elevated MET amplification, and similar VEGFR-2 inhibition by vandetanib. Note that phospho-MET in PC-9/VanR was suppressed following EGFR inhibition by an irreversible EGFR-TKI, indicating that MET signaling of PC-9/VanR was dependent on EGFR signaling and that MET amplification was not the primary mechanism of resistance to vandetanib. In contrast to the in vitro experiment, vandetanib effectively inhibited the growth of PC-9/VanR tumors in an in vivo xenograft model through the antiangiogenesis effects of VEGFR-2 inhibition. In conclusion, the multitarget TKI vandetanib induced or selected for the EGFR T790M mutation as observed previously with highly selective EGFR-TKIs. However, vandetanib retained significant efficacy in vivo against xenografts harboring the T790M mutation, providing a strong scientific rationale for investigating vandetanib in clinical settings where acquired resistance through emergence of EGFR T790M mutations limits the effectiveness of highly selective EGFR-TKIs.

DOI： 10.1158/0008-5472.CAN-08-4204

Effects of Vandetanib on Lung Adenocarcinoma Cells Harboring Epidermal Growth Factor Receptor T790M Mutation In vivo

Eiki Ichihara, Kadoaki Ohashi, Nagio Takigawa, Masahiro Osawa, Atsuko Ogino, Mitsune Tanimoto, Katsuyuki Kiura

CANCER RESEARCH 69 ( 12 ) 5091 - 5098 2009.6

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER ASSOC CANCER RESEARCH

DOI： 10.1158/0008-5472.CAN-08-4204

Vandetanib処置後の肺腺癌細胞株のEGFR T 790M変異の出現(Emergence of The EGFR T 790 M Mutation in A Lung Adenocarcinoma Cell Line after Vandetanib Treatment)

Kubo Toshio, Ohashi Kadoaki, Osawa Masahiro, Takeda Hiromasa, Ichihara Eiki, Fujii Masanori, Kashihara Hiromi, Takigawa Nagio, Tanimoto Mitsune, Kiura Katsuyuki

日本呼吸器学会雑誌 47 ( 増刊 ) 341 - 341 2009.5

Synchronous pulmonary MALT lymphoma and pulmonary adenocarcinoma after metachronous gastric MALT lymphoma and gastric adenocarcinoma. International journal

Eiki Ichihara, Masahiro Tabata, Nagio Takigawa, Yumiko Sato, Eisaku Kondo, Motoi Aoe, Katsuyuki Kiura, Mitsune Tanimoto

Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 3 ( 11 ) 1362 - 3 2008.11

Ichihara Eiki, Ohashi Kadoaki, Takigawa Nagio, Ogino Atsuko, Tanimoto Mitsune, Kiura Katsuyuki

日本呼吸器学会雑誌 46 ( 増刊 ) 354 - 354 2008.5

Pseudoprogression of lung cancer after concomitant chemoradiotherapy. International journal

Eiki Ichihara, Katsuyuki Kiura, Nagio Takigawa, Masako Omori, Motoi Aoe, Mitsune Tanimoto, Hiroshi Date

Japanese journal of clinical oncology 38 ( 2 ) 140 - 2 2008.2

Language：English Publishing type：Research paper (scientific journal) Publisher：OXFORD UNIV PRESS

We observed re-enlargement of a squamous cell carcinoma without recurrence. The tumour regressed markedly after concomitant chemoradiotherapy, but within 1 month, we supposed that the tumour had enlarged again and resection was performed. The resected tissue showed evidence of haemorrhage and several lymphocytes and macrophages, but no malignant cells were detected. We herein report a rare case of lung cancer showing a pathological complete response despite re-enlargement of tumour lesion.

DOI： 10.1093/jjco/hym166

[Coinfection with Mycoplasma pneumoniae and Chlamydophila pneumoniae in a middle-aged adult].

Toshio Kubo, Nagio Takigawa, Yasushi Tanimoto, Eiki Ichihara, Masahiro Tabata, Nobuaki Miyahara, Arihiko Kanehiro, Katsuyuki Kiura, Mitsune Tanimoto

Nihon Kokyuki Gakkai zasshi = the journal of the Japanese Respiratory Society 45 ( 10 ) 808 - 11 2007.10

Language：Japanese Publishing type：Research paper (scientific journal)

A 47-year-old man who suffered from fever and dry cough visited a local clinic. His symptoms temporarily improved with oral administration of ciprofloxacin, however, he was admitted to our hospital because of exacerbation. IgM antibody for Mycoplasma pneumoniae was positive and IgM antibody titer for Chlamydophila pneumoniae showed a high value of 7.12 index. Thus, coinfection was diagnosed. The findings of chest X-ray and computed tomography were compatible with atypical pneumonia. Clarithromycin improved his condition, and 10 weeks later, antibody values for Mycoplasma pneumoniae by the particle agglutination test decreased from 10,240 times to 640 times and those by the complement-fixation test also decreased from 1024 times to 256 times. The IgM antibody for Chlamydophila pnetumoniae decreased to 0.13. This is the first case developing coinfection with Mycoplasma pneumoniae and Chlamydophila pneumoniae in a middle-aged patient to date.

[Azygos vein aneurysm occurring simultaneously with hemoptysis].

Eiki Ichihara, Masahiro Kaneko, Hiroshi Fujii, Kyousuke Ishihara

Nihon Kokyuki Gakkai zasshi = the journal of the Japanese Respiratory Society 45 ( 6 ) 479 - 82 2007.6

Language：Japanese Publishing type：Research paper (scientific journal)

A 64-year-old man was admitted with hemoptysis. A chest X-ray showed a well-defined round nodule at the right tracheobronchial angle. Enhanced computed tomography revealed the superior vena cava to be completely occluded while the azygos vein was also observed to have formed an aneurysm. Bronchoscopy showed the submucosal bronchial vessels at the right second carina to be markedly dilated, and thus considered them to be the likely cause of hemoptysis. Based on the above findings, we considered the following events as the most likely to have taken place: The superior vena cava was completely occluded due to the long-term placement of a pacemaker. The blood flow of head and upper limbs could not sufficiently return to the heart, but instead flowed into the azygos vein via the collateral circulation. This resulted in both the formation of the azygos vein aneurysm and an elevated venous pressure of the bronchial vein. Due to this pressure elevation, the bronchial vein and small vessels had both ruptured, thereby inducing the onset of hemoptysis.

Combination of SN-38 with gefitinib or imatinib overcomes SN-38-resistant small-cell lung cancer cells. International journal

Nagio Takigawa, Masami Takeyama, Toshiyuki Kozuki, Takuo Shibayama, Akiko Hisamoto, Katsuyuki Kiura, Atsuhiko Tada, Katsuyuki Hotta, Shigeki Umemura, Kadoaki Ohashi, Yoshiro Fujiwara, Saburo Takata, Eiki Ichihara, Masahiro Osawa, Masahiro Tabata, Mitsune Tanimoto, Kiyoshi Takahashi

Oncology reports 17 ( 5 ) 983 - 7 2007.5

Language：English Publishing type：Research paper (scientific journal) Publisher：SPANDIDOS PUBL LTD

Irinotecan is one of the effective anticancer agents for small-cell lung cancer (SCLC) and 7-ethyl-10-hydroxy-campthothecin (SN-38) is an active metabolite of irinotecan. Gefitinib and imatinib are tyrosine kinase inhibitors which have clinical activities in several malignancies and they are also potent inhibitors of breast cancer resistance protein (BCRP) transporter, which confers the resistance of topoisomerase I inhibitors including SN-38 and topotecan. The cytotoxicity of SN-38, gefitinib and imatinib for the SN-38-resistant cells (SBC-3/SN-38) from human SCLC cells, SBC-3, was evaluated using AlamarBlue assay. The drug concentration required to inhibit the growth of tumor cells by 50% (IC50) for 96-h exposure was used to evaluate the cytotoxicity. BCRP expression was determined by Western blotting and immunofluorescence staining. Intracellular topotecan accumulation was evaluated by flow cytometry. No differences were observed in the IC50 values (mean +/- SD) of the tyrosine kinase inhibitors between the SBC-3 cells and the SBC-3/SN-38 cells: 15+/-1.6 and 12+/-2.8 microM of gefitinib, respectively; 15+/-0.51 and 14+/-3.9 microM of imatinib, respectively. The SBC-3/SN-38 was 9.5-fold more resistant to SN-38 than the parental SBC-3. The SBC-3/SN-38 restored sensitivity to SN-38 when combined with 8 microM gefitinib or 8 microM imatinib, even though the IC50 values of SN-38 combined with gefitinib or imatinib in the SBC-3 cells did not change. BCRP was equally overexpressed in the SBC-3/SN-38 with and without gefitinib or imatinib. In addition, the BCRP expression on the SBC-3/SN-38 cell membrane with and without gefitinib seemed to be equal. Gefitinib increased intracellular accumulation of topotecan in the SBC-3/SN-38 cells. Gefitinib or imatinib reversed SN-38-resistance in these SCLC cells, possibly due to intracellular accumulation of SN-38 without any change in BCRP quantity. Irinotecan with gefitinib or imatinib might be effective for SCLC refractory to irinotecan.

[Characteristics of asthma patients who need repeated hospitalization; frequency of use of systemic corticosteroids, emergency and unscheduled hospital visits and habitual use of sleeping pills].

Masahiro Kaneko, Kyousuke Ishihara, Takashi Hajiro, Hiroshi Fujii, Eiki Ichihara

Arerugi = [Allergy] 56 ( 5 ) 477 - 84 2007.5

Language：Japanese Publishing type：Research paper (scientific journal)

BACKGROUND: This study aimed to analyze the characteristics of frequently hospitalized patients. METHODS: The clinical characteristics of 310 cases having hospitalization episodes (206 patients) for asthma attack analyzed retrospectively based on their clinical records. RESULTS: Nineteen out of the 206 patients were hospitalized more than just three times during the study period. Mean age (once hospitalization group 50.0+/-1.5 y.o., twice- 53.0+/-2.6 y.o., > or = 3 times- 56.6+/-2.0 y.o., p=0.02) and the ratio of female (once- 55.2%, twice- 61.5%, > or = 3 times- 78.9%, p=0.04) were higher among the groups. The frequency of use of systemic corticosteroids (once- 23.6%, twice- 50.0%, > or = 3 times- 59.8%, p<0.01), emergency and unscheduled hospital visits (once- 0.5+/-0.1 times/6M, twice- 1.3+/-0.3 times/6M, > or = 3 times- 2.7+/-0.2 times/6M, p<0.01), and habitual use of sleeping pills (once- 11.8%, twice- 30.8%, > or = 3 times- 47.4%, p<0.01) were significantly different among the groups. CONCLUSION: Among the patients who need repeated hospitalization, the frequency of use of systemic corticosteroids, emergency and unscheduled hospital visits, and habitual use of sleeping pills were higher.