Faculty Profiles - ICHIHARA Eiki

Papers - ICHIHARA Eiki

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Reappraisal of short-term low-volume hydration in cisplatin-based chemotherapy: results of a prospective feasibility study in advanced lung cancer in the Okayama Lung Cancer Study Group Trial 1002. International journal

Katsuyuki Hotta, Nagio Takigawa, Akiko Hisamoto-Sato, Eiki Ichihara, Kenichiro Kudo, Koji Uchida, Kayo Yanase-Nakamura, Hisaaki Tanaka, Yuka Kato, Masahiro Tabata, Mitsune Tanimoto, Katsuyuki Kiura

Japanese journal of clinical oncology 43 ( 11 ) 1115 - 23 2013.11

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

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: This study demonstrated prospectively the feasibility of short-term low-volume hydration.

DOI： 10.1093/jjco/hyt128

Usefulness of endobronchial ultrasound-guided transbronchial needle aspiration in distinguishing sarcoidosis from recurrent cancer in patients with lymphadenopathy after surgery. International journal

Daisuke Minami, Nagio Takigawa, Hiromi Hayakawa, Makoto Mizuta, Kenichiro Kudo, Kozi Uchida, Eiki Ichihara, Akiko Sato, Katsuyuki Hotta, Masahiro Tabata, Mitsune Tanimoto, Katsuyuki Kiura

Japanese journal of clinical oncology 43 ( 11 ) 1110 - 4 2013.11

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

OBJECTIVE: Endobronchial ultrasound-guided transbronchial needle aspiration is a new minimally invasive test for investigating mediastinal and hilar lymphadenopathy. It is sometimes difficult to distinguish between a recurrent malignant lymph node and lymphadenopathy due to sarcoidosis in patients who develop lymphadenopathy after surgery for a malignant tumor. METHODS: Between December 2009 and October 2012, we performed endobronchial ultrasound-guided transbronchial needle aspiration in 13 selected patients with a suspected recurrence in the mediastinum and/or hilum of the lung after surgical resection of a malignant tumor. We examined their medical records to obtain information on the diagnosis, the sizes of lymph nodes, the number of needle passes and other complications. RESULTS: Definitive diagnoses were made using endobronchial ultrasound-guided transbronchial needle aspiration in 10 patients (three lung adenocarcinomas, one prostate carcinoma, one renal cell carcinoma, one neuroendocrine tumor and four sarcoidosis). Pathological specimens showing non-caseating granulomas led to the diagnosis of sarcoidosis in four patients; their previous malignancies had been papillary adenocarcinoma of the thyroid, carcinoma of the gingiva, thymoma and bladder cancer, but no recurrences were observed. The median of the longest diameter in 15 lymph nodes was 22 mm (range 13-35), and the median number of needle passes was two times (range 1-5) without severe complications. CONCLUSIONS: Endobronchial ultrasound-guided transbronchial needle aspiration might be useful in differentiating between benign lymphadenopathy, including sarcoidosis, and cancer recurrence in patients with mediastinal or hilar lymphadenopathy after surgical resection of a malignant tumor.

DOI： 10.1093/jjco/hyt123

Impact of physical size on gefitinib efficacy in patients with non-small cell lung cancer harboring EGFR mutations. International journal

Eiki Ichihara, Katsuyuki Hotta, Nagio Takigawa, Kenichiro Kudo, Yuka Kato, Yoshihiro Honda, Hiromi Hayakawa, Daisuke Minami, Akiko Sato, Masahiro Tabata, Mitsune Tanimoto, Katsuyuki Kiura

Lung cancer (Amsterdam, Netherlands) 81 ( 3 ) 435 - 439 2013.9

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER IRELAND LTD

Gefitinib is an essential drug for the treatment of non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) gene mutations. The approved dosage is 250 mg/body/day without adjustment for physical size such as body surface area (BSA), and the impact of physical size on the efficacy of gefitinib has not been evaluated. Here, we sought to clarify this issue using a retrospective cohort. We reviewed the medical records of patients with consecutive advanced NSCLC harboring EGFR mutations who underwent gefitinib monotherapy at Okayama University Hospital. In total, 101 patients were included in this study, and the median BSA in this cohort was 1.5 m(2). The median progression-free survival (PFS) of the patients with higher BSA (≥1.5 m(2)) was significantly worse than that of those with lower BSA (< 1.5 m(2)) (10.4 vs. 18.0 months; p = 0.019, log-rank test). Multivariate analysis also showed a significant impact of BSA on PFS (hazards ratio, 2.34; 95% confidence interval, 1.78-2.89; p = 0.002). By contrast, no significant association between BSA and PFS was observed in those undergoing cytotoxic chemotherapy (4.0 vs. 5.1 months; p = 0.989, log-rank test), suggesting that BSA is a predictive, rather than a prognostic, marker for gefitinib therapy in EGFR-mutated NSCLC. In conclusion, BSA affected PFS in patients with EGFR-mutated NSCLC who underwent gefitinib monotherapy, suggesting the need for appraisal of BSA-based dose adjustment, even for this molecular target-based therapy.

DOI： 10.1016/j.lungcan.2013.05.021

Antitumor impact of p14ARF on gefitinib-resistant non-small cell lung cancers. International journal

Ken Saito, Nagio Takigawa, Naoko Ohtani, Hidekazu Iioka, Yuki Tomita, Ryuzo Ueda, Junya Fukuoka, Kazuhiko Kuwahara, Eiki Ichihara, Katsuyuki Kiura, Eisaku Kondo

Molecular cancer therapeutics 12 ( 8 ) 1616 - 28 2013.8

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

Activation of the epidermal growth factor receptor (EGFR) has been observed in many malignant tumors and its constitutive signal transduction facilitates the proliferation of tumors. EGFR-tyrosine kinase inhibitors, such as gefitinib, are widely used as a molecular-targeting agent for the inactivation of EGFR signaling and show considerable therapeutic effect in non-small cell lung cancers harboring activating EGFR mutations. However, prolonged treatment inevitably produces tumors with additional gefitinib-resistant mutations in EGFR, which is a critical issue for current therapeutics. We aimed to characterize the distinct molecular response to gefitinib between the drug-resistant and drug-sensitive lung adenocarcinoma cells in order to learn about therapeutics based on the molecular information. From the quantitative PCR analysis, we found a specific increase in p14(ARF) expression in gefitinib-sensitive lung adenocarcinoma clones, which was absent in gefitinib-resistant clones. Moreover, mitochondria-targeted p14(ARF) triggered the most augmented apoptosis in both clones. We identified the amino acid residues spanning from 38 to 65 as a functional core of mitochondrial p14(ARF) (p14 38-65 a.a.), which reduced the mitochondrial membrane potential and caused caspase-9 activation. The synthesized peptide covering the p14 38-65 a.a. induced growth suppression of the gefitinib-resistant clones without affecting nonneoplastic cells. Notably, transduction of the minimized dose of the p14 38-65 peptide restored the response to gefitinib like that in the sensitive clones. These findings suggest that the region of p14(ARF) 38-65 a.a. is critical in the pharmacologic action of gefitinib against EGFR-mutated lung adenocarcinoma cells and has potential utility in the therapeutics of gefitinib-resistant cancers.

DOI： 10.1158/1535-7163.MCT-12-1239

Acquired resistance to EGFR inhibitors is associated with a manifestation of stem cell-like properties in cancer cells. International journal

Kazuhiko Shien, Shinichi Toyooka, Hiromasa Yamamoto, Junichi Soh, Masaru Jida, Kelsie L Thu, Shinsuke Hashida, Yuho Maki, Eiki Ichihara, Hiroaki Asano, Kazunori Tsukuda, Nagio Takigawa, Katsuyuki Kiura, Adi F Gazdar, Wan L Lam, Shinichiro Miyoshi

Cancer research 73 ( 10 ) 3051 - 61 2013.5

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

Acquired resistance to EGF receptor (EGFR) tyrosine kinase inhibitor (TKI) is a critical problem in the treatment of lung cancer. Although several mechanisms have been shown to be responsible for acquired resistance, all mechanisms have not been uncovered. In this study, we investigated the molecular and cellular profiles of the acquired resistant cells to EGFR-TKI in EGFR-mutant lung cancers. Four EGFR-mutant cell lines were exposed to gefitinib by stepwise escalation and high-concentration exposure methods, and resistant sublines to gefitinib were established. The molecular profiles and cellular phenotypes of these resistant sublines were characterized. Although previously reported, alterations including secondary EGFR T790M mutation, MET amplification, and appearance of epithelial-to-mesenchymal transition (EMT) features were observed, these 2 drug-exposure methods revealed different resistance mechanisms. The resistant cells with EMT features exhibited downregulation of miRNA-200c by DNA methylation. Furthermore, the HCC827-derived subline characterized by the high-concentration exposure method exhibited not only EMT features but also stem cell-like properties, including aldehyde dehydrogenase isoform 1 (ALDH1A1) overexpression, increase of side-population, and self-renewal capability. Resistant sublines with stem cell-like properties were resistant to conventional chemotherapeutic agents but equally sensitive to histone deacetylase and proteasome inhibitors, compared with their parental cells. ALDH1A1 was upregulated in clinical samples with acquired resistance to gefitinib. In conclusion, our study indicates that the manner of EGFR-TKI exposure influences the mechanism of acquired resistance and the appearance of stem cell-like property with EGFR-TKI treatment.

DOI： 10.1158/0008-5472.CAN-12-4136

Afatinib prolongs survival compared with gefitinib in an epidermal growth factor receptor-driven lung cancer model. International journal

Takashi Ninomiya, Nagio Takigawa, Eiki Ichihara, Nobuaki Ochi, Toshi Murakami, Yoshihiro Honda, Toshio Kubo, Daisuke Minami, Kenichiro Kudo, Mitsune Tanimoto, Katsuyuki Kiura

Molecular cancer therapeutics 12 ( 5 ) 589 - 97 2013.5

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

An irreversible ErbB family blocker is expected to inhibit tumors with activating epidermal growth factor receptor (EGFR) mutations more strongly than reversible EGFR tyrosine kinase inhibitors and to overcome acquired resistance to the T790M secondary mutation. Eleven-week-old transgenic mice with Egfr exon 19 deletion mutation were treated with afatinib, gefitinib, or vehicle for 4 weeks. All mice were sacrificed at 15 weeks of age, and the number of superficial left lung tumors with a long axis exceeding 1 mm was counted. The afatinib-treated group had significantly fewer tumors than the vehicle group (P < 0.01) and tended to have fewer tumors than the gefitinib-treated group (P = 0.06). Pathologically, gefitinib-treated mice had clearer, more nodular tumors than afatinib-treated mice. Immunoblotting showed that afatinib suppressed not only pEGFR but also pHER2, and induced apoptosis for longer periods than gefitinib. Subsequently, when each drug was administered 5 days per week until death, afatinib significantly enhanced mouse survival compared with gefitinib (median survival time: 456 days vs. 376.5 days; log-rank test, P < 0.01). Finally, the combination of afatinib with bevacizumab was found to be superior to either drug alone in exon 19 deletion/T790M and L858R/T790M xenograft tumors. Overall, afatinib was more potent than gefitinib in tumors harboring an exon 19 deletion mutation, and the combination of afatinib with bevacizumab efficiently suppressed tumors harboring the T790M secondary mutation.

DOI： 10.1158/1535-7163.MCT-12-0885

Vandetanib is effective in EGFR-mutant lung cancer cells with PTEN deficiency. International journal

Hiromasa Takeda, Nagio Takigawa, Kadoaki Ohashi, Daisuke Minami, Itaru Kataoka, Eiki Ichihara, Nobuaki Ochi, Mitsune Tanimoto, Katsuyuki Kiura

Experimental cell research 319 ( 4 ) 417 - 23 2013.2

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER INC

The effectiveness of vandetanib, an agent that targets RET, VEGFR and EGFR signaling, against EGFR-mutant lung cancer cells with PTEN loss was investigated. Two EGFR mutant non-small cell lung cancer (NSCLC) cell lines, PC-9 (PTEN wild type) and NCI-H1650 (PTEN null), were used. We transfected an intact PTEN gene into H1650 cells and knocked down PTEN expression in PC-9 cells using shRNA. The effectiveness of gefitinib and vandetanib was assessed using a xenograft model. While PC-9 cells were more resistant to vandetanib than gefitinib, H1650 cells were more sensitive to vandetanib than gefitinib. Both gefitinib and vandetanib suppressed the activation of EGFR and MAPK in H1650 cells, although phosphorylated AKT levels were not affected. In an H1650 cell xenograft model, vandetanib was also more effective than gefitinib. Although PTEN-transfected H1650 cells did not show restoration of sensitivity to gefitinib in vitro, the xenograft tumors responded to gefitinib and vandetanib. Knockdown of PTEN in PC-9 cells caused resistance to gefitinib. In conclusion, vandetanib might be effective in NSCLC with EGFR mutations that lack PTEN expression. The contribution of PTEN absence to vandetanib activity in NSCLC cells harboring EGFR mutations should be further examined.

DOI： 10.1016/j.yexcr.2012.12.018

Synergistic effect of olaparib with combination of cisplatin on PTEN-deficient lung cancer cells. International journal

Daisuke Minami, Nagio Takigawa, Hiromasa Takeda, Minoru Takata, Nobuaki Ochi, Eiki Ichihara, Akiko Hisamoto, Katsuyuki Hotta, Mitsune Tanimoto, Katsuyuki Kiura

Molecular cancer research : MCR 11 ( 2 ) 140 - 8 2013.2

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

PARP enzyme plays a key role in the cellular machinery responsible for DNA damage repair. PTEN is a tumor-suppressor gene deactivating PI3K downstream of EGFR signaling. We hypothesize that PTEN-deficient lung cancer cells suppressed DNA damage signaling and that the absence of PTEN can sensitize these cells to a concurrent treatment of a DNA-damaging agent (cisplatin) and a PARP inhibitor (olaparib). To investigate the effect of olaparib and cisplatin on PTEN-deficient lung tumors, two EGFR-mutant (deletion in exon19) non-small cell lung cancer (NSCLC) cell lines, PC-9 (PTEN wild-type) and H1650 (PTEN loss), were used. We transfected intact PTEN gene into H1650 cells (H1650(PTEN+)) and knocked down PTEN expression in the PC-9 cells (PC-9(PTEN-)) using short hairpin RNA (shRNA). Combination of cisplatin with olaparib showed a synergistic effect in vitro according to the combination index in H1650 cells. Restoration of PTEN in the H1650 cells decreased sensitivity to the combination. Ablation of PTEN in PC-9 cells increased sensitivity to olaparib and cisplatin. We also examined the effectiveness of cisplatin and olaparib in a xenograft model using H1650 and PC-9(PTEN-) cells. The combination of cisplatin with olaparib was more effective than each agent individually. This effect was not observed in a xenograft model using H1650(PTEN+) and PC-9 cells. Mechanistic investigations revealed that PTEN deficiency caused reductions in nuclear RAD51 and RPA focus formation and phosphorylated Chk1 and Mre11. Thus, genetic inactivation of PTEN led to the suppression of DNA repair.

DOI： 10.1158/1541-7786.MCR-12-0401

Progression-free survival and overall survival in phase III trials of molecular-targeted agents in advanced non-small-cell lung cancer. International journal

Katsuyuki Hotta, Etsuji Suzuki, Massimo Di Maio, Paolo Chiodini, Yoshiro Fujiwara, Nagio Takigawa, Eiki Ichihara, Martin Reck, Christian Manegold, Lothar Pilz, Akiko Hisamoto-Sato, Masahiro Tabata, Mitsune Tanimoto, Frances A Shepherd, Katsuyuki Kiura

Lung cancer (Amsterdam, Netherlands) 79 ( 1 ) 20 - 6 2013.1

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER IRELAND LTD

BACKGROUND: We examined how crossover therapy might affect the association between progression-free survival (PFS) and overall survival (OS) in non-small cell lung cancer (NSCLC). METHODS: We extracted PFS- and OS-hazard ratios (HRs) in phase III trials of molecular-targeted agents for advanced NSCLC. Their relationship was modeled in a linear function with the coefficient of determination (R-squared) to assess the correlation between PFS and OS. RESULTS: Thirty-four trials with 35 pairs for the investigational and reference arms were identified (24,158 patients). Overall, there was little correlation between PFS- and OS-HRs (R-squared = 0.14), suggesting PFS-HR could account only for 14% of variation in OS-HR. The median proportion of crossover therapy per trial was 20%. If patients seldom crossed over (none or <1%), the association between PFS- and OS-HRs was strong (R-squared = 0.69). When the proportion of crossover was ≥1%, however, R-squared declined considerably (≥1% to <20% crossover, R-squared = 0.27; ≥20% to <40%, R-squared = 0.06; and ≥40%, R-squared = 0.27). CONCLUSIONS: A PFS advantage seldom is associated with an OS advantage any longer. Our analysis suggests this is due to a high level of crossover now that an increasing number of active agents are available for NSCLC.

DOI： 10.1016/j.lungcan.2012.10.007

Subpopulation of small-cell lung cancer cells expressing CD133 and CD87 show resistance to chemotherapy. International journal

Toshio Kubo, Nagio Takigawa, Masahiro Osawa, Daijiro Harada, Takashi Ninomiya, Nobuaki Ochi, Eiki Ichihara, Hiromichi Yamane, Mitsune Tanimoto, Katsuyuki Kiura

Cancer science 104 ( 1 ) 78 - 84 2013.1

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY

Tumors are presumed to contain a small population of cancer stem cells (CSCs) that initiate tumor growth and promote tumor spreading. Multidrug resistance in CSCs is thought to allow the tumor to evade conventional therapy. This study focused on expression of CD133 and CD87 because CD133 is a putative marker of CSCs in some cancers including lung, and CD87 is associated with a stem-cell-like property in small-cell lung cancer (SCLC). Six SCLC cell lines were used. The expression levels of CD133 and CD87 were analyzed by real-time quantitative reverse transcription-polymerase chain reaction and flow cytometry. CD133+/- and CD87+/- cells were isolated by flow cytometry. The drug sensitivities were determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Non-obese diabetic/severe combined immunodeficiency mice were used for the tumor formation assay. SBC-7 cells showed the highest expression levels of both CD133 and CD87 among the cell lines. CD133-/CD87-, CD133+/CD87-, and CD133-/CD87+ cells were isolated from SBC-7 cells; however, CD133+/CD87+ cells could not be obtained. Both CD133+/CD87- and CD133-/CD87+ subpopulations showed a higher resistance to etoposide and paclitaxel and greater re-populating ability than the CD133-/CD87- subpopulation. CD133+/CD87- cells contained more G0 quiescent cells than CD133-/CD87- cells. By contrast, CD133-/CD87- cells showed the highest tumorigenic potential. In conclusion, both CD133 and CD87 proved to be inadequate markers for CSCs; however, they might be beneficial for predicting resistance to chemotherapy.

DOI： 10.1111/cas.12045

A definite case of (L)-carbocisteine-induced pneumonia with CATCH22 syndrome.

Kenichiro Kudo, Eiki Ichihara, Akiko Hisamoto, Katsuyuki Hotta, Nobuaki Miyahara, Yasushi Tanimoto, Sadaharu Akagi, Katsuya Kato, Mitsune Tanimoto, Katsuyuki Kiura

Internal medicine (Tokyo, Japan) 52 ( 1 ) 97 - 100 2013

Language：English Publishing type：Research paper (scientific journal) Publisher：JAPAN SOC INTERNAL MEDICINE

A 32-year-old male with CATCH22 syndrome presented with a high fever and productive cough after taking drugs for acute bronchitis, including (L)-carbocisteine. Chest radiography revealed ground-glass opacities in the bilateral lung fields. He had a history of similar pneumonia. Under the assumption of drug-induced pneumonia, or bacterial or viral pneumonia, all drugs including (L)-carbocisteine were discontinued, and antibiotics were started. A drug-induced lymphocyte stimulation test was positive only for (L)-carbocisteine. The only drug in common between this and the previous episode of pneumonia was (L)-carbocisteine. We thus concluded that this was a definite case of (L)-carbocisteine-induced pneumonia in a patient with CATCH22 syndrome.

DOI： 10.2169/internalmedicine.52.7882

Influence of the timing of tumor regression after the initiation of chemoradiotherapy on prognosis in patients with limited-disease small-cell lung cancer achieving objective response. International journal

Masanori Fujii, Katsuyuki Hotta, Nagio Takigawa, Akiko Hisamoto, Eiki Ichihara, Masahiro Tabata, Mitsune Tanimoto, Katsuyuki Kiura

Lung cancer (Amsterdam, Netherlands) 78 ( 1 ) 107 - 11 2012.10

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER IRELAND LTD

PURPOSE: Chemoradiotherapy (CHRT) yields a favorable antitumor activity in patients with limited-stage small-cell lung cancer (LD-SCLC) with a response rate of around 80%. Even in such responders, the majority recur, indicating the importance of identifying a subset of patients with a poor outcome earlier through the treatment. We investigated whether the timing of obtaining tumor regression with the CHRT could affect the prognosis in LD-SCLC patients who finally achieved the objective response through the treatment. PATIENTS AND METHODS: We retrospectively reviewed medical charts of 70 LD-SCLC patients who obtained complete response (CR) or partial response (PR) with the 3 or 4 cycles of first-line CHRT between 1988 and 2006. RESULTS: In the whole 70 patients with CR/PR, the median survival time and median progression free survival (PFS) were 39.6 and 12.3months, respectively. Fifty-two (74.3%) of the 70 patients entered CR/PR after the first cycle of CHRT, and their 2-year survival rates were significantly longer than that in the remaining 18 patients without entering CR/PR yet at the end of first cycle (72.3% and 7.1%, respectively, p<0.001). Cox regression analysis showed that the early response to the treatment was a significant prognostic factors (hazard ratio=0.098; 95% confidence interval=0.036-0.269). Regarding PFS, similar findings were observed. CONCLUSIONS: Patients without entering CR/PR yet after the first course had a poorer outcome even though the objective response was finally confirmed through the treatment. Development of more effective treatments for these high-risk patients is warranted to improve their poor prognosis.

DOI： 10.1016/j.lungcan.2012.07.001

JAK2-related pathway induces acquired erlotinib resistance in lung cancer cells harboring an epidermal growth factor receptor-activating mutation. International journal

Daijiro Harada, Nagio Takigawa, Nobuaki Ochi, Takashi Ninomiya, Masayuki Yasugi, Toshio Kubo, Hiromasa Takeda, Eiki Ichihara, Kadoaki Ohashi, Saburo Takata, Mitsune Tanimoto, Katsuyuki Kiura

Cancer science 103 ( 10 ) 1795 - 802 2012.10

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors, such as gefitinib and erlotinib, are effective for non-small cell lung cancer with activating EGFR mutations. However, even in patients with an initial dramatic response to such a drug, acquired resistance develops after 6-12 months. A secondary mutation of T790M in EGFR and amplification of the MET gene account for this resistance; however, the mechanism(s) of approximately 30% of acquired resistance cases remain unknown. We established an erlotinib-resistant lung cancer cell line named PC-9/ER3 that harbors an EGFR mutation after continuously exposing PC-9 cells to erlotinib. PC-9/ER3 cells were 136-fold more resistant to erlotinib than the parental cells. Although the PC-9/ER3 cells did not carry the T790M mutation or MET amplification and had similar levels of phosphorylated (p) STAT3, pJAK2 increased in the resistant cells. It was found in the present study that 3-12 h of exposure to erlotinib in both cell lines did not affect pJAK2 expression, but did result in increased pSTAT3 expression. pAkt in PC-9/ER3 cells was less suppressed than in PC-9 cells, although pEGFR and pMAPK were markedly suppressed in both cell lines. The combined treatment of erlotinib plus a JAK2 inhibitor (JSI-124) suppressed pAkt in PC-9/ER3 cells. Similarly, the combination of erlotinib plus JSI-124 or siRNA against JAK2 restored sensitivity to erlotinib in PC-9/ER3 cells. The combination of erlotinib plus JSI-124 was also effective for reducing PC-9/ER3 tumors in a murine xenograft model. Our results suggest that the activation of JAK2 partially accounts for acquired erlotinib resistance.

DOI： 10.1111/j.1349-7006.2012.02363.x

Phase II study of irinotecan and amrubicin in patients with relapsed non-small cell lung cancer: Okayama Lung Cancer Study Group Trial 0402. International journal

Naoyuki Nogami, Katsuyuki Hotta, Yoshihiko Segawa, Nagio Takigawa, Shinobu Hosokawa, Isao Oze, Masanori Fujii, Eiki Ichihara, Takuo Shibayama, Atsuhiko Tada, Noboru Hamada, Masatoshi Uno, Akihiko Tamaoki, Shoichi Kuyama, Genyo Ikeda, Masahiro Osawa, Saburo Takata, Masahiro Tabata, Mitsune Tanimoto, Katsuyuki Kiura

Acta oncologica (Stockholm, Sweden) 51 ( 6 ) 768 - 73 2012.7

Language：English Publishing type：Research paper (scientific journal) Publisher：TAYLOR & FRANCIS LTD

BACKGROUND: The survival advantage achieved by existing anti-cancer agents as second-line therapy for relapsed non-small cell lung cancer (NSCLC) is modest and further improvement of treatment outcome is desired. Combination chemotherapy with irinotecan and amrubicin for advanced NSCLC has not been fully evaluated. METHODS: The primary endpoint of this phase II clinical trial was objective response. Patients with NSCLC who had been treated previously with one or two chemotherapy agents were enrolled. Irinotecan and amrubicin were both administered on Days 1 and 8 of a 21-day cycle, at doses of 100 mg/m(2) and 40 mg/m(2), respectively. RESULTS: Between 2004 and 2006, 31 patients received a total of 101 courses; the median number of courses administered was three (range, one to six). Objective response was obtained in nine of the 31 patients (29.0% response rate; 95% confidence interval (CI), 12.1-46.0%). With a median follow-up time of 43.9 months, median survival time and the median progression-free survival time were 14.2 and 4.0 months, respectively. Myelosuppression was the most frequently observed adverse event, with grade 3/4 neutropenia in 51% of patients. Febrile neutropenia developed after nine courses (9%) and resulted in one treatment-related death. Cardiac toxicity and diarrhea, possibly specific for both agents, were infrequent and manageable. CONCLUSION: Combination chemotherapy with irinotecan and amrubicin is effective in patients with NSCLC but showed moderate toxicities in second- or third-line settings.

DOI： 10.3109/0284186X.2011.648342

[Case report: Two cases of adult Langerhans cell histiocytosis treated with systemic chemotherapy].

Kenichiro Kudo, Eiki Ichihara, Akiko Hisamoto, Katsuyuki Hotta, Koichi Ichimura, Yasushi Tanimoto, Masahiro Tabata, Nagio Takigawa, Mitsune Tanimoto, Katsuyuki Kiura

Nihon Naika Gakkai zasshi. The Journal of the Japanese Society of Internal Medicine 101 ( 5 ) 1386 - 8 2012.5

Treatment-related death in patients with small-cell lung cancer in phase III trials over the last two decades. International journal

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

PloS one 7 ( 8 ) e42798 2012

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

INTRODUCTION: Treatment-related death (TRD) remains a serious problem in small-cell lung cancer (SCLC), despite recent improvements in supportive care. However, few studies have formally assessed time trends in the proportion of TRD over the past two decades. The aim of this study was to determine the frequency and pattern of TRD over time. METHODS: We examined phase 3 trials conducted between 1990 and 2010 to address the role of systemic treatment for SCLC. The time trend was assessed using linear regression analysis. RESULTS: In total, 97 trials including nearly 25,000 enrolled patients were analyzed. The overall TRD proportion was 2.95%. Regarding the time trend, while it was not statistically significant, it tended to decrease, with a 0.138% decrease per year and 2.76% decrease per two decades. The most common cause of death was febrile neutropenia without any significant time trend in its incidence over the years examined (p = 0.139). However, deaths due to febrile neutropenia as well as all causes in patients treated with non-platinum chemotherapy increased significantly (p = 0.033). CONCLUSIONS: The overall TRD rate has been low, but not negligible, in phase III trials for SCLC over the past two decades.

DOI： 10.1371/journal.pone.0042798

Favorable response of heavily treated Wilms' tumor to paclitaxel and carboplatin. International journal

Saeko Ozaki, Nagio Takigawa, Eiki Ichihara, Katsuyuki Hotta, Isao Oze, Etsuko Kurimoto, Soichiro Fushimi, Tetsuya Ogino, Masahiro Tabata, Mitsune Tanimoto, Katsuyuki Kiura

Onkologie 35 ( 5 ) 283 - 6 2012

Language：English Publishing type：Research paper (scientific journal) Publisher：KARGER

BACKGROUND: Heavily treated Wilms' tumor responding to the combination of paclitaxel and carboplatin has not yet been reported. CASE REPORT: A 17-year-old man presented with hematuria. He received a diagnosis of Wilms' tumor with multiple lung metastases and was treated with preoperative chemotherapy including vincristine, dactinomycin, and doxorubicin, a right nephrectomy, and adjuvant chemotherapy, followed by pulmonary metastasectomy. During the next 8 years, he suffered from 4 relapses and has been treated with multiple anticancer agents including high-dose chemotherapy with autologous peripheral blood stem cell transplantation. Finally, the disease progressed due to peritoneal and pleural metastases. With opioid administration for left shoulder pain due to pleural metastasis, he received combination chemotherapy with carboplatin (area under the curve = 4) and paclitaxel (175 mg/m(2)) on day 1. After 2 cycles, he achieved a partial response with mild toxicity. He received 7 cycles of the chemotherapy and the time to progression was 200 days. CONCLUSION: In a refractory case after intensive treatments, we succeeded to control the disease for a while.

DOI： 10.1159/000338532

W2-2 気管内チューブを用いたEBUS-TBNAの使用経験(EBUS-TBNA,ワークショップ2,第35回日本呼吸器内視鏡学会学術集会)

南大輔, 瀧川奈義夫, 村上斗司, 谷口暁彦, 市原英基, 久本晃子, 堀田勝幸, 宮原信明, 谷本安, 田端雅彦, 金廣有彦, 谷本光音, 木浦勝行

気管支学 34 S123 2012

Targeting angiogenesis in cancer therapy.

Eiki Ichihara, Katsuyuki Kiura, Mitsune Tanimoto

Acta medica Okayama 65 ( 6 ) 353 - 62 2011.12

Language：English Publishing type：Research paper (scientific journal) Publisher：OKAYAMA UNIV MED SCHOOL

Angiogenesis is an essential process in tumor growth. The concept of angiogenesis, when proposed by Folksman in 1971, had a great impact on cancer research and therapy, as the survival and proliferation of cancer depend on angiogenesis, which could be a target of cancer therapy. In subsequent decades, numerous antiangiogenic agents were developed, and some of them have been applied clinically. However, angiogenesis includes a complex and multistep process that has not been sufficiently elucidated. In this review, we focus on signaling pathways related with tumor angiogenesis and several antiangiogenic agents approved by the United States Food and Drug Administration or under investigation.

Establishment of pemetrexed-resistant non-small cell lung cancer cell lines. International journal

Dan Zhang, Nobuaki Ochi, Nagio Takigawa, Yasushi Tanimoto, Yanyan Chen, Eiki Ichihara, Katsuyuki Hotta, Masahiro Tabata, Mitsune Tanimoto, Katsuyuki Kiura

Cancer letters 309 ( 2 ) 228 - 35 2011.10

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER IRELAND LTD

Pemetrexed (PEM), a multitargeted antifolate with manageable toxicity, is active against non-squamous non-small cell lung cancer; however, most patients eventually acquire resistance to PEM. To elucidate the resistant mechanism, we established PEM-resistant lung adenocarcinoma cell lines. Two parental cell lines, PC-9 and A549, were treated with step-wise increasing concentrations of PEM. Growth inhibition was determined by the 3-[4,5-dimethyl-thizol-2-yl]-2,5-diphenyltetrazolium bromide assay. Expression of the genes encoding thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT) was analyzed by quantitative real-time reverse transcriptase polymerase chain reaction. The four PC-9 sublines were more resistant than the PC-9 cell line to PEM (2.2-, 2.9-, 8.4-, and 14.3-fold, respectively). The four A549 sublines also showed more resistance to PEM (7.8-, 9.6-, 42.3-, and 42.4-fold, respectively) than the parent cell line. All resistant sublines showed cross-resistance to cisplatin, but not to docetaxel, vinorelbine, 5-fluorouracil, or the active metabolite of irinotecan, SN-38. All PEM-resistant sublines expressed more TS than the parental cells, by polymerase chain reaction and Western blotting. DHFR was significantly increased in the four PEM-resistant A549 sublines. GARFT did not correlate with resistance to PEM. In summary, PEM-resistant cells remained sensitive to docetaxel, vinorelbine, 5-fluorouracil, and irinotecan. TS expression appeared to be associated with resistance to PEM.

DOI： 10.1016/j.canlet.2011.06.006

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