Faculty Profiles - HOTTA Katsuyuki

活性化型の上皮増殖因子受容体(EGFR)変異を有する肺がん細胞における低用量アファチニブとセツキシマブの併用療法に対するベバシズマブの効果(The impact of bevacizumab on combination low-dose afatinib and cetuximab therapy in lung cancer cells harboring activated EGFR mutations)

Reappraisal of short-term low-volume hydration in cisplatin-based chemotherapy; hoping for it as a public domain. International journal

Katsuyuki Hotta, Kiichiro Ninomiya, Nagio Takigawa, Mitsune Tanimoto, Katsuyuki Kiura

Japanese journal of clinical oncology 45 ( 6 ) 603 - 4 2015.6

Kudo Kenichiro, Ohashi Kadoaki, Ichihara Eiki, Kubo Hisao, Minami Daisuke, Hisamoto Akiko, Hotta Katsuyuki, Tanimoto Mitsune, Kiura Katsuyuki

日本呼吸器学会誌 4 ( 増刊 ) 348 - 348 2015.3

A phase II study of cisplatin plus S-1 with concurrent thoracic radiotherapy for locally advanced non-small-cell lung cancer: the Okayama Lung Cancer Study Group Trial 0501. International journal

Naoyuki Nogami, Nagio Takigawa, Katsuyuki Hotta, Yoshihiko Segawa, Yuka Kato, Toshiyuki Kozuki, Isao Oze, Daizo Kishino, Keisuke Aoe, Hiroshi Ueoka, Shoichi Kuyama, Shingo Harita, Toshiaki Okada, Shinobu Hosokawa, Koji Inoue, Kenichi Gemba, Takuo Shibayama, Masahiro Tabata, Mitsuhiro Takemoto, Susumu Kanazawa, Mitsune Tanimoto, Katsuyuki Kiura

Lung cancer (Amsterdam, Netherlands) 87 ( 2 ) 141 - 7 2015.2

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

BACKGROUND: 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 (40mg/m(2) on days 1, 8, 29 and 36) and S-1 (80mg/m(2) on days 1-14 and 29-42) and TRT (60Gy). The primary endpoint was the response rate. RESULTS: A 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.

DOI： 10.1016/j.lungcan.2014.11.001

Publication of Lung Cancer Clinical Trials in Japan

Ochi Nobuaki, Honda Yoshihiro, Yamane Hiromichi, Umemura Shigeki, Hotta Katsuyuki, Tanimoto Mitsune, Kiura Katsuyuki, Takigawa Nagio

Haigan 55 ( 7 ) 1070 - 1074 2015

Language：Japanese Publisher：The Japan Lung Cancer Society

Objective. The University Hospital Medical Information Network (UMIN)-Clinical Trials Registry (CTR) is a unique web-based registry of clinical trials in Japan. Clinical trials must be registered to a public database when submitting to medical journals. We evaluated the current status of the publication of Japanese lung cancer clinical trials using the UMIN-CTR. Methods. We searched for trials that had been registered to the UMIN-CTR before October 2005 to identify publications associated with the trial results in the UMIN-CTR database. Forty-eight trials concerning lung cancer treatment were found. A final search for publications was performed using the PubMed and UMIN-CTR databases on December 2014. Results. Thirty-one (64.6%) trials were published. Among them, 16 showed positive results concerning primary endpoints and 15 had negative ones. There was no significant difference in publication rates according to the number of participants (≥100 and <100). The studies in which a planned final analysis date in the UMIN-CTR was described by an investigator were significantly more frequently published than those without this description (84.2% vs 51.4%, p=0.021). Conclusion. Approximately two-thirds of trials including negative trials have been published. The UMIN-CTR serves a function as the Japanese clinical trial registry.

DOI： 10.2482/haigan.55.1070

CiNii Article

Other Link： http://search.jamas.or.jp/link/ui/2016209040

Factor associated with failure to administer subsequent treatment after progression in the first-line chemotherapy in EGFR-mutant non-small cell lung cancer: Okayama Lung Cancer Study Group experience. International journal

Yuka Kato, Katsuyuki Hotta, Nagio Takigawa, Naoyuki Nogami, Toshiyuki Kozuki, Akiko Sato, Eiki Ichihara, Kenichiro Kudo, Isao Oze, Masahiro Tabata, Tetsu Shinkai, Mitsune Tanimoto, Katsuyuki Kiura

Cancer chemotherapy and pharmacology 73 ( 5 ) 943 - 50 2014.5

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

PURPOSE: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.

DOI： 10.1007/s00280-014-2425-9

Src mediates ERK reactivation in gefitinib resistance in non-small cell lung cancer. International journal

Nobuaki Ochi, Nagio Takigawa, Daijiro Harada, Masayuki Yasugi, Eiki Ichihara, Katsuyuki Hotta, Masahiro Tabata, Mitsune Tanimoto, Katsuyuki Kiura

Experimental cell research 322 ( 1 ) 168 - 77 2014.3

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

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.

DOI： 10.1016/j.yexcr.2014.01.007

肺癌診断におけるガイドシース併用気管支腔内超音波断層法の導入効果

南大輔, 瀧川奈義夫, 二宮貴一朗, 森近大介, 後藤田裕子, 萱谷紘枝, 田村朋季, 久保寿夫, 佐藤晃子, 堀田勝幸, 宮原信明, 金廣有彦, 田端雅弘, 谷本光音, 木浦勝行

気管支学 36 ( Suppl. ) S149 - S149 2014.3

超音波気管支鏡ガイド下針生検(EBUS-TBNA)におけるBIOEVALUATORを使用した迅速細胞診断の有用性

南大輔, 瀧川奈義夫, 森近大介, 二宮貴一朗, 後藤田裕子, 萱谷紘江, 田村朋季, 久保寿夫, 佐藤晃子, 堀田勝幸, 宮原信明, 金廣有彦, 田端雅弘, 谷本光音, 木浦勝行

気管支学 36 ( 2 ) 205 - 205 2014.3

気管支鏡検査で診断し外科的切除を行った肺原発悪性黒色腫の1例

萱谷紘枝, 南大輔, 渡邉元嗣, 山本寛斉, 宗淳一, 久保寿夫, 堀田勝幸, 田端雅弘, 豊岡伸一, 三好新一郎, 谷本光音, 木浦勝行

気管支学 36 ( 2 ) 208 - 208 2014.3

Src mediates ERK reactivation in gefitinib resistance in non-small cell lung cancer Reviewed

Nobuaki Ochi, Nagio Takigawa, Daijiro Harada, Masayuki Yasugi, Eiki Ichihara, Katsuyuki Hotta, Masahiro Tabata, Mitsune Tanimoto, Katsuyuki Kiura

Experimental cell research 322 ( 1 ) 168 - 177 2014.3

Publishing type：Research paper (scientific journal) Publisher：Elsevier

DOI： 10.1016/j.yexcr.2014.01.007

肺腺癌に合併し診断に苦慮した続発性クリプトコッカス症の2例

森近大介, 南大輔, 二宮貴一郎, 入江真大, 葉山牧夫, 山本寛斎, 堀田勝幸, 宮原信明, 田端雅弘, 三好新一郎, 谷本光音, 木浦勝行

気管支学 36 ( 2 ) 210 - 210 2014.3

Invasive Mucinous Adenocarcinoma Mimicking Organizing Pneumonia Associated with Mycobacterium fortuitum Infection Reviewed

Daisuke Morichika, Nobuaki Miyahara, Katsuyuki Hotta, Yoshiko Okamoto, Daisuke Minami, Masahiro Irie, Yasushi Tanimoto, Arihiko Kanehiro, Mitsune Tanimoto, Katsuyuki Kiura

INTERNAL MEDICINE 53 ( 24 ) 2795 - 2799 2014

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

We herein report the case of a 68-year-old man diagnosed with invasive mucinous adenocarcinoma of the lungs. Chest computed tomography showed subpleural ground-glass opacity and small nodules with cavitation. A culture of the bronchoalveolar lavage fluid resulted in the detection of Mycobacterium fortuitum. The patient's lung consolidation rapidly progressed; however, repeated bronchoscopy showed no atypical cells, thus suggesting a diagnosis of organizing pneumonia associated with M. fortuitum infection. However, the surgical biopsy specimen was diagnostic for adenocarcinoma, with no mycobacterial infection. Invasive mucinous adenocarcinoma should not be excluded in the differential diagnosis of patients with clinical features of organizing pneumonia and nontuberculous mycobacterium infection, even if a transbronchial biopsy confirms the absence of malignancy.

DOI： 10.2169/internalmedicine.53.2783

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

Synergistic effect of olaparib with combination of cisplatin on PTEN-deficient lung cancer cells Reviewed

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

Molecular Cancer Research 11 ( 2 ) 140 - 148 2013.2

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

PARP enzyme plays a key role in the cellular machinery responsible for DNA damage repair. PTEN is a tumorsuppressor gene deactivating PI3K downstreamofEGFR signaling.Wehypothesize 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 aDNA-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 (PTENwild-type) and H1650 (PTEN loss), were used. We transfected intact PTEN gene into H1650 cells (H1650PTEN+) and knocked down PTEN expression in the PC-9 cells (PC-9PTEN-) 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-9PTEN- cells. The combination of cisplatin with olaparib was more effective than each agent individually. This effect was not observed in a xenograft model using H1650PTEN+ 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. Mol Cancer Res
11(2)
140-8. © 2012 AACR.

DOI： 10.1158/1541-7786.MCR-12-0401

Scopus

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

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

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)

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