Faculty Profiles - HOTTA Katsuyuki

Papers - HOTTA Katsuyuki

Division display >> ／ All the affair displays 1 - 192 of about 192

Efficacy of amivantamab, a bi-specific antibody targeting EGFR and MET, in ALK-rearranged non-small-cell lung cancer cell lines. International journal

Tatsuya Nishi, Ayako Morita, Naofumi Hara, Go Makimoto, Kiichiro Ninomiya, Masanori Fujii, Kammei Rai, Kadoaki Ohashi, Katsuyuki Hotta, Masahiro Tabata, Yosuke Togashi, Yoshinobu Maeda, Eiki Ichihara

Lung cancer (Amsterdam, Netherlands) 201 108415 - 108415 2025.3

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

BACKGROUND: Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) are highly effective in treating ALK-rearranged non-small-cell lung cancer (NSCLC). However, at least 40% of patients develop acquired resistance during treatment. Adaptive or acquired resistance to ALK TKIs could be mediated through epidermal growth factor receptor (EGFR) and mesenchymal-epithelial transition factor (MET) signaling. Sixteen percent of acquired resistance cases are linked to bypass signaling. METHODS: In this study, we evaluated the effects of amivantamab, a bi-specific antibody targeting both EGFR and MET, on ALK-rearranged NSCLC cells. We investigated the effect of amivantamab on the ALK-rearranged NSCLC cell lines H3122, ABC-19, and ABC-11. RESULTS: Combining alectinib with amivantamab resulted in greater inhibition of cell growth inhibition in H3122 and ABC-19 cells compared to alectinib alone, but not in ABC-11 cells. EGFR TKI erlotinib showed similar efficacy in H3122 and ABC-19 cells, whereas MET TKI tepotinib was ineffective in both, suggesting that the efficacy of amivantamab is through EGFR inhibition. Unlike H3122 and ABC-19 cells, ABC-11 cells were resistant to EGFR/MET signaling inhibition. Interestingly, amivantamab enhanced alectinib efficacy against ABC-11 cells in the presence of peripheral blood mononuclear cells (PBMCs), despite showing no effect alone without PBMCs, suggesting action through non-signal inhibitory mechanisms. Finally, we treated alectinib-resistant cellswith alectinib, with or without amivantamab, and found that amivantamab restored the sensitivity of these cells to alectinib. CONCLUSION: The bi-specific antibody amivantamab, which targets EGFR and MET, enhanced the efficacy of alectinib through both signal and non-signal inhibitory mechanisms in ALK-rearranged NSCLC cells.

DOI： 10.1016/j.lungcan.2025.108415

Five-year outcomes with gefitinib induction and chemoradiotherapy in EGFR-mutant stage III non-small-cell lung cancer: LOGIK0902/OLCSG0905 phase II study

Katsuyuki Hotta, Sho Saeki, Shinya Sakata, Masafumi Yamaguchi, Daijiro Harada, Akihiro Bessho, Kentaro Tanaka, Koji Inoue, Koji Inoue, Kenichi Gemba, Toshio Kubo, Akiko Sato, Eiki Ichihara, Hiromi Watanabe, Junji Kishimoto, Yoshiyuki Shioyama, Kuniaki Katsui, Kenji Sugio, Katsuyuki Kiura

International Journal of Clinical Oncology 30 ( 3 ) 497 - 503 2025.2

Publishing type：Research paper (scientific journal) Publisher：Springer Science and Business Media LLC

Abstract

Background

We previously showed the 2-year OS rate, the primary endpoint, of 90% in a phase II trial of gefitinib induction followed by chemoradiotherapy (CRT) in unresectable, stage III, EGFR-mutant, non-small-cell lung cancer (NSCLC). However, neither long-term survival data nor late-phase adverse event profiles have been presented.

Patients and methods

Patients with unresectable, EGFR-mutant, stage III NSCLC were administered gefitinib monotherapy for 8 weeks. After confirming no disease progression during induction therapy, cisplatin and docetaxel on days 1, 8, 29, and 36 with concurrent radiotherapy at a total dose of 60 Gy were subsequently administered.

Results

In the enrolled twenty patients, the 5-year OS rate and median survival time were 70.0% [95% confidence interval: 45.1–85.3] and 5.5 years [4.91-NE], respectively, whereas 5-year PFS rate and median PFS time were 15.0% (3.7–33.5) and 1.4 years [0.69–2.29], respectively. Efficacy did not seem influenced even if radiation field was re-planed in response to the effect of gefitinib induction. As for late adverse events, pulmonary fibrosis occurred in 7 patients (35%). The median time from completion of CRT to the occurrence of the event was 245 days. All were grade 1, and there was no evidence of cavitation of the lesions or chronic infections such as Aspergillus infection during the course of the disease. One case of small cell lung cancer occurred during the period.

Conclusions

With longer follow-up time, we demonstrated favorable efficacy with tolerable toxicity profiles in the EGFR-TKI induction followed by standard CRT in EGFR-mutant, stage III, NSCLC.

Trial registration numbers

UMIN00005086. https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=brows&action=brows&recptno=R000006047&type=summary&language=EjRCTs071180036. https://jrct.niph.go.jp/latest-detail/jRCTs071180036

DOI： 10.1007/s10147-025-02696-3

Other Link： https://link.springer.com/article/10.1007/s10147-025-02696-3/fulltext.html

A Prompt Diagnosis and Treatment of a Case of Nuclear Protein of the Testis Carcinoma Characterized by a Bronchial Lesion and High Serum Alpha-fetoprotein Level Following Genomic Testing.

Hiroaki Matsuura, Go Makimoto, Naohiro Oda, Kiichiro Ninomiya, Hisao Higo, Masanori Fujii, Kammei Rai, Eiki Ichihara, Kadoaki Ohashi, Katsuyuki Hotta, Masahiro Tabata, Yoshinobu Maeda

Internal medicine (Tokyo, Japan) 63 ( 19 ) 2655 - 2660 2024.10

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

Nuclear protein of the testis carcinoma (NUTC) is a rare and aggressive malignancy. We herein report a case of NUTC in the lung characterized by a bronchial lesion and elevated alpha-fetoprotein levels. A 35-year-old Japanese man presented to our institution with suspected advanced lung cancer based on a histological examination. Subsequently, next-generation sequencing (NGS) yielded a positive BRD4-NUTM1 fusion. In addition, positive NUT immunostaining of the lung biopsy specimen confirmed NUTC in the lungs. Systemic chemotherapy and radiotherapy showed a temporary response, with decreased serum alpha-fetoprotein levels. We highlight this case of a prompt diagnosis by NGS of NUTC in a young individual with a rapidly progressing tumor.

DOI： 10.2169/internalmedicine.2938-23

A Case of Single-lung Transplant in a Patient with Mycobacterium avium Pulmonary Disease Successfully Treated with Amikacin Liposome Inhalation Suspension. Reviewed

Taichi Ozeki, Hisao Higo, Hiroki Omori, Shunta Mori, Shin Tanaka, Go Makimoto, Kiichiro Ninomiya, Akihiko Taniguchi, Masanori Fujii, Kentaro Miyoshi, Kammei Rai, Eiki Ichihara, Kadoaki Ohashi, Seiichiro Sugimoto, Katsuyuki Hotta, Masahiro Tabata, Shinichi Toyooka, Yoshinobu Maeda, Nobuaki Miyahara

Internal medicine (Tokyo, Japan) 2024.9

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

A 55-year-old man presented to our hospital with idiopathic pulmonary fibrosis (IPF). He was registered with the Japan Organ Transplant Network the following year due to disease progression. Treatment with clarithromycin, ethambutol, and rifampicin for complications of Mycobacterium avium pulmonary disease was initiated, but sputum conversion could not be achieved. The administration of an amikacin liposome inhalation suspension (ALIS) resulted in sputum conversion, and single-lung transplantation was performed. ALIS therapy was continued after lung transplantation, and no M. avium disease was observed for 15 months. ALIS may cause M. avium pulmonary disease with additional indications for lung transplantation.

DOI： 10.2169/internalmedicine.3854-24

A randomized, open-label phase II study on the preventive effect of goshajinkigan against peripheral neuropathy induced by paclitaxel-containing chemotherapy: The OLCSG2101 study protocol. International journal

Naoki Nakamura, Go Makimoto, Takaaki Tanaka, Yuka Kato, Isao Oze, Toshiyuki Kozuki, Toshihide Yokoyama, Hirohisa Ichikawa, Shoichi Kuyama, Naofumi Hara, Yoshinobu Maeda, Katsuyuki Hotta

Respiratory investigation 62 ( 5 ) 897 - 900 2024.9

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

BACKGROUND: Paclitaxel (PTX) is an essential cytotoxic anticancer agent and a standard treatment regimen component for various malignant tumors, including advanced unresectable non-small cell lung cancer, thymic cancer, and primary unknown cancers. However, chemotherapy-induced peripheral neuropathy (CIPN) caused by PTX is a significant adverse event that may lead to chemotherapy discontinuation and deterioration of the quality of life (QOL). Although treatment modalities such as goshajinkigan (GJG), pregabalin, and duloxetine are empirically utilized for CIPN, there is no established evidence for an agent as a preventive measure. We designed a randomized phase II trial (OLCSG2101) to investigate whether prophylactic GJG administration can prevent the onset of CIPN induced by PTX. METHODS: This study was designed as a two-arm, prospective, randomized, multicenter phase II trial. The patients will be randomly assigned to either the GJG prophylaxis arm (Arm A) or the GJG non-prophylaxis arm (Arm B), using cancer type (lung cancer or not) and age (<70 years or not) as adjustment factors. A total of 66 patients (33 in each arm) will be enrolled. DISCUSSION: The results of this study may contribute to better management of CIPN, which can enable the continuation of chemotherapy and maintenance of the patient's QOL. ETHICS AND DISSEMINATION: Ethical approval was obtained from the certified review board of Okayama University (approval no. CRB21-005) on September 28, 2021. Results will be published in peer-reviewed journals and presented at national and international conferences. TRIAL REGISTRATION: Japan Registry of Clinical Trials (registration number jRCTs061210047).

DOI： 10.1016/j.resinv.2024.07.017

Concomitant osimertinib and antituberculosis therapy in an elderly patient with EGFR-mutated lung cancer and pulmonary tuberculosis: A case report. International journal

Hiroaki Matsuura, Hisao Higo, Tadahiro Kuribayashi, Akihiko Tamaoki, Takamasa Nakasuka, Mari Uno, Go Makimoto, Kiichiro Ninomiya, Masanori Fujii, Kammei Rai, Eiki Ichihara, Katsuyuki Hotta, Nobuaki Miyahara, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura, Kadoaki Ohashi

Thoracic cancer 15 ( 17 ) 1390 - 1394 2024.6

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

The concurrent incidence of lung cancer and tuberculosis is expected to escalate due to the projected growth in the older population. Combination therapy with osimertinib and antituberculosis drugs has not been well-established. We report a case of successful treatment involving the concomitant administration of osimertinib and antituberculosis drugs in an older patient, an 89-year-old female, diagnosed with epidermal growth factor receptor (EGFR)-mutant lung cancer and pulmonary tuberculosis. Accumulating evidence is warranted to develop an optimal treatment strategy for patients with lung cancer and tuberculosis.

DOI： 10.1111/1759-7714.15324

Impacts of probiotics on the efficacies of immune checkpoint inhibitors with or without chemotherapy for patients with advanced non-small-cell lung cancer. International journal

Ayako Morita, Eiki Ichihara, Koji Inoue, Keiichi Fujiwara, Toshihide Yokoyama, Daijiro Harada, Chihiro Ando, Hirohisa Kano, Naohiro Oda, Tomoki Tamura, Nobuaki Ochi, Haruyuki Kawai, Masaaki Inoue, Naofumi Hara, Nobukazu Fujimoto, Hirohisa Ichikawa, Isao Oze, Katsuyuki Hotta, Yoshinobu Maeda, Katsuyuki Kiura

International journal of cancer 154 ( 9 ) 1607 - 1615 2024.5

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

The relationships between the therapeutic effects of immune checkpoint inhibitors (ICIs) and the intestinal flora have attracted increasing attention. However, the effects of oral probiotics on the efficacies of ICIs used to treat non-small-cell lung cancer (NSCLC) remain unclear. We investigated the effects of probiotics on the efficacies of ICIs in patients treated with and without chemotherapy. We investigated patients with advanced NSCLC on ICI monotherapy or combination ICI and chemotherapy using the Okayama Lung Cancer Study Group Immunotherapy Database (OLCSG-ID) and the Okayama Lung Cancer Study Group Immunochemotherapy Database (OLCSG-ICD). In total, 927 patients (482 on ICI monotherapy, 445 on an ICI + chemotherapy) were enrolled. Most were male, of good performance status, smokers, and without epidermal growth factor receptor (EGFR)/anaplastic lymphoma kinase (ALK) mutations. Probiotics were administered to 19% of patients on ICI monotherapies and 17% of those on ICIs + chemotherapy. Of the former patients, progression-free survival (PFS) and overall survival (OS) were significantly better in the probiotics group (PFS 7.9 vs. 2.9 months, hazard ratio [HR] 0.54, p < .001; OS not attained vs. 13.1 months, HR 0.45, p < .001). Among patients receiving ICI and chemotherapy, there were no significant differences in PFS between those on probiotics and not but OS was significantly better in the probiotics group (PFS 8.8 vs. 8.6 months, HR 0.89, p = .43; OS not attained vs. 22.6 months, HR 0.61, p = .03). Patients on probiotics experienced better outcomes following ICI treatment.

DOI： 10.1002/ijc.34842

Clinical characteristics of patients treated with immune checkpoint inhibitors in EGFR-mutant non-small cell lung cancer: CS-Lung-003 prospective observational registry study. International journal

Tadahiro Kuribayashi, Kadoaki Ohashi, Kazuya Nishii, Kiichiro Ninomiya, Yukari Tsubata, Nobuhisa Ishikawa, Masahiro Kodani, Nobuhiro Kanaji, Masahiro Yamasaki, Kazunori Fujitaka, Shoichi Kuyama, Nagio Takigawa, Nobukazu Fujimoto, Tetsuya Kubota, Masaaki Inoue, Keiichi Fujiwara, Shingo Harita, Ichiro Takata, Kenji Takada, Sachi Okawa, Katsuyuki Kiura, Katsuyuki Hotta

Journal of cancer research and clinical oncology 150 ( 2 ) 89 - 89 2024.2

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

PURPOSE: Immune checkpoint inhibitors (ICIs) are ineffective against epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC). This study aimed to investigate the clinical characteristics of patients who were treated or not treated with ICIs, and of those who benefit from immunotherapy in EGFR-mutant NSCLC. METHODS: We analyzed patients with unresectable stage III/IV or recurrent NSCLC harboring EGFR mutations using a prospective umbrella-type lung cancer registry (CS-Lung-003). RESULTS: A total of 303 patients who met the eligibility criteria were analyzed. The median age was 69 years; 116 patients were male, 289 had adenocarcinoma, 273 had major mutations, and 67 were treated with ICIs. The duration of EGFR-TKI treatment was longer in the Non-ICI group than in the ICI group (17.1 vs. 12.7 months, p < 0.001). Patients who received ICIs for more than 6 months were categorized into the durable clinical benefit (DCB) group (24 patients), and those who received ICIs for less than 6 months into the Non-DCB group (43 patients). The overall survival in the DCB group exhibited longer than the Non-DCB group (69.3 vs. 47.1 months), and an equivalent compared to that in the Non-ICI group (69.3 vs. 68.9 months). Multivariate analysis for time to next treatment (TTNT) of ICIs showed that a poor PS was associated with a shorter TTNT [hazard ratio (HR) 3.309; p < 0.001]. Patients who were treated with ICIs and chemotherapy combination were associated with a longer TTNT (HR 0.389; p = 0.003). In addition, minor EGFR mutation was associated with a long TTNT (HR 0.450; p = 0.046). CONCLUSION: ICIs were administered to only 22% of patients with EGFR-mutated lung cancer, and they had shorter TTNT of EGFR-TKI compared to other patients. ICI treatment should be avoided in EGFR mutated lung cancer with poor PS but can be considered for lung cancer with EGFR minor mutations. Pathological biomarker to predict long-term responders to ICI are needed.

DOI： 10.1007/s00432-024-05618-4

Protracted coronavirus disease 2019 after chimeric antigen receptor-T cell therapy successfully treated with sequential multidrug therapy. International journal

Masahiro Yamashita, Hisao Higo, Nobuharu Fujii, Chiaki Matsumoto, Go Makimoto, Kiichiro Ninomiya, Masanori Fujii, Kammei Rai, Eiki Ichihara, Kadoaki Ohashi, Katsuyuki Hotta, Masahiro Tabata, Yoshinobu Maeda, Nobuaki Miyahara

Respiratory medicine case reports 51 102104 - 102104 2024

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

A 56-year-old woman who received CD19 chimeric antigen receptor-T cell therapy for refractory diffuse large B-cell lymphoma developed severe coronavirus disease 2019 (COVID-19) and was treated with nirmatrelvir/ritonavir in April 2022. However, she experienced persistent fatigue and cough and fever in June. Computed tomography revealed bilateral ground-glass opacities (GGO), and the patient was treated with corticosteroids for organizing pneumonia after COVID-19. Partial improvement was observed, but new GGO appeared despite corticosteroid therapy. Genome analysis of severe acute respiratory syndrome coronavirus 2 detected Omicron variant BA.1.1.2, which was prevalent at the time of initial infection. The patient was diagnosed with protracted COVID-19 and was treated with remdesivir, molnupiravir, nirmatrelvir/ritonavir, and tixagevimab/cilgavimab. These treatments appeared to contribute to the improvement of protracted COVID-19.

DOI： 10.1016/j.rmcr.2024.102104

CDK4/6 signaling attenuates the effect of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in EGFR-mutant non-small cell lung cancer. International journal

Naofumi Hara, Eiki Ichihara, Hirohisa Kano, Chihiro Ando, Ayako Morita, Tatsuya Nishi, Sachi Okawa, Takamasa Nakasuka, Atsuko Hirabae, Masaya Abe, Noboru Asada, Kiichiro Ninomiya, Go Makimoto, Masanori Fujii, Toshio Kubo, Kadoaki Ohashi, Katsuyuki Hotta, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura

Translational lung cancer research 12 ( 10 ) 2098 - 2112 2023.10

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

BACKGROUND: Epidermal growth factor receptor (EGFR) mutations, such as exon 19 deletion and exon 21 L858R, are driver oncogenes of non-small cell lung cancer (NSCLC), with EGFR tyrosine kinase inhibitors (TKIs) being effective against EGFR-mutant NSCLC. However, the efficacy of EGFR-TKIs is transient and eventually leads to acquired resistance. Herein, we focused on the significance of cell cycle factors as a mechanism to attenuate the effect of EGFR-TKIs in EGFR-mutant NSCLC before the emergence of acquired resistance. METHODS: Using several EGFR-mutant cell lines, we investigated the significance of cell cycle factors to attenuate the effect of EGFR-TKIs in EGFR-mutant NSCLC. RESULTS: In several EGFR-mutant cell lines, certain cancer cells continued to proliferate without EGFR signaling, and the cell cycle regulator retinoblastoma protein (RB) was not completely dephosphorylated. Further inhibition of phosphorylated RB with cyclin-dependent kinase (CDK) 4/6 inhibitors, combined with the EGFR-TKI osimertinib, enhanced G0/G1 cell cycle accumulation and growth inhibition of the EGFR-mutant NSCLC in both in vitro and in vivo models. Furthermore, residual RB phosphorylation without EGFR signaling was maintained by extracellular signal-regulated kinase (ERK) signaling, and the ERK inhibition pathway showed further RB dephosphorylation. CONCLUSIONS: Our study demonstrated that the CDK4/6-RB signal axis, maintained by the MAPK pathway, attenuates the efficacy of EGFR-TKIs in EGFR-mutant NSCLC, and targeting CDK4/6 enhances this efficacy. Thus, combining CDK4/6 inhibitors and EGFR-TKI could be a novel treatment strategy for TKI-naïve EGFR-mutant NSCLC.

DOI： 10.21037/tlcr-23-99

A randomized phase II study of afatinib alone or combined with bevacizumab for treating chemo-naïve patients with non-small cell lung cancer harboring EGFR mutations. International journal

Takashi Ninomiya, Nobuhisa Ishikawa, Toshiyuki Kozuki, Shoichi Kuyama, Koji Inoue, Toshihide Yokoyama, Nobuhiro Kanaji, Masayuki Yasugi, Takuo Shibayama, Keisuke Aoe, Nobuaki Ochi, Kazunori Fujitaka, Masahiro Kodani, Yutaka Ueda, Kazuhiko Watanabe, Akihiro Bessho, Keisuke Sugimoto, Isao Oze, Katsuyuki Hotta, Katsuyuki Kiura

Lung cancer (Amsterdam, Netherlands) 184 107349 - 107349 2023.10

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

BACKGROUND: Adding bevacizumab to first-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) prolonged the progression-free survival (PFS), but limited data are available for second-generation EGFR-TKIs. AfaBev-CS is a randomized, phase II trial comparing afatinib plus bevacizumab and afatinib alone as first-line treatment. PATIENTS AND METHODS: Untreated patients with non-squamous non-small cell lung cancer (NSCLC) harboring EGFR mutations (Del19 or L858R) were enrolled and randomly assigned to receive either afatinib (30 mg) plus bevacizumab (AfaBev group) or afatinib (40 mg) monotherapy (Afa group). The primary endpoint was PFS. The power was >50% under the assumptions of a median PFS of 12 months for the Afa group and hazard ratio (HR) of 0.6 for the AfaBev group. RESULTS: Between August 2017 and September 2019, 100 patients were enrolled. There was no significant difference in PFS between the groups. The median PFS was 16.3 and 16.1 months for the AfaBev and Afa groups, respectively, with an HR of 0.865 (95% confidence interval [CI], 0.539 to 1.388; p = 0.55). In terms of overall survival, there was no significant difference between the groups (HR, 0.84; 95% CI, 0.39 to 1.83; p = 0.67). The overall response rate was 82.6% and 76.6% in the AfaBev and Afa groups, respectively (p = 0.61). Grade ≥ 3 diarrhea, hypertension, acneiform rash, paronychia, and stomatitis were frequently observed in the AfaBev group. CONCLUSIONS: This study failed to show efficacy of AfaBev over Afa for improving PFS in untreated patients with EGFR-mutated NSCLC.

DOI： 10.1016/j.lungcan.2023.107349

Severe Cytokine Release Syndrome and Immune Effector Cell-associated Neurotoxicity Syndrome in a Man Receiving Immune Checkpoint Inhibitors for Lung Cancer: A Case Report.

Takaaki Tanaka, Masataka Taoka, Go Makimoto, Kiichiro Ninomiya, Hisao Higo, Masanori Fujii, Eiki Ichihara, Kadoaki Ohashi, Katsuyuki Hotta, Masahiro Tabata, Yoshinobu Maeda

Internal medicine (Tokyo, Japan) 2023.9

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

A 55-year-old man with stage IV lung adenocarcinoma was treated with cisplatin, pemetrexed, nivolumab, and ipilimumab. Approximately 100 days after treatment initiation, he became disoriented and presented to the emergency department with a high fever. Blood tests revealed liver and kidney dysfunctions. Subsequently, the patient developed generalized convulsions that required intensive care. He was clinically diagnosed with cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Organ damage was gradually controlled with immunosuppressive drugs, including steroids, and the patient was discharged. Successful treatment is rare in patients with CRS, including ICANS, during immune checkpoint inhibitor treatment for solid tumors.

DOI： 10.2169/internalmedicine.2429-23

Efficacy of gilteritinib in comparison with alectinib for the treatment of ALK-rearranged non-small cell lung cancer. International journal

Chihiro Ando, Eiki Ichihara, Tatsuya Nishi, Ayako Morita, Naofumi Hara, Kenji Takada, Takamasa Nakasuka, Hiromi Watanabe, Hirohisa Kano, Kazuya Nishii, Go Makimoto, Takumi Kondo, Kiichiro Ninomiya, Masanori Fujii, Toshio Kubo, Kadoaki Ohashi, Ken-Ichi Matsuoka, Katsuyuki Hotta, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura

Cancer science 2023.9

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

Gilteritinib is a multitarget tyrosine kinase inhibitor (TKI), approved for the treatment of FLT3-mutant acute myeloid leukemia, with a broad range of activity against several tyrosine kinases including anaplastic lymphoma kinase (ALK). This study investigated the efficacy of gilteritinib against ALK-rearranged non-small cell lung cancers (NSCLC). To this end, we assessed the effects of gilteritinib on cell proliferation, apoptosis, and acquired resistance responses in several ALK-rearranged NSCLC cell lines and mouse xenograft tumor models and compared its efficacy to alectinib, a standard ALK inhibitor. Gilteritinib was significantly more potent than alectinib, as it inhibited cell proliferation at a lower dose, with complete attenuation of growth observed in several ALK-rearranged NSCLC cell lines and no development of drug tolerance. Immunoblotting showed that gilteritinib strongly suppressed phosphorylated ALK and its downstream effectors, as well as mesenchymal-epithelial transition factor (MET) signaling. By comparison, MET signaling was enhanced in alectinib-treated cells. Furthermore, gilteritinib was found to more effectively abolish growth of ALK-rearranged NSCLC xenograft tumors, many of which completely receded. Interleukin-15 (IL-15) mRNA levels were elevated in gilteritinib-treated cells, together with a concomitant increase in the infiltration of tumors by natural killer (NK) cells, as assessed by immunohistochemistry. This suggests that IL-15 production along with NK cell infiltration may constitute components of the gilteritinib-mediated antitumor responses in ALK-rearranged NSCLCs. In conclusion, gilteritinib demonstrated significantly improved antitumor efficacy compared with alectinib against ALK-rearranged NSCLC cells, which can warrant its candidacy for use in anticancer regimens, after further examination in clinical trial settings.

DOI： 10.1111/cas.15958

Efficacy of immune checkpoint inhibitor monotherapy in elderly patients with non-small-cell lung cancer. International journal

Toshio Kubo, Eiki Ichihara, Daijiro Harada, Koji Inoue, Keiichi Fujiwara, Sinobu Hosokawa, Daizo Kishino, Haruyuki Kawai, Nobuaki Ochi, Naohiro Oda, Naofumi Hara, Katsuyuki Hotta, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura

Respiratory investigation 61 ( 5 ) 643 - 650 2023.9

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

BACKGROUND: Limited information on anticancer therapy for super-elderly patients with non-small-cell lung cancer is available. Immune checkpoint inhibitors offer long-term survival to elderly patients aged ≥65 years with non-small-cell lung cancer. However, the efficacy and safety of immune checkpoint inhibitors in more elderly patients are not well understood. METHODS: We retrospectively evaluated the efficacy and safety of immune checkpoint inhibitors in patients aged ≥85 years with advanced non-small-cell lung cancer at nine centers using the Okayama Lung Cancer Study Group-Immunotherapy Database. RESULTS: Among 531 patients who received immune checkpoint inhibitors, 16 were aged ≥85 years (median, 86.5 years; range, 85-93 years). Many had high programmed death-ligand 1 expression and received pembrolizumab as first-line therapy. The objective response rate, median progression-free survival, and median survival time were 25% (95% confidence interval: 1-49), 2.8 months (95% confidence interval: 1.7-4.5), and not reached (95% confidence interval: 4.7-not reached), respectively. Moreover, the 4-year overall survival rate was 60.8% (95% confidence interval: 29.3-81.7), and a long-lasting effect of immune checkpoint inhibitors was observed even in patients aged ≥85 years. The incidence of immune-related and grade ≥3 immune-related adverse events was 32% and 6%, respectively. CONCLUSIONS: The effect and toxicity of immune checkpoint inhibitors for patients aged ≥85 years were acceptable. Immune checkpoint inhibitors may be a treatment option for patients aged ≥85 years.

DOI： 10.1016/j.resinv.2023.06.005

原発性肺癌との鑑別を要しAFPが著明高値であったNUT Carcinomaの1例

松浦宏昌, 槇本剛, 小田尚廣, 大橋圭明, 二宮貴一朗, 藤井昌学, 市原英基, 堀田勝幸, 田端雅弘, 木浦勝行

気管支学 45 ( 2 ) 148 - 148 2023.3

PD-1 blockade augments CD8+ T cell dependent antitumor immunity triggered by Ad-SGE-REIC in Egfr-mutant lung cancer. International journal

Takamasa Nakasuka, Kadoaki Ohashi, Kazuya Nishii, Atsuko Hirabae, Sachi Okawa, Nahoko Tomonobu, Kenji Takada, Chihiro Ando, Hiromi Watanabe, Go Makimoto, Kiichiro Ninomiya, Masanori Fujii, Toshio Kubo, Eiki Ichihara, Katsuyuki Hotta, Masahiro Tabata, Hiromi Kumon, Yoshinobu Maeda, Katsuyuki Kiura

Lung cancer (Amsterdam, Netherlands) 178 1 - 10 2023.2

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

OBJECTIVES: No immunotherapeutic protocol has yet been established in never-smoking patients with lung cancer harboring driver oncogenic mutations, such as epidermal growth factor receptor (EGFR) mutations. The immunostimulatory effect of Ad-REIC, a genetically engineered adenovirus vector expressing a tumor suppressor gene, reduced expression in immortalized cells (REIC), has been investigated in clinical trials for various solid tumors. However, the immunostimulatory effect of the Ad-REIC in EGFR-mutant lung cancer with a non-inflamed tumor microenvironment (TME) has not been explored. MATERIALS AND METHODS: We used a syngeneic mouse model developed by transplanting Egfr-mutant lung cancer cells into single or double flanks of C57BL/6J mice. Ad-SGE-REIC, a 2nd-generation vector with an enhancer sequence, was injected only into the tumors from one flank, and its antitumor effects were assessed. Tumor-infiltrating cells were evaluated using immunohistochemistry or flow cytometry. The synergistic effects of Ad-SGE-REIC and PD-1 blockade were also examined. RESULTS: Injection of Ad-SGE-REIC into one side of the tumor induced not only a local antitumor effect but also a bystander abscopal effect in the non-injected tumor, located on the other flank. The number of PD-1+CD8+ T cells increased in both injected and non-injected tumors. PD-1 blockade augmented the local and abscopal antitumor effects of Ad-SGE-REIC by increasing the number of CD8+ T cells in the TME of Egfr-mutant tumors. Depletion of CD8+ cells reverted the antitumor effect, suggesting they contribute to antitumor immunity. CONCLUSION: Ad-SGE-REIC induced systemic antitumor immunity by modifying the TME status from non-inflamed to inflamed, with infiltration of CD8+ T cells. Additionally, in Egfr-mutant lung cancer, this effect was enhanced by PD-1 blockade. These findings pave the way to establish a novel combined immunotherapy strategy with Ad-SGE-REIC and anti-PD-1 antibody for lung cancer with a non-inflamed TME.

DOI： 10.1016/j.lungcan.2023.01.018

肺膿瘍を合併し急速な増大を認めたが,迅速に診断しテポチニブが奏効したMET陽性肺癌の1例

目瀬優衣, 槇本剛, 藤井昌学, 市原英基, 大橋圭明, 木浦勝行, 久保寿夫, 田端雅弘, 二宮貴一朗, 堀田勝幸

肺癌 63 ( 1 ) 68 - 69 2023.2

肺膿瘍を合併し急速な増大を認めたが,迅速に診断しテポチニブが奏効したMET陽性肺癌の1例

目瀬優衣, 槇本剛, 藤井昌学, 市原英基, 大橋圭明, 木浦勝行, 久保寿夫, 田端雅弘, 二宮貴一朗, 堀田勝幸

肺癌 63 ( 1 ) 68 - 69 2023.2

Randomized phase II study of daily versus alternate-day administrations of S-1 for the elderly patients with completely resected pathological stage IA (tumor diameter > 2 cm)-IIIA of non-small cell lung cancer: Setouchi Lung Cancer Group Study 1201. International journal

Hiromasa Yamamoto, Junichi Soh, Norihito Okumura, Hiroyuki Suzuki, Masao Nakata, Toshiya Fujiwara, Kenichi Gemba, Isao Sano, Takuji Fujinaga, Masafumi Kataoka, Yasuhiro Terazaki, Nobukazu Fujimoto, Kazuhiko Kataoka, Shinji Kosaka, Motohiro Yamashita, Hidetoshi Inokawa, Masaaki Inoue, Hiroshige Nakamura, Yoshinori Yamashita, Katsuyuki Hotta, Hiroshige Yoshioka, Satoshi Morita, Keitaro Matsuo, Junichi Sakamoto, Hiroshi Date, Shinichi Toyooka

PloS one 18 ( 5 ) e0285273 2023

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

BACKGROUND: It is shown that the postoperative adjuvant chemotherapy for non-small cell lung cancer (NSCLC) was associated with survival benefit in an elderly population. We aimed to analyze the feasibility and efficacy of alternate-day S-1, an oral fluoropyrimidine, for adjuvant chemotherapy in elderly patients with completely resected pathological stage IA (tumor diameter > 2 cm) to IIIA (UICC TNM Classification of Malignant Tumours, 7th edition) NSCLC. METHODS: Elderly patients were randomly assigned to receive adjuvant chemotherapy for one year consisting of either alternate-day oral administration of S-1 (80 mg/m2/day) for 4 days a week (Arm A) or a daily oral administration of S-1 (80 mg/m2/day) for 14 consecutive days followed by 7-day rest (Arm B). The primary endpoint was feasibility (treatment completion rate), which was defined as the proportion of patients who completed the allocated intervention for 6 months with a relative dose intensity (RDI) of 70% or more. RESULTS: We enrolled 101 patients in which 97 patients received S-1 treatment. The treatment completion rate at 6 months was 69.4% in Arm A and 64.6% in Arm B (p = 0.67). Treatment completion rate in Arm B tended to be lower compared to Arm A, as the treatment period becomes longer (at 9 and 12 months). RDI of S-1 at 12 months and completion of S-1 administration without dose reduction or postponement at 12 months was significantly better in Arm A than in Arm B (p = 0.026 and p < 0.001, respectively). Among adverse events, anorexia, skin symptoms and lacrimation of any grade were significantly more frequent in Arm B compared with Arm A (p = 0.0036, 0.023 and 0.031, respectively). The 5-year recurrence-free survival rates were 56.9% and 65.7% for Arm A and B, respectively (p = 0.22). The 5-year overall survival rates were 68.6% and 82.0% for Arm A and B, respectively (p = 0.11). CONCLUSION: Although several adverse effects were less frequent in Arm A, both alternate-day and daily oral administrations of S-1 were demonstrated to be feasible in elderly patients with completely resected NSCLC. TRIAL REGISTRATION: Unique ID issued by UMIN: UMIN000007819 (Date of registration: Apr 25, 2012) https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000009128. Trial ID issued by jRCT: jRCTs061180089 (Date of registration: Mar 22, 2019, for a shift toward a "specified clinical trial" based on Clinical Trials Act in Japan) https://jrct.niph.go.jp/en-latest-detail/jRCTs061180089.

DOI： 10.1371/journal.pone.0285273

The Effect of Pleural Effusion on Prognosis in Patients with Non-Small Cell Lung Cancer Undergoing Immunochemotherapy: A Retrospective Observational Study. International journal

Tomoka Nishimura, Eiki Ichihara, Toshihide Yokoyama, Koji Inoue, Tomoki Tamura, Ken Sato, Naohiro Oda, Hirohisa Kano, Daizo Kishino, Haruyuki Kawai, Masaaki Inoue, Nobuaki Ochi, Nobukazu Fujimoto, Hirohisa Ichikawa, Chihiro Ando, Katsuyuki Hotta, Yoshinobu Maeda, Katsuyuki Kiura

Cancers 14 ( 24 ) 2022.12

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

Objectives: Combined immune checkpoint inhibitor (ICI) therapy and chemotherapy has become the standard treatment for advanced non-small-cell lung cancer (NSCLC). Pleural effusion (PE) is associated with poor outcomes among patients with NSCLC undergoing chemotherapy. However, minimal data exists on PE for patients undergoing combined ICI and chemotherapy. Therefore, we investigated how PE affects survival outcomes in patients with NSCLC undergoing this combined therapy. Methods: We identified patients with advanced NSCLC undergoing chemotherapy and ICI therapy from the Okayama Lung Cancer Study Group−Immune Chemotherapy Database (OLCSG−ICD) between December 2018 and December 2020; the OLCSG−ICD includes the clinical data of patients with advanced NSCLC from 13 institutions. Then, we analyzed the treatment outcomes based on the presence of PE. Results: We identified 478 patients who underwent combined ICI therapy and chemotherapy; 357 patients did not have PE, and 121 patients did have PE. Patients with PE had significantly shorter progression-free survival (PFS) and overall survival (OS) than those without PE (median PFS: 6.2 months versus 9.1 months; p < 0.001; median OS: 16.4 months versus 27.7 months; p < 0.001). The negative effect of PE differed based on the patient’s programmed cell death-ligand 1 (PD-L1) expression status; with the effect being more evident in patients with high PD-L1 expression. In addition, PFS and OS did not differ between patients who did and did not undergo bevacizumab treatment; thus, bevacizumab-containing regimens did not improve the survival outcomes for patients with PE. Conclusion: PE is associated with poor outcomes among patients with NSCLC undergoing combined ICI therapy and chemotherapy.

DOI： 10.3390/cancers14246184

osimertinibが誘導する抗腫瘍免疫はM2マクロファージの抑制により増強される

大川祥, 大橋圭明, 西井和也, 中須賀崇匡, 平生敦子, 高田健二, 西村淳, 栗林忠弘, 安東千裕, 西達也, 森田絢子, 槇本剛, 二宮貴一朗, 藤井昌学, 市原英基, 堀田勝幸, 田端雅弘, 前田嘉信, 木浦勝行

肺癌 62 ( 6 ) 657 - 657 2022.11

CD8陽性細胞抵抗性Egfr肺癌に対するSTING agonistによる抗腫瘍免疫の誘導

西村淳, 大橋圭明, 栗林忠弘, 森田絢子, 西達也, 大川祥, 高田健二, 安東千裕, 中須賀崇匡, 西井和也, 平生敦子, 二宮貴一朗, 槇本剛, 藤井昌学, 市原英基, 堀田勝幸, 田端雅弘, 前田嘉信, 木浦勝行

肺癌 62 ( 6 ) 754 - 754 2022.11

EGFR変異陽性肺癌に対するAd-SGE-REICと抗PD-1抗体併用による抗腫瘍免疫賦活効果

中須賀崇匡, 大橋圭明, 西井和也, 平生敦子, 大川祥, 高田健二, 西村淳, 栗林忠弘, 安東千裕, 西達也, 森田絢子, 槇本剛, 二宮貴一朗, 藤井昌学, 市原英基, 堀田勝幸, 田端雅弘, 前田嘉信, 木浦勝行

肺癌 62 ( 6 ) 715 - 715 2022.11

EGFR阻害が誘導するEgfr肺癌に対する抗腫瘍免疫を逐次的VEGFR-2/PD-1阻害が増強する

西井和也, 大橋圭明, 冨田秀太, 中須賀崇匡, 平生敦子, 大川祥, 西村淳, 安東千裕, 槇本剛, 二宮貴一朗, 加藤有加, 久保寿夫, 市原英基, 堀田勝幸, 田端雅弘, 豊岡伸一, 鵜殿平一郎, 前田嘉信, 木浦勝行

肺癌 62 ( 6 ) 657 - 657 2022.11

More than one-third of advanced non-small-cell lung cancer patients do not receive immunochemotherapy due to intolerance. International journal

Chihiro Ando, Eiki Ichihara, Toshihide Yokoyama, Koji Inoue, Tomoki Tamura, Keiichi Fujiwara, Naohiro Oda, Hirohisa Kano, Daizo Kishino, Kazuhiko Watanabe, Masaaki Inoue, Nobuaki Ochi, Fumie Onishi, Hirohisa Ichikawa, Hiroshi Kobe, Sayaka Tachibana, Katsuyuki Hotta, Yoshinobu Maeda, Katsuyuki Kiura

Journal of cancer research and clinical oncology 2022.10

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

BACKGROUND: Combination therapy with immune checkpoint inhibitors (ICIs) and chemotherapy (ICI + chemotherapy) has become the standard first line treatment for driver oncogene-negative advanced non-small-cell lung cancer (NSCLC). However, it may be more toxic compared to monotherapy, which limits its use. Moreover, the feasibility of the combination therapy in clinical practice remains unknown. METHODS: We conducted a cohort study to determine the implementation rate of ICI + chemotherapy in clinical practice. We retrospectively reviewed clinical data from advanced NSCLC patients who received systemic therapy at 13 institutions between December 2018 and December 2020. RESULTS: After excluding 154 patients with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) gene alterations, a total of 919 NSCLC patients were included. Among them, 442 were treated with ICI + chemotherapy (48%), whereas 477 were treated with other therapies (52%). Among these 477 patients, 340 did not receive ICI + chemotherapy because of intolerance (71%); thus, more than one-third of the advanced NSCLC patients do not benefit from the combination therapy due to intolerance. Among the 659 NSCLC patients for whom PD-L1 was < 50% or unknown, only 342 received the ICI + chemotherapy combination (52%) even though it is considered preferable to either therapy alone; the remaining 318 patients were treated with other therapies (48%). Among the 318 patients who did not receive ICI + chemotherapy, 274 were intolerant to it (86%). CONCLUSION: Our results revealed that a substantial proportion of advanced NSCLC patients did not benefit from ICI + chemotherapy due to intolerance. As treatments for NSCLC are moving toward combinations for greater efficacy, their feasibility in clinical practice must be taken into consideration.

DOI： 10.1007/s00432-022-04415-1

COVID-19 Vaccine-Associated Lymphadenopathy Mimicking Regrowth of Axillary Lymph Node Metastasis of Lung Adenocarcinoma.

Taku Noumi, Hiromi Watanabe, Kiichiro Ninomiya, Kadoaki Ohashi, Eiki Ichihara, Toshio Kubo, Go Makimoto, Yuka Kato, Masanori Fujii, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Hotta, Katsuyuki Kiura

Acta medica Okayama 76 ( 5 ) 593 - 596 2022.10

Language：English

We encountered a woman with re-enlarged axillary lymph nodes during a computed tomography (CT) scan for surveillance of lung adenocarcinoma with axillary lymph node metastasis at the initial diagnosis that had shrunk with standard chemotherapy. We first suspected cancer recurrence and considered a change in the chemotherapeutic regimen. However, after careful history taking regarding the timing of her Coronavirus Disease 2019 (COVID-19) vaccination, and subsequent careful, close follow-up, radiological shrinkage suggested a strictly benign cause. Especially in lung cancer with a medical history of axillary lymph node involvement, cliniciansshould be aware that vaccine-associated lymphadenopathy can mimic cancer recurrence and sometimesprompt serious misjudgment regarding a current treatment course and strategy.

DOI： 10.18926/AMO/64041

Fulminant Myocarditis for Non-small-cell Carcinoma of the Lung with Nivolumab and Ipilimumab Plus Chemotherapy: A Case Report. Reviewed

Tomoka Nishimura, Kiichiro Ninomiya, Mitsutaka Nakashima, Satoshi Akagi, Tadahiro Kuribayashi, Hisao Higo, Katsuyuki Hotta, Yoshinobu Maeda, Hiroshi Ito, Katsuyuki Kiura

Internal medicine (Tokyo, Japan) 62 ( 9 ) 1319 - 1322 2022.9

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

A 59-year-old man with a high level of antinuclear antibody received nivolumab and ipilimumab plus chemotherapy for lung cancer. Two weeks after the second course, he was admitted with a fever and severe fatigue. Laboratory studies showed elevated markers of myocardial damage, and a myocardial biopsy showed inflammatory cell infiltration, damaged myocardial fibers. Myocarditis was diagnosed as an immune-related adverse event (irAE), and high-dose corticosteroids were initiated. However, his cardiac function rapidly worsened, and he died on the fifth day after admission. There is no established treatment strategy for fulminant myocarditis as an irAE, and the further exploration of viable treatment strategies is required.

DOI： 10.2169/internalmedicine.0505-22

CD8+ T-cell responses are boosted by dual PD-1/VEGFR2 blockade after EGFR inhibition in Egfr-mutant lung cancer. Reviewed International journal

Kazuya Nishii, Kadoaki Ohashi, Shuta Tomida, Takamasa Nakasuka, Atsuko Hirabae, Sachi Okawa, Jun Nishimura, Hisao Higo, Hiromi Watanabe, Hirohisa Kano, Chihiro Ando, Go Makimoto, Kiichiro Ninomiya, Yuka Kato, Toshio Kubo, Eiki Ichihara, Katsuyuki Hotta, Masahiro Tabata, Shinichi Toyooka, Heiichiro Udono, Yoshinobu Maeda, Katsuyuki Kiura

Cancer immunology research 10 ( 9 ) 1111 - 1126 2022.7

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

Epidermal growth factor receptor (EGFR) is the most frequently mutated driver oncogene in non-smoking-related, non-small-cell lung cancer (NSCLC). EGFR-mutant NSCLC has a non-inflamed tumor microenvironment (TME), with low infiltration by CD8+ T cells and, thus, immune checkpoint inhibitors, such as anti-programmed cell death-1 (anti-PD-1) have weak anti-tumor effects. Here, we showed that CD8+ T-cell responses were induced by an EGFR-tyrosine kinase inhibitor (TKI) in syngeneic Egfr-mutant NSCLC tumors, which was further pronounced by sequential dual blockade of PD-1 and vascular endothelial growth factor receptor 2 (VEGFR2). However, simultaneous triple blockade had no such effect. PD-1/VEGFR2 dual blockade did not exert tumor-inhibitory effects without pre-treatment with the EGFR-TKI, suggesting that treatment schedule is crucial for efficacy of the dual blockade therapy. Pre-treatment with EGFR-TKI increased the CD8+ T-cell/regulatory T-cell (Treg) ratio, while also increasing expression of immunosuppressive chemokines and chemokine receptors, as well as increasing the number of M2-like macrophages, in the TME. Discontinuing EGFR-TKI treatment reversed the transient increase of immunosuppressive factors in the TME. The subsequent PD-1/VEGFR2 inhibition maintained increased numbers of infiltrating CD8+ T cells and CD11c+ dendritic cells. Depletion of CD8+ T cells in vivo abolished tumor growth inhibition by EGFR-TKI alone and the sequential triple therapy, suggesting that EGFR inhibition is a prerequisite for the induction of CD8+ T-cell responses. Our findings could aid in developing an alternative immunotherapy strategy in patients with cancers that have driver mutations and a non-inflamed TME.

DOI： 10.1158/2326-6066.CIR-21-0751

Pembrolizumab in advanced NSCLC patients with poor performance status and high PD-L1 expression: OLCSG 1801.

Shinobu Hosokawa, Eiki Ichihara, Daijiro Harada, Shoichi Kuyama, Koji Inoue, Kenichi Gemba, Hirohisa Ichikawa, Yuka Kato, Naohiro Oda, Isao Oze, Tomoki Tamura, Toshiyuki Kozuki, Takahiro Umeno, Toshio Kubo, Katsuyuki Hotta, Akihiro Bessho, Yoshinobu Maeda, Katsuyuki Kiura

International journal of clinical oncology 27 ( 7 ) 1139 - 1144 2022.7

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

BACKGROUND: The role of pembrolizumab in the treatment of poor performance status (PS) patients remains unclear. PATIENTS AND METHODS: We conducted a phase II trial to investigate the efficacy and safety of pembrolizumab as first-line therapy for non-small-cell lung cancer (NSCLC) patients with PSs of 2-3 and programmed cell death ligand 1 (PD-L1) expression ≥ 50%. The primary endpoint of this study was the objective response rate (ORR). RESULTS: Fourteen patients treated at eight institutions were enrolled. Most patients had PS 2 (12/14; 86%) and others had PS 3 (2/14; 14%). The ORR was 57.1% (95% confidence interval 28.9-82.3%), which met the primary endpoint. The median progression-free survival (PFS) and 1-year PFS rates were 5.8 months and 20.0%, respectively. At the time of data cut-off, one patient had received treatment for more than 1 year; another patient had received treatment for more than 2 years. Nine patients had improved PS with treatment (Wilcoxon signed-rank test, p = 0.003). Two patients had immune-related adverse events ≥ grade 3: grades 5 and 3 elevation in alanine and aspartate aminotransferases. Two PS 3-stage patients were diagnosed with clinically progressive disease prior to initial computed tomography; both died within 2 months. CONCLUSION: Pembrolizumab was effective for the treatment of NSCLC patients with a poor PS and PD-L1 level ≥ 50%. However, given the poor outcomes of the PS 3 patients, the drug is not indicated for such patients. Adverse events, including liver dysfunction, should be carefully monitored. REGISTRATION ID: UMIN000030955.

DOI： 10.1007/s10147-022-02164-2

Three doses of mRNA COVID‐19 vaccine protects from SARS‐CoV‐2 infections in Japan International journal

Katsuyuki Hotta, Etsuji Suzuki, Eiki Ichihara, Katsuyuki Kiura

Journal of Internal Medicine 292 ( 4 ) 687 - 689 2022.6

大量喀血に対して気管支動脈塞栓術と気管支充填術が奏効したALK陽性肺癌の1例

藤岡佑輔, 田岡征高, 槇本剛, 栗林忠弘, 松浦宏昌, 下西惇, 二宮貴一朗, 肥後寿夫, 久保寿夫, 大橋圭明, 堀田勝幸, 宮原信明, 田端雅弘, 木浦勝行

気管支学 44 ( Suppl. ) S307 - S307 2022.5

First and repeat rebiopsy for detecting EGFR T790M mutation in non-small-cell lung cancer: CS-Lung-003 prospective observational registry study. Reviewed International journal

Kenichiro Kudo, Kazuya Nishii, Go Makimoto, Nobuhisa Ishikawa, Yukari Tsubata, Masahiro Kodani, Nobukazu Fujimoto, Masahiro Yamasaki, Tetsuya Kubota, Nagio Takigawa, Kazunori Fujitaka, Nobuhiro Kanaji, Takuo Shibayama, Junko Itano, Chihiro Ando, Katsuyuki Hotta, Katsuyuki Kiura

Journal of cancer research and clinical oncology 148 ( 8 ) 1869 - 1877 2022.4

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

PURPOSE: Osimertinib is still essential for the treatment of epidermal growth factor receptor (EGFR)-T790M-positive non-small-cell lung cancer (NSCLC) even in a relapsed setting, which suggests the importance of rebiopsy. The clinical value of repeat rebiopsy in patients with NSCLC who are T790M-negative on a first rebiopsy remains unclear. In this study, we examined the status of the first rebiopsy and evaluated the frequency of repeat rebiopsy of T790M-negative tumors detected by the first rebiopsy. METHODS: We reviewed 144 patients with NSCLC with major EGFR mutations, but not T790M, who received first- or second-generation EGFR tyrosine kinase inhibitors (TKIs), registered in the prospective, umbrella-type lung cancer patient registry (CS-Lung-003). RESULTS: Overall, 63 patients (44%) underwent the first rebiopsy. In the first rebiopsy, 51 (81%) and 12 (19%) of 63 underwent histological/cytological rebiopsy and liquid biopsy with the blood sampling, respectively. In the repeat rebiopsy, 23 (85%) and 4 (15%) of 27 underwent histological/cytological rebiopsy and liquid biopsy, respectively. The most frequently rebiopsied site was a pulmonary lesion (n = 24, 38.7%). Overall, 29 (46.0%) of 63 patients harbored the T790M mutation. Interestingly, a high detection rate of cancer cells did not necessarily indicate a high detection rate of the T790M mutation (p < 0.01). Among 34 patients with T790M-negative tumors confirmed on the first rebiopsy, 20 (58.8%) underwent repeat rebiopsies following interval therapy, revealing that seven (36.8%) had T790M-positive tumors. Osimertinib yielded median progression-free survival of 11.8 and 16.2 months in patients with the 790M mutation detected by the first rebiopsy and repeat rebiopsy, respectively. CONCLUSION: In our prospective cohort, the T790M mutation was detected in 46% of patients who underwent the first rebiopsy. Repeat rebiopsy may increase the ability to detect the T790M mutation positivity rate.

DOI： 10.1007/s00432-021-03893-z

がん遺伝子パネル検査を行った胸腺がん5例の検討

久保寿夫, 二宮貴一朗, 槇本剛, 加藤有加, 藤井昌学, 市原英基, 大橋圭明, 堀田勝幸, 田端雅弘, 前田嘉信, 木浦勝行

日本呼吸器学会誌 11 ( 増刊 ) 279 - 279 2022.4

Identification of targetable kinases in idiopathic pulmonary fibrosis. International journal

Hisao Higo, Kadoaki Ohashi, Shuta Tomida, Sachi Okawa, Hiromasa Yamamoto, Seiichiro Sugimoto, Satoru Senoo, Go Makimoto, Kiichiro Ninomiya, Takamasa Nakasuka, Kazuya Nishii, Akihiko Taniguchi, Toshio Kubo, Eiki Ichihara, Katsuyuki Hotta, Nobuaki Miyahara, Yoshinobu Maeda, Shinichi Toyooka, Katsuyuki Kiura

Respiratory research 23 ( 1 ) 20 - 20 2022.2

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

BACKGROUND: Tyrosine kinase activation plays an important role in the progression of pulmonary fibrosis. In this study, we analyzed the expression of 612 kinase-coding and cancer-related genes using next-generation sequencing to identify potential therapeutic targets for idiopathic pulmonary fibrosis (IPF). METHODS: Thirteen samples from five patients with IPF (Cases 1-5) and eight samples from four patients without IPF (control) were included in this study. Six of the thirteen samples were obtained from different lung segments of a single patient who underwent bilateral pneumonectomy. Gene expression analysis of IPF lung tissue samples (n = 13) and control samples (n = 8) was performed using SureSelect RNA Human Kinome Kit. The expression of the selected genes was further confirmed at the protein level by immunohistochemistry (IHC). RESULTS: Gene expression analysis revealed a correlation between the gene expression signatures and the degree of fibrosis, as assessed by Ashcroft score. In addition, the expression analysis indicated a stronger heterogeneity among the IPF lung samples than among the control lung samples. In the integrated analysis of the 21 samples, DCLK1 and STK33 were found to be upregulated in IPF lung samples compared to control lung samples. However, the top most upregulated genes were distinct in individual cases. DCLK1, PDK4, and ERBB4 were upregulated in IPF case 1, whereas STK33, PIM2, and SYK were upregulated in IPF case 2. IHC revealed that these proteins were expressed in the epithelial layer of the fibrotic lesions. CONCLUSIONS: We performed a comprehensive kinase expression analysis to explore the potential therapeutic targets for IPF. We found that DCLK1 and STK33 may serve as potential candidate targets for molecular targeted therapy of IPF. In addition, PDK4, ERBB4, PIM2, and SYK might also serve as personalized therapeutic targets of IPF. Additional large-scale studies are warranted to develop personalized therapies for patients with IPF.

DOI： 10.1186/s12931-022-01940-y

Massive hemoptysis in a post-operative patient with recurrent lung cancer successfully treated by the combination therapy of Endobronchial Watanabe Spigot and bronchial artery embolization. International journal

Masataka Taoka, Go Makimoto, Noriyuki Umakoshi, Kiichiro Ninomiya, Hisao Higo, Yuka Kato, Masanori Fujii, Toshio Kubo, Eiki Ichihara, Kadoaki Ohashi, Katsuyuki Hotta, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura

Respiratory medicine case reports 38 101669 - 101669 2022

Language：English

A 76-year-old woman who was treated with lorlatinib for postoperative recurrent anaplastic lymphoma kinase-positive lung adenocarcinoma visited our hospital with massive hemoptysis. Chest computed tomography showed massive bleeding from the right upper lobe; however, the cause of bleeding was unclear. After bronchial artery embolization (BAE), bronchial occlusion was performed using an Endobronchial Watanabe Spigot (EWS) that was easily placed because BAE had reduced the bleeding volume. Treatment with BAE alone was inadequate; however, additional therapy with EWS after BAE successfully controlled the massive hemoptysis, especially in this patient who underwent lobectomy to prevent respiratory dysfunction.

DOI： 10.1016/j.rmcr.2022.101669

Successful and Prompt Treatment with Tepotinib for Lung Adenocarcinoma Harboring MET Exon 14 Skipping Mutation Combined with Lung Abscess Formation: A Case Report. International journal

Go Makimoto, Atsushi Shimonishi, Kadoaki Ohashi, Kiichiro Ninomiya, Hisao Higo, Yuka Kato, Masanori Fujii, Toshio Kubo, Eiki Ichihara, Katsuyuki Hotta, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura

Case reports in oncology 15 ( 2 ) 494 - 498 2022

Language：English

Tepotinib, the novel MET-tyrosine kinase inhibitor, shows an antitumor effect for patients with non-small-cell lung cancer (NSCLC) harboring MET exon 14 skipping mutation. In January 2022, the AmoyDx® Pan Lung Cancer polymerase chain reaction Panel (AmoyDx® panel), which had a shorter turnaround time than the conventional test, was launched in Japan as a tepotinib companion test. We report a patient with an advanced MET-mutant NSCLC promptly diagnosed using the AmoyDx® panel and successfully treated with tepotinib. Although the patient's performance status (PS) worsened due to the rapid tumor progression and lung abscess formation, the tumor shrank immediately after tepotinib treatment with marked PS improvement.

DOI： 10.1159/000524326

複視・有痛性筋痙攣を有し急速に歩行困難を来たした胸腺腫に伴う傍腫瘍性神経症候群の1例

野海拓, 加藤有加, 二宮貴一朗, 槇本剛, 久保寿夫, 藤井昌学, 市原英基, 大橋圭明, 堀田勝幸, 田端雅弘, 木浦勝行, 前田嘉信

肺癌 61 ( 7 ) 1010 - 1010 2021.12

Significance of PD-L1 expression in the cytological samples of non-small cell lung cancer patients treated with immune checkpoint inhibitors. International journal

Naofumi Hara, Eiki Ichihara, Daijiro Harada, Koji Inoue, Keiichi Fujiwara, Shinobu Hosokawa, Daizo Kishino, Kawai Haruyuki, Nobuaki Ochi, Naohiro Oda, Katsuyuki Hotta, Yoshinobu Maeda, Katsuyuki Kiura

Journal of cancer research and clinical oncology 147 ( 12 ) 3749 - 3755 2021.12

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

OBJECTIVES: The programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) in tumor tissue samples is an established clinical biomarker for non-small cell lung cancer (NSCLC). However, the significance of PD-L1 expression in other types of samples has not been fully investigated. PATIENTS AND METHODS: We conducted a multicenter retrospective cohort study of advanced NSCLC patients who received ICI treatment during the clinical course and investigated the effects of ICIs according to PD-L1 expression in cytology samples, including cell block and endobronchial ultrasound-guided (EBUS) transbronchial needle aspiration (TBNA) samples. RESULTS: A total of 264 patients were included in this study: PD-L1 expression was determined in cell block or TBNA specimens in 55 patients, and in tissue samples in 209 patients. Among the former patients, the median progression-free survival (PFS) of those with a TPS for PD-L1 ≥ 50% was significantly longer compared to that of those with a TPS < 50% (6.5 vs. 1.9 months, respectively, p = 0.008). When the cutoff value was set at 1%, the median PFS was 4.2 months in patients with a TPS ≥ 1% and 1.5 months in patients with a TPS < 1% (p < 0.001). CONCLUSION: PD-L1 expression determined using cytology specimens predicts the efficacy of ICIs.

DOI： 10.1007/s00432-021-03615-5

免疫チェックポイント阻害薬投与後に筋炎合併筋無力症様症状を呈した3症例

久保寿夫, 加藤有加, 二宮貴一朗, 槇本剛, 藤井昌学, 市原英基, 大橋圭明, 堀田勝幸, 田端雅弘, 前田嘉信, 木浦勝行

肺癌 61 ( 6 ) 701 - 701 2021.10

Marginal Zone Lymphoma and Lung Adenocarcinoma with an EGFR Exon 19 E746-S752del Mutation in a Patient with IgG4-related Disease

Sachi Okawa, Kammei Rai, Nobuharu Fujii, Yuka Gion, Kiichiro Ninomiya, Yuka Kato, Akihiko Taniguchi, Toshio Kubo, Eiki Ichihara, Kadoaki Ohashi, Nobuaki Miyahara, Katsuyuki Hotta, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura

Internal Medicine 60 ( 17 ) 2831 - 2837 2021.9

A randomized trial of sodium alginate prevention of esophagitis in LA-NSCLC receiving chemoradiotherapy: OLCSG1401. International journal

Kiichiro Ninomiya, Toshihide Yokoyama, Katsuyuki Hotta, Isao Oze, Kuniaki Katsui, Tae Hata, Hiroshige Yoshioka, Akihiro Bessho, Shinobu Hosokawa, Shoichi Kuyama, Kenichiro Kudo, Toshiyuki Kozuki, Daijiro Harada, Masayuki Yasugi, Toshi Murakami, Masamoto Nakanishi, Nagio Takigawa, Yoshinobu Maeda, Katsuyuki Kiura

Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer 29 ( 9 ) 5237 - 5244 2021.9

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

BACKGROUND: Radiation esophagitis is a critical adverse event that needs to be appropriately managed while administering thoracic irradiation. This trial aimed to investigate whether sodium alginate has preventative effects on esophagitis in patients with non-small-cell lung cancer (NSCLC) receiving concurrent chemoradiotherapy (CRT). METHODS: Patients with untreated stage III NSCLC who were eligible for concurrent CRT were randomly assigned at a 1:1:1 ratio to receive one of the following treatments: initial or late use of oral sodium alginate (arms A and B) or water as control (arm C). The primary endpoint was the proportion of patients developing G3 or worse esophagitis. RESULTS: Overall, 94 patients were randomly assigned between February 2014 and September 2018. The study was prematurely terminated because of slow accrual. The proportions of patients with G3 or worse esophagitis were 12.5%, 9.8%, and 19.4% in arms A, B, and C, respectively. Patients receiving sodium alginate had fewer onsets of G3 esophagitis; however, differences compared with arm C were not significant (A vs. C: p = 0.46; B vs. C: p = 0.28). The rates of grade 3 or worse non-hematologic toxicities besides esophagitis were 29%, 26%, and 43% in arms A, B, and C, respectively. Interestingly, compared with arm C, a low rate of febrile neutropenia was observed in arm A (3.1% vs. 19.4%: p = 0.04). CONCLUSIONS: Sodium alginate did not show significant preventative effects on radiation-induced esophagitis in patients with NSCLC. The frequency of CRT-induced febrile neutropenia was lower in the early use sodium alginate arm. TRIAL REGISTRATION: ClinicalTrials.gov Identifier Registry number: UMIN000013133.

DOI： 10.1007/s00520-021-06092-1

Triple therapy with osimertinib, bevacizumab and cetuximab in EGFR-mutant lung cancer with HIF-1α/TGF-α expression. International journal

Kazuya Nishii, Kadoaki Ohashi, Hiromi Watanabe, Go Makimoto, Takamasa Nakasuka, Hisao Higo, Kiichiro Ninomiya, Yuka Kato, Toshio Kubo, Kammei Rai, Eiki Ichihara, Katsuyuki Hotta, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura

Oncology letters 22 ( 3 ) 639 - 639 2021.9

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

Osimertinib, a third generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, is the standard treatment for patients with lung cancer harboring EGFR T790M; however, acquired resistance is inevitable due to genetic and epigenetic changes in cancer cells. In addition, a recent randomized clinical trial revealed that the combination of osimertinib and bevacizumab failed to exhibit superior progression-free survival compared with osimertinib alone. The present study aimed to investigate the effect of triple therapy with osimertinib, bevacizumab and cetuximab in xenograft tumors with different initial tumor volumes (conventional model, 200 mm3 and large model, 500 mm3). The results demonstrated that osimertinib significantly inhibited tumor growth in both the conventional and large models; however, maximum tumor regression was attenuated in the large model in which hypoxia-inducible factor-1α (HIF-1α) and transforming growth factor-α (TGF-α) expression levels increased. Although the combination of osimertinib and bevacizumab exerted a greater inhibitory effect on tumor growth compared with osimertinib in the conventional model, the effect of this combination therapy was attenuated in the large model. TGF-α attenuated sensitivity to osimertinib in vitro; however, this negative effect was counteracted by the combination of osimertinib and cetuximab, but not osimertinib and bevacizumab. In the large xenograft tumor model, the triple therapy induced the greatest inhibitory effect on tumor growth compared with osimertinib alone and its combination with bevacizumab. Clinical trials of the triple therapy are required for patients with lung cancer with EGFR mutations and HIF-1α/TGF-α.

DOI： 10.3892/ol.2021.12900

Pulmonary Aspergilloma and Allergic Bronchopulmonary Aspergillosis Following the 2018 Heavy Rain Event in Western Japan: A Case Report.

Eri Ando, Takamasa Nakasuka, Toshio Kubo, Akihiko Taniguchi, Kiichiro Ninomiya, Yuka Kato, Eiki Ichihara, Kadoaki Ohashi, Kammei Rai, Katsuyuki Hotta, Masaomi Yamane, Nobuaki Miyahara, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura

Internal medicine (Tokyo, Japan) 61 ( 3 ) 379 - 383 2021.8

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

A 16-year-old boy with asthma participated in recovery volunteer work following the 2018 heavy rains in Japan. One month later, he experienced chest pain and dyspnea. Chest computed tomography revealed a cavity with a fungal ball, and Aspergillus fumigatus was detected in his bronchoalveolar lavage fluid. He was treated with voriconazole, but new consolidations appeared rapidly. He also experienced allergic bronchopulmonary aspergillosis. After prednisolone prescription, the consolidations improved; however, his asthma worsened. He underwent partial lung resection to avoid allergens, and his symptoms improved. We must recognize cases of infection after a disaster, especially in patients with chronic respiratory diseases.

DOI： 10.2169/internalmedicine.7124-21

Survival of chemo-naïve patients with EGFR mutation-positive advanced non-small cell lung cancer after treatment with afatinib and bevacizumab: updates from the Okayama Lung Cancer Study Group Trial 1404. International journal

Takashi Ninomiya, Naoyuki Nogami, Toshiyuki Kozuki, Daijiro Harada, Toshio Kubo, Kadoaki Ohashi, Eiki Ichihara, Shoichi Kuyama, Kenichiro Kudo, Akihiro Bessho, Makoto Sakugawa, Nobukazu Fujimoto, Keisuke Aoe, Daisuke Minami, Keisuke Sugimoto, Nobuaki Ochi, Nagio Takigawa, Katsuyuki Hotta, Yoshinobu Maeda, Katsuyuki Kiura

Japanese journal of clinical oncology 51 ( 8 ) 1269 - 1276 2021.8

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

BACKGROUND: In a phase I study, afatinib (30 mg/body daily) plus bevacizumab (15 mg/kg every 3 weeks) was well tolerated and showed favourable outcomes in patients with epidermal growth factor receptor (EGFR)-mutant advanced non-small-cell lung cancer. Herein, we report the 2-year progression-free survival, overall survival and safety profile of these patients. METHODS: Chemo-naïve patients with EGFR-mutant advanced non-small-cell lung cancer were enrolled. One group of patients received 40 mg afatinib daily and 15 mg/kg bevacizumab every 3 weeks (level 0) until disease progression or severe toxicity. Another group of patients received 30 mg afatinib daily and the same dose of bevacizumab (level 1). Dose-limiting toxicity was the primary endpoint, whereas long-term progression-free survival, overall survival and tolerability were secondary endpoints. Survival rates were estimated using the Kaplan-Meier method. RESULTS: The study included 19 patients (level 0: 5; level - 1: 14). Until the data cut-off date, seven patients continued the treatment, whereas 12 discontinued due to disease progression (n = 5) or toxicity (n = 7). The median PFS was 24.2 months, while the median overall survival was not reached. All patients developed adverse effects. Diarrhoea and skin rash were frequently observed as severe adverse events (grade 3). A secondary EGFR mutation (T790M) was detected in two patients after progression. CONCLUSIONS: Prolonged follow-up revealed that combination therapy with afatinib and bevacizumab might improve survival outcomes in EGFR-mutant advanced non-small-cell lung cancer patients and seems to be promising. TRIAL REGISTRATION: UMIN000015944.

DOI： 10.1093/jjco/hyab084

SHP2 Inhibition Enhances the Effects of Tyrosine Kinase Inhibitors in Preclinical Models of Treatment-naïve ALK-, ROS1-, or EGFR-altered Non-small Cell Lung Cancer. International journal

Hirohisa Kano, Eiki Ichihara, Hiromi Watanabe, Kazuya Nishii, Chihiro Ando, Takamasa Nakasuka, Kiichiro Ninomiya, Yuka Kato, Toshio Kubo, Kammei Rai, Kadoaki Ohashi, Katsuyuki Hotta, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura

Molecular cancer therapeutics 20 ( 9 ) 1653 - 1662 2021.6

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

After molecular-targeted therapy, some cancer cells may remain that are resistant to therapies targeting oncogene alterations, such as those in the genes encoding the EGFR and anaplastic lymphoma kinase (ALK) as well as c-ros oncogene 1 (ROS1). The mechanisms underlying this type of resistance are unknown. In this article, we report the potential role of Src homology 2 domain-containing phosphatase 2 (SHP2) in the residual cells of ALK/ROS1/EGFR-altered non-small cell lung cancer (NSCLC). Molecular-targeted therapies failed to inhibit the ERK signaling pathway in the residual cells, whereas the SHP2 inhibitor SHP099 abolished their remaining ERK activity. SHP099 administered in combination with molecular-targeted therapy resulted in marked growth inhibition of cancer cells both in vitro and in vivo Thus, treatment combining an SHP2 inhibitor and a tyrosine kinase inhibitor may be a promising therapeutic strategy for oncogene-driven NSCLC.

DOI： 10.1158/1535-7163.MCT-20-0965

A case of dramatic reduction in cancer-associated thrombus following initiation of pembrolizumab in patient with a poor performance status and PD-L1+ lung adenocarcinoma harboring CCDC6-RET fusion gene and NF1/TP53 mutations. International journal

Takamasa Nakasuka, Kadoaki Ohashi, Hiromi Watanabe, Toshio Kubo, Shingo Matsumoto, Koichi Goto, Katsuyuki Hotta, Yoshinobu Maeda, Katsuyuki Kiura

Lung cancer (Amsterdam, Netherlands) 156 1 - 4 2021.6

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

OBJECTIVES: Pembrolizumab is a standard treatment for non-small cell lung cancer (NSCLC) with high-PD-L1 expression; however, its effect is dismal in patients with poor physical condition. Additionally, the effect of immunotherapy is generally limited in NSCLC harboring driver mutations such asEGFR, ALK, or RET gene aberrations. RESULTS: We report the beneficial effect of pembrolizumab in a patient with poor performance status and PD-L1+ lung adenocarcinoma with theCCDC6-RET fusion gene and co-occurring NF1/TP53 mutations, complicated by multiple cancer-associated thrombi and respiratory failure. CONCLUSIONS: Further studies are warranted to establish the role of co-occurring NF1/TP53 mutations as a positive predictive biomarker for pembrolizumab in NSCLC harboring RET fusion genes.

DOI： 10.1016/j.lungcan.2021.03.022

A novel osimertinib-resistant human lung adenocarcinoma cell line harbouring mutant EGFR and activated IGF1R. International journal

Go Makimoto, Kiichiro Ninomiya, Toshio Kubo, Ryota Sunami, Yuka Kato, Eiki Ichihara, Kadoaki Ohashi, Kammei Rai, Katsuyuki Hotta, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura

Japanese journal of clinical oncology 51 ( 6 ) 956 - 965 2021.5

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

OBJECTIVE: A third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), osimertinib, is the standard treatment for patients with non-small cell lung cancer harbouring mutant EGFR. Unfortunately, these patients inevitably acquire resistance to EGFR-TKI therapies, including osimertinib. However, the mechanism associated with this resistance remains unclear. METHODS: A 63-year-old Japanese female with lung adenocarcinoma underwent right upper lobectomy (pT1bN2M0 pStage IIIA, EGFR Ex21 L858R). She manifested post-operative tumour recurrence with multiple lung metastases 8 months later and began gefitinib treatment. The lung lesions re-grew 15 months later, and EGFR T790M mutation was detected in the lung metastasis re-biopsy. She was administered osimertinib; however, it relapsed with pleural effusion 16 months later. We isolated cells from the osimertinib-resistant pleural effusion to establish a novel cell line, ABC-31. RESULTS: Although the EGFR L858R mutation was detected in ABC-31 cells, the T790M mutation was lost. ABC-31 cells were resistant to EGFR-TKIs, including osimertinib. Phospho-receptor tyrosine kinase array revealed activation of the insulin-like growth factor 1 receptor (IGF1R), whereas overexpression of the IGF1R ligand, IGF2, induced IGF1R activation in ABC-31 cells. Combination therapy using EGFR-TKIs and IGF1R inhibitor acted synergistically in vitro. She was re-administered osimertinib since EGFR-TKIs and IGF1R inhibitor combination therapy was impossible in clinical practice. This had a slight and short-lived effect. CONCLUSIONS: Taken together, we have successfully established a new osimertinib-resistant lung adenocarcinoma cell line with activated IGF1R. These ABC-31 cells will help develop novel therapeutic strategies for patients with lung adenocarcinoma resistant to specific treatment via IGF1R activation.

DOI： 10.1093/jjco/hyab048

VEGFR2 blockade augments the effects of tyrosine kinase inhibitors by inhibiting angiogenesis and oncogenic signaling in oncogene-driven non-small-cell lung cancers. International journal

Hiromi Watanabe, Eiki Ichihara, Hiroe Kayatani, Go Makimoto, Kiichiro Ninomiya, Kazuya Nishii, Hisao Higo, Chihiro Ando, Sachi Okawa, Takamasa Nakasuka, Hirohisa Kano, Naofumi Hara, Atsuko Hirabae, Yuka Kato, Takashi Ninomiya, Toshio Kubo, Kammei Rai, Kadoaki Ohashi, Katsuyuki Hotta, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura

Cancer science 112 ( 5 ) 1853 - 1864 2021.5

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

Molecular agents targeting the epidermal growth factor receptor (EGFR)-, anaplastic lymphoma kinase (ALK)- or c-ros oncogene 1 (ROS1) alterations have revolutionized the treatment of oncogene-driven non-small-cell lung cancer (NSCLC). However, the emergence of acquired resistance remains a significant challenge, limiting the wider clinical success of these molecular targeted therapies. In this study, we investigated the efficacy of various molecular targeted agents, including erlotinib, alectinib, and crizotinib, combined with anti-vascular endothelial growth factor receptor (VEGFR) 2 therapy. The combination of VEGFR2 blockade with molecular targeted agents enhanced the anti-tumor effects of these agents in xenograft mouse models of EGFR-, ALK-, or ROS1-altered NSCLC. The numbers of CD31-positive blood vessels were significantly lower in the tumors of mice treated with an anti-VEGFR2 antibody combined with molecular targeted agents compared with in those of mice treated with molecular targeted agents alone, implying the antiangiogenic effects of VEGFR2 blockade. Additionally, the combination therapies exerted more potent antiproliferative effects in vitro in EGFR-, ALK-, or ROS1-altered NSCLC cells, implying that VEGFR2 inhibition also has direct anti-tumor effects on cancer cells. Furthermore, VEGFR2 expression was induced following exposure to molecular targeted agents, implying the importance of VEGFR2 signaling in NSCLC patients undergoing molecular targeted therapy. In conclusion, VEGFR2 inhibition enhanced the anti-tumor effects of molecular targeted agents in various oncogene-driven NSCLC models, not only by inhibiting tumor angiogenesis but also by exerting direct antiproliferative effects on cancer cells. Hence, combination therapy with anti-VEGFR2 antibodies and molecular targeted agents could serve as a promising treatment strategy for oncogene-driven NSCLC.

DOI： 10.1111/cas.14801

VEGFR2 blockade augments the effects of tyrosine kinase inhibitors by inhibiting angiogenesis and oncogenic signaling in oncogene-driven non-small-cell lung cancers

Hiromi Watanabe, Eiki Ichihara, Hiroe Kayatani, Go Makimoto, Kiichiro Ninomiya, Kazuya Nishii, Hisao Higo, Chihiro Ando, Sachi Okawa, Takamasa Nakasuka, Hirohisa Kano, Naofumi Hara, Atsuko Hirabae, Yuka Kato, Takashi Ninomiya, Toshio Kubo, Kammei Rai, Kadoaki Ohashi, Katsuyuki Hotta, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura

CANCER SCIENCE 112 ( 5 ) 1853 - 1864 2021.5

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

Molecular agents targeting the epidermal growth factor receptor (EGFR)-, anaplastic lymphoma kinase (ALK)- or c-ros oncogene 1 (ROS1) alterations have revolutionized the treatment of oncogene-driven non-small-cell lung cancer (NSCLC). However, the emergence of acquired resistance remains a significant challenge, limiting the wider clinical success of these molecular targeted therapies. In this study, we investigated the efficacy of various molecular targeted agents, including erlotinib, alectinib, and crizotinib, combined with anti-vascular endothelial growth factor receptor (VEGFR) 2 therapy. The combination of VEGFR2 blockade with molecular targeted agents enhanced the anti-tumor effects of these agents in xenograft mouse models of EGFR-, ALK-, or ROS1-altered NSCLC. The numbers of CD31-positive blood vessels were significantly lower in the tumors of mice treated with an anti-VEGFR2 antibody combined with molecular targeted agents compared with in those of mice treated with molecular targeted agents alone, implying the antiangiogenic effects of VEGFR2 blockade. Additionally, the combination therapies exerted more potent antiproliferative effects in vitro in EGFR-, ALK-, or ROS1-altered NSCLC cells, implying that VEGFR2 inhibition also has direct anti-tumor effects on cancer cells. Furthermore, VEGFR2 expression was induced following exposure to molecular targeted agents, implying the importance of VEGFR2 signaling in NSCLC patients undergoing molecular targeted therapy. In conclusion, VEGFR2 inhibition enhanced the anti-tumor effects of molecular targeted agents in various oncogene-driven NSCLC models, not only by inhibiting tumor angiogenesis but also by exerting direct antiproliferative effects on cancer cells. Hence, combination therapy with anti-VEGFR2 antibodies and molecular targeted agents could serve as a promising treatment strategy for oncogene-driven NSCLC.

DOI： 10.1111/cas.14801

The effects of antibiotics on the efficacy of immune checkpoint inhibitors in patients with non-small-cell lung cancer differ based on PD-L1 expression. International journal

Nobuaki Ochi, Eiki Ichihara, Nagio Takigawa, Daijiro Harada, Koji Inoue, Takuo Shibayama, Shinobu Hosokawa, Daizo Kishino, Shingo Harita, Naohiro Oda, Naofumi Hara, Katsuyuki Hotta, Yoshinobu Maeda, Katsuyuki Kiura

European journal of cancer (Oxford, England : 1990) 149 73 - 81 2021.5

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

BACKGROUND: Immune checkpoint inhibitors (ICIs) are essential for treatment of various malignancies, including non-small-cell lung cancer (NSCLC). Recently, several studies have shown that the gut microbiome plays an important role in ICI treatment of solid cancers, and antibiotic (ATB) use had a negative impact on the outcomes of ICI treatment via dysbiosis in the gut. However, whether this is applicable to NSCLC remains unclear. The impact of ATBs based on PD-L1 expression also remains unclear. METHODS: We retrospectively reviewed the medical records of patients with NSCLC who received ICI monotherapy (anti-PD-1 or anti-PD-L1 antibody) at nine institutions from December 2015 to May 2018. Outcomes with use of ATBs during the 2 months before or a month after initiation of ICI treatment, including progression-free survival (PFS) and overall survival (OS), were investigated using the Kaplan-Meier method. Multivariate analysis was also conducted using a Cox proportional hazards model. RESULTS: A total of 531 patients were included in this study, among whom 98 (18.5%) received ATBs before or after ICI treatment. ATB use was significantly associated with a shorter median OS (11.7 months in the ATB group vs. 16.1 months in the non-ATB group; p = 0.028), whereas the difference in PFS was not significant (3.5 months in both the groups; p = 0.287). We next investigated the association based on PD-L1 expression in the 265 patients for whom PD-L1 expression was determined. There was no significant difference in the median OS or PFS between patients with NSCLC and PD-L1 expression <50% receiving ATBs and those not receiving ATBs (PFS: 3.3 vs. 2.8 months, p = 0.88; OS: 9.5 vs. 17.1 months, p = 0.24). Conversely, patients with NSCLC and PD-L1 expression ≥50% receiving ATBs showed significantly shorter median PFS and OS (PFS: 4.2 vs. 9.4 months, p = 0.012; OS: 11.9 vs. 28.4 months, p = 0.011). The impact of ATBs in patients with NSCLC and PD-L1 expression ≥50% was more significant than that in the entire cohort. CONCLUSIONS: Our results indicate that the impact of ATB use on the efficacy of ICIs differed based on PD-L1 expression in patients with advanced NSCLC. A negative impact of ATB use was found in patients with NSCLC and PD-L1 expression ≥50% but not in those with PD-L1 expression <50%.

DOI： 10.1016/j.ejca.2021.02.040

Comparison of bronchoscopy and computed tomography-guided needle biopsy for re-biopsy in non-small cell lung cancer patients. International journal

Hirohisa Kano, Toshio Kubo, Kiichiro Ninomiya, Eiki Ichihara, Kadoaki Ohashi, Kammei Rai, Katsuyuki Hotta, Masahiro Tabata, Takao Hiraki, Susumu Kanazawa, Yoshinobu Maeda, Katsuyuki Kiura

Respiratory investigation 59 ( 2 ) 240 - 246 2021.3

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

BACKGROUND: New therapeutic drugs have been developed for non-small cell lung cancer (NSCLC), and the prognosis of advanced NSCLC patients has improved. However, resistance to these drugs is a concern, and re-biopsy is necessary to determine the mechanism of drug resistance. There are many reports about the protocols for re-biopsy, including techniques such as bronchoscopy and computed tomography-guided needle biopsy (CTNB); however, there is no consensus on which method is optimal. Therefore, we retrospectively reviewed the bronchoscopy and CTNB re-biopsies conducted at our hospital. METHODS: We retrospectively analyzed 79 cases of re-biopsies with bronchoscopy or CTNB in patients with NSCLC from January 2014 to December 2016 at our institute. RESULTS: Forty-nine cases of bronchoscopy and 30 cases of CTNB were taken for re-biopsy. The diagnostic rates of bronchoscopy and CTNB were 83.7% and 100%, respectively (p = 0.023). The complication rates of bronchoscopy and CTNB were 18.4% and 36.7%, respectively (p = 0.11), with a statistically significant difference in the incidence of pneumothorax (0% vs. 23.3%, respectively; p < 0.01). Pneumothorax required drainage in 6.7% of all CTNB cases. There were no fatalities in either group. CONCLUSIONS: CTNB showed a higher diagnostic rate; however, it was associated with a higher rate of complications such as pneumothorax. Hence, the optimal modality must be determined individually for each patient.

DOI： 10.1016/j.resinv.2020.12.001

Crizotinib for recurring non-small-cell lung cancer with EML4-ALK fusion genes previously treated with alectinib: A phase II trial. International journal

Daijiro Harada, Hideko Isozaki, Toshiyuki Kozuki, Toshihide Yokoyama, Hiroshige Yoshioka, Akihiro Bessho, Shinobu Hosokawa, Ichiro Takata, Nagio Takigawa, Katsuyuki Hotta, Katsuyuki Kiura

Thoracic cancer 12 ( 5 ) 643 - 649 2021.3

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

BACKGROUND: The efficacy of crizotinib treatment for recurring EML4-ALK-positive non-small cell lung cancer (NSCLC) previously treated with alectinib is unclear. Based on our preclinical findings regarding hepatocyte growth factor/mesenchymal epithelial transition (MET) pathway activation as a potential mechanism of acquired resistance to alectinib, we conducted a phase II trial of the anaplastic lymphoma kinase/MET inhibitor, crizotinib, in patients with alectinib-refractory, EML4-ALK-positive NSCLC. METHODS: Patients with ALK-rearranged tumors treated with alectinib immediately before enrolling in the trial received crizotinib monotherapy. The objective response rate was the primary outcome of interest. RESULTS: Nine (100%) patients achieved a partial response with alectinib therapy with a median treatment duration of 6.7 months. Crizotinib was administered with a median treatment interval of 50 (range, 20-433) days. The overall response rate was 33.3% (90% confidence interval [CI]: 9.8-65.5 and 95% CI: 7.5-70.1), which did not reach the predefined criteria of 50%. Two (22%) patients who achieved a partial response had brain metastases at baseline. Progression-free survival (median, 2.2 months) was not affected by the duration of treatment with alectinib. The median survival time was 24.1 months. The most common adverse events were an increased aspartate transaminase/alanine transaminase (AST/ALT) ratio (44%) and appetite loss (33%); one patient developed transient grade 4 AST/ALT elevation, resulting in treatment discontinuation. Other adverse events were consistent with those previously reported; no treatment-related deaths occurred. CONCLUSIONS: Although the desired response rate was not achieved, crizotinib monotherapy following treatment with alectinib showed efficacy alongside previously described adverse events.

DOI： 10.1111/1759-7714.13825

Novel prospective umbrella-type lung cancer registry study for clarifying clinical practice patterns: CS-Lung-003 study protocol. International journal

Kazuya Nishii, Masaaki Inoue, Hideto Obata, Yutaka Ueda, Toshiyuki Kozuki, Masahiro Yamasaki, Tomonori Moritaka, Yoshikazu Awaya, Keisuke Sugimoto, Kenichi Gemba, Shoichi Kuyama, Hirohisa Ichikawa, Takuo Shibayama, Tetsuya Kubota, Masahiro Kodani, Daizo Kishino, Nobukazu Fujimoto, Nobuhisa Ishikawa, Yukari Tsubata, Tomoya Ishii, Kazunori Fujitaka, Katsuyuki Hotta, Katsuyuki Kiura

Thoracic cancer 12 ( 5 ) 725 - 731 2021.3

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

INTRODUCTION: Conventional cancer registries are suitable for simple surveillance of cancer patients, including disease frequency and distribution, demographics, and prognosis; however, the collected data are inadequate to clarify comprehensively diverse clinical questions in daily practice. METHODS: We constructed an umbrella-type lung cancer patient registry (CS-Lung-003) integrating multiple related prospective observational studies (linked studies) that reflect clinical questions about lung cancer treatment. The primary endpoint of this registry is to clarify daily clinical practice patterns in lung cancer treatment; a key inclusion criterion is pathologically diagnosed lung cancer. Under this registry, indispensable clinical items are detected in advance across all active linked studies and gathered prospectively and systematically to avoid excessive or insufficient data collection. Researchers are to input information mutually, irrespective of the relevance to each researcher's own study. Linked studies under the umbrella of the CS-Lung-003 registry will be updated annually with newly raised clinical questions; some linked studies will be newly created, while others will be deleted after the completion of the analysis. Enrollment began in July 2017. DISCUSSION: We successfully launched the umbrella-type CS-Lung-003 registry. Under this single registry, researchers collaborate on patient registration and data provision for their own and other studies. Thus, the registry will produce results for multiple domains of study, providing answers to questions about lung cancer treatment raised by other researchers. Through such analysis of each linked study, this registry will contribute to the comprehensive elucidation of actual daily practice patterns in lung cancer treatment. KEY POINTS: CS-Lung-003 registry directly integrates multiple linked studies created under the umbrella of this cancer registry to solve various clinical questions regarding daily practice patterns of lung cancer treatment.

DOI： 10.1111/1759-7714.13789

Impact of previous thoracsic radiation therapy on the efficacy of immune checkpoint inhibitors in advanced non-smasll-cell lung cancer. International journal

Shinobu Hosokawa, Eiki Ichihara, Akihiro Bessho, Daijiro Harada, Koji Inoue, Takuo Shibayama, Daizo Kishino, Shingo Harita, Nobuaki Ochi, Naohiro Oda, Naofumi Hara, Katsuyuki Hotta, Yoshinobu Maeda, Katsuyuki Kiura

Japanese journal of clinical oncology 51 ( 2 ) 279 - 286 2021.2

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

OBJECTIVES: Studies investigating the association between radiation therapy and the efficacy of immune checkpoint inhibitors in advanced non-small-cell lung cancer have provided inconsistent results, likely due to relatively small cohort sizes. This study investigated the effect of previous thoracic radiation therapy on the efficacy of immune checkpoint inhibitor therapy in a large non-small-cell lung cancer cohort. PATIENTS AND METHODS: We conducted a retrospective cohort study using data from 531 non-small-cell lung cancer patients who received monotherapy with programmed cell death protein 1/programmed death-ligand 1 inhibitors at nine institutions. The effects of thoracic radiation therapy on the efficacy of immune checkpoint inhibitors were investigated. RESULTS: A total of 531 non-small-cell lung cancer patients treated with immune checkpoint inhibitors were included in this study. The progression-free survival period was significantly longer in patients that had received thoracic radiation therapy before immune checkpoint inhibitor therapy compared to those without previous thoracic radiation therapy (median progression-free survival 5.0 vs. 3.0 months, P = 0.0013). A multivariate analysis showed that thoracic radiation therapy was an independent predictive factor of improved progression-free survival (hazard ratio of progression-free survival: 0.79, P = 0.049). In contrast, extra-thoracic radiation therapy was associated with inferior outcomes (median progression-free survival 3.0 vs. 4.2 months, P = 0.0008). CONCLUSION: Previous thoracic radiation therapy, but not prior extra-thoracic radiation therapy, enhanced the efficacy of anti-programmed cell death protein 1/programmed death-ligand 1 therapy in non-small-cell lung cancer patients.

DOI： 10.1093/jjco/hyaa180

Randomized study comparing mannitol with furosemide for the prevention of cisplatin-induced renal toxicity in non-small cell lung cancer: The OLCSG1406 trial. International journal

Go Makimoto, Katsuyuki Hotta, Isao Oze, Kiichiro Ninomiya, Masamoto Nakanishi, Naofumi Hara, Hirohisa Kano, Hiromi Watanabe, Yusuke Hata, Kazuya Nishii, Takamasa Nakasuka, Junko Itano, Takashi Ninomiya, Toshio Kubo, Kadoaki Ohashi, Eiki Ichihara, Daisuke Minami, Akiko Sato, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura

Asia-Pacific journal of clinical oncology 17 ( 1 ) 101 - 108 2021.2

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

AIM: Evidence is lacking on the best standard method for forced diuresis to prevent cisplatin-induced nephrotoxicity. We compared the cisplatin-induced nephrotoxicity prevention effect of furosemide or mannitol in patients with advanced non-small cell lung cancer. METHODS: Patients with advanced non-small cell lung cancer suitable to receive cisplatin-containing regimen were randomly assigned to receive furosemide or mannitol with appropriate hydration. The primary endpoint was the proportion of ≥ grade 1 serum creatinine elevation in the first cycle. RESULTS: The trial was terminated early with 44 (22 per arm) of the planned 66 patients because of slow accrual. Patients' characteristics were well balanced with median baseline creatinine clearance of 98.0 and 95.1 mL/min in the furosemide and mannitol arms, respectively. In the first cycle, two (9%) and four (18%) patients developed grade 1 creatinine elevation (P = .66), respectively, despite no ≥ grade 2 toxicity. The median times to develop the worst creatinine score were 10 and 8 days, respectively. For all cycles, median times to recover to grade 0 were 56 and 20 days, respectively. The furosemide arm was characterized by relatively high urine output after cisplatin administration (900 vs 550 mL/h), low frequency of unplanned additional hydration (14% vs 32%), and high incidence of hyponatremia (18% and 5%) compared with the mannitol arm. Both arms showed similar progression-free survival and overall survival. CONCLUSION: The preventive effect of the two forced diuretics on cisplatin-induced nephrotoxicity was not significantly different. However, the two diuretics have some distinct types of clinical presentations.

DOI： 10.1111/ajco.13423

Characteristics of patients with EGFR-mutant non-small-cell lung cancer who benefited from immune checkpoint inhibitors. International journal

Eiki Ichihara, Daijiro Harada, Koji Inoue, Takuo Shibayama, Shinobu Hosokawa, Daizo Kishino, Shingo Harita, Nobuaki Ochi, Naohiro Oda, Naofumi Hara, Katsuyuki Hotta, Yoshinobu Maeda, Katsuyuki Kiura

Cancer immunology, immunotherapy : CII 70 ( 1 ) 101 - 106 2021.1

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

OBJECTIVES: Immune checkpoint inhibitors (ICIs) are less effective in non-small-cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations. However, a small percentage of patients with EGFR-mutant NSCLC do respond, and the characteristics of these patients are not known. Here, we identify the characteristics of patients who may respond to ICI therapy for EGFR-mutant NSCLC. PATIENTS AND METHODS: The medical records of NSCLC patients with EGFR mutations who received PD-1/PD-L1 antibody monotherapy at nine institutions were reviewed. RESULTS: In total, 58 patients with EGFR-mutant NSCLC were analyzed. Various clinical factors such as smoking history and EGFR mutation type were not associated with progression-free survival (PFS) of ICIs, while the PFS of prior EGFR tyrosine kinase inhibitors (TKIs) was inversely associated with that of ICIs. Patients who responded to prior EGFR TKIs for > 10 months exhibited a significantly shorter response to ICIs compared to those who had responded for ≤ 10 months (PFS of ICI: 1.6 vs. 1.9 months; hazard ratio: 2.54; 95% confidence interval 1.26-5.12; p = 0.009). However, patients who responded to ICIs for > 6 months responded to prior EGFR TKIs for significantly shorter periods compared to those who responded to ICIs for ≤ 6 months (PFS of prior EGFR TKI: 5.3 vs. 12.1 months; log-rank test: p = 0.0025). CONCLUSION: The duration of response to prior EGFR TKIs could be a predictive marker of ICI therapy in EGFR-mutant NSCLC patients.

DOI： 10.1007/s00262-020-02662-0

Immune checkpoint inhibitor efficacy and safety in older non-small cell lung cancer patients. International journal

Toshio Kubo, Hiromi Watanabe, Kiichiro Ninomiya, Kenichiro Kudo, Daisuke Minami, Etsuko Murakami, Nobuaki Ochi, Takashi Ninomiya, Daijiro Harada, Masayuki Yasugi, Eiki Ichihara, Kadoaki Ohashi, Kammei Rai, Keiichi Fujiwara, Katsuyuki Hotta, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura

Japanese journal of clinical oncology 50 ( 12 ) 1447 - 1453 2020.12

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

OBJECTIVES: Immune checkpoint inhibitors offer longer survival than chemotherapy in several clinical trials for advanced non-small cell lung cancer. In subset analyses of clinical trials, immune checkpoint inhibitors extended survival in patients aged ≥65 years, but the effects in patients aged ≥75 years are controversial. We performed multicenter, collaborative and retrospective analyses of immune checkpoint inhibitor efficacy and safety in non-small cell lung cancer patients aged ≥75 years. METHODS: We retrospectively studied 434 advanced non-small cell lung cancer patients who received immune checkpoint inhibitors from December 2015 to December 2017, and retrospectively applied the Geriatric (G) 8 screening tool with medical records. RESULTS: Of the 434 patients who received immune checkpoint inhibitors, 100 were aged ≥75 years. Five patients with performance status 3 were omitted from the final analysis. Immune checkpoint inhibitors were given as a first-line treatment to 20 patients. The objective response rates, median progression-free survival rates and median survival times were 35.0%, 6.1 months and 10.7 months for first-line treatment, and 20.0%, 2.9 months and 14.7 months for second- or later-line treatments, respectively. The median modified G8 score was 11.0. The median survival time was longer in the high modified G8 (≥12.0) group than in the low modified G8 (≤11.0) group (18.7 vs. 8.7 months; P = 0.02). Likewise, the median survival time was 15.5 months (performance status 0-1) vs. 3.2 months (performance status 2) (P < 0.01). The grade ≥ 2 immune-related adverse events incidence was 36.8%. CONCLUSIONS: In this study, immune checkpoint inhibitors were effective and tolerable for patients aged ≥75 years. The modified G8 screening tool and performance status were associated with the outcome of older non-small cell lung cancer patients treated with immune checkpoint inhibitors.

DOI： 10.1093/jjco/hyaa152

Detection of epidermal growth factor receptor mutations in exhaled breath condensate using droplet digital polymerase chain reaction. International journal

Kazuya Nishii, Kadoaki Ohashi, Tomoki Tamura, Kiichiro Ninomiya, Takehiro Matsubara, Satoru Senoo, Hirohisa Kano, Hiromi Watanabe, Naohiro Oda, Go Makimoto, Hisao Higo, Yuka Kato, Takashi Ninomiya, Toshio Kubo, Hiromasa Yamamoto, Shuta Tomida, Katsuyuki Hotta, Masahiro Tabata, Shinichi Toyooka, Yoshinobu Maeda, Katsuyuki Kiura

Oncology letters 20 ( 6 ) 393 - 393 2020.12

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

The detection of certain oncogenic driver mutations, including those of epidermal growth factor receptor (EGFR), is essential for determining treatment strategies for advanced non-small cell lung cancer (NSCLC). The current study assessed the feasibility of testing exhaled breath condensate (EBC) for EGFR mutations by droplet digital PCR (ddPCR). Samples were collected from 12 patients with NSCLC harboring EGFR mutations that were admitted to Okayama University Hospital between June 1, 2014 and December 31, 2017. A total of 21 EBC samples were collected using the RTube™ method and EGFR mutations (L858R, exon 19 deletions or T790M) were assessed through ddPCR analysis (EBC-ddPCR). A total of 3 healthy volunteer samples were also tested to determine a threshold value for each mutation. Various patient characteristics were determined, including sex (3 males and 9 females), age (range 54-81 years; median, 66 years), smoking history (10 had never smoked; 2 were former smokers), histology (12 patients exhibited adenocarcinoma), clinical stage (9 patients were stage IV; 3 exhibited post-operative recurrence) and EGFR mutation type (4 had L858R; 8 had exon 19 deletions; 8 had T790M). EBC-ddPCR demonstrated positive droplets in 8 of the 12 patients. The sensitivity and specificity of each mutation was as follows: 27.3 and 80.0% for EGFR L858R, 30.0 and 90.9% for EGFR Ex19del, and 22.2 and 100% for EGFR T790M. EBC-ddPCR analysis of EGFR mutations exhibited modest sensitivity and acceptable specificity. EBC-ddPCR is a minimally invasive and replicable procedure and may be a complementary method for EGFR testing in patients where blood or tissue sampling proves difficult.

DOI： 10.3892/ol.2020.12256

Impact of HER2 expression on EGFR-TKI treatment outcomes in lung tumors harboring EGFR mutations: A HER2-CS study subset analysis. International journal

Kadoaki Ohashi, Kiichiro Ninomiya, Hiroshige Yoshioka, Akihiro Bessho, Takuo Shibayama, Keisuke Aoe, Nobuhisa Ishikawa, Toshiyuki Kozuki, Haruyuki Kawai, Shoichi Kuyama, Seigo Miyoshi, Kazunori Fujitaka, Hideto Obata, Yukari Tsubata, Yoshikazu Awaya, Masaaki Inoue, Koji Inoue, Naokatsu Horita, Hiroyuki Yanai, Katsuyuki Hotta, Katsuyuki Kiura

Lung cancer (Amsterdam, Netherlands) 150 83 - 89 2020.12

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

OBJECTIVES: Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are standard treatment for EGFR-mutated non-small-cell lung carcinoma (NSCLC); however, a biomarker to predict their efficacy has not been established. Although human epidermal growth factor receptor-2 (HER2) aberrations constitute a potential mechanism for acquired resistance to EGFR-TKIs, the impact of HER2 on EGFR-TKI treatment outcomes has not been systematically evaluated. In this post-hoc subgroup study, we examined the impact of HER2 on the effect of EGFR-TKIs in patients with NSCLC harboring EGFR mutations. MATERIALS AND METHODS: Of 1126 patients with NSCLC enrolled into a prospective cohort study (HER2-CS study), we analyzed data of 356 (32 %) patients with EGFR-mutant tumors. HER2 protein expression levels were determined by immunohistochemistry (IHC) with the gastric cancer criteria. Patients were divided either to an HER2-P group (HER2-IHC2+/3+) or an HER2-N group (HER2-IHC0/1+). We primarily assessed differences in the time-to-treatment failure (TTF) of EGFR-TKI between the groups. RESULTS: The HER2 scoring was as follows: IHC0 (n = 76, 21 %), IHC1+ (n = 199, 56 %), IHC2+ (n = 72, 20 %), and IHC3+ (n = 9, 3 %). The patients' demographics were similar in the HER2-P and HER2-N groups. The HER2-P group showed a significantly shorter EGFR-TKI TTF than the HER2-N group (hazard ratio [HR]: 1.657, 95 % confidence interval [CI]: 1.076-2.552; median: 13.3 vs. 19.1 months). The magnitude of the negative impact of TTF was especially dependent on performance status (PS). HER2 expression significantly deteriorated the TTF in the subgroup with PS 2 (HR: 5.497, 95 % CI: 1.510-20.02), but not in that with better PS (HR: 1.437, 95 % CI: 0.899-2.298) (pinteraction = 0.015). CONCLUSION: In the current cohort, HER2 protein expression in EGFR-mutant NSCLC may have a negative impact on the effect of EGFR-TKIs, the effect of which was PS dependent.

DOI： 10.1016/j.lungcan.2020.09.024

Beneficial effect of erlotinib and trastuzumab emtansine combination in lung tumors harboring EGFR mutations. International journal

Hiroe Kayatani, Kadoaki Ohashi, Kiichiro Ninomiya, Go Makimoto, Kazuya Nishii, Hisao Higo, Hiromi Watanabe, Hirohisa Kano, Yuka Kato, Takashi Ninomiya, Toshio Kubo, Kammei Rai, Eiki Ichihara, Katsuyuki Hotta, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura

Biochemical and biophysical research communications 532 ( 3 ) 341 - 346 2020.11

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

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) is the standard therapy for non-small cell lung cancer (NSCLC) harboring EGFR mutations, but the resistance is inevitable. The drug-tolerant persister cancer cells are thought to be involved in the resistance. We recently reported that HER2 expression had a negative impact on time-to-treatment-failure in patients with EGFR mutant NSCLC. In this study, we hypothesized that HER2 might be a potential target for alternative combination therapy in NSCLC harboring EGFR mutations. In vitro study showed that the level of HER2 expression had no correlation with the sensitivity to EGFR-TKI, erlotinib but showed some correlation with HER2-inhibitor, ado-trastuzumab emtansine (T-DM1) in multiple EGFR-mutant lung cancer cell lines. In addition, HER2 expression was increased in persister cancer cells in 11-18 cell line harboring EGFR L858R or HCC827 cell line harboring EGFR exon 19 deletion after the exposure to erlotinib in vitro and in vivo. The combination of erlotinib and T-DM1 showed a superior inhibitory effect on cell proliferation compared with those of the erlotinib or T-DM1 alone in either 11-18 or HCC827 cells in vitro. The combination therapy also induced a significantly greater inhibitory effect on tumor growth in xenograft model in mice transplanted with either 11-18 or HCC827 cells compared with erlotinib alone or T-DM1 alone. No body weight loss was observed in these mice. These results suggested that the combination therapy with EGFR-TKI and T-DM1 might be a potentially promising strategy for treating lung cancer harboring EGFR mutations.

DOI： 10.1016/j.bbrc.2020.07.055

Utility of immune checkpoint inhibitors in non-small-cell lung cancer patients with poor performance status. International journal

Hirohisa Kano, Eiki Ichihara, Daijiro Harada, Koji Inoue, Hiroe Kayatani, Shinobu Hosokawa, Daizo Kishino, Kazuhiko Watanabe, Nobuaki Ochi, Naohiro Oda, Naofumi Hara, Kiichiro Ninomiya, Katsuyuki Hotta, Yoshinobu Maeda, Katsuyuki Kiura

Cancer science 111 ( 10 ) 3739 - 3746 2020.10

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

Most clinical trials of non-small-cell lung cancer (NSCLC) exclude patients with poor ECOG performance status (PS). Thus, the efficacy of immune checkpoint inhibitors (ICIs) in patients with poor PS remains unclear. Herein, we used data from a retrospective cohort to assess the potential clinical benefits of ICIs in NSCLC patients with poor PS. Data from NSCLC patients who received ICI monotherapy at 9 institutions between December 2015 and May 2018 were retrospectively analyzed. After excluding 4 patients who lacked PS data, a total of 527 ICI-treated patients, including 79 patients with PS 2 or higher, were used for our analyses. The progression-free survival (PFS) and overall survival (OS) of patients with PS 2 or higher were significantly shorter compared with those of PS 0-1 patients (median PFS, 4.1 vs 2.0 months; P < .001 and median OS, 17.4 vs 4.0 months; P < .001). Among NSCLC patients with programmed cell death protein-ligand 1 (PD-L1) expression of 50% or higher who were treated with pembrolizumab as first-line therapy, the median PFS times of patients with PS 2 and 0-1 were 7.3 and 8.1 months, respectively. There was no significant difference in PFS between patients with PS 2 and 0-1 (P = .321). Although poor PS was significantly associated with worse outcomes in NSCLC patients treated with ICIs, pembrolizumab as a first-line treatment in NSCLC patients expressing high levels of PD-L1 could provide a clinical benefit, even in patients with PS 2.

DOI： 10.1111/cas.14590

Egfr改変肺癌マウスモデルを用いたEGFR-TKI、抗VEGFR-2抗体と抗PD-1抗体併用療法の検討

西井和也, 大橋圭明, 中須賀崇匡, 平生敦子, 大川祥, 渡邉洋美, 狩野裕久, 原尚史, 安東千裕, 二宮貴一朗, 加藤有加, 二宮崇, 久保寿夫, 頼冠名, 市原英基, 堀田勝幸, 田端雅弘, 鵜殿平一郎, 前田嘉信, 木浦勝行

肺癌 60 ( 6 ) 531 - 531 2020.10

Egfr改変肺癌マウスモデルを用いたAd-SGE-REICの抗腫瘍効果の検討

中須賀崇匡, 大橋圭明, 西井和也, 平生敦子, 大川祥, 安東千裕, 原尚史, 狩野裕久, 渡邉洋美, 二宮貴一朗, 加藤有加, 二宮崇, 久保寿夫, 頼冠名, 市原英基, 堀田勝幸, 田端雅弘, 前田嘉信, 木浦勝行

肺癌 60 ( 6 ) 528 - 528 2020.10

Successful Re-administration of Osimertinib in Osimertinib-induced Interstitial Lung Disease with an Organizing Pneumonia Pattern: A Case Report and Literature Review.

Junko Itano, Hisao Higo, Kadoaki Ohashi, Go Makimoto, Kazuya Nishii, Katsuyuki Hotta, Nobuaki Miyahara, Yoshinobu Maeda, Katsuyuki Kiura

Internal medicine (Tokyo, Japan) 59 ( 6 ) 823 - 828 2020.3

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

Osimertinib is the standard therapy for epidermal-growth-factor-receptor (EGFR)-mutant lung cancers. We herein report a case of osimertinib-induced interstitial lung disease (OsiILD) with an organizing pneumonia (OP) pattern and provide a literature-based review. Six months after osimertinib administration, a 75-year-old woman with right pleural carcinomatosis developed ILD with an OP pattern. After salvage chemotherapy, osimertinib with corticosteroid was successfully re-administered. A literature review suggested that 1) OsiILD with an OP pattern was rare but should be recognized, and 2) re-administration of osimertinib in OsiILD was successful in select patients. A criterion that determines whether a patient would benefit from re-administration is warranted.

DOI： 10.2169/internalmedicine.3689-19

Influence of age on the efficacy of immune checkpoint inhibitors in advanced cancers: a systematic review and meta-analysis. International journal

Kiichiro Ninomiya, Isao Oze, Yuka Kato, Toshio Kubo, Eiki Ichihara, Kammei Rai, Kadoaki Ohashi, Toshiyuki Kozuki, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura, Katsuyuki Hotta

Acta oncologica (Stockholm, Sweden) 59 ( 3 ) 249 - 256 2020.3

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

Background: Immune checkpoint inhibitors (ICIs) represent a paradigm shift in the development of cancer treatment. However, it remains to be clarified whether the benefits that they confer differ according to patient age. We conducted a systematic review and meta-analysis to assess age differences in the benefits of ICI treatment.Methods: We systematically searched the PubMed database for randomised controlled trials of ICIs, including PD-1, PD-L1 and CTLA-4 inhibitors across multiple cancer types, such as melanoma, lung cancer and gastric cancer. We extracted trials including hazard ratios (HRs) for death stratified by patient age (cut-off age, 65 years). The primary objective of this study was to assess the difference in ICI efficacy between younger and older patients. We calculated pooled HRs and 95% confidence intervals (CIs) for younger and older cancer patients, and assessed data heterogeneity.Results: We identified 3999 studies in our search. Of these, 24 eligible randomised trials, including a total of 8157 (57%) younger and 6104 (43%) older cancer patients, fulfilled the criteria for our study and were thus further analysed. The pooled HRs of the younger and older patients were 0.76 (95% CI: 0.69-0.84) and 0.80 (95% CI: 0.71-0.86), respectively; the difference in ICI efficacy between younger and older cancer patients was not significant (p = .82). Regarding the PD-1 and PD-L1 inhibitors, the survival benefit was similar in both age groups (HR: 0.74; p = .96), whereas for the CTLA-4 inhibitors, there tended to be less survival benefit for older versus younger patients (HR: 0.90 and 0.77, respectively; p = .26).Conclusions: The survival benefit conferred by ICI was not age-dependent, amongst patients aged 65 years or younger. However, age-dependent benefits may vary amongst different types of ICIs.

DOI： 10.1080/0284186X.2019.1695062

Patients' preferences and perceptions of lung cancer treatment decision making: results from Okayama lung cancer study group trial 1406. International journal

Go Makimoto, Katsuyuki Hotta, Isao Oze, Kiichiro Ninomiya, Masamoto Nakanishi, Naofumi Hara, Hirohisa Kano, Hiromi Watanabe, Yusuke Hata, Kazuya Nishii, Takamasa Nakasuka, Junko Itano, Takashi Ninomiya, Toshio Kubo, Kadoaki Ohashi, Eiki Ichihara, Daisuke Minami, Akiko Sato, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura

Acta oncologica (Stockholm, Sweden) 59 ( 3 ) 324 - 328 2020.3

Nivolumab for the treatment of unresectable pleural mesothelioma. International journal

Katsuyuki Hotta, Nobukazu Fujimoto, Toshiyuki Kozuki, Keisuke Aoe, Katsuyuki Kiura

Expert opinion on biological therapy 20 ( 2 ) 109 - 114 2020.2

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

Introduction: Platinum-based chemotherapy is the current first-line standard therapy for unresectable malignant pleural mesothelioma (MPM). Recently, immune-checkpoint inhibitors (ICI) have been intensively investigated as treatment options for this disease. Nivolumab, an anti-programmed cell death (PD)-1 agent, was one of the first drugs used and is representative of available ICIs.Areas covered: This review discusses previous relevant reports and current ongoing trials of nivolumab. The efficacy and safety of nivolumab have been investigated mostly in second-line or later treatment settings as both monotherapy and in combination with other ICIs. Particularly, nivolumab monotherapy yielded promising efficacy with an objective response rate of 29% and median overall survival of 17.3 months in salvage settings in the single-arm, Japanese phase 2 trial (MERIT). Notably, the study led to Japanese approval of nivolumab for unresectable recurrent MPM. Several trials with monotherapy or cotherapy with nivolumab have commenced, including randomized trials of nivolumab monotherapy vs. placebo in the salvage setting, and cotherapy with nivolumab and ipilimumab vs. the platinum doublet in the frontline setting.Expert opinion: Nivolumab seems like a reasonable option for unresectable, relapsed MPM despite the lack of randomized trial data. Ongoing pivotal trials will confirm its efficacy.

DOI： 10.1080/14712598.2020.1703945

The impact of body mass index on the efficacy of anti-PD-1/PD-L1 antibodies in patients with non-small cell lung cancer. International journal

Eiki Ichihara, Daijiro Harada, Koji Inoue, Ken Sato, Shinobu Hosokawa, Daizo Kishino, Kazuhiko Watanabe, Nobuaki Ochi, Naohiro Oda, Naofumi Hara, Katsuyuki Hotta, Yoshinobu Maeda, Katsuyuki Kiura

Lung cancer (Amsterdam, Netherlands) 139 140 - 145 2020.1

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

OBJECTIVES: Body mass index (BMI) is reported to be associated with the efficacy of immune checkpoint inhibitors (ICIs) in solid tumors such as melanomas. However, it remains unclear whether such a relationship exists in non-small cell lung cancer (NSCLC) treated with programmed cell death protein 1 (PD-1)/ programmed death-ligand 1(PD-L1) inhibitors. The purpose of this study was to investigate the relationship between BMI and the efficacy of ICI treatment in patients with advanced NSCLC. MATERIALS AND METHODS: The medical records of NSCLC patients who received PD-1/PD-L1 antibody monotherapy at nine institutions between December 2015 and May 2018 were reviewed retrospectively. The effect of BMI was investigated in two cohorts. Cohort 1 included patients with NSCLCs with high PD-L1 expression (≥ 50 %) treated with pembrolizumab as first-line therapy, and cohort 2 included patients with NSCLCs treated with nivolumab/pembrolizumab/atezolizumab as second- or later-line treatment. RESULTS: A total of 513 from nine institutions were analyzed (84 in cohort 1, 429 in cohort 2). Using a BMI cut-off value of 22 kg/m2, which is an ideal BMI in our country (high BMI:22.0 and low BMI:22.0), there was no significant difference in the PFS or OS between the high and low BMI patients in cohort 1. However, in cohort 2, survival was significantly longer in patients with a high versus low BMI (PFS: 3.7 vs. 2.8 months, p = 0.036; OS: 15.4 vs. 13.5 months, p = 0.021). CONCLUSION: BMI was significantly associated with the efficacy of ICIs in patients with NSCLC treated with second- or later-line PD-1/PD-L1 inhibitors in our cohort.

DOI： 10.1016/j.lungcan.2019.11.011

Rapid Acquisition of Alectinib Resistance in ALK-Positive Lung Cancer With High Tumor Mutation Burden. International journal

Go Makimoto, Kadoaki Ohashi, Shuta Tomida, Kazuya Nishii, Takehiro Matsubara, Hiroe Kayatani, Hisao Higo, Kiichiro Ninomiya, Akiko Sato, Hiromi Watanabe, Hirohisa Kano, Takashi Ninomiya, Toshio Kubo, Kammei Rai, Eiki Ichihara, Katsuyuki Hotta, Masahiro Tabata, Shinichi Toyooka, Minoru Takata, Yoshinobu Maeda, Katsuyuki Kiura

Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 14 ( 11 ) 2009 - 2018 2019.11

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

INTRODUCTION: The highly selective ALK receptor tyrosine kinase (ALK) inhibitor alectinib is standard therapy for ALK-positive lung cancers; however, some tumors quickly develop resistance. Here, we investigated the mechanism associated with rapid acquisition of resistance using clinical samples. METHODS: Autopsied samples were obtained from lung, liver, and renal tumors from a 51-year-old male patient with advanced ALK-positive lung cancer who had acquired resistance to alectinib in only 3 months. We established an alectinib-resistant cell line (ABC-14) from pleural effusion and an alectinib/crizotinib-resistant cell line (ABC-17) and patient-derived xenograft (PDX) model from liver tumors. Additionally, we performed next-generation sequencing, direct DNA sequencing, and quantitative real-time reverse transcription polymerase chain reaction. RESULTS: ABC-14 cells harbored no ALK mutations and were sensitive to crizotinib while also exhibiting MNNG HOS transforming gene (MET) gene amplification and amphiregulin overexpression. Additionally, combined treatment with crizotinib/erlotinib inhibited cell growth. ABC-17 and PDX tumors harbored ALK G1202R, and PDX tumors metastasized to multiple organs in vivo, whereas the third-generation ALK-inhibitor, lorlatinib, diminished tumor growth in vitro and in vivo. Next-generation sequencing indicated high tumor mutation burden and heterogeneous tumor evolution. The autopsied lung tumors harbored ALK G1202R (c. 3604 G>A) and the right renal metastasis harbored ALK G1202R (c. 3604 G>C); the mutation thus comprised different codon changes. CONCLUSIONS: High tumor mutation burden and heterogeneous tumor evolution might be responsible for rapid acquisition of alectinib resistance. Timely lorlatinib administration or combined therapy with an ALK inhibitor and other receptor tyrosine-kinase inhibitors might constitute a potent strategy.

DOI： 10.1016/j.jtho.2019.07.017

A Long-term Response to Nivolumab in a Case of PD-L1-negative Lung Adenocarcinoma with an EGFR Mutation and Surrounding PD-L1-positive Tumor-associated Macrophages.

Hiromi Watanabe, Kadoaki Ohashi, Kazuya Nishii, Keisuke Seike, Go Makimoto, Katsuyuki Hotta, Yoshinobu Maeda, Katsuyuki Kiura

Internal medicine (Tokyo, Japan) 58 ( 20 ) 3033 - 3037 2019.10

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

Anti-programmed cell death 1 (PD-1) antibodies have poor efficacy in epidermal growth factor receptor (EGFR)-mutated lung cancer. We herein report a 72-year-old man with programmed cell death-ligand 1 (PD-L1)-negative lung adenocarcinoma harboring an EGFR mutation that responded to nivolumab for more than 2 years. A pathological examination revealed infiltration of CD8-positive lymphocytes and macrophages expressing CD68, CD206, and PD-L1 into the PD-L1-negative tumor; CD206 expression is a marker of immunosuppressive tumor-associated macrophages (TAMs). The presence of PD-L1-positive TAMs in the tumor environment might be a predictor of a positive response to anti-PD-1 antibodies.

DOI： 10.2169/internalmedicine.2875-19

EGFR-TKI acquired resistance in lung cancers harboring EGFR mutations in immunocompetent C57BL/6J mice. International journal

Hisao Higo, Kadoaki Ohashi, Go Makimoto, Kazuya Nishii, Kenichiro Kudo, Hiroe Kayatani, Hiromi Watanabe, Hirohisa Kano, Kiichiro Ninomiya, Katsuyuki Hotta, Yoshinobu Maeda, Katsuyuki Kiura

Lung cancer (Amsterdam, Netherlands) 136 86 - 93 2019.10

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

OBJECTIVES: Lung cancers harboring epidermal growth factor receptor (EGFR) mutations inevitably develop resistance to EGFR tyrosine-kinase inhibitors (EGFR-TKIs). Therefore, we sought to establish clinically relevant lung-cancer mouse models to achieve deep remission of cancers. MATERIALS AND METHODS: We previously established two transgenic lung-cancer mouse models harboring human EGFR exon 21 L858R substitution (hLR) and mouse Egfr exon 19 deletion (mDEL) in the C57BL/6 J background. Lung tumors from these two transgenic mouse strains were transplanted subcutaneously into BALB/c-nunu mice or C57BL/6 J mice. RESULTS: The transplanted tumors developed the ability to grow on the subcutaneous tissue, peritoneum, or lung of C57BL/6 J mice. While hLR tumors could grow only in C57BL/6 J mice carrying the transgene, mDEL tumors could grow in wild-type C57BL/6 J mice. The tumors maintained EGFR-dependency, and, thus, the EGFR-TKI gefitinib inhibited tumor growth; however, similar to human lung cancers, hLR and mDEL tumors acquired resistance in 60 and 200 days, respectively, following gefitinib administration. Secondary EGFR T790 M mutation in hLR tumors and secondary Egfr T792I mutation in mDEL tumors developed; however, no MET activation was detected. Accordingly, the third-generation EGFR-TKI osimertinib effectively inhibited gefitinib-resistant tumors in vivo. Furthermore, gefitinib-resistant tumors developed resistance to osimertinib in 100 days. CONCLUSION: These syngeneic lung-cancer mouse models harboring EGFR mutations are suitable for studying the drug-resistance mechanisms and the role of the tumor microenvironment. Further investigation with these mouse models is warranted for developing next-generation treatment strategies for lung cancer.

DOI： 10.1016/j.lungcan.2019.08.019

Programmed cell death-ligand 1 expression and efficacy of cisplatin-based chemotherapy in lung cancer: A sub-analysis of data from the two Okayama Lung Cancer Study Group prospective feasibility studies. International journal

Kazuya Nishii, Katsuyuki Hotta, Kiichiro Ninomiya, Yuka Kato, Eiki Ichihara, Kadoaki Ohashi, Takashi Ninomiya, Toshio Kubo, Kammei Rai, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura

Respiratory investigation 57 ( 5 ) 460 - 465 2019.9

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

BACKGROUND: Cisplatin-based chemotherapy remains the mainstay treatment for advanced lung cancer; however, it remains controversial whether the efficacy of chemotherapy can be modulated by the immune-checkpoint status. In this study, we investigated the relationship between programmed cell death-ligand 1 (PD-L1) expression status and the efficacy of cisplatin-based chemotherapy by using individual patient data and pathological specimens obtained during our two previously performed prospective studies on the feasibility of short-term low-volume hydration in patients with advanced lung cancer who received cisplatin-based chemotherapy. METHODS: Among 91 patients who participated in the two aforementioned trials, those with assessable tumor specimens were included in this sub-analysis. PD-L1 expression levels were determined using immunohistochemical staining, while the Response Evaluation Criteria in Solid Tumors, version 1.1, were used for determining treatment efficacy. RESULTS: Thirty-two patients were investigated. PD-L1 expression was observed in 8 patients (25.0%; the PD-L1-positive group), with 2 exhibiting a PD-L1 expression of 50% or more. None of the patients in the PD-L1-positive group responded to treatment, while the overall response rate in the PD-L1-negative group was 20.8% (5 of 24; P = 0.296). Both the progression-free survival and overall survival rates were worse in the PD-L1-positive group than in the PD-L1-negative group (3.7 vs. 5.9 months [P = 0.018] and 5.8 vs. 37.3 months [P = 0.070], respectively). CONCLUSION: PD-L1 expression was negatively correlated with survival in patients receiving cisplatin-based chemotherapy.

DOI： 10.1016/j.resinv.2019.04.004

The effect and safety of immune checkpoint inhibitor rechallenge in non-small cell lung cancer. International journal

Hiromi Watanabe, Toshio Kubo, Kiichiro Ninomiya, Kenichiro Kudo, Daisuke Minami, Etsuko Murakami, Nobuaki Ochi, Takashi Ninomiya, Daijiro Harada, Masayuki Yasugi, Eiki Ichihara, Kadoaki Ohashi, Keiichi Fujiwara, Katsuyuki Hotta, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura

Japanese journal of clinical oncology 49 ( 8 ) 762 - 765 2019.8

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

INTRODUCTION: Immune checkpoint inhibitors (ICIs) have demonstrated long survival for the treatment of advanced non-small cell lung cancer (NSCLC). However, the effect and safety of ICI rechallenge have not been fully evaluated. The aim of this study was to investigate the efficacy and safety of ICI rechallenge in NSCLC patients. METHODS: We defined 'rechallenge' as re-administration of ICIs for patients who were previously treated with ICIs and discontinued treatment for any reason, and received subsequent chemotherapy. We retrospectively analyzed the histories of 434 patients with advanced NSCLC who received ICIs from December 2015 to December 2017 at seven centers. RESULTS: A total of 317 patients discontinued the ICI treatment, and 14 patients (4.4%) received ICI rechallenge. All 14 patients discontinued the first ICI due to disease progression. Eight patients received the same kind of ICIs, and six patients received different ICIs. Median progression-free survival and overall survival were 1.5 months [95% confidence interval (CI): 0.8-2.6] and 6.5 months [95% CI: 1.4-19.0], respectively. The objective response rate was 7.1%, and the disease control rate was 21.4%. Two of three patients who achieved at least a stable disease, received radiotherapy between the first and second ICIs. Adverse events were not significantly different compared with the first ICIs. CONCLUSIONS: In this study, the effect of ICI rechallenge was limited. Careful consideration of the administration of ICI rechallenge is necessary. This report involved a small number of cases, so further large prospective studies are warranted to confirm the efficacy of ICI rechallenge and to investigate predictive markers to identify a patient population in which ICI rechallenge is effective.

DOI： 10.1093/jjco/hyz066

A Prospective Cohort Study to Define the Clinical Features and Outcome of Lung Cancers Harboring HER2 Aberration in Japan (HER2-CS STUDY). International journal

Kiichiro Ninomiya, Tae Hata, Hiroshige Yoshioka, Kadoaki Ohashi, Akihiro Bessho, Shinobu Hosokawa, Nobuhisa Ishikawa, Masahiro Yamasaki, Takuo Shibayama, Keisuke Aoe, Toshiyuki Kozuki, Shingo Harita, Yutaka Ueda, Toshi Murakami, Nobukazu Fujimoto, Hiroyuki Yanai, Shinichi Toyooka, Minoru Takata, Katsuyuki Hotta, Katsuyuki Kiura

Chest 156 ( 2 ) 357 - 366 2019.8

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

BACKGROUND: Human epidermal growth factor 2 (HER2) is a potential driver oncogene. Although HER2-targeted precision therapy has been tested in non-small cell lung cancer (NSCLC), the demographic characteristics of HER2-positive NSCLC have not been systematically defined. METHODS: Patients with pathologically confirmed stage IIIB/IV or recurrent NSCLC, Eastern Cooperative Oncology Group performance status 0 to 2, were prospectively registered. HER2 immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) assays were performed to screen patients. HER2 mutations were identified by using direct gene sequencing. The aim of this study was to clarify the frequency, characteristics, and outcome of HER2-positive NSCLC. HER2 was defined as positive if the tumor harbored IHC3+, IHC2+/FISH+, or exon 20 insertion mutations. RESULTS: Of the 1,126 tumors screened, 34 (3.0%) were IHC3+, and 34 (3.0%) were IHC2+/FISH+. Among the 724 epidermal growth factor receptor wild-type tumors, 21 (2.9%) were HER2-mutant tumors, including A775-G776insYVMA (n = 15). Interestingly, the IHC3+ tumors and mutant tumors were entirely exclusive. Female patients had HER2-mutant tumors more frequently, whereas both IHC3+ and IHC2+/FISH+ tumors were detected more often in male subjects and smokers. Patients with an HER2-aberrant tumor had a significantly worse prognosis than those with epidermal growth factor receptor-positive and anaplastic lymphoma kinase-positive tumors, possibly due to the low proportion that received HER2-targeted therapies (n = 15 [26%]) and low response rates of 0% and 14% in patients with HER2-overexpressing and HER2-mutant tumors, respectively. CONCLUSIONS: This prospective large-scale cohort study is the first to show comprehensively the frequency and clinical demographic characteristics of those with HER2-positive advanced lung tumors in detail, providing critical historical data for future drug development against HER2-positive NSCLC. Future treatment strategies would be developed stratified according to the types of HER2 aberrations. TRIAL REGISTRY: UMIN Registration No. 000017003; URL: https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000019691.

DOI： 10.1016/j.chest.2019.01.011

The effect and safety of immune checkpoint inhibitor rechallenge in non-small cell lung cancer

Hiromi Watanabe, Toshio Kubo, Kiichiro Ninomiya, Kenichiro Kudo, Daisuke Minami, Etsuko Murakami, Nobuaki Ochi, Takashi Ninomiya, Daijiro Harada, Masayuki Yasugi, Eiki Ichihara, Kadoaki Ohashi, Keiichi Fujiwara, Katsuyuki Hotta, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura

JAPANESE JOURNAL OF CLINICAL ONCOLOGY 49 ( 8 ) 762 - 765 2019.8

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

Introduction: Immune checkpoint inhibitors (ICIs) have demonstrated long survival for the treatment of advanced non-small cell lung cancer (NSCLC). However, the effect and safety of ICI rechallenge have not been fully evaluated. The aim of this study was to investigate the efficacy and safety of ICI rechallenge in NSCLC patients.Methods: We defined 'rechallenge' as re-administration of ICIs for patients who were previously treated with ICIs and discontinued treatment for any reason, and received subsequent chemotherapy. We retrospectively analyzed the histories of 434 patients with advanced NSCLC who received ICIs from December 2015 to December 2017 at seven centers.Results: A total of 317 patients discontinued the ICI treatment, and 14 patients (4.4%) received ICI rechallenge. All 14 patients discontinued the first ICI due to disease progression. Eight patients received the same kind of ICIs, and six patients received different ICIs. Median progression-free survival and overall survival were 1.5 months [95% confidence interval (CI): 0.8-2.6] and 6.5 months [95% CI: 1.4-19.0], respectively. The objective response rate was 7.1%, and the disease control rate was 21.4%. Two of three patients who achieved at least a stable disease, received radiotherapy between the first and second ICIs. Adverse events were not significantly different compared with the first ICIs.Conclusions: In this study, the effect of ICI rechallenge was limited. Careful consideration of the administration of ICI rechallenge is necessary. This report involved a small number of cases, so further large prospective studies are warranted to confirm the efficacy of ICI rechallenge and to investigate predictive markers to identify a patient population in which ICI rechallenge is effective.

DOI： 10.1093/jjco/hyz066

A phase I/II trial of weekly nab-paclitaxel for pretreated non-small-cell lung cancer patients without epidermal growth factor receptor mutations and anaplastic lymphoma kinase rearrangement. International journal

Daijiro Harada, Toshiyuki Kozuki, Naoyuki Nogami, Akihiro Bessho, Shinobu Hosokawa, Nobuaki Fukamatsu, Katsuyuki Hotta, Kadoaki Ohashi, Toshio Kubo, Hiroshige Yoshioka, Toshihide Yokoyama, Naoyuki Sone, Shoichi Kuyama, Kenichiro Kudo, Masayuki Yasugi, Nagio Takigawa, Isao Oze, Katsuyuki Kiura

Asia-Pacific journal of clinical oncology 15 ( 4 ) 250 - 256 2019.8

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

AIM: We investigated the efficacy, safety and optimal schedule of nanoparticle albumin-bound paclitaxel monotherapy as second- or third-line treatment for non-small-cell lung cancer patients without epidermal growth factor receptor mutation and anaplastic lymphoma kinase rearrangement. METHODS: Patients with pretreated advanced non-small-cell lung cancer without epidermal growth factor receptor mutation and anaplastic lymphoma kinase rearrangement were included. The patients were administered 100 mg/m2 of nanoparticle albumin-bound paclitaxel on days 1, 8, 15 and 22 (level 0) or on days 1, 8 and 15 (level -1) every 4 weeks during phase I of the trial. The primary endpoint was objective response rate. The estimated objective response rate was 15% and the threshold was 5% with an α error of 0.05 and β error of 0.2 in phase II. RESULTS: The recommended schedule was determined as level -1 in phase I. The characteristics of the 55 patients enrolled in phase II were as follows: median age = 66 years, male/female = 40/15, second/third line = 34/21 and adenocarcinoma/squamous cell carcinoma/large cell carcinoma/others = 34/17/2/2. Objective response rate was 7.3% (95% confidence interval, 2.0-17.6%). Median progression-free survival was 3.4 months. Treatment-related grade 3 or 4 toxicities were neutropenia (36.4%), febrile neutropenia (5.5%) and pulmonary infection (3.6%). Three patients had grade 2 pneumonitis and one treatment-related death occurred due to adult respiratory distress syndrome. CONCLUSION: This study failed to meet predefined primary endpoints for pretreated patients with advanced non-small-cell lung cancer without epidermal growth factor receptor mutation and anaplastic lymphoma kinase rearrangement.

DOI： 10.1111/ajco.13147

Recent trends in the treatment of unresectable stage III non-small-cell lung cancer. International journal

Go Makimoto, Katsuyuki Hotta, Katsuyuki Kiura

Respiratory investigation 57 ( 4 ) 330 - 336 2019.7

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

Approximately 20-25% of non-small-cell lung cancer (NSCLC) is diagnosed when the disease has progressed to clinical stage III. At this stage, and even if the cancer is considered unresectable, the treatment strategy should aim to achieve a cure. At the time of the initial diagnosis, it is necessary for medical oncologists to devise the best treatment strategy for each patient by composing a multidisciplinary treatment team including thoracic surgeons and radiation oncologists. In this review, we summarize prior pivotal clinical trials in unresectable clinical stage III NSCLC. Furthermore, we review very recent clinical trials evaluating the efficacy of immune checkpoint inhibitors in the treatment of NSCLC.

DOI： 10.1016/j.resinv.2019.03.004

Beneficial Effect of Osimertinib Readministration in Non-small-cell Lung Cancer Harboring an Epidermal Growth Factor Receptor (EGFR) Mutation with a History of Acquired Resistance to Osimertinib.

Go Makimoto, Kadoaki Ohashi, Satoru Senoo, Katsuyuki Hotta, Yoshinobu Maeda, Katsuyuki Kiura

Internal medicine (Tokyo, Japan) 58 ( 11 ) 1625 - 1627 2019.6

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

We herein report a case of the beneficial effect of osimertinib readministration in non-small-cell lung cancer (NSCLC) harboring an epidermal growth factor receptor (EGFR) mutation. A 69-year-old non-smoking woman was diagnosed with advanced NSCLC harboring an EGFR exon19 deletion and T790M. She was treated with osimertinib for two years but eventually acquired resistance. After 1.5 years of salvage chemotherapies, osimertinib was re-administered. She has been effectively and safely treated with osimertinib readministration for over 10 months. A prospective study is warranted to evaluate the efficacy and safety of osimertinib readministration in NSCLC with EGFR mutations.

DOI： 10.2169/internalmedicine.2152-18

Successful Treatment of Metastatic Urothelial Carcinoma after Accurate Diagnosis by Immunohistochemistry.

Go Makimoto, Hisakazu Nishimori, Reiko Kondo, Hiroyuki Yanai, Morito Sugimoto, Naohiro Oda, Toshio Kubo, Katsuyuki Hotta, Masahiro Tabata, Katsuyuki Kiura, Yoshinobu Maeda

Acta medica Okayama 73 ( 3 ) 279 - 284 2019.6

Language：English

Urothelial carcinoma usually presents with hematuria, but cases of multiple lymphadenopathy with elevated S-pancreas-1 antigen (SPan-1) levels have not been reported. A 62-year-old Japanese man with lymphadenopathies was diagnosed with an adenocarcinoma of unknown origin and transferred to our hospital for further diagnosis. Serum carbohydrate antigen 19-9 and SPan-1 levels were extremely elevated. Uroplakin III immunostaining was positive in the inguinal lymph node, and cystoscopy revealed the presence of invasive urothelial carcinoma. Treatment with cisplatin and gemcitabine promoted a complete metabolic response for > 4 years. The detection of uroplakin III and serum SPan-1 might help diagnose urothelial carcinoma.

DOI： 10.18926/AMO/56873

Re-administration of osimertinib in osimertinib-acquired resistant non-small-cell lung cancer. International journal

Eiki Ichihara, Katsuyuki Hotta, Kiichiro Ninomiya, Toshio Kubo, Kadoaki Ohashi, Kammei Rai, Hisaaki Tanaka, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura

Lung cancer (Amsterdam, Netherlands) 132 54 - 58 2019.6

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

BACKGROUND: Osimertinib is a tyrosine kinase inhibitor (TKI) that is an essential agent for the treatment of epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC). However, there is no established strategy for treatment following acquired resistance to this agent. One potential strategy for treating acquired resistance to EGFR TKIs is re-administration, which has been evaluated mainly using first- or second-generation EGFR TKIs. However, no clinical data are available with which to determine the significance of re-administration of osimertinib, a third-generation EGFR TKI. The aim of this study was to evaluate the efficacy of re-administering osimertinib to patients who had acquired resistance to this agent. PATIENTS AND METHODS: We reviewed the medical records of consecutive patients with advanced NSCLC harboring EGFR-activating mutations and secondary T790M, who had undergone osimertinib re-administration to treat acquired resistance. RESULTS: Seventeen patients were re-administered osimertinib after acquiring resistance to osimertinib. Of these, two received osimertinib to treat carcinomatous meningitis without any measurable lesion. Responses were evaluated in the remaining 15 patients. The objective response and disease control rates were 33% and 73%, respectively. Tumor shrinkage by osimertinib re-administration was associated with that due to initial osimertinib treatment (r = 0.585, 95% confidence interval [CI]: 0.104-0.844). In the remaining two patients without measurable lesions, one exhibited improved clinical symptoms following osimertinib re-administration. The median progression-free survival (PFS) time of all 17 patients was 4.1 months (95% CI: 1.9-6.7). The toxicity of re-administration was low, without interruption of the treatment due to adverse events (AEs). Most patients had grade 2 AEs or lower. CONCLUSIONS: Re-administration of osimertinib for EGFR-mutant NSCLC yielded modest activity with tolerable toxicity.

DOI： 10.1016/j.lungcan.2019.02.021

Chemoradiotherapy for locally advanced lung cancer patients with interstitial lung abnormalities. International journal

Hisao Higo, Toshio Kubo, Satoko Makimoto, Go Makimoto, Hiroki Ihara, Yoshihisa Masaoka, Takashi Ninomiya, Eiki Ichihara, Kadoaki Ohashi, Akiko Sato, Katsuyuki Hotta, Masahiro Tabata, Nagio Takigawa, Yoshinobu Maeda, Katsuyuki Kiura

Japanese journal of clinical oncology 49 ( 5 ) 458 - 464 2019.5

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

INTRODUCTION: Although chemoradiotherapy for locally advanced lung cancer has the potential for cure, treatment is avoided in patients with interstitial lung disease because of the risk for severe radiation pneumonitis. Interstitial lung abnormalities (ILA) can be evaluated using high-resolution computed tomography (HRCT) to assess interstitial changes. In this study, we retrospectively examined the feasibility and efficacy of chemoradiotherapy for locally advanced lung cancer patients with ILA. METHODS: Patients who underwent chemoradiotherapy for locally advanced lung cancer at Okayama University Hospital between 2012 and 2015 were reviewed retrospectively. HRCT prior to treatment was evaluated by one pulmonologist and two radiologists using a sequential reading method. RESULTS: Of the 77 patients enrolled in this study, ILA was present in 25 (32.5%) and indeterminate ILA in 24 patients; 28 patients did not have ILA. Desaturation at rest (SpO2 < 95%) and honeycombing on HRCT were not observed in ILA patients. Only one patient with ILA had a low vital capacity (%VC < 80%). Severe radiation pneumonitis (≥Grade 2) occurred in 36.0% of the patients with ILA, but it was controllable; Grade 4 or 5 was not observed. Multivariate analysis showed that >25% of the lung volume receiving >20 Gy was risk factors of severe radiation pneumonitis, but ILA was not. The 2-year survival rates of patients with and without ILA were 56.8% and 74.1%, respectively, but the difference was not significant (P = 0.33). CONCLUSIONS: Chemoradiotherapy was feasible and effective in some patient population with ILA without desaturation, low VC and honeycombing on HRCT.

DOI： 10.1093/jjco/hyz016

Recent treatment strategy for advanced squamous cell carcinoma of the lung in Japan.

Satoru Senoo, Kiichiro Ninomiya, Katsuyuki Hotta, Katsuyuki Kiura

International journal of clinical oncology 24 ( 5 ) 461 - 467 2019.5

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER JAPAN KK

Squamous cell carcinoma of the lung is associated with smoking in its development and comprises about 20-30% of all lung cancers. Its treatment strategy had been limited for the past decades, inevitably resulting in the poor outcome. However in the 2010s, it has dramatically changed mainly with the recent clinical introduction of immune checkpoint inhibitors. In this review, we will introduce various clinical studies involving squamous cell carcinoma of the lung.

DOI： 10.1007/s10147-019-01424-y

Rapid and Long-term Response of Pulmonary Pleomorphic Carcinoma to Nivolumab.

Satoru Senoo, Takashi Ninomiya, Go Makimoto, Kazuya Nishii, Hirohisa Kano, Hiromi Watanabe, Yusuke Hata, Toshio Kubo, Takehiro Tanaka, Katsuyuki Hotta, Yoshinobu Maeda, Katsuyuki Kiura

Internal medicine (Tokyo, Japan) 58 ( 7 ) 985 - 989 2019.4

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

Pulmonary pleomorphic carcinoma (PPC) is a rare very aggressive subtype of non-small cell lung cancer. We herein report a case of PPC that showed a rapid response to nivolumab. The patient, whose multiple tumors had progressed very aggressively, was treated with nivolumab, an anti-programmed cell death-1 (PD-1) antibody. The tumors dramatically shrank after one cycle of nivolumab. The tumors were positive for programmed cell death ligand 1 (PD-L1). An immunohistochemical analysis revealed numerous PD-1+, CD68+ and CD206+ macrophages. This PD-1 antibody may be a good treatment option, especially in tumors that express PD-L1 and which show PD-1+ macrophage infiltration.

DOI： 10.2169/internalmedicine.0890-18

Phase 2 Study of Afatinib Alone or Combined With Bevacizumab in Chemonaive Patients With Advanced Non-Small-Cell Lung Cancer Harboring EGFR Mutations: AfaBev-CS Study Protocol. International journal

Takashi Ninomiya, Nobuhisa Ishikawa, Koji Inoue, Toshio Kubo, Masayuki Yasugi, Takuo Shibayama, Tadashi Maeda, Kazunori Fujitaka, Masahiro Kodani, Toshihide Yokoyama, Shoichi Kuyama, Nobuaki Ochi, Yutaka Ueda, Seigo Miyoshi, Toshiyuki Kozuki, Yoshihiro Amano, Tetsuya Kubota, Keisuke Sugimoto, Akihiro Bessho, Tomoya Ishii, Kazuhiko Watanabe, Isao Oze, Katsuyuki Hotta, Katsuyuki Kiura

Clinical lung cancer 20 ( 2 ) 134 - 138 2019.3

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

Afatinib, a second-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), has demonstrated a significant survival benefit over platinum-based chemotherapy in a first-line setting in advanced non-small-cell lung cancer (NSCLC) harboring EGFR exon 19 deletion. In addition, we and other groups have shown there to be favorable progression-free survival (PFS) outcomes, with acceptable toxicity profiles, with bevacizumab and first-generation EGFR-TKI combination therapy. On the basis of the above, we hypothesized that a combination of bevacizumab and afatinib could potentially improve efficacy. In our phase 1 study, a daily 30 mg dose of afatinib and 15 mg/kg intravenous bevacizumab every 3 weeks was well tolerated and was defined as the recommended dose. We have initiated a randomized phase 2 trial comparing afatinib (30 mg daily) and bevacizumab (15 mg/kg every 3 weeks) with afatinib (40 mg daily) alone for nonsquamous NSCLC harboring EGFR common mutations as a first-line therapy. A total of 100 patients will be enrolled onto this study and randomized in a 1:1 ratio. Patients will continue to receive treatment until disease progression or unacceptable toxicity. The primary end point is PFS, and the secondary end points are overall survival, tumor response, and time to treatment failure. The power is greater than 50% under the assumptions of a median PFS of 12 months for the afatinib group and a hazard ratio of 0.6 for the combination group (2-sided α = 0.05). We hypothesize that the combination therapy will be more efficacious than standard therapies for EGFR-mutant NSCLC patients.

DOI： 10.1016/j.cllc.2018.10.008

Significance of re-biopsy of histological tumor samples in advanced non-small-cell lung cancer in clinical practice.

Katsuyuki Hotta, Kiichiro Ninomiya, Eiki Ichihara, Katsuyuki Kiura

International journal of clinical oncology 24 ( 1 ) 41 - 45 2019.1

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER JAPAN KK

The significance of evaluating oncogenes, including EGFR mutations, ALK abnormalities, and PD-L1 expression has become broadly recognized with recent advances in molecular biology. It is now extremely important to investigate tumor oncogene status in each patient at the initial diagnosis. By contrast, the significance of conducting a re-biopsy in the salvage setting has not been systematically reviewed. This review reports that the significance of a re-biopsy varies depending on the clinical situation.

DOI： 10.1007/s10147-018-1344-x

A Phase II Trial of First-Line Combination Chemotherapy With Cisplatin, Pemetrexed, and Nivolumab for Unresectable Malignant Pleural Mesothelioma: A Study Protocol. International journal

Nobukazu Fujimoto, Keisuke Aoe, Toshiyuki Kozuki, Isao Oze, Katsuya Kato, Takumi Kishimoto, Katsuyuki Hotta

Clinical lung cancer 19 ( 5 ) e705-e707 2018.9

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

BACKGROUND: The purpose of this study is to assess the efficacy and safety of combination chemotherapy with cisplatin, pemetrexed, and nivolumab for unresectable malignant pleural mesothelioma (MPM). PATIENTS AND METHODS: Patients with untreated, advanced, or metastatic MPM who meet the inclusion and exclusion criteria will be included. A total of 18 patients will be enrolled from 4 Japanese institutions within 1 year. Combination chemotherapy with cisplatin (75 mg/m2), pemetrexed (500 mg/m2), and nivolumab (360 mg/person) is administered every 3 weeks for a total of 4 to 6 cycles. Then, maintenance therapy with nivolumab will be administered until disease progression, unacceptable toxicities, or the patient's condition meets the withdrawal criteria. The primary end point is the centrally reviewed overall response rate. The secondary end points include the disease control rate, overall survival, progression-free survival, and adverse events. CONCLUSION: This phase II trial evaluating first-line combination chemotherapy for unresectable MPM commenced in January 2018. This is the first prospective trial to evaluate the effect of an anti-programmed death-1 antibody combined with cisplatin and pemetrexed for unresectable MPM.

DOI： 10.1016/j.cllc.2018.05.001

Is Surgery after Chemoradiotherapy Feasible in Lung Cancer Patients with Superior Vena Cava Invasion? Reviewed

Hiroki Sato, Junichi Soh, Katsuyuki Hotta, Kuniaki Katsui, Susumu Kanazawa, Katsuyuki Kiura, Shinichi Toyooka

Annals of thoracic and cardiovascular surgery : official journal of the Association of Thoracic and Cardiovascular Surgeons of Asia 24 ( 3 ) 131 - 138 2018.6

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

PURPOSE: The purpose of this study is to explore the possibility of surgery after chemoradiotherapy (CRT) for locally advanced-non-small-cell lung cancer (LA-NSCLC) with superior vena cava (SVC) resection in terms of prognosis and early and late postoperative course. METHODS: The medical records of NSCLC patients who underwent surgery after CRT at our institution between January 2001 and March 2016 were reviewed. We evaluated the feasibility of surgery with SVC resection after CRT. RESULTS: A total of 8 LA-NSCLC patients were enrolled in this study. The SVC management included a graft replacement in two patients, pericardial patch repair in two, and direct suture closure in four. A complete resection was achieved in seven of the eight patients (87.5%). Postoperative early and late complication rate (Clavien-Dindo classification ≥ grade III) was 25%. All the complications were manageable, and no treatment-related deaths occurred in this series. Although seven out of eight patients showed good patency of reconstructed SVC, one patient exhibited the SVC occlusion during long-term follow-up period. Regarding the prognosis, the 5-year overall survival (OS) rate was 60.0%, and the 2-year recurrence-free survival (RFS) rate was 75.0%. CONCLUSION: Our results suggest that surgery with SVC resection after CRT is a feasible procedure in terms of clinical outcomes and postoperative course.

DOI： 10.5761/atcs.oa.18-00027

Quality of life of survivors of malignant pleural mesothelioma in Japan: A cross sectional study Reviewed

Yasuko Nagamatsu, Isao Oze, Keisuke Aoe, Katsuyuki Hotta, Katsuya Kato, Junko Nakagawa, Keiko Hara, Takumi Kishimoto, Nobukazu Fujimoto

BMC Cancer 18 ( 1 ) 350 2018.3

Language：English Publishing type：Research paper (scientific journal) Publisher：BioMed Central Ltd.

Background: Previous studies have indicated that people with malignant pleural mesothelioma (MPM) have a poor quality of life (QOL)
however, information about the QOL of people with MPM in Japan is anecdotal. The aims of this study were to investigate the QOL of survivors of MPM in Japan and to determine the factors that correlate with their QOL. Methods: This was a cross sectional study. The included patients were those diagnosed with MPM in Japan. We created a self-administered questionnaire consisting of 64 questions. The questionnaires were sent to hospitals and patient advocacy groups, distributed to the patients, completed, and sent back to the researchers by postal mail. QOL was assessed with the European Organization for Research and Treatment of Cancer 16 questionnaire (QLQ) and the short version of the core domains of the Comprehensive Quality of Life Outcome questionnaire (CoQoLo). Results: In total, 133 questionnaires were collected. The QLQ assessments demonstrated that the survivors of MPM most frequently complained of fatigue, pain, sleep disturbances, and dyspnea. The symptom scales were acceptable, but the functional scales were significantly poorer for the patients with poor performance statuses (PSs). The short CoQoLo assessment was very unfavorable for 'Being free from physical pain.' Being a long-term survivor and a survivor with a poor PS were significantly correlated with poor global health status. Conclusions: Survivors of MPM have impaired function, a variety of symptoms, and lower QOL. Survivors of MPM, even those in good physical condition, need broad support.

DOI： 10.1186/s12885-018-4293-x

A phase I trial of afatinib and bevacizumab in chemo-naïve patients with advanced non-small-cell lung cancer harboring EGFR mutations: Okayama Lung Cancer Study Group Trial 1404. International journal

Takashi Ninomiya, Naoyuki Nogami, Toshiyuki Kozuki, Daijiro Harada, Toshio Kubo, Kadoaki Ohashi, Shoichi Kuyama, Kenichiro Kudo, Akihiro Bessho, Nobuaki Fukamatsu, Nobukazu Fujimoto, Keisuke Aoe, Takuo Shibayama, Keisuke Sugimoto, Nagio Takigawa, Katsuyuki Hotta, Katsuyuki Kiura

Lung cancer (Amsterdam, Netherlands) 115 103 - 108 2018.1

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

OBJECTIVE: In advanced epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC), treatment with afatinib, a second-generation EGFR-tyrosine kinase inhibitor (TKI), confers a significant survival benefit over platinum-based chemotherapy. The first-generation EGFR-TKIs gefitinib and erlotinib in combination with bevacizumab have improved progression-free survival. We hypothesized that the combination of afatinib with bevacizumab would further improve efficacy, and conducted a phase I trial to test this hypothesis. MATERIALS AND METHODS: Untreated patients with advanced EGFR-mutant NSCLC were enrolled. The primary endpoint was safety. Two doses of afatinib, 40mg/day (level 0) and 30mg/day (level -1), were evaluated in combination with 15mg/kg bevacizumab every 3 weeks. Optimal dosing was determined by dose-limiting toxicity (DLT), with the concentration at which ≤4 of 12 patients experienced toxicity considered the recommended dose. RESULTS: Nineteen patients were enrolled (level 0:5, level -1:14). Three of the five patients at level 0 experienced a DLT, which indicated that this dose was unfeasible. Three patients at level -1 developed a DLT of grade 3 non-hematological toxicity, which was soon resolved. Grade 3 or worse adverse events were experienced by all five patients at dose level 0 (diarrhea in 2, skin rash in 1, hypoxia in 1, and paronychia in 1), and by three patients at level -1 (diarrhea in 2 and anorexia in 1). Among 16 evaluable patients, 1 had a complete response, 12 had partial responses, and 0 had progressive disease. CONCLUSION: Afatinib plus bevacizumab (level -1) was well tolerated and showed evidence of favorable disease control. This combination therapy may represent a potent therapeutic option for patients with EGFR-mutant NSCLC.

DOI： 10.1016/j.lungcan.2017.11.025

Discomfort during bronchoscopy performed after endobronchial intubation with fentanyl and midazolam: a prospective study. International journal

Daisuke Minami, Nagio Takigawa, Hirohisa Kano, Takashi Ninomiya, Toshio Kubo, Eiki Ichihara, Kadoaki Ohashi, Akiko Sato, Katsuyuki Hotta, Masahiro Tabata, Mitsune Tanimoto, Katsuyuki Kiura

Japanese journal of clinical oncology 47 ( 5 ) 434 - 437 2017.5

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

Objective: Although endobronchial intubation during a bronchoscopic examination is useful for invasive procedures, it is not routine practice in Japan. The present study evaluated discomfort due to endobronchial intubation using fentanyl and midazolam sedation during bronchoscopy. Methods: Thirty-nine patients were enrolled prospectively from November 2014 to September 2015 at Okayama University Hospital. Fentanyl (20 µg) was administered to the patients just before endobronchial intubation, and fentanyl (10 µg) and midazolam (1 mg) were added as needed during the procedure. A questionnaire survey was administered 2 h after the examination. In the questionnaire, patient satisfaction was scored using a visual analog scale as follows: excellent (1 point), good (2 points), normal (3 points), uncomfortable (4 points) and very uncomfortable (5 points). An additional question ('Do you remember the bronchoscopic examination?') was also asked. Predefined parameters (blood pressure, heart rate, oxygen saturation and complications) were recorded. Results: The enrolled patients included 22 males and 17 females; their median age was 70 (range: 28-88) years. The patients received a mean dose of 47.9 µg of fentanyl (range: 30-90 µg) and 2.79 mg of midazolam (range: 1-7 mg). In total, 28 patients (71.7%) agreed to undergo a second bronchoscopic examination; the mean levels of discomfort and for the re-examination were 2.07 points each. About 41% of the patients remembered the bronchoscopic examination. No severe complications were reported. Conclusion: Endobronchial intubation using fentanyl and midazolam sedation during an invasive bronchoscopic procedure might be recommended. Clinical Trial Registration: UMIN000015578 in the UMIN Clinical Trials Registry.

DOI： 10.1093/jjco/hyx022

同時化学放射線療法後の手術により治療した局所進行性NSCLCの生存者における第二原発性癌(Second primary cancer in survivors of locally advanced NSCLC treated with concurrent chemoradiation followed by surgery)

Makimoto Go, Kubo Toshio, Oze Isao, Ohashi Kadoaki, Hotta Katsuyuki, Takigawa Nagio, Toyooka Shinichi, Katsui Kuniaki, Tanimoto Mitsune, Kiura Katsuyuki

日本呼吸器学会誌 6 ( 増刊 ) 345 - 345 2017.3

野生型EGFR遺伝子を有する高齢者未治療進行非小細胞肺癌に対するカルボプラチンとS-1併用療法の第2相試験(OLCSG1202)

西井和也, 二宮貴一朗, 久保寿夫, 久山彰一, 別所昭宏, 越智宣敬, 堀田勝幸, 瀧川奈義夫, 谷本光音, 木浦勝行

日本内科学会雑誌 106 ( Suppl. ) 257 - 257 2017.2

Randomized feasibility study of S-1 for adjuvant chemotherapy in completely resected Stage IA non-small-cell lung cancer: results of the Setouchi Lung Cancer Group Study 0701 Reviewed

Junichi Soh, Norihito Okumura, Masao Nakata, Hiroshige Nakamura, Minoru Fukuda, Masafumi Kataoka, Shinsuke Kajiwara, Yoshifumi Sano, Motoi Aoe, Kazuhiko Kataoka, Katsuyuki Hotta, Keitaro Matsuo, Shinichi Toyooka, Hiroshi Date

JAPANESE JOURNAL OF CLINICAL ONCOLOGY 46 ( 8 ) 741 - 747 2016.8

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

Objective: The aim of this multicenter study was to determine the appropriate administration schedule for S-1, an oral fluoropyrimidine, for adjuvant chemotherapy in patients with completely resected pathological-Stage IA ( tumor diameter, 2-3 cm) non-small-cell lung cancer.
Methods: Patients were randomly assigned to receive adjuvant chemotherapy consisting of either the 4-week oral administration of S-1 ( 80-120 mg/body/day) followed by a 2-week rest ( Group A), or the 2-week oral administration of S-1 ( 80-120mg/body/day) followed by a 1-week rest ( Group B). The duration of adjuvant chemotherapy was 1 year in both arms. The primary endpoint was compliance, namely drug discontinuation-free survival, which was calculated using the Kaplan-Meier method with log-rank test.
Results: Eighty patients were enrolled in this study, and 76 patients actually received S-1 treatment. The drug discontinuation-free survival rates at 1 year were 49.1% in Group A and 52.7% in Group B ( P = 0.373). The means of the relative dose intensities were 55.3% in Group A and 64.6% in Group B ( P = 0.237). There were no treatment-related deaths. Patients with grade 3/ 4 toxicities were significantly more frequent in Group A ( 40.5%) than in Group B ( 15.4%, P = 0.021). The 2-year relapse-free survival rates were 97.5% in Group A and 92.5% in Group B, and the 2-year overall survival rates were 100% in both groups.
Conclusions: The feasibility showed no significant difference between the two groups among patients with completely resected Stage IA ( tumor diameter, 2-3 cm) non-small-cell lung cancer.

DOI： 10.1093/jjco/hyw062

Development of a skin rash within the first week and the therapeutic effect in afatinib monotherapy for EGFR-mutant non-small cell lung cancer (NSCLC): Okayama Lung Cancer Study Group experience. International journal

Kenichiro Kudo, Katsuyuki Hotta, Akihiro Bessho, Naoyuki Nogami, Toshiyuki Kozuki, Shoichi Kuyama, Koji Inoue, Shingo Harita, Toshiaki Okada, Kenichi Gemba, Masanori Fujii, Nagio Takigawa, Naohiro Oda, Mitsune Tanimoto, Katsuyuki Kiura

Cancer chemotherapy and pharmacology 77 ( 5 ) 1005 - 9 2016.5

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

BACKGROUND: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are now key agents in treating EGFR-mutant non-small cell lung cancer (NSCLC). The efficacy of gefitinib or erlotinib monotherapy can be predicted by the development of a skin rash. However, it has not been fully evaluated if this is the case with afatinib monotherapy. METHODS: We retrospectively studied 49 consecutive patients with EGFR-mutant NSCLC who received afatinib therapy between 2009 and 2015. The relationship of several toxicities with tumor response was examined. RESULTS: Grade 2, or more severe, common adverse events (AEs) included skin rash in 17 patients (35 %), diarrhea in 19 (39 %) and mucositis in 15 (31 %). Of these, the number of patients who developed ≥Grade 2 AEs during the first week after the initiation of afatinib therapy was: five patients had skin rash (10 %), 12 patients had diarrhea (25 %) and four patients had mucositis (8 %). As for an objective response, 21 (43 %) of the 49 had a partial response. Associating the AEs with the antitumor effect, those who had a ≥Grade 2 skin rash within the first week tended to have a greater tumor response compared with those without a rash (80 vs. 39 %; p = 0.077). CONCLUSION: Our small study demonstrated that the early development of a skin rash might be associated with the response to afatinib monotherapy.

DOI： 10.1007/s00280-015-2910-9

インターロイキン-6はEGFRに変異を有する進行性のNSCLC患者におけるゲフィチニブの治療効果に関する価値のある予測マーカである(Interleukin6 is a Valuable Predictive Marker for Therapeutic Effect of Gefitinib in Patients with Advanced NSCLC Harboring EGFR mutations)

Tamura Tomoki, Hotta Katsuyuki, Kato Yuka, Gotoda Hiroko, Tanaka Takehiro, Ichimura Koichi, Kubo Toshio, Ohashi Kadoaki, Ichihara Eiki, Kiura Katsuyuki

日本呼吸器学会誌 5 ( 増刊 ) 373 - 373 2016.3

EGFR変異型の非小細胞肺がんの移植モデルに対するエルロチニブと併用した抗VEGFR-2抗体の有効性(Efficacy of an Anti-VEGFR-2 Antibody in Combination with Erlotinib on EGFR Mutant Non-Small Cell Lung Cancer Xenograft Models)

Kayatani Hiroe, Ohashi Kadoaki, Kubo Toshio, Kudo Kenichiro, Imao Takeshi, Kato Yuka, Ninomiya Takashi, Hotta Katsuyuki, Tanimoto Mitsune, Kiura Katsuyuki

日本呼吸器学会誌 5 ( 増刊 ) 364 - 364 2016.3

Gefitinib Combined With Standard Chemoradiotherapy in EGFR-Mutant Locally Advanced Non-Small-Cell Lung Cancer: The LOGIK0902/OLCSG0905 Intergroup Study Protocol. International journal

Katsuyuki Hotta, Jiichiro Sasaki, Sho Saeki, Nagio Takigawa, Kuniaki Katsui, Koichi Takayama, Naoyuki Nogami, Yoshiyuki Shioyama, Akihiro Bessho, Junji Kishimoto, Mitsune Tanimoto, Katsuyuki Kiura, Yukito Ichinose

Clinical lung cancer 17 ( 1 ) 75 - 9 2016.1

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

Herein, we describe an ongoing phase II trial in patients with locally advanced non-small-cell lung cancer (NSCLC) with mutated epidermal growth factor receptor (EGFR). Patients with chemotherapy-naive locally advanced disease with active EGFR mutations will receive the induction treatment, specified as gefitinib monotherapy (250 mg/body) for 8 weeks. Patients whose disease has not progressed during the induction therapy will receive cisplatin and docetaxel (40 mg/m(2)) on days 1, 8, 29, and 36, and concurrent 3-dimensional conformal thoracic radiotherapy with a single daily fraction of 2 Gy, for 5 consecutive days each week to provide a total dose of 60 Gy. The primary end point is overall survival at 24 months. A target sample size of 21 evaluable patients is considered sufficient to validate an expected rate of 85%, and 60% would be the lower limit of interest, with 80% power and a 1-sided α of 5%. Secondary end points include toxicity, response rate, and overall survival. This study will clarify whether tyrosine kinase inhibitors targeted to EGFR can produce a maximal effect in selected NSCLC patients with the relevant driver mutation, even in the locally advanced setting.

DOI： 10.1016/j.cllc.2015.08.004

Path and challenges of the clinical trial network construction of the cancer drug―Through the lung cancer registry tumor specimen banking in Chugoku and Shikoku district―

Kiura Katsuyuki, Hotta Katsuyuki, Toyooka Shiinichi

Neurological Therapeutics 33 ( 5 ) S99 - S99 2016

Short-term low-volume hydration in cisplatin-based chemotherapy: a feasibility study in lung cancer (OLCSG1201)

Kiichiro Ninomiya, Katsuyuki Hotta, Hiroko Gotoda, Daisuke Morichika, Eiki Ichihara, Akiko Sato, Masahiro Tabata, Mitsune Tanimoto, Katsuyuki Kiura

ANNALS OF ONCOLOGY 26 80 - 80 2015.11

Impact of body surface area on survival in EGFR-mutant non-small cell lung cancer patients treated with gefitinib monotherapy: observational study of the Okayama Lung Cancer Study Group 0703. International journal

Kenichiro Kudo, Katsuyuki Hotta, Eiki Ichihara, Hiroshige Yoshioka, Kei Kunimasa, Kazuya Tsubouchi, Masahiro Iwasaku, Yuka Kato, Isao Oze, Nagio Takigawa, Mitsune Tanimoto, Katsuyuki Kiura

Cancer chemotherapy and pharmacology 76 ( 2 ) 251 - 6 2015.8

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

BACKGROUND: The approved dose of gefitinib is fixed, without adjustment for physical size. We demonstrated previously that its efficacy was affected by body surface area (BSA) in patients with EGFR-mutant non-small cell lung cancer (NSCLC). To validate these observations, we assessed the association between BSA and the efficacy of gefitinib using a different patient cohort. METHODS: Prospective cohort data from 115 NSCLC patients with EGFR-mutant tumours, who received gefitinib monotherapy between 2007 and 2012, were analysed. RESULTS: Gefitinib was less effective in individuals with a high BSA (≥1.5 m(2)) in EGFR-mutant NSCLC compared with those with a low BSA (<1.5 m(2)). The median progression-free survival (PFS) in the high- and low-BSA groups was 4.2 and 8.5 months, respectively, although there was no difference in survival among the whole NSCLC cohort. Multivariate analysis also showed a significant effect of BSA on PFS (hazard ratio 1.72; 95 % confidence interval 1.08-2.74; p = 0.021). Sensitivity analysis revealed that the use of the BSA cut-off level around 1.50 m(2) was robust for detecting subpopulations that would benefit less from gefitinib monotherapy. CONCLUSION: We found in the prospective cohort data that BSA could affect the efficacy of gefitinib monotherapy in patients with EGFR-mutant NSCLC, suggesting that BSA-based dose setting of gefitinib monotherapy might be further investigated, despite the fact that no molecular-targeted agent described to date undergoes dose adjustment according to BSA.

DOI： 10.1007/s00280-015-2789-5

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

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)

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

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

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

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

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

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

A phase II study of amrubicin and topotecan combination therapy in patients with relapsed or extensive-disease small-cell lung cancer: Okayama Lung Cancer Study Group Trial 0401. International journal

Naoyuki Nogami, Katsuyuki Hotta, Shoichi Kuyama, Katsuyuki Kiura, Nagio Takigawa, Kenichi Chikamori, Takuo Shibayama, Daizo Kishino, Shinobu Hosokawa, Akihiko Tamaoki, Shingo Harita, Masahiro Tabata, Hiroshi Ueoka, Tetsu Shinkai, Mitsune Tanimoto

Lung cancer (Amsterdam, Netherlands) 74 ( 1 ) 80 - 4 2011.10

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

BACKGROUNDS: Chemotherapy is a mainstay in the treatment of extensive-disease small-cell lung cancer (ED-SCLC), although the survival benefit remains modest. We conducted a phase II trial of amrubicin (a topoisomerase II inhibitor) and topotecan (a topoisomerase I inhibitor) in chemotherapy-naïve and relapsed SCLC patients. METHODS: Amrubicin (35 mg/m(2)) and topotecan (0.75 mg/m(2)) were administered on days 3-5 and 1-5, respectively. The objective response rate (ORR) was set as the primary endpoint, which was assessed separately in chemotherapy-naïve and relapsed cases. RESULTS: Fifty-nine patients were enrolled (chemotherapy-naïve 31, relapsed 28). The ORRs were 74% and 43% in the chemotherapy-naïve and relapsed cases, respectively. Survival data were also promising, with a median progression-free survival time and median survival time of 5.3 and 14.9 months and 4.7 and 10.2 months in the chemotherapy-naïve and relapsed cases, respectively. Even refractory-relapsed cases responded to the treatment favorably (27% ORR). The primary toxicity was myelosuppression with grades 3 or 4 neutropenia in 97% of the patients, which led to grades 3 or 4 febrile neutropenia in 41% of the patients and two toxic deaths. CONCLUSION: This phase II study showed the favorable efficacy and moderate safety profiles of a topotecan and amrubicin two-drug combination especially in relapsed patients with ED-SCLC.

DOI： 10.1016/j.lungcan.2011.01.018

[A relapse of small-cell lung cancer ten years after concomitant chemoradiotherapy followed by high-dose chemotherapy with autologous peripheral blood stem cell transfusion].

Akihiko Taniguchi, Nagio Takigawa, Katsuyuki Hotta, Tadashi Matsumura, Mitsune Tanimoto, Katsuyuki Kiura

Nihon Kokyuki Gakkai zasshi = the journal of the Japanese Respiratory Society 49 ( 9 ) 697 - 701 2011.9

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

A 57-year-old man had limited-disease small cell lung cancer in the left lower lobe of the lung. He was treated with chemotherapy with concurrent accelerated hyperfractionated thoracic radiation, followed by high-dose chemotherapy with autologous peripheral blood stem cell transplantation. He had obtained a complete response for 10 years until the tumor in the left lower lobe was detected by positron emission tomography. Bronchoscopic brushing cytology revealed small cell cancer, which was considered to be local relapse by staging work-up. He achieved a partial response with chemotherapy consisting of cisplatin and irinotecan. The progression-free survival rate at 5 years in limited-disease small cell lung cancer ranges from 10% to 25%. Although it was difficult to distinguish the relapse of lung cancer from second primary lung cancer, we considered this case as relapse because the tumor had the same cytology in the same lobe as the previous primary tumor. The residual cells refractory to concomitant chemoradiotherapy followed by high-dose chemotherapy with stem cell transplantation had survived and proliferated after 10 years.

進行非小細胞肺癌に対する抗癌剤治療の第III相試験におけるPFSとOSとの関連に関する検討

堀田勝幸, 木浦勝行, 藤原義朗, 瀧川奈義夫, 久本晃子, 田端雅弘, 谷本光音

日本癌治療学会誌 46 ( 2 ) 469 - 469 2011.9

Benefits and Adverse Events Among Elderly Patients Receiving Concurrent Chemoradiotherapy for Locally Advanced Non-small Cell Lung Cancer Analysis of the Okayama Lung Cancer Study Group Trial 0007 Reviewed

Nagio Takigawa, Katsuyuki Kiura, Yoshihiko Segawa, Katsuyuki Hotta, Akihiko Tamaoki, Yoshiyuki Tokuda, Takuya Nagata, Kazuhiko Watanabe, Kenichi Gemba, Tomonori Moritaka, Naokatsu Horita, Hiromasa Takeda, Niro Okimoto, Mitsuhiro Takemoto, Keitaro Matsuo, Tetsu Shinkai, Masahiro Tabata, Hiroshi Ueoka, Susumu Kanazawa, Mitsune Tanimoto

JOURNAL OF THORACIC ONCOLOGY 6 ( 6 ) 1087 - 1091 2011.6

Language：English Publishing type：Research paper (scientific journal) Publisher：LIPPINCOTT WILLIAMS & WILKINS

Introduction: Thoracic radiotherapy (RT) with concurrent chemotherapy may be offered to selected elderly patients with locally advanced non-small cell lung cancer. The Okayama Lung Cancer Study Group (OLCSG) 0007 trial with patients up to 75 years showed that with concurrent RT, docetaxel and cisplatin (DP) chemotherapy was an alternative to mitomycin C, vindesine, and cisplatin (MVP) chemotherapy.
Methods: Of the 99 patients in the DP arm, 73 were younger than 70 years and 26 were 70 years or older. Of the 101 patients in the MVP arm, 75 were younger than 70 years and 26 were 70 years or older. Overall survival (OS) and progression-free survival (PFS) were calculated using the Kaplan-Meier method and were compared using an early period weighted log-rank test. Toxicities and treatment intensities were compared by chi(2) and t tests, respectively.
Results: OS and PFS tended to be longer in the DP arm versus MVP arm: median OS (months), 27.5 versus 22.9 (p = 0.109) and 25.6 versus 23.4 (p = 0.064) in the >= 70-year and <70-year groups, respectively; median PFS (months), 19.0 versus 11.5 (p = 0.175) and 12.0 versus 9.3 (p = 0.132) in the >= 70-year and less than 70-year groups, respectively. Severe toxicity (neutropenia, esophagitis, and pneumonitis) rates did not differ between age groups. Nevertheless, the absence of statistically significant differences in this retrospective analysis might be due to the small number of patients. Radiation intensity was similar between the groups, but chemotherapy intensity was lower in the >= 70-year group.
Conclusion: Chemotherapy with concurrent RT may be effective and tolerable in elderly patients with locally advanced non-small cell lung cancer.

DOI： 10.1097/JTO.0b013e318213f86a

Other Link： http://orcid.org/0000-0003-1761-6314

Cure- or Care-Oriented Regimen for Stage III Non-Small-Cell Lung Cancer? Reviewed

Katsuyuki Hotta, Nagio Takigawa, Keitaro Matsuo, Katsuyuki Kiura

JOURNAL OF CLINICAL ONCOLOGY 29 ( 11 ) E320 - E320 2011.4

A phase I study of S-1 with concurrent thoracic radiotherapy in elderly patients with localized advanced non-small cell lung cancer. International journal

Nagio Takigawa, Katsuyuki Kiura, Katsuyuki Hotta, Shinobu Hosokawa, Naoyuki Nogami, Keisuke Aoe, Kenichi Gemba, Keiichi Fujiwara, Shingo Harita, Mitsuhiro Takemoto, Kengo Himei, Tetsu Shinkai, Yoshirou Fujiwara, Saburo Takata, Masahiro Tabata, Susumu Kanazawa, Mitsune Tanimoto

Lung cancer (Amsterdam, Netherlands) 71 ( 1 ) 60 - 4 2011.1

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

S-1, an oral 5-fluorouracil derivative, is effective against advanced non-small cell lung cancer (NSCLC) with mild toxicity and synergistic effects with radiation in preclinical trials. In this phase I study, we evaluated the dose-limiting toxicity and recommended dose of S-1 for a future phase II study when administered concurrently with thoracic radiation (total dose of 60 Gy at 2 Gy per daily fraction) in elderly patients (>75 years old) with localized advanced NSCLC. S-1 was administered on days 1-14 and 29-42 at the following dosages: 60, 70, and 80 mg/m(2)/day. Twenty-two previously untreated patients were enrolled in this study. Dose-limiting toxicity included febrile neutropenia, thrombocytopenia, stomatitis, and pneumonitis. One patient had grade 5 radiation pneumonitis. No other patient experienced radiation pneumonitis or esophagitis exceeding grade 2. The recommended dose for S-1 was determined to be 80 mg/m(2)/day, which produced an overall response rate of 75% (n=12). The median progression-free survival time was 11.5 months (95% confidence interval: 7.1-15.8 months) with a median follow-up time of 27.9 months. These results indicate that concurrent treatment with S-1 and thoracic radiation is a feasible option for NSCLC in the elderly. A phase II study is currently under way.

DOI： 10.1016/j.lungcan.2010.04.012

P2-1 再燃の診断に気管支鏡検査が有用であった慢性好酸球性肺炎の1例(IgG4関連肺疾患/びまん性,ポスター2,第34回日本呼吸器内視鏡学会学術集会)

能島大輔, 谷本安, 栗本悦子, 村上斗司, 二宮崇, 堀田勝幸, 瀧川奈義夫, 宮原信明, 金廣有彦, 田端雅弘, 木浦勝行, 片岡幹男, 久本晃子, 丸川将臣, 谷本光音

気管支学 33 S229 2011

Association between poor performance status and risk for toxicity during erlotinib monotherapy in Japanese patients with non-small cell lung cancer: Okayama Lung Cancer Study Group experience Reviewed International journal

Katsuyuki Hotta, Katsuyuki Kiura, Nagio Takigawa, Etsuji Suzuki, Hiroshige Yoshioka, Toshiaki Okada, Daizo Kishino, Hiroshi Ueoka, Koji Inoue, Masahiro Tabata, Mitsune Tanimoto

Lung Cancer 70 ( 3 ) 308 - 312 2010.12

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

Background: The relationship between poor performance status (PS) and toxicity during chemotherapy is controversial. We examined this for erlotinib monotherapy in non-small cell lung cancer (NSCLC) patients.
Patients and methods: Toxicity during the first month of therapy was recorded in 209 patients receiving erlotinib for NSCLC, and its association with PS was assessed.
Results: Of 209 patients, 52, 115, 30 and 12 had a PS of 0, 1, 2 and 3-4, respectively. Treatment was discontinued in 26% of patients within 1 month, with a higher rate in poorer PS patients (17%, 25%, 37% and 42%). Discontinuation was predominantly due to disease progression, rather than adverse events, in both the whole cohort (82% vs. 18%) and the poorest PS subgroup (100% vs. 0%). Three, two, and four patients with a PS of 1,2 and 3-4, respectively, died within 1 month; all six deaths of PS 2-4 patients were attributed to disease progression. Treatment interruption and dose reduction rates were similar among the subgroups. The principal adverse event was skin rash, with identical incidence in all PS subgroups.
Conclusions: Poor PS is unlikely to increase the risk for toxicity during erlotinib monotherapy, but was related to low compliance, probably because of disease progression rather than treatment-related toxicity. (C) 2010 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.lungcan.2010.03.008

Desire for Information and Involvement in Treatment Decisions Lung Cancer Patients' Preferences and Their Physicians' Perceptions: Results from Okayama Lung Cancer Study Group Trial 0705 Reviewed

Katsuyuki Hotta, Katsuyuki Kiura, Nagio Takigawa, Hiroshige Yoshioka, Hidetoshi Hayashi, Hajime Fukuyama, Akihiro Nishiyama, Toshihide Yokoyama, Shoichi Kuyama, Shigeki Umemura, Yuka Kato, Naoyuki Nogami, Yoshihiko Segawa, Masayuki Yasugi, Masahiro Tabata, Mitsune Tanimoto

JOURNAL OF THORACIC ONCOLOGY 5 ( 10 ) 1668 - 1672 2010.10

Language：English Publishing type：Research paper (scientific journal) Publisher：LIPPINCOTT WILLIAMS & WILKINS

Introduction: This study explores patient preferences for involvement in lung cancer treatment decisions and the extent of concordance between the views of patients and physicians on decisional roles. The impact of demographic and psychosocial characteristics on the decisional role of patients is also examined.
Methods: Patients with relapsed non-small cell lung cancer who were candidates for a phase II trial of erlotinib monotherapy were recruited. Patients were interviewed after they had learned of their relapse and the treatment decision had been made but before pharmacologic intervention.
Results: Most of the 28 participants were married, had a smoking history, and were well educated. They reported moderate levels of depression and anxiety. Initially, 14% of the patients reported a preference for active decision making; later, 29% believed that the primary responsibility for the treatment decision had been theirs. Only 54% of the patients agreed with the physician's assessment of how the treatment decision was made (kappa = 0.31; test of symmetry, p = 0.23). The depression score was significantly associated with a patient's preferred level of control (p < 0.01).
Conclusions: The limited concordance between patient preference and perception and between patient and physician perceptions regarding how the treatment decision was made suggests that physicians should more accurately identify patient preferences by directly asking patients at the beginning of each clinical encounter.

DOI： 10.1097/JTO.0b013e3181f1c8cb

Phase III Trial Comparing Docetaxel and Cisplatin Combination Chemotherapy With Mitomycin, Vindesine, and Cisplatin Combination Chemotherapy With Concurrent Thoracic Radiotherapy in Locally Advanced Non-Small-Cell Lung Cancer: OLCSG 0007 Reviewed

Yoshihiko Segawa, Katsuyuki Kiura, Nagio Takigawa, Haruhito Kamei, Shingo Harita, Shunkichi Hiraki, Yoichi Watanabe, Keisuke Sugimoto, Takuo Shibayama, Toshiro Yonei, Hiroshi Ueoka, Mitsuhiro Takemoto, Susumu Kanazawa, Ichiro Takata, Naoyuki Nogami, Katsuyuki Hotta, Akio Hiraki, Masahiro Tabata, Keitaro Matsuo, Mitsune Tanimoto

JOURNAL OF CLINICAL ONCOLOGY 28 ( 20 ) 3299 - 3306 2010.7

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER SOC CLINICAL ONCOLOGY

Purpose To demonstrate the efficacy of docetaxel and cisplatin (DP) chemotherapy with concurrent thoracic radiotherapy (TRT) for patients with locally advanced non-small-cell lung cancer (LA-NSCLC).
Patients and Methods Patients age 75 years or younger with LA-NSCLC, stratified by performance status, stage, and institution, were randomly assigned to two arms consisting of DP (docetaxel 40 mg/m(2) and cisplatin 40 mg/m(2) on days 1, 8, 29, and 36) or mitomycin, vindesine, and cisplatin (MVP) chemotherapy with concurrent TRT.
Results Between July 2000 and July 2005, 200 patients were allocated into either the DP or MVP arm. The survival time at 2 years, a primary end point, was favorable to the DP arm (P = .059 by a stratified log-rank test as a planned analysis and P = .044 by an early-period, weighted log-rank as an unplanned analysis). There was a trend toward improved response rate, 2-year survival rate, median progression-free time, and median survival in the DP arm (78.8%, 60.3%, 13.4 months, and 26.8 months, respectively) compared with the MVP arm (70.3%, 48.1%, 10.5 months, and 23.7 months, respectively), which was not statistically significant (P > .05). Grade 3 febrile neutropenia occurred more often in the MVP arm than in the DP arm (39% v 22%, respectively; P = .012), and grade 3 to 4 radiation esophagitis was likely to be more common in the DP arm than in the MVP arm (14% v 6%, P = .056).
Conclusion DP chemotherapy combined with concurrent TRT is an alternative to MVP chemotherapy for patients with LA-NSCLC.

DOI： 10.1200/JCO.2009.24.7577

Other Link： http://orcid.org/0000-0003-1761-6314

A Phase II Trial of Erlotinib Monotherapy in Pretreated Patients with Advanced Non-small Cell Lung Cancer Who Do Not Possess Active EGFR Mutations Okayama Lung Cancer Study Group Trial 0705 Reviewed

Hiroshige Yoshioka, Katsuyuki Hotta, Katsuyuki Kiura, Nagio Takigawa, Hidetoshi Hayashi, Shingo Harita, Shoichi Kuyama, Yoshihiko Segawa, Haruhito Kamei, Shigeki Umemura, Akihiro Bessho, Masahiro Tabata, Mitsune Tanimoto

JOURNAL OF THORACIC ONCOLOGY 5 ( 1 ) 99 - 104 2010.1

Language：English Publishing type：Research paper (scientific journal) Publisher：LIPPINCOTT WILLIAMS & WILKINS

Backgrounds: Efficacy of gefitinib therapy strongly depends on epidermal growth factor receptor (EGFR)-mutation status in Asian patients with non-small cell lung cancer. Recently, the survival advantage of erlotinib, another tyrosine kinase inhibitor, was not affected by EGFR mutation status in a phase III trial, indicating that patients with EGFR-wild-type (EGFR-wt) tumors might also benefit from this tyrosine kinase inhibitor. The aim of this trial was to evaluate the efficacy and toxicity of erlotinib in Japanese patients with EGFR-wt tumors.
Methods: The primary end point was an objective response. Patients with EGFR-wt tumors previously receiving one to three chemotherapy regimens were enrolled in this trial. The mutation status was assessed using the peptide nucleic acid-locked nucleic acid polymerase chain reaction clamp method. Erlotinib was administered (150 mg/d) until disease progression or unacceptable toxicities occurred.
Results: Thirty patients were enrolled between January and December 2008. Objective response was observed in one patient (3.3%), and the disease became stable in 18 patients (60.0%). Skin rash was the most common side effect. Grades 3-4 adverse events included pulmonary embolism, keratitis, and anemia. Two other patients developed interstitial lung disease (grades 1 and 2). Nevertheless, all these events were reversible, resulting in no treatment-related deaths. With a median follow-Lip time of 10.7 months, the median survival time and median progression-free survival times were 9.2 and 2.1 months, respectively.
Conclusion: This is the first prospective biomarker study showing that erlotinib therapy for pretreated patients with EGFR-wt tumors seems to have a modest activity with no irreversible toxicity.

P8-8 血性の気管支肺胞洗浄液所見のために診断が遅れた肺胞蛋白症の1例(感染・びまん性肺疾患,ポスター8,第33回日本呼吸器内視鏡学会学術集会)

谷口暁彦, 谷本安, 能島大輔, 小崎佐恵子, 南大輔, 田中寿明, 高田三郎, 堀田勝幸, 宮原信明, 瀧川奈義夫, 金廣有彦, 田端雅弘, 木浦勝行, 片岡幹男, 谷本光音

気管支学 32 S200 2010

Comprehensive analysis of EGFR signaling pathways in Japanese patients with non-small cell lung cancer. Reviewed International journal

Shinobu Hosokawa, Shinichi Toyooka, Yoshiro Fujiwara, Masaki Tokumo, Junichi Soh, Nagio Takigawa, Katsuyuki Hotta, Tadashi Yoshino, Hiroshi Date, Mitsune Tanimoto, Katsuyuki Kiura

Lung cancer (Amsterdam, Netherlands) 66 ( 1 ) 107 - 13 2009.10

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

PURPOSE: Translational approach is essentially needed to return the achievement of basic researches to oncological practice. The molecular associations among EGFR mutation and the components of EGFR signaling pathways have been extensively studied in laboratory experiments, although were still controversial. Moreover, the impact of downstream signaling of EGFR on clinical features in patients with non-small cell lung cancer (NSCLC) remains undetermined. PATIENTS AND METHODS: A total of 93 surgically resected NSCLC patients were recruited the study. EGFR mutation status was analyzed by direct sequence method. The protein expression levels of EGFR, phosphorylated EGFR (pEGFR), phosphorylated Akt (pAkt), and phosphorylated MAPK (pMAPK) were determined by immunohistochemistry. RESULTS: There were 37 (40%) patients whose tumor harboring EGFR mutations (1 in exon 18, 22 in exon 19, and 14 in exon 21). Protein expression of EGFR, pEGFR, pAkt, and pMAPK was detected in 61 (66%), 27 (29%), 58 (62%), and 41 (44%) patients, respectively. The expression of pAkt was significantly associated with female gender and never-smoking history, and it was frequently upregulated in tumors harboring EGFR mutations (p<0.05, each). Phosphorylation of EGFR was closely correlated with the EGFR protein expression (p<0.05), but not with the EGFR mutations. In regard to patient survival, none of the molecular biomarkers was predictive for survival after surgical resection, but pMAPK expression was predictive for poor prognosis after gefitinib treatment in patients with postoperative recurrence (p<0.05), suggesting the strong linkage between pMAPK expression and survival benefit from gefitinib. CONCLUSION: Our result could provide new insight into MAP kinase signaling when we treat NSCLC patients with gefitinib.

DOI： 10.1016/j.lungcan.2009.01.005

EGFR mutation, but not sex and smoking, is independently associated with favorable prognosis of gefitinib-treated patients with lung adenocarcinoma Reviewed

Shinichi Toyooka, Toshimi Takano, Takayuki Kosaka, Katsuyuki Hotta, Keitaro Matsuo, Shuji Ichihara, Yoshiro Fujiwara, Junichi Soh, Hiroki Otani, Katsuyuki Kiura, Keisuke Aoe, Yasushi Yatabe, Yuichiro Ohe, Tetsuya Mitsudomi, Hiroshi Date

Japanese Journal of Lung Cancer 49 ( 4 ) 409 - 415 2009.8

Language：Japanese

Objective. Intensive research has been conducted to identify factors associated with favorable clinical outcomes of gefitinib-treated patients with non-small-cell lung cancer. Epidermal growth factor receptor (EGFR) mutations have been reported as a predictive factor for favorable prognosis of gefitinib-treated patients with lung adenocarcinoma. However, its confounding with sex and smoking makes EGFR mutations' unique effect on patient survival. In this study, we analyzed a large-scale database to determine the survival impact of EGFR mutation against those of sex and smoking after gefitinib therapy. Materials and Methods. EGFR mutations in exon19 and exon21 defined as drug-sensitive EGFR mutations were examined to investigate the impact of EGFR mutation, sex, and smoking status on survival of 362 gefitinib-treated patients with lung adenocarcinoma. Results. Drug-sensitive EGFR mutations were detected in 169 patients (46.7%). The multivariate analysis including EGFR, sex and smoking status showed that drug-sensitive EGFR mutations were significantly related to prolonged overall survival (OS) (Hazard ratio = 0.48, 95% confidence interval = 0.36-0.63, P &lt
0.001) (PFS: Hazard ratio, 0.29, 95% confidence interval = 0.22-0.37, P &lt
0.001) and progression-free survival (PFS) (P &lt
0.001). In addition, we investigated 1) the impact of sex and smoking status according to EGFR status and 2) the impact of EGFR status according to sex and smoking status on survival. Sex and smoking status were not significantly associated with prolonged OS and PFS according to EGFR status. Drug-sensitive EGFR mutations were significantly associated with prolonged OS and PFS according to sex or smoking status. Conclusion. Our results indicated that drug-sensitive EGFR mutations were the only factor for prolonged survival of patients treated with gefitinib, suggesting that patient selection based on EGFR status for gefitinib therapy will lead to better understanding the effect of gefitinib as well as a better outcome for patients with lung adenocarcinoma. © 2009 The Japan Lung Cancer Society.

DOI： 10.2482/haigan.49.409

Other Link： http://orcid.org/0000-0003-1761-6314

A phase I study of combination S-1 plus cisplatin chemotherapy with concurrent thoracic radiation for locally advanced non-small cell lung cancer. International journal

Kenichi Chikamori, Daizo Kishino, Nagio Takigawa, Katsuyuki Hotta, Naoyuki Nogami, Haruhito Kamei, Shoichi Kuyama, Kenichi Gemba, Mitsuhiro Takemoto, Susumu Kanazawa, Hiroshi Ueoka, Yoshihiko Segawa, Saburo Takata, Masahiro Tabata, Katsuyuki Kiura, Mitsune Tanimoto

Lung cancer (Amsterdam, Netherlands) 65 ( 1 ) 74 - 9 2009.7

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

A combination of S-1, a newly developed oral 5-fluorouracil derivative, and cisplatin is reported to show anti-tumour activity against advanced non-small cell lung cancer (NSCLC). Because S-1 shows synergistic effects with radiation, we conducted a phase I study to evaluate the maximum tolerated doses (MTDs), recommended doses (RDs), and dose-limiting toxicities (DLTs) of cisplatin and S-1 when combined with concurrent thoracic radiation (total dose of 60 Gy with 2 Gy per daily fraction) in patients with locally advanced NSCLC. Chemotherapy consisted of two 4-week cycles of cisplatin administered on days 1 and 8, and S-1 administered on days 1-14. S-1/cisplatin dosages (mg/m(2)/day) were escalated as follows: 60/30, 60/40, 70/40, 80/40 and 80/50. Twenty-two previously untreated patients were enrolled. The MTDs and RDs for S-1/cisplatin were 80/50 and 80/40, respectively. DLTs included febrile neutropaenia, thrombocytopaenia, bacterial pneumonia and delayed second cycle of chemotherapy. No patient experienced radiation pneumonitis>grade 2 and only one patient experienced grade 3 radiation oesophagitis. The overall response rate was 86.4% with a median survival time of 24.4 months. These results indicate that combination cisplatin-S-1 chemotherapy with concurrent thoracic radiation would be a feasible treatment option and a phase II study is currently under way.

DOI： 10.1016/j.lungcan.2008.10.019

慢性閉塞性肺疾患(COPD)を合併した進行肺非小細胞癌(NSCLC)の予後

原田大二郎, 瀧川奈義夫, 木浦勝行, 谷本安, 堀田勝幸, 平木章夫, 宮原信明, 田端雅弘, 金廣有彦, 谷本光音

日本呼吸器学会雑誌 47 ( 増刊 ) 300 - 300 2009.5

Sex difference in the influence of smoking status on the responsiveness to gefitinib monotherapy in adenocarcinoma of the lung: Okayama Lung Cancer Study Group experience Reviewed

Katsuyuki Hotta, Katsuyuki Kiura, Nagio Takigawa, Shoichi Kuyama, Yoshihiko Segawa, Toshiro Yonei, Kenichi Gemba, Keisuke Aoe, Takuo Shibayama, Keisuke Matsuo, Haruhito Kamei, Yoshiro Fujiwara, Akihiko Bessho, Tomonori Moritaka, Keisuke Sugimoto, Masahiro Tabata, Hiroshi Ueoka, Mitsune Tanimoto

JOURNAL OF CANCER RESEARCH AND CLINICAL ONCOLOGY 135 ( 1 ) 117 - 123 2009.1

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

Background Gefitinib is effective in patients with lung adenocarcinoma. Smoking status also affects the responsiveness to gefitinib, but it has not been fully evaluated whether a sex difference exists in the influence of smoking on the efficacy of gefitinib in patients with lung adenocarcinoma.
Methods We reviewed the clinical records of 260 Japanese patients with lung adenocarcinoma who received gefitinib therapy ( 250 mg/day), and whose smoking status was known. Tumour response and survival were evaluated and stratified by smoking status and gender.
Results Among the 260 patients, 157 were male (60%). Median pack-years was 40 ( range 8 - 160) and 23 ( range 1 74) in male and female smokers, respectively. Objective response was observed in 62 (23.8%) of the 260 patients, and 1-year overall survival and progression-free survival were 45.1 and 24.3%, respectively. Multivariate analysis revealed that smoking status (pack-years) was an independent predictive factor for response to gefitinib [ odds ratio ( OR) = 0.971, 95% confidence interval (CI) = 0.947 - 0.995; P = 0.0159] in male patients, but not in female patients ( OR = 0.999, 95% CI = 0.957 - 1.042). Additionally, pack-years significantly influenced the overall survival in males ( hazard ratio = 1.010; 95% CI = 1.002 - 1018, P = 0.0169), while differential survival of females was not significantly predicted by this factor ( P = 0.7639).
Conclusions In male patients with lung adenocarcinoma, cumulative smoking significantly affected response and survival following gefitinib treatment, while in female patients, responsiveness to gefitinib was independent of smoking status. These results suggest that the influence of smoking habit on responsiveness to gefitinib is gender specific.

DOI： 10.1007/s00432-008-0431-1

PO8-3 血液悪性腫瘍の治療中に出現した胸部異常影に対する気管支鏡検査(びまん性疾患,ポスター8,第32回日本呼吸器内視鏡学会学術集会)

村上斗司, 瀧川奈義夫, 谷本安, 二宮崇, 栗本悦子, 能島大輔, 本多宣裕, 堀田勝幸, 宮原信明, 田端雅弘, 金廣有彦, 木浦勝行, 谷本光音

気管支学 31 S157 2009

PO11-1 非乾酪性類上皮細胞肉芽腫病変を伴ったために診断に苦慮したホジキンリンパ腫の1例(リンパ腫・胸腺・胸膜腫瘍,ポスター11,第32回日本呼吸器内視鏡学会学術集会)

栗本悦子, 谷本安, 瀧川奈義夫, 二宮崇, 能島大輔, 村上斗司, 本多宣裕, 堀田勝幸, 宮原信明, 田端雅弘, 金廣有彦, 木浦勝行, 谷本光音, 片岡幹男

気管支学 31 S165 2009

41.気管支鏡下生検で診断された19年後の再発乳癌の1例(第17回日本呼吸器内視鏡学会中国四国支部会)

村上斗司, 木浦勝行, 瀧川奈義夫, 能島大輔, 本多宣裕, 二宮崇, 栗本悦子, 堀田勝幸, 宮原信明, 谷本安, 田端雅弘, 金廣有彦, 谷本光音

気管支学 31 ( 3 ) 178 - 178 2009

A case of advanced non-small-cell lung cancer who responded slowly to gefitinib monotherapy after long-term disease stabilization. International journal

Katsuyuki Hotta, Katsuyuki Kiura, Akinori Shirahige, Saburo Takata, Nagio Takigawa, Masahiro Tabata, Hirokazu Watanabe, Mitsune Tanimoto

Acta oncologica (Stockholm, Sweden) 48 ( 3 ) 471 - 3 2009

Paradoxical Clinical Effects of Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors for Acute Myelogenous Leukemia Reviewed

Katsuyuki Hotta, Katsuyuki Kiura, Nagio Takigawa, Keitaro Matsuo, Masahiro Tabata, Yoshiro Fujiwara, Mitsune Tanimoto

JOURNAL OF CLINICAL ONCOLOGY 26 ( 35 ) 5826 - 5827 2008.12

すりガラス陰影を伴う肺腺癌の進展におけるEGFRシグナルの関与

高田三郎, 瀧川奈義夫, 大橋圭明, 畝川芳彦, 山下素弘, 寺本典弘, 新海哲, 上月稔幸, 堀田勝幸, 田端雅弘, 木浦勝行, 谷本光音

肺癌 48 ( 5 ) 511 - 511 2008.10

非小細胞性肺癌の日本人患者におけるゲフィチニブ単剤療法の効果と喫煙状況との関連(Association of the benefit from gefitinib monotherapy with smoking status in Japanese patients with non-small-cell lung cancer)

藤原義朗, 徳田佳之, 堀田勝幸, 木浦勝行, 瀧川奈義夫, 田端雅弘, 上岡博, 谷本光音

日本癌治療学会誌 43 ( 2 ) 639 - 639 2008.10

再発非小細胞肺癌(NSCLC)症例に対するゲフィチニブ治療後の生存期間と喫煙歴との相互作用に関する検討

堀田勝幸, 木浦勝行, 瀧川奈義夫, 藤原義朗, 田端雅弘, 上岡博, 谷本光音

肺癌 48 ( 5 ) 477 - 477 2008.10

ゲフィチニブ単剤療法が施行された肺非小細胞癌における予後因子としての血清KL-6

藤原義朗, 木浦勝行, 瀧川奈義夫, 豊岡伸一, 堀田勝幸, 宗淳一, 宮原信明, 谷本安, 金廣有彦, 田端雅弘, 加藤勝也, 伊達洋至, 谷本光音

日本呼吸器学会雑誌 46 ( 増刊 ) 131 - 131 2008.5

ERCC1 protein expression predicts the response of cisplatin-based neoadjuvant chemotherapy in non-small-cell lung cancer. Reviewed International journal

Tetsuya Fujii, Shinichi Toyooka, Kouichi Ichimura, Yoshiro Fujiwara, Katsuyuki Hotta, Junichi Soh, Hiroshi Suehisa, Naruyuki Kobayashi, Motoi Aoe, Tadashi Yoshino, Katsuyuki Kiura, Hiroshi Date

Lung cancer (Amsterdam, Netherlands) 59 ( 3 ) 377 - 84 2008.3

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

The excision repair cross-complementation group 1 (ERCC1) and BRCA1 have been identified as predictors of clinical outcomes among patients with non-small-cell lung cancer (NSCLC) treated with cisplatin-based chemotherapy. In this study, we immunohistochemically examined the ERCC1 and BRCA1 protein expression levels in 35 patients with metastatic mediastinal lymph nodes obtained prior to treatment as retrospective study. These patients had been enrolled in our studies on neoadjuvant chemotherapy with cisplatin and irinotecan (15 patients) or chemoradiotherapy with cisplatin and docetaxel plus concurrent thoracic radiation (20 patients). The relations between the ERCC1 or BRCA1 protein expression and the clinical outcomes of the patients were then examined. The rates of radiological response and pathological effectiveness were significantly higher among patients with ERCC1-negative tumors, compared with those with positive tumors in the neoadjuvant chemotherapy group (radiological response rates; 100% vs. 42.8%, P=0.013; pathological effectiveness; 100% vs. 47.1%, P=0.038), but no associations were observed in the neoadjuvant chemoradiotherapy group. Regarding survival, no significant differences in overall survival or disease-free survival were observed between patients with ERCC1-negative and positive tumors in both the neoadjuvant chemotherapy and chemoradiotherapy groups. In summary, we showed that a ERCC1-negative protein status was significantly related to tumor responsiveness to neoadjuvant chemotherapy with cisplatin and irinotecan, but such a status was not a clear prognostic predictor to cisplatin-based neoadjuvant therapy in NSCLC patients. Further study is needed to clarify the value of molecular predictors for customizing therapy for patients with NSCLC.

DOI： 10.1016/j.lungcan.2007.08.025

Epidermal growth factor receptor mutation, but not sex and smoking, is independently associated with favorable prognosis of gefitinib-treated patients with lung adenocarcinoma Reviewed

Shinichi Toyooka, Toshimi Takano, Takayuki Kosaka, Katsuyuki Hotta, Keitaro Matsuo, Shuji Ichihara, Yoshiro Fujiwara, Junichi Soh, Hiroki Otani, Katsuyuki Kiura, Keisuke Aoe, Yasushi Yatabe, Yuichiro Ohe, Tetsuya Mitsudomi, Hiroshi Date

CANCER SCIENCE 99 ( 2 ) 303 - 308 2008.2

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

Epidermal growth factor receptor (EGFR) mutations have been reported as a predictive factor for favorable prognosis of gefitinib-treated patients with lung adenocarcinoma. However, its confounding with sex and smoking makes it unclear whether the EGFR mutation is independently associated with prolonged patient survival. In this study, we analyzed a large-scale database to discriminate the survival impact of EGFR mutations against those of sex and smoking after gefitinib therapy. EGFR mutations in exon19 and exon21 named drug-sensitive EGFR mutations were examined to investigate the impact of EGFR mutation, sex, and smoking status on survival of 362 gefitinib-treated patients with lung adenocarcinoma. Drug-sensitive EGFR mutations were detected in 169 patients (46.7%). The multivariate analysis including EGFR, sex, and smoking status showed that drug-sensitive EGFR mutations were significantly related to longer overall survival (OS) (P < 0.001) and progression-free survival (PFS) (P < 0.001). In addition, we investigated the impact of sex and smoking status according to EGFR mutation status, and the impact of EGFR mutation status according to sex and smoking status on survival. Sex and smoking status were not significantly associated with longer OS and PFS according to EGFR mutation status. Drug-sensitive EGFR mutations were significantly associated with longer OS and PFS according to sex or smoking status. Our results indicated that drug-sensitive EGFR mutations were the only independent factor for longer survival of patients treated with gefitinib, suggesting that patient selection based on EGFR mutation status for gefitinib therapy will lead to a better outcome for patients with lung adenocarcinoma.

DOI： 10.1111/j.1349-7006.2007.00688.x

Elevated serum level of sialylated glycoprotein KL-6 predicts a poor prognosis in patients with non-small cell lung cancer treated with gefitinib. Reviewed International journal

Yoshiro Fujiwara, Katsuyuki Kiura, Shinichi Toyooka, Katsuyuki Hotta, Masahiro Tabata, Nagio Takigawa, Junichi Soh, Yasushi Tanimoto, Arihiko Kanehiro, Katsuya Kato, Hiroshi Date, Mitsune Tanimoto

Lung cancer (Amsterdam, Netherlands) 59 ( 1 ) 81 - 7 2008.1

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

PURPOSE: The factors affecting survival after gefitinib treatment in patients with non-small cell lung cancer (NSCLC) remain to be fully elucidated, although epidermal growth factor receptor (EGFR) mutation is a substantial prognostic factor. KL-6 has been studied as a useful indicator for interstitial lung diseases; however, it was first discovered as a lung cancer-related antigen. The aim of this study was to investigate the prognostic value of the serum KL-6 levels in advanced NSCLC patients treated with gefitinib and thus determine its association with the EGFR mutation status. PATIENTS AND METHODS: Between September 2002 and September 2005, 41 patients with NSCLC were treated with gefitinib after having their serum KL-6 levels measured at Okayama University Hospital. EGFR mutations were analyzed by direct sequence methods. RESULTS: The serum KL-6 levels ranged from 199 to 9080U/ml (median, 550U/ml), and 54% of 41 patients showed a level higher than the cut-off level of 500U/ml. The median progression-free survival (PFS) time and the median overall survival (OS) time were 4.7 months and 13.9 months, respectively. Multivariate analyses revealed that the elevated KL-6 level was an independent adverse prognostic factor for PFS (hazard ratio: 2.278, p=0.040) as well as OS (hazard ratio: 4.858, p=0.002) in NSCLC patients treated with gefitinib. The EGFR mutation status was analyzed in 22 patients (54%). Among those with wild-type EGFR, the patients with high serum KL-6 levels also had a worse survival than those within normal serum KL-6 levels (6.5 months versus 13.3 months, p=0.0194). CONCLUSION: Our data suggest that NSCLC patients with high serum KL-6 levels tended to have a poor clinical outcome when treated with gefitinib.

DOI： 10.1016/j.lungcan.2007.07.018

How Can We Increase the Number of Participants in Lung Cancer Screening?(The 22nd Lung Cancer Mass Screening Seminar)

Masakage Mieko, Nishii Kenji, Hotta Katsuyuki, Tabata Masahiro, Takigawa Nagio, Kiura Katsuyuki, Ueoka Hiroshi

Japanese Journal of Lung Cancer 47 ( 6 ) 743 - 750 2007.10

Language：Japanese Publisher：The Japan Lung Cancer Society

Recently, the number of participants in lung cancer screening has been decreasing in Okayama Prefecture, which may lower the screening effects to improve lung cancer mortality and as a result many municipalities may stop lung cancer screening in the near future. In Japan, lung cancer screening has already been abandoned in 109 (5%) municipalities, since they considered that the effectiveness of lung cancer screening was inferior to that of screening programs for other cancers. In this report, we discussed the following issues in lung cancer screening today by analyzing questionnaires for bureaucrat responsible for lung cancer screening. Due to their insufficient knowledge about lung cancer, up-to-date information or cumulative knowledge was not efficiently used in screening. Though the bureaucrat understood the importance of quality control of screening, quality control was not included in the specification form for public bidding for selecting the screening agency. It was surprising that some officers understood neither the difference between tuberculosis screening and lung cancer screening nor the purpose of screening. These results indicate that these officers failed to explain the necessity of lung cancer screening for the community and emphasize the usefulness of selecting the appropriate agency with high accuracy for the financial manager. In conclusion, the bureaucrat responsible for lung cancer screening have to understand "cancer screening with high quality" in the nation's statement, and give equal opportunities for lung cancer screening to the community. The screening agency has the responsibility to increase the number of participation of individuals in lung cancer screening.

DOI： 10.2482/haigan.47.743

Other Link： http://search.jamas.or.jp/link/ui/2008089614

抗悪性腫瘍薬の至適投与法確立を目指して非小細胞肺癌(NSCLC)症例における、腫瘍EGFR遺伝子変異の殺細胞性抗癌剤治療効果への影響の検討

堀田勝幸, 木浦勝行, 豊岡伸一, 瀧川奈義夫, 宗淳一, 藤原義朗, 田端雅弘, 伊達洋至, 谷本光音

肺癌 47 ( 5 ) 450 - 450 2007.10

肺非小細胞癌における治療前血清KL-6値とゲフィチニブ単剤療法の治療効果の関連

藤原義朗, 木浦勝行, 瀧川奈義夫, 豊岡伸一, 堀田勝幸, 宗淳一, 田端雅弘, 加藤勝也, 伊達洋至, 谷本光音

肺癌 47 ( 5 ) 629 - 629 2007.10

腰髄液腔・腹腔短絡術(LPシャント)とゲフィチニブ投与が著効した癌性髄膜炎

久保寿夫, 瀧川奈義夫, 木浦勝行, 梅村茂樹, 高田三郎, 堀田勝幸, 田端雅弘, 谷本光音, 豊岡伸一, 伊達洋至

肺癌 47 ( 5 ) 672 - 672 2007.10

Impact of HER2 and EGFR gene status on gefitinib-treated patients with nonsmall-cell lung cancer. Reviewed International journal

Junichi Soh, Shinichi Toyooka, Shuji Ichihara, Yoshiro Fujiwara, Katsuyuki Hotta, Hiroshi Suehisa, Naruyuki Kobayashi, Kouichi Ichimura, Keisuke Aoe, Motoi Aoe, Katsuyuki Kiura, Hiroshi Date

International journal of cancer 121 ( 5 ) 1162 - 7 2007.9

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

We previously examined the relationship between epidermal growth factor receptor (EGFR) status and clinical outcomes of nonsmall-cell lung cancer (NSCLC) patients treated with gefitinib. In our study, we additionally examined HER2 status and investigate the impact of genetic status as predictors in Japanese NSCLC patients treated with gefitinib. The HER2 copy number status was determined by fluorescence in situ hybridization assay and mutation of HER2 exon 20 was determined by direct sequencing in 74 patients to investigate the relationship between molecular statuses including HER2 and EGFR and the clinical outcomes of patients treated with gefitinib. The high HER2 copy number was identified in 32 (43.2%) of 74 NSCLC patients and no HER2 exon 20 mutations were found. The high HER2 copy number was significantly associated with the sensitivity to gefitinib (p = 0.0045) and a prolonged progression-free survival (PFS) (p = 0.0089) in a univariate analysis, but not in a multivariate analysis. Multivariate analyses exhibited that the drug-sensitive EGFR mutation was an independent predictive factor of a better sensitivity to gefitinib (OR = 41.9, p = 0.002), prolonged overall survival (HR = 0.32, p = 0.019) and PFS (HR = 0.31, p = 0.0045). The high EGFR copy number might have a weak association with better response and prognosis without statistical significance. In conclusion, the drug-sensitive EGFR mutation, rather than HER2 and EGFR copy numbers, is a determinant of favorable clinical outcomes in gefitinib-treated patients with NSCLC, although the high HER2 copy number, to some extent, may influence the gefitinib effect.

DOI： 10.1002/ijc.22818

Epidermal growth factor receptor mutation status and adjuvant chemotherapy with uracil-tegafur for adenocarcinoma of the lung Reviewed

Hiroshi Suehisa, Shinichi Toyooka, Katsuyuki Hotta, Akiko Uchida, Junichi Soh, Yoshiro Fujiwara, Keitaro Matsuo, Mamoru Ouchida, Minoru Takata, Katsuyuki Kiura, Hiroshi Date

JOURNAL OF CLINICAL ONCOLOGY 25 ( 25 ) 3952 - 3957 2007.9

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER SOC CLINICAL ONCOLOGY

Purpose
Adjuvant chemotherapy with uracil- tegafur has been demonstrated to prolong survival among patients with resected lung adenocarcinomas. Epidermal growth factor receptor ( EGFR) mutations have been reported to be present in lung adenocarcinomas. The present study evaluated whether the EGFR status could be used as a biologic predictor of the outcome of adjuvant chemotherapy with uracil- tegafur.
Patients and Methods
The EGFR mutational status of 187 patients with resected lung adenocarcinomas was determined using a polymerase chain reaction - based assay for EGFR exons 19 and 21; the results were then correlated with the effect of adjuvant uracil- tegafur chemotherapy on survival. The antiproliferative effect of fluorouracil ( FU) on adenocarcinoma cell lines with EGFR wild-type or mutant type status was examined by measuring the inhibitory concentrations at 50% ( IC(50)s).
Results
Among the 187 patients, 68 received uracil- tegafur as adjuvant chemotherapy, and 119 were not treated with any chemotherapeutic agents. EGFR mutations were present in 79 patients ( 43%). Overall, the adjuvant chemotherapy with uracil- tegafur significantly prolonged survival compared with the control group ( hazard ratio = 0.38; P =.005). The survival benefit of adjuvant chemotherapy with uracil- tegafur was also examined after stratifying the patients according to EGFR mutation status. Adjuvant chemotherapy significantly prolonged survival among patients with EGFR wild- type tumors ( hazard ratio = 0.34; P =.013) but not among patients with EGFR mutant tumors. In an in vitro experiment, the IC(50)s of EGFR mutant cells to FU were higher than those of wild-type cells, indicating that EGFR wild- type cells are more sensitive to FU than mutant cells.
Conclusion
EGFR status influenced the effect of adjuvant chemotherapy with uracil- tegafur. Adjuvant chemotherapy could be customized based on EGFR status.

DOI： 10.1200/JCO.2007.11.8646

Other Link： http://orcid.org/0000-0003-1761-6314

Clinical significance of epidermal growth factor receptor gene mutations on treatment outcome after first-line cytotoxic chemotherapy in Japanese patients with non-small cell lung cancer. Reviewed International journal

Katsuyuki Hotta, Katsuyuki Kiura, Shinichi Toyooka, Nagio Takigawa, Junichi Soh, Yoshiro Fujiwara, Masahiro Tabata, Hiroshi Date, Mitsune Tanimoto

Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 2 ( 7 ) 632 - 7 2007.7

Language：English Publishing type：Research paper (scientific journal) Publisher：LIPPINCOTT WILLIAMS & WILKINS

INTRODUCTION: The relationship between the EGFR gene mutation status and clinical outcome has not fully been assessed in patients with non-small cell lung cancer (NSCLC) who received cytotoxic agents. The aim of this study was to clarify its association. We also examined whether this association could be affected by previous gefitinib treatment. METHODS: Patients with advanced or postoperative recurrent NSCLC who received both cytotoxic chemotherapy and gefitinib monotherapy in their treatment course were included in this study. An EGFR mutation was determined in exons 19 and 21 by direct sequencing. RESULTS: Of 194 Japanese patients with advanced or relapsed NSCLC assessable for mutation analysis, 60 received both cytotoxic chemotherapy and gefitinib monotherapy through their treatment courses. EGFR mutations significantly affected progression-free survival (PFS) in the first-line cytotoxic chemotherapy regimens in the multivariate analysis (hazard ratio for PFS = 0.422; p = 0.0422). In contrast, in 28 (47%) of the 60 patients who also received cytotoxic chemotherapy after the relapse to gefitinib monotherapy, there were no differences in PFS stratified by EGFR mutation status. The sensitivity to gefitinib was, however, correlated with EGFR mutation status, and its sensitivity was retained even in the second-line treatment setting in patients with EGFR mutations. CONCLUSIONS: EGFR mutations were therefore significantly associated with a better PFS in the first-line cytotoxic chemotherapy regimens. However, its association was not observed in the cytotoxic regimens administered after the relapse to gefitinib monotherapy, whereas gefitinib sensitivity was associated with an EGFR mutation even in the second-line or later treatment settings.

DOI： 10.1097/JTO.0b013e318074bc0d

EGFR変異とUFTによる肺腺癌術後補助療法の関連性についての検討

末久弘, 豊岡伸一, 堀田勝幸, 内田亜希子, 宗淳一, 木浦勝行, 浅野博昭, 藤原義朗, 松尾恵太郎, 青江基, 高田穣, 清水信義, 伊達洋至

日本呼吸器外科学会雑誌 21 ( 3 ) 404 - 404 2007.4

The impact of epidermal growth factor receptor gene status on gefitinib-treated Japanese patients with non-small-cell lung cancer. Reviewed International journal

Shuji Ichihara, Shinichi Toyooka, Yoshiro Fujiwara, Katsuyuki Hotta, Hisayuki Shigematsu, Masaki Tokumo, Junichi Soh, Hiroaki Asano, Kouichi Ichimura, Keisuke Aoe, Motoi Aoe, Katsuyuki Kiura, Kenji Shimizu, Hiroshi Date, Nobuyoshi Shimizu

International journal of cancer 120 ( 6 ) 1239 - 47 2007.3

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

We investigated the relationships between genetic factors and clinical outcome in Japanese non-small-cell lung cancer (NSCLC) patients treated with gefitinib. Ninety-eight NSCLC patients who had been treated with gefitinib, were screened for mutations in epidermal growth factor receptor (EGFR) exons 18-21, KRAS exon2, and polymorphisms including the CA simple sequence repeat in intron1 (CA-SSR1) and single nucleotide polymorphisms in the promoter region (-216G/T and -191C/A), using a PCR-based assay and direct sequencing. The EGFR copy number status was also evaluated using a fluorescence in situ hybridization assay. EGFR and KRAS mutations were found in 38 (38.8%) and 8 (8.2%) of the 98 patients, respectively. A high EGFR copy number status was identified in 31 (41.3%) of the 75 assessable patients. Drug-sensitive EGFR mutations limited to exon19 deletions and L858R were independent predictive factors of a stronger sensitivity to gefitinib (p = 0.0002), the overall survival (OS) (p = 0.0036), and prolonged progression-free survival (PFS) (p < 0.0001). The EGFR copy number status was not related to a sensitivity to gefitinib and prolonged OS and PFS. Regarding polymorphisms, patients with a short CA-SSR1 showed a prolonged OS as compared with those with a long length in patients with a drug-sensitive EGFR mutation, although this difference was not significant (p = 0.13). Thus, drug-sensitive EGFR mutations predict a favorable clinical outcome and a high EGFR copy number may not be related to clinical benefits in gefitinib-treated Japanese patients with NSCLC. Our findings also suggest that the CA-SSR1 length may influence the clinical outcome in patients with a drug-sensitive EGFR mutation.

DOI： 10.1002/ijc.22513

Recent improvement in the survival of patients with advanced nonsmall cell lung cancer enrolled in phase III trials of first-line, systemic chemotherapy Reviewed

Katsuyuki Hotta, Yoshiro Fujiwara, Keitaro Matsuo, Takeshi Suzuki, Katsuyuki Kiura, Masahiro Tabata, Nagio Takigawa, Hiroshi Ueoka, Mitsune Tanimoto

CANCER 109 ( 5 ) 939 - 948 2007.3

Language：English Publishing type：Research paper (scientific journal) Publisher：JOHN WILEY & SONS INC

BACKGROUND. Few studies have assessed formally whether treatment outcomes have improved substantially over the years for patients with advanced nonsmall cell lung cancer (NSCLC) enrolled in Phase III trials. The objective of the current investigation was to determine the time trends in outcomes for the patients in those trials.
METHODS. The literature was searched to identify trials that addressed the role of chemotherapy regimens in the first-line setting for the treatment of advanced NSCLC. Trends were tested by using multiple regression analysis.
RESULTS. In total, 121 Phase III trials were identified that involved 42,768 patients with 263 chemotherapy arms and 11 best supportive care (BSC) arms, all of which were initiated between 1982 and 2002. Although the number of randomized patients and the proportion of patients with metastatic disease had increased over the years, the number of patients with a poor performance status who were accrued into the trials had decreased. Cisplatin-based chemotherapy was been investigated most frequently during the period. The multiple regression analysis revealed a significant improvement in median survival and in the median time to disease progression over the years, with annual prolongations of 0.1203 months (3.609 days) and 0.0617 months (1.851 days), respectively (P < .0001 and P < .0130, respectively). In addition, the use of cisplatin and carboplatin was associated significantly with survival prolongation. The median survival for patients who received BSC also increased progressively over the years (P = .0487).
CONCLUSIONS. The survival of patients with NSCLC in Phase III trials improved slowly but steadily over time, although the main factors responsible for this improvement remain unknown. Nonetheless, the current results also suggested that novel targets and new agents will be required in the future fight against advanced NSCLC.

DOI： 10.1002/cncr.22478

Other Link： http://orcid.org/0000-0003-1761-6314

Gefitinib induces premature senescence in non-small cell lung cancer cells with or without EGFR gene mutation. International journal

Katsuyuki Hotta, Masahiro Tabata, Katsuyuki Kiura, Toshiyuki Kozuki, Akiko Hisamoto, Hideki Katayama, Nagio Takigawa, Nobukazu Fujimoto, Keiichi Fujiwara, Hiroshi Ueoka, Mitsune Tanimoto

Oncology reports 17 ( 2 ) 313 - 7 2007.2

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

Despite its tremendous antitumor effect in a subset of patients with non-small cell lung cancer (NSCLC), the exact mechanism of gefitinib-induced cell death has not been fully determined. In this study, forms of cell death in various NSCLC cell lines after gefitinib exposure was analyzed to elucidate the cell death mechanism of gefitinib. Though higher concentration of gefitinib (10 microM) induced extensive apoptosis in two cell lines (EGFR-mutated PC-9 cells and EGFR wild- type EBC-2/R cells), clinically relevant concentrations of gefitinib (1 microM) induced prominent premature senescence instead of apoptosis in these cells. This induction of senescence was preceded by immediate increase of p16INK4A, p21WAF1/Cip1 and p27Kip1 levels and subsequent G1 cell cycle arrest. These phenomena were not observed in gefitinib-resistant (RERF-LC-MS) cells. Additionally, ex vivo exposure to gefitinib induced senescence in short-term cultured tumor cells that were obtained from malignant pleural effusion of a patient with NSCLC, whose tumor was later revealed to be clinically sensitive to gefitinib. Our results indicate that senescence might be a major anti-tumor mechanism of gefitinib in these NSCLC cells regardless of the EGFR gene mutation status.

非喫煙歴による術後再発非小細胞肺癌患者の長期生存予測(Never-smoking history predicts long-term survival in patients with non-small cell lung cancer with postoperative recurrence)

藤原義朗, 木浦勝行, 田端雅弘, 瀧川奈義夫, 谷本安, 堀田勝幸, 松尾恵太郎, 豊岡伸一, 佐野由文, 青江基, 伊達洋至, 谷本光音

日本癌治療学会誌 41 ( 2 ) 671 - 671 2006.9

A phase I and pharmacological study of amrubicin and topotecan in patients of small-cell lung cancer with relapsed or extensive-disease small-cell lung cancer. International journal

Takuo Shibayama, Katsuyuki Hotta, Nagio Takigawa, Atsuhiko Tada, Hiroshi Ueoka, Shingo Harita, Katsuyuki Kiura, Masahiro Tabata, Yoshihiko Segawa, Naoyuki Nogami, Shoichi Kuyama, Tetsu Shinkai, Mitsune Tanimoto

Lung cancer (Amsterdam, Netherlands) 53 ( 2 ) 189 - 95 2006.8

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

Cisplatin-based chemotherapy is considered to be a standard treatment in patients with relapsed or extensive-disease (ED) small-cell lung cancer (SCLC), the survival benefit remains modest. Relapsed or ED-SCLC patients were enrolled. Topotecan and amrubicin were administered on Days 1-5 and on Days 3-5, respectively. Nine patients received a total of 24 cycles. Since all three patients experienced dose-limiting toxicity (grade 4 neutropenia lasting for more than 4 days, grade 3 febrile neutropenia, and grade 4 thrombocytopenia) at the third dose level (topotecan: 0.75 mg/m2, amrubicin 40 mg/m2), the maximum tolerated dose was determined to be this dose level. Objective response was observed in six patients (67%). The maximum concentration (Cmax) and area under the plasma concentration-time curve (AUC) of amrubicin increased in a dose-dependent manner. Amrubicin did not influence the pharmacokinetics of topotecan. The Cmax and AUC of amrubicin were correlated with the duration of grade 4 neutropenia. The mean Cmax of topotecan on day 2 in responders (22.9+/-3.6) was significantly higher than that in non-responders (10.9+/-0.4). This phase I study showed the safety and activity of two-drug combination of amrubicin and topotecan in patients with relapsed or ED-SCLC.

A phase I study of 3-day topotecan and cisplatin in elderly patients with small-cell lung cancer. International journal

Keiichi Fujiwara, Hiroshi Ueoka, Katsuyuki Kiura, Masahiro Tabata, Nagio Takigawa, Katsuyuki Hotta, Shigeki Umemura, Keisuke Sugimoto, Takuo Shibayama, Haruhito Kamei, Shingo Harita, Niro Okimoto, Mitsune Tanimoto

Cancer chemotherapy and pharmacology 57 ( 6 ) 755 - 60 2006.6

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

PURPOSE: The aim of this phase I study was to determine the maximum-tolerated dose (MTD) in elderly patients with small-cell lung cancer (SCLC). PATIENTS AND METHODS: Patients aged over 75 years with previously untreated SCLC were enrolled in this study. Both topotecan and cisplatin were administered on days 1-3 and repeated every 3 weeks. The starting dose of topotecan was 0.5 mg/m2/day, while cisplatin was fixed at the dose of 20 mg/m2/day. Patients with limited disease (LD) SCLC received thoracic irradiation after the completion of chemotherapy. RESULTS: Twenty-one elderly patients were enrolled in this study and received a total of 59 cycles. The major hematological toxicity was neutropenia and non-hematological toxicities including diarrhea were generally mild and reversible. The MTD of topotecan was determined as 1.2 mg/m2/day. The recommended phase II study dose of topotecan was determined as 1.0 mg/m2/day with cisplatin 20 mg/m2/day daily for 3 days. An objective response was observed in 6 of 10 patients (60%) with LD-SCLC and 6 of 11 (55%) with extensive disease (ED) SCLC. The median survival time in patients with LD-SCLC and those with ED-SCLC were 16.0 and 11.0 months, respectively. CONCLUSION: The combination chemotherapy of 3-day topotecan and cisplatin appears to be tolerable and effective in elderly patients with SCLC.

定位脳照射後に長期不変である肺癌脳転移の検討

大橋圭明, 木浦勝行, 田端雅弘, 瀧川奈義夫, 堀田勝幸, 上月稔幸, 梅村茂樹, 内田亜希, 荻野敦子, 藤原義郎, 谷本光音

日本呼吸器学会雑誌 44 ( 増刊 ) 264 - 264 2006.6

Clustered incidence of acute promyelocytic leukemia during gefitinib treatment for non-small-cell lung cancer: experience at a single institution. International journal

Keitaro Matsuo, Katsuyuki Kiura, Masahiro Tabata, Akiko Uchida, Katsuyuki Hotta, Daigo Niiya, Shiro Kubonishi, Atsuko Ogino, Yoshiro Fujiwara, Hiromi Nakajima, Katsuji Shinagawa, Fumihiko Ishimaru, Hiroshi Ueoka, Mitsune Tanimoto

American journal of hematology 81 ( 5 ) 349 - 54 2006.5

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

Although gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, has been shown a significant activity for recurrent non-small-cell lung cancer (NSCLC), its long-term adverse effect with its continuous usage has hitherto not been clearly elucidated. Subjects were 108 consecutive NSCLC cases who were treated with gefitinib between November 2001 and December 2004 at our single institution. A crude incidence rate ratio was calculated by ratio of crude incidence rate in our subject to population-based incident rate of all leukemia (ICD: C91-95) in the same region. The 95% confidence intervals (CIs) were calculated based upon a Poisson distribution. Three cases of acute promyelocytic leukemia (APL) occurred during gefitinib treatment, and these patients' past treatment histories are presented herein. No other malignancy was identified. All of the cases were diagnosed at the stage of mild-to-moderate cytopenia, especially thrombocytopenia, without disseminated intravascular coagulation. All presented a normal karyotype with positive PML-RARalpha in RT-PCR, indicating submicroscopic translocation. They responded well to APL treatments, including all-trans-retinoic acid. The crude incident rate ratio was 639.9 (95% confidence interval: 131.6-1,878.9, P < 0.0001) when the APL incidence in this cohort was compared to all leukemia cases in the general population in the same district in Japan. Thus we had three cases of secondary APL patients within the gefitinib-treated NSCLC cohort. Although we cannot exclude an effect of past exposure of other cytotoxic agents and radiotherapy as a cause of APL, APL inducibility of gefitinib should be clarified in the further study.

The combination effect of amrubicin with cisplatin or irinotecan for small-cell lung cancer cells. International journal

Nagio Takigawa, Masako Takeyama, Takuo Shibayama, Atsuhiko Tada, Noriko Kawata, Chiharu Okada, Keisuke Aoe, Toshiyuki Kozuki, Katsuyuki Hotta, Masahiro Tabata, Katsuyuki Kiura, Hiroshi Ueoka, Mitsune Tanimoto, Kiyoshi Takahashi

Oncology reports 15 ( 4 ) 837 - 42 2006.4

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

The single agent of amrubicin is active in untreated small-cell lung cancer (SCLC). Cytotoxicity of amrubicinol, the active form of amrubicin, was evaluated in a parent SCLC cell line (SBC-3); an active metabolite of irinotecan, 7-ethyl-10-hydroxy-camptothecin (SN-38)-resistant subline (SBC-3/SN-38); and cisplatin-resistant subline (SBC-3/CDDP) using AlamarBlue assay. Interaction of the combined drugs was evaluated by median-effect plot analysis, and the fraction of apoptotic cells was determined using flow cytometry. SBC-3/SN-38 was 34-fold more resistant to SN-38 and SBC-3/CDDP was 7.2-fold more resistant to cisplatin than parental SBC-3. However, these resistant sublines retained sensitivity to amrubicinol (1.8- and 1.7-fold, respectively). Simultaneous exposure of SBC-3/SN-38 cells to amrubicinol and cisplatin showed a synergistic effect. Simultaneous exposure of SBC-3/CDDP cells to amrubicinol and SN-38 displayed synergistic or additive effects. The two-drug combination produced an increase of apoptotic cells compared to each single agent alone in both resistant cells. These findings suggest that amrubicin alone and in combination with cisplatin or irinotecan is effective against SCLC refractory to irinotecan and/or cisplatin.

Relationship between epidermal growth factor receptor gene mutations and the severity of adverse events by gefitinib in patients with advanced non-small cell lung cancer. International journal

Yoshiro Fujiwara, Katsuyuki Kiura, Shinichi Toyooka, Nagio Takigawa, Masaki Tokumo, Katsuyuki Hotta, Motoi Aoe, Masahiro Tabata, Keitaro Matsuo, Hiroshi Date, Mitsune Tanimoto

Lung cancer (Amsterdam, Netherlands) 52 ( 1 ) 99 - 103 2006.4

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

PURPOSE: Recent reports have demonstrated that mutation of epidermal growth factor receptor (EGFR) gene is predictive factor for tumor responsiveness to gefitinib suggesting the importance of EGFR status for the treatment of the patients with non-small cell lung cancer (NSCLC). However, the relationship between EGFR mutation and adverse events of gefitinib is still unknown. The aim of this study was to evaluate its correlation. PATIENTS AND METHODS: Twenty-six tumor samples from Japanese NSCLC patients who received gefitinib in Okayama University Hospital between November 2000 and October 2004 were examined exons 18-21 of EGFR using direct sequence method. We retrospectively reviewed the clinical records and compared EGFR mutation status with adverse events during gefitinib treatment. RESULTS: Of all 26 patients, EGFR mutation (exon 19 in-frame deletion, 6; exon 21 L858R, 5), were detected in 11 patients (42.3%). The principal adverse event was skin rash (89%), diarrhea (39%), and liver injury (39%). Grade 3 or more adverse events were not common. EGFR mutation status was correlated with neither its frequency nor severity of adverse events during gefitinib treatment including skin rash, diarrhea, liver injury, and interstitial lung disease. As expected, objective response rate of those with EGFR mutations was significantly higher than those without EGFR mutations (78% versus 21%, P<0.001). CONCLUSION: Our study did not demonstrate the presence of close relationships between EGFR mutation status and adverse events during gefitinib treatment.

血清Arginine vasopressin(AVP)値と進展型小細胞肺癌の予後に関する検討

梅村茂樹, 上岡博, 堀田勝幸, 畝川芳彦, 瀧川奈義夫, 田端雅弘, 木浦勝行, 上月稔幸, 久本晃子, 徳田佳之, 大橋圭明, 別所昭宏, 新海哲, 谷本光音

肺癌 45 ( 5 ) 501 - 501 2005.11

Induction chemotherapy, surgical resection, and high-dose chemotherapy for mediastinal nonseminomatous germ-cell tumor Reviewed

Hiroshi Date, Katsuyuki Kiura, Hiroshi Ueoka, Masahiro Tabata, Katsuyuki Hotta, Hideki Katayama, Itaru Kataoka, Mitsune Tanimoto

Journal of Thoracic and Cardiovascular Surgery 130 ( 4 ) 1205 - 1206 2005.10

Systemic tumor embolism mimicking gefitinib ('IRESSA')-induced interstitial lung disease in a patient with lung cancer.

Shigeki Umemura, Daizo Kishino, Masahiro Tabata, Katsuyuki Kiura, Katsuyuki Hotta, Kenji Nishii, Yasushi Tanimoto, Arihiko Kanehiro, Kenji Notohara, Hiroshi Ueoka, Mitsune Tanimoto

Internal medicine (Tokyo, Japan) 44 ( 9 ) 979 - 82 2005.9

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

We describe a 55-year-old man with advanced adenocarcinoma of the lung who received gefitinib ('IRESSA'). After gefitinib administration for 7 months, computed tomography scan of the chest demonstrated diffuse ground glass opacity and he was suspected to have developed gefitinib-induced interstitial lung disease (ILD). However, transbronchial lung biopsy (TBLB) revealed tumor cells in the middle-size lung vessels. Afterwards, multiple infarctions of the brain, spleen and left kidney were detected. Then, he was considered to have developed systemic tumor emboli, a rare complication. The clinical presentation of this patient was difficult to discriminate from that of ILD, and TBLB was useful in the differential diagnosis.

転移を有する,あるいは再発した小細胞肺癌患者に対するトポテカン(T)とアムルビシン(A)の併用療法の第I相試験

大橋圭明, 堀田勝幸, 瀧川奈義夫, 田端雅弘, 木浦勝行, 谷本光音, 柴山卓夫, 畝川芳彦, 張田信悟, 上岡博, 平木俊吉

肺癌 45 ( 4 ) 396 - 397 2005.8

進行非小細胞肺癌に対するイリノテカン(CPT-11)+アムルビシン(AMR)併用療法の臨床第I相試験

藤原義朗, 堀田勝幸, 木浦勝行, 田端雅弘, 梅村茂樹, 荻野敦子, 内田亜希子, 畝川芳彦, 新海哲, 張田信吾, 沖本二郎, 上岡博, 谷本光音

日本呼吸器学会雑誌 43 ( 増刊 ) 159 - 159 2005.4

Identification of epigenetic aberrant promoter methylation in serum DNA is useful for early detection of lung cancer. International journal

Keiichi Fujiwara, Nobukazu Fujimoto, Masahiro Tabata, Kenji Nishii, Keitaro Matsuo, Katsuyuki Hotta, Toshiyuki Kozuki, Motoi Aoe, Katsuyuki Kiura, Hiroshi Ueoka, Mitsune Tanimoto

Clinical cancer research : an official journal of the American Association for Cancer Research 11 ( 3 ) 1219 - 25 2005.2

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

PURPOSE: The purpose of this study is to evaluate the usefulness of serum DNA methylation of five tumor suppressor genes for early detection of lung cancer. EXPERIMENTAL DESIGN: Methylation status in serum DNA from 200 patients undergoing bronchofiberscopic examination for abnormal findings on chest radiograph detected by lung cancer screening or surveillance was examined using methylation-specific PCR. RESULTS: Ninety-one patients were given a pathologic diagnosis of lung cancer, 9 other malignant diseases, and 100 nonmalignant pulmonary diseases. In patients with lung cancer, methylation was detected in 18.7% for MGMT, 15.4% for p16(INK4a), 12.1% for RASSF1A, 11.0% for DAPK, and 6.6% for RAR-beta, which was higher compared with that in patients with nonmalignant diseases. Age and smoking status seemed to associate with methylation status. Sensitivity, specificity, and predictive value of methylation in at least one gene for diagnosis of lung cancer were 49.5%, 85.0%, and 75.0%, respectively. Adjusted odds ratio (95% confidence interval) for having lung cancer was 5.28 (2.39-11.7) for patients with methylation in one gene and 5.89 (1.53-22.7) for those with methylation in two or more genes. It is of note that methylation was identified in 50.9% of stage I lung cancer patients, whereas serum protein tumor markers were positive in 11.3% of them. CONCLUSIONS: These results suggest that identification of promoter methylation of tumor suppressor genes in serum DNA could be useful for early detection of lung cancer.

Safety and efficacy of gefitinib treatment in elderly patients with non-small-cell lung cancer: Okayama Lung Cancer Study Group experience. International journal

Katsuyuki Hotta, Hiroshi Ueoka, Katsuyuki Kiura, Masahiro Tabata, Atsuko Ogino, Shigeki Umemura, Shingo Harita, Kenichi Gemba, Toshiro Yonei, Akihiro Bessho, Tadashi Maeda, Mitsune Tanimoto

Acta oncologica (Stockholm, Sweden) 44 ( 7 ) 717 - 22 2005

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

We evaluated the safety and efficacy of gefitinib treatment in elderly patients with non-small-cell lung cancer (NSCLC). We retrospectively compared toxicity, response and survival outcomes for gefitinib in patients aged 75 years or older (elderly group) with the same outcomes in patients aged younger than 75 years. In total, 350 patients were eligible for this analysis, of whom 92 were in the elderly group and 258 in the non-elderly group. In the elderly group, adverse events were generally mild to moderate and grade 3-4 adverse events were observed in 8 (9%) patients. The objective response rate (17 vs. 21% for elderly vs. non-elderly, respectively) and median survival time (7.6 vs. 9.3 months) were also similar in the two groups. Multivariate analysis revealed elderly patients with lower Brinkman index tended to be more sensitive to gefitinib (odds ratio: 4.57, 95% confidence interval: 0.91-22.72, p = 0.0642). In this study, treatment with gefitinib appeared to be as safe and effective in elderly patients (aged 75 or older) with NSCLC as in non-elderly patients.

Gefitinib ('Iressa', ZD1839) may restore chemosensitivity in NSCLC patients? International journal

Keiichi Fujiwara, Katsuyuki Kiura, Kenichi Gemba, Yoshiko Ogata, Katsuyuki Hotta, Daizo Kishino, Masahiro Tabata, Hiroshi Ueoka, Mitsune Tanimoto

Anticancer research 25 ( 1B ) 547 - 9 2005

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

Gefitinib ('Iressa, ZD1839) has promising antitumor activity in non-small cell lung cancer (NSCLC). However, patients with advanced NSCLC have few treatment options available if they are refractory to gefitinib. We describe four cases of patients with advanced NSCLC who previously responded to gefitinib and obtained significant tumor regression through retreatment with other cytotoxic agents. Gefitinib might restore chemosensitivity to previously chemorefractory patients.

Interstitial lung disease in Japanese patients with non-small cell lung cancer receiving gefitinib: an analysis of risk factors and treatment outcomes in Okayama Lung Cancer Study Group. International journal

Katsuyuki Hotta, Katsuyuki Kiura, Masahiro Tabata, Shingo Harita, Kenichi Gemba, Toshiro Yonei, Akihiro Bessho, Tadashi Maeda, Tomonori Moritaka, Takuo Shibayama, Keisuke Matsuo, Katsuya Kato, Arihiko Kanehiro, Yasushi Tanimoto, Keitaro Matsuo, Hiroshi Ueoka, Mitsune Tanimoto

Cancer journal (Sudbury, Mass.) 11 ( 5 ) 417 - 24 2005

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

UNLABELLED: Risk factors for the development of interstitial lung disease in patients with non-small cell lung cancer receiving gefitinib and the prognostic factors after interstitial lung disease development have not been established. The aim of this study was to retrospectively identify and evaluate these possible factors. PATIENTS AND METHODS: We reviewed the clinical records and radiographs of 365 consecutive patients with non-small cell lung cancer who received gefitinib in West Japan between 2000 and 2003. RESULTS: In total, 330 patients were eligible for interstitial lung disease evaluation, and 15 patients (4.5%) were finally confirmed to have developed interstitial lung disease by blinded expert review. Multivariate analysis revealed that preexisting pulmonary fibrosis, poor performance status, and prior thoracic irradiation were independent risk factors for interstitial lung disease, with odds ratios of 21.0 (95% confidence interval, 5.12-86.3, P < 0.0001), 9.70 (2.27-41.4, P = 0.001), and 4.33 (1.27-14.8, P = 0.019), respectively. Among the 15 patients who developed interstitial lung disease, eight have died of the condition. Short interval from the initiation of gefitinib treatment to the onset of interstitial lung disease, acute interstitial pneumonia pattern, and the presence of pre-existing pulmonary fibrosis were associated with poor prognosis. DISCUSSION: Our results suggest the importance of patient selection for gefitinib treatment based on interstitial lung disease risk factors in the Japanese population identified.

非小細胞肺癌患者のgefitinib治療におけるInterstitial Lung Disease(ILD)発症の危険因子の解析

米井敏郎, 佐藤利雄, 堀田勝幸, 加藤勝也, 田端雅弘, 木浦勝行, 張田信吾, 上岡博, 平木俊吉, 谷本光音

肺癌 44 ( 5 ) 351 - 351 2004.10

Gefitinib有効症例の増悪(PD)時における抗癌剤再投与

藤原慶一, 木浦勝行, 玄馬顕一, 堀田勝幸, 細川忍, 見元淳子, 宮武和代, 田端雅弘, 上岡博, 谷本光音

肺癌 44 ( 5 ) 636 - 636 2004.10

岡山肺癌治療研究会におけるゲフィチニブの使用経験

堀田勝幸, 上岡博, 木浦勝行, 田端雅弘, 藤原慶一, 久本晃子, 岡田俊明, 上月稔幸, 谷本光音

肺癌 43 ( 5 ) 586 - 586 2003.10

非小細胞肺癌(NSCLC)株を用いた新規分子標的治療薬Gefitinibによるsenescence誘導に関する検討(EVIDENCE OF GEFITINIB ("IRESSA", ZD1839)-INDUCED SENESCENT-LIKE GROWTH ARREST IN NON-SMALL-CELL LUNG CANCER (NSCLC) CELLS)

堀田勝幸, 田端雅弘, 木浦勝行, 片山英樹, 上岡博, 谷本光音

日本癌学会総会記事 62回 359 - 359 2003.8

化学療法前後に樹立された非小細胞肺癌株EBC-2とEBC-2/RにおけるZD1839の感受性の差異の検討(Effect of the EGFR tyrosine kinase inhibitor ZD1839 in a ZD1839 sensitive non-small cell lung cancer cell line)

片山英樹, 田端雅弘, 木浦勝行, 堀田勝幸, 上岡博, 谷本光音

日本癌学会総会記事 62回 358 - 358 2003.8

【肺癌治療の個別化】肺癌の病期と治療

木浦勝行, 堀田勝幸, 田端雅弘, 上岡博, 西井研治

肺癌の臨床 5 ( 3 ) 247 - 253 2003.5

進行非小細胞肺癌(NSCLC)患者におけるイリノテカン(I)とパクリタキセル(P)の分割投与法(I/P)の第I相試験

堀田勝幸, 上岡博, 田端雅弘, 木浦勝行, 久山彰一, 谷本光音

日本呼吸器学会雑誌 41 ( 増刊 ) 210 - 210 2003.3

【肺がんの分子生物学・バイオセラピーの現状と将来】肺がんにおけるHER2/neuの意義

久山彰一, 堀田勝幸, 田端雅弘, 木浦勝行, 上岡博

肺癌の臨床 5 ( 2 ) 175 - 180 2003.1

Successful treatment of limited disease-small cell lung cancer with multimodality treatment consisting of concurrent chemoradiotherapy, high-dose chemotherapy with autologous peripheral blood stem cell transplantation and surgical resection Reviewed

Katsuyuki Hotta, Hiroshi Ueoka, Katsuyuki Kiura, Masahiro Tabata, Eisei Kondoh, Yoshihiko Segawa, Hiroshi Date, Nobuyoshi Shimizu, Tadashi Yoshino, Mine Harada, Mitsune Tanimoto

Internal Medicine 42 ( 12 ) 1223 - 1227 2003

Language：English Publishing type：Research paper (scientific journal) Publisher：Japanese Society of Internal Medicine

A 65-year-old man with limited disease-small cell lung cancer was treated with concurrent chemoradiotherapy which resulted in a partial response. He further received high-dose chemotherapy with autologous peripheral blood stem cell transplantation. Development of non-small cell carcinoma was, however, suspected at a site of the residual nodule in cytological examination using bronchoscopy. He then underwent lobectomy, which revealed that the nodule was composed of necrotic tissue. He has been alive without recurrence for seven years. This multimodality treatment appeared to be effective for this patient. However, further investigation is necessary to clarify the role of multimodality treatment.

DOI： 10.2169/internalmedicine.42.1223

進行非小細胞肺癌(NSCLC)に対するパクリタキセル(P)+イリノテカン(C)併用療法の臨床第I相試験

市川裕久, 堀田勝幸, 久山彰一, 岸野大蔵, 藤本伸一, 見元淳子, 田端雅弘, 木浦勝行, 上岡博, 谷本光音

肺癌 42 ( 6 ) 651 - 651 2002.10

生前に診断できた肺癌心臓転移の2例

藤原慶一, 上月稔幸, 岡田俊明, 徳田佳之, 細川忍, 岸野大蔵, 堀田勝幸, 田端雅弘, 木浦勝行, 上岡博, 谷本光音

肺癌 42 ( 5 ) 473 - 473 2002.10

非小細胞肺癌の化学療法非小細胞肺癌既治療症例に対するCisplatin,Docetaxel,Irinotecan併用化学療法

藤本伸一, 上岡博, 木浦勝行, 田端雅弘, 平木章夫, 片山英樹, 岸野大蔵, 堀田勝幸, 久山彰一, 谷本光音

肺癌 41 ( 5 ) 439 - 439 2001.9

急速な臨床経過をたどったLarge cell neuro-endocrine carcinoma(LCNEC)の3例

藤原慶一, 上岡博, 木浦勝行, 田端雅弘, 平木章夫, 藤本伸一, 片山英樹, 岸野大蔵, 堀田勝幸, 谷本光音

肺癌 41 ( 5 ) 585 - 585 2001.9

高齢者小細胞肺癌に対するcarboplatin,etoposide併用療法

多田敦彦, 河原伸, 上岡博, 木浦勝行, 田端雅弘, 堀田勝幸, 肥山淳一郎, 青江啓介, 瀧川奈義夫, 亀井治人

肺癌 38 ( 4 ) 357 - 357 1998.8

　 PREV - NEXT 　

1