Kinoshita Ichiro

Hokkaido University HospitalProfessor
Last Updated :2025/06/07

■Researcher basic information

Degree

  • MD, PhD, Hokkaido University

Researchmap personal page

Research Keyword

  • 腫瘍内科学
  • 呼吸器内科学

Research Field

  • Life sciences, Respiratory medicine

Educational Organization

■Career

Career

  • Jun. 2021 - Present
    Hokkaido University, Hokkaido University Hospital, 教授
  • Jul. 2019 - Present
    Hokkaido University Hospital, Division of Clinical Cancer Genomics, Professor, Japan
  • Sep. 2012 - Jun. 2019
    Hokkaido University, Department of Medical Oncology, Graduate School of Medicine, Associate Professor
  • 2005
    - 北海道大学講師(大学院医学研究科腫瘍内科学分野) 講師
  • 2005
    - Lecturer
  • 2004
    - 北海道大学助手(大学院医学研究科腫瘍内科学分野) 助手
  • 2004
    - Research Associate
  • 2001
    - 北海道大学助手(医学部附属病院内科学第一講座) 助手
  • 2001
    - Research Associate

Educational Background

  • 1988, Hokkaido University, School of Medicine, 医学科, Japan
  • 1988, Hokkaido University, Faculty of Medicine

Committee Memberships

  • 2020 - Present
    日本癌学会, 評議員
  • 2010 - Present
    日本臨床腫瘍学会, 教育委員会教育企画部会委員, Society
  • 2006 - Present
    日本臨床腫瘍学会, 協議員, Society
  • 2005 - Present
    北海道癌談話会, 評議員, Society
  • 2004 - Present
    北海道癌治療研究会, 事務局, Society
  • 2002 - Present
    日本肺癌学会, 評議員, Society
  • 2004 - 2005
    日本肺癌学会, ワークショップ事務局, Society
  • 2004
    日本肺癌学会, 選挙管理委員会, Society

■Research activity information

Awards

  • 2009, Travel Award               

Papers

  • Impact of baseline renal impairment on severe neutropenia development in pemetrexed and carboplatin thoracic cancer treatment.
    Yoshitaka Saito, Osamu Taniguchi, Yoh Takekuma, Jun Sakakibara-Konishi, Yasushi Shimizu, Ichiro Kinoshita, Mitsuru Sugawara
    Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer, 32, 12, 829, 829, 27 Nov. 2024, [International Magazine]
    English, Scientific journal, BACKGROUND: Carboplatin (CBDCA) plus pemetrexed (PEM) is a commonly-used thoracic cancer treatment. As both CBDCA and PEM are excreted via the kidneys, renal impairment (RI) can lead to severe neutropenia, the most typical adverse event in the treatment. We aimed to determine the impact of baseline RI on the development of severe neutropenia following real-world CBDCA + PEM-containing treatments. METHODS: Patients with thoracic cancer receiving CBDCA + PEM-containing treatments (n = 155) were divided into a control group (baseline creatinine clearance [CCr] ≥ 60 mL/min) and an RI group (baseline CCr < 60 mL/min) and retrospectively evaluated. The primary endpoint was the incidence of severe neutropenia during the first cycle. We also assessed factors associated with the development of severe neutropenia. RESULTS: Severe neutropenia during the first cycle was confirmed in 41.2% of the patients in the RI group, which was significantly higher than that in the control group (20.7%, P = 0.02). Additionally, severe neutropenia during all evaluation periods was also more prevalent in the RI group compared to the control group (47.1% vs. 24.8%, P = 0.02). In contrast, the incidence of severe thrombocytopenia was not different. Multivariate logistic regression analyses identified RI as a risk factor for severe neutropenia (adjusted odds ratio 2.71; 95% confidence interval 1.18-6.21, P = 0.02 for the first cycle; 2.62, 1.17-5.84, P = 0.02 for all evaluation periods). CONCLUSION: Our study revealed that patients with baseline RI exhibited severe neutropenia after CBDCA + PEM-containing treatments.
  • Effect of baseline anemia on the efficacy of docetaxel and ramucirumab for advanced non-small cell lung cancer treatment.
    Yoshitaka Saito, Yoh Takekuma, Jun Sakakibara-Konishi, Yasushi Shimizu, Ichiro Kinoshita, Mitsuru Sugawara
    BMC cancer, 24, 1, 1301, 1301, 21 Oct. 2024, [International Magazine]
    English, Scientific journal, BACKGROUND: Docetaxel (DOC) and ramucirumab (RAM) is one of the most effective regimens for advanced non-small cell lung cancer (NSCLC) treatment. In our previous study, baseline anemia was identified as a preventive factor against the development of severe adverse effects during the first treatment cycle. It was hypothesized that anemia directly promotes tumor angiogenesis, leading to the elevation of RAM efficacy with increased DOC delivery to tumors, while reducing DOC delivery to other organs, potentially mitigating severe adverse effects. If this hypothesis is correct, patients with baseline anemia may have better clinical outcomes than those with normal hemoglobin levels. In this study, we aimed to investigate the effect of baseline anemia on the efficacy of DOC + RAM in treating advanced NSCLC in a real-word setting. METHODS: Patients with advanced NSCLC receiving DOC + RAM (n = 72) were retrospectively assessed. They were categorized into a control group with normal baseline hemoglobin levels and an anemia group with baseline anemia. The primary endpoint was progression-free survival (PFS) evaluation. RESULTS: Patients in the anemia group had a significantly shorter PFS than that of patients in the control group (median PFS: 3.2 and 6.2 months; 95% confidence interval [CI]: 2.2-4.8 and 4.3-9.9 months, respectively;P = 0.008). In addition, the disease control rate in the anemia group was 65.8%, which was significantly lower than that in the control group (93.6%; P = 0.007). Overall survival tended to be shorter in patients with anemia than in controls, although the difference was not statistically significant (P = 0.07). Multivariate Cox hazard analysis suggested that baseline anemia was a singular risk factor for poor PFS (adjusted hazard ratio 1.84, 95% CI 1.08-3.13; P = 0.02). The incidence of severe adverse effects did not differ between the two groups. CONCLUSIONS: This study suggests that the PFS of patients with anemia treated with DOC + RAM for advanced NSCLC is shorter than that of those without the symptoms.
  • Evaluation of the risk factors for the failure of a single prophylactic dose of anticholinergic drugs for irinotecan-induced cholinergic symptoms.
    Takuya Watanabe, Yoshitaka Saito, Yoh Takekuma, Yasushi Shimizu, Ichiro Kinoshita, Yoshito Komatsu, Mitsuru Sugawara
    International journal of clinical pharmacology and therapeutics, 03 Mar. 2024, [International Magazine]
    English, Scientific journal, OBJECTIVE: Irinotecan (IRI) is an anticancer drug that is frequently used to treat colorectal, gastric, and pancreatic cancers. Its side effects include cholinergic symptoms, such as diarrhea, abdominal pain, nausea, and hyperhidrosis. Anticholinergic medicines are frequently used for treatment or prophylaxis; however, the risk factors for the failure of a single prophylactic anticholinergic administration remain unclear. Moreover, an appropriate anticholinergic drug for prophylaxis remains unknown. Thus, we aimed to identify the risk factors associated with the failure of a single prophylactic dose of anticholinergic drugs for IRI-induced cholinergic symptoms and to evaluate the usefulness of multiple prophylactic doses of anticholinergic drugs. MATERIALS AND METHODS: Patients who underwent IRI treatment for colorectal, gastric, or pancreatic cancer and received prophylactic anticholinergic drugs for IRI-induced cholinergic symptoms (n = 135) were retrospectively evaluated. Univariate and multivariate logistic regression analyses were performed to identify the risk factors for failure of a single prophylactic dose of anticholinergic drugs. We also evaluated the efficacy of multiple prophylactic anticholinergic drug administration. RESULTS: Based on univariate and multivariate analyses, colorectal cancer, female sex, and prophylactic use of scopolamine butyl bromide were identified as risk factors for failure of a single prophylactic dose of anticholinergic drugs. The efficacy of multiple prophylactic doses was confirmed to be 95% of the patients who had a single prophylactic failure due to temporary effect but symptom appearance after a certain period of time (wearing-off). CONCLUSION: We determined that colorectal cancer, female sex, and prophylactic use of scopolamine butyl bromide were risk factors associated with the failure of a single prophylactic dose of anticholinergic drugs, and that multiple prophylactic doses for wearing-off can be a promising method.
  • 最新技術を用いた消化器診療 当院における大腸癌に対するがんゲノムプロファイリング検査の現状
    田邊 裕貴, 佐藤 広崇, 大竹 晋, 小林 進, 高橋 裕之, 山本 昌代, 高橋 慶太郎, 田中 宏樹, 佐々木 高明, 高橋 賢治, 菊地 順子, 大原 克仁, 木下 一郎, 水上 裕輔
    日本消化器病学会北海道支部例会・日本消化器内視鏡学会北海道支部例会プログラム・抄録集, 134回・128回, 34, 34, 日本消化器病学会-北海道支部, Mar. 2024
    Japanese
  • 最新技術を用いた消化器診療 当院における大腸癌に対するがんゲノムプロファイリング検査の現状               
    田邊 裕貴, 佐藤 広崇, 大竹 晋, 小林 進, 高橋 裕之, 山本 昌代, 高橋 慶太郎, 田中 宏樹, 佐々木 高明, 高橋 賢治, 菊地 順子, 大原 克仁, 木下 一郎, 水上 裕輔
    日本消化器病学会北海道支部例会・日本消化器内視鏡学会北海道支部例会プログラム・抄録集, 134回・128回, 34, 34, 日本消化器病学会-北海道支部, Mar. 2024
    Japanese
  • Dabrafenib and trametinib administration in patients with BRAF V600E/R or non-V600 BRAF mutated advanced solid tumours (BELIEVE, NCCH1901): a multicentre, open-label, and single-arm phase II trial.
    Tatsunori Shimoi, Kuniko Sunami, Makoto Tahara, Satoshi Nishiwaki, Shota Tanaka, Eishi Baba, Masashi Kanai, Ichiro Kinoshita, Hidekazu Shirota, Hideyuki Hayashi, Naohiro Nishida, Toshio Kubo, Nobuaki Mamesaya, Yayoi Ando, Natsuko Okita, Taro Shibata, Kenichi Nakamura, Noboru Yamamoto
    EClinicalMedicine, 69, 102447, 102447, Mar. 2024, [International Magazine]
    English, Scientific journal, BACKGROUND: BRAF V600 mutations are common in melanoma, thyroid, and non-small-cell lung cancers. Despite dabrafenib and trametinib being standard treatments for certain cancers, their efficacy across various solid tumours remains unelucidated. The BELIEVE trial assessed the efficacy of dabrafenib and trametinib in solid tumours with BRAF V600E/R or non-V600 BRAF mutations. METHODS: Between October 1, 2019, and June 2022, at least 50 patients with measurable and seven without measurable diseases examined were enrolled in a subcohort of the BELIEVE trial (NCCH1901, jRCTs031190104). BRAF mutated solid tumour cases other than BRAF V600E mutated colorectal cancer, melanoma, and non-small cell lung cancer cases were included. Patients with solid tumours received dabrafenib (150 mg) twice daily and trametinib (2 mg) once daily until disease progression or intolerable toxicity was observed. The primary endpoint was overall response rate (ORR), and secondary endpoints included progression-free survival (PFS), 6-month PFS, and overall survival (OS). Bayesian analysis was performed using a prior distribution with a 30% expected response rate [Beta (0.6, 1.4)]. FINDINGS: Fourty-seven patients with measurable disease, mainly with the BRAF V600E mutation (94%), and three others with non-V600E BRAF mutations (V600R, G466A, and N486_P490del) were enrolled. The primary sites included the thyroid gland, central nervous system, liver, bile ducts, colorectum, and pancreas. The confirmed ORR was 28.0%; the expected value of posterior distribution [Beta (14.6, 37.4)] was 28.1%, although the primary endpoint was achieved, not exceeding an unexpectedly high response rate of 60% obtained using Bayesian analysis. The disease control rate (DCR) was 84.0%. The median PFS was 6.5 months (95% confidence interval [CI]; 4.2-7.2 months, 87.8% at 6 months). Responses were observed across seven tumour types. Median OS was 9.7 months (95% CI, 7.5-12.2 months). Additional patients without measurable diseases had a median PFS of 4.5 months. Adverse events (AEs) were consistent with previous reports, with 45.6% of patients experiencing grade ≥3 AEs. INTERPRETATION: This study reported promising efficacy against BRAF V600-mutant tumours. Dabrafenib and trametinib would offer a new therapeutic option for rare cancers, such as high-grade gliomas, biliary tract cancer, and thyroid cancer. FUNDING: This study was funded by the Japan Agency for Medical Research and Development (22ck0106622h0003) and a Health and Labour Sciences Research Grant (19EA1008).
  • Evaluation of Prediabetes in Cisplatin-induced Nephrotoxicity in the Short Hydration Method: A Subgroup Analysis
    YOSHITAKA SAITO, TATSUHIKO SAKAMOTO, MASAKI KOBAYASHI, YOH TAKEKUMA, ISSEI HIGUCHI, KEISUKE OKAMOTO, JUN SAKAKIBARA-KONISHI, YASUSHI SHIMIZU, ICHIRO KINOSHITA, MITSURU SUGAWARA
    In Vivo, 38, 2, 800, 806, Anticancer Research USA Inc., 28 Feb. 2024
    Scientific journal
  • KRAS変異陽性大腸癌に対する治療標的分子としてのCD73/NT5E発現に関する分子病理学的検討               
    田中 佑実, 畑中 佳奈子, 奥村 麻美, 南家 綾江, 結城 敏志, 本間 重紀, 木下 一郎, 松野 吉宏, 畑中 豊
    日本病理学会会誌, 113, 1, 310, 310, (一社)日本病理学会, Feb. 2024
    Japanese
  • Polymorphisms of the PD-L1 gene 3'-untranslated region are associated with the expression of PD-L1 in non-small cell lung cancer.
    Yoshihito Ohhara, Utano Tomaru, Ichiro Kinoshita, Kanako C Hatanaka, Takuro Noguchi, Yutaka Hatanaka, Toraji Amono, Yoshihiro Matsuno, Hirotoshi Dosaka-Akita
    Genes, chromosomes & cancer, 63, 1, e23216, Jan. 2024, [International Magazine]
    English, Scientific journal, Recent results show that polymorphisms of programmed death ligand 1 (PD-L1, also known as CD274 or B7-H1) might be used as a possible marker for effectiveness of chemotherapy and cancer risk. However, the effect of PD-L1 gene variations on PD-L1 expression remain unclear. Given the post-transcriptional machinery in tumor PD-L1 expression, we investigated single nucleotide polymorphisms (SNPs) in the 3'-untranslated region (3'-UTR) of the PD-L1 gene, rs4143815 and rs4742098, using formalin-fixed paraffin-embedded sections of 154 patients with non-small cell lung cancers (NSCLCs). In rs4143815, the GG genotype showed significant association with PD-L1 expression (P = 0.032). In rs4742098, the AA genotype was significantly associated with histology and PD-L1 expression (P = 0.022 and P = 0.008, respectively). In multivariate logistic regression analysis, the AA genotype in rs4742098 was correlated with PD-L1 expression (odds ratio 0.408, P = 0.048). Interestingly, approximately 10% of the NSCLC cases showed somatic mutation when we compared genotypes of these SNPs between NSCLC tissues and non-tumor tissues from the same patients. In addition, cases with somatic mutation showed higher levels of PD-L1 expression than cases with germline mutation in rs4143815 GG. In conclusion, we demonstrated that the rs4143815 and rs4742098 SNPs in the 3'-UTR of PD-L1 were associated with tumor PD-L1 expression in NSCLCs.
  • Association Between Multisystem Immune-related Adverse Events and Progression-free Survivals in PD-1/PD-L1 Inhibitor Monotherapy.
    Atsushi Yamaguchi, Yoshitaka Saito, Keisuke Okamoto, Ayako Furugen, Katsuya Narumi, Yoh Takekuma, Jun Sakakibara-Konishi, Yasushi Shimizu, Ichiro Kinoshita, Mitsuru Sugawara, Masaki Kobayashi
    In vivo (Athens, Greece), 38, 6, 2886, 2896, 2024, [International Magazine]
    English, Scientific journal, BACKGROUND/AIM: Immune-related adverse events (irAEs) occur in various organs, and sometimes multiply following treatment with immune checkpoint inhibitors (ICIs). This study aimed to determine the association between the number of irAEs and clinical outcomes. PATIENTS AND METHODS: This was a retrospective study that included patients with lung cancer, melanoma, and head and neck cancer who were treated with anti-programmed cell death (ligand) 1 (PD-1/PD-L1) monotherapy. We evaluated the association between the number of irAEs and progression-free survival (PFS) in the simple Cox regression analysis. To eliminate the immortal-time bias, an additional landmark analysis was performed. RESULTS: In total, 92, 69, and 37 patients were allocated to the no, single, and multisystem irAEs groups, respectively. The multisystem irAEs were associated with better PFS compared to the no irAE group. In contrast, at the 12-week landmark, multisystem irAEs were associated with poor PFS compared to the no irAEs group. Furthermore, the rate of treatment suspension owing to irAEs in the multisystem irAEs group (62.5%) was higher than that in the single irAE group (17.3%) at the 12-week landmark. CONCLUSION: The incidence of multisystem irAEs was associated with improved clinical outcomes in patients with lung cancer, melanoma, and head and neck cancer treated with PD-1/PD-L1 inhibitor monotherapy. However, these results may be influenced by a potential immortal-time bias. When accounting for this bias, the early development of multisystem irAEs within 12 weeks was linked to treatment suspension and poorer clinical outcomes.
  • Evaluation of Efficacy of Adding Aprepitant to Palonosetron and Dexamethasone in Carboplatin and Etoposide Therapy.
    Tatsuhiko Sakamoto, Moeko Kado, Yoshitaka Saito, Kazuki Uchiyama, Ryota Kanno, Osamu Taniguchi, Yoh Takekuma, Jun Sakakibara-Konishi, Yasushi Shimizu, Ichiro Kinoshita, Mitsuru Sugawara
    Biological & pharmaceutical bulletin, 47, 6, 1189, 1195, 2024, [Domestic magazines]
    English, Scientific journal, Although carboplatin (CBDCA) is classified as a moderately emetogenic agent, the majority of guidelines recommend the use of a neurokinin-1 receptor antagonist in addition to a 5-hydroxytryptamine type 3 receptor antagonist with dexamethasone (DEX) for CBDCA-containing chemotherapy because of its higher emetogenic risk. However, the additional efficacy of aprepitant (APR) in CBDCA-containing treatment remains controversial, and data on multiple-day treatments are limited. Etoposide (ETP) was administered on days 1-3 in the CBDCA + ETP regimen, and it is important to evaluate suitable antiemetic therapy for the regimen. Therefore, we evaluated the efficacy of additional APR in CBDCA + ETP. Patients were divided into two groups and retrospectively evaluated. One was the control group, which was prophylactically administered palonosetron (PALO) and DEX, and the other was the APR group, which received APR orally with PALO and DEX. The primary endpoint was complete response (CR) between the groups. The overall CR rates were 75.0 and 76.4% in the control and APR groups, respectively, with no significant difference (p = 1.00). In the acute phase, it was 88.9 and 97.2%, respectively, and 86.1 and 79.2% in the delayed phase, respectively, without significant differences (p = 0.10 and 0.38, respectively). The incidence and severity of nausea, vomiting, and anorexia were not significantly different between the two groups in the acute and delayed phases. Our findings suggest that combining APR with PALO and DEX does not improve the CR rate in CBDCA + ETP therapy.
  • Detection of factors related to treatment reduction in docetaxel and ramucirumab for non-small cell lung cancer treatment.
    Yoshitaka Saito, Shinya Tamaki, Daisuke Hirate, Shinya Takada, Kenta Takahashi, Yoh Takekuma, Jun Sakakibara-Konishi, Yasushi Shimizu, Ichiro Kinoshita, Mitsuru Sugawara
    Scientific reports, 13, 1, 19457, 19457, 09 Nov. 2023, [Peer-reviewed], [International Magazine]
    English, Scientific journal, Treatment using docetaxel (DOC) and ramucirumab (RAM) is an effective regimen in second or later line advanced non-small cell lung carcinoma (NSCLC) treatment. However, it induces severe adverse effects, resulting in treatment reduction such as dose reduction and/or discontinuation. This study aimed to reveal the factor(s) associated with treatment reduction in DOC + RAM. We retrospectively evaluated patients with advanced NSCLC (n = 155). Treatment reduction of the second course due to severe adverse effects was conducted in 25.8% of the participants, and relative dose intensity at the second course was 95.7 ± 8.4% for DOC and 91.9 ± 24.8% for RAM. Multivariate logistic regression analyses identified that baseline anemia and prophylactic granulocyte colony-stimulating factor (G-CSF) administration are preventive factors for the reduction (adjusted odds ratio, 0.29; 95% confidence interval, 0.12-0.66; P = 0.004 for baseline anemia, 0.18; 0.08-0.42; P < 0.0001 for prophylactic G-CSF administration). The primary cause of the reduction was febrile neutropenia, and the same factors were identified. Our study revealed that patients with baseline anemia and prophylactic G-CSF administration have less risk for treatment reduction in DOC + RAM for NSCLC treatment.
  • A Learning Program for Treatment Recommendations by Molecular Tumor Boards and Artificial Intelligence
    Kuniko Sunami, Yoichi Naito, Yusuke Saigusa, Toraji Amano, Daisuke Ennishi, Mitsuho Imai, Hidenori Kage, Masashi Kanai, Hirotsugu Kenmotsu, Keigo Komine, Takafumi Koyama, Takahiro Maeda, Sachi Morita, Daisuke Sakai, Makoto Hirata, Mamoru Ito, Toshiyuki Kozuki, Hiroyuki Sakashita, Hidehito Horinouchi, Yusuke Okuma, Atsuo Takashima, Toshio Kubo, Shuichi Hironaka, Yoshihiko Segawa, Yoshihiro Yakushijin, Hideaki Bando, Akitaka Makiyama, Tatsuya Suzuki, Ichiro Kinoshita, Shinji Kohsaka, Yuichiro Ohe, Chikashi Ishioka, Kouji Yamamoto, Katsuya Tsuchihara, Takayuki Yoshino
    JAMA Oncology, 10, 1, 95, 102, American Medical Association (AMA), Nov. 2023, [Peer-reviewed]
    Scientific journal, Importance

    Substantial heterogeneity exists in treatment recommendations across molecular tumor boards (MTBs), especially for biomarkers with low evidence levels; therefore, the learning program is essential.

    Objective

    To determine whether a learning program sharing treatment recommendations for biomarkers with low evidence levels contributes to the standardization of MTBs and to investigate the efficacy of an artificial intelligence (AI)–based annotation system.

    Design, Setting, and Participants

    This prospective quality improvement study used 50 simulated cases to assess concordance of treatment recommendations between a central committee and participants. Forty-seven participants applied from April 7 to May 13, 2021. Fifty simulated cases were randomly divided into prelearning and postlearning evaluation groups to assess similar concordance based on previous investigations. Participants included MTBs at hub hospitals, treating physicians at core hospitals, and AI systems. Each participant made treatment recommendations for each prelearning case from registration to June 30, 2021; participated in the learning program on July 18, 2021; and made treatment recommendations for each postlearning case from August 3 to September 30, 2021. Data were analyzed from September 2 to December 10, 2021.

    Exposures

    The learning program shared the methodology of making appropriate treatment recommendations, especially for biomarkers with low evidence levels.

    Main Outcomes and Measures

    The primary end point was the proportion of MTBs that met prespecified accreditation criteria for postlearning evaluations (approximately 90% concordance with high evidence levels and approximately 40% with low evidence levels). Key secondary end points were chronological enhancements in the concordance of treatment recommendations on postlearning evaluations from prelearning evaluations. Concordance of treatment recommendations by an AI system was an exploratory end point.

    Results

    Of the 47 participants who applied, 42 were eligible. The accreditation rate of the MTBs was 55.6% (95% CI, 35.3%-74.5%; P &amp;lt; .001). Concordance in MTBs increased from 58.7% (95% CI, 52.8%-64.4%) to 67.9% (95% CI, 61.0%-74.1%) (odds ratio, 1.40 [95% CI, 1.06-1.86]; P = .02). In postlearning evaluations, the concordance of treatment recommendations by the AI system was significantly higher than that of MTBs (88.0% [95% CI, 68.7%-96.1%]; P = .03).

    Conclusions and Relevance

    The findings of this quality improvement study suggest that use of a learning program improved the concordance of treatment recommendations provided by MTBs to central ones. Treatment recommendations made by an AI system showed higher concordance than that for MTBs, indicating the potential clinical utility of the AI system.
  • Risk factor analysis for cisplatin-induced nephrotoxicity with the short hydration method in diabetic patients.
    Yoshitaka Saito, Masaki Kobayashi, Shinya Tamaki, Katsuyuki Nakamura, Daisuke Hirate, Kenta Takahashi, Yoh Takekuma, Jun Sakakibara-Konishi, Yasushi Shimizu, Ichiro Kinoshita, Mitsuru Sugawara
    Scientific reports, 13, 1, 17126, 17126, 10 Oct. 2023, [International Magazine]
    English, Scientific journal, The occurrence of cisplatin (CDDP)-induced nephrotoxicity (CIN) has decreased with advancements in supportive care. In contrast, we reported that baseline diabetes mellitus (DM) complications significantly worsen CIN. This study aimed to determine further risk factors associated with CIN development in DM patients. Patients with thoracic cancer requiring DM pharmacotherapy, who received CDDP (≥ 60 mg/m2)-containing regimens using the short hydration method (n = 140), were enrolled in this retrospective multicenter observational study. The primary endpoint of the present study was the elucidation of risk factors (patient factors, DM medication influence, and treatment-related factors) associated with CIN development in patients with DM. Cisplatin-induced nephrotoxicity occurred in 22.1% of patients with DM. The median worst variation of serum creatinine levels and creatinine clearance (worst level - baseline level) was 0.16 mg/dL (range: - 0.12-1.41 mg/dL) and - 15.9 mL/min (- 85.5-24.3 mL/min), respectively. Multivariate logistic regression analyses identified female sex as the singular risk factor for CIN development in the DM population (adjusted odds ratio; 2.87, 95% confidence interval; 1.08-7.67, P = 0.04). Diabetes mellitus medication and treatment-related factors did not affect CIN development. In conclusion, our study revealed that female sex is significantly associated with CIN development in patients with DM and thoracic cancer.
  • Early prediction of treatment outcome for lenvatinib using 18F-FDG PET/CT in patients with unresectable or advanced thyroid carcinoma refractory to radioiodine treatment: a prospective, multicentre, non-randomised study.
    Satoshi Takeuchi, Kenji Hirata, Keiichi Magota, Shiro Watanabe, Rika Moku, Akihiko Shiiya, Jun Taguchi, Shin Ariga, Tomohiro Goda, Yoshihito Ohhara, Takurou Noguchi, Yasushi Shimizu, Ichiro Kinoshita, Rio Honma, Yasushi Tsuji, Akihiro Homma, Hirotoshi Dosaka-Akita
    EJNMMI research, 13, 1, 69, 69, 17 Jul. 2023, [International Magazine]
    English, Scientific journal, BACKGROUND: Lenvatinib is widely used to treat unresectable and advanced thyroid carcinomas. We aimed to determine whether 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) performed 1 week after lenvatinib treatment initiation could predict treatment outcomes. RESULTS: This was a prospective, nonrandomised, multicentre study. Patients with pathologically confirmed differentiated thyroid carcinoma (DTC) and lesions refractory to radioiodine treatment were eligible for inclusion. Patients were treated with 24 mg lenvatinib as the initial dose and underwent PET/CT examination 1 week after treatment initiation. Contrast-enhanced CT was scheduled at least 4 weeks later as the gold standard for evaluation. The primary endpoint was to evaluate the discrimination power of maximum standardised uptake value (SUVmax) obtained by PET/CT compared to that obtained by contrast-enhanced CT. Evaluation was performed using the area under the receiver operating characteristic (ROC-AUC) curve. Twenty-one patients were included in this analysis. Receiver operating characteristic (ROC) curve analysis yielded an AUC of 0.714 for SUVmax after 1 week of lenvatinib treatment. The best cut-off value for the treatment response for SUVmax was 15.211. The sensitivity and specificity of this cut-off value were 0.583 and 0.857, respectively. The median progression-free survival was 26.3 months in patients with an under-cut-off value and 19.7 months in patients with an over-cut-off value (P = 0.078). CONCLUSIONS: The therapeutic effects of lenvatinib were detected earlier than those of CT because of decreased FDG uptake on PET/CT. PET/CT examination 1 week after the initiation of lenvatinib treatment may predict treatment outcomes in patients with DTC. TRIAL REGISTRATION: This trial was registered in the University Hospital Medical Information Network (UMIN) Clinical Trials Registry (number UMIN000022592) on 6 June, 2016.
  • Assessment for the timing of comprehensive genomic profiling tests in patients with advanced solid cancers.
    Kanako Hagio, Junko Kikuchi, Kohichi Takada, Hiroki Tanabe, Minako Sugiyama, Yoshihito Ohhara, Toraji Amano, Satoshi Yuki, Yoshito Komatsu, Takahiro Osawa, Kanako C Hatanaka, Yutaka Hatanaka, Takashi Mitamura, Ichiro Yabe, Yoshihiro Matsuno, Atsushi Manabe, Akihiro Sakurai, Atsushi Ishiguro, Masato Takahashi, Hiroshi Yokouchi, Hirohito Naruse, Yusuke Mizukami, Hirotoshi Dosaka-Akita, Ichiro Kinoshita
    Cancer science, 19 May 2023, [International Magazine]
    English, Scientific journal, Comprehensive genomic profiling (CGP) tests have been covered by public insurance in Japan for patients with advanced solid tumors who have completed or are completing standard treatments or do not have them. Therefore, genotype-matched drug candidates are often unapproved or off-label, and improving clinical trial access is critical, involving the appropriate timing of CGP tests. To address this issue, we analyzed the previous treatment data for 441 patients from an observational study on CGP tests discussed by the expert panel at Hokkaido University Hospital between August 2019 and May 2021. The median number of previous treatment lines was two; three or more lines accounted for 49%. Information on genotype-matched therapies was provided to 277 (63%). Genotype-matched clinical trials were ineligible because of an excess number of previous treatment lines or use of specific agents were found in 66 (15%) patients, with the highest proportion in breast and prostate cancers. Many patients met the exclusion criteria of one to two or more treatment lines across cancer types. In addition, previous use of specific agents was a frequent exclusion criterion for breast, prostate, colorectal, and ovarian cancers. The patients with tumor types with a low median number (two or fewer) of previous treatment lines, including most rare cancers, primary unknown cancers, and pancreatic cancers, had significantly fewer ineligible clinical trials. The earlier timing of CGP tests may improve access to genotype-matched clinical trials, with their proportion varying by cancer type. Each relevant society needs to advocate the desirable timing of CGP testing nationwide.
  • Efficacy of antacids for cisplatin-induced gastrointestinal symptoms in the treatment of lung cancer.
    Osamu Taniguchi, Yoshitaka Saito, Yoh Takekuma, Hirotoshi Akita, Ichiro Kinoshita, Yasushi Shimizu, Naofumi Shinagawa, Mitsuru Sugawara
    International journal of clinical pharmacology and therapeutics, 61, 6, 246, 254, 27 Mar. 2023, [International Magazine]
    English, Scientific journal, OBJECTIVE: Chemotherapy-induced nausea and vomiting (CINV) and chemotherapy-associated dyspepsia syndrome (CADS) are frequently appearing adverse effects of cisplatin (CDDP)-containing chemotherapy. Antiemetic guidelines suggest that the administration of antacids such as proton pump inhibitors (PPIs) or histamine type-2 receptor antagonists be considered for CADS, although their efficacy for treating these symptoms remains unknown. This study aimed to reveal whether antacids attenuate gastrointestinal symptoms in CDDP-containing chemotherapy. MATERIALS AND METHODS: In total, 138 patients with lung cancer who received ≥ 75 mg/m2 CDDP-containing regimens were enrolled in this retrospective study. Patients were divided into an antacid group including patients administered PPIs or vonoprazan during all chemotherapy periods and controls without antacid administration. The primary endpoint was the comparison of anorexia incidence during the first cycle of chemotherapy. Secondary endpoints were CINV evaluation and risk factor analysis for the incidence of anorexia using logistic regression analysis. RESULTS: The incidence of anorexia during the first cycle was 54.4% in the control group and 60.3% in the antacid group, without significant differences (p = 0.60). The incidence of nausea was also similar between the groups (p = 1.00). Multivariate analysis suggested that antacid administration was not associated with anorexia. CONCLUSION: Baseline antacid administration does not affect gastrointestinal symptoms associated with CDDP-containing treatment in lung cancer.
  • EGFR変異陽性肺癌におけるCD24発現の検討               
    椎谷 研彦, 野口 卓郎, 外丸 詩野, 有賀 伸, 高島 雄太, 品川 尚文, 木下 一郎, 松野 吉宏, 榊原 純, 秋田 弘俊
    日本病理学会会誌, 112, 1, 247, 247, (一社)日本病理学会, Mar. 2023
    Japanese
  • Crystalline silica-exposed human lung epithelial cells presented enhanced anchorage-independent growth with upregulated expression of BRD4 and EZH2 in autocrine and paracrine manners.
    Motoo Katabami, Ichiro Kinoshita, Shin Ariga, Yasushi Shimizu, Hirotoshi Dosaka-Akita
    PloS one, 18, 5, e0285354, 2023, [International Magazine]
    English, Scientific journal, Crystalline silica-induced inflammation possibly facilitates carcinogenesis. Here, we investigated its effect on lung epithelium damage. We prepared conditioned media of immortalized human bronchial epithelial cell lines (hereinafter bronchial cell lines) NL20, BEAS-2B, and 16HBE14o- pre-exposed to crystalline silica (autocrine crystalline silica conditioned medium), a phorbol myristate acetate-differentiated THP-1 macrophage line, and VA13 fibroblast line pre-exposed to crystalline silica (paracrine crystalline silica conditioned medium). As cigarette smoking imposes a combined effect on crystalline silica-induced carcinogenesis, a conditioned medium was also prepared using the tobacco carcinogen benzo[a]pyrene diol epoxide. Crystalline silica-exposed and growth-suppressed bronchial cell lines exhibited enhanced anchorage-independent growth in autocrine crystalline silica and benzo[a]pyrene diol epoxide conditioned medium compared with that in unexposed control conditioned medium. Crystalline silica-exposed nonadherent bronchial cell lines in autocrine crystalline silica and benzo[a]pyrene diol epoxide conditioned medium showed increased expression of cyclin A2, cdc2, and c-Myc, and of epigenetic regulators and enhancers, BRD4 and EZH2. Paracrine crystalline silica and benzo[a]pyrene diol epoxide conditioned medium also accelerated the growth of crystalline silica-exposed nonadherent bronchial cell lines. Culture supernatants of nonadherent NL20 and BEAS-2B in crystalline silica and benzo[a]pyrene diol epoxide conditioned medium had higher EGF concentrations, whereas those of nonadherent 16HBE14o- had higher TNF-α levels. Recombinant human EGF and TNF-α promoted anchorage-independent growth in all lines. Treatment with EGF and TNF-α neutralizing antibodies inhibited cell growth in crystalline silica conditioned medium. Recombinant human TNF-α induced BRD4 and EZH2 expression in nonadherent 16HBE14o-. The expression of γH2AX occasionally increased despite PARP1 upregulation in crystalline silica-exposed nonadherent lines with crystalline silica and benzo[a]pyrene diol epoxide conditioned medium. Collectively, crystalline silica- and benzo[a]pyrene diol epoxide-induced inflammatory microenvironments comprising upregulated EGF or TNF-α expression may promote crystalline silica-damaged nonadherent bronchial cell proliferation and oncogenic protein expression despite occasional γH2AX upregulation. Thus, carcinogenesis may be cooperatively aggravated by crystalline silica-induced inflammation and genotoxicity.
  • EGFR inhibition in EGFR-mutant lung cancer cells perturbs innate immune signaling pathways in the tumor microenvironment.
    Akihiko Shiiya, Takuro Noguchi, Utano Tomaru, Shin Ariga, Yuta Takashima, Yoshihito Ohhara, Jun Taguchi, Satoshi Takeuchi, Yasushi Shimizu, Ichiro Kinoshita, Tomonobu Koizumi, Yoshihiro Matsuno, Naofumi Shinagawa, Jun Sakakibara-Konishi, Hirotoshi Dosaka-Akita
    Cancer science, 18 Dec. 2022, [International Magazine]
    English, Scientific journal, Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) elicit potent cell cycle arrest in EGFR-mutant non-small-cell lung cancer (NSCLC) cells. However, little is known about the mechanisms through which these drugs alter the tumor phenotype that contributes to the immune escape of EGFR-mutant cells. Using EGFR-mutant NSCLC cell lines and tissue samples from patients, we investigated the changes in immune checkpoints expressed in tumor cells following EGFR inhibition. Subsequently, we also analyzed the role of soluble factors from the dying tumor cells in the activation of immune signaling pathways involved in therapy resistance. Upon EGFR-TKI treatment, we found that EGFR-mutant cells upregulated the expression of innate immune checkpoint CD24 in vitro. We then analyzed biopsy samples from six patients who developed resistance to a first-generation EGFR-TKI without the acquired T790M mutation. Immunohistochemistry revealed that levels of tumor CD24 expression were increased upon treatment compared with those from pre-treatment samples. Monocyte-derived macrophages facilitated antibody-dependent cellular phagocytosis when EGFR-TKI-treated EGFR-mutant cells were incubated with anti-CD24 antibodies in vitro, suggesting that CD24 may be a therapeutical target for EGFR-mutant lung cancer. Moreover, EGFR inhibition accelerated the release of cell-free DNA (cfDNA) from dying tumor cells, which activated the type I interferon signaling pathways in human THP-1 monocytes in a stimulator of interferon genes-dependent manner. Our study indicates that EGFR inhibition in EGFR-mutant NSCLC cells fosters a tumor microenvironment associated with immune escape. Thus, CD24 targeted therapy and cfDNA monitoring may contribute to improved treatment outcomes in patients with EGFR-mutant NSCLC.
  • Diabetes mellitus degenerates cisplatin-induced nephrotoxicity in short hydration method: a propensity score-matching analysis
    Yoshitaka Saito, Tatsuhiko Sakamoto, Yoh Takekuma, Masaki Kobayashi, Keisuke Okamoto, Naofumi Shinagawa, Yasushi Shimizu, Ichiro Kinoshita, Mitsuru Sugawara
    Scientific Reports, 12, 1, Springer Science and Business Media LLC, 17 Dec. 2022
    Scientific journal, Abstract

    Cisplatin (CDDP)-induced nephrotoxicity (CIN) is dose-limiting. We revealed that co-administration of non-steroid anti-inflammatory drugs and baseline comorbidity of diabetes mellitus (DM) are associated with CIN development in the short hydration method; however, the results were accessorily obtained without appropriate power calculation. This study aimed to demonstrate the influence of DM complications on CIN incidence in a real-world setting. Lung cancer patients receiving CDDP (≥ 75 mg/m2)-containing regimens with a short hydration method (n = 227) were retrospectively evaluated. The patients were divided into control and baseline DM complication groups. The primary endpoint was the evaluation of CIN incidence between the groups. Propensity score-matching was performed to confirm the robustness of the primary analysis results. CIN occurred in 6.8% of control and 27.0% of DM patients, respectively, with a significant difference in all-patient populations (P = 0.001). In addition, variation of serum creatinine and creatinine clearance significantly worsened in DM patients. Similar results were obtained in a propensity-matched population. Multivariate logistic regression analysis found that DM complication is a singular risk factor for CIN development (adjusted odds ratio; 4.31, 95% confidence interval; 1.62–11.50, P = 0.003). In conclusion, our study revealed that baseline DM complications significantly worsen CIN.
  • Concordance Between Recommendations From Multidisciplinary Molecular Tumor Boards and Central Consensus for Cancer Treatment in Japan
    Yoichi Naito, Kuniko Sunami, Hidenori Kage, Keigo Komine, Toraji Amano, Mitsuho Imai, Takafumi Koyama, Daisuke Ennishi, Masashi Kanai, Hirotsugu Kenmotsu, Takahiro Maeda, Sachi Morita, Daisuke Sakai, Kousuke Watanabe, Hidekazu Shirota, Ichiro Kinoshita, Masashiro Yoshioka, Nobuaki Mamesaya, Mamoru Ito, Shinji Kohsaka, Yusuke Saigusa, Kouji Yamamoto, Makoto Hirata, Katsuya Tsuchihara, Takayuki Yoshino
    JAMA Network Open, 5, 12, e2245081, e2245081, American Medical Association (AMA), 05 Dec. 2022, [Peer-reviewed]
    English, Scientific journal, Importance

    Quality assurance of molecular tumor boards (MTBs) is crucial in cancer genome medicine.

    Objective

    To evaluate the concordance of recommendations by MTBs and centrally developed consensus treatment recommendations at all 12 leading institutions for cancer genomic medicine in Japan using 50 simulated cases.

    Design, Setting, and Participants

    This was a prospective quality improvement study of 50 simulated cancer cases. Molecular tumor boards from 12 core hospitals independently recommended treatment for 50 cases blinded to the centrally developed consensus treatment recommendations. The study’s central committee consisted of representatives from all 12 core hospitals in Japan who selected the 50 simulated cases from The Cancer Genome Atlas database, including frequently observed genomic alterations. The central committee recommended centrally developed consensus treatment. The concordance rate for genomically matched treatments between MTBs and centrally developed consensus treatment recommendations was evaluated. Data analysis was conducted from January 22 to March 3, 2021.

    Exposures

    Simulated cases of cancer.

    Main Outcomes and Measures

    The primary outcome was concordance, defined as the proportion of recommendations by MTBs concordant with centrally developed consensus treatment recommendations. A mixed-effects logistic regression model, adjusted for institutes as a random intercept, was applied. High evidence levels were defined as established biomarkers for which the treatment was ready for routine use in clinical practice, and low evidence levels were defined as biomarkers for genomically matched treatment that were under investigation.

    Results

    The Clinical Practice Guidance for Next-Generation Sequencing in Cancer Diagnosis and Treatment (edition 2.1) was used for evidence-level definition. The mean concordance between MTBs and centrally developed consensus treatment recommendations was 62% (95% CI, 57%-65%). Each MTB concordance varied from 48% to 86%. The concordance rate was higher in the subset of patients with colorectal cancer (100%; 95% CI, 94.0%-100%), ROS1 fusion (100%; 95% CI, 85.5%-100%), and high evidence level A/R (A: 88%; 95% CI, 81.8%-93.0%; R:100%; 95% CI, 92.6%-100%). Conversely, the concordance rate was lower in cases of cervical cancer (11%; 95% CI, 3.1%-26.1%), TP53 mutation (16%; 95% CI, 12.5%-19.9%), and low evidence level C/D/E (C: 30%; 95% CI, 24.7%-35.9%; D: 25%; 95% CI, 5.5%-57.2%; and E: 18%; 95% CI, 13.8%-23.0%). Multivariate analysis showed that evidence level (high [A/R] vs low [C/D/E]: odds ratio, 4.4; 95% CI, 1.8-10.8) and TP53 alteration (yes vs no: odds ratio, 0.06; 95% CI, 0.03-0.10) were significantly associated with concordance.

    Conclusions and Relevance

    The findings of this study suggest that genomically matched treatment recommendations differ among MTBs, particularly in genomic alterations with low evidence levels wherein treatment is being investigated. Sharing information on matched therapy for low evidence levels may be needed to improve the quality of MTBs.
  • Expression of karyopherin alfa 2 and karyopherin beta 1 correlate with poor prognosis in gastric cancer.
    Yoshihito Ohhara, Ichiro Kinoshita, Akira Suzuki, Makoto Imagawa, Jun Taguchi, Takuro Noguchi, Satoshi Takeuchi, Yasushi Shimizu, Hideyuki Seki, Junichi Suzuki, Hirotoshi Dosaka-Akita
    Oncology, 21 Oct. 2022, [International Magazine]
    English, Scientific journal, INTRODUCTION: Karyopherin alfa 2 (KPNA2) and karyopherin beta 1 (KPNB1), constitute nuclear transport protein complexes involved in nuclear import, and are significant in tumor progression. Although high KPNA2 expression was associated with poor prognosis in solid tumors, the relationship between KPNA2 and KPNB1 expression and their prognostic role in gastric cancer (GC) remains unclear. METHODS: Immunohistochemistry was used to correlate the expression of KPNA2 and KPNB1 with various features, including clinicopathologic characteristics in 130 patients with GC and survival in 94 patients with invasive lesions extending to the submucosa or deeper. RESULTS: High expression of KPNA2 and KPNB1 was found in 25% and 36% of the patients, respectively. Both were significantly related to tumor depth, lymph node metastasis, lymphatic invasion, venous invasion, and Ki-67 expression. KPNA2 expression was significantly related to that of KPNB1 (P < 0.001). Patients with high KPNB1 expression had poorer prognosis than those with low expression (P = 0.027), as was also observed in case of KPNA2 (P < 0.001). Patients with high expression of both KPNA2 and KPNB1 accounted for 18% and had a poorer prognosis than those with high expression of either and those with low expression of both (P = 0.001). Multivariate analysis revealed that high expression of both KPNA2 and KPNB1 was an independent prognostic factor in patients with GC (HR 3.46, 95% CI 1.64-2.73, P = 0.001). CONCLUSION: KPNA2 expression was correlated with KPNB1 expression, and high co-expression of KPNA2 and KPNB1 may represent a strong prognostic biomarker in GC.
  • Effect of comprehensive cancer genomic profiling on therapeutic strategies and clinical outcomes in patients with advanced biliary tract cancer: A prospective multicenter study
    Kohichi Takada, Tomohiro Kubo, Junko Kikuchi, Makoto Yoshida, Ayako Murota, Yohei Arihara, Hajime Nakamura, Hiroyuki Nagashima, Hiroki Tanabe, Shintaro Sugita, Yumi Tanaka, Ayana Miura, Yoshihito Ohhara, Atsushi Ishiguro, Hiroshi Yokouchi, Yasuyuki Kawamoto, Yusuke Mizukami, Hirofumi Ohnishi, Ichiro Kinoshita, Akihiro Sakurai
    Frontiers in Oncology, 12, Frontiers Media SA, 02 Sep. 2022
    Scientific journal, Characterization of the genomic landscape of biliary tract cancer (BTC) may lead to applying genotype-matched therapy for patients with this disease. Evidence that comprehensive cancer genomic profiling (CGP) guides genotype-matched therapy to improve clinical outcomes is building. However, the significance of CGP in patients with BTC remains unclarified in clinical practice. Therefore, the purposes of this study were to assess the utility of CGP and identify associations between clinical outcomes and genomic alterations in patients with BTC. In this prospective analysis, detection rates for actionable genomic alterations and access rates for genotype-matched therapy were analyzed in 72 patients with advanced BTC who had undergone commercial CGP. Cox regression analyses assessed relationships between overall survival and genomic alterations detected with CGP. The most common genomic alterations detected were TP53 (41, 56.9%), followed by CDKN2A/B (24, 33.3%/20, 27.8%), and KRAS (20, 27.8%). Actionable genomic alterations were identified in 58.3% (42/72) of patients. Detection rates for FGFR2 fusions, IDH1 mutations, and BRAF V600E were low in this cohort. Eight (11.1%) patients received genotype-matched therapy. For patients with intrahepatic cholangiocarcinoma (ICC), CDKN2A/B loss was associated with shorter overall survival. These real-world data demonstrate that CGP can identify therapeutic options in patients with advanced BTC. CDKN2A/B loss was identified as a poor prognostic factor in patients with ICC. Thus, this study provides a rationale for considering CGP in planning therapeutic strategies for advanced BTC.
  • A multicenter investigator-initiated Phase 2 trial of E7090 in patients with advanced or recurrent solid tumor with fibroblast growth factor receptor (FGFR) gene alteration: FORTUNE trial.
    Yohei Chiba, Kazuki Sudo, Yuki Kojima, Hitomi Okuma, Shinji Kohsaka, Ryunosuke Machida, Masahiko Ichimura, Kenta Anjo, Kazumi Kurishita, Natsuko Okita, Kenichi Nakamura, Ichiro Kinoshita, Masanobu Takahashi, Junichi Matsubara, Hitoshi Kusaba, Kan Yonemori, Masamichi Takahashi
    BMC cancer, 22, 1, 869, 869, 09 Aug. 2022, [International Magazine]
    English, Scientific journal, BACKGROUND: Aberrant fibroblast growth factor receptor (FGFR) signaling can substantially influence oncogenicity. Despite that FGFR gene abnormality is often detected by cancer genome profiling tests, there is no tumor-agnostic approval yet for these aberrations. E7090 (tasurgratinib) is an orally available selective tyrosine kinase inhibitor of FGFR1-3. Specific FGFR alterations were previously reported to be highly sensitive to E7090 based on a high-throughput functional evaluation method, called mixed-all-nominated-mutants-in-one (MANO) method, narrowing down the most promising targets. This trial was focused on the alterations identified by the MANO method and was performed under the nationwide large registry network for rare cancers in Japan (MASTER KEY Project). METHODS/DESIGN: This single-arm Phase 2 trial was designed to evaluate the safety and efficacy of E7090 in patients with advanced or recurrent solid tumors harboring FGFR alterations. Three cohorts were set based on the type of FGFR alterations and the results of MANO method. A maximum of 45 patients will be enrolled from 5 institutions over 2.5 years. E7090 will be administered once daily as an oral single agent in 28-day cycles. The primary endpoint is the objective overall response rate; whereas, the secondary endpoints include progression-free survival, overall survival, disease control rate, safety, duration of response, and time to response. Ethics approval was granted by the National Cancer Center Hospital Certified Review Board. Patient enrollment began in June 2021. DISCUSSION: A unique investigator-initiated multicenter Phase 2 trial was designed based on the results of preclinical investigation aiming to acquire the approval of E7090 for solid tumors harboring FGFR gene alterations. The findings may serve as a novel model for the development of tumor-agnostic molecular targeted therapies against rare genetic abnormalities. TRIAL REGISTRATION: Japan Registry of Clinical Trial: jRCT2031210043 (registered April 20, 2021) ClinicalTrials.gov: NCT04962867 (registered July 15, 2021).
  • Risk Factor Analysis for the Occurrence of Severe Adverse Effects in Eribulin Treatment.
    Yoshitaka Saito, Yoh Takekuma, Takashi Takeshita, Takuro Noguchi, Satoshi Takeuchi, Yasushi Shimizu, Ichiro Kinoshita, Hirotoshi Dosaka-Akita, Mitsuru Sugawara
    Anticancer research, 42, 7, 3693, 3700, Jul. 2022, [International Magazine]
    English, Scientific journal, BACKGROUND/AIM: Eribulin is an effective chemotherapeutic agent for the treatment of metastatic breast cancer and advanced or metastatic soft-tissue sarcomas. However, severe adverse effects (SAEs) occur in 30-40% of the patients, and significantly reduce the patients' quality of life and disturb the recommended treatment schedules. Neutropenia is the main cause of treatment suspension, delay, and/or dose reductions, also leading to relative dose intensity reduction. This study aimed to examine the risk factors for SAE occurrence after eribulin treatment. PATIENTS AND METHODS: Eighty patients with metastatic breast cancer or advanced or metastatic soft tissue sarcoma who received eribulin were retrospectively evaluated. Risk factors for SAE occurrence in the first cycle were primarily assessed. In addition, factors associated with SAE occurrence during all treatment cycles were evaluated. RESULTS: SAEs in the first cycle occurred in 45% of patients. The primary SAE was neutropenia (91.7%). The incidence of SAEs during all treatment cycles was 61.3%. Multivariate analyses suggested that lower baseline neutrophil and hemoglobin levels were risk factors for SAE occurrence and severe neutropenia incidence in the first cycle. An independent factor associated with SAE occurrence during all cycles was age ≥65 years and a tendency was confirmed for baseline anemia. CONCLUSION: Baseline neutropenia and anemia were risk factors for SAE occurrence during the first eribulin treatment cycle. Age ≥65 years was also associated with SAE occurrence during all treatment cycles. Patients with these risk factors should be carefully monitored for assessment and prophylaxis.
  • Suitability of Oral Rehydration Solution (ORS) for Use in the Cisplatin Short Hydration Method.
    Yoshitaka Saito, Yoh Takekuma, Masaki Kobayashi, Naofumi Shinagawa, Takuro Noguchi, Satoshi Takeuchi, Yasushi Shimizu, Ichiro Kinoshita, Hirotoshi Dosaka-Akita, Mitsuru Sugawara
    Anticancer research, 42, 6, 3185, 3193, Jun. 2022, [International Magazine]
    English, Scientific journal, BACKGROUND/AIM: Short hydration is a method to change partial intravenous hydration to oral to administer cisplatin (CDDP); however, the most suitable form of oral hydration is unknown. This study aimed to determine whether oral rehydration solution (ORS) affects CDDP-induced nephrotoxicity (CIN) and electrolyte imbalance. PATIENTS AND METHODS: Lung cancer patients (n=200) who had received CDDP-including regimens (CDDP dosage ≥75 mg/m2) were retrospectively evaluated. We used logistic analysis to evaluate whether ORS intake could be a preventive factor for CIN (≥grade 2 serum creatinine elevation). Moreover, incidence of CIN and electrolyte imbalance and the variation in serum creatinine and electrolyte levels were compared between ORS and non-ORS (control) patients. RESULTS: CIN occurred in 9.8% of ORS patients, and 7.5% of non-ORS patients (p=0.79). The variation in serum creatinine level was also similar in both groups. Multivariate analysis suggested that ORS intake does not affect CIN, although CIN was associated with the coadministration of non-steroidal anti-inflammatory drugs and the presence of diabetes mellitus. The variations in serum electrolyte levels did not differ, and incidence of hyponatremia, hypokalemia, and hypochloremia was also similar between the groups. Moreover, patients in ORS group experienced significantly more anorexia compared to controls, and approximately 40% of the patients were unable to continue ORS intake. CONCLUSION: ORS intake in CDDP short hydration regimens does not affect CIN and CDDP-induced electrolyte imbalance; however, its intake is associated with the incidence of anorexia suggesting that ORS should not be used for oral hydration.
  • 進行固形がん患者に対する保険診療による包括的がんゲノムプロファイリング検査の実施時期についての検討               
    菊地 順子, 大原 克仁, 天野 虎次, 矢部 一郎, 小松 嘉人, 松野 吉宏, 石黒 敦, 水上 裕輔, 櫻井 晃洋, 木下 一郎
    日本内科学会雑誌, 111, Suppl., 190, 190, (一社)日本内科学会, Feb. 2022
    Japanese
  • Notable therapeutic response in a patient with systemic juvenile xanthogranuloma with KIF5B-ALK fusion.
    Minako Sugiyama, Shinsuke Hirabayashi, Yukitomo Ishi, Junko Kikuchi, Ayako Ishikura, Hiroaki Motegi, Yuki Ueda, Saori Sawai, Kazuya Hara, Yukayo Terashita, Yuko Cho, Emi Takakuwa, Shohei Honda, Shigeru Yamaguchi, Ichiro Kinoshita, Atsushi Manabe
    Pediatric blood & cancer, 68, 11, e29227, Nov. 2021, [Peer-reviewed], [International Magazine]
    English
  • Pharmacokinetics, Safety, and Efficacy of Trastuzumab Deruxtecan with Concomitant Ritonavir or Itraconazole in Patients with HER2-Expressing Advanced Solid Tumors.
    Shunji Takahashi, Masato Karayama, Masato Takahashi, Junichiro Watanabe, Hironobu Minami, Noboru Yamamoto, Ichiro Kinoshita, Chia-Chi Lin, Young-Hyuck Im, Issei Achiwa, Emi Kamiyama, Yasuyuki Okuda, Caleb Lee, Yung-Jue Bang
    Clinical cancer research : an official journal of the American Association for Cancer Research, 23 Aug. 2021, [Peer-reviewed], [International Magazine]
    English, Scientific journal, PURPOSE: To evaluate drug-drug interactions between the human epidermal growth factor receptor 2 (HER2)-targeted antibody-drug conjugate trastuzumab deruxtecan (T-DXd; DS-8201a) and the OATP1B/CYP3A inhibitor ritonavir or the strong CYP3A inhibitor itraconazole. PATIENTS AND METHODS: Patients with HER2-expressing advanced solid tumors were enrolled in this phase I, open-label, single-sequence crossover study (NCT03383692) and received i.v. T-DXd 5.4 mg/kg every 3 weeks. Patients received ritonavir (cohort 1) or itraconazole (cohort 2) from day 17 of cycle 2 through the end of cycle 3. Primary endpoints were maximum serum concentration (C max) and partial area under the concentration-time curve from beginning of cycle through day 17 (AUC17d) for T-DXd and deruxtecan (DXd) with (cycle 3) and without (cycle 2) ritonavir or itraconazole treatment. RESULTS: Forty patients were enrolled (cohort 1, n = 17; cohort 2, n = 23). T-DXd C max was similar whether combined with ritonavir [cohort 1, cycle 3/cycle 2; 90% confidence interval (CI): 1.05 (0.98-1.13)] or itraconazole [cohort 2, 1.03 (0.96-1.09)]. T-DXd AUC17d increased from cycle 2 to 3; however, the cycle 3/cycle 2 ratio upper CI bound remained at ≤1.25 for both cohorts. For DXd (cycle 3/cycle 2), C max ratio was 0.99 (90% CI, 0.85-1.14) for cohort 1 and 1.04 (0.92-1.18) for cohort 2; AUC17d ratio was 1.22 (1.08-1.37) and 1.18 (1.11-1.25), respectively. The safety profile of T-DXd plus ritonavir or itraconazole was consistent with previous studies of T-DXd monotherapy. T-DXd demonstrated promising antitumor activity across HER2-expressing solid-tumor types. CONCLUSIONS: T-DXd was safely combined with ritonavir or itraconazole without clinically meaningful impact on T-DXd or DXd pharmacokinetics.
  • [Development of a System for Providing Cancer Genomic Medicine in Hokkaido-From the Standpoint of a Designated Core Hospital for Cancer Genomic Medicine].
    Ichiro Kinoshita, Junko Kikuchi, Yoshihito Ohhara, Toraji Amano, Hirotoshi Akita
    Gan to kagaku ryoho. Cancer & chemotherapy, 48, 7, 882, 886, Jul. 2021, [Domestic magazines]
    Japanese, Scientific journal, Hokkaido University Hospital has been designated as a Core Hospital for Cancer Genomic Medicine and developed a system to provide cancer genomic medicine in Hokkaido with its liaison hospitals. Since being reimbursed in June 2019, comprehensive cancer genome profiling (CGP) testing showed certain therapeutic efficacy in patients with no standard treatment options, but it also revealed some problems such as the small number of patients who can receive therapeutic drugs matched with gene abnormalities. Since candidate drugs are often unapproved or off-label, it is necessary to smoothly introduce clinical trials, advanced medical treatment system, and patient-proposed health care service. At our hospital, we are focusing on sharing information on clinical trials being conducted in Hokkaido, launching investigator-initiated clinical trials, promoting patient-proposed health care service, promoting a registry study of genetic profiling and targeted therapies in patients with rare cancers and accompanying clinical trials, and incorporating pediatric cancer patients. This paper describes Hokkaido's cancer genomic medicine provision system, including its exit strategy, and the human resource development that serve as its foundation.
  • Expression of the immunoproteasome subunit β5i in non-small cell lung carcinomas.
    Takayuki Kiuchi, Utano Tomaru, Akihiro Ishizu, Makoto Imagawa, Sari Iwasaki, Akira Suzuki, Noriyuki Otsuka, Yoshihito Ohhara, Ichiro Kinoshita, Yoshihiro Matsuno, Hirotoshi Dosaka-Akita, Masanori Kasahara
    Journal of clinical pathology, 74, 5, 300, 306, May 2021, [Peer-reviewed], [International Magazine]
    English, Scientific journal, AIM: The immunoproteasome is a specific proteasome isoform whose proteolytic activity enhances the generation of antigenic peptides to be presented by major histocompatibility complex class I molecules to CD8+ T cells. Physiologically, it is expressed abundantly in immune cells and is induced in somatic cells by cytokines, especially interferon-γ. Recently, variable expression of immunoproteasomes has been demonstrated in different types of cancers. However, the clinical significance of immunoproteasome expression in malignant tumours is poorly understood. In this study, we performed clinicopathological evaluation of immunoproteasome subunit β5i in non-small cell lung carcinomas (NSCLCs). METHODS: Tumour tissues were collected from 155 patients with NSCLCs, and immunohistochemical analysis for β5i was performed in relation to the prognosis of patients. RESULTS: High expression of β5i was found in about 20% of all NSCLCs and was found significantly more frequently (40%) in the adenocarcinoma subset. High expression of β5i was associated with a better 5-year relative survival rate in patients with pStage I to II adenocarcinoma and was also a significant and independent favourable prognostic factor in adenocarcinoma patients. In addition, when we performed in vitro analysis using NSCLC cell lines, combined treatment with the immunoproteasome-specific inhibitor ONX0914 and the proteasome inhibitor MG132 enhanced cell death in β5i-expressing NSCLC cell lines. CONCLUSION: The expression of immunoproteasome can be explored as both a prognostic factor and a potential therapeutic target in NSCLCs. Since immunoproteasomes have crucial role in the antigen presentation, further studies may help to provide essential knowledge for therapeutic strategies in anticancer immunotherapy.
  • Clinical significance of comprehensive genomic profiling tests covered by public insurance in patients with advanced solid cancers in Hokkaido, Japan.
    Junko Kikuchi, Yoshihito Ohhara, Kohichi Takada, Hiroki Tanabe, Kazuteru Hatanaka, Toraji Amano, Kanako C Hatanaka, Yutaka Hatanaka, Takashi Mitamura, Momoko Kato, Yuka Shibata, Ichiro Yabe, Akira Endoh, Yoshito Komatsu, Yoshihiro Matsuno, Minako Sugiyama, Atsushi Manabe, Akihiro Sakurai, Masato Takahashi, Hirohito Naruse, Yoshihiro Torimoto, Hirotoshi Dosaka-Akita, Ichiro Kinoshita
    Japanese journal of clinical oncology, 51, 5, 753, 761, 30 Apr. 2021, [Peer-reviewed], [Last author, Corresponding author], [International Magazine]
    English, Scientific journal, BACKGROUND: Comprehensive cancer genomic profiling has been used recently for patients with advanced solid cancers. Two cancer genomic profiling tests for patients with no standard treatment are covered by Japanese public health insurance since June 2019. METHODS: We prospectively analyzed data of 189 patients with solid cancers who underwent either of the two-cancer genomic profiling tests at Hokkaido University Hospital and its liaison hospitals and whose results were discussed in molecular tumor board at Hokkaido University Hospital between August 2019 and July 2020. RESULTS: All 189 patients had appropriate results. Actionable gene alterations were identified in 93 patients (49%). Frequent mutations included PIK3CA (12%) mutation, BRCA1/2 alteration (7%), ERBB2 amplification (6%) and tumor mutation burden-High (4%). The median turnaround time from sample shipping to acquisition by the expert panel was 26 days. Although 115 patients (61%) were provided with information for genotype-matched therapies, only 21 (11%) received them. Notably, four of eight patients below the age of 20 years were provided information for genotype-matched therapies, and three received them. Their response rates and disease control rates were 29% and 67%, respectively. Most patients who did not undergo the genotype-matched therapies were provided information for only investigational drugs in phases I and II at distant clinical trial sites in central Japan. Twenty-six patients were informed of suspected germline findings, while 11 patients (42%) received genetic counseling. CONCLUSIONS: The publicly reimbursed cancer genomic profilings may lead to the modest but favorable therapeutic efficacy of genotype-matched therapy for solid cancer patients with no standard therapy. However, poor access to genotype-matched therapy needs to be resolved.
  • Impact of clinical targeted sequencing on endocrine responsiveness in estrogen receptor-positive, HER2-negative metastatic breast cancer.
    Kanako Hagio, Toraji Amano, Hideyuki Hayashi, Takashi Takeshita, Tomohiro Oshino, Junko Kikuchi, Yoshihito Ohhara, Ichiro Yabe, Ichiro Kinoshita, Hiroshi Nishihara, Hiroko Yamashita
    Scientific reports, 11, 1, 8109, 8109, 14 Apr. 2021, [Peer-reviewed], [International Magazine]
    English, Scientific journal, Clinical targeted sequencing allows for the selection of patients expected to have a better treatment response, and reveals mechanisms of resistance to molecular targeted therapies based on actionable gene mutations. We underwent comprehensive genomic testing with either our original in-house CLHURC system or with OncoPrime. Samples from 24 patients with estrogen receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer underwent targeted sequencing between 2016 and 2018. Germline and somatic gene alterations and patients' prognosis were retrospectively analyzed according to the response to endocrine therapy. All of the patients had one or more germline and/or somatic gene alterations. Four patients with primary or secondary endocrine-resistant breast cancer harbored germline pathogenic variants of BRCA1, BRCA2, or PTEN. Among somatic gene alterations, TP53, PIK3CA, AKT1, ESR1, and MYC were the most frequently mutated genes. TP53 gene mutation was more frequently observed in patients with primary endocrine resistance compared to those with secondary endocrine resistance or endocrine-responsive breast cancer. Recurrent breast cancer patients carrying TP53-mutant tumors had significantly worse overall survival compared to those with TP53-wild type tumors. Our 160-gene cancer panel will be useful to identify clinically actionable gene alterations in breast cancer in clinical practice.
  • Impact of histamine type-2 receptor antagonists on the anticancer efficacy of gefitinib in patients with non-small cell lung cancer.
    Yoshitaka Saito, Yoh Takekuma, Masaki Kobayashi, Naofumi Shinagawa, Yasushi Shimizu, Ichiro Kinoshita, Hirotoshi Dosaka-Akita, Ken Iseki, Mitsuru Sugawara
    European journal of clinical pharmacology, 77, 3, 381, 388, Mar. 2021, [Peer-reviewed], [International Magazine]
    English, Scientific journal, PURPOSE: Gefitinib is one of the standard treatments for non-small cell lung cancer (NSCLC) with epidermal growth factor receptor mutations. It has been reported that acid suppressants (AS) decrease the anti-tumor effect of gefitinib by reducing its solubility. AS is sometimes necessary in cancer patients; however, previous reports have not shown the most compatible AS with gefitinib administration in cancer patients. This study was conducted to determine if histamine type 2 receptor antagonists (H2RAs) can affect the anti-tumor efficacy of gefitinib. METHODS: Eighty-seven patients with NSCLC who were administered gefitinib were retrospectively investigated. Patients who were co-administered H2RA were compared with non-AS control patients. H2RA was administered once a day at about 3-5 or 8-12 h after gefitinib intake. The primary endpoint of this study was progression-free survival (PFS), and secondary endpoints were overall survival (OS), overall response rate (ORR), and adverse effects. RESULTS: Median PFS in H2RA group and control group was 8.0 months and 9.0 months, respectively, with no significant difference (p = 0.82). The incidence of liver dysfunction was significantly less in patients administered H2RA, whereas there were no differences between the two groups with regard to skin toxicity and diarrhea. Multivariate analysis suggested that H2RA co-administration is not a risk factor for worse PFS and OS (hazard ratio of 0.95, 0.86; 95% confidence interval of 0.60-1.48, 0.52-1.43; p = 0.82 and 0.60, respectively). CONCLUSION: This study demonstrated that concomitant administration of H2RA with gefitinib does not affect the efficacy of gefitinib.
  • Clinical practice guidance for next-generation sequencing in cancer diagnosis and treatment (edition 2.1).
    Yoichi Naito, Hiroyuki Aburatani, Toraji Amano, Eishi Baba, Toru Furukawa, Tetsu Hayashida, Eiso Hiyama, Sadakatsu Ikeda, Masashi Kanai, Motohiro Kato, Ichiro Kinoshita, Naomi Kiyota, Takashi Kohno, Shinji Kohsaka, Keigo Komine, Itaru Matsumura, Yuji Miura, Yoshiaki Nakamura, Atsushi Natsume, Kazuto Nishio, Katsutoshi Oda, Naoyuki Oda, Natsuko Okita, Kumiko Oseto, Kuniko Sunami, Hideaki Takahashi, Masayuki Takeda, Shimon Tashiro, Shinichi Toyooka, Hideki Ueno, Shinichi Yachida, Takayuki Yoshino, Katsuya Tsuchihara
    International journal of clinical oncology, 26, 2, 233, 283, Feb. 2021, [Peer-reviewed], [Domestic magazines]
    English, Scientific journal, BACKGROUND: To promote precision oncology in clinical practice, the Japanese Society of Medical Oncology, the Japanese Society of Clinical Oncology, and the Japanese Cancer Association, jointly published "Clinical practice guidance for next-generation sequencing in cancer diagnosis and treatment" in 2017. Since new information on cancer genomic medicine has emerged since the 1st edition of the guidance was released, including reimbursement for NGS-based multiplex gene panel tests in 2019, the guidance revision was made. METHODS: A working group was organized with 33 researchers from cancer genomic medicine designated core hospitals and other academic institutions. For an impartial evaluation of the draft version, eight committee members from each society conducted an external evaluation. Public comments were also made on the draft. The finalized Japanese version was published on the websites of the three societies in March 2020. RESULTS: The revised edition consists of two parts: an explanation of the cancer genomic profiling test (General Discussion) and clinical questions (CQs) that are of concern in clinical practice. Particularly, patient selection should be based on the expectation that the patient's post-test general condition and organ function will be able to tolerate drug therapy, and the optimal timing of test should be considered in consideration of subsequent treatment plans, not limited to treatment lines. CONCLUSION: We expect that the revised version will be used by healthcare professionals and will also need to be continually reviewed in line with future developments in cancer genome medicine.
  • METex14 skipping testing guidance for lung cancer patients: The guidance from the biomarker committee, the Japan lung cancer society
    Yasushi Yatabe, Koichi Goto, Shingo Matsumoto, Yutaka Hatanaka, Naoko Arakane, Sadakatsu Ikeda, Akira Inoue, Ichiro Kinoshita, Hideharu Kimura, Tomohiro Sakamoto, Miyako Satouchi, Junichi Shimizu, Kuniko Sunami, Koji Tsuta, Shinichi Toyooka, Kazuto Nishio, Kazumi Nishino, Masashi Mikubo, Tomoyuki Yokose, Hirotoshi Dosaka-Akita
    Japanese Journal of Lung Cancer, 61, 5, 361, 370, Japan Lung Cancer Society, 2021
    English, Scientific journal
  • Appropriate use of cancer comprehensive genome profiling assay using circulating tumor DNA
    Kuniko Sunami, Hideaki Bando, Yasushi Yatabe, Yoichi Naito, Hideaki Takahashi, Katsuya Tsuchihara, Shinichi Toyooka, Koshi Mimori, Shinji Kohsaka, Hiroyuki Uetake, Ichiro Kinoshita, Keigo Komine, Masayuki Takeda, Tetsu Hayashida, Kenji Tamura, Kazuto Nishio, Noboru Yamamoto, Hiroyuki Aburatani, Takashi Khono, Hiroyuki Mano, Tetsuo Noda, Daisuke Aoki, Yuko Kitagawa, Masaki Mori, Gaku Muto, Hirotoshi Akita, Chikashi Ishioka, Issei Imoto, Hidehiko Miyake, Tomosho Nakayama
    Cancer Science, 112, 9, 3911, 3917, 2021, [Peer-reviewed], [International Magazine]
    English, Scientific journal
  • Multiplex gene-panel testing for lung cancer patients.
    Yasushi Yatabe, Kuniko Sunami, Koichi Goto, Kazuto Nishio, Naoko Aragane, Sadakatsu Ikeda, Akira Inoue, Ichiro Kinoshita, Hideharu Kimura, Tomohiro Sakamoto, Miyako Satouchi, Junichi Shimizu, Koji Tsuta, Shinichi Toyooka, Kazumi Nishino, Yutaka Hatanaka, Shingo Matsumoto, Masashi Mikubo, Tomoyuki Yokose, Hirotoshi Dosaka-Akita
    Pathology international, 70, 12, 921, 931, Dec. 2020, [Peer-reviewed], [International Magazine]
    English, Scientific journal, The year 2019 was considered to be the first year of cancer genome medicine in Japan, with three gene-panel tests using next-generation sequencing (NGS) techniques being introduced into clinical practice. Among the three tests, the Oncomine CDx Target test was approved under the category of regular molecular testing for lung cancer, which meant that this test could be used to select patients for molecularly targeted drugs. Conversely, the other two tests, NCC OncoPanel and FoundationOne CDx, were assigned to be used under the National Cancer Genome Medicine Network, and implementation was restricted to patients for whom standard treatment was completed or expected to be completed. These NGS tests can detect a series of genetic alterations in individual tumors, which further promotes the development of therapeutic agents and elucidates molecular pathways. The NGS tests require appropriate tissue size and tumor cell content, which can be accessed only by pathologists. In this report, we review the current reimbursement schema in our national healthcare policy and the requirements of the specimens for NGS testing based on the recently published 'Guidance of Gene-panel Testing Using Next-Generation Sequencers for Lung Cancer', by the Japanese Society of Lung Cancer.
  • Clinical impact of a cancer genomic profiling test using an in-house comprehensive targeted sequencing system.
    Hideyuki Hayashi, Shigeki Tanishima, Kyoko Fujii, Ryo Mori, Chihiro Okada, Emmy Yanagita, Yuka Shibata, Ryosuke Matsuoka, Toraji Amano, Takahiro Yamada, Ichiro Yabe, Ichiro Kinoshita, Yoshito Komatsu, Hirotoshi Dosaka-Akita, Hiroshi Nishihara
    Cancer science, 111, 10, 3926, 3937, Oct. 2020, [Peer-reviewed], [International Magazine]
    English, Scientific journal, Precision medicine is a promising strategy for cancer treatment. In this study, we developed an in-house clinical sequencing system to perform a comprehensive cancer genomic profiling test as a clinical examination and analyzed the utility of this system. Genomic DNA was extracted from tumor tissues and peripheral blood cells collected from 161 patients with different stages and types of cancer. A comprehensive targeted amplicon exome sequencing for 160 cancer-related genes was performed using next-generation sequencing (NGS). The sequencing data were analyzed using an original bioinformatics pipeline, and multiple cancer-specific gene alterations were identified. The success rate of our test was 99% (160/161), while re-biopsy was required for 24% (39/161) of the cases. Potentially actionable and actionable gene alterations were detected in 91% (145/160) and 46% (73/160) of the patients, respectively. The actionable gene alterations were frequently detected in PIK3CA (9%), ERBB2 (8%), and EGFR (4%). High tumor mutation burden (TMB) (≥10 mut/Mb) was observed in 12% (19/160) of the patients. The secondary findings in germline variants considered to be associated with hereditary tumors were detected in 9% (15/160) of the patients. Seventeen patients (11%, 17/160) were treated with genotype-matched therapeutic agents, and the response rate was 47% (8/17). The median turnaround time for physicians was 20 days, and the median survival time after the initial visit was 8.7 months. The results of the present study prove the feasibility of implementing in-house clinical sequencing as a promising laboratory examination technique for precision cancer medicine.
  • Phase II trial of combination treatment with S-1/cetuximab in patients with platinum-ineligible recurrent and/or metastatic squamous cell carcinoma of the head and neck
    Jun Taguchi, Yasushi Shimizu, Shin Ariga, Tomohiro Goda, Yoshihito Ohhara, Rio Honma, Takuro Noguchi, Satoshi Takeuchi, Ichiro Kinoshita, Toraji Amano, Takatsugu Mizumachi, Satoshi Kano, Miki Takahara, Takahisa Abe, Akihiro Homma, Hirotoshi Dosaka-Akita
    INTERNATIONAL JOURNAL OF CLINICAL ONCOLOGY, 26, 1, 51, 58, Sep. 2020, [Peer-reviewed], [Domestic magazines]
    English, Scientific journal
  • A randomized phase II trial of cisplatin plus gemcitabine versus carboplatin plus gemcitabine in patients with completely resected non-small cell lung cancer: Hokkaido Lung Cancer Clinical Study Group Trial (HOT0703).
    Shin-Ichi Fukumoto, Satoshi Oizumi, Masao Harada, Noriaki Sukoh, Kosuke Nakano, Satoshi Fuke, Jun Sakakibara-Konishi, Kei Takamura, Kenichiro Ito, Yuka Fujita, Yutaka Nishigaki, Toshiyuki Harada, Kenji Akie, Ichiro Kinoshita, Toraji Amano, Hiroshi Isobe, Hirotoshi Dosaka-Akita, Masaharu Nishimura
    Cancer chemotherapy and pharmacology, 86, 1, 117, 127, Jul. 2020, [Peer-reviewed], [International Magazine]
    English, Scientific journal, PURPOSE: This study evaluated the efficacy and safety of platinum plus gemcitabine (P/G) combinations as postoperative adjuvant chemotherapies for non-small cell lung cancer. METHODS: Patients with postoperative stage IB-IIIA non-small cell lung cancer were randomly assigned to receive either cisplatin plus gemcitabine (GP arm) or carboplatin plus gemcitabine (GC arm) every 3 weeks for four cycles. The primary endpoint was 2-year disease-free survival (DFS). Secondary endpoints were safety, feasibility, overall survival (OS), and biomarker analyses. RESULTS: A total of 102 patients were randomized (stage IB, 22%; II, 36%; IIIA, 42%; histology: 74% adenocarcinoma). Of the 51 patients in each arm, 37 (73%) completed 4 cycles. During follow-up (median 5.8 years; range 0.1-9.7 years), estimated DFS and OS rates at 2 years were 59.6% and 86.3% with GP and 68.0% and 86.3% with GC, respectively. No significant difference in DFS was noted between arms (P = 0.163), although 3-, 4-, and 5-year DFS rates were higher with GC. Hematological toxic effects were comparable and non-hematological toxic effects were infrequent. DFS was significantly higher in the excision repair cross-complementation group 1 (ERCC1)-low group than in the ERCC1-high group for the GP arm (P = 0.045). CONCLUSION: Both P/G combination regimens were feasible and well-tolerated, and thus may represent valid options for postoperative adjuvant treatment of non-small cell lung cancer. Although no significant differences in DFS were evident between regimens, the present data favor the adoption of GC for further evaluation. CLINICAL TRIAL REGISTRATION: UMIN-CTR ( https://www.umin.ac.jp/ctr/ ) identifier: UMIN000000913.
  • がん遺伝子パネル検査の二次的所見の開示希望に関わる因子の検討 北海道大学での症例をもとに
    吉岡 正博, 山田 崇弘, 柴田 有香, 近藤 知大, 林 秀幸, 西原 広史, 矢部 一郎, 秋田 弘俊, 武藤 学, 木下 一郎, 小杉 真司
    日本遺伝カウンセリング学会誌, 41, 2, 75, 75, 日本遺伝カウンセリング学会, Jun. 2020
    Japanese
  • Evaluating the immunoproteasome as a potential therapeutic target in cisplatin-resistant small cell and non-small cell lung cancer.
    Tetsuaki Shoji, Eiki Kikuchi, Junko Kikuchi, Yuta Takashima, Megumi Furuta, Hirofumi Takahashi, Kosuke Tsuji, Makie Maeda, Ichiro Kinoshita, Hirotoshi Dosaka-Akita, Jun Sakakibara-Konishi, Satoshi Konno
    Cancer chemotherapy and pharmacology, 85, 5, 843, 853, 30 Mar. 2020, [Peer-reviewed], [International Magazine]
    English, Scientific journal, PURPOSE: We evaluated the expression of proteasome subunits to assess whether the proteasome could be a therapeutic target in cisplatin-resistant lung cancer cells. METHODS: Cisplatin-resistant (CR) variants were established from three non-small cell lung cancer (NSCLC) cell lines (A549, H1299, and H1975) and two small cell lung cancer (SCLC) cell lines (SBC3 and SBC5). The expression of proteasome subunits, the sensitivity to immunoproteasome inhibitors, and 20S proteasomal proteolytic activity were examined in the CR variants of the lung cancer cell lines. RESULTS: All five CR cell lines highly expressed one or both of the immunoproteasome subunit genes, PSMB8 and PSMB9, while no clear trend was observed in the expression of constitutive proteasome subunits. The CR cells expressed significantly higher levels of PSMB8 and PSMB9 proteins, as well. The CR variants of the H1299 and SBC3 cell lines were more sensitive to immunoproteasome inhibitors, and had significantly more proteasomal proteolytic activity than their parental counterparts. CONCLUSIONS: The immunoproteasome may be an effective therapeutic target in a subset of CR lung cancers. Proteasomal proteolytic activity may be a predictive marker for the efficacy of immunoproteasome inhibitors in cisplatin-resistant SCLC and NSCLC.
  • [Coexistence of IgG4-related autoimmune hepatitis and inflammatory pseudotumors of the liver:a case report].
    Yasuyo Adachi, Norikazu Iwata, Yasushi Adachi, Hiroko Nakamura, Takefumi Kikuchi, Masahiro Nakamura, Hiroaki Mita, Yukinari Yoshida, Ichiro Kinoshita, Yoshifumi Ishii, Takao Endo
    Nihon Shokakibyo Gakkai zasshi = The Japanese journal of gastro-enterology, 117, 6, 532, 541, 2020, [Domestic magazines]
    Japanese, Scientific journal, IgG4-related autoimmune hepatitis (IgG4-AIH) is characterized by hepatic inflammation and is considered an IgG4-related disease. Several inflammatory pseudotumors (IPTs) are also considered as IgG4-related diseases;however, there have been no reports of cases wherein both diseases occurred concurrently. An older adult with liver dysfunction was admitted to the hospital and was diagnosed with IgG4-AIH following a liver biopsy;IgG4-positive plasma cell infiltration in the portal tract and high serum IgG4 concentration were detected. A few months following biopsy, imaging studies revealed two IPTs in the liver. The patient was diagnosed with cryptogenic organized pneumonia several months after imaging and was treated with steroids in a different hospital. Her liver dysfunction improved, and one of the two IPTs disappeared in response to steroid treatment. The following is an account of a rare case of IgG4-AIH with IPTs of the liver.
  • Bromodomain and extraterminal domain inhibition synergizes with WEE1-inhibitor AZD1775 effect by impairing nonhomologous end joining and enhancing DNA damage in nonsmall cell lung cancer.
    Takashima Y, Kikuchi E, Kikuchi J, Suzuki M, Kikuchi H, Maeda M, Shoji T, Furuta M, Kinoshita I, Dosaka-Akita H, Sakakibara-Konishi J, Konno S
    International journal of cancer, 146, 4, 1114, 1124, Jun. 2019, [Peer-reviewed], [International Magazine]
    English, Scientific journal, Bromodomain and extraterminal domain (BET) inhibitors are broadly active against distinct types of cancer, including nonsmall cell lung cancer (NSCLC). Previous studies have addressed the effect of BET-inhibiting drugs on the expression of oncogenes such as c-Myc, but DNA damage repair pathways have also been reported to be involved in the efficacy of these drugs. AZD1775, an inhibitor of the G2-M cell cycle checkpoint kinase WEE1, induces DNA damage by promoting premature mitotic entry. Thus, we hypothesized that BET inhibition would increase AZD1775-induced cytotoxicity by impairing DNA damage repair. Here, we demonstrate that combined inhibition of BET and WEE1 synergistically suppresses NSCLC growth both in vitro and in vivo. Two BET inhibitors, JQ1 and AZD5153, increased and prolonged AZD1775-induced DNA double-strand breaks (DSBs) and concomitantly repressed genes related to nonhomologous end joining (NHEJ), including XRCC4 and SHLD1. Furthermore, pharmaceutical inhibition of BET or knockdown of the BET protein BRD4 markedly diminished NHEJ activity, and the BET-inhibitor treatment also repressed myelin transcription factor 1 (MYT1) expression and promoted mitotic entry with subsequent mitotic catastrophe when combined with WEE1 inhibition. Our findings reveal that BET proteins, predominantly BRD4, play an essential role in DSB repair through the NHEJ pathway, and further suggest that combined inhibition of BET and WEE1 could serve as a novel therapeutic strategy for NSCLC.
  • Efficacy of additional dexamethasone administration for the attenuation of paclitaxel-associated acute pain syndrome.
    Saito Y, Kobayashi M, Yamada T, Sakakibara-Konishi J, Shinagawa N, Kinoshita I, Dosaka-Akita H, Iseki K
    Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer, 28, 1, 221, 227, Apr. 2019, [Peer-reviewed], [International Magazine]
    English, Scientific journal, PURPOSE: Paclitaxel-associated acute pain syndrome (P-APS) affects 80% of patients undergoing therapy. Although it has been shown that prednisone administration for 5 days relieves P-APS, detailed results have not been reported thus far. Therefore, in this study, we evaluated the preventive effect of dexamethasone (DEX) administration against P-APS. METHODS: A total of 60 patients who received carboplatin (area under the curve; AUC = 5-6) plus paclitaxel (200 mg/m2) (plus bevacizumab 15 mg/kg, if non-squamous carcinoma of lung) were enrolled. Eight milligrams of DEX was orally administered on days 2 and 3 to the DEX group patients, and the frequency, severity, duration of P-APS, and other adverse effects in the first cycle were retrospectively evaluated and compared to those observed in control group patients, who were not administered DEX on days 2 and 3. RESULTS: No difference in terms of patient characteristics, except for type of cancer, was observed between groups. The results showed that the frequency of all grade P-APS was approximately 70% and there was no difference between groups. Frequency of ≥ G2 P-APS was 40% in the control group and 14% in the DEX group, demonstrating a significant reduction. Duration of P-APS was 5.8 days in the control group and 4.3 days in the DEX group, which tended to become shorter following additional DEX administration, although this was not significant. Adverse effects other than P-APS induced by chemotherapy were similar between the two groups. CONCLUSION: Additional DEX administration is safe and useful for the attenuation of the severity of P-APS.
  • DLL3 regulates the migration and invasion of small cell lung cancer by modulating Snail.
    Furuta M, Kikuchi H, Shoji T, Takashima Y, Kikuchi E, Kikuchi J, Kinoshita I, Dosaka-Akita H, Sakakibara-Konishi J
    Cancer science, 110, 5, 1599, 1608, Mar. 2019, [Peer-reviewed], [International Magazine]
    English, Scientific journal, Delta-like protein 3 (DLL3) is a ligand of Notch signaling, which mediates cell-fate decisions and is tumor-suppressive or oncogenic depending on the cellular context. Previous studies show that DLL3 is highly expressed in small cell lung cancer (SCLC) but not in normal lung tissue, suggesting that DLL3 might be associated with neuroendocrine tumorigenesis. However, its role in SCLC remains unclear. To investigate the role of DLL3 in tumorigenesis in SCLC, we performed loss-of-function and gain-of-function assays using SCLC cell lines. In vitro analysis of cell migration and invasion by transwell assay showed that DLL3 knockdown reduced migration and invasion of SCLC cells, whereas DLL3 overexpression increased these activities. In addition, DLL3 positively regulated SNAI1 expression and knockdown of SNAI1 attenuated the migration and invasion ability of SCLC cells. Moreover, upregulated DLL3 expression induced subcutaneous tumor growth in mouse models. These results indicate that DLL3 promoted tumor growth, migration and invasion in an SCLC model by modulating SNAI1/Snail.
  • [Paclitaxel-associated Acute Pain Syndrome Similarly Occurs in the Patients with or without Previously Administered Non-steroidal Anti-inflammatory Drugs Prior to Paclitaxel Administration].
    Saito Y, Yamada T, Kobayashi M, Sakakibara-Konishi J, Shinagawa N, Kinoshita I, Dosaka-Akita H, Iseki K
    Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan, 139, 12, 1601, 1608, 2019, [Peer-reviewed], [Domestic magazines]
    Japanese, Scientific journal, Paclitaxel (PTX)-associated acute pain syndrome (P-APS) is characterized by disabling but transient arthralgia and myalgia in up to 80% of patients administered with PTX. Non-steroidal anti-inflammatory drugs (NSAIDs) are widely administered to patients with cancer who have pain or fever, and are mainly used to manage P-APS. In this study, we investigated how P-APS appear in the patients who were administered NSAIDs prior to PTX injection. The incidence or severity and duration of P-APS in patients previously administered NSAIDs were compared to those of patients who were not administered NSAIDs. The relationship between previously administered NSAIDs and rescue administration for the relief of P-APS was also evaluated. It was revealed that the incidence and duration of P-APS were 72% and 4.67±2.30 d, respectively, in the control group and 84% and 6.19±3.30 d, respectively, in the NSAIDs group. There was no significant difference in the incidence and duration and the severity of P-APS between the two groups. Patients who were previously administered NSAIDs tended to obtain less pain relief from NSAIDs administered as rescue medications, and needed other medication. Univariate and multivariate analysis revealed no correlation between previously administered NSAIDs or patient characteristics and the incidence of P-APS. In this study, it was found that clinical condition that needs NSAIDs and previously administered NSAIDs prior to PTX injection do not affect the incidence, severity, and duration of P-APS. These results will help in educating patients about their medications and will contribute to the management of P-APS.
  • EGFR-TKI初期耐性におけるPD-L1発現や腫瘍浸潤Tリンパ球についての検討
    高島 雄太, 榊原 純, 畑中 豊, 畑中 佳奈子, 大原 克仁, 大泉 聡史, 樋田 泰浩, 加賀 基知三, 木下 一郎, 秋田 弘俊, 松野 吉宏, 品川 尚文
    肺癌, 58, 6, 633, 633, (NPO)日本肺癌学会, Oct. 2018, [Peer-reviewed]
    Japanese
  • Late Onset of Non-islet Cell Tumor Hypoglycemia Managed via Multidisciplinary Treatment in a Patient with a Solitary Fibrous Tumor.
    Takeuchi S, Goda T, Taguchi J, Douhata Y, Honma R, Ariga S, Ohhara Y, Shimizu Y, Kinoshita I, Fukuda I, Nagashima Y, Akita H
    Internal medicine (Tokyo, Japan), 57, 16, 2431, 2436, Aug. 2018, [Peer-reviewed]
  • Early prediction of lenvatinib treatment efficacy by using 18F-FDG PET/CT in patients with unresectable or advanced thyroid carcinoma that is refractory to radioiodine treatment: a protocol for a non-randomized single-arm multicenter observatio
    Takeuchi S, Shiga T, Hirata K, Taguchi J, Magota K, Ariga S, Gouda T, Ohhara Y, Homma R, Shimizu Y, Kinoshita I, Tsuji Y, Homma A, Iijima H, Tamaki N, Dosaka-Akita H
    BMJ open, 8, 8, e021001, Aug. 2018, [Peer-reviewed], [International Magazine]
    English, Scientific journal, INTRODUCTION: Lenvatinib, an oral molecular targeted drug, is used to treat patients with unresectable or advanced thyroid carcinoma that is refractory to radioiodine treatment. Effective methods for evaluating molecular targeted drugs are a critical unmet need owing to their expensive costs and unique adverse events. The aim of this study is to determine whether 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT at 1 week after commencing lenvatinib can predict treatment outcomes. DESIGN AND METHODS: This study is planned as a non-randomised single-arm multicentre study; patients with pathologically confirmed differentiated thyroid carcinoma (DTC) with lesions that are refractory to radioiodine treatment are eligible. The main exclusion criteria are medullary or anaplastic carcinoma, prior treatment with chemotherapy, poor general condition and thromboembolism-requiring treatment. Patients to be included in the study will be treated with lenvatinib and undergo FDG-PET/CT examination twice: before and 1 week after the initiation of treatment. Contrast-enhanced CT, the gold standard for evaluation, will be performed at least 4 weeks after the initiation of treatment. The primary objective is to evaluate the ability of the lesion maximum standard uptake value for FDG PET/CT performed 1 week after the initiation of treatment to predict outcomes compared with the response evaluation obtained via contrast-enhanced CT performed at least 4 weeks after the initiation of treatment. ETHICS AND DISSEMINATION: This study is conducted in accordance with the Declaration of Helsinki and has received ethical approval from the institutional review board of the Hokkaido University Hospital (approval number: 015-402). The results of this study will be disseminated through a presentation at a conference and the publication of the data in a peer-reviewed journal. The study will be implemented and reported in line with the SPIRIT statement. TRIAL REGISTRATION NUMBER: UMIN000022592.
  • Stereotactic body radiotherapy to treat small lung lesions clinically diagnosed as primary lung cancer by radiological examination: A prospective observational study.
    Inoue T, Katoh N, Ito YM, Kimura T, Nagata Y, Kuriyama K, Onishi H, Yoshitake T, Shioyama Y, Iizuka Y, Inaba K, Konishi K, Kokubo M, Karasawa K, Kozuka T, Tanaka K, Sakakibara-Konishi J, Kinoshita I, Shirato H
    Lung cancer (Amsterdam, Netherlands), 122, 107, 112, Aug. 2018, [Peer-reviewed], [International Magazine]
    English, Scientific journal, OBJECTIVES: Even with advanced image guidance, biopsies occasionally fail to diagnose small lung lesions, which are highly suggestive of primary lung cancer by radiological examination. The aim of this study was to evaluate the outcome of stereotactic body radiotherapy (SBRT) to treat small lung lesions clinically diagnosed as primary lung cancer. MATERIALS AND METHODS: This is a prospective, multi-institutional observation study. Strict inclusion and exclusion criteria were determined in a nation-wide consensus meeting and used to include patients who were clinically diagnosed with primary lung cancer using precise imaging modalities, for whom further surgical intervention was not feasible, who refused watchful waiting, and who were highly tolerable of SBRT with informed consent. SBRT was performed with 48 Gy in 4 fractions at the tumor isocenter. RESULTS: From August 2009 to August 2014, 62 patients from 11 institutions were enrolled. Their median age was 80 years. The tumors ranged in size from 9 to 30 mm in diameter (median, 18 mm). The median follow-up interval was 55 months. The 3-year overall survival rate was 83.3% (95% confidence interval (CI) 71.1-90.7%) for all the patients and 94.7% (95% CI 68.1-99.2%) for the patients younger than 75 years. Local failure, regional lymph node metastases and distant metastases occurred in 4 (6.4%), 3 (4.8%) and 11 (17.7%) patients, respectively. Grades 3 and 4 toxicities were observed in 8 (12.9%) patients and 1 (1.6%) patient, respectively. No grade 5 toxicities were observed. CONCLUSIONS: SBRT is safe and effective for patients with small lung lesions clinically diagnosed as primary lung cancer that satisfied the proposed strict indication criteria as previously reported. A prospective interventional study is required to ascertain if SBRT is an alternative strategy for these patients.
  • Genomic testing for pancreatic cancer in clinical practice as real-world evidence.
    Hayashi H, Tanishima S, Fujii K, Mori R, Okamura Y, Yanagita E, Matsuoka R, Amano T, Kinoshita I, Komatsu Y, Dosaka-Akita H, Nishihara H
    Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.], 18, 6, 647, 654, Jul. 2018, [Peer-reviewed], [International Magazine]
    English, Scientific journal, BACKGROUND: Precision medicine guided by comprehensive genome sequencing represents a potential treatment strategy for pancreatic cancer. However, clinical sequencing for pancreatic cancer entails several practical difficulties. We have launched an in-house clinical sequencing system and started genomic testing for patients with cancer in clinical practice. We have analyzed the clinical utility of this system in pancreatic cancer. METHODS: We retrospectively reviewed 20 patients with pancreatic cancer who visited our division. Genomic DNA was extracted from both tumor tissue and peripheral blood mononuclear cells obtained from the patients. We performed a comprehensive genomic testing using targeted amplicon sequencing for 160 cancer-related genes. The primary endpoints were the detection rates of potential actionable and druggable gene alterations. The secondary endpoints were the detection rate of secondary germline findings, the rate of re-biopsy required for genome sequencing, survival time after the initial visit (post-sequencing survival time), and turnaround time. RESULTS: Although re-biopsy was required for 25% (5/20) of all patients, genomic testing was performed in all patients. Actionable and druggable gene alterations were detected in 100% (20/20) and 35% (7/20) of patients, respectively, whereas secondary germline findings were detected in 5% (1/20) of patients. The median turnaround times for physicians and patients were 20 and 26 days, respectively. The median post-sequencing survival time was 10.3 months. Only 10% (2/20) of all patients were treated with therapeutic agents based on the outcomes of genomic testing. CONCLUSIONS: The clinical application of comprehensive genomic testing for pancreatic cancer was feasible and promising in clinical practice.
  • Clinicopathologic Features and Immune Microenvironment of Non-Small-cell Lung Cancer With Primary Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors.
    Takashima Y, Sakakibara-Konishi J, Hatanaka Y, Hatanaka KC, Ohhara Y, Oizumi S, Hida Y, Kaga K, Kinoshita I, Dosaka-Akita H, Matsuno Y, Nishimura M
    Clinical lung cancer, 19, 4, 352, 359.e1, Jul. 2018, [Peer-reviewed]
  • Updated survival outcomes of NEJ005/TCOG0902: a randomised phase II study of concurrent versus sequential alternating gefitinib and chemotherapy in previously untreated non-small cell lung cancer with sensitive EGFR mutations.
    Satoshi Oizumi, Shunichi Sugawara, Koichi Minato, Toshiyuki Harada, Akira Inoue, Yuka Fujita, Makoto Maemondo, Satoshi Watanabe, Kazuhiko Ito, Akihiko Gemma, Yoshiki Demura, Shinichi Fukumoto, Hiroshi Isobe, Ichiro Kinoshita, Satoshi Morita, Kunihiko Kobayashi, Koichi Hagiwara, Keisuke Aiba, Toshihiro Nukiwa
    ESMO open, 3, 2, e000313, 2018, [International Magazine]
    English, Scientific journal, Background: The North-East Japan Study Group (NEJ) 005/Tokyo Cooperative Oncology Group (TCOG) 0902 study has reported that first-line concurrent and sequential alternating combination therapies of an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (gefitinib) plus platinum-based doublet chemotherapy (carboplatin/pemetrexed) offer promising efficacy with predictable toxicities for patients with EGFR-mutant non-small cell lung cancer. However, overall survival (OS) data were insufficient in the primary report because of the lack of death events. Patients and methods: Progression-free survival (PFS) and OS were re-evaluated at the final data cut-off point (March 2017) for the entire population (n=80). Results: At the median follow-up time of 35.6 months, 88.8% of patients had progressive disease and 77.5% of patients had died. Median PFS was 17.5 months for the concurrent regimen and 15.3 months for the sequential alternating regimen (P=0.13). Median OS was 41.9 and 30.7 months, respectively (P=0.036). Updated response rates were similar in both groups (90.2% and 82.1%, respectively; P=0.34). Patients with Del19 tumours displayed relatively better OS (median: 45.3 vs 33.3 months, respectively) than those with L858R (31.4 vs 28.9 months, respectively). No severe adverse events, including interstitial lung disease, occurred in the period since the primary report. Conclusions: This updated analysis confirms that PFS is improved with first-line combination therapy compared with gefitinib monotherapy and that the concurrent regimen, in particular, offers an OS benefit of 42 months in the EGFR-mutated setting. Our ongoing NEJ009 study will clarify whether this combination strategy can be incorporated into routine clinical practice. Trial registration number: UMIN C000002789, Post-results.
  • A phase II study of carboplatin, pemetrexed, and bevacizumab followed by erlotinib and bevacizumab maintenance for nonsquamous non-small cell lung cancer with wild-type EGFR (HOT1101)               
    Taichi Takashina, Hajime Asahina, Satoshi Oizumi, Noriyuki Yamada, Masao Harada, Kei Takamura, Hiroshi Yokouchi, Toshiyuki Harada, Osamu Honjo, Takahiro Ogi, Naoto Morikawa, Ichiro Kinoshita, Ryoichi Honda, Kosuke Nakano, Kenya Kanazawa, Toraji Amano, Hirotoshi Dosaka‐Akita, Hiroshi Isobe, Masaharu Nishimura on behalf of, Hokkaido Lung, Cancer Clinical, Study Group
    Int J Clin Oncol., 2018, [Peer-reviewed]
  • Numb has distinct function in lung adenocarcinoma and squamous cell carcinoma.               
    Kikuchi H, Sakakibara-Konishi J, Furuta M, Kikuchi E, Kikuchi J, Oizumi S, Hida Y, Kaga K, Kinoshita I, Dosaka-Akita H, Nishimura M
    Oncotarget., 9, 29379, 29391, 2018, [Peer-reviewed]
  • EGFR遺伝子変異とEGFRチロシンキナーゼ阻害薬(EGFR-TKI)に対する反応が異なる肺3重癌の1例               
    合田 智宏, 木下 一郎, 堂畑 雄一, 有賀 伸, 田口 純, 本間 理央, 竹内 啓, 清水 康, 秋田 弘俊, 品川 尚文, 樋田 泰浩, 加賀 基知三
    肺癌, 57, 7, 915, 915, (NPO)日本肺癌学会, Dec. 2017, [Peer-reviewed]
    Japanese
  • A randomized phase II trial of erlotinib vs. S-1 as a third- or fourth-line therapy for patients with wild-type EGFR non-small cell lung cancer (HOT1002)
    Yasuyuki Ikezawa, Hajime Asahina, Satoshi Oizumi, Masahiro Watanabe, Kei Takamura, Yasutaka Kawai, Noriyuki Yamada, Toshiyuki Harada, Ichiro Kinoshita, Yuka Fujita, Eisaku Miyauchi, Takahiro Ogi, Toraji Amano, Megumi Furuta, Jun Sakakibara-Konishi, Hiroshi Nishihara, Hirotoshi Dosaka-Akita, Hiroshi Isobe, Masaharu Nishimura
    CANCER CHEMOTHERAPY AND PHARMACOLOGY, 80, 5, 955, 963, Nov. 2017, [Peer-reviewed]
    English, Scientific journal
  • Thymoma-associated multi-organ autoimmunity: two cases and a review of the literature
    K. Shiba, Y. Fujita, H. Miyazawa, K. Muramatsu, M. Watanabe, M. Nishimura, S. Shinkuma, T. Nomura, W. Nishie, J. Taguchi, I. Kinoshita, H. Shimizu
    JOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY AND VENEREOLOGY, 31, 7, E324, E326, Jul. 2017, [Peer-reviewed]
    English
  • Autophagy-dependent regulation of tumor metastasis by myeloid cells
    Masahisa Jinushi, Tomoko Morita, Zhihang Xu, Ichiro Kinoshita, Hirotoshi Dosaka-Akita, Hideo Yagita, Yutaka Kawakami
    PLOS ONE, 12, 7, e0179357, Jul. 2017, [Peer-reviewed]
    English, Scientific journal
  • Combined antitumor effect of gamma-secretase inhibitor and ABT-737 in Notch-expressing non-small cell lung cancer
    Jun Sakakibara-Konishi, Yasuyuki Ikezawa, Satoshi Oizumi, Junko Kikuchi, Eiki Kikuchi, Hidenori Mizugaki, Ichiro Kinoshita, Hirotoshi Dosaka-Akita, Masaharu Nishimura
    INTERNATIONAL JOURNAL OF CLINICAL ONCOLOGY, 22, 2, 257, 268, Apr. 2017, [Peer-reviewed]
    English, Scientific journal
  • Premedication with intravenous magnesium has a protective effect against cisplatin-induced nephrotoxicity
    Yoshitaka Saito, Masaki Kobayashi, Takehiro Yamada, Kumiko Kasashi, Rio Honma, Satoshi Takeuchi, Yasushi Shimizu, Ichiro Kinoshita, Hirotoshi Dosaka-Akita, Ken Iseki
    SUPPORTIVE CARE IN CANCER, 25, 2, 481, 487, Feb. 2017, [Peer-reviewed]
    English, Scientific journal
  • Intravenous magnesium premedication has prophylactic efficacy against cisplatin-induced nephrotoxicity without an influence on serum magnesium level.               
    Saito Y, Kobayashi M, Yamada T, Kasashi K, Honma R, Takeuchi S, Shimizu Y, Kinoshita I, Dosaka-Akita H, Iseki K
    Support Care Cancer., 25, 481, 487, 2017, [Peer-reviewed]
  • A phase II study of bevacizumab with carboplatin-pemetrexed in non-squamous non-small cell lung carcinoma patients with malignant pleural effusions: North East Japan Study Group Trial NEJ013A
    Kazuhiro Usui, Shunichi Sugawara, Masaru Nishitsuji, Yuka Fujita, Akira Inoue, Atsuto Mouri, Hiroshi Watanabe, Hiroshi Sakai, Ichiro Kinoshita, Yoshihito Ohhara, Makoto Maemondo, Hiroshi Kagamu, Koichi Hagiwara, Kunihiko Kobayashi
    LUNG CANCER, 99, 131, 136, Sep. 2016, [Peer-reviewed]
    English, Scientific journal
  • Role of targeted therapy in metastatic colorectal cancer
    Yoshihito Ohhara, Naoki Fukuda, Satoshi Takeuchi, Rio Honma, Yasushi Shimizu, Ichiro Kinoshita, Hirotoshi Dosaka-Akita
    WORLD JOURNAL OF GASTROINTESTINAL ONCOLOGY, 8, 9, 642, 655, Sep. 2016, [Peer-reviewed]
    English
  • Phase II study of carboplatin/ pemetrexed/bevacizumab for non-squamous NSCLC with carcinomatous pleuritis (NEJ013A)
    Miyauchi Eisaku, Usui Kazuhiro, Sugawara Shunichi, Nishitsuji Masaru, Fujita Yuka, Mouri Atsuto, Watanabe Hiroshi, Sakai Hiroshi, Kinoshita Ichiro, Hagiwara Koichi
    ANNALS OF ONCOLOGY, 27, 01 Jul. 2016, [Peer-reviewed]
  • Combined inhibition of EZH2 and histone deacetylases as a potential epigenetic therapy for non-small-cell lung cancer cells
    Taichi Takashina, Ichiro Kinoshita, Junko Kikuchi, Yasushi Shimizu, Jun Sakakibara-Konishi, Satoshi Oizumi, Masaharu Nishimura, Hirotoshi Dosaka-Akita
    CANCER SCIENCE, 107, 7, 955, 962, Jul. 2016, [Peer-reviewed]
    English, Scientific journal
  • Novel signaling collaboration between TGF-beta and adaptor protein Crk facilitates EMT in human lung cancer
    Aiman Z. Elmansuri, Mishie A. Tanino, Roshan Mahabir, Lei Wang, Taichi Kimura, Hiroshi Nishihara, Ichiro Kinoshita, Hirotoshi Dosaka-Akita, Masumi Tsuda, Shinya Tanaka
    ONCOTARGET, 7, 19, 27094, 27107, May 2016, [Peer-reviewed]
    English, Scientific journal
  • The Coordinated Actions of TIM-3 on Cancer and Myeloid Cells in the Regulation of Tumorigenicity and Clinical Prognosis in Clear Cell Renal Cell Carcinomas
    Yoshihiro Komohara, Tomoko Morita, Dorcas A. Annan, Hasita Horlad, Koji Ohnishi, Sohsuke Yamada, Toshiyuki Nakayama, Shohei Kitada, Shinya Suzu, Ichiro Kinoshita, Hirotoshi Dosaka-Akita, Koichi Akashi, Motohiro Takeya, Masahisa Jinushi
    CANCER IMMUNOLOGY RESEARCH, 3, 9, 999, 1007, Sep. 2015, [Peer-reviewed]
    English, Scientific journal
  • Randomized phase II trial comparing amrubicin with re-challenge of platinum doublet in patients with sensitive-relapsed small-cell lung cancer: North Japan Lung Cancer Study Group trial 0702
    Akira Inoue, Shunichi Sugawara, Makoto Maemondo, Yoshiaki Mori, Satoshi Oizumi, Masao Harada, Kageaki Taima, Naoto Morikawa, Takashi Ishida, Ichiro Kinoshita, Hiroshi Watanabe, Toshiro Suzuki, Taku Nakagawa, Ryota Saito, Toshihiro Nukiwa
    LUNG CANCER, 89, 1, 61, 65, Jul. 2015, [Peer-reviewed]
    English, Scientific journal
  • Feasibility and efficacy of induction docetaxel, cisplatin, and 5-fluorouracil chemotherapy combined with concurrent weekly cisplatin chemoradiotherapy for locally advanced head and neck squamous cell carcinoma
    Takatsugu Mizumachi, Akihiro Homma, Tomohiko Kakizaki, Tomohiro Sakashita, Satoshi Kano, Hiromitsu Hatakeyama, Kazuhiko Tsuchiya, Koichi Yasuda, Rikiya Onimaru, Hiroki Shirato, Jun Taguchi, Yasushi Shimizu, Ichiro Kinoshita, Hirotoshi Akita, Satoshi Fukuda
    INTERNATIONAL JOURNAL OF CLINICAL ONCOLOGY, 20, 3, 431, 437, Jun. 2015, [Peer-reviewed]
    English, Scientific journal
  • Factors associated with a poor response to gefitinib in the NEJ002 study: Smoking and the L858R mutation
    Tatsuro Fukuhara, Makoto Maemondo, Akira Inoue, Kunihiko Kobayashi, Shunichi Sugawara, Satoshi Oizumi, Hiroshi Isobe, Akihiko Gemma, Masao Harada, Hirohisa Yoshizawa, Ichiro Kinoshita, Yuka Fujita, Yasuo Saijo, Koichi Hagiwara, Satoshi Morita, Toshihiro Nukiwa
    LUNG CANCER, 88, 2, 181, 186, May 2015, [Peer-reviewed]
    English, Scientific journal
  • Expression of Fucosyltransferase 8 Is Associated with an Unfavorable Clinical Outcome in Non-Small Cell Lung Cancers
    Rio Honma, Ichiro Kinoshita, Eiji Miyoshi, Utano Tomaru, Yoshihiro Matsuno, Yasushi Shimizu, Satoshi Takeuchi, Yuka Kobayashi, Kichizo Kaga, Naoyuki Taniguchi, Hirotoshi Dosaka-Akita
    ONCOLOGY, 88, 5, 298, 308, 2015, [Peer-reviewed]
    English, Scientific journal
  • Low expression levels of microRNA-124-5p correlated with poor prognosis in colorectal cancer via targeting of SMC4
    Takafumi Jinushi, Yoshihiko Shibayama, Ichiro Kinoshita, Satoshi Oizumi, Masahisa Jinushi, Tadahiro Aota, Toshiyuki Takahashi, Shoichi Horita, Hirotoshi Dosaka-Akita, Ken Iseki
    CANCER MEDICINE, 3, 6, 1544, 1552, Dec. 2014, [Peer-reviewed]
    English, Scientific journal
  • Phase II trial of carboplatin and pemetrexed as first-line chemotherapy for non-squamous non-small cell lung cancer, and correlation between the efficacy/toxicity and genetic polymorphisms associated with pemetrexed metabolism: Hokkaido Lung Cancer Clinical Study Group Trial (HOT) 0902
    Kenya Kanazawa, Hiroshi Yokouchi, Xintao Wang, Takashi Ishida, Yuka Fujita, Satoru Fujiuchi, Toshiyuki Harada, Masao Harada, Kei Takamura, Satoshi Oizumi, Ichiro Kinoshita, Yutaka Katsuura, Osamu Honjo, Tetsuya Kojima, Hirotoshi Dosaka-Akita, Hiroshi Isobe, Mitsuru Munakata, Masaharu Nishimura
    CANCER CHEMOTHERAPY AND PHARMACOLOGY, 74, 6, 1149, 1157, Dec. 2014, [Peer-reviewed]
    English, Scientific journal
  • Expression of α1,6-fucosyltransferase is associated with prognosis and histology in non-small cell lung cancers               
    Honma R, Kinoshita I, Miyoshi E, Tomaru U, Matsuno Y, Shimizu Y, Takeuchi S, Kobayashi Y, Kaga K, Taniguchi N, Akita DH
    Oct. 2014, [Peer-reviewed]
    English, Scientific journal
  • HPV-associated lung cancers: an international pooled analysis
    Camille Ragin, Monisola Obikoya-Malomo, Sungjin Kim, Zhengjia Chen, Rafael Flores-Obando, Denise Gibbs, Chihaya Koriyama, Francisco Aguayo, Jill Koshiol, Neil E. Caporaso, Giovanna E. Carpagnano, Marco Ciotti, Hirotoshi Dosaka-Akita, Masashi Fukayama, Akiteru Goto, Demetrios A. Spandidos, Vassilis Gorgoulis, Danielle A. M. Heideman, Robert A. A. van Boerdonk, Kenzo Hiroshima, Reika Iwakawa, Nikolaos G. Kastrinakis, Ichiro Kinoshita, Suminori Akiba, Maria T. Landi, H. Eugene Liu, Jinn-Li Wang, Ranee Mehra, Fadlo R. Khuri, Wan-Teck Lim, Taofeek K. Owonikoko, Suresh Ramalingam, Emmanuela Sarchianaki, Kari Syrjanen, Ming-Sound Tsao, Jenna Sykes, Siew Wan Hee, Jun Yokota, Apostolos Zaravinos, Emanuela Taioli
    CARCINOGENESIS, 35, 6, 1267, 1275, Jun. 2014, [Peer-reviewed]
    English, Scientific journal
  • Cancer Stem-like Cells Derived from Chemoresistant Tumors Have a Unique Capacity to Prime Tumorigenic Myeloid Cells
    Tsunaki Yamashina, Muhammad Baghdadi, Akihiro Yoneda, Ichiro Kinoshita, Shinya Suzu, Hirotoshi Dosaka-Akita, Masahisa Jinushi
    CANCER RESEARCH, 74, 10, 2698, 2709, May 2014, [Peer-reviewed]
    English, Scientific journal
  • Randomized phase II study of concurrent gefitinib and chemotherapy versus sequential alternating gefitinib and chemotherapy in previously untreated non-small cell lung cancer (NSCLC) with sensitive EGFR mutations: NEJ005/TCOG0902.
    Satoshi Oizumi, Shunichi Sugawara, Koichi Minato, Toshiyuki Harada, Akira Inoue, Yuka Fujita, Makoto Maemondo, Hirohisa Yoshizawa, Kazuhiko Ito, Akihiko Gemma, Masaru Nishitsuji, Masao Harada, Hiroshi Isobe, Ichiro Kinoshita, Satoshi Morita, Kunihiko Kobayashi, Koichi Hagiwara, Minoru Kurihara, Toshihiro Nukiwa
    JOURNAL OF CLINICAL ONCOLOGY, 32, 15, May 2014, [Peer-reviewed]
    English
  • CD133 expression: a potential prognostic marker for non-small cell lung cancers
    Hidenori Mizugaki, Jun Sakakibara-Konishi, Junko Kikuchi, Jun Moriya, Kanako C. Hatanaka, Eiki Kikuchi, Ichiro Kinoshita, Satoshi Oizumi, Hirotoshi Dosaka-Akita, Yoshihiro Matsuno, Masaharu Nishimura
    INTERNATIONAL JOURNAL OF CLINICAL ONCOLOGY, 19, 2, 254, 259, Apr. 2014, [Peer-reviewed]
    English, Scientific journal
  • TIM-4 Glycoprotein-Mediated Degradation of Dying Tumor Cells by Autophagy Leads to Reduced Antigen Presentation and Increased Immune Tolerance
    Muhammad Baghdadi, Akihiro Yoneda, Tsunaki Yamashina, Hiroko Nagao, Yoshihiro Komohara, Shigenori Nagai, Hisaya Akiba, Marc Foretz, Hironori Yoshiyama, Ichiro Kinoshita, Hirotoshi Dosaka-Akita, Motohiro Takeya, Benoit Viollet, Hideo Yagita, Masahisa Jinushi
    IMMUNITY, 39, 6, 1070, 1081, Dec. 2013, [Peer-reviewed]
    English, Scientific journal
  • Updated overall survival results from a randomized phase III trial comparing gefitinib with carboplatin-paclitaxel for chemo-naive non-small cell lung cancer with sensitive EGFR gene mutations (NEJ002)
    A. Inoue, K. Kobayashi, M. Maemondo, S. Sugawara, S. Oizumi, H. Isobe, A. Gemma, M. Harada, H. Yoshizawa, I. Kinoshita, Y. Fujita, S. Okinaga, H. Hirano, K. Yoshimori, T. Harada, Y. Saijo, K. Hagiwara, S. Morita, T. Nukiwa
    ANNALS OF ONCOLOGY, 24, 1, 54, 59, Jan. 2013, [Peer-reviewed]
    English, Scientific journal
  • A phase II study of amrubicin as a third-line or fourth-line chemotherapy for patients with non-small cell lung cancer: Hokkaido Lung Cancer Clinical Study Group Trial (HOT) 0901.
    Toshiyuki Harada, Satoshi Oizumi, Kenichiro Ito, Kei Takamura, Eiki Kikuchi, Tomoya Kuda, Shunichi Sugawara, Aya Suzuki, Makoto Maemondo, Yuka Fujita, Ichiro Kinoshita, Akira Inoue, Fumihiro Hommura, Yutaka Katsuura, Hirotoshi Dosaka-Akita, Hiroshi Isobe, Masaharu Nishimura
    The oncologist, 18, 4, 439, 45, 2013, [Peer-reviewed], [International Magazine]
    English, Amrubicin, a third-generation synthetic anthracycline agent, has favorable clinical activity and acceptable toxicity for the treatment of patients with non-small cell lung cancer (NSCLC) and small cell lung cancer. We conducted this study to evaluate the efficacy and safety of amrubicin for advanced NSCLC patients as a third- or fourth-line therapy. Eligible patients had recurrent or refractory advanced NSCLC after second- or third-line therapy. Patients received amrubicin, 35 mg/m(2) i.v. on days 1-3 every 3 weeks. The primary endpoint was the disease control rate (DCR). Secondary endpoints were the overall survival (OS) time, progression-free survival (PFS) time, response rate, and toxicity profile. Of the 41 patients enrolled, 26 received amrubicin as a third-line and 15 received it as a fourth-line therapy. The median number of treatment cycles was two (range, 1-9). Objective responses were complete response (n = 0), partial response (n = 4), stable disease (n = 21), progressive disease (n = 15), and not evaluable (n = 1), resulting in a DCR of 61.0% (95% confidence interval, 46.0%-75.9%). The overall response rate was 9.8% (95% confidence interval, 0.6%-18.8%). The median PFS interval was 3.0 months, median OS time was 12.6 months, and 1-year survival rate was 53.7%. Grade 3 or 4 hematological toxicities were neutropenia (68%), anemia (12%), thrombocytopenia (12%), and febrile neutropenia (17%). Nonhematological toxicities were mild and reversible. No treatment-related deaths were observed. Amrubicin showed significant clinical activity with manageable toxicities as a third- or fourth-line therapy for patients with advanced NSCLC. This study provides relevant data for routine practice and future prospective trials evaluating third- or fourth-line treatment strategies for patients with advanced NSCLC.
  • Epigenetic therapy with 3-deazaneplanocin A, an inhibitor of the histone methyltransferase EZH2, inhibits growth of non-small cell lung cancer cells
    Junko Kikuchi, Taichi Takashina, Ichiro Kinoshita, Eiki Kikuchi, Yasushi Shimizu, Jun Sakakibara-Konishi, Satoshi Oizumi, Victor E. Marquez, Masaharu Nishimura, Hirotoshi Dosaka-Akita
    LUNG CANCER, 78, 2, 138, 143, Nov. 2012, [Peer-reviewed]
    English, Scientific journal
  • Tumor-infiltrating DCs suppress nucleic acid-mediated innate immune responses through interactions between the receptor TIM-3 and the alarmin HMGB1
    Shigeki Chiba, Muhammad Baghdadi, Hisaya Akiba, Hironori Yoshiyama, Ichiro Kinoshita, Hirotoshi Dosaka-Akita, Yoichiro Fujioka, Yusuke Ohba, Jacob V. Gorman, John D. Colgan, Mitsuomi Hirashima, Toshimitsu Uede, Akinori Takaoka, Hideo Yagita, Masahisa Jinushi
    NATURE IMMUNOLOGY, 13, 9, 832, 842, Sep. 2012, [Peer-reviewed]
    English, Scientific journal
  • Expression of Bim, Noxa, and Puma in non-small cell lung cancer
    Jun Sakakibara-Konishi, Satoshi Oizumi, Junko Kikuchi, Eiki Kikuchi, Hidenori Mizugaki, Ichiro Kinoshita, Hirotoshi Dosaka-Akita, Masaharu Nishimura
    BMC CANCER, 12, 286, Jul. 2012, [Peer-reviewed]
    English, Scientific journal
  • Quality of Life with Gefitinib in Patients with EGFR-Mutated Non-Small Cell Lung Cancer: Quality of Life Analysis of North East Japan Study Group 002 Trial
    Satoshi Oizumi, Kunihiko Kobayashi, Akira Inoue, Makoto Maemondo, Shunichi Sugawara, Hirohisa Yoshizawa, Hiroshi Isobe, Masao Harada, Ichiro Kinoshita, Shoji Okinaga, Terufumi Kato, Toshiyuki Harada, Akihiko Gemma, Yasuo Saijo, Yuki Yokomizo, Satoshi Morita, Koichi Hagiwara, Toshihiro Nukiwa
    ONCOLOGIST, 17, 6, 863, 870, Jun. 2012, [Peer-reviewed]
    English, Scientific journal
  • ATM-mediated DNA damage signals mediate immune escape through integrin-αvβ3-dependent mechanisms.
    Masahisa Jinushi, Shigeki Chiba, Muhammad Baghdadi, Ichiro Kinoshita, Hirotoshi Dosaka-Akita, Koyu Ito, Hironori Yoshiyama, Hideo Yagita, Toshimitsu Uede, Akinori Takaoka
    Cancer research, 72, 1, 56, 65, 1, 01 Jan. 2012, [Peer-reviewed], [International Magazine]
    English, Although the tumor microenvironment plays a critical role in tumor progression and metastasis, the relationship between chemotherapy resistance and modulation of the tumor microenvironment remains unclear. Here, we report a novel mechanism showing how constitutive DNA damage signals in therapy-resistant tumor cells suppress antitumor immunity in an integrin-αvβ3-dependent manner. Integrin-αvβ3 was upregulated on various therapy-resistant tumor cells through chronic activation of ATM/Chk2-and NFκB-mediated pathways. Inhibiting tumor-specific expression of integrin-αvβ3 improved therapeutic responses to anticancer drugs by stimulating endogenous host immune systems. Mechanistic investigations revealed that tumor-specific integrin-αvβ3 expression targeted dendritic cells, facilitating their ability to phagocytose viable therapy-resistant tumor cells and thereby impaired their ability to cross-prime antigen-specific T lymphocytes. Together, our results clarify the detrimental effects of constitutive DNA damage signals to chemosensitivity and antitumor immunity. Furthermore, these findings suggest that integrin-αvβ3 targeting may benefit patients' refractory to current anticancer regimens by defeating DNA damage signaling-induced immune escape.
  • Dendritic cell-derived TIM-3 is a universal repressor of nucleic acids-mediated antitumor innate immune responses.
    Chiba S, Baghdadi M, Akiba H, Kinoshita I, Yoshiyama H, Hirashima M, Dosaka-Akita H, Uede T, Takaoka A, Yagita H, Jinushi M
    Nat Immunol, 13, 9, 832, 842, 2012
  • Phase I study of concurrent real-time tumor-tracking thoracic radiation therapy with paclitaxel and carboplatin in locally advanced non-small cell lung cancer
    Jun Sakakibara-Konishi, Satoshi Oizumi, Ichiro Kinoshita, Naofumi Shinagawa, Junko Kikuchi, Mototsugu Kato, Tetsuya Inoue, Norio Katoh, Rikiya Onimaru, Hiroki Shirato, Hirotoshi Dosaka-Akita, Masaharu Nishimura
    LUNG CANCER, 74, 2, 248, 252, Nov. 2011, [Peer-reviewed]
    English, Scientific journal
  • F-18-Fluorothymidine PET/CT as an early predictor of tumor response to treatment with cetuximab in human lung cancer xenografts
    Satoshi Takeuchi, Songji Zhao, Yuji Kuge, Yan Zhao, Ken-Ichi Nishijima, Toshiyuki Hatano, Yasushi Shimizu, Ichiro Kinoshita, Nagara Tamaki, Hirotoshi Dosaka-Akita
    ONCOLOGY REPORTS, 26, 3, 725, 730, Sep. 2011, [Peer-reviewed]
    English, Scientific journal
  • Tumor-associated macrophages regulate tumorigenicity and anticancer drug responses of cancer stem/initiating cells
    Masahisa Jinushi, Shigeki Chiba, Hironori Yoshiyama, Kenkichi Masutomi, Ichiro Kinoshita, Hirotoshi Dosaka-Akita, Hideo Yagita, Akinori Takaoka, Hideaki Tahara
    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 108, 30, 12425, 12430, Jul. 2011, [Peer-reviewed]
    English, Scientific journal
  • Minichromosome maintenance (MCM) protein 4 as a marker for proliferation and its clinical and clinicopathological significance in non-small cell lung cancer
    Junko Kikuchi, Ichiro Kinoshita, Yasushi Shimizu, Eiki Kikuchi, Kayoko Takeda, Hiroyuki Aburatani, Satoshi Oizumi, Jun Konishi, Kichizo Kaga, Yoshihiro Matsuno, Michael J. Birrer, Masaharu Nishimura, Hirotoshi Dosaka-Akita
    LUNG CANCER, 72, 2, 229, 237, May 2011, [Peer-reviewed]
    English, Scientific journal
  • A case of high-grade neuroendocrine carcinoma that improved with bevacizumab plus modified FOLFOX6 as the fourth-line chemotherapy
    Satoshi Takeuchi, Rio Honma, Jun Taguchi, Toraji Amano, Yasushi Shimizu, Ichiro Kinoshita, Kanako Kubota, Yoshihiro Matsuno, Hirotoshi Dosaka-Akita
    Case Reports in Oncology, 4, 2, 260, 266, 2, May 2011, [Peer-reviewed]
    English, Scientific journal
  • Phase II Study of Irinotecan plus S-1 Combination for Previously Untreated Advanced Non-Small Cell Lung Cancer: Hokkaido Lung Cancer Clinical Study Group Trial (HOT) 0601
    Kenji Akie, Satoshi Oizumi, Shigeaki Ogura, Naofumi Shinagawa, Eiki Kikuchi, Shinichi Fukumoto, Masao Harada, Ichiro Kinoshita, Tetsuya Kojima, Toshiyuki Harada, Yuka Fujita, Yoshinobu Ohsaki, Hirotoshi Dosaka-Akita, Hiroshi Isobe, Masaharu Nishimura
    ONCOLOGY, 81, 2, 84, 90, 2011
    English, Scientific journal
  • Expression of LGR5, an Intestinal Stem Cell Marker, During Each Stage of Colorectal Tumorigenesis
    Kayoko Takeda, Ichiro Kinoshita, Yasushi Shimizu, Yoshihiro Matsuno, Toshiaki Shichinohe, Hirotoshi Dosaka-Akita
    ANTICANCER RESEARCH, 31, 1, 263, 270, Jan. 2011
    English, Scientific journal
  • Superior vena cava syndrome
    Jun Taguchi, Ichiro Kinoshita, Hirotoshi Akita
    Japanese Journal of Cancer and Chemotherapy, 38, 4, 518, 523, Japanese Journal of Cancer and Chemotherapy Publishers Inc., 2011, [Peer-reviewed]
    Japanese, Scientific journal
  • Phase I study of concurrent real-time tumor-tracking thoracic radiation therapy with paclitaxel and carboplatin in locally advanced non-small cell lung cancer.
    Sakakibara-Konishi J, Oizumi S, Kinoshita I, Shinagawa N, Kikuchi J, Kato M, Inoue T, Katoh N, Onimaru R, Shirato H, Dosaka-Akita H, Nishimura M
    Lung Cancer, 74, 2, 248, 52, 2011, [Peer-reviewed]
  • 18F‐Fluorothymidine(FLT)による抗EGFR抗体薬の早期治療効果予測               
    竹内啓, 趙松吉, 趙松吉, 久下裕司, 趙莞, 西嶋剣一, 波多野利行, 清水康, 木下一郎, 玉木長良, 秋田弘俊
    日本臨床腫瘍学会学術集会プログラム・抄録集, 9th, 367, 2011
    English, Research society
  • 大腸発癌における腸管幹細胞マーカーLgr5発現の腫瘍内分布の変化(Distinctive distribution of expression of Lgr5, an intestinal stem cell marker in each stage of colorectal tumorigenesis)               
    武田 香陽子, 木下 一郎, 清水 康, 秋田 弘俊
    日本癌学会総会記事, 69回, 487, 487, (一社)日本癌学会, Aug. 2010
    English
  • Gefitinib or Chemotherapy for Non-Small-Cell Lung Cancer with Mutated EGFR.
    Makoto Maemondo, Akira Inoue, Kunihiko Kobayashi, Shunichi Sugawara, Satoshi Oizumi, Hiroshi Isobe, Akihiko Gemma, Masao Harada, Hirohisa Yoshizawa, Ichiro Kinoshita, Yuka Fujita, Shoji Okinaga, Haruto Hirano, Kozo Yoshimori, Toshiyuki Harada, Takashi Ogura, Masahiro Ando, Hitoshi Miyazawa, Tomoaki Tanaka, Yasuo Saijo, Koichi Hagiwara, Satoshi Morita, Toshihiro Nukiwa
    NEW ENGLAND JOURNAL OF MEDICINE, 362, 25, 2380, 2388, Jun. 2010
    English, Scientific journal
  • Distinctive Expression of the Polycomb Group Proteins Bmi1 Polycomb Ring Finger Oncogene and Enhancer of Zeste Homolog 2 in Nonsmall Cell Lung Cancers and Their Clinical and Clinicopathologic Significance
    Junko Kikuchi, Ichiro Kinoshita, Yasushi Shimizu, Eiki Kikuchi, Jun Konishi, Satoshi Oizumi, Kichizo Kaga, Yoshihiro Matsuno, Masaharu Nishimura, Hirotoshi Dosaka-Akita
    CANCER, 116, 12, 3015, 3024, Jun. 2010
    English, Scientific journal
  • Phase II Study of Gefitinib Readministration in Patients with Advanced Non-Small Cell Lung Cancer and Previous Response to Gefitinib
    Hajime Asahina, Satoshi Oizumi, Akira Inoue, Ichiro Kinoshita, Takashi Ishida, Yuka Fujita, Noriaki Sukoh, Masao Harada, Makoto Maemondo, Yasuo Saijo, Hirotoshi Dosaka-Akita, Hiroshi Isobe, Toshihiro Nukiwa, Masaharu Nishimura
    ONCOLOGY, 79, 5-6, 423, 429, 2010
    English, Scientific journal
  • ヒト癌細胞移植マウスにおける抗EGFR抗体(cetuximab)による分子標的療法:FLTを用いた早期治療効果評価               
    竹内啓, 趙松吉, 久下祐司, 趙莞, 西嶋剣一, 波多野利行, 清水康, 木下一郎, 玉木長良, 秋田弘俊
    日本臨床腫瘍学会学術集会プログラム・抄録集, 8th, 188, 2010
    English, Research society
  • ヒト癌細胞移植マウスにおける抗VEGF抗体(Bevacizumab)による分子標的療法:FLTを用いた早期治療効果評価               
    趙松吉, 久下裕司, 趙芫, 竹内啓, 波多野利行, 西嶋剣一, 木下一郎, 秋田弘毅, 玉木長良
    核医学, 46, 3, S260-S261, 2009
    English, Research society
  • Simultaneous blockade of AP-1 and phosphatidylinositol 3-kinase pathway in non-small cell lung cancer cells
    J. Kikuchi, I. Kinoshita, Y. Shimizu, S. Oizumi, M. Nishimura, M. J. Birrer, H. Dosaka-Akita
    BRITISH JOURNAL OF CANCER, 99, 12, 2013, 2019, Dec. 2008
    English, Scientific journal
  • Clinicopathological significance of expression of p-c-Jun, TCF4 and beta-Catenin in colorectal tumors
    Kayoko Takeda, Ichiro Kinoshita, Yasushi Shimizu, Yusuke Ohba, Tomoo Itoh, Yoshihiro Matsuno, Toshiaki Shichinohe, Hirotoshi Dosaka-Akita
    BMC CANCER, 8, 328, Nov. 2008
    English, Scientific journal
  • Minichromosome maintenance protein(MCM)4の非小細胞肺癌の細胞増殖における役割
    菊地 順子, 木下 一郎, 清水 康, 武田 香陽子, 油谷 浩幸, 大泉 聡, 西村 正治, 秋田 弘俊
    肺癌, 48, 5, 449, 449, (NPO)日本肺癌学会, Oct. 2008
    Japanese
  • 非小細胞肺癌においてMinichromosome maintenance(MCM)4タンパク質は細胞増殖と分化のマーカーである(Minichromosome maintenance protein 4 as a marker for proliferation and differentiation in non-small cell lung cancer)               
    菊地 順子, 木下 一郎, 清水 康, 武田 香陽子, 油谷 浩幸, 大泉 聡史, 西村 正治, 秋田 弘俊
    日本癌学会総会記事, 67回, 102, 102, (一社)日本癌学会, Sep. 2008
    English
  • [Non-small-cell lung cancer].
    Akita H, Kinoshita I
    Gan to kagaku ryoho. Cancer & chemotherapy, 35, 720, 724, 5, May 2008, [Peer-reviewed]
  • Growth inhibition of non-small cell lung cancer cells by AP-1 blockade using a cJun dominant-negative mutant
    Y. Shimizu, I. Kinoshita, J. Kikuchi, K. Yamazaki, M. Nishimura, M. J. Birrer, H. Dosaka-Akita
    BRITISH JOURNAL OF CANCER, 98, 5, 915, 922, Mar. 2008
    English, Scientific journal
  • ヒト大腸癌切除標本におけるpcJun、TCF4及びβカテニンの核発現の臨床病理学的意義(Clinicopathologic significance of nuclear expression of pcJun, TCF4 and beta-Catenin in resected human colorectal tumors)               
    武田 香陽子, 木下 一郎, 清水 康, 秋田 弘俊
    日本癌学会総会記事, 66回, 265, 265, (一社)日本癌学会, Aug. 2007
    English
  • Clinical benefit of readministration of gefitinib for initial gefitinib-responders with non-small cell lung cancer
    Hiroshi Yokouchi, Koichi Yamazaki, Ichiro Kinoshita, Jun Konishi, Hajime Asahina, Noriaki Sukoh, Masao Harada, Kenji Akie, Shigeaki Ogura, Takashi Ishida, Mitsuru Munakata, Hirotoshi Dosaka-Akita, Hiroshi Isobe, Masaharu Nishimura
    BMC CANCER, 7, 51, Mar. 2007
    English, Scientific journal
  • High incidence of extracellular matrix metalloproteinase inducer expression in non-small cell lung cancers
    Nobuyuki Hakuma, Tomoko Betsuyaku, Ichiro Kinoshita, Tomoo Itoh, Kichizo Kaga, Satoshi Kondo, Masaharu Nishimura, Hirotoshi Dosaka-Akita
    ONCOLOGY, 72, 3-4, 197, 204, 2007
    English, Scientific journal
  • Increase in soluble CD138 in bronchoalveolar lavage fluid of multicentric Castleman's disease
    Masaru Hasegawa, Tomoko Betsuyaku, Nobuya Yoshida, Yasuyuki Nasuhara, Ichiro Kinoshita, Satoshi Ohta, Tomoo Itoh, Pyong Woo Park, Masaharu Nishimura
    RESPIROLOGY, 12, 1, 140, 143, Jan. 2007, [Peer-reviewed]
    English, Scientific journal
  • Non-responsiveness to gefitinib in a patient with lung adenocarcinoma having rare EGFR mutations S7681 and V769L
    Hajime Asahina, Koichi Yamazaki, Ichiro Kinoshita, Hiroshi Yokouchi, Hirotoshi Dosaka-Akita, Masaharu Nishimura
    LUNG CANCER, 54, 3, 419, 422, Dec. 2006
    English, Scientific journal
  • Non-responsiveness to gefitinib in a patient with lung adenocarcinoma having rare EGFR mutations S7681 and V769L
    Hajime Asahina, Koichi Yamazaki, Ichiro Kinoshita, Hiroshi Yokouchi, Hirotoshi Dosaka-Akita, Masaharu Nishimura
    LUNG CANCER, 54, 3, 419, 422, Dec. 2006, [Peer-reviewed]
    English, Scientific journal
  • Epithelioid sarcoma presenting as pulmonary cysts with cancer antigen 125 expression
    Eiki Kikuchi, Ichiro Kinoshita, Koichi Yamazaki, Tomoo Itoh, Tadamichi Shimizu, Hiroshi Shimizu, Masaharu Nishimura
    RESPIROLOGY, 11, 6, 826, 829, Nov. 2006, [Peer-reviewed]
    English, Scientific journal
  • A phase II trial of gefitinib as first-line therapy for advanced non-small cell lung cancer with epidermal growth factor receptor mutations
    H. Asahina, K. Yamazaki, I. Kinoshita, N. Sukoh, M. Harada, H. Yokouchi, T. Ishida, S. Ogura, T. Kojima, Y. Okamoto, Y. Fujita, H. Dosaka-Akita, H. Isobe, M. Nishimura
    BRITISH JOURNAL OF CANCER, 95, 8, 998, 1004, Oct. 2006
    English, Scientific journal
  • Phase II study of carboplatin and weekly paclitaxel in advanced non-small cell lung cancer
    Megumi Nakadate, Koichi Yamazaki, Jun Konishi, Ichiro Kinoshita, Noriaki Sukoh, Masao Harada, Kenji Akie, Shigeaki Ogura, Takashi Ishida, Mitsuru Munakata, Hirotoshi Dosaka-Akita, Hiroshi Isobe, Masaharu Nishimura
    ANTICANCER RESEARCH, 26, 5B, 3767, 3772, Sep. 2006
    English, Scientific journal
  • Establishment and characterization of amylase-producing lung adenocarcinoma cell line, IMEC-2
    Hiroshi Yokouchi, Koichi Yamazaki, Hajime Asahina, Masahiko Shigemura, Takanori Moriyama, Kazuo Takaoka, Jun Moriya, Tomoo Itoh, Ichiro Kinoshita, Hirotoshi Dosaka-Akita, Yutaka Tsutsumi, Masaharu Nishimura
    ANTICANCER RESEARCH, 26, 4B, 2821, 2827, Jul. 2006
    English, Scientific journal
  • Susceptibility to oxygen desaturation during bronchoscopy in elderly patients with pulmonary fibrosis
    N Shinagawa, K Yamazaki, Kinoshita, I, S Ogura, M Nishimura
    RESPIRATION, 73, 1, 90, 94, 2006, [Peer-reviewed]
    English, Scientific journal
  • E1AF/PEA3 activates the Rho/Rho-associated kinase pathway to increase the malignancy potential of non-small-cell lung cancer cells
    N Hakuma, Kinoshita, I, Y Shimizu, K Yamazaki, K Yoshida, M Nishimura, H Dosaka-Akita
    CANCER RESEARCH, 65, 23, 10776, 10782, Dec. 2005
    English, Scientific journal
  • E1AF/PEA3 activates the Rho/Rho-associated kinase pathway to increase the malignancy potential of non-small-cell lung cancer cells
    N Hakuma, Kinoshita, I, Y Shimizu, K Yamazaki, K Yoshida, M Nishimura, H Dosaka-Akita
    CANCER RESEARCH, 65, 23, 10776, 10782, Dec. 2005, [Peer-reviewed]
    English, Scientific journal
  • Cyclin A is a c-Jun target gene and is necessary for c-Jun-induced anchorage-independent growth in RAT1a cells
    M Katabami, H Donninger, F Hommura, VD Leaner, Kinoshita, I, JFB Chick, MJ Birrer
    JOURNAL OF BIOLOGICAL CHEMISTRY, 280, 17, 16728, 16738, Apr. 2005
    English, Scientific journal
  • Cyclin A is a c-Jun target gene and is necessary for c-Jun-induced anchorage-independent growth in RAT1a cells
    M Katabami, H Donninger, F Hommura, VD Leaner, Kinoshita, I, JFB Chick, MJ Birrer
    JOURNAL OF BIOLOGICAL CHEMISTRY, 280, 17, 16728, 16738, Apr. 2005, [Peer-reviewed]
    English, Scientific journal
  • Expression of N-acetylglucosaminyltransferase V in the development of human esophageal cancers: Immunohistochemical data from carcinomas and nearby noncancerous lesions
    Y Ishibashi, H Dosaka-Akita, E Miyoshi, M Shindoh, M Miyamoto, Kinoshita, I, H Miyazaki, T Itoh, S Kondo, M Nishimura, N Taniguchi
    ONCOLOGY, 69, 4, 301, 310, 2005
    English, Scientific journal
  • 「気管支肺胞洗浄所見の変化を追跡したgefitinibによる間質性肺炎の1例」               
    『日本呼吸器学会雑誌』, 43巻, 466, 70, 2005
  • Analysis of the response and toxicity to gefitinib of non-small cell lung cancer
    J Konishi, K Yamazaki, Kinoshita, I, H Isobe, S Ogura, S Sekine, T Ishida, R Takashima, M Nakadate, S Nishikawa, T Hattori, H Asahina, M Imura, E Kikuchi, J Kikuchi, N Shinagawa, H Yokouchi, M Munakata, H Dosaka-Akita, M Nishimura
    ANTICANCER RESEARCH, 25, 1B, 435, 441, Jan. 2005, [Peer-reviewed]
    English, Scientific journal
  • Expression of N-acetylglucosaminyltransferase V in the development of human esophageal cancers: Immunohistochemical data from carcinomas and nearby noncancerous lesions
    Y Ishibashi, H Dosaka-Akita, E Miyoshi, M Shindoh, M Miyamoto, Kinoshita, I, H Miyazaki, T Itoh, S Kondo, M Nishimura, N Taniguchi
    ONCOLOGY, 69, 4, 301, 310, 2005, [Peer-reviewed]
    English, Scientific journal
  • Endobronchial ultrasonography with guide-sheath for peripheral pulmonary lesions
    E Kikuchi, K Yamazaki, N Sukoh, J Kikuchi, H Asahina, M Imura, Y Onodera, N Kurimoto, Kinoshita, I, M Nishimura
    EUROPEAN RESPIRATORY JOURNAL, 24, 4, 533, 537, Oct. 2004
    English, Scientific journal
  • Phase I trial of carboplatin and weekly paclitaxel in patients with advanced non-small-cell lung cancer
    Junko Kikuchi, Koichi Yamazaki, Ichiro Kinoshita, Hajime Asahina, Mikado Imura, Eiki Kikuchi, Jun Konishi, Naofumi Shinagawa, Hiromitsu Oki, Hirotoshi Dosaka-Akita, Masaharu Nishimura
    Japanese Journal of Clinical Oncology, 34, 9, 505, 509, Sep. 2004
    English, Scientific journal
  • Phase I trial of carboplatin and weekly paclitaxel in patients with advanced non-small-cell lung cancer
    J Kikuchi, K Yamazaki, Kinoshita, I, H Asahina, M Imura, E Kikuchi, J Konishi, N Shinagawa, H Oki, H Dosaka-Akita, M Nishimura
    JAPANESE JOURNAL OF CLINICAL ONCOLOGY, 34, 9, 505, 509, Sep. 2004, [Peer-reviewed]
    English, Scientific journal
  • B7-h1 expression on non-small cell lung cancer cells and its relationship with tumor-infiltrating lymphocytes and their PD-1 expression
    J Konishi, K Yamazaki, M Azuma, Kinoshita, I, H Dosaka-Akita, M Nishimura
    CLINICAL CANCER RESEARCH, 10, 15, 5094, 5100, Aug. 2004, [Peer-reviewed]
    English, Scientific journal
  • Paraneoplastic cerebellar degeneration (PCD) associated with squamous cell carcinoma of the lung
    J Konishi, K Yamazaki, K Chikai, K Nagashima, K Sakai, Kinoshita, I, H Dosaka-Akita, M Nishimura
    INTERNAL MEDICINE, 43, 7, 602, 606, Jul. 2004
    English, Scientific journal
  • Paraneoplastic cerebellar degeneration (PCD) associated with squamous cell carcinoma of the lung
    J Konishi, K Yamazaki, K Chikai, K Nagashima, K Sakai, Kinoshita, I, H Dosaka-Akita, M Nishimura
    INTERNAL MEDICINE, 43, 7, 602, 606, Jul. 2004, [Peer-reviewed]
    English, Scientific journal
  • Expression of N-acetylglucosaminiyltranseferase V in non-small cell lung cancers: its association with prognosis and histology.
    Akita H D, Miyoshi E, Suzuki O, Itoh T, Kinoshita I, Yamazaki K, Nishimura M, Katoh H, Taniguchi N
    Clninical Cancer Res. 10, 1773-1779, May 2004
    English, Scientific journal
  • Retinoic acid inhibits interleukin-4-induced eotaxin production in a human bronchial epithelial cell line
    K Takamura, Y Nasuhara, M Kobayashi, T Betsuyaku, Y Tanino, Kinoshita, I, E Yamaguchi, S Matsukura, RP Schleimer, M Nishimura
    AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY, 286, 4, L777, L785, Apr. 2004
    English, Scientific journal
  • Retinoic acid inhibits interleukin-4-induced eotaxin production in a human bronchial epithelial cell line
    K Takamura, Y Nasuhara, M Kobayashi, T Betsuyaku, Y Tanino, Kinoshita, I, E Yamaguchi, S Matsukura, RP Schleimer, M Nishimura
    AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY, 286, 4, L777, L785, Apr. 2004, [Peer-reviewed]
    English, Scientific journal
  • [A case of paclitaxel-induced pneumonitis].
    Taniguchi N, Shinagawa N, Kinoshita I, Nasuhara Y, Yamazaki K, Yamaguchi E, Akita H, Nishimura M
    Nihon Kokyuki Gakkai zasshi = the journal of the Japanese Respiratory Society, 42, 158, 163, 2, Feb. 2004, [Peer-reviewed]
  • 「パクリタキセル投与との関連が示唆された薬剤性肺炎の1例」               
    『日本呼吸器学会雑誌』, 42, 158, 163, 2004
  • A case of squamous cell lung cancer in association with remitting seronegative symmetrical synovitis with pitting edema (RS3PE) Syndrome
    Masayuki Suga, Koichi Yamazaki, Kunio Hamada, Ichiro Kinoshita, Hirotoshi Akita, Masaharu Nishimura
    Japanese Journal of Lung Cancer, 44, 1, 61, 66, Japan Lung Cancer Society, 2004
    Japanese, Scientific journal
  • CD4(+) T cells in cancer stroma, not CD8(+) T cells in cancer cell nests, are associated with favorable prognosis in human non-small cell lung cancers
    O Wakabayashi, K Yamazaki, S Oizumi, F Hommura, Kinoshita, I, S Ogura, H Dosaka-Akita, M Nishimura
    CANCER SCIENCE, 94, 11, 1003, 1009, Nov. 2003
    English, Scientific journal
  • CD4(+) T cells in cancer stroma, not CD8(+) T cells in cancer cell nests, are associated with favorable prognosis in human non-small cell lung cancers
    O Wakabayashi, K Yamazaki, S Oizumi, F Hommura, Kinoshita, I, S Ogura, H Dosaka-Akita, M Nishimura
    CANCER SCIENCE, 94, 11, 1003, 1009, Nov. 2003, [Peer-reviewed]
    English, Scientific journal
  • AP-1 complexes containing cJun and JunB cause cellular transformation of Rat1a fibroblasts and share transcriptional targets
    VD Leaner, Kinoshita, I, MJ Birrer
    ONCOGENE, 22, 36, 5619, 5629, Aug. 2003
    English, Scientific journal
  • Granulocyte-macrophage colony-stimulating factor gene-transduced tumor cells combined with tumor-derived gp96 inhibit tumor growth in mice
    T Kojima, K Yamazaki, Y Tamura, S Ogura, K Tani, J Konishi, N Shinagawa, Kinoshita, I, N Hizawa, E Yamaguchi, H Dosaka-Akita, M Nishimura
    HUMAN GENE THERAPY, 14, 8, 715, 728, May 2003
    English, Scientific journal
  • Identification of cJun-responsive genes in Rat-1a cells using multiple techniques: increased expression of stathmin is necessary for cJun-mediated anchorage-independent growth
    Kinoshita, I, Leaner, V, M Katabami, RG Manzano, P Dent, A Sabichi, MJ Birrer
    ONCOGENE, 22, 18, 2710, 2722, May 2003
    English, Scientific journal
  • Predictive value of expression of P53, Bcl-2 and lung resistance-related protein for response to chemotherapy in non-small cell lung cancers
    T Harada, S Ogura, K Yamazaki, Kinoshita, I, T Itoh, H Isobe, K Yamashiro, H Dosaka-Akita, M Nishimura
    CANCER SCIENCE, 94, 4, 394, 399, Apr. 2003
    English, Scientific journal
  • [A case of Mycobacterium avium pulmonary disease detected as multiple small nodular shadows and diagnosed by CT guided transbronchial biopsy with ultrathin bronchoscopy].
    Watanabe K, Shimizu Y, Oizumi S, Shinagawa N, Kinoshita I, Yamazaki K, Onodera Y, Saito H, Yamaguchi E, Dosaka-Akita H, Nishimura M
    Nihon Kokyuki Gakkai zasshi = the journal of the Japanese Respiratory Society, 41, 107, 111, 2, Feb. 2003, [Peer-reviewed]
  • A Case of Mycobacterium avium Pulmonary Disease Detected as Multiple Small Nodular Shadows and Diagnosed by CT Guided Transbronchial Biopsy with Ultrathin Bronchoscopy
    WATANABE Kaori, SHIMIZU Yasushi, OIZUMI Satoshi, SHINAGAWA Naofumi, KINOSHITA Ichiro, YAMAZAKI Koichi, ONODERA Yuya, SAITO Hiroshi, YAMAGUCHI Etsuro, DOSAKA-AKITA Hirotoshi, NISHIMURA Masaharu
    日本呼吸器学会雑誌, 41, 2, 107, 111, 2003
    Japanese
  • A Case of Endobronchial Metastasis of Renal Cell Carcinoma Successfully Removed Under Bronchoscopy Using Argon Plasma Coagulation
    Hakuma Nobuyuki, Yamazaki Koichi, Fukumoto Shinichi, Yokouchi Hiroshi, Harada Toshiyuki, Wakabayashi Osamu, Kinoshita Ichiro, Ogura Shigeaki, Dosaka-Akita Hirotoshi, Nishimura Masaharu
    The Journal of the Japan Society for Respiratory Endoscopy, 25, 2, 114, 117, The Japan Society for Respiratory Endoscopy, 2003
    Japanese, Background, Argon plasma coagulation (APC) has been mainly used to treat gastrointestinal hemorrhage, but has recently also been applied to the treatment of airway stenosis. Case. A 48-year-old woman who had undergone right nephrectomy because of renal cell carcinoma at age 40 complained of dyspnea and cough in April 2000. Bronchoscopic examination revealed severe stenosis of the left main bronchus due to endobronchial metastasis of renal cell carcinoma and stenosis of the right truncus intermedius due to extrinsic compression caused by right hilar lymph nodal metastasis. The tumor in the left main bronchus was removed by forceps under bronchoscopy with the use of APC. Then, a Z stent could be successfully inserted into the right truncus intermedius, which led to the dramatic improvement of her symptoms. Conclusion. The use of APC was effective for the treatment of airway stenosis in this case. (JJSB. 2003 ; 25 : 114-117)
  • Mediastinal lymph node staging by FDG-PET in patients with non-small cell lung cancer: Analysis of false-positive FDG-PET findings
    J Konishi, K Yamazaki, E Tsukamoto, N Tamaki, Y Onodera, T Otake, T Morikawa, Kinoshita, I, H Dosaka-Akita, M Nishimura
    RESPIRATION, 70, 5, 500, 506, 2003
    English, Scientific journal
  • Mediastinal lymph node staging by FDG-PET in patients with non-small cell lung cancer: Analysis of false-positive FDG-PET findings
    J Konishi, K Yamazaki, E Tsukamoto, N Tamaki, Y Onodera, T Otake, T Morikawa, Kinoshita, I, H Dosaka-Akita, M Nishimura
    RESPIRATION, 70, 5, 500, 506, 2003, [Peer-reviewed]
    English, Scientific journal
  • N-acetylgalactosaminyl transferase-3 is a potential new marker for non-small cell lung cancers
    H Dosaka-Akita, Kinoshita, I, K Yamazaki, H Izumi, T Itoh, H Katoh, M Nishimura, K Matsuo, Y Yamada, K Kohno
    BRITISH JOURNAL OF CANCER, 87, 7, 751, 755, Sep. 2002
    English, Scientific journal
  • CL100 expression is down-regulated in advanced epithelial ovarian cancer and its re-expression decreases its malignant potential
    RG Manzano, LM Montuenga, M Dayton, P Dent, Kinoshita, I, S Vicent, GJ Gardner, PM Nguyen, YH Choi, J Trepel, N Auersperg, MJ Birrer
    ONCOGENE, 21, 28, 4435, 4447, Jun. 2002
    English, Scientific journal
  • CL100 expression is down-regulated in advanced epithelial ovarian cancer and its re-expression decreases its malignant potential
    RG Manzano, LM Montuenga, M Dayton, P Dent, Kinoshita, I, S Vicent, GJ Gardner, PM Nguyen, YH Choi, J Trepel, N Auersperg, MJ Birrer
    ONCOGENE, 21, 28, 4435, 4447, Jun. 2002, [Peer-reviewed]
    English, Scientific journal
  • Increased expression of beta-catenin predicts better prognosis in nonsmall cell lung carcinomas
    F Hommura, K Furuuchi, K Yamazaki, S Ogura, Kinoshita, I, M Shimizu, T Moriuchi, H Katoh, M Nishimura, H Dosaka-Akita
    CANCER, 94, 3, 752, 758, Feb. 2002
    English, Scientific journal
  • Predictive value of expression of p16(INK4A), retinoblastoma and p53 proteins for the prognosis of non-small cell lung cancers
    F Hommura, H Dosaka-Akita, Kinoshita, I, T Mishina, H Hiroumi, S Ogura, H Katoh, Y Kawakami
    BRITISH JOURNAL OF CANCER, 81, 4, 696, 701, Oct. 1999
    English, Scientific journal
  • Cyclin D1 expression in non-small-cell lung cancers: its association with altered p53 expression, cell proliferation and clinical outcome
    T Mishina, H Dosaka-Akita, Kinoshita, I, F Hommura, T Morikawa, H Katoh, Y Kawakami
    BRITISH JOURNAL OF CANCER, 80, 8, 1289, 1295, Jun. 1999
    English, Scientific journal
  • Frequent loss of gelsolin expression in non-small cell lung cancers of heavy smokers
    H Dosaka-Akita, F Hommura, H Fujita, Kinoshita, I, M Nishi, T Morikawa, H Katoh, Y Kawakami, N Kuzumaki
    CANCER RESEARCH, 58, 2, 322, 327, Jan. 1998
    English, Scientific journal
  • Altered retinoblastoma protein expression in nonsmall cell lung cancer - Its synergistic effects with altered ras and p53 protein status on prognosis
    H DosakaAkita, SX Hu, M Fujino, M Harada, Kinoshita, I, HJ Xu, N Kuzumaki, Y Kawakami, WF Benedict
    CANCER, 79, 7, 1329, 1337, Apr. 1997
    English, Scientific journal
  • Altered p16(INK4) and retinoblastoma protein status in non-small cell lung cancer: Potential synergistic effect with altered p53 protein on proliferative activity
    Kinoshita, I, H DosakaAkita, T Mishina, K Akie, M Nishi, H Hiroumi, F Hommura, Y Kawakami
    CANCER RESEARCH, 56, 24, 5557, 5562, Dec. 1996
    English, Scientific journal
  • PROGNOSTIC-SIGNIFICANCE OF P53 AND RAS P21 EXPRESSION IN NONSMALL CELL LUNG-CANCER
    M FUJINO, H DOSAKAAKITA, M HARADA, H HIROUMI, KINOSHITA, I, K AKIE, Y KAWAKAMI
    CANCER, 76, 12, 2457, 2463, Dec. 1995
    English, Scientific journal
  • SIMULTANEOUS USE OF THE PCR-SSCP METHOD AND IMMUNOHISTOCHEMISTRY FOR INCREASING THE DETECTION EFFICACY OF P53 ABNORMALITIES IN HUMAN LUNG-CANCER
    M FUJINO, H DOSAKAAKITA, M KATO, KINOSHITA, I, K AKIE, Y KAWAKAMI
    AMERICAN JOURNAL OF CLINICAL PATHOLOGY, 104, 3, 319, 324, Sep. 1995
    English, Scientific journal
  • INHIBITION OF PROLIFERATION BY L-MYC ANTISENSE DNA FOR THE TRANSLATIONAL INITIATION SITE IN HUMAN SMALL-CELL LUNG-CANCER
    H DOSAKAAKITA, K AKIE, H HIROUMI, KINOSHITA, I, Y KAWAKAMI, A MURAKAMI
    CANCER RESEARCH, 55, 7, 1559, 1564, Apr. 1995
    English, Scientific journal
  • HUMAN PAPILLOMAVIRUS TYPE-18 DNA AND E6-E7 MESSENGER-RNA ARE DETECTED IN SQUAMOUS-CELL CARCINOMA AND ADENOCARCINOMA OF THE LUNG
    KINOSHITA, I, H DOSAKAAKITA, M SHINDOH, M FUJINO, K AKIE, M KATO, K FUJINAGA, Y KAWAKAMI
    BRITISH JOURNAL OF CANCER, 71, 2, 344, 349, Feb. 1995
    English, Scientific journal
  • ABNORMAL P53 EXPRESSION IN HUMAN LUNG-CANCER IS ASSOCIATED WITH HISTOLOGIC SUBTYPES AND PATIENT SMOKING HISTORY
    H DOSAKAAKITA, M SHINDOH, M FUJINO, KINOSHITA, I, K AKIE, M KATOH, Y KAWAKAMI
    AMERICAN JOURNAL OF CLINICAL PATHOLOGY, 102, 5, 660, 664, Nov. 1994
    English, Scientific journal

Other Activities and Achievements

Books and other publications

  • 入門腫瘍内科学               
    篠原出版新社, 2009

Affiliated academic society

  • American Society of Clinical Oncology               
  • 世界肺癌学会               
  • 日本乳癌学会               
  • 日本分子標的治療学会               
  • 日本臨床腫瘍学会               
  • 日本臨床細胞学会               
  • 日本呼吸器学会               
  • 日本気管支学会               
  • 日本癌治療学会               
  • 日本癌学会               
  • アメリカ癌学会               
  • 北海道癌談話会               
  • 北海道癌治療研究会               
  • 日本肺癌学会               
  • アジア太平洋呼吸器学会               
  • 日本内科学会               

Works

  • スライドセミナー内科系:日本臨床細胞学会北海道支部会               
    2009

Research Themes

  • A Study on Predicting the Effectiveness of Cancer Immunotherapy
    Grants-in-Aid for Scientific Research
    01 Apr. 2022 - 31 Mar. 2025
    菊地 順子, 畑中 佳奈子, 天野 虎次, 畑中 豊, 木下 一郎
    Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (C), Hokkaido University, 22K07292
  • 小細胞肺癌におけるProx1によるNotch pathwayの制御機構、治療開発
    科学研究費助成事業
    01 Apr. 2021 - 31 Mar. 2024
    榊原 純, 木下 一郎
    Prox1の小細胞肺癌(SCLC)における腫瘍原性に与える影響についての研究;SCLC細胞株のProx1の発現を最初に確認した。4つの(SCLC細胞株(MS-1、HCC827、SBC-3,SBC-5)を使用しProx1の発現をウエスタンブロットを用いてタンパク発現を確認したところMS-1、HCC827でProx1の発現を認め残りの2つのSBC-3とSBC-5のSCLC細胞株の発現は低かった。さらにPCRでもProx-1の発現を確認しタンパク発現とmRNAの発現が同様の結果であることを確認した。このため発現抑制のための実験にはMS-1とHCC827を使用することにした。Prox1の機能解析のために2つの細胞株でsiRNAを用いてProx1の発現が抑制されていることを確認した。増殖能についてMTT assayを行ったところProx1の抑制によりコントロールと比較して細胞増殖は増加した。clnogenic assayも行いMTT assayの結果と同様にProx1の抑制によりcolony数が増加した。さらにinvasion assayとmigration assayをtranswell chamberを用いて確認したところProx1の抑制によりコントロールと比較して細胞遊走能、浸潤能ともに増加した。
    Prox1とNotch pathwayの関連についての検討:Prox1の抑制時にNotch 関連タンパク(Notch1-4、HES-1、HEY-1)の発現をウエスタンブロットにて確認したがコントロールと比較してProx1抑制時にNotch関連タンパク発現に変化を認めなかった。さらにPCRでmRNAについても検討したがProx1の発現の抑制時に変化を認めなかった。
    CDDP耐性株におけるProx1の影響:当科でCDDP耐性株を当科で樹立しておりCDDP耐性株(MS-1)においてProx1の発現を確認したところProx1の発現が低下しており薬剤耐性との関与が考えられた。
    日本学術振興会, 基盤研究(C), 北海道大学, 21K08195
  • Optimization of treatment strategy with EZH2 inhibitor for solid cancer with SWI/SNF alteration
    Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    01 Apr. 2020 - 31 Mar. 2023
    木下 一郎
    エピジェネティクスを標的にした新たながん治療が期待される中、クロマチン再構成を担うSWI/SNF複合体構成因子の異常が、ヒストンH3K27メチル化酵素EZH2に対する阻害薬のバイオマーカーとなる可能性が示された。初年度の研究で、SWI/SNFの状態の異なる種々の細胞株におけるEZH2阻害薬と、ヒストンH3K4脱メチル化酵素KDM5の抗腫瘍効果を検討したが、検討した細胞株におけるEZH2阻害薬Tazemetostat単剤での細胞障害活性が低く、KDM4阻害薬との併用効果も認められなかった。一方、種々のエピジェネティクス治療薬と、関連する因子の分子標的治療薬の併用効果を検討し、複数の細胞株で、Clonogenic法におけるHDAC阻害薬vorinostatとCDK4/6阻害薬palbociclibの相乗効果を見出した。
    令和3年度は、両薬剤の相乗効果をソフトアガロース法によるクローン形成能によって解析した。Clonogenic法と同様、SWI/SNFの異常のある細胞株を主体とした5種類の細胞株に相乗効果を認め、4種類の細胞株には認めなかった。遺伝子変異やRNA発現データをCancer Cell Line Encyclopedia (CCLE)から入手し、相乗効果を認めた細胞グループと認めなかった細胞グループでの違いを比較した。相乗効果のある5細胞株の中4細胞株に共通する遺伝子変異を4つ認めたが、全てに共通する遺伝子異常は認めなかった。一方、RNA発現についてVolcano plotで検討したところ、相乗効果の有無により発現比の顕著な遺伝子を複数認めた。このうち、相乗効果のある細胞株全てに高発現している遺伝子も見出された。
    Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (C), Hokkaido University, 20K07691
  • Numb has distinct roles in lung adenocarcinoma and squamous cell carcinomaus us
    Grants-in-Aid for Scientific Research
    01 Apr. 2018 - 31 Mar. 2021
    sakakibara jun
    To investigate the role of Numb in tumorigenesis of lung adenocarcinoma and squamous cell carcinoma, we firstly performed loss-of-function and gain-of-function assays. Moreover, Numb expression was investigated in surgically resected lung adenocarcinoma and squamous cell carcinoma tissues by immunohistochemistry and correlations with prognosis were analyzed. Numb suppressed the proliferation, migration, and invasion of adenocarcinoma cells. In contrast, Numb promoted the proliferation, migration, and invasion of squamous cell carcinoma cells. High Numb expression was associated with favorable prognosis in patients with lung adenocarcinoma, but not in those with squamous cell carcinoma. Collectively, our data demonstrate that Numb plays distinct roles in lung adenocarcinoma and squamous cell carcinoma. In lung adenocarcinoma, Numb impairs tumor growth, whereas in lung squamous cell carcinoma it may promote proliferation.
    Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (C), Hokkaido University, 18K08130
  • Development of potential therapy using histone modifying enzyme inhibitor to overcome drug resistance of non-small lung cancer
    Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    01 Apr. 2017 - 31 Mar. 2020
    Kinoshita Ichiro
    PBIT, a small molecule inhibitor of the JARID1a/b histone demethylases, restored the drug sensitivity of multiple drug-resistant persister cells that were established from NSCLC lines. In addition, PBIT prevented the expansion of EGFR-TKI-resistant persisters through modifying secretomes from EGFR-TKI sensitive cells by inhibiting downregulation of FRA1 expression via prevention of decreased H3K4me3 levels at FRA1 promoter regions. These findings suggest the potential efficacy of PBIT as a novel therapeutic strategy for lung cancer and have particularly important implications in restoring drug resistance in NSCLC, given that patients with activating EGFR mutations who are given EGFR-targeted therapies commonly develop resistance.
    Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (C), Hokkaido University, 17K09639
  • Combined inhibition of stem cell markers and histone modification enzymes in non-small cell lung cancer
    Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    01 Apr. 2014 - 31 Mar. 2017
    Kinoshita Ichiro, JINUSHI Masahisa, AKITA Hirotoshi
    EGFR-tyrosine kinase inhibitor (TKI) resistant non-small lung cancer (NSCLC) cell H1975 had 1% side population fraction, which showed increased tumorigenicity, elevated expression of stem cell markers and histone H3K27 trimethyl transferase EZH2, suggesting that EZH2 may play a role in maintenance of cancer stem cells. The combined treatment with inhibitors of the EZH2 and the histone deacetylases HDACs showed synergistic growth suppressive effects, suppression of EGFR signaling, and decrease in the in vivo tumor growth of H1975 cells, suggesting that the combined pharmacological targeting of the histone modification enzymes may provide more effective epigenetic therapeutics for NSCLCs including those with EGFR-TKI-resistant mutations.
    Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (C), Hokkaido University, Principal investigator, Competitive research funding, 26461175
  • Study on EGFR-TKI resistance using FRET biosensor
    Grants-in-Aid for Scientific Research Grant-in-Aid for Challenging Exploratory Research
    01 Apr. 2014 - 31 Mar. 2016
    Akita Hirotoshi, Ohba Yusuke, Kinoshita Ichiro
    EGFR-TKI resistant cells were isolated in three non-small cell lung cancer (NSCLC) cell lines, using FRET biosensor and flow cytometer. cDNA microarray analysis showed common gene expression changes among the resistant cells. Annotation analysis revealed three up-regulated pathways and five down-regulated pathways. The ABC transporter system was included in the genes and pathways, which were found to be changed in relation to the acquired resistance, suggesting that this system could be involved in the resistance to EGFR-TKI in NSCLCs.
    Japan Society for the Promotion of Science, Grant-in-Aid for Challenging Exploratory Research, Hokkaido University, 26670414
  • Combined antitumor effec ot g-secretase inbitiro and ABT-737
    Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    01 Apr. 2012 - 31 Mar. 2015
    SAKAKIBARA Jun, KINOSHITA Ichiro
    Inhibition of Notch by gamma-secretase inhibitor (GSI) has been shown to have an antitumor effect in Notch expressing non-small cell lung cancer (NSCLC) and induce apoptosis through modulation of Bcl-2 family proteins. ABT-737, a BH3-only mimetic, targets the prosurvival Bcl-2 family and also induces apoptosis. GSI XX or ABT-737 alone inhibited cell proliferation in a dose dependent manner and combination drug treatment showed a synergistic antitumor effect in Notch expressing NSCLC in vitro. In vivo, this drug combination significantly suppressed tumor proliferation compared to single drug treatment. Phospho-Bcl-2 was down-regulated and Bax was up-regulated by both the single and combination drug treatments. Bim was induced by single drug treatment and was enhanced by combination treatment. Combination treatment-induced apoptosis was decreased by Bim inhibition, suggesting that the antitumor effect of the drug combination was dependent on Bim.
    Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (C), Hokkaido University, 24591146
  • Targeted therapy for cancer stem-like cells of non-small cell lung cancers with inhibition of the cJun transcription factor
    Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    2011 - 2013
    KINOSHITA Ichiro, SHIMIZU Yasushi
    Sphere forming capacity under serum-free culture, indicative of cancer stem cells, were decreased by cJun inhibition in non-small lung cancer (NSCLC) cells, while sphere forming cells did not show enhanced tumorigenicity in SCID mice.
    Meanwhile, an inhibitor of histone methyltransferase EZH2 involved in stem cell maintenance via epigenetic regulation suppressed growth of NSCLC cells. An inhibitor of histone deacetylase (HDAC), another epigenetic regulator, showed a synergistic growth suppressive effect with the EZH2 inhibitor. Combined epigenetic therapy with an EZH2 inhibitor and an HDAC inhibitor may represent an effective approach for NSCLCs.
    Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (C), Hokkaido University, Principal investigator, Competitive research funding, 23591132
  • Alteration of fucosylation and biomarker development in lung cancer
    Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    2010 - 2012
    AKITA Hirotoshi, KINOSHITA Ichiro
    High 〓1-6 fucosyltransferase (〓1-6 FucT) expression is more frequently found in adenocarcinomas than squamous cell carcinomas, and is correlated with advanced pN status in adenocarcinomas. High 〓1,6-FT expression is associated with an unfavorable clinical outcome in potentially curatively resected and pStage I adenocarcinomas. These findings suggest that 〓1,6-FT and its core-fucosylated products could be promisingbiomarkers and therapeutic targets for NSCLCs, especially for adenocarcinomas.
    Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (C), Hokkaido University, 22501029
  • Identification of novel molecular targets for lung cancer based on different sensitivity to AP-1 blockade
    Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    2008 - 2010
    KINOSHITA Ichiro, AKITA Hirotoshi
    We identified 27 genes suppressed by blockade of AP-1, an oncogenic transcription factor, in lung cancer cells sensitive to the AP-1 blockade using microarray analysis. Among them, knockdown of MCM 4, a component of DNA replication licensing complex, by siRNA reduced cell growth in multiple lung cancer cells. Immunohistochemical analysis in surgically resected lung cancers demonstrated that MCM4 expression was correlated with proliferation markers including Ki-67. MCM4 may play an important role for growth of lung cancers and be a novel molecular target for lung cancer.
    Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (C), Hokkaido University, Principal investigator, Competitive research funding, 20590909
  • 肺癌および随伴肺疾患における糖転移酵素の発現異常に関する研究
    科学研究費助成事業 萌芽研究
    2006 - 2007
    秋田 弘俊, 三善 英知, 木下 一郎
    本研究では、糖転移酵素α1,6-フコース転移酵素に着目して、非小細胞肺癌における発現異常(発現の低下・喪失)を免疫組織化学法で解析し、臨床病理学的因子、患者予後、細胞増殖能、各種分子マーカー発現、他の糖転移酵素発現との関係を解析して、非小細胞肺癌におけるα1,6-フコース転移酵素の発現異常の臨床病理学的意義を明らかにすることを目的とした。
    非小細胞肺癌手術摘出腫瘍220腫瘍を材料として、α1,6‐フコース転移酵素の発現について特異抗体を用いて免疫組織化学法(Streptavidin biotin法)で解析した。肺癌組織における解析と同時に、肺葉切除された同一手術摘出材料内に存在する正常肺・気管支組織おける発現や随伴する非腫瘍性疾患肺組織における発現を解析した。α1,6‐フコース転移酵素に対する特異抗体は、大阪大学大学院医学研究科生化学・分子生物学教室が開発したものを用い、抗体の希釈濃度は1600倍とした。抗原賦活法としてオートクレーブ法を用いたところ、メチルグリーンで十分な核染色が得られず、ヘマトキシリンでは核染色が得られた。
    α1,6-フコース転移酵素の発現は、正常気管支上皮細胞、正常気管支腺細胞では認められた。非小細胞肺癌においては、組織型では腺癌に比べて扁平上皮癌で発現の低下が認められた。また腺癌のなかでは、分化度では高分化なものに比べて低分化なもので発現の低下が認められ、臨床病理学的な意義が示唆された。
    日本学術振興会, 萌芽研究, 北海道大学, Coinvestigator not use grants, Competitive research funding, 18659235
  • Research on Molecular Therapeutic Targets and Biomarkers for the Diagnosis and Stratification in Lung Cancer
    Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)
    2004 - 2006
    AKITA Hirotoshi, KINOSHITA Ichiro, YAMAZAKI Koichi
    The aim of this research is to identify molecular therapeutic targets and Biomarkers for the diagnosis and stratification in lung cancer.
    We searched for genes specifically overexpressed in lung cancer through microarray analysis, and identified seven genes, including AKRB1B10, in squamous cell carcinoma (SCC) of the lung. AKR1B10 was overexpressed in most cases with SCC, which is closely associated with smoking, and in many adenocarcinomas from smokers. These results suggest that AKR1B10 is a potential diagnostic marker specific to smokers' non-small cell lung cancers (NSCLCs) and might be involved in tobacco-related carcinogenesis.
    We next studied on the biomarker in molecular targeting therapy using EGF receptor (EGFR)-tyrosine kinase inhibitors (TKIs). Retrospective analyses have shown that activating mutations in exons 18-21 of the EGFR gene are a predictor of response to EGFR-TKIs. We conducted a phase II study to evaluate the efficacy and safety of gefitinib, one of EGFR-TKIs, as first-line therapy for advanced NSCLCs with EGFR mutations. For mutation analysis, DNA was extracted from paraffin-embedded tissues and EGFR mutations were analysed by direct sequence of PCR products. Twenty (24%) of the 82 patients analysed had EGFR mutations. Sixteen patients were enrolled and treated with gefitinib. Twelve patients had objective response and response rate was 75%. This study has shown that mutations (deletions in exon 19 and L858R point mutation in exon 21) of the EGFR gene are a predictor of response to EGFR-TKIs.
    Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (B), Hokkaido University, Coinvestigator not use grants, Competitive research funding, 16390231
  • Growth inhibition of non-small cell lung cancer cells by AP-1 blockade using a cJun dominant negative mutant, TAM67
    Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    2004 - 2005
    KINOSHITA Ichiro
    AP-1, a transcription factor transducing multiple mitogen growth signals, may be a useful target for gene and molecular target therapy. A previous study has demonstrated that cJun, a major constituent of AP-1, is frequently overexpressed in non-small cell lung cancers (NSCLCs). Therefore, in this study, we investigated the effect of AP-1 blockade on the growth of NSCLC cells using a cJun dominant negative mutant, TAM67. Transiently transfected TAM67 inhibited AP-1 transcriptional activity in NSCLC cell lines, H520 and H1299 cells. Colony forming efficiency of H1299 was much reduced by TAM67, while that of H520 was not. To elucidate the effect of TAM67 on the growth of H1299, we established H1299 clones that expressed TAM67 under the control of doxycycline-inducible promoter. Luciferase assay confirmed that the induction of TAM67 decreased AP-1 activity. MTT assay demonstrated that TAM67 inhibited cell growth. Flow cytometry analysis showed that TAM67 induced G1 cell cycle arrest. TAM67 also inhibited anchorage-independent growth determined by soft agarose assay, and Furthermore, we demonstrated that tumor growth was inhibited under the condition of expressing TAM67 in nude mice. These results suggest that AP-1 transcriptional activity plays an essential role in the growth of at least a part of NSCLC cells and that AP-1 can be a potential target for the treatment of NSCLCs.
    Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (C), HOKKAIDO UNIVERSITY, Principal investigator, Competitive research funding, 16590729
  • 肺癌のAP-1を標的にした遺伝子治療に関する基礎的研究 転写因子E1AF/PEA3に関する研究 肺癌のEGFRの異常とGefitinib感受性               
    Competitive research funding