Development of a novel prognostic marker for pancreatic cancer chemotherapy as an indicator of MDSC reduction due to myelosuppression.

• Project/Area Number: 20K16081
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 47060:Clinical pharmacy-related
• Research Institution: Gifu Pharmaceutical University
• Principal Investigator: Fujii Hironori 岐阜薬科大学, 薬学部, 客員共同研究員 (90775173)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000); Fiscal Year 2022: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2021: ¥260,000 (Direct Cost: ¥200,000、Indirect Cost: ¥60,000); Fiscal Year 2020: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
• Keywords: 重篤な好中球減少 / MDSC / がん化学療法 / 生存期間 / フローサイトメトリー解析 / 不死時間バイアス / 時間依存性Cox回帰分析 / MDSCs / 膵がん / 治療効果 / 大腸がん / 切除不能進行膵がん / FOLFIRINOX療法 / 好中球減少 / 予後マーカー

Outline of Research at the Start

我々は、切除不能進行膵がんにおいて、FOLFIRINOX療法(FX)による重篤な好中球減少は生存期間の延長と有意に相関することを報告しており(Cancers.2018,10,454)、そのメカニズムとして、Myeloid derived suppressor cell(MDSC)の関与を考えた。MDSCsは未熟な骨髄細胞であり、がんや炎症により末梢血中に誘導され、強力な免疫抑制作用を示す。膵がん患者で末梢血中MDSC増加の程度が大きく、その関与が多いと考えられる。本研究では、FXが投与される膵がん患者の効果判定のバイオマーカーとして、好中球減少やMDSC濃度変化と治療効果の関係を明らかにする。

Outline of Final Research Achievements

Patients with severe neutropenia may have decreased myeloid derived suppressor cells (MDSC), which may be an indicator of the efficacy of anticancer drugs.
First, to establish a system for measuring MDSC concentration, we investigated conditions using three types of cultured human leukemia cells, HL60, NB4, and KG-1, and were able to isolate all cells as CD11b+CD14- CD33+ by flow cytometry analysis. In addition, severe neutropenia was used as a surrogate marker of MDSC decline and its association with overall survival (OS) was examined. Time-dependent Cox regression analysis with immortality time bias was performed in patients treated with trifluridine tipiracil hydrochloride and bevacizumab. Results showed that severe neutropenia was significantly associated with prolonged OS.

Academic Significance and Societal Importance of the Research Achievements

本研究では、骨髄由来免疫抑制細胞(MDSC)濃度測定系の確立を行ったのちに、トリフルリジンチピラシル塩酸塩とベバシズマブ併用療法の重篤な好中球減少をMDSCの低下のサロゲートマーカーと仮定し、治療効果との関連を検討した。本研究で、ヒト検体を用いてMDSCを測定することはコロナ禍でできなかったが、時間依存性COX回帰分析を用いて、重篤な好中球減少と治療効果との関連を明らかにできたことで、重篤な好中球減少を指標にしたがん化学療法の治療効果予測の可能性を高めることにつながった。今後ヒト検体を用いて、MDSC濃度を調べることで治療効果の向上に大きく貢献できるものと考える。

Research Products

• [Journal Article] Association Between Peripheral Neuropathy Induced by Oxaliplatin at First-line Chemotherapy and Efficacy of Paclitaxel at Second-line Chemotherapy in Patients With Advanced Gastric Cancer (2022)
  • Author(s): Fujii H, Sadaka S, Ajisawa K, Okumura N, Makiyama A, Iihara H, Yasufuku I, Ohata K, Kobayashi R, Tanaka Y, Hayashi H, Suzuki A
  • Journal Title: Anticancer Resarch Volume: 42 Issue: 9 Pages: 4581-4588
  • DOI: 10.21873/anticanres.15961
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Impact of First-Line FOLFIRINOX-Induced Peripheral Neuropathy on the Efficacy of Second-Line GnP in Patients with Unresectable Advanced Pancreatic Cancer (2022)
  • Author(s): Sadaka S, Iwashita T, Fujii H, Kato-Hayashi H, Ohata K, Uemura S, Shimizu M, Suzuki A
  • Journal Title: Journal of Clinical Medicine Volume: 11 Issue: 19 Pages: 5895-5895
  • DOI: 10.3390/jcm11195895
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Association between the Co-administration of Histamine H2 Receptor Antagonists and the Effectiveness of Capecitabine in Patients with Colorectal Cancer: Propensity Score Analysis (2022)
  • Author(s): Yamazaki T, Uozumi R, Kawazoe H, Kitazume Y, Iihara H, Fujii H, Takahashi M, Arai T, Murachi Y, Sato Y, Mikami T, Hashiguchi K, Yoshizawa T, Takahashi K, Fujita Y, Hosokawa Y, Morozumi I, Tsuchiya M, Yokoyama A, Hashimoto H, Furukawa T.
  • Journal Title: Journal of Cancer Volume: 13 Issue: 10 Pages: 3073-3083
  • DOI: 10.7150/jca.73385
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Proton pump inhibitors affect capecitabine efficacy in patients with stage II-III colorectal cancer: a multicenter retrospective study (2022)
  • Author(s): Kitazume Y, Kawazoe H, Uozumi R, Yoshizawa T, Iihara H, Fujii H, Takahashi M, Arai T, Murachi Y, Sato Y, Mikami T, Hashiguchi K, Yamazaki T, Takahashi K, Fujita Y, Hosokawa Y, Morozumi I, Tsuchiya M, Yokoyama A, Hashimoto H, Yamaguchi M.
  • Journal Title: Scientific Reports Volume: 12 Issue: 1 Pages: 6561-6561
  • DOI: 10.1038/s41598-022-10008-2
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] One-Day Versus Three-Day Dexamethasone with NK1RA for Patients Receiving Carboplatin and Moderate Emetogenic Chemotherapy: A Network Meta-analysis (2022)
  • Author(s): Watanabe D, Iihara H, Fujii H, Makiyama A, Nishida S, Suzuki A.
  • Journal Title: Oncologist Volume: 27 Issue: 6 Pages: e524-e532
  • DOI: 10.1093/oncolo/oyac060
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Cancer cachexia as a determinant of efficacy of first?line pembrolizumab in patients with advanced non?small cell lung cancer (2022)
  • Author(s): Fujii Hironori、Araki Ayumu、Iihara Hirotoshi、Kaito Daizo、Hirose Chiemi、Kinomura Motohiko、Yamazaki Mizuki、Endo Junki、Inui Toshiya、Yanase Komei、Sasaki Yuka、Gomyo Takenobu、Sakai Chizuru、Kawae Daisuke、Kitamura Yu、Fukui Masachika、Kobayashi Ryo、Ohno Yasushi、Suzuki Akio
  • Journal Title: Molecular and Clinical Oncology Volume: 16 Issue: 4 Pages: 91-91
  • DOI: 10.3892/mco.2022.2524
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Pharmaceutical intervention for adverse events improves quality of life in patients with cancer undergoing outpatient chemotherapy. (2022)
  • Author(s): Fujii H, Ueda Y, Hirose C, Ohata K, Sekiya K, Kitahora M, Sadaka S, Yamamoto S, Watanabe D, Kato-Hayashi H, Iihara H, Kobayashi R, Kaburaki M, Matsuhashi N, Takahashi T, Makiyama A, Yoshida K, Suzuki A.
  • Journal Title: Journal of Pharmaceutical Health Care and Sciences Volume: 8 Issue: 1 Pages: 8-8
  • DOI: 10.1186/s40780-022-00239-w
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Association of albumin-bilirubin score in patients with colorectal cancer receiving later-line chemotherapy with regorafenib. (2021)
  • Author(s): Daichi Watanabe, Hironori Fujii, Yunami Yamada, Nobuhisa Matsuhashi, Akitaka Makiyama, Hirotoshi Iihara, Takao Takahashi, Shigeru Kiyama, Ryo Kobayashi, Kazuhiro Yoshida, Akio Suzuki
  • Journal Title: International journal of clinical oncology Volume: 26 Issue: 7 Pages: 1257-1263
  • DOI: 10.1007/s10147-021-01910-2
  • Peer Reviewed
• [Journal Article] Comparison of chemotherapy-induced nausea and vomiting between gemcitabine plus nab-paclitaxel combination chemotherapy and gemcitabine monotherapy in patients with advanced pancreatic cancer. (2021)
  • Author(s): Ohata K, Fujii H, Sadaka S, Kato-Hayashi H, Iihara H, Kobayashi R, Uemura S, Iwashita T, Shimizu M, Suzuki A.
  • Journal Title: Anticancer Research Volume: 41 Issue: 7 Pages: 3643-3648
  • DOI: 10.21873/anticanres.15154
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Anorexia, pain and peripheral neuropathy are associated with a decrease in quality of life in patients with advanced pancreatic cancer receiving outpatient chemotherapy: a retrospective observational study (2021)
  • Author(s): Fujii H, Koda M, Sadaka S, Ohata K, Kato-Hayashi H, Iihara H, Kobayashi R, Ishihara T, Uemura S, Iwashita T, Hayashi H, Sugiyama T, Shimizu M, Suzuki A.
  • Journal Title: Journal of Pharmaceutical Health Care and Sciences Volume: 7 Issue: 1 Pages: 27-27
  • DOI: 10.1186/s40780-021-00210-1
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Primary Prophylaxis of Febrile Neutropenia With Pegfilgrastim in Small-cell Lung Cancer Patients Receiving Amrubicin as Second-line Therapy (2021)
  • Author(s): SATO YUKINA、IIHARA HIROTOSHI、KINOMURA MOTOHIKO、HIROSE CHIEMI、FUJII HIRONORI、ENDO JUNKI、YANASE KOMEI、KAITO DAIZO、SASAKI YUKA、GOMYO TAKENOBU、SAKAI CHIZURU、IWAI MASAMICHI、TSUBOI YOSHIKI、ISHIHARA TAKUMA、KOBAYASHI RYO、OHNO YASUSHI、SUZUKI AKIO
  • Journal Title: Anticancer Research Volume: 41 Issue: 3 Pages: 1615-1620
  • DOI: 10.21873/anticanres.14923
  • Peer Reviewed
• [Journal Article] Impact of Anti-angiogenic Agents on Chemotherapy Efficacy in Patients With Metastatic Colorectal Cancer: Second-line FOLFIRI Plus Bevacizumab or Aflibercept (2021)
  • Author(s): YAMADA YUNAMI、MATSUHASHI NOBUHISA、FUJII HIRONORI、MAKIYAMA AKITAKA、IIHARA HIROTOSHI、TAKAHASHI TAKAO、WATANABE DAICHI、KIYAMA SHIGERU、KOBAYASHI RYO、SUZUKI AKIO、YOSHIDA KAZUHIRO
  • Journal Title: Anticancer Research Volume: 41 Issue: 1 Pages: 533-541
  • DOI: 10.21873/anticanres.14805
  • Peer Reviewed
• [Journal Article] Dose Adjustment of Oxaliplatin Based on Renal Function in Patients With Metastatic Colorectal Cancer (2020)
  • Author(s): WATANABE DAICHI、FUJII HIRONORI、MATSUHASHI NOBUHISA、IIHARA HIROTOSHI、YAMADA YUNAMI、ISHIHARA TAKUMA、TAKAHASHI TAKAO、YOSHIDA KAZUHIRO、SUZUKI AKIO
  • Journal Title: Anticancer Research Volume: 40 Issue: 4 Pages: 2379-2386
  • DOI: 10.21873/anticanres.14207
  • Peer Reviewed