Liquid Biopsy for the Diagnosis of Malignant Lymphoma in Patients with Fever of Unknown Origin

• Project/Area Number: 18K15402
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 52010:General internal medicine-related
• Research Institution: Fujita Health University
• Principal Investigator: Akinao Okamoto 藤田医科大学, 医学部, 講師 (80775049)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: Liquid biopsy / Oncology / cell free DNA / Lymphoma / liquid biopsy / droplet digital PCR / Droplet digital PCR / NGS / リキッドバイオプシー / 悪性リンパ腫 / リキッド・バイオプシー / 不明熱

Outline of Final Research Achievements

Lymphomas, which are difficult to diagnose, are an extremely large group of diseases that cause fever of unknown origin. We focused on cell free DNA (cfDNA) in plasma and found a method for highly accurate diagnosis by analyzing MYD88 and CD79b mutations specific to intravascular large B-cell lymphoma, B cell/T cell receptor gene rearrangements, and comprehensive gene mutations by liquid biopsy using droplet digital PCR and next-generation sequencers. In order to verify the accuracy and efficacy of this method in clinical practice, we have started a new prospective multicenter clinical study, LILY4 STUDY (UMIN000040061).

Academic Significance and Societal Importance of the Research Achievements

本研究により、診断困難なリンパ腫を採血のみで診断で診断および、診断補助ができる可能性が高まった。その結果、不明熱により、原因不明で亡くなる患者さんが減少する可能性がある。
また、本研究が確立した検査は、感度・特異度ともに極めて高い。その結果、リンパ腫外の疾患の可能性が相対的に高まるため、主として膠原病などのリンパ腫外の患者に対する治療方針の決定にも極めて有用である。
また、高齢者、中枢、腹腔内病変など、手術が困難である患者に対しても応用できる可能性が示唆される。

Research Products

• [Journal Article] Frequent genetic alterations in immune checkpoint-related genes in intravascular large B-cell lymphoma (2021)
  • Author(s): Shimada Kazuyuki、Yoshida Kenichi、Suzuki Yasuhiro、Iriyama Chisako、Inoue Yoshikage、Sanada Masashi、Kataoka Keisuke、Yuge Masaaki、Takagi Yusuke、Kusumoto Shigeru、Masaki Yasufumi、Ito Takahiko、Inagaki Yuichiro、Okamoto Akinao、Kuwatsuka Yachiyo、Nakatochi Masahiro、Shimada Satoko、Miyoshi Hiroaki et al.
  • Journal Title: Blood Volume: 137 Issue: 11 Pages: 1491-1502
  • DOI: 10.1182/blood.2020007245
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Truncated RUNX1 generated from the fusion of RUNX1 to antisense GRIK2 via a cryptic chromosome translocation enhances sensitivity to granulocyte colony-stimulating factor (2020)
  • Author(s): Abe A, Yamamoto Y, Katsumi A, Yamamoto H, Okamoto A, Inaguma Y, Iriyama C, Tokuda M, Okamoto M, Emi N, Tomita A.
  • Journal Title: Cytogenetic and Genome Research Volume: - Issue: 5 Pages: 255-263
  • DOI: 10.1159/000508012
  • Peer Reviewed / Open Access
• [Journal Article] D-Index-Guided Early Antifungal Therapy Versus Empiric Antifungal Therapy for Persistent Febrile Neutropenia: A Randomized Controlled Noninferiority Trial. (2020)
  • Author(s): Kanda Y1, Kimura S, Iino M, Fukuda T, Sakaida E, Oyake T, Yamaguchi H, Fujiwara SI, Jo Y, Okamoto A, Fujita H, Takamatsu Y, Saburi Y, Matsumura I, Yamanouchi J, Shiratori S, Gotoh M, Nakamura S, Tamura K
  • Journal Title: J Clin Oncol. Volume: Epub Issue: 8 Pages: 815-822
  • DOI: 10.1200/jco.19.01916
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma arising in patient with a history of EBV-positive mucocutaneous ulcer and EBV-positive nodal polymorphous B-lymphoproliferative disorder (2019)
  • Author(s): Daroontum T, Kohno K, Inaguma Y, Okamoto A, Okamoto M, Kimura Y, Nagahama M, Sakakibara A, Satou A, Nakamura S
  • Journal Title: Pathology International Volume: 69 Issue: 1 Pages: 37-41
  • DOI: 10.1111/pin.12738
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Role of exosomes as a proinflammatory mediator in the development of EBV-associated lymphoma. (2018)
  • Author(s): Higuchi H, Yamakawa N, Imadome KI, Yahata T, Kotaki R, Ogata J, Kakizaki M, Fujita K, Lu J, Yokoyama K, Okuyama K, Sato A, Takamatsu M, Kurosaki N, Alba SM, Azhim A, Horie R, Watanabe T, Kitamura T, Ando K, Kashiwagi T, Matsui T, Okamoto A, Handa H, Kuroda M, Nakamura N, Kotani A.
  • Journal Title: Blood Volume: 131 Issue: 23 Pages: 2552-2567
  • DOI: 10.1182/blood-2017-07-794529
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Rearrangement of VPS13B, a causative gene of Cohen syndrome, in a case of RUNX1-RUNX1T1 leukemia with t(8;12;21). (2017)
  • Author(s): Abe A, Yamamoto Y, Katsumi A, Okamoto A, Tokuda M, Inaguma Y, Yamamoto K, Yanada M, Kanie T, Tomita A, Akatsuka Y, Okamoto M, Kameyama T, Mayeda A, Emi N.
  • Journal Title: Int J Hematol. Volume: - Issue: 2 Pages: 208-212
  • DOI: 10.1007/s12185-017-2387-x
  • Peer Reviewed / Open Access
• [Presentation] 初発時の遺伝子変異解析が病型診断に有用であったろ胞性ヘルパーT細胞表現型を有するPTCLの１例 (2021)
  • Author(s): 加藤駿晴、岡本晃直 、入山智沙子 、安田貴彦、後藤尚絵、加留部謙之介、三好寛明、眞田昌、堀部敬三、冨田章裕
  • Organizer: 第10回 日本血液学会東海地方会
• [Presentation] Liquid biopsyが補助診断に有効であった血管内大細胞型B細胞リンパ腫の一例 (2021)
  • Author(s): 岡本晃直、真田昌、齊藤繁紀、伊庭佐知子、齊藤統子、山本秀行、徳田倍将、水野紘樹、後藤尚江、入山智沙子、中村栄男、冨田章裕
  • Organizer: 第61回 リンパ網内系学会
  • Int'l Joint Research
• [Presentation] Detection of central nervous system lymphomas by genetic analyses using cerebrospinal fluid (2020)
  • Author(s): Chisako Iriyama，Kennichiro Murate，Sachiko Iba，Akinao Okamoto， Hideyuki Yamamoto，Masutaka Tokuda，Yukiya Yamamoto， Masataka Okamoto，Hirohisa Watanabe，Akihiro Tomita
  • Organizer: 第82回 日本血液学会
• [Presentation] Detailed Assessment of Blood Culture and Clinical Factors in Febrile Neutropenia Patients with High-Risk Hematological Malignancy in Japan: A Subgroup Analysis of the Cedmic Trial (2020)
  • Author(s): Okamoto A, Kanda Y, Kimura SI, Oyake T, Tamura K
  • Organizer: 62nd ASH Annual Meeting and Exposition
  • Int'l Joint Research
• [Presentation] 中枢浸潤リンパ腫において，髄液中可溶性IL-2Rは上昇する (2019)
  • Author(s): 岡本晃直，入山智沙子，稲熊容子，岡本昌隆，冨田章裕
  • Organizer: 日本リンパ網内系学会
• [Presentation] 髄液のフローサイトメトリーおよび遺伝子検査が診断に有用であった脊髄B細胞性悪 性リンパ腫の一例 (2019)
  • Author(s): 齋藤聡一郎，入山智沙子，村手健一郎，武藤多津郎，佐藤あかね， 神原彩那，岡本晃直，稲熊容子，岡部麻子，山田勢至，浦野誠， 金田典雄，恵美宜彦，岡本昌隆，冨田章裕
  • Organizer: 日本リンパ網内系学会