研究者業績

叶川 直哉

カノガワ ナオヤ  (Naoya Kanogawa)

基本情報

所属
千葉大学 大学院医学研究院消化器内科学 助教 (診療講師)
学位
医学博士(2015年3月 千葉大学大学院医学研究院)

研究者番号
50866994
J-GLOBAL ID
202201020601182051
researchmap会員ID
R000032283

研究キーワード

 4

学歴

 2

論文

 83
  • Junjie Ao, Na Qiang, Hiroaki Kanzaki, Masato Nakamura, Risa Kakiuchi, Jiaqi Zhang, Ryuta Kojima, Keisuke Koroki, Masanori Inoue, Naoya Kanogawa, Ryo Nakagawa, Takayuki Kondo, Sadahisa Ogasawara, Shingo Nakamoto, Ryosuke Muroyama, Jun Kato, Naoya Kato
    American journal of physiology. Cell physiology 327(4) C1150-C1161 2024年10月1日  
    In the era of immunotherapy, lenvatinib (LEN) still holds an important position in the sequential treatment of advanced hepatocellular carcinoma (HCC). However, the sustained therapeutic effect of LEN is not sufficient, and there is a need to address the development of resistance. Neuropilin-1 (NRP1) is known to act as a coreceptor for epidermal growth factor receptor (EGFR), Met, and vascular endothelial growth factor receptor 2 (VEGFR2), which have been reported to be involved in LEN resistance. In this study, we used cell culture and in vivo xenograft models to evaluate the contribution of NRP1 in the acquisition of LEN resistance in HCC as well as the potential of NRP1 as a therapeutic target. LEN resistance increased EGF/EGFR and hepatocyte growth factor (HGF)/Met signaling in liver cancer cells and VEGFA/VEGFR2 and HGF/Met signaling in vascular endothelial cells, thereby promoting cell proliferation, cell migration, and angiogenesis. We found that activation of NRP1 is essential for the enhancement of these signaling. In addition, NRP1 inhibition combined with LEN therapy synergistically improved the antitumor effects against LEN-resistant HCC, indicating that NRP1 is an attractive therapeutic target.NEW & NOTEWORTHY We demonstrated that neuropilin-1 (NRP1) was an essential coreceptor mediating the activation of multiple signaling pathways in the acquisition of resistance to lenvatinib (LEN) in HCC. The addition of NRP1 inhibition to LEN had a synergistic antitumor effect on LEN-resistant HCC in culture and in vivo xenograft models.
  • 小笠原 定久, 叶川 直哉, 加藤 直也
    日本消化器病学会雑誌 121(9) 737-744 2024年9月10日  
    進行肝細胞癌に対する薬物療法は,複合免疫療法の登場により大きな変革期を迎えている.アテゾリズマブ・ベバシズマブ併用療法およびデュルバルマブ・トレメリムマブ併用療法は,従来の標準治療であったソラフェニブと比較して全生存期間を有意に延長することが示された.しかし,複合免疫療法においても一定の割合で不応例が存在し,その抵抗性メカニズムとして,抗原認識の減少,T細胞の遊走・浸潤の阻害,エフェクター機能の抑制などが知られている.本稿では,複合免疫療法時代における進行肝細胞癌治療の新たな課題として浮上した免疫療法不応例について,その臨床的な特徴や機序,そして今後克服すべき課題について概説する.
  • Kazufumi Kobayashi, Sadahisa Ogasawara, Ei Itobayashi, Tomomi Okubo, Norio Itokawa, Kazuyoshi Nakamura, Michihisa Moriguchi, Shunji Watanabe, Masafumi Ikeda, Hidekatsu Kuroda, Tomokazu Kawaoka, Atsushi Hiraoka, Yutaka Yasui, Teiji Kuzuya, Rui Sato, Hiroaki Kanzaki, Keisuke Koroki, Masanori Inoue, Masato Nakamura, Soichiro Kiyono, Naoya Kanogawa, Takayuki Kondo, Shingo Nakamoto, Yoshihito Ozawa, Kaoru Tsuchiya, Masanori Atsukawa, Hiroshi Aikata, Takeshi Aramaki, Shiro Oka, Naoki Morimoto, Masayuki Kurosaki, Yoshito Itoh, Namiki Izumi, Naoya Kato
    Investigational new drugs 42(4) 394-404 2024年8月  
    This study aimed to complement the results of the REACH-2 study by prospectively evaluating the safety and efficacy of ramucirumab in advanced hepatocellular carcinoma (HCC) in a real-world setting. This was an open-label, nonrandomized, multicenter, prospective study conducted at 13 institutions in Japan (jRCTs031190236). The study included Child-Pugh Class A patients with advanced HCC who had received pretreatment with atezolizumab plus bevacizumab (Atez/Bev) or lenvatinib. Ramucirumab was introduced as a second-line treatment after Atez/Bev or lenvatinib and as a third-line treatment after Atez/Bev and lenvatinib. Between May 2020 and July 2022, we enrolled 19 patients, including 17 who received ramucirumab. Additionally, seven patients received lenvatinib, another seven patients received Atez/Bev, and three patients received Atez/Bev followed by lenvatinib as prior treatment. The primary endpoint was a 6-month progression-free survival (PFS) rate, which was 14.3%. The median PFS and overall survival were 3.7 and 12.0 months, respectively. The most common grade ≥ 3 adverse events (AEs) were hypertension (23.5%), proteinuria (17.6%), and neutropenia (11.8%). The discontinuation rate due to AEs was 29.4%. Six patients progressed from Child-Pugh A to B after treatment with ramucirumab. Thirteen patients were eligible for post-ramucirumab treatment, including systemic therapy. Despite the limited number of patients, the efficacy of ramucirumab was comparable to that observed in the REACH-2 study when used after lenvatinib and Atez/Bev. However, the incidence of AEs was higher than that in the REACH-2 study.
  • Tomomi Ozaki, Sae Yumita, Sadahisa Ogasawara, Makoto Fujiya, Takahiro Tsuchiya, Ryohei Yoshino, Midori Sawada, Teppei Akatsuka, Ryo Izai, Chihiro Miwa, Takuya Yonemoto, Kentaro Fujimoto, Hidemi Unozawa, Kisako Fujiwara, Ryuta Kojima, Hiroaki Kanzaki, Keisuke Koroki, Masanori Inoue, Kazufumi Kobayashi, Masato Nakamura, Soichiro Kiyono, Naoya Kanogawa, Takayuki Kondo, Ryo Nakagawa, Shingo Nakamoto, Naoya Kato
    Hepatology research : the official journal of the Japan Society of Hepatology 2024年6月29日  
    Cytokine release syndrome (CRS) is a systemic inflammatory syndrome that causes fatal circulatory failure due to hypercytokinemia, and subsequent immune cell hyperactivation caused by therapeutic agents, pathogens, cancers, and autoimmune diseases. In recent years, CRS has emerged as a rare, but significant, immune-related adverse event linked to immune checkpoint inhibitor therapy. Furthermore, several previous studies suggested that damage-associated molecular patterns (DAMPs) could be involved in malignancy-related CRS. In this study, we present a case of severe CRS following combination therapy with durvalumab and tremelimumab for advanced hepatocellular carcinoma, which recurred during treatment, as well as an analysis of cytokine and DAMPs trends. A 35-year-old woman diagnosed with hepatocellular carcinoma underwent a partial hepatectomy. Due to cancer recurrence, she started a combination of durvalumab and tremelimumab. Then, 29 days post-administration, she developed fever and headache, initially suspected as sepsis. Despite antibiotics, her condition worsened, leading to disseminated intravascular coagulation and hemophagocytic syndrome. The clinical course and elevated serum interleukin-6 levels led to a CRS diagnosis. Steroid pulse therapy was administered, resulting in temporary improvement. However, she relapsed with increased interleukin-6, prompting tocilizumab treatment. Her condition improved, and she was discharged on day 22. Measurements of inflammatory cytokines interferon-γ, tumor necrosis factor-α, and DAMPs, along with interleukin-6, using preserved serum samples, confirmed marked elevation at CRS onset. CRS can occur after the administration of any immune checkpoint inhibitor, with the most likely trigger being the release of DAMPs associated with tumor collapse.
  • Kisako Fujiwara, Takayuki Kondo, Kentaro Fujimoto, Sae Yumita, Keita Ogawa, Takamasa Ishino, Miyuki Nakagawa, Terunao Iwanaga, Satoshi Tsuchiya, Keisuke Koroki, Hiroaki Kanzaki, Masanori Inoue, Kazufumi Kobayashi, Soichiro Kiyono, Masato Nakamura, Naoya Kanogawa, Sadahisa Ogasawara, Shingo Nakamoto, Tetsuhiro Chiba, Jun Koizumi, Jun Kato, Naoya Kato
    Journal of gastroenterology 59(6) 515-525 2024年6月  
    BACKGROUND: During systemic therapy, the management of portal hypertension (PH)-related complications is vital. This study aimed to clarify factors associated with the incidence and exacerbation of PH-related complications, including the usefulness of contrast-enhanced computed tomography (CECT) in the management of PH-related complications during systemic therapy. METHODS: A total of 669 patients who received systemic therapy as first-line treatment (443 patients for sorafenib, 131 for lenvatinib, and 90 for atezolizumab/bevacizumab [ATZ/BEV]) were enrolled in this retrospective study. Additionally, the lower esophageal intramural vessel diameters (EIV) on CECT and endoscopic findings in 358 patients were compared. RESULTS: The cutoff values of the EIV diameter on CECT were 3.1 mm for small, 5.1 mm for medium, and 7.6 mm for large varices, demonstrating high concordance with the endoscopic findings. esophageal varices (EV) bleeding predictors include EIV ≥ 3.1 mm and portal vein tumor thrombosis (PVTT). In patients without EV before systemic therapy, factors associated with EV exacerbation after 3 months were EIV ≥ 1.9 mm and ATZ/BEV use. Predictors of hepatic encephalopathy (HE) include the ammonia level or portosystemic shunt diameter ≥ 6.8 mm. The incidence of HE within 2 weeks was significantly higher (18%) in patients with an ammonia level ≥ 73 μmol/L and a portosystemic shunt ≥ 6.8 mm. The exacerbating factors for ascites after 3 months were PVTT and low albumin levels. CONCLUSIONS: Careful management is warranted for patients with risk factors for exacerbation of PH-related complications; moreover, the effective use of CECT is clinically important.

MISC

 148

講演・口頭発表等

 33